CREATE TABLE IF NOT EXISTS `kegg` (
  `pathid` int(5) NOT NULL DEFAULT '0',
  `pathname` varchar(58) DEFAULT NULL,
  `url` varchar(77) DEFAULT NULL,
  PRIMARY KEY (`pathid`),
  KEY `pathid` (`pathid`),
  KEY `pathid_2` (`pathid`)
) ENGINE=InnoDB DEFAULT CHARSET=utf8;

--
-- Daten für Tabelle `kegg`
--

INSERT INTO `kegg` (`pathid`, `pathname`, `url`) VALUES
(10, 'Glycolysis / Gluconeogenesis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00010&show_description=show'),
(20, 'Citrate cycle (TCA cycle)', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00020&show_description=show'),
(30, 'Pentose phosphate pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00030&show_description=show'),
(40, 'Pentose and glucuronate interconversions', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00040&show_description=show'),
(51, 'Fructose and mannose metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00051&show_description=show'),
(52, 'Galactose metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00052&show_description=show'),
(53, 'Ascorbate and aldarate metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00053&show_description=show'),
(61, 'Fatty acid biosynthesis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00061&show_description=show'),
(71, 'Fatty acid metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00071&show_description=show'),
(100, 'Steroid biosynthesis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00100&show_description=show'),
(120, 'Primary bile acid biosynthesis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00120&show_description=show'),
(140, 'Steroid hormone biosynthesis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00140&show_description=show'),
(190, 'Oxidative phosphorylation', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00190&show_description=show'),
(230, 'Purine metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00230&show_description=show'),
(232, 'Caffeine metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00232&show_description=show'),
(240, 'Pyrimidine metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00240&show_description=show'),
(250, 'Alanine, aspartate and glutamate metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00250&show_description=show'),
(260, 'Glycine, serine and threonine metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00260&show_description=show'),
(270, 'Cysteine and methionine metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00270&show_description=show'),
(280, 'Valine, leucine and isoleucine degradation', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00280&show_description=show'),
(290, 'Valine, leucine and isoleucine biosynthesis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00290&show_description=show'),
(310, 'Lysine degradation', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00310&show_description=show'),
(330, 'Arginine and proline metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00330&show_description=show'),
(340, 'Histidine metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00340&show_description=show'),
(350, 'Tyrosine metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00350&show_description=show'),
(360, 'Phenylalanine metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00360&show_description=show'),
(380, 'Tryptophan metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00380&show_description=show'),
(410, 'beta-Alanine metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00410&show_description=show'),
(460, 'Cyanoamino acid metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00460&show_description=show'),
(480, 'Glutathione metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00480&show_description=show'),
(500, 'Starch and sucrose metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00500&show_description=show'),
(511, 'Other glycan degradation', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00511&show_description=show'),
(520, 'Amino sugar and nucleotide sugar metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00520&show_description=show'),
(531, 'Glycosaminoglycan degradation', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00531&show_description=show'),
(533, 'Glycosaminoglycan biosynthesis - keratan sulfate', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00533&show_description=show'),
(561, 'Glycerolipid metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00561&show_description=show'),
(562, 'Inositol phosphate metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00562&show_description=show'),
(563, 'Glycosylphosphatidylinositol(GPI)-anchor biosynthesis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00563&show_description=show'),
(564, 'Glycerophospholipid metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00564&show_description=show'),
(565, 'Ether lipid metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00565&show_description=show'),
(590, 'Arachidonic acid metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00590&show_description=show'),
(591, 'Linoleic acid metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00591&show_description=show'),
(592, 'alpha-Linolenic acid metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00592&show_description=show'),
(600, 'Sphingolipid metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00600&show_description=show'),
(604, 'Glycosphingolipid biosynthesis - ganglio series', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00604&show_description=show'),
(620, 'Pyruvate metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00620&show_description=show'),
(640, 'Propanoate metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00640&show_description=show'),
(650, 'Butanoate metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00650&show_description=show'),
(670, 'One carbon pool by folate', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00670&show_description=show'),
(740, 'Riboflavin metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00740&show_description=show'),
(790, 'Folate biosynthesis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00790&show_description=show'),
(830, 'Retinol metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00830&show_description=show'),
(860, 'Porphyrin and chlorophyll metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00860&show_description=show'),
(900, 'Terpenoid backbone biosynthesis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00900&show_description=show'),
(910, 'Nitrogen metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00910&show_description=show'),
(920, 'Sulfur metabolism', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00920&show_description=show'),
(980, 'Metabolism of xenobiotics by cytochrome P450', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00980&show_description=show'),
(982, 'Drug metabolism - cytochrome P450', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00982&show_description=show'),
(983, 'Drug metabolism - other enzymes', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa00983&show_description=show'),
(1100, 'Metabolic pathways', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa01100&show_description=show'),
(2010, 'ABC transporters', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa02010&show_description=show'),
(3008, 'Ribosome biogenesis in eukaryotes', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03008&show_description=show'),
(3010, 'Ribosome', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03010&show_description=show'),
(3013, 'RNA transport', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03013&show_description=show'),
(3015, 'mRNA surveillance pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03015&show_description=show'),
(3018, 'RNA degradation', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03018&show_description=show'),
(3030, 'DNA replication', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03030&show_description=show'),
(3040, 'Spliceosome', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03040&show_description=show'),
(3050, 'Proteasome', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03050&show_description=show'),
(3060, 'Protein export', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03060&show_description=show'),
(3320, 'PPAR signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03320&show_description=show'),
(3410, 'Base excision repair', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03410&show_description=show'),
(3420, 'Nucleotide excision repair', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03420&show_description=show'),
(3430, 'Mismatch repair', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03430&show_description=show'),
(3440, 'Homologous recombination', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa03440&show_description=show'),
(4010, 'MAPK signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04010&show_description=show'),
(4012, 'ErbB signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04012&show_description=show'),
(4020, 'Calcium signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04020&show_description=show'),
(4060, 'Cytokine-cytokine receptor interaction', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04060&show_description=show'),
(4062, 'Chemokine signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04062&show_description=show'),
(4070, 'Phosphatidylinositol signaling system', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04070&show_description=show'),
(4080, 'Neuroactive ligand-receptor interaction', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04080&show_description=show'),
(4110, 'Cell cycle', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04110&show_description=show'),
(4114, 'Oocyte meiosis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04114&show_description=show'),
(4115, 'p53 signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04115&show_description=show'),
(4120, 'Ubiquitin mediated proteolysis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04120&show_description=show'),
(4140, 'Regulation of autophagy', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04140&show_description=show'),
(4141, 'Protein processing in endoplasmic reticulum', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04141&show_description=show'),
(4142, 'Lysosome', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04142&show_description=show'),
(4144, 'Endocytosis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04144&show_description=show'),
(4145, 'Phagosome', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04145&show_description=show'),
(4146, 'Peroxisome', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04146&show_description=show'),
(4150, 'mTOR signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04150&show_description=show'),
(4210, 'Apoptosis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04210&show_description=show'),
(4260, 'Cardiac muscle contraction', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04260&show_description=show'),
(4270, 'Vascular smooth muscle contraction', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04270&show_description=show'),
(4310, 'Wnt signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04310&show_description=show'),
(4320, 'Dorso-ventral axis formation', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04320&show_description=show'),
(4330, 'Notch signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04330&show_description=show'),
(4340, 'Hedgehog signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04340&show_description=show'),
(4350, 'TGF-beta signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04350&show_description=show'),
(4360, 'Axon guidance', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04360&show_description=show'),
(4370, 'VEGF signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04370&show_description=show'),
(4380, 'Osteoclast differentiation', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04380&show_description=show'),
(4510, 'Focal adhesion', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04510&show_description=show'),
(4512, 'ECM-receptor interaction', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04512&show_description=show'),
(4514, 'Cell adhesion molecules (CAMs)', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04514&show_description=show'),
(4520, 'Adherens junction', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04520&show_description=show'),
(4530, 'Tight junction', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04530&show_description=show'),
(4540, 'Gap junction', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04540&show_description=show'),
(4610, 'Complement and coagulation cascades', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04610&show_description=show'),
(4612, 'Antigen processing and presentation', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04612&show_description=show'),
(4614, 'Renin-angiotensin system', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04614&show_description=show'),
(4620, 'Toll-like receptor signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04620&show_description=show'),
(4621, 'NOD-like receptor signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04621&show_description=show'),
(4622, 'RIG-I-like receptor signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04622&show_description=show'),
(4623, 'Cytosolic DNA-sensing pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04623&show_description=show'),
(4630, 'Jak-STAT signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04630&show_description=show'),
(4640, 'Hematopoietic cell lineage', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04640&show_description=show'),
(4650, 'Natural killer cell mediated cytotoxicity', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04650&show_description=show'),
(4660, 'T cell receptor signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04660&show_description=show'),
(4662, 'B cell receptor signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04662&show_description=show'),
(4664, 'Fc epsilon RI signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04664&show_description=show'),
(4666, 'Fc gamma R-mediated phagocytosis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04666&show_description=show'),
(4670, 'Leukocyte transendothelial migration', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04670&show_description=show'),
(4672, 'Intestinal immune network for IgA production', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04672&show_description=show'),
(4720, 'Long-term potentiation', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04720&show_description=show'),
(4722, 'Neurotrophin signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04722&show_description=show'),
(4730, 'Long-term depression', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04730&show_description=show'),
(4740, 'Olfactory transduction', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04740&show_description=show'),
(4742, 'Taste transduction', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04742&show_description=show'),
(4810, 'Regulation of actin cytoskeleton', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04810&show_description=show'),
(4910, 'Insulin signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04910&show_description=show'),
(4912, 'GnRH signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04912&show_description=show'),
(4914, 'Progesterone-mediated oocyte maturation', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04914&show_description=show'),
(4916, 'Melanogenesis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04916&show_description=show'),
(4920, 'Adipocytokine signaling pathway', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04920&show_description=show'),
(4930, 'Type II diabetes mellitus', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04930&show_description=show'),
(4940, 'Type I diabetes mellitus', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04940&show_description=show'),
(4950, 'Maturity onset diabetes of the young', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04950&show_description=show'),
(4960, 'Aldosterone-regulated sodium reabsorption', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04960&show_description=show'),
(4962, 'Vasopressin-regulated water reabsorption', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04962&show_description=show'),
(4970, 'Salivary secretion', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04970&show_description=show'),
(4971, 'Gastric acid secretion', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04971&show_description=show'),
(4972, 'Pancreatic secretion', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04972&show_description=show'),
(4973, 'Carbohydrate digestion and absorption', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04973&show_description=show'),
(4974, 'Protein digestion and absorption', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04974&show_description=show'),
(4975, 'Fat digestion and absorption', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04975&show_description=show'),
(4976, 'Bile secretion', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04976&show_description=show'),
(4977, 'Vitamin digestion and absorption', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa04977&show_description=show'),
(5010, 'Alzheimer''s disease', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05010&show_description=show'),
(5012, 'Parkinson''s disease', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05012&show_description=show'),
(5014, 'Amyotrophic lateral sclerosis (ALS)', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05014&show_description=show'),
(5016, 'Huntington''s disease', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05016&show_description=show'),
(5020, 'Prion diseases', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05020&show_description=show'),
(5100, 'Bacterial invasion of epithelial cells', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05100&show_description=show'),
(5110, 'Vibrio cholerae infection', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05110&show_description=show'),
(5120, 'Epithelial cell signaling in Helicobacter pylori infection', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05120&show_description=show'),
(5130, 'Pathogenic Escherichia coli infection', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05130&show_description=show'),
(5131, 'Shigellosis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05131&show_description=show'),
(5140, 'Leishmaniasis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05140&show_description=show'),
(5142, 'Chagas disease (American trypanosomiasis)', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05142&show_description=show'),
(5143, 'African trypanosomiasis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05143&show_description=show'),
(5144, 'Malaria', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05144&show_description=show'),
(5145, 'Toxoplasmosis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05145&show_description=show'),
(5146, 'Amoebiasis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05146&show_description=show'),
(5150, 'Staphylococcus aureus infection', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05150&show_description=show'),
(5160, 'Hepatitis C', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05160&show_description=show'),
(5200, 'Pathways in cancer', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05200&show_description=show'),
(5210, 'Colorectal cancer', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05210&show_description=show'),
(5211, 'Renal cell carcinoma', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05211&show_description=show'),
(5212, 'Pancreatic cancer', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05212&show_description=show'),
(5213, 'Endometrial cancer', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05213&show_description=show'),
(5214, 'Glioma', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05214&show_description=show'),
(5215, 'Prostate cancer', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05215&show_description=show'),
(5216, 'Thyroid cancer', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05216&show_description=show'),
(5217, 'Basal cell carcinoma', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05217&show_description=show'),
(5218, 'Melanoma', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05218&show_description=show'),
(5219, 'Bladder cancer', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05219&show_description=show'),
(5220, 'Chronic myeloid leukemia', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05220&show_description=show'),
(5221, 'Acute myeloid leukemia', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05221&show_description=show'),
(5222, 'Small cell lung cancer', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05222&show_description=show'),
(5223, 'Non-small cell lung cancer', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05223&show_description=show'),
(5310, 'Asthma', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05310&show_description=show'),
(5320, 'Autoimmune thyroid disease', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05320&show_description=show'),
(5322, 'Systemic lupus erythematosus', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05322&show_description=show'),
(5323, 'Rheumatoid arthritis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05323&show_description=show'),
(5330, 'Allograft rejection', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05330&show_description=show'),
(5332, 'Graft-versus-host disease', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05332&show_description=show'),
(5340, 'Primary immunodeficiency', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05340&show_description=show'),
(5410, 'Hypertrophic cardiomyopathy (HCM)', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05410&show_description=show'),
(5412, 'Arrhythmogenic right ventricular cardiomyopathy (ARVC)', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05412&show_description=show'),
(5414, 'Dilated cardiomyopathy', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05414&show_description=show'),
(5416, 'Viral myocarditis', 'http://www.genome.jp/kegg-bin/show_pathway?map=hsa05416&show_description=show');

-- --------------------------------------------------------

--
-- Tabellenstruktur für Tabelle `mir`
--

CREATE TABLE IF NOT EXISTS `mir` (
  `geneid` varchar(12) DEFAULT NULL,
  `symbol` varchar(15) DEFAULT NULL,
  `synonyms` varchar(71) DEFAULT NULL,
  `cytoband` varchar(15) DEFAULT NULL,
  `description` varchar(15) DEFAULT NULL,
  `gene_type` varchar(7) DEFAULT NULL,
  `url` varchar(64) DEFAULT NULL,
  `frequency` int(1) DEFAULT NULL,
  `numtargets` int(3) DEFAULT NULL
) ENGINE=InnoDB DEFAULT CHARSET=utf8;

--
-- Daten für Tabelle `mir`
--

INSERT INTO `mir` (`geneid`, `symbol`, `synonyms`, `cytoband`, `description`, `gene_type`, `url`, `frequency`, `numtargets`) VALUES
('MIMAT0000255', 'hsa-miR-34a-5p', 'MIRN34A|miRNA34A|mir-34', '1p36.22|1p36.22', 'microRNA 34a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000255', 2, 137),
('MIMAT0004676', 'hsa-miR-34b-3p', 'MIRN34B|miRNA34B', '11q23.1', 'microRNA 34b', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0004676', 2, 49),
('MIMAT0000686', 'hsa-miR-34c-5p', 'MIRN34C|miRNA34C', '11q23.1', 'microRNA 34c', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000686', 2, 136),
('MIMAT0000431', 'hsa-miR-140-5p', 'MIRN140|miRNA140', '16q22.1', 'microRNA 140', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000431', 1, 80),
('MIMAT0001627', 'hsa-miR-433-3p', 'MIRN433|hsa-mir-433|miRNA433', '14q32.2', 'microRNA 433', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0001627', 1, 42),
('MIMAT0000272', 'hsa-miR-215-5p', 'MIRN215|miRNA215|mir-215', '1q41', 'microRNA 215', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000272', 1, 57),
('MIMAT0000076', 'hsa-miR-21-5p', 'MIRN21|hsa-mir-21|miR-21|miRNA21', '17q23.1', 'microRNA 21', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000076', 1, 54),
('MIMAT0000435', 'hsa-miR-143-3p', 'MIRN143', '5q32', 'microRNA 143', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000435', 2, 68),
('MIMAT0000426', 'hsa-miR-132-3p', 'MIRN132|miRNA132', '17p13.3', 'microRNA 132', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000426', 1, 66),
('MIMAT0000459', 'hsa-miR-193a-3p', 'MIRN193|MIRN193A', '17q11.2', 'microRNA 193a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000459', 1, 90),
('MIMAT0001339', 'hsa-miR-422a', 'MIRN422A', '15q22.31', 'microRNA 422a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0001339', 1, 70),
('MIMAT0000092', 'hsa-miR-92a-3p', 'MIR92-1|MIRN92-1|MIRN92A-1|MIRN92A1|miRNA92-1', '13q31.3', 'microRNA 92a-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000092', 4, 56),
('MIMAT0000689', 'hsa-miR-99b-5p', 'MIRN99B', '19q13.41', 'microRNA 99b', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000689', 1, 13),
('MIMAT0000232', 'hsa-miR-199a-3p', 'MIR-199-s|MIRN199A1', '19p13.2', 'microRNA 199a-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000232', 1, 69),
('MIMAT0000093', 'hsa-miR-93-5p', 'MIRN9|MIRN93|hsa-mir-93|miR-93', '7q22.1', 'microRNA 93', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000093', 2, 74),
('MIMAT0000447', 'hsa-miR-134-5p', 'MIRN134', '14q32.31', 'microRNA 134', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000447', 1, 79),
('MIMAT0000070', 'hsa-miR-17-5p', 'MIR17-5p|MIR91|MIRN17|MIRN91|hsa-mir-17|miR-17|miR17-3p|miRNA17|miRNA91', '13q31.3', 'microRNA 17', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000070', 3, 75),
('MIMAT0000072', 'hsa-miR-18a-5p', 'MIR18|MIRN18|MIRN18A|hsa-mir-18|hsa-mir-18a|miR-18|miRNA18A', '13q31.3', 'microRNA 18a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000072', 3, 73),
('MIMAT0000073', 'hsa-miR-19a-3p', 'MIRN19A|hsa-mir-19a|miR-19a|miRNA19A', '13q31.3', 'microRNA 19a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000073', 4, 94),
('MIMAT0000074', 'hsa-miR-19b-3p', 'MIRN19B1|miR-19b-1|miRNA19B1', '13q31.3', 'microRNA 19b-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000074', 3, 94),
('MIMAT0000075', 'hsa-miR-20a-5p', 'MIR20|MIRN20|MIRN20A|hsa-mir-20|hsa-mir-20a|miR-20|miRNA20A', '13q31.3', 'microRNA 20a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000075', 4, 73),
('MIMAT0000721', 'hsa-miR-369-3p', 'MIR369-3|MIRN369|MIRN369-3|hsa-mir-369', '14q32.31', 'microRNA 369', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000721', 1, 54),
('MIMAT0000737', 'hsa-miR-382-5p', 'MIRN382|hsa-mir-382', '14q32.31', 'microRNA 382', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000737', 1, 44),
('MIMAT0003164', 'hsa-miR-544a', 'MIR544|MIRN544|hsa-mir-544|hsa-mir-544a', '-', 'microRNA 544a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0003164', 1, 89),
('MIMAT0000423', 'hsa-miR-125b-5p', 'MIRN125B1', '11q24.1', 'microRNA 125b-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000423', 1, 103),
('MIMAT0000433', 'hsa-miR-142-5p', 'MIRN142', '17q22', 'microRNA 142', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000433', 1, 40),
('MIMAT0000417', 'hsa-miR-15b-5p', 'MIRN15B|hsa-mir-15b|miR-15b', '3q25.33', 'microRNA 15b', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000417', 1, 118),
('MIMAT0000069', 'hsa-miR-16-5p', 'MIRN16-1|miRNA16-1', '13q14.2', 'microRNA 16-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000069', 2, 113),
('MIMAT0000256', 'hsa-miR-181a-5p', 'MIR213|MIRN181A1|MIRN213|hsa-mir-181a-1|mir-213', '1q32.1', 'microRNA 181a-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000256', 1, 78),
('MIMAT0000257', 'hsa-miR-181b-5p', 'MIRN181B1', '1q32.1', 'microRNA 181b-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000257', 1, 78),
('MIMAT0004559', 'hsa-miR-181c-3p', 'MIRN181C|mir-181c', '19p13.13', 'microRNA 181c', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0004559', 1, 39),
('MIMAT0000258', 'hsa-miR-181c-5p', 'MIRN181C|mir-181c', '19p13.13', 'microRNA 181c', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000258', 1, 76),
('MIMAT0000084', 'hsa-miR-27a-3p', 'MIR27|MIRN27A', '19p13.13', 'microRNA 27a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000084', 1, 113),
('MIMAT0000100', 'hsa-miR-29b-3p', 'MIRN29B1|miRNA29B1', '7q32.3', 'microRNA 29b-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000100', 3, 116),
('MIMAT0001631', 'hsa-miR-451a', 'MIR451|MIRN451|hsa-mir-451|hsa-mir-451a', '17q11.2', 'microRNA 451a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0001631', 2, 14),
('MIMAT0000437', 'hsa-miR-145-5p', 'MIRN145|miR-145|miRNA145', '5q32', 'microRNA 145', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000437', 1, 93),
('MIMAT0000261', 'hsa-miR-183-5p', 'MIRN183|miR-183|miRNA183', '7q32.2', 'microRNA 183', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000261', 2, 97),
('MIMAT0000068', 'hsa-miR-15a-5p', 'MIRN15A|hsa-mir-15a|miRNA15A', '13q14.2', 'microRNA 15a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000068', 1, 119),
('MIMAT0000086', 'hsa-miR-29a-3p', 'MIRN29|MIRN29A|hsa-mir-29|hsa-mir-29a|miRNA29A', '7q32.3', 'microRNA 29a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000086', 2, 114),
('MIMAT0000103', 'hsa-miR-106a-5p', 'MIRN106A|mir-106', 'Xq26.2', 'microRNA 106a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000103', 1, 75),
('MIMAT0000680', 'hsa-miR-106b-5p', 'MIRN106B', '7q22.1', 'microRNA 106b', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000680', 1, 75),
('MIMAT0000445', 'hsa-miR-126-3p', 'MIRN126|miRNA126', '9q34.3', 'microRNA 126', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000445', 1, 10),
('MIMAT0000444', 'hsa-miR-126-5p', 'MIRN126|miRNA126', '9q34.3', 'microRNA 126', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000444', 1, 17),
('MIMAT0000425', 'hsa-miR-130a-3p', 'MIRN130A|miRNA130A', '11q12.1', 'microRNA 130a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000425', 1, 97),
('MIMAT0000691', 'hsa-miR-130b-3p', 'MIRN130B|mir-130b', '-', 'microRNA 130b', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000691', 1, 98),
('MIMAT0000427', 'hsa-miR-133a-3p', 'MIRN133A1', '18q11.2', 'microRNA 133a-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000427', 1, 73),
('MIMAT0000770', 'hsa-miR-133b', 'MIRN133B|miRNA133B|mir-133b', '6p12.2', 'microRNA 133b', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000770', 1, 73),
('MIMAT0000434', 'hsa-miR-142-3p', 'MIRN142', '17q22', 'microRNA 142', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000434', 1, 43),
('MIMAT0000436', 'hsa-miR-144-3p', 'MIRN144', '17q11.2', 'microRNA 144', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000436', 1, 90),
('MIMAT0000451', 'hsa-miR-150-5p', 'MIRN150|miRNA150', '19q13.33', 'microRNA 150', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000451', 1, 94),
('MIMAT0001412', 'hsa-miR-18b-5p', 'MIRN18B|hsa-mir-18b', 'Xq26.2', 'microRNA 18b', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0001412', 1, 73),
('MIMAT0000461', 'hsa-miR-195-5p', 'MIRN195|miRNA195', '17p13.1', 'microRNA 195', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000461', 1, 114),
('MIMAT0000226', 'hsa-miR-196a-5p', 'MIRN196-1|MIRN196A1', '17q21.32', 'microRNA 196a-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000226', 1, 58),
('MIMAT0001080', 'hsa-miR-196b-5p', 'MIRN196B|miR-196b|miRNA196B', '7p15.2', 'microRNA 196b', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0001080', 1, 59),
('MIMAT0000462', 'hsa-miR-206', 'MIRN206|miRNA206', '6p12.2', 'microRNA 206', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000462', 1, 71),
('MIMAT0001413', 'hsa-miR-20b-5p', 'MIRN20B|hsa-mir-20b', 'Xq26.2', 'microRNA 20b', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0001413', 1, 74),
('MIMAT0004494', 'hsa-miR-21-3p', 'MIRN21|hsa-mir-21|miR-21|miRNA21', '17q23.1', 'microRNA 21', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0004494', 1, 84),
('MIMAT0000280', 'hsa-miR-223-3p', 'MIRN223|miRNA223|mir-223', 'Xq12', 'microRNA 223', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000280', 2, 68),
('MIMAT0000081', 'hsa-miR-25-3p', 'MIRN25|hsa-mir-25|miR-25', '7q22.1', 'microRNA 25', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000081', 1, 57),
('MIMAT0022696', 'hsa-miR-301a-3p', 'MIRN301|MIRN301A', '17q22', 'microRNA 301a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0022696', 1, 67),
('MIMAT0004958', 'hsa-miR-301b', 'MIRN301B', '22q11.21', 'microRNA 301b', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0004958', 1, 95),
('MIMAT0004504', 'hsa-miR-31-3p', 'MIRN31|hsa-mir-31|miR-31', '9p21.3', 'microRNA 31', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0004504', 1, 47),
('MIMAT0000089', 'hsa-miR-31-5p', 'MIRN31|hsa-mir-31|miR-31', '9p21.3', 'microRNA 31', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000089', 1, 79),
('MIMAT0000707', 'hsa-miR-363-3p', 'MIR-363|MIRN363|hsa-mir-363', 'Xq26.2', 'microRNA 363', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000707', 1, 61),
('MIMAT0000727', 'hsa-miR-374a-5p', 'MIRN374|MIRN374A|hsa-mir-374', 'Xq13.2', 'microRNA 374a', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000727', 1, 44),
('MIMAT0002177', 'hsa-miR-486-5p', 'MIRN486|hsa-mir-486', '8p11.21', 'microRNA 486', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0002177', 1, 59),
('MIMAT0002820', 'hsa-miR-497-5p', 'MIRN497|hsa-mir-497', '17p13.1', 'microRNA 497', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0002820', 1, 116),
('MIMAT0000442', 'hsa-miR-9-3p', 'MIRN9-1|hsa-mir-9-1|miRNA9-1', '1q22', 'microRNA 9-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000442', 1, 52),
('MIMAT0000441', 'hsa-miR-9-5p', 'MIRN9-1|hsa-mir-9-1|miRNA9-1', '1q22', 'microRNA 9-1', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000441', 2, 68),
('MIMAT0000430', 'hsa-miR-138-5p', 'MIRN138-2', '16q13', 'microRNA 138-2', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000430', 1, 125),
('MIMAT0000271', 'hsa-miR-214-3p', 'MIRN214|miRNA214|mir-214', '1q24.3', 'microRNA 214', 'miscRNA', 'http://www.mirbase.org/cgi-bin/mature.pl?mature_acc=MIMAT0000271', 1, 126);

-- --------------------------------------------------------

--
-- Tabellenstruktur für Tabelle `omim`
--

CREATE TABLE IF NOT EXISTS `omim` (
  `mimid` int(6) NOT NULL DEFAULT '0',
  `url` varchar(62) DEFAULT NULL,
  PRIMARY KEY (`mimid`),
  KEY `mimid` (`mimid`)
) ENGINE=InnoDB DEFAULT CHARSET=utf8;

--
-- Daten für Tabelle `omim`
--

INSERT INTO `omim` (`mimid`, `url`) VALUES
(100640, 'http://www.omim.org/entry/100640?search=138670&highlight100640'),
(100650, 'http://www.omim.org/entry/100650?search=138670&highlight100650'),
(100800, 'http://www.omim.org/entry/100800?search=138670&highlight100800'),
(101200, 'http://www.omim.org/entry/101200?search=138670&highlight101200'),
(101400, 'http://www.omim.org/entry/101400?search=138670&highlight101400'),
(101600, 'http://www.omim.org/entry/101600?search=138670&highlight101600'),
(102500, 'http://www.omim.org/entry/102500?search=138670&highlight102500'),
(102560, 'http://www.omim.org/entry/102560?search=138670&highlight102560'),
(102575, 'http://www.omim.org/entry/102575?search=138670&highlight102575'),
(102579, 'http://www.omim.org/entry/102579?search=138670&highlight102579'),
(102582, 'http://www.omim.org/entry/102582?search=138670&highlight102582'),
(102620, 'http://www.omim.org/entry/102620?search=138670&highlight102620'),
(102630, 'http://www.omim.org/entry/102630?search=138670&highlight102630'),
(102910, 'http://www.omim.org/entry/102910?search=138670&highlight102910'),
(103072, 'http://www.omim.org/entry/103072?search=138670&highlight103072'),
(103260, 'http://www.omim.org/entry/103260?search=138670&highlight103260'),
(103275, 'http://www.omim.org/entry/103275?search=138670&highlight103275'),
(103280, 'http://www.omim.org/entry/103280?search=138670&highlight103280'),
(103285, 'http://www.omim.org/entry/103285?search=138670&highlight103285'),
(103850, 'http://www.omim.org/entry/103850?search=138670&highlight103850'),
(104300, 'http://www.omim.org/entry/104300?search=138670&highlight104300'),
(104750, 'http://www.omim.org/entry/104750?search=138670&highlight104750'),
(104751, 'http://www.omim.org/entry/104751?search=138670&highlight104751'),
(105120, 'http://www.omim.org/entry/105120?search=138670&highlight105120'),
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(614583, 'http://www.omim.org/entry/614583?search=138670&highlight614583'),
(614592, 'http://www.omim.org/entry/614592?search=138670&highlight614592'),
(614613, 'http://www.omim.org/entry/614613?search=138670&highlight614613'),
(614680, 'http://www.omim.org/entry/614680?search=138670&highlight614680'),
(614689, 'http://www.omim.org/entry/614689?search=138670&highlight614689'),
(614701, 'http://www.omim.org/entry/614701?search=138670&highlight614701'),
(614731, 'http://www.omim.org/entry/614731?search=138670&highlight614731'),
(614732, 'http://www.omim.org/entry/614732?search=138670&highlight614732'),
(614733, 'http://www.omim.org/entry/614733?search=138670&highlight614733'),
(614740, 'http://www.omim.org/entry/614740?search=138670&highlight614740'),
(614748, 'http://www.omim.org/entry/614748?search=138670&highlight614748'),
(614752, 'http://www.omim.org/entry/614752?search=138670&highlight614752');

-- --------------------------------------------------------

--
-- Tabellenstruktur für Tabelle `pfam`
--

CREATE TABLE IF NOT EXISTS `pfam` (
  `pfamid` varchar(7) DEFAULT NULL,
  `url` varchar(39) DEFAULT NULL
) ENGINE=InnoDB DEFAULT CHARSET=utf8;

--
-- Daten für Tabelle `pfam`
--

INSERT INTO `pfam` (`pfamid`, `url`) VALUES
('PF00797', 'http://pfam.sanger.ac.uk/family/PF00797'),
('PF00018', 'http://pfam.sanger.ac.uk/family/PF00018'),
('PF07714', 'http://pfam.sanger.ac.uk/family/PF07714'),
('PF00017', 'http://pfam.sanger.ac.uk/family/PF00017'),
('PF08919', 'http://pfam.sanger.ac.uk/family/PF08919'),
('PF01451', 'http://pfam.sanger.ac.uk/family/PF01451'),
('PF00149', 'http://pfam.sanger.ac.uk/family/PF00149'),
('PF00022', 'http://pfam.sanger.ac.uk/family/PF00022'),
('PF00307', 'http://pfam.sanger.ac.uk/family/PF00307'),
('PF00435', 'http://pfam.sanger.ac.uk/family/PF00435'),
('PF08726', 'http://pfam.sanger.ac.uk/family/PF08726'),
('PF01421', 'http://pfam.sanger.ac.uk/family/PF01421'),
('PF08516', 'http://pfam.sanger.ac.uk/family/PF08516'),
('PF00200', 'http://pfam.sanger.ac.uk/family/PF00200'),
('PF01562', 'http://pfam.sanger.ac.uk/family/PF01562'),
('PF00211', 'http://pfam.sanger.ac.uk/family/PF00211'),
('PF00596', 'http://pfam.sanger.ac.uk/family/PF00596'),
('PF00214', 'http://pfam.sanger.ac.uk/family/PF00214'),
('PF02877', 'http://pfam.sanger.ac.uk/family/PF02877'),
('PF08063', 'http://pfam.sanger.ac.uk/family/PF08063'),
('PF05406', 'http://pfam.sanger.ac.uk/family/PF05406'),
('PF00644', 'http://pfam.sanger.ac.uk/family/PF00644'),
('PF00533', 'http://pfam.sanger.ac.uk/family/PF00533'),
('PF00645', 'http://pfam.sanger.ac.uk/family/PF00645'),
('PF01414', 'http://pfam.sanger.ac.uk/family/PF01414'),
('PF07657', 'http://pfam.sanger.ac.uk/family/PF07657'),
('PF00008', 'http://pfam.sanger.ac.uk/family/PF00008'),
('PF07645', 'http://pfam.sanger.ac.uk/family/PF07645'),
('PF05221', 'http://pfam.sanger.ac.uk/family/PF05221'),
('PF00670', 'http://pfam.sanger.ac.uk/family/PF00670'),
('PF00069', 'http://pfam.sanger.ac.uk/family/PF00069'),
('PF00169', 'http://pfam.sanger.ac.uk/family/PF00169'),
('PF00433', 'http://pfam.sanger.ac.uk/family/PF00433'),
('PF00171', 'http://pfam.sanger.ac.uk/family/PF00171'),
('PF00274', 'http://pfam.sanger.ac.uk/family/PF00274'),
('PF00245', 'http://pfam.sanger.ac.uk/family/PF00245'),
('PF05111', 'http://pfam.sanger.ac.uk/family/PF05111'),
('PF00147', 'http://pfam.sanger.ac.uk/family/PF00147'),
('PF11838', 'http://pfam.sanger.ac.uk/family/PF11838'),
('PF01433', 'http://pfam.sanger.ac.uk/family/PF01433'),
('PF00191', 'http://pfam.sanger.ac.uk/family/PF00191'),
('PF05972', 'http://pfam.sanger.ac.uk/family/PF05972'),
('PF00514', 'http://pfam.sanger.ac.uk/family/PF00514'),
('PF05923', 'http://pfam.sanger.ac.uk/family/PF05923'),
('PF05956', 'http://pfam.sanger.ac.uk/family/PF05956'),
('PF05937', 'http://pfam.sanger.ac.uk/family/PF05937'),
('PF05924', 'http://pfam.sanger.ac.uk/family/PF05924'),
('PF03372', 'http://pfam.sanger.ac.uk/family/PF03372'),
('PF00653', 'http://pfam.sanger.ac.uk/family/PF00653'),
('PF00619', 'http://pfam.sanger.ac.uk/family/PF00619'),
('PF00089', 'http://pfam.sanger.ac.uk/family/PF00089'),
('PF00531', 'http://pfam.sanger.ac.uk/family/PF00531'),
('PF00020', 'http://pfam.sanger.ac.uk/family/PF00020'),
('PF00229', 'http://pfam.sanger.ac.uk/family/PF00229'),
('PF00104', 'http://pfam.sanger.ac.uk/family/PF00104'),
('PF00105', 'http://pfam.sanger.ac.uk/family/PF00105'),
('PF02166', 'http://pfam.sanger.ac.uk/family/PF02166'),
('PF00071', 'http://pfam.sanger.ac.uk/family/PF00071'),
('PF00891', 'http://pfam.sanger.ac.uk/family/PF00891'),
('PF00764', 'http://pfam.sanger.ac.uk/family/PF00764'),
('PF02260', 'http://pfam.sanger.ac.uk/family/PF02260'),
('PF00454', 'http://pfam.sanger.ac.uk/family/PF00454'),
('PF11640', 'http://pfam.sanger.ac.uk/family/PF11640'),
('PF02259', 'http://pfam.sanger.ac.uk/family/PF02259'),
('PF00306', 'http://pfam.sanger.ac.uk/family/PF00306'),
('PF02874', 'http://pfam.sanger.ac.uk/family/PF02874'),
('PF00006', 'http://pfam.sanger.ac.uk/family/PF00006'),
('PF08064', 'http://pfam.sanger.ac.uk/family/PF08064'),
('PF00041', 'http://pfam.sanger.ac.uk/family/PF00041'),
('PF07686', 'http://pfam.sanger.ac.uk/family/PF07686'),
('PF10514', 'http://pfam.sanger.ac.uk/family/PF10514'),
('PF00452', 'http://pfam.sanger.ac.uk/family/PF00452'),
('PF02984', 'http://pfam.sanger.ac.uk/family/PF02984'),
('PF00134', 'http://pfam.sanger.ac.uk/family/PF00134'),
('PF02180', 'http://pfam.sanger.ac.uk/family/PF02180'),
('PF00594', 'http://pfam.sanger.ac.uk/family/PF00594'),
('PF01462', 'http://pfam.sanger.ac.uk/family/PF01462'),
('PF06393', 'http://pfam.sanger.ac.uk/family/PF06393'),
('PF12201', 'http://pfam.sanger.ac.uk/family/PF12201'),
('PF00097', 'http://pfam.sanger.ac.uk/family/PF00097'),
('PF00431', 'http://pfam.sanger.ac.uk/family/PF00431'),
('PF01400', 'http://pfam.sanger.ac.uk/family/PF01400'),
('PF00019', 'http://pfam.sanger.ac.uk/family/PF00019'),
('PF00688', 'http://pfam.sanger.ac.uk/family/PF00688'),
('PF08515', 'http://pfam.sanger.ac.uk/family/PF08515'),
('PF01064', 'http://pfam.sanger.ac.uk/family/PF01064'),
('PF06553', 'http://pfam.sanger.ac.uk/family/PF06553'),
('PF07679', 'http://pfam.sanger.ac.uk/family/PF07679'),
('PF08311', 'http://pfam.sanger.ac.uk/family/PF08311'),
('PF02029', 'http://pfam.sanger.ac.uk/family/PF02029'),
('PF00648', 'http://pfam.sanger.ac.uk/family/PF00648'),
('PF01067', 'http://pfam.sanger.ac.uk/family/PF01067'),
('PF00168', 'http://pfam.sanger.ac.uk/family/PF00168'),
('PF00656', 'http://pfam.sanger.ac.uk/family/PF00656'),
('PF01335', 'http://pfam.sanger.ac.uk/family/PF01335'),
('PF01146', 'http://pfam.sanger.ac.uk/family/PF01146'),
('PF00853', 'http://pfam.sanger.ac.uk/family/PF00853'),
('PF08504', 'http://pfam.sanger.ac.uk/family/PF08504'),
('PF00079', 'http://pfam.sanger.ac.uk/family/PF00079'),
('PF07654', 'http://pfam.sanger.ac.uk/family/PF07654'),
('PF06365', 'http://pfam.sanger.ac.uk/family/PF06365'),
('PF01130', 'http://pfam.sanger.ac.uk/family/PF01130'),
('PF00193', 'http://pfam.sanger.ac.uk/family/PF00193'),
('PF00335', 'http://pfam.sanger.ac.uk/family/PF00335'),
('PF11831', 'http://pfam.sanger.ac.uk/family/PF11831'),
('PF00581', 'http://pfam.sanger.ac.uk/family/PF00581'),
('PF06617', 'http://pfam.sanger.ac.uk/family/PF06617'),
('PF01049', 'http://pfam.sanger.ac.uk/family/PF01049'),
('PF00028', 'http://pfam.sanger.ac.uk/family/PF00028'),
('PF08758', 'http://pfam.sanger.ac.uk/family/PF08758'),
('PF02234', 'http://pfam.sanger.ac.uk/family/PF02234'),
('PF12796', 'http://pfam.sanger.ac.uk/family/PF12796'),
('PF00023', 'http://pfam.sanger.ac.uk/family/PF00023'),
('PF07392', 'http://pfam.sanger.ac.uk/family/PF07392'),
('PF00046', 'http://pfam.sanger.ac.uk/family/PF00046'),
('PF04731', 'http://pfam.sanger.ac.uk/family/PF04731'),
('PF07716', 'http://pfam.sanger.ac.uk/family/PF07716'),
('PF00236', 'http://pfam.sanger.ac.uk/family/PF00236'),
('PF00007', 'http://pfam.sanger.ac.uk/family/PF00007'),
('PF12179', 'http://pfam.sanger.ac.uk/family/PF12179'),
('PF01093', 'http://pfam.sanger.ac.uk/family/PF01093'),
('PF00001', 'http://pfam.sanger.ac.uk/family/PF00001'),
('PF00664', 'http://pfam.sanger.ac.uk/family/PF00664'),
('PF00005', 'http://pfam.sanger.ac.uk/family/PF00005'),
('PF00402', 'http://pfam.sanger.ac.uk/family/PF00402'),
('PF01410', 'http://pfam.sanger.ac.uk/family/PF01410'),
('PF00093', 'http://pfam.sanger.ac.uk/family/PF00093'),
('PF01391', 'http://pfam.sanger.ac.uk/family/PF01391'),
('PF00092', 'http://pfam.sanger.ac.uk/family/PF00092'),
('PF00014', 'http://pfam.sanger.ac.uk/family/PF00014'),
('PF02210', 'http://pfam.sanger.ac.uk/family/PF02210'),
('PF07731', 'http://pfam.sanger.ac.uk/family/PF07731'),
('PF07732', 'http://pfam.sanger.ac.uk/family/PF07732'),
('PF00394', 'http://pfam.sanger.ac.uk/family/PF00394'),
('PF02173', 'http://pfam.sanger.ac.uk/family/PF02173'),
('PF00170', 'http://pfam.sanger.ac.uk/family/PF00170'),
('PF02135', 'http://pfam.sanger.ac.uk/family/PF02135'),
('PF02172', 'http://pfam.sanger.ac.uk/family/PF02172'),
('PF09030', 'http://pfam.sanger.ac.uk/family/PF09030'),
('PF06001', 'http://pfam.sanger.ac.uk/family/PF06001'),
('PF00439', 'http://pfam.sanger.ac.uk/family/PF00439'),
('PF08214', 'http://pfam.sanger.ac.uk/family/PF08214'),
('PF00569', 'http://pfam.sanger.ac.uk/family/PF00569'),
('PF00412', 'http://pfam.sanger.ac.uk/family/PF00412'),
('PF00354', 'http://pfam.sanger.ac.uk/family/PF00354'),
('PF00011', 'http://pfam.sanger.ac.uk/family/PF00011'),
('PF00525', 'http://pfam.sanger.ac.uk/family/PF00525'),
('PF05337', 'http://pfam.sanger.ac.uk/family/PF05337'),
('PF00047', 'http://pfam.sanger.ac.uk/family/PF00047'),
('PF01109', 'http://pfam.sanger.ac.uk/family/PF01109'),
('PF00059', 'http://pfam.sanger.ac.uk/family/PF00059'),
('PF00084', 'http://pfam.sanger.ac.uk/family/PF00084'),
('PF00090', 'http://pfam.sanger.ac.uk/family/PF00090'),
('PF00219', 'http://pfam.sanger.ac.uk/family/PF00219'),
('PF00112', 'http://pfam.sanger.ac.uk/family/PF00112'),
('PF08127', 'http://pfam.sanger.ac.uk/family/PF08127'),
('PF07966', 'http://pfam.sanger.ac.uk/family/PF07966'),
('PF00026', 'http://pfam.sanger.ac.uk/family/PF00026'),
('PF08246', 'http://pfam.sanger.ac.uk/family/PF08246'),
('PF02167', 'http://pfam.sanger.ac.uk/family/PF02167'),
('PF00067', 'http://pfam.sanger.ac.uk/family/PF00067'),
('PF06583', 'http://pfam.sanger.ac.uk/family/PF06583'),
('PF01248', 'http://pfam.sanger.ac.uk/family/PF01248'),
('PF07717', 'http://pfam.sanger.ac.uk/family/PF07717'),
('PF04408', 'http://pfam.sanger.ac.uk/family/PF04408'),
('PF00271', 'http://pfam.sanger.ac.uk/family/PF00271'),
('PF00035', 'http://pfam.sanger.ac.uk/family/PF00035'),
('PF00270', 'http://pfam.sanger.ac.uk/family/PF00270'),
('PF04732', 'http://pfam.sanger.ac.uk/family/PF04732'),
('PF00038', 'http://pfam.sanger.ac.uk/family/PF00038'),
('PF02017', 'http://pfam.sanger.ac.uk/family/PF02017'),
('PF09033', 'http://pfam.sanger.ac.uk/family/PF09033'),
('PF00186', 'http://pfam.sanger.ac.uk/family/PF00186'),
('PF12413', 'http://pfam.sanger.ac.uk/family/PF12413'),
('PF03028', 'http://pfam.sanger.ac.uk/family/PF03028'),
('PF12777', 'http://pfam.sanger.ac.uk/family/PF12777'),
('PF12780', 'http://pfam.sanger.ac.uk/family/PF12780'),
('PF08393', 'http://pfam.sanger.ac.uk/family/PF08393'),
('PF07728', 'http://pfam.sanger.ac.uk/family/PF07728'),
('PF08385', 'http://pfam.sanger.ac.uk/family/PF08385'),
('PF00681', 'http://pfam.sanger.ac.uk/family/PF00681'),
('PF02825', 'http://pfam.sanger.ac.uk/family/PF02825'),
('PF13639', 'http://pfam.sanger.ac.uk/family/PF13639'),
('PF00782', 'http://pfam.sanger.ac.uk/family/PF00782'),
('PF00692', 'http://pfam.sanger.ac.uk/family/PF00692'),
('PF00595', 'http://pfam.sanger.ac.uk/family/PF00595'),
('PF00778', 'http://pfam.sanger.ac.uk/family/PF00778'),
('PF00610', 'http://pfam.sanger.ac.uk/family/PF00610'),
('PF02377', 'http://pfam.sanger.ac.uk/family/PF02377'),
('PF12316', 'http://pfam.sanger.ac.uk/family/PF12316'),
('PF02319', 'http://pfam.sanger.ac.uk/family/PF02319'),
('PF00322', 'http://pfam.sanger.ac.uk/family/PF00322'),
('PF00812', 'http://pfam.sanger.ac.uk/family/PF00812'),
('PF00058', 'http://pfam.sanger.ac.uk/family/PF00058'),
('PF01030', 'http://pfam.sanger.ac.uk/family/PF01030'),
('PF00757', 'http://pfam.sanger.ac.uk/family/PF00757'),
('PF00096', 'http://pfam.sanger.ac.uk/family/PF00096'),
('PF11928', 'http://pfam.sanger.ac.uk/family/PF11928'),
('PF11914', 'http://pfam.sanger.ac.uk/family/PF11914'),
('PF00575', 'http://pfam.sanger.ac.uk/family/PF00575'),
('PF07541', 'http://pfam.sanger.ac.uk/family/PF07541'),
('PF00536', 'http://pfam.sanger.ac.uk/family/PF00536'),
('PF01404', 'http://pfam.sanger.ac.uk/family/PF01404'),
('PF01652', 'http://pfam.sanger.ac.uk/family/PF01652'),
('PF00178', 'http://pfam.sanger.ac.uk/family/PF00178'),
('PF02218', 'http://pfam.sanger.ac.uk/family/PF02218'),
('PF01223', 'http://pfam.sanger.ac.uk/family/PF01223'),
('PF00100', 'http://pfam.sanger.ac.uk/family/PF00100'),
('PF00113', 'http://pfam.sanger.ac.uk/family/PF00113'),
('PF03952', 'http://pfam.sanger.ac.uk/family/PF03952'),
('PF08778', 'http://pfam.sanger.ac.uk/family/PF08778'),
('PF08447', 'http://pfam.sanger.ac.uk/family/PF08447'),
('PF11413', 'http://pfam.sanger.ac.uk/family/PF11413'),
('PF00989', 'http://pfam.sanger.ac.uk/family/PF00989'),
('PF07699', 'http://pfam.sanger.ac.uk/family/PF07699'),
('PF07647', 'http://pfam.sanger.ac.uk/family/PF07647'),
('PF03834', 'http://pfam.sanger.ac.uk/family/PF03834'),
('PF00633', 'http://pfam.sanger.ac.uk/family/PF00633'),
('PF06733', 'http://pfam.sanger.ac.uk/family/PF06733'),
('PF06777', 'http://pfam.sanger.ac.uk/family/PF06777'),
('PF13307', 'http://pfam.sanger.ac.uk/family/PF13307'),
('PF00752', 'http://pfam.sanger.ac.uk/family/PF00752'),
('PF00867', 'http://pfam.sanger.ac.uk/family/PF00867'),
('PF00756', 'http://pfam.sanger.ac.uk/family/PF00756'),
('PF12743', 'http://pfam.sanger.ac.uk/family/PF12743'),
('PF02159', 'http://pfam.sanger.ac.uk/family/PF02159'),
('PF12497', 'http://pfam.sanger.ac.uk/family/PF12497'),
('PF02198', 'http://pfam.sanger.ac.uk/family/PF02198'),
('PF04621', 'http://pfam.sanger.ac.uk/family/PF04621'),
('PF11616', 'http://pfam.sanger.ac.uk/family/PF11616'),
('PF00856', 'http://pfam.sanger.ac.uk/family/PF00856'),
('PF00051', 'http://pfam.sanger.ac.uk/family/PF00051'),
('PF09396', 'http://pfam.sanger.ac.uk/family/PF09396'),
('PF00373', 'http://pfam.sanger.ac.uk/family/PF00373'),
('PF03623', 'http://pfam.sanger.ac.uk/family/PF03623'),
('PF01821', 'http://pfam.sanger.ac.uk/family/PF01821'),
('PF00698', 'http://pfam.sanger.ac.uk/family/PF00698'),
('PF00550', 'http://pfam.sanger.ac.uk/family/PF00550'),
('PF08242', 'http://pfam.sanger.ac.uk/family/PF08242'),
('PF02801', 'http://pfam.sanger.ac.uk/family/PF02801'),
('PF00106', 'http://pfam.sanger.ac.uk/family/PF00106'),
('PF00107', 'http://pfam.sanger.ac.uk/family/PF00107'),
('PF00975', 'http://pfam.sanger.ac.uk/family/PF00975'),
('PF00109', 'http://pfam.sanger.ac.uk/family/PF00109'),
('PF00111', 'http://pfam.sanger.ac.uk/family/PF00111'),
('PF12160', 'http://pfam.sanger.ac.uk/family/PF12160'),
('PF08702', 'http://pfam.sanger.ac.uk/family/PF08702'),
('PF00167', 'http://pfam.sanger.ac.uk/family/PF00167'),
('PF01230', 'http://pfam.sanger.ac.uk/family/PF01230'),
('PF00254', 'http://pfam.sanger.ac.uk/family/PF00254'),
('PF00515', 'http://pfam.sanger.ac.uk/family/PF00515'),
('PF00250', 'http://pfam.sanger.ac.uk/family/PF00250'),
('PF00040', 'http://pfam.sanger.ac.uk/family/PF00040'),
('PF00039', 'http://pfam.sanger.ac.uk/family/PF00039'),
('PF01239', 'http://pfam.sanger.ac.uk/family/PF01239'),
('PF03024', 'http://pfam.sanger.ac.uk/family/PF03024'),
('PF11865', 'http://pfam.sanger.ac.uk/family/PF11865'),
('PF08771', 'http://pfam.sanger.ac.uk/family/PF08771'),
('PF01392', 'http://pfam.sanger.ac.uk/family/PF01392'),
('PF01759', 'http://pfam.sanger.ac.uk/family/PF01759'),
('PF00210', 'http://pfam.sanger.ac.uk/family/PF00210'),
('PF00226', 'http://pfam.sanger.ac.uk/family/PF00226'),
('PF10409', 'http://pfam.sanger.ac.uk/family/PF10409'),
('PF00320', 'http://pfam.sanger.ac.uk/family/PF00320'),
('PF00273', 'http://pfam.sanger.ac.uk/family/PF00273'),
('PF09164', 'http://pfam.sanger.ac.uk/family/PF09164'),
('PF00103', 'http://pfam.sanger.ac.uk/family/PF00103'),
('PF00123', 'http://pfam.sanger.ac.uk/family/PF00123'),
('PF00002', 'http://pfam.sanger.ac.uk/family/PF00002'),
('PF02793', 'http://pfam.sanger.ac.uk/family/PF02793'),
('PF00029', 'http://pfam.sanger.ac.uk/family/PF00029'),
('PF03508', 'http://pfam.sanger.ac.uk/family/PF03508'),
('PF10582', 'http://pfam.sanger.ac.uk/family/PF10582'),
('PF01301', 'http://pfam.sanger.ac.uk/family/PF01301'),
('PF03074', 'http://pfam.sanger.ac.uk/family/PF03074'),
('PF00120', 'http://pfam.sanger.ac.uk/family/PF00120'),
('PF03951', 'http://pfam.sanger.ac.uk/family/PF03951'),
('PF00446', 'http://pfam.sanger.ac.uk/family/PF00446'),
('PF00342', 'http://pfam.sanger.ac.uk/family/PF00342'),
('PF00788', 'http://pfam.sanger.ac.uk/family/PF00788'),
('PF08947', 'http://pfam.sanger.ac.uk/family/PF08947'),
('PF02155', 'http://pfam.sanger.ac.uk/family/PF02155'),
('PF01094', 'http://pfam.sanger.ac.uk/family/PF01094'),
('PF00003', 'http://pfam.sanger.ac.uk/family/PF00003'),
('PF07562', 'http://pfam.sanger.ac.uk/family/PF07562'),
('PF10606', 'http://pfam.sanger.ac.uk/family/PF10606'),
('PF00626', 'http://pfam.sanger.ac.uk/family/PF00626'),
('PF00043', 'http://pfam.sanger.ac.uk/family/PF00043'),
('PF02798', 'http://pfam.sanger.ac.uk/family/PF02798'),
('PF02837', 'http://pfam.sanger.ac.uk/family/PF02837'),
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('PF01630', 'http://pfam.sanger.ac.uk/family/PF01630'),
('PF01044', 'http://pfam.sanger.ac.uk/family/PF01044'),
('PF11980', 'http://pfam.sanger.ac.uk/family/PF11980'),
('PF00754', 'http://pfam.sanger.ac.uk/family/PF00754'),
('PF05478', 'http://pfam.sanger.ac.uk/family/PF05478'),
('PF00781', 'http://pfam.sanger.ac.uk/family/PF00781'),
('PF00013', 'http://pfam.sanger.ac.uk/family/PF00013'),
('PF09005', 'http://pfam.sanger.ac.uk/family/PF09005'),
('PF03343', 'http://pfam.sanger.ac.uk/family/PF03343'),
('PF01448', 'http://pfam.sanger.ac.uk/family/PF01448'),
('PF01426', 'http://pfam.sanger.ac.uk/family/PF01426'),
('PF07992', 'http://pfam.sanger.ac.uk/family/PF07992'),
('PF00070', 'http://pfam.sanger.ac.uk/family/PF00070'),
('PF00400', 'http://pfam.sanger.ac.uk/family/PF00400'),
('PF05806', 'http://pfam.sanger.ac.uk/family/PF05806'),
('PF01233', 'http://pfam.sanger.ac.uk/family/PF01233'),
('PF02799', 'http://pfam.sanger.ac.uk/family/PF02799'),
('PF11719', 'http://pfam.sanger.ac.uk/family/PF11719'),
('PF01061', 'http://pfam.sanger.ac.uk/family/PF01061'),
('PF00640', 'http://pfam.sanger.ac.uk/family/PF00640'),
('PF02179', 'http://pfam.sanger.ac.uk/family/PF02179'),
('PF03832', 'http://pfam.sanger.ac.uk/family/PF03832'),
('PF10522', 'http://pfam.sanger.ac.uk/family/PF10522'),
('PF03568', 'http://pfam.sanger.ac.uk/family/PF03568'),
('PF00076', 'http://pfam.sanger.ac.uk/family/PF00076'),
('PF05391', 'http://pfam.sanger.ac.uk/family/PF05391'),
('PF09757', 'http://pfam.sanger.ac.uk/family/PF09757'),
('PF12203', 'http://pfam.sanger.ac.uk/family/PF12203'),
('PF01344', 'http://pfam.sanger.ac.uk/family/PF01344'),
('PF07707', 'http://pfam.sanger.ac.uk/family/PF07707'),
('PF10377', 'http://pfam.sanger.ac.uk/family/PF10377'),
('PF03114', 'http://pfam.sanger.ac.uk/family/PF03114'),
('PF01505', 'http://pfam.sanger.ac.uk/family/PF01505'),
('PF11978', 'http://pfam.sanger.ac.uk/family/PF11978'),
('PF02148', 'http://pfam.sanger.ac.uk/family/PF02148'),
('PF06773', 'http://pfam.sanger.ac.uk/family/PF06773'),
('PF08945', 'http://pfam.sanger.ac.uk/family/PF08945'),
('PF03096', 'http://pfam.sanger.ac.uk/family/PF03096'),
('PF04505', 'http://pfam.sanger.ac.uk/family/PF04505'),
('PF04912', 'http://pfam.sanger.ac.uk/family/PF04912'),
('PF01553', 'http://pfam.sanger.ac.uk/family/PF01553'),
('PF08327', 'http://pfam.sanger.ac.uk/family/PF08327'),
('PF09229', 'http://pfam.sanger.ac.uk/family/PF09229'),
('PF05808', 'http://pfam.sanger.ac.uk/family/PF05808'),
('PF06821', 'http://pfam.sanger.ac.uk/family/PF06821'),
('PF03662', 'http://pfam.sanger.ac.uk/family/PF03662'),
('PF07915', 'http://pfam.sanger.ac.uk/family/PF07915'),
('PF00557', 'http://pfam.sanger.ac.uk/family/PF00557'),
('PF12721', 'http://pfam.sanger.ac.uk/family/PF12721'),
('PF04089', 'http://pfam.sanger.ac.uk/family/PF04089'),
('PF02019', 'http://pfam.sanger.ac.uk/family/PF02019'),
('PF01965', 'http://pfam.sanger.ac.uk/family/PF01965'),
('PF00385', 'http://pfam.sanger.ac.uk/family/PF00385'),
('PF01393', 'http://pfam.sanger.ac.uk/family/PF01393'),
('PF04706', 'http://pfam.sanger.ac.uk/family/PF04706'),
('PF04433', 'http://pfam.sanger.ac.uk/family/PF04433'),
('PF01593', 'http://pfam.sanger.ac.uk/family/PF01593'),
('PF10234', 'http://pfam.sanger.ac.uk/family/PF10234'),
('PF06631', 'http://pfam.sanger.ac.uk/family/PF06631'),
('PF12485', 'http://pfam.sanger.ac.uk/family/PF12485'),
('PF11466', 'http://pfam.sanger.ac.uk/family/PF11466'),
('PF08357', 'http://pfam.sanger.ac.uk/family/PF08357'),
('PF02671', 'http://pfam.sanger.ac.uk/family/PF02671'),
('PF08295', 'http://pfam.sanger.ac.uk/family/PF08295'),
('PF04000', 'http://pfam.sanger.ac.uk/family/PF04000'),
('PF01926', 'http://pfam.sanger.ac.uk/family/PF01926'),
('PF08701', 'http://pfam.sanger.ac.uk/family/PF08701'),
('PF08030', 'http://pfam.sanger.ac.uk/family/PF08030'),
('PF01794', 'http://pfam.sanger.ac.uk/family/PF01794'),
('PF08022', 'http://pfam.sanger.ac.uk/family/PF08022'),
('PF04969', 'http://pfam.sanger.ac.uk/family/PF04969'),
('PF05002', 'http://pfam.sanger.ac.uk/family/PF05002'),
('PF09032', 'http://pfam.sanger.ac.uk/family/PF09032'),
('PF03250', 'http://pfam.sanger.ac.uk/family/PF03250'),
('PF00034', 'http://pfam.sanger.ac.uk/family/PF00034'),
('PF03159', 'http://pfam.sanger.ac.uk/family/PF03159'),
('PF07719', 'http://pfam.sanger.ac.uk/family/PF07719'),
('PF01479', 'http://pfam.sanger.ac.uk/family/PF01479'),
('PF06701', 'http://pfam.sanger.ac.uk/family/PF06701'),
('PF06017', 'http://pfam.sanger.ac.uk/family/PF06017'),
('PF00632', 'http://pfam.sanger.ac.uk/family/PF00632'),
('PF09783', 'http://pfam.sanger.ac.uk/family/PF09783'),
('PF10856', 'http://pfam.sanger.ac.uk/family/PF10856'),
('PF06920', 'http://pfam.sanger.ac.uk/family/PF06920'),
('PF00658', 'http://pfam.sanger.ac.uk/family/PF00658'),
('PF06482', 'http://pfam.sanger.ac.uk/family/PF06482'),
('PF06121', 'http://pfam.sanger.ac.uk/family/PF06121'),
('PF08662', 'http://pfam.sanger.ac.uk/family/PF08662'),
('PF00091', 'http://pfam.sanger.ac.uk/family/PF00091'),
('PF03953', 'http://pfam.sanger.ac.uk/family/PF03953'),
('PF03764', 'http://pfam.sanger.ac.uk/family/PF03764'),
('PF03144', 'http://pfam.sanger.ac.uk/family/PF03144'),
('PF00679', 'http://pfam.sanger.ac.uk/family/PF00679'),
('PF00009', 'http://pfam.sanger.ac.uk/family/PF00009'),
('PF02037', 'http://pfam.sanger.ac.uk/family/PF02037'),
('PF02755', 'http://pfam.sanger.ac.uk/family/PF02755'),
('PF06293', 'http://pfam.sanger.ac.uk/family/PF06293'),
('PF03127', 'http://pfam.sanger.ac.uk/family/PF03127'),
('PF00790', 'http://pfam.sanger.ac.uk/family/PF00790'),
('PF00160', 'http://pfam.sanger.ac.uk/family/PF00160'),
('PF11704', 'http://pfam.sanger.ac.uk/family/PF11704'),
('PF10278', 'http://pfam.sanger.ac.uk/family/PF10278'),
('PF06535', 'http://pfam.sanger.ac.uk/family/PF06535'),
('PF06534', 'http://pfam.sanger.ac.uk/family/PF06534');

-- --------------------------------------------------------

--
-- Tabellenstruktur für Tabelle `pm`
--

CREATE TABLE IF NOT EXISTS `pm` (
  `pmid` int(8) NOT NULL DEFAULT '0',
  `author` varchar(263) DEFAULT NULL,
  `title` varchar(227) DEFAULT NULL,
  `journal` varchar(48) DEFAULT NULL,
  `year` varchar(4) DEFAULT NULL,
  `abstract` varchar(3357) DEFAULT NULL,
  `url` varchar(43) DEFAULT NULL,
  `tumor` varchar(3) DEFAULT NULL,
  `value` varchar(3) DEFAULT NULL,
  `addon` varchar(87) DEFAULT NULL,
  `frequency` int(2) DEFAULT NULL,
  PRIMARY KEY (`pmid`),
  KEY `pmid` (`pmid`)
) ENGINE=InnoDB DEFAULT CHARSET=utf8;


INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(2036639, 'Scheffer H, Kruize YC, Osinga J, Kuiken G, Oosterhuis JW, Leeuw JA, Schraffordt Koops H, Buys CH', 'Complete association of loss of heterozygosity of chromosomes 13 and 17 in osteosarcoma.', 'Cancer Genet Cytogenet', '1991', 'Complete association of loss of heterozygosity of chromosomes 13 and 17 in osteosarcoma. Mutations of the retinoblastoma (RB1) gene are not confined to retinoblastoma, but are also involved in the development of osteosarcoma. Structural aberrations within the RB1 gene have been studied in fresh samples of eleven cases of osteosarcoma. In five cases a rearrangement was detected, one of which was best explained as a partial duplication. The chromosomal mechanisms by which the nonmutated RB1 allele was lost appeared to be similar in frequency to those that have been reported for retinoblastoma. Loss of heterozygosity was observed for chromosomes 3, 11, 13, 17, and 22. However, when no loss of heterozygosity of chromosome 13 was detected, the other chromosomes retained their heterozygosity as well. A complete association of loss of heterozygosity of chromosomes 13 and 17 was observed. This can be taken as an indication of the involvement of another tumor suppressor gene at chromosome 17 in the initiation of osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/2036639', 'yes', 'no', 'NA', 1),
(2069168, 'Baker WJ, Hargis JB, Danesi R, La Rocca RV', 'The effect of rhGM-CSF on the proliferation of osteogenic sarcoma cells.', 'Am J Hematol', '1991', 'The effect of rhGM-CSF on the proliferation of osteogenic sarcoma cells. Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) promotes the growth of a variety of hematopoietic and nonhematopoietic cells, both benign and malignant. There is now evidence that osteoblast-like cells produce GM-CSF and their growth is stimulated by this cytokine in vitro. We have studied the effect of rhGM-CSF on DNA synthesis and cell proliferation in the human osteogenic sarcoma cell lines U-20S, G-292, MG-63, and HOS. RhGM-CSF stimulated a dose-dependent increase in radioactive thymidine incorporation in each of the four cell lines in the presence of serum-free media, and in two cell lines (HOS and U-20S) in the presence of fetal bovine serum (FBS). In addition, rhGM-CSF produced significant increases in cell proliferation in two cell lines (MG-63 and U-20S) in the presence of 2% FBS. These results suggest that GM-CSF may have an important role in the biology of human osteogenic sarcoma cells. The clinical implications of these findings merit further investigation.', 'http://www.ncbi.nlm.nih.gov/pubmed/2069168', 'no', 'no', 'NA', 1),
(2115647, 'Wu JX, Carpenter PM, Gresens C, Keh R, Niman H, Morris JW, Mercola D', 'The proto-oncogene c-fos is over-expressed in the majority of human osteosarcomas.', 'Oncogene', '1990', 'The proto-oncogene c-fos is over-expressed in the majority of human osteosarcomas. The expression of fos protein was examined in 30 cases of human osteosarcoma as formalin-fixed and paraffin-embedded tissue sections using two monoclonal antibodies and, for five cases, as frozen sections using 3 polyclonal antibodies. Nuclear antibody labeling intensities were determined either by visual scoring (3 pathologists) or by microdensitometry and included over 700 tumor, 350 normal and 150 benign tissue observations. Visual scores were shown to be linear with optical density with a correlation coefficient of 0.97. Analysis of the osteosarcoma cases at one antibody concentration revealed two groups: a minority (39%) with a low average visual score of 2 +/- 0.2 which was very similar to benign and normal tissues, and a majority (61%) with an average score of 3.1 +/- 0.3. The difference is highly significant (t-test), P less than or equal to 0.01. The results were supported by an analysis of partial immunotitration curves using a curve-fitting procedure which yielded estimates of FOSo (maximum relative fos protein concentration) which were ca. 150% increased for the majority tumor group compared to the minority group or benign or normal tissues. In previous studies of v-sis transformed cells, which exhibit ca. 300% over-expression of c-fos protein as observed here, antisense techniques were used to show that over-expression leads to increased growth and loss of contact inhibition. Thus the combined results suggest that steady state c-fos protein is significantly elevated in, and may contribute to, the aggressive growth properties of a majority of human osteosarcomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/2115647', 'yes', 'no', 'NA', 1),
(2143022, 'Mulligan LM, Matlashewski GJ, Scrable HJ, Cavenee WK', 'Mechanisms of p53 loss in human sarcomas.', 'Proc Natl Acad Sci U S A', '1990', 'Mechanisms of p53 loss in human sarcomas. An important role for the p53 gene in neoplastic transformation in vitro and in vivo has been imputed by functional studies and identification of tumor-acquired gene defects or alterations in its expression. To study the generality and mechanisms of p53 alteration in human cancer, we examined 241 tumors of several types for structural aberrations of the locus. Alterations of the gene or its RNA or protein products consistent with loss of function by either recessive or dominant mechanisms were identified among this set uniquely in rhabdomyosarcomas and osteosarcomas. The alterations of p53 in rhabdomyosarcoma tumors included cases with complete deletion of both p53 alleles, complete deletions of one allele with or without point mutation of the remaining allele, and absence of detectable RNA. Similarly, we detected homozygous deletion and lack of expression of p53 RNA or aberrant expression of p53 protein in osteosarcomas. These observations provide strong support for the inclusion of the p53 locus in the group of loci whose functional inactivation by either dominant or recessive modes plays a significant role in human cancer.', 'http://www.ncbi.nlm.nih.gov/pubmed/2143022', 'yes', 'no', 'NA', 1),
(2153840, 'Pollak MN, Polychronakos C, Richard M', 'Insulinlike growth factor I: a potent mitogen for human osteogenic sarcoma.', 'J Natl Cancer Inst', '1990', 'Insulinlike growth factor I: a potent mitogen for human osteogenic sarcoma. Insulinlike growth factor I (IGF-I) is among the peptide mitogens that play key roles in the regulation of normal skeletal growth. To investigate the possibility that certain skeletal neoplasms retain a sensitivity to mitogenic stimulation by IGF-I, we studied the effects of this growth factor on human osteosarcoma. Competitive-binding assays and affinity-labeling experiments on membranes prepared from MG-63 immortalized human osteosarcoma cells and primary human osteogenic sarcoma cells demonstrate the presence of specific IGF-I receptors. Furthermore, we show that IGF-I is a potent stimulator of proliferation of MG-63 cells in vitro and is active at concentrations as low as 10(-10) M. A blocking antibody against the IGF-I receptor (alpha-IR3) significantly reduces IGF-I-stimulated proliferation in a dose-dependent manner. These results are consistent with the hypothesis that at least a subset of human osteogenic sarcomas are responsive to IGF-I and indicate that it may be possible to exploit this responsiveness therapeutically.', 'http://www.ncbi.nlm.nih.gov/pubmed/2153840', 'no', 'no', 'NA', 2),
(2156959, 'Harsh GR, Keating MT, Escobedo JA, Williams LT', 'Platelet derived growth factor (PDGF) autocrine components in human tumor cell lines.', 'J Neurooncol', '1990', 'Platelet derived growth factor (PDGF) autocrine components in human tumor cell lines. Tumor cells may stimulate their own proliferation through an autocrine mechanism by simultaneously producing growth factors and growth factor receptors. We now report that numerous human tumor-derived cell lines simultaneously express the genes for platelet-derived growth factor (PDGF) A and B chains and the PDGF receptor (PDGF-R). Measurement of mRNA transcribed from these genes showed that among 16 malignant glioma cell lines tested, 15 expressed the PDGF A gene, 12 expressed the PDGF B gene, and 13 expressed the PDGF-R gene. Of three osteosarcoma lines, three expressed PDGF A, two expressed PDGF B, and three expressed PDGF-R. For eight malignant melanoma lines, seven expressed PDGF A, five expressed PDGF B, and three expressed PDGF-R genes. Thus, 13 of 16 malignant glioma, 3 of 3 osteosarcomas, and 3 of 8 malignant melanoma cell lines expressed the PDGF receptor gene and either or both PDGF genes. Five cell lines were tested for production of biologically active PDGF and PDGF receptor protein. Media conditioned by each of the five cell lines induced tyrosine phosphorylation of a protein identical in size to the PDGF receptor. These five cell lines also produced PDGF receptor protein as measured by Western blot analysis or metabolic labeling and immunoprecipitation using PDGF-R antibodies. The PDGF receptors of these cell lines were activated by human platelet PDGF or by recombinant AA or BB homodimers. Intracellular interaction of these receptors with the growth factor simultaneously produced may provide continuous stimulation to the proliferation of these cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/2156959', 'no', 'no', 'NA', 3),
(2166171, 'Pollak M, Richard M', 'Suramin blockade of insulinlike growth factor I-stimulated proliferation of human osteosarcoma cells.', 'J Natl Cancer Inst', '1990', 'Suramin blockade of insulinlike growth factor I-stimulated proliferation of human osteosarcoma cells. The polyanionic compound suramin is currently being evaluated for antineoplastic activity. On the basis of previous in vitro studies, it has been suggested that the mechanism of action of suramin may be related to its ability to attenuate the mitogenic effects of peptide growth factors, such as platelet-derived growth factor and epidermal growth factor. We recently reported that MG-63 human osteosarcoma cells are mitogenically responsive to insulinlike growth factor I (IGF-I). We now demonstrate for the first time that suramin interferes with the interaction between IGF-I and its receptor and abolishes in vitro IGF-I-stimulated proliferation of these osteosarcoma cells. The fact that cell proliferation resumes when suramin is removed indicates that this is not a cytotoxic effect. We conclude that IGF-I should be added to the list of growth factors whose bioactivity can be attenuated by suramin and that clinical studies of suramin and its analogues are indicated in IGF-I-receptor-positive malignancies such as osteogenic sarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/2166171', 'no', 'no', 'suramin', 1),
(2169996, 'Mechtersheimer G, Möller P', 'Expression of Ki-1 antigen (CD30) in mesenchymal tumors.', 'Cancer', '1990', 'Expression of Ki-1 antigen (CD30) in mesenchymal tumors. Expression of CD30(Ki-1) antigen has long been considered to be restricted to activated lymphocytes and related tumors. However, expression of this antigen has also been detected in embryonal carcinomas, in nonembryonal carcinomas, in malignant melanomas, and even in some myeloid cell lines and macrophages at late stages of differentiation. In this study, using monoclonal antibody Ki-1, expression of CD30 antigen was immunohistochemically examined in frozen sections of 28 benign and 63 malignant mesenchymal tumors. The authors found CD30 expressed in two of four leiomyomas, seven of 11 leiomysarcomas, one of six rhabdomyosarcomas, two of two aggressive fibromatoses, one of three fibrosarcomas, two of four synovial sarcomas, one giant cell tumors of tendon sheaths, all five malignant fibrous histiocytomas, all three osteosarcomas, one of three Ewing''s sarcomas, in a tumor cell subpopulation of two of ten malignant schwannomas, and in the Schwann cell compartment of one of two ganglioneuromas tested. Furthermore, CD30 was consistently expressed in the myoepithelial compartment of 13 fibroadenomas. However, all five lipomas, all seven liposarcomas, all three neuroblastomas, both ganglioneuroblastomas, both chondrosarcomas, and tumors of disputed origin tested were consistently CD30 negative. These findings indicate that, outside the lymphatic system, CD30 antigen is not restricted to epithelial neoplasms but may also be present in tumors of mesenchymal origin. The authors conclude that CD30 antigen, although having limited utility in the differential diagnosis of tumors of questionable histogenesis, may eventually define relevant subgroups within the main tumor categories.', 'http://www.ncbi.nlm.nih.gov/pubmed/2169996', 'yes', 'no', 'NA', 1),
(2233717, 'Diller L, Kassel J, Nelson CE, Gryka MA, Litwak G, Gebhardt M, Bressac B, Ozturk M, Baker SJ, Vogelstein B', 'p53 functions as a cell cycle control protein in osteosarcomas.', 'Mol Cell Biol', '1990', 'p53 functions as a cell cycle control protein in osteosarcomas. Mutations in the p53 gene have been associated with a wide range of human tumors, including osteosarcomas. Although it has been shown that wild-type p53 can block the ability of E1a and ras to cotransform primary rodent cells, it is poorly understood why inactivation of the p53 gene is important for tumor formation. We show that overexpression of the gene encoding wild-type p53 blocks the growth of osteosarcoma cells. The growth arrest was determined to be due to an inability of the transfected cells to progress into S phase. This suggests that the role of the p53 gene as an antioncogene may be in controlling the cell cycle in a fashion analogous to the check-point control genes in Saccharomyces cerevisiae.', 'http://www.ncbi.nlm.nih.gov/pubmed/2233717', 'no', 'no', 'NA', 1),
(2253237, 'Miller CW, Aslo A, Tsay C, Slamon D, Ishizaki K, Toguchida J, Yamamuro T, Lampkin B, Koeffler HP', 'Frequency and structure of p53 rearrangements in human osteosarcoma.', 'Cancer Res', '1990', 'Frequency and structure of p53 rearrangements in human osteosarcoma. Osteosarcoma is the most frequent childhood bone cancer (Tebbi, C. K., and Gaeta, J. Pediatr. Ann., 17:285-300, 1988). Using Southern blot mapping, we found that 11 of 60 (18%) osteosarcomas had altered restriction patterns of the p53 gene and that six of these had loss of the other p53 allele. In contrast, no alteration of the p53 gene was detected in 50 samples from other types of sarcomas. Fifty % of osteosarcoma cell lines (4 of 8) also had gross rearrangements of one p53 allele with loss of the second allele, and these had no detectable p53 mRNA. Osteosarcoma cell lines with no detectable alteration of the p53 gene contained abundant p53 transcripts. Taken together, data show that human osteosarcomas can have rearrangements of the p53 gene; these rearrangements may cause loss of normal constraints on cellular growth.', 'http://www.ncbi.nlm.nih.gov/pubmed/2253237', 'yes', 'no', 'NA', 1),
(2274789, 'Chen PL, Chen YM, Bookstein R, Lee WH', 'Genetic mechanisms of tumor suppression by the human p53 gene.', 'Science', '1990', 'Genetic mechanisms of tumor suppression by the human p53 gene. Mutations of the gene encoding p53, a 53-kilodalton cellular protein, are found frequently in human tumor cells, suggesting a crucial role for this gene in human oncogenesis. To model the stepwise mutation or loss of both p53 alleles during tumorigenesis, a human osteosarcoma cell line, Saos-2, was used that completely lacked endogenous p53. Single copies of exogenous p53 genes were then introduced by infecting cells with recombinant retroviruses containing either point-mutated or wild-type versions of the p53 cDNA sequence. Expression of wild-type p53 suppressed the neoplastic phenotype of Saos-2 cells, whereas expression of mutated p53 conferred a limited growth advantage to cells in the absence of wild-type p53. Wild-type p53 was phenotypically dominant to mutated p53 in a two-allele configuration. These results suggest that, as with the retinoblastoma gene, mutation of both alleles of the p53 gene is essential for its role in oncogenesis.', 'http://www.ncbi.nlm.nih.gov/pubmed/2274789', 'no', 'no', 'NA', 1),
(2287591, 'Bosse A, Vollmer E, Böcker W, Roessner A, Wuisman P, Jones D, Fisher LW', 'The impact of osteonectin for differential diagnosis of bone tumors. An immunohistochemical approach.', 'Pathol Res Pract', '1990', 'The impact of osteonectin for differential diagnosis of bone tumors. An immunohistochemical approach. 75 osteosarcoma at various grades of histologic differentiation, including chondroblastic and small cell variants, and 5 fibrosarcomas of bone, 5 Ewing''s sarcomas, 5 malignant fibrous histiocytomas of bone, 8 chondrosarcomas, and 2 dedifferentiated chondrosarcomas, were investigated immunohistochemically for evidence of osteonectin. According to the results of our study, osteonectin is present in all osteosarcomas, with special topographic preponderance in the osteoblastic and chondroblastic variants. Evidence of osteonectin was also found in all other bone tumors we had analysed so far. In chondrosarcomas, positive reactions appeared only in the vicinity of trabeculae and in dedifferentiated areas. Thus, osteonectin cannot be regarded as a bone-specific protein. Although a high affinity for the osseous matrix is one of its undoubted features, it is therefore unsuitable for differential diagnostic purposes.', 'http://www.ncbi.nlm.nih.gov/pubmed/2287591', 'yes', 'no', 'NA', 1),
(2298248, 'Adrian GS, Yang FM, Graves DT, Buchanan JM, Bowman BH', 'Expression of transferrin and vitamin D-binding protein genes in an osteogenic sarcoma cell line.', 'Exp Cell Res', '1990', 'Expression of transferrin and vitamin D-binding protein genes in an osteogenic sarcoma cell line. Expression of genes encoding transferrin and the vitamin D-binding protein is described in a cell line, U-2 OS, derived from a human osteogenic sarcoma. The mRNA transcripts of transferrin and vitamin D-binding protein were shown to be the lengths of those found in normal human liver. The cells synthesize and secrete the transferrin and vitamin D-binding proteins, in addition to human albumin and ceruloplasmin. The U-2 OS cells were successfully transfected with chimeric genes carrying 670 bp of the 5'' regulatory sequence of the human transferrin gene fused to a reporter chloramphenicol acetyltransferase gene. These data indicate that the appropriate transcriptional factors required for expression of four plasma proteins are produced by U-2 OS nuclei and that the U-2 OS cell line will be useful for studies analyzing regulation of these genes.', 'http://www.ncbi.nlm.nih.gov/pubmed/2298248', 'no', 'no', 'NA', 2),
(2443508, 'Dedhar S, Argraves WS, Suzuki S, Ruoslahti E, Pierschbacher MD', 'Human osteosarcoma cells resistant to detachment by an Arg-Gly-Asp-containing peptide overproduce the fibronectin receptor.', 'J Cell Biol', '1987', 'Human osteosarcoma cells resistant to detachment by an Arg-Gly-Asp-containing peptide overproduce the fibronectin receptor. MG-63 human osteosarcoma cells were selected for attachment and growth in the presence of increasing concentrations of a synthetic peptide containing the cell attachment-promoting Arg-Gly-Asp sequence derived from the cell-binding region of fibronectin. Cells capable of attachment and growth in 5-mM concentrations of a peptide having the sequence Gly-Arg-Gly-Asp-Ser-Pro overproduce the cell surface receptor for fibronectin. In contrast, these cells show no differences in the numbers of vitronectin receptor they express as compared with the parental MG-63 cells. In agreement with the resistance of the selected cells to detachment by the peptide, 25-fold more Arg-Gly-Asp-containing peptide is required to prevent the attachment of these cells to fibronectin-coated surfaces than is needed to inhibit the attachment of MG-63 cells to the same substrate. However, similar concentrations of this peptide inhibit attachment of both cell lines to vitronectin-coated surfaces. The increase in fibronectin receptor is due to an increase in the levels of mRNA encoding the fibronectin receptor. Because of the nature of the selection process, we reasoned that this increase might be due to amplification of the fibronectin receptor gene, but no increase in gene copy number was detected by Southern blot analysis. The peptide-resistant cells display a very different morphology from that of the MG-63 cells, one that has a greater resemblance to that of osteocytes. The resistant cells also grow much more slowly than the MG-63 cells. The increased fibronectin receptor and altered morphology and growth properties were stable for at least 3 mo in the absence of peptide. The enhanced expression of the fibronectin receptor on the resistant cells indicates that cells are capable of altering the amount of fibronectin receptor on their surface in response to environmental factors and that this may in turn affect the phenotypic properties of the cell.', 'http://www.ncbi.nlm.nih.gov/pubmed/2443508', 'no', 'no', 'NA', 1),
(2450880, 'Kirstein M, Baglioni C', 'Tumor necrosis factor stimulates proliferation of human osteosarcoma cells and accumulation of c-myc messenger RNA.', 'J Cell Physiol', '1988', 'Tumor necrosis factor stimulates proliferation of human osteosarcoma cells and accumulation of c-myc messenger RNA. The objective of this study was to establish whether human recombinant tumor necrosis factor (TNF) can significantly stimulate the proliferation of some tumor cells. Treatment with TNF had little or no effect on the growth of human tumor cells and murine NIH/3T3 cells cultured in medium with high serum concentration. Two tumor lines, SK-MEL-109 melanoma and HOS osteosarcoma cells, were adapted to grow in medium supplemented with 0.5% serum. The growth of these SK-MEL-109 cells was inhibited by TNF, but that of the HOS cells was greatly stimulated by TNF in a dose-dependent way. Treatment with 10 ng/ml of TNF resulted in a two-fold increase in the rate of cell division. This effect of TNF was also shown by measuring DNA and protein synthesis. The continuous presence of TNF was not required for its mitogenic activity on HOS cells cultured with 0.5% serum, since treatment for only one day with TNF resulted in prolonged growth stimulation. The failure of TNF to promote division of cells cultured in medium with 10% serum may possibly be explained by the presence of saturating amounts of growth factors in serum. Interferons abolished the mitogenic activity of TNF on HOS cells. Furthermore, TNF did not show synergism with insulin or epidermal growth factor in stimulating growth of these cells. The level of c-myc mRNA was increased five-fold after 30 minutes of treatment with TNF. This shows that TNF is a growth factor for HOS cells and that it induces accumulation of c-myc mRNA.', 'http://www.ncbi.nlm.nih.gov/pubmed/2450880', 'no', 'no', 'NA', 2),
(2488230, 'Strong LC, Williams WR, Ferrell RE, Tainsky MA', 'Genetic analysis of childhood sarcoma.', 'Princess Takamatsu Symp', '1989', 'Genetic analysis of childhood sarcoma. A survey of cancer in 159 3-year survivors of childhood soft tissue sarcoma and their relatives revealed a cancer excess in first-degree relatives primarily due to cancers occurring before the age of 35 years and a highly significant excess in relatives of patients with second malignant neoplasms. Tumors of soft tissue and bone, breast, and brain were in excess in relatives and as second malignant neoplasms in patients. To determine the most likely explanation for the observed cancer distribution, we applied segregation analysis under a unified version of the mixed model. The observed data were most compatible with a rare autosomal dominant gene with high penetrance (gene carriers had a 50% probability of cancer by age 30, increasing to 90% by age 60) as compared with a chance occurrence or a multifactorial explanation. We contrasted the relative odds of observing each pedigree under a sporadic, multifactorial, or major gene model, and identified 11 pedigrees in which familial clustering of cancer was significant, with the distribution of cancer strongly favoring a major gene in 9 pedigrees. The tumors in these kindreds have been associated with alterations in specific genetic loci by tumor-specific genetic analysis. In particular, we observed soft tissue sarcoma, osteosarcoma and premenopausal ductal breast carcinoma tumors, perhaps attributable to loss of the Rb-1 suppressor gene on chromosome 13q, in the same patients and families. Study of the cancer predisposition segregating in 10 families by genetic linkage with markers of chromosome 13q and the Rb-1 gene have to date given negative LOD scores at 0 = 0 of Z = -1.2 to -13.0.(ABSTRACT TRUNCATED AT 250 WORDS)', 'http://www.ncbi.nlm.nih.gov/pubmed/2488230', 'yes', 'no', 'NA', 1),
(2496060, 'Ikeda S, Sumii H, Akiyama K, Watanabe S, Ito S, Inoue H, Takechi H, Tanabe G, Oda T', 'Amplification of both c-myc and c-raf-1 oncogenes in a human osteosarcoma.', 'Jpn J Cancer Res', '1989', 'Amplification of both c-myc and c-raf-1 oncogenes in a human osteosarcoma. Fourteen human bone and soft part tumor tissues were screened by Southern blot hybridization using five oncogene probes (c-myc, c-K-ras, c-fos, c-raf-1, and N-myc). Amplification of c-myc was found in two osteosarcomas and one malignant fibrous histiocytoma. One of these osteosarcomas had amplified c-raf-1 gene. Rearrangement of the amplified gene was not observed. This is the first report of c-raf-1 amplification in human cancer tissues.', 'http://www.ncbi.nlm.nih.gov/pubmed/2496060', 'yes', 'no', 'NA', 2),
(2496522, 'Jundt G, Schulz A, Berghäuser KH, Fisher LW, Gehron-Robey P, Termine JD', 'Immunocytochemical identification of osteogenic bone tumors by osteonectin antibodies.', 'Virchows Arch A Pathol Anat Histopathol', '1989', 'Immunocytochemical identification of osteogenic bone tumors by osteonectin antibodies. 18 bone-forming tumours and tumour-like lesions were investigated immunocytochemically for the presence of osteonectin. A group of non-bone-forming skeletal tumours (five cartilage-forming tumours, four Ewing sarcomas and five extraskeletal sarcomas) served as controls. The studies showed that osteonectin antibodies react reliably with benign and malignant bone-forming tumours (two cases of fibrous dysplasia, three osteoid osteomas, 13 osteosarcomas). This finding was supported by protein blot studies. Osteonectin is formed by cells which do not yet possess the morphological phenotype of osteoblasts and may be regarded as a \\differentiation marker\\ of the osteoblastic lineage. Only chondroid bone (tissue in which chondrocytes were surrounded by osteoid matrix containing type I and type II collagen) showed a positive reaction. All other primary skeletal tumours and extraskeletal soft tissue tumours were completely negative.', 'http://www.ncbi.nlm.nih.gov/pubmed/2496522', 'yes', 'yes', 'NA', 1),
(2521862, 'Dedhar S', 'Regulation of expression of the cell adhesion receptors, integrins, by recombinant human interleukin-1 beta in human osteosarcoma cells: inhibition of cell proliferation and stimulation of alkaline phosphatase activity.', 'J Cell Physiol', '1989', 'Regulation of expression of the cell adhesion receptors, integrins, by recombinant human interleukin-1 beta in human osteosarcoma cells: inhibition of cell proliferation and stimulation of alkaline phosphatase activity. Recombinant human interleukin-1 beta, a mediator of osteoblastic cell function, was found to regulate the expression of the cell adhesion receptors, integrins, on human osteosarcoma cells. Interleukin-1 beta (IL-1 beta) at picomolar concentrations, specifically elevated approximately six- to tenfold the expression of the beta 1 subunit and its associated alpha subunits, but not the related vitronectin receptor, within 20 hours. Integrin beta 1 messenger RNA levels were elevated within 6 hours and peaked to tenfold higher levels after 20 hours exposure to IL-1 beta in two human osteosarcoma cell lines. The increase in the cell-surface beta 1 integrins resulted in a stronger binding of the IL-1 beta-treated cells to fibronectin. Cell growth was also inhibited by IL-1 beta, cell morphology was altered, and IL-1 beta-treated cells expressed an approximately two- to threefold higher alkaline phosphatase. This increase in alkaline phosphatase activity was found to be independent of the inhibition of cell proliferation. These data indicate that the beta 1 integrin family of cell surface receptors is a target for regulation by IL-1 beta, which also regulates cell proliferation and the expression of the osteoblastic phenotype in human osteosarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/2521862', 'no', 'no', 'NA', 4),
(2531855, 'Romano JW, Ehrhart JC, Duthu A, Kim CM, Appella E, May P', 'Identification and characterization of a p53 gene mutation in a human osteosarcoma cell line.', 'Oncogene', '1989', 'Identification and characterization of a p53 gene mutation in a human osteosarcoma cell line. The nuclear phosphoprotein p53 occurs at elevated levels in many transformed cells. Mutant forms of mouse p53 possess enhanced transforming activity compared with wild type p53. Mutant mouse p53 proteins form complexes with the 70 kDa family of heat shock proteins (HSPs). We previously demonstrated an association between p53 and the 70 kDa HSPs in the human osteosarcoma (HOS) derived cell line HOS-SL. We report here the molecular cloning and sequencing of the p53 gene from HOS-SL cells, and demonstrate that it is in fact mutant. Further, analysis of similar HOS-derived cell lines demonstrates that they also encode the same mutant form of p53, whereas the wild type form of p53 appears to be lost in these cells. Stability studies demonstrate an increased half life of the p53 protein in these cells, in keeping with its association with the HSP 70 proteins. A potential role for this p53 mutant in the transformation process is discussed.', 'http://www.ncbi.nlm.nih.gov/pubmed/2531855', 'no', 'no', 'NA', 2),
(2541615, 'Mechtersheimer G, Möller P', 'Expression of the common acute lymphoblastic leukemia antigen (CD10) in mesenchymal tumors.', 'Am J Pathol', '1989', 'Expression of the common acute lymphoblastic leukemia antigen (CD10) in mesenchymal tumors. The expression of the CD10 antigen, formerly designated as common acute lymphoblastic leukemia antigen and recently identified as neutral endopeptidase, was examined immunohistochemically in 26 benign and in 55 malignant mesenchymal tumors. CD10 expression was found in 4 of 4 leiomyomas, 7 of 10 leiomyosarcomas, 1 of 6 rhabdomyosarcomas, 2 of 2 Triton tumors, 1 of 2 aggressive fibromatoses, 1 of 3 fibrosarcomas, 1 of 4 synovial sarcomas, 1 of 1 giant cell tumors of tendon sheath, 4 of 4 malignant fibrous histiocytomas, 3 of 3 Ewing''s sarcomas, and 2 of 3 osteosarcomas. Furthermore, CD10 was expressed consistently in the myoepithelial compartment of 12 fibroadenomas and, in 7 of these cases, in a minor stromal cell population, probably of (myo-) fibroblastic origin. Tumors of adipose tissue (4 lipomas, 5 liposarcomas), tumors of autonomic ganglia (2 ganglioneuromas, 1 ganglioneuroblastoma, 2 neuroblastomas), tumors of peripheral nerves with purely schwannian differentiation (7 malignant schwannomas), and tumors of disputed origin were consistently CD10-negative, however, as were single cases of fibroma and chondrosarcoma. These findings indicate that the expression of CD10 is a frequent but not obligatory feature in some mesenchymal tumors. Therefore CD10 is of value in the differential diagnosis of mesenchymal tumors.', 'http://www.ncbi.nlm.nih.gov/pubmed/2541615', 'yes', 'yes', 'NA', 1),
(2600089, 'Heino J, Massagué J', 'Transforming growth factor-beta switches the pattern of integrins expressed in MG-63 human osteosarcoma cells and causes a selective loss of cell adhesion to laminin.', 'J Biol Chem', '1989', 'Transforming growth factor-beta switches the pattern of integrins expressed in MG-63 human osteosarcoma cells and causes a selective loss of cell adhesion to laminin. Transforming growth factor-beta (TGF-beta) induces a marked decrease in adhesion of MG-63 human osteosarcoma cells to laminin-coated surfaces, but does not significantly alter adhesion to fibronectin- or collagen-coated surfaces. We provide evidence that this effect is due to a switch in the repertoire of cell adhesion receptors in response to TGF-beta. MG-63 cells express high levels of alpha 3 beta 1-integrin, which is a polyspecific laminin/collagen/fibronectin receptor, and low levels of alpha 2 beta 1- and alpha 5 beta 1-integrins, which are collagen and fibronectin receptors, respectively. No other integrins of the beta 1-class could be detected in MG-63 cells. Treatment with TGF-beta 1 induces a marked (approximately 60%) decrease in the level of expression of alpha 3-integrin subunit mRNA and protein and a concomitant 8-fold increase in alpha 2-subunit expression. These responses become maximal 7-12 h after addition of TGF-beta 1 to the cells. Expression of alpha 5- and beta 1-integrin subunits also increases in response to TGF-beta 1, but to a lesser extent than alpha 2-subunit expression. Thus, as a result of TGF-beta action, the alpha 2 beta 1-collagen and alpha 5 beta 1-fibronectin receptors replace the alpha 3 beta 1-laminin/collagen/fibronectin receptor as the predominant integrins of the beta 1-class in MG-63 cells. These results suggest that one of the effects of TGF-beta is to modify the adhesive behavior of certain tumor cells by changing the binding specificity of the complement of integrins that they express.', 'http://www.ncbi.nlm.nih.gov/pubmed/2600089', 'no', 'no', 'NA', 4),
(2630171, 'Graves DT, Valentin-Opran A, Delgado R, Valente AJ, Mundy G, Piche J', 'The potential role of platelet-derived growth factor as an autocrine or paracrine factor for human bone cells.', 'Connect Tissue Res', '1989', 'The potential role of platelet-derived growth factor as an autocrine or paracrine factor for human bone cells. Platelet-derived growth factor, PDGF, is a potent mitogen for cells of mesenchymal origin such as fibroblasts, smooth muscle cells and glial cells. PDGF is thought to have the potential to act as both a paracrine and an autocrine factor. Studies described here extend these observations to human bone-derived cells. Exogenous PDGF induces biologic activity in two human osteogenic sarcoma cell lines and in one of these, the two PDGF genes, PDGF-1 and PDGF-2/c-sis are expressed. In addition, PDGF stimulates proliferation of normal osteoblastic cells derived from adult human cancellous bone. The expression of the PDGF-1 gene but not the PDGF-2/c-sis gene is demonstrated in normal human adult bone-derived cells by Northern blot analysis and synthesis of PDGF is shown by immunoprecipitation with PDGF antisera. These studies indicate that PDGF has the potential to act as a paracrine or autocrine regulator of bone cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/2630171', 'no', 'no', 'NA', 2),
(2659348, 'Clezardin P, Jouishomme H, Chavassieux P, Marie PJ', 'Thrombospondin is synthesized and secreted by human osteoblasts and osteosarcoma cells. A model to study the different effects of thrombospondin in cell adhesion.', 'Eur J Biochem', '1989', 'Thrombospondin is synthesized and secreted by human osteoblasts and osteosarcoma cells. A model to study the different effects of thrombospondin in cell adhesion. In this study we have shown by both immunofluorescence and immunoprecipitation techniques that human osteoblasts and osteosarcoma cells synthesize and secrete thrombospondin, a 450-kDa glycoprotein initially found in platelets. Immunofluorescence with a mouse monoclonal antibody to human platelet thrombospondin yielded specific granular staining within the cytoplasm of human osteoblasts. SDS/polyacrylamide gel electrophoresis analysis of immunoprecipitates obtained with polyclonal and monoclonal anti-thrombospondin antibodies allows the identification of thrombospondin in the cellular lysates and the culture media of biosynthetically labelled osteoblasts and osteosarcoma cells. Kinetic and dose/response studies of osteoblasts and of two osteosarcoma cell lines (MG-63, SaOs-2) were performed to assess the ability of these cells to adhere to thrombospondin and type-I collagen. Thrombospondin promoted the attachment of human osteoblasts whereas it inhibited the adhesion of MG-63 and SaOs-2 cells, both when it was directly adsorbed to plastic and when it was bound to type-I collagen. Therefore osteoblasts and osteosarcoma cells may be valuable tools to study the role of thrombospondin in cell adhesion.', 'http://www.ncbi.nlm.nih.gov/pubmed/2659348', 'no', 'no', 'NA', 1),
(2740144, 'Shew JY, Ling N, Yang XM, Fodstad O, Lee WH', 'Antibodies detecting abnormalities of the retinoblastoma susceptibility gene product (pp110RB) in osteosarcomas and synovial sarcomas.', 'Oncogene Res', '1989', 'Antibodies detecting abnormalities of the retinoblastoma susceptibility gene product (pp110RB) in osteosarcomas and synovial sarcomas. The retinoblastoma (RB) susceptibility gene is one member of a putative \\cancer suppressor gene\\ family in which loss of gene function is associated with tumor formation. Using antibodies generated against a trypE-RB fusion protein, we previously identified a nuclear phosphoprotein, pp110RB, as the RB gene product. Here we describe three additional polyclonal antibodies that were generated to separate epitopes of pp110RB with three synthetic peptides deduced from the RB cDNA sequence. All four antibodies could specifically recognize the same phosphoprotein in human cells. This protein was phosphorylated on serine and threonine, but not tyrosine, residues. RB homologous proteins with molecular masses of 105-128 kD were detected in other vertebrates, such as monkey, rodent, and chicken, by at least two antibodies, indicating evolutionary conservation of the RB gene. These antibodies were specific and sensitive for monitoring RB gene inactivation as demonstrated by screening several osteosarcoma and synovial sarcoma cell lines. Of nine cell lines examined, three expressed no immunoprecipitable normal RB protein. DNA rearrangement and abnormal RB mRNA were detected in two of these three cell lines, whereas RB protein was absent from one synovial sarcoma cell line in which normal-sized RB mRNA was clearly present. Therefore, direct immunoprecipitation of RB protein can reveal RB gene mutations that are undetectable by DNA and mRNA analysis. These results further support a crucial role for the RB gene in the oncogenesis of some mesenchymal tumors.', 'http://www.ncbi.nlm.nih.gov/pubmed/2740144', 'yes', 'no', 'NA', 1),
(2755701, 'Reissmann PT, Simon MA, Lee WH, Slamon DJ', 'Studies of the retinoblastoma gene in human sarcomas.', 'Oncogene', '1989', 'Studies of the retinoblastoma gene in human sarcomas. The retinoblastoma susceptibility gene, (RB), is a tumor suppressor gene which, when deleted is associated with the development of retinoblastoma. The observation that children with heritable retinoblastoma frequently develop second malignancies, principally sarcomas, led to the detection of similar RB gene deletions in some osteosarcomas. We studied 44 unselected sarcomas from patients with no antecedent retinoblastoma to determine the prevalence and nature of RB gene alterations. DNA and RNA were extracted from fresh tumors and analysed by Southern and Northern blotting. Three of nine osteosarcomas and 4 of 29 soft-tissue sarcomas had deletions of the RB gene. Four of these were full-length, and three were partial deletions of the gene. RNA from 5 of the 7 deleted tumors was studied, and 4 cases completely lacked the RB transcript. Transcripts were found in 19 of 20 tumors with an apparently intact RB gene, and in all the normal tissues studied. An additional tumor lacked the RB transcript, but the gene appeared intact at the DNA level. In total, 8 of 38 sarcomas were found to have alterations of the RB gene. These data indicate that the RB gene is inactivated in a significant number of sarcomas unrelated to retinoblastoma, and that the potential role for the gene in the pathogenesis of human malignancy may not be limited to retinoblastoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/2755701', 'yes', 'no', 'NA', 1),
(2776495, 'Schulz A, Jundt G', 'Immunohistological demonstration of osteonectin in normal bone tissue and in bone tumors.', 'Curr Top Pathol', '1989', 'Immunohistological demonstration of osteonectin in normal bone tissue and in bone tumors. Osteonectin is a noncollagenous protein of bone which is believed to be bone specific, since its concentration in bone tissue is 500- to 1000-fold higher than in other connective tissues. Immunohistochemistry with polyclonal osteonectin antibodies shows a highly specific marking of actively matrix-producing osteoblasts. Osteonectin is involved in the process of osteoid maturation and mineralization. Immunohistochemistry of osteonectin antibodies proved to be a valuable tool in the diagnosis of bone tumors. Since osteonectin production seems to be an early event in the differentiation of cells of the osteoblastic lineage, immunoreactivity of osteonectin antibodies is observed in types of osteosarcoma lacking osteoid production (anaplastic, fibroblastic) while corresponding types of soft tissue tumors remain unstained.', 'http://www.ncbi.nlm.nih.gov/pubmed/2776495', 'yes', 'yes', 'NA', 1),
(2786815, 'Dedhar S', 'Signal transduction via the beta 1 integrins is a required intermediate in interleukin-1 beta induction of alkaline phosphatase activity in human osteosarcoma cells.', 'Exp Cell Res', '1989', 'Signal transduction via the beta 1 integrins is a required intermediate in interleukin-1 beta induction of alkaline phosphatase activity in human osteosarcoma cells. In this report data are presented which demonstrate that the induction of an osteoblastic phenotype by interleukin-1 beta (IL-1 beta) requires an intermediate step involving signal transduction via the beta 1 family of integrin glycoproteins. Recombinant human IL-1 beta inhibits human osteosarcoma cell proliferation, stimulates integrin expression, and induces alkaline phosphatase activity, a marker of osteoinductive and osteoblastic phenotype. The approximately 10-fold stimulation of expression of the beta 1 integrins occurs rapidly (within 20 to 40 h), whereas the alkaline phosphatase activity is not induced until at least 5 days after the addition of IL-1 beta. To determine whether the early stimulation of integrin expression is required for the subsequent expression of alkaline phosphatase activity, polyclonal as well as monoclonal antibodies directed against the alpha 5 and beta 1 integrin subunits were added to cultures at the same time as IL-1 beta. These antibodies inhibited by 55 to 82% the longer term induction of the osteoblastic differentiation marker, alkaline phosphatase activity, but did not however affect the IL-1 beta-induced stimulation of integrin expression or the inhibition of cell proliferation. In addition, at the concentrations used, there was no effect of the antibodies on cell attachment. These data suggest that the stimulation of integrin expression by IL-1 beta, and the resulting enhanced integrin-extracellular matrix interactions, is a required intermediate event in the IL-1 beta regulation of osteoblastic cell differentiation. The data also suggest that the integrins are capable of signal transduction resulting in altered gene expression, and may also play a crucial role in modulating cytokine-mediated effects on cell differentiation.', 'http://www.ncbi.nlm.nih.gov/pubmed/2786815', 'no', 'no', 'NA', 3),
(2878716, 'Hovig E, Winberg JO, Fodstad O, Brøgger A, Gedde-Dahl T', 'Chromosome 13 instability and esterase D expression in an osteosarcoma cell line.', 'Cancer Genet Cytogenet', '1987', 'Chromosome 13 instability and esterase D expression in an osteosarcoma cell line. In order to assess the involvement of the 13q14 region in the development of osteosarcoma, both osteosarcoma tumor cells and normal tissue from a retinoblastoma patient previously used in restriction fragment length polymorphism studies, and sarcoma cells and normal fibroblasts from other tumor patients, have been investigated with respect to esterase D (E.C. 3.1.1.1) expression and chromosome pattern. In spite of an increased number of apparently normal chromosomes #13, a 50% reduction in esterase D activity in osteosarcoma cells from the retinoblastoma patient was observed. This suggests that loss of the RB1 gene or an OSRC gene closely linked to the ESD and RB1 gene loci is involved in the development of the osteosarcoma tumor. No reduction in esterase D expression was seen in four other sarcoma cell lines.', 'http://www.ncbi.nlm.nih.gov/pubmed/2878716', 'no', 'no', 'NA', 2),
(2898286, 'Toguchida J, Ishizaki K, Sasaki MS, Ikenaga M, Sugimoto M, Kotoura Y, Yamamuro T', 'Chromosomal reorganization for the expression of recessive mutation of retinoblastoma susceptibility gene in the development of osteosarcoma.', 'Cancer Res', '1988', 'Chromosomal reorganization for the expression of recessive mutation of retinoblastoma susceptibility gene in the development of osteosarcoma. Recent evidence indicates that the mutation of retinoblastoma susceptibility (RB) gene is also involved in the development of osteosarcoma. We studied 30 cases of osteosarcoma for the structural anomalies of the RB gene by Southern hybridization analysis with cDNA probes of the RB gene. Thirteen cases (43%) showed structural anomalies of the RB gene. They included the total or partial deletion, or rearrangement of the RB gene; seven with homozygous deletions and six with hemizygous deletions or rearrangements. By the use of restriction fragment length polymorphism fragments as chromosome markers, those seven tumors having homozygous deletions and four of six tumors having hemizygous anomalies showed the loss of heterozygosity at other loci on chromosome 13. Among those tumors with no apparent structural changes of the RB gene, seven cases showed the loss of heterozygosity on chromosome 13, and altogether the loss of heterozygosity by either homozygosity or hemizygosity was found in 18 (64%) of 28 informative cases. The loss of heterozygosity was also found for nine of 10 other chromosomes, of which chromosome 17 showed the highest frequency (77%). The tumors with loss of chromosome 13 alleles also showed additional losses of alleles on other chromosomes, while tumors retaining heterozygosity of chromosome 13 also retained heterozygosity at the informative loci on other chromosomes. Southern hybridization and karyotype analysis in some selected cases suggest that the concerted loss of heterozygosity at multiple loci may be a consequence of the polyploidization-segregation process.', 'http://www.ncbi.nlm.nih.gov/pubmed/2898286', 'yes', 'no', 'NA', 1),
(2918936, 'Toguchida J, Ishizaki K, Sasaki MS, Nakamura Y, Ikenaga M, Kato M, Sugimot M, Kotoura Y, Yamamuro T', 'Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma.', 'Nature', '1989', 'Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma. Successive loss of function of both alleles of the retinoblastoma susceptibility gene (RB) on human chromosome 13 seems to be critical in the development of retinoblastoma and osteosarcoma. In cases where the tumour is familial and susceptibility is inherited, a mutation in one of the alleles is carried in the germline. We have recently shown that cytogenetically visible germline mutations are usually in the paternally derived gene. Such a bias would not be expected for sporadic (non-familial) tumours, where both mutations occur in somatic tissue, but there has been some indication of a bias towards initial somatic mutation in the paternally derived gene on chromosome 11 in sporadic Wilms tumour. We have now examined 13 sporadic osteosarcomas and find evidence which indicates that in 12 cases the initial mutation was in the paternal gene, suggesting the involvement of germinal imprinting in producing the differential susceptibility of the two genes to mutation.', 'http://www.ncbi.nlm.nih.gov/pubmed/2918936', 'yes', 'no', 'NA', 1);
INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(2978869, 'Ehrhart JC, Duthu A, Ullrich S, Appella E, May P', 'Specific interaction between a subset of the p53 protein family and heat shock proteins hsp72/hsc73 in a human osteosarcoma cell line.', 'Oncogene', '1988', 'Specific interaction between a subset of the p53 protein family and heat shock proteins hsp72/hsc73 in a human osteosarcoma cell line. We report here immunological evidence for the specific association between p53 and hsp72/hsc73 heat shock proteins in a human cell line derived from an osteosarcoma. The same association between p53 and hsp72/hsc73 was observed in HOS-TE85 clone 5 from which the HOS-SL cell line was derived. This association was indicated by the co-immunoprecipitation from HOS-SL of both p53 and hsp72/hsc73 proteins observed with either an anti-p53 monoclonal antibody (PAb421) or an antiserum specifically reacting with hsp72/hsc73 heat shock proteins. Furthermore, Western blot analysis allowed us to show that hsp72/hsc73 proteins did not share an epitope with p53, confirming that the co-immunoprecipitation of p53 and hsp72/hsc73 was attributable to the physical association of the proteins. Data obtained from SDS-PAGE show that the HOS-SL cells expressed two forms of p53 with distinct molecular weights. Both forms contained several species with different isoelectric points ranging between pH 6.0 and 6.5. The data obtained from both 1D and 2D gel analyses consistently show that the p53 proteins involved in the association with hsp72/hsc73 were mainly the species that migrated with the slower mobility in the SDS dimension. The possibility is discussed that the HOS-SL p53 variant forming a complex with hsp72/hsc73 contains an activating mutation for transformation.', 'http://www.ncbi.nlm.nih.gov/pubmed/2978869', 'no', 'no', 'NA', 2),
(3057504, 'Dedhar S, Gaboury L, Galloway P, Eaves C', 'Human granulocyte-macrophage colony-stimulating factor is a growth factor active on a variety of cell types of nonhemopoietic origin.', 'Proc Natl Acad Sci U S A', '1988', 'Human granulocyte-macrophage colony-stimulating factor is a growth factor active on a variety of cell types of nonhemopoietic origin. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a member of a family of glycoprotein hormones that stimulate the proliferation and differentiation of hemopoietic cells in vitro and in vivo. We now report that human GM-CSF can also stimulate the proliferation of two osteogenic sarcoma cell lines, a breast carcinoma cell line, a simian virus 40-transformed marrow stromal cell line, and normal marrow fibroblast precursors. These findings suggest a more general regulatory function of GM-CSF on nonhemopoietic cell types than previously anticipated. They also raise the possibility of adverse side effects of GM-CSF therapy in patients whose malignant cells may be directly stimulated by this molecule and suggest a previously unanticipated role of GM-CSF gene activation in the evolution of solid tumors and in the pathogenesis of myelofibrosis.', 'http://www.ncbi.nlm.nih.gov/pubmed/3057504', 'no', 'no', 'NA', 1),
(3162593, 'Weichselbaum RR, Beckett M, Diamond A', 'Some retinoblastomas, osteosarcomas, and soft tissue sarcomas may share a common etiology.', 'Proc Natl Acad Sci U S A', '1988', 'Some retinoblastomas, osteosarcomas, and soft tissue sarcomas may share a common etiology. DNA and RNA were extracted from primary human osteosarcomas and soft tissue sarcomas obtained from patients without retinoblastoma and were analyzed by hybridization with a cDNA probe for RB mRNA; absence or alterations of the RB gene are associated with development of retinoblastoma. Most of the osteosarcomas or soft tissue sarcomas examined by us did not express detectable levels of RB mRNA, whereas normal cells and epithelial tumor cells did. One osteosarcoma expressed a 2.4-kilobase transcript in addition to a normal 4.7-kilobase species. Our data suggest that transcriptional inactivation or post-transcriptional down-regulation of the RB gene may be important in the etiology of some osteosarcomas and soft tissue sarcomas as well as retinoblastomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/3162593', 'yes', 'no', 'NA', 1),
(3165250, 'Schulz A, Jundt G, Berghäuser KH, Gehron-Robey P, Termine JD', 'Immunohistochemical study of osteonectin in various types of osteosarcoma.', 'Am J Pathol', '1988', 'Immunohistochemical study of osteonectin in various types of osteosarcoma. Polyclonal antibodies against osteonectin, a 32 kd non-collagenous bone protein, were applied for the histogenetic identification of variously differentiated osteosarcoma tissues. A strong positive reaction was found in matrix-producing osteosarcoma cells of the osteoblastic type, but pleomorphic or fibrosarcomatous osteosarcoma tissues reacted focally positive as well. Because the production of osteonectin depends on the osteoblastlike function of the individual tumor cell, a homogeneous immunocytochemical staining of all tumor cells cannot be expected. Nevertheless, the immunocytochemical demonstration of osteonectin in osteolytic tumors that produce no or scarcely any matrix seems to be a valuable tool for establishment of their osteogenic origin.', 'http://www.ncbi.nlm.nih.gov/pubmed/3165250', 'yes', 'yes', 'NA', 1),
(3166362, 'Nakamura T, Nakamura K, Stinson RA', 'Release of alkaline phosphatase from human osteosarcoma cells by phosphatidylinositol phospholipase C: effect of tunicamycin.', 'Arch Biochem Biophys', '1988', 'Release of alkaline phosphatase from human osteosarcoma cells by phosphatidylinositol phospholipase C: effect of tunicamycin. Alkaline phosphatase (orthophosphoric-monoester phosphohydrolase [alkaline optimum], EC 3.1.3.1) expressed in two human osteosarcoma cell lines (Saos-2 and KTOO5) in culture was the tissue nonspecific type and was released from the plasma membrane by phosphatidylinositol (PI) phospholipase C. Despite a difference of 10-fold between the two cell lines in the amount of alkaline phosphatase expressed, the phospholipase solubilized nearly all of the phosphatase from resuspended cells of the two lines. Alkaline phosphatase released with Nonidet-P40 from Saos-2 cells had a Mr of 445,000 by gradient gel electrophoresis in the absence of detergent; that released by PI-phospholipase C was 200,000. The subunit Mr of both solubilized forms was 86,000. Thus, tetrameric alkaline phosphatase in the membrane is attached by a PI-glycan moiety and is converted to dimers when released by PI-phospholipase C. Tunicamycin treatment of Saos-2 cells in culture affected the release of alkaline phosphatase by a high concentration of PI-phospholipase C, but not by a low concentration; both the rate and extent of release were lower from treated cells. However, the enzyme released from the treated cells was in two forms with different molecular weights; it seems that both glycosylated and nonglycosylated dimers were transported to the cell surface and incorporated into the plasma membrane. Glycosylation does not appear to be necessary for alkaline phosphatase to be anchored in the membrane via PI.', 'http://www.ncbi.nlm.nih.gov/pubmed/3166362', 'no', 'no', 'NA', 1),
(3477902, 'Bacci G, Picci P, Orlandi M, Avella M, Manfrini M, Pignatti G, Dallari D, Manduchi R', 'Prognostic value of serum alkaline phosphatase in osteosarcoma.', 'Tumori', '1987', 'Prognostic value of serum alkaline phosphatase in osteosarcoma. In 163 patients with osteosarcoma of the extremities treated with adjuvant chemotherapy, serum alkaline phosphatase (SAP) levels were evaluated before treatment and successively closely monitored in an attempt to determine whether serum levels of this enzyme had clinical value in predicting the course of the disease. Of 121 patients with elevated preoperative SAP levels, 78 (64%) recurred. Of 42 patients with normal preoperative SAP levels, only 8 (19%) recurred (P less than 0.00001). Of the 140 patients locally treated with amputation, SAP returned to normal values in 77 patients; 46 of these (59%) relapsed. Of the 21 patients whose SAP remained elevated after amputation, all but 2 relapsed (90%). Among 119 patients with normal postoperative values of SAP, at the time of relapse SAP resulted elevated in 22 of 41 patients (53%). These data confirm that in osteosarcoma, preoperative SAP levels have a definite value in establishing the prognosis and that posttreatment follow-up examination should include SAP determination, since persistent elevated or increasing values herald the appearance of a recurrence.', 'http://www.ncbi.nlm.nih.gov/pubmed/3477902', 'yes', 'yes', 'NA', 2),
(3479235, 'Masuda H, Yokota J, Battifora H, Cline M', 'Events on different chromosomes alter the genes for the two peptides of platelet-derived growth factor in an osteogenic sarcoma.', 'Cancer Genet Cytogenet', '1987', 'Events on different chromosomes alter the genes for the two peptides of platelet-derived growth factor in an osteogenic sarcoma. Platelet derived growth factor consists of dimers of partially homologous peptides (A and B) encoded by separate genes on different chromosomes. A clinically aggressive osteogenic sarcoma had both an amplified A-chain gene on chromosome #7 and a reduplication of all or part of chromosome #22 containing the B-chain (c-sis) gene. Other oncogenes on chromosomes #1, #2, #5, #6, #7, #8, #11, #12, #14, and #15 were not reduplicated or amplified. These observations are consistent with the hypothesis of autocrine stimulation of growth of some sarcomas in humans, and indicate that amplification and reduplication of related genes on different chromosomes can occur in tumors in vivo.', 'http://www.ncbi.nlm.nih.gov/pubmed/3479235', 'yes', 'no', 'NA', 2),
(6297258, 'Yoshida H, Akeho M, Orido T, Yumoto T, Furuse K, Maeyama I, Tanaka T', 'Enzyme histochemical study on bone tumors.', 'Acta Med Okayama', '1982', 'Enzyme histochemical study on bone tumors. A total of 19 cases with bone tumors, including six osteosarcomas. three giant cell tumors of bone, one malignant fibrous histiocytoma, four nonossifying fibromas, four chondromas and one chondrosarcoma, were examined as to enzyme histochemistry; the enzymes consisted of alkaline phosphatase (ALPase), acid phosphatase (ACPase), nonspecific esterase (NSE), adenosine triphosphatase (ATPase), 5''-nucleotidase (5''-Nucl) and beta-glucuronidase (beta-Gl). Osteosarcoma was strongly positive for ALPase followed by 5''-Nucl. Giant cell tumor, malignant fibrous histiocytoma and nonossifying fibroma showed enzyme histochemistry similar to each other: multinucleated giant cells and round cells in these tumors were strongly positive for ACPase, NSE, ATPase and 5''-Nucl simulating osteoclasts and histiocytes, whereas spindle cells were positive for ATPase and 5''-Nucl in their cytoplasm and weakly positive for ACPase. Chondroma and chondrosarcoma were focally positive for ACPase and NSE; the ACPase was sensitive to tartaric acid treatment. These observations showed that ALPase activity is very characteristic to osteosarcoma, and is useful for its diagnosis. From enzyme histochemistry, giant cell tumor, malignant fibrous histiocytoma and nonossifying fibroma can be regarded as a histiocyte-derived tumor of bone in contrast to osteosarcoma and cartilaginous tumors.', 'http://www.ncbi.nlm.nih.gov/pubmed/6297258', 'yes', 'no', 'NA', 2),
(6930152, 'Broström LA, Ingimarsson S, Strander H, Eklund G', 'Correlation between prognostic factors and blood variables in osteosarcoma.', 'Acta Med Scand', '1980', 'Correlation between prognostic factors and blood variables in osteosarcoma. Prognostic factors and the blood chemistry were analyzed prior to treatment in 33 consecutive patients with primary osteosarcoma. The only variables of blood chemistry with values outside the normal range were alkaline phosphatase and ESR, which were increased. There was a correlation between certain prognostic factors and between some of these and a number of the blood variables. The degree of malignancy tended to be lower in the female than in the male patients. Distally located tumors tended to be smaller and were assessed with a less marked effect on the blood variables than those located proximally.', 'http://www.ncbi.nlm.nih.gov/pubmed/6930152', 'yes', 'no', 'NA', 2),
(7473836, 'Pinski J, Schally AV, Groot K, Halmos G, Szepeshazi K, Zarandi M, Armatis P', 'Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone.', 'J Natl Cancer Inst', '1995', 'Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone. Insulin-like growth factor I (IGF-I) may be involved in the proliferation of human osteosarcomas. Most of the IGF-I found in blood is produced in the liver, where transcription of the IGF-I gene is regulated by growth hormone (GH). Recently, we synthesized various potent antagonists of GH-releasing hormone (GH-RH), including [Ibu0, D-Arg2, Phe(4-Cl)6, Abu15, Nle27]hGH-RH(1-28)Agm, which is also called MZ-4-71.We investigated the effects of this antagonist on the growth of the human osteosarcoma cell lines SK-ES-1 and MNNG/HOS, transplanted into nude mice or cultured in vitro.Nude male mice bearing SK-ES-1 and MNNG/HOS tumors were treated for 4 and 3 weeks, respectively, with MZ-4-71 administered from osmotic minipumps at a dose of 40 micrograms per animal per day. Tumor volume, tumor weight, and levels of receptors for IGF-I were determined. IGF-I levels in serum, tumor, and liver tissue were measured by radioimmunoassay. In other experiments, tumor-bearing nude mice were treated subcutaneously for 3 weeks with the GH-RH agonist hGH-RH(1-29)NH2 or with MZ-4-71 for 13 days at doses of 50 micrograms per animal per day. Effects of MZ-4-71, hGH-RH(1-29)NH2, and human GH (hGH) on cell proliferation and on the production of IGF-I and cyclic adenosine monophosphate were also evaluated in SK-ES-1 and MNNG/HOS cells in vitro.The growth of SK-ES-1 and MNNG/HOS tumors in nude mice was significantly inhibited by MZ-4-71, as measured by a reduction in tumor volume and weight (all P values < .05). MZ-4-71 treatment of either SK-ES-1 or MNNG/HOS tumor-bearing animals decreased tumor tissue IGF-I levels. The growth of MNNG/HOS xenografts was stimulated by hGH-RH(1-29)NH2 (P < .01). IGF-I levels in serum of tumor-bearing nude mice treated subcutaneously for 13 days with MZ-4-71 were decreased (both P values < .01). High-affinity binding sites for IGF-I were demonstrated on cell membranes of SK-ES-1 and MNNG/HOS tumors. In cell cultures of both osteosarcomas, IGF-I production was stimulated by 25 ng/mL hGH but was not changed by 10 ng/mL hGH-RH(1-29)NH2 or 5 microM MZ-4-71. Incorporation of [3H]thymidine into DNA in SK-ES-1 (but not MNNG/HOS) cells was increased by 25 ng/mL IGF-I (P < .01). The proliferation rate of the two cell lines was not affected by 5-50 ng/mL hGH-RH(1-29)NH2 or 1-80 ng/mL hGH but was suppressed by 10(-6)-10(-5) M MZ-4-71.Our findings demonstrate that the GH-RH antagonist MZ-4-71 can significantly inhibit the growth of SK-ES-1 and MNNG/HOS osteosarcomas in mice.', 'http://www.ncbi.nlm.nih.gov/pubmed/7473836', 'no', 'no', 'MZ-4-71', 2),
(7477118, 'Baldini N, Scotlandi K, Barbanti-Bròdano G, Manara MC, Maurici D, Bacci G, Bertoni F, Picci P, Sottili S, Campanacci M', 'Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome.', 'N Engl J Med', '1995', 'Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. Increased levels of P-glycoprotein occur in some osteosarcomas. In this study we determined the relation between P-glycoprotein status and outcome in patients with high-grade osteosarcoma.P-glycoprotein status was determined immunohistochemically in specimens of osteosarcoma of the extremities (stage II) from 92 patients who were treated with surgery and chemotherapy. The P-glycoprotein status was analyzed in relation to the length of event-free survival.The presence of increased levels of P-glycoprotein in the osteosarcoma was significantly associated with a decreased probability of remaining event-free after diagnosis (P = 0.002). In a multivariate analysis, P-glycoprotein status (P = 0.001) and the extent of tumor necrosis after preoperative chemotherapy (P = 0.04) were independent predictors of clinical outcome. The risk of adverse events was increased substantially (rate ratio, 3.37; 95 percent confidence interval, 1.60 to 7.10) among patients with increased levels of P-glycoprotein in tumor cells, as compared with patients who did not have increased levels of P-glycoprotein in tumor cells.In patients with high-grade osteosarcoma treated with surgery and chemotherapy, the presence of increased levels of P-glycoprotein in tumor cells is associated with a significantly increased risk of adverse events and is independent of the extent of necrosis after preoperative chemotherapy.', 'http://www.ncbi.nlm.nih.gov/pubmed/7477118', 'yes', 'yes', 'NA', 1),
(7502710, 'de Bart AC, Quax PH, Löwik CW, Verheijen JH', 'Regulation of plasminogen activation, matrix metalloproteinases and urokinase-type plasminogen activator-mediated extracellular matrix degradation in human osteosarcoma cell line MG63 by interleukin-1 alpha.', 'J Bone Miner Res', '1995', 'Regulation of plasminogen activation, matrix metalloproteinases and urokinase-type plasminogen activator-mediated extracellular matrix degradation in human osteosarcoma cell line MG63 by interleukin-1 alpha. Plasmin-mediated extracellular proteolysis has been implicated in the degradation of bone in normal and pathological conditions. Normal and malignant osteoblasts can produce both tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). We have used the osteosarcoma cell line MG63 to address the question of whether the enhanced bone turnover in osteosarcomas is mediated by t-PA or by u-PAA and to study the effect of the cytokine interleukin-1 alpha (IL-1 alpha), known to influence bone degradation, on the plasminogen activator production and extracellular matrix degradation in malignant osteoblastic cells. Furthermore, the effect of IL-1 alpha on the synthesis of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) was analyzed. u-PA production by MG63 was high (approximately 180 ng/10(6) cells/24 h). Also t-PA and PAI-1 production was observed. u-PA production was rapidly increased in MG63 by IL-1 alpha (10 ng/ml), whereas an effect on t-PA production was only found after a prolonged incubation and hardly any effect of IL-1 alpha on PAI-1 production was observed. mRNA analysis revealed similar effects. u-PA receptor (u-PAR) mRNA was detectable in MG63 cells and could be increased by IL-1 alpha after 24 h. In MG63, u-PA-mediated extracellular matrix degradation was detectable, and IL-1 alpha increased the u-PA-mediated matrix degradation (approximately 2-fold). Under control conditions in MG63, only MMP-2, TIMP-1, and TIMP-2 mRNA could be observed. After the addition of IL-1 alpha, a very rapid increase in MMP-1 and MMP-3 mRNA could be observed as well as a moderate increase in TIMP-1 mRNA. The presence of MMP-2 was demonstrated by gelatin zymography. These results show that IL-1 alpha can stimulate u-PA production and can regulate extracellular proteolytic activity mainly via u-PA induction in the MG63 osteosarcoma cell line. Furthermore, IL-1 alpha has a strong stimulating effect on the production of MMP-1 and MMP-3. These findings suggest that u-PA and possibly MMP-1 and MMP-3 play an important role in the process of bone turnover in osteosarcomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/7502710', 'no', 'no', 'NA', 5),
(7506120, 'Yoshikawa H, Rettig WJ, Takaoka K, Alderman E, Rup B, Rosen V, Wozney JM, Lane JM, Huvos AG, Garin-Chesa P', 'Expression of bone morphogenetic proteins in human osteosarcoma. Immunohistochemical detection with monoclonal antibody.', 'Cancer', '1994', 'Expression of bone morphogenetic proteins in human osteosarcoma. Immunohistochemical detection with monoclonal antibody. Bone morphogenetic proteins (BMP) induce ectopic bone formation in vivo and may play a role in normal bone development. In addition, bone morphogenetic activity, as measured in a bone-forming assay in immunodeficient, athymic nu/nu mice, is present in a proportion of osteosarcomas; this activity, which may be mediated by BMP, is correlated with a poor prognosis.The development of a monoclonal antibody against recombinant human BMP-2, AbH3b2/17, has allowed immunohistochemical localization of BMP in tumor tissues. Cryostat sections of osteosarcomas (21 tumor samples), chondrosarcomas (5 samples), and Ewing''s sarcomas of bone (5 samples) were examined with AbH3b2/17 using the avidin-biotin-immunoperoxidase method.The authors found AbH3b2/17 immunoreactivity in 12 of the 21 osteosarcoma samples (57% sensitivity) obtained from 20 patients. For one patient, samples of the primary lesion and a subsequent metastasis were tested, and only the latter showed AbH3b2/17 immunoreactivity. The chondrosarcomas and Ewing''s sarcomas examined showed no immunoreactivity. In antigen-positive osteosarcomas, AbH3b2/17 immunostaining was localized predominantly in the cytoplasm of tumor cells. Moreover, the proportion of AbH3b2/17-reactive cells varied among osteosarcomas with disparate histologic features.The authors identified a rapid and widely applicable method for detecting BMP expression in intact tissues, which may complement and enhance the bone-forming assay in nu/nu mice as a prognostic procedure in osteosarcomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/7506120', 'yes', 'no', 'NA', 2),
(7513549, 'Hoogerwerf WA, Hawkins AL, Perlman EJ, Griffin CA', 'Chromosome analysis of nine osteosarcomas.', 'Genes Chromosomes Cancer', '1994', 'Chromosome analysis of nine osteosarcomas. Although recurrent chromosome abnormalities have been identified in several histologic subtypes of sarcomas, no consistent rearrangement has yet been found in osteosarcomas. Cytogenetic analyses of nine cases of osteosarcoma are reported, including seven newly diagnosed tumors and two recurrent tumors. There were seven high-grade osteosarcomas, one periosteal osteosarcoma, and one well-differentiated sarcoma. All tumors were studied in short-term primary culture. Modal number ranged from near diploid to near triploid. Seven tumors had complex karyotypes with multiple structural abnormalities; two had only normal karyotypes. The retinoblastoma gene on chromosome 13 and the TP53 gene on chromosome 17 have been involved in osteosarcoma. Five tumors had loss of a whole copy of chromosome 13, and three of these also had a loss of a whole copy of chromosome 17. However, these losses were observed in the setting of numerous other chromosome losses. Numerous structural abnormalities were observed, many involving additions of unidentified material, unbalanced translocations, or deletions. Structural abnormalities with similar breakpoints involving 6q, 8q, 9q, and 14p were seen in two or three tumors each. When the tumors in this series were added to the 18 published cases, the pericentromeric regions of chromosomes 1, 3, and 14, and segments 6q15-21, 8q24, 9q34, 12p13, 17p13, and 19q13, were found to be involved in five or more structural rearrangements. Molecular analyses of these chromosome regions may yield genes important in the pathogenesis of osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/7513549', 'yes', 'no', 'NA', 2),
(7518993, 'Chano T, Matsumoto K, Ishizawa M, Morimoto S, Hukuda S, Okabe H', 'Periosteal osteosarcoma and parosteal chondrosarcoma evaluated by double immunohistochemical staining. Report of 2 cases.', 'Acta Orthop Scand', '1994', 'Periosteal osteosarcoma and parosteal chondrosarcoma evaluated by double immunohistochemical staining. Report of 2 cases. Differentiation of periosteal osteosarcoma and parosteal (periosteal) chondrosarcoma by conventional histology may be difficult. One case each of clinically and histologically proven periosteal osteosarcoma and parosteal chondrosarcoma were evaluated by a double-immunohistochemical staining method using proliferating cell nuclear antigen (PCNA) and S-100 protein (S-100). Conventional histology showed proliferation of both osteoblastic and chondroblastic cells in the periosteal osteosarcoma, while there was a growth of only chondroblastic tumor cells in the parosteal chondrosarcoma. Immunohistochemical studies indicated that the nuclei of chondroblastic cells recognized by S-100 were PCNA-negative, while osteoblastic stromal cells were PCNA-positive in the periosteal osteosarcoma. In contrast, chondroblastic cells in the parosteal chondrosarcoma were both S-100- and PCNA-positive. Our findings suggest that periosteal osteosarcoma is characterized by the proliferation of osteoblastic stromal cells, whereas parosteal chondrosarcoma is characterized by the proliferation of chondroblastic cells. This method of double immunohistochemical staining, using PCNA and S-100, may be useful in differentiating these chondroblastic tumors.', 'http://www.ncbi.nlm.nih.gov/pubmed/7518993', 'yes', 'no', 'NA', 1),
(7528503, 'Iizuka M, Yamauchi M, Ando K, Hori N, Furusawa Y, Itsukaichi H, Fukutsu K, Moriya H', 'Quantitative RT-PCR assay detecting the transcriptional induction of vascular endothelial growth factor under hypoxia.', 'Biochem Biophys Res Commun', '1994', 'Quantitative RT-PCR assay detecting the transcriptional induction of vascular endothelial growth factor under hypoxia. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay was used to examine the induction of vascular endothelial growth factor (VEGF) transcript in human osteosarcoma cells, MG-63, under hypoxic culture condition. Using this assay system, the expression of VEGF mRNA was estimated eight-fold higher when cells were cultured under hypoxic condition. Transcription level of hypoxanthine phosphoribosyl transferase (HPRT) mRNA was also examined as an internal control. HPRT mRNA level under hypoxia was reduced to one fourteenth. Secretion of VEGF into the cell culture medium was implied by its stimulating activity on the growth of mouse vascular endothelial cultured cells in vitro.', 'http://www.ncbi.nlm.nih.gov/pubmed/7528503', 'no', 'no', 'NA', 1),
(7531202, 'Yamagata M, Kimata K', 'Repression of a malignant cell-substratum adhesion phenotype by inhibiting the production of the anti-adhesive proteoglycan, PG-M/versican.', 'J Cell Sci', '1994', 'Repression of a malignant cell-substratum adhesion phenotype by inhibiting the production of the anti-adhesive proteoglycan, PG-M/versican. Malignantly transformed cells usually display a rosette-like morphology of substratum adhesions (called podosomes) and disorganized microfilaments, and are often associated with elevated production of chondroitin sulphate. We previously showed that many tissues and cells express alternatively spliced multiforms of the large chondroitin sulphate proteoglycan termed PG-M (versican is one of the short transcripts). Since PG-M/versican inhibits many types of cell-substratum adhesion and is found to be excluded from focal contacts of cultured fibroblasts, it is likely that this proteoglycan is generally involved in regulating cell-substratum adhesion. We report here that PG-M/versican is selectively excluded from podosomes of human osteosarcoma cells and that specific inhibition of its biosynthesis by an antisense method suppresses such a malignant cell-adhesive phenotype. The results support the idea that PG-M/versican acts as an anti-adhesive molecule and raise the possibility that PG-M/versican controls one type of cancer cell behaviour.', 'http://www.ncbi.nlm.nih.gov/pubmed/7531202', 'no', 'no', 'NA', 1),
(7541624, 'Carvalho RS, Scott JE, Yen EH', 'The effects of mechanical stimulation on the distribution of beta 1 integrin and expression of beta 1-integrin mRNA in TE-85 human osteosarcoma cells.', 'Arch Oral Biol', '1995', 'The effects of mechanical stimulation on the distribution of beta 1 integrin and expression of beta 1-integrin mRNA in TE-85 human osteosarcoma cells. Mechanical stimulation of the skeleton alters the metabolism of bone cells, but the effects of mechanical strain on the cytoskeleton of osteoblasts are poorly understood. While changes in the distribution of the cytoskeleton in mechanically strained cells have been reported, little is known about the pathways by which these changes are transduced into cell functions. Human osteosarcoma (HOS) TE-85 cells were cultured in Dubelcco''s modified Eagle''s medium/F-12 and grown to confluency in Flexercell type I dishes in a humidified incubator with 5% CO2 and 95% air. Intermittent strain (3 cycles/min) was applied to the cells for periods of 15 and 30 min, 2, 4 and 24 h, and 3, 5, 7, 10, 14, 20 and 28 days. Unstrained cells were used as controls. The distribution of beta 1 integrin was studied immunocytochemically. Total RNA was isolated at every period of time and Northern blots were used to study the effects of strain on the levels of beta 1-integrin expression. The results indicated that mechanical strain increased the synthesis of beta 1 integrin. Northern blots showed that beta 1 mRNA expression was increased significantly (p < 0.005) at 30 min and 3 days of strain application. Strain also affected beta 1 distribution markedly in 24-h cultures. The response of HOS cells to mechanical strain demonstrates that the cytoskeleton of the osteoblast adapts to strain through the stimulation of specific cytoskeletal and receptor proteins. These results suggest a pathway through which mechanical strain is transmitted to the osteoblastic-like cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/7541624', 'no', 'no', 'NA', 1),
(7559091, 'Miyakoshi J, Yamagishi N, Ohtsu S, Takebe H', 'Changes in radiation sensitivity of human osteosarcoma cells after p53 introduction.', 'Jpn J Cancer Res', '1995', 'Changes in radiation sensitivity of human osteosarcoma cells after p53 introduction. Human osteosarcoma SAOS-2 cells, which have a deletion in p53 gene, were transfected with plasmid pMSVneop53 containing human p53 cDNA and neomycin-resistance gene. Three clones (SAOS-MC10, SAOS-MC11 and SAOS-MC43) among 60 clones expressed p53 mRNA. No p53 protein was observed in SAOS-MC10, while SAOS-MC11 and SAOS-MC43 produced p53 protein. The molecular weight of p53 protein in SAOS-MC43 was lower than that in SAOS-MC11, SAOS-MC11 and SAOS-MC43 were more sensitive and more resistant, respectively, to ionizing radiation than the parental SAOS-2. We suggest that exogenous p53 protein might be one of the factors determining cellular radiosensitivity.', 'http://www.ncbi.nlm.nih.gov/pubmed/7559091', 'no', 'no', 'NA', 1),
(7576109, 'Isfort RJ, Cody DB, Lovell G, Doersen CJ', 'Analysis of oncogenes, tumor suppressor genes, autocrine growth-factor production, and differentiation state of human osteosarcoma cell lines.', 'Mol Carcinog', '1995', 'Analysis of oncogenes, tumor suppressor genes, autocrine growth-factor production, and differentiation state of human osteosarcoma cell lines. Human osteosarcoma and fibrosarcoma cell lines were investigated for alterations in oncogenes, tumor suppressor genes, and growth factors, all of which have been implicated in tumor formation. Characterization of oncogenes that are involved in osteosarcoma formation, including the c-fos and c-myc oncogenes, indicated that all six osteosarcoma cell lines examined had 5- to 20-fold amplification of the c-myc oncogene, whereas neither of two fibrosarcoma cell lines c-myc amplification. Interestingly, only three of six osteosarcoma cell lines displayed altered c-myc immediate-early gene function. c-fos was found to be normal, both at the gene and functional levels, in all six osteosarcoma and both fibrosarcoma cell lines tested. Characterization of two tumor suppressor genes, p53 and RB1, that have been implicated in osteosarcoma formation indicated that p53 was altered in five of six osteosarcoma cell lines, whereas RB1 was altered in only two or six of these cell lines. Neither RB1 nor p53 was found to be altered in the fibrosarcoma cell lines tested. An additional transformation marker, autocrine growth-factor production, was observed in all six osteosarcoma cell lines and both fibrosarcoma cell lines examined. Finally, the differentiation state of the osteosarcoma cell lines was investigated via the bone differentiation markers alkaline phosphates and osteocalcin. Alkaline phosphatase activity was observed in four of six osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined. The alkaline phosphatase activity was a result of the expression of the bone/liver/kidney alkaline phosphatase isoform. High-level osteocalcin expression was observed in one of the osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined, although all cell lines demonstrated low-level osteocalcin expression. Together, these data demonstrate that relatively undifferentiated osteosarcomas commonly display c-myc amplification, p53 and RB1 mutation, and autocrine growth-factor production, all of which may play a role in osteosarcomagenesis.', 'http://www.ncbi.nlm.nih.gov/pubmed/7576109', 'no', 'no', 'NA', 6),
(7585551, 'Huang RP, Liu C, Fan Y, Mercola D, Adamson ED', 'Egr-1 negatively regulates human tumor cell growth via the DNA-binding domain.', 'Cancer Res', '1995', 'Egr-1 negatively regulates human tumor cell growth via the DNA-binding domain. Human HT1080 fibrosarcoma cells, subclone H4, express little or no Egr-1 (Zif/268, Krox 24), an early growth response gene encoding a transcription factor. Phorbol ester (but not serum) treatment only can elicit a small increase in Egr-1 expression in H4, in contrast to the normally rapid, high transient expression of Egr-1 observed after the addition of a wide range of stimulating agents to normal or immortalized cell lines. Because several human tumor cell lines express little Egr-1, we tested the hypothesis that this loss was causal to transformation. We report here that the expression of exogenous mouse Egr-1 in H4 cells inhibits transformed growth in a dose-dependent manner and significantly suppresses tumorigenicity in athymic mice. By overexpression of the fragment in Egr-1 that is responsible for its DNA-binding activity, the zinc-finger domain, we show that this domain has a similar activity. Moreover, the expression of antisense mRNA encoding the DNA-binding domain increases the transformed character of the H4 cells. One possible conclusion is that endogenous Egr-1-like genes perform growth-regulatory functions. Other human tumor lines are also growth suppressed by Egr-1 overexpression including ZR-75-1 breast carcinoma, U251 glioblastoma, and to a lesser extent, SAOS-2 osteosarcoma cells. These results are surprising in light of the \\early growth response\\ character of Egr-1 but extend our earlier report of suppression of growth in v-sis-transformed NIH3T3 cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/7585551', 'no', 'no', 'NA', 1),
(7585620, 'Skotzko M, Wu L, Anderson WF, Gordon EM, Hall FL', 'Retroviral vector-mediated gene transfer of antisense cyclin G1 (CYCG1) inhibits proliferation of human osteogenic sarcoma cells.', 'Cancer Res', '1995', 'Retroviral vector-mediated gene transfer of antisense cyclin G1 (CYCG1) inhibits proliferation of human osteogenic sarcoma cells. Genetic changes found in human osteogenic sarcoma cells, including loss of the p53 and Rb tumor suppressor elements and overexpression of the cyclin G1 (CYCG1) proto-oncogene, suggest the potential of gene transfer as a treatment for metastatic disease. In this study, we examined the effects of antisense cyclin G1, in comparison with antisense cyclin D1 (CYCD1) and enforced expression of the universal cyclin-dependent kinase inhibitor p21WAF1/CIP1 on the proliferation of human MG-63 osteosarcoma cells. Retroviral vectors bearing antisense CYCG1 as well as antisense CYCD1 and WAF1/CIP1 (in sense orientation) driven by the Moloney murine leukemia virus long terminal repeat promoter inhibited the growth and/or survival of transduced MG-63 cells in 2-7 day cultures. This represents the first demonstration that cyclin G1 is essential for the survival and/or growth of human osteosarcoma cells. Cytostatic and cytopathic effects were accompanied by a significant increase in the incidence of apoptosis, as determined by immunocytochemical analysis of DNA fragmentation. Furthermore, transduction of MG-63 cells with a retroviral vector bearing the suicide gene, herpes simplex thymidine kinase (HStk), induced cell death on treatment with ganciclovir, exhibiting pronounced bystander effects. Taken together, the data affirm the feasibility of modulating inducible cell cycle control enzymes as a potential gene therapy approach in the clinical management of osteogenic sarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/7585620', 'no', 'no', 'NA', 3),
(7591308, 'Nakayama T, Toguchida J, Wadayama B, Kanoe H, Kotoura Y, Sasaki MS', 'MDM2 gene amplification in bone and soft-tissue tumors: association with tumor progression in differentiated adipose-tissue tumors.', 'Int J Cancer', '1995', 'MDM2 gene amplification in bone and soft-tissue tumors: association with tumor progression in differentiated adipose-tissue tumors. We have studied 107 bone and soft-tissue sarcomas and 8 lipomas for amplification of the MDM2 gene. This gene was amplified in 3 out of 67 osteosarcomas, 3 out of 20 malignant fibrous histiocytomas, 4 out of 20 liposarcomas, and 4 out of 8 lipomas. The amplification was associated with overexpression of mRNA. In osteosarcomas, contrary to previous findings, all amplifications were observed in primary lesions. In liposarcomas, the amplification was seen exclusively in well-differentiated tumors with high frequency (4/5) but not in other subtypes (0/15). In addition, MDM2 amplification was also frequently found in deep-seated intra- or intermuscular lipomas (4/5). Hence, it is suggested that MDM2 amplification plays a significant role in the development of differentiated adipose-tissue tumors. Three well-differentiated liposarcomas with MDM2 amplification coexisted with high-grade dedifferentiated sarcomas, in which MDM2 amplification was also observed. Interestingly, in 2 of these cases, the grades of amplification correlated with the histological grades, indicating an important role of MDM2 overexpression in tumor progression.', 'http://www.ncbi.nlm.nih.gov/pubmed/7591308', 'yes', 'yes', 'NA', 1),
(7593131, 'Oda Y, Walter H, Radig K, Röse I, Neumann W, Roessner A', 'Immunohistochemical analysis of nm23 protein expression in malignant bone tumors.', 'J Cancer Res Clin Oncol', '1995', 'Immunohistochemical analysis of nm23 protein expression in malignant bone tumors. Expression levels of nm23 protein in 72 malignant bone tumors comprising 41 osteosarcomas, 22 chondrosarcomas, 6 Ewing''s sarcomas, and 2 malignant fibrous histiocytomas were examined immunohistochemically, using anti-nm23 protein polyclonal antibody, and compared with 51 cases of benign bone tumors or tumor-like lesions. Malignant bone tumors showed significantly higher nm23 protein expression than benign bone tumors or tumor-like lesions (P < 0.0001). In chondrosarcoma, nm23 expression increased in high-grade tumors (grade I versus grade II and III: P = 0.0229). In the cases of osteosarcoma, however, grade IV osteosarcomas showed decreased expression of nm23 compared with grade III tumors (P = 0.0122). There was no significant relationship between nm23 expression and histological type. nm23 expression had no correlation with metastatic potential in osteosarcoma, although the therapy was not uniform in our cases. Furthermore, in 6 cases of osteosarcoma and 1 case of Ewing''s sarcoma, there was no clear tendency for a decrease of nm23 in the metastatic sites compared with primary sites, as reported in breast cancer. These results showed that, in contrast to reports on breast cancer and experimental models, nm23 protein expression in human bone tumors may be associated with malignant potentiality, except in cases of osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/7593131', 'yes', 'yes', 'NA', 1),
(7607566, 'Ambartsumian N, Tarabykina S, Grigorian M, Tulchinsky E, Hulgaard E, Georgiev G, Lukanidin E', 'Characterization of two splice variants of metastasis-associated human mts1 gene.', 'Gene', '1995', 'Characterization of two splice variants of metastasis-associated human mts1 gene. The mts1 gene is one of the genes specifically expressed in mouse metastatic tumors and tumor cell lines. In this paper, we present data on cloning and sequencing of two variants of human mts1 cDNAs (hu-mts1 and hu-mts1 (var)), as well as of the corresponding region in the human genome. Comparison of the genomic sequence with the sequence of the mts1 cDNAs demonstrates presence of two alternatively spliced variants of the mts1 in the human osteosarcoma cell line (OHS). The alternative splicing occurs within the 5''-untranslated region (UTR) of human mts1 pre-mRNA. Both splice variants, hu-mts1 and hu-mts1 (var), retain similar stability in the cells, contain one open reading frame coding for the MTS1 protein and differ only slightly in their translational capacity. The splice variants demonstrate dramatic variations in the level of expression in different human tissues and in human tumor cell lines. Although we have not revealed substantial differences in the mode of action of the two splice variants in the cells, the observed tissue specificity of expression supports the notion that it plays an important role in determining the activity of mts1 in different tissues.', 'http://www.ncbi.nlm.nih.gov/pubmed/7607566', 'no', 'no', 'NA', 1),
(7612954, 'Chano T, Ishizawa M, Matsumoto K, Morimoto S, Hukuda S, Okabe H', 'The identity of proliferating cells in bone tumors with cartilaginous components: evaluation by double-immunohistochemical staining using proliferating cell nuclear antigen and S-100 protein.', 'Eur J Histochem', '1995', 'The identity of proliferating cells in bone tumors with cartilaginous components: evaluation by double-immunohistochemical staining using proliferating cell nuclear antigen and S-100 protein. S-100 protein (S-100) appears to be a marker for bone tumors of cartilaginous origin. Any analyses of proliferative activity in S-100-positive tumor cells, however, has not yet been presented. This study assessed the proliferative activity of those cells by means of a double-immunohistochemical staining method using proliferating cell nuclear antigen (PCNA) and S-100. The most intense reactivity for S-100 was found in the well-differentiated chondrocytes of enchondromas, osteochondromas, and osteosarcomas. On the contrary, the more immature the tumor cells were, the more intensely positive they were for PCNA. In parosteal chondrosarcoma, exceptionally, PCNA-positive as well as S-100-positive cells were abundant, suggesting that these proliferating cells produced S-100. In periosteal osteosarcoma, however, the proliferating cells labeled by PCNA revealed little reactivity for S-100. This immunohistochemical method is potentially useful to know the identity and origin of proliferating cells and may sometimes be diagnostic for bone tumors containing cartilaginous elements.', 'http://www.ncbi.nlm.nih.gov/pubmed/7612954', 'yes', 'no', 'NA', 1),
(7614454, 'Strauss EA, Hosler MR, Herzog P, Salhany K, Louie R, Felix CA', 'Complex replication error causes p53 mutation in a Li-Fraumeni family.', 'Cancer Res', '1995', 'Complex replication error causes p53 mutation in a Li-Fraumeni family. We demonstrated a germline p53 replication error in two generations of a Li-Fraumeni family affected with liposarcoma, adrenocortical carcinoma, and osteosarcoma. The trinucleotide repeat mutation changed 5''-AGT GTG GTG GTG-3'' at codons 215-218 to 5''-AGT TGG TTG GTG GTG-3''. The predicted protein would be elongated by one amino acid (val216-->trp leu) without a change in charge. Detection of p53 in the adrenal tumor by immunostaining suggested that the mutant protein was expressed. Persistence of the mutation in the germline may suggest a defect in DNA repair in the family member first affected. This is the first report where germline transmission of replication-damaged p53 trinucleotide repeats is associated with the Li-Fraumeni syndrome.', 'http://www.ncbi.nlm.nih.gov/pubmed/7614454', 'yes', 'no', 'NA', 1),
(7621257, 'Wang J, Bucana CD, Roth JA, Zhang WW', 'Apoptosis induced in human osteosarcoma cells is one of the mechanisms for the cytocidal effect of Ad5CMV-p53.', 'Cancer Gene Ther', '1995', 'Apoptosis induced in human osteosarcoma cells is one of the mechanisms for the cytocidal effect of Ad5CMV-p53. Recombinant adenovirus Ad5CMV-p53 induced a strong cytocidal effect in Saos-LM2 cells. This cell line, derived from human osteosarcoma Saos-2 cells, has a homozygous deletion of the p53 gene. By using immunocytochemical and Western blot analyses, we demonstrated that Ad5CMV-p53 effectively infected Saos-LM2 cells at multiplicities of infection of 10 to 50 plaque-forming units/cell and mediated a high-level expression of the exogenous wild-type p53 protein in the cells. Growth of the infected cells was greatly suppressed whereas that of mock- or control virus-infected cells was not. Because wild-type p53 induces apoptosis in certain types of cells, we studied DNA fragmentation in situ in the Ad5CMV-p53-infected Saos-LM2 cells by terminal deoxynucleotidyl transferase assays, which yielded positive nuclear staining. Further analysis of the Ad5CMV-p53-infected Saos-LM2 cells by light and electron microscopy demonstrated that the cells underwent the characteristic morphological changes of apoptosis such as plasma-membrane blebbing, nuclear condensation, and fragmentation. These changes were not observed in mock- or control virus-infected cells. Our results on Saos-LM2 cells indicate that apoptosis induced by Ad5CMV-p53 may be one of the mechanisms underlying the cytocidal effect of Ad5CMV-p53.', 'http://www.ncbi.nlm.nih.gov/pubmed/7621257', 'no', 'no', 'NA', 1),
(7639117, 'Fitzsimmons RJ, Ryaby JT, Magee FP, Baylink DJ', 'IGF-II receptor number is increased in TE-85 osteosarcoma cells by combined magnetic fields.', 'J Bone Miner Res', '1995', 'IGF-II receptor number is increased in TE-85 osteosarcoma cells by combined magnetic fields. Human osteosarcoma-derived osteoblast-like cells, TE-85, were used to assess the effect of a low frequency alternating magnetic field in combination with a controlled static magnetic field (combined magnetic fields, CMF) on insulin-like growth factor receptor regulation. In our culture system, application of a 15.3 Hz CMF induces a calculated maximum electrical potential in the culture media of 10(-5) V/m. Initial characterization of TE-85 cells demonstrated that (a) TE-85 cells contain both type I insulin-like growth factor (IGF-I) and IGF-II receptors and (b) dose dependence for IGF-stimulated cell proliferation were comparable to the affinities of the IGF''s binding to membrane binding sites (i.e., receptors had dissociation constants in the low nanomolar concentration range). The studies with CMF exposure revealed that CMF treatment for 30 minutes increased the number of IGF-II receptors in a frequency-dependent manner without affecting the number of IGF-I receptors. The CMF-dependent increase in IGF-II receptor number was associated with a significant increase in the IGF-II dissociation constant. These results indicate that a membrane receptor levels can be altered by short-term exposure to low-energy, low-frequency electromagnetic fields and suggest a potential biochemical mechanism for electromagnetic effects on bone formation and remodeling.', 'http://www.ncbi.nlm.nih.gov/pubmed/7639117', 'no', 'no', 'NA', 1);
INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(7640224, 'Maelandsmo GM, Berner JM, Flørenes VA, Forus A, Hovig E, Fodstad O, Myklebost O', 'Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas--relationship to amplification and mRNA levels of CDK4 and CCND1.', 'Br J Cancer', '1995', 'Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas--relationship to amplification and mRNA levels of CDK4 and CCND1. Homozygous deletions of the putative tumour-suppressor gene CDKN2, which encodes an inhibitor of cdk4, have been detected in a high percentage of cancer cell lines of various histological types. In the present study, 109 human sarcomas were examined for homozygous deletions and for mRNA expression levels of the CDKN2 gene. Altogether, deletions were found in only eight (7%) of the cases, but, interestingly, in two (of eight) malignant Schwannomas and in two (of five) rhabdomyosarcomas. In comparison, such deletions were seen in only one (of 21) osteosarcomas and in none of 20 MFHs and 21 liposarcomas. Notably, highly elevated CDKN2 mRNA levels were found in 33% of the sarcomas, whereas no detectable transcript was present in 12 normal tissues. Amplifications of CDK4 and CCND1 (cyclin D1) were observed in 11% and 4% of the sarcomas respectively, but never in tumours with CDKN2 deletions. The level of CDK4 mRNA expression was increased in nine tumours in addition to the 12 samples with CDK4 amplification. Increased levels of the cyclin D1 transcript was found in 37 cases, four with and 33 without amplification. The data indicate that aberrations of these functionally related genes, or in regulation of the expression of the kinase, the activator or the inhibitor, may participate in sarcoma development. Furthermore, the data suggest that homozygous CDKN2 deletions may be of dissimilar significance in different sarcoma subtypes.', 'http://www.ncbi.nlm.nih.gov/pubmed/7640224', 'yes', 'no', 'NA', 3),
(7641470, 'Anderson HC, Hsu HH, Raval P, Hunt TR, Schwappach JR, Morris DC, Schneider DJ', 'The mechanism of bone induction and bone healing by human osteosarcoma cell extracts.', 'Clin Orthop Relat Res', '1995', 'The mechanism of bone induction and bone healing by human osteosarcoma cell extracts. Saos-2 cultured human osteosarcoma cells contain an extractable bone inducing agent that can induce heterotopic bone in the muscle of Nu/Nu mice. A semipurified GuHCl extract of Saos-2 cells also can promote healing and complete bony union in otherwise non-healing surgically induced defects of rat femur. Northern blot analyses indicate expression of mRNAs for bone morphogenetic proteins (BMP)-1, 2, 3, 4, 6 and transforming growth factor beta (TGF beta) in Saos-2 cells, and BMP-2, 3, 4, 5, 7 and TGF beta in nonosteoinductive U20S human osteosarcoma cells. Saos-2 cells exceeded U20S cells in expression levels of BMP-1, 3, 4 and TGF beta, whereas U20S cells expressed higher levels of BMP-2, 6 and also expressed trace amounts of BMP-5 and 7 not seen in Saos-2 cells. The authors hypothesize that Saos-2 cells contain an optimal admixture of known bone growth factors plus possible other unknown components that, acting alone or in combination with bone morphogenetic protein and/or TGF beta, can induce bone. Although bone inducing agent-induced heterotopic bones have half lives of only a few weeks, the reparative bone induced by bone inducing agent in femoral defects gives every indication of being permanent and self-sustaining. This suggests a fundamental difference between heterotopic and orthotopic osteoprogenitor cells with those involved in orthotopic bone repair more closely resembling the committed or determined osteoprogenitor cells of marrow as described by Friedenstein.', 'http://www.ncbi.nlm.nih.gov/pubmed/7641470', 'no', 'no', 'NA', 8),
(7660382, 'Imanishi T, Abe Y, Suto R, Higaki S, Ueyama Y, Nakamura M, Tamaoki N, Fukuda H, Imai N', 'Expression of the human multidrug resistance gene (MDR1) and prognostic correlation in human osteogenic sarcoma.', 'Tokai J Exp Clin Med', '1994', 'Expression of the human multidrug resistance gene (MDR1) and prognostic correlation in human osteogenic sarcoma. The overexpression of P-glycoprotein (P-Gp), encoded by the human multidrug resistant gene (MDRA), decreases lipophilic drug accumulation in multidrug resistant cells in vitro. It is still not clear whether P-Gp contribute to the problem of multidrug resistance (MDR) in osteogenic sarcoma (OS). We examined the MDR1 expression of 20 OS specimens (11 primary tumors, 10 xenografts, 1 overlapping), by Northern blotting and by the reverse transcriptase-polymerase chain reaction (RT-PCR), and evaluated by the relationship between MDR1 expression and patient prognosis. RT-PCR revealed MDR1 expression in 9/20 OS; 5/11 primary tumors and 5/10 OS-xenografts; northern blotting revealed MDR1 expression in only 5/20 OS. One primary OS specimen and its corresponding xenograft had similar levels of MDR1 expression. All 20 patients with OS were treated with chemotherapeutic protocols including doxorubicin, cisplatin, methotrexate and ifosfamide. Eight of 9 OS-patients expressing MDR1 were resistant to chemotherapy and had a poor prognosis. The relationship between MDR1 expression and poor prognosis in the 20 OS-patients was significant (p < 0.01). The results support the assumption that MDR1 expression is related to MDR in human OS.', 'http://www.ncbi.nlm.nih.gov/pubmed/7660382', 'yes', 'yes', 'NA', 1),
(7684391, 'Conover CA, Kiefer MC', 'Regulation and biological effect of endogenous insulin-like growth factor binding protein-5 in human osteoblastic cells.', 'J Clin Endocrinol Metab', '1993', 'Regulation and biological effect of endogenous insulin-like growth factor binding protein-5 in human osteoblastic cells. U-2 human osteosarcoma cells secrete a 29/32/34 kilodalton (kDa) insulin-like growth factor binding protein (IGFBP) identified as O-glycosylated IGFBP-5. Treatment of U-2 cells with IGF-I markedly increased medium levels of IGFBP-5 in a concentration- and time-dependent manner; other skeletal regulatory factors (GH, insulin, PTH, dexamethasone, beta-estradiol, 1,25-dihydroxyvitamin D3, transforming growth factor-beta) had no effect. IGF-I increased IGFBP-5 levels in the culture medium 10-fold without influencing IGFBP-5 messenger RNA abundance. IGF-I, IGF-II, and the IGF-I analog [1-27Gly(4)38-70] IGF-I bound IGFBP-5 with high affinity and, when added to U-2 cultures, effectively promoted IGFBP-5 accumulation in the medium. On the other hand, des(1-3)IGF-I and [QAYL]IGF-I, IGF-I analogs that did not bind IGFBP-5, failed to elicit an increase in medium IGFBP-5. Cell-free incubation of recombinant human (rh) IGFBP-5 in U-2 conditioned medium resulted in a marked reduction of detectable rhIGFBP-5; the presence of IGF-I or IGF-II peptide partially prevented this decrease. By immunoblot analysis, loss of intact rhIGFBP-5 (29-kDa unreduced, 34-kDa reduced) coincided with the appearance of a 16-kDa proteolytic fragment. U-2 conditioned medium contained immunoreactive IGFBP-5 at 29-34-kDa, 20-kDa, 17-kDa, and 16-kDa. Endogenous IGFBP-5 inhibited IGF-I but not des(1-3)IGF-I-stimulated U-2 cell proliferation. In conclusion, IGF peptides can regulate the availability of IGFBP-5 in osteoblast-like cells by impeding IGFBP-5 proteolysis. The biological consequence of increased medium IGFBP-5 appears to be decreased cell responsiveness to IGF-I stimulation.', 'http://www.ncbi.nlm.nih.gov/pubmed/7684391', 'no', 'no', 'NA', 2),
(7685168, 'Kindmark A, Törmä H, Johansson A, Ljunghall S, Melhus H', 'Reverse transcription-polymerase chain reaction assay demonstrates that the 9-cis retinoic acid receptor alpha is expressed in human osteoblasts.', 'Biochem Biophys Res Commun', '1993', 'Reverse transcription-polymerase chain reaction assay demonstrates that the 9-cis retinoic acid receptor alpha is expressed in human osteoblasts. The 9-cis retinoic acid receptor (RXR) alpha, a co-regulator of the thyroid hormone and vitamin D receptors, has previously been shown to be expressed predominantly in metabolic organs such as the liver and the kidney. In this study we have used a reverse transcription polymerase chain reaction (RT-PCR) to examine the expression of retinoic acid (RA) nuclear receptors in primary human osteoblasts and in SaOS-2, a human osteosarcoma-derived cell line with osteoblastic characteristics. Our results demonstrate that human osteoblasts express RXR alpha, as well as the all-trans RA receptors (RAR) alpha, beta, and gamma. These data further establish bone as a major target for retinoids and suggest that RA can regulate vitamin D and thyroid hormone actions in osteoblasts.', 'http://www.ncbi.nlm.nih.gov/pubmed/7685168', 'no', 'no', 'NA', 1),
(7693339, 'Rong S, Jeffers M, Resau JH, Tsarfaty I, Oskarsson M, Vande Woude GF', 'Met expression and sarcoma tumorigenicity.', 'Cancer Res', '1993', 'Met expression and sarcoma tumorigenicity. The met protooncogene tyrosine kinase receptor (Met) and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), ordinarily constitute a paracrine signaling system in which cells of mesenchymal origin produce the ligand, which binds to the receptor that is predominantly expressed in cells of epithelial origin. However, mouse NIH/3T3 fibroblasts overexpressing Met induce tumor formation in nude mice via an autocrine mechanism (S. Rong et al., Mol. Cell. Biol., 12: 5152-5158, 1992). In this study, we report that human cell lines established from various sarcomas express high levels of activated Met receptor. HGF/SF is also detected in the human sarcoma cell lines but at a reduced level when compared to primary fibroblasts. These properties, high Met expression and reduced ligand levels, are indistinguishable from the properties of NIH/3T3 tumor explant cells overexpressing Met (S. Rong et al., Mol. Cell. Biol., 12: 5152-5158, 1992; S. Rong et al., Cell Growth & Differ., 4: 563-569, 1993). Moreover, paraffin-embedded sections of primary tumors from human osteosarcomas, chondrosarcomas, and leiomyosarcoma stain intensely for Met and/or HGF/SF and display extensive tumor cell heterogeneity with regard to both paracrine and autocrine stimulation. On the basis of these findings, we propose that Met-HGF/SF autocrine signaling may contribute to the tumorigenic process in human sarcomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/7693339', 'yes', 'no', 'NA', 2),
(7705958, 'Multhoff G, Botzler C, Wiesnet M, Müller E, Meier T, Wilmanns W, Issels RD', 'A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells.', 'Int J Cancer', '1995', 'A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. It is suggested that members of the heat-shock protein (HSP) 70 and 90 families are involved in intracellular antigen processing and the presentation of cell-membrane-anchored antigens. We show that non-lethal heat shock (41.8 degrees C) causes comparable rates of HSP72 (about 20x) and HSP73 (about 3x) synthesis in both tumor (including human Ewing''s sarcoma, ES and osteosarcoma cells, HOS58) and normal cells (including EBV-transformed B-LCL, PBL and fibroblasts derived from healthy human volunteers). However, following non-lethal heat stress and a recovery period at 37 degrees C, flow cytometric analysis with a specific MAb showed HSP72 to be expressed only on the cell surface of tumor cells. The cell-surface localization of HSP72 was confirmed by Western-blot analysis of separated membranes and by immunoprecipitation with the HSP72-specific MAb. In addition, co-incubation of untreated tumor cells with supernatants from lethally heat-shocked cells, which contain HSP72, did not lead to HSP72 cell-surface expression. Thus, non-specific association of HSP72 molecules with the outer plasma membrane is unlikely. In conclusion, despite comparable cytoplasmic HSP72 induction, human tumor cells differ from normal cells in their capacity to express HSP72 on their surface. This might imply clinical application as a means to target a stress-inducible, tumor-specific immune response.', 'http://www.ncbi.nlm.nih.gov/pubmed/7705958', 'no', 'no', 'NA', 2),
(7735558, 'Kandel RA, Campbell S, Noble-Topham S, Bell R, Andrulis IL', 'Correlation of p-glycoprotein detection by immunohistochemistry with mdr-1 mRNA levels in osteosarcomas. Pilot study.', 'Diagn Mol Pathol', '1995', 'Correlation of p-glycoprotein detection by immunohistochemistry with mdr-1 mRNA levels in osteosarcomas. Pilot study. All the factors that influence prognosis in patients with osteosarcomas have not been fully determined. One reported predictor of poor outcome is increased multi-drug resistant gene (mdr-1) expression, as measured by reverse transcription and polymerase chain reaction (RT-PCR). We examined whether immunostaining for p-glycoprotein, the protein product of mdr-1, could be used instead of RT-PCR to indicate the presence of the multidrug-resistant phenotype. The sensitivity of the immunostaining was determined using KB cell sublines. For 13 cases of osteosarcoma, samples were immunostained for p-glycoprotein and the levels of mdr-1 expression quantitated with use of RT-PCR. Three osteosarcomas with undetectable levels of mdr-1 expression by RT-PCR were negative immunohistochemically. Ten cases showed mdr-1 expression ranging from approximately 1 to 32 copies of mdr-1 mRNA/cell. Of these cases, five cases contained occasional tumour cells with positive immunostaining. There was no correlation between levels of expression and the presence or number of immunoreactive cells. These results indicate that the presence of p-glycoprotein immunostaining does not reliably correlate with the level of mdr-1 expression. However it may be useful in conjunction with RT-PCR to further define different subgroups of osteosarcomas that may have different prognoses, and this is currently under investigation.', 'http://www.ncbi.nlm.nih.gov/pubmed/7735558', 'yes', 'no', 'NA', 1),
(7768643, 'Boulanger J, Reyes-Moreno C, Koutsilieris M', 'Mediation of glucocorticoid receptor function by the activation of latent transforming growth factor beta 1 in MG-63 human osteosarcoma cells.', 'Int J Cancer', '1995', 'Mediation of glucocorticoid receptor function by the activation of latent transforming growth factor beta 1 in MG-63 human osteosarcoma cells. We analyzed glucocorticoid receptor function using ligand binding assays, DNA band-shift analysis and trans-activation of the murine mammary tumor virus-thymidine kinase-chloramphenicol acetyltransferase reporter gene in transiently transfected MG-63 human osteosarcoma cells. Dexamethasone increased the distribution of MG-63 cells in the G1/G0 phase of the cell cycle, thus decreasing the rate of DNA synthesis and cell growth. Its effect on MG-63 cell growth was neutralized by RU486 and anti-transforming growth factor beta 1 (TGF beta 1) antibody. In addition, (i) dexamethasone increased the levels of active TGF beta 1 in MG-63-conditioned media without significantly altering the expression of TGF beta 1 mRNA in MG-63 cells and (ii) TGF beta 1 inhibited proliferation of MG-63 cells. Therefore, we conclude that glucocorticoid receptor function is mediated by the activation of latent-TGF beta 1 in MG-63 osteosarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/7768643', 'no', 'no', 'Dexamethasone|RU486', 2),
(7789337, 'Fitzsimmons RJ, Ryaby JT, Mohan S, Magee FP, Baylink DJ', 'Combined magnetic fields increase insulin-like growth factor-II in TE-85 human osteosarcoma bone cell cultures.', 'Endocrinology', '1995', 'Combined magnetic fields increase insulin-like growth factor-II in TE-85 human osteosarcoma bone cell cultures. In vitro exposure to low-energy, combined magnetic fields (CMF) increased the release of insulin-like growth factor (IGF)-II from human TE-85 osteosarcoma cells. Short-term CMF exposure of only 10 min increased IGF-II levels in conditioned medium 1 h post CMF exposure. IGF-II levels were measured with a radioreceptor assay using H-35 cells that contain abundant IGF-II but not IGF-I receptors. This assay also uses a recently validated BioGel P-10 acid gel filtration method to remove IGF binding protein before quantitation of either IGF-I or IGF-II. In addition to an increase in IGF-II levels, DNA synthesis, as an index of cell proliferation, was increased during the 24-h period post CMF exposure. A monoclonal antibody against IGF-II blocked the increase in cell proliferation following CMF exposure, whereas a control monoclonal antibody against osteocalcin did not attenuate the mitogenic action of CMF exposure. The effect of CMF exposure to increase both cell proliferation and IGF-II was cell-density dependent with greater stimulation by CMF observed at lower densities. Together, these data are consistent with the hypothesis that CMF exposure stimulates release/production of IGF-II from bone cells and that increased IGF-II then promotes an increase in cell proliferation.', 'http://www.ncbi.nlm.nih.gov/pubmed/7789337', 'no', 'no', 'NA', 1),
(7794813, 'Ringbom-Anderson T, Sandberg M, Andersson G, Akerman KE', 'Phenotypic modification of human osteosarcoma cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate.', 'Cell Growth Differ', '1995', 'Phenotypic modification of human osteosarcoma cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Treatment of the U-2 OS human osteosarcoma cell line with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) dramatically decreased the rate of DNA synthesis. This decrease in proliferation as well as the change in morphology of the TPA-treated cells can be blocked by the protein kinase C inhibitor GF 109203X. The U-2 OS cells are known to express the c-sis oncogene [platelet-derived growth factor (PDGF) B-chain], PDGF-A, and receptors for PDGF, thus providing a potential autocrine loop of growth stimulation. TPA was found to induce the expression of both the PDGF-A and the PDGF-B chains. However, the levels of the PDGF receptor beta subunits and of the PDGF-BB inducable tyrosine phosphorylation of the PDGF receptor were markedly reduced. The TPA treatment of the U-2 OS cells also induced changes typical for maturing bone cells, such as increased expression levels of alkaline phosphatase and osteopontin. The expression levels of type I collagen and bone sialoprotein were reduced. The results show a TPA-dependent down-regulation of the PDGF receptor beta subunits that correlates with an increased expression of osteoblast phenotypic markers.', 'http://www.ncbi.nlm.nih.gov/pubmed/7794813', 'no', 'no', '12-O-tetradecanoylphorbol-13-acetate|GF 109203X', 6),
(7802648, 'Mahonen A, Mäenpää PH', 'Steroid hormone modulation of vitamin D receptor levels in human MG-63 osteosarcoma cells.', 'Biochem Biophys Res Commun', '1994', 'Steroid hormone modulation of vitamin D receptor levels in human MG-63 osteosarcoma cells. The effects of steroid and thyroid hormones are mediated by intracellular hormone receptors. An important mechanism modulating target tissue responsiveness to hormones is homologous and heterologous regulation of the receptors. We have characterized the expression of steroid hormone receptors in human MG-63 osteosarcoma cells. The MG-63 cells express receptor mRNAs for glucocorticoids, estrogen, retinoic acid, and 1,25(OH)2D3. We found that only the vitamin D receptor (VDR) mRNA concentration was influenced by the hormones. The stability of the VDR message was identical in control, dexamethasone- and estradiol-treated cells. On the other hand, both 1,25(OH)2D3 and retinoic acid separately stabilized the VDR mRNA levels increasing the apparent half-life by 11 h and 6 h, respectively. The VDR protein levels, however, as measured by immunoprecipitation, increased only after the 1,25(OH)2D3 treatment.', 'http://www.ncbi.nlm.nih.gov/pubmed/7802648', 'no', 'no', 'dexamethasone|estradiol|retinoic acid|1,25(OH)2D3', 1),
(7817811, 'Pirskanen A, Jääskeläinen T, Mäenpää PH', 'Effects of transforming growth factor beta 1 on the regulation of osteocalcin synthesis in human MG-63 osteosarcoma cells.', 'J Bone Miner Res', '1994', 'Effects of transforming growth factor beta 1 on the regulation of osteocalcin synthesis in human MG-63 osteosarcoma cells. Treatment of human MG-63 osteosarcoma cells with human recombinant transforming growth factor beta 1 (TGF-beta 1) was found to inhibit cell proliferation. In addition, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-induced osteocalcin synthesis was greatly influenced by TGF-beta 1. Dose- and time-dependent inhibition was seen both in medium osteocalcin and the corresponding mRNA concentrations. Furthermore, TGF-beta 1 decreased osteocalcin synthesis modulated negatively by dexamethasone or positively by retinoic acid. The stability of osteocalcin mRNA was not decreased by the TGF-beta 1 treatment, but in vitro transcription assays demonstrated diminished osteocalcin gene transcription caused by the TGF-beta 1 treatment. Binding of vitamin D receptor (VDR) to an oligonucleotide probe containing the osteocalcin vitamin D response element (VDRE) was not influenced by TGF-beta 1, however. Incubation of the cells with the serine/threonine kinase inhibitor H-7 did not block the ability of TGF-beta 1 to decrease osteocalcin synthesis but caused a further inhibition. Also, the 1,25(OH)2D3-induced osteocalcin synthesis was decreased by H-7 treatment, suggesting that phosphorylation as such is involved in the transcriptional activation mechanism of VDR. These results demonstrate that TGF-beta 1 is a strong inhibitor of the synthesis of osteocalcin, a calcium binding protein participating in bone mineralization, by counteracting the stimulatory effects of other hormones on its synthesis. We further suggest that TGF-beta 1 affects the synthesis of osteocalcin at the level of transcription through mechanism(s) different from the serine/threonine kinase pathway.', 'http://www.ncbi.nlm.nih.gov/pubmed/7817811', 'no', 'no', '1,25-dihydroxyvitamin D3|dexamethasone|retinoic acid', 3),
(7826985, 'Häkel C, Ueda Y, Tsuchya H, Herrera A, Blasius S, Roessner A', 'Plasminogen activators and their inhibitor in osteosarcomas and other bone tumors.', 'Zentralbl Pathol', '1994', 'Plasminogen activators and their inhibitor in osteosarcomas and other bone tumors. The concentrations of the plasminogen activators u-PA and t-PA as well as the inhibitor PAI-1 were studied immunohistochemically in 35 osteosarcoma specimens compared to 15 Ewing''s sarcomas and various other bone lesions. The immunoreactivities of plasminogen activators in osteosarcoma specimens were significantly higher than PAI-1. Biochemically in cell cultures and immunohistochemically in the pathological specimens of the osteosarcomas u-PA was the dominant antigen, all factors showing a generally strong reactivity. Here a relation to the malignancy and invasivity of the tumors could be seen, which was comparable to the results in other tumors. This correlation, however, could not be detected in Ewing''s sarcomas. On the whole low immunoreactivity of all enzymes, and of u-PA in particular, could be seen. In comparison in some benign lesions (fibrous dysplasias, aneurysmal bone cysts) the immunohistochemical reactions were distinctly stronger. Dominant antigens did not exist in Ewing''s sarcomas. In all mesenchymal tumors studied the immunohistochemical localisation and concentration of the antigens showed a definite correlation with their histological differentiation. Chondroblastic differentiations in different tumors (chondrosarcomas, enchondromas, chondroblastic osteosarcomas) or chondroid parts were always negative for both activators and the inhibitor, especially in their central parts. Here, the biological malignancy was not decisive for the result.', 'http://www.ncbi.nlm.nih.gov/pubmed/7826985', 'yes', 'no', 'NA', 1),
(7828148, 'Forus A, Flørenes VA, Maelandsmo GM, Fodstad O, Myklebost O', 'The protooncogene CHOP/GADD153, involved in growth arrest and DNA damage response, is amplified in a subset of human sarcomas.', 'Cancer Genet Cytogenet', '1994', 'The protooncogene CHOP/GADD153, involved in growth arrest and DNA damage response, is amplified in a subset of human sarcomas. The C/EBP-homologous transcription factor CHOP (GADD153) is inducible by growth inhibition or DNA damage, and has been shown to be oncogenically activated by the specific (12;16) translocation in human myxoid liposarcoma. We have now found CHOP amplification in two sarcoma cell lines with previously reported amplification of the nearby GLI gene. Among 98 other human sarcomas of various types, CHOP was amplified in a hemangiopericytoma, a liposarcoma, and two osteosarcoma. High constitutive expression levels of CHOP were observed in tumors with gene amplification, but also in some other samples. The nearby MDM2 gene, which codes for a protein that may inactivate wild-type p53, has previously been reported to be frequently amplified in sarcoma. In our sarcoma panel, MDM2 was amplified in 9 cases. MDM2 and CHOP were co-amplified in two of these, whereas the two osteosarcomas had amplified CHOP but not MDM2. CHOP was amplified in both cell lines with GLI amplification, and MDM2 only in one. No mutations in the TP53 gene have been found in samples with amplification of MDM2. In contrast, the cell line in which CHOP but not MDM2 was amplified had mutated TP53, suggesting that selection of this amplicon was not mediated through p53 inactivation.', 'http://www.ncbi.nlm.nih.gov/pubmed/7828148', 'yes', 'no', 'NA', 3),
(7833115, 'Stein U, Walther W, Wunderlich V', 'Point mutations in the mdr1 promoter of human osteosarcomas are associated with in vitro responsiveness to multidrug resistance relevant drugs.', 'Eur J Cancer', '1994', 'Point mutations in the mdr1 promoter of human osteosarcomas are associated with in vitro responsiveness to multidrug resistance relevant drugs. Among human sarcomas, osteosarcomas usually display high intrinsic mdr1 expression while malignant fibrous histiocytomas (MFH) do not. A comparative polymerase chain reaction (PCR)-based sequence analysis of the mdr1 promoter revealed point mutations in seven out of nine osteosarcomas at nucleotides +103 (2 cases T-->C) and +137 (5 cases G-->T). No changes were seen in eight MFHs. When COS cells transfected with CAT constructs containing the T-->C chloramphenicol acetyltransferase mutant mdr1 promoters were treated with vincristine or doxorubicin, expression of the CAT gene was enhanced to a higher extent than with constructs containing wild-type or G-->T-mutant mdr1 promoters. We suggest that there is a correlation between the type of mdr1 promoter mutation and responsiveness to MDR relevant drugs.', 'http://www.ncbi.nlm.nih.gov/pubmed/7833115', 'yes', 'no', 'vincristine|doxorubicin', 1),
(7835281, 'Elias JA, Tang W, Horowitz MC', 'Cytokine and hormonal stimulation of human osteosarcoma interleukin-11 production.', 'Endocrinology', '1995', 'Cytokine and hormonal stimulation of human osteosarcoma interleukin-11 production. Osteoclast-mediated bone resorption plays a crucial role in osseous remodeling. Osteoblasts are important regulators of this activity, in part through their ability to produce osteoclast-regulating soluble factors such as interleukin-6 (IL-6). IL-11 is a newly appreciated pleotropic cytokine whose spectrum of biological activities overlaps with that of IL-6. As a result, we hypothesized that osteoblasts are an important skeletal source of this cytokine. To test this hypothesis, we characterized the IL-11 production of unstimulated and stimulated SaOS-2 human osteosarcoma cells. Unstimulated cells produced modest amounts of IL-11. The osteotropic agents recombinant IL-1 (0.25-5 ng/ml), transforming growth factor-beta 1 (0.1-10 ng/ml), PTH (10(-8)-10(-11) M), and PTH-related peptide ((10(-8)-10-11 M) further increased SaOS-2 cell IL-11 protein production and messenger RNA accumulation. These stimulatory effects were dose and time dependent, and the IL-11 that was produced was bioactive, as demonstrated by its ability to stimulate the proliferation of T10D plasmacytoma cells. The protein kinase-C activator, 12-O-Tetra-decanoylphorbol 13-acetate, and a variety of cAMP agonists [forskolin, prostaglandin E1, prostaglandin E2, and (Bu)2AMP] also stimulated osteoblast IL-11 protein production and messenger RNA accumulation. In contrast, recombinant IL-4, recombinant interferon-gamma, and endotoxin did not stimulate SaOS-2 cells in a similar fashion. Importantly, the ability to produce IL-11 was not a unique property of SaOS-2 cells, because primary human trabecular bone osteoblasts also produced significant amounts of bioactive IL-11 when stimulated with transforming growth factor-beta 1. These studies demonstrate that appropriately stimulated human osteoblasts and osteoblast-like cells are potent producers of IL-11 and suggest that osteoblast-derived IL-11 may be an important component of the cytokine network mediating osteoblast-osteoclast communication in normal and pathological bone remodeling.', 'http://www.ncbi.nlm.nih.gov/pubmed/7835281', 'no', 'no', 'NA', 3),
(7850751, 'Antillón-Klüssmann F, García-Delgado M, Villa-Elízaga I, Sierrasesúmaga L', 'Mutational activation of ras genes is absent in pediatric osteosarcoma.', 'Cancer Genet Cytogenet', '1995', 'Mutational activation of ras genes is absent in pediatric osteosarcoma. Activation of ras oncogenes is found in human cancers; overall it is observed in 15% of all neoplasms. The purpose of this study was to assess the extent of involvement of ras oncogenes in osteosarcoma. Tumor samples from a series of 49 pediatric patients diagnosed with osteosarcoma and treated at our institution were evaluated. Paraffin-embedded tumor samples from diagnostic biopsies, from tumor en bloc resection tissue after neoadjuvant chemotherapy, and samples from metastases were examined in search of point mutations in H, K, and N-ras genes at codons 12 and 61 by means of polymerase chain reaction (PCR), slot-blotting, and radioactive labeled specific DNA probes. A total of 92 archival samples were studied. No point mutations activating these genes were found. These findings suggest that the activation by point mutations at codons 12 and 61 of the H, K, and N-ras genes does not play a role in the pathogenesis of human osteosarcoma. Since no point mutations in codons 12 and 61 were detected, it was not possible to establish any correlation between the ras genes and clinical or histologic findings.', 'http://www.ncbi.nlm.nih.gov/pubmed/7850751', 'yes', 'no', 'NA', 3),
(7859736, 'Haas-Kogan DA, Kogan SC, Levi D, Dazin P, T''Ang A, Fung YK, Israel MA', 'Inhibition of apoptosis by the retinoblastoma gene product.', 'EMBO J', '1995', 'Inhibition of apoptosis by the retinoblastoma gene product. Tissue homeostasis and the prevention of neoplasia require regulatory co-ordination between cellular proliferation and apoptosis. Several cellular proteins, including c-myc and E2F, as well as viral proteins such as E1A, have dual functions as positive regulators of apoptosis and proliferation. The product of the retinoblastoma tumor suppressor gene, pRb, binds these proteins and is known to function in growth suppression. To examine whether pRb may function as a negative regulator of both proliferation and apoptosis, we analyzed apoptosis induced in transfected derivatives of the human osteosarcoma cell line SAOS-2. Ionizing radiation induced apoptosis in a time- and dose-dependent manner in SAOS-2 cells, which lack pRb expression. In both a transient and stable transfection assay, SAOS-2 derivatives expressing wild-type (wt) pRb exhibited increased viability and decreased apoptosis following treatment at a variety of radiation doses. Expression in SAOS-2 of a mutant pRb that fails to complex with several known binding partners of pRb, including E1A and E2F, did not protect SAOS-2 cells from apoptosis. Radiation exposure induced a G2 arrest in SAOS-2 and in derivatives expressing pRb. Inhibition of DNA synthesis and cell cycle progression by aphidicolin treatment failed to protect SAOS-2 cells or pRb-expressing isolates from undergoing apoptosis. Our data document a novel function for pRb in suppressing apoptosis and suggest that several proteins shown to induce apoptosis, including E1A, E2F and c-myc, may do so by interfering with the protective function of pRb.', 'http://www.ncbi.nlm.nih.gov/pubmed/7859736', 'no', 'no', 'NA', 2),
(7862451, 'Ferracini R, Di Renzo MF, Scotlandi K, Baldini N, Olivero M, Lollini P, Cremona O, Campanacci M, Comoglio PM', 'The Met/HGF receptor is over-expressed in human osteosarcomas and is activated by either a paracrine or an autocrine circuit.', 'Oncogene', '1995', 'The Met/HGF receptor is over-expressed in human osteosarcomas and is activated by either a paracrine or an autocrine circuit. The c-MET oncogene encodes the receptor for the Hepatocyte Growth Factor/Scatter Factor (HGF), a cytokine that stimulates the invasive growth of normal and neoplastic cells. The Met/HGF receptor is expressed by epithelial cells and its ligand by cells of mesenchymal origin. Receptor-ligand interaction occurs via a paracrine circuit. We studied the expression of the Met/HGF receptor and of its ligand in mesenchymal human tumours by examining 39 clinical samples of bone tumours. The Met/HGF receptor was not detectable in the majority of bone tumours, as expected from their mesenchymal origin. Notably, the receptor was overexpressed in 60% of the osteosarcomas examined. In 12 osteosarcoma cell lines the Met/HGF receptor was overexpressed, phosphorylated by HGF stimulation and fully functional. HGF was detected in two out of seven clinical specimens of osteosarcoma. The ligand and the receptor are co-expressed in two clonal osteosarcoma cell lines. In these lines the Met/HGF receptor was constitutively phosphorylated; phosphorylation was suppressed by suramin treatment, a known blocker of autocrine loops. These data suggest that activation of the Met/HGF receptor by a paracrine or an autocrine mechanism might play a role in the particularly aggressive behaviour of osteosarcomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/7862451', 'yes', 'no', 'NA', 2),
(7904171, 'Stein U, Wunderlich V, Haensch W, Schmidt-Peter P', 'Expression of the mdr1 gene in bone and soft tissue sarcomas of adult patients.', 'Eur J Cancer', '1993', 'Expression of the mdr1 gene in bone and soft tissue sarcomas of adult patients. The expression of the mdr1 gene was evaluated at the RNA level by northern and slot blot analysis, and at the protein level by immunohistochemistry, in a total of 29 bone and 32 soft tissue sarcomas. All patients, mainly adults, had not received previous chemotherapy. Of the tumours investigated, 69% were mdr1-positive. An intermediate mdr1 expression was observed most frequently, with the exception of osteosarcomas (high) and malignant fibrous histiocytomas (low). Detection of P-glycoprotein in selected tumours revealed consistent results. However, no conclusion can be drawn as yet regarding correlation of mdr1 expression and drug resistance in patients.', 'http://www.ncbi.nlm.nih.gov/pubmed/7904171', 'yes', 'no', 'NA', 1),
(7911380, 'Dockhorn-Dworniczak B, Poremba C, Dantcheva R, Stücker A, Brömmelkamp E, Blasius S, Mellin W, Roessner A, Yandell DW, Böcker W', 'Rapid detection of loss of heterozygosity of chromosome 17p by polymerase chain reaction-based variable number of tandem repeat analysis and detection of single-strand conformation polymorphism of intragenic p53 polymorphisms.', 'Virchows Arch', '1994', 'Rapid detection of loss of heterozygosity of chromosome 17p by polymerase chain reaction-based variable number of tandem repeat analysis and detection of single-strand conformation polymorphism of intragenic p53 polymorphisms. Intragenic restriction site polymorphisms in amino acid residue 72 in exon 4 and a Mspl polymorphism in intron 6 of the p53 tumour suppressor gene can both serve as polymorphic markers. Probe YNZ22 (D17S5) is a highly polymorphic, variable number of tandem repeat (VNTR) marker which maps to chromosome 17p13.1 where the p53 gene is located. Locus specific amplification by polymerase chain reaction (PCR) technique and subsequent non-isotopic single-strand conformation polymorphism analysis of the PCR fragments was used for the detection of loss heterozygosity (LOH) of 17p including the p53 gene locus. In combination with a PCR-based method for the analysis of the VNTR locus D17S5 using unique sequences flanking the polymorphic region of YNZ22 we investigated tumour DNA and corresponding constitutional DNA from 69 patients, including 39 patients with gastric cancer, 21 patients with osteosarcomas and 9 patients with Ewing''s sarcomas. Using all three methods, 49/69 (71%) patients were informative for LOH, which revealed allelic loss in 5/39 (12.8%) gastric cancers, 1/9 (11.1%) Ewing''s sarcoma, and 4/20 (20%) osteosarcomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/7911380', 'yes', 'no', 'NA', 1),
(7912235, 'Scotlandi K, Serra M, Manara MC, Lollini PL, Maurici D, Del Bufalo D, Baldini N', 'Pre-treatment of human osteosarcoma cells with N-methylformamide enhances P-glycoprotein expression and resistance to doxorubicin.', 'Int J Cancer', '1994', 'Pre-treatment of human osteosarcoma cells with N-methylformamide enhances P-glycoprotein expression and resistance to doxorubicin. N-methylformamide (NMF), a powerful differentiating agent, has been extensively used in experimental and preclinical cancer chemotherapy studies, alone or in association with conventional anti-cancer drugs. To evaluate the use of this molecule in the treatment of osteosarcoma (OS), we have analyzed the effects of NMF and doxorubicin (DXR) on DXR-sensitive and -resistant human OS cell lines. Our study shows that NMF exerts remarkable effects on cell proliferation and, in Saos-2 and SARG cells, also induces differentiation, as shown by increasing alkaline phosphatase activity. Moreover, NMF increases the cytotoxic activity of DXR when administered after the drug, in both DXR-sensitive and -resistant cells. However, when this agent is given before DXR, it enhances P-glycoprotein expression in U-2 OS cell lines. This over-expression is associated with reduced DXR accumulation within cells and with significant enhancement of resistance to DXR.', 'http://www.ncbi.nlm.nih.gov/pubmed/7912235', 'no', 'no', 'N-methylformamide|doxorubicin', 2),
(7912239, 'Sakayama K, Masuno H, Miyazaki T, Okumura H, Shibata T, Okuda H', 'Existence of lipoprotein lipase in human sarcomas and carcinomas.', 'Jpn J Cancer Res', '1994', 'Existence of lipoprotein lipase in human sarcomas and carcinomas. Aqueous extracts of acetone/ether powders of surgically obtained specimens of human tumors hydrolyzed 3H-labeled triolein in a dose-dependent manner. The lipolytic activity in these extracts was inhibited by anti-lipoprotein lipase (LPL) IgG dose-dependently, 25 micrograms of anti-LPL IgG causing 95% inhibition of the activity. Thus, LPL accounts for most of the lipolytic activity in extracts of acetone/ether powders of the tumors. All sarcomas and carcinomas examined contained LPL activity. Western blotting showed that they gave a band corresponding to that of human adipose tissue LPL (M(r) = 57,000). Immunocytochemical studies showed that LPL was present in cultured human osteosarcoma cells and distributed throughout the cells. We determined the proliferating cell nuclear antigen (PCNA)-labeling index as an indicator of the proliferative activity of tumor cells and measured LPL activity in extracts of tumors in areas corresponding to those used for determining the PCNA-labeling index. In malignant fibrous histiocytomas, the PCNA-labeling index in area a, which corresponds to the subcapsular region, was higher than that in area b, which corresponds to the central region. The LPL activity in area a was 10 times that in area b. In rectal cancer, the index in area c, which corresponds to the subserosal region, was higher than that in area d, which corresponds to the submucosal region. The LPL activity in area c was 1.9 times that in area d. These findings indicate heterogeneity in the distributions of LPL activity within tumors and higher levels of LPL activity in tumors that are proliferating actively.', 'http://www.ncbi.nlm.nih.gov/pubmed/7912239', 'no', 'no', 'NA', 2),
(7926730, 'Iavarone A, Garg P, Lasorella A, Hsu J, Israel MA', 'The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein.', 'Genes Dev', '1994', 'The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Cell growth and differentiation are usually antagonistic. Proteins of the basic helix-loop-helix (bHLH) family bind DNA and play important roles in the differentiation of specific cell types. Id proteins heterodimerize with bHLH transcription factors, blocking their activation of lineage-specific gene expression and thereby inhibiting cellular differentiation. To examine the effect of Id-2 on cell proliferation, we overexpressed Id-2 in the human osteosarcoma cell line U2OS. Id-2 expression in U2OS reduced the serum requirement for growth and stimulated cellular proliferation by shortening the doubling time and increasing the percentage of cells in S phase. We demonstrated that Id-2 expression was able to reverse the inhibition of cellular proliferation and the block in cell cycle progression mediated by the product of the retinoblastoma tumor suppressor gene pRB. This effect was not associated with changes in the state of pRb phosphorylation in transfected cells. In vitro, unphosphorylated pRb from cell lysates specifically bound Id-2 but was not able to bind a mutated form of Id-2 lacking the HLH domain that also did not antagonize the growth arrest by pRb. In vitro-synthesized pRb containing mutations within the E1A/large T-binding pocket did not bind Id-2. However, wild-type pRb was able to bind to a region of Id-2 corresponding to only the HLH domain. In vivo, a physical association between Id-2 and pRb was seen in cross-linked extracts from SAOS-2 cells transfected with Id-2 and pRb. Our data identify a role for Id-2 in the regulation of cellular proliferation and suggest that the interaction between Id-2 and pRB is a molecular pathway over which synchronous changes in growth and differentiation are mediated in vivo.', 'http://www.ncbi.nlm.nih.gov/pubmed/7926730', 'no', 'no', 'NA', 2),
(7983504, 'Bacci G, Ferrari S, Sangiorgi L, Picci P, Casadei R, Orlandi M, Iantorno D, Battistini A, Zanone A', 'Prognostic significance of serum lactate dehydrogenase in patients with osteosarcoma of the extremities.', 'J Chemother', '1994', 'Prognostic significance of serum lactate dehydrogenase in patients with osteosarcoma of the extremities. Six hundred and fifty-six patients with osteosarcoma of the extremities (107 metastatic and 549 with localized disease) were followed from 2.5 to 20 years (average: 10 years) to evaluate whether their pretreatment serum lactate dehydrogenase (LDH) enzyme levels had a clinical value in predicting the course of the disease. The percentage of patients who had an elevated serum LDH at the time of diagnosis was significantly higher in those patients with metastatic disease than those who had localized disease (64% versus 33%, p < 0.0001). For those who presented with localized disease and had an increased serum LDH level, far more ultimately developed a relapse of disease (60% versus 38%, p < 0.0001) than those patients with a normal pre-treatment value. The prognostic significance of the serum LDH was more pronounced for the 247 patients treated with adjuvant chemotherapy (relapse rate of 72% versus 48%; p < 0.0002) than the 271 patients treated with neoadjuvant chemotherapy (relapse rate: 46% versus 28%, p < 0.005). Following treatment, serum LDH levels almost uniformly returned to normal and no correlation between postoperative levels and relapse of disease could be identified. We have demonstrated that in patients with osteosarcoma of the extremities, pretreatment serum LDH levels have a definite prognostic value which should be considered when comparing the results achieved with different therapeutic protocols and in planning new randomized clinical trials.', 'http://www.ncbi.nlm.nih.gov/pubmed/7983504', 'yes', 'yes', 'NA', 1),
(8003023, 'Kumar R, Haugen JD', 'Human and rat osteoblast-like cells express stathmin, a growth-regulatory protein.', 'Biochem Biophys Res Commun', '1994', 'Human and rat osteoblast-like cells express stathmin, a growth-regulatory protein. We used the differential display polymerase chain reaction method of Liang and Pardee (Science (1992) 257:967-971) to identify a growth-regulatory protein, stathmin or oncoprotein 18, in human and rat osteoblast-like cells. When messenger ribonuleic acid from human osteosarcoma (Saos-2) cells treated with 10(-8)M 1,25-dihydroxyvitamin D3 was compared with that of cells treated with vehicle alone by this method, we observed an increase in the intensity of a band that on subsequent DNA sequence analysis was found to encode stathmin. We examined normal human osteoblast-like cells, transformed human osteoblast-like cells (HOBIT), human osteosarcoma cells (Saos-2), and rat osteoblast cell (ROS 17/2.8, ROS 25/1) lines for the presence of the messenger RNA for stathmin. All osteoblast-like cells examined expressed the RNA for this protein. Western analysis of the protein of these cells with a polyclonal antibody directed against stathmin showed the presence of a M(r) 19,000 band. We conclude that human and rat osteoblast-like cells express stathmin and that this protein could play a role in regulation of the growth of these cells in response to various hormonal stimuli.', 'http://www.ncbi.nlm.nih.gov/pubmed/8003023', 'no', 'no', 'NA', 1),
(8032535, 'Kawashima A, Nakanishi I, Tsuchiya H, Roessner A, Obata K, Okada Y', 'Expression of matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) induced by tumour necrosis factor alpha correlates with metastatic ability in a human osteosarcoma cell line.', 'Virchows Arch', '1994', 'Expression of matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) induced by tumour necrosis factor alpha correlates with metastatic ability in a human osteosarcoma cell line. We have examined the correlation between matrix metalloproteinase (MMP) expression and metastatic properties of a low metastatic osteosarcoma cell line, osteosarcoma takase (OST), under stimulation by tumour necrosis factor alpha (TNF alpha). In vivo, OST cells exhibited significantly increased colonization in the lungs of nude mice in a dose-dependent manner when they were treated by TNF alpha prior to injection. In vitro, TNF alpha enhanced tumour cell invasion through the reconstituted basement membrane in a transwell chamber up to 2.5-fold. Gelatin zymography and sandwich enzyme immunoassays demonstrated marked production of MMP-9 [92-kDa gelatinase/type IV collagenase (gelatinase B)] but not MMP-2 [72-kDa gelatinase/type IV collagenase (gelatinase A)], MMP-3 (stromelysin-1) or MMP-7 (matrilysin). Motility of the tumour cells and adhesion to cultured endothelial cells were slightly increased by the TNF alpha treatment up to 1.6-fold and 1.4-fold, respectively, while the growth rate was decreased. These results suggest that upregulation of MMP-9 together with enhanced motility and endothelial adhesion contribute to the increased metastatic ability of OST cells induced by TNF alpha treatment.', 'http://www.ncbi.nlm.nih.gov/pubmed/8032535', 'no', 'no', 'NA', 2),
(8033827, 'Ikegami A, Inoue S, Hosoi T, Kaneki M, Mizuno Y, Akedo Y, Ouchi Y, Orimo H', 'Cell cycle-dependent expression of estrogen receptor and effect of estrogen on proliferation of synchronized human osteoblast-like osteosarcoma cells.', 'Endocrinology', '1994', 'Cell cycle-dependent expression of estrogen receptor and effect of estrogen on proliferation of synchronized human osteoblast-like osteosarcoma cells. Dual fluoroimmunohistochemical staining of estrogen receptor (ER) and bromodeoxyuridine was performed in a human osteoblastic osteosarcoma cell line, HOS TE85 cells. ER immunoreactivity was observed preferentially in the nuclei of the cells that were bromodeoxyuridine positive. ER expression at various phases of the cell cycle was investigated in HOS TE85 cells, which were synchronized at the G1/S phase boundary by intermittent exposure to thymidine and hydroxyurea. ER immunoreactivity became detectable in the S phase, decreased in the G2/M and G1 phases, and then reappeared in the S phase of the next cell cycle. Western blot analysis also showed that ER protein exists in these cells and increases in the S phase. Moreover, Northern blot analysis demonstrated that the expression of ER messenger RNA increases in the early S phase, gradually decreases during the progress of the cell cycle, and increases again in the S phase of the subsequent cell cycle. Interestingly, 17 beta-estradiol (10(-8) M) increased cell number and [3H]thymidine incorporation into DNA in the synchronized HOS TE85 cells, whereas this effect was not observed in the nonsynchronized HOS TE85 cells. The present studies suggest that the cell cycle-dependent regulation may contribute to the heterogeneity of ER expression in osteoblastic cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/8033827', 'no', 'no', 'NA', 1);
INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(8034301, 'Hamelin R, Barichard F, Henry I, Junien C, Thomas G', 'Single base pair germ-line deletion in the p53 gene in a cancer predisposed family.', 'Hum Genet', '1994', 'Single base pair germ-line deletion in the p53 gene in a cancer predisposed family. A family with an aggregation of adrenocortical carcinoma, rhabdomyosarcoma, osteosarcoma, and early onset breast cancer was referred to our laboratory. Because this aggregation was reminiscent of Li-Fraumeni syndrome, germ-line mutation of the p53 tumor suppressor gene was sought in the DNA of two affected members. The highly conserved regions spanning exons 5 to 8 of the p53 gene were screened by a previously validated denaturing gradient gel electrophoresis method. A single base pair deletion at codon 215 was detected in constitutional DNA of the two patients, and in the DNA extracted from an adrenocortical carcinoma tumor specimen of the propositus. This deletion is predicted to lead to the formation of a truncated p53 protein, a relatively rare event in Li-Fraumeni families. The spectrum of tumors observed in this family does not differ markedly from the spectrum observed in families with missense p53 mutations.', 'http://www.ncbi.nlm.nih.gov/pubmed/8034301', 'yes', 'no', 'NA', 1),
(8039112, 'Yoshikawa H, Rettig WJ, Lane JM, Takaoka K, Alderman E, Rup B, Rosen V, Healey JH, Huvos AG, Garin-Chesa P', 'Immunohistochemical detection of bone morphogenetic proteins in bone and soft-tissue sarcomas.', 'Cancer', '1994', 'Immunohistochemical detection of bone morphogenetic proteins in bone and soft-tissue sarcomas. Bone morphogenetic proteins (BMPs) are potent inducers of bone formation. Functional and immunohistochemical studies have identified BMPs in a subset of osteosarcomas. In the present study, the authors extend the analysis of BMP expression to other bone and soft tissue sarcomas.Monoclonal antibody AbH3b2/17 against human BMP-2 and BMP-4 was used in avidin-biotin-immunoperoxidase assays with frozen sections of bone tumors (71 specimens), soft tissue sarcomas (69 specimens), and normal tissues.Among bone tumors, BMP was detected in osteosarcomas (17 of 29 samples), malignant fibrous histiocytomas (MFHs) (6 of 6), and the spindle cell sarcomatous components of spindle cell (dedifferentiated) chondrosarcomas (4 of 4), but not in conventional chondrosarcomas (0 of 10) or Ewing''s sarcomas (0 of 14). Histologic subtypes of osteosarcoma differed for BMP expression, with 8 of 9 fibrohistiocytic, 9 of 13 osteoblastic, and 0 of 5 chondroblastic lesions showing immunostaining. In all BMP-positive bone tumors, immunostaining was localized in the cytoplasm of primitive mesenchymal cells, with little or no staining in tumor matrix and more mature osteoblastic/chondrocytic cells. Among soft tissue sarcomas, MFHs (11 of 12), liposarcomas (5 of 11), leiomyosarcomas (3 of 9), and malignant schwannomas (3 of 8) showed cytoplasmic BMP immunostaining. Synovial sarcomas (0 of 9), rhabdomyosarcomas (0 of 8), and fibrosarcomas (0 of 7) were BMP-negative. All normal human tissues tested, including the tissues of a 16-week-old fetus, lacked BMP immunoreactivity.Bone morphogenetic protein is expressed in a subset of osteosarcomas, a high proportion of MFHs of bone and soft tissue, and in spindle cell chondrosarcomas. In these tumors, BMP is localized predominantly to the cytoplasm of malignant cells with primitive mesenchymal features; no or little BMP is detected in the more differentiated elements of bone and soft tissue sarcomas. Different histologic types of bone and soft tissue sarcomas may mimic discrete stages of mesenchymal differentiation as defined by BMP expression and histologic criteria.', 'http://www.ncbi.nlm.nih.gov/pubmed/8039112', 'yes', 'no', 'NA', 2),
(8050825, 'Kloen P, Jennings CL, Gebhardt MC, Springfield DS, Mankin HJ', 'Expression of transforming growth factor-beta (TGF-beta) receptors, TGF-beta 1 and TGF-beta 2 production and autocrine growth control in osteosarcoma cells.', 'Int J Cancer', '1994', 'Expression of transforming growth factor-beta (TGF-beta) receptors, TGF-beta 1 and TGF-beta 2 production and autocrine growth control in osteosarcoma cells. Transforming growth factor-beta (TGF-beta) is a polypeptide with multiple physiological functions. Isoforms of this growth factor have important roles in control of the cell cycle, in regulation of cell-cell interactions and in growth and development. Malignant transformation has been shown to be associated with increased expression of TGF-beta. Since bone is the largest storage site and producer of TGF-beta, we speculated on the existence of an autocrine mechanism in osteosarcoma, a malignant bone tumor. Expression of TGF-beta cell surface receptors, effects on growth of TGF-beta and TGF-beta antibodies and production of 2 TGF-beta isoforms were studied in a panel of 7 osteosarcoma cell lines. In contrast to most previous reports on the effects of TGF-beta on osteosarcoma cell growth, we found a mitogenic effect of TGF-beta 1 in 4 of 7 osteosarcoma cell lines. Receptor profiles for TGF-beta were aberrant in 5 of the 7 cell lines tested, and production of TGF-beta 1 and TGF-beta 2 varied among cell lines. Addition of anti-TGF-beta antagonized the effects of endogenous TGF-beta. Our results suggest a potential role of TGF-beta in autocrine growth control of osteosarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/8050825', 'no', 'no', 'NA', 2),
(8052269, 'Furlanetto RW, Harwell SE, Frick KK', 'Insulin-like growth factor-I induces cyclin-D1 expression in MG63 human osteosarcoma cells in vitro.', 'Mol Endocrinol', '1994', 'Insulin-like growth factor-I induces cyclin-D1 expression in MG63 human osteosarcoma cells in vitro. The insulin-like growth factors (IGFs) stimulate cell division by modulating events occurring during the prereplicative (G1) phase of the cell cycle, but identification of the critical events has proved difficult. Recent observations suggest that progression through the cell cycle is dependent on the activation of a group of serine-threonine-specific protein kinases whose activities are regulated by accessory proteins, termed cyclins. The identification of cyclin species expressed during G1 has led to the hypothesis that modulation of cyclin expression may be the critical event regulated by growth factors. The present studies were undertaken to determine whether the IGFs regulate the expression of specific G1 cyclins in MG63, a human cell line that is unusually responsive to IGF, and to characterize this effect. We found that in these cells IGF-I stimulates the cyclin-dependent kinases, and that stimulation is associated with an increase in cyclin-D1 mRNA and protein expression. The increase in cyclin-D1 occurs early in G1 and corresponds to the portion of the cell cycle in which IGF acts on these cells. The increase in cyclin-D1 mRNA is due at least in part to an increase in the rate of transcription initiation of the gene. The mRNA levels of cyclin-B1 (a G2 cyclin) and two cyclin-dependent kinases, cdc2 and cdk2, also increased in response to IGF, but at later times. These results are consistent with the hypothesis that IGF modulation of D-type cyclin expression plays a role in the regulation of cell replication.', 'http://www.ncbi.nlm.nih.gov/pubmed/8052269', 'no', 'no', 'NA', 5),
(8058007, 'Russo CL, McIntyre J, Goorin AM, Link MP, Gebhardt MC, Friend SH', 'Secondary breast cancer in patients presenting with osteosarcoma: possible involvement of germline p53 mutations.', 'Med Pediatr Oncol', '1994', 'Secondary breast cancer in patients presenting with osteosarcoma: possible involvement of germline p53 mutations. Second malignancies following treatment for osteosarcoma are unusual. Breast cancer occurring in patients with osteosarcoma has been reported following therapeutic chest irradiation. We now report three cases of breast cancer occurring in young women who were successfully treated for osteosarcoma. These women had not received therapeutic chest irradiation and in two of the three women there was no family history of breast cancer. Peripheral blood was available for study from one case. Of import, this case demonstrated a germline mutation in exon 7 of the tumor suppressor gene, p53. The mutation was detected by constant denaturing gradient gel electrophoresis and confirmed by DNA sequencing. In this particular patient, inactivation of the p53 gene may be involved in the development of both the first and second malignancy.', 'http://www.ncbi.nlm.nih.gov/pubmed/8058007', 'yes', 'no', 'NA', 1),
(8064888, 'Flørenes VA, Maelandsmo GM, Forus A, Andreassen A, Myklebost O, Fodstad O', 'MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status.', 'J Natl Cancer Inst', '1994', 'MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status. Alterations of the TP53 tumor suppressor gene appear to be implicated in the tumorigenesis and progression of several types of human cancer, including different histologic subtypes of sarcomas. The MDM2 (murine double minute-2) gene encodes a nuclear phosphoprotein that may interact with both mutant and wild-type p53 proteins, thereby inhibiting p53-mediated transactivation in a dose-dependent manner. Recently it has been suggested that mdm2 and p53 proteins are components of an autoregulatory loop in which the MDM2 gene is transactivated by p53.Our purpose was to examine the frequency of MDM2 amplifications in larger panels of sarcomas, determine if the mRNA level could be elevated in tumors without concomitant gene amplification, and relate MDM2 findings to the TP53 status of the tumors.Sarcoma tissue of different histologic subtypes was obtained from 68 patients at the time of surgery and from 26 human xenografts in nude mice. In addition, two human sarcoma cell lines (OSA and U2OS) were studied. Genomic DNA from tumor tissue, in vitro cell lines, and peripheral blood cells were isolated by Southern-blot analysis methods to determine MDM2 gene amplification. Tumor DNA was analyzed for possible TP53 gene mutations in exons 5, 7, and 8 by constant denaturing gel electrophoresis. To determine the MDM2 and TP53 mRNA levels, Northern-blot analysis was performed.Amplification of the MDM2 gene was detected in 10 tumors (10.3%). Whereas MDM2 amplification and/or over-expression were found only in two (U2OS and OSA cell lines) of 18 osteosarcomas, one of 20 malignant fibrous histiocytomas (MFHs), and in none of 14 leiomyosarcomas, such alterations were observed in two of two fibrosarcomas, three of six malignant schwannomas, three of 19 liposarcomas, and in the one hemangiopericytoma examined. MDM2 overexpression was found in all nine examined cases with and in three tumors without amplification. TP53 mutations were detected in 12 cases (five osteosarcomas, four MFHs, and three leiomyosarcomas), of which none showed amplification, but one had increased levels of MDM2 mRNA. None of the fibrosarcomas, malignant schwannomas, and liposarcomas examined had mutated TP53. The six sarcomas that showed high TP53 mRNA expression in the absence of gene mutation also had elevated levels of MDM2 mRNA.The present data provide further indications that increased MDM2 expression level, caused by gene amplification or altered regulation of transcription, is involved in tumor progression of some, but not all, sarcoma subtypes.', 'http://www.ncbi.nlm.nih.gov/pubmed/8064888', 'yes', 'no', 'NA', 2),
(8080687, 'Kloen P, Jennings CL, Gebhardt MC, Springfield DS, Mankin HJ', 'Suramin inhibits growth and transforming growth factor-beta 1 (TGF-beta 1) binding in osteosarcoma cell lines.', 'Eur J Cancer', '1994', 'Suramin inhibits growth and transforming growth factor-beta 1 (TGF-beta 1) binding in osteosarcoma cell lines. Autocrine production of growth factors has been shown to be involved in the multistep process of tumorigenesis. The ability of suramin, a polyanionic anti-parasitic drug, to block growth factor-induced cell proliferation makes it a potential antineoplastic drug. We studied the effects of suramin on seven osteosarcoma cell lines. Using clinically achievable concentrations of suramin (50-400 micrograms/ml), we found a time- and dose-dependent inhibition of [3H]thymidine incorporation. We also showed that suramin is able, dose-dependently, to prevent binding of transforming growth factor (TGF)-beta 1 to its receptors. DNA synthesis inhibition by suramin was attenuated by TGF-beta 1 in some cell lines. Two cell lines that were inhibited by TGF-beta 1 were affected similarly by suramin as cell lines that were stimulated by TGF-beta 1. In conclusion, in five out of seven osteosarcoma cell lines, we showed a correlation between inhibition of growth factor-stimulated mitogenesis and binding of TGF-beta 1 to its receptor. Similar effects in TGF-beta 1-inhibited osteosarcoma cell lines suggest involvement of other mechanisms and/or growth factors. However, suramin proves to be a potent inhibitor of osteosarcoma cell proliferation in vitro.', 'http://www.ncbi.nlm.nih.gov/pubmed/8080687', 'no', 'no', 'suramin', 1),
(8099316, 'van den Berg S, Rahmsdorf HJ, Herrlich P, Kaina B', 'Overexpression of c-fos increases recombination frequency in human osteosarcoma cells.', 'Carcinogenesis', '1993', 'Overexpression of c-fos increases recombination frequency in human osteosarcoma cells. We have shown previously that overexpression of c-Ha-ras, v-mos or c-fos increases the spontaneous level of chromosomal aberrations and gene mutations in NIH 3T3 cells, and that reduction of the Fos protein level inhibits aberration induction by c-Ha-ras and v-mos and also by irradiation with ultraviolet light (van den Berg et al., Mol. Carcinogenesis, 4, 460-466). In order to examine whether fos is also involved in DNA recombination, thymidine kinase (tk) deficient human osteosarcoma cells containing two versions of the herpes simplex virus tk gene inactivated by base insertion were either transiently or stably transfected with various fos expression plasmids. The frequency of tk+ revertants was significantly enhanced both upon transient transfection with RSV-promoter-fos gene constructs and by stimulation of Fos synthesis in stably transfected cells harbouring an inducible metallothionein promoter-fos construct. No such increases were observed in cells transfected with plasmids containing a truncated version of c-fos. The data indicate that c-fos is involved in generating various types of genetic changes including homologous recombination; a role of c-fos in genetic instability may contribute to its action in tumor promotion and progression.', 'http://www.ncbi.nlm.nih.gov/pubmed/8099316', 'no', 'no', 'NA', 1),
(8117620, 'Forus A, Flørenes VA, Maelandsmo GM, Meltzer PS, Fodstad O, Myklebost O', 'Mapping of amplification units in the q13-14 region of chromosome 12 in human sarcomas: some amplica do not include MDM2.', 'Cell Growth Differ', '1993', 'Mapping of amplification units in the q13-14 region of chromosome 12 in human sarcomas: some amplica do not include MDM2. Amplification of cellular oncogenes may be important for the development and progression of malignant tumors. In human sarcomas, amplification of several genes located to the q13-14 region of chromosome 12 has been reported. Because the mdm2 protein seems to inactivate the tumor suppressor protein p53, a selective growth advantage of 12q13-14 amplification has previously been assigned to increased copy number and expression of the MDM2 gene. We have analyzed a panel of 98 human sarcomas of different subtypes to characterize the 12q13-14 amplica and determine which of the genes GLI, A2MR, SAS, MDM2, and GADD153 (CHOP) in this region was most consistently amplified. MDM2 was amplified in 9 of the tumors, SAS in 10, GADD153 in 4, GLI in 2, and A2MR in 2. Amplification was, in most cases, associated with increased expression of the corresponding gene. SAS and MDM2 were coamplified in 8 of the tumors, whereas GADD153, GLI, and A2MR were only amplified together with SAS. One liposarcoma showed amplification of MDM2 alone, whereas two osteosarcomas and a rhabdomyosarcoma cell line showed amplification of SAS and GADD153 (CHOP) but not MDM2. It is suggested that the selective target for these amplica may be an as yet unidentified gene localized between SAS and MDM2.', 'http://www.ncbi.nlm.nih.gov/pubmed/8117620', 'yes', 'no', 'NA', 5),
(8123038, 'Boscoboinik D, Galeotti T, Azzi A', 'Vinblastine-dependent down-modulation of TNF receptors in human osteosarcoma cells is mediated by protein kinase C activity.', 'Biochem Biophys Res Commun', '1994', 'Vinblastine-dependent down-modulation of TNF receptors in human osteosarcoma cells is mediated by protein kinase C activity. The binding of tumor necrosis factor (TNF) to a human osteogenic sarcoma cell line (Saos-2) was investigated. These cells express two types of receptors as determined by specific monoclonal antibodies. Vinblastine induced a down-modulation of these receptors weaker than the one produced by phorbol esters or okadaic acid treatment. On exposure of cells to 10 microM vinblastine for two hours an approximately 55-65% diminution of TNF binding was observed, but only 20% reduction occurred under long-term vinblastine treatment. TNF receptor down-modulation induced by vinblastine was partially prevented by protein kinase C inhibitors or protein kinase C depletion. It is suggested that the regulation of TNF binding to each one of its receptors in Saos-2 cells always occurs in a phosphorylation-dependent manner.', 'http://www.ncbi.nlm.nih.gov/pubmed/8123038', 'no', 'no', 'vinblastine', 2),
(8159609, 'Stracca-Pansa V, Dickman PS, Zamboni G, Bevilacqua PA, Ninfo V', 'Extracellular matrix of small round cell tumors of childhood: an immunohistochemical study of 67 cases.', 'Pediatr Pathol', 'NA', 'Extracellular matrix of small round cell tumors of childhood: an immunohistochemical study of 67 cases. Sixty-seven childhood tumors were studied immunohistochemically for the extracellular matrix element type IV collagen, laminin, and fibronectin. Tumors included Ewing''s sarcoma, primitive neuroectodermal tumor, small cell osteosarcoma, neuroblastoma or ganglioneuroblastoma, rhabdomyosarcoma, and lymphoma. It was found that small cell osteosarcoma was often positive for fibronectin but not type IV collagen or laminin, a new observation. In the lymphomas, matrix proteins were rarely found. Ewing''s sarcoma was variably positive for type IV collagen and laminin, but fibronectin was absent. Extracellular laminin and fibronectin were found in one of two cases of primitive neuroectodermal tumor. In neuroblastoma and ganglioneuroblastoma, the matrix components were rarely found. These results, discrepant with findings in cultured cells, may reflect the altered capacity of tumors to produce these proteins in vitro, which suggests that caution should be exercised in drawing conclusions regarding the nature or histogenesis of tumors from data obtained with cultured tumor cells. Embryonal rhabdomyosarcoma frequently contained all matrix elements in the extracellular space and in a dotlike pattern in the cytoplasm; alveolar rhabdomyosarcoma rarely contained these proteins and never exhibited the dotlike pattern. The frequent finding of matrix proteins in embryonal rhabdomyosarcoma but only rarely in alveolar rhabdomyosarcoma and the unique immunostaining pattern in embryonal rhabdomyosarcoma may prove to be a useful adjunct in the diagnosis of childhood tumors.', 'http://www.ncbi.nlm.nih.gov/pubmed/8159609', 'yes', 'yes', 'NA', 1),
(8164043, 'McIntyre JF, Smith-Sorensen B, Friend SH, Kassell J, Borresen AL, Yan YX, Russo C, Sato J, Barbier N, Miser J', 'Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma.', 'J Clin Oncol', '1994', 'Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. We investigated the possibility that a significant proportion of children with osteosarcoma harbor germline mutations of the p53 tumor suppressor gene and, therefore, this subgroup of pediatric cancer patients should be considered for large-scale predictive testing.Genomic DNA extracted from peripheral-blood leukocytes from 235 unselected children with osteosarcoma from 33 institutions were screened for the presence of germline p53 mutations using constant denaturant gel electrophoresis (CDGE). Exons 5 through 8 were evaluated in all patients and exon 2 and exon 9 were analyzed in 59 and 95 patients, respectively. Those samples that showed aberrant migration on CDGE were sequenced or analyzed by restriction enzyme digestion of polymerase chain reaction (PCR) products to confirm the nature of the gene alteration.In 18 samples, CDGE showed fragments of the p53 gene with altered electrophoretic mobilities compared with wild-type p53. DNA sequencing showed that 11 samples had an identical, previously described polymorphism. The other seven contained heterozygous p53 mutations located in exon 5 (n = 3), exon 6 (n = 1), exon 7 (n = 1), and exon 8 (n = 2). Six alterations were missense mutations and one was a nonsense mutation. Three of these patients had first-degree relatives with cancer. One of these three kindreds had a family history consistent with Li-Fraumeni syndrome (LFS).We identified germline p53 mutations in seven of 235 (3.0%) children with osteosarcoma. Four of these mutations were found in patients who did not have first-degree relatives with cancer. Although genetic transmission of the altered p53 gene could not be tested in this survey because of how it was designed, it is possible that predictive testing for p53 mutations could identify unaffected relatives of gene carriers who also have a high risk for the development of cancer. This study provides evidence for the importance of considering children with osteosarcoma for predictive testing for germline p53 mutations.', 'http://www.ncbi.nlm.nih.gov/pubmed/8164043', 'yes', 'no', 'NA', 1),
(8166715, 'Kamihagi K, Katayama M, Ouchi R, Kato I', 'Osteonectin/SPARC regulates cellular secretion rates of fibronectin and laminin extracellular matrix proteins.', 'Biochem Biophys Res Commun', '1994', 'Osteonectin/SPARC regulates cellular secretion rates of fibronectin and laminin extracellular matrix proteins. Osteonectin (OTN) has been implicated in controlling cell adhesivity onto substratum and extracellular matrix (ECM) remodeling. Significant amounts of OTN were synthesized not only by normal fibroblasts and endothelial cells, but also by HT-1080 fibrosarcoma and MG-63 osteosarcoma cells. Levels of secreted OTN were likely to be slightly elevated by the addition of exogenous placental laminin (LN), but not by supplementation of plasma fibronectin (FN). Exogenously supplemented purified bone OTN was not apparently incorporated into the ECM of the adhering cells and had no effect on cell spreading and growth, whereas secretion of type I collagen or FN in the tumor cells was moderately diminished in the presence of soluble OTN. Concentration-dependent down-regulation of cellular LN secretion appeared to be most significant, suggesting that OTN participates in regulating extracellular secretion of ECM components in the cells either with or without the ability to synthesize cellular OTN.', 'http://www.ncbi.nlm.nih.gov/pubmed/8166715', 'no', 'no', 'NA', 2),
(8168113, 'Kappel CC, Velez-Yanguas MC, Hirschfeld S, Helman LJ', 'Human osteosarcoma cell lines are dependent on insulin-like growth factor I for in vitro growth.', 'Cancer Res', '1994', 'Human osteosarcoma cell lines are dependent on insulin-like growth factor I for in vitro growth. Osteogenic sarcoma is the most common bone tumor of childhood and typically occurs during the adolescent growth spurt when growth hormone and insulin-like growth factor I (IGF-I) may be at their lifetime highest levels. Since IGF-I is involved in normal bone growth and differentiation, we have evaluated the possible role of IGF-I signaling in the growth of human osteogenic sarcoma cell lines. In this study, we demonstrate that in vitro survival of cells is dependent on exogenously supplied IGF-I. Furthermore, we show that these cells display functional IGF-I receptors on their surface and that in vitro growth is inhibited by blocking these receptors either by monoclonal antibodies or by antisense oligonucleotides. These data demonstrate that human osteogenic sarcoma cell lines are dependent on signaling through the IGF-I receptor for in vitro survival and proliferation. Furthermore, they suggest that modulation of the growth hormone/IGF-I axis may affect the growth of these tumors in vivo.', 'http://www.ncbi.nlm.nih.gov/pubmed/8168113', 'no', 'no', 'NA', 2),
(8187094, 'Wadayama B, Toguchida J, Shimizu T, Ishizaki K, Sasaki MS, Kotoura Y, Yamamuro T', 'Mutation spectrum of the retinoblastoma gene in osteosarcomas.', 'Cancer Res', '1994', 'Mutation spectrum of the retinoblastoma gene in osteosarcomas. We have performed an intensive mutation survey of the Rb gene in 63 osteosarcomas. Loss of heterozygosity (LOH) at the Rb locus was analyzed by using polymerase chain reaction at four intronic polymorphic sites, and 62.9% (39 of 62) of tumors showed LOH. Mutation analysis of the Rb gene was performed by Southern blot for structural anomalies, polymerase chain reaction-single strand conformation polymorphism analysis followed by direct genomic sequencing for subtle mutations, and immunohistochemistry for protein expression. The frequencies of each type of abnormalities were: structural anomalies, 28.6% (18 of 63); subtle mutations, 6.0% (3 of 50); negative protein expression, 53.6% (30 of 56); 54.5% (18 of 33) of tumors with LOH at the Rb locus were proved to show negative Rb expression, while 50.0% (11 of 22) of tumors without LOH also showed negative Rb, indicating that LOH at the Rb locus in osteosarcoma will not necessarily correlate with the actual inactivation of the Rb gene at the protein level. Findings in primary tumors were correlated with clinical outcome, and the presence of LOH and DNA alterations of the Rb gene were proved to indicate poor prognosis.', 'http://www.ncbi.nlm.nih.gov/pubmed/8187094', 'yes', 'yes', 'NA', 1),
(8208533, 'Radinsky R, Fidler IJ, Price JE, Esumi N, Tsan R, Petty CM, Bucana CD, Bar-Eli M', 'Terminal differentiation and apoptosis in experimental lung metastases of human osteogenic sarcoma cells by wild type p53.', 'Oncogene', '1994', 'Terminal differentiation and apoptosis in experimental lung metastases of human osteogenic sarcoma cells by wild type p53. Human SAOS-2 osteogenic sarcoma cells are not metastatic in nude mice and do not express p53. We have selected a variant line (SAOS-LM2) that is tumorigenic and metastatic in nude mice. These cells were transfected with the p53 wild-type (p53wt) or mutated (p53mut 143A) gene, whose expression was verified by reverse transcriptase PCR, cDNA sequencing, and protein immunoprecipitation. Cells were injected i.v. into nude mice, and 4 months later, the mice were necropsied. All cell lines produced a similar number of visible lung metastases, albeit of different sizes. Microscopic examination revealed that most lung metastases in mice injected with p53wt cells (but not p53mut 143A or control cells) consisted of osteoid matrix and apoptotic cells. Expression of either p53wt or p53mut 143A verified the origin of the metastases. These data suggest that transfection of SAOS-LM2 cells with p53wt is associated with in vivo induction of terminal differentiation and apoptosis that inhibit progressive growth of metastases.', 'http://www.ncbi.nlm.nih.gov/pubmed/8208533', 'no', 'no', 'NA', 1),
(8217129, 'Issing WJ, Wustrow TP, Oeckler R, Mezger J, Nerlich A', 'An association of the RB gene with osteosarcoma: molecular genetic evaluation of a case of hereditary retinoblastoma.', 'Eur Arch Otorhinolaryngol', '1993', 'An association of the RB gene with osteosarcoma: molecular genetic evaluation of a case of hereditary retinoblastoma. A 24-year-old male patient with hereditary retinoblastoma and a poorly differentiated osteoblastic osteogenic sarcoma was found to carry a mutant RB1 allele in all cells. This findings was most likely a point mutation or microdeletion because Southern blot analysis of peripheral blood DNA failed to disclose any structural aberration of the RB1 gene. A somatic mutation (deletion) affecting the other allele was found in the osteosarcoma cells. Management of tumor by external radiotherapy in early age is questioned because the effect of irradiation is to significantly increase the total incidence of second tumors above the already high incidence in non-irradiated patients.', 'http://www.ncbi.nlm.nih.gov/pubmed/8217129', 'yes', 'no', 'NA', 1),
(8226793, 'Albers MW, Williams RT, Brown EJ, Tanaka A, Hall FL, Schreiber SL', 'FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line.', 'J Biol Chem', '1993', 'FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line. Upon entering a cell the natural product rapamycin, like the structurally related immunosuppressant FK506, associates with members of the FKBP family of proteins. One or more of the resulting FKBP-rapamycin complexes blocks signaling pathways emanating from some growth factor receptors. Recently, the addition of rapamycin was shown to inhibit the phosphorylation and activation of a 70-kDa ribosomal S6 protein kinase, which normally occurs minutes after the activation of certain cytokine and growth factor receptors. We now report that rapamycin can be added 4 to 6 h after the addition of serum growth factors to quiescent human osteosarcoma cells and still arrest these cells in G1. This window of action correlates with the inducible appearance of a cyclin-dependent kinase (cdk) activity, and the induction of this activity is inhibited by the addition of rapamycin. Furthermore, p36cyclin D1 associates with this cdk protein complex in lysates of untreated cells, but does not associate with this cdk protein complex in lysates of rapamycin-treated cells. Together, these studies demonstrate that FKBP-rapamycin can modulate a cyclin-dependent kinase activity and a cyclin D1-cdk association during early G1 in MG-63 human osteosarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/8226793', 'no', 'no', 'rapamycin', 2),
(8260365, 'Wadayama B, Toguchida J, Yamaguchi T, Sasaki MS, Yamamuro T', 'p53 expression and its relationship to DNA alterations in bone and soft tissue sarcomas.', 'Br J Cancer', '1993', 'p53 expression and its relationship to DNA alterations in bone and soft tissue sarcomas. The p53 gene is one of the best studied tumour suppressor genes. Recently we performed mutation analysis on the p53 gene in a large number of bone and soft tissue sarcomas, and found that approximately one-third of the sarcomas have some type of DNA alteration at the p53 locus (Toguchida et al., 1992). However, the expression of the p53 protein resulting from these alterations still remains to be clarified. In this study, p53 expression in the sarcoma tissues was analysed immunohistochemically using antibody PAb421 (Oncogene Science) and its relationship to DNA alterations was examined. Of 113 tumours, 29 (25.7%) showed positive staining for the p53 protein. These included 19 of 67 osteosarcomas, five of 20 chondrosarcomas, four of 11 malignant fibrous histiocytomas (MFHs) and one Ewing''s sarcoma. In chondrosarcomas, most of the p53-positive tumours belonged to highly malignant and atypical tumour types (dedifferentiated or mesenchymal type), suggesting a role for p53 mutation in the progression of cartilaginous tumours. All the cases with a missense mutation showed strongly positive staining, while no immunoreactivity was observed in the remaining three-quarters with DNA alterations including gross rearrangement, frame-shift mutation, nonsense mutation or mutation at splicing site except in one case. These results demonstrated the dominance of the p53 mutations with null protein expression in bone and soft tissue sarcomas, showing a unique characteristic of these types of tumours compared with other malignancies such as colon carcinomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/8260365', 'yes', 'no', 'NA', 1),
(8276785, 'Marmiroli S, Ognibene A, Bavelloni A, Cinti C, Cocco L, Maraldi NM', 'Interleukin 1 alpha stimulates nuclear phospholipase C in human osteosarcoma SaOS-2 cells.', 'J Biol Chem', '1994', 'Interleukin 1 alpha stimulates nuclear phospholipase C in human osteosarcoma SaOS-2 cells. Interleukin 1 (IL-1) is one of the most potent stimulators of bone resorption. However, the early biochemical events elicited by IL-1 receptor binding are not fully understood. Here we show that in human osteosarcoma SaOS-2 cells the treatment with IL-1 alpha is able to evoke a rapid and transient increase of nuclear phospholipase C (PLC) activity. A parallel decrease of nuclear phosphatidylinositol monophosphate and phosphatidylinositol bisphosphate is observed. All these events are strictly confined to the nuclear compartment without affecting the cytoplasmatic inositol lipid pool. In addition we show that by Western blot analysis with specific monoclonal antibodies the PLC gamma is located both in the cytoplasm and in the nucleus, while PLC beta appears exclusively localized in the nucleus. Moreover, the increase of PLC activity in response to IL-1 alpha is completely neutralized by monoclonal antibody against the beta-form. While confirming the existence of an autonomous nuclear phosphoinositide signaling system, our data clearly indicate that in SaOS-2 cells one of the earliest events following IL-1 alpha treatment is the breakdown of nuclear phosphatidylinositol monophosphate and phosphatidylinositol bisphosphate because of the activation of a specific nuclear PLC isoform.', 'http://www.ncbi.nlm.nih.gov/pubmed/8276785', 'no', 'no', 'NA', 3),
(8281940, 'Pirskanen A, Jääskeläinen T, Mäenpää PH', 'Insulin-like growth factor-1 modulates steroid hormone effects on osteocalcin synthesis in human MG-63 osteosarcoma cells.', 'Eur J Biochem', '1993', 'Insulin-like growth factor-1 modulates steroid hormone effects on osteocalcin synthesis in human MG-63 osteosarcoma cells. The 1,25-dihydroxyvitamin-D3-(calcitriol)-induced medium osteocalcin and cellular osteocalcin mRNA concentrations are increased in a dose-dependent and time-dependent manner by prior treatment of the human MG-63 osteosarcoma cells with insulin-like growth factor-I (IGF-I). In addition, IGF-I reverses the inhibitory effects of dexamethasone and enhances the effects of retinoic acid on osteocalcin synthesis. The stimulatory effect of IGF-I on osteocalcin synthesis is accompanied by stabilization of osteocalcin mRNA and a decrease of AP-1 binding to the osteocalcin promoter. The binding of the vitamin-D receptor (VDR) to its cognate response element is not affected by IGF-I. In contrast to its effects on osteocalcin synthesis, both baseline and calcitriol-stimulated alkaline phosphatase activities are decreased by IGF-I treatment. Furthermore, IGF-I has mitogenic effects on MG-63 cells. The proliferation of the cells and the levels of c-jun mRNA are greatly increased during IGF-I treatment. Calcitriol reduces or eliminates both these effects. The low concentrations of IGF-I used in this study suggest that IGF-I is an important normal regulator of the synthesis of osteocalcin, a bone calcium-binding protein participating in bone mineralization, by modulating the effects of steroid hormones on its synthesis.', 'http://www.ncbi.nlm.nih.gov/pubmed/8281940', 'no', 'no', 'dexamethasone|calcitrol', 4),
(8287230, 'Ladanyi M, Park CK, Lewis R, Jhanwar SC, Healey JH, Huvos AG', 'Sporadic amplification of the MYC gene in human osteosarcomas.', 'Diagn Mol Pathol', '1993', 'Sporadic amplification of the MYC gene in human osteosarcomas. The MYC proto-oncogene has been shown to be overexpressed in several types of sarcomas, including some osteosarcomas. In most cases, the overexpression is due to gene amplification. The total number of osteosarcoma patients studied, however, remains too small to derive any conclusions regarding the true prevalence and the possible clinical significance of MYC gene amplification. To address the issue more thoroughly, we studied 27 specimens from 25 patients with high-grade osteosarcoma (16 primary, 11 metastatic; 11 adult, 14 pediatric) for MYC gene alterations by Southern blot analysis. Two of 27 specimens (7%) showed MYC gene amplification: a primary fibrohistiocytic osteosarcoma of the femur in a 37-year-old man showed threefold amplification, and a primary Paget''s osteosarcoma of the tibia in a 60-year-old man showed fourfold amplification. None of the specimens tested showed MYC gene rearrangement (zero of 27) or activating point mutations at the PvuII site in MYC exon-1 (zero of 26). Hence, the MYC gene is amplified in a subset of osteosarcomas. The possible clinical or biological significance of MYC gene amplification in osteosarcoma may warrant further investigation.', 'http://www.ncbi.nlm.nih.gov/pubmed/8287230', 'yes', 'no', 'NA', 1),
(8288590, 'Santala P, Larjava H, Nissinen L, Riikonen T, Määttä A, Heino J', 'Suppressed collagen gene expression and induction of alpha 2 beta 1 integrin-type collagen receptor in tumorigenic derivatives of human osteogenic sarcoma (HOS) cell line.', 'J Biol Chem', '1994', 'Suppressed collagen gene expression and induction of alpha 2 beta 1 integrin-type collagen receptor in tumorigenic derivatives of human osteogenic sarcoma (HOS) cell line. Cell-matrix interactions and intergrin-type cell adhesion receptors are involved in the regulation of tumor cell invasion and metastasis. We have analyzed the expression of matrix proteins and their cellular receptors in human osteosarcoma cells (HOS) and in their virally (KHOS-NP) and chemically (HOS-MNNG) transformed tumorigenic subclones. Transformation decreased dramatically the cellular mRNA levels of alpha 1(I) collagen. Concomitantly with down-regulation of collagen mRNA levels the synthesis of the collagen receptor, alpha 2 beta 1 integrin, was induced. No alpha 2 integrin mRNA was found in HOS cells, suggesting that its expression was regulated most probably at the transcriptional level. 5-Azacytidine alone or combined with alpha 2 integrin-stimulating cytokines, transforming growth factor-beta 1, and interleukin-1 beta, did not turn on the alpha 2 integrin gene. In chemically transformed cells, however, alpha 2 integrin expression could be regulated by cytokines. Thus, we suggest that HOS cells have a strong element, probably other than cell culture-generated de novo promoter methylation, suppressing alpha 2 integrin expression and that this factor is lost in both chemical and viral transformation. Furthermore, the mechanism used by cytokines and malignant transformation to increase alpha 2 integrin expression seems not to be identical. Other transformation-related changes in beta 1 integrins were (i) reduction of the intracellular pool of precursor beta 1 (in HOS-MNNG cells), leading to faster maturation rate of beta 1 subunit and slower maturation rate of alpha subunits, and (ii) decreased electrophoretic mobility of both alpha and beta 1 subunits. At the cellular level both chemical and viral transformation increased cell adhesion to type I collagen.', 'http://www.ncbi.nlm.nih.gov/pubmed/8288590', 'no', 'no', 'NA', 3),
(8374897, 'Ozisik YY, Meloni AM, Zalupski MM, Ryan JR, Qureshi F, Sandberg AA', 'Deletion of chromosome 13 in osteosarcoma secondary to irradiation.', 'Cancer Genet Cytogenet', '1993', 'Deletion of chromosome 13 in osteosarcoma secondary to irradiation. The cytogenetic analysis of a radiation-induced osteosarcoma in a 31-year-old male is presented. Complex karyotypic changes with numerical and structural abnormalities, including a del(13)(q12.3q21.1), were observed. This deletion may indicate that loss of RB1 gene (locus in 13q14) may be involved in the development of radiation-induced osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/8374897', 'yes', 'no', 'NA', 1),
(8391387, 'Karikó K, Kuo A, Boyd D, Okada SS, Cines DB, Barnathan ES', 'Overexpression of urokinase receptor increases matrix invasion without altering cell migration in a human osteosarcoma cell line.', 'Cancer Res', '1993', 'Overexpression of urokinase receptor increases matrix invasion without altering cell migration in a human osteosarcoma cell line. Proteolysis triggered by receptor-bound urokinase-type plasminogen activator (uPA) involves a cascade of species-specific molecular interactions. To study the role of the uPA receptor (uPAR) in such interactions, a human osteosarcoma cell line (HOS), which normally expresses low levels of uPAR, was transfected with human uPAR complementary DNA. One of several stably transformed clonal cells lines, designated 2A2, was characterized and compared to the parental HOS, revealing the following: (a) stable incorporation of uPAR complementary DNA into the genome demonstrated by Southern blot analysis; (b) a 10-fold increase in steady state mRNA levels of uPAR assessed by Northern blot analysis; (c) a 2-fold increase in the surface expression of glycosylphosphatidylinositol anchored uPAR protein determined by enzyme-linked immunosorbent assay and by the specific binding of radiolabeled single chain uPA; (d) a 2-fold increase in internalization and degradation of radiolabeled uPA/PAI-1 complexes; and (e) a 2-fold increase in receptor-bound uPA-mediated plasmin generation measured by the cleavage of a chromogenic substrate and degradation of 125I-labeled laminin. The involvement of uPAR in cellular processes was determined by comparing 2A2 and HOS cells in in vitro migration and invasion assays. The migration of 2A2 cells were slower on fibronectin-coated surfaces in a linear under-agarose assay, but both cell lines migrated at the same rate on uncoated polycarbonate filters in Boyden chamber assays. In the invasion experiments, 4 times more 2A2 than HOS cells penetrated through the barrier of reconstituted basement membrane Matrigel. These data suggest that uPAR does not potentiate random cell migration but facilitates matrix degradation and subsequent cell invasion.', 'http://www.ncbi.nlm.nih.gov/pubmed/8391387', 'no', 'no', 'NA', 2),
(8401536, 'Smith-Sørensen B, Gebhardt MC, Kloen P, McIntyre J, Aguilar F, Cerutti P, Børresen AL', 'Screening for TP53 mutations in osteosarcomas using constant denaturant gel electrophoresis (CDGE).', 'Hum Mutat', '1993', 'Screening for TP53 mutations in osteosarcomas using constant denaturant gel electrophoresis (CDGE). We have previously developed conditions to screen for TP53 point mutations inside the conserved domains II-V of the gene by using constant denaturant gel electrophoresis (CDGE). The present study reports conditions for screening more of the codons in the frequently mutated region exon 5-8 and for detecting mutations in sequences encoding functional domains in the N- and C-terminal part of the protein. The ability of the CDGE technique to detect mutations was studied using controls with known sequence deviations. The resolution power of the technique to separate different types of mutations was tested by using seven different single base pair mutants all residing in a stretch of four base pairs. All mutants were separated from the wild type. The established CDGE screening strategy was then used to look for mutations in DNA from 28 osteosarcomas. Six (21.5%) of the samples were shown to have a TP53 mutation, and the exact characterization was performed by direct sequencing. All of these were within the frequently reported mutated region exon 5-8.', 'http://www.ncbi.nlm.nih.gov/pubmed/8401536', 'yes', 'no', 'NA', 1),
(8402575, 'Perego P, Casati G, Gambetta RA, Soranzo C, Zunino F', 'Effect of modulation of protein kinase C activity on cisplatin cytotoxicity in cisplatin-resistant and cisplatin-sensitive human osteosarcoma cells.', 'Cancer Lett', '1993', 'Effect of modulation of protein kinase C activity on cisplatin cytotoxicity in cisplatin-resistant and cisplatin-sensitive human osteosarcoma cells. The effect of modulation of protein kinase C (PKC) activity by 12-O-tetradecanoylphorbol-13-acetate (TPA) on cisplatin cytotoxicity was examined in a human osteosarcoma U2-OS cell line and in a U2-OS variant (U2-OS/Pt) selected after continuous exposure to increasing concentrations of cisplatin. U2-OS/Pt cells showed a 7.5-fold resistance to the drug. A 24 h exposure of cells to TPA caused a potentiation of cisplatin cytotoxicity in sensitive and in resistant cells; under these conditions, PKC activity was shown to be down-regulated. In contrast, a short-term exposure of cells to TPA did not affect cisplatin cytotoxicity in U2-OS or in U2-OS/Pt cells. These results support the involvement of PKC in cellular response to cisplatin. However, this enzyme is probably not directly implicated in the mechanisms of acquired resistance in this cell system.', 'http://www.ncbi.nlm.nih.gov/pubmed/8402575', 'no', 'no', '12-O-tetradecanoylphorbol-13-acetate|cisplatin', 1),
(8416741, 'Ladanyi M, Cha C, Lewis R, Jhanwar SC, Huvos AG, Healey JH', 'MDM2 gene amplification in metastatic osteosarcoma.', 'Cancer Res', '1993', 'MDM2 gene amplification in metastatic osteosarcoma. The human homologue of the murine double minute 2 gene (MDM2), a p53-binding protein which may act as a regulator of p53 protein function, has recently been cloned. Initial studies of this gene in a variety of human tumors have shown frequent gene amplification in most types of sarcomas, including osteosarcomas. Amplification of the MDM2 gene may produce a functional inactivation of the p53 protein. To examine possible clinical or pathological correlates of MDM2 gene amplification in osteosarcoma, we studied 28 specimens on 26 patients with high grade osteosarcoma (16 primary, 11 metastatic, and 1 local recurrence) for MDM2 gene amplification by Southern blot analysis, using two MDM2 complementary DNA probes isolated by polymerase chain reaction. Four specimens (14%) showed amplification, including 3 metastases and 1 local recurrence. None of the primary osteosarcoma specimens had detectable MDM2 gene amplification. None of the specimens tested showed MDM2 gene rearrangement. In the present series, MDM2 gene amplification was detected significantly more frequently in metastatic or recurrent osteosarcomas than it was in primary osteosarcomas (P = 0.02). Our data suggest that MDM2 gene amplification may be associated with tumor progression and metastasis in osteosarcoma. Further investigation is warranted on the potential clinicopathological correlates of MDM2 gene amplification in osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/8416741', 'yes', 'yes', 'NA', 1),
(8418091, 'Ueda Y, Dockhorn-Dworniczak B, Blasius S, Mellin W, Wuisman P, Böcker W, Roessner A', 'Analysis of mutant P53 protein in osteosarcomas and other malignant and benign lesions of bone.', 'J Cancer Res Clin Oncol', '1993', 'Analysis of mutant P53 protein in osteosarcomas and other malignant and benign lesions of bone. Alterations of tumour suppressor genes are considered crucial steps in the development of human cancers. Expressions of p53 protein, a product of the tumour suppressor gene altered most commonly in human cancers examined so far, were investigated immunohistochemically in 18 osteosarcomas and 40 other malignant and benign lesions of bone. A monoclonal antibody clone PAb240, which recognizes a common conformational epitope of mutant p53 proteins, stained nuclei of tumour cells in 12 of 18 osteosarcomas (67%). Six tumours (33%) particularly showed positive immunoreactions in more than half of the tumour cells. PAb240 also stained tumour cells in a small number of other malignant bone tumours, such as malignant fibrous histiocytoma, chondrosarcoma, and Ewing''s sarcomas. Furthermore, a small number of cells of giant-cell tumours were positively stained. In contrast, PAb240 was completely negative in 21 benign bone tumours and reactive lesions examined. Another monoclonal antibody clone PAb1801, which reacts with both wild- and mutant-type p53 protein, reacted in nuclei of tumour cells of 7 osteosarcomas (39%). Most of those also reacted with PAb240. PAb1801 was expressed much more frequently in other malignant bone tumours and giant-cell tumours. In addition, PAb1801 showed intranuclear positive reactions in tumour cells of a benign chondroblastoma, and reactive cells such as actively proliferating preosteoblasts in a myositis ossificans and osteoclast-like giant cells in a giant-cell tumour. The immunoelectron-microscopic observation that p53 protein was localized in euchromatic areas of nuclei of osteosarcoma cells supported the specificity of immunoreaction for p53 protein, indicating an active role of p53 protein in the regulation of DNA synthesis and transcription. These findings suggest that point mutation of the p53 gene is frequently involved in the development of osteosarcomas. PAb240 may be a useful tool not only in screening point mutations of the p53 gene in osteosarcomas but also in the differential diagnosis between osteosarcomas and reactive bone-forming lesions. Expressions of mutant p53 protein were not correlated with any clinical or pathological factors examined, although the results should be confirmed in studies of a large number of osteosarcomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/8418091', 'yes', 'no', 'NA', 1);
INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(8425179, 'Andreassen A, Oyjord T, Hovig E, Holm R, Flørenes VA, Nesland JM, Myklebost O, Høie J, Bruland OS, Børresen AL', 'p53 abnormalities in different subtypes of human sarcomas.', 'Cancer Res', '1993', 'p53 abnormalities in different subtypes of human sarcomas. In this report we examined p53 alterations at the DNA, mRNA, and protein levels on tissue from 39 patients with different subtypes of sarcoma. Loss of heterozygosity for the chromosome 17p region was found in 60, 63, and 33% of 10 informative osteosarcomas, 11 malignant fibrous histiocytomas, and 6 leiomyosarcomas, respectively. In addition, 2 of 10 tumors belonging to a heterogeneous group of soft tissue sarcomas showed loss of heterozygosity. Elevated levels of p53 mRNA were found in six tumors, four had a truncated transcript, and in six patients no mRNA was detected. In most cases, elevated transcript levels were accompanied by overexpression of protein as studied by immunohistochemistry, whereas the presence of truncated transcripts was associated with negative immunostaining. Point mutations in exons 5, 7, or 8 of the TP53 gene were detected in seven tumors. Six of these expressed high levels of mRNA and protein, probably reflecting a point mutation in one of the alleles and loss of the other. Three of the mutations have not previously been described. Taken together, p53 abnormalities were found in approximately 65% of the osteosarcomas, malignant fibrous histiocytomas, and leiomyosarcomas examined and in 30% of the other soft tissue tumors. The results indicate that the TP53 gene is involved in the tumorigenesis of several sarcoma subtypes in a higher fraction of cases than was previously recognized.', 'http://www.ncbi.nlm.nih.gov/pubmed/8425179', 'yes', 'no', 'NA', 1),
(8435797, 'Bacci G, Picci P, Ferrari S, Orlandi M, Ruggieri P, Casadei R, Ferraro A, Biagini R, Battistini A', 'Prognostic significance of serum alkaline phosphatase measurements in patients with osteosarcoma treated with adjuvant or neoadjuvant chemotherapy.', 'Cancer', '1993', 'Prognostic significance of serum alkaline phosphatase measurements in patients with osteosarcoma treated with adjuvant or neoadjuvant chemotherapy. It is known that many patients with osteosarcoma have high serum alkaline phosphatase (SAP) levels. The prognostic significance of this finding, however, is still controversial.The pretreatment SAP levels of 656 patients with osteosarcoma of the extremities (107 metastatic and 549 localized at presentation) were examined to evaluate whether the enzyme levels had a clinical value in predicting the course of the disease.The percentage of patients with increased SAP levels was significantly higher in the metastatic group than in the group of patients with localized disease (91.5% versus 61.3%; P < 0.001). In the latter group, treated with adjuvant and neoadjuvant chemotherapy, the relapse rate was significantly higher in patients with elevated pretreatment SAP levels than in those with normal levels (55.1% versus 26.4%; P < 0.001). Among patients with elevated SAP levels, the percentage of relapses was higher in patients with high levels of the enzyme in comparison with patients with moderately elevated values (66.4% versus 47%; P < 0.05). After treatment, SAP levels almost always return to normal values, and a correlation between postoperative levels of the enzyme and prognosis could not be made.These data demonstrate that in osteosarcoma of the extremities, pretreatment SAP levels have a prognostic value and they should be considered when comparing the results achieved with different therapeutic protocols and in planning new randomized clinical trials.', 'http://www.ncbi.nlm.nih.gov/pubmed/8435797', 'yes', 'yes', 'NA', 1),
(8479749, 'Eeles RA, Warren W, Knee G, Bartek J, Averill D, Stratton MR, Blake PR, Tait DM, Lane DP, Easton DF', 'Constitutional mutation in exon 8 of the p53 gene in a patient with multiple primary tumours: molecular and immunohistochemical findings.', 'Oncogene', '1993', 'Constitutional mutation in exon 8 of the p53 gene in a patient with multiple primary tumours: molecular and immunohistochemical findings. We report a constitutional mutation of codon 273 in exon 8 of the p53 gene. The affected individual has developed multiple independent benign and malignant tumours (tricholemmoma of the scalp, multiple trichoepitheliomata of the face, osteosarcoma of the ovary, bilateral breast cancer, malignant fibrous histiocytoma of the thigh and endometrial adenocarcinoma) and belongs to a family with some, but not all, features of the Li-Fraumeni syndrome. The mutation, found in both blood lymphocyte and tumour specimens, is a cytosine to thymine transition at codon 273, resulting in an amino acid change from arginine to cysteine. The mother and sister of the index case both died of tumours at an early age. We have demonstrated that formalin-preserved material from these tumours contains the same C-->T mutation at codon 273, indicating that this mutation has probably been transmitted through the germline. All tumours from the index case, both benign and malignant, showed immunohistochemical positivity with four antibodies to the p53 protein. Positive staining was also seen in scattered nuclei of morphologically normal epidermal keratinocytes and pilosebaceous cells, but not in lymphocytes or other morphologically normal cells from the index case. However, a similar staining pattern in apparently normal tissue was also observed in 13/48 sections from other individuals with various skin conditions (melanocytic naevi, psoriasis and normal skin adjacent to malignant melanoma and fibrous histiocytomas), suggesting that this pattern of p53 staining may not be unique to individuals with constitutional p53 mutations.', 'http://www.ncbi.nlm.nih.gov/pubmed/8479749', 'yes', 'no', 'NA', 1),
(8507187, 'Rogalsky V, Todorov G, Moran D', 'Translocation of retinoblastoma protein associated with tumor cell growth inhibition.', 'Biochem Biophys Res Commun', '1993', 'Translocation of retinoblastoma protein associated with tumor cell growth inhibition. Immunocytochemistry revealed an association between growth inhibition and a translocation of retinoblastoma protein (pRB) to the nucleoli of U-2 osteosarcoma cells inhibited in their growth by the negative growth factor NCPI (natural cell proliferation inhibitor). Similar phenomenon was demonstrated by Western blot analysis and immunocytochemistry in U937 leukemic cells inhibited in their growth and induced to differentiate by 12-O-tetradecanoylphorbol acetate (TPA). Total nuclear extract of control U937 cells gave an intense 110 KD band, while total nuclear extract of TPA treated cells produced an intense 60 KD band and a weak 110 KD band. No bands were observed for the purified nucleoli of control cells, but the purified nucleoli of TPA treated cells produced a 60 KD band. These results suggest that in the process of cell growth inhibition and differentiation, specific proteolysis of pRB and its translocation to the nucleolus may occur.', 'http://www.ncbi.nlm.nih.gov/pubmed/8507187', 'no', 'no', 'NCPI', 1),
(8513277, 'Ozaki T, Ikeda S, Kawai A, Inoue H, Oda T', 'Alterations of retinoblastoma susceptible gene accompanied by c-myc amplification in human bone and soft tissue tumors.', 'Cell Mol Biol (Noisy-le-grand)', '1993', 'Alterations of retinoblastoma susceptible gene accompanied by c-myc amplification in human bone and soft tissue tumors. The present study was undertaken to examine oncogene abnormalities in human bone and soft tissue tumors. Twenty four tumor tissues and one human cell strain established from an osteosarcoma were examined by Southern blot analysis using a recessive oncogene (p0.9R and p3.8R derived from a cDNA of the Rb gene) and eight dominant oncogenes (c-myc, c-K-ras, c-fos, c-raf-1, c-fms, c-sis, N-myc, and c-erb B) as probes. Homozygous deletions or other alterations within the Rb locus were found in 3 of 6 osteosarcomas, 1 osteosarcoma cell line, 1 of 3 malignant fibrous histiocytomas and 1 of 2 Ewing''s sarcomas. On the other hand, amplification of c-myc was found in 2 osteosarcomas and 1 osteosarcoma cell line. All cases with c-myc amplification had alterations in the structure of the Rb locus, and these patients showed rapid clinical malignancy progression and a probable tendency to bone metastases. Results of this study suggest that structural alterations of the Rb gene and amplification of c-myc might play an important role in the clinical course and pathogenesis of osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/8513277', 'yes', 'yes', 'NA', 2),
(8519637, 'Ilhan I, Erekul S, Ateşalp S, Ilhan O, Akar N', 'p53 codon 213 (A-G) polymorphism in a Turkish population.', 'Pediatr Hematol Oncol', 'NA', 'p53 codon 213 (A-G) polymorphism in a Turkish population. We studied a rare polymorphism at exon 6 (CD 213) of the p53 gene in a healthy Turkish population (n = 26) and in Turks with different types of tumors such as malignant lymphoma (n = 12), osteosarcoma (n = 5), and nasopharyngeal sarcoma (n = 4). The polymorphic allele was found in only one of the malignant lymphoma patients (4.16%). Our data revealed that CD 213 (A-G) polymorphism is very rare in the Turkish population and there is no association with the tumors.', 'http://www.ncbi.nlm.nih.gov/pubmed/8519637', 'yes', 'no', 'NA', 1),
(8550801, 'Velez-Yanguas MC, Kalebic T, Maggi M, Kappel CC, Letterio J, Uskokovic M, Helman LJ', '1 alpha, 25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531) modulation of insulin-like growth factor-binding protein-3 and induction of differentiation and growth arrest in a human osteosarcoma cell line.', 'J Clin Endocrinol Metab', '1996', '1 alpha, 25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531) modulation of insulin-like growth factor-binding protein-3 and induction of differentiation and growth arrest in a human osteosarcoma cell line. 1 alpha,25-Dihydroxycholecalciferol [1,25-(OH)2D3] is a potent differentiating agent in a variety of tumor cell lines. However, the induction of severe hypercalcemia has limited its clinical use. Several analogs have been synthesized that retain the antiproliferative differentiating effects of 1,25-(OH)2D3, but do not have the calcitropic effect of the parent compound. One such analog, 1 alpha,25(OH)2-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531), can induce differentiation in HL-60 cells and does not induce hypercalcemia in animal models. We, therefore, evaluated the effect of Ro24-5531 on a human osteosarcoma cell line, MG-63. Compared with 1,25-(OH)2D3, the analog Ro24-5531 is 10-100 times more potent as an inhibitor of MG-63 cell proliferation, as determined by [3H]thymidine incorporation and/or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The inhibition in cell growth is accompanied by a decrease in the expression of p34cdc2 (> 4-fold), a protein critically involved in cell cycle regulation. Ro24-5531 treatment of MG-63, at a concentration of 10(-8) mol/L, induced expression of the bone differentiation markers biglycan and osteocalcin, as determined by Northern analysis. These data suggest that Ro24-5531 treatment induces growth arrest coupled with differentiation. To begin to evaluate the mechanisms by which Ro24-5531 may exert an effect, we evaluated the effect of Ro24-5531 on components of the insulin-like growth factor I (IGF-I) signaling pathway, an important regulator of normal bone growth and differentiation. The expression of IGF-binding protein (IGFBP), IGFBP-3 messenger ribonucleic acid, and protein levels are increased 20-fold after 72 h of treatment with Ro24-5531 and are associated with a marked increase in detectable binding of ligand to binding protein, as measured by RRA. These data suggest an association between Ro24-5531-induced growth arrest and increased expression of IGFBP-3.', 'http://www.ncbi.nlm.nih.gov/pubmed/8550801', 'no', 'no', 'Ro24-5531', 2),
(8562155, 'Serra M, Scotlandi K, Manara MC, Maurici D, Benini S, Sarti M, Campanacci M, Baldini N', 'Analysis of P-glycoprotein expression in osteosarcoma.', 'Eur J Cancer', '1995', 'Analysis of P-glycoprotein expression in osteosarcoma. Current treatment of high-grade osteosarcoma combines surgical removal of the lesion with chemotherapy. In this study we evaluated whether the expression of P-glycoprotein, a protein closely associated with multidrug resistance, may be helpful in identifying the patients whose tumours will be further resistant to specific agents. By using multidrug-resistant osteosarcoma cell lines as standards, the expression of P-glycoprotein was evaluated in 105 cases of primary and metastatic osteosarcoma by semiquantitative immunofluorescence. Overexpression of the protein was shown in 23% of primary and in 50% of metastatic lesions. In 38 cases, homogeneously treated and followed-up for at least 24 months, overexpression of P-glycoprotein appeared to be associated with a higher relapse rate and with a trend toward a worse outcome. These data support the role of P-glycoprotein in the response to chemotherapy and its involvement in the determination of the outcome of osteosarcoma patients.', 'http://www.ncbi.nlm.nih.gov/pubmed/8562155', 'yes', 'yes', 'NA', 1),
(8603340, 'Miller CW, Aslo A, Campbell MJ, Kawamata N, Lampkin BC, Koeffler HP', 'Alterations of the p15, p16,and p18 genes in osteosarcoma.', 'Cancer Genet Cytogenet', '1996', 'Alterations of the p15, p16,and p18 genes in osteosarcoma. Activation of cyclin-dependent kinases (CDKs) by interaction with cyclins regulates progression through cell cycle checkpoints. This process is counterbalanced by CDK inhibitors (CDKIs), which can inhibit progression through the cell cycle. Because CDKI expression acts to inhibit cellular proliferation, CDKIs may have a role as tumor suppressors. One class of CDKIs, characterized by the presence of ankyrin repeats, has at least four members (p15INK4B), p16INK4, p18, and p19). Two of these, p15INK4B, p16INK4, have been mapped to chromosome 9p21, a region of frequent loss in a wide variety of cancers. Alterations of p16INK4 have been detected in various tumors and cell lines. We analyzed p15INK4B, p16INK4, and p18 alterations in 52 osteosarcomas (including 11 explants), and 23 other various sarcomas. Single-stranded conformation polymorphism analysis [polymerase chain reaction (PCR-SSCP)] of the coding regions of these CDKI genes detected a missense mutation of p16INK4 exon 1 in one soft tissue sarcoma. Southern blotting detected complete deletion of p15INK4B and p16INK4 genes in osteosarcomas from 2 patients and a soft tissue sarcoma from another individual. Loss of heterozygosity (LOH) at chromosome 9p21 was observed with a microsatellite probe closely linked to the INK4 genes in the latter case. Deletions of both p15INK4B and p16INK4 genes were detected in five of eight osteosarcoma cell lines. By contrast, no alterations of p18 were detected in any sample. Together these data suggest that alterations of the p15INK4B and p16INK4 genes, but not p18, may occur in approximately 5% of sarcomas. However, deletions of the p15INK4B and P16INK4 genes are frequent in osteosarcoma cell lines and probably have a role in tumor cell growth in culture. Notably, all seven detectable deletions involved both p15INK4B and p16INK4 genes, suggesting that both contribute individual tumor suppressor activity.', 'http://www.ncbi.nlm.nih.gov/pubmed/8603340', 'yes', 'no', 'NA', 2),
(8616838, 'Sala A, Casella I, Grasso L, Bellon T, Reed JC, Miyashita T, Peschle C', 'Apoptotic response to oncogenic stimuli: cooperative and antagonistic interactions between c-myb and the growth suppressor p53.', 'Cancer Res', '1996', 'Apoptotic response to oncogenic stimuli: cooperative and antagonistic interactions between c-myb and the growth suppressor p53. c-myb, a protooncogene prevalently expressed in the hematopoietic tissue, is a transcription factor that contains a DNA-binding domain and an acidic domain and is able to transactivate specific viral and cellular genes. In this report, we show that c-myb can stimulate apoptosis in both the murine promyelocytic 32D and the human osteosarcoma SAOS2 cell lines when coexpressed with p53. Apoptosis is accompanied by increased transactivation of the cell death-associated BAX gene. This effect is c-myb specific, because B-myb is not able to cooperate with p53 in the induction of BAX transcription and apoptosis. Immunoprecipitation studies and gel shift analysis indicate that c-myb does not directly interact with the BAX promoter or the p53 protein but, rather, cooperates through an indirect mechanism. Consistent with the existence of a functional link between c-myb and p53, we also observed that c-myb represses p53-induced activation of the WAF-1 promoter and induces proliferation of SAOS2 cells growth arrested by p53. These results might contribute to the elucidation of the mechanisms underlying p53-dependent pathways of oncogene-induced apoptosis and provide a further example of DNA-binding independent myb activity.', 'http://www.ncbi.nlm.nih.gov/pubmed/8616838', 'no', 'no', 'NA', 4),
(8625324, 'Scotlandi K, Serra M, Nicoletti G, Vaccari M, Manara MC, Nini G, Landuzzi L, Colacci A, Bacci G, Bertoni F, Picci P, Campanacci M, Baldini N', 'Multidrug resistance and malignancy in human osteosarcoma.', 'Cancer Res', '1996', 'Multidrug resistance and malignancy in human osteosarcoma. In osteosarcoma, resistance to chemotherapy and metastatic spread are the most important mechanisms responsible for the failure of current multimodal therapeutic programs. We have shown previously that overexpression of the MDR1 gene product P-glycoprotein is the most important predictor of an adverse clinical course in patients with osteosarcoma. treated with chemotherapy. In this study, we analyzed the relationship between P-glycoprotein expression and local aggressiveness and systemic dissemination of multidrug-resistant (MDR) human osteosarcoma cells. Compared to parental sensitive cells, MDR cells showed a decreased tumorigenicity,and metastatic ability in athymic mice, together with a reduced migratory and invasive ability and a lower homotypic adhesion ability in vitro, suggesting that P-glycoprotein overexpression is associated with a less malignant phenotype. These experimental observations were confirmed by clinical data. In fact, the time of appearance of lung metastases in a series of osteosarcoma patients treated with chemotherapy was significantly shorter in the group of cases with no expression of P-glycoprotein in the primary lesion compared to the group with P-glycoprotein overexpression. Moreover, the incidence of P-glycoprotein overexpression was found to be higher among patients with localized disease at the clinical onset than in patients with evidence of metastasis at the time of diagnosis. These data indicate that, in osteosarcoma, the MDR phenotype is not associated with a more aggressive behavior both in vitro and in clinical settings, suggesting that the previously shown association of the MDR phenotype with a worse outcome in osteosarcoma is not related to a higher metastatic ability of cells with P-glycoprotein overexpression but is more likely due to their lack of responsiveness to cytotoxic drugs.', 'http://www.ncbi.nlm.nih.gov/pubmed/8625324', 'yes', 'no', 'NA', 1),
(8630943, 'Onda M, Matsuda S, Higaki S, Iijima T, Fukushima J, Yokokura A, Kojima T, Horiuchi H, Kurokawa T, Yamamoto T', 'ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma.', 'Cancer', '1996', 'ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma. It has been reported that the c-erbB-2 protooncogene is frequently amplified and overexpressed in many types of cancers, except sarcomas and hematological malignancies.Expression of ErbB-2 in the tumors of 26 patients with conventional osteosarcoma was evaluated by immunoblotting. DNA from osteosarcoma tissues that expressed ErbB-2 were analyzed by Southern blot hybridization to examine gross rearrangement of the gene. The DNA was also surveyed for the presence of genetic mutation in the transmembrane domain of ErbB-2 by polymerase chain reaction-single-stranded DNA conformation polymorphism analysis. In addition, possible correlation of ErbB-2 expression with gender, age, histopathologic subtype, and response to chemotherapy was analyzed. Survival analysis was performed by the Kaplan-Meier test using the approximate chi-square statistic for the log-rank test.The ErbB-2 protein was detected in 11 of 26 osteosarcoma tissues (42%) by immunoblot analysis. Expression of ErbB-2 was confirmed by immunohistochemical studies using specific anti-ErbB-2 monoclonal antibody. However, neither amplification of the c-erbB-2 gene nor evidence of significant genetic mutation was found in these osteosarcomas. Expression of ErbB-2 examined by immunoblotting was most strongly correlated with early pulmonary metastases (P < 0.05). Among the entire group of 26 patients in this study, Kaplan-Meier life table survival of the patients with apparent ErbB-2 expression was significantly worse than that of the patients with little ErbB-2 expression (P < 0.01).In 42% of the osteosarcomas, the tumor cells expressed ErbB-2. Expression of ErbB-2 was strongly correlated with early pulmonary metastasis and poor survival rate for the patient. These data suggest that ErbB-2 plays a significant role in aggressive tumor growth and in the promotion of metastatic potential in osteosarcomas. ErbB-2 in the osteosarcoma tissues would be a useful prognostic marker for patients.', 'http://www.ncbi.nlm.nih.gov/pubmed/8630943', 'yes', 'yes', 'NA', 1),
(8636759, 'Feugeas O, Guriec N, Babin-Boilletot A, Marcellin L, Simon P, Babin S, Thyss A, Hofman P, Terrier P, Kalifa C, Brunat-Mentigny M, Patricot LM, Oberling F', 'Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma.', 'J Clin Oncol', '1996', 'Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma. The usual therapy of osteosarcoma is neoadjuvant chemotherapy, followed by surgery, then by postoperative chemotherapy. There is no prognostic factor to predict, at diagnosis, the histologic response and final outcome. Inactivation of the retinoblastoma-susceptibility gene RB is associated with the pathogenesis of several human cancers. In primary osteosarcomas, loss of heterozygosity (LOH) at the RB locus has been found in greater than 60% of cases. The aim of this study was to determine the potential early prognostic value of LOH of RB gene on the biopsy material at diagnosis.Forty-seven patients with primary osteosarcoma, treated in four French institutions, were studied. LOH was studied by polymerase chain reaction (PCR) of an informative RB DNA polymorphism.Assessment of LOH at the RB gene could be completed on 34 heterozygous patients only. LOH was found in 24 cases (70%). The event-free survival (EFS) rate at 60 months is 100% for patients without LOH, 43% for all patients with RB LOH, and 65% for nonmetastatic patients with RB LOH. The difference in EFS is highly significant at P = .008 and P = .024, respectively. Histologic response after preoperative chemotherapy did not show significant correlation with LOH status.RB gene LOH appears to be an early predictive feature for osteosarcomas that indicates a potential unfavorable outcome. RB LOH study might shortly help to identify high-risk patients earlier. If this is verified, therapy could then be adapted earlier to the individual''s real risk of relapse.', 'http://www.ncbi.nlm.nih.gov/pubmed/8636759', 'yes', 'yes', 'NA', 1),
(8662647, 'Liang Y, Robinson DF, Dennig J, Suske G, Fahl WE', 'Transcriptional regulation of the SIS/PDGF-B gene in human osteosarcoma cells by the Sp family of transcription factors.', 'J Biol Chem', '1996', 'Transcriptional regulation of the SIS/PDGF-B gene in human osteosarcoma cells by the Sp family of transcription factors. Expression of PDGF-B, the gene encoding the platelet-derived growth factor B chain, has been implicated as a participant in an autocrine growth loop in the human osteosarcoma cell line U2-OS. In previous work, we identified a primary site in the PDGF-B promoter, the SIS proximal element (SPE), which is critical for transcription of the PDGF-B gene in U2-OS cells. We also identified Sp1 as one of the SPE-binding proteins in U2-OS nuclear extracts. In the present work, we have identified another SPE-binding protein to be Sp3. Gel mobility shift assays showed that both Sp1 and Sp3 require the CACCC motif within the SPE for binding. In vitro transcription assays showed that Sp1 or/and Sp3 is necessary for transcription of the PDGF-B gene. Cotransfection experiments functionally demonstrated that Sp1 and Sp3 can independently or additively activate the PDGF-B promoter through the SPE as well as a synthetic promoter. However, the CACCC motif within the SPE is not the only site within the minimal PDGF-B promoter through which Sp1/Sp3 acts; additional nested deletion analyses showed that multiple cis-acting elements within the minimal promoter are required for full level transcription of the PDGF-B gene in U2-OS cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/8662647', 'no', 'no', 'NA', 3),
(8670156, 'Sakayama K, Masuno H, Okumura H, Shibata T, Okuda H', 'Recombinant human tumour necrosis factor-alpha suppresses synthesis, activity and secretion of lipoprotein lipase in cultures of a human osteosarcoma cell line.', 'Biochem J', '1996', 'Recombinant human tumour necrosis factor-alpha suppresses synthesis, activity and secretion of lipoprotein lipase in cultures of a human osteosarcoma cell line. The effect of recombinant human tumour necrosis factor-alpha (TNF-alpha) on synthesis, activity and secretion of lipoprotein lipase (LPL) was examined using a human osteosarcoma cell line, osteosarcoma Takase (OST). Treatment of OST cells with TNF-alpha decreased LPL synthesis, resulting in a decrease in expression of activity and secretion of LPL. When OST cells were incubated with glycerol tri[1-14C]palmitate, TNF-alpha decreased dose- and time-dependently the production of 14CO2 and the amounts of radioactivity incorporated into cellular triacylglycerol and phospholipid. The similar reduction of synthesis and activity of LPL as suppression of CO2 production and cellular lipid synthesis indicated that the suppression of 14CO2 production and 14C-labelled lipid synthesis was secondary. TNF-alpha also suppressed expression of proliferating cell nuclear antigen, indicating that it had an anti-proliferative activity on OST cells. The findings suggest that one cause of the anti-proliferative activity of TNF-alpha is the suppression of the LPL-mediated supply of non-esterified fatty acids as an energy source for growth.', 'http://www.ncbi.nlm.nih.gov/pubmed/8670156', 'no', 'no', 'NA', 3),
(8692530, 'Liu PP, Leung KS, Kumta SM, Lee KM, Fung KP', 'Bone-specific alkaline phosphatase in plasma as tumour marker for osteosarcoma.', 'Oncology', 'NA', 'Bone-specific alkaline phosphatase in plasma as tumour marker for osteosarcoma. The levels of bone-specific alkaline phosphatase (BALP) in plasma and tumour tissue samples of 20 Chinese patients with osteosarcoma in Hong Kong were measured by the wheat germ lectin precipitation technique. The plasma BALP levels in these patients were significantly higher than those of the normal subjects (p < 0.001), and also significantly higher than those of patients with benign bone tumor and those of patients with malignant tumor metastasized to the bone (p < 0.0001). Considering the prognostic value of BALP for osteosarcoma, the plasma BALP levels at the time of diagnosis were found to be significantly related to the rate of disease recurrence (p < 0.05). Furthermore, at the time of relapse, the plasma BALP levels in the group of recurrent osteosarcoma patients were significantly higher than those of osteosarcoma patients showing no recurrence (p < 0.05). When ALP was assayed in the tumor tissue, the BALP levels were also significantly higher than those of the control cortical bone extracts in the same group of patients (p < 0.05). We conclude that plasma BALP is a sensitive and specific biochemical parameter in the diagnosis and the subsequent monitoring of osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/8692530', 'yes', 'yes', 'NA', 1),
(8703379, 'Lee SY, Jeon DG, Lee JS, Hwang CS, Huh K, Lee TW, Hong SI', 'Deletion of Rb1 gene in late osteosarcoma from survivor of unilateral retinoblastoma--a case report.', 'J Korean Med Sci', '1996', 'Deletion of Rb1 gene in late osteosarcoma from survivor of unilateral retinoblastoma--a case report. It has been well known that the survivors of retinoblastoma are prone to have osteosarcoma. But the secondary tumor usually occurs in bilateral, hereditary type of retinoblastoma. We report one case of osteosarcoma in a survivor of unilateral, sporadic retinoblastoma. A fourteen year old male presented with a painfully swollen distal forearm of 2 month duration. He had enucleated his left eye 10 years ago due to retinoblastoma with no other adjuvant therapy. We managed him with our conventional protocol and identified deletion of Rb gene from his pathological specimen by using the PCR-RFLP method. This result is unusual for unilateral nonhereditable retinoblastoma and may suggest gene level change even in sporadic cases. And Rb gene study may be helpful for unilateral, sporadic retinoblastoma patient in detecting the possibility of late osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/8703379', 'yes', 'no', 'NA', 1),
(8717113, 'Park YK, Yang MH, Park HR', 'The impact of osteonectin for differential diagnosis of osteogenic bone tumors: an immunohistochemical and in situ hybridization approach.', 'Skeletal Radiol', '1996', 'The impact of osteonectin for differential diagnosis of osteogenic bone tumors: an immunohistochemical and in situ hybridization approach. Thirty-three osteosarcomas at various grades of histologic differentiation, including chondroblastic, osteoblastic, and fibroblastic variants, were investigated immunohistochemically for evidence of osteonectin. Twenty-two cases of varying types of osteosarcoma were examined with in situ hybridization for mRNA expression of osteonectin. Immunohistochemically, osteonectin was present in all the osteosarcomas in this study. With in situ hybridization, 12 out of 22 osteosarcomas showed a positive signal. Two osteochondrosarcomas, seven chondrosarcomas, and one mesenchymal chondrosarcoma were also studied with regard to the localization of osteonectin, either immunohistochemically or by in situ hybridization. Immunohistochemically, osteonectin was present in all the chondroid lesions except for one osteochondroma. However, in situ hybridization of osteonectin mRNA was negative in all the chondroid lesions we studied. This study revealed that immunohistochemical localization of osteonectin is not useful in providing conclusive diagnosis of osteosarcoma. In situ hybridization of osteonectin mRNA might be useful in differentiating osteosarcoma from nonsteogenic bone tumors.', 'http://www.ncbi.nlm.nih.gov/pubmed/8717113', 'yes', 'yes', 'NA', 1),
(8717537, 'LInd M, Eriksen EF, Bünger C', 'Bone morphogenetic protein-2 but not bone morphogenetic protein-4 and -6 stimulates chemotactic migration of human osteoblasts, human marrow osteoblasts, and U2-OS cells.', 'Bone', '1996', 'Bone morphogenetic protein-2 but not bone morphogenetic protein-4 and -6 stimulates chemotactic migration of human osteoblasts, human marrow osteoblasts, and U2-OS cells. Bone morphogenetic proteins (BMPs) have important functions for the differentiation of bone cells, but the exact role for bone remodeling and bone healing still needs to be defined. Migration of bone forming cells is an important physiological event both during bone healing and bone remodeling. The chemotatic properties of the bone morphogenetic protein family of growth factors have not been investigated. In this study the chemotactic effects of the bone morphogenetic proteins BMP-2, -4, and -6 have been quantitated toward human osteoblasts, human marrow stromal osteoblasts, and U2-OS human osteosarcoma cells. BMP-2 stimulated the migration of human stromal osteoblasts, human osteoblasts, and U2-OS cells with bell-shaped response curves in a dose-dependent manner with a 300% increase in cell migration at 1.0 ng/mL for human stromal osteoblasts and a 170-180% increase for human osteoblasts and U2-OS cells. At higher concentrations, migration decreased to background levels. BMP-4 and -6 did not show any effect on cellular migration. This study shows that BMP-2 can stimulate in vitro migration of human osteoblasts and human osteosarcoma cells. BMP-2 might play a role in the chemotactic recruitment of especially undifferentiated osteoblasts during bone remodeling and bone healing.', 'http://www.ncbi.nlm.nih.gov/pubmed/8717537', 'no', 'no', 'NA', 1),
(8726395, 'Sutherland MK, Hui DU, Rao LG, Wylie JN, Murray TM', 'Immunohistochemical localization of the estrogen receptor in human osteoblastic SaOS-2 cells: association of receptor levels with alkaline phosphatase activity.', 'Bone', '1996', 'Immunohistochemical localization of the estrogen receptor in human osteoblastic SaOS-2 cells: association of receptor levels with alkaline phosphatase activity. We have previously shown that the combination of estrogen (E2) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] enhanced alkaline phosphatase (ALP) activity in human osteosarcoma SaOS-2 cells which had been grown in the presence of 10 nmol/L dexamethasone (SaOS + DEX cells). To determine whether this increase in ALP activity was associated with changes in receptor protein levels for E2 (ER) in individual SaOS + DEX cells, a monoclonal antibody to ER and a histochemical stain for ALP were used localize the expression of these proteins in fixed cells. Western and Northern blot analyses were used to determine whether E2 and 1,25(OH)2D3 affected immunoreactive ER protein and mRNA levels, respectively. Our results showed that immunohistochemical staining for ER was primarily nuclear, whereas histochemical staining for ALP was cytosolic. Treatment of cells with 1,25(OH)2D3, E2, or E2 + 1,25(OH)2D3 increased the levels of both ER and ALP activity, as visualized by enhanced cellular staining. Western analyses showed that 1,25(OH)2D3 and E2, separately and in combination, significantly increased ER protein levels. 1,25(OH)2D3 enhanced ER levels in a dose-dependent manner [analysis of variance (ANOVA), F = 3.91, p < 0.05]; this effect was augmented by E2 (ANOVA, F = 5.98, p < 0.005). In comparison, 17 alpha-E2 + 1,25(OH)2D3 and tamoxifen + 17 beta-E2 + 1,25(OH)2D3 did not increase ER levels compared with those obtained with 17 beta-E2 + 1,25(OH)2D3. ER mRNA levels were not significantly increased by E2, 1,25(OH)2D3, or E2 + 1,25(OH)2D3 together. In contrast, in a population of SaOS cells which had been in culture longer (approximately 40 passages more) than the previous cells, E2 + 1,25(OH)2D3 did not enhance ALP activity or ER levels above those obtained with 1,25(OH)2D3 alone. These results showed that in responsive SaOS cells, E2 enhanced both the stimulatory effects of 1,25(OH)2D3 on ALP activity and the activation of ER. Thus changes in ALP activity are associated with changes in ER levels in SaOS + DEX cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/8726395', 'no', 'no', 'NA', 2),
(8750062, 'Park HR, Park YK', 'Expression of p53 protein, PCNA, and Ki-67 in osteosarcomas of bone.', 'J Korean Med Sci', '1995', 'Expression of p53 protein, PCNA, and Ki-67 in osteosarcomas of bone. Expressions of p53 protein, a product of the tumor suppressor gene were studied in osteosarcomas relating to various prognostic factors. Thirty-four osteosarcomas were investigated immunohistochemically with a monoclonal antibody clone PAb240, which recognizes a common conformational epitope of mutant p53 proteins and another clone PAb1801, which reacts with both wild- and mutant-type p53 proteins. The results were compared with expressions of proliferating cell nuclear antigen (PCNA) and Ki-67 providing a simple method for the assessment of growth fractions of tumors. PAb240 stained nuclei and cytoplasm of tumor cells in 8 of 34 osteosarcomas (23.5%), whereas PAb1801 reacted in all 34 osteosarcomas (100%). Fifteen tumors (44.1%) showed positivity for PAb1801 in more than half of the tumor cells. Twelve patients were alive and thirteen were dead. Tumors from 9 patients (75%) who survived revealed only focal positive immunoreactions with PAb1801 and tumors from 6 patients (46.1%) who died revealed diffuse reactions. Twelve cases (35.3%) showed a high PCNA index (> 40%) and fibroblastic osteosarcomas revealed the highest PCNA positivity. Twenty-two cases (64.7%) revealed a very low Ki-67 index (less than 10%) and Ki-67 index showed a good correlation with PCNA positivity (r = 0.6247). Expressions of both wild-and mutant-type p53 protein, PCNA, and Ki-67 were not correlated with other clinical or pathological parameters.', 'http://www.ncbi.nlm.nih.gov/pubmed/8750062', 'yes', 'no', 'NA', 3),
(8781571, 'Miller CW, Aslo A, Won A, Tan M, Lampkin B, Koeffler HP', 'Alterations of the p53, Rb and MDM2 genes in osteosarcoma.', 'J Cancer Res Clin Oncol', '1996', 'Alterations of the p53, Rb and MDM2 genes in osteosarcoma. Molecular defects affecting tumor-suppressor genes are an important step in the genesis of sarcomas. For example, inheritance of a defective Rb or p53 gene predisposes the carrier to develop osteosarcoma, among other malignancies. In this study, we have assessed the occurrence of p53, Rb and MDM2 alterations in the same samples of osteosarcomas, along with representative samples of various other sarcomas. Point mutations of the p53 gene were found in 13 of 42 osteosarcomas and 1 of 8 leiomyosarcomas, and gross rearrangement of the p53 gene was demonstrated in 5 of 37 osteosarcomas. The retinoblastoma susceptibility gene (Rb) was either rearranged or deleted in 7 of 37 osteosarcomas, 1 of 7 soft-tissue sarcomas and 1 of 4 Ewing sarcomas. Remarkably, 5 of the osteosarcomas having Rb alterations also had p53 mutations. Amplification and overexpression of the MDM2 oncogene may lead to increased MDM2-p53 binding resulting in inactivation of p53 function. A two- to threefold increase in the copy number of MDM2 was detected in 7 of 37 samples, 5 of which were osteosarcomas. Amplification of the MDM2 gene occurred independently of p53 mutation; one sample having threefold amplification of MDM2 also had a p53 mutation. In summary, 34 alterations of the p53, Rb and MDM2 genes were found in 26 of 42 (62%) osteosarcomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/8781571', 'yes', 'no', 'NA', 3),
(8793483, 'Radig K, Schneider-Stock R, Oda Y, Neumann W, Mittler U, Roessner A', 'Mutation spectrum of p53 gene in highly malignant human osteosarcomas.', 'Gen Diagn Pathol', '1996', 'Mutation spectrum of p53 gene in highly malignant human osteosarcomas. In this study, we analyzed the spectrum of p53 tumor suppressor gene mutations in 40 highly malignant osteosarcomas, one osteosarcoma metastasis, and one osteoblastoma with malignant transformation. Using predominantly formalin-fixed and paraffin-embedded material, we performed polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis of exons 4-8 and direct sequencing. Molecular genetic findings were correlated with immunohistochemical detection of p53 protein. A total of eight alterations (19%) were identified. Two splice mutations were detected in one case of a highly malignant osteosarcoma and its metastasis, and in one osteoblastoma with focal malignant transformation. Four of the mutations were missense mutations, one was of the silent type. These data correspond to the results found in the literature on bone and soft tissue tumors. Therefore, retrospective studies of p53 gene turn out to be quite appropriate for molecular biologic examinations.', 'http://www.ncbi.nlm.nih.gov/pubmed/8793483', 'yes', 'no', 'NA', 1),
(8821948, 'Mousses S, McAuley L, Bell RS, Kandel R, Andrulis IL', 'Molecular and immunohistochemical identification of p53 alterations in bone and soft tissue sarcomas.', 'Mod Pathol', '1996', 'Molecular and immunohistochemical identification of p53 alterations in bone and soft tissue sarcomas. p53 has been shown to suppress tumor growth by regulating the cell cycle and by triggering apoptosis. Acquired somatic mutations of the p53 gene have been observed in a variety of human malignancies, and these result in a loss of its tumor suppressor function. To examine the occurrence of p53 abnormalities in bone and soft tissue sarcomas, 113 tumors were subjected to molecular analysis and mutations were confirmed in 16 tumors. The frequency of p53 alterations varied among the different subtypes of bone and soft tissue sarcomas, being observed predominantly in osteosarcomas (8/34 cases), rhabdomyosarcomas (2/3 cases), Ewing''s sarcomas (1/5 cases), and liposarcomas (3/21 cases). In contrast, p53 gene mutations were detected at a lower frequency in malignant fibrous histiocytomas (2/34 cases) and not at all in nine chondrosarcomas and five leiomyosarcomas. Immunohistochemical staining of p53 protein was performed on 69 cases and compared to the DNA results. For 64 cases the results were concordant: 56 sarcomas were considered to have wild-type p53 by both techniques. As well, increased p53 protein expression was observed in eight of the nine tumors with p53 gene mutations. However, positive p53 staining was also seen in four sarcomas which had no detectable p53 mutations in exons 5 through 9. Because some sarcomas exhibit amplification and overexpression of MDM-2, which may interact with p53 and cause stabilization of wild-type p53 protein, we examined these tumors for MDM-2 amplification. None of the tumors with MDM-2 amplification exhibited p53 immunopositivity. Very weak p53 reactivity was detected in four malignant fibrous histiocytomas that had received either chemotherapy or radiotherapy. Of 16 metastatic lesions examined, only one contained a p53 mutation. In addition, for five cases in which both the original lesion and its metastases were analyzed, p53 alterations were not observed in the metastases if the tumor was wild-type at presentation. These data suggest that p53 alterations occur at different frequencies in various subtypes of sarcoma and, although detected in metastatic lesions, are not associated more frequently with progression.', 'http://www.ncbi.nlm.nih.gov/pubmed/8821948', 'yes', 'no', 'NA', 1),
(8835762, 'Park IC, Lee SY, Jeon DG, Lee JS, Hwang CS, Hwang BG, Lee SH, Hong WS, Hong SI', 'Enhanced expression of cathepsin L in metastatic bone tumors.', 'J Korean Med Sci', '1996', 'Enhanced expression of cathepsin L in metastatic bone tumors. Cathepsin L is a kind of cystein proteases which are known to facilitate the invasion and metastasis of tumor cells by degrading the components of basement membrane and extracellular matrix. This study was undertaken to investigate the expression of cathepsin L by Northern blot analysis with radiolabeled cDNA specific for cathepsin L in six normal tissues, two osteosarcoma cell lines, MG-63 and Saos-2, six primary bone tumors and six metastatic bone tumors. In six normal tissues, the highest level of cathepsin L was expressed in liver with the descending order of liver > lung > thymus > ovary > kidney > esophagus. One of the two osteosarcoma cell lines established from the primary sites expressed a high level of cathepsin L mRNA. Out of six primary bone tumors, three (50%) expressed cathepsin L mRNA, while all (100%) of six metastatic bone tumors expressed the mRNA. These results demonstrating the higher frequency of expression of cathepsin L in metastatic bone tumors suggest that cathepsin L may participate in tumor invasion and metastasis.', 'http://www.ncbi.nlm.nih.gov/pubmed/8835762', 'yes', 'no', 'NA', 1),
(8840973, 'Ko SC, Cheon J, Kao C, Gotoh A, Shirakawa T, Sikes RA, Karsenty G, Chung LW', 'Osteocalcin promoter-based toxic gene therapy for the treatment of osteosarcoma in experimental models.', 'Cancer Res', '1996', 'Osteocalcin promoter-based toxic gene therapy for the treatment of osteosarcoma in experimental models. Osteocalcin (OC), a noncollagenous bone matrix protein, is expressed in high levels by osteoblasts. To determine whether the OC promoter mediates cell-specific gene expression in cells of osteoblast lineage, we constructed a recombinant adenovirus, Ad-OC-TK, which contains the OC promoter that drives the expression of herpes simplex virus thymidine kinase (TK). We tested the expression of TK by this virus in osteoblast cell lines as well as in non-osteoblastic cell lines by assessing the enzyme activity of TK in vitro. Whereas the OC promoter failed to drive the expression of the TK gene in several non-osteoblastic cell lines such as WH, a human bladder transitional carcinoma, and NIH 3T3, an embryonic mouse fibroblast cell line, the OC promoter mediated high levels of expression in osteoblast cell lines including murine ROS and human MG-63 cells. The addition of acyclovir (ACV), a pro-drug for the inhibition of cell proliferation, resulted in the induction of osteoblast-specific cell death in vitro. Intratumoral injection of Ad-OC-TK into murine ROS osteosarcoma abolished tumor growth in a host treated with subsequent i.p. ACV injection in vivo. The Ad-OC-TK virus plus ACV treatment appears to be highly selective in blocking the growth of both murine and human osteosarcoma cell lines in vitro and murine osteosarcoma in vivo.', 'http://www.ncbi.nlm.nih.gov/pubmed/8840973', 'no', 'no', 'acyclovir', 1),
(8855972, 'Lee PD, Noble-Topham SE, Bell RS, Andrulis IL', 'Quantitative analysis of multidrug resistance gene expression in human osteosarcomas.', 'Br J Cancer', '1996', 'Quantitative analysis of multidrug resistance gene expression in human osteosarcomas. We evaluated the MDR1 expression levels in 77 osteosarcomas and investigated whether MDR1 mRNA expression in osteosarcomas varies with location within the tumour, following chemotherapy, or after metastasis. We modified the semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) assay to determine accurately the levels of MDR1 mRNA expression in clinical specimens. We show that specimens collected from multiple locations in six tumours revealed very little variation in MDR1 expression suggesting that the levels of MDR1 in these tumours do not vary greatly with location within the tumour mass. In a comparison of pre and post-chemotherapy specimens it was found that MDR1 levels did not change appreciably following chemotherapy in 16 of 20 cases. In addition, in eight of ten specimens obtained before and after metastasis, the amount of MDR1 mRNA was found to remain relatively constant despite metastatic spread. Thus, many osteosarcomas exhibited intrinsic expression of MDR1 mRNA before multidrug regimens which invariably included doxorubicin and, in most cases, MDR1 expression was not induced following chemotherapeutic treatment. Our results suggest that some osteosarcoma patients may have primary tumours which are resistant to doxorubicin. These individuals may benefit from different chemotherapeutic regimens, e.g. the addition of MDR reversal agents.', 'http://www.ncbi.nlm.nih.gov/pubmed/8855972', 'yes', 'yes', 'NA', 1),
(8863670, 'Scotlandi K, Baldini N, Oliviero M, Di Renzo MF, Martano M, Serra M, Manara MC, Comoglio PM, Ferracini R', 'Expression of Met/hepatocyte growth factor receptor gene and malignant behavior of musculoskeletal tumors.', 'Am J Pathol', '1996', 'Expression of Met/hepatocyte growth factor receptor gene and malignant behavior of musculoskeletal tumors. Overexpression of the hepatocyte growth factor receptor (Met/HGF receptor), a transmembrane tyrosine kinase encoded by the met proto-oncogene, has been associated with tumor progression in different human carcinomas. More recently, the Met/HGF receptor has also been described in tumor cell lines of mesenchymal origin, suggesting the existence of an autocrine loop that may contribute to the pathogenesis of sarcomas. In this study, we analyzed the expression of Met/HGF receptor by Western blotting and immunohistochemistry in frozen samples of 87 primary tumors of bone and soft tissues. Among benign tumors, overexpression was consistently found only in giant-cell tumor, a locally aggressive lesion that may also, although rarely, spread to the lung. Among malignant lesions, the presence of the Met/HGF receptor was detected in a relevant percentage of primaries and in almost all of the recurrences. The highest levels of Met/HGF receptor were found in osteosarcoma, a highly aggressive tumor that typically permeates the host bone and rapidly expands to the soft tissues. On the contrary, only low levels of Met/HGF receptor were found in chondrosarcoma, a slowly growing tumor that usually expands without massive destruction of the surrounding structures. These data indicate an association of Met/HGF expression with local aggressiveness in human mesenchymal tumors. The finding of Met/HGF receptor overexpression in all of the osteosarcomas suggests a role for the met proto-oncogene in the pathogenesis of this tumor.', 'http://www.ncbi.nlm.nih.gov/pubmed/8863670', 'yes', 'no', 'NA', 2);
