Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant tumors of the thyroid gland vary considerably in aggressiveness, ranging from a well-differentiated, clinically indolent, to an undifferentiated, often lethal phenotype. Undifferentiated (anaplastic) thyroid tumors are supposed to be derived, through a process of progression, from previously differentiated neoplasms. A common genetic alteration in thyroid tumors is the rearrangement of the tyrosine kinase-encoding RET proto-oncogene, leading to the generation of chimeric RET/PTC oncogenes. To define the characteristics of the thyroid tumor subset with RET rearrangements, we have investigated its activation by a combined immunohistochemistry and reverse transcription-PCR approach in a series of 316 well-characterized thyroid tumors representative of the main diagnostic groups. RET activation was detected in 81 of 201 (40.3%) papillary carcinomas. It correlated with tumors exhibiting the "classic" morphological features of papillary cancer or with the microcarcinoma subtype (P = 0.017). RET activation in papillary carcinoma was not associated with clinical markers (such as large tumor size, extrathyroidal extension, or metastases) of increased morbidity. Follicular-type neoplasms (61 adenomas and 22 carcinomas), as well as the aggressive poorly differentiated (15 cases) or undifferentiated (anaplastic) carcinomas (17 cases), were negative. This study demonstrates that all thyroid carcinomas harboring activating RET rearrangements exhibit a well-differentiated phenotype, that of papillary carcinoma, and indicates that the subset of RET/PTC-positive papillary carcinomas do not progress to more aggressive, less differentiated tumor phenotypes.
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PMID:RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. 1058 93

Small-cell lung cancer (SCLC) cells may express somatostatin receptors [14]. Receptor-positive tissue can be visualised in vivo by scintigraphy with radiolabelled somatostatin analogues. In a prospective study we examined 18 patients with histologically proven SCLC for the diagnostic value of somatostatin receptor scintigraphy using indium-111 pentetreotide. Planar whole body scanning was performed 4 and 24 hours after administration. Additional SPECT imaging of the thorax and the abdomen was done at 24 hours. The results were compared with conventional staging procedures: ultrasound, x-ray, computed tomography and bone scintigraphy. In all 18 patients the primary tumour was correctly identified. Out of 13 patients with mediastinal lymphoma formation 10 patients showed positive SRS. In 2 more patients SRS showed mediastinal uptake while CT scanning was negative. The detection of distant metastases in patients with extensive disease was true positive in 8 cases (OSS, HEP, BRA), false negative in 4 cases (PLE, ADR, HEP), corresponding to a sensitivity of 67%. In 2 patients cerebral metastases were no longer detectable by SRS after previous local irradiation. Even though the method is limited in respect of revealing distant metastases in the upper abdominal area due to physiological uptake in liver, spleen and kidneys, differentiation between limited disease (LD) and extensive disease (ED) was possible in all cases. We conclude that [111In]pentetreotide scintigraphy is a suitable method for the detection of SCLC primary tumours and a substantial tool for differentiation between LD and ED if combined with ultrasonography of the upper abdomen.
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PMID:[Diagnostic value of somatostatin receptor scintigraphy with indium-111 pentetreotide in small-cell bronchial carcinoma]. 955 59

When mutations of the RETproto-oncogene were found in 1993 to account for hereditary medullary thyroid carcinoma (MTC), surgeons obtained the opportunity to operate on patients prophylactically (i. e., at a clinically asymptomatic stage). Whether this approach is justified, and, if so, when and to which extent surgery should be performed remained to be clarified. A questionnaire was sent to all surgical departments in Germany and Austria. All of the patients who fulfilled the following criteria were enrolled: (1) preoperatively proved RET mutation; (2) age </= 20 years, (3) clinically asymptomatic thyroid C cell disease; and (4) TNM classification pT0-1/pNX/pN0-1/M0. Seventy-five patients were identified, and fifteen mutations were detected in six codons. Two adolescents had unilateral pheochromocytomas as part of the multiple endocrine neoplasia II (MEN-II) syndrome. No hyperparathyroidism was noted. All patients underwent total thyroidectomy, and 57 patients went on to have lymph node dissection. Parathyroid glands were removed in 34 patients and autografted in 11. Histopathology revealed MTC in 46 patients (61%, youngest 4 years); C cell hyperplasia (CCH) only was detected in the other 29 patients. Three patients had lymph node metastases (LNMs) the youngest being age 14 years. Calcitonin levels were not useful for differentiating between CCH and MTC, but in all patients with LNMs at least the stimulated calcitonin levels were assayed. After surgery, five patients (6.7%) sustained permanent hypoparathyroidism, and one patient (1.3%) had a permanent unilateral recurrent nerve palsy. All but three patients (96%) were biochemically cured. In conclusion, prophylactic total thyroidectomy can be performed safely in experienced centers. We recommend prophylactic total thyroidectomy at age 6. Cervicocentral lymph node dissection should be included when calcitonin levels are elevated or if patients are older than 10 years. Bilateral lymph node dissection should be performed if LNMs are suspected or when patients with elevated calcitonin are older than 15 years.
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PMID:Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. 960 92

Xenografts from four metastatic renal cell carcinomas (RCCs) were established in immunodeficient mice. All tumors exhibited cytogenetic features specific for the papillary subtype, namely, partial or total polysomy of chromosomes 7 and 17 and integrity of 3p. Cytogenetic analysis of the initial and xenografted tumors indicated that although clonal characteristics were consistently maintained in xenografts derived from metastases, a minor clone had been selected for in the xenografts derived from the primary tumors. Reverse painting and comparative genomic hybridization (CGH) allowed us to localize minimal overrepresented genomic regions to 7q31, where the MET protooncogene is located, and to 17q. Other overrepresented regions were 8q in all xenografts and Xq22-qter in three of them. The gain of genetic material from these regions may be a key factor ensuring the papillary nature of RCCs and their survival in xenografts.
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PMID:Overrepresentation of 7q31 and 17q in renal cell carcinomas. 962 28

RET proto-oncogene mutation results in a dominant autosomic inherited syndrome (MEN 2) presenting three distinct subtypes: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). Detection of RET proto-oncogene mutation is a predictor before clinical or biochemical evidence of the disease is present and leads to preventive thyroid removal since there is no effective treatment for metastases. The aim of the present study was to characterize mutations in the RET proto-oncogene in affected patients and to identify potential carriers in their families. Two families with FMTC (5 and 6 members), 4 with MEN 2A (5, 5, 4 and 3 members) and 2 with MEN 2B (5 and 1 members), were studied. DNA was obtained from blood samples in all patients and from thyroid or from pheonochromocytoma tissues in patients submitted to surgery. PCR amplification was performed using specific primers for exons 10, 11 and 16, followed by direct sequencing. Mutations at codon 634 in exon 11 were found in 16 subjects with FMTC and MEN 2A: TGC --> CGC (cysteine to arginine) in 9 cases, TGC --> TAC (cysteine to tyrosine) in 3, and TGC --> TTC (cysteine to phenilalanine) in 4. A unique mutation of codon 918 in exon 16, ATG --> ACG (methionine to threonine), was found in both MEN 2B affected patients. The mutations detected in DNA from peripheral blood were the same as those present in DNA extracted from tumor material. RET mutations were detected in all affected patients, confirming the diagnosis, and in 10 members of their families. In five of the carriers total thyroidectomy was performed. Anatomopathological study showed C-cells hyperplasia or in-situ microcarcinoma in two children (9 and 12 y) with no clinical signs of diseases and medullary thyroid carcinoma in three adults, who were previously unaware of the presence of thyroid nodules. The early detection of RET mutation followed by total thyroidectomy may prevent the development of the disease, specially in affected families, and avoid the fatal outcome of delayed medullary thyroid carcinoma diagnosis.
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PMID:[Early diagnosis of multiple endocrine neoplasia type 2 (MEN 2) by detection of mutated RET proto-oncogene carriers]. 970 52

We investigated the dynamics of the genetic changes that are associated with two types of glioma recurrence, that is, progression from a lower-grade to a high-grade tumor (7 cases) and development of a same high-grade recurrence (15 cases). Each pair of tumors was analyzed for TP53 mutation, EGFR amplification, and loss of heterozygosity for tumor suppressor genes (TP53, RB1, CDKN2A, PTEN, DMBT1) and tumor suppressor gene regions (1p36, 19q13, 11p15, 10p15) known to be frequently implicated in glioma tumorigenesis. By comparing the genetic changes in the primary and corresponding secondary tumors, we found that additional loss of CDKN2A and/or RB1, encoding important components of the cell cycle regulatory pathway, was the most frequent genetic change in both types of recurrence development (10 of 22 cases, 45%). Additional loss of heterozygosity for the 10p15 region, for PTEN, and/or for DMBT1 in the recurrent tumor was noted in 7 of 22 cases (32%), suggesting that additional inactivation of tumor suppressor genes on chromosome 10 is another important feature of glioma relapse. Less frequent additional losses were detected for chromosome regions 11p15 and 19q13 (3 of 22 cases, 14%, each). We conclude that glioma recurrences are characterized by an increased involvement of tumor suppressor genes, even in those cases in which the primary and secondary tumor are of the same high malignancy grade.
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PMID:Dynamics of genetic alterations associated with glioma recurrence. 973 18

Biological evidence suggests that interference with the function of the angiogenic growth factor receptor VEGFR2 (flk1/KDR) is a particularly promising strategy to inhibit tumor-induced angiogenesis. Proof of concept was established by developing a monoclonal rat anti-mouse VEGFR2 antibody (DC101) and showing that it potently blocked the binding of VEGF to its receptor, inhibited VEGF-induced signaling, and strongly blocked tumor growth in mice through an anti-angiogenic mechanism. Since DC101 does not cross-react with the human VEGFR2 KDR, anti-KDR monoclonal antibodies were generated by standard hybridoma technology and by using phage display library. High affinity antibodies (Kd = 4.9 x 10(-10)-1.1 x 10(-9) M) were found with both approaches. The anti-KDR antibodies compete on an equimolar basis with VEGF for binding to KDR and inhibit with similar potency the VEGF-induced signaling and mitogenesis in human endothelial cells. Although these antibodies cannot be tested for in vivo efficacy in standard murine tumor models because of lack of species cross-reactivity, the similarity of their in vitro properties with those of DC101 suggests that they may be effective in blocking KDR function in vivo.
Cancer Metastasis Rev 1998 Jun
PMID:Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. 977 Jan 11

The goal of our study was to develop a panel of tumor cell lines along with paired non-malignant cell lines or strains collected from breast cancers, predominantly primary tumors. From a total of 189 breast tumor samples consisting of 177 primary tumors and 12 metastatic tissues, we established 21 human breast tumor cell lines that included 18 cell lines derived from primary tumors and 3 derived from metastatic lesions. Cell lines included those from patients with germline BRCA1 and FHIT gene mutations and others with possible genetic predisposition. For 19 tumor cell lines, we also established one or more corresponding non-malignant cell strains or B lymphoblastoid (BL) lines, which included 16 BL lines and 7 breast epithelial (2) or stromal (5) cell strains. The present report describes clinical, pathological and molecular information regarding the normal and tumor tissue sources along with relevant personal information and familial medical history. Analysis of the breast tumor cell lines indicated that most of the cell lines had the following features: they were derived from large tumors with or without axillary node metastases; were aneuploid and exhibited a moderate to poorly differentiated phenotype; were estrogen receptor (ER)- and progesterone receptor (PR)-negative; and overexpressed p53 and HER2/neu proteins. Of 13 patients with primary breast cancers receiving curative intent mastectomies, 7 were dead after a mean period of 10 months. Our panel of paired tumor and non-malignant cell lines should provide important new reagents for breast cancer research.
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PMID:Characterization of paired tumor and non-tumor cell lines established from patients with breast cancer. 983 71

FLT3-ligand (FL) is a recently described cytokine that stimulates the proliferation and differentiation of hematopoietic progenitors both in vivo and in vitro and, when administered to mice, induces an accumulation of dendritic cells (DC) in different lymphoid and nonlymphoid organs and tissues, including the liver. We have studied the antitumor effect of FL administered alone or in combination with IL-12 in a day 3 murine liver metastasis model. FL significantly reduced the number of hepatic metastases (36.00 +/- 11.00 vs 92.00 +/- 10.19 in control group, p < 0.05). Histologic evaluation of the livers revealed that FL induced a significant infiltration of the tumor border by lymphocytes and DC associated with increased number of apoptotic figures. Immunohistochemical analysis demonstrated that FL significantly enhanced the number of DC in the liver parenchyma and within the liver metastases, as well as the number of CD4+ and CD8+ T lymphocytes. These data support the suggestion that DC may be directly involved in the antitumor effect of FL. Interestingly, the antitumor effect of FL was greatly reduced by the NK depletion. Combination of FL and IL-12 resulted in greater antitumor efficacy than these cytokines alone. In summary, we have shown that FL has significant antitumor effect on preexisting murine C3 liver tumors that is mediated by NK cells. We have also demonstrated that the FL/IL-12 combination has an enhanced antitumor activity in the same murine tumor model.
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PMID:FLT3-ligand administration inhibits liver metastases: role of NK cells. 983 2

Our research goal is to better understand the mechanisms controlling the initiation and progression of thyroid diseases. One such disease, papillary thyroid carcinoma (PTC), is the leading endocrine malignancy in the United States. Recently, a family of related fusion proteins, RET/PTC1-5, has been implicated in the early stages of PTC. Although all five members of this family have the c-RET proto-oncogene kinase domain in their COOH terminus, little is known about how these genes alter follicular cell biology. Consequently, to answer questions related to the mechanism of the RET/PTC fusion protein action, we have devised a molecular genetic strategy to study PTC using a mouse model of thyroid disease. A new member of this fusion oncogene family, RET/PTC3, which has been implicated in more cases of solid tumor carcinoma (79%) than PTC1 or PTC2 and predominates (80%) in radiation-induced thyroid cancer of children, was investigated in our study. We have generated transgenic mice expressing human RET/PTC3 exclusively in the thyroid. These mice develop thyroid hyperplasia, solid tumor variants of papillary carcinoma and metastatic cancer. This new transgenic line will be useful in deciphering the molecular and biological mechanisms that cause PTC and histological variations in humans.
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PMID:The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. 985 89


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