Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current treatments for preventing thrombotic diseases are associated with a significant risk of bleeding. Improved anticoagulant agents are therefore still required. The specificity and pharmacokinetics properties of monoclonal antibodies to coagulation factors allow novel anticoagulation approaches. Treatment with human antibodies or humanized mouse monoclonal antibodies should avoid unacceptable side effects due to immune response to the drug. Such antibodies were developed against three coagulation factor: Tissue factor (TF), Factor IX (FIX) and Factor VIII (FVIII). A fully humanized antibody was successfully derived from a mouse monoclonal antibodies to TF. In vivo studies with monoclonal antibodies to TF demonstrated efficient antithrombotic activity. Anti-TF antibodies may also prove useful in cardiovascular disorders and cancer, given the role of TF in these diseases. Mouse and human monoclonal antibodies to FIX were also efficient to prevent thrombosis in animal models of venous and arterial thrombosis and in stroke. A humanized anti-FIX antibody was tested in phase I study in healthy volunteers. The pharmacokinetics of the antibody were determined by the rapid formation of stable complexes with newly synthesised FIX. Human anti-FVIII antibodies inhibiting only partially FVIII activity were recently described. Investigations in mice have established that treatment with such anti-FVIII antibodies is efficient to prevent deep vein thrombosis. Given the low concentration of FVIII in plasma and the long half-life of antibody, treatment with anti-FVIII antibody could be very convenient, allowing one administration every month. Altogether, monoclonal antibodies to coagulation factor appear as promising novel antithrombotic drugs.
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PMID:The use of antibodies to coagulation factors for anticoagulant therapy. 1537 13

Since fine-needle aspiration biopsy (FNAB) was introduced, the value of frozen section (FS) has been questioned. This study compares FNAB and FS sensitivities among the usual form of papillary thyroid cancer (uPTC) and variants of PTC such as tall cell (tcPTC), follicular (fPTC), and Hurthle cell (HcPTC). A total of 257 patients who underwent preoperative FNAB, intraoperative FS, and thyroidectomy for PTC were, randomly selected from a database of a university teaching hospital in Toronto. There were 218 females (84.8%) and 39 males (15.2%), from 19 to 89 years of age (mean of 44 years), having uPTC (n = 212), fPTC (n = 24), HcPTC (n = 14), and tcPTC (n = 7). Data were analyzed using chi2 test. Sensitivities were calculated by division of true positives and by the sum of true positives and false negatives. True positives had to reflect a conclusive diagnosis of cancer. The FNAB sensitivities were uPTC (39.2%), fPTC (25%), HcPTC (42.9%), tcPTC (85.7%), similar to FS sensitivities (p = 0.497) for uPTC (44.3%), fPTC (16.7%), HcPTC (42.9%), and tcPTC (71.4%). Use of FS following FNAB increased sensitivities for uPTC to 56.1%, fPTC to 29.2%, and tcPTC to 100%. In addition, FS did not increase FNAB sensitivity in HcPTC. Combination FNAB plus FS failed in 43.9% of uPTC, 70.8% of fPTC, and 57.1% of HcPTC. We concluded that FNAB and FS sensitivity vary with PTC subtype and are still necessary for selection and treatment. The recognition of morphologic subtypes of PTC from the FNAB could optimize the selection of patients for intraoperative FS, enhance the preoperative assessment of prognosis, facilitate the surgical planning, and simplify the preparation of postoperative adjuvant therapy.
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PMID:Role of fine-needle aspiration biopsy and frozen section in the management of papillary thyroid carcinoma subtypes. 1559 61

Recent molecular studies have provided new insights into thyroid carcinogenesis. In thyroid papillary carcinomas at least three initiating events may occur, which are point mutations in the BRAF and RAS genes and RET/PTC rearrangements. Tumors harboring mutant BRAF and RAS are prone to progression to poorly differentiated and anaplastic carcinoma, but most likely require additional mutations to trigger this process. In thyroid follicular carcinomas, two known initiating events are RAS mutations and PAX8-PPARgamma rearrangements, and RAS predisposes to dedifferentiation of follicular carcinomas. p53 and beta-catenin mutations, found with increasing incidence in poorly differentiated and anaplastic carcinomas but not in well-differentiated tumors, may serve as a direct molecular trigger of tumor dedifferentiation. Additional evidence for progression from a preexisting well-differentiated carcinoma to poorly differentiated and anaplastic carcinoma comes from the studies of loss of heterozygosity and comparative genomic hybridization. Molecular studies, although limited by the lack of uniform histologic criteria for poorly differentiated carcinomas, revealed no genetic mutations or chromosomal abnormalities that are unique for poorly differentiated carcinoma and not present in well-differentiated or anaplastic carcinomas. This suggests that poorly differentiated carcinoma, as a group, represents a distinct step in the evolution from well-differentiated to anaplastic thyroid carcinoma, rather than an entirely separate type of thyroid malignancy.
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PMID:Genetic alterations involved in the transition from well-differentiated to poorly differentiated and anaplastic thyroid carcinomas. 1568 56

Papillary thyroid carcinomas are characterized in 70% of cases by the presence of either a RET/PTC rearrangement, or an activating point mutation of RAS or BRAF genes that induce a constitutive activation of the MAP kinase pathway. Follicular carcinomas are characterized by the presence of a RAS mutation or of a PAX8-PPARgamma rearrangement. Inactivating mutations of the p53 gene are found only in anaplastic thyroid carcinomas.
Bull Cancer 2005 Jan
PMID:[Oncogenes and thyroid tumors]. 1568 24

The immune response might suppress thyroid cancer recurrence. Although the factors that control this are unknown, CD-40 and CD-40 ligand might be important. To test this, we stained 36 papillary (PTC) and four follicular (FTC) thyroid carcinomas for CD-40 (n = 37) and CD-40 ligand (n = 36) and graded staining from absent (grade 0) to intense (grade 3). Follicular cells of the majority of thyroid tumors expressed CD-40 (30/37, 81%) and CD-40 ligand (15/24, 69%). Cancers from young patients (< or =21 years of age) that expressed CD-40 contained more numerous lymphocytes/high-power field (36 +/- 11) than cancers that failed to express CD-40 (4 +/- 3, p = 0.01), but there was no correlation with clinical outcome. Among young patients, CD-40 ligand expression was more intense in multifocal (1.1 +/- 0.2 vs. 0.45 +/- 0.2, p = 0.037), aggressive (1.14 +/- 0.14 vs. 0.65 +/- 0.2, p = 0.05) and recurrent tumors (1.2 +/- 0.2 vs. 0.65 +/- 0.2, p = 0.05) and associated with reduced disease-free survival (p = 0.03). We conclude that the majority of thyroid cancers express CD-40 and CD-40 ligand. In patients < or =21 years of age, tumors with intense expression of CD-40 ligand are more often multifocal, aggressive, and recurrent.
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PMID:Thyroid cancers express CD-40 and CD-40 ligand: cancers that express CD-40 ligand may have a greater risk of recurrence in young patients. 1575 67

The RET proto-oncogene is responsible for the development of several human inherited and non-inherited diseases. Germline point mutations were identified in multiple endocrine neoplasia types 2A and 2B, and familial medullary thyroid carcinoma. More than 10 rearranged forms of RET, referred to as RET/PTC 1-9, ELKS/RET and RFP/RET, have been cloned from sporadic and radiation-associated papillary thyroid carcinomas. These mutations induced oncogenic activation of RET tyrosine kinase by different mechanisms. To date, various kinds of therapeutic approaches have been developed for the treatment of RET-associated cancers, including tyrosine kinase inhibitors, gene therapy with dominant negative RET mutants, and RNA interference to abrogate oncogenic mutant RET expression. RET and some signaling molecules that function downstream of RET could be potential targets for the development of selective cancer therapeutics.
Cancer Sci 2005 Mar
PMID:The RET proto-oncogene: a molecular therapeutic target in thyroid cancer. 1577 16

Thyroid cancers have been the main medical consequence of the Chernobyl accident. On the basis of their pathological features and of the fact that a large proportion of them demonstrate RET-PTC translocations, these cancers are considered as similar to classical sporadic papillary carcinomas, although molecular alterations differ between both tumours. We analysed gene expression in post-Chernobyl cancers, sporadic papillary carcinomas and compared to autonomous adenomas used as controls. Unsupervised clustering of these data did not distinguish between the cancers, but separates both cancers from adenomas. No gene signature separating sporadic from post-Chernobyl PTC (chPTC) could be found using supervised and unsupervised classification methods although such a signature is demonstrated for cancers and adenomas. Furthermore, we demonstrate that pooled RNA from sporadic and chPTC are as strongly correlated as two independent sporadic PTC pools, one from Europe, one from the US involving patients not exposed to Chernobyl radiations. This result relies on cDNA and Affymetrix microarrays. Thus, platform-specific artifacts are controlled for. Our findings suggest the absence of a radiation fingerprint in the chPTC and support the concept that post-Chernobyl cancer data, for which the cancer-causing event and its date are known, are a unique source of information to study naturally occurring papillary carcinomas.
Br J Cancer 2005 Apr 25
PMID:Absence of a specific radiation signature in post-Chernobyl thyroid cancers. 1581 49

Oxyphil or Hurthle cell tumours of the thyroid are characterised by their consistent excessive number of mitochondria. A recently discovered gene, GRIM-19 has been found to fulfil two roles within the cell: as a member of the interferon-beta and retinoic acid-induced pathway of cell death, and as part of the mitochondrial Complex I assembly. In addition, a gene predisposing to thyroid tumours with cell oxyphilia (TCO) has been mapped to chromosome 19p13.2 in one family. A cluster of genes involved in mitochondrial metabolism occurs in this region; one of these is GRIM-19. We have searched for GRIM-19 mutations in a series of 52 thyroid tumours. Somatic missense mutations in GRIM-19 were detected in three of 20 sporadic Hurthle cell carcinomas. A germline mutation was detected in a Hurthle cell papillary carcinoma arising in a thyroid with multiple Hurthle cell nodules. No mutations were detected in any of the 20 non-Hurthle cell carcinomas tested, nor in any of 96 blood donor samples. In one of the sporadic Hurthle cell papillary carcinomas positive for GRIM-19 mutation, we have also detected a ret/PTC-1 rearrangement. No GRIM-19 mutations were detected in any of the six cases of known familial Hurthle cell tumour tested, so that our results do not support the identification of GRIM-19 as the TCO gene. The GRIM-19 mutations we have detected are the first nuclear gene mutations specific to Hurthle cell tumours to be reported to date; we propose that such mutations can be involved in the genesis of sporadic or familial Hurthle cell tumours through the dual function of GRIM-19 in mitochondrial metabolism and cell death.
Br J Cancer 2005 May 23
PMID:Somatic and germline mutation in GRIM-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid. 1590 Mar 3

The Pendred syndrome gene (PDS) encodes a transmembrane protein, pendrin, which is expressed in follicular thyroid cells and participates in the apical iodide transport. Pendrin expression has been studied in various thyroid neoplasms by means of immunohistochemistry (IHC), Western blot and RT-quantitative real-time PCR. The expression was related to the functional activity of the thyroid tissue. Follicular cells of normal, nodular goitre and Graves' disease tissues express pendrin at the apical pole of the thyrocytes. In follicular adenomas, pendrin was detected in cell membranes and cytoplasm simultaneously in 10 out of 15 cases. Pendrin protein was detected in 73.3 and 76.7% of the follicular (FTC) and papillary (PTC) thyroid carcinomas, respectively, where pendrin was solely localised inside the cytoplasm. An extensive intracellular immunostaining of pendrin was observed in six out of 11 (54.5%) of positive FTCs and 19 out of 23 (82%) of PTCs. Focal reactivity was detected in one follicular- and three papillary carcinomas, whereas pendrin protein was absent in three of 15 FTC and four of 30 PTC; mRNA of pendrin was detected in 92.4% of thyroid tumours. The relative mRNA expression of pendrin was lower in cancers than in normal thyroid tissues (P<0.001). The pendrin protein level was found to parallel its mRNA expression, which was not, however, related to the tumour size and tumour stage. In conclusion, pendrin is expressed in the majority of differentiated thyroid tumours with high individual variability but its targeting to the apical cell membrane is affected.
Br J Cancer 2005 Jul 11
PMID:Expression of pendrin in benign and malignant human thyroid tissues. 1594 36

The variety of diseases caused by mutations in RET receptor tyrosine kinase provides a classic example of phenotypic heterogeneity. Gain-of-function mutations of RET are associated with human cancer. Gene rearrangements juxtaposing the tyrosine kinase domain to heterologous gene partners have been found in sporadic papillary carcinomas of the thyroid (PTC). These rearrangements generate chimeric RET/PTC oncogenes. In the germline, point mutations of RET are responsible for multiple endocrine neoplasia type 2 (MEN 2A and 2B) and familial medullary thyroid carcinoma (FMTC). Both MEN 2 mutations and PTC gene rearrangements potentiate the intrinsic tyrosine kinase activity of RET and, ultimately, activate the RET downstream targets. Loss-of-function mutations of RET cause Hirschsprung's disease (HSCR) or colonic aganglionosis. A deeper understanding of the molecular signaling of normal versus abnormal RET activity in cancer will enable the development of potential new treatments for patients with sporadic and inherited thyroid cancer or MEN 2 syndrome. We now review the role and mechanisms of RET signaling in development and carcinogenesis.
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PMID:RET tyrosine kinase signaling in development and cancer. 1598 21


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