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91.
Marcuello E Altés A del Rio E César A Menoyo A Baiget M 《International journal of cancer. Journal international du cancer》2004,112(5):733-737
Thymidylate synthase (TS) is the primary target of 5-fluorouracil (5-FU). A VNTR polymorphism in the TS promoter region is associated with the efficacy of 5-FU-based chemotherapy in colorectal cancer. A common G>C SNP at the 12th nucleotide of the second repeat in the TS*3 alleles has been recently described. The combination of SNP and VNTR allows the definition of 3 TS alleles: *2, *3G and *3C. The aim of our study was to evaluate the predictive value of clinical response and survival of these new defined TS alleles. TS genotypes of 89 patients diagnosed with metastatic colorectal cancer and undergoing 5-FU-based chemotherapy were carried out. The clinical outcome was evaluated according to the genotype (high expression genotype: *2R/*3G; *3C/*3G; *3G/*3G; and low expression genotype: *2R/*2R; *2R/*3C; *3C/*3C. A higher overall response was observed in the group of patients with a low expression genotype (p = 0.035). The probability of achieving a clinical response of patients with a low expression-related genotype was 2.9 higher than that of the other group (95% CI = 1.03-5.6, p = 0.04). The median time to progression was 12 months and 9 months in the low and high expression groups, respectively (p = 0.07, log rank test). Overall survival was significantly longer in the low expression group. In this group the median OS was not achieved at 50 months of follow-up in contrast to the 20 months observed in the high expression group (p = 0.03). TS genotype was an independent predictor of progression-free and overall survival in the Cox regression models after adjustment to the other clinical variables. The selection of patients who are likely to respond to 5-FU therapy may be considerably improved if the TS genotype were to include both the VNTR and the SNP located within the promoter region of the gene. 相似文献
92.
Changes in growth hormone-releasing hormone (GHRH), GHRH-receptor (R), somatostatin and interleukin (IL)-1beta mRNA levels were determined in fetal rat hypothalamic cultures after administration of IL-1beta (1, 10, 100 ng/ml, 2 h incubation), and in adult rat hypothalamus 5 h after intracerebroventricular injection of IL-1beta (2.5 and 25 ng). IL-1beta stimulated GHRH-R mRNA expression both in vitro (10 and 100 ng/ml) and in vivo (2.5 and 25 ng). Somatostatin mRNA was significantly stimulated and GHRH mRNA slightly reduced in vitro, while these mRNA species were not altered in vivo in response to IL-1beta. IL-1beta stimulated its own expression both in vitro (10 and 100 ng/ml) and in vivo (25 ng). IL-1beta-induced mRNA responses occurred 2 h after treatment in vitro (incubation times, 30 min to 6 h). IL-1beta also elicited slight GHRH releases in vitro. Up-regulation of hypothalamic GHRH-R by IL-1beta may explain previous findings suggesting that IL-1beta stimulates GHRH activity. 相似文献
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The kappa intronic (MiE(kappa)) and 3' (3'E(kappa)) enhancers are both quantitatively important to, but not essential for, immunoglobulin kappa rearrangement. To determine the functional redundancy between these two enhancers, B cells derived from mutant embryonic stem cells--in which both MiE(kappa) and 3'E(kappa) were deleted on both kappa alleles--were analyzed for kappa rearrangement. Our findings indicate that these double-mutant B cells have essentially no kappa rearrangement but do rearrange and express lambda. Therefore, these two kappa enhancers share essential roles in activating V(kappa)J(kappa) rearrangement. Our findings also indicate that the two kappa enhancers play overlapping and distinct roles in the demethylation of kappa in B cells. 相似文献
95.
Development in vertebrates follows distinctive pathways of cellular differentiation. Starting from the zygote, newly formed cells continually differentiate until they reach a final mature fate. Whether differentiating into a neuron, a hepatocyte or a myofibril, every normal cell, with the exception of developing lymphocytes, carries the same genetic information enclosed within its nucleus. To acquire distinct cellular identities, cells need to control gene expression in a very regulated way. Genes encoding factors required for identity at a particular developmental stage need to be appropriately activated, whereas genes required for identity during the previous developmental stage are often silenced. Moreover, once a cell becomes terminally differentiated, 'heritable' gene expression must be maintained in all daughter cells and, thus, faithfully recapitulated after each cellular division. 相似文献
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Muscle herniation can be defined as protrusion of a portion of muscle through an acquired or congenital defect of enclosing fascia. Although it is usually a cosmetic problem, it can lead to local pain and tenderness after prolonged exertion. In this report, we present a case of flexor digitorum superficialis muscle herniation in a 58-year-old man. The radiographic, ultrasonographic and magnetic resonance imaging findings are described with dynamic examination, permitting demonstration of muscle herniation through the fascial defect during muscle contraction. 相似文献
99.
Rooney S Alt FW Lombard D Whitlow S Eckersdorff M Fleming J Fugmann S Ferguson DO Schatz DG Sekiguchi J 《The Journal of experimental medicine》2003,197(5):553-565
In developing lymphocytes, the recombination activating gene endonuclease cleaves DNA between V, D, or J coding and recombination signal (RS) sequences to form hairpin coding and blunt RS ends, which are fused to form coding and RS joins. Nonhomologous end joining (NHEJ) factors repair DNA double strand breaks including those induced during VDJ recombination. Human radiosensitive severe combined immunodeficiency results from lack of Artemis function, an NHEJ factor with in vitro endonuclease/exonuclease activities. We inactivated Artemis in murine embryonic stem (ES) cells by targeted mutation. Artemis deficiency results in impaired VDJ coding, but not RS, end joining. In addition, Artemis-deficient ES cells are sensitive to a radiomimetic drug, but less sensitive to ionizing radiation. VDJ coding joins from Artemis-deficient ES cells, which surprisingly are distinct from the highly deleted joins consistently obtained from DNA-dependent protein kinase catalytic subunit-deficient ES cells, frequently lack deletions and often display large junctional palindromes, consistent with a hairpin coding end opening defect. Strikingly, Artemis-deficient ES cells have increased chromosomal instability including telomeric fusions. Thus, Artemis appears to be required for a subset of NHEJ reactions that require end processing. Moreover, Artemis functions as a genomic caretaker, most notably in prevention of translocations and telomeric fusions. As Artemis deficiency is compatible with human life, Artemis may also suppress genomic instability in humans. 相似文献
100.