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Klaus G. Griewank Rajmohan Murali Bastian Schilling Tobias Schimming Inga M?ller Iris Moll Marion Schwamborn Antje Sucker Lisa Zimmer Dirk Schadendorf Uwe Hillen 《PloS one》2013,8(11)
Activating mutations in the TERT promoter were recently identified in up to 71% of cutaneous melanoma. Subsequent studies found TERT promoter mutations in a wide array of other major human cancers. TERT promoter mutations lead to increased expression of telomerase, which maintains telomere length and genomic stability, thereby allowing cancer cells to continuously divide, avoiding senescence or apoptosis. TERT promoter mutations in cutaneous melanoma often show UV-signatures. Non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma, are very frequent malignancies in individuals of European descent. We investigated the presence of TERT promoter mutations in 32 basal cell carcinomas and 34 cutaneous squamous cell carcinomas using conventional Sanger sequencing. TERT promoter mutations were identified in 18 (56%) basal cell carcinomas and in 17 (50%) cutaneous squamous cell carcinomas. The recurrent mutations identified in our cohort were identical to those previously described in cutaneous melanoma, and showed a UV-signature (C>T or CC>TT) in line with a causative role for UV exposure in these common cutaneous malignancies. Our study shows that TERT promoter mutations with UV-signatures are frequent in non-melanoma skin cancer, being present in around 50% of basal and squamous cell carcinomas and suggests that increased expression of telomerase plays an important role in the pathogenesis of these tumors. 相似文献
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Wiebke Sondermann Klaus G. Griewank Bastian Schilling Elisabeth Livingstone Julia C. Leyh Natalia Rompoti Ioana Cosgarea Tobias Schimming Dirk Schadendorf Lisa Zimmer Uwe Hillen 《PloS one》2015,10(4)
We have previously demonstrated an impact of the BRAF inhibitor vemurafenib on patient lymphocyte counts. In the current study, the extent to which concomitant use of corticosteroids in BRAF inhibitor treated patients affects lymphocyte counts and predisposes to infection was investigated. A cohort of 102 patients receiving either the selective BRAF inhibitor vemurafenib or dabrafenib was analyzed. The amount of patients receiving either medication with or without systemic corticosteroids (dexamethasone) was determined and lymphocyte counts before and under therapy assessed. Additionally, the number and severity of infections occurring in these groups was analyzed. Vemurafenib treatment led to a considerable decrease in lymphocyte cell counts, with 62.3% of patients having lymphopenia. Dabrafenib treated patients only rarely demonstrated lymphopenia (12.5%). Dexamethasone co-administration further diminished lymphocyte counts. Lymphopenias were observed in 84.6% of patients receiving vemurafenib and dexamethasone. In our cohort, infections were noted in 9 patients, 4 of these were severe and 2 eventually fatal. All 9 cases with infections demonstrated lymphopenia, 8 of these had received dexamethasone and 7 of these a therapy with vemurafenib. Our findings demonstrate a significant lymphopenia in patients treated with the BRAF inhibitor vemurafenib, which is further augmented by dexamethasone and predisposes to infection. If validated in other studies, risk of infection should be considered when applying corticosteroids in combination with BRAF inhibitors, in particular vemurafenib. 相似文献
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Partial 18S rRNA sequences of five chelicerate arthropods plus a
crustacean, myriapod, insect, chordate, echinoderm, annelid, and
platyhelminth were compared. The sequence data were used to infer phylogeny
by using a maximum-parsimony method, an evolutionary-distance method, and
the evolutionary-parsimony method. The phylogenetic inferences generated by
maximum-parsimony and distance methods support both monophyly of the
Arthropoda and monophyly of the Chelicerata within the Arthropoda. These
results are congruent with phylogenies based on rigorous cladistic analyses
of morphological characters. Results support the inclusion of the
Arthropoda within a spiralian or protostome coelomate clade that is the
sister group of a deuterostome clade, refuting the hypothesis that the
arthropods represent the "primitive" sister group of a protostome coelomate
clade. Bootstrap analyses and consideration of all trees within 1% of the
length of the most parsimonious tree suggest that relationships between the
nonchelicerate arthropods and relationships within the chelicerate clade
cannot be reliably inferred with the partial 18S rRNA sequence data. With
the evolutionary-parsimony method, support for monophyly of the Arthropoda
is found in the majority of the combinations analyzed if the coelomates are
used as "outgroups." Monophyly of the Chelicerata is supported in most
combinations assessed. Our analyses also indicate that the
evolutionary-parsimony method, like distance and parsimony, may be biased
by taxa with long branches. We suggest that a previous study's inference of
the Arthropoda as paraphyletic may be the result of (a) having two few
arthropod taxa available for analysis and (b) including long-branched taxa.
相似文献
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We investigated the protective effect of vitamin D against liver damage caused by carbon tetrachloride (CCl4). Twenty-four male rats were divided into four equal groups: G1, untreated controls; G2, administered CCl4; G3, administered both CCl4 and vitamin D for 10 weeks; G4, administered CCl4 for 10 weeks and vitamin D for 12 weeks. At the end of experiment, intracardiac blood samples were taken and liver samples were removed. Hepatic damage due to CCl4 was assessed using biochemistry and histopathology. Glutathione (GSH) levels decreased, while malondialdehyde (MDA) levels increased in liver tissues of G2. Alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl-transaminase (GGT) levels increased, while albumin (ALB) levels decreased. Hepatocyte degeneration, lobular disorder, sinusoid dilation, focal necrotic areas, hyperemia, and glycogen loss were observed. Hepatic fibrosis was observed around portal areas and central veins. Bridging fibrous septa were formed between portal veins. By immunohistochemistry, both matrix metalloproteinase-9 (MMP-9) and desmin reactivity were increased. All aspects of liver damage were at least partially prevented in rats treated with vitamin D. Vitamin D appears to act as an antioxidant and anti-fibrotic to protect the rat liver against damage. 相似文献
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S Vamsee Raju Jody H Tate Sandra KG Peacock Ping Fang Robert A Oster Mark T Dransfield Steven M Rowe 《Respiratory research》2014,15(1):18