The evolutionary conservation of the core components necessary for the extrinsic apoptotic signaling pathway, in Medaka fish

<p>Abstract</p> <p>Background</p> <p>Death receptors on the cell surface and the interacting cytosolic molecules, adaptors and initiator caspases, are essential as core components of the extrinsic apoptotic signaling pathway. While the apoptotic machinery governing the extrinsic signaling pathway is well characterized in mammals, it is not fully understood in fish.</p> <p>Results</p> <p>We identified and characterized orthologs of mammalian Fas, FADD and caspase-8 that correspond to the death receptor, adaptor and initiator caspase, from the Medaka fish (<it>Oryzias latipes</it>). Medaka Fas, caspase-8 and FADD exhibited protein structures similar to that of their mammalian counterparts, containing a death domain (DD), a death effector domain (DED) or both. Functional analyses indicated that these molecules possess killing activity in mammalian cell lines upon overexpression or following activation by apoptotic stimuli, suggesting similar pro-apoptotic functions in the extrinsic pathway as those in mammals. Genomic sequence analysis revealed that the Medaka <it>fas </it>(<it>tnfrsf6</it>), <it>fadd </it>and <it>caspase-8 </it>(<it>casp8</it>) genes are organized in a similar genomic structure as the mammalian genes. Database search and phylogenetic analysis revealed that the <it>fas </it>gene, but not the <it>fadd </it>and <it>casp8 </it>genes, appear to be present only in vertebrates.</p> <p>Conclusion</p> <p>Our results indicate that the core components necessary for the extrinsic apoptotic pathway are evolutionarily conserved in function and structure across vertebrate species. Based on these results, we presume the mechanism of apoptosis induction via death receptors was evolutionarily established during the appearance of vertebrates.</p

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Caspase-8 cleavage of the interleukin-21 (IL-21) receptor is a negative feedback regulator of IL-21 signaling

AbstractWe screened a library of human single-transmembrane proteins (sTMPs), produced by a cell-free system, using a luminescent assay to identify those that can be cleaved by caspase-8 (CASP8). Of the 407 sTMPs screened, only the interleukin-21 receptor (IL21R), vezatin (VEZT), and carbonic anhydrase XIV were cleaved at Asp344, Asp655 and Asp53, respectively. We confirmed that IL21R and VEZT were also cleaved in apoptotic HeLa cells with the cleavage sites. Interestingly, IL21R was cleaved within 30min after apoptosis induction. Furthermore the CASP8-cleaved form of IL21R did not induce phosphorylation at Tyr705 of STAT3. Our results suggest that the interleukin-21 signaling cascade is negatively regulated by CASP8

Hormonal Therapy Resistant Estrogen-receptor Positive Metastatic Breast Cancer Cohort (HORSE-BC) Study : Current Status of Treatment Selection in Japan

The Hormonal therapy resistant estrogen-receptor positive metastatic breast cancer cohort (HORSE-BC) study is a multicenter observational study evaluating the efficacy and safety of secondary endocrine therapy (ET) for postmenopausal cases of metastatic breast cancer (MBC) with poor response to primary ET. In this initial report we analyze the HORSE-BC baseline data to clarify the current status of treatment selection for MBC in Japan. Baseline data for the 50 patients enrolled in HORSE-BC were analyzed, including patient characteristics, types of secondary ET, and reasons for selecting secondary ET. Postoperative recurrence was detected in 84% of patients (42/50) and de novo stage IV breast cancer in 16% (8/50). Forty-one patients (41/50; 82%) received fulvestrant, 5 patients (10%) received selective estrogen receptor modulators (SERMs), 3 patients (6%) received ET plus a mammalian target of rapamycin (mTOR) inhibitor, and 1 patient received an aromatase inhibitor (AI) as the secondary ET. Forty-five patients selected their secondary ET based on its therapeutic effect, while 14 patients selected it based on side effects. Most patients with progression after primary ET selected fulvestrant as the secondary ET based on its therapeutic and side effects. We await the final results from the HORSE-BC study

Memleketin ilk Türk futbolcusu F. Hüsnü Kayacan

Taha Toros Arşivi, Dosya Adı: Galatasarayİstanbul Kalkınma Ajansı (TR10/14/YEN/0033) İstanbul Development Agency (TR10/14/YEN/0033

Molecular techniques and their limitations shape our view of the holobiont

It is now recognised that the biology of almost any organism cannot be fully understood without recognising the existence and potential functional importance of associated microbes. Arguably, the emergence of this holistic viewpoint may never have occurred without the development of a crucial molecular technique, 16S rDNA amplicon sequencing, which allowed microbial communities to be easily profiled across a broad range of contexts. A diverse array of molecular techniques are now used to profile microbial communities, infer their evolutionary histories, visualise them in host tissues, and measure their molecular activity. In this review, we examine each of these categories of measurement and inference with a focus on the questions they make tractable, and the degree to which their capabilities and limitations shape our view of the holobiont

Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes

Sirtuin 1 (Sirt1), a NAD[superscript +]-regulated deacetylase with numerous known positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. It is known to have protective effects against age-related disease, including diabetes. Here we investigated the protective role of Sirt1 in diabetic renal damage. We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria occurred in streptozotocin-induced or obese (db/db) diabetic mice. PT-specific SIRT1 transgenic and Sirt1 knockout mice showed prevention and aggravation of the glomerular changes that occur in diabetes, respectively, and nondiabetic knockout mice exhibited albuminuria, suggesting that Sirt1 in PTs affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by SIRT1-mediated epigenetic regulation in podocytes contributed to albuminuria. We did not observe these phenomena in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PTs to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the autofluorescence of photoactivatable NMN and injection of fluorescence-labeled NMN. In human subjects with diabetes, the levels of SIRT1 and Claudin-1 were correlated with proteinuria levels. These results suggest that Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function.Japan. Ministry of Education, Culture, Sports, Science and Technology (Grant 22790800

High testosterone levels in prostate tissue obtained by needle biopsy correlate with poor-prognosis factors in prostate cancer patients

Background: There is currently no consensus on the correlations between androgen concentrations in prostate tissue and blood and stage and pathological grade of prostate cancer. In this study, we used a newly-developed ultra-sensitive liquid-chromatography tandem mass spectrometry method to measure testosterone (T) and dihydrotestosterone (DHT) concentrations in blood and needle biopsy prostate specimens from patients with prostate cancer.Methods: We analyzed androgen levels in 196 men diagnosed with prostate cancer. All patients had undergone systematic needle biopsy, and an additional needle biopsy from the peripheral zone was conducted for the simultaneous determination of T and DHT. We analyzed the relationships between T and DHT levels in tissue and blood and Gleason score, clinical stage, and percentage of positive biopsy cores, using multivariate analysis. Results: The median T and DHT levels in blood were 3551.0 pg/mL and 330.5 pg/mL, respectively. There was a strong correlation between serum T and DHT. The median T and DHT levels in prostate tissue were 0.5667 pg/mg and 7.0625 pg/mg, respectively. In multivariate analysis, serum prostate-specific antigen and tissue T levels were significantly associated with poor prognosis; high T levels in prostate tissue were significantly related to high Gleason score (p = 0.041), advanced clinical stage (p = 0.002), and a high percentage of positive biopsy cores (p = 0.001). Conclusions: The results of this study indicate that high T levels in prostate tissue are related to high Gleason score, advanced clinical stage, and a high percentage of positive biopsy cores in patients with prostate cancer. T level in needle biopsy specimens may therefore be a useful prognostic factor in prostate cancer patients

Molecular analysis of the BCR-ABL1 kinase domain in chronic-phase chronic myelogenous leukemia treated with tyrosine kinase inhibitors in practice: Study by the Nagasaki CML Study Group

An appropriate trigger for BCR-ABL1 mutation analysis has not yet been established in unselected cohorts of chronic-phase chronic myelogenous leukemia patients. We examined 92 patients after 12 months of tyrosine kinase inhibitor (TKI) treatment in Nagasaki Prefecture, Japan. Univariate analysis revealed that significant factors associated with not attaining a major molecular response (MMR) were the presence of the minor BCR-ABL1 fusion gene, a low daily dose of TKI, and the emergence of BCR-ABL1 kinase domain mutations conferring resistance to imatinib. Factors associated with the loss of sustained MMR were a low daily dose of TKI and the emergence of alternatively spliced BCR-ABL1 mRNA with a 35-nucleotide insertion. Taken together, our results suggest that the search for BCR-ABL1 mutations should be initiated if patients have not achieved MMR following 12 months of TKI treatment