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Xenin is a peptide that is co-secreted with the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), from intestinal K-cells in response to feeding. Studies demonstrate that xenin has appetite suppressive effects and modulates glucose-induced insulin secretion. The present study was undertaken to determine the bioactivity and antidiabetic properties of two C-terminal fragment xenin peptides, namely xenin 18-25 and xenin 18-25 Gln. In BRIN-BD11 cells, both xenin fragment peptides concentration-dependently stimulated insulin secretion, with similar efficacy as the parent peptide. Neither fragment peptide had any effect on acute feeding behaviour at elevated doses of 500 nmol/kg bw. When administered together with glucose to normal mice at 25 nmol/kg bw, the overall insulin secretory effect was significantly enhanced in both xenin 18-25 and xenin 18-25 Gln treated mice, with better moderation of blood glucose levels. Twice daily administration of xenin 18-25 or xenin 18-25 Gln for 21 days in high fat fed mice did not affect energy intake, body weight, circulating blood glucose or body fat stores. However, circulating plasma insulin concentrations had a tendency to be elevated, particularly in xenin 18-25 Gln mice. Both treatment regimens significantly improved insulin sensitivity by the end of the treatment period. In addition, sustained treatment with xenin 18-25 Gln significantly reduced the overall glycaemic excursion and augmented the insulinotropic response to an exogenous glucose challenge on day 21. In harmony with this, GIP-mediated glucose-lowering and insulin-releasing effects were substantially improved by twice daily xenin 18-25 Gln treatment. Overall, these data provide evidence that C-terminal octapeptide fragments of xenin, such as xenin 18-25 Gln, have potential therapeutic utility for type 2 diabetes.

Aims/hypothesis Glucose-dependent insulinotropic polypeptide (GIP) and xenin, regulatory gut hormones secreted from enteroendocrine K cells, exert important effects on metabolism. In addition, xenin potentiates the biological actions of GIP. The present study assessed the actions and therapeutic utility of a (DAla 2 )GIP/xenin-8-Gln hybrid peptide, in comparison with the parent peptides (DAla 2 )GIP and xenin-8-Gln. Methods Following confirmation of enzymatic stability, insulin secretory activity of (DAla 2 )GIP/xenin-8-Gln was assessed in BRIN-BD11 beta cells. Acute and persistent glucose-lowering and insulin-releasing effects were then examined in vivo. Finally, the metabolic benefits of twice daily injection of (DAla 2 )GIP/xenin-8-Gln was determined in high-fat-fed mice. Results All peptides significantly ( p  < 0.05 to p  < 0.001) enhanced in vitro insulin secretion from pancreatic clonal BRIN-BD11 cells, with xenin (and particularly GIP)-related signalling pathways, being important for this action. Administration of (DAla 2 )GIP or (DAla 2 )GIP/xenin-8-Gln in combination with glucose significantly ( p  < 0.05) lowered blood glucose and increased plasma insulin in mice, with a protracted response of up to 4 h. All treatments elicited appetite-suppressive effects ( p  < 0.05), particularly (DAla 2 )GIP/xenin-8-Gln and xenin-8-Gln at elevated doses of 250 nmol/kg. Twice-daily administration of (DAla 2 )GIP/xenin-8-Gln or (DAla 2 )GIP for 21 days to high-fat-fed mice returned circulating blood glucose to lean control levels. In addition, (DAla 2 )GIP/xenin-8-Gln treatment significantly ( p  < 0.05) reduced glycaemic levels during a 24 h glucose profile assessment. Neither of the treatment regimens had an effect on body weight, energy intake or circulating insulin concentrations. However, insulin sensitivity was significantly ( p  < 0.001) improved by both treatments. Interestingly, GIP-mediated glucose-lowering ( p  < 0.05) and insulin-releasing ( p  < 0.05 to p  < 0.01) effects were substantially improved by (DAla 2 )GIP and (DAla 2 )GIP/xenin-8-Gln treatment. Pancreatic islet and beta cell area ( p  < 0.001), as well as pancreatic insulin content ( p  < 0.05), were augmented in (DAla 2 )GIP/xenin-8-Gln-treated mice, related to enhanced proliferation and decreased apoptosis of beta cells, whereas (DAla 2 )GIP evoked increases ( p  < 0.05 to p  < 0.01) in islet number. Conclusions/interpretation These studies highlight the clear potential of GIP/xenin hybrids for the treatment of type 2 diabetes.

Among 230 HIV-positive women in New York City, we examined the association of retrospective self-reports of sexual and physical abuse, current coping strategies and depressive symptomatology (CES-D scores). Results revealed a high prevalence of abuse in childhood (50%) and adulthood (68%); 7% reported physical assault or rape in the last 90 days. As expected, childhood abuse was significantly correlated with both adult and recent trauma, and each type of trauma correlated with CES-D scores. Childhood abuse also positively correlated with the frequency of current adaptive and avoidant coping strategies, although avoidant coping had a stronger (negative) association with CES-D scores. Hierarchical regression analyses revealed the association between childhood abuse and CES-D scores persisted even after controlling for relevant demographic variables, more recent trauma and coping strategies. Implications for improving the psychological functioning of women living with HIV/AIDS are discussed.

Dear Editor, The current standard 12-core systematic transrectal ultrasound （TRUS）-guided biopsy in prostate cancer diagnosis has the disadvantages of overdetecting indolent tumors, while failing to identify clinically significant cancers in up to 35%.1 Advances in imaging techniques, notably the multiparametric magnetic resonance imaging （mpMRI）, allow clinically significant prostate cancers to be detected with more precise localization） Fusion of MRI and real-time TRUS enables targeted biopsy of suspicious lesions, overcoming human error, and inability of biopsy site tracking in cognitive fusion？ Multiple Western series have suggested a higher detection rate, higher specificity, and better risk stratification with fusion biopsy.

We investigated the performance characteristics of prostate-specific antigen （PSA） and PSA density （PSAD） in Chinese men. All Chinese men who underwent transrectal ultrasound-guided prostate biopsy （TRUS-PB） from year 2000 to 2013 were included. The receiver operating characteristic （ROC） curves for both PSA and PSAD were analyzed. The sensitivity, specificity, positive predictive value （PPV） and negative predictive value （NPV） at different cut-off levels were calculated. A total of 2606 Chinese men were included. For the ROC, the area under curve was 0.770 for PSA （P〈 0.001） and 0.823 for PSAD （P〈 0.001）. PSA of 4.5 ng ml^-1 had sensitivity of 94.4%, specificity of 14.1%, PPV of 29.5%, and NPV of 86.9%; PSAD of 0.12 ng ml^-1cc^-1 had sensitivity of 94.5%, specificity of 26.6%, PPV of 32.8%, and NPV of 92.7%. On multivariate logistic regression analyses, PSA cut-off at 4.5 ng ml^-1 （OR 1.61, 95% CI 1.05-2.45, P = 0.029） and PSAD cut-off at 0.12 ng ml^-1 cc^-1 （OR 6.22, 95% CI 4.20-9.22, P 〈 0.001） were significant predictors for prostate cancer detection on TRUS-PB. In conclusion, the performances of PSA and PSAD at different cut-off levels in Chinese men were very different from those in Caucasians. PSA of 4.5 ng ml^-1 and PSAD of O. 12 ng ml^-1 cc^-1 had near 95% sensitivity and were significant predictors of prostate cancer detection in Chinese men.

我们分析了经直肠超声引导下穿刺活检后前列腺癌的检出率与直肠指检和前列腺特异性抗原水平的关系以及中国人群检出前列腺癌的危险因素。我们从数据库中检索了自2000年到2013年所有首次接受经直肠超声引导下前列腺穿刺活检的中国男性的数据。结合直肠指检的发现以及前列腺特异性抗原水平（〈 4, 4-10, 10.1-20,20.1-50 , 〉 50ng/ml）分析了前列腺癌的检出率。使用多因素Logistic回归研究了前列腺癌检出的潜在危险因素。共有2606中国男性人群纳入该研究。在直肠指检正常的患者中，不同前列腺特异性抗原水平（〈 4, 4-10,10.1-20, 20.1-50, 〉 50 ng/ml）患者前列腺癌的检出率分别为8.6％，13.4％，21.8％，41.7％和85.2％。在直肠指检异常的患者中，不同前列腺特异性抗原水平（〈 4, 4-10, 10.1-20, 20.1-50, 〉 50 ng/ml）患者前列腺癌的检出率分别为12.4%, 30.2%, 52.7%, 80.6%和96.4%。多因素Logistic回归分析提示：老龄、较小的前列腺体积、更多针数的穿刺活检、直肠指检异常发现、较高的PSA水平都与增大的前列腺癌检出风险相关（P 〈0.001）。与西方人群相比，中国男性人群的前列腺癌检出率较低。考虑到不同的危险因素，可以采用个体化的方式来决定是否采取经直肠超声引导下穿刺活检。

Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. Here we report hypoxia as a cause of MDSC accumulation. Using hepatocellular carcinoma (HCC) as a cancer model, we show that hypoxia, through stabilization of hypoxia-inducible factor-1 (HIF-1), induces ectoenzyme, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2/CD39L1), in cancer cells, causing its overexpression in HCC clinical specimens. Overexpression of ENTPD2 is found as a poor prognostic indicator for HCC. Mechanistically, we demonstrate that ENTPD2 converts extracellular ATP to 5′-AMP, which prevents the differentiation of MDSCs and therefore promotes the maintenance of MDSCs. We further find that ENTPD2 inhibition is able to mitigate cancer growth and enhance the efficiency and efficacy of immune checkpoint inhibitors. Our data suggest that ENTPD2 may be a good prognostic marker and therapeutic target for cancer patients, especially those receiving immune therapy. Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape. Here, the authors show that in hepatocellular carcinoma, hypoxia induces the expression of ENTPD2 on cancer cells leading to elevated extracellular 5′-AMP, which in turn promote the maintenance of MDSCs by preventing their differentiation.