Identification of glycoprotein Ib as a target for autoantibody in idiopathic (autoimmune) thrombocytopenic purpura

An antibody (DIL) from a patient with idiopathic thrombocytopenic purpura (ITP) was shown to have autospecificity on the basis of reactions with autologous platelets that were identical to those obtained with platelets from normal subjects. DIL antibody also reacted strongly in an immunofluorescence test with platelets from a patient with Glanzmann's thrombasthenia, but failed to react with platelets from a patient with the Bernard-Soulier syndrome who was known to be deficient in glycoprotein Ib (GPIb). Purified GPIb and control platelets, but not Bernard-Soulier platelets, inhibited the lytic activity of DIL. Using the GPIb-specific monoclonal antibody AP1 and one-dimensional rocket electrophoresis into gels containing rabbit antihuman platelet membrane antibody, it was shown that staphylococcal protein A-Sepharose beads coated with DIL antibody selectively remove GPIb from solubilized platelet preparations. By crossed immunoelectrophoresis it was found that DIL recognizes a determinant on GPIb on the membrane side of the cleavage site of the platelet calcium- activated protease (calpain). These studies provide direct evidence for binding of a platelet autoantibody to a determinant on GPIb relatively close to the site of insertion of this protein into the platelet membrane.     

诱导化疗在局部晚期头颈癌中的作用

作为标准化的非手术治疗,诱导化疗(ICT)在治疗局部晚期头颈鳞癌已有几十年的历史,但是关于其作用尚存争议。同期放化疗(CRT)是目前标准化的非手术治疗,然而由于ICT能够使肿瘤体积缩小,提高放疗的可行性,改善患者对放疗的耐受力,增加放疗后器官功能保留的可能性及降低远处转移率。所以,对ICT的研究从未停止。该文对近期随机试验进行回顾分析,与手术或单独CRT比较,评估ICT中紫杉醇的价值。Meta分析比较ICT中紫杉醇和顺铂及5氟尿嘧啶的作用。之前的随机试验中,并没有ICT提高生存率的报道。但     

A large real‐world cohort study examining the effects of long‐term entecavir on hepatocellular carcinoma and HBsAg seroclearance

Real‐world studies examining reduction in risk of hepatocellular carcinoma (HCC) in patients receiving antivirals are limited by the small size of the studies, or by data insufficiency and heterogeneity with short follow‐up duration. We aimed to examine the real‐world long‐term outcome of patients receiving entecavir treatment on HCC incidence and HBsAg seroclearance. The incidence of HCC in 1225 entecavir‐treated patients between 2002 and 2015 was compared with the HCC incidence estimated using the REACH‐B, GAG‐HCC and CU‐HCC scores. Standardized incidence ratios (SIR) were calculated. The impact of entecavir treatment on HBsAg seroclearance was also explored. The median follow‐up of the cohort was 6.6 years, with 66 cases of HCC development. Using the REACH‐B model, the reduction of HCC risk was significant from year 6 onwards with SIR of 0.68 (95% CI 0.535‐0.866) at year 10. In subgroup patients without cirrhosis, consistent risk reduction was observed from the fifth year and the SIR reached 0.51 (95% CI 0.271‐0.704) by year 10. Benefit in cirrhotic patients was demonstrated when using the GAG‐HCC and CU‐HCC score, with the SIR at year 10 being 0.38 (95% CI 0.259‐0.544) and 0.46 (95% CI 0.314‐0.659), respectively. The cumulative rate of HBsAg seroclearance was 5.2%. HBsAg level at third year of treatment and baseline‐to‐3‐year percentage reduction was predictive of subsequent HBsAg seroclearance. In conclusion, long‐term entecavir therapy was associated with significant reduction in the risk of HCC in the real world. However, HBsAg seroclearance rate remained low. Additional therapy may be considered in patients with adverse predictive factors for subsequent HBsAg seroclearance.     

Ovarian HBV replication following ovulation induction in female hepatitis B carriers undergoing IVF treatment: A prospective observational study

Hepatitis B virus (HBV) can be found in ovarian tissues. This study compared HBV DNA levels in follicular fluid collected during oocyte retrieval with paired serum samples in HBV carriers after ovarian stimulation during IVF treatment for infertility. Sixty‐four HBV carrier women referred to the Assisted Reproductive Units of two Hong Kong hospitals were recruited. At oocyte retrieval, the follicular fluid aspirated from the first follicle was collected for study. In 22 women, the first follicular fluid sample from both ovaries was similarly collected and studied. These women were also tested for liver function test and HBeAg. In 28 (43.8%) women, HBV DNA was detected in follicular fluid and the level correlated with serum levels (Spearman's correlation P < .001). There was concordant detection of HBV DNA in both ovaries, and the levels were significantly correlated (Spearman's correlation P = .029). In 40% of women with FF HBV DNA, the follicular fluid:serum ratio was >1.0, suggesting stimulation of HBV replication. These women also had significantly different liver function test results. Increased HBV replication exists in 40% of women with HBV DNA detected in follicular undergoing ovarian stimulation during IVF treatment.     

Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions

Aims/hypothesis

Diabetes mellitus represents a significant burden on the health of the global population. Both type 1 and type 2 diabetes share a common feature of a reduction in functional beta cell mass. A newly discovered ubiquitination molecule HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase (HUWE1 [also known as MULE or ARF-BP1]) is a critical regulator of p53-dependent apoptosis. However, its role in islet homeostasis is not entirely clear.

Methods

We generated mice with pancreas-specific deletion of Huwe1 using a Cre-loxP recombination system driven by the Pdx1 promoter (Pdx1cre ⁺ Huwe1 ^fl/fl) to assess the in vivo role of HUWE1 in the pancreas.

Results

Targeted deletion of Huwe1 in the pancreas preferentially activated p53-mediated beta cell apoptosis, leading to reduced beta cell mass and diminished insulin exocytosis. These defects were aggravated by ageing, with progressive further decline in insulin secretion and glucose homeostasis in older mice. Intriguingly, Huwe1 deletion provided protection against genotoxicity, such that Pdx1cre ⁺ Huwe1 ^fl/fl mice were resistant to multiple-low-dose-streptozotocin-induced beta cell apoptosis and diabetes.

Conclusion/interpretation

HUWE1 expression in the pancreas is essential in determining beta cell mass. Furthermore, HUWE1 demonstrated divergent roles in regulating beta cell apoptosis depending on physiological or genotoxic conditions.