Hepatitis B virus large surface protein is priming for hepatocellular carcinoma development via induction of cytokinesis failure

Chronic hepatitis B virus (HBV) infection is a main risk factor for development of liver cirrhosis and hepatocellular carcinoma (HCC). Although HBV vaccination and antiviral therapy lead to substantial risk reduction for HCC development, it is evident that both can reduce, but not completely eliminate the risk. High serum levels of HBV surface antigen (HBsAg) were shown to predict disease progression of chronic HBV infection in patients harboring low viral load, and in line with this, HBV surface proteins were shown to exert oncogenic functions. As HBsAg seroclearance is infrequently achieved in patients who have undergone antiviral therapy, it is necessary to gain further insights into molecular mechanisms of HBsAg seroclearance failure after antiviral therapy and HCC development mediated by HBV surface proteins. A recent study published in this journal has shown that the HBsAg large surface protein (LHBs) contributes to HCC development by inducing cytokinesis failure and consequent aneuploidy via induction of DNA damage and polo-like kinase 1 (PLK1)-mediated G2/M checkpoint failure in hepatocytes. Inhibition of PLK1 by a PLK1-specific small molecule inhibitor was shown to restore G2/M checkpoint in vitro and to reduce tumor burden in vivo. The initial LHBs-induced hepatocyte aneuploidy may give rise to further aneuploidy and thereby lead to self-propagating cycles of chromosomal instability driving intra-tumor heterogeneity and clonal cancer evolution. Thus, LHBs-induced cytokinesis failure may be a priming event for HCC development. In conclusion, the study not only provides further mechanistic insights into the oncogenic role of LHBs, but also identifies a potential target to interfere with the vicious circle of LHBs-induced aneuploidy, which may be especially useful in patients showing failure of HBsAg seroclearance after antiviral therapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

新生大鼠原代肝细胞四氯化碳损伤模型与叶下珠保肝活性成分的提取与初步分离

目的：采用大鼠原代肝细胞四氯化碳化学性损伤模型，结合四甲基偶氮噻唑蓝比色法的体外药理模型，对传统中草药叶下珠的活性成分进行提取和初步分离，追踪叶下珠保肝护肝的活性单体成分。方法：实验于2006—05／12在浙江大学药学院中药开发及评价重点研究实验室完成。①制备新生大鼠原代肝细胞四氯化碳损伤的药理模型。②叶下珠提取物的制备：采用水、体积分数为0.95的乙醇对叶下珠活性成分进行回流提取。③活性成分的初步分离：依次用石油醚、氯仿、乙酸乙酯、正丁醇萃取；应用AB-8大孔吸附树脂分步洗脱法，即体积分数为0.1～0.9的乙醇洗脱。④采用四甲基偶氮噻唑蓝比色法，通过保护率及增生指数，观察回流提取物、各萃取物及AB-8大孔树脂各洗脱部位对大鼠四氯化碳损伤原代肝细胞的保护作用。结果：①正丁醇萃取物对大鼠四氯化碳损伤原代肝细胞的保护率及其增生指数高于阳性对照槲皮素及其他各萃取物（P〈0．05-0．01）。②正丁醇萃取物中，体积分数为0.1，0.3，0.5的乙醇洗脱部分对大鼠四氯化碳损伤原代肝细胞具有保护作用，但体积分数为0.1的乙醇洗脱部分保护作用最强，显著高于阳性对照槲皮素及其他各处理组（P〈0．01），体积分数为0.1乙醇洗脱部分在剂量为200g／L时，保护率为64．43％，增生指数达到2．952。结论：叶下珠保肝护肝的有效部位为正丁醇萃取物中AB-8大孔吸附树脂体积分数为0.1的乙醇洗脱部分。但叶下珠中保肝的有效单体成分还没有确定，有待进一步实验证明。     

Orion和Window颈椎前路钢板置入对颈椎稳定性影响的生物力学评估

目的:以Orion为代表的静力性钢板有较高植骨不融合率;Window钢板属动力性钢板,理论上有减少应力遮挡的作用,促进植骨融合。本文通过比较Orion和Window两种颈椎前路钢板生物力学特点对颈椎单椎间减压植骨融合模型稳定性的影响,为临床应用提供理论依据。方法:实验于2004-10/2005-05在上海大学生物力学研究所完成。①实验分组:取新鲜小牛颈椎标本12具,平均年龄1个月,随机数字表法分成两组,Orion组:用Orion钢板固定;Window组:用Window钢板固定;每组6具。②实验方法及评估:用生物力学测定仪测定正常颈椎C4/5节段在前屈、后伸、侧屈、旋转时的运动范围,然后切除C4/5椎间盘,制成模型,测定植骨加钢板,植骨块缩短1mm加钢板固定后颈椎相应节段在150N的载荷下的运动范围,植骨块的长度根据测量椎间隙的高度而定。结果:纳入小牛颈椎标本12具,均进入结果分析。Orion和Window钢板在前屈、后伸、侧屈、旋转时初始稳定性相似(P>0.05),其中Orion钢板在前屈时与正常颈椎相比稳定性提高,差异有显著性(P<0.05),在后伸、侧屈、旋转时差异无显著性(P>0.05);Window钢板与正常标本相比,在前屈、后伸时稳定性提高且差异有显著性(P<0.05),在侧屈、旋转时差异无显著性(P>0.05)。在植骨缩短后,两种钢板的稳定性均下降,Orion钢板在前屈时稳定性仍较正常颈椎好,差异有显著性意义(P<0.05),在后伸、侧屈、旋转时差异无显著性(P>0.05);Window钢板在前屈时稳定性比正常颈椎好,差异显著(P<0.05),在后伸时差异无显著性(P>0.05),在侧屈、旋转时不能达到正常颈椎的稳定性(P<0.05)。结论:Orion钢板在植骨与植骨块缩短后以及Window钢板在植骨后均能提供有效的稳定性,Window钢板在植骨缩短后不能提供有效的稳定性。     

IMPROVED TOLERABILITY OF FELODIPINE COMPARED WITH AMLODIPINE IN ELDERLY HYPERTENSIVES: A RANDOMISED,DOUBLE-BLIND STUDY IN 535 PATIENTS,FOCUSING ON VASODILATORY ADVERSE EVENTS

SUMMARY The primary aim of this double-blind, parallel group trial was to compare incidence of newly occurring vasodilatory adverse events in elderly patients treated with recommended once-daily doses of felodipine extended release (ER) or amlodipine. A total of 535 patients over 65 years old with a sitting diastolic blood pressure of 90-115 mmHg and/or systolic blood pressure 160-220 mmHg, were recruited at 46 centres worldwide. Patients were randomised to felodipine ER 2.5 mg or amlodipine 5 mg. If blood pressure was >160/90 mmHg after three or six weeks, felodipine ER was increased to 5 and 10 mg and amlodipine to 10 mg. After nine weeks, average doses of felodipine ER and amlodipine were 5.5 mg and 7.3 mg, respectively. Newly occurring vasodilatory adverse events were reported by 32% of felodipine ER patients and 43% of amlodipine patients (p=0.007). Both treatments effectively reduced blood pressure 24 hours post-dose. Using a low starting dose and individual titration, felodipine ER achieves good control of blood pressure with few vasodilatory side-effects.     

A MULTICENTRE STUDY TO COMPARE THE THERAPEUTIC EFFICACY OF SUSTAINED-RELEASE DILTIAZEM AND ENALAPRIL IN THE TREATMENT OF PATIENTS WITH MILD TO MODERATE HYPERTENSION

SUMMARY A 14-week study was conducted in order to compare the efficacy and tolerability of a twice-daily sustained-release diltiazem preparation (120 or 180 mg) and once-daily enalapril (10 or 20 mg). Patients not achieving an adequate response after 6 weeks on monotherapy were given a combination therapy of twice-daily diltiazem 120 mg and once-daily enalapril 10 mg. Of the 147 patients admitted to the study, 70 received diltiazem and 77 received enalapril; 17 patients subsequently received combination therapy. Blood pressure reductions in patients completing 12 weeks of therapy were (sitting values): diltiazem 120 mg, 10.2/15.2 mmHg; diltiazem 180 mg, 19.1/14.7 mmHg; enalapril 10 mg, 25.7/17.5 mmHg; enalapril 20 mg, 19.6/14.0 mmHg; and combination therapy, 24.6/15.1 mmHg. No significant differences in the incidence level of individual symptoms were seen between the two groups: 34 (49%) in the diltiazem, 37 (48%) in the enalapril group; and, between weeks 6 and 12, 9 (53%) patients taking combination therapy. Two patients withdrew from the enalapril group and 8 from the diltiazem group. No unexpected side-effects were seen during the study and no deaths occurred in any treatment group. Twice-daily sustained-release diltiazem 120 or 180 mg was shown to be an effective antihypertensive agent and equal in efficacy and patient acceptability to once-daily enalapril 10 or 20 mg. Combination therapy effectively lowered blood pressure in patients in whom monotherapy was ineffective.     

Topical clindamycin versus systemic tetracycline in the treatment of acne: Results of a multiclinic trial

In a multiclinic double-blind trial, 305 patients with moderate to severe acne vulgaris were treated with oral tetracycline hydrochloride, 250 mg (N: 103), a 1% solution of clindamycin phosphate (N: 105), or placebo (N: 97) twice daily for 8 weeks. The response to treatment was evaluated by lesion counts and overall clinical improvement at 2, 4, 6, and 8 weeks. Both topical clindamycin and oral tetracycline significantly reduced papule and pustule counts compared to placebo; they were rated significantly higher than placebo on the physician's and the patient's overall evaluation at the end of the treatment period. No serious side effects were reported with any of the study medications.     

Loss of tumor suppressor mir-203 mediates overexpression of LIM and SH3 Protein 1 (LASP1) in high-risk prostate cancer thereby increasing cell proliferation and migration

Several studies have linked overexpression of the LIM and SH3 domain protein 1 (LASP1) to progression of breast, colon, liver, and bladder cancer. However, its expression pattern and role in human prostate cancer (PCa) remained largely undefined.Analysis of published microarray data revealed a significant overexpression of LASP1 in PCa metastases compared to parental primary tumors and normal prostate epithelial cells. Subsequent gene-set enrichment analysis comparing LASP1-high and -low PCa identified an association of LASP1 with genes involved in locomotory behavior and chemokine signaling. These bioinformatic predictions were confirmed in vitro as the inducible short hairpin RNA-mediated LASP1 knockdown impaired migration and proliferation in LNCaP prostate cancer cells.By immunohistochemical staining and semi-quantitative image analysis of whole tissue sections we found an enhanced expression of LASP1 in primary PCa and lymph node metastases over benign prostatic hyperplasia. Strong cytosolic and nuclear LASP1 immunoreactivity correlated with PSA progression. Conversely, qRT-PCR analyses for mir-203, which is a known translational suppressor of LASP1 in matched RNA samples revealed an inverse correlation of LASP1 protein and mir-203 expression. Collectively, our results suggest that loss of mir-203 expression and thus uncontrolled LASP1 overexpression might drive progression of PCa.     

Initiation of health-behaviour change among employees participating in a web-based health risk assessment with tailored feedback

Background  

Primary prevention programs at the worksite can improve employee health and reduce the burden of cardiovascular disease. Programs that include a web-based health risk assessment (HRA) with tailored feedback hold the advantage of simultaneously increasing awareness of risk and enhancing initiation of health-behaviour change. In this study we evaluated initial health-behaviour change among employees who voluntarily participated in such a HRA program.     

Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08)

Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in multiple myeloma. The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. Twelve patients with advanced hematologic malignancies were treated with nelfinavir (2500–5000 mg/day p.o., days 1–14, 3+3 dose escalation) and bortezomib (1.3 mg/m², days 1, 4, 8, 11; 21-day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2×2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly up-regulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising activity in advanced, bortezomib-refractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance.