Tenofovir disoproxil fumarate monotherapy for nucleos(t)ide analogue-na?ve and nucleos(t)ide analogue-experienced chronic hepatitis B patients

Background/Aims

This study investigated the antiviral effects of tenofovir disoproxil fumarate (TDF) monotherapy in nucleos(t)ide analogue (NA)-naive and NA-experienced chronic hepatitis B (CHB) patients.

Methods

CHB patients treated with TDF monotherapy (300 mg/day) for ≥12 weeks between December 2012 and July 2014 at a single center were retrospectively enrolled. Clinical, biochemical, and virological parameters were assessed every 12 weeks.

Results

In total, 136 patients (median age 49 years, 96 males, 94 HBeAg positive, and 51 with liver cirrhosis) were included. Sixty-two patients were nucleos(t)ide (NA)-naïve, and 74 patients had prior NA therapy (NA-exp group), and 31 patients in the NA-exp group had lamivudine (LAM)-resistance (LAM-R group). The baseline serum hepatitis B virus (HBV) DNA level was 4.9±2.3 log IU/mL (mean±SD), and was higher in the NA-naïve group than in the NA-exp and LAM-R groups (5.9±2.0 log IU/mL vs 3.9±2.0 log IU/mL vs 4.2±1.7 log IU/mL, P<0.01). The complete virological response (CVR) rate at week 48 in the NA-naïve group (71.4%) did not differ significantly from those in the NA-exp (71.3%) and LAM-R (66.1%) groups. In multivariate analysis, baseline serum HBV DNA was the only predictive factor for a CVR at week 48 (hazard ratio, 0.809; 95% confidence interval, 0.729-0.898), while the CVR rate did not differ with the NA experience.

Conclusions

TDF monotherapy was effective for CHB treatment irrespective of prior NA treatment or LAM resistance. Baseline serum HBV DNA was the independent predictive factor for a CVR.     

稳定期慢性阻塞性肺疾病的抗生素治疗进展

慢性阻塞性肺疾病(COPD)是一种呼吸系统常见的慢性疾病,炎症反应在其发生、发展过程中是导致一系列病理生理改变的重要机制.根据病程可分为稳定期和急性加重期,目前的研究表明对于易出现急性加重的患者,一年内长期使用阿奇霉素或红霉素可减少急性加重风险(A级证据),至于长期使用抗生素的安全性和有效性仍待更多的研究.现针对稳定期COPD的抗生素治疗作一综述,探讨不同给药方式及抗生素种类对COPD患者的益处、不良反应以及耐药性的影响,旨在为临床工作提供参考.     

C-JNK信号通路对糖尿病大鼠心肌Ito钾通道重构的影响

目的研究c-JNK信号通路在糖尿病(DM)大鼠左室心肌细胞电压门控钾通道(Kv)重构中的作用和内在调控机制。方法将50只健康SD大鼠随机分为DM组[n=25,采用链尿佐菌素(STZ)诱导成模]和对照组(sham)(n=25)。应用全细胞膜片钳方法记录DM组与sham组大鼠心室肌瞬时外向钾电流(Ito);使用非放射性JNK激酶分析kit进行c-Jun活性测定。应用JNK抑制剂SP600125(10M)对DM大鼠心肌细胞进行体外孵育,观察孵育前后心肌细胞Ito的变化。用硫氧还蛋白还原酶(TrxR)抑制剂金诺芬(AF)对经JNK抑制剂SP600125孵育的大鼠心肌细胞进行处理,观察处理前后心肌细胞Ito的变化。应用抗Kv4.2抗体对Kv4.2的含量进行检测,检测结果使用UVP生物成像系统进行分析。结果DM组心肌JNK活性显著升高超过1倍,而Ito显著降低[Sham组:(31.2±3.4)pA/pF,n=16;DM组:(15.4±3.1)pA/pF,n=17;P<0.05]。DM大鼠心室肌细胞经JNK抑制剂SP600125(10 M)处理4 h后,Ito电流密度可恢复至Sham组水平[DM+SP600125组:(31.9±3.8)pA/pF,n=18;Sham组:(31.2±3.4)pA/pF,n=16;P<0.05];且sham组经SP600125处理后的最大Ito电流强度[(29.8±3.4)pA/pF,n=9]和未经处理的sham组无统计学差异。DM心肌经膜渗透性蛋白抑制剂JNKI-1(10 M)处理后,Ito密度也有显著增加,而sham组经相同处理后无改变。TrxR抑制剂AF显著抑制了SP600125对DM大鼠心肌Ito电流的增大作用[DM+AF+SP600125:(15.5±3.2)pA/pF,n=17],而AF对sham组Ito无明显影响。JNK抑制剂SP600125治疗后DM大鼠心肌的Kv4.2蛋白表达量显著增大,尽管未完全恢复到sham组心肌水平,但与先前在DM大鼠心肌所观察到的Ito电流改变一致。而JNK抑制并没有明显改变sham组心肌的Kv4.2蛋白表达量。结论DM大鼠心肌钾通道重构是氧化还原敏感的,可能通过持续性激活c-JNK信号通路促进Ito重构。在DM心肌中,JNK活性显著增高,Kv通道的电流密度降低;抑制JNK信号通路后可显著改善Kv通道重构,这一过程可能被硫氧还原蛋白系统所调控。     

Nodal promotes the generation of M2‐like macrophages and downregulates the expression of IL‐12

Nodal, a member of the TGF‐β superfamily, is an embryonic morphogen that is upregulated in different types of tumors. Nodal increases the tumorigenesis by inducing angiogenesis and promoting metastasis. Importantly, Nodal inhibition suppresses the growth and invasion of tumor. Since tumor‐associated macrophages (TAMs) are the major infiltrating leukocytes in most cancers, we investigated whether Nodal is involved in the differentiation of TAMs. Our results revealed that Nodal inhibition in tumor microenvironment upregulated the production of IL‐12 in macrophages and reversed TAMs to classically activated macrophage phenotype. In contrast, treatment with recombinant Nodal (rNodal) decreased the expression of IL‐12 in murine macrophages. Furthermore, rNodal promoted macrophage polarization to an alternatively activated macrophage‐like/TAM phenotype and modulated its function. These results suggest that Nodal may play an important role in macrophage polarization and downregulation of IL‐12. The rescued antitumor function of TAMs via the inhibition of Nodal expression could be a new therapeutic strategy for cancer treatment.     

Amplification and over‐expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells

Gene amplifications in the 17q chromosomal region are observed frequently in breast cancers. An integrative bioinformatics analysis of this region nominated the MAP3K3 gene as a potential therapeutic target in breast cancer. This gene encodes mitogen‐activated protein kinase kinase kinase 3 (MAP3K3/MEKK3), which has not yet been reported to be associated with cancer‐causing genetic aberrations. We found that MAP3K3 was amplified in approximately 8–20% of breast cancers. Knockdown of MAP3K3 expression significantly inhibited cell proliferation and colony formation in MAP3K3‐amplified breast cancer cell lines MCF‐7 and MDA‐MB‐361 but not in MAP3K3 non‐amplified breast cancer cells. Knockdown of MAP3K3 expression in MAP3K3‐amplified breast cancer cells sensitized breast cancer cells to apoptotic induction by TNFα and TRAIL, as well as doxorubicin, VP‐16 and fluorouracil, three commonly used chemotherapeutic drugs for treating breast cancer. In addition, ectopic expression of MAP3K3, in collaboration with Ras, induced colony formation in both primary mouse embryonic fibroblasts and immortalized human breast epithelial cells (MCF‐10A). Combined, these results suggest that MAP3K3 contributes to breast carcinogenesis and may endow resistance of breast cancer cells to cytotoxic chemotherapy. Therefore, MAP3K3 may be a valuable therapeutic target in patients with MAP3K3‐amplified breast cancers, and blocking MAP3K3 kinase activity with a small molecule inhibitor may sensitize MAP3K3‐amplified breast cancer cells to chemotherapy. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Tandem Action of SNS–Cr and CGC–Ti in Preparation of Ethylene–1‐Hexene Copolymers from Ethylene Feedstock

Ethylene–1‐hexene copolymer materials, ranging from semicrystalline linear low‐density poly­ethylene (LLDPE) to completely amorphous polyethylenes (PEs), are prepared from ethylene alone in a single reactor by the tandem polymerization of bis(2‐dodecylsulfanyl‐ethyl)amine–CrCl₃ (SNS–Cr) and (N‐tert‐butylamido) (tetramethylcyclopentadienyl)–titanium dichloride (CGC–Ti) at 75 °C and under atmospheric pressure. The polymerization activities are on the order of 10⁵–10⁶ g (mol Ti)^?1 h^?1. 1‐Hexene incorporation in the resulting copolymers can be adjusted by varying the Cr–Ti molar ratio and/or applying a short period of pre‐trimerization. Copolymers with high 1‐hexene incorporation up to 15 mol% are obtained. Few vinyl and vinylene chain ends are detected by ¹³C NMR, suggesting that 1‐hexene does not act as a chain‐transfer agent. Narrow molecular‐weight distributions with polydispersities from 1.9 to 2.6 are obtained, characteristic of a single‐active‐site nature of the catalyst system.

     

2019 Chinese Hypertension League guidelines on home blood pressure monitoring

In China, automated blood pressure monitors have been readily available for home use. Home blood pressure monitoring has been indispensable in the management of hypertension. There is therefore a need to establish guidelines for home blood pressure monitoring on the basis of the 2012 consensus document. In this guidelines document, the committee put forward recommendations on the selection and calibration of blood pressure measuring devices, the frequency (times) and duration (days) of blood pressure measurement, and the diagnostic threshold of home blood pressure.