泛素化及自噬参与蛋白降解及抗原提呈的研究进展

细胞内所有的蛋白质都在不断的被降解,并被新合成的蛋白质所取代。真核细胞内主要有两条蛋白降解途径,分别为泛素一蛋白酶体系统途径和白噬途径,两条途径都在维持细胞内稳态方面起着重要的作用。泛素-蛋白酶体系统是由泛素介导的一种高度复杂的蛋白降解机制,它通过一种特定的方式降解并再循环利用细胞内的蛋白,而自噬是一种自我降解过程,它通过溶酶体介导的方式降解蛋白。被降解的蛋白可以被提呈至MHCⅡ类分子或MHCⅠ类分子,从而激发有效的T细胞反应。此文就这两个途径参与蛋白降解及抗原提呈的相关研究进展进行综述。     

Definitive chemoradiotherapy with capecitabine and cisplatin for elder patients with locally advanced squamous cell esophageal cancer

Purpose

The aim of this retrospective study is to evaluate the feasibility and efficacy of concurrent chemoradiotherapy (CCRT) or sequential chemoradiotherapy (SCRT) with capecitabine and cisplatin for elderly patients with locally advanced esophageal squamous cell carcinoma (ESCC).

Methods

A total of 75 patients elder than 65 years with histologically proven stage II–III ESCC were enrolled, in whom 40 patients were treated with CCRT consisted of two cycles of intravenous cisplatin and oral capecitabine during and after radiotherapy and 35 patients were treated with SCRT as two cycles of capecitabine plus cisplatin before and after radiotherapy. Response rate, overall survival, progression-free survival and toxicity were compared.

Results

The overall response rate (CR + PR) in the CCRT group (91.6 %) was significantly higher than that in the SCRT group (67.7 %), P = 0.023. The median PFS and median OS were significantly higher in CCRT group (19.7 and 33.6 months) than those in SCRT group (11.6 and 15.7 months), P < 0.05. The acute toxic effect was more severe in the CCRT group than in the SCRT group, but the grade 3–4 acute toxicities were similar in two groups.

Conclusions

It suggested that both CCRT and SCRT with capecitabine and cisplatin are tolerable and effective for elderly patients with locally advanced ESCC. Concurrent CRT might be superior to SCRT.     

Role of induction and consolidation chemotherapy in elderly acute myeloid leukemia patients

The present study sought to elucidate the role of induction and consolidation therapy in elderly patients. We retrospectively collected data of 477 patients who were aged over 60 years at the time of acute myeloid leukemia (AML) diagnosis. The median overall survival (OS) was 339 days in the induction group (n = 266) and 86 days in the best supportive care group (n = 211) (P < 0.001). In the induction group, the complete remission (CR) rate was 58.3 %, and treatment-related death was 15.4 %. Successful induction was related to good performance [Eastern Cooperative Oncology Group (ECOG <2)] [hazard ratio (HR) 3.215; P = 0.002]. Mortality correlated with failure to achieve CR (HR 4.059; P < 0.001) and poor performance status (ECOG >2) (HR 2.731; P = 0.035). In CR patients, poor karyotype and absence of consolidation (HR 2.313; P = 0.003) correlated with mortality. More than one cycle of consolidation was associated with better OS (P < 0.001). Lack of salvage therapy was associated with mortality in patients who did not achieve CR (HR 3.223; P = 0.005). Intensive induction in patients with good performance and >1 cycle of consolidation after CR may be the best strategy for improving OS in elderly AML patients.     

Cross-regulation by TLR4 and T cell Ig mucin-3 determines severity of liver injury in a CCl4-induced mouse model

Acute liver injury is a common pathological basis for a variety of acute liver diseases in the clinic, which can eventually lead to liver fibrosis and even liver failure. In this study, we found that T cell Ig and mucin domain protein 3 (Tim-3) and TLR4 receptors play important roles in CCl4-induced acute liver injury. Tim-3 is a negative regulator that is expressed by T cells and macrophages. Using antibodies against Tim-3 (anti-Tim-3 Ab), we studied the Tim-3 signal in an animal model of acute liver injury and found that a large number of inflammatory factors were upregulated. In vitro experimental data shown that anti-Tim-3 Ab treatment increased interferon-ɣ production by concanavalin A (ConA)-stimulated spleen T cells, and we found that the expression level of interleukin (IL)-6 was increased in a macrophage/spleen T cell coculture system, while administration of galectin-9 (Gal-9, a Tim-3 ligand) reduced the IL-6 production. This indicates the importance of the Tim-3/Gal-9 signalling pathway in maintaining hepatic homeostasis. The Tim-3 signalling pathway inhibits TLR4-mediated NF-κB activity, and an anti-Tim-3 Ab does not affect the liver injury in TLR4-deficient mice. Regulation between Tim-3 and TLR4 determines the severity of liver damage. The negative regulation of Tim-3 reflects the protective mechanisms of patients with impaired liver function, and these results provide important information about innate and adaptive responses in the regulation of liver damage. This finding is potentially important for the study of early liver injury.     

Mild degenerative changes of hip cartilage in elderly patients: an available sample representative of early osteoarthritis

This study investigated the cellular and molecular changes which occur in cartilage from adults with femoral neck fracture (FNF) and osteoarthritis (OA), and explored the similarities in hip cartilage obtained from elderly patients and patients with early OA. Femoral heads were retrieved from 23 female patients undergoing total hip arthroplasty (THA). This group included 7 healthy patients with FNF (hFNF), 8 elderly adults with FNF (eFNF), and 8 elderly patients with hip OA (OA). After high-field MRI T2 mapping, osteochondral plugs were harvested from the weight-bearing area of femoral heads for subsequent macroscopic, histologic, and immunochemical evaluation. Additionally, the contents of cartilage matrix were analyzed, and gene expression was detected. The surface of cartilage from hFNF and eFNF patients appeared smooth, regular, and elastic, whereas it showed irregularities, thinning, and defects in OA patients. Elevated T2 values and decreased accumulation of glycosaminoglycans (GAGs) were detected in cartilage from eFNF patients. Furthermore, type I collagen accumulation was slightly increased and type X collagen concentration was obviously elevated in eFNF patients; however, type II collagen distribution and the contents and anisotropy of collagen fibrils in eFNF patients showed no significant changes. Consistent with histology and immunohistochemical results, aggrecan was downregulated and type X collagen was upregulated, while collagens types I and II showed no significant changes in eFNF patients. The cellular and molecular characteristics of hip cartilage in eFNF patients who showed no symptoms of OA were similar to those in patients with mild OA. Thus, eFNF cartilage can serve as a comparative specimen for use in studies investigating early OA.     

氟哌啶醇预防危重症患者谵妄发生的Meta分析

目的系统评价氟哌啶醇预防危重患者发生谵妄的疗效和安全性。 方法计算机检索Medline、EMbase、The Cochrane Library、维普数据库、中国知网、中国生物医学文献数据库数据库从建库至2018年9月的关于氟哌啶醇预防危重症患者谵妄疗效的随机对照试验（RCT）。由2位研究者按照纳入与排除标准独立筛选文献、提取资料和评价质量后,采用RevMan 5.2软件进行Meta分析。 结果共纳入4个RCT,2 455例患者。Meta分析结果显示,试验组与对照组危重症患者间28 d谵妄发病率[相对危险度（RR） = 0.96,95%置信区间（CI）（0.65,1.43）,Z = 0.19,P = 0.85]、28 d无谵妄及无昏迷时间[均数差（MD） = 0.05,95%CI（-0.06,0.15）,Z = 0.88,P = 0.38]、28 d存活率[RR = 1.00,95%CI（0.97,1.04）,Z = 0.23,P = 0.82]、ICU住院时间[MD = -0.18,95%CI（-2.00,1.64）,Z = 0.20,P = 0.84]的比较,差异均无统计学意义。且在严重不良反应方面,两组患者间QTc间期延长[RR = 1.18,95%CI（0.83,1.67）,Z = 0.92,P = 0.36]、锥体外系症状[RR = 1.07,95%CI（0.69,1.67）,Z = 0.31,P = 0.76]、过度镇静[RR = 1.90,95%CI（0.77,4.66）,Z = 1.40,P = 0.16]发生的比较,差异也均无统计学意义。 结论氟哌啶醇不能预防危重症患者谵妄的发生,且对预后也没有明显改善作用。     

利福平外用致原位肝移植术后患者过敏反应1例

肝炎后肝硬化患者,原发性肝癌行原位肝移植术,于术后7 d皮肤破溃处涂利福平胶囊粉后出现过敏反应．利福平为临床常用的广谱抗菌素,外用后快速导致过敏反应未见报道, 该病例既往无过敏史,特殊之处在于为原位肝移植术后患者,移植术后用药有很多特殊之处,可供参考的资料不多．抗过敏治疗上以尽快纠正低氧血症对移植肝功能的恢复至关重要．     

Attenuation of inflammation in streptozotocin-induced diabetic rabbits by Matricaria chamomilla oil: A focus on targeting NF- κ B and NLRP3 signaling pathways

Objectives: The present study was conducted to investigate the protective effects of chamomile oil from Matricaria chamomilla against type 1 diabetes mellitus(T1 DM) and its potential mechanisms.Methods: T1 DM was established in male New Zealand white rabbits via a single intraperitoneal infusion of streptozotocin(STZ)(80 mg/kg body weight-1, dissolved in 0.2 m L of normal saline). Different doses of chamomile oil(25, 50 and 100 mg/kg) were orally administrated to STZ induced diabetic rabbits for 21 consecutive days. The expression of pro-inflammatory cytokines was determined using ELISA assay. The expression of NF-κB and NLRP3 was measured using Western blot assay.Results: Compared with normal rabbits, STZ-induced diabetic rabbits exhibited significant increased levels of blood glucose and decreased levels of serum insulin that were reversed using middle and high tested dose of chamomile oil. Likewise, STZ-induced diabetic rabbits showed a significant increased expression of NF-κB and NLRP3 proteins in the pancreas tissue that was reversed by high tested dose of chamomile oil.Conclusion: Collectively, our findings demonstrated that chamomile oil possesses anti-hyperglycemic, and anti-inflammatory activities in STZ-induced diabetic rabbits by targeting inflammatory cytokines and NF-κB and NLRP3 signaling pathways.