Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy

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Atypical cutaneous γδ T cell proliferation with morphologic features of lymphoma but with clinical features and course of PLEVA or lymphomatoid papulosis

Reactive lymphoid infiltrates of the skin composed predominantly of gamma‐delta (γδ) T cells are not well described in the literature. Herein we report a case of an otherwise healthy 4‐year‐old male who presented with a waxing and waning papular rash characterized by small, discrete crusted papules spread across his trunk, face and extremities. Clinical evaluation revealed no evidence of systemic disease. Microscopic examination revealed a dermal, perivascular infiltrate of highly atypical lymphocytes with a γδ T cell phenotype, worrisome for primary cutaneous γδ T cell lymphoma. The clinical course, however, was that of a reactive condition and prompted consideration of a diagnosis of pityriasis lichenoides et varioliformis acuta (PLEVA) and lymphomatoid papulosis (LyP). In many ways, this case defies current classification schemes and seems to expand the spectrum of reactive γδ T cell infiltrates of the skin.     

批准用于奶牛的抗菌药物分析

我国奶牛养殖规模不断扩大,奶业产值比重逐步提高,给奶牛疫病防治带来巨大压力。奶牛乳房炎及细菌性肺炎等呼吸系统疾病和细菌性肠炎等消化系统疾病最为常见,抗菌药物的使用成为主要防治手段。但抗菌药物的不当使用易使细菌产生耐药性,增加临床治疗的成本和难度,危害我国奶牛产业发展。本文对截至2021年7月我国和美国、英国、日本、欧盟批准用于奶牛的抗菌药物产品进行整理、统计与分析,包括抗菌药物的分类、剂型以及适应证等,旨在为我国奶牛用抗菌药物管理、合理用药和新兽药开发提供参考。     

Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.     

The prognostic role of tumour‐infiltrating lymphocytes in oral squamous cell carcinoma: A meta‐analysis

It has been suggested that tumour‐infiltrating lymphocytes (TILs) are associated with the progression of oral squamous cell carcinoma (OSCC). However, the prognostic value of TILs is inconclusive due to the heterogeneity of immune cells within the tumour microenvironment. In this meta‐analysis, we aimed to assess the prognostic value of TILs in OSCC. The PubMed, Cochrane, Embase, Scopus and Web of Science databases were searched up to April 20, 2019, and 33 studies were ultimately included in this meta‐analysis. Our pooled meta‐analysis showed that high infiltration of CD8⁺ TILs, CD45RO⁺ TILs and CD57⁺ TILs favoured better overall survival (OS). However, high infiltration of CD68⁺ macrophages and CD163⁺ macrophages was associated with poor prognosis in OSCC. These findings suggest that CD8⁺ TILs, CD45RO⁺ TILs, CD57⁺ TILs, CD68⁺ macrophages and CD163⁺ macrophages might serve as novel prognostic factors and therapeutic targets in OSCC.     

豚鼠耳蜗微血管内皮细胞体外通透性的研究

目的　研究豚鼠耳蜗微血管内皮细胞的体外通透性特征。方法　在成功建立豚鼠耳蜗微血管内皮细胞体外通透性模型的基础上 ,研究该体外模型跨细胞电阻及对12 5I 牛血清白蛋白的通透性。结果　①耳蜗微血管内皮细胞在培养增殖过程中其跨细胞电阻呈动态变化过程 ,以 5× 10 4/cm2 的细胞密度接种时 ,7d左右电阻到达峰值 ,其跨细胞电阻峰值大小为 (118 9± 18 5 )Ω/cm2 ;②体外模型中加入12 5I 牛血清白蛋白后 ,其通透性呈上升期抛物线型曲线 ,90min内几乎呈直线。结论　跨细胞电阻及对12 5I 牛血清白蛋白变化曲线能反映体外耳蜗微血管内皮细胞的通透性特征     

树突状细胞激活的肿瘤浸润性淋巴细胞体外对自体肝癌细胞杀伤活性的研究

目的探讨树突状细胞(DC)激活的肿瘤浸润性淋巴细胞(TIL)体外对自体肝癌细胞杀伤活性.方法从肝癌患者外周血获取DC,应用粒/巨噬细胞集落刺激因子(GM-CSF)、白细胞介素-4(IL-4)和肿瘤抗原激活DC,然后用DC来激活TIL,观察TIL在体外对自体肝癌细胞的杀伤活性.结果DC激活的TIL具有很高的对自体肝癌细胞杀伤活性,杀伤率为(89.39±3.05)%,明显高于未经DC激活的TIL、CD激活的T淋巴细胞和未经DC激活的T淋巴细胞对自体肝癌细胞的杀伤率.结论肝癌患者外周血DC能诱导TIL产生高效而特异的抗肝癌免疫.     

On the Role of Proteasomes in Cell Biology and Proteasome Inhibition as a Novel Frontier in the Development of Immunosuppressants

The proteasome, a large protease complex in cells, is the major machinery for protein degradation. It was previously considered a humble garbage collector, performing housekeeping duties to remove misfolded or spent proteins. Until recently, the interests of immunologists in proteasomes were focused largely on its role in antigen processing. Its real importance in cell biology has only been revealed contemporarily due to the availability of relatively specific inhibitors. It has now become increasingly clear that many aspects of immune responses highly depend on proper proteasome activity. Recently, a proteasome inhibitor has been successfully used to prevent acute as well as ongoing heart allograft rejection in mice. Such inhibitors are also efficacious in treating several autoimmune diseases, such as arthritis, psoriasis, and probably type I diabetes, in animal models. Phase II and III clinical trials of proteasome inhibitors in treating various tumors have shown promising results, and the side-effects of these drugs are tolerable. Therefore, proteasome inhibition represents a new and promising frontier in immunosuppressant development.     

Preparation of protected peptidyl thioester intermediates for native chemical ligation by Nα‐9‐fluorenylmethoxycarbonyl (Fmoc) chemistry: considerations of side‐chain and backbone anchoring strategies,and compatible protection for N‐terminal cysteine*,†

Abstract: Native chemical ligation has proven to be a powerful method for the synthesis of small proteins and the semisynthesis of larger ones. The essential synthetic intermediates, which are C‐terminal peptide thioesters, cannot survive the repetitive piperidine deprotection steps of N^α‐9‐fluorenylmethoxycarbonyl (Fmoc) chemistry. Therefore, peptide scientists who prefer to not use N^α‐t‐butyloxycarbonyl (Boc) chemistry need to adopt more esoteric strategies and tactics in order to integrate ligation approaches with Fmoc chemistry. In the present work, side‐chain and backbone anchoring strategies have been used to prepare the required suitably (partially) protected and/or activated peptide intermediates spanning the length of bovine pancreatic trypsin inhibitor (BPTI). Three separate strategies for managing the critical N‐terminal cysteine residue have been developed: (i) incorporation of N^α‐9‐fluorenylmethoxycarbonyl‐S‐(N‐methyl‐N‐phenylcarbamoyl)sulfenylcysteine [Fmoc‐Cys(Snm)‐OH], allowing creation of an otherwise fully protected resin‐bound intermediate with N‐terminal free Cys; (ii) incorporation of N^α‐9‐fluorenylmethoxycarbonyl‐S‐triphenylmethylcysteine [Fmoc‐Cys(Trt)‐OH], generating a stable Fmoc‐Cys(H)‐peptide upon acidolytic cleavage; and (iii) incorporation of N^α‐t‐butyloxycarbonyl‐S‐fluorenylmethylcysteine [Boc‐Cys(Fm)‐OH], generating a stable H‐Cys(Fm)‐peptide upon cleavage. In separate stages of these strategies, thioesters are established at the C‐termini by selective deprotection and coupling steps carried out while peptides remain bound to the supports. Pilot native chemical ligations were pursued directly on‐resin, as well as in solution after cleavage/purification.     

正常人外周血淋巴细胞 IL—2受体免疫放射测定

采用~(125)I 标记小鼠抗人IL—2受体(P55)的抗Tac(CD_(25))单克隆抗体,成功地建立了人IL—2受体的免疫放射分析法,动态观察了人外周血淋巴细胞经PHA 刺激24、48和72h 后IL—2受体表达的时间曲线,通过Scatchard 作图分析表明~(125)I—抗Tac 单克隆抗体与PHA 活化的上述三个时间点的T 淋巴细胞的最大结合容量(B_(max))分别为43000位点/细胞、54000位点/细胞和61000位点/细胞。本研究为临床IL—2受体检测提供一种简便的免疫放射测定法。