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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B cell and B cell-related pathways for novel cancer treatments

B cells are recognized as the main effector cells of humoral immunity which suppress tumor progression by secreting immunoglobulins, promoting T cell response, and killing cancer cells directly. Given these properties, their anti-tumor immune response in the tumor micro-environment (TME) is of great interest. Although T cell-related immune responses have become a therapeutic target with the introduction of immune checkpoint inhibitors, not all patients benefit from these treatments. B cell and B cell-related pathways (CCL19, −21/CCR7 axis and CXCL13/CXCR5 axis) play key roles in activating immune response through humoral immunity and local immune activation via tertiary lymphoid structure (TLS) formation. However they have some protumorigenic works in the TME. Thus, a better understanding of B cell and B cell-related pathways is necessary to develop effective cancer control. In this review, we summarize recent evidences regarding the roles of B cell and B cell-related pathways in the TME and immune response and discuss their potential roles for novel cancer treatment strategies.     

Reduction of BMP6‐induced bone formation by calcium phosphate in wild‐type compared with nude mice

Nude mice have been extensively used to investigate the potency of tissue engineering strategies for bone repair. However, the contribution of pro‐inflammatory and proregenerative stimuli of the host for the process of new bone formation and integration remains poorly understood. In this study, ectopic bone formation was investigated in nude (Nu) versus wild‐type (WT) mice. Calcium phosphate (CaP) scaffolds (CopiOs [Zimmer] and Bio‐Oss [Geistlich]) were loaded with different concentrations of rhBMP6 (40, 120, and 240 ng/mm³ rhBMP6) and implanted subcutaneously in Nu (BALB/c and NMR1) and WT (BALB/c and c57BL/6) mice. CaP scaffolds loaded with rhBMP6 did not form bone in WT mice. However, in Nu mice, 40 ng/mm³ rhBMP6 was sufficient to generate relevant volumes of new bone at 6 weeks after implantation. Looking into potential underlying mechanisms, TNF‐α blocking antibodies were injected intraperitoneally but could not restore bone formation. Also, mouse periosteal cells (mPDCs) seeded in CopiOs loaded with rhBMP6 did not significantly improve the outcome. Abrogation of bone formation was associated with dense cellular infiltration, in particular with the presence of CD3+ T‐lymphocytes. To probe a correlation between calcium ions and impaired bone formation in WT mice, type 1 collagen gels were loaded with rhBMP6 and calcium chloride and injected subcutaneously. These gels generated new bone in WT mice despite the increased percentage of CD3+ cells at Day 3 after implantation as compared with control gels. Overall, this study illustrated the negative effect of the inflammatory host response on the bone‐forming capacity of rhBMP6 coated on bioceramic scaffolds.     

家庭群居爆发型新型冠状病毒肺炎的临床与胸部HRCT表现

目的 探讨家庭群居爆发型新型冠状病毒肺炎（简称"新冠肺炎"）（novel coronavirus pneumonia，NCP）的临床与胸部HRCT表现特点。方法 收集2020年2月3所医院经核酸检测阳性确诊的新冠肺炎患者10例（4个家庭），其中男性6例（中位年龄60.5岁），女性4例（中位年龄59岁）。所有患者均接受胸部CT扫描并行薄层HRCT重建，由两名10年以上工作经验放射科医生共同阅片分析新冠肺炎HRCT病变发生部位、形态、分布、密度等特点，以及治疗前后HRCT征象变化。并收集临床和实验室指标进行分析和总结。结果 本组4个家庭中首例确诊病例均有武汉确诊病例或武汉疫区接触史，4例为输入型病例（占40%），平均潜伏期5 d。实验室检查中5例（50%）外周血白细胞总数降低，4例（40%）淋巴细胞明显降低；8例（80%）C-反应蛋白增高，10例（100%）乳酸脱氢酶增高。10例（100%）患者胸部CT均有阳性表现，其中7例（70%）表现为双肺散在分布磨玻璃密度影（ground glass opacity，GGO），病变界限大多清楚。8例（80%）累及多个肺叶，2例（20%）为单肺叶病变。绝大多数病灶位于胸膜下和肺外周处，以双肺下叶为著。5例患者（50%）病变内可见细支气管充气征，9例患者（90%）病变内可见增粗细小血管影。7例患者（70%）治疗后复查胸部CT，3例（30%）原肺内胸膜下病变出现不同程度实变及纤维化，2例（20%）实变影转变为GGO，1例（10%）原肺内GGO消失，又出现新发GGO，1例（10%）病变范围有增大。结论 新冠肺炎具有家庭群居爆发的特点，均可有输入性病例，潜伏期较短，其胸部HRCT表现具有一定特征性，且有助于治疗后患者病变动态观察；结合流行病学和实验室检查有助于对NCP做出临床诊断和提供疫情防控的可靠依据。     

抗PD-(L)1、抗CTLA-4免疫治疗标志物研究进展

免疫检查点抑制剂已经改变了包括肺癌、黑色素瘤等许多肿瘤的治疗情况，并且在一些难治性肿瘤中表现出持久的应答率，然而在部分接受治疗的患者中表现出无反应及严重免疫相关副作用。为了优化免疫疗法的使用，可能需要多种临床应答的预测性标志物。本研究回顾了几种潜在有效生物标志物的可用数据，通过免疫组化检测肿瘤细胞和免疫细胞中PD-L1的表达，提示其是一种临床疗效的良好预测标志物;且PD-L1表达阴性者经免疫治疗后仍可获益。PD-L1表达在肿瘤内是动态和异质性的:在原发性灶和转移灶之间或在穿刺标本和大体标本之间表达不一致。肿瘤突变负荷与新抗原的高比率可获得持久获益。外周血标志物也可作为潜在标志物，增加的绝对淋巴细胞计数（ALC）与疾病控制和生存显著相关。在这篇综述中，我们旨在讨论抗PD-（L）1与抗CTLA-4 免疫治疗相关标志物研究现状，为临床运用提供指导，以便能够准确筛选出从这些治疗中获益更多的患者。     

Extracellular vesicles and asthma: A review of the literature

Asthma is a chronic, recurrent and incurable allergy‐related respiratory disease characterized by inflammation, bronchial hyperresponsiveness and narrowing of the airways. Extracellular vesicles (EVs) are a universal feature of cellular function and can be detected in different bodily fluids. Recent evidence has shown the possibility of using EVs in understanding the pathogenesis of asthma, including their potential as diagnostic and therapeutic tools. Studies have reported that EVs released from key cells involved in asthma can induce priming and activation of other asthma‐associated cells. A literature review was conducted on all current research regarding the role and function of EVs in the pathogenesis of asthma via the PRISMA statement method. An electronic search was performed using EMBASE and PubMed through to November 2018. The EMBASE search returned 76 papers, while the PubMed search returned 211 papers. Following duplicate removal, titles and abstracts were screened for eligibility with a total of 34 studies included in the final qualitative analysis. The review found evidence of association between the presence of EVs and physiological changes characteristic of asthma, suggesting that EVs are involved in the pathogenesis, with the weight of evidence presently favouring deleterious effects of EVs in asthma. Numerous studies highlighted differences in exosomal contents between EVs of healthy and asthmatic individuals, which could be employed as potential diagnostic markers. In some circumstances, EVs were also found to be suppressive to disease, but more often promote inflammation and airway remodelling. In conclusion, EVs hold immense potential in understanding the pathophysiology of asthma, and as diagnostic and therapeutic markers. While more research is needed for definitive conclusions and their application in medical practice, the literature presented in this review should encourage further research and discovery within the field of EVs and asthma.     

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Numerous recent studies have been performed to elucidate the function of microglia, macrophages, and astrocytes in inflammatory diseases of the central nervous system. Regarding myeloid cells a core pattern of activation has been identified, starting with the activation of resident homeostatic microglia followed by recruitment of blood borne myeloid cells. An initial state of proinflammatory activation is at later stages followed by a shift toward an-anti-inflammatory and repair promoting phenotype. Although this core pattern is similar between experimental models and inflammatory conditions in the human brain, there are important differences. Even in the normal human brain a preactivated microglia phenotype is evident, and there are disease specific and lesion stage specific differences in the contribution between resident and recruited myeloid cells and their lesion state specific activation profiles. Reasons for these findings reside in species related differences and in differential exposure to different environmental cues. Most importantly, however, experimental rodent studies on brain inflammation are mainly focused on autoimmune encephalomyelitis, while there is a very broad spectrum of human inflammatory diseases of the central nervous system, triggered and propagated by a variety of different immune mechanisms.     

SiO2 Nanoparticule-induced size-dependent genotoxicity – an in vitro study using sister chromatid exchange,micronucleus and comet assay

Fine particles with a characteristic size smaller than 100?nm (i.e. nanoparticlesspread out in nowadays life. Silicon or Si, is one of the most abundant chemical elements found on the Earth. Its oxide forms, such as silicate (SiO₄) and silicon dioxide, also known as silica (SiO₂), are the main constituents of sand and quartz contributing to 90% of the Earth's crust. In this work, three genotoxicity systems “sister chromatid exchange, cytokinesis block micronucleus test and single cell gel electrophoresis (comet) assay” were employed to provide further insight into the cytotoxic and mutagenic/genotoxic potential of SiO₂ nanoparticules (particle size 6?nm, 20?nm, 50?nm) in cultured peripheral blood lymphocytes as in vitro. It was observed that there is a significant decrease in Mitotic index (MI), Cytokinesis block proliferation index (CBPI), proliferation index (PRI) values expressed as Cell Kinetic parameters compared with negative control (p?2 (6?nm, 20?nm, 50?nm) (p?p?p?2 nanoparticles at different size (6, 20, 50?nm) progressively increased the SCE frequency and DNA damage on the basis the AU values compared with negative control (p?2 nanoparticules is dependent to particule size.