CD200 maintains the region-specific phenotype of microglia in the midbrain and its role in Parkinson's disease

Microglia are a specialized population of tissue macrophages in the mammalian brain. Microglial phenotype is tightly regulated by local environmental factors, although little is known about these factors and their region-preferred roles in regulating local neuroinflammatory responses. We hypothesized that microglia in different brain regions respond differently to neuroinflammatory stimulation and that CD200, an anti-inflammatory protein mainly originated from neurons, acts as a local cue inhibiting microglia activation in the midbrain. We utilized a CD200-deficient mouse line to analyze the phenotypic role of CD200 in the regulation of normal neuron–microglia homeostasis in the midbrain and in the dopaminergic degeneration in an α-synuclein overexpression model of PD. We found that systemic administration of an endotoxin lipopolysaccharide induced a region-preferred change in CD200 expression in the midbrain. Similarly, CD200^−/− mice showed a regional preference in an enhancement of microglia activation and baseline inflammatory levels in the midbrain and dopamine neuron loss in the substantia nigra (SN). In a mouse model of Parkinson's disease (PD) induced by rAAV-hSYN injection into the SN, CD200^−/− mice showed more dopamine neuron loss in the SN than wild type mice. Activation of CD200 receptors with a CD200 fusion protein alleviated the neuroinflammation and neuronal death in the SN of PD mice. These findings demonstrate that CD200 is essential for the midbrain homeostasis and acts as a critical local regulator in controlling microglial properties related to the PD pathogenesis.     

A juvenile case of epilepsy-associated,isocitrate dehydrogenase wild-type/histone 3 wild-type diffuse glioma with a rare BRAF A598T mutation

Here, we report a juvenile (18-year-old male) case of epilepsy-associated, isocitrate dehydrogenase wild-type/histone 3 wild-type diffuse glioma with a rare BRAF mutation and a focal atypical feature resembling diffuse astrocytoma. The patient presented with refractory temporal lobe epilepsy. Subsequently, magnetic resonance imaging revealed a hyperintense lesion in the right temporal lobe on fluid attenuated inversion recovery images. The patient underwent right lateral temporal lobectomy and amygdalohippocampectomy. Histopathologically, the tumor showed isomorphic, diffuse, infiltrative proliferation of glial tumor cells and intense CD34 immunoreactivity. The tumor cells were immunonegative for isocitrate dehydrogenase 1 (IDH1) R132H and BRAF V600E. Notably, the tumor cells showed the lack of nuclear staining for α-thalassemia/mental retardation syndrome, X-linked (ATRX). In addition, the Ki-67 labeling index, using a monoclonal antibody MIB-1, was elevated focally at tumor cells with p53 immunoreactivity. Molecular analyses identified a BRAF^A598T mutation, the first case reported in a glioma. BRAF^A598T is predicted to result in loss of kinase action; however, inactive mutants can stimulate mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling through CRAF activation. Thus, according to the recent update of the consortium to inform molecular and practical approaches to central nervous system tumor taxonomy (cIMPACT-NOW update 4), our case is also compatible with diffuse glioma with the mitogen-activated protein kinase (MAPK) pathway alteration. Thorough immunohistochemical and molecular studies are necessary for diagnosis of epilepsy-associated, diffuse gliomas. Partial resemblance in histopathological and molecular genetic features to diffuse astrocytoma also calls for attention.     

结直肠癌微环境中细胞因子的表达及其与CD16a mRNA表达的相关性研究

目的探讨结直肠癌肿瘤微环境中细胞因子的表达及其与CD16a mRNA表达的关系。方法分别采用实时荧光定量PCR法和流式细胞术微球阵列法(CBA法)检测42例结直肠癌组织及其癌旁组织中CD16a mRNA和8种细胞因子[包括白细胞介素(IL)-2、IL-4、IL-6、IL-10、IL-12、肿瘤坏死因子-α(TNF-α)、γ-干扰素(IFN-γ)和血管内皮生长因子(VEGF)]的表达水平,分析两者之间的相关性。结果结直肠癌组织中IL-6、TNF-α和VEGF的表达水平高于癌旁组织(P<0.05),而IL-2、IL-4、IL-10、IL-12和IFN-γ在2种组织中的表达水平比较差异均无统计学意义(P>0.05)。术前CEA正常组的IL-6和VEGF的表达水平高于术前CEA升高组(P<0.05)。相关性分析结果显示:结直肠癌组中IL-6的相对表达水平与CD16a mRNA的表达水平呈负相关(P<0.05)。结论结直肠癌组织中IL-6、TNF-α和VEGF的表达水平较癌旁组织明显升高,提示促血管生成作用及免疫抑制增强。此外,结直肠癌肿瘤微环境中CD16a mRNA的表达与IL-6的表达呈负相关。     

Does choice of antiretroviral drugs matter for inflammation?

Introduction: The massive implementation of combination antiretroviral therapy (cART) has forever changed the landscape of HIV infection. This unprecedented success has turned HIV infection into a manageable chronic disease. The increased survival of people living with HIV is, however, shadowed by a high burden of aging-related comorbidities. The pathogenic basis underlying this excess of co-morbid conditions is most likely a persistent inflammatory and immune activation state, despite an optimal control of HIV replication, which in turn has largely been attributed to bacterial or bacterial products translocation from the gut.

Area covered: This review is focused on the relationship between cART and the chronic inflammatory and immune activation status in otherwise virologically well-controlled people living with HIV (PLWH). Particular focus will be placed on the differences, if any, between distinct cART modalities, with emphasis on less-drug cART regimens, and especially on dual therapies.

Expert opinion: Research to address the increased inflammatory and immune activation status of cART-treated, HIV-infected patients, should focus on adjuvant means of therapy, rather than on the cART regime itself. With current antiretrovirals, no difference between dual and triple regimens has been demonstrated, provided that virological and immunological outcomes be non-inferior.     

Use of Patient and Disease Characteristics as Predictive Indicators of Rituximab Infusion-Related Reactions in Adult Malignant Hematology Patients at an Academic Medical Center

BackgroundIdentification of predictive indicators for rituximab infusion-related reactions (R-IRRs) may allow clinicians to modify treatment plans for patients at high risk of reaction to reduce incidence. Use of predictive indicators would significantly improve the patient experience, reduce hospital resource utilization, and decrease infusion chair time.Patients and MethodsThis retrospective, single-center, observational study evaluated 173 adult malignant hematology patients who received their first dose of rituximab inpatient between July 31, 2015 and July 31, 2018. Patients were excluded if they received prior rituximab, and/or induction chemotherapy, or were pregnant at the time of exposure. The primary outcome was the overall incidence of R-IRRs during the study period. The secondary outcomes were associations between specific patient and disease characteristics and R-IRRs.ResultsOf the 173 patients evaluated, 109 met inclusion criteria and 64 were excluded. The overall incidence of R-IRRs was 31 (28.4%) of 109. The following patient and disease characteristics were significantly associated with R-IRRs on univariate analysis: higher actual body weight (P = .04), diagnosis (P = .01), lower hemoglobin (P = .02), and bone marrow involvement (P = .001). In a confirmatory stepwise regression model, higher actual body weight (P = .01) and bone marrow involvement (P = .003) were positively associated with R-IRRs.ConclusionActual body weight and bone marrow involvement may be utilized as potential predictive indicators of R-IRRs. Further study is needed to validate these indicators and determine appropriate utilization in practice.     

A Positive Feedback Loop Between Th17 Cells and Dendritic Cells in Patients with Endplate Inflammation

Background: Endplate inflammation remains a difficult disease to treat, in part due to its unclear pathology. Previous experiments showed that patients with idiopathic inflammation presented a systemic upregulation of Th17 cells. Here, we investigated how this change might affect the inflammatory environment in endplate inflammation.

Methods: Peripheral blood was obtained from patients and healthy controls, and Th17 cells were examined.Results: Th17 cells significantly increased the differentiation of CD11c+ and DC-SIGN+ dendritic cells (DCs) from circulating monocytes in the absence of exogenous stimulation as well as in the presence of LPS stimulation. Th17 cells also increased CD80 and CD86 expression by DCs. Importantly, although Th17 cells from both healthy controls and patients with endplate inflammation could induce CD11c, DC-SIGN, CD80, and CD86 expression, Th17 cells from patients with endplate inflammation showed significantly more potent capacity. Both contact-dependent and IL-17-dependent mechanisms were employed by Th17 cells, since blocking cell-to-cell contact significantly inhibited Th17-mediated differentiation of CD11c+ DCs, and neutralization of IL-17 reduced the expression of CD80 and CD86. Strikingly, DCs following incubation with Th17 cells, but not the DCs derived directly from monocytes without Th17 cells, could significantly promote the expression of IL-17 from naive CD4+ T cells.

Conclusions: These results demonstrated that Th17 cells from patients with endplate inflammation could potently induce the differentiation and activation of DCs that preferentially promoted IL-17 response in a positive feedback loop.     

一种由大体积恶性胸腔积液中分离肿瘤细胞的方法初探

背景与目的恶性胸腔积液（malignant plural effusion, MPE）是液体活检基因检测的常用标本来源，本研究评估一种从大体积MPE中分离肿瘤细胞方法的分离效果及其在基因检测中的应用前景。方法收集20例伴MPE的晚期肺癌患者一次胸腔积液引流的全部MPE（> 500 mL），联合运用细胞分离介质Percoll和Ficoll分离肿瘤细胞，统计分离情况。对其中既往行组织基因检测的肺腺癌患者，分别使用胸腔积液上清游离DNA（tumor derived DNA from pleural effusion supernatant, etDNA），总细胞DNA及分离肿瘤细胞DNA（DNA from tumor cells in pleural effusion, ETC-DNA）3种成分进行二代基因测序，比较检测情况。结果从MPE中分离得到细胞中位数量8.50×10⁴个（上下四分位间距9.25×10³-3.75×10⁵），肿瘤细胞纯度85.50%±5.80%。对10例既往行组织表皮生长因子受体（epidermal growth factor receptor, EGFR）基因检测的患者，etDNA、总细胞DNA及ETC-DNA EGFR基因突变检出率分别为70.00%、50.00%、70.00%。ETC-DNA基因检测阳性率与组织（P > 0.999, kappa=1.000）和etDNA（P > 0.999, kappa=1.000）一致性均良好。etDNA、总细胞DNA、ETC-DNA EGFR基因突变中位丰度分别为16.05%（4.78%-43.06%）、1.09%（0.00%-2.39%）和33.02%（18.50%-76.70%）。ETC-DNA检测丰度倾向高于etDNA，但差异无统计学意义。结论该提取方法可以有效地从大体积MPE中分离出大量高纯度肿瘤细胞，利用提取出的肿瘤细胞进行基因检测可能可以提高基因检测效能，值得进一步研究。