HIFα Regulates Developmental Myelination Independent of Autocrine Wnt Signaling

The developing CNS is exposed to physiological hypoxia, under which hypoxia-inducible factor α (HIFα) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanisms of HIFα in developmental myelination remain incompletely understood. A previous concept proposes that HIFα regulates CNS developmental myelination by activating the autocrine Wnt/β-catenin signaling in oligodendrocyte progenitor cells (OPCs). Here, by analyzing a battery of genetic mice of both sexes, we presented in vivo evidence supporting an alternative understanding of oligodendroglial HIFα-regulated developmental myelination. At the cellular level, we found that HIFα was required for developmental myelination by transiently controlling upstream OPC differentiation but not downstream oligodendrocyte maturation and that HIFα dysregulation in OPCs but not oligodendrocytes disturbed normal developmental myelination. We demonstrated that HIFα played a minor, if any, role in regulating canonical Wnt signaling in the oligodendroglial lineage or in the CNS. At the molecular level, blocking autocrine Wnt signaling did not affect HIFα-regulated OPC differentiation and myelination. We further identified HIFα–Sox9 regulatory axis as an underlying molecular mechanism in HIFα-regulated OPC differentiation. Our findings support a concept shift in our mechanistic understanding of HIFα-regulated CNS myelination from the previous Wnt-dependent view to a Wnt-independent one and unveil a previously unappreciated HIFα–Sox9 pathway in regulating OPC differentiation.SIGNIFICANCE STATEMENT Promoting disturbed developmental myelination is a promising option in treating diffuse white matter injury, previously called periventricular leukomalacia, a major form of brain injury affecting premature infants. In the developing CNS, hypoxia-inducible factor α (HIFα) is a key regulator that adapts neural cells to physiological and pathologic hypoxic cues. The role and mechanism of HIFα in oligodendroglial myelination, which is severely disturbed in preterm infants affected with diffuse white matter injury, is incompletely understood. Our findings presented here represent a concept shift in our mechanistic understanding of HIFα-regulated developmental myelination and suggest the potential of intervening with an oligodendroglial HIFα-mediated signaling pathway to mitigate disturbed myelination in premature white matter injury.     

高乳酸血症-卒中样发作综合征型线粒体脑肌病一家系两代四例报告

线粒体脑肌病属于罕见性母系遗传病，本文回顾性分析了1家4例高乳酸血症-卒中样发作综合征（MELAS）型线粒体脑肌病患者，其主要表现为卒中样发作、头痛、癫痫、高乳酸血症、肌肉不耐受疲劳、高级智能下降、听力下降和身材矮小等，结合特征性影像学变化、基因检测及肌肉活检明确诊断，并结合文献对只有女儿能将其线粒体DNA（mt-DNA）传递给下一代的母系遗传MELAS型线粒体脑肌病临床特点进行了总结分析，旨在帮助临床认识此病，进一步提高MELAS型线粒体脑肌病的临床诊断率。     

2016至2018年某医院真菌血流感染者流行病学特征及耐药性分析

目的分析真菌性血流感染的病原菌分布以及耐药特征，为真菌血流感染的早期合理用药提供理论依据。 方法回顾性分析武汉大学人民医院2016年1月至2018年12月收治的真菌性血流感染者的菌群、科室分布以及耐药性。 结果入组192例真菌血流感染者的血培养样本中共分离192株真菌，其中白色念珠菌检出率为31.77%（61/192），其次热带念珠菌检出率为18.75%（36/192）；重症医学科检出率最高为33.85%（65/192）。所有菌株均对两性霉素B敏感，对其他抗菌药物耐药率分别为5-氟胞嘧啶4.49%（9/192）、伊曲康唑5.73%（11/192）、氟康唑10.94%（21/192）和伏立康唑11.46%（22/192）；除两性霉素B外，2016至2018年真菌对其他抗菌药物的耐药率均逐年上升，其中2018年所分离192株光滑念珠菌对伊曲康唑耐药菌率达46.7%。 结论真菌血流感染病原菌以念珠菌属为主，对目前抗真菌药物具有较高敏感性，但耐药率逐年上升，加强监测血培养病原菌变化及耐药趋势对指导临床用药至关重要。     

Molecular profiling of Chinese R-CHOP treated DLBCL patients: Identifying a high-risk subgroup

Diffuse large B-cell lymphoma (DLBCL) is a clinically aggressive and heterogenous disease. Although most patients can be cured by immunochemotherapy, 30% to 40% patient will ultimately develop relapsed or refractory disease. Here, we investigated the molecular landscapes of patients with diverse responses to R-CHOP. We performed capture-based targeted sequencing on baseline samples of 105 DLBCL patients using a panel consisting of 112 lymphoma-related genes. Subsequently, 81 treatment-naïve patients with measurable disease and followed for over 1 year were included for survival analysis. Collectively, the most commonly seen mutations included IGH fusion (69%), PIM1(33%), MYD88 (29%), BCL2 (29%), TP53 (29%), CD79B (25%) and KMT2D (24%). Patients with TP53 mutations were more likely to have primary refractory disease (87.0% vs 50.0%, P = .009). For those with TP53 disruptive mutations, 91.7% patients were in the primary refractory group. Interestingly, BCL-2 somatic hypermutation was only seen in patients without primary refractory disease (P = .014). In multivariate analysis, BCL-2 amplification (hazard ratio [HR] = 2.94, P = .022), B2M mutation (HR = 2.99, P = .017) and TP53 mutation (HR = 3.19, P < .001) were independently associated with shorter time to progression (TTP). Furthermore, TP53 mutations was correlated with worse overall survival (P = .049). Next, we investigated mutation landscape in patients with wild-type (WT) TP53 (n = 58) and found that patients harboring MYD88 L265P had significantly inferior TTP than those with WT or non-265P (P = .046). Our study reveals the mutation spectrum of treatment-naive Chinese DLBCL patients. It also confirms the clinical significance of TP53 mutations and indicates the prognostic value of MYD88 L265P in TP53 WT patients.     

生物样品中天麻素测定方法及药代动力学研究进展＊

天麻素是从兰科植物天麻的块茎中提取分离而得，现已人工合成。天麻素药理作用广泛，如镇痛、镇静安眠、促智、保护神经元、降血压、抗惊厥、抗癫痫、抗氧化、抗衰老、改善微循环等，且安全、无明显毒副作用，其相关制剂在临床上亦被广泛用于心脑血管及神经精神系统疾病，如头痛、冠心病、高血压、后循环缺血性眩晕、突发性耳聋、癫痫、神经衰弱及脑卒中等。考虑到天麻素临床治疗上述疾病常与其他药物或治疗方法联用，故其体内过程及其药代动力学性质不容忽视。目前，有关天麻素综述多集中于药理作用和临床应用方面，而其药代动力学综述鲜见报道。随着天麻素药代动力学研究日渐深入，本研究将从其样品前处理、测定方法、药物ADME过程及影响体内过程的因素等方面较系统全面地对天麻素近年来的药代动力学研究作一综述，以期对天麻素制剂工艺及临床联合配伍应用有所裨益。