基于巨噬细胞极化研究“赤芍-附片”治疗慢加急性肝衰竭的作用机制

目的 研究赤芍-附片对慢加急性肝衰竭（ACLF）大鼠的治疗作用及其对M1/M2型巨噬细胞极化的影响。方法 将SD雄性大鼠随机分为正常组、模型组、乳果糖组（乳果糖 1.8 g·kg^-1）、中药组（赤芍-附片 5.85 g·kg^-1），每组6只。采用牛血清白蛋白皮下及尾静脉注射联合腹腔注射D-半乳糖+脂多糖急性攻击建立ACLF模型，并予以相应药物灌胃1周，空白组和模型组予以蒸馏水灌胃。利用苏木素-伊红（HE）染色观察肝组织病理变化，实时荧光定量聚合酶链式反应（Real-time PCR）、蛋白免疫印迹法（Western blot）、免疫组化等方法比较各组大鼠肝组织CD86、诱导型一氧化氮合酶（iNOS）、CD206、精氨酸酶1（Arg1） mRNA和蛋白表达水平。结果 与正常组比较，模型组大鼠肝组织假小叶形成，肝细胞形态变化、坏死，伴大量炎性细胞浸润，CD86、iNOS mRNA及蛋白表达均显著上调（P<0.01）；与模型组比较，各给药组肝组织坏死及炎性浸润均改善，CD86、iNOS mRNA及蛋白表达下调（P<0.01），而CD206、Arg1 mRNA及蛋白表达上调（P<0.05，P<0.01），与乳果糖组比较，中药组上调CD206、Arg1作用更优（P<0.01）。结论 ACLF大鼠存在M1/M2型巨噬细胞极化失衡，失衡向M1方向偏移，赤芍-附片通过促进肝脏巨噬细胞向M2方向极化，抑制M1型巨噬细胞活化，减轻肝衰竭炎症反应。     

First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric,gastroesophageal junction and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis

First-line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC) has poor median overall survival (OS; <1 year). We report efficacy and safety results from Chinese patients in the phase III global CheckMate 649 study of nivolumab plus chemotherapy vs chemotherapy for the first-line treatment of GC/GEJC/esophageal adenocarcinoma (EAC). Chinese patients with previously untreated advanced or metastatic GC/GEJC/EAC were randomized to receive nivolumab (360 mg Q3W or 240 mg Q2W) plus chemotherapy (XELOX [capecitabine and oxaliplatin] Q3W or FOLFOX [oxaliplatin, leucovorin and 5-fluorouracil] Q2W), nivolumab plus ipilimumab (not reported) or chemotherapy alone. OS, blinded independent central review-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety are reported. Of 1581 patients enrolled and randomized, 208 were Chinese. In these patients, nivolumab plus chemotherapy resulted in clinically meaningful improvement in median OS (14.3 vs 10.2 months; HR 0.61 [95% CI: 0.44-0.85]), median PFS (8.3 vs 5.6 months; HR 0.57 [95% CI: 0.40-0.80]), ORR (66% vs 45%) and median DOR (12.2 vs 5.6 months) vs chemotherapy, respectively. The safety profile was acceptable, with no new safety signals observed. Consistent with results from the global primary analysis of CheckMate 649, nivolumab plus chemotherapy demonstrated a clinically meaningful improvement in OS and PFS and higher response rate vs chemotherapy and an acceptable safety profile in Chinese patients. Nivolumab plus chemotherapy represents a new standard first-line treatment for Chinese patients with non-HER2-positive advanced GC/GEJC/EAC.     

基于超分子“印迹模板”理论探讨中药升降浮沉

在前期提出超分子化学对中药四性理论特殊影响的基础上,进一步分析中药升降浮沉的历史沿革、研究概况,并运用超分子"印迹模板"理论对中药"升降浮沉"理论进行解析,提出对中药"升降浮沉"的评价方法。人体与中药均是印迹模板印迹作用的聚集体,在印迹模板作用规律下,不同类型的中药成分与人体的靶点通过"锁-钥"关系以非共价键结合,中药客体超分子通过键的作用可纠正人体主体超分子在自识别、自组织、自组装、自复制过程时发生的寒热、气机失调。人体具备抵抗外界病邪侵袭的能力,有赖于其气机"升降出入"的正常;中药具有"升降浮沉"的性能并能祛除病疾,有赖于其能调整人体气机紊乱,或顺应气机、祛邪外出以增强机体免疫的能力。基于此,在分析中药"升降浮沉"药理作用的基础上,探究其物质基础,并建立中药"升降浮沉"的评价方法,通过超分子印迹模板理论对中药升降浮沉进行剖析,揭示其科学内涵,推动中药药性理论不断创新。     

Differentiating early Parkinson's disease and multiple system atrophy with parkinsonism by saccade velocity profiles

ObjectivePatients with Parkinson's disease (PD) and multiple system atrophy both present predominantly with parkinsonism at early stages, whereas cerebellar symptoms are largely masked in multiple system atrophy with parkinsonism (MSAP). We sought to determine whether the velocity profiles of saccades could be used to differentiate between these two disorders, revealing the underlying basal ganglia and/or cerebellar dysfunction and brainstem pathology in these disorders.MethodsSixteen MSA-P patients, 63 PD patients, and 36 age-matched normal subjects performed the visually guided (VGS) and memory-guided saccade (MGS) tasks. Targets were presented at eccentricities of 5, 10, 20, and 30 degrees. The amplitude, peak velocity, and duration of saccades were compared among subject groups. Duration was further subdivided into acceleration and deceleration periods, corresponding to the times before and after peak velocity. These parameters correlated with the severity of Parkinsonism as assessed by the UPDRS motor score.ResultsHypometria predominated in both PD and MSAP patients, whereas hypermetria, frequently noted in cerebellar ataxia, was rarely observed. Saccades in MSAP were characterized both by prolonged acceleration and deceleration periods with reduced peak velocity. In contrast, the velocity profile of PD patients was characterized mainly by the prolonged deceleration period. The changes observed in velocity profiles of MGS deteriorated with advancing severity of parkinsonism in MSAP and PD patients.ConclusionSaccade profiles provide useful information for differentiating between PD and MSAP at early stages. While the changes in velocity profiles may be explained by the cerebellar and brainstem pathology in MSAP, the changes in velocity profile in both PD and MSAP correlated significantly with increasing severity of Parkinsonism in both disorders, suggesting a link with striatonigral pathology.SignificanceThe differential changes in saccade velocity profiles of MSAP and PD may be used as a measure indexing the progression of cerebellar and basal ganglia dysfunction as well as for assessing the functional improvement when clinical treatment becomes available.     

DARC: Deep adaptive regularized clustering for histopathological image classification

In recent years, deep learning as a state-of-the-art machine learning technique has made great success in histopathological image classification. However, most of deep learning approaches rely heavily on the substantial task-specific annotations, which require experienced pathologists’ manual labelling. As a result, they are laborious and time-consuming, and many unlabeled pathological images are difficult to use without experts’ annotations. To mitigate the requirement for data annotation, we propose a self-supervised Deep Adaptive Regularized Clustering (DARC) framework to pre-train a neural network. DARC iteratively clusters the learned representations and utilizes the cluster assignments as pseudo-labels to learn the parameters of the network. To learn feasible representations and encourage the representations to become more discriminative, we design an objective function combining a network loss with a clustering loss using an adaptive regularization function, which is updated adaptively throughout the training process to learn feasible representations. The proposed DARC is evaluated on three public datasets, including NCT-CRC-HE-100K, PCam and LC25000. Compared to the strategy of training from scratch, fine-tuning using the pre-trained weights of DARC can obviously boost the accuracy of neural networks on histopathological classification. The accuracy of using the network trained using DARC pre-trained weights with only 10% labeled data is already comparable to the network trained from scratch with 100% training data. The network using DARC pre-trained weights achieves the fastest convergence speed on the downstream classification task. Moreover, visualization through t-distributed stochastic neighbor embedding (t-SNE) shows that the learned representations are generalizable and discriminative.     

鼻咽癌早期筛查的研究进展

目的鼻咽癌作为我国南部地区常见的恶性肿瘤，对人类健康及生命带来了极大的危害，鼻咽癌的病理及解剖特性决定了其以放射治疗为主的治疗方法，鼻咽癌的分期与患者的预后密切相关，因此早期干预可以极大地提高患者的远期生存率，而寻找合适的筛查手段对鼻咽癌的早期发现至关重要，基于此，本文对鼻咽癌的早期筛查的研究新进展作一综述。     

Antiretroviral therapy improves neurocognitive impairment in people living with HIV? A meta-analysis

ObjectivesAlthough effective antiretroviral therapy (ART) has been used for more than two decades, HIV-associated neurocognitive disorder remains prevalent. Thus, whether ART can improve neurocognitive impairment is controversial. This review aims to explore the effects of ART on cognitive impairment in people living with HIV (PLWH).MethodsA systematic literature search was conducted in eight databases (PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP, China Biology Medicine disc, and WanFang) to identify studies that compare cognitive function between study groups who are administered and not administered ART. We searched for articles published up to April 2019. Article evaluation and data extraction were independently conducted by two reviewers.ResultsSixteen articles (6,694 participants)—14 cross-sectional studies and 2 cohort studies—were included in this meta-analysis. The cross-sectional studies demonstrated that ART group did not perform better than the non-ART group (OR = 1.16; 95% CI, 1.03–1.30). However, the cohort studies reported a significant improvement in cognitive function at three months (OR = 4.01; 95% CI, 2.35–6.85) and six months (OR = 9.24; 95% CI, 1.71–49.96) after ART initiation compared with the baseline data. No significant cognitive improvement was found in participants younger than 55 years old, but the two cross-sectional studies showed that ART may improve cognitive function in PLWH under 65 years old with poor physical condition and immune status.ConclusionsART could improve cognitive function in PLWH with poor physical condition and immune status, but it does not considerably improve cognition in the entire PLWH population.