基于文本挖掘和生物医学数据库的新型冠状病毒肺炎药物发现

目的 基于文本挖掘技术和生物医学数据库对新型冠状病毒肺炎（COVID-19）相关文献进行数据挖掘分析，探究COVID-19及其主要症状发热、咳嗽、呼吸障碍相关基因靶点，筛选潜在有效的化学药和中药。方法 使用GenCLiP 3网站获取COVID-19和其主要症状咳嗽、发热、呼吸障碍共4个关键词的共有靶点，在METASCAPE数据库中对其进行基因本体（GO）和通路富集分析，再利用String数据库和Cytoscape软件构建共有靶点的蛋白质相互作用网络，筛选获得核心基因，运用DGIdb数据库、SymMap数据库针对核心基因进行中西医治疗药物预测。结果 获得COVID-19及其主要症状共有基因靶点28个，其中有IL2、IL1B、CCL2等核心基因16个，使用DGIdb数据库筛选获得与16个关键靶点相互作用的化学药包括沙利度胺、来氟米特、环孢素等28种，中药包括虎杖、黄芪、芦荟等70味。结论 COVID-19及其主要症状的病理机制可能和CD4、KNG1、VEGFA等28个共有基因相关，可能通过介导TNF、IL-17等信号通路参与COVID-19病理过程。潜在有效药物可能通过作用相关靶点通路起到治疗COVID-19的作用。     

Exploring the potential of exosomes in diagnosis and drug delivery for pancreatic ductal adenocarcinoma

Pancreatic cancer (PC) is a cancer of the digestive system, and pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90% of all PC cases. Exosomes derived from PDAC (PDAC-exosomes) promote PDAC development and metastasis. Exosomes are nanoscale vesicles secreted by most cells, which can carry biologically active molecules and mediate communication and cargo transportation among cells. Recent studies have focused on transforming exosomes into good drug delivery systems (DDSs) to improve the clinical treatment of PDAC. This review considers PDAC as the main research object to introduce the role of PDAC-exosomes in PDAC development and metastasis. This review focuses on the following two themes: (a) the great potential of PDAC-exosomes as new diagnostic markers for PDAC, and (b) the transformation of exosomes into potential DDSs.     

Phylogenetic groups and antimicrobial resistance characteristics of Escherichia coli strains isolated from clinical samples in North Iran

Background and study aimExtraintestinal pathogenic Escherichia coli (ExPEC) is one of the most common bacterial pathogens, which causes a remarkable amount of morbidity and mortality. This study was designed to determine the antibiotic resistance profiles, phylogenetic groups, and subgroup analyses among the ExPEC strains isolated from hospitalized patients in north Iran.Patients and MethodsThis cross-sectional investigation was conducted at five educational hospitals in Rasht in north Iran. Using standard microbiological tests, 150 E. coli isolates were identified. The antibiotic susceptibility pattern of all isolates was determined using the disk diffusion method. The double disk phenotypic confirmatory test was performed to detect extended-spectrum β-lactamase (ESBL)-producing isolates. A triplex polymerase chain reaction (PCR) was performed to determine the phylogenetic group of each strain.ResultsThe results of antibiogram pattern showed that E. coli isolates were mostly non-susceptible to ampicillin (79.3%), followed by nalidixic acid (75.3%) and cephalothin (70%), whereas nitrofurantoin (94.7%) was the most effective agent, followed by imipenem (92.7%). The rate of ESBL-producing isolates was 53.3% (80/150). Multiplex PCR screening revealed that the most common phylogroup was the B2 group (97 isolates; 64.6%), followed by the D group (34, 22.7%). In contrast, phylogroup analyses showed that B2₃ (50.7%) and D₂ (16.4%) were the most common subgroups.ConclusionsOur findings indicated a considerable rate of antibiotic resistance and ESBL-producing isolates among E. coli strains isolated from clinical samples. Moreover, we reported a tendency that most isolates belonged to the B2 and D phylogroups. As a result, the detection of genotypic identical or similar isolates indicated that these isolates have an endurance capability in the hospital environment and could be transmitted among patients.     

Correlation analysis of intestinal flora and pathological process of type 2 diabetes mellitus

ObjectiveTo observe the relationship between the different stages of type 2 diabetes mellitus (T2DM) and the intestinal flora and verify its underlying mechanism.MethodsT2DM rats were generated by high-fat diet (HFD) combined with intraperitoneal streptozotocin (STZ) injection. The rats were divided into four groups: the control group (fed with normal feed for 1 month), the HFD group (fed with HFD for 1 month), the T2DM group (HFD combined with STZ and blood glucose ≥11.1 mM), and the unformed T2DM model (Un-mod) group (HFD combined with STZ and blood glucose <11.1 mM). Feces were collected, and bacterial communities in the fecal samples were analyzed by 16S rRNA gene sequencing. The content of short-chain fatty acids (SCFAs) in feces was measured by gas chromatography. Western blot and quantitative real-time polymerase chain reaction were used to detect the expression of G protein-coupled receptor 41 (GPR41) and GPR43.ResultsAt different stages of T2DM, the intestinal flora and SCFAs content of rats were significantly decreased (all P < .05). Our results indicated that g__Prevotella had a significant negative correlation, and g__Ruminococcus_torques_group and g__lachnoclastic had a significant positive correlation with blood glucose. The content of SCFAs, in particular acetate and butyrate, in rat feces of different stages of T2DM were significantly reduced, as well as GPR41 and GPR43 expression. The results in the Un-mod group were similar to the T2DM group, and the expression of GPR41 and GPR43 proteins were significantly higher than those in the T2DM group (both P < .001).ConclusionThe intestinal flora–SCFAs–GPR41/GPR43 network may be important in the development of T2DM. Decreasing blood glucose levels by regulating the intestinal flora may become a new therapeutic strategy for T2DM, which has very important clinical and social values.     

The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies

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早孕期监测子宫动脉多普勒参数在预测低危人群不良妊娠结局的价值

目的 建立妊娠11~13+6周子宫动脉多普勒参数在低危人群中的正常参考值，同时评估其对不良妊娠结局的预测价值。方法 收集2019年6月至2021年6月于我院行产前超声检查的妊娠11~13+6周孕妇，根据妊娠结局分组。收集两侧子宫动脉多普勒指标，包括搏动指数（PI）、阻力指数（RI）、舒张早期是否有切迹，以及孕妇基本临床资料和胎儿出生信息，将以上相关参数进行统计学分析。结果 最终纳入800例孕妇，包括正常妊娠结局组740例和不良妊娠结局组60例。两组孕妇体质量指数（BMI）、分娩孕周和胎儿出生体质量比较，差异均有统计学意义（均P＜0.05）。随着孕周的增加，子宫动脉两侧平均搏动指数（mPI）、平均阻力指数（mRI）和两侧舒张早期切迹检出率均呈逐渐下降的趋势。ROC曲线分析显示，mPI、mRI及两侧舒张早期切迹预测妊娠结局的曲线下面积（AUC）分别为0.542、0.574、0.521，三者联合预测妊娠结局的AUC为0.648；孕妇BMI、年龄mPI、mRI及两侧舒张早期切迹预测妊娠结局的AUC为0.751。结论 建立了低危人群在妊娠11~13+6周子宫动脉多普勒参数的正常参考值范围。在妊娠11~13+6周单纯应用子宫动脉多普勒参数预测妊娠结局的价值有限，将子宫动脉参数与临床相关指标结合可提高对不良妊娠结局的预测价值。     

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.