胰腺癌仍然是最致命的恶性肿瘤之一,对传统疗法的抵抗使其生存率在过去几十年内几乎未有改善,而基于肿瘤免疫的胰腺癌治疗策略,如免疫检查点抑制剂、治疗性疫苗和联合免疫疗法正显示出新的治疗希望.尽管临床试验中探索的诸多免疫疗法尚未报道出显著的治疗效果,但毋庸置疑的是免疫治疗将是胰腺癌预后改善甚至治愈的重要希望.本文介绍了目前胰腺癌免疫疗法的相关进展及遇到的瓶颈,并提出了进一步的优化方向和解决方案,希望为胰腺癌免疫治疗发展提供参考.

Pancreatic cancer is a highly malignant tumor of the digestive system,especially metastatic pancreatic cancer is characterized by short course of disease,rapid progression and high mortality. Although gemcitabine has become the standard treatment for advanced pancreatic cancer,the therapeutic effect still falls short of the expected survival. Therefore,a variety of treatments such as radiotherapy and chemotherapy,immunotherapy,targeted therapy and nanotechnology have been gradually developed in clinic,however,the effect of single drug therapy for metastatic pancreatic cancer is not satisfactory at present. Researchers are considering the combination therapy to explore new treatment schemes,and there are many clinical and basic studies of combined immunotherapy for metastatic pancreatic cancer. However,the treatment in this field is still controversial. This article reviews the research progress of combined immunotherapy for metastatic pancreatic cancer in recent years.

目的 分析KPNA4在胰腺癌中的临床意义和潜在作用机制.方法 联合TCGA、GTEx和GEO数据库评估KPNA4在肿瘤和正常组织中的表达水平,收集临床样本通过免疫组化进一步验证.通过Cox分析和生存分析评估KPNA4对胰腺癌患者预后的影响,生物信息学分析用于预测KPNA4的相关功能和潜在机制.结果 生物信息学分析和免疫组化结果显示KPNA4的mRNA和蛋白表达水平在胰腺癌组织中均上调(P<0.05),相关性分析显示其mRNA表达水平与肿瘤大小(r=0.261,P<0.001)和淋巴结转移(r=0.193,P<0.05)正相关.生存分析显示KPNA4的mRNA高表达组患者的生存时间短于低表达组(P<0.001).Cox多因素分析显示KPNA4是胰腺癌患者预后的独立危险因素(95％CI 1.132～2.808,P<0.05).富集分析显示KPNA4参与了TGF-β信号通路、细胞外基质受体相互作用等多种肿瘤相关的生物学过程.结论 KPNA4在胰腺癌中异常上调,与患者的肿瘤大小和淋巴结转移呈正相关,并且预示着不良预后.KPNA4可能是胰腺癌诊断和治疗的潜在生物标记物.

胰腺癌是世界上最致命的恶性肿瘤之一,目前胰腺癌的病因尚未完全明确,是肿瘤研究领域的一个热点.近年来大量研究表明,胰腺癌的发生发展可能与消化道微生物群密切相关.近期研究发现,某些口腔、胃肠道和胰腺内的细菌、真菌和肝细胞病毒可能在胰腺癌发病机制中发挥潜在的病因作用.具体机制主要包括维持炎症、调节免疫系统、影响新陈代谢和改变肿瘤的微环境.在这篇综述中,探讨了消化道微生物与胰腺癌之间的联系,探讨微生物群在胰腺癌诊断和治疗中的潜在应用,并深入了解消化道微生物群在胰腺癌中的作用.

目的 卫生微生物学是预防医学等专业的专业基础课,通过开展全英文教学,拟为顺利推进该课程的全英文建设、探索行之有效的教学模式提供参考.方法 以兰州大学卫生微生物学全英文课程为例,通过课前、课后的问卷调查,从学生对全英文教学的认同度、期望、教学反馈和收获等方面进行教学效果分析,并结合期末考试成绩,初步论证开设全英文专业课的可行性.结果 调查结果表明,学生有较好的英语水平,且过半的学生认同全英文课程,并期望以此提高英语运用能力.尽管学生专业英语词汇积累有限,需花费更多时间预习和复习,但英文教学与命题并未对学生的考试成绩造成影响.结论 面向公共卫生专业本科生开展全英文专业课是具有可行性的,且通过师生的共同努力可以取得良好的教学效果.

Clinical and experimental evidence indicates that tumour-associated macrophages support cancer progression. Moreover, macrophage-derived extracellular vesicles (EVs) are involved in pathogenesis of multiple cancers, yet the functions of molecular determinants in which have not been fully understood. Herein, we aim to understand whether macrophage modulates pancreatic ductal adenocarcinoma (PDAC) progression in an EV-dependent manner and the underlying mechanisms. microRNA (miR)-365 was experimentally determined to be enriched in the EVs from M2 macrophages (M2-EVs), which could be transferred into PDAC cells. Using a co-culture system, M2-EVs could enhance the proliferating, migrating and invading potentials of PDAC cells, while inhibition of miR-365 in M2-EVs could repress these malignant functions. B-cell translocation gene 2 (BTG2) was identified to be a direct target of miR-365, while the focal adhesion kinase (F/ATP)-dependent tyrosine kinase (AKT) pathway was activated by miR-365. We further demonstrated that overexpression of BTG2 could delay the progression of PDAC in vitro, whereas by impairing BTG2-mediated anti-tumour effect, M2-EV-miR-365 promoted PDAC progression. For validation, a nude mouse model of tumorigenesis was established, in which we found that targeting M2-EV-miR-365 contributed to suppression of tumour growth. Collectively, M2-EVs carry miR-365 to suppress BTG2 expression, which activated FAK/AKT pathway, thus promoting PDAC development.

Vibrio vulnificus is a zoonotic bacterium that is capable of causing highly lethal diseases in humans; this pathogen is responsible for 95% of all seafood-related deaths in the United States. Arylamine N -acetyltransferases (NAT, E.C. 2.3.1.5) is a major family of xenobiotic-metabolizing enzymes that can biotransform aromatic amine chemicals. In this research, to evaluate the effect of NAT on acetyl group transformation in arylamine antibiotics, we first used sequence alignment to study the structure of V. vulnificus NAT [(VIBVN)NAT]. The nat gene encodes a protein of 260 amino acids, which has an approximate molecular mass of 30 kDa. Then we purified recombinant (VIBVN)NAT and determined the enzyme activity by PNPA and DTNB methods. The DTNB method indicates that this prokaryotic NAT has a particular substrate specificity towards aromatic substrates. However, (VIBVN)NAT lost most of its activity after treatment with high concentrations of urea and H 2 O 2 . In addition, we also explored the stability of the enzyme at different temperatures and pH values. In analyzing the influence of metal ions, the enzyme activity was significantly inhibited by Zn 2+ and Cu 2+ . The kinetic parameters K m and V max were determined using hydralazine, isoniazid, 4 -amino salicylic acid, and 4 -chloro- 3 -methylaniline as substrates, and the T m , T agg and size distribution of (VIBVN)NAT were observed. In particular, a molecular docking study on the structure of (VIBVN)NAT was conducted to understand its biochemical traits. These results showed that (VIBVN)NAT could acetylate various aromatic amine substrates and contribute to arylamine antibiotic resistance in V. vulnificus .

Objectives: To analyze the clinical and imaging features of acute ischemic stroke (AIS) related to gastrointestinal malignant tumor, and to explore the prognostic factors. Methods: Clinical data of consecutive patients with gastrointestinal malignant tumor complicated with AIS admitted to the Department of Neurology and Oncology in Lanzhou University Second Hospital from April 2015 to April 2019 were retrospectively analyzed. Patients were divided into good prognosis (mRS 0–2) and poor prognosis (mRS > 2) based on a 90-day mRS score after discharge. The multivariate logistic regression model was used to analyze the prognostic factors. Results: A total of 68 patients were enrolled with an average age of 61.78 ± 6.65 years, including 49 men (72.06%). There were 18 patients in the good prognosis group and 50 patients in the poor prognosis group. The univariate analysis showed that Hcy, D-dimer, thrombin–antithrombin complex (TAT), and three territory sign in magnetic resonance imaging (MRI) were the risk factors for poor prognosis. Multivariate analysis showed that increased D-dimer (OR 4.497, 95% CI 1.014–19.938) and TAT levels (OR 4.294, 95% CI 1.654–11.149) were independent risk factors for the prognosis in such patients. Conclusion: Image of patients with gastrointestinal malignant tumor-related AIS is characterized by three territory sign (multiple lesions in different vascular supply areas). Increased TAT and D-dimer levels are independent prognostic risk factors. TAT is more sensitive to predict prognosis than D-dimer.

Objective To investigate the effect of PLGA-PEG scaffold incorporating angiopoietin 1(Ang1) loaded nanoparticle that was injected into the infarcted area of rat heart to protect the heart from infarction and explore potential mechanisms. Methods Rat models of myocardial infarction were replicated,and one week later SD rats were randomly divided into 3 groups:Ang1-PLGA-PEG injection group [injected with 100 μL nanoparticle suspension, about (1.61±0.05)μg Ang1](n=9),Ang1 injection group[injected with PBS solution of angiopoietin1(100 μL, 25 ng/μL)](n=8),the model control group(injected with 100 μL PBS solution)(n=8). Four weeks after injection,cardiac function was examined by echocardiography,scar tissue hyperplasia was measured by Masson staining, cardiomyocyte apoptosis and angiogenesis were detected by immunofluorescence. Results In comparison with other two groups,Ang1-PLGA-PEG injection group showed an increased blood vessel density in the infarcted area and maturity(P＜0.05),which prevented cardiomyocyte apoptosis (P＜0.05) The area of myocardial infarction was significantly decreased(P＜0.05), the remodeling of cardiomyopathy was reduced and these changes improved cardiac function (P＜0.05). Compared with the model control group, pure Ang1 injected into the surrounding area did not show curative effect (P＜0.05). Conclusions Injection of Ang1-PLGA-PEG nanoparticles into the infarcted area of left ventricle may promote vascular proliferation and facilitate the survival of cardiomyocytes,It provides an experimental basis for clinical application.

外泌体直径在40～100 nm,是多种活性细胞分泌产生的胞外囊泡,其内的微小RNA(miRNA)广泛参与肿瘤疾病的发生进展.胰腺癌是一种起病隐匿、发展迅速的消化系统恶性肿瘤,具有早期诊断困难、治疗效果不佳等特点.近年来研究表明,外泌体中的miRNA在胰腺癌的侵袭、转移和耐药中扮演着重要角色,对胰腺癌的临床研究有着重要意义.在此,针对胰腺癌相关的外泌体miRNA及其与胰腺癌的关系和相互作用进行综述.

The new coronavirus COVID-19, also known as SARS-CoV-2, has infected more than 300,000 patients and become a global health emergency due to the very high risk of spread and impact of COVID-19. There are no specific drugs or vaccines against COVID-19, thus effective antiviral agents are still urgently needed to combat this virus. Herein, the FEP (free energy perturbation)-based screening strategy is newly derived as a rapid protocol to accurately reposition potential agents against COVID-19 by targeting viral proteinase Mpro. Restrain energy distribution (RED) function was derived to optimize the alchemical pathway of FEP, which greatly accelerated the calculations and first made FEP possible in the virtual screening of the FDA-approved drugs database. As a result, fifteen out of twenty-five drugs validated in vitro exhibited considerable inhibitory potencies towards Mpro. Among them, the most potent Mpro inhibitor dipyridamole potentially inhibited NF-kB signaling pathway and inflammatory responses, and has just finished the first round clinical trials. Our result demonstrated that the FEP-based screening showed remarkable advantages in prompting drug repositioning against COVID-19.

BACKGROUND:The optimal interventions for unprotected left main coronary artery (ULMCA) disease have long been debated, and long-term clinical studies comparing single stenting to double stenting strategies for ULMCA are currently lacking.METHODS:We plan to perform a systematic review and meta-analysis of clinical trials comparing single stenting with double stents strategy for ULMCA disease. We will search PubMed, EMBASE, Web of science and Cochrane Library using a comprehensive strategy. The related conference proceedings and reference lists of the included studies will also be checked to identify additional studies. Two reviewers will screen retrieved records, extract information and assess the risk of bias independently. STATA software will be used to conduct data synthesis. There is no requirement of ethical approval and informed consent.RESULTS:This study will be submitted to a peer-reviewed journal for publication.CONCLUSION:We hope it will provide a relatively comprehensive reference for clinical practice and future relevant clinical trials.ETHICS AND DISSEMINATION:Ethics approval and patient consent are not required, as this study is a systematic review and meta-analysis.INPLASY REGISTRATION NUMBER:INPLASY2020110030.

主动脉瓣钙化(CAVD)是钙结节在主动脉瓣膜表面异位蓄积,导致主动脉瓣膜增厚、功能性狭窄,继而引起血流动力学紊乱,诱发心血管疾病及相关并发症,已成为心血管疾病的重要致死原因之一.目前CAVD的发病机制尚不明确,但最新研究证明其与很多分子生物学过程有关,包括转化生长因子-β (TGF-β)、骨形成蛋白(BMP)、Wnt、Notch、Sox9、胞外膜泡及机械压力和流量.

Objective: To evaluate the efficacy and safety of different bridging anticoagulant therapies in patients undergoing mechanical heart valve replacement (MHVR) surgery. Methods: Consecutive patients undergoing MHVR surgery from January 2018 to December 2018 in First Hospital of Lanzhou University were prospectively enrolled in this study. Patients were divided into unfractionated heparin (UFH) group and low molecular weight heparin (LMWH) group according to the postoperative bridging anticoagulation methods. Preoperative clinical data and postoperative related time and cost parameters, including drainage time, duration of stay in intensive care unit (ICU), postoperative time (interval from end of operation to discharge) and INR stabilization time (interval from start of bridge anticoagulation to INR value reaching the standard for 2 consecutive days) of all enrolled patients were collected, and all patients were followed up for 4 weeks and thromboembolic or bleeding events were analyzed. Multivariate logistic regression was used to determine the independent prognostic factors of thromboembolic or bleeding events after MHVR receiving various bridging anticoagulant therapies. Results: A total of 217 patients were included in the study, including 120 patients in the UFH group and 97 patients in the LMWH group. Stroke occurred in two patients in the UFH group, while no stroke event occurred in the LMWH group. The incidence of bleeding events was significantly higher (9.28%(9/97) vs. 1.67%(2/120), P=0.02), while the drainage time, duration of stay in ICU, postoperative time, INR stabilization time were all significantly shorter in LMWH group than in UFH group (all P<0.05). Multivariate logistic regression analysis showed that bridging anticoagulation therapies (OR=0.18, 95%CI 0.04-0.86, P=0.03), fibrinogen level (OR=1.99, 95%CI 1.16-3.41, P=0.01) and creatinine level (OR=1.05, 95%CI 1.01-1.08, P=0.04) were independent prognostic factors for bleeding events. Conclusion: LMWH use is associated with increased risk of bleeding events, but can significantly reduce the drainage time, duration of stay in ICU, postoperative time, INR stabilization time in patients post MHVR surgery.

目的:对比分站式杂交冠状动脉血运重建(HCR)与常规不停跳冠状动脉旁路移植术(CABG)治疗多支病变的疗效. 方法:收集同一时期内冠状动脉粥样硬化性心脏病(冠心病)多支病变患者61例,经心内科、心外科联合会诊评估病情后,分为行分站式HCR患者27例(HCR组)和行CABG患者34例(CABG组).收集并比较2组患者的基线资料、术前检查结果、术前SYNTAX评分和欧洲心血管手术危险因素评分系统(EuroSCORE)评分、手术资料、术后情况、住院时间和花费、术后院内并发症.所有患者随访1年,记录主要不良心脑血管事件(MACCE)和次要不良事件. 结果:2组患者的基线特征基本一致.HCR组的手术时间、切口大小、出血量均明显小于CABG组(P＜0.05),2组最终再血管化的血管数量差异无统计学意义(P＞0.05).HCR组的24 h和48 h胸腔引流量、胸腔引流带管时间、红细胞及血浆用量、呼吸机辅助呼吸时间、ICU时间和总住院时间均明显低于CABG组(P＜0.05).CABG组术后各类并发症的发生率高于HCR组(P＜0.05),2组均无院内死亡.所有患者术后最长随访1年,两组MACCE和次要不良事件发生率的差异无统计学意义(P＞0.05). 结论:对于冠心病多支病变患者,分站式HCR有更好的围术期表现,以及不劣于CABG的花费及早期随访结果.

随着心脏病治疗技术的发展,微创治疗已经成为心脏病治疗的主要研究方向.其中,先天性心脏病因为解剖结构复杂,受限于影像技术,大部分仍未开展微创手术.本研究回顾近年先天性心脏病微创治疗影像支持的相关研究后,主要介绍新兴的3D旋转血管造影、心脏3D打印技术和辐射安全技术,并提出展望.

The tumor-suppressor function of p53 makes it an attractive drug target. Efforts were mostly put on stabilization of the functional p53 or reactivation of mutated p53. Previous studies have shown that small molecules targeting Loop1/Sheet3 (L1/S3) can reactivate the R175H-p53 and stabilize p53 in vitro. Since the L1/S3 pocket is shared by the mutate and the wild type (WT) p53, virtual screening is introduced to identify natural products targeting the L1/S3 of WT p53. Considering the high flexibility of Loop1, ensemble docking method is utilized for different clusters of the L1/S3. Seven conformations were chosen for docking. As one of the 181 selected candidates, torilin not only improved p53 activity, but also increased p21 protein expression level, which lies downstream of p53, therefore suppressing HCT116 cancer cell growth. Torilin may covalently bind to Cys124 of p53 by 2-methyl-2-butenal (2M2B) group, as torilin derivatives, which do not contain the 2M2B group, were not able to increase the p53 transcription activity. In conclusion, this study demonstrated that L1/S3 of WT-p53 is a druggable pocket, and torilin has a potential cytotoxicity through activating the p53 pathway.

目的:对无保护左主干(ULMCA)疾病的最佳介入策略是富有争议的,并缺乏单支架技术与双支架技术治疗ULMCA的临床效果比较.本研究通过Meta分析评估两种干预技术的临床效果.方法:计算机检索PubMed、EMbase、The Cochrane Library、中国生物医学文献数据库(CBM)、中国知网和万方数据库,检索有关单支架技术对比双支架技术治疗ULMCA疾病的临床试验,检索时限均为从建库至2019年1月.由2名评价员独立筛选文献、提取资料和评价纳入研究的质量,采用Stata 15.0软件进行Meta分析.结果:最终纳入15项回顾性队列研究,共计5 721例患者,其中单支架治疗患者3 308例,双支架治疗患者2 413例.与双支架相比较,单支架技术与较低的主要不良心血管事件(MACE)(OR=0.71,95％CI:0.54～0.94)及较低的靶病灶血运重建(TLR) (OR=0.55,95％ CI:0.47～0.64)风险相关.单支架与双支架技术在全因死亡率、心血管死亡率、心肌梗死(MI)和支架栓塞(ST)方面差异无统计学意义.结论:在治疗ULMCA方面,与双支架相比,单支架技术可降低发生MACE和TLR的风险,具有更好的临床治疗效果.

临床资料 患者,男,66岁,主因“间断胸闷气促25年,加重8月”收住入院.体检示:一般可,血压118/78 mm Hg,颈静脉不充盈,右胸下部听诊呼吸音减低,可闻及湿罗音,心界左下扩大,心率89次/min,心律齐,主动脉瓣区有粗糙喷射性收缩期杂音,腹部(—),四肢脉搏细弱,双下肢轻度水肿.辅助检查:心脏超声示主动脉瓣环钙化,瓣叶增厚、钙化、粘连,二叶式主动脉瓣,瓣口开放面积0.65 cm2,最大跨瓣压差110 mm Hg,主动脉瓣环内径为19 mm,左心房内径34 mm,左心室舒张期末内径71 mm,左心室射血分数(LVEF) 29％.主动脉及冠状动脉(冠脉)计算机断层扫描血管造影(CTA)示患者主动脉瓣Type 0型二叶瓣,中度钙化,钙化集中在左瓣窦,左右冠脉均发自左瓣窦.

临床资料患者男性,26岁,1个月前无明显诱因出现胸闷、气短,吸气时胸部疼痛,呼吸困难,未予诊治.2周前以上症状明显加重,伴有咳嗽、咳痰、咯血.就诊与当地医院,测得纤维蛋白原(FIB)6.37 g/L,D-dimer 4.68 μg/mL,血沉(ESR) 55 mm/h.胸部增强CT提示,肺动脉主干及左肺动脉分叉多发充盈缺损,下肢静脉彩超提示,右下肢静脉局部中低回声块附壁.诊断为:肺栓塞(pulmonary thromboembolism,PTE),深静脉血栓(deep vein thrombosis,DVT).行“下腔静脉滤器置入术+左肺动脉置管溶栓术”,给予抗凝、溶栓治疗后复查CT病变未见减小.考虑是血栓时间长,溶栓效果差,遂转我科进一步诊治.