The International Severe Asthma Registry (ISAR) was established in 2017 to advance the understanding of severe asthma and its management, thereby improving patient care worldwide. As the first global registry for adults with severe asthma, ISAR enabled individual registries to standardize and pool their data, creating a comprehensive, harmonized dataset with sufficient statistical power to address key research questions and knowledge gaps. Today, ISAR is the largest repository of real-world data on severe asthma, curating data on nearly 35,000 patients from 28 countries worldwide, and has become a leading contributor to severe asthma research. Research using ISAR data has provided valuable insights on the characteristics of severe asthma, its burdens and risk factors, real-world treatment effectiveness, and barriers to specialist care, which are collectively informing improved asthma management. Besides changing clinical thinking via research, ISAR aims to advance real-world practice through initiatives that improve registry data quality and severe asthma care. In 2024, ISAR refined essential research variables to enhance data quality and launched a web-based data acquisition and reporting system (QISAR), which integrates data collection with clinical consultations and enables longitudinal data tracking at patient, center, and population levels. Quality improvement priorities include collecting standardized data during consultations and tracking and optimizing patient journeys via QISAR and integrating primary/secondary care pathways to expedite specialist severe asthma management and facilitate clinical trial recruitment. ISAR envisions a future in which timely specialist referral and initiation of biologic therapy can obviate long-term systemic corticosteroid use and enable more patients to achieve remission.

Surgery for a symptomatic epiphrenic esophageal diverticulum (EED) typically involves a diverticulectomy with myotomy and partial fundoplication. A 54-year-old male patients presented with postprandial retrosternal pain and regurgitation. A contrast-enhanced computed tomography scan revealed an 8 × 6 × 7 cm left-sided EED. We planned the EED excision using the da Vinci Xi robot (Intuitive Surgical) from an abdominal transhiatal approach.The lower esophagus was looped, followed by the mobilization of the diverticulum and division of its neck using a robotic stapler. A 7-cm long esophagogastric myotomy was performed on the right side with a Toupet fundoplication. The total operative time was 240 minutes with a blood loss of 200 mL. An oral contrast study on postoperative day 1 showed no leak, and the patient was discharged the next day on an oral soft diet. The robotic transhiatal approach to treat EED is safe and may successfully overcome the difficulties of exposure and reach encountered in conventional laparoscopic surgery.

Background/Aims: Panenteric gastrointestinal dysmotility in diabetic gastroenteropathy remains incompletely understood. We aim to (1) compare gastrointestinal transit times, contractile activity, and pH levels between individuals with and without diabetic gastroenteropathy and (2) investigate associations between symptoms and contractile activity. Methods: We compared 37 healthy individuals to 68 individuals with diabetic gastroenteropathy. Gastrointestinal segmental transit times, contractile activity, and pH were measured with SmartPill. The Gastroparesis Cardinal Symptom Index and the Gastrointestinal Symptom Rating Scale were used to evaluate symptoms. Results: Compared to controls, individuals with diabetic gastroenteropathy had prolonged median gastric emptying time (3.3 [IQR, 2.5-4.4] vs 2.5 [IQR, 1.9-3.6] hours, P = 0.023), antroduodenal transition time (23 [IQR, 8-52] vs 11 [IQR, 2-25] minutes, P = 0.015), colonic transit times (36.0 [IQR, 17.3-53.5) vs 20.8 [IQR, 14.0-28.8] hours, P = 0.004), and whole-gut transit time (46.1 [IQR, 24.3-72.9] vs 28.7 [IQR, 22.0-42.7] hours, P = 0.002). The diabetes group had lower antral contraction frequency (1.5 [IQR, 0.9-2.1] vs 2.5 [IQR, 1.5-3.9] contractions per minute, P = 0.004) and sum of amplitudes (1941 [1377-2763] vs 2975 [1734-5337] mmHg, P = 0.004).In contrast, the diabetes group had higher colonic sum of amplitudes and area under the contraction curve. The antral contraction frequency was unassociated with gastrointestinal symptoms. Still, the overall stomach contraction frequency increased by 30% (P < 0.001) and 15% (P = 0.003) in individuals with diabetes for each incremental increase in nausea and reflux scores, respectively. Conclusions Gastrointestinal transit times, as well as antral and colonic contractile activity, differed between individuals with diabetic gastroenteropathy and controls. The overall gastric contraction frequency was associated with symptom severity.

Background/Aims: Functional lumen imaging probe (FLIP) Panometry has demonstrated utility in the assessment of esophageal motility as a complement to existing methodologies like high-resolution manometry. However, as FLIP is typically performed with sedation during routine endoscopy, there is potential for impact of sedation agents on esophageal motility. We aim to examine the effects of conscious sedation with midazolam and fentanyl on FLIP Panometry metrics and classification. Methods: A cross-over study was conducted on 12 healthy, asymptomatic volunteers that completed FLIP while sedated with intravenous fentanyl and midazolam and while awake on a separate day. FLIP was performed in the same manner in both conditions with transoral placement of the FLIP and stepwise FLIP filling. During awake FLIP, subjects also rated the presence and intensity of esophageal perception. Results: In both experimental conditions, all subjects demonstrated normal motility. The esophagogastric junction distensibility index was lower (median [interquartile range]: 5.8 [5.15-6.85] vs 8.9 [7.68-9.38] mm 2 /mmHg; P = 0.025), and the FLIP pressure was higher (46.5 [38.125-52.5] vs 33 [26-36.8] mmHg; P = 0.010) in the sedated condition compared to the awake condition. Maximum esophagogastric junction diameter and body distensibility plateau were no different between conditions (P = 0.999 and P = 0.098, respectively). Perception of esophageal sensation during awake FLIP was reported in 7/12 (58%) subjects. Conclusions While numeric differences in FLIP Panometry metrics were observed between sedated and awake FLIP in healthy subjects, these differences did not change the FLIP Panometry diagnosis. Sedated FLIP offers a well-tolerated method to assess esophageal motility during endoscopy.

[摘 要] 免疫细胞介导的药物递送系统是以免疫细胞为载体，利用细胞固有的趋化作用将治疗药物靶向递送至特定病灶部位，因其具有优异的生物相容性、低免疫原性、组织特异性归巢及易穿过生物屏障等多重优势，已成为药物递送和疾病治疗的重要手段。本文系统论述免疫细胞的载药策略和单核细胞、中性粒细胞、间充质干细胞和树突状细胞等作为载体细胞的生物学特性、主要优缺点，以及应用于肿瘤治疗的最新研究进展，为深入研究免疫细胞介导的药物递送系统和临床转化提供重要参考。

[摘 要] 目的：探讨KH型剪切调节蛋白（KHSRP）靶向调控JAK1/STAT3信号轴对食管胃结合部腺癌（AEG）细胞增殖、迁移和侵袭及移植瘤生长与肺转移的影响。方法：收集2017年1月至2018年12月间在淮河医院确诊的64例AEG组织和癌旁组织标本及临床资料，采用免疫组化法观察AEG组织和癌旁组织中KHSRP的表达水平。qPCR法检测AEG细胞OE-19、TE-7、BIC-1、FLO-1、SK-GT-4、BE-3与正常食管上皮细胞Het-1A中KHSRP的表达差异。通过慢病毒载体对KHSRP进行敲减和过表达处理，分别转染OE-19与TE-7细胞、FLO-1与SK-GT-4细胞，实验分为sh-NC组、sh-KHSRP组和Vector组、KHSRP过表达组（KHSRP组）。采用qPCR法检测敲减或过表达效率，CCK-8法、Transwell小室法分别检测敲减或过表达KHSRP对AEG细胞增殖、迁移和侵袭的影响。构建小鼠异种移植瘤和肺转移模型，观察KHSRP对移植瘤体内生长和转移的作用。WB法验证KHSRP靶向JAK/STAT信号通路。细胞拯救实验验证KHSRP是否通过调节JAK1/STAT3信号通路促进AEG细胞的恶性进程。结果：与癌旁组织相比，AEG组织中KHSRP表达水平显著增高（P < 0.05或P < 0.01）。细胞功能实验分析显示，KHSRP过表达在体外均显著促进AEG细胞增殖、迁移和侵袭（P < 0.05或P < 0.01）。动物实验结果显示，KHSRP在裸鼠体内具有促进AEG细胞移植瘤生长与肺转移的作用（P < 0.05或P < 0.01）。在敲减KHSRP后，JAK/STAT信号通路中JAK1、STAT3磷酸化水平均明显降低，过表达KHSRP后情况则均反之（P < 0.05或P < 0.01）。细胞拯救实验显示，KHSRP可以逆转敲减JAK1/STAT3对细胞增殖、迁移和侵袭的抑制作用（P < 0.05或P < 0.01）。结论：KHSRP通过激活JAK1/STAT3信号通路调控AEG细胞转移的恶性进程，KHSRP有望成为AEG临床治疗的潜在靶点。

[摘 要] 目的：探究蛋白酪氨酸磷酸酶D（PTPRD）去甲基化通过PI3K/Akt/mTOR通路对胃癌细胞增殖、迁移及化疗耐药性的影响。方法：体外培养胃癌细胞MKN-74、MKN-45和人胃黏膜上皮细胞GES-1并检测PTPRD表达。常规培养MKN-45细胞及耐药MKN-45/5-FU细胞，分别转染PTPRD空载体（NC组、NC/5-FU组）、PTPRD过表达腺病毒（PTPRD组、PTPRD/5-FU组）、shRNA空载体（sh-NC组、sh-NC/5-FU组）、shRNA-PTPRD慢病毒（sh-PTPRD组、sh-PTPRD/5-FU组）和PTPRD过表达腺病毒 + 10 μmol/L 740Y-P处理（PTPRD + 740Y-P组、PTPRD + 740Y-P/5-FU组）。MTT法、划痕愈合实验检测各组细胞的增殖活力和迁移能力，细胞自噬实验检测细胞的自噬水平，WB法检测细胞中EMT和PI3K/Akt/mTOR通路相关蛋白的表达。采用0、2.5、5、10、20、40 μmol/L的5-aza处理MKN-45细胞，qPCR法、MTT法检测细胞中PTPRD mRNA表达和细胞增殖活力。结果：PTPRD mRNA和蛋白在胃癌细胞中均呈低表达（P < 0.05）。与MKN-45组相比，PTPRD组自噬体与自噬溶酶体数量、PTPRD、上皮钙黏素（E-cadherin）、BAX蛋白表达均增加（均P < 0.05），细胞增殖活力、细胞迁移率、p-PI3K、波形蛋白（vimentin）、p-Akt、p-mTOR蛋白表达均降低（均P < 0.05），sh-PTPRD组细胞增殖活力、细胞迁移率、p-PI3K、vimentin、p-Akt、p-mTOR蛋白表达均增加（均P < 0.05），自噬体与自噬溶酶体数量、PTPRD、E-cadherin、BAX蛋白表达均减少（均P < 0.05）；与PTPRD组相比，PTPRD + 740Y-P组细胞增殖活力、细胞迁移率、p-PI3K、vimentin、p-Akt、p-mTOR蛋白表达均增加（均P < 0.05），自噬体与自噬溶酶体数量、PTPRD、E-cadherin、BAX蛋白表达减少（均P < 0.05）。随着5-aza浓度的增加，MKN-45细胞中PTPRD mRNA表达增加、细胞增殖活力均降低（均P < 0.05）。与MKN-45/5-FU组相比，PTPRD/5-FU组细胞迁移率、细胞增殖活力均降低（均P < 0.05），sh-PTPRD/5-FU组细胞迁移率、细胞增殖活力均增加（均P < 0.05）；与PTPRD/5-FU组相比，PTPRD + 740Y-P/5-FU组细胞迁移率、细胞增殖活力均增加（均P < 0.05）。结论：PTPRD在胃癌细胞中呈低表达状态，PTPRD去甲基化可能通过抑制PI3K/Akt/mTOR信号通路抑制胃癌细胞增殖、迁移并增强其对化疗的敏感性。

[摘 要] 目的：探讨iSEND免疫评分联合肺癌免疫治疗预后指数（LIPI）在评估非小细胞肺癌（NSCLC）接受免疫治疗预后中的价值。方法：通过回顾性分析2018年2月至2023年2月期间100例接受免疫治疗的晚期NSCLC患者的临床资料，收集并整理患者的iSEND免疫评分和LIPI数据，根据iSEND免疫评分和LIPI分别将患者分为3组（不良组、中等组和良好组），运用Kaplan-Meier方法绘制生存曲线分析所有患者和不同组别患者的无进展生存期（PFS），运用Cox回归分析评估影响患者预后的风险因素。结果：在接受免疫治疗后，NSCLC患者的ORR为42.00%（42/100），DCR为82.00%（82/100）。iSEND免疫评分和LIPI不良组ORR和DCR均最低，良好组均最高，不同组别ORR和DCR比较均有统计学意义（均P < 0.01）。100例NSCLC患者的中位PFS为7.63个月[95% CI（7.23, 8.05）]，iSEND免疫评分不良组、中等组和良好组的中位PFS分别为4.69、6.58和8.99个月，iSEND免疫评分良好组的PFS最长，其次为中等组，不良组最短（χ2=125.391，P < 0.000 1）。LIPI不良组、中等组和良好组的中位PFS分别为4.54、6.39和8.49个月，以LIPI良好组的PFS最长，其次为中等组（χ2 = 115.707，P < 0.000 1）。Cox多因素分析提示，ECOG PS > 1、远处转移、iSEND免疫评分≥ 2分和LIPI ≥ 2分是影响患者独立预后的风险因素。结论：iSEND免疫评分和LIPI可作为评估NSCLC免疫治疗预后的良好指标，具有一定的临床价值。

Background/Aims: Systemic Inflammation (SI) is considered a key mechanism in disease progression and development of complications in decompensated liver cirrhosis. SI is mainly driven by portal hypertension and bacterial translocation. Transjugular intrahepatic portosystemic shunt (TIPS) insertion represents an effective treatment for portal hypertension. This study aims to investigate the impact of TIPS insertion on SI and bacterial translocation. Methods: We prospectively included 59 cirrhotic patients undergoing TIPS insertion. Blood samples were collected at TIPS insertion and follow-up (FU) 1, 3, 6, and 12 months thereafter. At all time points, we performed a comprehensive analysis of SI including 43 soluble inflammatory markers (SIMs), and surrogates of bacterial translocation (sCD14, sCD163). To investigate long-term kinetics of SI, C-reactive protein (CRP) and white blood cells (WBC) were retrospectively analyzed in a cohort of 177 patients up to 3 years after TIPS insertion. Results: At TIPS insertion, 30/43 SIMs, sCD14, and sCD163 measured significantly higher in cirrhotic patients compared to healthy controls. By FU6 25 SIMs and sCD14 measured at significantly lower levels compared to baseline. Interestingly, in patients with TIPS indication of refractory ascites, IL-6 decreased to levels documented in earlier stages of cirrhosis. In long-term follow-up, CRP levels significantly decreased after TIPS insertion, which translated into lower mortality in Cox regression analysis (HR 0.968, p=0.042). Notably, patients with residual ascites post-TIPS showed significantly higher CRP and IL-6 levels across all follow-ups compared to patients with resolved ascites. Conclusions Decreasing portal hypertension via TIPS insertion leads to a significant attenuation of SI and bacterial translocation over time.