Strategies that enhance the function of chimeric antigen receptor-modified T (CAR-T) cells for solid tumors are critical. Inhibitory immuno-checkpoints blockade could potentially enhance CAR-T cell function. TIM-3 is an important negative regulator of T cell activity, but whether TIM-3 blockade could affect CAR-T cell function remains unclear. In our study, we successfully constructed TIM-3-silenced CAR-T cells by dual-promoter lentivirus vectors that simultaneously express the TIM-3 targeting short hairpin RNA (shRNA) and a third-generation CAR recognizing HER2. We demonstrated that down-regulation of TIM-3 did not affect the phenotype of CAR-T cells. CAR-T cells with TIM-3 blockade exhibited higher lytic cytotoxicity to target cells in vitro. Additionally, TIM-3-silenced CAR-T cells displayed robust anti-tumor activity in a murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates the effect of down-regulation of immune checkpoint TIM-3 on the anti-tumor function of CAR T cells, providing new ideas for improving the potency of CAR-T cell therapies in solid tumors.

This study aims to develop online calculators using machine learning models to predict survival probabilities for early- and late-onset colorectal cancer (EOCRC and LOCRC) over a 1- to 8-year period. We extracted data on 117,965 CRC patients from the published database spanning 2010 to 2021, divided into training and internal testing datasets. The data of 200 CRC patients from Chongqing Hospital of Jiangsu Province Hospital was used as the external testing dataset. We conducted univariate and multivariate regression analyses on the training dataset to identify key survival factors and develop predictive machine learning models. The models were evaluated using internal and external testing datasets based on AUC, accuracy, precision, recall, and F1 score. Web-based calculators were subsequently developed to predict survival curves for EOCRC and LOCRC patients under different treatment strategies. In the multivariate Cox regression analysis, 16 and 18 variables were independently significant survival factors for EOCRC and LOCRC, respectively. In the EOCRC group, the machine learning models achieved AUC values of 0.880 and 0.804 in the internal and external testing cohorts. For the LOCRC group, the machine learning models exhibited AUC values of 0.857 and 0.823 in the internal and external testing cohorts. The online calculators, powered by trained machine learning models, are accessible at https://eocrc-surv.streamlit.app/ and https://locrc-surv.streamlit.app/ . These tools estimate survival probabilities for EOCRC and LOCRC patients under various treatment strategies and display the corresponding survival curves post-treatment over the 1- to 8-year period. This study successfully developed online calculators using machine learning algorithms to predict 1- to 8-year survival probabilities for EOCRC and LOCRC patients under various treatment strategies.

Type Ⅳ hiatal hernia with a high risk usually presents sudden or suddenly worsening epigastric pain,vomiting,and dysphagia.It is not conducive to early diagnosis and treatment when symptoms are atypical.Type Ⅳ hiatal hernia with severe anemia is rare.This article reports an atypical case of type Ⅳ hiatal hernia with melena and severe anemia as the main manifestations,aiming to improve clinicians' identification of the atypical clinical presentations of type Ⅳ hiatal hernia.

POEMS syndrome is a rare disease caused by monoclonal plasma cell proliferative disorder.The typical signs include peripheral neuropathy,organ enlargement,endocrine disease,M proteinemia,and skin changes.In clinical practice,the atypical,complex,and changeable clinical manifestations of this syndrome can easily lead to misdiagnosis and missed diagnosis.A case of POEMS syndrome with peripheral edema and ascites as the main manifestations is reported in this paper.

Objective To investigate the killing efficacy of chimeric antigen receptor T (CAR-T) cells targeting epithelial cellular adhesion molecule (EpCAM) in several hepatoma cell lines. Methods Flow cytometry was used to detect the expression of EpCAM in hepatoma cells (SK-hep1, Hep-G2, HuH7 and BEL-7402). After EpCAM -targeting CAR-T cells were constructed using lentiviral vectors with CAR genes, flow cytometry was used to detect the expression of EpCAM-CAR in the obtained cells, and to analyze the CD3/4/8 phenotype of CAR-T cells without transfection of lentiviral vectors. Then the effector cells and target cells were co-cultured, and LDH release assay and ELISA were used to detect the release of LDH and major cytokines in the supernatant. Results EpCAM was highly expressed in Hep-G2, HuH7 and BEL-7402 cells, but not in SK-hep1 cells. Flow cytometry showed that the expression rate of EpCAM-CAR was 43.21% in CAR-T cells after lentivirus infection. Flow cytometry also indicated that up to 95.1% of peripheral blood mononuclear cells (PBMCs) were CD3 positive, of which 61.40% were CD8+ T cells and 32.13% were CD4+ T cells. LDH release assay revealed that the obtained CAR-T cells had stronger direct killing ability on EpCAM-positive hepatoma cell lines Hep-G2, HuH7, and BEL-7402. ELISA showed that EpCAM-positive target cells Hep-G2, HuH7, and BEL-7402 induced CAR-T cells to release more IFN-γ and TNF-α. For SK-hep1 cells with negative EpCAM expression, IFN-γ and TNF-α releases were not significantly different between the CAR-T group and the control group, and the levels of these 2 cytokines werw increased with the increase of E ∶T ratio. Results Compared with ordinary CAR-T cells, EpCAM-targeting CAR-T cells have a stronger killing effect on EpCAM-positive hepatocellular carcinoma cells.

Crizotinib is an oral [anaplastic lymphoma kinase](https://en.wikipedia.org/wiki/Anaplastic_lymphoma_kinase) and [c-ros oncogene 1](https://en.wikipedia.org/wiki/C-ros_oncogene_1) inhibitor, which is approved by the Food and Drug Administration for the treatment of metastatic non-small cell lung cancer (NSCLC). The 2011 Clinical trials demonstrated excellent treatment response, survival, and few side effects. We report a case of severe ulcerative oesophagitis with stenosis that was not reported in the 2011 Clinical trials and earlier studies.

上消化道早癌筛查技能教学是目前内镜教学培训的空缺点和难点.本研究以来自基层已掌握基本胃镜操作技术的进修内镜医师为教学对象,建立了关于上消化道早癌诊断的规范化培训方案.培训周期共12周;教学内容包括理论培训、早癌意识培训、规范的胃镜操作技术、早期食管癌的内镜诊断、早期胃癌的内镜诊断,以及理论和技能结业考核;考核通过后进行早癌病例比赛.通过问卷调查,100％(15/15)的学员认为上消化道早癌诊断规范化培训用于提高上消化道早癌检出率是必要的,且能明显提高学员上消化道早癌的诊断水平.因此,本研究上消化道早癌诊断规范化培训流程总体设置合理,值得进一步推广.

Objective(s): Gallbladder interstitial Cajal-like cells (ICLCs) are known as some of the players in the complex motility mechanisms affecting gallbladder motility. This study aims to explore the mechanism of guinea-pig gallbladder motility disorders during Acute Cholecystitis (AC), focusing on the relationships between neutrophil alterations, gallbladder ICLCs, and smooth muscle contractility.Materials and Methods: Forty-eight guinea pigs were randomly divided into four groups: normal, sham, common bile duct ligation (CBDL), and anti-PMN (anti-polymorphonuclear antibody treated +CBDL). Hematoxylin and eosin-stained slides from each gallbladder sample were examined for inflammation, and myeloperoxidase (MPO) activity was evaluated. The contractile response of gallbladder muscle to Ach, CCK-8, and KCl was registered by a tension transducer, and ultrastructure features of ICLCs were observed.Results: Pretreatment with anti-PMN significantly reduced the circulating neutrophils by 80% and also considerably decreased the gallbladder MPO activity by 52.9% compared with the CBDL group (P<0.05). After adding Ach, CCK-8, and KCl, the contraction ability in CBDL and anti-PMN groups was lower than those of normal and sham groups (P<0.05), and they were increased substantially in the anti-PMN group compared with the CBDL group (P<0.05). Transmission electron microscopy confirmed that the cytoplasm of the neutrophils was full of granules, and neutrophils contacted closely with ICLCs. The ultrastructure of ICLCs in the anti-PMN group was less inflamed and the endoplasmic reticulum was mildly dilated, and cell processes also increased.Conclusion: Anti-PMN could relieve the ultrastructure injury of ICLCs and alleviate gallbladder dysmotility during AC. Neutrophils may damage gallbladder ICLCs at first followed by dysmotility.

Background and Aim Considering the limitation of varying acid suppression of proton pump inhibitors, this study was aimed to assess the efficacy, safety, and dose-effect relationship of keverprazan, a novel potassium-competitive acid blocker, in the treatment of duodenal ulcer (DU) compared with lansoprazole. Methods A randomized, double-blind, double-dummy, multicenter, low-dose, high-dose, and positive-drug parallel-controlled study was conducted to verify the non-inferiority of keverprazan (20 or 30 mg) to lansoprazole of 30 mg once daily for 4 to 6 weeks and dose-effect relationship of keverprazan in the treatment of patients with active DU confirmed by endoscopy. Results Of the 180 subjects randomized, including 55 cases in the keverprazan_20 mg group, 61 cases in the keverprazan_30 mg group, and 64 cases in the lansoprazole_30 mg group, 168 subjects (93.33%) completed the study. The proportions of healed DU subjects in the keverprazan_20 mg, keverprazan_30 mg, and lansoprazole_30 mg groups were respectively 87.27%, 90.16%, and 79.69% at week 4 (P = 0.4595) and were respectively 96.36%, 98.36%, and 92.19% at week 6 (P = 0.2577). The incidence of adverse events in the keverprazan_20 mg group was lower than that in the lansoprazole_30 mg (P = 0.0285) and keverprazan_30 mg groups (P = 0.0398). Conclusions Keverprazan was effective and non-inferior to lansoprazole in healing DU. Based on the comparable efficacy and safety data, keverprazan of 20 mg once daily is recommended for the follow-up study of acid-related disorders. (Trial registration number: ChiCTR2100043455.)

目的 通过系统评价的方式探讨幽门螺杆菌(Helicobacter pylori,H.pylori)感染与类风湿性关节炎的关系,以及根除H.pylori对类风湿性关节炎患者临床症状及炎症指标的影响.方法 计算机检索中国知网(CNKI)、维普网(VIP)、万方数据知识服务平台、中国生物医学文献数据(CBM)、Web of Science、PubMed、Cochrane Library、Embase等数据库,收集有关H.pylori感染与类风湿性关节炎关系的病例对照研究进行系统评价,Meta分析采用RevMan 5.2进行,并对部分研究进行描述性评价.结果 在H.pylori感染与类风湿性关节炎关系的研究中,共纳入6项研究,931例患者.Meta分析结果显示,H.pylori感染率在类风湿性关节炎患者中与普通人群中差异无统计学意义(OR=1.09,95％CI:0.79～1.51,P=0.59).根除H.pylori治疗后,相比对照组,试验组的关节肿胀数目更少、C反应蛋白及血沉水平更低,差异有统计学意义(MD=-3.84,95％CI:-7.16～-0.51,P=0.02;MD=-5.33,95％CI:-8.30～-2.36,P=0.0004;MD=-8.77,95％CI:-13.83～-3.70,P=0.0007).结论 类风湿性关节炎患者中H.pylori感染率与普通人群的感染率无差异,但根除H.pylori治疗后,类风湿性关节炎患者的临床症状及炎症指标明显改善.

Introduction:Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers globally, with significant cell heterogeneity and poor prognosis. Distant metastasis in ESCC is one of the key factors that affects the prognosis of patients.Methods and results:Starting with the analysis of ESCC single-cell sequencing data, we constructed a single-cell atlas of ESCC in detail and clarified the cell heterogeneity within tumor tissues. Through analysis of epithelial-mesenchymal transition (EMT) levels, gene expression, and pathway activation, we revealed the existence of a novel subpopulation of SAA1+ malignant cells in ESCC that are highly aggressive and closely associated with distant metastasis of ESCC. In vitro wound healing and transwell assays confirmed a strong invasion capacity of ESCC tumor cells with high expression of SAA1. Then, we constructed an effective and reliable prediction model based on the gene expression pattern of SAA1+ malignant cell subpopulations and confirmed that patients in the high-risk group had significantly worse prognosis than those in the low-risk group in the training cohort, internal verification cohort and external verification cohort.Discussion:This manuscript contributes to exploration of the heterogeneity of ESCC tumor tissues and the search for new ESCC subpopulations with special biological functions. These results contribute to our understanding of the underlying mechanisms of distant metastasis of ESCC and thus provide a theoretical basis for improved therapies.

目的 总结Crohn病的误诊情况,分析误诊原因,并探讨预防策略.方法 对2011—2021年曾误诊的30例Crohn病的临床资料进行分析,并对疑诊及初诊Crohn病患者进行电话随访.结果 本组出现腹痛22例,腹泻14例,伴随全身症状7例,血便5例,体质量下降3例,有结核病史及结核接触史3例,腹部包块2例,有阑尾炎手术史、肛周脓肿手术史6例.误诊为肠结核10例,阑尾炎7例,胃窦炎3例,溃疡性结肠炎2例,结肠炎2例,腹腔脓肿、不全性肠梗阻、肛瘘、胃肠炎、回盲部溃疡、肠易激综合征各1例;其中误诊为胃窦炎、肛瘘、阑尾炎各1例均被二次误诊为肠结核.23例根据病史、临床表现、肠镜及病理、影像学等检查明确诊断,7例根据术后病理结果明确诊断.30例确诊后2例失访,4例治疗好转后自行停药并未复查肠镜,其余患者均规律治疗,其中18例目前规律生物制剂治疗,4例在治疗过程中出现并发症后行手术治疗,病情均稳定.结论 Crohn病需在诊疗过程中全程随访,密切监测病情变化,尽可能缩短延误治疗时间,避免并发症产生.

Objective To compare the conventional treatment and continuous veno-venous haemofiltration (CVVH) in severe acute pancreatitis (SAP) for the prevention of pseudocyst and walled-off necrosis. Patients and Methods. Forty-two patients were divided into two treatment groups: conventional treatment group contained 24 patients and CVVH had 18. Conventional treatment group patients were treated symptomatically and according to the causes. CVVH group patients were treated symptomatically, and CVVH was done within 2 hours of admission. Results In both groups, there was a decrease in amylase, lipase, CRP, IL-6, IL-10, TNF-alpha, Ranson score, Balthazar score, and APACHE-II score after 72 hours, but the decrease was significantly greater in CVVH patients. There were no any local pancreatic complications in CVVH patients, but 1 patient had an acute peripancreatic fluid collection, 2 patients had pseudocyst, and 2 patients had walled-off necrosis (WON), and a mortality one was seen in the conventional treatment group. Conclusion The present study shows that early CVVH may be able to prevent the formation of pseudocyst and win in SAP patients.

A 59-year-old man was admitted with a 1-year history of recurrent diarrhea and abdominal pain. Colonoscopy performed the previous year showed multiple colonic ulcers, which were confirmed by pathology. Repeat colonoscopy demonstrated a sigmoid ulcer with stenosis that could not be traversed with an adult colonoscope.

目的 评估重庆地区四种常用抗幽门螺杆菌(H.plyori)根治方案的疗效.方法 回顾性分析2019年1月至2019年9月于我院诊断为H.plyori感染患者的资料,将1088例患者根据治疗方案不同分为4组,分别为:CT-quad组(铋剂四联克拉霉素+替硝唑+雷贝拉唑)、AO-quad组(铋剂四联阿莫西林+奥硝唑+雷贝拉唑)、AL-quad组(铋剂四联阿莫西林+左氧氟沙星+雷贝拉唑)及AO-trip组(三联阿莫西林+奥硝唑+雷贝拉唑).各组疗程均2周,4周后复查13 C尿素呼气试验,比较各组患者H.pylori根治率.此外分析根治失败危险因素及成本-效果比.结果 各组根治率分别为:CT-quad组54.5％,AO-quad组78.5％,AL-quad组80.6％,AO-trip组65.7％.其中AO-quad组疗效优于CT-quad组(OR=3.226,95％CI:2.337～4.453,P<0.001),优于AO-trip组(OR=1.972,95％CI:1.266～3.07,P=0.003).AL-quad组疗效优于CT-quad组(OR=3.155,95％CI:2.288～4.351,P<0.001),但同AO-quad组疗效比较,差异无统计学意义(P=0.743).AO-quad组中≥60岁患者较<40岁患者根治失败率更高(OR=2.762,95％CI:1.214～4.628,P=0.015).AO-quad成本-效果比最佳.结论 重庆地区首选铋剂四联阿莫西林+奥硝唑方案,其根治率同铋剂四联阿莫西林+左氧氟沙星方案疗效相似但具有成本-效果优势.不宜选用铋剂四联克拉霉素+替硝唑方案.年龄可能是根治失败的影响因素.

Three-dimensional organoids have been recently established from various tissue-specific progenitors (such as intestinal stem cells), induced pluripotent stem cells, or embryonic stem cells. These cultured self-sustaining stem cell-based organoids may become valuable systems to study the roles of tissue-specific stem cells in tissue genesis and disease development. It is thus conceivable that effective genetic manipulations in such organoids may allow us to reconstruct disease processes and/or develop novel therapeutics. Recombinant adenoviruses are one of the most commonly used viral vectors for in vitro and in vivo gene deliveries. In this study, we investigate if adenoviruses can be used to effectively deliver transgenes into the cultured "mini-gut" organoids derived from intestinal stem cells. Using adenoviral vectors that express fluorescent proteins, we demonstrate that adenoviruses can effectively deliver transgenes into the cultured 3-D "mini-gut" organoids. The transgene expression can last at least 10 days in the cultured organoids. As a proof-of-principle experiment, we demonstrate that adenovirus-mediated noggin expression effectively support the survival and self-renewal of mini-gut organoids, while adenovirus-mediated expression of BMP4 inhibits the self-sustainability and proliferation of the organoids. Thus, our results strongly suggest that adenovirus vectors can be explored as effective gene delivery vehicles to introduce genetic manipulations in 3-D organoids.

[This corrects the article DOI: 10.1371/journal.pone.0093608.].

红细胞分布宽度(RDW)是反映红细胞体积异质性的指标,其值在计算公式上由(红细胞体积的标准差/平均红细胞体积)× 100％得出[1],即红细胞体积的变异系数.许多年来RDW几乎仅应用于诊断贫血相关疾病[2],而近年开始广泛用于慢性阻塞性肺疾病[3]、心力衰竭[4]、冠心病[5]、肾功能不全[6]及各系统肿瘤[7]等疾病中,也有研究显示RDW在临床中运用不仅限于慢性疾病人群,也可作为一般人群的预后指标[8].本文就RDW在肝脏疾病中的应用进展作一综述.