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Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response

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Genes & Diseases 2023年第4期10卷 1552-1563页

作者： Wenchang Yang Yaxin Wang tao Wang Chengguo Li Liang Shi Peng Zhang Yuping Yin kaixiong tao Ruidong Li Department of Gastrointestinal Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China Department of Critical Care Medicine Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China

Inflammatory bowel disease(IBD)is a chronic relapsing gastrointestinal disorder,while the treatment effect is not satisfactory.Immune responsive gene 1(IRG1)is a highly ex-pressed gene in macrophage in response to inflammatory response and catalyzes the production of itaconate.Studies have reported that IRG1/itaconate has a significant antioxidant effect.This study aimed to investigate the effect and mechanism of IRG1/itaconate on dextran sulfate so-dium(DSS)-induced colitis in vivo and in vitro.In vivo experiments,we found IRG1/itaconate ex-erted protective effects against acute colitis by increasing mice weight,the length of colon,reducing disease activity index and colonic inflammation.Meanwhile,IRG1 deletion aggravated the macrophages/CD4+/CD8+T-cell accumulation,and increased the release of interleukin(IL)-1b,tumor necrosis factor-a(TNF-a),IL-6,the activation of nuclear factor-kB(NF-kB)/mitogen-activated protein kinase(MAPK)signaling pathway,and gasdermin D(GSDMD)mediated pyrop-tosis.Four-octyl itaconate(4-OI),a derivative of itaconate,attenuated these changes,therefore relieved DSS-induced colitis.In vitro experiment,we found 4-OI inhibited the reactive oxygen species production,thereby inhibiting the activation of MAPK/NF-kB signaling pathway in RAW264.7 and murine bone-marrow-derived macrophages.Simultaneously,we found 4-OI inhib-ited caspase1/GSDMD-mediated pyroptosis to reduce the release of cytokines.Finally,we found anti-TNF-a agent reduced the severity of DSS-induced colitis and inhibited gasdermin E(GSDME)-mediated pyroptosis in vivo.Meanwhile,our study revealed that 4-OI inhibited caspase3/GSDME-mediated pyroptosis induced by TNF-a in vitro.Taken together,IRG1/itaconate exerted a pro-tective role in DSS-induced colitis by inhibiting inflammatory response and GSDMD/GSDME-medi-ated pyroptosis,which could be a promising candidate for IBD therapy.

关键词： Colitis Gasdermin D Gasdermin E Inflammation IRG1

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Examined lymph node numbers influence prognosis in rectal cancer treated with neoadjuvant therapy

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Cancer Pathogenesis and Therapy 2023年第3期1卷 168-176页

作者： Liyu Zhu Lin Wang Zhidong Gao Yujian Zeng kaixiong tao Quan Wang Xinming Li Huanhu Zhang Zhanlong Shen Jing Zhou Kai Shen Yingjiang Ye Aiwen Wu Department of Gastroenterological Surgery Peking University People's HospitalBeijing 100044China Laboratory of Surgical Oncology Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People's HospitalBeijing 100044China Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Department of Gastrointestinal SurgeryPeking University Cancer Hospital&InstituteBeijing 100142China Yunnan Institute of Digestive Disease Department of Gastrointestinal and Hernia SurgeryThe First Affiliated Hospital of Kunming Medical UniversityKunmingYunnan 650032China Department of Gastrointestinal Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China Department of Gastrointestinal and Anal Surgery The First Hospital of Jilin UniversityChangchunJilin 130021China Department of Gastrointestinal and Anal Surgery Huangshi Central HospitalHuangshiHubei 435000China Department of Gastrointestinal Surgery Weihai Municipal HospitalWeihaiShandong 264200China

Background:The number of lymph nodes examined(LNe)is often insufficient in patients with rectal cancer(RC)treated with neoadjuvant therapy;however,its prognostic value remains controversial.Thus,we retrospectively explored whether LNe had an influence on staging and prognosis and investigated whether there was a cut-off value for better prognosis in patients with RC treated with neoadjuvant therapy.Methods:Data were collected from seven prospective hospital databases in China from July 2002 to May 2018.Binary logistic regression models were used to predict lymph node metastasis.The cut-off value for LNe was determined using X-tile 3.6.1.Survival outcomes and risk factors were analyzed using the log-rank test and Cox regression model.Results:A total of 482 patients were included,of whom 459 had complete overall survival(OS)information.Using the percentile method,the total number of lymph nodes examined(TLNe)was 14-16(40th-60th percentile),and the proportion of patients with lymph node metastasis reached a maximum of 48.1%.Cox multivariate analysis showed that the odds ratio(OR)remained the highest when TLNe was 14-16(OR=3.379,P=0.003).The 3-year and 5-year OS were 85.4% and 77.8%,respectively.Negative lymph nodes examined(NLNe)of≤6 was an independent risk factor for 3-year and 5-year OS(3-year OS 71.1%vs.85.9%,P=0.004;5-year OS 66.3%vs.74.3%,P=0.035).Subgroup analysis for patients with ypN+showed that higher 3-year and 5-year OS were achieved when the TLNe was>10,78.8%vs.54.0%(P=0.005),and 60.8%vs.36.0%(P=0.012),respectively.Patients with ypN0M0 had a higher 5-year OS when the TLNe was>19(P=0.055).Conclusion:The TLNe and NLNe influenced the staging accuracy and demonstrated prognostic value in patients with RC treated with neoadjuvant therapy.

关键词： Lymph nodes examined Prognosis Staging accuracy Rectal cancer Neoadjuvant therapy

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新辅助放化疗对经腹会阴联合直肠切除术后会阴伤口恢复的影响

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中华胃肠外科杂志 2024年第6期27卷 615-620页

作者：汪赓姚潇吴远珏陶凯雄高金波华中科技大学同济医学院附属协和医院胃肠外科武汉广州医科大学公共卫生学院广州

目的观察术前开展新辅助放化疗对需要接受经腹会阴联合直肠切除术(APR)患者的会阴部伤口愈合情况的影响。方法采用回顾性队列研究方法, 分析华中科技大学同济医学院附属协和医院2018年1月到2021年12月期间, 经过病理检查确诊为低位直肠... 详细信息

目的观察术前开展新辅助放化疗对需要接受经腹会阴联合直肠切除术(APR)患者的会阴部伤口愈合情况的影响。方法采用回顾性队列研究方法, 分析华中科技大学同济医学院附属协和医院2018年1月到2021年12月期间, 经过病理检查确诊为低位直肠癌并接受了APR手术的219例患者的病例资料, 其中直接手术158例(直接手术组), 术前单纯化疗后手术35例(术前单纯化疗组), 术前放化疗后再手术26例(术前放化疗组)。主要观察指标为术后30 d内伤口并发症发生情况。对会阴伤口愈合情况予以分级:伤口异常有渗出但通过换药和敷料外敷好转, 定义为"乙级";伤口渗出严重、化脓、有恶臭, 需要拆开换药, 定义为"丙级";如同时伴有排除其他原因的发热, 定义为"丙级并发热"。记录患者一般情况、肿瘤情况、肛周伤口愈合情况和术中术后恢复情况。结果全组患者均顺利完成手术。直接手术组、术前单纯化疗组和术前放化疗组患者的手术时间分别为240.0(180.0～300.0)min、240.0(225.0～270.0)min和270.0(240.0～356.2)min, 差异有统计学意义(H=6.508, P=0.039)。术前放化疗组和术前单纯化疗组会阴伤口并发症发生率分别为34.6%(9/26)和22.9%(8/35), 高于直接手术组(10.1%, 16/158), 通过logistic回归模型校正患者年龄和性别后, 术前放化疗组和术前单纯化疗组的并发症发生风险仍高于直接手术组(OR=4.6, 95%CI:1.7～12.7;OR=2.6, 95%CI:1.0～6.8), 差异均有统计学意义(均P<0.05)。直接手术组、术前单纯化疗组和术前放化疗组患者的住院时间分别为9.5(7.0～12.0)d、10.0(8.0～17.0)d和11.5(9.0～19.5)d, 差异无统计学意义(H=0.569, P=0.752)。但是通过广义线性模型校正患者年龄和性别后, 术前放化疗组住院时间长于直接手术组[β(95%CI):4.4(0.5～8.4), P=0.028]。术后经评估, 219例患者中有155例需要术后辅助化疗, 其中伤口并发症患者放弃后续治疗的比例高于未发生伤口并发症患者[32.2%(10/31)比16.1%(20/124)], 差异有统计学意义(χ2=4.133, P=0.023)。结论低位直肠癌新辅助放化疗会增加会阴伤口感染及不愈合等并发症的发生风险。

关键词：直肠肿瘤经腹会阴联合切除新辅助放化疗并发症

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Evaluation of early liquid drinking after radical gastrectomy in gastric cancer:a Chinese multicenter propensity score matching analysis

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Gastroenterology Report 2023年第1期11卷 331-339页

作者： Yue Zhang kaixiong tao Jinlong Yu Chao Chen Quan Zheng Sanlin Lei Xiaogang Zhong Lixin Liu Wei Wang Qiang Wang En Li Yuwen Luo Guanrong Zhang Xingyu Feng Yong Li Junjiang Wang Department of Gastrointestinal Surgery Department of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesSouthern Medical UniversityGuangzhouGuangdongP.R.China Shantou University Medical College ShantouGuangdongP.R.China Department of Gastrointestinal Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP.R.China Department of General Surgery Zhujiang Hospital of Southern Medical UniversityGuangzhouGuangdongP.R.China Department of Gastrointestinal Surgery Huizhou Municipal Central HospitalHuizhouGuangdongP.R.China Department of Gastrointestinal Surgery Guangdong Second Provincial General HospitalGuangzhouGuangdongP.R.China Department of Gastrointestinal Surgery The Second Xiangya Hospital of Central South UniversityChangshaHunanP.R.China Department of Surgical Treatment of Gastrointestinal Hernia and Fistula The People’s Hospital of Guangxi Zhuang Autonomous RegionGuangxi Academy of Medical SciencesNanningGuangxiP.R.China Department of General Surgery The Third Affiliated Hospital of Southern Medical UniversityGuangzhouGuangdongP.R.China Department of Gastrointestinal Surgery The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Hospital of Traditional Chinese MedicineGuangzhouGuangdongP.R.China Department of Gastrointestinal Surgery Guangzhou First People’s HospitalGuangzhouGuangdongP.R.China Department of Gastrointestinal Surgery Meizhou People’s HospitalMeizhouGuangdongP.R.China lnformation and Statistics Center Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesSouthern Medical UniversityGuangzhouGuangdongP.R.China

Background:Enhanced recovery after surgery is used in gastrointestinal surgery.This study aimed to access the effects of early liquid drinking(ELD)on gastrointestinal function recovery in patients with gastric cancer(GC)who underwent radical gastrectomy,as high-quality evidence on the outcomes of ELD after gastrectomy is currently lacking.Methods:Clinicopathological data of patients with GC from 11 centers were retrospectively analysed.Clinical outcomes were investigated in 555 patients,including 225 who started drinking liquid within 48 h(ELD group)of surgery and 330 who started drinking liquid after flatus resumption(traditional liquid drinking[TLD]group).Propensity score matching(PSM)analysis was performed using a match ratio of 1:1 and 201 patients were selected from each group for the analysis.Primary outcome was time to first passage of flatus.Secondary outcomes included time to first defecation,post-operative hospitalization days,occurrence of short-term post-operative complications,and hospitalization costs.Results:After PSM,baseline characteristics were not significantly different between the two groups.The time to first flatus(2.7261.08 vs 3.3661.39 days),first defecation(4.3461.85 vs 4.7761.61 days),and post-operative hospital stay(8.2764.02 vs 12.9464.43 days)were shorter in the ELD group than in the TLD group(all P<0.05).The ELD group had lower hospitalization costs than the TLD group([7.8362.44 vs 8.7863.41]104 RMB,P=0.041).No significant differences were observed in the incidence of post-operative complications.Conclusions:Compared with TLD,post-operative ELD could promote rapid recovery of gastrointestinal function and reduce hospitalization costs;moreover,ELD does not increase the risk of post-operative complications.

关键词： gastric cancer early liquid drinking traditional liquid drinking gastrointestinal function propensity score matching

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Prognostic factors of primary gastrointestinal stromal tumors： a cohort study based on high-volume centers

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Chinese Journal of Cancer Research 2018年第1期30卷 61-71页

作者： Xuechao Liu Haibo Qiu Peng Zhang Xingyu Feng tao Chen Yong Li kaixiong tao Guoxin Li Xiaowei Sun Zhiwei Zhou Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou 510060 China Department of Gastric Surgery Sun Yat-sen University Cancer Center Guangzhou 510060 China Department ofGeneral Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China Department of General Surgery Guangdong General Hospital Guangzhou 510080 China Department of General Surgery Southern Medical University Nanfang Hospital Guangzhou 510060 China

Objective： We aimed to evaluate the clinicopathologic characteristics, immunohistochemical expression and prognostic factors of patients with primary gastrointestinal stromal tumors（GISTs）.Methods： Data from 2,570 consecutive GIST patients from four medical centers in China（January2001–December 2015） were reviewed. Survival curves were constructed by the Kaplan-Meier method, and Cox regression models were used to identify independent prognostic factors.Results： Of the included patients, 1,375（53.5%） were male, and the patient age range was 18 to 95（median, 58）years. The tumors were mostly found in the stomach（64.5%）, small intestine（25.1%） and colorectal region（5.1%）.At the time of diagnosis, the median tumor size was 4.0（range： 0.1–55.0） cm, and the median mitotic index per 50 high power fields（HPFs） was 3（range： 0–254）. Of the 2,168 resected patients, 2,009（92.7%） received curative resection. According to the modified National Institutes of Health（NIH） classification, 21.9%, 28.9%, 14.1% and35.1% were very low-, low-, intermediate-and high-risk tumors, respectively. The rate of positivity was 96.4% for c-Kit, 87.1% for CD34, 96.9% for delay of germination 1（DOG-1）, 8.0% for S-100, 31.0% for smooth muscle actin（SMA） and 5.1% for desmin. However, the prognostic value of each was limited. Multivariate analysis showed that age, tumor size, mitotic index, tumor site, occurrence of curative resection and postoperative imatinib were independent prognostic factors. Furthermore, we found that high-risk patients benefited significantly from postoperative imatinib（P〈0.001）, whereas intermediate-risk patients did not（P=0.954）.Conclusions： Age, tumor size, mitotic index, tumor site, occurrence of curative resection and postoperative imatinib were independent prognostic factors in patients with GISTs. Moreover, determining whether intermediate-risk patients can benefit from adjuvant imatinib would be of considerable interest in future studies.

关键词： Gastrointestinal stromal tumor immunohistochemical analysis prognosis targeted therapy imatinib

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The apoptosis induction effect of siRNA recombinant expression vector targeting Livin gene in human colon cancer cells

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The Chinese-German Journal of Clinical Oncology 2008年第6期7卷 344-347页

作者： Ming Cai Guobin Wang kaixiong tao Changxue Cai Department of General Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China Department of Pathogenic Biology School of Basic Medical Sciences Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China

Objective:To construct siRNA recombinant expression vector targeting Livin gene and observe the apoptosis induction effect of it in human colon cancer cells. Methods:SiRNA recombinant expression vector targeting Livin gene was constructed and transfected into human colon cancer cell. The effect of siRNA recombinant expression vector was detected by RT-PCR, Western blot, MTT reduction assay and flow cytometry. Results: It was confirmed by restriction endonuclease and sequence analysis that siRNA recombinant expression vector targeting Livin gene was constructed successfully. Inhibition ra-tio of Livin siRNA at mRNA and protein levels were 30.18% and 28.88%. The growth of cancer cells was inhibited significantly and the apoptotic ratio was 13.36 ± 1.45%. Conclusion: The siRNA recombinant expression vector targeting Livin gene has been constructed successfully. It not only can inhibit the expression of Livin gene but also can induce apoptosis in human colon cancer cells remarkably.

关键词： Livin靶向siRNA 大肠癌细胞调亡治疗方法

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Laparoscopic sigmoid vaginoplasty in women withMayer-Rokitansky-Kuster-Hauser syndrome

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Frontiers of Medicine 2009年第3期3卷 347-351页

作者： Yi SHEN Guobin WANG Zhoufang XIONG kaixiong tao Zehua WANG Department of Obstetrics and Gynecology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China

The feasibility and clinical therapeutic effects of laparoscopic sigmoid vaginoplasty in women with Mayer-Rokitansky-Kuster-Hauser syndrome(MRKHs)were explored.The records of 11 MRKHs patients who underwent laparoscopic sigmoid vaginoplasty from 2003 to 2005 were reviewed,and long-term results were evaluated by follow-up.The mean operating time was 234 min(range,130–300 min),the mean hospital stay was 9.4 days(range,7–15 days),and the mean hemoglobin drop was 1.91 g/dL(range,1.6–3.2 g/dL).A functional neovagina was created measuring 11 to 14 cm in length and twoﬁngers in breadth in all patients.No introitus stenosis was observed.No intra-operative or postoperative bowel complication occurred.At the 3rd postoperative month,theﬁrst intercourse began.One patient was lost to follow-up.One had no intercourse and was required to wear vaginal mold occasionally.None of the other nine women(100%)complained of local irritation or dyspar-eunia.They were satisﬁed with their sexual life.The cosmetic results were excellent.The laparoscopic sigmoid vaginoplasty realizes to make a functional neovagina.The main advantage is its minimal invasiveness.It is an ideal procedure for MRKHs patients.

关键词： Mayer-Rokitansky-Kuster-Hauser syndrome laparoscopy sigmoid transplantation vaginoagenesis

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局部进展期胃癌新辅助治疗的现状与展望

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中华实验外科杂志 2024年第2期41卷 197-200页

作者：尹玉平陶凯雄华中科技大学同济医学院附属协和医院胃肠外科武汉430022

胃癌是全球第五大常见恶性肿瘤和第四大肿瘤相关死亡原因。鉴于早期筛查的开展不足以及胃癌发病隐匿且进展迅速的特点, 我国胃癌患者在初诊时大部分已进入进展期。目前新辅助治疗在进展期胃癌临床诊疗中愈来愈被重视, 其能够降低肿瘤临... 详细信息

胃癌是全球第五大常见恶性肿瘤和第四大肿瘤相关死亡原因。鉴于早期筛查的开展不足以及胃癌发病隐匿且进展迅速的特点, 我国胃癌患者在初诊时大部分已进入进展期。目前新辅助治疗在进展期胃癌临床诊疗中愈来愈被重视, 其能够降低肿瘤临床分期, 提高手术R0切除率及降低术后复发转移风险, 从而延长患者生存期。同时近年来, 包括本中心在内的多项临床研究表明, 新辅助化疗联合免疫治疗相较于单纯化疗, 极大提升了进展期胃癌患者的病理缓解率, 但目前仍存在一系列值得探讨的问题。笔者通过回溯国内外相关研究, 从临床及基础转化两个方向阐述进展期胃癌新辅助治疗的发展历程及目前的热点问题。

关键词：胃癌免疫治疗

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美国国立综合癌症网络临床实践指南:胃癌(2023.V2)更新解读

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临床外科杂志 2024年第1期32卷 31-33页

作者：杜雨强蒋祈张鹏陶凯雄华中科技大学同济医学院附属协和医院胃肠外科武汉430022 湖北省微创外科医学研究中心

2023年8月29日,美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)发布了2023.V2版胃癌临床实践指南(以下简称指南)。新版指南在NCCN胃癌临床指南2022.V1、V2及2023.V1版的基础上,主要围绕微卫星高度不稳定(microsatellite instability-high,MSI-H)或错配修复缺陷(deficient mismatch repair,d MMR)的胃癌病人,在诊断评估及围手术期治疗等方面做出系列更新。

关键词：胃癌美国国立综合癌症网络指南解读

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直肠肛管区特殊类型肿瘤的诊治进展

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临床外科杂志 2024年第5期32卷 546-548页

作者：田红坤杜雨强林曜张鹏陶凯雄华中科技大学同济医学院附属协和医院胃肠外科武汉430022

直肠肛管区存在诸如直肠神经内分泌肿瘤、胃肠间质瘤、肛管鳞癌、直肠肛管黑色素瘤、原发性直肠淋巴瘤等特殊类型肿瘤,其临床特征与直肠癌存在差异,且发病率较低,导致临床医师对其认识不足。本文对直肠肛管区特殊类型肿瘤的临床诊疗进... 详细信息

直肠肛管区存在诸如直肠神经内分泌肿瘤、胃肠间质瘤、肛管鳞癌、直肠肛管黑色素瘤、原发性直肠淋巴瘤等特殊类型肿瘤,其临床特征与直肠癌存在差异,且发病率较低,导致临床医师对其认识不足。本文对直肠肛管区特殊类型肿瘤的临床诊疗进展进行综述。

关键词：直肠神经内分泌肿瘤胃肠间质瘤肛管鳞癌直肠肛管黑色素瘤原发性直肠淋巴瘤

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