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Response to letter to the editor regarding: "Alcohol-associated liver disease increases the risk of muscle reduction and mortality in patients with cirrhosis". 回复致编辑的信,内容涉及"酒精相关肝病会增加肝硬化患者肌肉萎缩和死亡的风险"。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-04 DOI: 10.1007/s00535-024-02153-4
Tatsunori Hanai, Kayoko Nishimura, Shinji Unome, Takao Miwa, Yuki Nakahata, Kenji Imai, Atsushi Suetsugu, Koji Takai, Masahito Shimizu
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引用次数: 0
Immunological dynamics in MASH: from landscape analysis to therapeutic intervention. MASH 的免疫动态:从景观分析到治疗干预。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-14 DOI: 10.1007/s00535-024-02157-0
Lawan Rabiu, Pengchao Zhang, Lukman O Afolabi, Muhammad A Saliu, Salisu M Dabai, Rabiatu B Suleiman, Khalid I Gidado, Mark A Ige, Abdulrahman Ibrahim, Guizhong Zhang, Xiaochun Wan

Metabolic dysfunction-associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis (NASH), is a multifaceted liver disease characterized by inflammation and fibrosis that develops from simple steatosis. Immune and inflammatory pathways have a central role in the pathogenesis of MASH, yet, how to target immune pathways to treat MASH remains perplexed. This review emphasizes the intricate role that immune cells play in the etiology and pathophysiology of MASH and highlights their significance as targets for therapeutic approaches. It discusses both current strategies and novel therapies aimed at modulating the immune response in MASH. It also highlights challenges in liver-specific drug delivery, potential off-target effects, and difficulties in targeting diverse immune cell populations within the liver. This review is a comprehensive resource that integrates current knowledge with future perspectives in the evolving field of MASH, with the goal of driving forward progress in medical therapies designed to treat this complex liver disease.

代谢功能障碍相关性脂肪性肝炎(MASH),以前称为非酒精性脂肪性肝炎(NASH),是一种以炎症和纤维化为特征的多发性肝病,由单纯性脂肪变性发展而来。免疫和炎症通路在 MASH 的发病机制中起着核心作用,然而,如何针对免疫通路治疗 MASH 仍是一个难题。本综述强调了免疫细胞在 MASH 的病因学和病理生理学中扮演的复杂角色,并强调了它们作为治疗方法靶点的重要性。综述讨论了旨在调节 MASH 免疫反应的现有策略和新型疗法。它还强调了肝脏特异性给药、潜在的脱靶效应以及针对肝脏内不同免疫细胞群的困难。这篇综述是一份综合资料,整合了不断发展的MASH领域的现有知识和未来展望,旨在推动治疗这种复杂肝病的医学疗法取得进展。
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引用次数: 0
Small extracellular vesicles derived from adipose mesenchymal stem cells alleviate intestinal fibrosis by inhibiting the FAK/Akt signaling pathway via MFGE8. 源自脂肪间充质干细胞的小细胞外囊泡通过MFGE8抑制FAK/Akt信号通路,从而缓解肠纤维化。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-01 Epub Date: 2024-09-21 DOI: 10.1007/s00535-024-02152-5
Zhizhong Xiong, Xianzhe Li, Minghao Xie, Jianping Guo, Shi Yin, Dayin Huang, Longyang Jin, Caiqin Wang, Fengxiang Zhang, Chaobin Mao, Huaxian Chen, Dandong Luo, Haijie Tang, Xijie Chen, Lei Lian

Background: Intestinal fibrosis is one of the most frequent and severe complications of Crohn's disease. Accumulating studies have reported that adipose mesenchymal stem cell-derived small extracellular vesicles (AMSC-sEVs) could alleviate renal fibrosis, hepatic fibrosis, etc., while their potential for treating intestinal fibrosis remains uncertain. Therefore, this study aims to determine the therapeutic effects of AMSC-sEVs on intestinal fibrosis and identify the mechanisms underlying these effects.

Methods: AMSC-sEVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blot. Whether AMSC-sEVs exert antifibrotic effects was investigated in two different murine models of intestinal fibrosis. Besides, AMSC-sEVs were co-cultured with primary human fibroblasts and CCD18co during transforming growth factor (TGF)-β1 stimulation. Label-free proteomics and rescue experiments were performed to identify candidate molecules in AMSC-sEVs. Transcriptome sequencing revealed changes in mRNA levels among different groups. Lastly, proteins related to relevant signaling pathways were identified by western blotting, and their expression and activation status were assessed.

Results: AMSC-sEVs positively expressed CD63 and Alix and presented a classical "rim of a cup" and granule shape with approximately 43-100 nm diameter. AMSCs significantly alleviated intestinal fibrosis through secreted sEVs in vitro and in vivo. The milk fat globule-EGF factor 8 (MFGE8) was stably enriched in AMSC-sEVs and was an active compound contributing to the treatment of intestinal fibrosis by AMSCs. Mechanistically, AMSC-sEV-based therapies attenuated intestinal fibrosis by inhibiting the FAK/Akt signaling pathway.

Conclusions: MFGE8-containing AMSC-sEVs attenuate intestinal fibrosis, partly through FAK/Akt pathway inhibition.

背景:肠纤维化是克罗恩病最常见、最严重的并发症之一:肠纤维化是克罗恩病最常见、最严重的并发症之一。越来越多的研究报道,脂肪间充质干细胞衍生的小细胞外囊泡(AMSC-sEVs)可缓解肾纤维化、肝纤维化等,但其治疗肠纤维化的潜力仍不确定。因此,本研究旨在确定AMSC-sEVs对肠纤维化的治疗作用,并找出这些作用的机制:方法:使用透射电子显微镜、纳米颗粒跟踪分析和免疫印迹对 AMSC-sEVs 进行表征。在两种不同的小鼠肠纤维化模型中研究了 AMSC-sEV 是否具有抗纤维化作用。此外,在转化生长因子(TGF)-β1刺激下,AMSC-sEVs与原代人成纤维细胞和CCD18co共同培养。进行了无标记蛋白质组学和拯救实验,以确定 AMSC-sEVs 中的候选分子。转录组测序显示了不同组间 mRNA 水平的变化。最后,通过Western印迹鉴定了与相关信号通路有关的蛋白质,并评估了它们的表达和激活状态:结果:AMSC-sEVs 阳性表达 CD63 和 Alix,呈典型的 "杯缘 "和颗粒状,直径约为 43-100 nm。AMSCs 通过分泌的 sEVs 在体外和体内明显缓解了肠纤维化。牛奶脂肪球-EGF因子8(MFGE8)稳定地富集在AMSC-sEVs中,是AMSCs治疗肠纤维化的活性化合物。从机制上讲,基于AMSC-sEV的疗法通过抑制FAK/Akt信号通路减轻了肠纤维化:结论:含MFGE8的AMSC-sEV可部分通过抑制FAK/Akt通路减轻肠纤维化。
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引用次数: 0
Association of circulating cytokine levels and tissue-infiltrating myeloid cells with achalasia: results from Mendelian randomization and validation through clinical characteristics and single-cell RNA sequencing. 循环细胞因子水平和组织浸润髓系细胞与贲门失弛缓症的关系:孟德尔随机分析的结果以及临床特征和单细胞 RNA 测序的验证。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-08 DOI: 10.1007/s00535-024-02155-2
Xin-Yue Li, An-Yi Xiang, Xin-Yang Liu, Ke-Hao Wang, Yun Wang, Hai-Ting Pan, Ji-Yuan Zhang, Lu Yao, Zu-Qiang Liu, Jia-Qi Xu, Xiao-Qing Li, Zhao-Chao Zhang, Wei-Feng Chen, Ping-Hong Zhou, Quan-Lin Li

Background: Achalasia is a rare motility disorder of the esophagus often accompanied by immune dysregulation, yet specific underlying mechanisms remain poorly understood.

Methods: We utilized Mendelian randomization (MR) to explore the causal effects of cytokine levels on achalasia, with cis-expression/protein quantitative trait loci (cis-eQTLs/pQTLs) for 47 cytokines selected from a genome-wide association study (GWAS) meta-analysis and GWAS data for achalasia obtained from FinnGen. For cytokines significantly linked to achalasia, we analyzed their plasma concentrations and expression differences in the lower esophageal sphincter (LES) using enzyme-linked immunosorbent assay and single-cell RNA sequencing (scRNA-seq) profiling, respectively. We further employed bioinformatics approaches to investigate underlying mechanisms.

Results: We revealed positive associations of circulating Eotaxin, macrophage inflammatory protein-1b (MIP1b), soluble E-selectin (SeSelectin) and TNF-related apoptosis-inducing ligand (TRAIL) with achalasia. When combining MR findings with scRNA-seq data, we observed upregulation of TRAIL (OR = 2.70, 95% CI, 1.20-6.07), encoded by TNFSF10, in monocytes and downregulation of interleukin-1 receptor antagonist (IL-1ra) (OR = 0.70, 95% CI 0.59-0.84), encoded by IL1RN, in FOS_macrophages in achalasia. TNFSF10high monocytes in achalasia displayed activated type I interferon signaling, and IL1RNlow FOS_macrophages exhibited increased intercellular communications with various lymphocytes, together shaping the proinflammatory microenvironment of achalasia.

Conclusions: We identified circulating Eotaxin, MIP1b, SeSelectin and TRAIL as potential drug targets for achalasia. TNFSF10high monocytes and IL1RNlow macrophages may play a role in the pathogenesis of achalasia.

背景:贲门失弛缓症是一种罕见的食道运动障碍,通常伴有免疫失调,但其具体的内在机制仍不甚明了:我们利用孟德尔随机化方法(MR)探讨了细胞因子水平对贲门失弛缓症的因果效应,并从全基因组关联研究(GWAS)荟萃分析中选出了47种细胞因子的顺式表达/蛋白定量性状位点(cis-eQTLs/pQTLs),以及从FinnGen获得的贲门失弛缓症GWAS数据。对于与贲门失弛缓症有明显关联的细胞因子,我们分别采用酶联免疫吸附测定法和单细胞 RNA 测序(scRNA-seq)分析法分析了它们的血浆浓度和在食管下括约肌(LES)中的表达差异。我们进一步采用生物信息学方法研究其潜在机制:结果:我们发现循环中的Eotaxin、巨噬细胞炎症蛋白-1b(MIP1b)、可溶性E-选择素(SeSelectin)和TNF相关凋亡诱导配体(TRAIL)与贲门失弛缓症呈正相关。将 MR 研究结果与 scRNA-seq 数据相结合,我们观察到 TNFSF10 编码的 TRAIL 在单核细胞中上调(OR = 2.70,95% CI,1.20-6.07),而 IL1RN 编码的白细胞介素-1 受体拮抗剂(IL-1ra)在 FOS_macrophages 中下调(OR = 0.70,95% CI 0.59-0.84)。贲门失弛缓症中TNFSF10高的单核细胞显示出活化的I型干扰素信号,而IL1RN低的FOS_巨噬细胞显示出与各种淋巴细胞的细胞间通讯增加,共同形成了贲门失弛缓症的促炎性微环境:我们发现循环中的Eotaxin、MIP1b、SeSelectin和TRAIL是治疗贲门失弛缓症的潜在药物靶点。TNFSF10高的单核细胞和IL1RN低的巨噬细胞可能在贲门失弛缓症的发病机制中发挥作用。
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引用次数: 0
Alcohol-associated liver disease increases the risk of muscle loss and mortality in patients with cirrhosis. 酒精相关肝病会增加肝硬化患者肌肉萎缩和死亡的风险。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-01 Epub Date: 2024-09-23 DOI: 10.1007/s00535-024-02154-3
Izadora Luiza Kunzler, Marco Antônio Da Croce, Fernando Fornari
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引用次数: 0
Effects of SGLT2 inhibitors on the onset of esophageal varices and extrahepatic cancer in type 2 diabetic patients with suspected MASLD: a nationwide database study in Japan. SGLT2 抑制剂对疑似 MASLD 的 2 型糖尿病患者食管静脉曲张和肝外癌症发病的影响:日本全国数据库研究。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-11 DOI: 10.1007/s00535-024-02158-z
Takumi Kawaguchi, Yoshiyuki Fujishima, Daisuke Wakasugi, Fusayo Io, Yuri Sato, Saeko Uchida, Yukiko Kitajima

Background & aim: SGLT2 inhibitors (SGLT2i) improve hepatic steatosis in patients with type 2 diabetes mellitus (T2DM) and MASLD. We aimed to investigate the impact of SGLT2i on the incidence of liver-related events and extrahepatic cancer compared to DPP4 inhibitors (DPP4i) in patients with T2DM and suspected MASLD using a medical claims database in Japan.

Methods: We conducted a retrospective study using a Japanese medical claims database. Among patients with T2DM who were prescribed SGLT2i or DPP4i (n = 1,628,656), patients with suspected MASLD were classified into SGLT2i (n = 4204) and DPP4i (n = 4204) groups. Effects of SGLT2i on the following outcomes were compared to DPP4i: (1) changes in HbA1c and ALT levels after 6 months, (2) changes in hepatic fibrosis index, and (3) the incidence of liver-related events/extrahepatic cancer over 12 months.

Results: After 6 months, DPP4i significantly decreased HbA1c levels compared to SGLT2i. In contrast, SGLT2i significantly decreased ALT levels compared to DPP4i. SGLT2i significantly decreased FIB-4 index compared to DPP4i over 12 months. Although no significant difference was observed in the incidence of overall liver-related events between the two groups, SGLT2i significantly reduced the incidence of esophageal varices (HR 0.12, 95%CI 0.01-0.95, P = 0.044). Moreover, SGLT2i significantly suppressed the incidence of extrahepatic cancer (HR 0.50, 95%CI 0.30-0.84, P = 0.009) compared to DPP4i.

Conclusion: SGLT2i was more beneficial than DPP4i in improving the hepatic inflammation and fibrosis indices. Moreover, SGLT2i suppressed the incidence of esophageal varices and extrahepatic cancer compared to DPP4i. SGLT2i may suppress life-threatening events in patients with T2DM and suspected MASLD.

背景和目的:SGLT2 抑制剂(SGLT2i)可改善 2 型糖尿病(T2DM)和 MASLD 患者的肝脂肪变性。我们旨在利用日本的医疗索赔数据库,调查与 DPP4 抑制剂(DPP4i)相比,SGLT2i 对 T2DM 和疑似 MASLD 患者肝脏相关事件和肝外癌症发病率的影响:我们利用日本医疗索赔数据库进行了一项回顾性研究。在处方 SGLT2i 或 DPP4i 的 T2DM 患者(n = 1628656 人)中,疑似 MASLD 患者被分为 SGLT2i 组(n = 4204 人)和 DPP4i 组(n = 4204 人)。比较了 SGLT2i 和 DPP4i 对以下结果的影响:(1) 6 个月后 HbA1c 和 ALT 水平的变化;(2) 肝纤维化指数的变化;(3) 12 个月内肝脏相关事件/肝外癌的发生率:6个月后,与SGLT2i相比,DPP4i能显著降低HbA1c水平。相反,与 DPP4i 相比,SGLT2i 能显著降低 ALT 水平。与 DPP4i 相比,SGLT2i 能在 12 个月内明显降低 FIB-4 指数。虽然两组患者的总体肝脏相关事件发生率无明显差异,但 SGLT2i 能显著降低食管静脉曲张的发生率(HR 0.12,95%CI 0.01-0.95,P = 0.044)。此外,与 DPP4i 相比,SGLT2i 能明显抑制肝外癌的发病率(HR 0.50,95%CI 0.30-0.84,P = 0.009):结论:在改善肝脏炎症和纤维化指数方面,SGLT2i 比 DPP4i 更为有益。此外,与 DPP4i 相比,SGLT2i 可抑制食管静脉曲张和肝外癌症的发病率。SGLT2i可抑制T2DM和疑似MASLD患者发生危及生命的事件。
{"title":"Effects of SGLT2 inhibitors on the onset of esophageal varices and extrahepatic cancer in type 2 diabetic patients with suspected MASLD: a nationwide database study in Japan.","authors":"Takumi Kawaguchi, Yoshiyuki Fujishima, Daisuke Wakasugi, Fusayo Io, Yuri Sato, Saeko Uchida, Yukiko Kitajima","doi":"10.1007/s00535-024-02158-z","DOIUrl":"10.1007/s00535-024-02158-z","url":null,"abstract":"<p><strong>Background & aim: </strong>SGLT2 inhibitors (SGLT2i) improve hepatic steatosis in patients with type 2 diabetes mellitus (T2DM) and MASLD. We aimed to investigate the impact of SGLT2i on the incidence of liver-related events and extrahepatic cancer compared to DPP4 inhibitors (DPP4i) in patients with T2DM and suspected MASLD using a medical claims database in Japan.</p><p><strong>Methods: </strong>We conducted a retrospective study using a Japanese medical claims database. Among patients with T2DM who were prescribed SGLT2i or DPP4i (n = 1,628,656), patients with suspected MASLD were classified into SGLT2i (n = 4204) and DPP4i (n = 4204) groups. Effects of SGLT2i on the following outcomes were compared to DPP4i: (1) changes in HbA1c and ALT levels after 6 months, (2) changes in hepatic fibrosis index, and (3) the incidence of liver-related events/extrahepatic cancer over 12 months.</p><p><strong>Results: </strong>After 6 months, DPP4i significantly decreased HbA1c levels compared to SGLT2i. In contrast, SGLT2i significantly decreased ALT levels compared to DPP4i. SGLT2i significantly decreased FIB-4 index compared to DPP4i over 12 months. Although no significant difference was observed in the incidence of overall liver-related events between the two groups, SGLT2i significantly reduced the incidence of esophageal varices (HR 0.12, 95%CI 0.01-0.95, P = 0.044). Moreover, SGLT2i significantly suppressed the incidence of extrahepatic cancer (HR 0.50, 95%CI 0.30-0.84, P = 0.009) compared to DPP4i.</p><p><strong>Conclusion: </strong>SGLT2i was more beneficial than DPP4i in improving the hepatic inflammation and fibrosis indices. Moreover, SGLT2i suppressed the incidence of esophageal varices and extrahepatic cancer compared to DPP4i. SGLT2i may suppress life-threatening events in patients with T2DM and suspected MASLD.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"1120-1132"},"PeriodicalIF":6.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Association between homologous recombination deficiency and time to treatment failure to platinum-based chemotherapy for pancreatic cancer by using the C-CAT database. 利用 C-CAT 数据库分析同源重组缺陷与胰腺癌铂类化疗失败时间之间的关系。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-11-21 DOI: 10.1007/s00535-024-02173-0
Kazunaga Ishigaki, Yurie Tokito, Naminatsu Takahara, Hiroto Nishio, Go Endo, Koshiro Fukuda, Kota Ishida, Rintaro Fukuda, Shinya Takaoka, Hiroki Oyama, Kensaku Noguchi, Tatsunori Suzuki, Tatsuya Sato, Tomotaka Saito, Tsuyoshi Hamada, Koji Miyabayashi, Yasuyoshi Sato, Yousuke Nakai, Hidenori Kage, Katsutoshi Oda, Mitsuhiro Fujishiro

Background: Since homologous recombination deficiency (HRD) is relatively uncommon in pancreatic cancer (PC), its impact on time-to-treatment failure (TTF) among patients undergoing systemic chemotherapy for unresectable and recurrent PC remains uncertain.

Methods: Among patients with unresectable and recurrent PC enrolled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database by July 2023, a total of 1394 patients who underwent first-line chemotherapy with either gemcitabine plus nab-paclitaxel (GnP) or FOLFIRINOX (FFX) and received tissue-based CGP tests after disease progression were included in this study. HRD was defined as the presence of germline or somatic genetic mutations in homologous recombination repair (HRR)-related genes such as ATM, BARD1, BRIP1, BRCA1/2, CHEK2, CDK12, PALB, and RAD51C/D. We investigated the correlation between HRD and TTF among patients treated with GnP and FFX.

Results: First-line chemotherapy consisted of GnP in 69% of the cases and FFX in 31%. The CGP tests used were NCC OncoPanel and FoundationOne CDx in 26% and 74%, respectively. HRR-related genetic abnormalities were identified in 107 patients (7.6%): BRCA2 (n = 51), ATM (n = 34), BRCA1 (n = 9), PALB2 (n = 9), among others. In the GnP cohort, the median TTF was comparable between the HRD and non-HRD groups (5.3 vs 4.6 months, P = 0.44). Conversely, in the FFX cohort, it was significantly longer in the HRD group compared to the non-HRD group (7.3 vs. 4.7 months, p < 0.01).

Conclusions: Our findings suggest that HRR-related genetic abnormalities might be predictive of TTF in platinum-based chemotherapy for PC.

背景:由于同源重组缺陷(HRD)在胰腺癌(PC)中相对不常见,其对接受全身化疗治疗不可切除和复发性PC患者治疗失败时间(TTF)的影响仍不确定:在2023年7月之前加入癌症基因组学和先进治疗中心(Center for Cancer Genomics and Advanced Therapeutics,C-CAT)数据库的不可切除和复发性PC患者中,共有1394名患者接受了吉西他滨+纳布-紫杉醇(GnP)或FOLFIRINOX(FFX)一线化疗,并在疾病进展后接受了基于组织的CGP检测。HRD定义为同源重组修复(HRR)相关基因(如ATM、BARD1、BRIP1、BRCA1/2、CHEK2、CDK12、PALB和RAD51C/D)出现种系或体细胞基因突变。我们研究了接受GnP和FFX治疗的患者中HRD和TTF之间的相关性:结果:69%的一线化疗包括GnP,31%的一线化疗包括FFX。使用的 CGP 检测分别为 NCC OncoPanel 和 FoundationOne CDx(分别占 26% 和 74%)。在 107 例患者(7.6%)中发现了与 HRR 相关的基因异常:BRCA2(51 例)、ATM(34 例)、BRCA1(9 例)、PALB2(9 例)等。在GnP队列中,HRD组和非HRD组的中位TTF相当(5.3个月 vs 4.6个月,P = 0.44)。相反,在 FFX 队列中,与非 HRD 组相比,HRD 组的中位 TTF 明显更长(7.3 个月 vs. 4.7 个月,P 结论:我们的研究结果表明,与 HRR 相关的遗传因素可能会影响患者的中位 TTF:我们的研究结果表明,HRR相关基因异常可能是PC铂类化疗中TTF的预测因素。
{"title":"Association between homologous recombination deficiency and time to treatment failure to platinum-based chemotherapy for pancreatic cancer by using the C-CAT database.","authors":"Kazunaga Ishigaki, Yurie Tokito, Naminatsu Takahara, Hiroto Nishio, Go Endo, Koshiro Fukuda, Kota Ishida, Rintaro Fukuda, Shinya Takaoka, Hiroki Oyama, Kensaku Noguchi, Tatsunori Suzuki, Tatsuya Sato, Tomotaka Saito, Tsuyoshi Hamada, Koji Miyabayashi, Yasuyoshi Sato, Yousuke Nakai, Hidenori Kage, Katsutoshi Oda, Mitsuhiro Fujishiro","doi":"10.1007/s00535-024-02173-0","DOIUrl":"https://doi.org/10.1007/s00535-024-02173-0","url":null,"abstract":"<p><strong>Background: </strong>Since homologous recombination deficiency (HRD) is relatively uncommon in pancreatic cancer (PC), its impact on time-to-treatment failure (TTF) among patients undergoing systemic chemotherapy for unresectable and recurrent PC remains uncertain.</p><p><strong>Methods: </strong>Among patients with unresectable and recurrent PC enrolled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database by July 2023, a total of 1394 patients who underwent first-line chemotherapy with either gemcitabine plus nab-paclitaxel (GnP) or FOLFIRINOX (FFX) and received tissue-based CGP tests after disease progression were included in this study. HRD was defined as the presence of germline or somatic genetic mutations in homologous recombination repair (HRR)-related genes such as ATM, BARD1, BRIP1, BRCA1/2, CHEK2, CDK12, PALB, and RAD51C/D. We investigated the correlation between HRD and TTF among patients treated with GnP and FFX.</p><p><strong>Results: </strong>First-line chemotherapy consisted of GnP in 69% of the cases and FFX in 31%. The CGP tests used were NCC OncoPanel and FoundationOne CDx in 26% and 74%, respectively. HRR-related genetic abnormalities were identified in 107 patients (7.6%): BRCA2 (n = 51), ATM (n = 34), BRCA1 (n = 9), PALB2 (n = 9), among others. In the GnP cohort, the median TTF was comparable between the HRD and non-HRD groups (5.3 vs 4.6 months, P = 0.44). Conversely, in the FFX cohort, it was significantly longer in the HRD group compared to the non-HRD group (7.3 vs. 4.7 months, p < 0.01).</p><p><strong>Conclusions: </strong>Our findings suggest that HRR-related genetic abnormalities might be predictive of TTF in platinum-based chemotherapy for PC.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The landscape of 142 Epstein-Barr viral whole genomes in gastric cancer. 胃癌中 142 个 Epstein-Barr 病毒全基因组的分布情况。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-11-21 DOI: 10.1007/s00535-024-02170-3
Yuki Kojima, Motoharu Hamada, Azumi Naruse, Kimitoshi Goto, Htet Thiri Khine, Haruto Arai, Yuta Akutsu, Akira Satou, Masato Nakaguro, Seiichi Kato, Yasuhiro Kodera, Yasushi Yatabe, Yuka Torii, Jun-Ichi Kawada, Takayuki Murata, Hiroshi Kimura, Shuji Takiguchi, Hiroshi Inagaki, Hiromi Kataoka, Yusuke Okuno

Background: A substantial portion of gastric cancer (GC) is linked to Epstein-Barr virus (EBV) infection. The characteristics of this viral genome, such as specific viral strains and large structural variations, influence the progression of diseases like nasopharyngeal carcinoma and hematological malignancy. However, the EBV genomes from GC have not been thoroughly characterized.

Methods: Our study involved 849 consecutive GC patients diagnosed at Nagoya City University Hospital, Japan (NCU cohort). We detected EBV from formalin-fixed, paraffin-embedded sections using a novel direct PCR-based rapid detection method. Additionally, we analyzed 142 EBV whole genomes (125 newly sequenced) from GC, comparing them with 205 genomes from other EBV-associated diseases.

Results: We identified 32 (3.8%) patients associated with EBVaGC in the NCU cohort. Moreover, the direct PCR identified several GC specimens containing EBV-infected lymphocytes or their follicles. The dominant viral strain in GC was type 1 EBV, prevalent in most parts of the world, and no GC-specific strain was identified. We found no significant associations between single-nucleotide variants in the viral genome and GC. Structural variations of the EBV genome were infrequent in GC (4 cases, 2.1%), contrasting with EBV-associated hematological malignancy, which frequently carries large deletions.

Conclusions: This study is the first to uncover the genomic variations of EBV in GC. While EBV is definitively linked to GC, the characteristics of its genomes do not strongly correlate with disease development or progression. Our findings on viral genomes supplement the current understanding of human genomes in EBVaGC.

背景:相当一部分胃癌(GC)与 Epstein-Barr 病毒(EBV)感染有关。这种病毒基因组的特征,如特定的病毒株和巨大的结构变异,影响着鼻咽癌和血液恶性肿瘤等疾病的进展。然而,来自 GC 的 EBV 基因组尚未被彻底鉴定:我们的研究涉及在日本名古屋市立大学医院确诊的连续 849 例 GC 患者(NCU 队列)。我们使用一种基于 PCR 的新型直接快速检测方法检测了福尔马林固定、石蜡包埋切片中的 EBV。此外,我们还分析了来自 GC 的 142 个 EBV 全基因组(其中 125 个是新测序的),并将它们与来自其他 EBV 相关疾病的 205 个基因组进行了比较:我们在NCU队列中发现了32名(3.8%)与EBVaGC相关的患者。此外,直接 PCR 还发现了几例含有 EBV 感染淋巴细胞或其滤泡的 GC 标本。GC 中的主要病毒株是 1 型 EBV,流行于世界大部分地区,没有发现 GC 特异性病毒株。我们发现病毒基因组中的单核苷酸变异与 GC 之间没有明显的关联。EBV基因组的结构变异在GC中并不常见(4例,2.1%),这与EBV相关的血液恶性肿瘤形成鲜明对比,后者经常携带大量缺失:本研究首次发现了EBV在GC中的基因组变异。虽然 EBV 与 GC 有明确的联系,但其基因组的特征与疾病的发生或发展并无密切关系。我们对病毒基因组的发现补充了目前对 EBVaGC 中人类基因组的认识。
{"title":"The landscape of 142 Epstein-Barr viral whole genomes in gastric cancer.","authors":"Yuki Kojima, Motoharu Hamada, Azumi Naruse, Kimitoshi Goto, Htet Thiri Khine, Haruto Arai, Yuta Akutsu, Akira Satou, Masato Nakaguro, Seiichi Kato, Yasuhiro Kodera, Yasushi Yatabe, Yuka Torii, Jun-Ichi Kawada, Takayuki Murata, Hiroshi Kimura, Shuji Takiguchi, Hiroshi Inagaki, Hiromi Kataoka, Yusuke Okuno","doi":"10.1007/s00535-024-02170-3","DOIUrl":"https://doi.org/10.1007/s00535-024-02170-3","url":null,"abstract":"<p><strong>Background: </strong>A substantial portion of gastric cancer (GC) is linked to Epstein-Barr virus (EBV) infection. The characteristics of this viral genome, such as specific viral strains and large structural variations, influence the progression of diseases like nasopharyngeal carcinoma and hematological malignancy. However, the EBV genomes from GC have not been thoroughly characterized.</p><p><strong>Methods: </strong>Our study involved 849 consecutive GC patients diagnosed at Nagoya City University Hospital, Japan (NCU cohort). We detected EBV from formalin-fixed, paraffin-embedded sections using a novel direct PCR-based rapid detection method. Additionally, we analyzed 142 EBV whole genomes (125 newly sequenced) from GC, comparing them with 205 genomes from other EBV-associated diseases.</p><p><strong>Results: </strong>We identified 32 (3.8%) patients associated with EBVaGC in the NCU cohort. Moreover, the direct PCR identified several GC specimens containing EBV-infected lymphocytes or their follicles. The dominant viral strain in GC was type 1 EBV, prevalent in most parts of the world, and no GC-specific strain was identified. We found no significant associations between single-nucleotide variants in the viral genome and GC. Structural variations of the EBV genome were infrequent in GC (4 cases, 2.1%), contrasting with EBV-associated hematological malignancy, which frequently carries large deletions.</p><p><strong>Conclusions: </strong>This study is the first to uncover the genomic variations of EBV in GC. While EBV is definitively linked to GC, the characteristics of its genomes do not strongly correlate with disease development or progression. Our findings on viral genomes supplement the current understanding of human genomes in EBVaGC.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Association between advanced fibrosis and epigenetic age acceleration among individuals with MASLD. 晚期纤维化与 MASLD 患者表观遗传年龄加速之间的关系。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-11-20 DOI: 10.1007/s00535-024-02181-0
Haili Wang, Zhenqiu Liu, Hong Fan, Chengnan Guo, Xin Zhang, Yi Li, Suzhen Zhao, Luojia Dai, Ming Zhao, Tiejun Zhang

Background: The biological process of aging plays an important role in the progress of liver fibrosis. However, epidemiological evidence about the associations between advanced fibrosis and epigenetic age acceleration (EAA) among individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) is limited.

Methods: We utilized publicly available DNA methylation data (GSE180474) for our analysis. Five EAA measures were calculated in this study, including IEAA, PhenoAA, GrimAA, DunedinPACE, and DNAmTLAA. Separate linear regression models were conducted to explore the associations between different fibrosis grades and each measure of EAA.

Results: A total of 325 participants were included in this study, with a mean (± SD) age of 48.56 ± 11.50 years. Of these participants, 64.6% with no fibrosis, 16.9% with bridging fibrosis, 11.1% with incomplete cirrhosis, and 7.4% with cirrhosis. After adjusting for demographics and medication status, MASLD individuals with advanced fibrosis were associated with a 5% increase in the pace of aging (DunedinPACE, β = 0.05, 95% CI: 0.03-0.07) and a 10% decrease in DNAmTLAA (β = -0.10, 95% CI: -0.13 to -0.07) compared those without fibrosis. Similarly, higher stages of fibrosis were associated with an increased pace of aging (DunedinPACE, β = 0.02, 95% CI: 0.01-0.03, Ptrend < 0.001) and decreased DNAmTLAA (β = -0.05, 95% CI: -0.07 to -0.04, Ptrend < 0.001). However, no significant association was found between advanced fibrosis and IEAA, PhenoAA, and GrimAA.

Conclusions: Our findings suggest that advanced fibrosis was associated with an accelerated pace of aging, as measured by the third-generation EA measure DunedinPACE, and shorter telomere length, captured by DNAmTLAA, among individuals with MASLD. This finding has potential prognostic implications and suggests EAA may serve as a surrogate marker of therapeutic efficacy in MASLD.

背景:生物衰老过程在肝纤维化的进展过程中起着重要作用。然而,有关代谢功能障碍相关性脂肪性肝病(MASLD)患者肝纤维化晚期与表观遗传年龄加速(EAA)之间关系的流行病学证据却很有限:我们利用公开的 DNA 甲基化数据(GSE180474)进行分析。本研究计算了五种 EAA 测量值,包括 IEAA、PhenoAA、GrimAA、DunedinPACE 和 DNAmTLAA。我们分别建立了线性回归模型,以探讨不同纤维化等级与每种 EAA 指标之间的关联:本研究共纳入 325 名参与者,平均(± SD)年龄为 48.56 ± 11.50 岁。在这些参与者中,64.6%无纤维化,16.9%为桥接纤维化,11.1%为不完全肝硬化,7.4%为肝硬化。在对人口统计学和用药状况进行调整后,与无纤维化者相比,纤维化晚期的 MASLD 患者的衰老速度增加了 5%(DunedinPACE,β = 0.05,95% CI:0.03-0.07),DNAmTLAA 降低了 10%(β = -0.10,95% CI:-0.13 至 -0.07)。同样,纤维化程度越高,衰老速度越快(DunedinPACE,β = 0.02,95% CI:0.01-0.03,Ptrend 趋势结论):我们的研究结果表明,在 MASLD 患者中,晚期纤维化与第三代 EA 测量 DunedinPACE 测定的老化速度加快和 DNAmTLAA 测定的端粒长度缩短有关。这一发现具有潜在的预后意义,并表明 EAA 可作为 MASLD 疗效的替代标志物。
{"title":"Association between advanced fibrosis and epigenetic age acceleration among individuals with MASLD.","authors":"Haili Wang, Zhenqiu Liu, Hong Fan, Chengnan Guo, Xin Zhang, Yi Li, Suzhen Zhao, Luojia Dai, Ming Zhao, Tiejun Zhang","doi":"10.1007/s00535-024-02181-0","DOIUrl":"https://doi.org/10.1007/s00535-024-02181-0","url":null,"abstract":"<p><strong>Background: </strong>The biological process of aging plays an important role in the progress of liver fibrosis. However, epidemiological evidence about the associations between advanced fibrosis and epigenetic age acceleration (EAA) among individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) is limited.</p><p><strong>Methods: </strong>We utilized publicly available DNA methylation data (GSE180474) for our analysis. Five EAA measures were calculated in this study, including IEAA, PhenoAA, GrimAA, DunedinPACE, and DNAmTLAA. Separate linear regression models were conducted to explore the associations between different fibrosis grades and each measure of EAA.</p><p><strong>Results: </strong>A total of 325 participants were included in this study, with a mean (± SD) age of 48.56 ± 11.50 years. Of these participants, 64.6% with no fibrosis, 16.9% with bridging fibrosis, 11.1% with incomplete cirrhosis, and 7.4% with cirrhosis. After adjusting for demographics and medication status, MASLD individuals with advanced fibrosis were associated with a 5% increase in the pace of aging (DunedinPACE, β = 0.05, 95% CI: 0.03-0.07) and a 10% decrease in DNAmTLAA (β = -0.10, 95% CI: -0.13 to -0.07) compared those without fibrosis. Similarly, higher stages of fibrosis were associated with an increased pace of aging (DunedinPACE, β = 0.02, 95% CI: 0.01-0.03, P<sub>trend</sub> < 0.001) and decreased DNAmTLAA (β = -0.05, 95% CI: -0.07 to -0.04, P<sub>trend</sub> < 0.001). However, no significant association was found between advanced fibrosis and IEAA, PhenoAA, and GrimAA.</p><p><strong>Conclusions: </strong>Our findings suggest that advanced fibrosis was associated with an accelerated pace of aging, as measured by the third-generation EA measure DunedinPACE, and shorter telomere length, captured by DNAmTLAA, among individuals with MASLD. This finding has potential prognostic implications and suggests EAA may serve as a surrogate marker of therapeutic efficacy in MASLD.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
YAP acts as an independent prognostic marker and regulates growth and metastasis of gastrointestinal stromal tumors via FBXW7-YAP pathway. YAP是一种独立的预后标志物,通过FBXW7-YAP通路调控胃肠道间质瘤的生长和转移。
IF 6.9 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-11-18 DOI: 10.1007/s00535-024-02180-1
Xiyu Wu, Kohei Yamashita, Chihiro Matsumoto, Weiliyun Zhang, Ming Ding, Kazuto Harada, Keisuke Kosumi, Kojiro Eto, Satoshi Ida, Yuji Miyamoto, Masaaki Iwatsuki

Background: Although imatinib (IM) and subsequent tyrosine kinase inhibitors (TKIs) significantly improve the prognosis of GIST patients by delaying metastasis and recurrence, most patients experience limited efficacy due to toxicity and secondary resistance. We evaluated Yes-associated protein (YAP), a coactivator of the Hippo pathway accounting for IM resistance and aggressive GIST phenotypes, in GISTs. The degradation of YAP is mediated by FBXW7, and FBXW7 predicts recurrence and IM efficacy for GIST patients. Here, we aimed to identify the potential of YAP as a prognostic marker for patients with GISTs, and the molecular mechanism of FBXW7-YAP pathway in GIST cells.

Methods: We measured YAP expression in 167 GIST cases using immunohistochemical staining, correlated its expression levels with clinicopathological features, and the molecular mechanism underlying the FBXW7-YAP pathway was further examined in vitro and in vivo.

Results: Compared to 80 (47.9%) cases in the low YAP expression group, 87 (52.1%) cases with high YAP expression associated with a poorer prognosis in terms of overall survival (P = 0.004) and recurrence-free survival (P = 0.003). YAP expression was identified as a significant independent factor affecting the 5-year overall survival (P = 0.005) and recurrence-free survival rates (P = 0.007). Moreover, YAP was directly targeted by FBXW7 to affect proliferation, invasion, and migration in GIST cells. High YAP expression correlated with FBXW7 deficiency, as shown in xenograft and metastasis mouse models.

Conclusions: YAP expression serves as a predictive marker of recurrence for GIST patients with curative resection, highlighting its potential as a novel therapeutic target that warrants further investigation.

背景:尽管伊马替尼(IM)和后续的酪氨酸激酶抑制剂(TKIs)通过延缓转移和复发显著改善了GIST患者的预后,但由于毒性和继发性耐药性,大多数患者的疗效有限。我们评估了GISTs中的Yes-相关蛋白(YAP),它是Hippo通路的辅助激活剂,导致IM耐药和侵袭性GIST表型。YAP的降解由FBXW7介导,而FBXW7可预测GIST患者的复发和IM疗效。在此,我们旨在确定YAP作为GIST患者预后标志物的潜力,以及FBXW7-YAP通路在GIST细胞中的分子机制:我们采用免疫组化染色法检测了167例GIST病例中YAP的表达,将其表达水平与临床病理特征相关联,并在体外和体内进一步研究了FBXW7-YAP通路的分子机制:结果:与 YAP 低表达组的 80 例(47.9%)相比,YAP 高表达组的 87 例(52.1%)在总生存期(P = 0.004)和无复发生存期(P = 0.003)方面预后较差。YAP表达被认为是影响5年总生存率(P = 0.005)和无复发生存率(P = 0.007)的重要独立因素。此外,FBXW7 直接靶向 YAP,影响 GIST 细胞的增殖、侵袭和迁移。正如异种移植和转移小鼠模型所示,YAP的高表达与FBXW7的缺乏有关:结论:YAP的表达可作为治愈性切除术后GIST患者复发的预测标志物,突出了其作为新型治疗靶点的潜力,值得进一步研究。
{"title":"YAP acts as an independent prognostic marker and regulates growth and metastasis of gastrointestinal stromal tumors via FBXW7-YAP pathway.","authors":"Xiyu Wu, Kohei Yamashita, Chihiro Matsumoto, Weiliyun Zhang, Ming Ding, Kazuto Harada, Keisuke Kosumi, Kojiro Eto, Satoshi Ida, Yuji Miyamoto, Masaaki Iwatsuki","doi":"10.1007/s00535-024-02180-1","DOIUrl":"10.1007/s00535-024-02180-1","url":null,"abstract":"<p><strong>Background: </strong>Although imatinib (IM) and subsequent tyrosine kinase inhibitors (TKIs) significantly improve the prognosis of GIST patients by delaying metastasis and recurrence, most patients experience limited efficacy due to toxicity and secondary resistance. We evaluated Yes-associated protein (YAP), a coactivator of the Hippo pathway accounting for IM resistance and aggressive GIST phenotypes, in GISTs. The degradation of YAP is mediated by FBXW7, and FBXW7 predicts recurrence and IM efficacy for GIST patients. Here, we aimed to identify the potential of YAP as a prognostic marker for patients with GISTs, and the molecular mechanism of FBXW7-YAP pathway in GIST cells.</p><p><strong>Methods: </strong>We measured YAP expression in 167 GIST cases using immunohistochemical staining, correlated its expression levels with clinicopathological features, and the molecular mechanism underlying the FBXW7-YAP pathway was further examined in vitro and in vivo.</p><p><strong>Results: </strong>Compared to 80 (47.9%) cases in the low YAP expression group, 87 (52.1%) cases with high YAP expression associated with a poorer prognosis in terms of overall survival (P = 0.004) and recurrence-free survival (P = 0.003). YAP expression was identified as a significant independent factor affecting the 5-year overall survival (P = 0.005) and recurrence-free survival rates (P = 0.007). Moreover, YAP was directly targeted by FBXW7 to affect proliferation, invasion, and migration in GIST cells. High YAP expression correlated with FBXW7 deficiency, as shown in xenograft and metastasis mouse models.</p><p><strong>Conclusions: </strong>YAP expression serves as a predictive marker of recurrence for GIST patients with curative resection, highlighting its potential as a novel therapeutic target that warrants further investigation.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Journal of Gastroenterology
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