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Present and future of new systemic therapies for early and intermediate stages of hepatocellular carcinoma

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World Journal of Gastroenterology 2024年第19期30卷 2512-2522页

作者： Juan Jose Urquijo-Ponce Carlos Alventosa-Mateu Mercedes Latorre-Sánchez Inmaculada Castelló-Miralles Moisés Diago Hepatology Unit department of digestive Diseases Consorcio Hospital General Universitario of ValenciaValencia 46014Spain

Hepatocellular carcinoma(HCC)is a high mortality neoplasm which usually appears on a cirrhotic *** therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at *** the current deployment of treatments with curative intent(liver resection/local ablation and liver transplantation)in early and intermediate stages,a high rate of HCC recurrence persists,underscoring a pivotal clinical *** systemic therapies(ST),particularly immunotherapy,have demonstrate promising outcomes in terms of increase overall survival,but they are currently bound to the advanced stage of *** review provides a comprehensive analysis of the literature,encompassing studies up to March 10,2024,evaluating the impact of novel ST in the early and intermediate HCC stages,specially focusing on the findings of neoadjuvant and adjuvant regimens,aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative *** also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative ***,we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.

关键词： Hepatocellular carcinoma Early stage Intermediate stage Neoadjuvant Adjuvant Systemic therapy

Cellular zinc metabolism and zinc signaling:from biological functions to diseases and therapeutic targets

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Signal Transduction and Targeted Therapy 2024年第2期9卷 401-441页

作者： Bonan Chen Peiyao Yu Wai Nok Chan Fuda Xie Yigan Zhang Li Liang Kam Tong Leung Kwok Wai Lo Jun Yu Gary M.K.Tse Wei Kang Ka Fai To department of Anatomical and Cellular pathology State Key Laboratory of Translational OncologyPrince of Wales HospitalThe Chinese University of Hong KongHong KongChina State Key Laboratory of digestive Disease Institute of Digestive DiseaseThe Chinese University of Hong KongHong KongChina CUHK-Shenzhen Research Institute The Chinese University of Hong KongShenzhenChina department of pathology Nanfang Hospital and Basic Medical CollegeSouthern Medical UniversityGuangdong Province Key Laboratory of Molecular Tumor PathologyGuangzhouChina Institute of Biomedical Research Taihe HospitalHubei University of MedicineShiyanChina department of Pediatrics The Chinese University of Hong KongHong KongChina department of Medicine and Therapeutics The Chinese University of Hong KongHong KongChina

Zinc metabolism at the cellular level is critical for many biological processes in the body.A key observation is the disruption of cellular homeostasis,often coinciding with disease *** an essential factor in maintaining cellular equilibrium,cellular zinc has been increasingly spotlighted in the context of disease *** research suggests zinc’s involvement in promoting malignancy and invasion in cancer cells,despite its low tissue *** has led to a growing body of literature investigating zinc’s cellular metabolism,particularly the functions of zinc transporters and storage mechanisms during cancer *** transportation is under the control of two major transporter families:SLC30(ZnT)for the excretion of zinc and SLC39(ZIP)for the zinc ***,the storage of this essential element is predominantly mediated by metallothioneins(MTs).This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression,with a special focus on *** also compile a summary of clinical trials involving zinc *** the main localization of zinc transporters at the cell membrane,the potential for targeted therapies,including small molecules and monoclonal antibodies,offers promising avenues for future exploration.

关键词： metabolism invasion involvement

BTF3L4 Overexpression Mediates APAP-induced Liver Injury in Mouse and Cellular Models

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Journal of Clinical and Translational Hepatology 2024年第3期12卷 245-256页

作者： Junchao Lin Aqiang Fan Zhujin Yifu Qibing Xie Liu Hong Wei Zhou State Key Laboratory of Cancer Biology National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive DiseasesAir Force Military Medical UniversityXi’anShaanxiChina department of digestive Surgery Xijing HospitalAir Force Military Medical UniversityXi’anShaanxiChina

Background and Aims:Acetaminophen(APAP)-induced liver injury(AILI)has an increasing incidence ***,the mechanisms contributing to such liver injury are largely unknown and no targeted therapy is currently *** study aimed to investigate the effect of BTF3L4 overexpression on apoptosis and inflammation regulation in vitro and in ***:We performed a proteomic analysis of the AILI model and found basic transcription factor 3 like 4(BTF3L4)was the only outlier transcription factor overexpressed in the AILI model in ***3L4 overexpression increased the degree of liver injury in the AILI ***:BTF3L4 exerts its pathogenic effect by inducing an inflammatory response and damaging mitochondrial *** BTF3L4 expression increases the degree of apoptosis,reactive oxygen species generation,and oxidative stress,which induces cell death and liver *** damage of mitochondrial function by BTF3L4 triggers a cascade of events,including reactive oxygen species accumulation and oxidative *** to the available AILI data,BTF3L4 expression is positively associated with inflammation and may be a potential biomarker of ***:Our results suggest that BTF3L4 is a pathogenic factor in AILI and may be a potential diagnostic maker for AILI.

关键词： BTF3L4 APAP-induced liver injury Apoptosis Mitochondrial morphology Inflammation

RNA modifications in the progression of liver diseases:from fatty liver to cancer

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Science China(Life Sciences) 2024年第10期67卷 2105-2119页

作者： Simiao Li Wajahat Z Mehal Xinshou Ouyang department of Internal Medicine Section of Digestive DiseasesYale University School of MedicineNew Haven CT 06520USA

Non-alcoholic fatty liver disease(NAFLD)has emerged as a prominent global health concern associated with high risk of metabolic syndrome,and has impacted a substantial segment of the *** disease spectrum ranges from simple fatty liver to non-alcoholic steatohepatitis(NASH),which can progress to cirrhosis and hepatocellular carcinoma(HCC)and is increasingly becoming a prevalent indication for liver *** existing therapeutic options for NAFLD,NASH,and HCC are limited,underscoring the urgent need for innovative treatment *** into gene expression,particularly RNA modifications such as N6methyladenosine(m^(6)A),hold promising avenues for *** modifications play integral roles in RNA metabolism and cellular functions,encompassing the entire NAFLD-NASH-HCC *** review will encompass recent insights on diverse RNA modifications,including m^(6)A,pseudouridine(Ψ),N^(1)-methyladenosine(m^(1)A),and 5-methylcytidine(m^(5)C)across various RNA *** will uncover their significance in crucial aspects such as steatosis,inflammation,fibrosis,and ***,prospective research directions and therapeutic implications will be explored,advancing our comprehensive understanding of the intricate interconnected nature of these pathological conditions.

关键词： m^(6)A RNA modification NASH NAFLD HCC fatty liver

Refractory autoimmune hemolytic anemia in a patient with systemic lupus erythematosus and ulcerative colitis:A case report

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World Journal of Clinical Cases 2024年第13期12卷 2286-2292页

作者： Dai-Xing Chen Yue Wu Sui-Feng Zhang Xiao-Jun Yang department of digestive System Chongqing Traditional Chinese Medicine HospitalChongqing 400021China

BACKGROUND Ulcerative colitis(UC)and systemic lupus erythematosus(SLE)are both systemic immunoreactive diseases,and their pathogenesis depends on the interaction between genes and environmental *** are no reports of UC with SLE in China,but six cases of SLE with UC have been reported in *** combination of these two diseases has distinct effects on the pathogenesis of both *** SUMMARY A female patient(30 years old)came to our hospital due to dull umbilical pain,diarrhea and mucous bloody stool in August 2018 and was diagnosed with *** symptoms were relieved after oral administration of mesalazine(1 g po tid)or folic acid(5 mg po qd),and the patient were fed a control *** June 24,2019,the patient was admitted for treatment due to anemia and *** hospitalization,the patient had repeated low-grade fever and a progressively decreased Hb *** tests revealed positive antinuclear antibody test,positive anti-dsDNA antibody,0.24 g/L C3(0.9-1.8 g/L),0.04 g/L C4(0.1-0.4 g/L),32.37 g/L immunoglobulin(8-17 g/L),and 31568.1 mg/24 h total 24-h urine protein(0-150 mg/24 h).The patient was diagnosed with SLE involving the joints,kidneys and blood *** reported cases of SLE were retrieved from PubMed to characterize clinicopathological features and identify prognostic factors for *** The patient was discharged in remission after a series of treatments,such as intravenous methylprednisolone sodium succinate,intravenous human immunoglobulin,cyclophosphamide injection,and plasma *** discharge,the patient took oral prednisone acetate tablets,cyclosporine capsules,hydroxychloroquine sulfate tablets and other treatments for symptoms and was followed up regularly for 1 month,after which the patient's condition continued to improve and stabilize.

关键词： Plasma exchange Autoimmune hemolytic anemia Systemic lupus erythematosus Ulcerative colitis Case report

Bile acids,gut microbiota,and therapeutic insights in hepatocellular carcinoma

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Cancer Biology & Medicine 2024年第2期21卷 144-162页

作者： Yang Song Harry CH Lau Xiang Zhang Jun Yu Institute of digestive Disease and department of Medicine and Therapeutics State Key Laboratory of Digestive DiseaseLi Ka Shing Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong KongChina department of Gastroenterology Zhongshan Hospital Xiamen UniversityXiamen 361004China

Hepatocellular carcinoma(HCC)is a prevalent and aggressive liver *** interplay between bile acids(BAs)and the gut microbiota has emerged as a critical factor in HCC development and *** normal conditions,BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and *** gut microbiota plays a critical role in BA metabolism,and BAs are endogenous signaling molecules that help maintain liver and intestinal *** note,dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis,thereby leading to liver inflammation and fibrosis,and ultimately contributing to HCC ***,understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying *** this review,we comprehensively explore the roles and functions of BA metabolism,with a focus on the interactions between BAs and gut microorganisms in ***,therapeutic strategies targeting BA metabolism and the gut microbiota are discussed,including the use of BA agonists/antagonists,probiotic/prebiotic and dietary interventions,fecal microbiota transplantation,and engineered *** summary,understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.

关键词： Bile acid gut microbiota hepatocellular carcinoma therapeutics microbiota modulation

To drain or not to drain after distal pancreatectomy: reflexions on the PANDORINA trial

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Hepatobiliary Surgery and Nutrition 2024年第4期13卷 675-677页

作者： Maxime Constant Alexandre Doussot department of digestive and Surgical Oncology Liver Transplantation UnitCHU BesanconBesançonFrance

We read with great interest the PANDORINA study(1).This international multicenter(mostly from the Netherlands)randomized controlled trial aimed at determining whether omitting drainage after distal pancreatectomy(DP)was equivalent in terms of complications to systematic drainage *** primary outcome was the occurrence of severe complications at 90 days defined as Dindo-Clavien grade≥*** main secondary outcome was the occurrence of grade B–C postoperative pancreatic fistula(POPF)at 90 *** both outcomes,the non-inferiority threshold was set at 8%.Randomization was performed intraoperatively,stratified by annual center volume(high volume defined as DP≥40/year)and the risk of POPF according to the distal fistula risk score(D-FRS)combining pancreas thickness(high risk,>19 mm)and main pancreatic duct diameter(high risk,>3 mm)measured both at the isthmus(2).

关键词： Drainage distal pancreatectomy(DP) randomized controlled trial

Bowel function and inflammation: Is motility the other side of the coin?

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World Journal of Gastroenterology 2024年第14期30卷 1963-1967页

作者： Alba Panarese Division of Gastroenterology and digestive Endoscopy Department of Medical SciencesCentral Hospital-Azienda OspedalieraTaranto 74123Italy

Digestion and intestinal absorption allow the body to sustain itself and are the emblematic functions of the *** the flip side,functions also arise from its role as an interface with the ***,the gut houses microorganisms,collectively known as the gut microbiota,which interact with the host,and is the site of complex immune *** role in human pathology is complex and scientific evidence is progressively elucidating the functions of the gut,especially regarding the pathogenesis of chronic intestinal diseases and inflammatory conditions affecting various organs and *** editorial aims to highlight and relate the factors involved in the pathogenesis of intestinal and systemic inflammation.

关键词： Motility Inflammation Pathogenesis Vitamin D Microbiota Gut Chronic intestinal pseudo-obstruction

Prognostic significance and relationship of SMAD3 phosphoisoforms and VEGFR-1 in gastric cancer:A clinicopathological study

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World Journal of Gastrointestinal Oncology 2024年第1期16卷 118-132页

作者： Shi-Lin Lv Pei Guo Jun-Rong Zou Ren-Sheng Chen Ling-Yu Luo De-Qiang Huang Hospital of Gastroenterology Institute of Digestive DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchang 330006Jiangxi ProvinceChina department of pathology Shenzhen Hospital of Southern Medical UniversityShenzhen 518000Guangdong ProvinceChina Institute of Urology The First Affiliated Hospital of Gannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina department of pathology The First Affiliated Hospital of Nanchang UniversityNanchang 330006Jiangxi ProvinceChina

BACKGROUND The TGF-β/SMAD3 and VEGFR-1 signaling pathways play important roles in gastric cancer ***3 phosphorylation is a crucial prognostic marker in gastric *** To determine the prognostic value and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric *** This was a single-center observational study which enrolled 98 gastric cancer patients and 82 adjacent normal gastric tissues from patients aged 32-84 years(median age 65)between July 2006 and April *** were followed up until death or the study ended(median follow-up duration of 28.5 mo).The samples were used to generate tissue microarrays(TMAs)for immunohistochemical(IHC)*** expressions of TGF-β1,pSMAD3C(S423/425),pSMAD3L(S204),and VEGFR-1 in gastric cancer(GC)tumor tissue and normal tissue were measured by IHC staining using TMAs obtained from 98 GC *** and survival information of the patients was recorded by Outdo Biotech from May 2007 to July *** relationship between TGF-β1,pSMAD3C(S423/425),pSMAD3L(S204),and VEGFR-1 protein expression levels was analyzed using Pearson's correlation *** relationship between protein expression levels and clinicopathological parameters was analyzed using the Chi-squared test.A survival curve was generated using the Kaplan-Meier survival *** TGFβ-1 and VEGFR-1 expression was significantly upregulated in gastric cancer tissue compared to adjacent noncancerous *** positive expression of phosphorylated isoforms of Smad3 varied depending on the phosphorylation site[pSMAD3C(S423/425):51.0%and pSMAD3L(S204):31.6%].High expression of pSMAD-3L(S204)was significantly correlated with larger tumors(P=0.038)and later N stages(P=0.035).Additionally,high expression of VEGFR-1 was closely correlated with tumor size(P=0.015)and pathological grading(P=0.013).High expression of both pSMAD3L(S204)and VEGFR-1 was associated with unfavorable outcomes in terms of overall survival(OS).Multiva

关键词： Gastric cancer pSMAD3L(S204) pSMAD3C(S423/425) Survival Transforming growth factor-β1 VEGFR-1