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TGF-βsignaling in health,disease,and therapeutics

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1466-1505页

作者： Ziqin Deng Tao Fan Chu Xiao He Tian Yujia Zheng Chunxiang Li Jie He department of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

ransforming growth factor(TGF)-βis a multifunctional cytokine expressed by almost every tissue and cell *** signal transduction of TGF-βcan stimulate diverse cellular responses and is particularly critical to embryonic development,wound healing,tissue homeostasis,and immune homeostasis in *** dysfunction of TGF-βcan play key roles in many diseases,and numerous targeted therapies have been developed to rectify its pathogenic *** the past decades,a large number of studies on TGF-βsignaling have been carried out,covering a broad spectrum of topics in health,disease,and ***,a comprehensive overview of TGF-βsignaling is required for a general picture of the studies in this *** this review,we retrace the research history of TGF-βand introduce the molecular mechanisms regarding its biosynthesis,activation,and signal *** also provide deep insights into the functions of TGF-βsignaling in physiological conditions as well as in pathological ***-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are *** the summary of previous knowledge and recent updates,this review aims to provide a systematic understanding of TGF-βsignaling and to attract more attention and interest to this research area.

关键词： homeostasis healing wound

Improving the value of molecular testing:current status and opportunities in colorectal cancer precision medicine

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cancer Biology & Medicine 2024年第1期21卷 21-28页

作者： Haiyun Li Linwei Guo Chenchen Wang Xin Hu Ye Xu department of Colorectal Surgery Fudan University Shanghai Cancer CenterShanghai 200032China department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China department of Gastrointestinal Medical Oncology Fudan University Shanghai Cancer CenterShanghai 200032China Precision cancer Medical Center Affiliated with Fudan University Shanghai cancer Center Shanghai 201315China

Colorectal cancer(CRC)is the second leading cause of cancer-related deaths *** radical resection with adjuvant chemotherapy remains the primary treatment choice for CRC,but the 5-year postoperative survival rate is only approximately 60%,and approximately one-third of patients with CRC experience recurrence within 2 years of ***,the transformation of high-throughput sequencing has accelerated the development of precision *** example,KRAS mutations indicate resistance to anti-epidermal growth factor receptor(EGFR)-targeted therapies in ***,molecular-guided individualized therapy has brought new promise in major clinical areas and challenges,such as novel biomarkers predicting sensitivity and resistance to immunotherapy for microsatellite stable(MSS)CRC.

关键词： cancer chemotherapy colorectal

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Phase Ib study of anti-EGFR antibody(SCT200) in combination with anti-PD-1 antibody(SCT-I10A) for patients with RAS/BRAF wild-type metastatic colorectal cancer

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cancer Biology & Medicine 2024年第7期21卷 636-650页

作者： Ming Bai Yao Lu Chunmei Shi Jianwei Yang Wei Li Xianli Yin Chenghui Huang Lin Shen Liangzhi Xie Yi Ba department of GI Medical Oncology Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and TherapyTianjin Tianjin's Clinical Research Center for Cancer Tianjin Key Laboratory of Digestive Cancer Fujian Medical University Union Hospital Fujian Provincial cancer Hospital cancer Center The First Hospital of Jilin University department of Medical Oncology Gastroenterology and Urology Hunan Cancer Hospital Affiliated Cancer Hospital of Xiangya School of Medicine Central South University department of Oncology The Third Xiangya Hospital Central South University department of Gastrointestinal Oncology Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Peking University Cancer Hospital and Institute Beijing Engineering Research Center of Protein and Antibody Sinocelltech Ltd. department of cancer Center Peking Union Medical College Hospital Chinese Academy of Medical Sciences

Objective: This study evaluated the safety and efficacy of an anti-epidermal growth factor receptor(EGFR) antibody(SCT200) and an anti-programmed cell death 1(PD-1) antibody(SCT-I10A) as third-line or subsequent therapies in patients with rat sarcoma viral oncogene(RAS)/v-raf murine sarcoma viral oncogene homolog B(BRAF) wild-type(wt) metastatic colorectal cancer(mCRC).Methods: We conducted a multicenter, open-label, phase Ib clinical trial. Patients with histologically confirmed RAS/BRAF wt m CRC with more than two lines of treatment were enrolled and treated with SCT-I10A and SCT200. The primary endpoints were the objective response rate(ORR) and safety. The secondary endpoints included disease control rate(DCR), progression-free survival(PFS), and overall survival(OS).Results: Twenty-one patients were enrolled in the study through January 28, 2023. The ORR was 28.57% and the DCR was 85.71%(18/21). The median PFS and OS were 4.14 and 12.84 months, respectively. The treatment-related adverse events(TRAEs) were tolerable. Moreover, compared with the monotherapy cohort from our previous phase I study evaluating SCT200 for RAS/BRAF wt m CRC in a third-line setting, no significant improvements in PFS and OS were observed in the combination ***: SCT200 combined with SCT-I10A demonstrated promising efficacy in previously treated RAS/BRAF wt m CRC patients with an acceptable safety profile. Further head-to-head studies with larger sample sizes are needed to validate whether the efficacy and safety of combined anti-EGFR and anti-PD-1 therapy are superior to anti-EGFR monotherapy in the third-line setting.(Registration No. NCT04229537).

关键词： Colorectal cancer SCT-I10A SCT200 epidermal growth factor receptor programmed cell death 1

Effects of dietary intervention on human diseases:molecular mechanisms and therapeutic potential

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1389-1422页

作者： Yu-Ling Xiao Yue Gong Ying-Jia Qi Zhi-Ming Shao Yi-Zhou Jiang Key Laboratory of Breast cancer in Shanghai Department of Breast SurgeryFudan University Shanghai Cancer CenterShanghaiChina department of Oncology Shanghai Medical CollegeFudanUniversityShanghai200032China

Diet,serving as a vital source of nutrients,exerts a profound influence on human health and disease ***,dietary interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative diseases,autoimmune diseases,cardiovascular diseases,and metabolic *** interventions have demonstrated substantial potential in modulating metabolism,disease trajectory,and therapeutic *** reprogramming is a hallmark of malignant progression,and a deeper understanding of this phenomenon in tumors and its effects on immune regulation is a significant challenge that impedes cancer *** intake,as a key environmental factor,can influence tumor *** evidence indicates that dietary interventions might affect the nutrient availability in tumors,thereby increasing the efficacy of cancer ***,the intricate interplay between dietary interventions and the pathogenesis of cancer and other diseases is *** encouraging results,the mechanisms underlying diet-based therapeutic strategies remain largely unexplored,often resulting in underutilization in disease *** this review,we aim to illuminate the potential effects of various dietary interventions,including calorie restriction,fasting-mimicking diet,ketogenic diet,protein restriction diet,high-salt diet,high-fat diet,and high-fiber diet,on cancer and the aforementioned *** explore the multifaceted impacts of these dietary interventions,encompassing their immunomodulatory effects,other biological impacts,and underlying molecular *** review offers valuable insights into the potential application of these dietary interventions as adjunctive therapies in disease management.

关键词： diseases metabolism potential

The evolution of cancer genomic medicine in Japan and the role of the National cancer Center Japan

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cancer Biology & Medicine 2024年第1期21卷 29-44页

作者： Teruhiko Yoshida Yasushi Yatabe Ken Kato Genichiro Ishii Akinobu Hamada Hiroyuki Mano Kuniko Sunami Noboru Yamamoto Takashi Kohno department of Genetic Medicine and Services National Cancer Center HospitalTokyo 104-0045Japan department of Diagnostic Pathology National Cancer Center HospitalTokyo 104-0045Japan Clinical Research Support Offce Clinical Research Coordinating SectionBiobank Translational Research Support SectionNational Cancer Center HospitalTokyo 104-0045Japan department of Pathology and Clinical Laboratories National Cancer Center Hospital EastChiba 277-8577Japan Division of Molecular Pharmacology National Cancer Center Research InstituteTokyo 104-0045Japan National cancer Center Research Institute Tokyo 104-0045Japan department of Laboratory Medicine National Cancer Center HospitalTokyo 104-0045Japan department of Experimental Therapeutics National Cancer Center HospitalTokyo 104-0045Japan Division of Genome Biology National Cancer Center Research InstituteTokyo 104-0045Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer *** the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and *** CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of *** back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be *** quantity and quality of these samples will be compatible with omics *** biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

关键词： cancer genomic medicine biobank patient-derived xenograft multi-gene panel test whole genome sequencing

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New therapeutic strategy with extracorporeal membrane oxygenation for refractory hepatopulmonary syndrome after liver transplant: A case report

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World Journal of Transplantation 2024年第1期14卷 210-214页

作者： Belinda Sánchez Pérez María Pérez Reyes Jose Aranda Narvaez Julio Santoyo Villalba Jose Antonio Perez Daga Claudia Sanchez-Gonzalez Julio Santoyo-Santoyo Hepatobiliary and Trasplantation Unit General and Digestive Surgery DepartmentUniversity Regional HospitalMalaga 29010Spain department of General and Digestive Surgery Regional University Hospital of MalagaMalaga 29010Spain

BACKGROUND Due to the lack of published literature about treatment of refractory hepatopulmonary syndrome(HPS)after liver transplant(LT),this case adds information and experience on this issue along with a treatment with positive *** is a complication of end-stage liver disease,with a 10%-30%incidence in cirrhotic *** can reverse the physiopathology of this process and restore normal ***,in some cases,refractory hypoxemia persists,and extracorporeal membrane oxygenation(ECMO)can be used as a rescue therapy with good *** SUMMARY A 59-year-old patient with alcohol-related liver cirrhosis and portal hypertension was included in the LT waiting list for *** had good liver function(Model for End-Stage Liver Disease score 12,Child-Pugh class B7).He had pulmonary fibrosis and a mild restrictive respiratory pattern with a basal oxygen saturation of 82%.The macroaggregated albumin test result was>*** demonstrated a forced expiratory volume in one second(FEV1)of 78%,forced vital capacity(FVC)of 74%,FEV1/FVC ratio of 81%,diffusion capacity for carbon monoxide of 42%,and carbon monoxide transfer coefficient of 57%.He required domiciliary oxygen at 2 L/min(16 h/d).The patient was admitted to the intensive care unit(ICU)and extubated in the first 24 h,needing high-flow therapy and non-invasive ventilation and inhaled nitric oxide *** was needed after 72 *** to the non-response to supportive therapies,installation of ECMO was decided with progressive recovery after 9 *** was possible on the tenth day,maintaining a high-flow nasal cannula and de-escalating to conventional oxygen therapy after 48 *** was discharged from ICU on postoperative day(POD)20 with a 90%-92%oxygen *** recycling was needed twice for acute *** patient was discharged from hospital on POD 27 with no symptoms,with an 89%-90%oxygen *** Due to the favorable results observed,ECMO could bec

关键词： Liver transplantation Hepatopulmonary syndrome Refractory hypoxemia Treatment Extracorporeal membrane oxygenation Case report

Novel prognostic factors after radical resection of hepatocellular carcinoma: Updating an old issue

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World Journal of Gastrointestinal Surgery 2024年第1期16卷 1-5页

作者： Lapo Bencini department of Oncology and Robotic Surgery Careggi Main Florence University and Regional HospitalFlorence 50134Italy

In this editorial,I comment on the article by Li et al published in the recent issue of the World Journal of Gastrointestinal Surgery in 2023,investigating the role of some novel prognostic factors for early survival after radical resection of liver *** cancer is an important burden among Asian and Western popu-lations,despite recent advances in both medicine(from virus eradication to systemic target therapies)and ***,survival after proven radical surgery remains poor,with recurrences being the *** prognostic scores have been developed and validated to select those patients who will best benefit from radical liver surgery,although the final general and oncological outcomes continue to be highly ***,no single biomarker can resolve all these issues for hepatocellular carcinoma,and it remains to be proven whether some of them main-tain predictive power in the long-term *** the ongoing era of“preci-sion”medicine,the novel prognostic markers,including immune inflammatory and nutritional indexes could be of great help in better stratify surgical candi-dates.

关键词： Hepatocellular carcinoma Liver cancer resection Liver surgery Prognostic factors Immune index Nutritional index

DNA-delivered monoclonal antibodies targeting the p53 R175H mutant epitope inhibit tumor development in mice

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Genes & Diseases 2024年第4期11卷 368-380页

作者： Dafei Chai Xu Wang Praveen Neeli Shan Zhou Xingfang Yu Kanaga Sabapathy Yong Li department of Medicine Section of Epidemiology and Population SciencesDan L Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTX 77030USA Division of Cellular&Molecular Research Humphrey Oei Institute of Cancer ResearchNational Cancer Centre SingaporeSingapore 168583Singapore

tThe tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense ***,there are currently no approved targeted therapies or immunotherapies against mutant ***,we characterized and inves-tigated a monoclonal antibody(mAb)that recognizes the mutant p53-R175H for its affinity,specificity,and activity against tumor cells in *** then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic *** results showed that the anti-R175H mAb specifically bound to the p53-R175H an-tigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells,with no cross-reactivity with wild-type *** cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular *** made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 *** vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in *** administration of the anti-R175H BsAb plasmid showed no therapeutic effects,yet potent anti-tumor activity was observed in combination with the anti-PD-1 *** results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.

关键词： BsAb Cytotoxicity mAb Mutant p53 PD-1 R175H

Phase II study of novel orally PI3Kα/δinhibitor TQ-B3525 in relapsed and/or refractory follicular lymphoma

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2193-2201页

作者： Huaqing Wang Jifeng Feng Yanyan Liu Zhengzi Qian Da Gao Xuehong Ran Hui Zhou Lihong Liu Binghua Wang Meiyun Fang Hebing Zhou Zhenqian Huang Shi Tao Zhuowen Chen Liping Su Hang Su Yu Yang Xiaobao Xie Huijing Wu Ping Sun Guoyu Hu Aibin Liang Zhiming Li department of Oncology Tianjin Union Medical Center of Nankai UniversityTianjin 300121PR China The Institute of Translational Medicine Tianjin Union Medical Center of Nankai UniversityTianjin 300121PR China department of Medical Oncology Jiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing 210009PR China department of Medical Oncology Henan Cancer HospitalThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhou 450003PR China department of Medical Oncology Tianjin Medical University Cancer Institute and HospitalTianjin 300060PR China department of Hematology The Affiliated Hospital of Inner Mongolia Medical College010050 HohhotPR China department of Hematology Weifang People’s HospitalThe First Affiliated Hospital of Weifang Medical University261000 WeifangPR China department of Lymphoma&Hematology Hunan Cancer HospitalThe Affiliated Cancer Hospital of Xiangya School of MedicineCentral South University410013 ChangshaPR China department of Hematology The Fourth Hospital of Hebei Medical University and Hebei Tumor Hospital050011 ShijiazhuangPR China department of Lymphoma Weihai Central Hospital264400 WeihaiPR China department of Hematology and Rheumatology The Affiliated Zhongshan Hospital of Dalian University116001 DalianPR China department of Hematology Beijing Luhe Hospital101199 BeijingPR China department of Hematology The First Affiliated Hospital of Guangzhou Medical University510120 GuangzhouPR China department of Hematology The First Affiliated Hospital of Hainan Medical College570102 HaikouPR China department of Hematology The First People’s Hospital of Foshan528000 FoshanPR China department of Hematology Shanxi Cancer Hospital030013 TaiyuanPR China department of Lymphoma Senior Department of HematologyThe Fifth Medical Center of Chinese PLA General Hospital100039 BeijingPR China department of Lymphoma and Head and Neck cancer Fujian Cancer Hospital350014 FuzhouPR China department of Hematology The First People’s Hospit

This registration study assessed clinical outcomes of TQ-B3525,the dual phosphatidylinositol-3-kinase(PI3K)α/δinhibitor,in relapsed and/or refractory follicular lymphoma(R/R FL).This phase II study(*** *** March 27,2020)comprised run-in stage and stage 2.R/R FL patients after≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until intolerable toxicity or disease *** endpoint was independent review committee(IRC)-assessed objective response rate(ORR).Based on results(ORR,88.0%;duration of response[DOR],11.8 months;progression-free survival[PFS],12.0 months)in 25 patients at run-in stage,second stage study was initiated and included 82 patients for efficacy/safety *** received prior-line(median,3)therapies,with 56.1%refractory to previous last therapies;73.2%experienced POD24 at *** stage 2,ORR was 86.6%(71/82;95%CI,77.3-93.1%),with 28(34.2%)complete *** control rate was 95.1%due to 7(8.5%)stable *** time to response was 1.8 *** 71 responders,median DOR was not reached;18-month DOR rate was 51.6%.with median follow-up of 13.3 months,median PFS was 18.5(95%CI,10.2-not estimable)*** overall survival(OS)was not reached by cutoff date;24-month OS rate was estimated as 86.1%.Response rates and survival data were consistent across all *** 3 or higher treatment-related adverse events were observed in 63(76.8%)cases,with neutropenia(22.0%),hyperglycemia(19.5%),and diarrhea(13.4%)being ***-B3525 showed favorable efficacy and safety for R/R FL patients after≥2 lines prior therapies.

关键词： lymphoma assessed initiated