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Recent advances and remaining challenges in lung cancer therapy

Chinese Medical Journal 2024年第5期137卷 533-546页

作者： Tasha Barr Shoubao Ma Zhixin Li Jianhua Yu Department of Hematology and Hematopoietic Cell Transplantation City of Hope National Medical CenterLos AngelesCalifornia 91010USA comprehensive cancer center City of HopeLos AngelesCalifornia 91010USA Department of Immuno-Oncology Beckman Research InstituteLos AngelesCalifornia 91010USA

Lung cancer remains the most common cause of cancer *** the continued research into new drugs and combination therapies,outcomes in lung cancer have been improved,and clinical benefits have been expanded to a broader patient ***,the overall cure and survival rates for lung cancer patients remain low,especially in metastatic *** the available lung cancer treatment options,such as surgery,radiation therapy,chemotherapy,targeted therapies,and alternative therapies,immunotherapy has shown to be the most *** exponential progress in immuno-oncology research and recent advancements made in the field of immunotherapy will further increase the survival and quality of life for lung cancer *** progress has been made in targeted therapies using tyrosine kinase inhibitors and monoclonal antibody immune checkpoint inhibitors with many US Food And Drug Administration(FDA)-approved drugs targeting the programmed cell death ligand-1 protein(e.g.,durvalumab,atezolizumab),the programmed cell death-1 receptor(e.g.,nivolumab,pembrolizumab),and cytotoxic T-lymphocyte-associated antigen 4(e.g.,tremelimumab,ipilimumab).Cytokines,cancer vaccines,adoptive T cell therapies,and Natural killer cell mono-and combinational therapies are rapidly being studied,yet to date,there are currently none that are FDA-approved for the treatment of lung *** this review,we discuss the current lung cancer therapies with an emphasis on immunotherapy,including the challenges for future research and clinical applications.

关键词： Lung cancer Therapy Immunotherapy Combination therapy Adoptive T cell therapies

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RNA m^(6)A reader YTHDF2 facilitates precursor miR-126 maturation to promote acute myeloid leukemia progression

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Genes & Diseases 2024年第1期11卷 382-396页

作者： Zheng Zhang Keren Zhou Li Han Andrew Small Jianhuang Xue Huilin Huang Hengyou Weng Rui Su Brandon Tan Chao Shen Wei Li Zhicong Zhao Ying Qing Xi Qin Kitty Wang Keith Leung Mark Boldin Chun-Wei Chen David Ann Zhijian Qian Xiaolan Deng Jianjun Chen Zhenhua Chen Department of Systems Biology Beckman Research Institute of City of HopeMonroviaCA 91016USA Irell and Manella Graduate School of Biological Sciences Beckman Research Institute of City of HopeDuarteCA 91010USA Gehr Family center for Leukemia Research City of HopeDuarteCA 91010USA Sun Yat-sen University cancer center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdong 510060China Guangzhou Laboratory GuangzhouGuangdong 510005China Bioland Laboratory GuangzhouGuangdong 51005China Department of Liver Surgery Renji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127China Department of Diabetes Complications and Metabolism Beckman Research Institute of City of HopeDuarteCA 91010USA Department of Biochemistry and Molecular Biology University of FloridaGainesvilleFL 32603USA Tongji Hospital Affiliated to Tongji University Frontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China School of Pharmacy China Medical UniversityShenyangLiaoning 110001China

As the most common internal modification of mRNA,Ne-methyladenosine(m^(6)A)and its regulators modulate gene expression and play critical roles in various biological and patholog-ical processes including *** was reported previously that m^(6)A methyltransferase(writer),methyltransferase-like 3(METTL3)adds m^(6)A in primary microRNAs(pri-miRNAs)and fa-cilitates its processing into precursor miRNAs(pre-miRNAs).However,it is unknown whether m^(6)A modification also plays a role in the maturation process of pre-miRNAs and(if so)whether such a function contributes to ***,we found that YTHDF2 is aberrantly overexpressed in acute myeloid leukemia(AML)patients,especially in relapsed patients,and plays an onco-genic role in ***,YTHDF2 promotes expression of miR-126-3p(also known as miR-126,as it is the main product of precursor miR-126(pre-miR-126)),a miRNA that was reported as an oncomiRNA in AML,through facilitating the processing of pre-miR-126 into mature ***,YTHDF2 recognizes m^(6)A modification in pre-miR-126 and recruits AGO2,a regulator of pre-miRNA processing,to promote the maturation of ***2 posi-tively and negatively correlates with miR-126 and miR-126's downstream target genes,respec-tively,in AML patients,and forced expression of miR-126 could largely rescue YTHDF2/Ythdf2 depletion-mediated suppression on AML cell growth/proliferation and leukemogenesis,indi-cating that miR-126 is a functionally important target of YTHDF2 in ***,our studies not only reveal a previously unappreciated YTHDF2/miR-126 axis in AML and highlight the ther-apeutic potential of targeting this axis for AML treatment,but also suggest that m^(6)A plays a role in pre-miRNA processing that contributes to tumorigenesis.

关键词： AML miR-126 N^(6)-methyladenosine Pre-miRNA maturation YTHDF2

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Dietary lycopene mitigates nonalcoholic steatohepatitis by regulating Nrf2/PPARα-dependent ferroptosis

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Food Science and Human Wellness 2024年

作者： Xunyu Song Daotong Li Jun Sun Xiaoying Zhang Li-Shu Wang Fang Chen College of Food Science and Nutritional Engineering， National Engineering Research Centre for Fruit and Vegetable Processing， Key Laboratory of Fruits and Vegetables Processing， Ministry of Agriculture Engineering Research Centre for Fruits and Vegetables Processing， Ministry of Education， China Agricultural University Department of Hematology and Hematopoietic Cell Transplantation comprehensive cancer center， city of hope National Medical center

The global burden of non-alcoholic steatohepatitis (NASH) is on the rise. Researchers recognize inhibiting ferroptosis， a form of cell death leading to iron-dependent oxidative damage， as a promising therapy for treating NASH. Lycopene， a natural antioxidant compound， exhibits various pharmacological properties. However， the anti-NASH efficacy of the dietary recommended concentration of lycopene and the role of lycopene in combating ferroptosis in NASH have remained unclear. Our study investigated lycopene’s impact on ferroptosis in various diet-induced mouse NASH models and corresponding cellular models， unveiling its anti-inflammatory and anti-fibrotic effects. Our findings demonstrated that lycopene notably reduced ferroptosis in MCD (methionine- and choline-deficient diet)-fed mice and a normal mouse hepatocyte cell line (NCTC1469) by restoring balanced ferrous iron levels， lipid reactive oxygen species， and normal mitochondrial morphology. These effects were linked to the regulation of ferroptosis markers GPX4 and PTGS2. Additionally， lycopene’s anti-ferroptosis action was validated in mice fed a high-fat， high-cholesterol diet and HepG2 cells treated with free fatty acid. Our transcriptomic analysis highlighted PPARα as a primary target of lycopene， crucial for activating the glutathione system because GW6471， a PPARα antagonist， blocked lycopene-induced GPX4 activation. Furthermore， Nrf2 played a crucial role in lycopene’s impact on iron metabolism-related proteins (FTH1 and TFR1). Notably， when inhibiting PPARα or Nrf2 in MCD-fed mice by GW6471 or ML385， lycopene’s protective effects against ferroptosis and NASH progression diminished. These findings underscore the crucial role of PPARα-mediated glutathione system activation and Nrf2-mediated iron metabolism modulation in lycopene's anti-ferroptosis effects.

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Existing and emerging biomarkers in hepatocellular carcinoma:relevance in staging,determination of minimal residual disease,and monitoring treatment response:a narrative review

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Hepatobiliary Surgery and Nutrition 2024年第1期13卷 39-55页

作者： Dana A.Dominguez Paul Wong Laleh G.Melstrom Department of Surgical Oncology City of Hope National Medical CenterDuarteCAUSA University of California San FranciscoSan FranciscoCAUSA

Background and Objective:With the development of novel active systemic therapies,the landscape of hepatocellular carcinoma(HCC)management is rapidly ***,HCC lacks sensitive and specific biomarkers to predict prognosis,monitor for minimal residual disease after locoregional therapy,and predict treatment *** this review,we aim to summarize the best supporting evidence for refining existing,and development of novel biomarkers for staging,prognosis,determination of minimal residual disease and monitoring treatment response in HCC,focusing on those with evidence in clinical ***:PubMed and Embase databases were searched using the keywords;hepatocellular carcinoma,biomarker,minimal residual disease,surveillance,prognosis,staging,alpha-fetoprotein(AFP),liquid biopsy,treatment response,adjuvant,*** clinical studies were *** Content and Findings:AFP remains the major workhorse as the most widely used biomarker in HCC,however,its lack of wide applicability due to the high proportion of patients with HCC who are AFP negative,limits its value throughout all stages of HCC *** work has been done to combine AFP with other clinical and serologic factors to increase its accuracy and utility as a ***,it is likely that other more novel biomarkers such as those obtained through liquid biopsy will provide the prognostic power necessary for applications such as detecting recurrence and predicting treatment *** biopsy provides not only a wealth of potential biomarkers including circulating tumor cells and cell-free RNA/DNA,but also the ability to examine the mutational characteristics of the tumor with next generation *** early evidence supports the potential impact of many new biomarkers,validation in large clinical trials is ***:This review highlights the paucity of sensitive and specific,widely applicable biomarkers,throughout all phases of management of

关键词： Hepatocellular carcinoma(HCC) biomarker liquid biopsy alpha-fetoprotein(AFP)

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Lack of evidence for germline WWP1 pathogenic variants in gastrointestinal polyposis and other phenotypes suggestive of PTEN-hamartoma-tumor syndrome

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Genes & Diseases 2024年第2期11卷 524-527页

作者： Noemi Gonzalez-Abuin Tirso Pons Teresa Fuster Isabel Quintana Mariona Terradas Gemma Aiza Joan Brunet Gabriel Capellá Heather Hampel Laura Valle Hereditary cancer Program Catalan Institute of OncologyOncobell ProgramIDIBELLHospitalet de LlobregatBarcelona 08908Spain Department of Immunology and Oncology National Center for BiotechnologySpanish National Research Council (CNB-CSIC)Madrid 28049Spain Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) Madrid 28029Spain Catalan Institute of Oncology IDIBGiGirona 17007Spain Division of Clinical cancer Genomics Department of Medical Oncology & Therapeutic ResearchCity of Hope National Cancer CenterDuarteCA 91010USA

Germline activating variants in WWP1,which encodes an E3 ubiquitin ligase that antagonizes PTEN tumor suppressive function,have been proposed as an alternative mechanism of PTEN inactivation in PTEN-hamartoma-tumor syndrome(PHTS)-like patients with wildtype PTEN.1 More specifically,heterozygous,potentially activating wwP1 variants were first identified by Lee et al in patients affected with gastrointestinal oligopolyposis,including adenomatous,hyperplastic/serrated,and hamartomatous polyps,and occasionally with colorectal cancer(Table 1).Subsequently,based on the PHTS phenotypic features,wWP1 mutational screening was performed in patients with thyroid nodules,2 or normocephalic autism spectrum disorder(ASD),3 where germline WWP1 variants were also identified(Table S1).

关键词： WWP1 gastrointestinal polyposis

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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

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APIR:Aggregating Universal Proteomics Database Search Algorithms for Peptide Identification with FDR Control

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Genomics, Proteomics & Bioinformatics 2024年第2期22卷 171-187页

作者： Yiling Elaine Chen Xinzhou Ge Kyla Woyshner MeiLu McDermott Antigoni Manousopoulou Scott B.Ficarro Jarrod A.Marto Kexin Li Leo David Wang Jingyi Jessica Li Department of Statistics and Data Science University of CaliforniaLos AngelesCA 90095USA Department of Immuno-Oncology Beckman Research InstituteCity of Hope National Medical CenterDuarteCA 91010USA Department of Quantitative and Computational Biology University of Southern CaliforniaLos AngelesCA 90089USA Department of cancer Biology and Blais Proteomics center Dana-Farber Cancer InstituteDepartment of PathologyBrigham and Women’s Hospital and Harvard Medical SchoolBostonMA 02215USA Department of Pediatrics City of Hope National Medical CenterDuarteCA 91010USA Bioinformatics Interdepartmental Program University of CaliforniaLos AngelesCA 90095USA Department of Human Genetics University of CaliforniaLos AngelesCA 90095USA Department of Computational Medicine University of CaliforniaLos AngelesCA 90095USA Department of Biostatistics University of CaliforniaLos AngelesCA 90095USA

Advances in mass spectrometry(MS)have enabled high-throughput analysis of proteomes in biological *** state-of-the-art MS data analysis relies on database search algorithms to quantify proteins by identifying peptide–spectrum matches(PSMs),which convert mass spectra to peptide *** database search algorithms use distinct search strategies and thus may identify unique ***,no existing approaches can aggregate all user-specified database search algorithms with a guaranteed increase in the number of identified peptides and a control on the false discovery rate(FDR).To fill in this gap,we proposed a statistical framework,Aggregation of Peptide Identification Results(APIR),that is universally compatible with all database search ***,under an FDR threshold,APIR is guaranteed to identify at least as many,if not more,peptides as individual database search algorithms *** of APIR on a complex proteomics standard dataset showed that APIR outpowers individual database search algorithms and empirically controls the *** data studies showed that APIR can identify disease-related proteins and post-translational modifications missed by some individual database search *** APIR framework is easily extendable to aggregating discoveries made by multiple algorithms in other high-throughput biomedical data analysis,e.g.,differential gene expression analysis on RNA sequencing *** APIR R package is available at https://***/yiling0210/APIR.

关键词： Shotgun proteomics Peptide–spectrum match Peptide identification Aggregation of lists FDR control

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The role of bile acids in human aging

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Medical Review 2024年第2期4卷 154-157页

作者： Lihua Jin Linsen Shi Wendong Huang Department of Diabetes Complications and Metabolism Arthur Riggs Diabetes and Metabolism Research InstituteBeckman Research InstituteCity of Hope National Medical Center1500 E.Duarte RoadDuarteCA 91010USA Department of Diabetes Complications and Metabolism Arthur Riggs Diabetes and Metabolism Research InstituteBeckman Research InstituteCity of Hope National Medical CenterDuarteCAUSA Irell&Manella Graduate School of Biomedical Science City of Hope National Medical Center1500 E.Duarte RoadDuarteCA 91010USA

Bile acids are recognized as important signaling molecules that enable fine-tuned inter-communication from the liver,through the intestine,to virtually any organ,thus encouraging their pleiotropic physiological *** is a complex natural process defined as a progressive decline in cellular and organismal functions.A causal link between bile acids and the aging process is ***,there are gaps in our understanding of the molecular mechanisms and precise targets responsible for the alteration of bile acid profiles and their role in the aging *** barrier dysfunction leads to endotoxemia,systemic inflammation,insulin resistance,diabetes,lipid accumulation,obesity and fatty liver diseases,and health decline and *** fact,intestinal barrier dysfunction is suggested to be an evolutionarily conserved hallmark of *** acids may modulate the aging process by regulating intestinal barrier integrity.

关键词： age bile acid gut microbiota enterohepatic circulation intestinal barrier

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Analysis of Epidemiological and Issues Encountered in Case Reports on Echinococcosis—China,2022

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China CDC weekly 2024年第6期6卷 100-104页

作者： Yan Kui Shuai Han Xiaojuan Zhang Guangzhong Shi Yale Yu Ruirui Li Peizheng Zhan Hongju Duan Wenbo Luo Benfu Li Shaoqi Ning Yalan Zhang Aiya Zhu Jingbo Xue National Institute of Parasitic Diseases Chinese Center for Disease Control and Prevention(Chinese Center for Tropical Diseases Research)National Health Commission Key Laboratory of Parasite and Vector BiologyWorld Health Organization Collaborating Center for Tropical DiseasesNational Center for International Research on Tropical DiseasesShanghaiChina Gansu Provincial center for Disease Control and Prevention Lanzhou CityGansu ProvinceChina The center for Disease Control and Prevention of Xinjiang Uygur Autonomous Region Urumuqi CityXinjiang Uygur Autonomous RegionChina Xinjiang Production and Construction Corps center for Disease Control and Prevention Urumuqi CityXinjiang Uygur Autonomous RegionChina Sichuan Provincial center for Disease Control and Prevention Chengdu CitySichuan ProvinceChina Qinhai Institute for Endemic Disease Control and Prevention Xining CityQinghai ProvinceChina Ningxia center for Disease Control and Prevention Yinchuan CityNingxia Hui Autonomous RegionChina Inner Mongolia Autonomous Region center for comprehensive Disease Control and Prevention Hohhot CityInner Mongolia AutonomousChina Yunnan Institute of Parasitic Diseases Puer CityYunnan ProvinceChina Shaanxi Provincial center for Disease Control and Prevention Xi'an CityShaanxi ProvinceChina Henan Provincial center for Disease Control and Prevention Zhengzhou CityHenan ProvinceChina Guizhou Provincial center for Disease Control and Prevention Guiyang CityGuizhou ProvinceChina

Summary What is already known about this topic?Echinococcosis is classified as a Class C infectious disease in *** is endemic in 370 counties located in the agricultural and pastoral regions of western *** is added by this report?This report provides a comprehensive overview of the cases of echinococcosis reported in China in *** a thorough evaluation conducted by provincial CDCs.

关键词： China Ech counties

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Effects of flue gas desulfurization gypsum and clover planting on qualities of soil and winter jujube in coastal saline-alkali orchard of north China

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Soil Ecology Letters 2024年第1期6卷 141-152页

作者： Qi Shao Xuejing Xia Guihua Li Hui Li Jitong Lin Yanhong Lou Quangang Yang Hui Wang Zhongchen Yang Hong Pan Yuping Zhuge National Engineering Research centerfor Efficient Utilization of Soil and Fertilizer Resources College of Resources and EnvironmentShandong Agricultural UniversityTai'an271018China Tai'an city Management comprehensive Service center Tai'an 271021China

Flue gas desulfurization gypsum and clover planting alleviated the soil salinization *** pH and total phosphorus affected the bacterial *** phosphorus affected the fungal *** gas desulfurization gypsum and clover planting improved jujube *** coastal area of Shandong Province,characterized by coastal saline tidal soil,is one of the main production areas of winter jujube in ***,the low soil fertility and poor soil structure in jujube orchard restricted the development of the jujube *** objectives of this study were to 1)evaluate the effect of application of flue gas desulfurization(FGD)gypsum and clover planting on soil quality improvement and soil microbial community structure of jujube orchard;2)investigate the effects of two measures on the nutrition and quality of winter *** results showed that FGD gypsum reduced the soil total salt content by 65.6%,and clover planting increased the soil organic matter content by 30.7%,which effectively alleviated the soil salinization stress and improved the soil *** pH and total phosphorus(TP)were the main determinants influencing bacterial community composition,and TP was the dominant factor of the fungal community composition in the saline-alkali ***,FGD gypsum addition and clover planting significantly increased the sugar degree and Vc content of winter jujube,thus improved jujube quality,and further contributed to the ecological sustainable development of winter jujube industry.

关键词： saline-alkali soils winter jujube bacterial community fungal community fue gas desulfurization gypsum clover planting

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