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CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

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Cellular & Molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling Colin A.Chavel Anand P.Sharda Mackenzie M.Lieberman Caitlin M.James Shivana M.Lightman Jason H.Tong Guanxi Qiao Tiffany R.Emmons Thejaswini Giridharan Shengqi Hou Andrew M.Intlekofer Richard M.Higashi Teresa W.M.Fan Andrew N.Lane Kevin H.Eng Brahm H.Segal Elizabeth A.Repasky Kelvin P.Lee Scott H.Olejniczak Department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Department of Medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA Department of cancer Genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Present address:University of Colorado Boulder BoulderCO 80309USA Present address:Dana Farber cancer Institute BostonMA 02215USA Present address:Massachusetts Institute of Technology BostonMA 02139USA Present address:Melvin and Bren Simon comprehensive cancer center Indiana University School of MedicineIndianapolisIN 46202USA

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been *** this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T *** doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose ***2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing *** these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector ***,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 PKM2

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Homeostatic regulation of NAD(H)and NADP(H)in cells

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Genes & Diseases 2024年第5期11卷 285-299页

作者： Luojun Chen Xiaoke Xing Pingfeng Zhang Lulu Chen Huadong Pei cancer center Renmin Hospital of Wuhan UniversityWuhanHubei 430062China Department of Oncology Georgetown Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashingtonDC 20057USA

Nicotinamide adenine dinucleotide(NAD^(+))/reduced NAD^(+)(NADH)and nicotinamide adenine dinucleotide phosphate(NADP^(+))/reduced NADP^(+)(NADPH)are essential metabolites involved in multiple metabolic pathways and cellular ***^(+)and NADH redox couple plays a vital role in catabolic redox reactions,while NADPH is crucial for cellular anabolism and antioxidant *** NAD(H)and NADP(H)homeostasis is crucial for normal physiological activity and is tightly regulated through various mechanisms,such as biosynthesis,consumption,recycling,and conversion between NAD(H)and NADP(H).The conversions between NAD(H)and NADP(H)are controlled by NAD kinases(NADKs)and NADP(H)phosphatases[specifically,metazoan SpoT homolog-1(MESH1)and nocturnin(NOCT)].NADKs facilitate the synthesis of NADP^(+)from NAD^(+),while MESH1 and NOCT convert NADP(H)into NAD(H).In this review,we summarize the physiological roles of NAD(H)and NADP(H)and discuss the regulatory mechanisms governing NAD(H)and NADP(H)homeostasis in three key aspects:the transcriptional and posttranslational regulation of NADKs,the role of MESH1 and NOCT in maintaining NAD(H)and NADP(H)homeostasis,and the influence of the circadian clock on NAD(H)and NADP(H)*** conclusion,NADKs,MESH1,and NOCT are integral to various cellular processes,regulating NAD(H)and NADP(H)*** of these enzymes results in various human diseases,such as cancers and metabolic ***,strategies aiming to restore NAD(H)and NADP(H)homeostasis hold promise as novel therapeutic approaches for these diseases.

关键词： MESH1 NAD(H) NADK NADP(H) Nocturnin

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Fantastic voyage: The journey of NLRP3 inflammasome activation

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Genes & Diseases 2024年第2期11卷 819-829页

作者： Xiangyong Que Sihao Zheng Qibin Song Huadong Pei Pingfeng Zhang cancer center Renmin Hospital of Wuhan UniversityWuhanHubei 430060China Department of Oncology Georgetown Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashingtonDC 20057USA

NLRP3 inflammasome,an intracellular multiprotein complex,can be activated by a range of pathogenic microbes or endogenous hazardous *** activation results in the release of cytokines such as IL-1β and IL-18,as well as Gasdermin D which eventually causes *** activation of NLRP3 inflammasome is under strict control and regulation by numerous pathways and *** excessive activation can lead to a persistent inflammatory response,which is linked to the onset and progression of severe *** studies have revealed that the subcellular localization of NLRP3 changes significantly during the activation *** this review,we review the current understanding of the molecular mechanism of NLRP3 inflammasome activation,focusing on the subcellular localization of NLRP3 and the associated regulatory *** aim to provide a comprehensive understanding of the dynamic transportation,activation,and degradation processes of NLRP3.

关键词： Inflammasome activation Innate immunity NLRP3 NLRP3 inflammasome Subcellular localization

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Robot-assisted uretero-enteric reimplantation for uretero-enteric anastomotic strictures following robot-assisted radical cystectomy: Surgical approach and outcomes over two decades

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Asian Journal of Urology 2024年第3期11卷 384-390页

作者： Abdul Wasay Mahmood Grace Harrington Zhe Jing Qiang Li Ahmed A.Hussein Khurshid A.Guru Department of Urology Roswell Park Comprehensive Cancer CenterElm and Carlton StreetsBuffaloNew YorkNYUSA

Objective:We described the technique and outcomes of robot-assisted repair of uretero-enteric strictures(UES)following robot-assisted radical cystectomy(RARC)and urinary ***:Retrospective review of our RARC database from November 2005 to August 2023 at Roswell Park comprehensive cancer center was *** who developed UES and ultimately underwent robot-assisted uretero-enteric reimplantation(RUER)were *** method was used to compute the cumulative incidence recurrence rate of UES after RUER.A multivariable regression model was used to identify variables associated with UES ***:A total of 123(15%)out of 808 RARC patients developed UES,of whom 52 underwent reimplantation(45 patients underwent RUER[n=55 cases]and seven patients underwent open ureteroenteric reimplantation).The median time from RARC to UES was 4.4(interquartile range 3.0e7.0)months,and the median time between UES and RUER was 5.2(interquartile range 3.2e8.9)*** 3-year recurrence rate after RUER is about 29%.On multivariable analysis,longer hospital stay(hazard ratio 1.37,95%confidence interval 1.16e1.61,p<0.01)was associated with recurrent UES after ***:RUER for UES after RARC is feasible with durable outcomes although a notable subset of patients experienced postoperative complications and UES recurrence.

关键词： Stricture Cystectomy Reimplantation Robot-assisted

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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

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The impact of broad glutamine metabolism inhibition on the tumor microenvironment

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Genes & Diseases 2024年第3期11卷 2-4页

作者： Tianhe Li Yun-Ta Chuang Tian-Li Wang Departments of Pathology Oncologyand Gynecology and ObstetricsThe Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMD 21231USA

Glutamine is an importantα-amino acid that provides carbon and nitrogen sources for the biosynthesis of nucleotides,proteins,and *** also generates metabolites that fuel the tricarboxylic acid cycle and maintain intracellular redox *** cells have a heightened metabolic dependence on glutamine to support incessant tumor growth and mitigate tumor microenvironmental stresses including hypoxia,nutrient depletion.

关键词： metabolism tumor microenvironment

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Risk prediction of advanced colorectal neoplasia varies by race and neighbourhood socioeconomic status

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Family Medicine and Community Health 2024年第S2期12卷 26-33页

作者： Xiangqing Sun Zhengyi Chen Gregory S Cooper Nathan A Berger Claudia Coulton Li Li Department of Family Medicine University of VirginiaCharlottesvilleVirginiaUSA Department of Population and Quantitative Health Sciences Case Western Reserve UniversityClevelandOhioUSA University Hospitals Cleveland Medical center ClevelandOhioUSA case comprehensive cancer center ClevelandOhioUSA Jack Joseph and Morton Mandel School of Applied Social SciencesCase Western Reserve UniversityClevelandOhioUSA

Objective Neighbourhood deprivation increases the risk of colorectal neoplasia and contributes to racial disparities observed in this *** race-specific advanced colorectal neoplasia(ACN)prediction models that include neighbourhood socioeconomic status has the potential to improve the accuracy of *** The study includes 1457 European Americans(EAs)and 936 African Americans(AAs)aged 50–80 years undergoing screening ***-specific ACN risk prediction models were developed for EAs and AAs,*** Deprivation Index(ADI),derived from 17 variables of neighbourhood socioeconomic status,was evaluated by adding it to the ACN risk prediction *** accuracy was evaluated by concordance statistic(C-statistic)for discrimination and Hosmer-Lemeshow goodness-of-fit test for *** With fewer predictors,the EA-specific and AA-specific prediction models had better prediction accuracy in the corresponding race/ethnic subpopulation than the overall *** with the overall model which had poor calibration(P_(Calibration)=0.053 in the whole population and P_(Calibration)=0.011 in AAs),the EA model had C-statistic of 0.655(95%CI 0.594 to 0.717)and P_(Calibration)=0.663;and the AA model had C-statistic of 0.637((95%CI 0.572 to 0.702)and P_(Calibration)=*** was a significant predictor of ACN in EAs(OR=1.24((95%CI 1.03 to 1.50),P=0.029),but not in AAs(OR=1.07((95%CI 0.89 to 1.28),P=0.487).Adding ADI to the EA-specific ACN prediction model substantially improved ACN calibration accuracy of the prediction across area deprivation groups(P_(Calibration)=0.924 with ADI vs P_(Calibration)=0.140 without ADI)in *** Neighbourhood socioeconomic status is an important factor to consider in ACN risk prediction ***,non-race-specific prediction models have poor ***-specific prediction models incorporating neighbourhood socioeconomic factors are needed to improve ACN predicti

关键词： colorectal neoplasia prediction

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Medical management of urolithiasis: Great efforts and limited progress

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Asian Journal of Urology 2024年第2期11卷 149-155页

作者： Victoria Jahrreiss Christian Seitz Fahad Quhal Department of Urology Comprehensive Cancer CenterMedical University of ViennaViennaAustria Department of Urology King Fahad Specialist HospitalDammamSaudi Arabia

Objective:To provide a comprehensive review on the existing literature on medical management of ***:A thorough literature review was performed using Medline,PubMed/PMC,Embase,and the Cochrane Database of Systematic Reviews up to December 2022 to identify publications on the medical management of *** that assessed dietary and pharmacologic management of urolithiasis were reviewed;studies on medical expulsive therapy were not included in this ***:Medical management of urolithiasis ranges from the prophylactic management of kidney stone disease to dissolution *** most treatment concepts have been long established,large randomized controlled trials are *** modification and increased fluid intake remain cornerstones in the conservative management of urolithiasis.A major limitation for medical management of urolithiasis is poor patient ***:Medical management of urolithiasis is more important in patients with recurrent urolithiasis and patients with metabolic abnormalities putting them at higher risk of developing *** medical management can be effective in limiting stone recurrence,medical interventions often fail due to poor compliance.

关键词： Medicalmanagement Medical therapy Urolithiasis Kidneystonedisease

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Inflammatory indicators such as systemic immune inflammation index(SIII),systemic inflammatory response index(SIRI),neutrophil-to-lymphocyte ratio(NLR)and platelet-to-lymphocyte ratio(PLR)as prognostic factors of curative hepatic resections for hepatocellular carcinoma

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Hepatobiliary Surgery and Nutrition 2024年第3期13卷 509-511页

作者： Paschalis Gavriilidis Timothy M.Pawlik Department of Surgery Colchester General HospitalColchesterUK Department of Surgery The Ohio State University Wexner Medical CenterJames Comprehensive Cancer CenterColumbusOHUSA

As the fifth most common gastrointestinal cancer worldwide,hepatocellular carcinoma(HCC)often presents at advanced stages of *** the subset of patients who present with tumor and liver-related features amenable to surgery,hepatic resection—in addition to transplantation—offers the best chance at curative-intent *** can be associated,however,with risk of complications and perioperative death especially among individuals with concomitant portal hypertension,liver fibrosis,cirrhosis,and portal vein thrombosis(1-3).Post-resection liver failure is also a major concern and can be a devasting complication following hepatic resection(4,5).Overall survival following hepatic resection of HCC ranges from only 30–50%,and recurrence can be common depending on the stage of *** turn,there is considerable interest in identifying markers to help stratify patients relative to risk of recurrence and prognosis to define which groups of patients may benefit the most from hepatic resection of HCC(1-5).

关键词： Hepatocellular carcinoma(HCC) systemic immune inflammation index(SIII) systemic inflammatory index neutrophil-to-lymphocyte ratio(NLR) platelet-to-lymphocyte ratio(PLR)

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cancer profiles in China and comparisons with the USA:a comprehensive analysis in the incidence,mortality,survival,staging,and attribution to risk factors

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Science China(Life Sciences) 2024年第1期67卷 122-131页

作者： Siyi He Changfa Xia He Li Maomao Cao Fan Yang Xinxin Yan Shaoli Zhang Yi Teng Qianru Li Wanqing Chen Office of cancer Screening National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

China faces a disproportionate cancer burden to the population size and is undergoing a transition in the cancer *** extracted data in five aspects of cancer incidence,mortality,survival,staging distributions,and attribution to risk factors in China,the USA and worldwide from open-source *** conducted a comprehensive secondary analysis of cancer profiles in China in the above aspects,and compared cancer statistics between China and the USA.A total of 4,546,400 new cancer cases and 2,992,600 deaths occurred in China in 2020,accounting for 25.1%and 30.2%of global cases,***-related cancers including lung cancer,colorectal cancer,and breast cancer showed an upward trend and have been the leading cancer types in China.41.6%of new cancer cases and 49.3%of cancer deaths occurred in digestive-system cancers in China,and the cancers of esophagus,nasopharynx,liver,and stomach in China accounted for over 40%of global ***-related cancers showed the highest population-attributable fractions among Chinese adults,and most cancers could be attributed to behavioral and metabolic *** proportions of stage I for most cancer types were much higher in the USA than in China,except for esophageal cancer(78.2%vs.41.1%).The 5-year relative survival rates in China have improved substantially during 2000–2014,whereas survival for most cancer types in the USA was significantly higher than in China,except for upper gastrointestinal *** findings suggest that although substantial progress has been made in cancer control,especially in digestive system cancers in China,there was still a considerable disparity in cancer burden between China and the *** robust policies on risk factors and standardized screening practices are urgently warranted to curb the cancer growth and improve the prognosis for cancer patients.

关键词： cancer burden survival rate neoplasm staging risk factors China

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