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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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Use of androgen deprivation therapy in prostate cancer： indications and prevalence

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Asian Journal of Andrology 2012年第2期14卷 177-186页

作者： Roisin M Connolly Michael A Carducci Emmanuel S Antonarakis Prostate cancer Research Program Department of Medical Oncology Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231-1000 USA

Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer, This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.

关键词： androgen deprivation therapy androgen synthesis anti-androgen prostate cancer

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Minimally invasive spleen-preserving distal pancreatectomy: Does splenic vessel preservation have better postoperative outcomes? A systematic review and meta-analysis

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Hepatobiliary & Pancreatic Diseases International 2015年第4期14卷 346-353页

作者： Fady Elabbasy Rahul Gadde Mena M Hanna Danny Sleeman Alan Livingstone Danny Yakoub Division of Surgical Oncology Department of Surgery Sylvester Comprehensive Cancer Center University of Miami-Miller School of Medicine

BACKGROUND： Minimally invasive spleen-preserving distal pancreatectomy （SPDP） can be performed with either splenic vessel preservation （SVP） or resection [Warshaw procedure （WP）]. The aim of this study was to evaluate the postoperative clinical outcomes of patients undergoing both methods. DATA SOURCES： Database search of PubMed, Embase, Scopus, Cochrane, and Google Scholar was performed （2000-2014）; key bibliographies were reviewed. Qualified studies compar- ing patients undergoing SPDP with either SVP or WP, and as- sessing postoperative complications were included. Calculated pooled risk ratio （RR） with the corresponding 95% confidence interval （CI） by random effects methods were used in the meta-analyses. RESULTS： The search yielded 215 studies, of which only 14 observational studies met our selection criteria. The studies included 943 patients in total; 652 （69%） underwent SVP and 291 （31%） underwent WP. Overall, there was a lower incidence of splenic infarction （RR=0.17; 95% Ch 0.09-0.33; P〈0.001）, gastric varices （RR=0.16; 95% Ch 0.05-0.51; P=0.002）, and intra/postoperative splenectomy （RR=0.20; 95% Ch 0.08-0.49; P〈0.001） in the SVP group. There was no difference in in- cidence of pancreatic fistula （WP vs SVP, 23.6% vs 22.9%;P=0.37）, length of hospital stay, operative time or blood loss. There was moderate cross-study heterogeneity. CONCLUSIONS： SVP is a safe, efficient and feasible technique that may be used to preserve the spleen. WP may be more suit- able for large tumors dose to the splenic hilum or those associ- ated with splenomegaly. Randomized clinical trials are justified to examine the long-term benefits of SVP-SPDP.

关键词： splenic infarction spleen-preserving distal pancreatectomy splenic vessel preservation Warshaw procedure gastric varices

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Genetic and epigenetic dependencies in colorectal cancer development

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Gastroenterology Report 2022年第1期10卷 115-131页

作者： Sehej Parmar Hariharan Easwaran cancer Genetics and Epigenetics OncologySidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMDUSA

Recent studies have mapped key genetic changes in colorectal cancer(CRC)that impact important pathways contributing to the multistep models for CRC initiation and *** parallel with genetic changes,normal and cancer tissues harbor epigenetic alterations impacting regulation of critical genes that have been shown to play profound roles in the tumor ***,these molecular changes are only loosely associated with heterogenous transcriptional programs,reflecting the heterogeneity in the various CRC molecular subtypes and the paths to CRC *** from mapping molecular alterations in early CRC lesions and use of experimental models suggest that the intricate dependencies of various genetic and epigenetic hits shape the early development of CRC via different pathways and its manifestation into various CRC *** highlight the dependency of epigenetic and genetic changes in driving CRC development and discuss factors affecting epigenetic alterations over time and,by extension,risk for cancer.

关键词： colorectal cancer epigenetics aging classification subtyping DNA methylation consensus molecular subtypes

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Yttrium-90 microsphere selective internal radiation therapy for liver metastases following systemic chemotherapy and surgical resection for metastatic adrenocortical carcinoma

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World Journal of Clinical Oncology 2018年第1期9卷 20-25页

作者： Mina S Makary Lawrence S Krishner Evan J Wuthrick Mark P Bloomston Joshua D Dowell Division of Vascular and Interventional Radiology Department of Radiology the Ohio State University Comprehensive Cancer Center Division of Medical Oncology Department of Internal Medicine the Ohio State University Comprehensive Cancer Center Department of Radiation Oncology the Ohio State University Comprehensive Cancer Center Division of Surgical Oncology Department of Surgery and James Cancer Hospital and Richard Solove Research Institute the Ohio State University Comprehensive Cancer Center

Adrenocortical carcinoma(ACC)is a rare malignancy with generally poor outcomes and limited treatment *** surgical resection can be curative for early local disease,most patients present with advanced ACC owing to nonspecific *** those patients,treatment options include systemic chemotherapy and locoregional therapies including radiofrequency ablation and transarterial *** present the first reported case of utilizing yttrium-90 microsphere selective internal radiation therapy(SIRT)in combination with first line EDP-M(Etoposide,Doxorubicin,Cisplatin,Mitotane)chemotherapy and debulking surgical primary tumor resection for treatment of metastatic *** complete radiologic response has been maintained after twelve months with resolution of clinical *** findings prompt the need for further consideration and studies to elucidate the role of SIRT in combination with systemic and surgical treatment for metastatic ACC.

关键词： Adrenocortical carcinoma Hepatic metastases Radioembolization Yttrium-90

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Prostate cancer epigenetics and its clinicalmplications

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Asian Journal of Andrology 2016年第4期18卷 549-558页

作者： Srinivasan Yegnasubramanian Sidney Kimmel comprehensive cancer center Department of Oncology Johns Hopkins University School of Medicine Baltimore Maryland USA

Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.

关键词： biomarkers DNA methylation epigenetics epigenomics prostatic neoplasms tumor

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An anti-tumor coup:TIM3 ablation activates the immune arsenal

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Signal Transduction and Targeted Therapy 2021年第10期6卷 2940-2941页

作者： KıvançGörgülü Derya Kabacaoğlu Hana Algül comprehensive cancer center Munich at the Klinikum rechts der Isar(CCCMTUM) Technical University of MunichMunichGermany

In a recent study published in Nature,Dixon et al.^(1) showed that TIM3 adjusts“tumor immune temperature”via the involvement of dendritic cells(DCs)with an altered inflammasome *** of TIM3 in DCs primarily escalated... 详细信息

关键词： TIM3 Dixon

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Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast cancer

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四川生理科学杂志 2025年第1期47卷 145-145页

作者： Charles E Geyer Jr the National Surgical Adjuvant Breast and Bowel Project AGO-B and Helios Klinikum Berlin–Buch Berlin Instituto do Câncer do Estado de São Paulo São Paulo Orlando Health cancer Institute Orlando FL the National center for Tumor Diseases Heidelberg University Hospital and German Cancer Research Center Heidelberg Hospital Universitario La Paz–Instituto de Investigación del Hospital Universitario La Paz Madrid Evangelische Kliniken Gelsenkirchen Gelsenkirchen L’Institut du cancer de Montpellier–Val d’Aurelle Montpellier Providence cancer Institute Portland OR the Department of Surgery Oncology and Gastroenterology University of Padua and Oncology 2 Istituto Oncologico Veneto IRCCS Padua Stanford University School of Medicine Stanford CA Arbeitsgemeinschaft Gynäkologische Onkologie–Breast and Sana Klinikum Offenbach Offenbach the National cancer Institute Mexico City the Department of Gynecology and Obstetrics University Hospital Erlangen Comprehensive Cancer Center Erlangen–EMN Friedrich–Alexander University Erlangen–Nuremberg Erlangen Yale University School of Medicine Yale Cancer Center and Smilow Cancer Hospital New Haven CT the All-Ireland Cooperative Oncology Research Group German Breast Group Neu-Isenburg Fudan University Shanghai cancer center Shanghai China Institute for Oncology and Radiology of Serbia Belgrade Grupo Médico Ángeles Guatemala City Guatemala Roche Products Welwyn Garden City United Kingdom F. Hoffmann–La Roche Basel Switzerland

Background:Patients with human epidermal growth factor receptor 2(HER2)-positive early breast cancer with residual invasive disease after neoadjuvant systemic therapy have a high risk of recurrence and *** primary analysis of KATHERINE,a phase 3,open-label trial,showed that the risk of invasive breast cancer or death was 50%lower with adjuvant trastuzumab emtansine(T-DM1)than with trastuzumab alone.

关键词： Survival cancer breast

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Dietary carbohydrate intake and risk of type 2 diabetes:a 16-year prospective cohort study

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Science China Life Sciences 2025年

作者： Lu Gan Yi Yang Bin Zhao Kai Yu Kehua Guo Fang Fang Zhiguang Zhou Demetrius Albanes Jiaqi Huang Key Laboratory of Diabetes Immunology Ministry of Education and Department of Metabolism and Endocrinology The Second Xiangya Hospital of Central South University CSU-Sinocare Research Center for Nutrition and Metabolic Health Xiangya School of Public Health Central South UniversityFurong Laboratory Division of cancer Epidemiology and Genetics National Cancer Institute NIH Department of Health and Human Services School of Computer Science and Engineering Central South University Institute of Environmental Medicine Karolinska Institute National Clinical Research center for Metabolic Diseases Key Laboratory of Diabetes Immunology Ministry of Education and Department of Metabolism and Endocrinology The Second Xiangya Hospital of Central South University

Despite considerable research underscoring the importance of carbohydrate intake in relation to the risk of type 2 diabetes(T2D), a comprehensive assessment of this relationship is currently lacking. We aimed to examine the associations of various types and food sources of dietary carbohydrate intake with the risk of T2D, to evaluate potential effect modification by other factors, including genetic susceptibility,and to explore the potential mediators for such associations. The present study included 161,872 participants of the UK Biobank who were free of prevalent cancer, cardiovascular disease, or diabetes, and had at least one validated 24-h dietary recall assessment. Multivariableadjusted age-stratified Cox proportional hazard regression models were applied to estimate hazard ratios(HRs) and 95% confidence intervals(CI) for the associations of various types and food sources of dietary carbohydrate intake with risk of T2D. During a median follow-up of13.6 years, 4,176 incident cases of T2D were identified. In the multivariable-adjusted models, a greater intake of fiber, carbohydrates from whole grains, and carbohydrates from non-starchy vegetables was significantly associated with a lower risk of T2D(highest vs. lowest quantile, HR [95% CI]=0.70 [0.62–0.79], 0.74 [0.67–0.82], and 0.83 [0.75–0.92], respectively, all P for trend <0.005). In contrast, a higher intake of starch and carbohydrate from starchy vegetables was associated with an increased risk of T2D(highest vs. lowest quantile, HR [95%CI]=1.31 [1.16–1.48] and 1.19 [1.09–1.31], respectively, both P for trend <0.005). Replacing one serving of refined grains or starchy vegetables with an equal amount of whole grains or non-starchy vegetables was associated with 4% to 10% lower risk of T2D(all P values <0.001).The observed associations were generally similar across population subgroups, including individuals with different genetic susceptibility to T2D. Mediation analyses of the inverse association between T

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Design of synthetic materials for intracellular delivery of RNAs： From siRNA-mediated gene silencing to CRISPR/Cas gene editing

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Nano Research 2018年第10期11卷 5310-5337页

作者： Jason B. Miller Daniel J. Siegwart Simmons comprehensive cancer center University of Texas Southwestern Medical Center Dallas TX 75390 USA Department of Biochemistry University of Texas Southwestern Medical Center Dallas TX 75390 USA

Ribonucleic acids （RNAs） possess great therapeutic potential and can be used to treat a variety of diseases. The unique biophysical properties of RNAs, such as high molecular weight, negative charge, hydrophilicity, low stability, and potential immunogenicity, require chemical modification and development of carriers to enable intracellular delivery of RNAs for clinical use. A variety of nanornaterials have been developed for the effective in vivo delivery of short/ small RNAs, messenger RNAs, and RNAs required for gene editing technologies including clustered regularly interspaced palindromic repeat （CRISPR）/Cas. This review outlines the challenges of delivering RNA therapeutics, explores the chemical synthesis of RNA modifications and carriers, and describes the efforts to design nanomaterials that can be used for a variety of clinical indications.

关键词： nucleic acid therapeutics nanoparticles synthetic nanomaterials RNA interference (RNAi) messenger RNA (mRNA) clustered regularly inter-spaced palindromic repeat(CRISPR)/Cas

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