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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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The use of a standardized Chinese herbal formula in patients with advanced lung cancer:a feasibility study

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Journal of Integrative Medicine 2018年第6期16卷 390-395页

作者： Goulnar Kasymjanova Anh-Thi Tran Victor Cohen Carmela Pepe Lama Sakr David Small Jason Scott Agulnik Robert Thomas Jagoe Peter Brojde Lung cancer Center Segal Cancer Center Jewish General Hospital

Objective： Increasing numbers of cancer patients are using Chinese herbs （CHs）. However, differences among prior studies make it difficult to draw firm conclusions about the clinical usefulness of any specific CH formula. The primary objective of this study was to establish the acceptability of taking a standardized CH formula for patients with advanced lung cancer. The secondary objective was to identify any toxicities attributable to this CH formula and to measure changes in quality of life. Methods： A single-arm, prospective study of a 6-week intervention with a selected CH formula in 15 patients with stage 4 nonsmall-cell lung cancer （NSCLC, Seventh American Joint Committee on cancer TNM staging system）. Results： Patients with advanced lung cancer were interested in using the CH formula. Completion （93%） and adherence （98%） levels were very high and most patients perceived the CH treatment as easy to take and were willing to take the CHs used in the study again if it was available. About half of the patients reported adverse events, all of which were mild （Grade 1 or 2） and only a small minority （8%） were poten- tially related to CHs. No biochemical or hematological evidence of toxicity was observed. Overall, there were improvement in quality of life, and reduced feelings of tiredness and sleepiness. Conclusion： This study provides preliminary evidence that short-term use of a carefully selected and pre- pared CH formula in patients with stage 4 NSCLC is acceptable and safe.

关键词： Lung cancer Chinese herbs Quality of life

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Teucrium polium plant extract provokes significant cell death in human lung cancer cells

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Health 2011年第6期3卷 366-369页

作者： Khadidja Haidara Amal Alachkar Ala-Eddin Al Moustafa segal cancer centre Lady Davis Institute for Medical ResearchMcGill UniversityMontrealCanada Faculty of Pharmacy/University of Aleppo AleppoSyria Syrian Research cancer centre of the Syrian Society against cancer AleppoSyria Department of Oncology McGill UniversityMontrealCanada Department of Mechanical Engineering Concordia UniversityMontrealCanada

Lung cancer is the first common malignancy worldwide;in view of the limited success of available treatment modalities for this cancer, alternative and complementary strategies need to be developed. On the other hand, Teucrium polium (TP) is a medicinal plant that has been used for more than two thousand years for treating many diseases such as abdominal pain, indigestion and diabetes in the Middle East. However, the effect of TP plant extract on hu-man non-small cell lung cancer (NSCLC) has not been investigated yet. In this study, we exam-ined the effects of TP extract on cell prolifera-tion, cell cycle progression and cell death in H322 and A549 lung cell lines. Our results show that TP plant extract inhibits cell proliferation and deregulates cell cycle progression. More importantly, TP plant extract causes a dramatic cell death in both cell lines in comparison with untreated cells. Our data suggest that this plant extract could have an important therapeutic role in the treatment of human NSCLC.

关键词： Teucrium Polium Plant Extract Lung cancer Cell Death

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Review:Proteomic technology for biomarker profiling in cancer: an update

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2006年第6期7卷 411-420页

作者： ALAOUI-JAMALI Moulay A. Lady Davis Institute for Medical Research and segal Comprehensive cancer Center of the Sir Mortimer B. Davis Jewish General Hospital Department of Oncology and Medicine McGill University Montreal Que. H3T 1E2 Canada

The progress in the understanding of cancer progression and early detection has been slow and frustrating due to the complex multifactorial nature and heterogeneity of the cancer syndrome. To date, no effective treatment is available for advanced cancers, which remain a major cause of morbidity and mortality. Clearly, there is urgent need to unravel novel biomarkers for early detection. Most of the functional information of the cancer-associated genes resides in the proteome. The later is an exceptionally complex biological system involving several proteins that function through posttranslational modifications and dynamic inter-molecular collisions with partners. These protein complexes can be regulated by signals emanating from cancer cells, their sur-rounding tissue microenvironment, and/or from the host. Some proteins are secreted and/or cleaved into the extracellular milieu and may represent valuable serum biomarkers for diagnosis purpose. It is estimated that the cancer proteome may include over 1.5 million proteins as a result of posttranslational processing and modifications. Such complexity clearly highlights the need for ultra-high resolution proteomic technology for robust quantitative protein measurements and data acquisition. This review is to update the current research efforts in high-resolution proteomic technology for discovery and monitoring cancer biomarkers.

关键词： cancer Biomarkers Proteomics

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Investigation of androgen receptor-dependent alternative splicing has identified a unique subtype of lethal prostate cancer

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Asian Journal of Andrology 2023年第3期25卷 296-308页

作者： Sean Seltzer Paresa N Giannopoulos Tarek A Bismar Mark Trifiro Miltiadis Paliouras Lady Davis Institute for Medical Research Segal Cancer Centre-Jewish General HospitalMontrealQC H3T 1E2Canada Cumming School of Medicine Department of Pathology and Laboratory MedicineUniversity of CalgaryCalgaryAB T2N 1N4Canada Department of Medicine Division of Experimental MedicineMcGill UniversityMontrealQC H4A 3J1Canada Department of Oncology McGill UniversityMontrealQC H4A 3T2Canada

A complete proteomics study characterizing active androgen receptor(AR)complexes in prostate cancer(PCa)cells identified a diversity of protein interactors with tumorigenic annotations,including known RNA splicing ***,we chose to further investigate the functional role of AR-mediated alternative RNA splicing in PCa disease *** selected two AR-interacting RNA splicing factors,Src associated in mitosis of 68 kDa(SAM68)and DEAD(Asp-Glu-Ala-Asp)box helicase 5(DDX5)to examine their associative roles in AR-dependent alternative RNA *** assess the true physiological role of AR in alternative RNA splicing,we assessed splicing profiles of LNCaP PCa cells using exon microarrays and correlated the results to PCa clinical *** a result,we were able to highlight alternative splicing events of clinical *** use of exon-mini gene cassettes illustrated hormone-dependent AR-mediated exon-inclusion splicing events with SAM68 or exon-exclusion splicing events with DDX5 *** physiological significance in PCa was investigated through the application of clinical exon array analysis,where we identified exon-gene sets that were able to delineate aggressive disease progression profiles and predict patient disease-free outcomes independently of pathological clinical *** a clinical dataset with patients categorized as prostate cancer-specific death(PCSD),these exon gene sets further identified a select group of patients with extremely poor disease-free ***,these results strongly suggest a nonclassical role of AR in mediating robust alternative RNA splicing in ***,AR-mediated alternative spicing contributes to aggressive PCa progression,where we identified a new subtype of lethal PCa defined by AR-dependent alternative splicing.

关键词： alternative RNA splicing androgen receptor exon-gene sets lethal prostate cancer subtype prostate cancer

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Cell transplantation therapy using pluripotent stem cells

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World Journal of Immunology 2013年第2期3卷 15-17页

作者： Noah Isakov The Shraga segal Department of Microbiology Immunology and Genetics Faculty of Health Sciences and the Cancer Research Center Ben Gurion University of the NegevBeer Sheva 84105 Israel

The 2012 Nobel Prize in Physiology or Medicine was awarded jointly to Sir John B Gurdon and Shinya Ya-manaka “for the discovery that mature cells can be re-programmed to become pluripotent”. Professor John B Gordon who pioneered the feld of somatic cell nuclear transfer was the frst to show that a nucleus of a ma-ture cell can be transplanted into an enucleated egg and give rise to a living organism. His pioneering “clon-ing” technique paved the way for genome reprogram-ming and has led to subsequent cloning of differentani-mal species. Professor Shinya Yamanaka revolutionized the fled of stem cell production by showing that the introduction of four selected genes into cells transform them into induced pluripotent stem cells that resemble embryonic stem cells and serve as promising cells for future regenerative medicine.

关键词： Stem cells Induced pluripotent stem cells Somatic cell nuclear transfer Nobel Prize

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Comment on "p38 MAPK inhibition alleviates experimental acute pancreatitis in mice"

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Hepatobiliary & Pancreatic Diseases International 2015年第3期14卷 330-330页

作者： Moulay Alaoui-Jamali Mc Gill University Depart. Medicine and Oncology Lady Davis Institute for Medical Research Segal Cancer Centre 3755 Chemin Cote Ste-Catherine Montreal Quebec H3T 1E2 Canada Professor

To the Editor：I read with great interest the article by Cao et al[1] re- porting a potential therapeutic utility of p38 inhibitors for acute pancreatitis. Using a preclinical mouse model where acute pancreatitis was induced by administra- tion of cerulein （a cholecystokinin analog derived from the tree frog Litoria caerulea）, the authors reported that the p38 MAPK inhibitor SB203580, administered intra- peritoneally before and after the first administration of cerulein, relieved signs associated with acute pancreatitis, including decreased HSP60 and HSP70 expression, and serum IL-6, amylase and lipase activities. Although the study remains descriptive and pharmacodynamic aspects were not examined in depth, it still has a merit as it undoubtedly provides a basis for further investigation into the potential utility of targeting p38 signaling for acute pancreatitis, a common serious condition that can be life-threatening.

关键词： MAPK p38 MAPK inhibition alleviates experimental acute pancreatitis in mice Comment on

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New insights into the role of intra-tumor genetic heterogeneity in carcinogenesis: identification of complex single gene variance within tumors

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Journal of cancer Metastasis and Treatment 2018年第1期4卷 428-441页

作者： Bruce Gottlieb Farbod Babrzadeh Kathleen Klein Oros Carlos Alvarado Chunlin Wang Baback Gharizadeh Mark Basik Celia MTGreenwood Lenore KBeitel Mark Trifiro Lady Davis Institute for Medical Research Jewish General HospitalMontrealQC H3T 1E2Canada segal cancer centre Jewish General HospitalMontrealQC H3T 1E2Canada Department of Human Genetics McGill UniversityMontrealQC H3A 0G4Canada Stanford Genome Technology Center Stanford UniversityPalo AltoCA 94304USA Department of Medicine McGill UniversityMontrealQC H3A 0G4Canada

Aim:Present cancer hypotheses are almost all based on the concept that accumulation of specific driver gene mutations cause *** discovery of intra-tumor genetic heterogeneity(ITGH),has resulted in this hypothesis being modified by assuming that most of these ITGH mutations are in passenger *** addition,accumulating ITGH data on driver gene mutations have revealed considerable genotype/phenotype *** study proposes to investigate this disconnect by examining the nature and degree of ITGH in breast ***:ITGH was examined in tumors using next generation sequencing of up to 68,000 reads and analysis tools that allowed for identification of distinct minority variants within single genes,i.e.,complex single gene variance(CSGV).Results:CSGV was identified in the androgen receptor genes in all breast tumors ***:Evidence of CSGV suggests that a selection-as opposed to a mutation-centric hypothesis could better explain *** hypothesis proposes that tumors develop by the selection of preexisting de novo mutations rather than just the accumulation of de novo ***,the role of selection pressures,such as changes in tissue microenvironments will likely be critical to our understanding of tumor resistance as well as the development of more effective treatment protocols.

关键词： Intra-tumor genetic heterogeneity breast cancer complex single gene variance

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Stellettin B renders glioblastoma vulnerable to poly (ADPribose) polymerase inhibitors via suppressing homologydirected repair

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1388-1391页

作者： Xin Peng Yingying Wang Shaolu Zhang Zhennan Tao Yuxiang Dai Francois X.Claret Moshe Elkabets Hou-Wen Lin Zhe-Sheng Chen Dexin Kong Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics School of PharmacyTianjin Medical UniversityTianjin 300070China Key Laboratory of Immune Microenvironment and Diseases(Ministry of Education) Tianjin Medical UniversityTianjin 300070China Department of Systems Biology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Neurosurgery the Affiliated Drum Tower HospitalSchool of MedicineNanjing UniversityNanjing 210008China The Shraga segal Department of Microbiology Immunology and GeneticsFaculty of Health SciencesBen-Gurion University of the NegevBeer-Sheva 84105Israel Research Center for Marine Drugs State Key Laboratory of Oncogenes and Related GenesDepartment of PharmacyRenji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai 200127China Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA

Dear Editor,Glioblastoma(GBM)is one of the most fatal brain *** first-line post-surgery regimens for GBM including radiotherapy and temozolomide(TMZ)chemotherapy show very limited efficacy.1,2 Novel therapeutic approaches for GBM patients are urgently *** products are important sources for drug discovery,especially in the field of cancer treatment.3 We previously isolated stellettin B(STELB)(Fig.1a)from marine sponge(Jaspis stellifera)and reported the remarkable and specific anticancer ***,a series of stellettins has been totally synthesized and the core chemical structure has been indicated.4 However,the specific mechanism and its role in regulating tumor biology remain largely unknown.

关键词： chemotherapy surgery render

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Glycans to improve efficacy and solubility of protein aggregation inhibitors

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Neural Regeneration Research 2021年第11期16卷 2215-2216页

作者： Ashim Paul Daniel segal Elsa Zacco Department of Molecular Microbiology and Biotechnology Shmunis School of Biomedicine and Cancer ResearchTel Aviv UniversityRamat AvivTel Aviv 6997801Israel RNA Central Lab Center for Human TechnologiesIstituto Italiano di Tecnologia16152 GenovaItaly

Misfolding and subsequent aberrant selfassembly of certain proteins into toxic amyloid deposits are hallmarks of various diseases,most notably neurodegenerative disorders such as Alzheimer’s disease(AD)and Parkinson’s disease(Chiti and Dobson,2017).Aromatic residues in amyloidogenic proteins have been shown to be key factors in protein oligomerization and fibrilization,mostly driven byπ-π*** with aromaticity,post-translational modifications can greatly affect a protein’s solubility and conformation and,as a consequence,its propensity to aggregate.

关键词： solubility aggregation mostly

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