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CXC family of chemokines as prognostic or predictive biomarkers and possible drug targets in colorectal cancer

World Journal of Gastroenterology 2018年第42期24卷 4738-4749页

作者： Sara Cabrero-de las Heras Eva Martínez-Balibrea program Against cancer therapeutic Resistance Catalan Institute of OncologyGermans Trias i Pujol health research institute program of Predictive and Personalized cancer Medicine Germans Trias i Pujol health research institute

Colorectal cancer(CRC) is the third most common cancer in men and the second most common cancer in women,worldwide. In the early stages of the disease, biomarkers predicting early relapse would improve survival rates.In metastatic patients, the use of predictive biomarkers could potentially result in more personalized treatments and better outcomes. The CXC family of chemokines(CXCL1 to 17) are small(8 to 10 kDa) secreted proteins that attract neutrophils and lymphocytes. These chemokines signal through chemokine receptors(CXCR) 1 to 8.Several studies have reported that these chemokines and receptors have a role in either the promotion or inhibition of cancer, depending on their capacity to suppress or stimulate the action of the immune system, respectively.In general terms, activation of the CXCR1/CXCR2 pathway or the CXCR4/CXCR7 pathway is associated with tumor aggressiveness and poor prognosis; therefore,the specific inhibition of these receptors is a possible therapeutic strategy. On the other hand, the lesser known CXCR3 and CXCR5 axes are generally considered to be tumor suppressor signaling pathways, and their stimulation has been suggested as a way to fight cancer.These pathways have been studied in tumor tissues(using immunohistochemistry or measuring mRNA levels)or serum [using enzyme-linked immuno sorbent assay(ELISA) or multiplexing techniques], among other sample types. Common variants in genes encoding for the CXC chemokines have also been investigated as possible biomarkers of the disease. This review summarizes themost recent findings on the role of CXC chemokines and their receptors in CRC and discusses their possible value as prognostic or predictive biomarkers as well as the possibility of targeting them as a therapeutic strategy.

关键词： Biomarkers Treatment Chemotherapy Oxaliplatin Irinotecan Immunotherapy Colorectal cancer CXC chemokines Immune system Bevacizumab

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Immune checkpoint inhibitors in clinical trials

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Chinese Journal of cancer 2014年第9期33卷 434-444页

作者： Elad Sharon Howard Streicher Priscila Goncalves Helen X.Chen cancer Therapy Evaluation program Division of Cancer Treatment and DiagnosisNational Cancer Institute Medical Oncology Service Center for Cancer ResearchNational Cancer Institute

Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called "immune checkpoints." These checkpoints serve to control or turn off the immune response when it is no longer needed to prevent tissue injury and autoimmunity. cancer cells have learned or evolved to use these mechanisms to evade immune control and elimination. The development of a new therapeutic class of drugs that inhibit these inhibitory pathways has recently emerged as a potent strategy in oncology. Three sets of agents have emerged in clinical trials exploiting this strategy. These agents are antibodybased therapies targeting cytotoxic T-lymphocyte antigen 4(CTLA4), programmed cell death 1(PD-1), and programmed cell death ligand 1(PD-L1). These inhibitors of immune inhibition have demonstrated extensive activity as single agents and in combinations. Clinical responses have been seen in melanoma, renal cell carcinoma, non-small cell lung cancer, and several other tumor types. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development.

关键词：临床试验免疫学检查站癌症程序性细胞死亡细胞毒性T淋巴细胞自身免疫性免疫控制

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Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

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Bone Research 2018年第2期6卷 167-176页

作者： Babita Madan Mitchell J.McDonald Gabrielle E.Foxa Cassandra R.Diegel Bart O.Williams David M.Virshup program in cancer and Stem Cell Biology Duke-NUS Medical School Center for cancer and Cell Biology and program for Skeletal Disease and Tumor Microenvironment Van Andel Research Institute Department of Pediatrics Duke University

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine（PORCN） that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159（ETC-159） had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably,simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family,mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors.Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

关键词： Wnt ETC Bone loss Wnt inhibition mitigated concurrent alendronate therapy

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Chemotherapy and its evolving role in the management of advanced prostate cancer

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Asian Journal of Andrology 2014年第3期16卷 334-340页

作者： Michael T Schweizer Emmanuel S Antonarakis Prostate cancer Research program Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore Maryland USA

Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer （CRPC）. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ＇level-1 evidence＇ that docetaxel-based chemotherapy led to prolongation in overall survival （OS）. This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents （e.g. abiraterone and enzalutamide） have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include： how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.

关键词： cabazitaxel chemotherapy cyclophosphamide docetaxel mitoxantrone prostate cancer taxanes

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Role of senescence induction in cancer treatment

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World Journal of Clinical Oncology 2018年第8期9卷 180-187页

作者： Shenghui Qin Bradley A Schulte Gavin Y Wang Department of Pathology and Laboratory Medicine Medical University of South Carolina Developmental cancer therapeutics program of Hollings cancer Center

Cellular senescence is a form of permanent cell cycle arrest that can be triggered by a variety of cell-intrinsic and extrinsic stimuli, including telomere shortening,DNA damage, oxidative stress, and exposure to chemotherapeutic agents and ionizing radiation. Although the induction of apoptotic cell death is a desirable outcome in cancer therapy, mutations and/or deficiencies in the apoptotic signaling pathways have been frequently identified in many human cancer types,suggesting the importance of alternative apoptosis-independent therapeutic approaches for cancer treatment. A growing body of evidence has documented that senescence induction in tumor cells is a frequent response to many anticancer modalities including cyclin-dependent kinases 4/6 small molecule inhibitor-based targeted therapeutics and T helper-1 cytokine-mediated immunotherapy. This review discusses the recent advances and clinical relevance of therapy-induced senescence in cancer treatment.

关键词： Cellular senescence cancer treatment Chemotherapy Ionizing radiation Cyclin-dependent kinases 4/6 inhibitor Aurora kinase inhibitor Immunotherapy T helper-1 cells T helper-1 cytokines

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Commentary on whole-grain intake and pancreatic cancer risk-the danish,diet,cancer and health cohort by Schacht et al.

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Hepatobiliary Surgery and Nutrition 2021年第5期10卷 702-704页

作者： Rick J.Jansen Department of Public Health GenomicsPhenomicsand Bioinformatics ProgramCenter for Immunization Research and Education(CIRE)Center for Diagnostic and Therapeutic Strategies in Pancreatic CancerNorth Dakota State UniversityFargoNDUSA

In their manuscript,“Whole-Grain Intake and Pancreatic cancer Risk-The Danish,Diet,cancer and Health Cohort”,Schacht et al.(1)report that total whole-grain product(per 50 g/d serving)intake was significantly associated with lower incidence of pancreatic cancer(HR:0.93;95%CI:0.86,1.00).A sex-specific analysis revealed that this association only held among men.However,neither total whole-grain(per 16-g serving)or specific individual whole-grain products and cereals were significantly associated with lower pancreatic cancer risk.In this commentary,I will describe some of the assumptions and biases associated with assessing dietary intake and attempting to find associations with disease.

关键词： intake cancer

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Parents' participation in physical activity predicts maintenance of some,but not all, types of physical activity in offspring during early adolescence:A prospective longitudinal study

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Journal of Sport and Health Science 2019年第3期8卷 273-279页

作者： Jennifer Brunei Jeffrey Gaudet Erin K.Wing Mathieu Bélanger School of Human Kinetics University of Ottawa Institut du Savoir Montfort (ISM) H?pital Montfort Cancer Therapeutic Program Ottawa Hospital Research Institute (OHRI) Centre de formation medicale du Nouveau-Brunswick Universite de Moncton Centre de formation médicale du Nouveau-Brunswick Université de Moncton

Purpose: We aimed to examine the longitudinal associations between parents' and youth's participation in physical activity(PA).Methods-: One hundred and ninety youth cuompleted self-admitiistered questionnaires 3 times per year from 2011 to 2015, and their parents completed an interviewer-administered questionnaire during a telephone interview once in2011-2012. Data on youth's and parents' activities were classified as interdependent or coactive/imdependent.Results: Youth with one or both parents who participated in interdependent activities were more likely to maintain participation in interdependent activities(hazard ratio(HR) = 3.63: 95% confidence interval(CI) = 1.30-10.17). Youth's sustained participation in coactive/independent activities was not associated with parents' participation in coactive/independent activities(HR= 0.97; 95%CI=0.46-2.06).Conclusion: Longitudinal associations between parents' and youth's participation in PA differed across type of PA. Encouraging parents' participation in interdependent activities may promote sustained participation in interdependent activities in youth.

关键词： Longitudinal Maintenance Parental behavior Physical activity Sports Youth

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cancer-cell-intrinsic mechanisms shaping the immunosuppressive landscape of prostate cancer

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Asian Journal of Andrology 2023年第2期25卷 171-178页

作者： Yini Zhu Loan Duong Xuemin Lu Xin Lu Department of Biological Sciences Boler-Parseghian Center for Rare and Neglected DiseasesHarper Cancer Research InstituteUniversity of Notre DameNotre DameIN 46556USA Integrated Biomedical Sciences Graduate program University of Notre DameNotre DameIN 46556USA Tumor Microenvironment and Metastasis program Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolisIN 46202USA

Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types,only a subset of patients shows meaningful clinical responses.In particular,advanced prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade therapy.This is primarily due to the immunosuppressive tumor microenvironment of prostate cancer.Therefore,it is paramount to understand how prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive microenvironment.Here,we review recent findings that reveal the roles of the genetic alterations,androgen receptor signaling,cancer cell plasticity,and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy resistance.Based on preclinical and clinical observations,a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in prostate cancer.

关键词： immune checkpoint blockade immunosuppression immunotherapy neuroendocrine prostate cancer prostate cancer

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Immunobiology and immunotherapy of HCC:spotlight on innate and innate-like immune cells

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Cellular & Molecular Immunology 2021年第1期18卷 112-127页

作者： Benjamin Ruf Bernd Heinrich Tim F.Greten Gastrointestinal Malignancy Section Thoracic and Gastrointestinal Malignancies BranchCentre for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA NCI CCR Liver cancer program National Institutes of HealthBethesdaMD 20892USA

Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types.The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma(HCC).Nevertheless,current immunotherapeutic approaches induce durable responses in only a subset of HCC patients.Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation,development,and progression of HCC,it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer.The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial,viral,and fungal antigens through the gut-liver axis.Here,we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them.We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.

关键词： HCC immunotherapy innate immunity tumor microenvironment

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Heat shock factor 1 is a direct anti-amyloid factor:connecting neurodegeneration and uncontrolledgrowth

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Neural Regeneration Research 2022年第3期17卷 559-560页

作者： Zijian Tang Chengkai Dai Mouse cancer Genetics program Center for Cancer ResearchNational Cancer InstituteFrederickMDUSA

Worldwide,more than 40 million people are afflicted with Alzheimer's disease(AD)(Esquerda-Canals et al.,2017).AD is a devastating neurodegenerative disroder characterized by progressive decline in cognitive abilities.A hallmark of AD and other neurodegenerative disorders in humans is the aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions(Iadanza et al.)。

关键词： amyloid al. Alzheimer

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