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Opportunities and challenges of CD47-targeted therapy in cancer immunotherapy

Oncology Research 2024年第1期32卷 49-60页

作者： QIUQIANG CHEN XUEJUN GUO WENXUE MA Key Laboratory for Translational Medicine The First Affiliated HospitalHuzhou University School of MedicineHuzhou313000China Department of Hematology Puyang Youtian General HospitalPuyang457001China Department of Medicine Moores Cancer CenterSanford Stem Cell InstituteUniversity of California San DiegoLa JollaSan Diego92093USA

cancer immunotherapy has emerged as a promising strategy for the treatment of cancer,with the tumor microenvironment(TME)playing a pivotal role in modulating the immune response.CD47,a cell surface protein,has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy.However,the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood.This comprehensive review aims to provide an overview of CD47’s multifaced role in TME regulation and immune evasion,elucidating its impact on various types of immunotherapy outcomes,including checkpoint inhibitors and CAR T-cell therapy.Notably,CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes,especially when combined with other immunotherapeutic approaches.The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47.Despite the demonstrated effectiveness of CD47-targeted therapies,there are potential problems,including unintended effects on healthy cells,hematological toxicities,and the development if resistance.Consequently,further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches,ultimately improving cancer treatment outcomes.Overall,this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.

关键词： CD47 cancer immunotherapy CD47-targeted therapies Tumor microenvironment Macrophage cancer cell Immune evasion Checkpoint inhibitors CAR T-cell therapy cancer treatment outcomes

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Game-changing insights on vertebral skeletal stem cells in bone metastasis and therapeutic horizons

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Oncology Research 2024年第1期32卷 95-98页

作者： QIUQIANG CHEN XIAOLEI ZHAO WENXUE MA Key Laboratory for Translational Medicine The First Affiliated HospitalHuzhou University School of MedicineHuzhou313000China Department of Urology Huaihe Hospital of Henan UniversityKaifeng475004China Department of Medicine Moores Cancer CenterSanford Stem Cell InstituteUniversity of California San DiegoLa Jolla92093USA

Greenblatt and his team have unveiled vertebral skeletal stem cells(vSSCs)as a critical player in the landscape of bone metastasis.This commentary delves into the transformative discoveries surrounding vSSCs,emphasizing their distinct role in bone metastasis compared to other stem cell lineages.We illuminate the unique properties and functions of vSSCs,which may account for the elevated susceptibility of vertebral bones to metastatic invasion.Furthermore,we explore the exciting therapeutic horizons opened by this newfound understanding.These include potential interventions targeting vSSCs,modulation of associated signaling pathways,and broader implications for the treatment and management of bone metastasis.By shedding light on these game-changing insights,we hope to pave the way for novel strategies that could revolutionize the prognosis and treatment landscape for cancer patients with metastatic bone disease.

关键词： Vertebral skeletal stem cells(vSSCs) Stem cell research Metastasis Breast prostate and lung cancers Spinal metastasis Matthew Greenblatt Genetic expressions

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Development,validation,and transportability of several machine-learned,non-exercise-based VO_(2max)prediction models for older adults

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Journal of Sport and Health Science 2024年第5期13卷 611-620页

作者： Benjamin T.Schumacher Michael J.LaMonte Andrea Z.LaCroix Eleanor M.Simonsick Steven P.Hooker Humberto Parada Jr. John Bellettiere Arun Kumar Herbert Wertheim School of Public Health and Human Longevity Science University of California San DiegoLa JollaCA 92093USA Department of Epidemiology and Environmental Health School of Public Health and Health ProfessionsUniversity at BuffaloState University of New YorkBuffaloNY 14214USA Translational Gerontology Branch Intramural Research ProgramNational Institute on AgingNational Institutes of HealthBaltimoreMD 21225USA College of Health and Human Services San Diego State UniversitySan DiegoCA 92182USA Division of Epidemiology and Biostatistics School of Public HealthSan Diego State UniversitySan DiegoCA 92182USA University of California San Diego moores cancer center La JollaCA 92093USA Computer Science and Engineering and Halicioglu Data Science Institute University of California San DiegoLa JollaCA 92093USA

Background:There exist few maximal oxygen uptake(VO_(2max))non-exercise-based prediction equations,fewer using machine learning(ML),and none specifically for older adults.Since direct measurement of VO_(2max)is infeasible in large epidemiologic cohort studies,we sought to develop,validate,compare,and assess the transportability of several ML VO_(2max)prediction algorithms.Methods:The Baltimore Longitudinal Study of Aging(BLSA)participants with valid VO2_(max)tests were included(n=1080).Least absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine(SVM)algorithms were trained to predict VO_(2max)values.We developed these algorithms for:(a)the overall BLSA,(b)by sex,(c)using all BLSA variables,and(d)variables common in aging cohorts.Finally,we quantified the associations between measured and predicted VO_(2max)and mortality.Results:The age was 69.0±10.4 years(mean±SD)and the measured VO_(2max)was 21.6±5.9 mL/kg/min.Least absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine yielded root mean squared errors of 3.4 mL/kg/min,3.6 mL/kg/min,3.4 mL/kg/min,3.6 mL/kg/min,and 3.5 mL/kg/min,respectively.Incremental quartiles of measured VO_(2max)showed an inverse gradient in mortality risk.Predicted VO_(2max)variables yielded similar effect estimates but were not robust to adjustment.Conclusion:Measured VO_(2max)is a strong predictor of mortality.Using ML can improve the accuracy of prediction as compared to simpler approaches but estimates of association with mortality remain sensitive to adjustment.Future studies should seek to reproduce these results so that VO_(2max),an important vital sign,can be more broadly studied as a modifiable target for promoting functional resiliency and healthy aging.

关键词： Cardiorespiratory fitness Prediction algorithms Epidemiology Mortality

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Design Strategies for Cellular Nanosponges as Medical Countermeasures

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Biomedical Engineering Frontiers 2023年第1期4卷 144-157页

作者： Shuyan Wang Dan Wang Mingxuan Kai Wei-Ting Shen Lei Sun Weiwei Gao Liangfang Zhang Department of NanoEngineering Chemical Engineering Programand Moores Cancer CenterUniversity of California San DiegoLa JollaCA 92093USA

The interest in using therapeutic nanoparticles to bind with harmful molecules or pathogens and subsequently neutralize their bioactivity has grown tremendously.Among various nanomedicine platforms,cell membrane-coated nanoparticles,namely,“cellular nanosponges,”stand out for their broadspectrum neutralization capability challenging to achieve in traditional countermeasure technologies.Such ability is attributable to their cellular function-based rather than target structure-based working principle.Integrating cellular nanosponges with various synthetic substrates further makes their applications exceptionally versatile and adaptive.This review discusses the latest cellular nanosponge technology focusing on how the structure–function relationship in different designs has led to versatile and potent medical countermeasures.Four design strategies are discussed,including harnessing native cell membrane functions for biological neutralization,functionalizing cell membrane coatings to enhance neutralization capabilities,combining cell membranes and functional cores for multimodal neutralization,and integrating cellular nanosponges with hydrogels for localized applications.Examples in each design strategy are selected,and the discussion is to highlight their structure–function relationships in complex disease settings.The review may inspire additional design strategies for cellular nanosponges and fulfill even broader medical applications.

关键词： sponge versatile integrating

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Targeting miRNA by CRISPR/Cas in cancer:advantages and challenges

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Military Medical Research 2024年第3期11卷 345-373页

作者： Bashdar Mahmud Hussen Mohammed Fatih Rasul Snur Rasool Abdullah Hazha Jamal Hidayat Goran Sedeeq Hama Faraj Fattma Abodi Ali Abbas Salihi Aria Baniahmad Soudeh Ghafouri-Fard Milladur Rahman Mark CGlassy Wojciech Branicki Mohammad Taheri Department of Biomedical Sciences Cihan University-ErbilErbilKurdistan Region 44001Iraq Department of Clinical Analysis College of PharmacyHawler Medical UniversityErbilKurdistan Region 44001Iraq Department of Pharmaceutical Basic Science Faculty of PharmacyTishk International UniversityErbilKurdistan Region 44001Iraq Medical Laboratory Science Lebanese French UniversityErbilKurdistan Region 44001Iraq Department of Biology College of EducationSalahaddin University-ErbilErbilKurdistan Region 44001Iraq Department of Medical Laboratory Science Komar University of Science and TechnologySulaymaniyah 46001Iraq Department of Medical Microbiology College of Health SciencesHawler Medical UniversityErbilKurdistan Region 44001Iraq Department of Biology College of ScienceSalahaddin University-ErbilErbilKurdistan Region 44001Iraq center of Research and Strategic Studies Lebanese French UniversityErbil 44001Iraq Institute of Human Genetics Jena University Hospital07747 JenaGermany Department of Medical Genetics School of MedicineShahid Beheshti University of Medical SciencesTehran 374-37515Iran Department of Clinical Sciences MalmöSection for SurgeryLund University22100 MalmöSweden Translational Neuro-Oncology Laboratory San Diego(UCSD)Moores Cancer CenterUniversity of CaliforniaSan DiegoCA 94720USA Faculty of Biology Institute of Zoology and Biomedical ResearchJagiellonian University31-007 KrakówPoland Urology and Nephrology Research center Shahid Beheshti University of Medical SciencesTehran 374-37515Iran

Clustered regulatory interspaced short palindromic repeats(CRISPR)has changed biomedical research and provided entirely new models to analyze every aspect of biomedical sciences during the last decade.In the study of cancer,the CRISPR/CRISPR-associated protein(Cas)system opens new avenues into issues that were once unknown in our knowledge of the non-coding genome,tumor heterogeneity,and precision medicines.CRISPR/Cas-based geneediting technology now allows for the precise and permanent targeting of mutations and provides an opportunity to target small non-coding RNAs such as microRNAs(miRNAs).However,the development of effective and safe cancer gene editing therapy is highly dependent on proper design to be innocuous to normal cells and prevent introducing other abnormalities.This study aims to highlight the cutting-edge approaches in cancer-gene editing therapy based on the CRISPR/Cas technology to target miRNAs in cancer therapy.Furthermore,we highlight the potential challenges in CRISPR/Cas-mediated miRNA gene editing and offer advanced strategies to overcome them.

关键词： CRISPR CRISPR/Cas9 CRISPR/Cas12 Gene editing miRNAs cancer therapy

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Science Bulletin 2024年第7期69卷 850-852页

作者：周晓东 Gregory Y.H.Lip 郑明华 Department of Cardiovascular Medicine the Heart Centerthe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000China Liverpool Centre for Cardiovascular Science at University of Liverpool Liverpool John Moores University and Liverpool Heart&Chest HospitalLiverpool L693BXUK Department of Clinical Medicine Aalborg UniversityAalborg 9000Denmark MAFLD Research center Department of Hepatologythe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000China Institute of Hepatology Wenzhou Medical UniversityWenzhou 325000China Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province Wenzhou 325000China

Heart failure with preserved ejection fraction(HFpEF)has an estimated incidence rate of approximately 27 cases per 10,000 person-year[1].Furthermore,the prevalence of HFpEF is on the rise and is expected to exceed that of heart failure with reduced ejection fraction(HFr EF)[2].In the near future,HFpEF is expected to become the predominant subtype of heart failure[2].

关键词： predominant fraction 射血分数保留型

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Nucleo-cytoplasmic communication in apoptotic response to genotoxic and inflammatorystress

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Cell Research 2005年第1期15卷 43-48页

作者： Jean Y. J. WANG La Jolla USA CA 92093-0322 San Diego Division of Biological Sciences and moores cancer center University of California

Genotoxic agents or inflammatory cytokines activate cellular stress responses and trigger programmed cell death. We have identified a signal transduction module, including three nuclear proteins that participate in the regulation of cell death induced by chemotherapeutic agents and tumor necrosis factor (TNF). In this nuclear signaling module, retino- blastoma protein (Rb) functions as an inhibitor of apoptotic signal transduction. Inactivation of Rb by phosphorylation or caspase-dependent cleavage/degradation is required for cell death to occur. Rb inhibits the Abl tyrosine kinase. Thus, Rb inactivation is a pre-requisite for Abl activation by DNA damage or TNF. Activation of nuclear Abl and its down- stream effector p73 induces mitochondriadependent cell death. The involvement of these nuclear signal transducers in TNF induced apoptosis, which does not require new gene expression, indicates that nuclear events other than transcrip- tion can contribute to extrinsic apoptotic signal transduction.

关键词： apoptosis DNA damage mitochondria TNF Rb Abl p73 p53.

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Surgical wound classification in otolaryngology:A state-of-the-art review

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2022年第2期8卷 139-144页

作者： Jeffrey D.Bernstein David J.Bracken Shira R.Abeles Ryan K.Orosco Philip A.Weissbrod Department of Otolaryngology University of California San DiegoLa JollaCaliforniaUSA Department of Medicine Division of Infectious Disease and Global Public HealthUniversity of California San DiegoSan DiegoCaliforniaUSA moores cancer center University of California San DiegoLa JollaCaliforniaUSA

Objective:To describe the issues related to the assignment of surgical wound classification as it pertains to Otolaryngology—Head&Neck surgery,and to present a simple framework by which providers can assign wound classification.Data Sources:Literature review.Conclusion:Surgical wound classification in its current state is limited in its utility.It has recently been disregarded by major risk assessment models,likely due to inaccurate and inconsistent reporting by providers and operative staff.However,if data accuracy is improved,this metric may be useful to inform the risk of surgical site infection.In an era of quality-driven care and reimbursement,surgical wound classification may become an equally important indicator of quality.

关键词： ENT health care spending OHNS otolaryngology quality improvement reimbursement surgical site infection wound classification

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Synthetic and immunological studies on the OCT4 immunodominant motif antigen-based anti-cancer vaccine

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cancer Biology & Medicine 2020年第1期17卷 132-141页

作者： Tingting Chen Kan Liu Jiangyao Xu Tianying Zhan Maixian Liu Li Li Zhiwen Yang Shuping Yuan Wenyi Zou Guimiao Lin Dennis ACarson Christina CNWu Xiaomei Wang Department of Physiology School of Basic Medical SciencesShenzhen University Health Sciences CenterShenzhen UniversityShenzhen 518060China Carson Lab Moores Cancer CenterUCSDLa Jolla 92093CAUSA

Objective:cancer stem cell is one of the important causes of tumorigenesis as well as a drug target in the treatment of malignant tumor.However,at present,there is no immune vaccine targeting these cells.Octamer-binding transcription factor 4(OCT4),a marker of embryonic stem cells and germ cells,often highly expresses in the early stages of tumorigenesis and is therefore a good candidate for cancer vaccine development.Methods:To identify the optimal carrier and adjuvant combination,we chemically synthesized and linked three different OCT4 epitope antigens to a carrier protein,keyhole limpet hemocyanin(KLH),combined with Toll-like receptor 9 agonist(TLR9).Results:Immunization with OCT4-3+TLR9 produced the strongest immune response in mice.In prevention assays,significant tumor growth inhibition was achieved in BABL/c mice treated with OCT4-3+TLR9(P<0.01).Importantly,the results showed that cytotoxic T lymphocyte activity and the inhibition of tumor growth were enhanced in mice immunized with OCT4-3 combined with TLR9.Meanwhile,multiple cytokines[such as interferon(IFN)-γ(P<0.05),interleukin(IL)-12(P<0.05),IL-2(P<0.01),and IL-6(P<0.05)]promoting cellular immune responses were shown to be greatly enhanced in mice immunized with OCT4-3+TLR9.Moreover,we considered safety considerations in terms of the composition of the vaccines to help facilitate the development of effective next-generation vaccines.Conclusions:Collectively,these experiments demonstrated that combination therapy with TLR9 agonist induced a tumor-specific adaptive immune response,leading to the suppression of primary tumor growth in testis embryonic carcinoma.

关键词： cancer prevention cancer immunology OCT4 TLR9 agonist

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Recent Progress in Capturing and Neutralizing Inflammatory Cytokines

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CCS Chemistry 2020年第3期2卷 376-389页

作者： Qiangzhe Zhang Hua Gong Weiwei Gao Liangfang Zhang Departments of NanoEngineering Chemical Engineering Programand Moores Cancer CenterUniversity of California San DiegoLa JollaCA 92093

Inflammatory cytokines are key players in modulating immune responses to mount effective host defense.However,excessive production of inflammatory cytokines contributes to the destructive components responsible for various inflammatory disorders.As a result,treatment strategies have been developed to lower the cytokine levels or block their bioactivity.In particular,therapeutic agents that directly capture and neutralize cytokines have gained significant attention as they bypass the interactions with the host cells,and therefore,are less likely to induce immunogenic response and clearance.Among them,“monoplex”platforms such as cytokine-neutralizing antibodies(CNAs)are commonly designed to target a specific cytokine for neutralization.Meanwhile,to address the multiplexity of the cytokine targets in diseases,multiplex platforms such as glycosaminoglycan-containing biomaterials and cell-membrane-coated nanoparticles are emerging.Herein,we have reviewed the recent progress of these cytokine-neutralizing platforms(CNPs)and discussed their applications in treating inflammatory disorders.Overall,understanding the structure–function relationships underlying these CNPs would lead to the design of novel therapeutics toward effective management of inflammatory diseases.

关键词： inflammatory disorder cytokine neutralization anticytokine monoplex multiplex

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