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CT103A, a forward step in multiple myeloma immunotherapies

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Blood Science 2021年第2期3卷 59-61页

作者： jie Xu j.joseph melenhorst Center for Cellular Immunotherapies Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA 19104USA Department of Hematology Shanghai Institute of HematologyRuijin Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiPR China

Even with the most potent,modern therapies,multiple myeloma(MM)remains a largely incurable disease.The reprogramming of a patient’s T-lymphocytes with a cancerassociated antigen-specific chimeric antigen receptor(CAR)has improved the outcome of patients with this debilitating disease.B cell maturation antigen(BCMA),a marker almost exclusively expressing by plasma cells,^(1) is the most attractive target for designing CAR-T cells against MM.

关键词： myeloma therapies attractive

The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1295-1303页

作者： jianshu Wei Yang Liu Chunmeng Wang Yajing Zhang Chuan Tong Guanghai Dai Wei Wang john E.j.Rasko j.joseph melenhorst Wenbin Qian Aibin Liang Weidong Han Department of Bio-therapeutic the First Medical CenterChinese PLA General Hospital100853 BeijingChina Department of Oncology the first Medical CenterChinese PLA General Hospital100853 BeijingChina State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityChengdu 610041China Collaborative Innovation Center for Biotherapy Chengdu 610041China Department of Cell and Molecular Therapies Royal Prince Alfred HospitalSydneyNSW 2006Australia Gene and Stem Cell Therapy Program Centenary InstituteUniversity of SydneySydneyNSW 2006Australia Central Clinical School Faculty of Medicine and HealthThe University of SydneyCamperdownNSW 2050Australia Department of Pathology and Laboratory Medicine Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104-515USA Department of Hematology The Second Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310009China Department of Hematology Shanghai Tongji HospitalTongji University School of MedicineShanghai 200065China State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases100853 BeijingChina

Chimeric antigen receptor T(CAR T)cell therapy has demonstrated efficacy in the treatment of haematologic malignancies.However,the accompanying adverse events,the most common of which is cytokine release syndrome(CRS),substantially limit its wide application.Due to its unique physiological characteristics,CRS in CAR T-cell treatment for B-cell non-Hodgkin lymphoma(BNHL)may exhibit some special features.Although existing guidelines had greatly promoted the recognition and management of CRS,many recommendations are not fully applicable to B-NHL.Therefore,it is imperative to identify responses that are specific to CRS observed following CAR T treatment for B-NHL.Based on underlying biological processes and known pathophysiological mechanisms,we tentatively propose a new model to illustrate the occurrence and evolution of CAR T-cell-therapy-related CRS in BNHL.In this model,tumour burden and bone marrow suppression are considered determinants of CRS.Novel phenomena after CAR T-cell infusion(such as local inflammatory response)are further identified.The proposed model will help us better understand the basic biology of CRS and recognize and manage it more rationally.

关键词： cytokine lymphoma treatment

Engineered T Cell Therapies from a Drug Development Viewpoint

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Engineering 2019年第1期5卷 140-149页

作者： Fang Chen joseph A. Fraietta Carl H. june Zhongwei Xu j. joseph melenhorst Simon F. Lacey Department of Pathology and Laboratory Medicine University of Pennsylvania Philadelphia PA 19104 USA Center for Cellular Immunotherapies University of Pennsylvania Philadelphia PA 19104 USA Parker Institute for Cancer Immunotherapy University of Pennsylvania Philadelphia PA 19104 USA Abramson Cancer Center University of Pennsylvania Philadelphia PA 19104 USA Department of Immunology Peking University Beijing 100871 China

Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike chemical compounds and proteins, cells are living, self-replicating drugs that can be engineered to possess exquisite specificity. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs), endowing them with the capacity to recognize and kill tumor cells and form a memory pool that is ready to strike back against persisting malignant cells. Anti-CD19 chimeric antigen receptor T cells (CART19s) have demonstrated a remarkable degree of clinical efficacy for certain malignancies. The process of developing CART19 essentially follows the conventional “one gene, one drug, one disease” paradigm derived from Paul Ehrlich’s “magic bullet” concept. With major players within the pharmaceutical industry joining forces to commercialize this new category of “living drugs,” it is useful to use CART19 as an example to examine the similarities and differences in its development, compared with that of a conventional drug. In this way, we can assimilate existing knowledge and identify the most effective approach for advancing similar strategies. This article reviews the use of biomarker-based assays to guide the optimization of CAR constructs, preclinical studies, and the evaluation of clinical efficacy;adverse effects (AEs);and CART19 cellular kinetics. Advanced technologies and computational tools that enable the discovery of optimal targets, novel CAR binding domains, and biomarkers predicting clinical response and AEs are also discussed. We believe that the success of CART19 will lead to the development of other engineered T cell therapies in the same manner that the discovery of arsphenamine initiated the era of synthetic pharmaceuticals.

关键词： Engineered T cell therapies Chimeric antigen receptor Drug development process Biomarkers CD19-specific chimeric antigen receptor Anti-CD19 chimeric antigen receptor T cells

Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis

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Cellular & Molecular Immunology 2024年第1期21卷 33-46页

作者： Anja Meyer Stephanie R.Zack Wes Nijim Adel Burgos Vishwa Patel Brian Zanotti Michael V.Volin M.Asif Amin Myles j.Lewis Costantino Pitzalis Shiva Arami joseph A.Karam Nadera j.Sweiss Shiva Shahrara jesse Brown VA Medical Center ChicagoILUSA Department of Medicine Division of RheumatologyThe University of Illinois at ChicagoChicagoILUSA Department of Microbiology and Immunology Midwestern UniversityDowners GroveILUSA Division of Rheumatology and Clinical Autoimmunity Center of Excellence University of MichiganAnn ArborMIUSA Centre for Experimental Medicine and Rheumatology William Harvey Research InstituteBarts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUnited Kingdom Centre for Experimental Medicine&Rheumatology William Harvey Research InstituteQueen Mary University of London and Barts NIHR BRC&NHS TrustLondonUK Department of Biomedical Sciences Humanitas Universityand Humanitas Research HospitalMilanItaly Department of Orthopedic Surgery the University of Illinois at ChicagoChicagoILUSA

A novel rheumatoid arthritis(RA)synovial fluid protein,Syntenin-1,and its receptor,Syndecan-1(SDC-1),are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes(FLS).Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9,IL-1β,IL-6,and CCL2 through SDC-1 ligation and HIF1α,or mTOR activation.Mechanistically,Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling.In Syntenin-1 reprogrammed endothelial cells,the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors,AMPK,PGC-1α,citrate,and inactive oxidative phosphorylation.Conversely,RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity.The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression.We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS,which are also represented in RA explants.Similar to RA explants,morphological and transcriptome studies authenticated the importance of VEGFR1/2,Notch1,RAPTOR,and HIF1αpathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals.Consistently,dysregulation of SDC-1,mTOR,and HIF1αnegated Syntenin-1 inflammatory phenotype in RA explants,while inhibition of HIF1αimpaired synovial angiogenic imprint amplified by Syntenin-1.In conclusion,since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood,targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.

关键词： Syntenin-1 Syndecan-1 RA FLS RA explants immunometabolism

Recovery rates of persistent post-COVID-19 olfactory dysfunction using psychophysical assessment:A longitudinal cohort study

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World journal of Otorhinolaryngology-Head and Neck Surgery 2024年第2期10卷 79-87页

作者： jeremy P.Tervo Patricia T.jacobson Brandon j.Vilarello Tiana M.Saak Francesco F.Caruana Liam W.Gallagher joseph B.Gary David A.Gudis Paule V.joseph D.P.Devanand Terry E.Goldberg jonathan B.Overdevest Columbia University Vagelos College of Physicians and Surgeons New YorkNew YorkUSA Department of Otolaryngology-Head and Neck Surgery New York-Presbyterian/Columbia University Irving Medical CenterNew YorkNew YorkUSA Department of Otolaryngology-Head and Neck Surgery University of PittsburghPittsburghPennsylvaniaUSA Department of Otolaryngology-Head and Neck Surgery University of MinnesotaMinneapolisMinnesotaUSA National Institute of Alcohol Abuse and Alcoholism Section of Sensory Science and Metabolism&National Institute of Nursing ResearchBethesdaMarylandUSA New York-Presbyterian/Columbia University Irving Medical Center New YorkNew YorkUSA

Objectives:Persistent olfactory dysfunction(OD)following loss of smell associated with SARS-CoV-2 infection is a major feature of long COVID.Perspectives on the prevalence of persistent OD predominantly rely on self-reported olfactory function.Few studies have tracked longitudinal rates of recovery using psychophysical assessment among patients presenting for evaluation of persistent OD beyond a window of acute recovery.Data anchored in standardized testing methods are needed to counsel patients who fail to acutely regain their sense of smell.This study aims to quantify the degree of persistent OD in post-COVID-19 patients who experience subjective and psychophysical OD.Methods:We grouped participants presenting for OD evaluation into cohorts based on both subjective and psychophysical olfactory status at a baseline assessment and assessed their olfactory abilities with a visual analogue scale and the Sniffin'Sticks extended test at baseline and 1-year time points.Participants had confirmed a history of COVID-19 by lab evaluation or clinical diagnosis if lab evaluation was not available.Results:Baseline olfactory evaluation was completed by 122 participants,53 of whom completed the 1-year follow-up assessment.Among participants presenting with perceived OD,74.5%had confirmed psychophysical OD at baseline,with 55.1%at 1-year follow-up.Participants had reliable trends in self-rated versus psychophysically tested olfactory function at both time points.The total threshold,discrimination,and identification(TDI)score improved by+3.25 points in the cohort with psychophysical OD(p=0.0005),with this improvement largely attributable to an increase in median threshold scores(+2.75 points;p=0.0004).Conclusions:OD persists in a significant number of patients who fail to acutely recovery their sense of smell after COVID-19,with many demonstrating lingering deficits at 1-year.Improvements in threshold,but not discrimination or identification,most significantly mediate improvement of total TDI score at follow-up.

关键词： long COVID olfaction post-COVID condition smell dysfunction

Tuning electronic properties of cobalt phthalocyanines for oxygen reduction and evolution reactions

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Science China Chemistry 2024年第1期67卷 398-407页

作者： jianlin jiang Zhen Liu Shuaijun Pan Xinnian Xia Bing Qin Yang Hu Xuxu Wang jiamin Lan Yu Gu Encai Ou Weijian Xu joseph j.Richardson Rui Guo SINOPEC Research Institute of Petroleum Processing Co. Ltd.Beijing 100083China College of Chemistry and Chemical Engineering Hunan UniversityChangsha 410082China College of Chemistry and Materials Science Hunan Agricultural UniversityChangsha 410128China Department of Chemical Engineering The University of MelbourneParkville 3010Australia College of Environmental Science and Engineering Hunan UniversityChangsha 410082China School of Engineering RMIT UniversityMelbourneVictoria 3001Australia

Metal–phthalocyanines are a class of catalytically active materials promising in energy conversion and storage fields(e.g.,electrocatalysis).However,understanding and controlling the electrochemical properties in metal-phthalocyanine systems is challenging.Herein,we elucidate the electrocatalytic origins of a series of cobalt-phthalocyanine molecular catalysts and finetune their electronic properties at the atomic level,both experimentally and computationally.The interactions between the cobalt center and the local coordination environment are regulated by introducing either electron-donating or electron-withdrawing groups on the phthalocyanine ligand,and the spin-orbit splitting of cobalt is increased by~0.15 eV compared with the nonsubstituted ligand.Specifically,the aminated cobalt phthalocyanine-based electrocatalysts exhibit low free energies in the ratedetermining steps of the oxygen reduction(-1.68 eV)and oxygen evolution reactions(0.37 eV).This contributes to the high electrocatalytic activity(e.g.,a halfwave potential of 0.84 V and an overpotential of 0.30 V at 10 mAcm^(-2)),featuring a high selectivity of a four-electron pathway(i.e.,a negligible by-product of hydrogen peroxide).These catalysts also exhibit exceptional kinetic current density(Tafel slope of 100 mV dec^(-1))in oxygen reduction reactions,in addition to a superior power density(158 mWcm^(-2))and a high cycling stability(>1,300 cycles)in Zn-air batteries,outperforming the commercial Pt/C and/or RuO2counterparts.

关键词： interfacial wettability molecular catalysts carbon nanotubes density functional theory electrochemistry

Modelling and Characterization of Basalt/Vinyl Ester/SiC Micro-and Nano-hybrid Biocomposites Properties Using Novel ANN–GA Approach

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journal of Bionic Engineering 2024年第2期21卷 938-952页

作者： Yesudhasan Thooyavan Lakshmi Annamali Kumaraswamidhas Robinson Dhas Edwin Raj.joseph Selvi Binoj Bright Brailson Mansingh Antony Sagai Francis Britto Alamry Ali Department of Mechanical Engineering Indian Institute of Technology Dhanbad(ISM)DhanbadJharkhand826004India Gati Shakti Vishwavidyalaya(GSV-A Central University Funded By GoI in the Ministry of Railways) LalbaugVadodaraGujarat390004India Institute of Mechanical Engineering Saveetha School of EngineeringSaveetha Institute of Medical and Technical Sciences(SIMATS)Saveetha UniversityChennaiTamilnadu602105India Metal joining Research Centre Department of Mechanical EngineeringSri Ramakrishna Engineering CollegeCoimbatoreTamilnadu641022India Department of Mechanical Engineering Rohini College of Engineering and TechnologyPalkulamTamil Nadu629401India Department of Mechanical Engineering College of Engineering in Al-KharjPrince Sattam Bin Abdulaziz University11942Al-KharjSaudi Arabia

Basalt fiber reinforcement in polymer matrix composites is becoming more and more popular because of its environmental friendliness and mechanical qualities that are comparable to those of synthetic fibers.Basalt fiber strengthened vinyl ester matrix polymeric composite with filler addition of nano-and micro-sized silicon carbide(SiC)element spanning from 2 weight percent to 10 weight percent was studied for its mechanical and wear properties.The application of Artificial Neural Network(ANN)to correlate the filler addition composition for optimum mechanical properties is required due to the non-linear mechanical and tribological features of composites.The stuffing blend and composition of the composite are optimized using the hybrid model and Genetic Algorithm(GA)to maximize the mechanical and wear-resistant properties.The predicted and tested ANN–GA optimal values obtained for the composite combination had a tensile,flexural,impact resilience,hardness and wear properties of 202.93 MPa,501.67 MPa,3.460 j/s,43 HV and 0.196 g,respectively,for its optimum combination of filler and reinforcement.It can be noted that the nano-sized SiC filler particle enhances most of the properties of the composite which diversifies its applications.The predicted mechanical and wear values of the developed ANN–GA model were in closer agreement with the experimental values which validate the model.

关键词： Hybrid polymer composite Prediction Process modelling Artificial neural networks Genetic algorithm

Treatment and prevention of epilepsy in onchocerciasis-endemic areas is urgently needed

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Infectious Diseases of Poverty 2024年第1期13卷 85-89页

作者： Robert Colebunders joseph Nelson Siewe Fodjo Olivia Kamoen Luis-jorge Amaral Amber Hadermann Chiara Trevisan Mark j.Taylor julia Gauglitz Achim Hoerauf Yasuaki Sato Katja Polman Maria-Gloria Basanez Dan Bhwana Thomson Lakwo Gasim Abd-Elfarag Sebastien D.Pion Global Health Institute University of AntwerpAntwerpBelgium Department of Neurology Heilig Hart ZiekenhuisLierBelgium Department of Public Health Institute of Tropical MedicineAntwerpBelgium Liverpool School of Tropical Medicine LiverpoolUK Department of Computer Science University of AntwerpAntwerpBelgium Institute of Medical Microbiology Immunology and ParasitologyUniversity Hospital BonnBonnGermany German Center for Infection Research(DZIF) Partner Site Bonn-CologneBonnGermany School of Global Humanities and Social Sciences Nagasaki UniversityNagasakiJapan MRC Centre for Global Infectious Disease Analysis and London Centre for Neglected TropicalDisease Research Department of Infectious Disease EpidemiologySchool of Public HealthImperial College LondonLondonUK National Institute for Medical Research TangaTanzania Vector Control Division Ministry of HealthKampalaUganda School of Public Health University of JubaJubaSouth Sudan Access for Humanity JubaSouth Sudan French National Research Institute for Sustainable Development MontpellierFrance

Background There is increasing epidemiological evidence supporting the association between onchocerciasis and seizures,reinforcing the concept of onchocerciasis-associated epilepsy(OAE).The aim of this paper is to provide an update on the new knowledge about OAE and to propose recommendations to the World Health Organization how to address this public health problem.Main text During the 2nd International Workshop on OAE held on 19-21 September,2023,in Antwerp,Belgium,participants recognised OAE as a substantial yet neglected public health problem,particularly in areas of sub-Saharan Africa where onchocerciasis remains hyperendemic.Evidence from prospective population-based studies suggest that strengthening onchocerciasis elimination efforts leads to a significant reduction of OAE incidence.There is a need to validate an OAE case definition to estimate the burden of disease and identify onchocerciasis-endemic areas requiring intensification of onchocerciasis elimination programmes and integration of epilepsy care t is expected that raising awareness about OAE will boost the population uptake of ivermectin.The implementation of a commu-nity-based epilepsy treatment programme offering free anti-seizure medications(ASMs)has shown high effectiveness in reducing the frequency of seizures and improving the overall quality of life of people with epilepsy.Conclusions To reduce OAE burden,enhanced collaboration between onchocerciasis and mental health pro-grammes at community,national,and international levels is required.Urgent efforts are needed to ensure the uninter-rupted provision of free ASMs in onchocerciasis-endemic areas.Furthermore,OAE should be included in the quantif-cation of the onchocerciasis disease burden.

关键词： Onchocerciasis Morbidity Burden of disease Prevention Ivermectin Epilepsy Nodding syndrome Treatment Children Policy

Ethanol steam reforming over Ni/ZSM-5 nanosheet for hydrogen production

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Chinese journal of Chemical Engineering 2024年第3期67卷 247-256页

作者： Porapak Suriya Shanshan Xu Shengzhe Ding Sarayute Chansai Yilai jiao joseph Hurd Daniel Lee Yuxin Zhang Christopher Hardacre Prasert Reubroycharoen Xiaolei Fan Department of Chemical Engineering School of EngineeringThe University of ManchesterManchester M139PLUnited Kingdom Program of Petrochemistry and Polymer Science Faculty of ScienceChulalongkorn UniversityBangkok10330Thailand Shenyang National Laboratory for Materials Science Institute of Metal ResearchChinese Academy of SciencesShenyang 110016China Liaoning Academy of Materials Shenyang 110167China Center of Excellence in Catalysis for Bioenergy and Renewable Chemicals(CBRC) andDepartment of Chemical TechnologyFaculty of ScienceChulalongkorn UniversityBangkok 10330Thailand Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute University of Nottingham Ningbo ChinaNingbo315100China

Compared to reforming reactions using hydrocarbons,ethanol steam reforming(ESR)is a sustainable alternative for hydrogen(H_(2))production since ethanol can be produced sustainably using biomass.This work explores the catalyst design strategies for preparing the Ni supported on ZSM-5 zeolite catalysts to promote ESR.Specifically,two-dimensional ZSM-5 nanosheet and conventional ZSM-5 crystal were used as the catalyst carriers and two synthesis strategies,i.e.,in situ encapsulation and wet impregnation method,were employed to prepare the catalysts.Based on the comparative characterization of the catalysts and comparative catalytic assessments,it was found that the combination of the in situ encapsulation synthesis and the ZSM-5 nanosheet carrier was the effective strategy to develop catalysts for promoting H_(2) production via ESR due to the improved mass transfer(through the 2-D structure of ZSM-5 nanosheet)and formation of confined small Ni nanoparticles(resulted via the in situ encapsulation synthesis).In addition,the resulting ZSM-5 nanosheet supported Ni catalyst also showed high Ni dispersion and high accessibility to Ni sites by the reactants,being able to improve the activity and stability of catalysts and suppress metal sintering and coking during ESR at high reaction temperatures.Thus,the Ni supported on ZSM-5 nanosheet catalyst prepared by encapsulation showed the stable performance with~88% ethanol conversion and~65% H_(2) yield achieved during a 48-h longevity test at 550-C.

关键词： ZSM-5 nanosheet In situ encapsulation Ni catalyst Ethanol steam reforming Hydrogen production