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DNA-delivered monoclonal antibodies targeting the p53 R175H mutant epitope inhibit tumor development in mice

Genes & Diseases 2024年第4期11卷 368-380页

作者： Dafei Chai Xu Wang Praveen Neeli Shan Zhou Xingfang Yu Kanaga Sabapathy Yong Li Department of medicine Section of Epidemiology and Population SciencesDan L Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTX 77030USA Division of Cellular&Molecular research Humphrey Oei Institute of Cancer ResearchNational Cancer Centre SingaporeSingapore 168583Singapore

tThe tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense ***,there are currently no approved targeted therapies or immunotherapies against mutant ***,we characterized and inves-tigated a monoclonal antibody(mAb)that recognizes the mutant p53-R175H for its affinity,specificity,and activity against tumor cells in *** then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic *** results showed that the anti-R175H mAb specifically bound to the p53-R175H an-tigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells,with no cross-reactivity with wild-type *** cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular *** made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 *** vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in *** administration of the anti-R175H BsAb plasmid showed no therapeutic effects,yet potent anti-tumor activity was observed in combination with the anti-PD-1 *** results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.

关键词： BsAb Cytotoxicity mAb Mutant p53 PD-1 R175H

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Promising use of metformin in treating neurological disorders:biomarker-guided therapies

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Neural Regeneration research 2024年第5期19卷 1045-1055页

作者： Allison Loan Charvi Syal Margarita Lui Ling He Jing Wang Regenerative medicine program Ottawa Hospital Research InstituteOttawaONCanada Department of Biology Faculty of ScienceUniversity of OttawaOttawaONCanada Department of Pediatrics and medicine Johns Hopkins Medical SchoolBaltimoreMDUSA Department of Cellular and Molecular medicine Faculty of MedicineUniversity of OttawaOttawaONCanada University of Ottawa Brain and Mind research Institute OttawaONCanada

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available *** most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy ***,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological *** that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological *** molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted *** this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

关键词： Alzheimer’s disease Huntington’s disease metformin mitochondrial perturbation multiple sclerosis neural degenerative diseases Parkinson’s disease stroke targeted therapy

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Interleukins in Epilepsy:Friend or Foe

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Neuroscience Bulletin 2024年第5期40卷 635-657页

作者： Yuan Dong Xia Zhang Ying Wang Neuropsychiatry research Institute The Affiliated Hospital of Qingdao UniversityQingdao UniversityQingdao266000China program in Cellular and Molecular medicine Boston Children’s HospitalBostonMA02115USA

Epilepsy is a chronic neurological disorder with recurrent unprovoked seizures,affecting~65 million *** in patients with epilepsy and animal models suggests a contribution of neuroinflammation to epileptogenesis and the development of ***(ILs),as one of the major contributors to neuroinflammation,are intensively studied for their association and modulatory effects on ictogenesis and *** are commonly divided into pro-and anti-inflammatory cytokines and therefore are expected to be pathogenic or neuroprotective in ***,both protective and destructive effects have been reported for many *** may be due to the complex nature of ILs,and also possibly due to the different disease courses that those ILs are involved *** this review,we summarize the contributions of different ILs in those processes and provide a current overview of recent research advances,as well as preclinical and clinical studies targeting ILs in the treatment of epilepsy.

关键词： Epilepsy Interleukins Neuroinflammation

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Molecular characterization and structure basis of a malonyltransferase with both substrate promiscuity and catalytic regiospecificity from Cistanche tubulosa

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2333-2348页

作者： Xiao Liu Yuyu Liu Xiping Xu Wenqian Huang Yaru Yan Yingxia Wang Weisheng Tian Ting Mo Xiaoxue Cui Jun Li She-Po Shi Pengfei Tu Modern research Center for Traditional Chinese medicine Beijing Research Institute of Chinese MedicineBeijing University of Chinese MedicineBeijing 100029China Modern research Center for Traditional Chinese medicine School of Chinese Materia MedicaBeijing University of Chinese MedicineBeijing 100029China

Enzymatic malonylation of natural glycosides provides a promising alternative method for drug-like malonylated glycosides ***,the catalytic potential and structural basis of plant malonyltransferase are far from being fully *** work identified a new malonyltransferase CtMaT1 from Cistanche *** displayed unprecedented mono-and/or di-malonylation activity toward diverse glucosides with different aglycons.A“one-pot”system by CtMaT1 and a malonyl-CoA synthetase was established to biosynthesize nine new malonylated *** investigations revealed that CtMaT1 possesses an adequately spacious acyl-acceptor pocket capable of accommodating diverse ***,it recognizes malonyl-CoA through strong electrotactic and hydrogen ***/MM calculation revealed the H167-mediated SN2 reaction mechanism of CtMaT1,while dynamic simulations detected the formation of stable hydrogen bonds between the glucose-6-OH group and H167,resulting in its high malonylation *** energy profiles of two isomeric glycosides highlighted lower reaction energy barriers towards glucoside substrates,emphasizing CtMaT1's preference for ***,a mutant CtMaT1H36A with notably increased di-malonylation activity was *** underlying molecular mechanism was illuminated through MM/GBSA binding free energy *** study significantly advances the understanding of plant acyltransferases from both functional and protein structural perspectives,while also providing a versatile tool for enzymatic malonylation applications in pharmacology.

关键词： Plant acyltransferase Malonyltransferase Malonylated glycosides Enzymatic catalysis Enzyme promiscuity

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Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease:beyond the role of amyloid beta

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Neural Regeneration research 2024年第1期19卷 80-83页

作者： Madia Lozupone Francesco Panza Neurodegenerative Disease Unit Department of Basic MedicineNeuroscienceand Sense OrgansUniversity of Bari Aldo MoroBariItaly Unit of research Methodology and Data Sciences for population Health National Institute of Gastroenterology“Saverio de Bellis”Research HospitalCastellana GrotteBariItaly

The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully *** exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid ***,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and *** role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural *** E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta *** exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial *** with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and ***,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease *** objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical *** genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its *** only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid *** rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucid

关键词： Alzheimer's disease amyloid-beta apolipoprotein E dementia glymphatic transport lipids neuropsychiatric symptoms neurovascular unit tau protein

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Machine learning applications in stroke medicine:advancements,challenges,and future prospectives

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Neural Regeneration research 2024年第4期19卷 769-773页

作者： Mario Daidone Sergio Ferrantelli Antonino Tuttolomondo Internal medicine and Stroke Care Ward Department of Health PromotionMother and Child CareInternal Medicine and Medical SpecialtiesUniversity of Palermo Molecular and Clinical medicine PhD program University of Palermo

Stroke is a leading cause of disability and mortality worldwide,necessitating the development of advanced technologies to improve its diagnosis,treatment,and patient *** recent years,machine learning techniques have emerged as promising tools in stroke medicine,enabling efficient analysis of large-scale datasets and facilitating personalized and precision medicine *** abstract provides a comprehensive overview of machine learning’s applications,challenges,and future directions in stroke *** introduced machine learning algorithms have been extensively employed in all the fields of stroke *** learning models have demonstrated remarkable accuracy in imaging analysis,diagnosing stroke subtypes,risk stratifications,guiding medical treatment,and predicting patient *** the tremendous potential of machine learning in stroke medicine,several challenges must be *** include the need for standardized and interoperable data collection,robust model validation and generalization,and the ethical considerations surrounding privacy and *** addition,integrating machine learning models into clinical workflows and establishing regulatory frameworks are critical for ensuring their widespread adoption and impact in routine stroke *** learning promises to revolutionize stroke medicine by enabling precise diagnosis,tailored treatment selection,and improved *** research and collaboration among clinicians,researchers,and technologists are essential for overcoming challenges and realizing the full potential of machine learning in stroke care,ultimately leading to enhanced patient outcomes and quality of *** review aims to summarize all the current implications of machine learning in stroke diagnosis,treatment,and prognostic *** the same time,another purpose of this paper is to explore all the future perspectives these techniques can provide in combating this disabling dis

关键词： cerebrovascular disease deep learning machine learning reinforcement learning stroke stroke therapy supervised learning unsupervised learning

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Increased number of symptoms during the acute phase of SARS-CoV-2 infection in athletes is associated with prolonged time to return to full sports performance—AWAREⅧ

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Journal of Sport and Health Science 2024年第3期13卷 280-287,I0001页

作者： Carolette Snyders Marlise Dyer Nicola Sewry Esme Jordaan Martin Schwellnus Sport Exercise Medicine and Lifestyle Institute(SEMLI)Faculty of Health SciencesUniversity of PretoriaPretoria 0083South Africa Section Sports medicine Faculty of Health SciencesUniversity of PretoriaPretoria 0083South Africa IOC research Centre of South Africa Pretoria 0083South Africa Biostatistics Unit South African Medical Research CouncilTygerberg 7505South Africa Statistics and population Studies Department University of the Western CapeCape Town 7535South Africa

Purpose The aim of the study was to identify factors associated with prolonged time to return to full performance(RTFP)in athletes with recent severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)*** Prospective cohort study with cross sectional analysis.A total of 84 athletes with confirmed SARS-CoV-2 infection assessed at a coronavirus disease 2019 recovery clinic gave a history of age,sex,type/level of sport,co-morbidities,pre-infection training hours,and 26 acute SARS-CoV-2 symptoms from 3 categories(“nose and throat”,“chest and neck”,and“whole body”/systemic).Data on days to RTFP were obtained by structured *** associated with RTFP were demographics,sport participation,history of co-morbidities,pre-infection training history,and acute symptoms(type,number).Outcomes were:(a)days to RTFP(median,interquartile range(IQR))in asymptomatic(n=7)and symptomatic athletes(n=77),and(b)hazard ratios(HRs;95%confidence interval)for symptomatic athletes with *** a factor(univariate,multiple models).HR0.05).Factors associated with prolonged RTFP(univariate models)were:females(HR=0.57;p=0.014),endurance athletes(HR=0.41;p<0.0001),co-morbidity number(HR=0.75;p=0.001),and respiratory disease history(HR=0.54;p=0.026).In symptomatic athletes,prolonged RTFP(multiple models)was significantly associated with increased“chest and neck”(HR=0.85;p=0.017)and“nose and throat”(HR=0.84;p=0.013)symptoms,but the association was more profound between prolonged RFTP and increased total number of“all symptoms”(HR=0.91;p=0.001)and“whole body”/systemic(HR=0.82;p=0.007)*** A larger number of total symptoms and specifically“whole body”/systemic symptoms during the acute phase of SARS-CoV-2 infection in athletes is associated with prolonged RTFP.

关键词： Athletes COVID-19 Performance Recovery Return to play

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Nurses'critical thinking disposition and professional commitment:a cross-sectional study

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Frontiers of Nursing 2024年第1期11卷 119-126页

作者： Mahtab Allah Tavakoli Golnaz Foroughameri Jamileh Farokhzadian Sedigheh Khodabandeh Shahraki Nursing research Center Kerman University of Medical SciencesKerman ***Iran Reproductive Health Family and Population Research CenterKerman University of Medical SciencesKerman ***Iran

Objective:High-quality and successful nursing care delivery in a variety of situations requires critical thinking training and professional *** present study aimed to investigate critical thinking disposition,professional commitment,and the relationship between these 2 variables among ***:As a result of stratified random sampling,201 nurses were enrolled in the present cross-sectional *** were gathered using a socio-demographic form,the Critical Thinking Disposition Inventory(CTDI),and the Nurses'Professional Commitment Scale(NPCS).Results:Although the critical thinking disposition scores were at a moderate level(115.70±13.55),the mean score for professional commitment was high(91.37±11.77).A positive correlation was found between critical thinking disposition and professional commitment(r=0.67,P=0.001).Conclusions:Nursing managers are urged to employ strategies to enhance nurses'critical thinking disposition and professional commitment.

关键词： critical thinking nursing education professional commitment skills strategies

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RoBGP:A Chinese Nested Biomedical Named Entity Recognition Model Based on RoBERTa and Global Pointer

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Computers, Materials & Continua 2024年第3期78卷 3603-3618页

作者： Xiaohui Cui Chao Song Dongmei Li Xiaolong Qu Jiao Long Yu Yang Hanchao Zhang School of Information Science and Technology Beijing Forestry UniversityBeijing100083China Engineering research Center for Forestry-Oriented Intelligent Information Processing of National Forestry and Grassland Administration Beijing100083China Division of Biostatistics Department of Population HealthGrossman School of MedicineNew York UniversityNew York10016USA

Named Entity Recognition(NER)stands as a fundamental task within the field of biomedical text mining,aiming to extract specific types of entities such as genes,proteins,and diseases from complex biomedical texts and categorize them into predefined entity *** process can provide basic support for the automatic construction of knowledge *** contrast to general texts,biomedical texts frequently contain numerous nested entities and local dependencies among these entities,presenting significant challenges to prevailing NER *** address these issues,we propose a novel Chinese nested biomedical NER model based on RoBERTa and Global Pointer(RoBGP).Our model initially utilizes the RoBERTa-wwm-ext-large pretrained language model to dynamically generate word-level initial *** then incorporates a Bidirectional Long Short-Term Memory network for capturing bidirectional semantic information,effectively addressing the issue of long-distance ***,the Global Pointer model is employed to comprehensively recognize all nested entities in the *** conduct extensive experiments on the Chinese medical dataset CMeEE and the results demonstrate the superior performance of RoBGP over several baseline *** research confirms the effectiveness of RoBGP in Chinese biomedical NER,providing reliable technical support for biomedical information extraction and knowledge base construction.

关键词： Biomedicine knowledge base named entity recognition pretrained language model global pointer

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Understanding the spectrum of non-motor symptoms in multiple sclerosis:insights from animal models

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Neural Regeneration research 2024年第1期19卷 84-91页

作者： Poornima D.E.Weerasinghe-Mudiyanselage Joong-Sun Kim Taekyun Shin Changjong Moon Department of Veterinary Anatomy and Animal Behavior College of Veterinary Medicine and BK21 FOUR programChonnam National UniversityGwangjuRepublic of Korea Department of Veterinary Anatomy College of Veterinary Medicine and Veterinary Medical Research InstituteJeju National UniversityJejuRepublic of Korea

Multiple sclerosis is a chronic autoimmune disease of the central nervous system and is generally considered to be a non-traumatic,physically debilitating neurological *** addition to experiencing motor disability,patients with multiple sclerosis also experience a variety of nonmotor symptoms,including cognitive deficits,anxiety,depression,sensory impairments,and ***,the pathogenesis and treatment of such non-motor symptoms in multiple scle rosis are still under *** studies for multiple sclerosis benefit from the use of disease-appropriate animal models,including experimental autoimmune *** to understanding the pathophysiology and developing treatments for non-motor symptoms,it is critical to chara cterize the animal model in terms of its ability to replicate certain non-motor features of multiple *** such,no single animal model can mimic the entire spectrum of *** review focuses on the non-motor symptoms that have been investigated in animal models of multiple sclerosis as well as possible underlying ***,we highlighted gaps in the literature to explain the nonmotor aspects of multiple sclerosis in expe rimental animal models,which will serve as the basis for future studies.

关键词： anxiety cognitive deficit depression experimental autoimmune encephalomyelitis motor disability neurological disorder pain pathophysiology preclinical study sensory impairments

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