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Targeted therapy for capillary-venous malformations

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Signal Transduction and Targeted Therapy 2024年第7期9卷 3024-3039页

作者： Lola Zerbib Sophia Ladraa Antoine Fraissenon Charles Bayard Marina Firpion Quitterie Venot Sanela Protic Clément Hoguin Amandine Thomas Sylvie Fraitag Jean-Paul Duong Sophie Kaltenbach Estelle Balducci Coline Lefevre Patrick Villarese Vahid Asnafi Christine Broissand Nicolas Goudin Ivan Nemazanyy Gwennhael Autret Bertrand Tavitian Christophe Legendre Nadia Arzouk Veronique Minard-Colin Caroline Chopinet Michael Dussiot Denise MAdams Tristan Mirault Laurent Guibaud Paul Isenring Guillaume Canaud universitéParis Cité ParisFrance INSErM U1151 Institut Necker-Enfants MaladesParisFrance Service d’Imagerie Pédiatrique Hôpital Femme-Mère-EnfantHCLBronFrance CrEATIS UMr 5220 Villeurbanne 69100France Service de radiologie Mère-Enfant Hôpital NordSaint EtienneFrance Service d’Anatomie pathologique Hôpital Necker-Enfants MaladesAP-HPParisFrance Laboratoire d’Oncohématologie Hôpital Necker-Enfants MaladesAP-HPParisFrance Pharmacie Hôpital Necker-Enfants MaladesAP-HPParisFrance Necker Bio-Image Analysis INSERM US24/CNRS UMS 3633ParisFrance Platform for Metabolic Analyses Structure Fédérative de Recherche NeckerINSERM US24/CNRS UMS 3633ParisFrance Plateforme Imageries du Vivant Universitéde ParisPARCCINSERMParisFrance Service de Néphrologie Transplantation AdultesHôpital Necker-Enfants MaladesAP-HPParisFrance Service de Transplantation Hôpital La PitiéSalpétrièreAP-HPParisFrance depar.ment of Pediatric and Adolescent Oncology INSERM 1015Gustave RoussyUniversitéParis-SaclayVillejuifFrance Service de Physiologie&Explorations Fonctionnelles Cardiovasculaires CHU de LilleLille 59000France INSErM U1163 Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic ImplicationsLaboratoire d’Excellence GR-ExParisFrance Division of Oncology Comprehensive Vascular Anomalies ProgramChildren’s Hospital of PhiladelphiaPhiladelphiaPAUSA Service de Médecine Vasculaire hôpital Européen Georges-PompidouParisFrance Nephrology research Group L’Hôtel-Dieu de Québec Research CenterDepartment of MedicineFaculty of MedicineLaval UniversityQuebecQC G1R2J6Canada unitéde médecine translationnelle et thérapies ciblées Hôpital Necker-Enfants MaladesAP-HPParisFrance CNrS UMr8253 Institut Necker-Enfants MaladesParisFrance

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK,an endothelial transmembrane receptor signaling through *** malformations are associated with pain,bleedings,thrombosis,pulmonary embolism,esthetic deformities and,in severe cases,life-threatening *** authorized medical treatment exists for patients with venous ***,we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient *** showed that these malformations only partially signal through AKT *** compared the efficacy of different drugs,including rapamycin,a mTOrC1 inhibitor,miransertib,an AKT inhibitor and alpelisib,a PI3Kαinhibitor at improving the lesions seen in the mouse *** demonstrated the effectiveness of alpelisib in preventing vascular malformations’occurrence,improving the already established ones,and prolonging *** these findings,we were authorized to treat 25 patients with alpelisib,including 7 children displaying PIK3CA(n=16)or TEK(n=9)-related capillary venous malformations resistant to usual therapies including sirolimus,debulking surgical procedures or percutaneous *** assessed the volume of vascular malformations using magnetic resonance imaging(MrI)for each *** demonstrated improvement in all 25 *** malformations previously considered intractable were reduced and clinical symptoms were *** showed a decrease of 33.4%and 27.8%in the median volume of PIK3CA and TEK malformations respectively,over 6 months on *** conclusion,this study supports PI3Kαinhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.

关键词： PIK3CA malformations venous

Cannabinoids and endocannabinoids as therapeutics for nervous system disorders:preclinical models and clinical studies

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Neural regeneration research 2024年第4期19卷 788-799页

作者： r.Scott Duncan Sean M.riordan Matthew C.Gernon Peter Koulen depar.ment of Ophthalmology School of MedicineUniversity of Missouri depar.ment of Biomedical Sciences School of MedicineUniversity of Missouri

Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human *** have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human *** of these include central nervous system(CNS)diseases and dysfunctions such as forms of epilepsy,multiple sclerosis,Parkinson’s disease,pain and neuropsychiatric *** addition,the endogenously produced cannabinoid lipids,endocannabinoids,are critical for normal CNS function,and if controlled or modified,may represent an additional therapeutic avenue for CNS *** review discusses in vitro cellular,ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS *** addition,the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS *** and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.

关键词： anandamide cannabidiol cannabinoid endocannabinoid epilepsy multiple sclerosis neurodegeneration neuroprotection tetrahydrocannabinol

施肥措施对滇中植烟土壤细菌群落结构和功能的影响

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烟草科技 2024年第7期57卷 65-74页

作者：张晓花温昌焘王克勤宋娅丽杨昕陈炳绅西南林业大学水土保持学院昆明市650224 云南省玉溪市红塔区水土保持工作站云南省玉溪市653100 云南省玉溪市水利局云南省玉溪市653199

为明确施肥措施对植烟土壤细菌群落结构和功能的影响,应用MiSeq高通量测序技术研究了烟田不同施肥措施[不施肥(CK)、有机肥(OM)、有机肥和化肥(OM+NPK)、化肥(NPK)]条件下土壤细菌群落多样性和组成的变化,并结合PICrUSt分析了土壤细菌... 详细信息

为明确施肥措施对植烟土壤细菌群落结构和功能的影响,应用MiSeq高通量测序技术研究了烟田不同施肥措施[不施肥(CK)、有机肥(OM)、有机肥和化肥(OM+NPK)、化肥(NPK)]条件下土壤细菌群落多样性和组成的变化,并结合PICrUSt分析了土壤细菌功能基因相对丰度的变化特征。结果表明:①不同施肥措施条件下土壤细菌群落多样性和丰富度差异不显著;优势菌门主要为变形菌门(Proteobacteria)、酸杆菌门(Acidobacteria)和放线菌门(Actinobacteria),约占总丰度的64.87%~68.51%;3种施肥处理土壤变形菌门、放线菌门的相对丰度均增加,酸杆菌门、绿弯菌门(Chloroflexi)、疣微菌门(Verrucomicrobia)的相对丰度降低。②共获得了6类一级功能和41类二级功能,一级功能中代谢为细菌群落最主要的功能;有机肥与化肥混施可显著降低细菌的膜运输、萜类化合物和聚酮化合物代谢的功能基因相对丰度,翻译、聚糖生物合成和代谢、复制和修复、细胞运动的功能基因相对丰度增加。③土壤细菌群落结构主要受有机碳、全磷、有效磷、碱解氮的影响。其中,碱解氮和有效磷是影响细菌功能的主要因子。因此,不同施肥措施条件对植烟土壤细菌α多样性无显著影响,但能显著改变细菌群落组成,进而影响土壤细菌功能基因的相对丰度。合理调控施肥种类、降低化肥施用比例有助于改善滇中植烟土壤的微生态环境。

关键词：植烟土壤施肥细菌群落细菌功能 PICrUSt分析

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Selenium and Iodine Deficiencies and Selenoprotein Function

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Biomedical and Environmental Sciences 1997年第2期10卷 129-135页

作者： JOHN r. ArTHUr FErGUS NICOL JULIE H. MITCHELL AND GEOFFrEY J. BECKETT(Division Of Biochemical Sciences, rowett research Institute, Bucksburn, Aberdeen AB21 9SB, UK cellular.endocr.nology unit,univer.ity depar.ment of clinical biochemistr., the r.yal in Division of Biochemical Sciences Rowett Research Institute Aberdeen UK.

This paper reviews some recent findings on the interactions between selenium deficiency and iodine deficency. Both micronutrients can control the levels of selenoprotein mrNAs, particularly in the thyroid and brain. When selenium and iodine supplies are limiting the compensatory mechanisms work to minimise adverse effects on thyroid hormone metabolsm and thus neurological developtnent. The mechanisms for regulation of selenoproteins in selenium and iodine deficiency are however very tissue-specific. For example, unlike the brain and thyroid,brown adipose tissue is unable to retain selenoproteins in selenium and iodine deficiency and is therefore at greater risk from injurious effects of the deficiencies.

关键词： gene Selenium and Iodine Deficiencies and Selenoprotein Function

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糖尿病足介入综合诊治临床指南(第九版)

介入放射学杂志 2024年第4期33卷 341-354页

作者：中国糖尿病足细胞与介入治疗技术联盟中国医师协会介入医师分会介入医学与生物工程技术委员会国家放射与治疗临床医学研究中心李茂全不详同济大学附属第十人民医院/同济大学介入血管研究所

糖尿病足作为糖尿病血管病常见并发症之一,具有高发病率、高致残率、高致死率和治愈率低的特点,严重影响糖尿病患者的身心健康和生活品质,却一直缺少统一的规范性治疗方法。中国糖尿病足细胞与介入治疗技术联盟曾于2015年制定了糖尿病... 详细信息

糖尿病足作为糖尿病血管病常见并发症之一,具有高发病率、高致残率、高致死率和治愈率低的特点,严重影响糖尿病患者的身心健康和生活品质,却一直缺少统一的规范性治疗方法。中国糖尿病足细胞与介入治疗技术联盟曾于2015年制定了糖尿病足介入综合诊治临床指南(第一版),在一定程度上填补了国内糖尿病足规范性治疗的空白,对于提高我国糖尿病足治疗水平起到了支撑作用。近10年来,随着诊断标准和治疗方式的更新,以及国内外相关研究的不断深入,联盟组织国内89家单位在第八版的基础上进行新的修订,并颁布第九版指南,以期进一步规范我国糖尿病足临床诊治工作。本指南较第八版主要增加了糖尿病足下肢动脉狭窄或闭塞的腔内治疗原则,强调血管重建优先重建直线血流的原则,至少建立1支能够从股浅动脉起始端到达足部病变部位的直接供血动脉,对于膝下动脉多支病变治疗时建议遵循“先易后难”的重建原则,先处理容易开通的病变动脉,保证至少有1支血管能够供应到足部。同时本版指南介绍了同济大学“五点法皮温”设备在糖尿病足诊治中的巨大应用价值。

关键词：糖尿病足糖尿病介入综合诊治临床指南

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural regeneration research 2025年第3期20卷 725-739页

作者： Benjamin r.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler depar.ment of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Center for Molecular Innovation and Drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam Center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

Spatial analysis of the osteoarthritis microenvironment: techniques, insights, and applications

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Bone research 2024年第1期12卷 1-19页

作者： Xiwei Fan Antonia rujia Sun reuben S.E.Young Isaac O.Afara Brett r.Hamilton Louis Jun Ye Ong ross Crawford Indira Prasadam Centre for Biomedical Technologies Queensland University of TechnologyBrisbaneQLDAustralia School of Mechanical Medical&Process EngineeringQueensland University of TechnologyBrisbaneQLDAustralia Central Analytical research Facility Queensland University of TechnologyBrisbaneQLDAustralia Molecular Horizons University of WollongongWollongongNSWAustralia depar.ment of Technical Physics University of Eastern FinlandKuopioFinland School of Electrical Engineering and Computer Science Faculty of EngineeringArchitecture and Information TechnologyUniversity of QueenslandBrisbaneQLDAustralia Centre for Microscopy and Microanalysis University of QueenslandBrisbaneQLDAustralia The Prince Charles Hospital BrisbaneQLDAustralia

Osteoarthritis(OA)is a debilitating degenerative disease affecting multiple joint tissues,including cartilage,bone,synovium,and adipose *** presents diverse clinical phenotypes and distinct molecular endotypes,including inflammatory,metabolic,mechanical,genetic,and synovial ***,innovative technologies are needed to support the development of effective diagnostic and precision therapeutic *** analysis of bulk OA tissue extracts has limitations due to technical constraints,causing challenges in the differentiation between various physiological and pathological phenotypes in joint *** issue has led to standardization difficulties and hindered the success of clinical *** insights into the spatial variations of the cellular and molecular structures in OA tissues,encompassing DNA,rNA,metabolites,and proteins,as well as their chemical properties,elemental composition,and mechanical attributes,can contribute to a more comprehensive understanding of the disease *** resolved biology enables biologists to investigate cells within the context of their tissue microenvironment,providing a more holistic view of cellular *** advances in innovative spatial biology techniques now allow intact tissue sections to be examined using various-omics lenses,such as genomics,transcriptomics,proteomics,and metabolomics,with spatial *** fusion of approaches provides researchers with critical insights into the molecular composition and functions of the cells and tissues at precise spatial ***,advanced imaging techniques,including high-resolution microscopy,hyperspectral imaging,and mass spectrometry imaging,enable the visualization and analysis of the spatial distribution of biomolecules,cells,and *** these molecular imaging outputs to conventional tissue histology can facilitate a more comprehensive characterization of disease *** review summarizes the rec

关键词： insight Spatial enable

Sustained adenosine release:revealing its impact on osteogenic signalling pathways of human mesenchymal stromal cells

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Engineered Regeneration

Engineered regeneration 2024年第2期5卷 255-268页

作者： Hadi Hajiali Jane McLaren Cristina Gonzalez-García Salah Abdelrazig Dong-Hyun Kim Matthew J.Dalby Manuel Salmerón-Sánchez Felicity r.A.J.rose School of Pharmacy Nottingham Biodiscovery InstituteUniversity of NottinghamNottinghamUK Healthcare Technologies Institute School of Chemical EngineeringUniversity of BirminghamBirminghamUK Centre for the cellular Microenvironment University of GlasgowGlasgowUK Centre for Analytical Bioscience Advanced Materials&Healthcare Technologies DivisionSchool of PharmacyUniversity of NottinghamNottinghamUK Marine Microbiomics Program in BiologyDivision of Science and MathematicsNew York University Abu Dhabi(NYUAD)P.O.Box 129188Abu DhabiUnited Arab Emirates

Non-healing fractures,a global health concern arising from trauma,osteoporosis,and tumours,can lead to severe ***,integral to cellular energy metabolism,gains prominence in bone regeneration via adeno-sine A2 B receptor *** study introduces a controlled-release system for localized adenosine delivery,fostering human mesenchymal stromal cell(hMSC)differentiation into functional bone *** study investi-gates how the ratio of lactic acid to glycolic acid in microparticles can influence adenosine release and explores the downstream effects on gene expression and metabolic profiles of osteogenic differentiation in hMSCs cultured in growth and osteoinductive *** into adenosine-modulated signalling pathways during MSC differenti-ation,with osteogenic factors,provide a comprehensive understanding of the pathways *** gene expression and metabolic profiles unravels adenosine’s regulatory mechanisms in MSC *** adenosine release from microparticles induces mineralization,synergizing with osteogenic media supplements,showcasing the potential of adenosine for treating critical bone defects and metabolic *** study high-lights the efficacy of a polymeric microparticle-based delivery system,offering novel strategies for bone *** adenosine’s roles and associated signalling pathways advances our comprehension of molecular mech-anisms steering bone regeneration,propelling innovative biomaterial,combined with metabolites,approaches for clinical use.

关键词： Adenosine release Osteogenic signalling pathways Human mesenchymal stromal cells Bone regeneration

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 depar.ment of Medicine Division of RheumatologyThe University of Illinois at ChicagoChicagoILUSA depar.ment 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 depar.ment of Biomedical Sciences Humanitas Universityand Humanitas Research HospitalMilanItaly depar.ment 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 ***,Syntenin-1 orchestrates rA FLS and endothelial cell invasion via SDC-1 and/or mTOr *** 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 ***,rA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP *** enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed rA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DrP1 *** 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 *** 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 ***,dysregulation of SDC-1,mTOr,and HIF1αnegated Syntenin-1 inflammatory phenotype in rA explants,while inhibition of HIF1αimpaired synovial angiogenic imprint amplified by *** 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