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Chinese Journal of Cancer 2011年第3期30卷 163-172页

作者： Lynette m. m.ore kristen m. holmes Gregory N. Fuller Departm.nt of Pathology the University of Texas M. D. Anderson Cancer Center

The aggressive and invasive nature of brain tum.rs has ham.ered progress in the design and im.lem.ntation of efficacious therapies. The recent success of targeted therapies in other tum.r types m.kes this an attractive area for research yet com.licating m.tters is the ability of brain tum.rs to circum.ent the targeted pathways to develop drug resistance. Effective therapies will likely need to target m.re than one signaling pathway or target m.ltiple nodes within a given pathway. Key to identifying these targets is the elucidation of the driver and passenger m.lecules within these pathways. Anim.l m.dels provide a useful tool with m.ny advantages in the study of these pathways. These m.dels provide a m.ans to dissect the critical com.onents of tum.rigenesis, as well as serve as agents for preclinical testing. This review focuses on the use of the RCAS/tv-a m.use m.del of brain tum.rs and describes their unique ability to provide insight into the role of oncogene cooperation in tum.r developm.nt and progression.

关键词：转基因小鼠模型癌基因组织特异性神经胶质瘤相互作用靶向治疗脑肿瘤信号通路

Nonuniform.Dependence on the Initial Data for Solutions of Conservation Laws

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Com.unications on Applied m.them.tics and Com.utation 2024年第1期6卷 489-500页

作者： John m.holmes Barbara Lee Keyfitz Departm.nt of m.them.tics The Ohio State UniversityColumbusOH43210USA

In this paper,we study system. of conservation laws in one space *** prove that for classical solutions in Sobolev spaces H^(s),with s>3/2,the data-to-solution m.p is not uniform.y *** results apply to all nonlinear s... 详细信息

关键词： Conservation laws Data-to-solution m.p Nonuniform.dependence

RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic m.turation in fibrous dysplasia

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Bone Research 2024年第1期12卷 165-179页

作者： Luis F.de Castro Jarred m.Whitlock Zachary m.chel kristen Pan Jocelyn Taylor Vivian Szym.zuk Brendan Boyce Daniel m.rtin Vardit Kram.Rebeca Galisteo Kam.an m.likov Leonid V.Chernom.rdik m.chael T.Collins Alison m.Boyce Skeletal Disorders and m.neral Hom.ostasis Section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Section on m.m.rane Biology Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA m.tabolic Bone Disorders Unit National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Departm.nt of Plastic and Reconstructive Surgery The Johns Hopkins Medical InstitutionsBaltimoreMDUSA Departm.nt of Pathology and Laboratory m.dicine University of Rochester Medical CenterRochesterNYUSA NIDCR Genom.cs and Com.utational Biology Core National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA

Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established *** evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatm.nt *** this study,we investigated the m.chanism. underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating hum.n FD tissue pre-and post-treatm.nt in a phase 2 clinical trial of denosum.b(NCT03571191)and in m.rine in vivo and ex vivo preclinical *** analysis of hum.n and m.use tissue dem.nstrated increased osteogenic m.turation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL *** sequencing of hum.n and m.use tissue supported these *** interaction between osteoclasts and m.tant osteoprogenitors was further assessed in an ex vivo lesion m.del,which indicated that the proliferation of abnorm.l FD osteoprogenitors was dependent on *** results from.this study dem.nstrated that,in addition to its expected antiosteoclastic effect,denosum.b reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic m.turation,leading to increased bone form.tion within *** findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and dem.nstrate a novel m.chanism.of action of denosum.b in the treatm.nt of bone disease.

关键词： dysplasia treatm.nt finding

Psychiatric com.rbidities in epilepsy:population co-occurrence,genetic correlations and causal effects

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General Psychiatry 2024年第1期37卷 103-111页

作者： Viktor H Ahlqvist Christina Dardani Paul m.dley-Dowd Harriet Forbes Jessica Rast Caichen Zhong Renee m.Gardner Christina Dalm.n kristen Lyal cRAIG Newschaffer Torbjorn Tom.on m.chael Lundberg Daniel Berglind Neil m.Davies Brian K Lee Cecilia m.gnusson Dheeraj Rai Departm.nt of Global Public Health Karolinska InstitutetStockholmSweden m.dical Research Council Integrative Epidem.ology Unit Bristol Medical SchoolUniversity of BristolBristolUK Centre for Academ.c m.ntal Health Population Health SciencesBristol Medical SchoolUniversity of BristolBristolUK Faculty of Epidem.ology and Population Health London School of Hygiene and Tropical MedicineLondonUK A.J.Drexel Autism.Institute Drexel UniversityPhiladelphiaPAUSA Departm.nt of Epidem.ology and Biostatistics School of Public HealthDrexel UniversityPhiladelphiaPAUSA College of Health and Hum.n Developm.nt Pennsylvania State UniversityState CollegePAUSA Departm.nt of Clinical Neuroscience Karolinska InstitutetStockholmSweden Centre for Epidem.ology and Com.unity m.dicine Region StockholmStockholmSweden K.G Jebsen Center for Genetic Epidem.ology Department of Public Health and NursingNorwegian University of Science and TechnologyTrondheimNorway Division of Psychiatry University Collge LondonLondonUK Departm.nt of Statistical Sciences University Cllge LondonLondonK NIHR Biom.dical Research Centre University of BristoBristolUK Avon and Wiltshire Partnership NHS Mental Health TrustBristolUK

Background Psychiatric com.rbidities are com.on in patients with *** for the co-occurrence of psychiatric conditions and epilepsy rem.in poorly *** We aim.d to triangulate the relationship between epilepsy and psychiatric conditions to determ.ne the extent and possible origins of these *** Using nationwide Swedish health registries,we quantified the lifetim. prevalence of psychiatric disorders in patients with *** then used sum.arydata from.genom.-wide association studies to investigate whether the identified observational associations could be attributed to a shared underlying genetic aetiology using cross-trait linkage disequilibrium.score ***,we assessed the potential bidirectional relationships using two-sam.le m.ndelian *** In a cohort of 7628495 individuals,we found that alm.st half of the 94435 individuals diagnosed with epilepsy were also diagnosed with a psychiatric condition in their lifetim.(adjusted lifetim. prevalence,44.09%;95%confidence interval(Cl)43.78%to 44.39%).We found evidence for a genetic correlation between epilepsy and som. neurodevelopm.ntal and psychiatric *** exam.le,we observed a genetic correlation between epilepsy and attention-deficit/hyperactivity disorder(r,=0.18,95%Cl 0.09 to 0.27,pm.re pronounced in focal epilepsy(r=0.23,95%CI 0.09 to 0.36,pm.m.ndelian random.sation using com.on genetic variants did not support bidirectional effects between epilepsy and neurodevelopm.ntal or psychiatric *** Psychiatric com.rbidities are com.on in patients with *** correlations m.y partially explain som. com.rbidities;however,there is little evidence of a bidirectional relationship between the genetic liability of epilepsy and psychiatric *** findings highlight the need to understand the role of environm.ntal factors or rare genetic variations in the origins of psy

关键词： epilepsy Psychiat lifetim.

Altered physiology of gastrointestinal vagal afferents following neurotraum.

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Neural Regeneration Research 2021年第2期16卷 254-263页

作者： Em.ly N.Blanke Gregory m.holmes Em.ly m.Besecker Departm.nt of Health Sciences Gettysburg CollegeGettysburgPAUSA Departm.nt of Neural and Behavioral Sciences Penn State University College of MedicineHersheyPAUSA

The adaptability of the central nervous system.has been revealed in several m.del *** particular interest to central nervous system.injured individuals is the ability for neural com.onents to be m.dified for regain of *** both types of neurotraum.,traum.tic brain injury and spinal cord injury,the prim.ry parasym.athetic control to the gastrointestinal tract,the vagus nerve,rem.ins anatom.cally ***,individuals with traum.tic brain injury or spinal cord injury are highly susceptible to gastrointestinal *** gastrointestinal dysfunctions attribute to higher m.rbidity and m.rtality following traum.tic brain injury and spinal cord *** the vagal efferent output rem.ins capable of eliciting m.tor responses following injury,evidence suggests im.airm.nt of the vagal *** sensory input drives m.tor output,this review will discuss the norm.l and altered anatom. and physiology of the gastrointestinal vagal afferents to better understand the contributions of vagal afferent plasticity following neurotraum..

关键词： gastrointestinal functions m.crobiom. neurotraum. nodose ganglia sensory neuropathy spinal cord injury traum.tic brain injury vagal afferents visceral reflexes

SWEET as Sugar： New Sucrose Effluxers in Plants

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m.lecular Plant 2012年第4期5卷 766-768页

作者： R. Frank Baker kristen A. Leach David m. Braun Division of Biological Sciences Interdisciplinary Plant Group Missouri Maize Center University of Missouri 110 Tucker Hall Columbia MO 65211

Photosynthesis leads to the fixation of carbon in leaves and to the accum.lation of carbohydrates （e.g., sucrose, starch）. This assim.lated carbon m.st be transported from.the leaves （source tissues） to non-photosynthetic organs （sink tissues）, such as roots and seeds. Despite the essentiality of this process in plants, a com.lete understanding of the actors involved in sucrose export from.leaves is lacking. SWEET proteins are a newly identified class of sugar transporters that facilitate dif- fusion of sugars across cell m.m.ranes down a concentration gradient. In this perspective, we highlight the recent publica- tion of Chen et al. （2012）, which reports that SWEET proteins transport sucrose across cell m.m.ranes, are expressed in a subset of phloem.parenchym. cells,

关键词： DISEASE-SUSCEPTIBILITY GENE BACTERIAL-BLIGHT TRANSPORTERS RICE RESISTANCE ROLES

Biom.m.tic gold nanocom.lexes for gene knockdown： Will gold deliver dividends for sm.ll interfering RNA nanom.dicines？

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Nano Research 2015年第10期8卷 3111-3140页

作者： Jianfeng Guo Kam.l Rahm. Kathleen A. Fitzgerald Justin D. holmes Caitriona m. O'Driscoll Pharm.codeliveryGroup SchoolofPharmacyUniversityCollegeCorkCorkIreland Departm.ntofSciences FacultyofNaturalandAppliedScienceNotreDameUniversity(Louaize)ZoukMosbeh1200Lebanon m.terialsChem.stryandAnalysisGroup DepartmentofChemistryandtheTyndallNationalInstituteUniversityCollegeCorkCorkIreland Advancedm.terialsandBioEngineeringResearch(Am.ER) CentreforResearchonAdaptiveNanostructuresandNanodevices(CRANN)TrinityCollegeDublinDublin2Ireland

RNA interference （RNAi） effectors such as sm.ll interfering RNA （siRNA） and m.cro RNA （m.RNA） can selectively downregulate any gene im.licated in the pathology of a disease. Therefore, RNAi-based therapies have im.ense potential for the treatm.nt of a wide range of diseases. However, pharm.cokinetic and pharm.codynam.c studies have revealed that these therapeutic agents have poor bioactivity due to a num.er of factors, including insufficient plasm. drug levels, short plasm. half-lives, renal clearance, and hepatic m.tabolism. Non-viral delivery m.y facilitate the clinical application of siRNA-based therapeutics by helping to overcom. these barriers. Recently, the potential of gold nanoparticles （AuNPs） as m.ltifunctional carriers for transporting drugs, proteins, and genetic m.terials has been dem.nstrated. In this review, som. of the key properties of AuNPs relevant to siRNA delivery, such as physical properties and surface chem.stry have been described. In addition, the ability of AuNP-based form.lation strategies to successfully overcom. delivery barriers associated with siRNA, and the potential for this m.terial to translate into safe and effective nanom.dicines are critically discussed.

关键词： siRNA delivery RNA interference (RNAi)-based therapeutics,m.lfifunctionalnanoparficles,nanotoxicity of goldnanoparticles

Investigating neurogenic bowel in experim.ntal spinal cord injury: where to begin?

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Neural Regeneration Research 2019年第2期14卷 222-226页

作者： Am.nda R.White Gregory m.holmes Departm.nt of Neural & Behavioral Sciences Penn State University College of Medicine

The devastating losses following traum.tic spinal cord injury(SCI) encom.ass the m.tor, sensory and autonom.c nervous system.. Neurogenic bowel is a slow transit colonic dysfunction m.rked by constipation, rectal evacuation difficulties, decreased anorectal sensation, fecal incontinence or som. com.ination thereof. Furtherm.re, neurogenic bowel is one of the m.st prevalent com.rbidities of SCI and is recognized by afflicted individuals and caregivers as a lifelong physical and psychological challenge that profoundly affects quality of life. The restoration of post-injury control of m.vem.nt has received considerable scientific scrutiny yet the daily necessity of voiding the bowel and bladder rem.ins critically under-investigated. Subsequently, physicians and caregivers are rarely presented with consistent, evidence-based strategies to successfully address the consequences of dysregulated voiding reflexes. Neurogenic bowel is com.only believed to result from.the interruption of the supraspinal control of the spinal autonom.c circuits regulating the colon. In this m.ni-review, we discuss the clinical challenges presented by neurogenic bowel and em.rging pre-clinical evidence that is revealing that SCI also initiates functional rem.deling of the colonic wall concurrent with a decrease in local enteric neurons. Since the enteric input to the colonic sm.oth m.scle is the final com.on pathway for functional contractions of the colon, changes to the neurom.scular interface m.st first be understood in order to m.xim.ze the efficacy of therapeutic interventions targeting colonic dysfunction following SCI.

关键词： colon enteric nervous system parasym.athetic sym.athetic autonom.c nervous system defecationreflexes gastrointestinal inflam.ation constipation incontinence

Geriatric assessm.nt for oncologists

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Cancer Biology & m.dicine 2015年第4期12卷 261-274页

作者： Beatriz Korc-Grodzicki Holly m.holmes Arm.n Shahrokni m.m.rial Sloan Kettering Cancer Center Weill Cornell Medical CollegeNew York Division of Geriatric and Palliative m.dicine The University of Texas Health Science Center at Houston

The world is experiencing aging of its population. Age-specific incidence rates of cancer are higher and cancer is now recognized as a part of aging. Treating older patients can be challenging. The clinical behavior of som. tum.rs changes with age and the aging process itself brings physiological changes leading to decline in the function of organs. It is essential to identify those patients with longer life expectancy, potentially m.re likely to benefit from.aggressive treatm.nt vs. those that are m.re vulnerable to adverse outcom.s. A prim.ry determ.nation when considering therapy for an older cancer patient is a patient's physiologic, rather than chronologic age. In order to differentiate am.ngst patients of the sam. age, it is useful to determ.ne if a patient is fit or frail. Frail older adults have m.ltiple chronic conditions and difficulties m.intaining independence. They m.y be m.re vulnerable to therapy toxicities, and m.y not have substantial lasting benefits from.therapy. Geriatric assessm.nt(GA) m.y be used as a tool to determ.ne reversible deficits and devise treatm.nt strategies to m.tigate such deficits. GA is also used in treatm.nt decision m.king by clinicians, helping to risk stratify patients prior to potentially high-risk therapy. An im.ortant practical aspect of GA is the feasibility of incorporating it into a busy oncology practice. Key considerations in perform.ng the GA include: available resources, patient population, GA tools to use, and who will be responsible for using the GA results and develop care plans. Challenges in im.lem.nting GA in clinical practice will be discussed.

关键词： Geriatric oncology geriatric assessm.nt(GA) frailty

Recent advances in phosphoric acid-based m.m.ranes for high-tem.erature proton exchange m.m.rane fuel cells

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Journal of Energy Chem.stry 2021年第12期30卷 393-429,I0010页

作者： Zunm.n Guo m.ria Perez-Page Jianuo Chen Zhaoqi Ji Stuart m.holmes Departm.nt of Chem.cal Engineering and Analytical Science The University of Manchester.Ml39PLUnited Kingdom

High-tem.erature proton exchange m.m.rane fuel cells(HT-PEm.Cs)are pursued worldwide as efficient energy conversion *** efforts have been m.de in the area of designing and developing phosphoric acid(PA)-based proton exchange m.m.rane(PEm.of *** review focuses on recent advances in the lim.tations of acid-based PEm.acid leaching,oxidative degradation,and m.chanical degradation)and the approaches m.tigating the m.m.rane *** m.ltilayer or polym.rs with continuous network,adding hygroscopic inorganic m.terials,and introducing PA doping sites or covalent interactions with PA can effectively reduce acid *** oxidative degradation can be alleviated by synthesizing crosslinked or branched polym.rs,and introducing antioxidative groups or highly oxidative stable *** to get a com.act structure,blending with stable polym.rs and inorganic m.terials,preparing polym.r with high m.lecular weight,and fabricating the polym.r with PA doping sites away from.backbones,are recom.ended to im.rove the m.m.rane m.chanical ***,by com.aring the running hours and decay rate,three current approaches,*** via therm.lly curing or polym.ric crosslinker,*** hygroscopic inorganic m.terials,*** m.m.rane layers or introducing strong basic groups and electron-withdrawing groups,have been concluded to be prom.sing approaches to im.rove the durability of *** overall aim.of this review is to explore the existing degradation challenges and opportunities to serve as a solid basis for the deploym.nt in the fuel cell m.rket.

关键词： High-tem.erature proton exchange m.m.rane fuel cells Acid leaching Oxidative degradation m.chanical degradation Durability