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mechanism-driven strategies for prevention of rheumatoid arthritis

Rheumatology & Autoimmunity 2022年第3期2卷 109-119页

作者： V.michael Holers Kristine A.Kuhn m.kristen demoruelle Jill m.Norris Gary S.Firestein Eddie A.James William H.Robinson Jane H.Buckner Kevin D.Deane Division of Rheumatology University of Colorado School of MedicineAuroraColoradoUSA Department of Epidemiology Colorado School of Public HealthAuroraColoradoUSA Division of Rheumatology Allergy and ImmunologyUniversity of California San DiegoLa JollaCaliforniaUSA Benaroya Research Institute SeattleWashingtonUSA Division of Immunology and Rheumatology Stanford UniversityStanfordCaliforniaUSA Department of medicine Division of RheumatologyVA Palo Alto Health Care SystemPalo AltoCaliforniaUSA

In seropositive rheumatoid arthritis(RA),the onset of clinically apparent inflammatory arthritis(IA)is typically preceded by a prolonged period of autoimmunity manifest by the presence of circulating autoantibodies that can include antibodies to citrullinated protein antigens(ACPA)and rheumatoid factor.This period before clinical IA can be designated preclinical RA in those individuals who have progressed to a clinical diagnosis of RA,and an“at‐risk”status in those who have not developed IA but exhibit predictive biomarkers of future clinical RA.With the goal of developing RA prevention strategies,studies have characterized immune phenotypes of preclinical RA/at-risk states.From these studies,a model has emerged wherein mucosal inflammation and dysbiosis may lead first to local autoantibody production,which should normally be transient,but instead is followed by a systemic spread of the autoimmunity as manifested by serum autoantibody elevations,ultimately driving the development of clinically identified joint inflammation.This model can be envisioned as the progression of disease development through serial“checkpoints”that in principle should constrain or resolve autoimmunity;however,instead,the checkpoints“fail”and clinical RA develops.Herein we review the immune processes that are likely to be present at each step and the potential therapeutic strategies that could be envisioned to delay,diminish,halt,or even reverse the progression to clinical RA.Notably,these prevention strategies could utilize existing therapies approved for clinical RA,therapies approved for other diseases that target relevant pathways in the preclinical/at-risk state,or approaches that target novel pathways.

关键词： autoimmune disease inflammation mucosa prevention rheumatoid arthritis

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RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation 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 michel kristen Pan Jocelyn Taylor Vivian Szymczuk Brendan Boyce Daniel martin Vardit Kram Rebeca Galisteo Kamran melikov Leonid V.Chernomordik michael T.Collins Alison m.Boyce Skeletal Disorders and mineral Homeostasis Section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Section on membrane Biology Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA metabolic Bone Disorders Unit National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Department of Plastic and Reconstructive Surgery The Johns Hopkins Medical InstitutionsBaltimoreMDUSA Department of Pathology and Laboratory medicine University of Rochester Medical CenterRochesterNYUSA NIDCR Genomics and Computational 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 treatments.Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment strategy.In this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical models.Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition.RNA sequencing of human and mouse tissue supported these findings.The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts.The results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within lesions.These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

关键词： dysplasia treatment finding

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Psychiatric comorbidities 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 madley-Dowd Harriet Forbes Jessica Rast Caichen Zhong Renee m Gardner Christina Dalman kristen Lyal cRAIG Newschaffer Torbjorn Tomson michael Lundberg Daniel Berglind Neil m Davies Brian K Lee Cecilia magnusson Dheeraj Rai Department of Global Public Health Karolinska InstitutetStockholmSweden medical Research Council Integrative Epidemiology Unit Bristol Medical SchoolUniversity of BristolBristolUK Centre for Academic mental Health Population Health SciencesBristol Medical SchoolUniversity of BristolBristolUK Faculty of Epidemiology and Population Health London School of Hygiene and Tropical MedicineLondonUK A.J.Drexel Autism Institute Drexel UniversityPhiladelphiaPAUSA Department of Epidemiology and Biostatistics School of Public HealthDrexel UniversityPhiladelphiaPAUSA College of Health and Human Development Pennsylvania State UniversityState CollegePAUSA Department of Clinical Neuroscience Karolinska InstitutetStockholmSweden Centre for Epidemiology and Community medicine Region StockholmStockholmSweden K.G Jebsen Center for Genetic Epidemiology Department of Public Health and NursingNorwegian University of Science and TechnologyTrondheimNorway Division of Psychiatry University Collge LondonLondonUK Department of Statistical Sciences University Cllge LondonLondonK NIHR Biomedical Research Centre University of BristoBristolUK Avon and Wiltshire Partnership NHS Mental Health TrustBristolUK

Background Psychiatric comorbidities are common in patients with epilepsy.Reasons for the co-occurrence of psychiatric conditions and epilepsy remain poorly understood.Aim We aimed to triangulate the relationship between epilepsy and psychiatric conditions to determine the extent and possible origins of these conditions.methods Using nationwide Swedish health registries,we quantified the lifetime prevalence of psychiatric disorders in patients with epilepsy.We then used summarydata from genome-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 regression.Finally,we assessed the potential bidirectional relationships using two-sample mendelian randomisation.Results In a cohort of 7628495 individuals,we found that almost half of the 94435 individuals diagnosed with epilepsy were also diagnosed with a psychiatric condition in their lifetime(adjusted lifetime prevalence,44.09%;95%confidence interval(Cl)43.78%to 44.39%).We found evidence for a genetic correlation between epilepsy and some neurodevelopmental and psychiatric conditions.For example,we observed a genetic correlation between epilepsy and attention-deficit/hyperactivity disorder(r,=0.18,95%Cl 0.09 to 0.27,pmore pronounced in focal epilepsy(r=0.23,95%CI 0.09 to 0.36,pm mendelian randomisation using common genetic variants did not support bidirectional effects between epilepsy and neurodevelopmental or psychiatric conditions.Conclusions Psychiatric comorbidities are common in patients with epilepsy.Genetic correlations may partially explain some comorbidities;however,there is little evidence of a bidirectional relationship between the genetic liability of epilepsy and psychiatric conditions.These findings highlight the need to understand the role of environmental factors or rare genetic variations in the origins of psychiatric comorbidities in epilepsy.

关键词： epilepsy Psychiat lifetime

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Kidney disease in patients with chronic liver disease:Does sex matter?

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World Journal of Clinical Cases 2023年第17期11卷 3980-3992页

作者： Katherine m Cooper Alessandro Colletta kristen moulton Kenneth m Ralto Deepika Devuni Department of medicine UMass Chan Medical SchoolWorcesterMA 01665United States Department of medicine Division of GastroenterologyUMass Chan Medical SchoolWorcesterMA 01665United States Department of medicine Division of Renal MedicineUMass Chan Medical SchoolWorcesterMA 01665United States

Kidney disease in patients with liver disease is serious and increases mortality.Up to 50%of patients hospitalized experience an episode of acute kidney injury.In general,men with liver disease are thought to be at increased risk of kidney disease.However,this association should be considered with caution because most studies use creatinine-based inclusion criteria,which is negatively biased against women.In this review,we synthesize data on sex differences in kidney disease in patients with chronic liver disease in the clinical setting and discuss potential physiologic underpinnings.

关键词： Sex differences Renal disease Gender disparity Hepatorenal syndrome Renal replacement therapy

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microbiological cultures and antimicrobial prophylaxis in patients undergoing total pancreatectomy with islet cell autotransplantation

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Hepatobiliary & Pancreatic Diseases International 2023年第4期22卷 426-429页

作者： kristen R Szempruch Anne m Lachiewicz Brittney m Williams Aman Kumar Xavier Baldwin Chirag S Desai Pharmacy Department University of North Carolina Medical CenterChapel HillNCUSA Division of Infectious Disease University of North Carolina Medical CenterChapel HillNCUSA Department of Surgery TransplantUniversity of North Carolina Medical CenterChapel HillNCUSA

To the Editor:Total pancreatectomy with islet cell autotransplantation(TPIAT)is a viable treatment option upon failed endoscopic and medical therapy for patients with chronic pancreatitis.This procedure involves surgical removal of the entire pancreas,isolation of islet cells and reinfusion of these cells into the liver via portal vein[1,2].The risk of contamination to the final islet cell product can occur at several stages of the isolation procedure[3].In order to ensure the sterility of the islet cell product,multiple samples from the preservation and cannulation solution,and the final islet cell product are sent for bacterial cultures.Prior studies have found variable clinical consequences of these cultures on infectious com-plications or graft function[3-9].Herein we aimed to determine the incidence of infection in 60 days post-TPIAT and its association with the culture data.

关键词： islet patients viable

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Immediate and long-term effects of invasive plant species on soil characteristics

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Soil Ecology Letters 2022年第3期4卷 276-288页

作者： Irene m.Unger Robert J.Kremer kristen S.Veum Keith W.Goyne Department of Biology and Chemistry Baker UniversityP.O.Box 65Baldwin CityKS 66006USA School of Natural Resources University of missouri 302 ABNR Bldg.ColumbiaMO 65211USA USDA-ARS Cropping Systems and Water Quality UnitUniversity of Missouri302 ABNR Bldg.ColumbiaMO 65211USA Department of Forest Resources and Environmental Conservation Virginia Tech324 Cheatham HallBlacksburgVA 24061USA

Invasive plant species may alter soil characteristics or interact with the soil microbial community resulting in a competitive advantage.Our objectives were to determine:i)if invasive plant species alter soil properties;and ii)the long-term effects of invasive plant species on soil properties and subsequent implications on ecological restoration efforts.We focused on Lespedeza cuneata,a plant that may be allelopathic.Soil samples were collected from four locations in Central missouri,USA:an old-field with abundant L.cuneata,two reconstructed sites,and a remnant prairie that has never been plowed.Soil health indictors were used to characterize soil properties at these sites.Nearly every soil property differed significantly between the unplowed prairie reference site and the other three sites.The reconstructed sites,however,generally did not differ from the invaded old-field.These results indicate that the reconstructed prairies are not fully recovered.Although above-ground traits,such as the plant community structure,appear similar to the prairie,the soil microbial community structure still resembles that of an invaded old-field site.These results indicate that more time may be needed before soil microbial populations fully recover after invasive plant removal.

关键词： Sericea lespedeza Legacy effects Soil microorganisms

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Functional recovery and muscle atrophy in pre-clinical models of peripheral nerve transection and gap-grafting in mice:effects of 4-aminopyridine

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Neural Regeneration Research 2023年第2期18卷 439-444页

作者： Jung Il Lee m A Hassan Talukder Zara Karuman Anagha A.Gurjar Prem Kumar Govindappa Jagadeeshaprasad m.Guddadarangaiah kristen m.manto Grant D.Wandling John P.Hegarty David L.Waning John C.Elfar Department of Orthopaedics and Rehabilitation Center for Orthopaedic Research and Translational ScienceThe Pennsylvania State University College of MedicineHersheyPAUSA Department of Orthopaedic Surgery Korea University Guro HospitalSeoulSouth Korea Department of Cellular and molecular Physiology The Pennsylvania State University College of MedicineHersheyPAUSA

We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0)and 7-mm isografting in 5-mm gap(G-5/7)models in the absence and presence of 4-AP treatment.Following surgery,sciatic functional index was determined wee kly to evaluate the direct in vivo global motor functional recovery.After 12 weeks,nerves were processed for whole-mount immunofluorescence imaging,and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber crosssectional area and minimal Feret's diameter.Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model.4-AP did not affect the sciatic functional index recovery in any model.Compared to STG,nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting.While muscle weight,cross-sectional area,and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7,4-AP treatment significantly increased right TA muscle mass,cross-sectional area,and minimal Feret's diameter in G-7/0 model.These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap,and 4-AP exerts diffe rential effects on functional recove ry and muscle atrophy.

关键词： 4-aminopyridine functional recovery muscle atrophy nerve gap nerve grafting nerve imaging nerve transection

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SWEET as Sugar： New Sucrose Effluxers in Plants

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molecular 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 accumulation of carbohydrates （e.g., sucrose, starch）. This assimilated carbon must 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 complete 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 membranes 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 membranes, are expressed in a subset of phloem parenchyma cells,

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

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Oncogene interactions are required for glioma development and progression as revealed by a tissue specific transgenic mouse model

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

作者： Lynette m. moore kristen m. Holmes Gregory N. Fuller Department of Pathology the University of Texas M. D. Anderson Cancer Center

The aggressive and invasive nature of brain tumors has hampered progress in the design and implementation of efficacious therapies. The recent success of targeted therapies in other tumor types makes this an attractive area for research yet complicating matters is the ability of brain tumors to circumvent the targeted pathways to develop drug resistance. Effective therapies will likely need to target more than one signaling pathway or target multiple nodes within a given pathway. Key to identifying these targets is the elucidation of the driver and passenger molecules within these pathways. Animal models provide a useful tool with many advantages in the study of these pathways. These models provide a means to dissect the critical components of tumorigenesis, as well as serve as agents for preclinical testing. This review focuses on the use of the RCAS/tv-a mouse model of brain tumors and describes their unique ability to provide insight into the role of oncogene cooperation in tumor development 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

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Sucrose transporter2 contributes to maize growth,development,and crop yield

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Journal of Integrative Plant Biology 2017年第6期59卷 390-408页

作者： kristen A.Leach Thu m.Tran Thomas L.Slewinski Robert B.meeley David m.Braun Division of Biological Sciences Interdisciplinary Plant Group Missouri Maize Center University of Missouri Columbia MO 65211 USA Department of Biology Pennsylvania State University University Park PA 16802 USA DuPont Pioneer Research & Development Johnston Iowa 50131 USA

During daylight, plants produce excess photo- synthates, including sucrose, which is temporarily stored in the vacuole. At night, plants remobilize sucrose to sustain metabolism and growth. Based on homology to other sucrose transporter （SUT） proteins, we hypothesized the maize （Zea mays） SUCROSE TRANSPORTER2 （ZmSUT2） protein functions as a sucrose/H^＋ symporter on the vacuolar membrane to export transiently stored sucrose. To understand the biological role of ZmSut2, we examined its spatial and temporal gene expression, determined the protein subcellular localization, and characterized loss-of- function mutations. ZmSut2 mRNA was ubiquitously expressed and exhibited diurnal cycling in transcript abundance. Expressing a translational fusion of ZmSUT2 fused to a red fluorescent protein in maize mesophyll cell protoplasts revealed that the protein localized to the tonoplast. Under field conditions, zmsut2 mutant plants grew slower, possessed smaller tassels and ears, and produced fewer kernels when compared to wild-type siblings, zmsut2 mutants also accumulated two-fold more sucrose, glucose, and fructose as well as starch in source leaves compared to wild type. These findings suggest （i） ZmSUT2 functions to remobilize sucrose out of the vacuole for subsequent use in growing tissues; and （ii） its function provides an important contribution to maize development and agronomic yield.

关键词： William J. Lucas, University of California, Davis, USAReceived Dec. 30, 2016 Accepted Feb. 10, 20171 Online on Feb. 16,2017

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