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Targeting α-synuclein by PD03 AFFITOPE■ and Anle 138b rescues neurodegenerative pathology in a model of multiple system atrophy:clinical relevance

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Translational Neurodegeneration 2020年第3期9卷 484-497页

作者： Miguel Lemos Serena Venezia Violetta Refolo Antonio Heras-Gavin Sabine Schmidhuber Armin Giese Andrei Leonov Sergey Ryazanov Christian Griesinger Gergana Galabova Guenther Safer Gregor karl Wenning Nadia Stefanova Division of Neurobiology Department of NeurologyInnsbruck Medical University6020 InnsbruckAustria AFFIRIS AG ViennaAustria Center for Neuropathology and Prion Research Ludwig-Maximilians-UniversityMunichGermany Max Planck Institute for Biophysical Chemistry GottingenGermany Present Address:Origenis GmbH MunichGermany

Background:Misfolded oligomeric α-synuclein plays a pivotal role in the pathogenesis of a-synucleinopathies including Parkinson's disease and multiple system atrophy,and its detection parallels activation of microglia and a loss of neurons in the substantia nigra pars *** we aimed to analyze the therapeutic efficacy of PD03,a new AFFITOPE■ immunotherapy approach,either alone or in combination with Anle138b,in a PLP-α-syn mouse ***:The PLP-α-syn mice were treated with PD03 immunotherapy,Anle138b,or a combination of *** months after study initiation,the mice underwent behavioral testing and were sacrificed for neuropathological *** treatment groups were compared to the vehicle group with regard to motor performance,nigral neuronal loss,microglial activation and α-synuclein ***:The PLP-α-syn mice receiving the PD03 or Anle138b single therapy showed improvement of gait deficits and preservation of nigral dopaminergic neurons associated with the reduced α-synuclein oligomer levels and decreased microglial *** combined therapy with Anle138b and PD03 resulted in lower lgG binding in the brain as compared to the single immunotherapy with ***:PD03 and Anle138b can selectively target oligomeric α-synuclein,resulting in attenuation of neurodegeneration in the PLP-α-syn *** approaches are potential therapies that should be developed further for disease modification in α-synucleinopathies.

关键词： α-Synuclein Immunotherapy Oligomer modulation Target engagement Substantia nigra Microglia

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Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia

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Genes & Diseases 2024年第1期11卷 413-429页

作者： Dongsheng Zhang Wenjuan Tang Haitao Niu William Tse Hai-Bin Ruan Helmut Dolznig Thomas Knosel Friedrich karl-Heinz Madeleine Themanns Jiang Wang Mingquan Song Lee Denson Lukas Kenner Richard Moriggl Yi Zheng Xiaonan Han Division of Hematology and Oncology Division of Cancer BiologyDepartment of MedicineMetroHealth Medical Center(MHMC)Case Western Reserve University(CWRU)School of MedicineClevelandOH 44109USA Cancer Genomics and Epigenomics Program Case Comprehensive Cancer CenterCase Western Reserve University(CWRU)ClevelandOH 44106USA Division of Gastroenterology Hepatology and NutritionCincinnati Children’s Hospital Medical Center(CCHMC)CincinnatiOH 45229USA Children’s Hospital of Fudan University Shanghai 201102China School of Medicine Jinan UniversityGuangzhouGuangdong 510632China Laboratory Animal Science(ILAS) Chinese Academy of Medical Science(CAMS)and Peking Union Medical College(PUMC)Beijing 100006China Department of Integrative Biology and Physiology University of Minnesota Medical SchoolMinneapolisMI 55455USA Institute of Medical Genetics Medical University of ViennaVienna 1040Austria Institute of Pathology Ludwig-Maximilians-University MunichMunich 80539Germany Institute of Biochemistry II University Hospital JenaJena 07743Germany Laboratory Animal Pathology University of Veterinary Medicine ViennaVienna 1210Austria Department of Pathology University of CincinnatiCincinnatiOH 45221USA Department of Gastroenterology The Affiliated Hospital of Qingdao UniversityQingdaoShandong 266005China Department of Pathology Medical University of ViennaVienna 1040Austria ludwig Boltzmann Institute for Cancer Research Vienna 1090Austria Medical University of Vienna Vienna 1040Austria Institute of Animal Breeding and Genetics University of Veterinary Medicine ViennaVienna 1210Austria Division of Experimental Hematology CCHMCCincinnatiOH 45229USA

CDC42 controls intestinal epithelial(IEC)stem cell(IESC)*** aberrant CDC42 initiates intestinal inflammation or neoplasia is *** utilized models of inflam-matory bowel diseases(IBD),colorectal cancer,aging,and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and *** specimens were collected to determine the levels of CDC42 in IBD or colorectal ***42 floxed mice were crossed with Villin-Cre,Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2,or Bmi1-CreERT2 mice to generate Cdc42 deficient ***,colitis,aging,and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation,IESC/progenitor regenerative capacity,and IEC *** studies revealed that increased CDC42 in colorectal cancer correlated with lower survival;in contrast,lower levels of CDC42 were found in the inflamed IBD *** Cdc42 depletion significantly reduced Lgr5+IEsCs,increased progenitors'hyperplasia,and induced mucosal inflammation,which led to crypt *** Cdc42 depletion markedly enhanced irra-diation-or chemical-induced *** or inhibition of Cdc42 reduced colonic Lgr5+IESC *** conclusion,depletion of Cdc42 reduces the IESC regeneration and IEC repair,leading to prolonged mucosal *** monogenic loss of Cdc42 in-duces mucosal inflammation,which could result in intestinal neoplasia in the context of aging.

关键词： Cell divisioncycle 42(CDC42) Colitis Colorectal cancer(CRC) Inflammatory bowel diseases(IBD) Intestinal epithelial cell(IEC) Intestinal epithelial stem cell(IESC) Irradiation

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Costs and cost-effectiveness of HIV early infant diagnosis in low- and middle-income countries: a scoping review

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Infectious Diseases of Poverty 2022年第4期11卷 9-28页

作者： Kira Elsbernd karl MFEmmert-Fees Amanda Erbe Veronica Ottobrino Arne Kroid Till Barnighausen Benjamin P Geisler Stefan Kohler Division of Infectious Diseases and Tropical Medicine Faculty of MedicineLudwig Maximilians UniversityMunichGermany Institute for Medical Information Processing Biometryand Epidemiology(IBE)Faculty of Medicine Ludwig Maximilian UniversityMunichGermany Department of Sports and Health Sciences Technical University of MunichMunichGermany Institute of Health Economics and Health Care Management Helmholtz Zentrum MunchenMunichGermany Heidelberg Institute of Global Health Heidelberg UniversityHeidelbergGermany Department of Health Management and Health Economics University of OsloOsloNorway German Center for Infection Research(DZiF) Partner SiteMunichGermany Massachusetts General Hospital/Harvard Medical School BostonMAUSA Institute of Social Medicine Epidemiology and HealthEconomicsCharite-Universitatsmedizin BerlinBerlinGermany

Background:Continuing progress in the global pediatric human immunodeficiency virus(HIV)response depends on timely identification and care of infants with *** countries scale-out improvements to HIV early infant diagnosis(EID),economic evaluations are needed to inform program design and *** scoping review aimed to summarize the available evidence and discuss practical implications of cost and cost-effectiveness analyses of HIV ***:We systematically searched bibliographic databases(Embase,MEDLINE and EconLit)and grey literature for economic analyses of HIV EID in low-and middle-income countries published between January 2008 and June *** extracted data on unit costs,cost savings,and incremental cost-effectiveness ratios as well as outcomes related to health and the HIV EID care process and summarized results in narrative and tabular *** converted unit costs to 2021 USD for easier comparison of costs across ***:After title and abstract screening of 1278 records and full-text review of 99 records,we included 29 studies:17 cost analyses and 12 model-based cost-effectiveness *** costs were 21.46-51.80 USD for point-of-care EID tests and 16.21-42.73 USD for laboratory-based EID *** cost-effectiveness analyses stated at least one of the interventions evaluated to be *** studies reported costs of EID testing strategies;however,few studies assessed the same intervention or reported costs in the same way,making comparison of costs across studies *** data availability of context-appropriate costs and outcomes of children with HIV as well as structural heterogeneity of cost-effectiveness modelling studies limits generalizability of economic analyses of HIV ***:The available cost and cost-effectiveness evidence for EID of HIV,while not directly comparable across studies,covers a broad range of interventions and suggests most interventions designed to improve EID are cost

关键词： Cost effectiveness Diagnostics Low-and middle-income countries Point of care Early infant diagnosis Health systems

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Mycophenolic Acid Absorption Profiles in Patients with Kidney or Combined Pancreas-Kidney Transplantation

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Open Journal of Nephrology 2012年第4期2卷 116-122页

作者： Jan M. Fertmann Helmut P. Arbogast Wolf-D. Illner Walter Land karl-W. Jauch Johannes N. Hoffmann Department of Surgery Klinikum Grosshadern Ludwig-Maximilians University of Munich Munich Germany Department of Surgery Klinikum Grosshadern Ludwig-Maximilians University of Munich Munich Germany Department of Surgery University of Duisburg-Essen Duisburg and Essen Germany

Background: Mycophenolate Mofetil (MMF) is widely used in organ transplant patients to avoid calcineurine inhibittor-associated side effects. Therapeutic monitoring of MMF is up to now perform by using trough level measurements (measurements before drug administration). The present study was designed to characterize potential differences in MMF absorption kinetics between patients with allogenic kidney transplantation [kidney Tx] and simultaneous pancreas kidney transplantation [PK Tx], which might for example occur due to diabetic gastrointestinal atony. Methods: A total of 64 pharmacokinetic profiles were prospectively studied in 44 adult kidney Tx and 20 PK Tx patients. To calculate AUC by the trapezoidal rule, mycophenolic acid (MPA) levels were measured in EDTA-plasma by an EMIT assay at 0, 0.5, 1, 2, 3, 4 6, and 12h after oral MMF administration between postoperative day 14 to 28 instable patients. Results: Substantial differences between kidney Tx and PK Tx patients were evident concerning: donor age, recipient age, number of mismatches, and kidney function (serum creatinine). Despite these dissimilarities pharmacokinetic absorption profiles did not significantly differ between patient groups as measured by AUC, C2, maximum MPA concentration (Cmax), and time until maximum absorption (Tmax). Astonishingly, concomitant cyclosporine and tacrolimus medication did not influence adsorption profiles. Only MPA concentrations 6h post administration correlated closely with AUC in both patient groups, whereas trough levels failed to be predictive for AUC. Conclusions: In our study population, MMF absorption kinetics did not differ between kidney and PK Tx patients and did not seem influenced by concomitant immunosuppressive medication. Therefore, MPA measurements during the absorption phase could be useful to better estimate AUC in patients with kidney Tx and PK Tx.

关键词： Mycophenolate Mofetil Mycophenolic Acid Pharmacokinetics Kidney Transplantation Pancreas-Kidney Transplantation

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Cell:新分子或可有效清除肝脏和血液中的脂肪

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现代生物医学进展 2017年第4期17卷 I0004-I0004页

作者： Brian Finan Christoffer Clemmensen Zhimeng Zhu Kerstin Stemmer Karine Gauthier Luisa M uuml ller Meri De Angelis Kristin Moreth Frauke Neff Diego Perez-Tilve Katrin Fischer Dominik Lutter Miguel A. S aacute nchez-Garrido Peng Liu Jan Tuckermann Mohsen Malehmir Marc E. Healy Achim Weber Mathias Heikenwalder Martin Jastroch Maximilian Kleinert Sigrid Jall Sara Brandt Fr eacute d eacute ric Flamant karl-Werner Schramm Heike Biebermann Yvonne D ouml ring Christian Weber Kirk M. Habegger Michaela Keuper Vasily Gelfanov Fa Liu Josef K ouml hrle Jan Rozman Helmut Fuchs Valerie Gailus-Durner Martin Hrabě de Angelis Susanna M. Hofmann Bin Yang Matthias H. Tsch ouml p Richard DiMarchi Timo D. M uuml ller Institute for Diabetes and Obesity Helmholtz Diabetes Center at Helmholtz Zentrum München German Research Center for Environmental Health (GmbH) 85764 Neuherberg German Division of Metabolic Diseases Department of Medicine Technische Universität München 80333 Munich German German Center for Diabetes Research (DZD) 85764 Neuherberg Germany Department of Chemistry Indiana University Bloomington IN 47405 USA Institut de Génomique Fonctionnelle de Lyon Université de Lyon Centre National de la Recherche Scientifique (CNRS) Institut National de la Recherche Agronomique (INRA) École Normale Supérieure de Lyon 69364 Lyon France Institute for Diabetes and Obesity Helmholtz Diabetes Center at Helmholtz Zentrum München German Research Center for Environmental Health (GmbH) 85764 Neuherberg Germany Molecular EXposomics Helmholtz Zentrum München German Research Center for Environmental Health (GmbH) 85764 Neuherberg Germany German Mouse Clinic Institute of Experimental Genetics Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany German Mouse Clinic Institute of Experimental Genetics Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg German Institute of Pathology Helmholtz Zentrum München German Research Center for Environmental Health 85764 Neuherberg Germany Division of Endocrinology Department of Internal Medicine Metabolic Diseases Institute University of Cincinnati College of Medicine Cincinnati OH 45237 USA Division of Metabolic Diseases Department of Medicine Technische Universität München 80333 Munich Germany Calibrium LLC Carmel IN 46032 USA Institute of Comparative Molecular Endocrinology University of Ulm 89081Ulm Germany Department of Pathology and Molecular Pathology University Zurich and University Hospital Zurich 8091 Zurich Switzerland Department of Medicine Institute for Cardiovascular Prevention Ludwig-Maximilians-Universität München 80336 Munich German Depar

肥胖和糖尿病持续上升代表着我们的社会所面临的一个重大的负担。脂肪肝和动脉粥样硬化是这些代谢疾病常见的后果，但是开发一种高效且又安全的能够逆转肥胖、胰岛素抵抗性、脂肪肝和动脉粥样硬化的药物仍然是全球头等的一项重大的科学... 详细信息

肥胖和糖尿病持续上升代表着我们的社会所面临的一个重大的负担。脂肪肝和动脉粥样硬化是这些代谢疾病常见的后果，但是开发一种高效且又安全的能够逆转肥胖、胰岛素抵抗性、脂肪肝和动脉粥样硬化的药物仍然是全球头等的一项重大的科学挑战。

关键词：脂肪肝 Cell 动脉粥样硬化血液肝脏清除分子代谢疾病

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