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A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3 (vol 111, pg 96, 2024)

AMERICAN JOURNAL OF HUMAN GENETICS 2024年第4期11卷 805-805页

作者： Paul, Maimuna S. Michener, Sydney L. Pan, Hongling Chan, Hiuling Pfliger, Jessica M. Rosenfeld, Jill A. Lerma, Vanesa C. Tran, Alyssa Longley, Megan A. Lewis, Richard A. Weisz-Hubshman, Monika Bekheirnia, Mir Reza Bekheirnia, Nasim Massingham, Lauren Zech, Michael Wagner, Matias Engels, Hartmut Cremer, Kirsten Mangold, Elisabeth Peters, Sophia Trautmann, Jessica Perne, Claudia Mester, Jessica L. Sacoto, Maria J. Guillen Person, Richard McDonnell, Pamela P. Cohen, Stacey R. Lusk, Laina Cohen, Ana S. A. Le Pichon, Jean-Baptiste Pastinen, Tomi Zhou, Dihong Engleman, Kendra Racine, Caroline Faivre, Laurence Moutton, Sebastien Denomme-Pichon, Anne-Sophie Koh, Hyun Yong Poduri, Annapurna Bolton, Jeffrey Knopp, Cordula Suh, Dong Sun Julia Maier, Andrea Toosi, Mehran Beiraghi Karimiani, Ehsan Ghayoor Maroofian, Reza Schaefer, Gerald Bradley Ramakumaran, Vijayalakshmi Vasudevan, Pradeep Banos-Pinero, Benito Pagnamenta, Alistair T. Prasad, Chitra Osmond, Matthew Schuhmann, Sarah Vasileiou, Georgia Russ-Hall, Sophie Scheffer, Ingrid E. Carvill, Gemma L. Mefford, Heather Bacino, Carlos A. Lee, Brendan H. Chao, Hsiao-Tuan Department of Pediatrics Section of Neurology and Developmental Neuroscience Baylor College of Medicine Houston TX USA Jan and Dan Duncan Neurological Research Institute Texas Children’s Hospital Houston TX USA Cain Pediatric Neurology Research Foundation Laboratories Jan and Dan Duncan Neurological Research Institute Houston TX USA Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA Augustana College Rock Island IL USA Summer Undergraduate Research Training (SMART) Program Baylor College of Medicine Houston TX USA Graduate Program in Electrical and Computer Engineering Rice University Houston TX USA Department of Psychology University of Houston Houston TX USA Department of Ophthalmology Baylor College of Medicine Houston TX USA Renal Genetics Clinic Baylor College of Medicine Houston TX USA Rhode Island Hospital and Hasbro Children’s Hospital Providence RI USA Institute of Neurogenomics Helmholtz Zentrum München Munich Germany Institute of Human Genetics School of Medicine Technical University Munich Germany Institute for Advanced Study Technical University of Munich Garching Germany Division of Pediatric Neurology Developmental Neurology and Social Pediatrics Dr. von Hauner Children’s Hospital Munich Germany Institute of Human Genetics School of Medicine University Hospital Bonn University of Bonn Bonn Germany GeneDx Gaithersburg MD USA Epilepsy NeuroGenetics Initiative (ENGIN) Division of Neurology Children’s Hospital of Philadelphia Philadelphia PA USA Department of Neurology Perelman School of Medicine University of Pennsylvania Philadelphia PA USA Children’s Mercy Kansas City Genomic Medicine Center The University of Missouri-Kansas City (UMKC) School of Medicine Kansas City MO USA Department of Pediatrics Children’s Mercy Kansas City Kansas City MO USA Children’s Mercy Research Institute Kansas City MO USA Children’s Mercy Hospital Kansas City MO USA University Hospital Dijon Franc

PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity of PPFIA3 variants in vivo, we generated transgenic fruit flies producing either human wild-type (WT) PPFIA3 or five missense variants using GAL4-UAS targeted gene expression systems. In the fly overexpression assays, we found that the PPFIA3 variants in the region encoding the N-terminal coiled-coil domain exhibited stronger phenotypes compared to those affecting the C-terminal region. In the loss-of-function fly assay, we show that the homozygous loss of fly Liprin-α leads to embryonic lethality. This lethality is partially rescued by the expression of human PPFIA3 WT, suggesting human PPFIA3 function is partially conserved in the fly. However, two of the tested variants failed to rescue the lethality at the larval stage and one variant failed to rescue lethality at the adult stage. Altogether, the human and fruit fly data reveal that the rare PPFIA3 variants are dominant-negative loss-of-function alleles that perturb multiple developmental processes and synapse formation.

关键词： neurodevelopmental disorder synaptic protein active zone protein Mendelian phenotypes fruit flies

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Clinical and histopathological spectrum of toxic erythema of chemotherapy in patients who have undergone allogeneic hematopoietic cell transplantation

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Hematology/ Oncology and Stem Cell Therapy 2019年第1期12卷 19-25页

作者： Hunjan, Manrup K. Nowsheen, Somaira Ramos-Rodriguez, Alvaro J. Hashmi, Shahrukh K. Bridges, Alina G. Lehman, Julia S. El-Azhary, Rokea St Johns Institute of Dermatology Guys and St Thomas’ Hospitals NHS Trust United Kingdom Mayo Clinic Medical Scientist Training Program Mayo Clinic School of Medicine Rochester MN United States Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Rochester MN United States Department of Internal Medicine Icahn School of Medicine at Mount Sinai West New York NY United States Department of Hematology and Oncology Mayo Clinic Rochester MN United States Department of Dermatology Mayo Clinic Rochester MN United States Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN United States

Objective/Background: Toxic erythema of chemotherapy (TEC) is a well-recognized adverse cutaneous reaction to chemotherapy. Similar to many skin diseases, the clinical presentations may vary. Our objective is to expand on the typical and atypical clinical and histopathological presentations of TEC. Methods: Forty patients with a diagnosis of TEC were included from 500 patients who had undergone an allogeneic hematopoietic stem cell transplant. Relevant information and demonstrative photos and pathology were selected. Results: Classic clinical presentations included hand and foot erythema and dysesthesias;atypical presentations included facial involvement, hyperpigmentation, dermatomyositis-like, and erythroderma associated with capillary leak syndrome. Conclusion: The diagnosis of TEC should be considered after a correlation of clinical and histological findings in conjunction with a timeline of chemotherapy administration. Suggested criteria for the diagnosis of TEC may be helpful to dermatologists and clinicians when caring for these patients. © 2018 King Faisal Specialist Hospital & Research Centre

关键词： Cancer Capillary leak syndrome (CLS) Chemotherapy Stem cell transplant Toxic epidermal necrolysis Toxic erythema of chemotherapy

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Mitigation of Chromosome Loss in Clinical CRISPR-Cas9-Engineered T Cells

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SSRN 2023年

作者： Tsuchida, Connor A. Brandes, Nadav Bueno, Raymund Trinidad, Marena Mazumder, Thomas Yu, Bingfei Hwang, Byungjin Chang, Christopher Liu, Jamin Sun, Yang Hopkins, Caitlin R. Parker, Kevin R. Qi, Yanyan Satpathy, Ansuman T. Stadtmauer, Edward A. Cate, Jamie H.D. Eyquem, Justin Fraietta, Joseph A. June, Carl H. Chang, Howard Y. Ye, Chun Jimmie Doudna, Jennifer A. University of California Berkeley - University of California San Francisco Graduate Program in Bioengineering University of California Berkeley BerkeleyCA United States Innovative Genomics Institute University of California Berkeley BerkeleyCA United States Division of Rheumatology Department of Medicine University of California San Francisco San FranciscoCA United States Center for Personal Dynamic Regulomes Stanford University StanfordCA United States Parker Institute for Cancer Immunotherapy Stanford University School of Medicine StanfordCA United States Biomedical Sciences Graduate Program University of California San Francisco San FranciscoCA United States Medical Scientist Training Program University of California San Francisco San FranciscoCA United States Department of Medicine University of California San Francisco San FranciscoCA United States Parker Institute for Cancer Immunotherapy San FranciscoCA United States Gladstone-UCSF Institute of Genomic Immunology San FranciscoCA United States Department of Biochemistry and Biophysics University of California San Francisco San FranciscoCA United States Abramson Cancer Center Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Parker Institute for Cancer Immunotherapy Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Center for Cellular Immunotherapies Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Department of Pathology and Laboratory Medicine Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Department of Microbiology Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Department of Pathology Stanford University School of Medicine StanfordCA United States Division of Hematology-Oncology Department of Medicine Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Department o

CRISPR-Cas9 genome editing has enabled advanced T cell therapies, but occasional loss of the targeted chromosome could be a safety concern. To investigate whether Cas9-induced chromosome loss is a universal phenomenon and evaluate its clinical significance, we conducted a systematic analysis in primary human T cells. Arrayed and pooled CRISPR screens revealed that partial or entire chromosome loss after Cas9-induced DNA cutting is a rare but generalized phenomenon, occurring also in pre-clinical chimeric antigen receptor T cells. T cells with chromosome loss persist for weeks in culture, implying potential interference with clinical use. A modified cell manufacturing process, employed in our first-in-human clinical trial of Cas9-engineered T cells, dramatically reduced chromosome loss while largely preserving genome editing efficacy. Expression of p53 correlated with the protection from chromosome loss observed with this protocol, suggesting both a mechanism and a strategy for T cell engineering that mitigates genotoxicity in the clinic. © 2023, The Authors. All rights reserved.

关键词： T-cells

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Author Correction: Efficient C•G-to-G•C base editors developed using CRISPRi screens, target-library analysis, and machine learning

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Nature biotechnology 2023年第11期41卷 1655页

作者： Luke W Koblan Mandana Arbab Max W Shen Jeffrey A Hussmann Andrew V Anzalone Jordan L Doman Gregory A Newby Dian Yang Beverly Mok Joseph M Replogle Albert Xu Tyler A Sisley Jonathan S Weissman Britt Adamson David R Liu Merkin Institute of Transformative Technologies in Healthcare Broad Institute of Harvard and MIT Cambridge MA USA. Department of Chemistry and Chemical Biology Harvard University Cambridge MA USA. Howard Hughes Medical Institute Harvard University Cambridge MA USA. Computational and Systems Biology Program Massachusetts Institute of Technology Cambridge MA USA. Department of Cellular and Molecular Pharmacology University of California San Francisco San Francisco CA USA. Department of Microbiology and Immunology University of California San Francisco San Francisco CA USA. Howard Hughes Medical Institute University of California San Francisco San Francisco CA USA. Whitehead Institute for Biomedical Research Cambridge MA USA. Department of Biology Massachusetts Institute of Technology Cambridge MA USA. Medical Scientist Training Program University of California San Francisco San Francisco CA USA. Tetrad Graduate Program University of California San Francisco San Francisco CA USA. Biomedical Sciences Graduate Program University of California San Francisco San Francisco CA USA. Department of Cellular and Molecular Pharmacology University of California San Francisco San Francisco CA USA. weissman@wi.mit.edu. Howard Hughes Medical Institute University of California San Francisco San Francisco CA USA. weissman@wi.mit.edu. Medical Scientist Training Program University of California San Francisco San Francisco CA USA. weissman@wi.mit.edu. Whitehead Institute for Biomedical Research Cambridge MA USA. weissman@wi.mit.edu. Department of Biology Massachusetts Institute of Technology Cambridge MA USA. weissman@wi.mit.edu. Department of Cellular and Molecular Pharmacology University of California San Francisco San Francisco CA USA. badamson@princeton.edu. Howard Hughes Medical Institute University of California San Francisco San Francisco CA USA. badamson@princeton.edu. Lewis-Sigler Institute for Integrative Genomics Princeton University Princ

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LC-MS/MS proteomics identifies plasma proteins related to cognition over 9-year follow-up

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Alzheimer's & Dementia 2025年第6期21卷

作者： Hailey A. Adegboye Khiry L. Patterson Julia Libby Yunyi Sun Panpan Zhang Dandan Liu W. Hudson Robb Amalia J. Peterson Keith R. Cole Albert B. Arul Nekesa C. Oliver Marsalas D. Whitaker Kimberly R. Pechman Logan Dumitrescu Corey J. Bolton Kaj Blennow Henrik Zetterberg Timothy J. Hohman Renã A. S. Robinson Angela L. Jefferson Vanderbilt Memory and Alzheimer's Center Vanderbilt University School of Medicine Nashville Tennessee USA Medical Scientist Training Program Vanderbilt University School of Medicine Nashville Tennessee USA Department of Chemistry Vanderbilt University Nashville Tennessee USA Department of Biostatistics Vanderbilt University Medical Center Nashville Tennessee USA Department of Neurology Vanderbilt University Medical Center Nashville Tennessee USA Department of Orthopaedic Surgery Vanderbilt University Medical Center Nashville Tennessee USA Department of Medicine Vanderbilt University Medical Center Nashville Tennessee USA Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden Paris Brain Institute ICM Hôpital Pitié Paris France Neurodegenerative Disorder Research Center Division of Life Sciences and Medicine and Department of Neurology Institute on Aging and Brain Disorders University of Science and Technology of China and First Affiliated Hospital of USTC Hefei China Department of Neurodegenerative Disease UCL Institute of Neurology Queen Square London UK UK Dementia Research Institute at UCL London UK Hong Kong Center for Neurodegenerative Diseases InnoHK Hong Kong China Wisconsin Alzheimer's Disease Research Center University of Wisconsin School of Medicine and Public Health University of Wisconsin-Madison Madison Wisconsin USA

INTRODUCTION This project identified plasma proteins predictive of cognitive decline across a robust neuropsychological protocol over a 9-year period. METHODS Vanderbilt Memory and Aging Project participants ( n = 336, 73 ± 7 years, 59% male, 87% non-Hispanic White, 10% Black/African American) underwent blood draw for baseline plasma protein abundance using mass spectrometry analysis of tandem mass tag (TMT)-labeled peptides and serial neuropsychological assessment (follow-up = 6.1 ± 2.3 years). Linear mixed-effects regressions related protein levels to neuropsychological outcomes in fully adjusted models. False discovery rate correction was applied. RESULTS Initial proteomics analyses yielded 3764 unique protein identifications across 23 16-plex TMT batches, and 686 proteins passed quality control. Proteins were identified predicting longitudinal decline in language (EGFR, RTN4RL2), information processing speed (EGFR, NOMO2, CLEC3B), executive function (A1BG), and visuospatial skills (RTN4RL2, GALNT1, SERPINA4, SERPINA5, C8A, ALDOB), but not episodic memory. DISCUSSION Large-scale proteomics analyses identified 10 plasma proteins that predicted subsequent cognitive decline over a 9-year follow-up in multiple cognitive domains. Highlights There were 3764 unique protein identifications across 23 16-plex TMT batches. Rigorous quality control yielded 686 proteins used as predictors in analyses. Identified proteins related to all domains assessed, except for episodic memory. Many proteins identified were differentially expressed in MCI.

关键词： Alzheimer's disease cognition LC-MS/MS mild cognitive impairment plasma proteomics

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75202 The New Normal: A Virtual Summer Foundations in Research

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Journal of Clinical and Translational Science 2021年第S1期5卷 62-62页

作者： Adriana Morales Gomez Kit Knier Joanna Yang Yowler Chris Pierret Linda M. Scholl Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Rochester MN USA Mayo Clinic Medical Scientist Training Program Mayo Clinic Rochester MN USA Department of Research Mayo Clinic Jacksonville FL USA Department of Biochemistry and Molecular Biology Mayo Clinic Rochester MN USA Office of Applied Scholarship and Education Science Mayo Clinic College of Medicine Mayo Clinic Rochester MN USA

ABSTRACT IMPACT: The Summer Foundation on Research gave undergraduate students the opportunity to do research despite the new normal - COVID-19 pandemic. OBJECTIVES/GOALS: The COVID-19 pandemic prevented domestic and international undergraduate students from attending in-person Mayo Clinic Summer Undergraduate Research programs. Mayo decided to redesign this program as a virtual, 4-week Summer Foundations in Research (SFIR) program. The goal of this program was to give students a scientific research experience. METHODS/STUDY POPULATION: The SFIR included an Introduction to Experimental Design, Dialogue methodology for communicating science, scientific mentoring, asynchronous online modules and a Resiliency component. Evaluations of the program were undertaken to gather feedback for program improvement and to assess the educational and mental health impact on participants. These evaluations asked student to rate each section of the program. Additionally, students were encouraged to provide their own comments and feedback. Statistical analysis of quantitative data was performed using excel. The qualitative data was studied using the identification, analysis and interpretation of patterns method per the student’s comments on each of the questions addressed in the survey. RESULTS/ANTICIPATED RESULTS: These evaluations revealed positive outcomes across program components: 66% of the participants found the Resiliency component extremely worthwhile, 80% of participants liked the experimental design and 70% liked the educational courses. Qualitative data showed that mentor/mentee interactions were highly valued, and both participants and faculty suggested increasing the amount of time devoted to these interactions. Small group discussions gave students the opportunity to get to know other peers and encouraged further discussions about science and the community. Participants suggested minor improvements to the program, such as re-creating the online modules specific for unde

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Publisher Correction: Structural basis of LRPPRC-SLIRP-dependent translation by the mitoribosome

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Nature structural & molecular biology 2024年第11期31卷 1809页

作者： Vivek Singh J Conor Moran Yuzuru Itoh Iliana C Soto Flavia Fontanesi Mary Couvillion Martijn A Huynen L Stirling Churchman Antoni Barrientos Alexey Amunts Science for Life Laboratory Department of Biochemistry and Biophysics Stockholm University Solna Sweden. Medical Scientist Training Program Department of Biochemistry and Molecular Biology University of Miami Miller School of Medicine Miami FL USA. Science for Life Laboratory Department of Biochemistry and Biophysics Stockholm University Solna Sweden. yuzuru.itoh@bs.s.u-tokyo.ac.jp. Department of Biological Sciences Graduate School of Science University of Tokyo Tokyo Japan. yuzuru.itoh@bs.s.u-tokyo.ac.jp. Blavatnik Institute Department of Genetics Harvard Medical School Boston MA USA. Department of Medical BioSciences Radboud University Medical Center Nijmegen The Netherlands. Blavatnik Institute Department of Genetics Harvard Medical School Boston MA USA. churchman@genetics.med.harvard.edu. Department of Neurology University of Miami Miller School of Medicine Miami FL USA. abarrientos@med.miami.edu. Science for Life Laboratory Department of Biochemistry and Biophysics Stockholm University Solna Sweden. alexey.amunts@***. Westlake University Hangzhou China. alexey.amunts@***.

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TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cells (vol 9, 12884, 2019)

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SCIENTIFIC REPORTS 2019年第1期9卷 12884-12884页

作者： Whillock, Amy L. Mambetsariev, Nurbek Lin, Wai W. Stunz, Laura L. Bishop, Gail A. Department of Microbiology & Immunology University of Iowa Iowa City IA USA. Immunology Graduate Program University of Iowa Iowa City IA USA. Medical Scientist Training Program University of Iowa Iowa City IA USA. Holden Comprehensive Cancer Center University of Iowa Iowa City IA USA. Northwestern Memorial Hospital Chicago IL USA. Sanford-Burnham-Prebys Medical Discovery Institute La Jolla CA USA. Department of Microbiology & Immunology University of Iowa Iowa City IA USA. gail-bishop@uiowa.edu. Internal Medicine University of Iowa Iowa City IA USA. gail-bishop@uiowa.edu. Immunology Graduate Program University of Iowa Iowa City IA USA. gail-bishop@uiowa.edu. Medical Scientist Training Program University of Iowa Iowa City IA USA. gail-bishop@uiowa.edu. Holden Comprehensive Cancer Center University of Iowa Iowa City IA USA. gail-bishop@uiowa.edu. VA Medical Center Iowa City IA USA. gail-bishop@uiowa.edu.

TRAF3 is a versatile intracellular adapter protein with multiple context-specific roles. Uniquely in B cells, TRAF3 deficiency enhances survival and increases the risk of transformation, as loss of TRAF3 is observed in several types of B cell cancers. Here, we report a new mechanism for TRAF3 in the restraint of B cell survival. We found that TRAF3 deficiency was associated with induction of the pro-survival kinase Pim2 in mouse primary B cells and human malignant B cell lines. The increase in Pim2 was independent of NF-κB2 activation but was ameliorated with inhibition of STAT3 expression or function. TRAF3 deficiency also led to a Pim2-dependent increase in c-Myc protein levels and was associated with reduced c-Myc ubiquitination. TRAF3-deficient primary B cells were less sensitive to cell death induced by the Pim inhibitors SGI-1776 and TP-3654. Interestingly, human malignant B cell lines with low expression of TRAF3 were more sensitive to Pim inhibition-induced cell death. Combination treatment of TRAF3-deficient B cells and B cell tumor lines with c-Myc inhibitors enhanced their sensitivity to Pim inhibition, suggesting a possible therapeutic strategy. TRAF3 thus suppresses a Pim2-mediated B cell survival axis, which can be a potential target for treatment of B cell malignancies.

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Obesity alters pathology and treatment response in inflammatory disease

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四川生理科学杂志 2022年第3期44卷 446-446页

作者： Sagar P Bapat NOMIS Center for Immunobiology and Microbial Pathogenesis The Salk Institute for Biological Studies La Jolla CA USA Gene Expression Laboratory The Salk Institute for Biological Studies La Jolla CA USA Medical Scientist Training Program University of California San Diego La Jolla CA USA Department of Laboratory Medicine University of California San Francisco San Francisco CA USA Department of Microbiology and Immunology University of California San Francisco San Francisco CA USA Diabetes Center University of California San Francisco San Francisco CA USA Medical Scientist Training Program University of California San Francisco CA USA Division of Pulmonary Critical Care Allergy and Sleep Department of Medicine University of California San Francisco San Francisco CA USA School of Pharmaceutical Sciences Xiamen University Xiamen China Department of Dermatology University of California San Diego La Jolla CA USA Department of Surgery University of California San Francisco San Francisco CA USA Department of Medicine University of California San Francisco San Francisco CA USA Sandler Asthma Basic Research Center University of California San Francisco San Francisco CA USA School of Medicine Wake Forest University Winston–Salem NC USA Department of Dermatology Icahn School of Medicine at Mount Sinai New York NY USA Lung Biology Center Department of Medicine University of California San Francisco San Francisco CA USA Department of Biomedical Science Graduate School Kyungpook National University Kyungpook National University Hospital Daegu South Korea Department of Dermatology University of California San Francisco San Francisco CA USA Department of Pathology University of California San Francisco San Francisco CA USA Department of Internal Medicine Division of Pulmonary Critical Care and Sleep Medicine University of Kentucky Lexington KY USA Pulmonary Critical Care Section Department of Medicine Veterans Affairs San Diego Hea

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune,allergic and inflammatory *** evidence indicates that obesity and metabolic disease can also influence the immune system1-7,although the mechanisms and effects on immunotherapy outcomes remain largely ***,using two models of atopic dermatitis,we show that lean and obese mice mount markedly different immune *** converted the classical type 2 T helper(TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 *** also observed divergent responses to biologic therapies targeting TH2 cytokines,which robustly protected lean mice but exacerbated disease in obese ***-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ(PPARγ)in TH2 cells from obese mice relative to lean mice.

关键词： dermatitis inflammatory allergic

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STAT1-mediated interferon signatures are associated with preclinical JAK inhibitor sensitivity in T-ALL

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Blood 2025年第23期145卷 blood2025028566页

作者： Xu, Jason Sussman, Jonathan H. Yang, Austin Yoshimura, Satoshi Hu, Jianzhong Chen, Changya Vincent, Tiffaney Bandyopadhyay, Shovik Li, Elizabeth Y. Lim, Tristan Elghawy, Omar Barsouk, Adam Karanfilovski, Damjan Wald, Shira L. Chen, Gregory M. Wu, David Newman, Haley Li, Alexander Sun, Yusha Chen, Chia-Hui Bernt, Kathrin Wood, Brent L. Winter, Stuart S. Dunsmore, Kimberly P. Raetz, Elizabeth Devidas, Meenakshi Pounds, Stanley Loh, Mignon Hunger, Stephen P. Chiang, Mark Y. Diorio, Caroline Di Giacomo, Danika Pölönen, Petri Mullighan, Charles G. Yang, Jun J. Tan, Kai Teachey, David T. Graduate Group in Genomics and Computational Biology Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Medical Scientist Training Program Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Division of Oncology and Center for Childhood Cancer Research Children's Hospital of Philadelphia Philadelphia PA United States Department of Pharmacy and Pharmaceutical Sciences St. Jude Children's Research Hospital Memphis TN United States Graduate Group in Cell and Molecular Biology University of Pennsylvania Philadelphia PA United States Department of Pediatrics Yale School of Medicine New Haven CT United States Department of Internal Medicine Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Department of Pathology Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Department of Pediatrics Perelman School of Medicine University of Pennsylvania Philadelphia PA United States Department of Pathology and Laboratory Medicine Children's Hospital Los Angeles Los Angeles CA United States Division of Hematology Oncology Children's Minnesota Eagan MN United States Division of Oncology University of Virginia Health Sciences Center Charlottesville VA United States Department of Pediatrics New York University Langone Health New York NY United States Department of Biostatistics St. Jude Children's Research Hospital Memphis TN United States 1Ben Towne Center for Childhood Cancer Research Seattle Children's Hospital Fred Hutch Cancer Center University of Washington Seattle WA United States Division of Hematology and Oncology University of Michigan Ann Arbor MI United States Department of Pathology St. Jude Children's Research Hospital Memphis TN United States Department of Chemistry Biology and Biotechnology University of Perugia Via del Giochetto Perugia Italy Center for Single-Cell Biology Children's Hospital of Philadelp

We used single-cell genomics to characterize a patient with T-cell acute lymphoblastic leukemia treated on the Children's Oncology Group AALL0434 with poor clinical outcome despite favorable genomic features, identifying a STAT1-mediated interferon-related transcriptional signature and inflammatory microenvironment associated with sensitivity to small-molecule JAK inhibition. © 2025 American Society of Hematology

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