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

Blood 2025年第23期145卷 2793-2798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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Defining new mechanistic roles for α II spectrin in cardiac function (vol 294, pg 9576, 2019)

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JOURNAL OF BIOLOGICAL CHEMISTRY 2019年第42期294卷 15557-15557页

作者： Lubbers, Ellen R. Murphy, Nathaniel P. Musa, Hassan Huang, Claire Yu-Mei Gupta, Rohan Price, Morgan V. Han, Mei Daoud, Georges E. Gratz, Daniel El Refaey, Mona Xu, Xianyao Hoeflinger, Nicole K. Friel, Emma L. Lancione, Peter Wallace, Michael J. Cavus, Omer Simmons, Samantha L. Williams, Jordan L. Skaf, Michel Koenig, Sara N. Janssen, Paul M. L. Rasband, Matthew N. Hund, Thomas J. Mohler, Peter J. From the [‡]Dorothy M. Davis Heart and Lung Research Institute and Frick Center for Heart Failure and Arrhythmia [§]Medical Scientist Training Program the Departments of [¶]Physiology and Cell Biology and [‡‡]Internal Medicine Division of Cardiovascular Medicine The Ohio State University College of Medicine and Wexner Medical Center Columbus Ohio 432310 the [‖]Department of Neuroscience and Integrative Molecular and Biomedical Sciences Graduate Program Baylor College of Medicine Houston Texas 77030 and the [**]Department of Biomedical Engineering The Ohio State University Columbus Ohio 432310 ↵To whom correspondence should be addressed: 110G DHLRI 473 West 12th Ave. Columbus OH 43210. Tel.: 614-292-5019 Fax: 614-247-7799 E-mail: Peter.Mohler{at}osumc.edu.

Spectrins are cytoskeletal proteins essential for membrane biogenesis and regulation and serve critical roles in protein targeting and cellular signaling. αII spectrin (SPTAN1) is one of two α spectrin genes and αII spectrin dysfunction is linked to alterations in axon initial segment formation, cortical lamination, and neuronal excitability. Furthermore, human αII spectrin loss-of-function variants cause neurological disease. As global αII spectrin knockout mice are embryonic lethal, the in vivo roles of αII spectrin in adult heart are unknown and untested. Here, based on pronounced alterations in αII spectrin regulation in human heart failure we tested the in vivo roles of αII spectrin in the vertebrate heart. We created a mouse model of cardiomyocyte-selective αII spectrin-deficiency (cKO) and used this model to define the roles of αII spectrin in cardiac function. αII spectrin cKO mice displayed significant structural, cellular, and electrical phenotypes that resulted in accelerated structural remodeling, fibrosis, arrhythmia, and mortality in response to stress. At the molecular level, we demonstrate that αII spectrin plays a nodal role for global cardiac spectrin regulation, as αII spectrin cKO hearts exhibited remodeling of αI spectrin and altered β-spectrin expression and localization. At the cellular level, αII spectrin deficiency resulted in altered expression, targeting, and regulation of cardiac ion channels Na_V1.5 and K_V4.3. In summary, our findings define critical and unexpected roles for the multifunctional αII spectrin protein in the heart. Furthermore, our work provides a new in vivo animal model to study the roles of αII spectrin in the cardiomyocyte.

关键词： heart heart failure adaptor protein ion channel cardiovascular disease cytoskeleton spectrin ankryin

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Integrated information theory (IIT) 4.0: Formulating the properties of phenomenal existence in physical terms

arXiv

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arXiv 2022年

作者： Albantakis, Larissa Barbosa, Leonardo Findlay, Graham Grasso, Matteo Haun, Andrew M. Marshall, William Mayner, William G.P. Zaeemzadeh, Alireza Boly, Melanie Juel, Bjørn E. Sasai, Shuntaro Fujii, Keiko David, Isaac Hendren, Jeremiah Lang, Jonathan P. Tononi, Giulio Department of Psychiatry University of Wisconsin MadisonWI53719 United States Fralin Biomedical Research Institute at VTC Virginia Tech RoanokeVA24016 United States Neuroscience Training Program University of Wisconsin MadisonWI53705 United States Department of Mathematics and Statistics Brock University St. CatharinesONL2S 3A1 Canada Department of Neurology University of Wisconsin MadisonWI53719 United States Institute of Basic Medical Sciences University of Oslo Oslo0372 Norway Araya Inc. Tokyo107-0052 Japan Graduate School Language & Literature Ludwig Maximilian University of Munich Munich80799 Germany

This paper presents Integrated Information Theory (IIT) 4.0. IIT aims to account for the properties of experience in physical (operational) terms. It identifies the essential properties of experience (axioms), infers the necessary and sufficient properties that its substrate must satisfy (postulates), and expresses them in mathematical terms. In principle, the postulates can be applied to any system of units in a state to determine whether it is conscious, to what degree, and in what way. IIT offers a parsimonious explanation of empirical evidence, makes testable predictions, and permits inferences and extrapolations. IIT 4.0 incorporates several developments of the past ten years, including a more accurate translation of axioms into postulates and mathematical expressions, the introduction of a unique measure of intrinsic information that is consistent with the postulates, and an explicit assessment of causal relations. By fully unfolding a system’s irreducible cause–effect power, the distinctions and relations specified by a substrate can account for the quality of experience. © 2022, CC BY.

关键词： Information theory

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Angiotensin AT 1 R Expressing Cells Within the Ventral Hypothalamus Modulate Integrative Control of Cardiometabolic Functions

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iScience 2025年

作者： Jhonatan Pasos Valerie A. Wagner Samuel B.R. Lawton Alyssa M. Madison Kush Nandani Natalia M. Mathieu Connie C. Grobe John J. Reho Bonnie P. Freudinger Alexander J. Sherman Daniel T. Brozoski Lisa L. Morselli Colin M.L. Burnett Jeffrey L. Segar Pablo Nakagawa Curt D. Sigmund Justin L. Grobe Department of Physiology Medical College of Wisconsin Milwaukee WI 53226 USA Universidad CES Medellin Antioquia Colombia Medical Scientist Training Program Medical College of Wisconsin Milwaukee WI 53226 USA Department of Pediatrics Division of Neonatology Medical College of Wisconsin Milwaukee WI 53226 USA Comprehensive Rodent Metabolic Phenotyping Core Medical College of Wisconsin Milwaukee WI 53226 USA Engineering Core Medical College of Wisconsin Milwaukee WI 53226 USA Department of Medicine / Division of Endocrinology and Molecular Medicine Medical College of Wisconsin Milwaukee WI 53226 USA Cardiovascular Center Medical College of Wisconsin Milwaukee WI 53226 USA Department of Medicine / Division of Cardiovascular Medicine Medical College of Wisconsin Milwaukee WI 53226 USA Department of Biomedical Engineering Medical College of Wisconsin Milwaukee WI 53226 USA Neuroscience Research Center Medical College of Wisconsin Milwaukee WI 53226 USA

Subtypes of Agouti-related peptide (AgRP) neurons can be distinguished based upon expression of angiotensin II receptors. The Type 1 subtype, which expresses the angiotensin type 1 receptor ( Agtr1a ), was examined for its role in the integrative control of cardiometabolic functions. Mice expressing Cre-recombinase via the Agtr1a locus received bilateral microinjection of an AAV vector encoding Cre-dependent expression of caspase-3 into the arcuate nucleus of mice housed at 22°C or 30°C. Ablation of Agtr1a + cells caused increased food intake, adiposity, resting metabolic rate and shifts in nutrient partitioning, elevated temperature preference, loss of core temperature defense, and changes in blood pressure and heart rate. Many phenotypes were ameliorated by housing animals at thermoneutrality. Thus, Agtr1a + cells in the ventral hypothalamus (including the Type 1 AgRP neuron) influence cardiometabolic control through modulation of thermoregulatory responses to cold. Some functions of these cells appear to oppose canonical roles of other AgRP neuron subtypes.

关键词： Agouti-related peptide Angiotensin Energy metabolism Thermoregulation

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Distribution-free multisample test based on optimal matching with applications to single cell genomics

arXiv

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arXiv 2019年

作者： Agarwal, Divyansh Mukherjee, Somabha Bhattacharya, Bhaswar B. Zhang, Nancy R. Graduate Group in Genomics and Computational Biology Medical Scientist Training Program Perelman School of Medicine University of Pennsylvania Department of Statistics Wharton School University of Pennsylvania

In this paper we propose a nonparametric graphical test based on optimal matching, for assessing the equality of multiple unknown multivariate probability distributions. Our procedure pools the data from the different classes to create a graph based on the minimum non-bipartite matching, and then utilizes the number of edges connecting data points from different classes to examine the closeness between the distributions. The proposed test is exactly distribution-free (the null distribution does not depend on the distribution of the data) and can be efficiently applied to multivariate as well as non-Euclidean data, whenever the inter-point distances are well-defined. We show that the test is universally consistent, and prove a distributional limit theorem for the test statistic under general alternatives. Through simulation studies, we demonstrate its superior performance against other common and well-known multisample tests. In scenarios where our test suggests distributional differences across classes, we also propose an approach for identifying which class or group contributes to this overall difference. The method is applied to single cell transcriptomics data obtained from the peripheral blood, cancer tissue, and tumor-adjacent normal tissue of human subjects with hepatocellular carcinoma and non-small-cell lung cancer. Our method unveils patterns in how biochemical metabolic pathways are altered across immune cells in a cancer setting, depending on the tissue location. All of the methods described herein are implemented in the R package multicross. Copyright © 2019, The Authors. All rights reserved.

关键词： Genes

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Ubiquitin and the DNA double-strand break repair pathway

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Genome Instability & Disease 2019年第2期1卷 69-80页

作者： Somaira Nowsheen Min Deng Zhenkun Lou Mayo Clinic Medical Scientist Training Program Mayo Clinic Alix School of Medicine and Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Rochester USA Division of Oncology Mayo Clinic Rochester USA

The ubiquitin system plays a central role in diverse cellular processes including DNA damage response. As such, it is not surprising that its dysfunction contributes to various diseases including cancer and neurodegenerative disorders. An understanding of the ubiquitin system is, therefore, important in devising treatments for such diseases. In this review, we discuss the central role of ubiquitin in DNA damage response, specifically DNA double-strand break repair. We focus on recent findings on the role of ubiquitin in the DNA double-strand break repair pathway, possible nodes of modulation, and finally their implications for treatment of various diseases.

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Author Correction: Senescent glia link mitochondrial dysfunction and lipid accumulation

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Nature 2024年第8026期632卷 E8页

作者： China N Byrns Alexandra E Perlegos Karl N Miller Zhecheng Jin Faith R Carranza Palak Manchandra Connor H Beveridge Caitlin E Randolph V Sai Chaluvadi Shirley L Zhang Ananth R Srinivasan F C Bennett Amita Sehgal Peter D Adams Gaurav Chopra Nancy M Bonini Medical Scientist Training Program Perelman School of Medicine University of Pennsylvania Philadelphia PA USA. Department of Biology University of Pennsylvania Philadelphia PA USA. Neuroscience Graduate Group Perelman School of Medicine University of Pennsylvania Philadelphia PA USA. Cancer Genome and Epigenetics Program Sanford Burnham Prebys Medical Discovery Institute La Jolla CA USA. Department of Chemistry Purdue University West Lafayette IN USA. Howard Hughes Medical Institute and Chronobiology and Sleep Institute Perelman School of Medicine at the University of Pennsylvania Philadelphia PA USA. Department of Psychiatry Perelman School of Medicine University of Pennsylvania Philadelphia PA USA. Division of Neurology Children's Hospital of Philadelphia Philadelphia PA USA. Purdue Institute for Integrative Neuroscience Purdue University West Lafayette IN USA. Purdue Institute for Drug Discovery Purdue University West Lafayette IN USA. Purdue Center for Cancer Research Purdue University West Lafayette IN USA. Purdue Institute of Inflammation Immunology and Infectious Disease Purdue University West Lafayette IN USA. Department of Biology University of Pennsylvania Philadelphia PA USA. nbonini@sas.upenn.edu. Neuroscience Graduate Group Perelman School of Medicine University of Pennsylvania Philadelphia PA USA. nbonini@sas.upenn.edu.

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Single-cell profiling of bone metastasis ecosystems from multiple cancer types reveals convergent and divergent mechanisms of bone colonization

Cell genomics

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Cell genomics 2025年 100888页

作者： Fengshuo Liu Yunfeng Ding Zhan Xu Xiaoxin Hao Tianhong Pan George Miles Siyue Wang Yi-Hsuan Wu Jun Liu Igor L Bado Weijie Zhang Ling Wu Yang Gao Liqun Yu David G Edwards Hilda L Chan Sergio Aguirre Michael Warren Dieffenbach Elina Chen Yichao Shen Dane Hoffman Luis Becerra Dominguez Charlotte Helena Rivas Xiang Chen Hai Wang Zbigniew Gugala Robert L Satcher Xiang H-F Zhang Lester and Sue Smith Breast Center Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA Dan L. Duncan Cancer Center Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA Department of Molecular and Cellular Biology Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA Graduate Program in Cancer and Cell Biology Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA. Department of Molecular and Cellular Biology Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA. Department of Orthopedic Oncology University of Texas MD Anderson Cancer Center Houston TX USA. Dan L. Duncan Cancer Center Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA. Graduate Program in Immunology and Microbiology Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA. Medical Scientist Training Program Baylor College of Medicine Houston TX 77030 USA. Graduate Program in Cancer and Cell Biology Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA Graduate Program in Integrative Molecular and Biomedical Sciences Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA. Graduate Program in Development Disease Models and Therapeutics Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA. College of Natural Sciences University of Texas at Austin 110 Inner Campus Drive Austin TX 78706 USA. Department of Orthopedic Surgery and Rehabilitation University of Texas Medical Branch Galveston TX USA. Department of Orthopedic Oncology University of Texas MD Anderson Cancer Center Houston TX USA. Electronic address: rlsatcher@***. McNair Medical Institute Baylor College of Medicine One Baylor Plaza Houston TX 77030 USA. Electronic address: xiangz@bcm.edu.

Bone is a common site for metastasis of solid cancers. The diversity of histological and molecular characteristics of bone metastases (BMs) remains poorly studied. Here, we performed single-cell RNA sequencing on 42 BMs from eight cancer types, identifying three distinct ecosystem archetypes, each characterized by an enrichment of specific immune cells: macrophages/osteoclasts, regulatory/exhausted T cells, or monocytes. We validated these archetypes by immunostaining on tissue sections and bioinformatic analysis of bulk RNA sequencing/microarray data from 158 BMs across more than 10 cancer types. Interestingly, we found only a modest correlation between the BM archetypes and the tissues of origin; BMs from the same cancer type often fell into different archetypes, while BMs from different cancer types sometimes converged on the same archetype. Additional analyses revealed parallel immunosuppression and bone remodeling mechanisms, some of which were experimentally validated. Overall, we discovered unappreciated heterogeneity of BMs across different cancers.

关键词： bone metastases convergent and divergent evolution immune archetypes immune evasion immunosuppression single-cell RNA sequencing tumor microenvironment

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Perioperative Stress, Inflammation, and Cancer Progression: Opportunities for Intervention in Breast and Colorectal Cancer Surgery Utilizing Beta-Adrenergic Blockade and COX-2 Inhibition

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Current Anesthesiology Reports 2018年第4期8卷 386-392页

作者： Fischer, Avital Ben-Eliyahu, Shamgar School of Medicine Medical Scientist Training Program University of California Irvine Irvine CA United States Sagol School of Neuroscience School of Psychological Sciences Tel Aviv University Tel Aviv 69978 Israel

Purpose of review: This review explores the blockade of cyclooxygenase (COX)-2/prostaglandin and catecholamine/beta(β)-adrenergic signaling as opportunities to enhance the curative potential of surgical excision of breast and colorectal cancer malignancies. Recent findings: Phase-II randomized placebo-controlled biomarker clinical trials, employing perioperative administration of the COX-2 inhibitor etodolac and the β-adrenergic antagonist propranolol, have shown improved biomarkers associated with both breast and colorectal cancer progression. Tumor epithelial-to-mesenchymal transition (EMT) status and tumor transcription activity levels of GATA-1, GATA-2, EGR3, and STAT-3 were reduced, while anti-cancer immune parameters within the tumor microenvironment improved perioperatively. Increased tumor-associated B cells and NK cells and reduced tumor-associated monocytes were noted. Reduced systemic pro-inflammatory markers IL-6 and CRP were indicated, starting before surgery. Summary: Improved biomarkers of tumor-associated (i) anti-metastatic transcriptional activity, (ii) anti-metastatic immune function, and (iii) reduced systemic inflammatory indices were observed following the combined administration of etodolac and propranolol. These findings support future investigation with larger clinical trials to test long-term cancer outcomes. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

关键词： Beta-adrenergic blockade Breast cancer Cancer progression Colorectal cancer COX-2 inhibition Perioperative stress Surgery

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Real-World Experiences With Yoga on Cancer-Related Symptoms in Women With Breast Cancer

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Global Advances In Health and Medicine 2021年第1期10卷

作者： Patel, Shruti R Zayas, Jacqueline Medina-Inojosa, Jose R Loprinzi, Charles Cathcart-Rake, Elizabeth J Bhagra, Anjali Olson, Janet E Couch, Fergus J Ruddy, Kathryn J Department of Internal Medicine Mayo Clinic Rochester MN United States Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic School of Medicine and the Mayo Clinic Medical Scientist Training Program Rochester MN United States Department of Cardiovascular Medicine Mayo Clinic Rochester MN United States Department of Medical Oncology Mayo Clinic Rochester MN United States Department of Medical Oncology University of Missouri Kansas City MO United States Department of Health Sciences Research Mayo Clinic Rochester MN United States Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN United States

Purpose: Integrative therapies such as yoga are potential treatments for many psychological and physical symptoms that occur during and/or after treatment for cancer. The purpose of the current study was to evaluate the patient-perceived benefit of yoga for symptoms commonly experienced by breast cancer survivors. Methods: 1,049 breast cancer survivors who had self-reported use of yoga on a follow up survey, in an ongoing prospective Mayo Clinic Breast Disease Registry (MCBDR), received an additional mailed yoga-focused survey asking about the impact of yoga on a variety of symptoms. Differences between pre- and post- scores were assessed using Wilcoxon Signed Rank Test. Results: 802/1,049 (76%) of women who were approached to participate, consented and returned the survey. 507/802 (63%) reported use of yoga during and/or after their cancer diagnosis. The vast majority of respondents (89.4%) reported some symptomatic benefit from yoga. The most common symptoms that prompted the use of yoga were breast/chest wall pain, lymphedema, and anxiety. Only 9% of patients reported that they had been referred to yoga by a medical professional. While the greatest symptom improvement was reported with breast/chest wall pain and anxiety, significant improvement was also perceived in joint pain, muscle pain, fatigue, headache, quality of life, hot flashes, nausea/vomiting, depression, insomnia, lymphedema, and peripheral neuropathy, (all p-values <0.004). Conclusion: Data supporting the use of yoga for symptom management after cancer are limited and typically focus on mental health. In this study, users of yoga often reported physical benefits as well as mental health benefits. Further prospective studies investigating the efficacy of yoga in survivorship are warranted. © The Author(s) 2021.

关键词： breast cancer complementary and alternative medicine survivorship symptom control yoga

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