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Paradox-driven adventures in the development of cancer immunology and immunotherapy

Genes & Diseases 2019年第3期6卷 224-231页

作者： Whitney Barham Joanina K.Gicobi Yiyi Yan Roxana S.Dronca Haidong Dong Mayo Clinic Medical Scientist Training Program Mayo ClinicRochesterMNUSA Mayo Clinic Graduate School of Biomedical Sciences Mayo ClinicRochesterMNUSA Department of Immunology Mayo ClinicRochesterMNUSA Department of Urology Mayo ClinicRochesterMNUSA Department of Medical Oncology Mayo ClinicRochesterMNUSA Division of Hematology and Medical Oncology Mayo ClinicJacksonvilleFLUSA

After more than one hundred years of documented trials,immunotherapy has become a standard of care in the treatment of human *** of the knowledge that led to recent breakthroughs seems quite logical from today’s point of ***,what we now cite as facts were originally considered paradoxes,meaning something contrary to expectations or perceived opinion at the *** order to make gains in the field of immunotherapy,one had to be willing to confront ideas and concepts that seemed to contradict one another,and reconcile how each could be *** is what led to new knowledge and ***,we highlight some of these paradoxes and the milestone discoveries that followed,each one critical for our understanding of immune checkpoint *** outlining some of the steps that we took and the challenges that we overcame,we hope to inspire and encourage future generations of researchers to confront the paradoxes that still permeate the field.

关键词： Biomarker Cancer immunotherapy Cytotoxic T cells Hyperprogression Immune checkpoints PD-L1 PD-1

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Is taurine an aging biomarker?

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Science (New York, N.Y.) 2025年第6751期388卷 eadl2116页

作者： Maria Emilia Fernandez Michel Bernier Nathan L Price Simonetta Camandola Miguel A Aon Kelli Vaughan Julie A Mattison Joshua D Preston Dean P Jones Toshiko Tanaka Qu Tian Marta González-Freire Luigi Ferrucci Rafael de Cabo Translational Gerontology Branch Intramural Research Program National Institute on Aging National Institutes of Health (NIH) Baltimore MD USA. Laboratory of Cardiovascular Sciences Intramural Research Program National Institute on Aging NIH Baltimore MD USA. Medical Scientist Training Program Emory University School of Medicine Atlanta GA USA. Nutrition and Health Sciences Laney Graduate School Emory University Atlanta GA USA. Division of Pulmonary Allergy and Critical Care Medicine Department of Medicine Emory University Atlanta GA USA. Health Research Institute of the Balearic Islands (IdISBa) Palma de Mallorca Spain.

Low circulating taurine concentrations have been proposed as a driver of the aging process. We found that circulating taurine concentrations increased or remained unchanged with age in three geographically distinct human cohorts as well as in nonhuman primates and mice when measured longitudinally (repeatedly in the same population) or cross-sectionally (sampling distinct populations at various ages). Moreover, considerable variability was observed in associations between taurine and age-related changes in health outcomes pertaining to gross motor function and energy homeostasis. Our results suggest that changes in circulating taurine are not a universal feature of aging and that its pleiotropic effects may be dependent on the temporal and physiological context of each individual.

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STING deletion protects against amyloid β–induced Alzheimer's disease pathogenesis

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Alzheimer's and Dementia 2025年第5期21卷 e70305页

作者： Thanos, Jessica M. Campbell, Olivia C. Cowan, Maureen N. Bruch, Katherine R. Moore, Katelyn A. Ennerfelt, Hannah E. Natale, Nick R. Mangalmurti, Aman Kerur, Nagaraj Lukens, John R. Department of Neuroscience Center for Brain Immunology and Glia (BIG) University of Virginia Charlottesville VA United States Neuroscience Graduate Program University of Virginia Charlottesville VA United States Brain Immunology and Glia Graduate Training Program University of Virginia Charlottesville VA United States Department of Neurology Massachusetts General Hospital Boston MA United States Department of Neurology and Neurological Sciences Stanford University Palo Alto CA United States Department of Ophthalmology and Visual Sciences the Ohio State University Wexner Medical Center Columbus OH United States Ohio State Havener Eye Institute the Ohio State University Wexner Medical Center Columbus OH United States Department of Microbial Infection and Immunity the Ohio State University Wexner Medical Center Columbus OH United States

INTRODUCTION: While immune dysfunction has been increasingly linked to Alzheimer's disease (AD) progression, many major innate immune signaling molecules have yet to be explored in AD pathogenesis using genetic targeting approaches. METHODS: To investigate a role for the key innate immune adaptor molecule, stimulator of interferon genes (STING), in AD, we deleted Sting1 in the 5xFAD mouse model of AD-related amyloidosis and evaluated the effects on pathology, neuroinflammation, gene expression, and cognition. RESULTS: Genetic ablation of STING in 5xFAD mice led to improved control of amyloid beta (Aβ) plaques, alterations in microglial activation status, decreased levels of neuritic dystrophy, and protection against cognitive decline. Moreover, rescue of neurological disease in STING-deficient 5xFAD mice was characterized by reduced expression of type I interferon signaling genes in both microglia and excitatory neurons. DISCUSSION: These findings reveal critical roles for STING in Aβ-driven neurological disease and suggest that STING-targeting therapeutics may offer promising strategies to treat AD. Highlights: Stimulator of interferon genes (STING) deficiency in the 5xFAD mouse model of Alzheimer's disease-related amyloidosis results in decreased amyloid beta (Aβ) deposition and altered microglial activation status. Protection against amyloidosis in STING-deficient 5xFAD mice is associated with decreased expression of genes involved in type I IFN signaling, improved neuronal health, and reduced levels of oxidative stress. Loss of STING in 5xFAD mice leads to improved spatial learning and memory. © 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

关键词： Alzheimer's disease amyloid beta amyloidosis innate immunity microglia neurodegenerative disease neuroimmunology STING

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Investigation of Cas9 antibodies in the human eye (vol 13, 1053, 2022)

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NATURE COMMUNICATIONS 2022年第1期13卷 1053-1053页

作者： Toral, Marcus A. Charlesworth, Carsten T. Ng, Benjamin Chemudupati, Teja Homma, Shota Nakauchi, Hiromitsu Bassuk, Alexander G. Porteus, Matthew H. Mahajan, Vinit B. Stanford University Molecular Surgery Program Department of Ophthalmology Byers Eye Institute Palo Alto USA (GRID:grid.168010.e) (ISNI:***) University of Iowa Medical Scientist Training Program and Graduate Program in Molecular Medicine Iowa City USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) Stanford University Department of Pediatrics Palo Alto USA (GRID:grid.168010.e) (ISNI:***) Stanford University Molecular Surgery Program Department of Ophthalmology Byers Eye Institute Palo Alto USA (GRID:grid.168010.e) (ISNI:***) University of Oxford Medical Sciences Division Oxford UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) Stanford University Molecular Surgery Program Department of Ophthalmology Byers Eye Institute Palo Alto USA (GRID:grid.168010.e) (ISNI:***) Stanford University Department of Genetics Palo Alto USA (GRID:grid.168010.e) (ISNI:***) Stanford University Department of Genetics Palo Alto USA (GRID:grid.168010.e) (ISNI:***) Stanford University School of Medicine Institute for Stem Cell Biology and Regenerative Medicine Palo Alto USA (GRID:grid.168010.e) (ISNI:***) University of Tokyo Division of Stem Cell Therapy Distinguished Professor Unit Institute of Medical Science Tokyo Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X) University of Iowa Departments of Pediatrics and Neurology and The Iowa Neuroscience Institute (INI) Iowa City USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) Stanford University Molecular Surgery Program Department of Ophthalmology Byers Eye Institute Palo Alto USA (GRID:grid.168010.e) (ISNI:***) Veterans Affairs Palo Alto Health Care System Palo Alto CA Palo Alto USA (GRID:grid.280747.e) (ISNI:0000 0004 0419 2556)

Preexisting immunity against Cas9 proteins in humans represents a safety risk for CRISPR–Cas9 technologies. However, it is unclear to what extent preexisting Cas9 immunity is relevant to the eye as it is targeted for early in vivo CRISPR–Cas9 clinical trials. While the eye lacks T-cells, it contains antibodies, cytokines, and resident immune cells. Although precise mechanisms are unclear, intraocular inflammation remains a major cause of vision loss. Here, we used immunoglobulin isotyping and ELISA platforms to profile antibodies in serum and vitreous fluid biopsies from human adult subjects and Cas9-immunized mice. We observed high prevalence of preexisting Cas9-reactive antibodies in serum but not in the eye. However, we detected intraocular antibodies reactive to S. pyogenes-derived Cas9 after S. pyogenes intraocular infection. Our data suggest that serum antibody concentration may determine whether specific intraocular antibodies develop, but preexisting immunity to Cas9 may represent a lower risk in human eyes than ***-existing antibodies against Cas9 proteins represent a potential issue for gene therapies, including those targeting the eye. Here the authors assess the presence of intraocular antibodies, and show that Cas9 antibodies were prevalent in human serum but not the eye, unless prior bacterial infection occurred.

关键词： CRISPR-Cas systems Visual system Translational immunology

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Proliferative and metastatic roles for Phospholipase D in mouse models of cancer

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Advances in Biological Regulation 2018年 67卷 134-140页

作者： Roth, Eric Frohman, Michael A. The Graduate Program in Molecular and Cellular Pharmacology The Medical Scientist Training Program the Department of Pharmacological Sciences Stony Brook University New York 11794 United States

Phospholipase D (PLD) activity has been proposed to facilitate multiple steps in cancer progression including growth, metabolism, angiogenesis, and mobility. The canonical enzymes PLD1 and PLD2 enact their diverse effects through hydrolyzing the membrane lipid phosphatidylcholine to generate the second messenger and signaling lipid phosphatidic acid (PA). However, the widespread expression of PLD1 and PLD2 in normal tissues and the additional distinct enzymatic mechanisms through which PA can be generated have produced uncertainty regarding the optimal settings in which PLD inhibition might ameliorate cancer. Recent studies in mouse model systems have demonstrated that inhibition or elimination of PLD activity reduces tumor growth and metastasis. One mechanism proposed for this outcome involves proliferative signaling mediated by receptor tyrosine kinases (RTK) and G protein-coupled receptors (GPCR), which is attenuated when downstream PLD signal propagation is suppressed. The reduced proliferative signaling has been reported to be compounded by dysfunctional energetic metabolism in the tumor cells under conditions of nutrient deprivation. Moreover, cancer cells lacking PLD activity display inefficiencies across multiple steps of the metastatic cascade, limiting the tumor's lethal spread. Using PLD isoform knockout mice, recent studies have reported on the net effects of inhibition and ablation in multiple cancer models through examining the role of PLD in the non-tumor cells comprising the stroma and microenvironment. The promising results of such in vivo studies, combined with the apparent low toxicity of highly-specific and potent inhibitors, highlights PLD as an attractive target for therapeutic inhibition in cancer. We discuss here the array of anti-tumor effects produced by PLD inhibition and ablation in cancer models with a focus on animal studies. © 2017 Elsevier Ltd

关键词： Angiogenesis Cancer Lipid signaling Metabolism Metastasis Phospholipase D

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Chronic effects of different neuromuscular training on hemodynamic responses estimated vo2max and walking performance in the elderly

Research Square

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Research Square 2021年

作者： Scartoni, Fabiana Rodrigues de Oliveira Sant’Ana, Leandro Vianna, Jeferson Macedo Machado, Sérgio Martin Dantas, Estélio Henrique Budde, Henning Stricto Sensu Graduate Program In Nursing and Biosciences PPgEnfBio The Federal University of The State of Rio de Janeiro UNIRIO Rio de Janeiro Brazil Laboratory of Sport and Exercise Sciences Catholic University of Petrópolis RJ Brazil Postgraduate Program in Physical Education Federal University of Juiz de Fora MG Brazil Strength Training Studies and Research Laboratory Federal University of Juiz de Fora MG Brazil Laboratory of Neuroscience of Physical Activity Salgado de Oliveira University RJ Brazil Laboratory of Physical Activity Neuroscience Salgado de Oliveira University Rio de Janeiro Brazil Faculty of Human Sciences Medical School Hamburg University of Applied Science and Medical University Hamburg20457 Germany

Resistance training is an excellent intervention for obtaining different physiological improvements in the elderly. The present study aimed to investigate the chronic effects of different neuromuscular training on cardiovascular, cardiorespiratory, and walking performance responses in the elderly. One hundred five people (64 women and 41 men) participated in the study, physically active, all over 60 years old. They were randomized to compose three groups: Strength Group, (n = 35), Resistance Group (n = 35), and Control Group, (n = 35). Both experimental groups (Strength Group and resistance group) performed four weeks of adaptation and 12 weeks of specific training. The Strength Group and the resistance group did four weeks adaptation phase and 12 weeks intervention load with 70-85% and 50-70%, respectively. The same exercise program was used in the experimental groups, using the alternating method by segment with the bench press, squat, one-sided curved stroke, leg extension, biceps curl, knee flexion, Triceps forehead. Both strength and resistance groups carried out two weekly sessions with an interval of at least 48 and a maximum of 72 hours. A pre and post-evaluation of resting heart rate (HR), blood pressure (systolic and diastolic), rate pressure product (RPP) was performed, and oxygen absorption (VO2max) and walking performance were estimated through the 1600 test meters. In systolic pressure, there was an improvement for the Strength Group (p=0.007) but not for the resistance group (p=0.172) and control group (p=0.999). Between groups, differences were observed between the Strength Group with the control group (p 0.05), but in the intergroup, for both variables, the difference was observed for the Strength Group and resistance group when compared with the control group (p © 2021, CC BY.

关键词： Blood pressure

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Cutaneous T-cell lymphoma with CNS involvement: a case series and review of the literature

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CNS Oncology 2023年第4期12卷 CNS105页

作者： Preston, Joshua D. Jansen, Caroline S. Kosaraju, Siddhartha Niyogusaba, Tim Zhuang, Tony Z. Iwamoto, Sally W. Hutto, Spencer K. Lechowicz, Mary Jo Allen, Pamela B. Medical Scientist Training Program Emory University School of Medicine Atlanta 30322 GA United States Nutrition & Health Sciences Laney Graduate School Emory University Atlanta 30322 GA United States Emory University School of Medicine Atlanta 30322 GA United States Division of Neuroradiology Department of Radiology & Imaging Sciences Emory University School of Medicine Atlanta 30322 GA United States Department of Medicine Massachusetts General Hospital Boston 02114 MA United States Department of Medicine Emory University School of Medicine Atlanta 30322 GA United States Department of Neurology Emory University School of Medicine Atlanta 30322 GA United States Department of Hematology & Medical Oncology Winship Cancer Institute Emory University Atlanta 30322 GA United States

Cutaneous T-cell lymphoma (CTCL) is a rare malignancy of the lymphocytes, which primarily presents with dermatologic lesions. Rarely, these lesions can progress to include visceral metastases, which, as reported here, can include metastases to the central nervous system (CNS). • This case series reports four cases of CTCL with CNS involvement, with varying histories, pathological characteristics, treatment regimens, treatment responses, and outcomes. • These four cases demonstrate the poor prognosis that CNS involvement of CTCL carries, as our patients had a median survival of 160 days following recognition of CNS involvement. • As CNS involvement does result in high morbidity and mortality, clinicians should be mindful of this potential manifestation of metastatic disease, despite its rarity. • Despite this poor prognosis, some patients did display clinical benefit following CNS-directed therapies, such as radiation, surgery, and high dose methotrexate. Importantly, these treatments may also provide symptomatic palliation, which is important for patient quality of life, even in the absence of survival benefit. • Given that outward manifestations of CNS involvement, such as neurologic symptoms, may be subtle or difficult to detect, careful follow-up and interdisciplinary evaluation of these patients are warranted. • While imaging and CSF sample are often used together to establish the diagnosis of CNS involvement in CTCL, our cases demonstrate that imaging alone may be sufficient in some cases. • Two of our cases demonstrate periorbital and ocular involvement. Our report, along with others, reinforce the importance of considering this presentation as high-risk for potential CNS progression. • This case series demonstrates the variable presentations and difficult prognoses represented by CNS metastases in CTCL. Further studies, improved treatment regimens, and more robust guidelines for management are needed to continue to improve outcomes for patients with CNS-metas

关键词： brain metastasis mycosis fungoides Sezary syndrome visceral

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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 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 in the Children's Oncology Group AALL0434 trial 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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