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Targeted tumor coating with antigenic, CTL-recognizable peptides via Annexin A5 chimeric constructs following chemotherapy redirects adaptive CD8+ T cell immunity for tumor clearance

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Cellular & Molecular Immunology 2021年第6期18卷 1578-1580页

作者： Tae Heung Kang Andrew Yang Yachea Tsai Louise Ferrall Chien-Fu Hung Institute of Biomedical Science and Technology Konkuk UniversitySeoulSouth Korea Genetics and Genomics Graduate Program Baylor College of MedicineHoustonTXUSA Medical Scientist Training Program Baylor College of MedicineHoustonTXUSA Department of Pathology Johns Hopkins UniversityBaltimoreMDUSA Department of Oncology Johns Hopkins UniversityBaltimoreMDUSA

A common drawback of many cancer immunotherapies,including immune checkpoint blockade,is their reliance on the expression of immunogenic tumor antigens by cancer cells for immune recognition and clearance,which limits their efficacy against cancers with weak antigenicity.1 To overcome this obstacle,we and others have explored strategies to harness the immune responses against nontumor antigens and redirect those immune responses to target tumor cells.2,3,4,5 In particular,we have pioneered a therapeutic strategy fusing tumor-targeting proteins with known antigenic peptide epitopes not naturally expressed by tumor cells,which are flanked by peptide sequences that can be recognized and cleaved by proteases overexpressed in most cancers.2,3 This strategy facilitates the targeted delivery of immunogenic peptides into tumor foci,the release of immunogenic peptides into the tumor microenvironment(TME)via tumor protease cleavage,and subsequent loading of these peptides onto major histocompatibility complex class 1(MHC-I)on the tumor cell surface,allowing the recognition of coated tumor cells by the respective peptide-specific cytotoxic CD8+T lymphocytes(CTLs)for elimination.

关键词： immunity overcome coating

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Epigenetic Control of an Auxiliary Subunit of Voltage-Gated Sodium Channels Regulates the Strength of Drug-Cue Associations and Relapse-Like Cocaine Seeking

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Biological Psychiatry 2025年

作者： Wood, Daniel J. Tsvetkov, Evgeny Comte-Walters, Susana Welsh, Colin L. Bloyd, Michelle Wood, Timothy G. Akiki, Rose Marie Anderson, Ethan M. Penrod, Rachel D. Madan, Lalima K. Ball, Lauren E. Taniguchi, Makoto Cowan, Christopher W. Department of Neuroscience Medical University of South Carolina Charleston South Carolina United States Medical Scientist Training Program Medical University of South Carolina Charleston South Carolina United States Department of Pharmacology and Immunology Medical University of South Carolina Charleston South Carolina United States

Background: Repeated use of addictive drugs produces long-lasting and prepotent drug-cue associations that increase vulnerability for relapse in individuals with a substance use disorder. Epigenetic factors, such as HDAC5 (histone deacetylase 5), play a key role in regulating the formation of drug-cue associations, but the underlying mechanisms remain unclear. Methods: We used a combination of molecular biology, cultured cells, tandem mass spectrometry, deacetylase activity measurements, co-immunoprecipitation, and molecular dynamics simulations to assess HDAC5 structure-activity relationships. In male and female Long Evans rats, we used viral-mediated expression of HDAC5 mutants in the nucleus accumbens (NAc) to test effects on cocaine intravenous self-administration and cue-reinstated cocaine seeking. We also used in silico analysis of single-nucleus RNA sequencing data, quantitative reverse transcriptase–polymerase chain reaction, viral-mediated expression of Scn4b short hairpin RNA, patch-clamp electrophysiology, and rat cocaine or sucrose SA to assess Scn4b's effects on NAc intrinsic excitability and cued reward seeking. Results: We discovered that 2 conserved cysteines located near HDAC5’s catalytic domain were required for its intrinsic deacetylase activity and that HDAC5’s deacetylase activity was required in NAc medium spiny neurons (MSNs) to limit relapse-like cue-reinstated cocaine seeking. Moreover, we found that HDAC5 limited cocaine-seeking, but not sucrose-seeking, behavior by reducing NAc MSN intrinsic excitability through the deacetylase-dependent repression of Scn4b, which codes for an auxiliary subunit of voltage-gated sodium channels. Conclusions: Our findings suggest that HDAC5’s control of NAc Scn4b expression governs the formation of cocaine-cue, but not sucrose-cue, associations through modulation of NAc MSN intrinsic excitability and drug-induced NAc plasticity mechanisms. © 2025 Society of Biological Psychiatry

关键词： Epigenetics Neuronal excitability Nucleus accumbens Reinstatement behavior Substance use disorder

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Cerebral Oxygenation Dynamics in Awake Behaving Mice

Cerebral Oxygenation Dynamics in Awake Behaving Mice

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Clinical and Translational Biophotonics, Translational 2022

作者： Zhang, Qingguang Roche, Morgane Gheres, Kyle W. Chaigneau, Emmanuelle Haselden, William D. Kedarasetti, Ravi T. Charpak, Serge Drew, Patrick J. Department of Engineering Science and Mechanics The Pennsylvania State University University ParkPA United States Institut National de la Santé et de la Recherche Médicale ParisU1128 France Laboratory of Neurophysiology and New Microscopies Université Paris Descartes Paris France Graduate Program in Molecular Cellular and Integrative Biosciences The Pennsylvania State University University ParkPA United States Medical Scientist Training Program and Neuroscience Graduate Program The Pennsylvania State University University ParkPA United States Department of Neurosurgery Department of Biomedical Engineering The Pennsylvania State University University ParkPA United States

We investigated (1) how and by what mechanisms voluntary exercise impacts brain tissue oxygenation, and (2) what is the origin of the 1/f-like oxygen fluctuations, in awake behaving mice. © 2022 The Author(s).

ISBN: (纸本)9781557528209

关键词： Mammals

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Orderly specification and precise laminar deployment of mouse cortical projection neuron types through intermediate progenitors

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Developmental Cell 2025年

作者： Huilgol, Dhananjay Levine, Jesse M. Galbavy, William Wang, Bor-Shuen Huang, Z. Josh Department of Neurobiology Duke University Medical Center Durham NC United States Department of Biomedical Engineering Duke University Durham NC United States Cold Spring Harbor Laboratory Cold Spring Harbor NY United States Program in Neuroscience and Medical Scientist Training Program Stony Brook University Stony Brook NY United States Program in Neuroscience Department of Neurobiology and Behavior Stony Brook University Stony Brook NY United States

The cerebral cortex comprises diverse types of glutamatergic projection neurons (PNs) generated from radial glial progenitors (RGs) through either direct neurogenesis (dNG) or indirect neurogenesis (iNG) via intermediate progenitors (IPs). A foundational concept in corticogenesis is the “inside-out” model, whereby successive generations of PNs sequentially migrate first to deep and then progressively to more superficial layers. However, its biological significance remains unclear, and the role of iNG in this process is unknown. Using genetic strategies linking PN birth dating to projection mapping in mice, we found that the laminar deployment of IP-derived PNs substantially deviates from a stringent inside-out rule: PNs destined to non-consecutive layers are generated at the same time, and different PN types of the same layer are generated at non-contiguous times. The overarching scheme of iNG is the sequential specification and precise laminar deployment of projection-defined PN types, which may contribute to the orderly assembly of cortical output channels and processing streams. © 2025 Elsevier Inc.

关键词： fate mapping indirect neurogenesis intermediate progenitors neocortex projection neurons

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Whole-body hyperthermia as a novel antidepressant therapy

Biomarkers in Neuropsychiatry

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Biomarkers in Neuropsychiatry 2025年 12卷 100124-100124页

作者： Gaitonde, Kevin D. Nasrallah, Henry A. Medical Scientist Training Program University of Cincinnati College of Medicine 3230 Eden Avenue Cincinnati 45267 OH United States Department of Psychiatry and Behavioral Neuroscience University of Cincinnati College of Medicine 260 Stetson Street Suite 3200 Cincinnati 45219 OH United States

First-line treatments for major depressive disorder include medication and cognitive behavioral therapy. While effective, pharmacotherapy often takes time to start demonstrating efficacy in symptomatic improvement and may be accompanied by adverse effects, indicating an ongoing need for new therapeutic approaches. A recently emerging somatic antidepressant intervention is whole-body hyperthermia, in which subjects are temporarily exposed to heat and then allowed to cool down. Recent studies employing hyperthermia-based strategies appear to show mood improvements both immediately and several weeks after the conclusion of treatment. However, published studies are often limited by their sample sizes and by their selection criteria. In this article, we review the literature on this novel approach and propose ideas regarding the possible physiological basis of this novel intervention and how it may be used in the future as adjunctive therapy with the current standard of care. © 2025 The Authors

关键词： Depression Hyperthermia Temperature Thermoregulation

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Semaphorin7A and PD-L1 cooperatively drive immunosuppression during mammary involution and breast cancer

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Cell Reports 2025年第5期44卷 115676页

作者： Elder, Alan M. Fairchild, Heather R. Kines, Kelsey T. Cozzens, Lauren M. Becks, Alexandria R. Slansky, Jill E. Anderson, Steven M. Lyons, Traci R. Division of Medical Oncology Department of Medicine School of Medicine University of Colorado Anschutz Medical Campus Aurora CO United States Cancer Biology Graduate Training Program University of Colorado Anschutz Medical Campus Aurora CO United States Medical Scientist Training Program University of Colorado Anschutz Medical Campus Aurora CO United States University of Colorado Cancer Center Aurora CO United States Department of Immunology and Microbiology School of Medicine University of Colorado Anschutz Medical Campus Aurora CO United States Young Women's Breast Cancer Translational Program University of Colorado Anschutz Medical Campus Aurora CO United States

Postpartum mammary gland remodeling after a pregnancy/lactation cycle is characterized by mechanisms of cell death and inflammation. Here, we show that SEMA7A promotes PD-L1 expression in immune cells of the mammary tissue during involution. These same phenotypes are mimicked in the microenvironment of SEMA7A-expressing tumors, which partially respond to αPD-1/αPD-L1 treatments in vivo. However, cells that remain after treatment are enriched for SEMA7A expression. Therefore, we tested a monoclonal antibody that directly targets SEMA7A-expressing tumors, in part, by reducing SEMA7A-mediated upregulation of PD-L1. In vivo, the SEMA7A monoclonal antibody reduces tumor growth and/or promotes complete regression of mouse mammary tumors, reduces some immunosuppressive phenotypes in the tumor microenvironment, and restores cytotoxic T cells, suggesting that SEMA7A may be a candidate for immune-based therapy for breast cancer patients. © 2025 The Author(s)

关键词： breast cancer CP: Cancer macrophage mammary gland involution PD-L1 semaphorin 7a tumor immunology tumor microenvironment

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Variable Presence of an Evolutionarily New Brain Structure Is Related to Trait Impulsivity

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Biological Psychiatry: Cognitive neuroscience and Neuroimaging 2025年

作者： Willbrand, Ethan H. Maboudian, Samira A. Elliott, Matthew V. Kellerman, Gabby M. Johnson, Sheri L. Weiner, Kevin S. Medical Scientist Training Program School of Medicine and Public Health University of Wisconsin-Madison Madison WI United States Helen Wills Neuroscience Institute University of California Berkeley Berkeley California United States Department of Neuroscience University of California Berkeley Berkeley California United States Department of Psychology University of California Berkeley Berkeley California United States

Background: Impulsivity is a multidimensional construct reflecting poor constraint over one's behaviors. Clinical psychology research has identified separable impulsivity dimensions that are each unique transdiagnostic indicators for psychopathology. However, despite this apparent clinical importance, the shared and unique neuroanatomical correlates of these factors remain largely unknown. Concomitantly, neuroimaging research has identified variably present human brain structures implicated in cognition and disorder: the folds (sulci) of the cerebral cortex located in the latest-developing and most evolutionarily expanded hominoid-specific association cortices. Methods: We tethered these 2 fields to test whether variability in one such structure in the anterior cingulate cortex (ACC)—the paracingulate sulcus (PCGS)—was related to individual differences in trait impulsivity. A total of 120 adult participants with internalizing or externalizing psychopathology completed a magnetic resonance imaging scan and the Three-Factor Impulsivity Index. Using precision imaging techniques, we manually identified the PCGS, when present, and acquired quantitative folding metrics (PCGS length and ACC local gyrification index). Results: Neuroanatomical-behavioral analyses revealed that participants with leftward or symmetrical PCGS patterns had greater severity of Lack of Follow Through (LFT)—which captures inattention and lack of perseverance—than those with rightward asymmetry. Neuroanatomical-functional analyses identified that the PCGS colocalized with a focal locus found in a neuroimaging meta-analysis on a feature underlying LFT. Neither quantitative folding metric related to any impulsivity dimension. Conclusions: This study advances understanding of the neuroanatomical correlates of impulsivity and establishes the notion that the topographical organization of distinct, hominoid-specific cortical expanses underlies separable impulsivity dimensions with robust, transdiagnostic

关键词： Cingulate cortex Impulsivity Neuroanatomy Neuroimaging Psychopathology Transdiagnostic

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Spatially Distributed Representation of Taste Quality in the Gustatory Insular Cortex of Behaving Mice (vol 31, pg 247, 2021)

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CURRENT BIOLOGY 2021年第2期31卷 450-450页

作者： Chen, Ke Kogan, Joshua F. Fontanini, Alfredo Department of Neurobiology and Behavior Stony Brook University Stony Brook NY 11794 USA Graduate Program in Neuroscience Stony Brook University Stony Brook NY 11794 USA Medical Scientist Training Program Stony Brook University Stony Brook NY 11794 USA

Visual, auditory, and somatosensory cortices are topographically organized, with neurons responding to similar sensory features clustering in adjacent portions of the cortex. Such topography has not been observed in the piriform cortex, whose responses to odorants are sparsely distributed across the cortex. The spatial organization of taste responses in the gustatory insular cortex (GC) is currently debated, with conflicting evidence from anesthetized rodents pointing to alternative and mutually exclusive models. Here, we rely on calcium imaging to determine how taste and task-related variables are represented in the superficial layers of GC of alert, licking mice. Our data show that the various stimuli evoke sparse responses from a combination of broadly and narrowly tuned neurons. Analysis of the distribution of responses over multiple spatial scales demonstrates that taste representations are distributed across the cortex, with no sign of spatial clustering or topography. Altogether, data presented here support the idea that the representation of taste qualities in GC of alert mice is sparse and distributed, analogous to the representation of odorants in piriform cortex.

关键词： gustatory cortex spatial representation taste two-photon imaging widefield imaging

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SPATIAL CRAVING PATTERNS IN MARIJUANA USERS: INSIGHTS FROM FMRI BRAIN CONNECTIVITY ANALYSIS WITH HIGH-ORDER GRAPH ATTENTION NEURAL NETWORKS

arXiv

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arXiv 2024年

作者： Ding, Jun-En Yang, Shihao Zilverstand, Anna Kulkarni, Kaustubh R. Gu, Xiaosi Liu, Fegn School of Systems and Enterprises Stevens Institute of Technology Hoboken United States Department of Psychiatry and Behavioral Sciences University of Minnesota MinneapolisMN55414 United States Medical Scientist Training Program The Icahn School of Medicine at Mount Sinai NY10027 United States Psychiatry and Neuroscience and directs the Center for Computational Psychiatry at Mount Sinai New York CityNY United States

The excessive consumption of marijuana can induce substantial psychological and social consequences. In this investigation, we propose an elucidative framework termed high-order graph attention neural networks (HOGANN) for the classification of Marijuana addiction, coupled with an analysis of localized brain network communities exhibiting abnormal activities among chronic marijuana users. HOGANN integrates dynamic intrinsic functional brain networks, estimated from functional magnetic resonance imaging (fMRI), using graph attention-based long short-term memory (GAT-LSTM) to capture temporal network dynamics. We employ a high-order attention module for information fusion and message passing among neighboring nodes, enhancing the network community analysis. Our model is validated across two distinct data cohorts, yielding substantially higher classification accuracy than benchmark algorithms. Furthermore, we discern the most pertinent subnetworks and cognitive regions affected by persistent marijuana consumption, indicating adverse effects on functional brain networks, particularly within the dorsal attention and frontoparietal networks. Intriguingly, our model demonstrates superior performance in cohorts exhibiting prolonged dependence, implying that prolonged marijuana usage induces more pronounced alterations in brain networks. The model proficiently identifies craving brain maps, thereby delineating critical brain regions for analysis. © 2024, CC BY.

关键词： Graph neural networks

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Immune checkpoint expression and relationships to anti-PD-L1 immune checkpoint blockade cancer immunotherapy efficacy in aged versus young mice

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Aging and Cancer 2022年第1期3卷 68-83页

作者： Garcia, Myrna G. Deng, Yilun Murray, Clare Reyes, Ryan M Padron, Alvaro Bai, Haiyan Kancharla, Aravind Gupta, Harshita Shen-Orr, Shai Curiel, Tyler J. South Texas Medical Scientist Training Program University of Texas Health San Antonio TX United States Graduate School of Biomedical Sciences University of Texas Health San Antonio TX United States Department of Medicine University of Texas Health San Antonio TX United States Senda Biosciences Cambridge MA United States Technion Israel Institute of Technology Haifa Israel Clayton Foundation for Research Houston TX United States Mays Cancer Center University of Texas Health San Antonio TX United States

Introduction: Aging is the biggest cancer risk, and immune checkpoint (IC) inhibition (ICI) is a revolutionary cancer immunotherapy approach. Nonetheless, there are limited preclinical/clinical data regarding aging effects on ICI outcomes or age effects on IC expression in different organs or tumors. Methods: Flow cytometry assessed IC on immune and non-immune cells in various organs in young and aged BL6 mice. Comparisons: aged versus young naïve WT versus interferon-γ^KO mice and WT challenged with B16F10 melanoma and treated with αPD-1 or αPD-L1 ICI. We co-cultured young and aged T cells and myeloid cells in vitro and used OMIQ analyses to test cell–cell interactions. Results: αPD-1 ICI treated melanoma in young and aged hosts, whereas αPD-L1 ICI was only effective in young. We found considerable, previously undescribed age effects on expression of various IC molecules participating in the ICI treatment, including PD-1, PD-L1, PD-L2, and CD80, in distinct organs and in the tumor. These data help explain differential ICI efficacy in young and aged hosts. Host interferon-γ influenced age effects on IC expression in both directions depending on specific IC molecule and tissue. IC expression was further affected by tumor challenge on immune, non-immune, and tumor cells in tumor and other organs. In in vitro co-culture, αPD-1 versus αPD-L1 distinctly influenced polyclonal T cells in young versus aged, suggesting mechanisms for distinct age-related ICI outcomes. Conclusion: Age affects IC expression on specific immune cells in an organ- and tissue-specific manner. ICs were generally higher on aged immune cells. High immune-cell PD-1 could help explain αPD-1 efficacy in aged. High co-expression of CD80 with PD-L1 on dendritic cells could help explain lack of αPD-L1 efficacy in aged hosts. Factors other than myeloid cells and interferon-γ also affect age-related IC expression and T cell function, meriting additional studies. © 2022 The Authors. Aging and Cancer

关键词： age cancer immunotherapy immune checkpoints interferon-γ PD-1 PD-L1

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