Medical Molecular Biology Commons^™

Adoptive Cell Therapies For Glioblastoma: A Quest For Cures From Within, Jia-Shiun Leu, Xin Ge, Charles Robin Yu, Guang Peng, Jiyong Liang

The Brown Foundation: Institute of Molecular Medicine

Glioblastomas (GBMs) are the most aggressive form of brain cancer recalcitrant to both current standard-of-care and immune checkpoint therapies that benefit other cancer patients. Adoptive cell therapies (ACT) using patients' own immune cells have long been explored as a treatment strategy, including the historically studied lymphokine-activated killer (LAK) cells, the evolving chimeric antigen receptor (CAR) directed immune cells, the newly emerging tumor-infiltrating T lymphocyte (TIL) therapies, and others. Preclinical and clinical studies have shown promise but also highlighted significant challenges. In this review, we summarize these findings, highlight recent developments, discuss current limitations, and emphasize how ACT may benefit from …

Claudins Interact With Lilrb Immune Inhibitory Receptors To Promote Myeloid Immunosuppression In Cancer, Xiaoye Liu, Ryan Huang, Zhiqiang Ku, Jingjing Xie, Heyu Chen, Yubo He, Qi Lou, Chengcheng Zhang, Xing Yang, Cheryl Lewis, Jade Homsi, Ankit Gupta, Lei Dong, Kenian Chen, Annabel Tu, Liming Du, Hailong Yu, Qing Hu, Meng Fang, Bufan Li, A E M Adan Khan, Caroline Simith, Samuel John, Lin Xu, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

The Brown Foundation: Institute of Molecular Medicine

The mechanisms underlying tumor cell-myeloid cell interactions in the tumor microenvironment (TME) remain unclear, and predictive biomarkers for patient response to myeloid checkpoint blockade are lacking. This study identified specific binding between tight junction claudins (CLDNs) and leukocyte immunoglobulin-like receptor subfamily B2 (LILRB2) and LILRB5. In multiple human cancer cohorts, the spatial proximity of LILRB2-positive macrophages to CLDN-expressing cancer cells correlated with clinical outcomes, highlighting this spatial relationship as a potential biomarker. In syngeneic LILRB2-transgenic and humanized mouse models, CLDN18.2-LILRB2 interactions triggered bidirectional signaling, enhanced the immunosuppressive activity of myeloid cells, and accelerated tumor progression. These effects were reversed by …

Transfusion In Transit: A Decade Of Prehospital Blood Transfusion In Pediatric Trauma, Krysta M Sutyak, Eunise C Chen, Lea Mock, Rudolfo Cabrera, Jeannette M Joly, Kuojen Tsao, Bryan A Cotton, David E Meyer, Charles S Cox, Kevin P Lally, Natalie A Drucker

The Brown Foundation: Institute of Molecular Medicine

Background: Prehospital blood transfusion improves mortality in adults, with limited evidence in children. This study describes prehospital blood transfusion in pediatric trauma patients and the impact on shock index, pediatric adjusted (SIPA).

Methods: This study is a retrospective cohort study of trauma patients younger than 18 years who received blood transfusions during helicopter transport to a Level 1 pediatric trauma center from 2011 to 2023. Primary outcome was change in SIPA at time of emergency department (ED) arrival with prehospital transfusion. Secondary subgroup analysis was performed based on transport origin.

Results: Of 137 patients, 58% (80 of 137 patients) were …

Affinity-Optimized Trop2 Antibodies Support Potent Antitumor Activity In Antibody-Drug Conjugates, Aiko Yamaguchi, Junping Hong, Leike Li, Kiyotaka Kobayashi, Chisato M Yamazaki, Summer Y Y Ha, Yasuaki Anami, Wei Xiong, Junquan Liu, Zhiqiang An, Ningyan Zhang, Kyoji Tsuchikama

The Brown Foundation: Institute of Molecular Medicine

Background: Trophoblast cell surface antigen 2 (TROP2) is frequently overexpressed in epithelial tumors and is associated with poor prognosis, making it an attractive therapeutic target. Antibody-drug conjugates (ADCs) directed against TROP2 show clinical benefit, but expression in normal tissues such as skin raises concerns about on-target, off-tumor toxicity. Strategies that improve antitumor efficacy without increasing toxicity are needed.

Methods: Using an in-house phage library, we identified and characterized a novel fully human monoclonal antibody recognizing a unique conformational epitope of TROP2 with reduced binding affinity. This antibody was engineered into homogeneous ADCs carrying auristatin and/or duocarmycin payloads. Comparative studies with …

Telomerase Knockout In Myeloid Cells Predisposes Mice To Foam Cell Formation, Dyslipidemia, Lung Fibrosis, And Cardiac Dysfunction, Zhanguo Gao, Yongmei Yu, David Wiggins, Eva M Sevick-Muraca, Mikhail G Kolonin

The Brown Foundation: Institute of Molecular Medicine

Aging-associated changes in myeloid cells are incompletely understood. One of the culprits of aging is the downregulation of the Tert gene coding for the catalytic subunit of telomerase. Studies of mouse models with Tert knockout (KO) in specific cells have revealed the importance of the telomere-independent noncanonical function of TERT in supporting mitochondrial metabolism and protection from cell senescence. To investigate the role of TERT in myeloid cells (MCs), we analyzed mice with Tert KO in the LysM+ lineage, indelibly labeled with membrane green fluorescent protein (mG). Macrophage numbers and properties in various organs were compared. Changes in the vasculature, …

Molecular Characterization Of Humanized Apoe Mouse Models Reveals Source And Genotype Dependent Differences, Na Wang, Gefei Yu, Zhen Wang, Alla Alnobani, Suren Jeevaratnam, Xue Zhang, Meghan Mcreynolds, Yuzhou Chang, Fangfang Qi, William Tauer, Cassandra Rosenberg, Melissa Wren, Tadafumi C Ikezu, Yuka A Martens, Minghui Wang, Bin Zhang, Gregory W Carter, Michael Sasner, David M Holtzman, Junmin Peng, Long-Jun Wu, Takahisa Kanekiyo, Chia-Chen Liu, Guojun Bu

The Brown Foundation: Institute of Molecular Medicine

Background

Humanized APOE targeted-replacement (TR) mice are essential tools for studying apoE isoform effects in Alzheimer’s disease (AD) and other apoE-related disorders. Despite their widespread use, existing APOE mouse models, generated with different gene targeting strategies, have not been directly compared in terms of apoE isoform expression, lipid profiles, and transcriptomic signatures. Such differences could impact how we interpret APOE genotype-related outcomes, as well as related underlying molecular mechanisms.

Methods

We conducted a comprehensive molecular comparison of humanized APOE mouse models from three sources: Taconic Biosciences (TAC), the Cure Alzheimer’s Fund (CAF), and The Jackson Laboratory (JAX). We assessed apoE …

Γδ T Cells At The Interface Of Innate And Adaptive Immunity In Cancer, Arnau Solé Casaramona, Martin F Bachmann, Eva Sevick-Muraca, Mona O Mohsen

The Brown Foundation: Institute of Molecular Medicine

γδ T cells are unconventional lymphocytes that bridge innate and adaptive immunity by combining recognition of stress-induced ligands independently of classical major histocompatibility complex molecules with the capacity to undergo clonal expansion and long-term adaptation. Their unusual ability to detect malignant transformation using semi-invariant T-cell receptors, butyrophilin recognition and natural killer-like receptors positions them as powerful effector cells in tumors that evade classical immune escape mechanisms. Furthermore, distinct γδ subsets have distinct phenotyping and specific tissue-residencies, which could be leveraged to modulate immunological responses. We evaluate engineered therapies and different experimental platforms for studying γδ T cell biology. We conclude …

Brain-Engrafted Monocyte-Derived Macrophages From Blood And Skull-Bone Marrow Exhibit Distinct Properties, Siling Du, Feiya Ou, Antoine Drieu, Eric Z Xu, Yumeng Cheng, Steffen E Storck, Tornike Mamuladze, Jay Cao, Nora Abduljawad, Bishan Bhattarai, Justin Rustenhoven, Niall Mortimer, Simone Brioschi, Khai Nguyen, Patrick Fernandes Rodrigues, Igor Smirnov, Daniel Gibson, J Michael White, Wandy Beatty, David Denardo, Qingyun Li, Michael Meers, Claudia Z Han, Na Sun, Florent Ginhoux, Marina Cella, Marco Colonna, Jonathan Kipnis

The Brown Foundation: Institute of Molecular Medicine

Microglia arise from yolk sac progenitors and are thought to persist throughout life with minimal input from adult hematopoiesis. However, whether brain-engrafted monocyte-derived macrophages (MDMs) exist at homeostasis and during turnover and how they function relative to yolk-sac-derived microglia (YSMs) remain unsettled. Here, we combine lineage tracing, pharmacological microglia depletion, and multi-omics profiling to define the ontogeny, identity, and function of brain parenchymal macrophages. Despite sharing the parenchymal milieu, MDMs display transcriptional and epigenetic landscapes distinct from YSMs. Fate-mapping reveals that brain-engrafted MDMs transiently express CD206, echoing a developmental stage of microglial precursors. MDM engraftment and polarization are modulated by …

Single Ventricle Physiology May Not Preclude Cardiac Repair In The Setting Of Congenital Diaphragmatic Hernia, Kylie I Holden, Michael C Scott, Ashley H Ebanks, Amir M Khan, D Michael Mcmullan, Anthony Johnson, Charles S Cox, Matthew T Harting, Damien J Lapar

The Brown Foundation: Institute of Molecular Medicine

Objective: Management for congenital heart disease (CHD) with congenital diaphragmatic hernia (CDH), particularly in single ventricle physiology, is challenging, with limited studies showing poor outcomes. This investigation evaluated outcomes for these complex patients.

Methods: This retrospective cohort study (2007-2022) from the CDH Study Group analyzed mortality in patients with CDH and single ventricle physiology, using standard statistical methods and Cox regression for estimation.

Results: A total of 9,261 CDH patients were identified, including 1,886 with CDH + CHD and 131 with single ventricle physiology. The median gestational age was 38 weeks and birthweight was 2.8 kg. Of 131 patients, 34 …

Estimating Population Structure Using Epigenome-Wide Methylation Data, Ziqing Wang, Kent D Taylor, Jerome I Rotter, Stephen S Rich, Yinan Zheng, Lifang Hou, Xiuqing Guo, Jan Bressler, Laura M Raffield, Yongmei Liu, Robert Kaplan, Donald M Lloyd-Jones, Alanna C Morrison, Myriam Fornage, Bruce M Psaty, Jennifer A Brody, Tamar Sofer

The Brown Foundation: Institute of Molecular Medicine

Population stratification is one of the source of inflation in epigenome-wide association studies (EWAS) when not properly accounted for. To address this, we developed methylation population scores (MPSs) to predict genetic principal components (GPCs) using a feature selection approach. We used multi-ethnic DNA methylation data from Illumina EPIC arrays across five cohorts, including MESA (n = 929), CARDIA (n = 1123), JHS (n = 1365), ARIC (n = 2338), and HCHS/SOL (n = 1475), randomly splitting participants into training (85%) and test (15%) sets. Within each cohort, associations between GPCs and CpG sites were estimated using linear regression adjusting for …

Human-Centered Design Of Patient Interviews: Capturing The Experiences Of Patients Recovering From Emergency Abdominal Surgery, Jenna L Marquard, Christie L Martin, Elizabeth C Wick, Amanda C Trofholz, Matthew S Loth, Suhyun Park, Genevieve B Melton

The Brown Foundation: Institute of Molecular Medicine

Objectives: Recognizing the challenges of at-home recovery following a truncated presurgical pathway for emergency laparotomy (EL) patients, we sought to identify barriers and facilitators to optimal recovery. This study aimed to develop a human-centered interview guide to capture the experiences of patients recovering at home after EL.

Methods: We employed an iterative human-centered design (HCD) approach to interview guide development, structured across 3 cycles. Each cycle refined the interview guide based on mock interviews and feedback from an interdisciplinary team. In cycle 1, we focused on creating a patient-centered, understandable guide. In cycle 2, we introduced a preinterview survey to …

Diversity And Immune Dynamics Of Choroid Plexus Macrophages Are Shaped By Distinct Developmental Origins, Siling Du, Khai M Nguyen, Alina Ulezko Antonova, Jose L Fachi, Patrick Fernandes Rodrigues, Alice Verdiani, Martina Molgora, Igor Smirnov, Jasmin Herz, Tornike Mamuladze, Jennifer Ponce, Amanda Swain, Mattia Bugatti, Susan Gilfillan, Marina Cella, William Vermi, Jonathan Kipnis, Marco Colonna, Simone Brioschi

The Brown Foundation: Institute of Molecular Medicine

The choroid plexus forms a key barrier and signaling interface between the brain and peripheral circulation, yet its immune landscape remains incompletely understood. Using single-cell transcriptomics combined with lineage and spatial tracing methods, we identified three biologically distinct populations of choroid plexus macrophages, defined by differential expression of CD163, MHCII or CD9. These subsets arise from separate hematopoietic waves, occupy distinct anatomical niches and differentially rely on CSF1 and IL-34 for survival. We found that TGFβ signaling is essential to maintain their tissue-specific identities, and deletion of Tgfbr2 in these cells induces broad phenotypic reprogramming. During neuroinflammation, choroid plexus macrophages …

Lipids Grease The Chain Of Cancer Progression, Joseph Rupert, Pham Hong Anh Cao, Daniel E Frigo, Mikhail G Kolonin

The Brown Foundation: Institute of Molecular Medicine

The role of lipids in cancer progression has become a fervent area of exploration. The crosstalk of tumors with adipose tissue is a complex but well-regulated orchestration of signaling pathways, lipid transporters, and enzymes. They regulate fatty acid synthesis, their deposition into lipid droplets (LDs) as triglycerides, induction of lipolysis, shuttling lipids across cells, and their systemic trafficking, modification, and catabolism. For the latter, lipid oxidation has emerged as a metabolic process of particular clinical importance. Products of lipid processing can become secondary messengers, contribute to reactive oxygen species (ROS) generation, stimulate the production of antioxidants, and, if left unchecked, …

Neutralization Of Sars-Cov-2 By Igm-14 Via Engagement Of Two Distinct Spike Epitopes, Yan Wang, Yanping Hu, Zhiqiang Ku, Jason Yeung, Jing Zou, Michael Woodson, Nikolai S Prokhorov, Ekaterina S Knyazhanskaya, Haiqing Zhao, Michael B Sherman, Zhiqiang An, Stephen F Carroll, Pei-Yong Shi, Petr G Leiman, Xuping Xie

The Brown Foundation: Institute of Molecular Medicine

Engineered immunoglobulin M (IgM) antibodies typically exhibit superior neutralization potency and avidity compared to their parental IgG counterparts, primarily due to multivalent binding to repeated epitopes on a targeting antigen. In this study, we characterize the neutralization breadth and mechanism of action of IgM-14, a previously reported intranasally deliverable antibody targeting SARS-CoV-2. IgM-14 demonstrates remarkably potent antiviral activity against all pre-Omicron variants but significantly reduced efficacy against Omicron BA.1, and complete loss of activity against the later subvariant JN.1. Resistance selection identified two key mutations in the receptor-binding domain (RBD), G476D and F486P, which disrupt IgM-14 binding and confer strong …

Glutamatergic Dysfunction Of Astrocytes In Paraventricular Nucleus Of Thalamus Contributes To Adult Anxiety Susceptibility In Adolescent Ethanol Exposed Mice, Aubrey Bennett, Hyunjung Kim, David Thomas, Peter Biggs, Roxan Ara, Asamoah Bosomtwi, Seungwoo Kang

The Brown Foundation: Institute of Molecular Medicine

Repeated ethanol exposure during adolescence increases adult anxiety risk, but the underlying mechanisms remain unclear. The paraventricular nucleus of the thalamus (PVT) has been considered a hub for controlling anxiety and is affected by experiences from early life. Thus, this study investigated how adolescent intermittent repeated ethanol exposure (AIE) affects the PVT activities and anxiety-related behaviors in adulthood. We found that AIE triggers anxiety-like behaviors and parallelly exhibited elevated firing rates and increased calcium signaling in the PVT neurons compared to control counterpart mice. Chemogenetic inhibition of PVT neurons reduced anxiety-like behaviors in AIE-treated animals, confirming PVT's role in adolescent …

Multi-Ancestry Genome-Wide Association Study And Meta-Analysis Of Lung Function Decline, Bonnie K Patchen, Jingwen Zhang, Nathan Gaddis, Traci M Bartz, Jing Chen, Catherine Debban, Hampton Leonard, Ngoc Quynh H Nguyen, Jungkyun Seo, Courtney Tern, Richard Allen, Dawn L Demeo, Myriam Fornage, Carl Melbourne, Melyssa Minto, Matthew Moll, George T O'Connor, Tess Pottinger, Bruce M Psaty, Stephen S Rich, Jerome I Rotter, Edwin K Silverman, Jeran Stratford, Chengyue Zhang, R Graham Barr, Michael H Cho, Sina A Gharib, Ani Manichaikul, Kari North, Elizabeth C Oelsner, Eleanor M Simonsick, Martin D Tobin, Bing Yu, Seung Hoan Choi, Josée Dupuis, Patricia A Cassano, Dana B Hancock

The Brown Foundation: Institute of Molecular Medicine

Background

Despite evidence for a genetic component, few genetic associations with lung function decline have been identified. We aimed to evaluate genome-wide associations and putative downstream functionality of genetic variants for lung function decline.

Methods

We conducted genome-wide association study (GWAS) analyses of decline in FEV1, FVC, and FEV1/FVC in 52,056 White (N = 44,988), Black (N = 5,788), Hispanic (N = 550), and Chinese American (N = 730) participants across seven general population cohorts. GWAS analyses were stratified by cohort, ancestry, and sex. Results were combined in cross-ancestry and ancestry-specific meta-analyses. Significant variants available in …

Human Microglia In Brain Assembloids Display Region-Specific Diversity And Respond To Hyperexcitable Neurons Carrying Scn2a Mutation, Jiaxiang Wu, Xiaoling Chen, Jingliang Zhang, Kyle Wettschurack, Morgan Robinson, Weihao Li, Yuanrui Zhao, Ye-Eun Yoo, Brody A Deming, Yue Shu, Akila D Abeyaratna, Zhefu Que, Dongshu Du, Matthew Tegtmeyer, Chongli Yuan, William C Skarnes, Zhong-Yin Zhang, Jean-Christophe Rochet, Long-Jun Wu, Yang Yang

The Brown Foundation: Institute of Molecular Medicine

Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABAB receptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders, including autism. Using chemogenetics to activate …

The Neuroprotective Effects Of Alpha-Tocopherol As An Anti-Inflammatory Agent: Mechanistic Insights And Therapeutic Challenges, Megumi H Seese, Yuanzhong Xu

The Brown Foundation: Institute of Molecular Medicine

Vitamin E (alpha-tocopherol, αToc), an antioxidant fat-soluble vitamin that prevents lipid peroxidation and modulates pro-inflammatory cytokine production, is well-known to be critical for neuroprotection. However, the underlying mechanism remains poorly understood. Accumulating evidence demonstrates that αToc influences neuroinflammatory processes. Here, we review recent research progress on the effects of αToc on neuroinflammation. Preclinical studies included in this narrative review were identified through PubMed searches using the keywords "alpha-tocopherol AND neuroinflammation or alpha-tocopherol AND brain AND inflammation". While many studies support a neuroprotective role of αToc, the magnitude and direction of its effects vary substantially depending on dosage, route of administration, …

Lymphatic Pumping Failure In The Arm Precedes Dermal Backflow And Breast Cancer-Related Lymphedema, Melissa B Aldrich, Meghan E Mcwain, Simona F Shaitelman, Rian E Kuhns, John C Rasmussen, Wendy A Woodward, Sarah M Desnyder, Wenyaw Chan, Eva M Sevick-Muraca

The Brown Foundation: Institute of Molecular Medicine

Background

Breast cancer patients who undergo regional nodal irradiation therapy (RNI) following neoadjuvant chemotherapy and mastectomy or lumpectomy with axillary lymph node dissection (ALND) frequently encounter breast cancer-related lymphedema (BCRL). Early detection and treatment can significantly improve outcomes. Previously, near-infrared fluorescence lymphatic imaging (NIRF-LI) detection of dermal backflow, or retrograde lymphatic flow into initial lymphatics, was shown to precede clinical BCRL diagnosis by 8–23 months. Herein, we hypothesize that lymphatic pump failure is responsible for dermal backflow and may be a target to prevent onset of BCRL symptoms.

Methods

Arm lymphatics in 51 patients with locally advanced breast cancer were …

Does Hla-B27 Status Influence Ixekizumab Efficacy In Axial Spondyloarthritis? Results From The Coast-V, Coast-W, And Coast-X Trials, John D Reveille, Martin Rudwaleit, Proton Rahman, Jose A Maldonado-Cocco, Marina Magrey, Rebecca Bolce, Khai Jing Ng, Theresa Hunter Gibble, Jeffrey Lisse, So Young Park, Andris Kronbergs, Victoria Navarro-Compán

The Brown Foundation: Institute of Molecular Medicine

Introduction: The human leukocyte antigen (HLA)-B27 is associated with axial spondyloarthritis (axSpA) and is a predictor of response to tumor necrosis factor inhibitors. However, limited data are available on HLA-B27 and interleukin-17 inhibitors. We evaluated the influence of HLA-B27 status on ixekizumab response through 52 weeks in patients with axSpA.

Methods: Data were analyzed from three randomized placebo-controlled trials: COAST-V (NCT02696785), COAST-W (NCT02696798), and COAST-X (NCT02757352). Patients fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria for radiographic (r)-axSpA or non-radiographic (nr)-axSpA. Patients were randomized to receive 80 mg ixekizumab every 2 weeks, 80 …

Gh Alters Lymphatic Vessels In Female Mice And Stat5 Phosphorylation In Human Lymphatic Endothelial Cells, Christopher Walsh, Emily Scott, Elise Wagner, Jerome Walsh, Shashank Reddy, Arshad Ahmad, Reetobrata Basu, Eva Sevick-Muraca, Rich Brody, Uday Sandbhor, Sebastian Neggers, John J Kopchick

The Brown Foundation: Institute of Molecular Medicine

Disruption of lymphatic function underlies a broad spectrum of inflammatory and metabolic disorders, yet the hormonal pathways that regulate lymphatic biology remain poorly defined. GH, which is implicated in similar disease states, has an unclear role in lymphatic homeostasis. To address this gap, we investigated how chronic alterations in GH signaling alter lymphatic structure and function. Using transgenic mouse lines with increased, decreased, or absent GH action, we quantified the effect of GH on lymphatic pumping rate and lymphangiogenic remodeling during wound healing using near-infrared fluorescent imaging. We also measured markers of lymphatic endothelial cells using Western blot and immunohistochemistry …

Corticotropin-Releasing Factor Neurons In The Bed Nucleus Of The Stria Terminalis Modulate Avoidance Behaviors And Feeding, Juan Manuel Romero, Shae-Marie Stafford-Trujillo, Mitzy Mendoza, Pey-Shyuan Chin, Snigdha Srivastava, Mikhail Kochukov, Qingchun Tong, Benjamin Russell Arenkiel

The Brown Foundation: Institute of Molecular Medicine

Introduction: Animals rely on defensive avoidance of exposed or potentially threatening environments as a fundamental survival strategy, often expressing this behavior as thigmotaxis, or a preference for the periphery of an open space. However, researchers still do not understand how neural circuits coordinate avoidance behavior with competing physiological drives such as feeding. In this study, we investigate how corticotropin-releasing factor (CRF)-expressing neurons in the bed nucleus of the stria terminalis (BNST) integrate environmental avoidance and feeding behavior.

Methods: We used adult male and female mice and applied fiber photometry to monitor BNST CRF neuronal activity in vivo. We performed both …

Targeting Nuclear Receptors In Muscular Dystrophies And Regenerative Myogenesis, Eira Mann, Hoang Vu, Vihang A Narkar, Yu Liu

The Brown Foundation: Institute of Molecular Medicine

Skeletal muscle is a highly plastic tissue with a robust capacity for regeneration, largely driven by resident satellite cells. Muscular dystrophies comprise a heterogeneous group of inherited disorders characterized by progressive muscle degeneration, chronic inflammation, and impaired regenerative capacity. Despite well-defined genetic etiologies, effective disease-modifying therapies for these disorders, as well as many acquired myopathies, remain limited. Emerging evidence identifies nuclear receptors (NRs) as key regulators of skeletal muscle homeostasis, integrating hormonal, metabolic, and environmental signals to control transcriptional programs governing mitochondrial function, metabolism, inflammation, and myogenesis. In this review, we summarize the diverse roles and mechanisms of action of …

Immune Checkpoint Inhibitor-Induced Cardiotoxicity: From Immune Mechanisms To Clinical Surveillance And Targeted Therapies, Nathan K Chen, Kathryn D Hok, Narsi Chokshi, Anthony Shadid, Haydn E Rich, Lavanya Gunamalai, Marie-Francoise Doursout, Nirmal K Banda, Pooja Shivshankar

The Brown Foundation: Institute of Molecular Medicine

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape across a broad range of malignancies by restoring antitumor immunity through blockade of key inhibitory immune pathways, including programmed death receptor-1 (PD-1), programmed death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Yet the same widespread immune activation that drives their therapeutic benefit renders patients susceptible to immune-related adverse events (irAEs). Among these cardiovascular toxicities have emerged as a particularly critical concern, drawing growing attention within the evolving field of cardio-oncology. ICI-associated cardiotoxicity encompasses a broad clinical spectrum, ranging from myocarditis and pericarditis to arrhythmias, heart failure, and vascular complications. Of these, …

Novel Physical And Biological Applications Of Carbon Ion Radiotherapy, Danushka Seneviratne, Prapannajeet Biswal, Sunil Krishnan

The Brown Foundation: Institute of Molecular Medicine

Carbon ion radiation therapy (CIRT) is a high-LET radiotherapy, which distinguishes itself from traditional low-LET radiation, such as photons and protons, through its unique physical aspects, biological attributes, and the dramatically increased damage it causes within cellular DNA. Given its distinctive characteristics, it is expected to improve the therapeutic ratio of radiation treatments and enhance treatment outcomes in traditionally radiation-resistant tumor histologies. Despite these unique properties, much remains to be understood regarding the clinical use of CIRT before its full potential can be realized. In this review, we summarize the distinct advantages of CIRT with regard to its physical and …

Titin-Related Familial Dilated Cardiomyopathy: Factors Associated With Disease Onset, Renee Johnson, Robert A Fletcher, Stacey Peters, Monique Ohanian, Magdalena Soka, Andrei Smolnikov, Katherine E Abihider, Michael J Ackerman, Flavie Ader, Mohammed M Akhtar, Ahmad S Amin, Euan A Ashley, John J Atherton, Rachel Austin, Annette F Baas, Richard D Bagnall, Samantha Barratt Ross, Jean-Louis Blouin, Emily E Brown, Henning Bundgaard, Douglas Cannie, Przemyslaw Chmielewski, Gemma Correnti, Maria Generosa Crespo-Leiro, Matteo Dal Ferro, Lisa M Dellefave-Castillo, Fernando Dominguez, Dennis Dooijes, Anne M Dybro, Youssef Ed Demri, Mohamed El Hachmi, Luis Escobar-Lopez, Sarah Jajesnica Foye, Maria Franaszczyk, Marta Gigli, Esther Gonzalez Lopez, Adeline Goudal, Sharon Graw, Michel Guipponi, Eric Haan, Jan Haas, Daniel J Hammersley, Frederikke G Hansen, Christopher S Hayward, Thomas Morris Hey, Stephane Heymans, Carolyn Y Ho, Arjan C Houweling, Jodie Ingles, Angela Ingrey, Andrew Jabbour, Paul A James, Joeri A Jansweijer, Jan D H Jongbloed, Anne M Keogh, Jose M Larrañaga-Moreira, Ronald H Lekanne Deprez, Ivan Macciocca, Peter S Macdonald, Nicolas Mansencal, Julia Mansour, Cristina Martinez-Veira, Barbara Mcdonough, Julie Mcgaughran, Kristen Medo, Marco Merlo, Ewa Michalak, Lorenzo Monserrat, Helen Mountain, Steven A Muller, Anne M Murphy, Brittney Murray, Emily C Oates, Elizabeth Ormondroyd, Nicholas Pachter, Alessia Paldino, Aurélien Palmyre, Naveen L Pereira, Kermshlise C Picard, Nicola Poplawski, Sanjay Prasad, Julie Proukhnitzky, Jean-Francois Pruny, Patricia Reant, Pascale Richard, Anne Ronan, Farbod Sedaghat-Hamedani, Christopher Semsarian, Garrett Storm, Sophie Stroeks, Petros Syrris, Matthew R G Taylor, Kate Thomson, Tina Thompson, J Peter Van Tintelen, Christoffer Rasmus Vissing, Kathryn E Waddell-Smith, Mathew Wallis, Dominica Zentner, Clare Arnott, Ali J Marian, Jaewon Oh, Siv Fokstuen, Cynthia A James, Roberto Barriales-Villa, Benjamin Meder, Karim Wahbi, John R Giudicessi, Victoria N Parikh, James S Ware, Nicolas Piriou, Caroline Rooryck, Neal K Lakdawala, Luisa Mestroni, Gianfranco Sinagra, Perry M Elliott, Hugh Watkins, Elizabeth M Mcnally, Philippe Charron, Karin Y Van Spaendonck-Zwarts, Pablo Garcia-Pavia, Maria Luisa Peña-Peña, Jens Mogensen, Alex Hoerby Christensen, Zofia T Bilińska, Torsten B Rasmussen, Jonathan G Seidman, Christine E Seidman, Anneline S J M Te Riele, Job A J Verdonschot, Yigal M Pinto, Imke Christiaans, Diane Fatkin

The Brown Foundation: Institute of Molecular Medicine

Background and aims: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv.

Methods: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM.

Results: A total of 3158 subjects in 1043 …

Epidemiological Patterns And Variability In Acute Brain Injury: A Multicenter Registry Analysis In South Korea's Neurocritical Care Units, Heewon Jeong, So Hee Park, Yoon-Hee Choo, Dong-Wan Kang, Yong Soo Kim, Bosco Seong Kyu Yang, Huimahn Alex Choi, Sung-Min Cho, Eun Jin Ha, Jiwoong Oh, Han-Gil Jeong

The Brown Foundation: Institute of Molecular Medicine

Background: Specialized neurocritical care (NCC) improves outcomes in acute brain injury (ABI), but significant variability exists in practices across and hospitals within South Korea's developing national NCC system. This study aims to assess clinical variability among patients with ABI across six tertiary NCC units (NCCUs) in South Korea and evaluate center-specific effects on clinical outcomes.

Methods: A multicenter registry of patients with ABI admitted to NCCUs between April 2023 and April 2024 was analyzed. A descriptive analysis was conducted to evaluate demographic, clinical, and treatment characteristics across centers. Variability across centers was quantified using the average standardized mean difference (SMD) …

Ddt Exposure Induces Microglial Activation And Disease-Associated Microglial Signatures: Relevance To Mechanisms Of Alzheimer’S Disease, Isha Mhatre-Winters, Aseel Eid, Nicole Blum, Yoonhee Han, Ferass M Sammoura, Long-Jun Wu, Jason R Richardson

The Brown Foundation: Institute of Molecular Medicine

Background: Alzheimer's disease (AD) is characterized by the presence of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the primary metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were significantly higher in AD patients compared to age-matched controls and that DDT exposure worsened AD pathology in animal models.

Objective: Here, we investigated the effect of DDT on neuroinflammation in primary mouse microglia (PMG) and C57BL/6J mice.

Methods: DDT-induced inflammatory and disease-associated microglial (DAM) gene expression were determined in PMG by qPCR and immunocytochemistry, with and without pretreatment with the sodium channel antagonist tetrodotoxin (TTX). Furthermore, …

Impact Of Common Variants On Brain Gene Expression From Rna To Protein To Schizophrenia Risk, Qiuman Liang, Yi Jiang, Annie W Shieh, Dan Zhou, Rui Chen, Feiran Wang, Meng Xu, Mingming Niu, Xusheng Wang, Dalila Pinto, Yue Wang, Lijun Cheng, Ramu Vadukapuram, Chunling Zhang, Kay Grennan, Gina Giase, Kevin P White, Junmin Peng, Bingshan Li, Chunyu Liu, Chao Chen, Sidney H Wang

The Brown Foundation: Institute of Molecular Medicine

Genetic variants influencing gene expression have been extensively studied at the transcriptional level. How these variants affect downstream processes remains unclear. We quantitated ribosome occupancy in prefrontal cortex samples from the BrainGVEX cohort and integrated these data with transcriptomic and proteomic profiles from the same individuals. Through cis-QTL mapping, we identified genetic variants associated with transcript level (eQTLs), ribosome occupancy (rQTLs), and protein level (pQTLs). Notably, only 34% of eQTLs have their effects propagated to the protein levels, suggesting widespread post-transcriptional attenuation. Using both a gene-based approach and a variant-based approach we identified omics-specific QTLs that associated with brain disorder …

Advances In Artificial Intelligence For Glioblastoma Radiotherapy Planning And Treatment, Reid Master, Nesha Rubin, James Sampson, Kamlesh K Yadav, Shruti Pandita, Aria Sabbagh, Anika Krishnan, Patrick J Silva, Kenneth S Ramos, Vincent Gregoire, Nikos Paragios, Sunil Krishnan, Tej K Pandita

The Brown Foundation: Institute of Molecular Medicine

Glioblastoma is an aggressive central nervous system tumor characterized by diffuse infiltration. Despite substantial advances in oncology, survival outcomes have shown little improvement over the past three decades. Radiotherapy remains a cornerstone of treatment; however, it faces several challenges, including considerable inter-observer variability in clinical target volume delineation, dose constraints associated with adjacent organs at risk, and the persistently poor prognosis of affected patients. Recent advances in artificial intelligence, particularly deep learning, have shown promise in automating radiation therapy mapping to improve consistency, accuracy, and efficiency. This narrative review explores current auto segmentation frameworks, dose mapping, and biologically informed radiotherapy …