Review
Abstract
The American Physician Scientists Association (APSA) was founded in 2003 with a mission to build a unified community for physician-scientist trainees. Over the past 2 decades, the APSA has played a pivotal role in fostering the development of future physician-scientists through mentorship, advocacy, and professional development. This year, the APSA hosted its 20th Annual Meeting in Chicago in collaboration with the Association of American Physicians and the American Society for Clinical Investigation. This milestone marks a moment of celebration and reflection, highlighting APSA’s enduring impact on the future of physician-scientist training.
Authors
Cynthia Y. Tang, Alex D. Waldman, Daniel C. Brock
Abstract
Long COVID is a debilitating condition that can develop after a SARS-CoV-2 infection and is characterized by a wide range of chronic symptoms, including weakness, neurocognitive impairment, malaise, fatigue, and many others, that affect multiple organ systems. At least 10% of individuals with a previous infection may develop long COVID, which affects their ability to perform daily functions and work. Despite its severity and widespread impact, this multisystemic condition remains poorly understood. Recent studies suggest that dysregulation of the complement system, a key component of the innate immune response, may contribute to the pathogenesis of long COVID, particularly in connection with coagulation, inflammation, and vascular injury. In this Review, we examine the evidence linking complement system dysregulation to long COVID and explore its potential role in driving disease pathology.
Authors
Rafael Bayarri-Olmos, William Bain, Akiko Iwasaki
Abstract
Transcription factors (TFs) play a pivotal role in the development and differentiation of T cells. Recent studies have highlighted unique transcriptional profiles in chimeric antigen receptor T (CAR-T) cells derived from patients with favorable clinical outcomes, suggesting a potential link between TF modulation and improved therapeutic efficacy. Although CAR-T cell therapies have shown some success in treating hematological malignancies, they are limited by challenges such as poor persistence, functional exhaustion, and tumor resistance. To overcome these limitations, researchers have attempted to enhance the efficacy of CAR-T cells through manipulation of TF expression. This Review provides a comprehensive overview of TF engineering in CAR-T cells and elucidates the complex regulatory network between TFs. Notably, modification of basic leucine zipper ATF-like transcription factor in CAR-T cells results in contradictory functional outcomes in different studies. We summarize the potential factors leading to such results and elucidate the importance of setting up a relevant in vitro model to evaluate the effect of TFs on CAR-T cells. In conclusion, this Review highlights the latest advances in TF modifications and proposes strategies for harnessing these insights to empower CAR-T cells with superior antitumor efficacy.
Authors
Ruoqi Chen, Lianqing Chen, Yu Tang, Xiaolin Shen, Yajie Wang, Peng Tang, Xingchao Shentu, Jie Sun
Abstract
The cardiopulmonary vasculature and its associated endothelial cells (ECs) play an essential role in sustaining life by ensuring the delivery of oxygen and nutrients. Beyond these foundational functions, ECs serve as key regulators of immune responses. Recent advances in single-cell RNA sequencing have revealed that the cardiopulmonary vasculature is composed of diverse EC subpopulations, some of which exhibit specialized immunomodulatory properties. Evidence for immunomodulation includes distinct expression profiles associated with antigen presentation, cytokine secretion, immune cell recruitment, translocation, and clearance — functions critical for maintaining homeostasis in the heart and lungs. In cardiopulmonary diseases, ECs undergo substantial transcriptional reprogramming, leading to a shift from homeostasis to an activated state marked by heightened immunomodulatory activity. This transformation has highlighted the critical role for ECs in disease pathogenesis and their potential as future therapy targets. This Review emphasizes the diverse functions of ECs in the heart and lungs, particularly adaptive and maladaptive immunoregulatory roles in cardiopulmonary health and disease.
Authors
Elisabeth Fließer, Katharina Jandl, Shiau-Haln Chen, Mei-Tzu Wang, Jonas C. Schupp, Wolfgang M. Kuebler, Andrew H. Baker, Grazyna Kwapiszewska
Abstract
Epilepsy has a profound impact on quality of life. Despite the development of new antiseizure medications (ASMs), approximately one-third of affected patients have drug-refractory epilepsy and are nonresponsive to medical treatment. Nearly all currently approved ASMs target neuronal activity through ion channel modulation. Recent human and animal model studies have implicated new immunotherapeutic and metabolomic approaches that may benefit patients with epilepsy. In this Review, we detail the proinflammatory immune landscape of epilepsy and contrast this with the immunosuppressive microenvironment in patients with glioma-related epilepsy. In the tumor setting, excessive neuronal activity facilitates immunosuppression, thereby contributing to subsequent glioma progression. Metabolic modulation of the IDH1-mutant pathway provides a dual pathway for reversing immune suppression and dampening seizure activity. Elucidating the relationship between neurons and immunoreactivity is an area for the prioritization and development of the next era of ASMs.
Authors
Shashwat Tripathi, Cody L. Nathan, Matthew C. Tate, Craig M. Horbinski, Jessica W. Templer, Joshua M. Rosenow, Timothy L. Sita, Charles D. James, Benjamin Deneen, Stephen D. Miller, Amy B. Heimberger
Abstract
Spinal muscular atrophy (SMA) is a pediatric-onset neuromuscular disorder caused by insufficient survival motor neuron (SMN) protein. SMN restorative therapies are now approved for the treatment of SMA; however, they are not curative, likely due to a combination of imperfect treatment timing, inadequate SMN augmentation, and failure to optimally target relevant organs. Here, we consider the implications of imperfect treatment administration, focusing specifically on outcomes for skeletal muscle. We examine the evidence that muscle plays a contributing role in driving neuromuscular dysfunction in SMA. Next, we discuss how SMN might regulate the health of myofibers and their progenitors. Finally, we speculate on therapeutic outcomes of failing to raise muscle SMN to healthful levels and present strategies to restore function to this tissue to ensure better treatment results.
Authors
Narendra N. Jha, Jeong-Ki Kim, Yoon-Ra Her, Umrao R. Monani
Abstract
Uterine vascular remodeling is intrinsic to the cycling and early pregnant endometrium. Maternal regulatory factors such as ovarian hormones, VEGF, angiopoietins, Notch, and uterine natural killer cells significantly mediate these vascular changes. In the absence of pregnancy, changes in uterine vessel morphology and function correlate with different stages of the human menstrual cycle. During early pregnancy, vascular remodeling in rodents and humans results in decreased uterine vascular resistance and increased vascular permeability necessary for pregnancy success. Aberrations in these adaptive vascular processes contribute to increased risk of infertility, abnormal fetal growth, and/or preeclampsia. This Review comprehensively summarizes uterine vascular remodeling in the human menstrual cycle, and in the peri- and post-implantation stages in rodent species (mice and rats).
Authors
Noura Massri, Rachel Loia, Jennifer L. Sones, Ripla Arora, Nataki C. Douglas
Abstract
Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the setting of trauma (tHO). HO has undergone intense investigation, especially over the last 50 years, as awareness has increased around improving clinical technologies and incidence, such as with ongoing wartime conflicts. Current treatments for tHO and FOP remain prophylactic and include NSAIDs and glucocorticoids, respectively, whereas other proposed therapeutic modalities exhibit prohibitive risk profiles. Contemporary studies have elucidated mechanisms behind tHO and FOP and have described new distinct niches independent of inflammation that regulate ectopic bone formation. These investigations have propagated a paradigm shift in the approach to treatment and management of a historically difficult surgical problem, with ongoing clinical trials and promising new targets.
Authors
Charles D. Hwang, Chase A. Pagani, Johanna H. Nunez, Masnsen Cherief, Qizhi Qin, Mario Gomez-Salazar, Balram Kadaikal, Heeseog Kang, Ashish R. Chowdary, Nicole Patel, Aaron W. James, Benjamin Levi
Abstract
MicroRNAs (miRNAs) belong to a class of endogenous small noncoding RNAs that regulate gene expression at the posttranscriptional level, through both translational repression and mRNA destabilization. They are key regulators of kidney morphogenesis, modulating diverse biological processes in different renal cell lineages. Dysregulation of miRNA expression disrupts early kidney development and has been implicated in the pathogenesis of developmental kidney diseases. In this Review, we summarize current knowledge of miRNA biogenesis and function and discuss in detail the role of miRNAs in kidney morphogenesis and developmental kidney diseases, including congenital anomalies of the kidney and urinary tract and Wilms tumor. We conclude by discussing the utility of miRNAs as potentially novel biomarkers and therapeutic agents.
Authors
Débora Malta Cerqueira, Maliha Tayeb, Jacqueline Ho
Abstract
In recent decades, immunotherapeutic strategies have been used to treat a wide range of pathologies, many of which were previously incurable, such as cancer and autoimmune disorders. Despite this unprecedented success, a considerable number of patients fail to respond to currently approved immunotherapies or develop resistance over time. Therefore, there is an urgent need to develop the next generation of immune-targeted therapies. Various members of the Ig superfamily play essential roles in regulating leukocyte functions. One such group, the leukocyte Ig-like receptors (LILRs), have been implicated in both innate and adaptive immune regulation. Human inhibitory LILRs (LILRBs) are primarily expressed on leukocytes and mediate their signaling through multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. Engagement of LILRBs by endogenous and pathogenic ligands can markedly suppress immune responses, leading to tolerance or immunoevasion, whereas blocking these inhibitory receptors can potentiate immune responses. In this Review, we discuss the immunoregulatory functions of human LILRBs and the potential of targeting them to manipulate immune responses in various pathologies.
Authors
Calvin D. De Louche, Ali Roghanian
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