Top read articles in the last 30 days
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Abstract
Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.
Authors
Kumar Sharma, Guanshi Zhang, Jens Hansen, Petter Bjornstad, Hak Joo Lee, Rajasree Menon, Leila Hejazi, Jian-Jun Liu, Anthony Franzone, Helen C. Looker, Byeong Yeob Choi, Roman Fernandez, Manjeri A. Venkatachalam, Luxcia Kugathasan, Vikas S. Sridhar, Loki Natarajan, Jing Zhang, Varun S. Sharma, Brian Kwan, Sushrut S. Waikar, Jonathan Himmelfarb, Katherine R. Tuttle, Bryan Kestenbaum, Tobias Fuhrer, Harold I. Feldman, Ian H. de Boer, Fabio C. Tucci, John Sedor, Hiddo Lambers Heerspink, Jennifer Schaub, Edgar A. Otto, Jeffrey B. Hodgin, Matthias Kretzler, Christopher R. Anderton, Theodore Alexandrov, David Cherney, Su Chi Lim, Robert G. Nelson, Jonathan Gelfond, Ravi Iyengar, for the Kidney Precision Medicine Project
Total views: 18015
Abstract
A major limitation of immunotherapy is the development of resistance resulting from cancer-mediated inhibition of host lymphocytes. Cancer cells release CCL2 to recruit classical monocytes expressing its receptor CCR2 for the promotion of metastasis and resistance to immunosurveillance. In the circulation, some CCR2-expressing classical monocytes lose CCR2 and differentiate into intravascular nonclassical monocytes that have anticancer properties but are unable to access extravascular tumor sites. We found that in mice and humans, an ontogenetically distinct subset of naturally underrepresented CCR2-expressing nonclassical monocytes was expanded during inflammatory states such as organ transplant and COVID-19 infection. These cells could be induced during health by treatment of classical monocytes with small-molecule activators of NOD2. The presence of CCR2 enabled these inducible nonclassical monocytes to infiltrate both intra- and extravascular metastatic sites of melanoma, lung, breast, and colon cancer in murine models, and they reversed the increased susceptibility of Nod2–/– mutant mice to cancer metastasis. Within the tumor colonies, CCR2+ nonclassical monocytes secreted CCL6 to recruit NK cells that mediated tumor regression, independent of T and B lymphocytes. Hence, pharmacological induction of CCR2+ nonclassical monocytes might be useful for immunotherapy-resistant cancers.
Authors
Xianpeng Liu, Ziyou Ren, Can Tan, Félix L. Núñez-Santana, Megan E. Kelly, Yuanqing Yan, Haiying Sun, Hiam Abdala-Valencia, Wenbin Yang, Qiang Wu, Takahide Toyoda, Marija Milisav, S. Marina Casalino-Matsuda, Emilia Lecuona, Emily Jeong Cerier, Lena J. Heung, Mohamed E. Abazeed, Harris Perlman, Ruli Gao, Navdeep S. Chandel, G.R. Scott Budinger, Ankit Bharat
Total views: 12114
Abstract
Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have a history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM and PN accelerated muscle regeneration in vivo by stimulating MuSCs, increased muscle strength during recovery, and overcame MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously declined during aging in model organisms and interindependently associated with muscle mass and walking speed in a cohort of 186 aged people. Collectively, our results establish the NAM/PN combination as a nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.
Authors
Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E. Jacot, Thibaut Desgeorges, José L. Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G. Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N. Feige
Total views: 3509
Abstract
Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a “don’t eat me” signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell–intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.
Authors
Shuai Wang, Tengfei Huang, Qiulian Wu, Huairui Yuan, Xujia Wu, Fanen Yuan, Tingting Duan, Suchet Taori, Yingming Zhao, Nathaniel W. Snyder, Dimitris G. Placantonakis, Jeremy N. Rich
Total views: 3464
Abstract
Chronic rejection (CR) after organ transplantation is alloimmune injury manifested by graft vascular remodeling and fibrosis that is resistant to immunosuppression. Single-cell RNA-Seq analysis of MHC class II–mismatched (MHCII-mismatched) heart transplants developing chronic rejection identified graft IL-33 as a stimulator of tissue repair pathways in infiltrating macrophages and Tregs. Using IL-33–deficient donor mice, we show that graft fibroblast–derived IL-33 potently induced amphiregulin (Areg) expression by recipient Tregs. The assessment of clinical samples also confirmed increased expression of Areg by intragraft Tregs also during rejection. Areg is an EGF secreted by multiple immune cells to shape immunomodulation and tissue repair. In particular, Areg is proposed to play a major role in Treg-mediated muscle, epithelium, and nerve repair. Assessment of recipient mice with Treg-specific deletion of Areg surprisingly uncovered that Treg secretion of Areg contributed to CR. Specifically, heart transplants from recipients with Areg-deficient Tregs showed less fibrosis, vasculopathy, and vessel-associated fibrotic niches populated by recipient T cells. Mechanistically, we show that Treg-secreted Areg functioned to increase fibroblast proliferation. In total, these studies identify how a dysregulated repair response involving interactions between IL-33+ fibroblasts in the allograft and recipient Tregs contributed to the progression of CR.
Authors
Jordan J.P. Warunek, Lu Fan, Xue Zhang, Sihua Wang, Steven M. Sanders, Tengfang Li, Lisa R. Mathews, Gaelen K. Dwyer, Michelle A. Wood-Trageser, Stephanie Traczek, Andrew Lesniak, Kassandra Baron, Hailey Spencer, Johnny Bou Saba, Emmanuel León Colón, Tracy Tabib, Robert Lafyatis, Mark A. Ross, Anthony J. Demetris, Simon C. Watkins, Steven A. Webber, Khodor I. Abou-Daya, Hēth R. Turnquist
Total views: 3186
Abstract
Type I IFNs (IFN-Is) induced by radiotherapy (RT) are critical for its efficacy, while the mechanism by which tumor cells inhibit IFN-I production remains largely unsolved. By an unbiased CRISPR screen, we identified hemeoxygenase 1 (HO-1) as an RT-related regulator of IFN-I production. Mechanistically, the ER-anchored, full-length HO-1 disrupted stimulator of IFN genes (STING) polymerization and subsequent coat protein complex II–mediated (COPII-mediated) ER-Golgi transportation, leading to hampered activation of downstream signaling. This process was exacerbated by the upregulation of HO-1 expression under RT. Importantly, RT also induced HO-1 cleavage. Cleaved HO-1 underwent nuclear translocation, interacted with cyclic GMP-AMP synthase (cGAS), and inhibited its nuclear export upon irradiation, leading to suppressed 2′3′-cyclic GMP-AMP (cGAMP) production. Furthermore, we revealed that HO-1 inhibitors could enhance local and distant tumor control of RT in vivo. Clinically, higher HO-1 expression was associated with a poorer prognosis and earlier tumor relapse after RT in multiple types of patient tumors. Collectively, through comprehensive inhibition of the cGAS/STING pathway, HO-1 strongly inhibited RT-induced IFN-I production, and targeting HO-1 was shown to be a promising RT-sensitizing therapeutic strategy.
Authors
Chuqing Zhang, Zhenji Deng, Jiawei Wu, Cong Ding, Zhe Li, Zhimin Xu, Weipeng Chen, Kaibin Yang, Hanmiao Wei, Tingxiang He, Liufen Long, Jun Ma, Cheng Xu, Xiaoyu Liang
Total views: 3074
Abstract
Upon RNA virus infection, the signaling adaptor MAVS forms functional prion-like aggregates on the mitochondrial outer membrane, which serve as a central hub that links virus recognition to downstream antiviral innate immune responses. Multiple mechanisms regulating MAVS activation have been revealed; however, the checkpoint governing MAVS aggregation remains elusive. Here, we demonstrated that the palmitoylation of MAVS at cysteine 79 (C79), which is catalyzed mainly by the palmitoyl S-acyltransferase ZDHHC12, was essential for MAVS aggregation and antiviral innate immunity upon viral infection in macrophages. Notably, the systemic lupus erythematosus–associated mutation MAVS C79F was associated with defective palmitoylation, resulting in low type I interferon (IFN) production. Accordingly, Zdhhc12 deficiency apparently impaired RNA virus–induced type I IFN responses, and Zdhhc12-deficient mice were highly susceptible to lethal viral infection. These findings reveal a previously unknown mechanism by which the palmitoylation of MAVS is a checkpoint for its aggregation during viral infection to ensure timely activation of antiviral defense.
Authors
Liqiu Wang, Mengqiu Li, Guangyu Lian, Shuai Yang, Jing Cai, Zhe Cai, Yaoxing Wu, Jun Cui
Total views: 2693
Abstract
Type 1 diabetes (T1D) develops spontaneously despite functional antigen presentation machinery in the thymus and a perceptible central tolerance process. We found that intrathymic enrichment with IL-4 fine tunes signaling through the IL-4/IL-13 heteroreceptor (HR) in early thymic progenitors (ETPs), augments negative selection of self-reactive T cells, sustains a diverse T cell repertoire devoid of clones expressing disease-associated T cell receptor (TCR) genes, and protects the nonobese diabetic (NOD) mouse from T1D. Indeed, optimal IL-4 activates STAT transcription factors to program ETP fate decision toward CD11c+CD8α+ dendritic cells (DCs) agile in negative T cell selection and clonal deletion of diabetogenic T cells. However, due to diminished invariant natural killer T (iNKT) 2 cell frequency in the NOD thymus, IL-4 is as suboptimal level, metering STAT activation to program ETP fate decision toward the T cell lineage leading to diminished negative selection, a clonally restricted TCR repertoire, and manifestation of spontaneous T1D. These insights uncover yet another interplay by which IL-4 affects T1D.
Authors
Alexis N. Cattin-Roy, Kimberly G. Laffey, Luan B. Le, Adam G. Schrum, Habib Zaghouani
Total views: 2534
Abstract
Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.
Authors
Leigh Goedeke, Yina Ma, Rafael C. Gaspar, Ali Nasiri, Jieun Lee, Dongyan Zhang, Katrine Douglas Galsgaard, Xiaoyue Hu, Jiasheng Zhang, Nicole Guerrera, Xiruo Li, Traci LaMoia, Brandon T. Hubbard, Sofie Haedersdal, Xiaohong Wu, John Stack, Sylvie Dufour, Gina Marie Butrico, Mario Kahn, Rachel J. Perry, Gary W. Cline, Lawrence H. Young, Gerald I. Shulman
Total views: 2386
Abstract
Ku70, a DNA repair protein, binds to the damaged DNA ends and orchestrates the recruitment of other proteins to facilitate repair of DNA double-strand breaks. Besides its essential role in DNA repair, several studies have highlighted nonclassical functions of Ku70 in cellular processes. However, its function in immune homeostasis and antitumor immunity remains unknown. Here, we discovered a marked association between elevated Ku70 expression and unfavorable prognosis in lung adenocarcinoma, focusing specifically on increased Ku70 levels in tumor-infiltrated Tregs. Using a lung-colonizing tumor model in mice with Treg-specific Ku70 deficiency, we demonstrated that deletion of Ku70 in Tregs led to a stronger antitumor response and slower tumor growth due to impaired immune-suppressive capacity of Tregs. Furthermore, we confirmed that Ku70 played a critical role in sustaining the suppressive function of human Tregs. We found that Ku70 bound to forkhead box protein P3 (FOXP3) and occupied FOXP3-bound genomic sites to support its transcriptional activities. These findings not only unveil a nonhomologous end joining–independent (NHEJ-independent) role of Ku70 crucial for Treg-suppressive function, but also underscore the potential of targeting Ku70 as an effective strategy in cancer therapy, aiming to both restrain cancer cells and enhance pulmonary antitumor immunity.
Authors
Qianru Huang, Na Tian, Jianfeng Zhang, Shiyang Song, Hao Cheng, Xinnan Liu, Wenle Zhang, Youqiong Ye, Yanhua Du, Xueyu Dai, Rui Liang, Dan Li, Sheng-Ming Dai, Chuan Wang, Zhi Chen, Qianjun Zhou, Bin Li
Total views: 2310
Abstract
Stress has long been associated with substance misuse and substance use disorders (SUDs). The past two decades have seen a surge in research aimed at understanding the underlying mechanisms driving this association. This Review introduces a multilevel “adaptive stress response” framework, encompassing a stress baseline, acute reaction, and recovery with return-to-homeostasis phase that occurs at varying response times and across domains of analysis. It also discusses evidence showing the disruption of this adaptive stress response in the context of chronic and repeated stressors, trauma, adverse social and drug-related environments, as well as with acute and chronic drug misuse and with drug withdrawal and abstinence sequelae. Subjective, cognitive, peripheral, and neurobiological disruptions in the adaptive stress response phases and their link to inflexible, maladaptive coping; increased craving; relapse risk; and maintenance of drug intake are also presented. Finally, the prevention and treatment implications of targeting this “stress pathophysiology of addiction” are discussed, along with specific aspects that may be targeted in intervention development to rescue stress-related alterations in drug motivation and to improve SUD treatment outcomes.
Authors
Rajita Sinha
Total views: 1671
Abstract
Myasthenia gravis (MG) stands as a prototypical antibody-mediated autoimmune disease: it is dependent on T cells and characterized by the presence of autoantibodies targeting proteins located on the postsynaptic surface of skeletal muscle, known as the neuromuscular junction. Patients with MG exhibit a spectrum of weakness, ranging from limited ocular muscle involvement to life-threatening respiratory failure. Recent decades have witnessed substantial progress in understanding the underlying pathophysiology, leading to the delineation of distinct subcategories within MG, including MG linked to AChR or MuSK antibodies as well as age-based distinction, thymoma-associated, and immune checkpoint inhibitor–induced MG. This heightened understanding has paved the way for the development of more precise and targeted therapeutic interventions. Notably, the FDA has recently approved therapeutic inhibitors of complement and the IgG receptor FcRn, a testament to our improved comprehension of autoantibody effector mechanisms in MG. In this Review, we delve into the various subgroups of MG, stratified by age, autoantibody type, and histology of the thymus with neoplasms. Furthermore, we explore both current and potential emerging therapeutic strategies, shedding light on the evolving landscape of MG treatment.
Authors
Henry J. Kaminski, Patricia Sikorski, S. Isabel Coronel, Linda L. Kusner
Total views: 1446
Abstract
Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. Although tremendous progress has been made in the field of ALD over the last 20 years, the pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. The potential translation of these studies into clinical practice and therapy is deliberated. We also discuss preclinical models of ALD, interplay of ALD and metabolic dysfunction, alcohol-associated liver cancer, the heterogeneity of ALD, and some potential translational research prospects for ALD.
Authors
Bryan Mackowiak, Yaojie Fu, Luca Maccioni, Bin Gao
Total views: 1315
Abstract
Over the last decade, several organoid models have evolved to acquire increasing cellular, structural, and functional complexity. Advanced lung organoid platforms derived from various sources, including adult, fetal, and induced pluripotent stem cells, have now been generated, which more closely mimic the cellular architecture found within the airways and alveoli. In this regard, the establishment of novel protocols with optimized stem cell isolation and culture conditions has given rise to an array of models able to study key cellular and molecular players involved in lung injury and repair. In addition, introduction of other nonepithelial cellular components, such as immune, mesenchymal, and endothelial cells, and employment of novel precision gene editing tools have further broadened the range of applications for these systems by providing a microenvironment and/or phenotype closer to the desired in vivo scenario. Thus, these developments in organoid technology have enhanced our ability to model various aspects of lung biology, including pathogenesis of diseases such as chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, and infectious disease and host-microbe interactions, in ways that are often difficult to undertake using only in vivo models. In this Review, we summarize the latest developments in lung organoid technology and their applicability for disease modeling and outline their strengths, drawbacks, and potential avenues for future development.
Authors
Ana I. Vazquez-Armendariz, Purushothama Rao Tata
Total views: 1228
Abstract
A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene (CLOCK), brain and muscle ARNT-Like 1 gene (BMAL1), period (PER), and cryptochrome (CRY), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential mechanistic links between circadian disruption and altered clock gene expression contributions to metabolic health–related pathologies. Findings have important implications for the treatment, prevention, and control of metabolic pathologies underlying leading causes of death and disability, including diabetes, cardiovascular disease, and cancer.
Authors
Lauren A. Schrader, Sean M. Ronnekleiv-Kelly, John B. Hogenesch, Christopher A. Bradfield, Kristen M.C. Malecki
Total views: 1112
Abstract
Cannabis has been legalized for medical and recreational purposes in multiple countries. A large number of people are using cannabis and some will develop cannabis use disorder (CUD). There is a growing recognition that CUD requires specific interventions. This Review will cover this topic from a variety of perspectives, with a particular emphasis on neurobiological findings and innovative treatment approaches that are being pursued. We will first describe the epidemiology and burden of disease of CUD, including risk factors associated with CUD (both in terms of general risk and genetic risk variants). Neurobiological alterations identified in brain imaging studies will be presented. Several psychosocial interventions that are useful for the management of CUD, including motivational enhancement therapy, behavioral and cognitive therapy, and contingency management, will be covered. Although no pharmacological interventions are yet approved for CUD, we present the most promising pharmacological interventions being tested.
Authors
Bernard Le Foll, Victor M. Tang, Sergio Rueda, Leanne V. Trick, Isabelle Boileau
Total views: 1050
Abstract
Herpesviruses establish latent infections, and most reactivate frequently, resulting in symptoms and virus shedding in healthy individuals. In immunocompromised patients, reactivating virus can cause severe disease. Persistent EBV has been associated with several malignancies in both immunocompromised and nonimmunocompromised persons. Reactivation and shedding occur with most herpesviruses, despite potent virus-specific antibodies and T cell immunity as measured in the blood. The licensure of therapeutic vaccines to reduce zoster indicates that effective therapeutic vaccines for other herpesviruses should be feasible. However, varicella-zoster virus is different from other human herpesviruses in that it is generally only shed during varicella and zoster. Unlike prophylactic vaccines, in which the correlate of immunity is antibody function, T cell immunity is the correlate of immunity for the only effective therapeutic herpesvirus vaccine–zoster vaccine. While most studies of therapeutic vaccines have measured immunity in the blood, cellular immunity at the site of reactivation is likely critical for an effective therapeutic vaccine for certain viruses. This Review summarizes the status of therapeutic vaccines for herpes simplex virus, cytomegalovirus, and Epstein-Barr virus and proposes approaches for future development.
Authors
Jeffrey I. Cohen
Total views: 1019
Abstract
Glioblastoma (GBM) is the most aggressive tumor in the central nervous system and contains a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages and microglia (TAMs) are a dominant population of immune cells in the GBM TME that contribute to most GBM hallmarks, including immunosuppression. The understanding of TAMs in GBM has been limited by the lack of powerful tools to characterize them. However, recent progress on single-cell technologies offers an opportunity to precisely characterize TAMs at the single-cell level and identify new TAM subpopulations with specific tumor-modulatory functions in GBM. In this Review, we discuss TAM heterogeneity and plasticity in the TME and summarize current TAM-targeted therapeutic potential in GBM. We anticipate that the use of single-cell technologies followed by functional studies will accelerate the development of novel and effective TAM-targeted therapeutics for GBM patients.
Authors
Fatima Khan, Lizhi Pang, Madeline Dunterman, Maciej S. Lesniak, Amy B. Heimberger, Peiwen Chen
Total views: 976
Abstract
Cerebral small vessel disease (cSVD) encompasses a heterogeneous group of age-related small vessel pathologies that affect multiple regions. Disease manifestations range from lesions incidentally detected on neuroimaging (white matter hyperintensities, small deep infarcts, microbleeds, or enlarged perivascular spaces) to severe disability and cognitive impairment. cSVD accounts for approximately 25% of ischemic strokes and the vast majority of spontaneous intracerebral hemorrhage and is also the most important vascular contributor to dementia. Despite its high prevalence and potentially long therapeutic window, there are still no mechanism-based treatments. Here, we provide an overview of the recent advances in this field. We summarize recent data highlighting the remarkable continuum between monogenic and multifactorial cSVDs involving NOTCH3, HTRA1, and COL4A1/A2 genes. Taking a vessel-centric view, we discuss possible cause-and-effect relationships between risk factors, structural and functional vessel changes, and disease manifestations, underscoring some major knowledge gaps. Although endothelial dysfunction is rightly considered a central feature of cSVD, the contributions of smooth muscle cells, pericytes, and other perivascular cells warrant continued investigation.
Authors
Nicolas Dupré, Antoine Drieu, Anne Joutel
Total views: 894
Abstract
Immune checkpoint blockade (ICB) has revolutionized modern cancer therapy, arousing great interest in the neuro-oncology community. While several reports show that subsets of patients with glioma exhibit durable responses to immunotherapy, the efficacy of this treatment has not been observed for unselected patient populations, preventing its broad clinical implementation for gliomas and glioblastoma (GBM). To exploit the maximum therapeutic potential of ICB for patients with glioma, understanding the different aspects of glioma-related tumor immune responses is of critical importance. In this Review, we discuss contributing factors that distinguish subsets of patients with glioma who may benefit from ICB. Specifically, we discuss (a) the complex interaction between the tumor immune microenvironment and glioma cells as a potential influence on immunotherapy responses; (b) promising biomarkers for responses to immune checkpoint inhibitors; and (c) the potential contributions of peripheral immune cells to therapeutic responses.
Authors
Víctor A. Arrieta, Crismita Dmello, Daniel J. McGrail, Daniel J. Brat, Catalina Lee-Chang, Amy B. Heimberger, Dhan Chand, Roger Stupp, Adam M. Sonabend
Total views: 872
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)