Top read articles in the last 30 days
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Abstract
BACKGROUND Improving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor-β receptor (TGF-βR) inhibitor that targets cancer-associated fibroblasts (CAFs) is promising for the enhancement of efficacy of immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy.METHODS We measured CAFs in vivo using the 68Ga-labeled fibroblast activation protein inhibitor-04 (68Ga-FAPI-04) for PET/CT imaging to guide the combination of TGF-β inhibition and immunotherapy. One hundred thirty-one patients with metastatic colorectal cancer (CRC) underwent 68Ga-FAPI and 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging. The relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed in patients. Mouse cohorts of metastatic CRC were treated with the TGF-βR inhibitor combined with KN046, which blocks programmed death ligand 1 (PD-L1) and CTLA-4, followed by 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses.RESULTS Patients with metastatic CRC demonstrated high uptake rates of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. The TGF-βR inhibitor enhanced tumor-infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamic changes of CAFs and tumor response to combined the TGF-βR inhibitor with immunotherapy.CONCLUSION 68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and the response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to guide precise TGF-β inhibition plus immunotherapy in CRC patients, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management.TRIAL REGISTRATION CFFSTS Trial, ChiCTR2100053984, Chinese Clinical Trial Registry.FUNDING National Natural Science Foundation of China (82072695, 32270767, 82272035, 81972260).
Authors
Ke Li, Wei Liu, Hang Yu, Jiwei Chen, Wenxuan Tang, Jianpeng Wang, Ming Qi, Yuyun Sun, Xiaoping Xu, Ji Zhang, Xinxiang Li, Weijian Guo, Xiaoling Li, Shaoli Song, Shuang Tang
Total views: 18550
Abstract
While clinical trials of human pluripotent stem cell–derived midbrain dopamine (mDA) neuron precursor grafts for Parkinson’s disease (PD) are ongoing, current protocols remain suboptimal. In particular, the yield of TH+ mDA neurons after in vivo grafting and the expression of certain mDA neuron and subtype-specific markers require improvement. Single-cell transcriptomic analyses of grafts have revealed low proportions of mDA neurons and substantial off-target contamination. Here, we present an optimized mDA neuron differentiation strategy that builds on our clinical-grade (“Boost”) protocol by adding FGF18 and IWP2 treatment (“Boost+”) at the neurogenesis stage. Boost+ mDA neurons show higher expression of EN1, PITX3, and ALDH1A1. Improvements in mDA neuron yield and transcriptional similarity to primary mDA neurons are observed in vitro and following transplantation. Single-nucleus RNA sequencing demonstrates enrichment of A9 mDA neurons within Boost+ grafts. Functional studies in vitro demonstrate increased dopamine production and release and improved electrophysiological properties. In vivo analyses show higher percentages of TH+ mDA neurons, resulting in efficient rescue of amphetamine-induced rotation behavior in the 6-OHDA rat model and rescue of deficits in some nondrug-induced assays, including the ladder rung assay, which are not improved by Boost mDA neurons. The Boost+ conditions present an optimized differentiation protocol with advantages for disease modeling and mDA neuron grafting paradigms.
Authors
Tae Wan Kim, Jinghua Piao, Vittoria D. Bocchi, So Yeon Koo, Se Joon Choi, Fayzan Chaudhry, Donghe Yang, Hyein S. Cho, Emiliano Hergenreder, Lucia Ruiz Perera, Subhashini Joshi, Zaki Abou Mrad, Nidia Claros, Shkurte Ademi Donohue, Yeong Eun Im, Hyo Jae Jeong, Anika K. Frank, Ryan M. Walsh, Eugene V. Mosharov, Doron Betel, Viviane Tabar, Lorenz Studer
Total views: 5856
Abstract
Cachexia is a metabolic wasting syndrome affecting many patients with cancer, with poor survival outcomes. Disturbed lipid metabolism is a hallmark of cachexia, and our previous work has identified increased levels of circulating ceramides, which are bioactive lipids with adverse effects in metabolic diseases, as biomarkers for cachexia in mouse models and patients. Here, we investigated the role of ceramides on cachexia development using the well-established C26 colon carcinoma model. We demonstrated that elevated ceramides in cachexia arose from increased liver synthesis. We showed that ceramides directly contributed to impaired mitochondrial function and energy homeostasis in cachexia target tissues. Targeting ceramide synthesis using miRNA interference, or myriocin, an approved compound targeting the key synthesis enzyme serine palmitoyltransferase (SPT), improved markers of muscle atrophy in cachectic male mice. Importantly, we demonstrated that key enzymes involved in ceramide production were also elevated in livers, but not in other organs, of patients with cancer cachexia, correlating with disease severity. Our data place ceramides as contributors to metabolic dysfunction in cachexia and highlight the suitability of the ceramide synthesis pathway for therapeutic targeting.
Authors
Pauline Morigny, Honglei Ji, Laura Cussonneau, Sabrina Zorzato, Yun Kwon, Fabien Riols, Doris Kaltenecker, Alisa Maier, Vignesh Karthikaisamy, Samantha Corrà, Tanja Krauss, Claudine Seeliger, Syed Qaaifah Gillani, Joël J. Tissink, Sandra Lacas-Gervais, Tuna Felix Samanci, Adriano Maida, Raul Terron-Exposito, Angela Trinca, Christine von Toerne, Leonardo Nogara, Melina Claussnitzer, Olga Prokopchuk, Jeannine Bachmann, Mauricio Berriel Diaz, Laure B. Bindels, Ondrej Kuda, Hans Hauner, Mark Haid, Stephan Herzig, Carlo Fiore Viscomi, Jerome Gilleron, Anja Zeigerer, Bert Blaauw, Maria Rohm
Total views: 3632
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 axis have revolutionized metastatic non–small cell lung cancer (mNSCLC) treatment. However, disease progression remains a concern, and the role of the complex tumor microenvironment (TME) in treatment failure is not fully understood.METHODS In this biomarker study involving 103 patients with mNSCLC, including 81 patients who received ICI treatment, we evaluated the association between heterogeneous immune cell subsets and ICI efficacy through single-cell spatial profiling of pretreatment tumor tissue, using a 29-marker multiplex IHC platform built for in-depth dissection of the TME.RESULTS Among various types of intratumoral lymphocytes, including Th1, Treg, and NK cells, only CD8+ T cells (tumor-infiltrating lymphocytes [TILs]) were associated with ICI efficacy. Computational tissue segmentation underscored the importance of direct physical interactions between CD8+ TILs and cancer cells for ICI efficacy. TIL phenotyping identified CD39/CD103/Ki-67 positivity as a hallmark of exhausted yet functional tumor-reactive CD8+ TILs. Immunosuppressive tumor-associated macrophages (TAMs) and cancer-associated fibroblasts were independent unfavorable adversaries. High CD73 expression on cancer cells was suggested to confer tolerance to ICI in EGFR/ALK-oncogene+ NSCLC, potentially through M2-TAM accumulation and aberrant angiogenesis.CONCLUSION Our study delineates the clinical relevance of heterogeneous immune cell subsets in ICI-treated mNSCLC, aiding the development of targeted therapeutic strategies.FUNDING Osaka Cancer Society, KANAE Foundation for the Promotion of Medical Science, SGH Foundation, and YOKOYAMA Foundation for Clinical Pharmacology.
Authors
Kohsuke Isomoto, Koji Haratani, Takahiro Tsujikawa, Shuta Tomida, Yusuke Makutani, Masayuki Takeda, Kimio Yonesaka, Kaoru Tanaka, Tsutomu Iwasa, Kazuko Sakai, Kazuto Nishio, Akihiko Ito, Kazuhiko Nakagawa, Hidetoshi Hayashi
Total views: 2665
Abstract
Alveolar type 2 cells (AT2s) are critical to lung regeneration, and the absence of large-scale methods to expand AT2s has hindered regenerative medicine efforts. We report a microcarrier-based, large-scale expansion method that was used to generate hundreds of billions of human AT2s. Through our process, expanded AT2s largely retained their phenotype. Furthermore, we showed that culture medium, substrate composition, and stiffness are all critical to the maintenance of AT2s. Finally, we showed that expanded AT2s can differentiate into alveolar type 1–like cells, both in vitro and in a decellularized porcine lung, demonstrating the utility of these cells for lung tissue engineering.
Authors
Lauren K. Rochelle, Rachael S. Van, Richard J. Ottman, Daren F. Robinson, Ashley R. Dockham, Amy K. Smith, Daniel P. Keeley, Jia C. Wang, Darell W. McCoy, Tyler R. Zimmerman, Bryan A. Fioret, Ryan W. Bonvillain, Thomas H. Petersen, Sarah S. Hogan, Laila C. Roudsari
Total views: 2644
Abstract
BACKGROUND The relationship between molecular subgroups in clear-cell renal cell carcinoma (ccRCC) and metastatic tropism is poorly understood.METHODS We analyzed over 5,000 metastatic sites from 305 treatment-naive ccRCC patients in the IMmotion150 phase II clinical trial, where patients were randomized to atezolizumab, atezolizumab/bevacizumab, or sunitinib.RESULTS Angiogenic tumors (clusters 1 and 2) had a higher rate of pancreatic (21% vs. 6.9%; P = 0.002) and lower absolute number of lymph node (2.5 vs. 4.2; P = 0.006) metastases. In contrast, proliferative tumors (clusters 4 and 5) exhibited a higher absolute number of lymph node metastases (5.5 vs. 3.5; P = 0.019). Patients with pancreatic metastases receiving sunitinib had higher odds of overall response (OR, 7.13; 95% CI, 1.81–28.07; P = 0.0049) and longer progression-free survival than those without pancreatic metastases (P = 0.02).CONCLUSION ccRCC metastatic tropism relates to molecular clusters that predict response to therapy for tumors that metastasize to the pancreas.TRIAL REGISTRATION ClinicalTrials.gov NCT01984242FUNDING NIH grants R01CA154475 and P50CA196516.
Authors
Gaelle Haddad, Junyu Guo, Yin Xi, Emin Albayrak, Mahrukh Huseni, Habib Hamidi, Romain Banchereau, Edward Kadel, Sarita Dubey, Corey Carter, Payal Kapur, James Brugarolas, Ivan Pedrosa
Total views: 2590
Abstract
Metabolic signals critically shape innate immune responses. Through pharmacological screening of metabolic pathways, we identified aspartate metabolism as a key regulator of cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling. Genetically or aminooxyacetic acid–mediated (AOA-mediated) pharmacologically reducing aspartate levels markedly potentiated the cGAS-STING pathway, leading to stronger upregulation of type I interferons and interferon-stimulated genes. Mechanistically, disruption of de novo pyrimidine synthesis, a major downstream pathway of aspartate, induced mtDNA replication stress and increased mtDNA double-strand breaks, promoting mtDNA release into the cytosol. Cytosolic mtDNA synergized with cGAS-STING agonists to upregulate Z-DNA binding protein 1 (ZBP1), which recruits RIPK1/3 to sustain IRF3 phosphorylation, forming a positive feedback loop that amplifies innate immune signaling. In immunocompetent mouse models, AOA enhanced the antitumor efficacy of STING agonists, chemotherapy, or radiotherapy, whereas aspartate supplementation abrogated these effects. Consistently, aspartate levels negatively correlated with antitumor immunity in colorectal cancer patient samples. Together, our study identifies aspartate–pyrimidine metabolism as a critical metabolic checkpoint that licenses STING signaling by enabling mtDNA stress to cooperate with agonist stimulation, driving type I interferon–dependent ZBP1 induction and feed-forward amplification of STING signaling, thus offering a promising strategy to enhance antitumor immunity.
Authors
Yuheng Liao, Hanze Wang, Hengxin Liu, Xi Chen, Renqiang Sun, Xie Li, Zhen Yang, Chenying Liu, Wei Wu, Ziqian He, Yuzheng Zhao, Ying Mao, Dan Ye, Hui Yang
Total views: 2562
Abstract
Skraban-Deardorff syndrome, a rare neurodevelopmental disorder caused by WD repeat domain 26 (WDR26) haploinsufficiency, is characterized by intellectual disability, seizures, autistic-like behaviors, and craniofacial anomalies. Despite its genetic association with variants disrupting the C-terminal to LisH (CTLH) E3 ubiquitin ligase complex, the molecular mechanisms linking WDR26 dysfunction to neurodevelopmental deficits remain unclear. Here, we demonstrate that Wdr26 heterozygous-KO mice (Wdr26+/–) recapitulated core clinical features of the syndrome, including learning and memory impairments, social dysfunction, heightened seizure susceptibility, and motor deficits, alongside rare craniofacial and dental abnormalities. Mechanistically, Wdr26 haploinsufficiency stabilized RUNX1 translocation partner 1 (RUNX1T1), a transcriptional coactivator critical for neuronal differentiation, by impairing its ubiquitination and proteasomal degradation, consequently disrupting the level of microtubule-associated protein 2 (MAP2), a key regulator of dendritic architecture and synaptic plasticity. Early intervention in neonatal Wdr26+/– mice (P0.5) using AAV-shRNA–mediated Runx1t1 knockdown reversed MAP2 overexpression and behavioral deficits. Notably, the antipsychotic risperidone ameliorated cognitive and social impairments in Wdr26+/– mice by upregulating WDR26 levels, suggesting a potential therapeutic avenue. Our findings not only establish the animal model as a robust preclinical tool but also define the WDR26/RUNX1T1/MAP2 regulatory axis as pivotal to the syndrome’s pathogenesis, while identifying actionable therapeutic targets.
Authors
Xingyun Xu, Yaohui Zhou, Shiyao Xu, Hongjie Zhou, Xuexia Lin, Yuhao Luo, Yu Xu, Zhigang Miao, Wei Ge, Hao Yang, Xingshun Xu
Total views: 2345
Abstract
Stimulant medications are widely prescribed for attention deficit hyperactivity disorder (ADHD) and have significant abuse liability. Here, we show that, consistent with clinical data, female mice exhibited enhanced behavioral sensitivity to stimulants, and we define sex- and hormone-dependent adaptations in the dopamine system that contributed to these effects. Single-nucleus RNA-seq of ventral tegmental area dopamine neurons revealed that projections to the nucleus accumbens (NAc) core, compared with other projection populations, were a hub of sexually dimorphic gene expression, including transcripts regulating dopamine synthesis, and transport. These molecular differences coincided with enhanced dopamine release and clearance in female mice, particularly during phases of the estrous cycle when estradiol levels were high. The stimulants amphetamine (a releaser) and methylphenidate (a reuptake inhibitor) more effectively increased dopamine levels in female mice under certain conditions. However, amphetamine showed more robust hormone-sensitive regulation, with potency reduced by ovariectomy and restored by direct estradiol replacement in the NAc core. Together, the findings indicate that even within a drug class, drugs with different mechanisms of action can leverage different aspects of sexually dimorphic dopamine function. This distinction highlights the notion that sex differences are not uniform but can be differentially sensitive to drug pharmacology.
Authors
Brooke A. Christensen, Jennifer Tat, Michael Z. Leonard, Soren D. Emerson, Shemuel Roberts, Eleanor B. Holmgren, Ainoa Konomi-Pilkati, Hannah B. Reiley, Devan M. Gomez, Lin Zheng, Hye Jean Yoon, Sofia H. Lago, Abigail L. Carr, Lillian J. Brady, Maxime Chevée, Erin S. Calipari
Total views: 2252
Abstract
Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utilization through the Randle cycle. Although inhibition of FAO has been investigated in heart failure, its overall therapeutic impact remains uncertain. To determine the consequences of enhanced FAO, we generated cardiomyocyte-specific ACC1 and ACC2 double-knockout (ACC dHKO) mice, which exhibit constitutively elevated FAO. ACC dHKO mice developed dilated cardiomyopathy and heart failure. Lipidomic analysis revealed marked depletion of cardiolipin caused by reduced linoleic acid, a direct consequence of excessive FAO. This cardiolipin deficiency impaired mitochondrial electron transport chain (ETC) activity, leading to mitochondrial dysfunction. Pharmacologic inhibition of FAO with etomoxir or oxfenicine restored cardiolipin levels, normalized ETC activity, and prevented cardiac dysfunction in ACC dHKO mice. These findings demonstrate that unrestrained FAO disrupts both lipid and energy homeostasis, culminating in heart failure in this model. Collectively, these results indicate that although FAO is essential for cardiac energy production, therapeutic strategies aimed at stimulating cardiac FAO may be detrimental rather than beneficial in heart failure.
Authors
Chai-Wan Kim, Goncalo Vale, Xiaorong Fu, Jeffrey G. McDonald, Chongshan Dai, Chao Li, Zhao V. Wang, Gaurav Sharma, Chalermchai Khemtong, Craig R. Malloy, Stanislaw Deja, Shawn C. Burgess, Matthew A. Mitsche, Jay D. Horton
Total views: 2239
Abstract
GLP-1 receptor agonist (GLP-1RA) medications have transformed the treatment of type 2 diabetes (T2D) and obesity, with robust evidence for cardiovascular and renal benefits. Nevertheless, GLP-1RA therapy is associated with a pattern of adverse events affecting their safety and tolerability. Here, we delineate mechanisms potentially leading to adverse responses to GLP-1RAs, describe the impact of side effects on treatment persistence, discuss potential mitigation strategies, and identify areas requiring further studies. Concerns that GLP-1RAs raise the risk for acute pancreatitis and pancreatic cancer have been dispelled by long-term clinical trials. However, GLP-1RAs may confer an increased risk for thyroid cancer. Sight-threatening eye complications resulting from rapid reductions in glycemia may be avoided by retinal screening and ophthalmologic treatment before GLP-1RA initiation. The slowing of gastric emptying with GLP-1RA treatment increases the propensity for retained gastric contents, which could increase the risk of aspiration during upper gastrointestinal endoscopy or general anesthesia. These risks may, however, be elevated in individuals with long-standing T2D even in the absence of GLP-1RA treatment. Improved pharmacovigilance and a more standardized, quantitative assessment of adverse events in clinical trials, particularly in the assessment of gastrointestinal symptoms, would facilitate definition of the benefit-risk relationship for individual medications and indications.
Authors
Ryan J. Jalleh, Nicholas J. Talley, Michael Horowitz, Michael A. Nauck
Total views: 8492
Abstract
Type 1 diabetes mellitus (T1D) has been recognized as a chronic autoimmune disease for five decades, but therapy has relied on the exogenous replacement of insulin, which is an imperfect substitute for normal β cell function. In recent years, there has been progress in the development of new therapeutics that target the primary causes of the disease: failed immunologic tolerance and β cell killing. One agent, teplizumab, was shown to attenuate loss of β cell function that occurs over time and delay progression to clinical disease in individuals at risk, leading to its regulatory approval in 2022. Other immunologic agents show promise in modulating the immunologic imbalance. Moreover, a role for β cells in T1D pathogenesis has been identified and may be targeted. Now that the first disease-modifying therapeutic agent is available, future studies may involve combinations of agents to extend immunologic tolerance and protect and restore β cells so that lasting metabolic remission can be achieved.
Authors
Kevan C. Herold, Carmella Evans-Molina
Total views: 4011
Abstract
Cancer diagnoses are prevalent in people with obesity and type 2 diabetes, and abundant clinical evidence supports the protective effects of weight loss for cancer prevention. Glucagon-like peptide-1 (GLP-1) receptor agonists have revolutionized obesity and type 2 diabetes medicine and alleviate many comorbidities of these metabolic diseases. In this Review, we summarize the current clinical evidence for GLP-1 receptor agonists and cancer risk, including thyroid, pancreatic, gastrointestinal, and hormone-dependent malignancies. With few exceptions, recent meta-analyses report that GLP-1 receptor therapies do not increase cancer incidence and may lower risk in some cases. Preclinical studies reinforce the anticancer effects of GLP-1 receptor therapies, even in non-obese models. However, there are still many opportunities for translational insight as the field grows. Immune-modulating effects of GLP-1 receptor agonists are reported in several preclinical cancer studies, which may reflect direct action on immune cells or result from improved metabolic function. We highlight ongoing clinical trials for GLP-1 receptor therapies in cancer patients, and offer considerations for preclinical studies, including perspectives on the timing and duration of GLP-1 receptor agonist treatment, concurrent use of standard anticancer therapies, and interpretation of models of cancer risk versus progression.
Authors
Estefania Valencia-Rincón, Rajani Rai, Vishal Chandra, Elizabeth A. Wellberg
Total views: 3431
Abstract
Therapies based on glucagon-like peptide-1 (GLP-1) reduce rates of cardiovascular and chronic kidney disease in people with type 2 diabetes and/or obesity, with ongoing clinical trials investigating their effects in people with metabolic liver disease, arthritis, and both substance use and neurodegenerative disorders. Acute and chronic activation of GLP-1 receptor signaling also reduces systemic and tissue inflammation in mice and humans, through weight loss–dependent and –independent mechanisms, actions that may contribute to the expanding spectrum of clinical benefits ascribed to GLP-1 medicines. In this Review, we highlight current understanding of the direct and indirect antiinflammatory effects and mechanisms of GLP-1 medicines in both preclinical and clinical studies, covering emerging concepts, clinical relevance, and areas of uncertainty that require further investigation.
Authors
Chi Kin Wong, Daniel J. Drucker
Total views: 3235
Abstract
Anemia affects one-third of the population globally and is marked by impaired erythropoiesis that results in substantial mortality and morbidity. Over the past few decades, our understanding of the molecular mechanisms underlying anemia has progressed but translating that knowledge into effective targeted therapeutics remains challenging. Preclinical and clinical studies substantiate the efficacy of modulating erythropoietin-driven signaling pathways to stimulate erythropoiesis. Additional approaches include strategies to maintain iron homeostasis and control iron metabolism, using small molecules and oral supplements. New frontiers in molecular regulation of anemia include perturbation of regulatory genes and spliceosome proteins in erythroid cells, as well as mutation-specific therapeutic approaches. Finally, new evidence supporting the importance of neuronal signaling and mitochondrial dynamics in shaping erythropoiesis is pointing toward novel interventions. Here, we discuss the molecular and genetic factors underlying defective erythropoiesis and highlight current and emerging therapies, including molecular targets to overcome drug resistance.
Authors
Nilesh Rai, Omar Abdel-Wahab, Lingbo Zhang
Total views: 2966
Abstract
Half of adults in the United States have hypertension as defined by clinical practice guidelines. Interestingly, women are generally more likely to be aware of their hypertension and have their blood pressure controlled with treatment compared with men, yet hypertension-related mortality is greater in women. This may reflect the fact that the female sex remains underrepresented in clinical and basic science studies investigating the effectiveness of therapies and the mechanisms controlling blood pressure. This Review provides an overview of the impact of the way hypertension research has explored sex as a biological variable (SABV). Emphasis is placed on epidemiological studies, hypertension clinical trials, the genetics of hypertension, sex differences in immunology and gut microbiota in hypertension, and the effect of sex on the central control of blood pressure. The goal is to offer historical perspective on SABV in hypertension, highlight recent studies that include SABV, and identify key gaps in SABV inclusion and questions that remain in the field. Through continued awareness campaigns and engagement/education at the level of funding agencies, individual investigators, and in the editorial peer review system, investigation of SABV in the field of hypertension research will ultimately lead to improved clinical outcomes.
Authors
Michael J. Ryan, John S. Clemmer, Roy O. Mathew, Jessica L. Faulkner, Erin B. Taylor, Justine M. Abais-Battad, Fiona Hollis, Jennifer C. Sullivan
Total views: 2867
Abstract
Recent advances in cerebrovascular genomics, single-cell biology, pharmacology, and gene editing technology are transforming our understanding of brain arteriovenous malformations (bAVMs) — a leading cause of pediatric hemorrhagic stroke. Once considered static anatomical defects, bAVMs are now recognized as dynamic, genetically driven lesions resulting from somatic mutations in KRAS, BRAF, and pathways involved in arteriovenous specification, angiogenesis, and vascular remodeling. By integrating human genetics, animal models, and endovascular innovations, researchers have uncovered convergent mechanisms that link endothelial Ras/MAPK hyperactivation to abnormal vessel growth and higher rupture risk. These insights provide a foundation for precision medicine approaches that combine molecular diagnostics — such as liquid or endoluminal biopsies — with mutation-specific pharmacotherapies and emerging CRISPR-based gene editing strategies. We suggest that genotype-guided interventions, tailored by spatial and developmental cerebrovascular context, could ultimately reclassify bAVMs from surgically incurable malformations to treatable molecular conditions.
Authors
Andrew T. Hale, Adam J. Kundishora, Pazhanichamy Kalailingam, Tanyeri Barak, Phan Q. Duy, Christopher M. Ramundo, Baojian Fan, Qiang Li, Priscilla K. Brastianos, Ganesh M. Shankar, Seth L. Alper, Benjamin P. Kleinstiver, Patricia L. Musolino, Kristopher T. Kahle
Total views: 2318
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: 2291
Abstract
Bone is a highly dynamic and purposefully organized structure that remodels constantly throughout adult life. Disordered bone remodeling, in which resorption of old bone by osteoclasts exceeds new bone formation by osteoblasts, results in bone loss, which, in turn, is associated with debilitating conditions, including osteoporosis and metastatic bone disease. The past decade has revealed vital new insights into the role of the central nervous system in skeletal regulation. These studies have led to a better understanding of physiologic circuitry, enabled us to revisit disease pathophysiology, and in doing so, prompted the creation of candidate therapeutics. The central neural control of bone is exerted through two arms — an amplitude-modulated (AM) neurohormonal arm that relies on changes in circulating levels of anterior and posterior pituitary hormones, which act on bone directly, and a frequency-modulated (FM) arm that arises from changes in the firing frequency of sympathetic, parasympathetic, and sensory nerves that innervate bone. Here, we review the medical consequences arising from the dysfunction of the AM and FM arms, as well as studies that have unmasked promising therapeutic targets.
Authors
Mone Zaidi, Se-Min Kim, Vitaly Ryu, Daria Lizneva, Terry F. Davies, Clifford J. Rosen, Tony Yuen, Andrea Giustina
Total views: 2267
Abstract
The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a central mediator of cytosolic DNA–induced innate immune responses, driving the production of type I IFNs and pro-inflammatory cytokines. Beyond its canonical role in cytosolic DNA sensing, increasing attention has been directed toward the noncanonical functions of cGAS and STING, particularly within the nucleus. Recent studies implicate dysregulated cGAS-STING signaling in neurodegenerative diseases and brain aging, with a prominent contribution to glial activation–associated neuroinflammation, a hallmark of many neurological disorders. In this Review, we first summarize the molecular mechanisms underlying the canonical cGAS-STING pathway in DNA sensing and innate immune activation. We then discuss emerging noncanonical roles of cGAS in chromatin organization and RNA metabolism, drawing on insights from evolutionary conservation and protein interactome analyses. Finally, we outline the involvement of cGAS-STING signaling in diverse aspects of brain function, including glial state regulation, neuronal homeostasis, blood-brain barrier integrity, and peripheral immune surveillance, highlighting their contributions to neuroinflammation and neuropathology. We also summarize current pharmacological inhibitors targeting cGAS and STING and discuss their therapeutic potential for modulating cGAS-STING signaling to manage brain disorders.
Authors
Weixi Feng, Abulimiti Aikedan, Subhash C. Sinha, Li Gan
Total views: 2220
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)