Top read articles in the last 30 days
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Abstract
BACKGROUND Previous epidemiologic studies of autoimmune diseases in the US have included a limited number of diseases or used metaanalyses that rely on different data collection methods and analyses for each disease.METHODS To estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from 6 large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time.RESULTS Our findings indicate that over 15 million people, or 4.6% of the US population, have been diagnosed with at least 1 autoimmune disease from January 1, 2011, to June 1, 2022, and 34% of those are diagnosed with more than 1 autoimmune disease. As expected, females (63% of those with autoimmune disease) were almost twice as likely as males to be diagnosed with an autoimmune disease. We identified the top 20 autoimmune diseases based on prevalence and according to sex and age.CONCLUSION Here, we provide, for what we believe to be the first time, a large-scale prevalence estimate of autoimmune disease in the US by sex and age.FUNDING Autoimmune Registry Inc., the National Heart Lung and Blood Institute, the National Center for Advancing Translational Sciences, the Intramural Research Program of the National Institute of Environmental Health Sciences.
Authors
Aaron H. Abend, Ingrid He, Neil Bahroos, Stratos Christianakis, Ashley B. Crew, Leanna M. Wise, Gloria P. Lipori, Xing He, Shawn N. Murphy, Christopher D. Herrick, Jagannadha Avasarala, Mark G. Weiner, Jacob S. Zelko, Erica Matute-Arcos, Mark Abajian, Philip R.O. Payne, Albert M. Lai, Heath A. Davis, Asher A. Hoberg, Chris E. Ortman, Amit D. Gode, Bradley W. Taylor, Kristen I. Osinski, Damian N. Di Florio, Noel R. Rose, Frederick W. Miller, George C. Tsokos, DeLisa Fairweather
Total views: 2711
Abstract
Allergic diseases have reached epidemic proportions globally, calling attention to the need for better treatment and preventive approaches. Herein, we developed allergen-encoding messenger RNA (mRNA)–lipid nanoparticle (LNP) strategies for both therapy and prevention of allergic responses. Immunization with allergen-encoded mRNA-LNPs modulated T cell differentiation, inhibiting the generation of T helper type 2 and type 17 cells upon allergen exposure in experimental asthma models induced by ovalbumin, and naturally occurring house dust mite (HDM) and the major HDM allergen Der p1. Allergen-specific mRNA-LNP treatment attenuated clinicopathology in both preventive and established allergy models, including reduction in eosinophilia, mucus production, and airway hypersensitivity, while enhancing production of allergen-specific IgG antibodies and maintaining low IgE levels. Additionally, allergen-specific mRNA-LNP vaccines in mice elicited a CD8+CD38+KLRG– T cell response as seen following SARS-CoV-2 mRNA vaccination in humans, underscoring a conserved immune mechanism across species, regardless of the mRNA-encoded protein. Notably, mRNA-LNP vaccination in combination with an mTOR inhibitor reduced the CD8+ T cell response without affecting the vaccine-induced anti-allergic effect in the preventive model of asthma. This technology renders allergen-specific mRNA-LNP therapy a promising approach for prevention and treatment of allergic diseases.
Authors
Yrina Rochman, Michael Kotliar, Andrea M. Klingler, Mark Rochman, Mohamad-Gabriel Alameh, Jilian R. Melamed, Garrett A. Osswald, Julie M. Caldwell, Jennifer M. Felton, Lydia E. Mack, Julie Hargis, Ian P. Lewkowich, Artem Barski, Drew Weissman, Marc E. Rothenberg
Total views: 2406
Abstract
Sulfite oxidase (SOX) deficiency is a rare inborn error of cysteine metabolism resulting in severe neurological damage. In patients, sulfite accumulates to toxic levels, causing a rise in the downstream products S-sulfocysteine, which mediates excitotoxicity, and thiosulfate, a catabolic intermediate/product of hydrogen sulfide (H2S) metabolism. Here, we report a full-body knockout mouse model for SOX deficiency (SOXD) with a severely impaired phenotype. Among the urinary biomarkers, thiosulfate showed a 45-fold accumulation in SOXD mice, representing the major excreted S-metabolite. Consistently, we found increased plasma H2S, which was derived from sulfite-induced release from persulfides, as demonstrated in vitro and in vivo. Mass spectrometry analysis of total protein persulfidome identified a major loss of S-persulfidation in 20% of the proteome, affecting enzymes in amino acids, fatty acid metabolism, and cytosolic iron-sulfur cluster biogenesis. Urinary amino acid profiles indicated metabolic rewiring and mitochondrial dysfunction, thus identifying an altered H2S metabolism and persulfidation in SOXD. Finally, oxidized glutathione and glutathione trisulfide were able to scavenge sulfite in vitro and in vivo, extending the lifespan of SOXD mice and providing a mechanistic concept of sulfite scavenging for the treatment of this severe metabolic disorder of cysteine catabolism.
Authors
Chun-Yu Fu, Joshua B. Kohl, Filip Liebsch, Davide D’Andrea, Tamás Ditrói, Seiryo Ogata, Franziska Neuser, Max Mai, Anna T. Mellis, Emilia Kouroussis, Masanobu Morita, Titus Gehling, José Angel Santamaria-Araujo, Sin Yuin Yeo, Heike Endepols, Michaela Křížková, Viktor Kozich, Marcus Krueger, Julia B. Hennermann, Uladzimir Barayeu, Takaaki Akaike, Peter Nagy, Milos Filipovic, Guenter Schwarz
Total views: 2135
Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung remodeling and collagen deposition that leads to respiratory failure. Myeloid cells are abundant in IPF lung and in murine lung fibrosis, but their functional effects are incompletely understood. Using mouse and human lung models, we show that ornithine produced by myeloid cells expressing arginase 1 (ARG1) serves as a substrate for proline and collagen synthesis by lung fibroblasts. The predominant ARG1-expressing myeloid cells in mouse lung were macrophages, but in IPF lung, high-dimensional imaging revealed ARG1 was expressed mainly in neutrophils. Small-molecule ARG1 inhibition suppressed both ornithine levels and collagen expression in cultured, precision-cut IPF lung slices and in murine lung fibrosis. These results were confirmed in macrophage-specific Arg1-KO mice. Furthermore, we found that this pathway is regulated by cell-to-cell crosstalk, starting with purinergic signaling: extracellular ATP receptor P2RX4 was necessary for fibroblast IL-6 expression, which, in turn, was necessary for ARG1 expression by myeloid cells. Taken together, our findings define an immune-mesenchymal circuit that governs profibrotic metabolism in lung fibrosis.
Authors
Preeti Yadav, Javier Gómez Ortega, Prerna Dabral, Whitney Tamaki, Charles Chien, Kai-Chun Chang, Nivedita Biswas, Sixuan Pan, Julia Nilsson, Xiaoyang Yin, Aritra Bhattacharyya, Kaveh Boostanpour, Tanay Jujaray, Jasper T. Wang, Tatsuya Tsukui, Christopher J. Molina, Vincent C. Auyeung, Dean Sheppard, Baosheng Li, Mazharul Maishan, Hiroki Taenaka, Michael A. Matthay, Rieko Muramatsu, Lenka Maliskova, Arnab Ghosh, Walter L. Eckalbar, Ari B. Molofsky, Stanley J. Tamaki, Trever G. Bivona, Adam R. Abate, Allon Wagner, Satish K. Pillai, Paul J. Wolters, Kevin M. Tharp, Mallar Bhattacharya
Total views: 2059
Abstract
Both adipocytes and hepatocytes have the capacity to store fat, but the factor(s) that determine fat distribution between these cell types remain unknown. In mice fed a high-fat diet, fat initially accumulates predominantly in adipocytes, while hepatic fat accumulation mainly emerges after the onset of epididymal adipocyte death that results in elevated free fatty acids to promote lipid accumulation in hepatocytes. However, it remains unclear whether other signals after adipocyte death are required to direct and/or promote hepatocytes to store fat and subsequently trigger metabolic dysfunction–associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease). Using genetically modified mouse models combined with bulk and single-cell RNA-Seq analysis, we demonstrated that visceral adipocyte death induced an accumulation of S100A8+ macrophages in the liver, which was partially induced by fatty acids and apoptotic adipocyte–derived extracellular vesicles. Macrophage-specific deletion of the S100a8 gene reduced hepatic fat accumulation and MASLD severity in mice. Mechanistically, S100A8+ macrophages suppressed cellular communication network factor 3 (CCN3), a negative regulator of CD36, thereby enhancing CD36 expression in hepatocytes. In conclusion, adipocyte death promotes hepatic infiltration of S100A8+ macrophages, which drive hepatocyte lipid storage and subsequently promote MASLD progression through CD36 upregulation, partially mediated by CCN3 suppression.
Authors
Yukun Guan, Yeonsoo Kim, Yang Wang, Ye Eun Cho, Xiaogang Xiang, Seung-Jin Kim, Tiantian Yao, Dechun Feng, Seonghwan Hwang, Bin Gao
Total views: 2056
Abstract
Toll like receptor (TLR) 7 and 9, endosomal sensors for RNA and DNA, are key mediators of autoreactivity. Although generally considered homologous, they paradoxically have opposing effects on lupus: TLR7 exacerbates the disease while TLR9 protects from it How they mediate opposing effects in autoimmunity remains undetermined. We hypothesized that differences in signaling qualities of the Toll-Interleukin 1 Receptor (TIR) domains of TLR7 and TLR9 could be responsible for their opposing effects. To test this, we introduced the TIR domain of TLR9 into the endogenous Tlr7 locus and the TLR7 TIR domain into the endogenous Tlr9 locus of mice, creating chimeric molecules termed TLR779 and TLR997. Lupus-prone MRL/lpr mice carrying Tlr779 had greatly ameliorated disease, while MRL/lpr mice carrying Tlr997 had markedly exacerbated disease compared with respective TlrWT mice. These experiments establish that TLR7 and TLR9 TIR domains have divergent properties and control disease quality, thus explaining the longstanding “TLR paradox”.
Authors
Claire Leibler, Kayla B. Thomas, Coralie Josensi, Russell C. Levack, Shuchi Smita, Shinu John, Daniel J. Wikenheiser, Sheldon Bastacky, Sebastien Gingras, Kevin M. Nickerson, Mark J. Shlomchik
Total views: 1962
Abstract
Severe systemic inflammatory reactions, including sepsis, often lead to shock, organ failure, and death, in part through an acute release of cytokines that promote vascular dysfunction. However, little is known about the vascular endothelial signaling pathways regulating the transcriptional profile in failing organs. Our work focused on signaling downstream of IL-6, due to its clinical importance as a biomarker for disease severity and predictor of mortality. Here, we show that loss of endothelial expression of the IL-6 pathway inhibitor SOCS3 promoted a type I IFN–like (IFNI-like) gene signature in response to endotoxemia in mouse kidneys and brains. In cultured primary human endothelial cells, IL-6 induced transient IFNI-like gene expression in a noncanonical, IFN-independent fashion. We further show that STAT3, which we had previously demonstrated to control IL-6–driven endothelial barrier function, was dispensable for this activity. Instead, IL-6 promoted a transient increase in cytosolic mitochondrial DNA and required STAT1, cGAS, STING, and IRF1, -3, and -4. Inhibition of this pathway in endothelial cell–specific STING-KO mice or global STAT1-KO mice led to reduced the severity of the response to acute endotoxemic challenge and prevented expression of an endotoxin-induced IFNI-like gene signature. These results suggest that permeability and DNA-sensing responses are driven by parallel pathways downstream of this cytokine, provide potential insights into the complex response to acute inflammatory responses, and offer the possibility of novel therapeutic strategies for independently controlling the intracellular responses to IL-6 in order to tailor the inflammatory response.
Authors
Nina Martino, Erin K. Sanders, Ramon Bossardi Ramos, Iria Di John Portela, Fatma Awadalla, Shuhan Lu, Dareen Chuy, Neil Poddar, Mei Xing G. Zuo, Uma Balasubramanian, Peter A. Vincent, Pilar Alcaide, Alejandro P. Adam
Total views: 1867
Abstract
BACKGROUND Following SARS-CoV-2 infection, approximately 10%–35% of patients with COVID-19 experience long COVID (LC), in which debilitating symptoms persist for at least 3 months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities.METHODS We utilized machine learning methods on biologic analytes provided over 12 months after hospital discharge from more than 500 patients with COVID-19 in the IMPACC cohort to identify a multiomics “recovery factor,” trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood mass cytometry by time of flight (CyTOF) protein levels. Recovery factor scores were tested for association with LC, disease severity, clinical parameters, and immune subset frequencies. Enrichment analyses identified biologic pathways associated with recovery factor scores.RESULTS Participants with LC had lower recovery factor scores compared with recovered participants. Recovery factor scores predicted LC as early as hospital admission, irrespective of acute COVID-19 severity. Biologic characterization revealed increased inflammatory mediators, elevated signatures of heme metabolism, and decreased androgenic steroids as predictive and ongoing biomarkers of LC. Lower recovery factor scores were associated with reduced lymphocyte and increased myeloid cell frequencies. The observed signatures are consistent with persistent inflammation driving anemia and stress erythropoiesis as major biologic underpinnings of LC.CONCLUSION The multiomics recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.TRIAL REGISTRATION ClinicalTrials.gov NCT04378777.FUNDING National Institute of Allergy and Infectious Diseases (NIAID), NIH (3U01AI167892-03S2, 3U01AI167892-01S2, 5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI057229-18, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07S1, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-1, 3U19AI1289130, U19AI128913-04S1, R01AI122220); NIH (UM1TR004528); and National Science Foundation (NSF) (DMS2310836).
Authors
Gisela Gabernet, Jessica Maciuch, Jeremy P. Gygi, John F. Moore, Annmarie Hoch, Caitlin Syphurs, Tianyi Chu, Naresh Doni Jayavelu, David B. Corry, Farrah Kheradmand, Lindsey R. Baden, Rafick-Pierre Sekaly, Grace A. McComsey, Elias K. Haddad, Charles B. Cairns, Nadine Rouphael, Ana Fernandez-Sesma, Viviana Simon, Jordan P. Metcalf, Nelson I. Agudelo Higuita, Catherine L. Hough, William B. Messer, Mark M. Davis, Kari C. Nadeau, Bali Pulendran, Monica Kraft, Chris Bime, Elaine F. Reed, Joanna Schaenman, David J. Erle, Carolyn S. Calfee, Mark A. Atkinson, Scott C. Brakenridge, Esther Melamed, Albert C. Shaw, David A. Hafler, Alison D. Augustine, Patrice M. Becker, Al Ozonoff, Steven E. Bosinger, Walter Eckalbar, Holden T. Maecker, Seunghee Kim-Schulze, Hanno Steen, Florian Krammer, Kerstin Westendorf, IMPACC Network, Bjoern Peters, Slim Fourati, Matthew C. Altman, Ofer Levy, Kinga K. Smolen, Ruth R. Montgomery, Joann Diray-Arce, Steven H. Kleinstein, Leying Guan, Lauren I.R. Ehrlich
Total views: 1623
Abstract
Through a combination of single-cell/single-nucleus RNA-Seq (sc/snRNA-Seq) data analysis, immunohistochemistry, and primary macrophage studies, we have identified pathogenic macrophages characterized by Tet methylcytosine dioxygenase 3 (TET3) overexpression (Toe-Macs) in 3 major human diseases associated with chronic inflammation: metabolic dysfunction–associated steatohepatitis (MASH), non–small cell lung cancer (NSCLC), and endometriosis. These macrophages are induced by common factors present in the disease microenvironment (DME). Crucially, the universal reliance on TET3 overexpression among these macrophages enabled their selective elimination as a single population, irrespective of heterogeneity in other molecular markers. In mice, depleting these macrophages via myeloid-specific Tet3 KO markedly mitigated disease progression, and the therapeutic effects were recapitulated pharmacologically using a TET3-specific small-molecule degrader. Through an unexpected mode of action, TET3 epigenetically regulated the expression of multiple genes key to the generation and maintenance of an inflammatory/immunosuppressive DME. We propose that Toe-Macs are a unifying feature of pathogenic macrophages that could be therapeutically targeted to treat MASH, NSCLC, endometriosis, and potentially other chronic inflammatory diseases.
Authors
Beibei Liu, Yangyang Dai, Zixin Wang, Jiahui Song, Yushu Du, Haining Lv, Stefania Bellone, Yang-Hartwich Yang, Andrew Kennedy, Songying Zhang, Muthukumaran Venkatachalapathy, Yulia Surovtseva, Penghua Wang, Gordon G. Carmichael, Hugh S. Taylor, Xuchen Zhang, Da Li, Yingqun Huang
Total views: 1603
Abstract
The role of endothelial dysfunction in tubulointerstitial fibrosis associated with chronic kidney disease (CKD) is not well understood. In this study, we demonstrate that the activation of the endothelial tyrosine kinase TIE2 alleviates renal pathology in experimental CKD in mice. TIE2 activation was achieved using a human angiopoietin-2–binding and TIE2-activating antibody (ABTAA) or through adult-induced endothelium-specific knockout of the vascular endothelial protein tyrosine phosphatase gene (Veptp). Both methods markedly protected CKD mice from endothelial dysfunction, peritubular capillary loss, tubular epithelial injury, and tubulointerstitial fibrosis. Conversely, silencing TIE2 through adult-induced endothelium-specific knockout of the Tie2 gene exacerbated CKD pathology. Additionally, we found that endothelial dysfunction promoted renal fibrosis not through endothelial-to-mesenchymal transition, as previously expected, but by inducing the expression of profibrotic PDGFB in tubular epithelial cells, a process that is inhibited by TIE2 activation. Our findings suggest that TIE2 activation via ABTAA warrants investigation as a therapy in human CKD, where there is a substantial unmet medical need.
Authors
Riikka Pietilä, Amanda Marks-Hultström, Liqun He, Sami Nanavazadeh, Susan E. Quaggin, Christer Betsholtz, Marie Jeansson
Total views: 1586
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: 14984
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: 5347
Abstract
Glucagon-like peptide-1 (GLP-1) was initially considered to be a hormone with a predominant role in regulating glucose metabolism by inducing insulin secretion, reducing glucagon secretion, and ameliorating insulin resistance, with the last effect being largely dependent on the induction of weight loss. In more recent years, the role of this peptide beyond metabolism has progressively been explored, including its impact on kidney physiology and kidney clinical outcomes in people with obesity with or without diabetes. Indeed, despite only modest expression of the GLP-1 receptor in the kidney, the renoprotective actions of GLP-1 and its receptor agonists have become an area of intensive investigation. This Review appraises the current status of GLP-1 peptide and its receptor agonists and focuses on the preclinical as well as recent seminal clinical findings defining the kidney benefits conferred by GLP-1 receptor agonist treatment in people living with type 2 diabetes and obesity.
Authors
Mark E. Cooper, Daniël H. van Raalte
Total views: 3187
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: 2885
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: 2829
Abstract
Bacteriophage (phage) therapy has emerged as a promising solution to combat the growing crisis of multidrug-resistant (MDR) infections. There are several international centers actively engaged in implementation of phage therapy, and recent case series have reported encouraging success rates in patients receiving personalized, compassionate phage therapy for difficult-to-treat infections. Nonetheless, substantial hurdles remain in the way of more widespread adoption and more consistent success. This Review offers a comprehensive overview of current phage therapy technologies and therapeutic approaches. We first delineate the common steps in phage therapy development, from phage bank establishment to clinical administration, and examine the spectrum of therapeutic approaches, from personalized to fixed phage cocktails. Using the framework of a conventional drug development pipeline, we then identify critical knowledge gaps in areas such as cocktail design, formulation, pharmacology, and clinical trial design. We conclude that, while phage therapy holds promise, a structured drug development pipeline and sustained government support are crucial for widespread adoption of phage therapy for MDR infections.
Authors
Minyoung Kevin Kim, Gina A. Suh, Grace D. Cullen, Saumel Perez Rodriguez, Tejas Dharmaraj, Tony Hong Wei Chang, Zhiwei Li, Qingquan Chen, Sabrina I. Green, Rob Lavigne, Jean-Paul Pirnay, Paul L. Bollyky, Jessica C. Sacher
Total views: 2284
Abstract
The renin-angiotensin-aldosterone system (RAAS) is a central regulator of cardiovascular, renal, and fluid homeostasis. Over the past century, our understanding of RAAS has evolved from a unidimensional circulatory hormone system to a complex network that includes local and intracellular signaling pathways. Aging profoundly impacts this system, influencing both systemic and tissue-specific RAAS activity. While levels of systemic RAAS components, such as plasma renin and aldosterone, decline with age, local RAAS components, particularly the proinflammatory angiotensin (Ang)II/AngII type 1 receptor (AT1R) axis, are upregulated in aging tissues, contributing to vasoconstriction, oxidative stress, inflammation, and fibrosis. Conversely, the protective arms of RAAS, the AngII/AT2R and Ang-(1–7)/Mas receptor pathways, are downregulated. Recent advances in geroscience have further illuminated how RAAS intersects with fundamental aging mechanisms, providing a mechanistic framework for understanding RAAS not only as a driver of age-related disease but also as a modifiable contributor to the aging process itself. In this Review, we summarize the evolution of RAAS biology, examine the molecular and functional consequences of aging on RAAS activity, and discuss the translational relevance of these findings. Finally, we explore emerging therapeutic strategies targeting RAAS components as potential interventions to promote healthy aging and reduce age-related disease burden, emphasizing a translational arc moving from bedside to bench and back, with the ultimate goal of improving patient outcomes.
Authors
Caglar Cosarderelioglu, Peter M. Abadir
Total views: 2195
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: 2101
Abstract
Pancreatic cancer (PC) is a devastating disease, due in part to its diagnosis frequently being made at an advanced stage. Ongoing efforts are aimed at identifying early-stage PC in high-risk individuals, as early detection leads to downstaging of PC and improvements in survival. However, there are a myriad of challenges that arise when trying to optimize PC early detection strategies, including selection of the appropriate high-risk individuals and selection of the test or combination of tests that should be performed. Here, we discuss the populations that are the strongest candidates for PC screening and review professional PC screening guidelines. We also summarize the current state of imaging techniques for early detection of PC and further review many studied biomarkers — ranging from nucleic acid targets, proteins, and the microbiome — to highlight the current state of the field and the challenges that remain in the years to come.
Authors
Michael J. Shen, Arsia Jamali, Bryson W. Katona
Total views: 1943
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: 1730
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)