Top read articles in the last 30 days
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Abstract
Growing evidence suggests that the pathogenesis of type 2 diabetes (T2D) involves dysfunctional central mechanisms, and, hence, the brain can be targeted to treat this disease. As an example, a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) can normalize hyperglycemia for weeks or months in rodent models of T2D. Convergent evidence implicates inhibition of a particular subset of neurons as a mediator of this FGF1 effect. Specifically, AgRP neurons, which are located in the hypothalamic arcuate nucleus (ARC) and are hyperactive in Lepob/ob mice and other rodent models of T2D. To investigate whether chronic AgRP neuron inactivation mimics the antidiabetic action of FGF1, we directed an adeno-associated virus (AAV) containing a cre-inducible tetanus toxin–GFP (TeTx-GFP) cassette (or cre-inducible AAV GFP control) to the ARC of obese, diabetic male Lepob/ob mice in which cre recombinase is expressed solely by AgRP neurons (Lepob/ob AgRP-Cre mice). We report that over a 10-wk period of observation, hyperglycemia was fully normalized by AgRP neuron inactivation. In contrast, changes in energy homeostasis parameters (food intake, energy expenditure, body weight, and fat mass) were not observed. We conclude that in diabetic male Lepob/ob mice, AgRP neuron hyperactivity is required for hyperglycemia but is dispensable for obesity.
Authors
Yang Gou, Micaela Glat, Vincent Damian, Caeley L. Bryan, Bao Anh Phan, Chelsea L. Faber, Arikta Trivedi, Matthew K. Hwang, Jarrad M. Scarlett, Gregory J. Morton, Michael W. Schwartz
Total views: 2952
Abstract
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. Clemastine fumarate, the over-the-counter antihistamine and muscarinic receptor blocker, has remyelinating potential in MS. A clemastine arm was added to an ongoing platform clinical trial, targeting residual activity by precision, biomarker-guided combination therapies of multiple sclerosis (TRAP-MS) (ClinicalTrials.gov NCT03109288), to identify a cerebrospinal fluid (CSF) remyelination signature and to collect safety data on clemastine in patients progressing independently of relapse activity (PIRA). The clemastine arm was stopped per protocol-defined criteria when 3 of 9 patients triggered individual safety stopping criteria. Clemastine-treated patients had significantly higher treatment-induced disability progression slopes compared with the remaining TRAP-MS participants. Quantification of approximately 7,000 proteins in CSF samples collected before and after clemastine treatment showed significant increases in purinergic signaling and pyroptosis. Mechanistic studies showed that clemastine with sublytic doses of extracellular adenosine triphosphate (ATP) activates inflammasome and induces pyroptotic cell death in macrophages. Clemastine with ATP also caused pyroptosis of induced pluripotent stem cell–derived human oligodendrocytes. Antagonist of the purinergic channel P2RX7, which is strongly expressed in oligodendrocytes and myeloid cells, blocked these toxic effects of clemastine. Finally, reanalysis of published single-nucleus RNA-Seq (snRNA-Seq) studies revealed increased P2RX7 expression and pyroptosis transcriptional signature in microglia and oligodendrocytes in the MS brain, especially in chronic active lesions. The CSF proteomic pyroptosis score was increased in untreated MS patients, was higher in patients with progressive than relapsing-remitting disease, and correlated significantly with the rates of MS progression. Collectively, this identifies pyroptosis as a likely mechanism of CNS injury underlying PIRA even outside of clemastine toxicity.
Authors
Joanna Kocot, Peter Kosa, Shinji Ashida, Nicolette A. Pirjanian, Raphaela Goldbach-Mansky, Karin Peterson, Valentina Fossati, Steven M. Holland, Bibiana Bielekova
Total views: 1991
Abstract
Glycosylation controls immune evasion, tumor progression, and metastasis. However, how tumor cell sialylation regulates immune evasion remains poorly characterized. ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to the glycans in glycoproteins, was overexpressed in an aggressive-type KPA (KrasG12D/+ Trp53R172H/+ Ad-Cre) lung adenocarcinoma (LUAD) model and patient samples. Proteomic and biochemical analysis indicated that ST6GalNAc-I mediated NECTIN2 sialylation in LUAD cells. ST6GalNAc-I–deficient tumor cells cocultured with T cells were more susceptible to T cell–mediated tumor cell killing, indicating a key role for NECTIN2 in T cell dysfunction. Mice injected with St6galnac-I–knockdown syngeneic cells showed reduced lung tumor incidence and Nectin2/Tigit-associated immunosuppression. ST6GalNAc-I–deficient cells exhibited reduced P-DMEA metabolite levels, while administration of P-DMEA promoted LUAD cell proliferation via MUC5AC. MUC5AC interacted and colocalized with PRRC1 in the Golgi, suggesting a potential role for PRRC1 in MUC5AC glycosylation. Mice injected with ST6GalNAc-I/MUC5AC-deficient cells (human LUAD) exhibited reduced lung tumor incidence, angiogenesis, and liver metastases. Mechanistically, ST6GalNAc-I/MUC5AC regulates VCAN-V1, a key factor in tumor matrix remodeling during angiogenesis and metastasis. These findings demonstrate that ST6GalNAc-I–mediated sialylation of NECTIN2/MUC5AC is critical for immune evasion and tumor angiogenesis. Targeting this pathway may prevent LUAD development and/or metastasis.
Authors
Muthamil Iniyan Appadurai, Sanjib Chaudhary, Ashu Shah, Gopalakrishnan Natarajan, Zahraa W. Alsafwani, Parvez Khan, Dhananjay D. Shinde, Subodh M. Lele, Lynette M. Smith, Mohd Wasim Nasser, Surinder Kumar Batra, Apar Kishor Ganti, Imayavaramban Lakshmanan
Total views: 1865
Abstract
Mechanisms by which mucosal regeneration is abrogated in inflammatory bowel disease (IBD) are still under investigation, and a role for an intestinal stem cell (ISC) defect is now emerging. Herein, we report an abnormal ISC death that occurs in Crohn’s disease, which exacerbates colitis, limits ISC-dependent mucosal repair, and is controlled through the death factor Transmembrane protein 219 (TMEM219). Large alterations in TMEM219 expression were observed in patients with Crohn’s disease, particularly in those with active disease and/or those who were nonresponders to conventional therapy, confirming that TMEM219 signaling is abnormally activated and leads to failure of the mucosal regenerative response. Mechanistic studies revealed a proapoptotic TMEM219-mediated molecular signature in Crohn’s disease, which associates with Caspase-8 activation and ISC death. Pharmacological blockade of the IGFBP3/TMEM219 binding/signal with the recombinant protein ecto-TMEM219 restored the self-renewal abilities of miniguts generated from patients with Crohn’s disease in vitro and ameliorated DSS-induced and T cell-mediated colitis in vivo, ultimately leading to mucosal healing. Genetic tissue-specific deletion of TMEM219 in ISCs in newly generated TMEM219fl/flLGR5cre mice revived their mucosal regenerative abilities both in vitro and in vivo. Our findings demonstrate that a TMEM219-dependent ISC death exacerbates colitis and that TMEM219 blockade reestablishes intestinal self-renewal properties in IBD.
Authors
Francesca D’Addio, Giovanni Amabile, Emma Assi, Anna Maestroni, Adriana Petrazzuolo, Cristian Loretelli, Ahmed Abdelasalam, Moufida Ben Nasr, Ida Pastore, Maria Elena Lunati, Vera Usuelli, Monica Zocchi, Andy Joe Seelam, Domenico Corradi, Stefano La Rosa, Virna Marin, Monique Zangarini, Marta Nardini, Stefano Porzio, Filippo Canducci, Claudia Nardini, Basset El Essawy, Manuela Nebuloni, Jun Yang, Massimo Venturini, Giovanni Maconi, Franco Folli, Silvio Danese, Gianvincenzo Zuccotti, Gianluca M. Sampietro, Sandro Ardizzone, Paolo Fiorina
Total views: 1859
Abstract
Red blood cells (RBCs) induce endothelial dysfunction in type 2 diabetes (T2D), but the mechanism by which RBCs communicate with the endothelium is unknown. This study tested the hypothesis that extracellular vesicles (EVs) secreted by RBCs act as mediators of endothelial dysfunction in T2D. Despite a lower production of EVs derived from RBCs of T2D patients (T2D RBC-EVs), their uptake by endothelial cells was greater than that of EVs derived from RBCs of healthy individuals (H RBC-EVs). T2D RBC-EVs impaired endothelium-dependent relaxation, and this effect was attenuated following inhibition of arginase in EVs. Inhibition of vascular arginase or oxidative stress also attenuated endothelial dysfunction induced by T2D RBC-EVs. Arginase-1 was detected in RBC-derived EVs, and arginase-1 and oxidative stress were increased in endothelial cells following coincubation with T2D RBC-EVs. T2D RBC-EVs also increased arginase-1 protein in endothelial cells following mRNA silencing and in the endothelium of aortas from endothelial cell arginase-1–knockout mice. It is concluded that T2D-RBCs induce endothelial dysfunction through increased uptake of EVs that transfer arginase-1 from RBCs to the endothelium to induce oxidative stress and endothelial dysfunction. These results shed important light on the mechanism underlying endothelial dysfunction mediated by RBCs in T2D.
Authors
Aida Collado, Rawan Humoud, Eftychia Kontidou, Maria Eldh, Jasmin Swaich, Allan Zhao, Jiangning Yang, Tong Jiao, Elena Domingo, Emelie Carlestål, Ali Mahdi, John Tengbom, Ákos Végvári, Qiaolin Deng, Michael Alvarsson, Susanne Gabrielsson, Per Eriksson, Zhichao Zhou, John Pernow
Total views: 1776
Abstract
Epidermal stem cells control homeostasis and regeneration of skin and hair. In the hair follicle (HF) bulge of mammals, populations of slow-cycling stem cells regenerate the HF during cyclical rounds of anagen (growth), catagen (regression), and telogen (quiescence). Multipotent epidermal cells are also present in the HF above the bulge area, contributing to the formation and maintenance of sebaceous gland and upper and middle portions of the HF. Here, we report that the transcription factor KROX20 is enriched in an epidermal stem cell population located in the upper/middle HF. Expression analyses and lineage tracing using inducible Krox20-CreERT showed that Krox20-lineage cells migrate out of this HF region and contribute to the formation of the bulge in the HF, serving as ancestors of bulge stem cells. In vivo depletion of these cells arrests HF morphogenesis. This study identifies a marker for an epidermal stem cell population that is indispensable for hair homeostasis.
Authors
Elnaz Ghotbi, Edem Tchegnon, Zhiguo Chen, Stephen Li, Tracey Shipman, Yong Wang, Jenny Raman, Yumeng Zhang, Renee M. McKay, Chung-Ping Liao, Lu Q. Le
Total views: 1735
Abstract
Tissue regenerative responses involve complex interactions between resident structural and immune cells. Recent reports indicate that accumulation of senescent cells during injury repair contributes to pathological tissue fibrosis. Using tissue-based spatial transcriptomics and proteomics, we identified upregulation of the immune checkpoint protein, cytotoxic T lymphocyte–associated protein 4 (CTLA4), on CD8+ T cells adjacent to regions of active fibrogenesis in human idiopathic pulmonary fibrosis and in a repetitive bleomycin lung injury murine model of persistent fibrosis. In humanized CTLA4-knockin mice, treatment with ipilimumab, an FDA-approved drug that targets CTLA4, resulted in accelerated lung epithelial regeneration and diminished fibrosis from repetitive bleomycin injury. Ipilimumab treatment resulted in the expansion of Cd3e+ T cells, diminished accumulation of senescent cells, and robust expansion of type 2 alveolar epithelial cells, facultative progenitor cells of the alveolar epithelium. Ex vivo activation of isolated CTLA4-expressing CD8+ cells from mice with established fibrosis resulted in enhanced cytolysis of senescent cells, suggesting that impaired immune-mediated clearance of these cells contributes to persistence of lung fibrosis in this murine model. Our studies support the concept that endogenous immune surveillance of senescent cells may be essential in promoting tissue regenerative responses that facilitate the resolution of fibrosis.
Authors
Santosh Yadav, Muralidharan Anbalagan, Shamima Khatun, Devadharshini Prabhakaran, Yasuka Matsunaga, Justin Manges, James B. McLachlan, Joseph A. Lasky, Jay Kolls, Victor J. Thannickal
Total views: 1706
Abstract
Altered protein homeostasis through proteasomal degradation of ubiquitinated proteins is a hallmark of many cancers. Ubiquitination, coordinated by E1, E2, and E3 enzymes, involves up to 40 E2-conjugating enzymes in humans to specify substrates and ubiquitin linkages. In a screen for E2 dependencies in acute myeloid leukemia (AML), ubiquitin conjugating enzyme E2 N (UBE2N) emerged as the top candidate. To investigate UBE2N’s role in AML, we characterized an enzymatically defective mouse model of UBE2N, revealing UBE2N’s requirement in AML without an impact on normal hematopoiesis. Unlike other E2s, which mediate lysine-48 (K48) polyubiquitination and degradation of proteins, UBE2N primarily synthesizes K63-linked chains, stabilizing or altering protein function. Proteomic analyses and a whole-genome CRISPR-activation screen in pharmacologically and genetically UBE2N-inhibited AML cells unveiled a network of UBE2N-regulated proteins, many of which are implicated in cancer. UBE2N inhibition reduced their protein levels, leading to increased K48-linked ubiquitination and degradation through the immunoproteasome and revealing UBE2N activity is enriched in immunoproteasome-positive AML. Furthermore, an interactome screen identified tripartite motif–containing protein 21 (TRIM21) as the E3 ligase partnering with activated UBE2N in AML to modulate UBE2N-dependent proteostasis. In conclusion, UBE2N maintains proteostasis in AML by stabilizing target proteins through K63-linked ubiquitination and prevention of K48 ubiquitin–mediated degradation by the immunoproteasome. Thus, inhibition of UBE2N catalytic function suppresses leukemic cells through selective degradation of critical proteins in immunoproteasome-positive AML.
Authors
Chiharu Ishikawa, Laura Barreyro, Avery M. Sampson, Kathleen M. Hueneman, Kwangmin Choi, Sophia Y. Philbrook, Issac Choi, Lyndsey C. Bolanos, Mark Wunderlich, Andrew G. Volk, Stephanie S. Watowich, Kenneth D. Greis, Daniel T. Starczynowski
Total views: 1637
Abstract
Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with unexplained hypoxemia that does not improve with dialysis. AKI induces remote lung inflammation with neutrophil recruitment in mice and humans, but which cellular cues establish neutrophilic inflammation and how it contributes to hypoxemia is not known. Here we report that AKI induced rapid intravascular neutrophil retention in lung alveolar capillaries without extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of substantial lung interstitial or alveolar edema. In contrast to direct ischemic lung injury, lung neutrophil recruitment during remote lung inflammation did not require cues from intravascular nonclassical monocytes or tissue-resident alveolar macrophages. Instead, lung neutrophil retention depended on the neutrophil chemoattractant CXCL2 released by activated classical monocytes. Comparative single-cell RNA-Seq analysis of direct and remote lung inflammation revealed that alveolar macrophages were highly activated and produced CXCL2 only in direct lung inflammation. Establishing a CXCL2 gradient into the alveolus by intratracheal CXCL2 administration during AKI-induced remote lung inflammation enabled neutrophils to extravasate. We thus discovered important differences in lung neutrophil recruitment in direct versus remote lung inflammation and identified lung capillary neutrophil retention that negatively affected oxygenation by causing a ventilation-perfusion mismatch as a driver of AKI-induced hypoxemia.
Authors
Yohei Komaru, Liang Ning, Carine Lama, Anusha Suresh, Eirini Kefaloyianni, Mark J. Miller, Shinichi Kawana, Hailey M. Shepherd, Wenjun Li, Daniel Kreisel, Andreas Herrlich
Total views: 1549
Abstract
BACKGROUND Lipogenesis contributes substantially to the pathological accumulation of intrahepatic triacylglycerol (IHTG) in metabolic dysfunction–associated steatotic liver disease (MASLD). Since hepatic lipogenesis is highly sensitive to energy intake, we hypothesized that mechanisms of MASLD regression induced by weight loss would be driven by a marked reduction in the lipogenic pathway.METHODS Overweight adults with high liver fat (HighLF; n = 9; IHTG ≥ 5.6% measured by 1H-magnetic resonance spectroscopy) or low (normal) liver fat (LowLF; n = 6; IHTG < 5.6%) received dietary counseling for 6 months and underwent comprehensive metabolic phenotyping during inpatient studies that captured fasting and fed states. Multiple stable isotopes were used to assess the contribution of lipogenesis, free fatty acids (FFAs), and dietary fat to IHTG.RESULTS Body weight loss (–10% ± 2%) reduced IHTG in individuals with MASLD (19.4% ± 3.6% to 4.5% ± 2.1%, P < 0.001). Insulin sensitivity improved significantly (46%, P < 0.01), while fasting FFA flux from adipose tissue was not different. VLDL-triacylglycerol (VLDL-TG) concentrations fell by 38% (P = 0.02) because of a 67% reduction in contribution from lipogenesis (P = 0.02), whereas the absolute contributions from FFAs and dietary fat to VLDL-TG were not different. Reduced lipogenesis was significantly associated with loss of IHTG.CONCLUSION These data underscore the primary role of lipogenesis in MASLD pathology and highlight the importance of controlling this pathway through treatment strategies.TRIAL REGISTRATION ClinicalTrials.gov (NCT01371396).FUNDING National Institutes of Health (NIH) grant RL1DK081187; Task Force for Obesity Research at Southwestern (TORS) NIH UL1DE019584; and Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences UL1-RR024982.
Authors
Jennifer E. Lambert, Maria A. Ramos-Roman, Maressa J. Valdez, Jeffrey D. Browning, Thomas Rogers, Elizabeth J. Parks
Total views: 1518
Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) diagnosis and management have evolved rapidly alongside the increasing prevalence of obesity and related complications. Hepatology has expanded its focus beyond late-stage cirrhosis and portal hypertension to earlier, complex MASLD cases in younger patients, necessitating closer collaboration with endocrinology. The renaming of nonalcoholic fatty liver disease (NAFLD) to MASLD reflects its pathophysiology, reduces stigma, and has prompted new research directions. Noninvasive tests such as liver stiffness measurement now play a crucial role in diagnosis, reducing reliance on invasive liver biopsies. However, advanced omics technologies, despite their potential to enhance diagnostic precision and patient stratification, remain underutilized in routine clinical practice. Behavioral factors, including posttraumatic stress disorder (PTSD) and lifestyle choices, influence disease outcomes and must be integrated into patient management strategies. Primary care settings are critical for early screening to prevent progression to advanced disease, yet sizable challenges remain in implementing effective screening protocols. This Review explores these evolving aspects of MASLD diagnosis and management, emphasizing the need for improved diagnostic tools, multidisciplinary collaboration, and holistic care approaches to address existing gaps and ensure comprehensive patient care across all healthcare levels.
Authors
Mette Munk Lauridsen, Kim Ravnskjaer, Lise Lotte Gluud, Arun J. Sanyal
Total views: 1656
Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) is rising among reproductive-aged individuals and in pregnancy. MASLD in pregnancy does increase such risks as gestational diabetes, preeclampsia, and preterm birth. Although routine screening for MASLD has not been established in pregnancy, individuals with metabolic comorbidities, such as type 2 diabetes mellitus, should be evaluated by liver imaging and liver panel. Preconception counseling should address potential risks as well as need for optimized metabolic health before and during pregnancy. Fibrosis assessment should ideally be completed before pregnancy, to identify cases of cirrhosis that may warrant additional preconception management, such as variceal screening, as well as comanagement with maternal-fetal medicine specialists. In patients with MASLD, aspirin is advised at 12 weeks of gestational age to lower preeclampsia risk. In the absence of cirrhosis, no additional blood test monitoring is needed. In the general population, breastfeeding has beneficial effects on metabolic health in birthing parents and offspring and thus should be encouraged in the setting of MASLD, including access to enhanced lactation support. Research needs include evaluation of the long-term risks of MASLD in pregnancy on metabolic health in birthing parents and infants, as well as safety data for MASLD-directed therapies during pregnancy and lactation.
Authors
Monika Sarkar, Tatyana Kushner
Total views: 1406
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: 1074
Abstract
Acute pain management has historically been dominated by opioids, whose efficacy is overshadowed by the risks of addiction, tolerance, and dependence, culminating in the global opioid crisis. To transcend this issue, we must innovate beyond opioid-based μ receptor treatments, identifying nonopioid analgesics with high efficacy and minimal adverse effects. This Review navigates the multifaceted landscape of inflammatory, neuropathic, and nociplastic pain, emphasizing mechanism-based analgesic targets tailored to specific pain conditions. We delve into the challenges and breakthroughs in clinical trials targeting ion channels, GPCRs, and other molecular targets. We also highlight the intricate crosstalk between different physiological systems and the need for multimodal interventions with distinct pharmacodynamics to manage acute and chronic pain, respectively. Furthermore, we explore emerging strategies, including gene therapy, stem cell therapy, cell type–specific neuromodulation, and AI-driven techniques for objective, unbiased pain assessment and research. These innovative approaches are poised to revolutionize pain management, paving the way for the discovery of safer and more effective analgesics.
Authors
Xiangsunze Zeng, Rasheen Powell, Clifford J. Woolf
Total views: 1052
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: 878
Abstract
Immune checkpoint inhibitors (ICIs) are widely used for cancer immunotherapy, yet only a fraction of patients respond. Remarkably, gut bacteria impact the efficacy of ICIs in fighting tumors outside of the gut. Certain strains of commensal gut bacteria promote antitumor responses to ICIs in a variety of preclinical mouse tumor models. Patients with cancer who respond to ICIs have a different microbiome compared with that of patients who don’t respond. Fecal microbiota transplants (FMTs) from patients into mice phenocopy the patient tumor responses: FMTs from responders promote response to ICIs, whereas FMTs from nonresponders do not promote a response. In patients, FMTs from patients who have had a complete response to ICIs can overcome resistance in patients who progress on treatment. However, the responses to FMTs are variable. Though emerging studies indicate that gut bacteria can promote antitumor immunity in the absence of ICIs, this Review will focus on studies that demonstrate relationships between the gut microbiome and response to ICIs. We will explore studies investigating which bacteria promote response to ICIs in preclinical models, which bacteria are associated with response in patients with cancer receiving ICIs, the mechanisms by which gut bacteria promote antitumor immunity, and how microbiome-based therapies can be translated to the clinic.
Authors
Francesca S. Gazzaniga, Dennis L. Kasper
Total views: 856
Abstract
Reduced kidney function is associated with increased risk of cardiovascular disease in addition to kidney disease progression. Kidney disease is considered an inflammatory state, based on elevated levels of C-reactive protein and inflammatory cytokines. A key mediator of cardiovascular and kidney disease progression in the setting of reduced kidney function is systemic and vascular inflammation. However, the exact pathways that link chronic kidney disease (CKD) with inflammation remain incompletely understood. For decades it has been known that factor D, the main activator of the alternative complement pathway, is increased in the plasma of patients with reduced kidney function. Recent biomarker evidence suggests alternative pathway activation in this setting. CKD, therefore, seems to alter the balance of alternative pathway proteins, promoting inflammation and potentially exacerbating complement-mediated diseases and CKD-associated complications. In this manuscript, we review the impact of reduced kidney function on biomarkers of the alternative complement pathway and the implications of alternative pathway activation on cardiovascular disease and kidney disease progression. Importantly, we highlight the need for ongoing research efforts that may lead to opportunities to target the alternative pathway of complement withx the goal of improving kidney and cardiovascular outcomes in persons with reduced kidney function.
Authors
Diana I. Jalal, Joshua M. Thurman, Richard J.H. Smith
Total views: 846
Abstract
Chronic pain affects more than 50 million Americans, with women disproportionately affected by severe pain, pain interference, and overall disability. The development of chronic pain is multifactorial and often begins with an incident of acute pain associated with an injury or a surgical procedure that transitions to persistent pain lasting for months or years. Despite this, there are limited clinical studies investigating sex differences in predictors and biomarkers for the transition to chronic pain. Several preclinical animal models have been developed to gain a better understanding of the mechanisms for the transition to chronic pain, and several sex-specific mechanisms have been identified across multiple systems. These preclinical models generally involve a multiple-insult approach, in which a priming insult enhances sensitivity to a subsequent induction stimulus. There is emerging evidence from preclinical research for several male-specific and female-specific mechanisms, as well as several studies showing shared mechanisms. Here, we review the clinical and preclinical literature covering sex differences in the periphery and immune system, the central nervous system, and the endocrine system related to the transition to chronic pain. We further highlight gaps in the literature and provide recommendations for future research to understand sex-specific differences in the transition to chronic pain.
Authors
Angela F. Smith, Ashley N. Plumb, Giovanni Berardi, Kathleen A. Sluka
Total views: 826
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: 814
Abstract
Vitiligo is an autoimmune disease that has been recognized, stigmatized, and treated for millennia. Recent translational research has revealed key mechanisms of disease, including cellular stress, innate immune activation, T cell–mediated elimination of melanocytes from the skin resulting in clinically apparent white spots, as well as stem cell regeneration that reverses established lesions. Many of these pathways have been targeted therapeutically, leading to the first FDA-approved medication to reverse the disease, with many more in clinical trials. Despite these impressive advances, many questions remain, which will be answered through integration of additional basic, translational, and clinical research studies. This vitiligo revolution has led to great excitement for individuals with vitiligo, those who know them, and the dermatologists who care for their patients. But just as importantly, these advances have great potential to shed light on autoimmune diseases that are more difficult to study, possibly leading to treatment advances that could not be achieved otherwise.
Authors
Khaled Ezzedine, Rim Tannous, Todd F. Pearson, John E. Harris
Total views: 808
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)