Citations

Abstract Extracellular vesicles (EVs) are membrane‐bound nanoparticles released by cells and are an important means of intercellular communication in physiological and pathological states. We provide an overview of recent advances in the understanding of EV biogenesis, cargo selection, recipient cell effects, and key considerations in isolation and characterization techniques. Studies on the physiological role of EVs have relied on cell‐based model systems due to technical limitations of studying endogenous nanoparticles in vivo . Several recent studies have elucidated the mechanistic role of EVs in liver diseases, including nonalcoholic fatty liver disease, viral hepatitis, cholestatic liver disease, alcohol‐associated liver disease, acute liver injury, and liver cancers. Employing disease models and human samples, the biogenesis of lipotoxic EVs downstream of endoplasmic reticulum stress and microvesicles via intracellular activation stress signaling are discussed in detail. The diverse cargoes of EVs including proteins, lipids, and nucleic acids can be enriched in a disease‐specific manner. By carrying diverse cargo, EVs can directly confer pathogenic potential, for example, recruitment and activation of monocyte‐derived macrophages in NASH and tumorigenicity and chemoresistance in hepatocellular carcinoma. We discuss the pathogenic role of EVs cargoes and the signaling pathways activated by EVs in recipient cells. We review the literature that EVs can serve as biomarkers in hepatobiliary diseases. Further, we describe novel approaches to engineer EVs to deliver regulatory signals to specific cell types, and thus use them as therapeutic shuttles in liver diseases. Lastly, we identify key lacunae and future directions in this promising field of discovery and development. © 2023 American Physiological Society. Compr Physiol 13:4631‐4658, 2023.

ABSTRACTObjectiveThe primary objective of this study is to review the evidence for aspirin use to prevent the growth of vestibular schwannomas (VS) and to propose a prospective trial to determine the progression‐free survival of VS patients after up to 42 months of treatment with aspirin. Secondary study objectives are to determine the effect of aspirin on VS growth, hearing function, serum biomarker levels, and the quality of life, as well as to determine the tolerability of aspirin treatment and whether serum biomarker and salicylate levels predict the response to aspirin.Study DesignLiterature review.SettingSix academic and private medical centers.MethodsReview of recent English literature regarding prophylactic aspirin use for VS.ResultsThe retrospective reviews on the utility of aspirin to prevent VS growth are inconclusive. Eighty‐four patients have been enrolled in a prospective double‐blinded, placebo‐controlled trial thus far to determine the effect of aspirin on VS.ConclusionsCompletion of a robust study design is necessary. The current aspirin dose has been well tolerated, with minimal adverse events to date.Level of EvidenceReview of retrospective studies: Level 4; Proposed randomized, placebo‐controlled, double‐blinded clinical trial: Level 2.

Abstract Objectives The aim of this study was to compare the measured physiological factors that limit running performance with real marathon results from world-class distance runners, evaluating the compatibility between measured data and predicted results based on the previously suggested model. Methods Four world-class East African marathon runners (three male, one female) underwent physiological running assessments to predict marathon performance times using a model based on V ˙ $\dot {\mathrm{V}}$ O 2 peak, percentage of V ˙ $\dot {\mathrm{V}}$ O 2 peak at the second ventilatory threshold, and running economy. Predictions were then compared to participants’ best marathon times. Results The measured V ˙ $\dot {\mathrm{V}}$ O 2 peak of the world-class runners was 75.1 ± 2.7 mL/kg/min. The second ventilatory threshold occurred at 85 ± 3 % of the peak, with a running economy of 63.7 ± 2.4 mL/kg/min at 19.6 ± 0.9 km/h. The predicted marathon performance time was 2:06:51 ± 0:03:17 h:min:s for the males and 2:17:36 h:min:s for the female. Comparing these predictions to their personal best times, the average difference was 00:55 ± 00:51 min:s (range: 00:20-02:08). Conclusions This research provides laboratory data on world-class road running athletes, reinforcing the link between marathon performance and V ˙ $\dot {\mathrm{V}}$ O 2 peak, the percentage of V ˙ $\dot {\mathrm{V}}$ O 2 peak at the second ventilatory threshold, and running economy. The examined athletes had lower V ˙ $\dot {\mathrm{V}}$ O 2 peak compared to predicted values, highlighting the importance of running economy and fractional utilization of V ˙ $\dot {\mathrm{V}}$ O 2 peak in achieving such performances. Future studies should continue to advance the field by including additional bioenergetic parameters measured during race conditions and expanding the participant cohort of elite marathoners, encompassing both sexes.

AbstractObjectiveNeuromodulation for pediatric refractory epilepsy (PRE) is preferred when the seizure onset zone is not amenable to surgical resection, due to multifocal onset or involvement of eloquent cortex. Given its rapidly evolving landscape, we describe our institutional experience with neurostimulation therapies including deep brain stimulation (DBS) of the anterior nucleus (DBS‐ANT), the centromedian nucleus (DBS‐CM), responsive neurostimulation (RNS), and chronic subthreshold stimulation (CSS) to treat PRE.MethodsA retrospective chart review was conducted to identify pediatric patients (≤18 years of age) who presented to our institution with PRE. Patients were included who had at least 1 year of follow‐up after neurostimulation was started. Patients with ≥50% seizure frequency reduction at last follow‐up compared to baseline were classified as responders.ResultsA total of 35 patients (21 females) were included in the series. Nine patients underwent DBS‐ANT, 9 underwent DBS‐CM (+ ANT in 7 patients), 5 underwent RNS, and 12 underwent CSS. The median age at seizure onset and surgery was 8 and 16 years, respectively. Structural lesions were the most common etiology of epilepsy (54%). Eighteen patients had prior interventions and 13 received invasive EEG. Post‐operative complications following neurostimulation implantation were noted in three patients (9%). However, no permanent deficits were noted. Median follow‐up time was 46 months (range 13–162 months). Twenty‐three patients (59%) were responders (3/9 DBS‐ANT; 7/9 DBS‐CM; 4/5 RNS; 9/12 CSS). Further, median seizure reduction was 25% (DBS‐ANT), 89% (DBS‐CM), 87% (RNS), and 88% (CSS) across the cohort. Six patients (17%) had improved subjective neurocognitive outcomes while the other 29 had stable neurocognitive outcomes.SignificanceDBS, RNS, and CSS are safe and effective options for PRE. An understanding of treatment approaches can optimize results by tailoring therapy to individual patients.Plain Language SummaryThis study investigates the use of various neurostimulation therapies for treating pediatric refractory epilepsy (PRE) including deep brain stimulation (DBS), responsive neurostimulation (RNS), and chronic subthreshold stimulation (CSS). Overall, neuromodulation was found to be effective in reducing seizures in most patients, with 59% of patients showing at least a 50% reduction in seizure frequency. Additionally, the treatments were generally safe, with few complications and no instances of permanent deficits.

Abstract Background: Resilience, quantified by the brief resilience scale (BRS), has been recognized for its role in pain and symptomatology in musculoskeletal conditions. The role of psychological factors in the clinical presentation and outcomes of FAI surgery continues to be poorly understood. Methods: This is a prospective multicenter study of FAI patients undergoing primary hip arthroscopy. PROMs were administered at baseline, 3-, and 6-months post-op and included the Patient Reported Outcomes Measurement Information System (PROMIS) domains of anxiety and depression, as well as Hip Disability and Osteoarthritis and Outcome Score (HOOS), modified Harris Hip Score (mHHS), and International Hip Outcome Tool (iHOT-12). Resilience was characterized by BRS score and divided into low (“L”, score<3), normal (“N”, score 3-4.3), and high resilience (“H”, score>4.3). Results: 675 patients were included with a mean age of 24.9±7.8 years and female predominance (56%). Mean BRS scores were 3.7±0.7 (1.5-5.0). 13.8% (n=93) had low resilience, 65.9% (n=445) had normal resilience, and 20.3% (n=137) had high resilience. Lower resilience had more severe symptoms in HOOS pain (p<0.001), HOOS sports (p=0.003), HOOS ADL (p<0.001), HOOS QoL (p<0.001), iHOT-12 (p=0.002), and mHHS (p<0.001). Anxiety (L: 50.5%/N: 14.4%/H: 2.2%) and depression (L: 38.7%/N: 8.8%/H: 2.9%) were higher in lower resilience groups (all p<0.001) and this trend stayed consistent in female and male sub-analyses with females having greater anxiety and depression symptoms. The follow-up cohort with 3- and 6-months follow-up was 487 patients and had similar baseline characteristics as the baseline cohort. Lower resilience had lower postoperative PROs (with similar change) (p<0.05). After treatment, rates of anxiety or depression decreased from 22.1% to 15.6% with the low resilience group having the highest change from 62.9% to 45.9%. Conclusion: Low resilience correlates with more severe symptoms and predicts anxiety/depression in FAI. 13.8% had low resilience while 20.3% had high resilience. Lower resilience had worse postoperative PROs. Particularly in patients with low resilience at presentation, rates of anxiety or depression symptoms decreased postoperatively. Further studies are needed to understand the role of resilience in longer-term outcomes of FAI and whether concurrent psychological treatment will help improve patient outcomes after hip arthroscopy for FAI.

Abstract Hepatocellular endocytosis is a highly dynamic process responsible for the internalization of a variety of different receptor ligand complexes, trophic factors, lipids, and, unfortunately, many different pathogens. The uptake of these external agents has profound effects on seminal cellular processes including signaling cascades, migration, growth, and proliferation. The hepatocyte, like other well‐polarized epithelial cells, possesses a host of different endocytic mechanisms and entry routes to ensure the selective internalization of cargo molecules. These pathways include receptor‐mediated endocytosis, lipid raft associated endocytosis, caveolae, or fluid‐phase uptake, although there are likely many others. Understanding and defining the regulatory mechanisms underlying these distinct entry routes, sorting and vesicle formation, as well as the postendocytic trafficking pathways is of high importance especially in the liver, as their mis‐regulation can contribute to aberrant liver pathology and liver diseases. Further, these processes can be “hijacked” by a variety of different infectious agents and viruses. This review provides an overview of common components of the endocytic and postendocytic trafficking pathways utilized by hepatocytes. It will also discuss in more detail how these general themes apply to liver‐specific processes including iron homeostasis, HBV infection, and even hepatic steatosis. © 2014 American Physiological Society. Compr Physiol 4:1403‐1417, 2014.

Abstract The autonomic nervous system is a key regulator of the cardiovascular system. In this review, we focus on how sex and aging influence autonomic regulation of blood pressure in humans in an effort to understand general issues related to the cardiovascular system as a whole. Younger women generally have lower blood pressure and sympathetic activity than younger men. However, both sexes show marked interindividual variability across age groups with significant overlap seen. Additionally, while men across the lifespan show a clear relationship between markers of whole body sympathetic activity and vascular resistance, such a relationship is not seen in young women. In this context, the ability of the sympathetic nerves to evoke vasoconstriction is lower in young women likely as a result of concurrent β 2 ‐mediated vasodilation that offsets α‐adrenergic vasoconstriction. These differences reflect both central sympatho‐inhibitory effects of estrogen and also its influence on peripheral vasodilation at the level of the vascular smooth muscle and endothelium. By contrast postmenopausal women show a clear relationship between markers of whole body sympathetic traffic and vascular resistance, and sympathetic activity rises progressively in both sexes with aging. These major findings in humans are discussed in the context of differences in population‐based trends in blood pressure and orthostatic intolerance. The many areas where there is little sex‐specific data on how the autonomic nervous system participates in the regulation of the human cardiovascular system are highlighted. © 2015 American Physiological Society. Compr Physiol 5:193‐215, 2015.

Abstract The human microbiome consists of the microorganisms associated with the body, such as bacteria, fungi, archaea, protozoa, and viruses, along with their gene content and products. These microbes are abundant in the digestive, respiratory, renal/urinary, and reproductive systems. While microbes found in other organs/tissues are often associated with diseases, some reports suggest their presence even in healthy individuals. Lack of microbial colonization does not indicate a lack of microbial influence, as their metabolites can affect distant locations through circulation. In a healthy state, these microbes maintain a mutualistic relationship and help shape the host's physiological functions. Unlike the host's genetic content, microbial gene content and expression are dynamic and influenced by factors such as ethnicity, genetic background, sex, age, lifestyle/diet, and psychological/physical conditions. Therefore, defining a healthy microbiome becomes challenging as it is context dependent and can vary over time for an individual. Although differences in microbial composition have been observed in various diseases, these changes may reflect host alterations rather than causing the disease itself. As the field is evolving, there is increased emphasis on understanding when changes in the microbiome are an important component of pathogenesis rather than the consequence of a disease state. This article focuses on the microbial component in the digestive and respiratory tracts—the primary sites colonized by microorganisms—and the physiological functions of microbial metabolites in these systems. It also discusses their physiological functions in the central nervous and cardiovascular systems, which have no microorganism colonization under healthy conditions based on human studies. © 2024 American Physiological Society. Compr Physiol 14:5491‐5519, 2024.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, primarily due to its complex tumor microenvironment (TME), which drives both disease progression and therapy resistance. Understanding the molecular mechanisms governing TME dynamics is essential for developing new treatment strategies for this devastating disease. In this study, we uncover an oncogenic role for Galectin-1 (Gal1), a glycan-binding protein abundantly expressed by activated pancreatic stellate cells (PSCs), a key component of the PDAC TME that orchestrates tumor progression. Our findings reveal that Gal1 expression is elevated in the nucleus of human PSCs in both tissue samples and cultured cell lines. Using chromatin immunoprecipitation followed by sequencing analysis (ChIP-seq), we identify Gal1 occupancy at the promoters of several cancer-associated genes, including KRAS , a pivotal oncogene involved in PDAC pathogenesis. We demonstrate that Gal1 binds to the KRAS promoter, sustaining KRAS expression in PSCs, which, in turn, maintains PSC activation and promotes the secretion of protumorigenic cytokines. Mechanistically, Gal1 is required to preserve histone H3 lysine 4 monomethylation levels and to recruit the histone methyltransferase MLL1 to target promoters. Collectively, our findings define a nuclear function of Gal1 in modulating the transcriptional landscape of cancer-associated genes in PSCs within the PDAC TME, mediated through an epigenetic mechanism. These insights enhance our understanding of PDAC pathology and open potential avenues for therapeutic interventions targeting intracellular Gal1.