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Showing papers by "Johns Hopkins University School of Medicine published in 2022"


Journal ArticleDOI
TL;DR: In this article , the authors present an overview of recent advances in epidemiology, pathophysiology, imaging, diagnosis, and treatment of chronic obstructive pulmonary disease (COPD).

77 citations


Journal ArticleDOI
TL;DR: In this article , a third SARS-CoV2 vaccine dose increased median total anti-spike (1.6-fold), pseudoneutralization (ACE2 blocking), and live-virus neutralization (nAb) against VOCs.

64 citations


Journal ArticleDOI
01 Jun 2022
TL;DR: XBP1 deficiency increased ROS production to promote hepatocellular pyroptosis by activating NLRP3/caspase-1/GSDMD signaling, which facilitated the extracellular release of mtDNA as mentioned in this paper .
Abstract: Hepatocellular cell death and macrophage proinflammatory activation contribute to the pathology of various liver diseases, during which XBP1 plays an important role. However, the function and mechanism of XBP1 in thioacetamide (TAA)-induced acute liver injury (ALI) remains unknown. Here, we investigated the effects of XBP1 inhibition on promoting hepatocellular pyroptosis to activate macrophage STING signaling during ALI. While both TAA- and LPS-induced ALI triggered XBP1 activation in hepatocytes, hepatocyte-specific XBP1 knockout mice exhibited exacerbated ALI with increased hepatocellular pyroptosis and enhanced macrophage STING activation. Mechanistically, mtDNA released from TAA-stressed hepatocytes could be engulfed by macrophages, further inducing macrophage STING activation in a cGAS- and dose-dependent manner. XBP1 deficiency increased ROS production to promote hepatocellular pyroptosis by activating NLRP3/caspase-1/GSDMD signaling, which facilitated the extracellular release of mtDNA. Moreover, impaired mitophagy was found in XBP1 deficient hepatocytes, which was reversed by PINK1 overexpression. Mitophagy restoration also inhibited macrophage STING activation and ALI in XBP1 deficient mice. Activation of XBP1-mediated hepatocellular mitophagy and pyroptosis and macrophage STING signaling pathway were observed in human livers with ALI. Collectively, these findings demonstrate that XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA/cGAS/STING signaling of macrophages, providing potential therapeutic targets for ALI.

36 citations


Journal ArticleDOI
TL;DR: In this article , the authors performed high-dimensional single-cell RNA sequencing (scRNA-seq) on four patient tumors pretreatment and posttreatment from a neoadjuvant trial of patients with advanced-stage head and neck squamous cell carcinoma that were treated with the αPD-1 therapy, nivolumab.
Abstract: Cancer-associated fibroblasts (CAF) have been implicated as potential mediators of checkpoint immunotherapy response. However, the extensive heterogeneity of these cells has precluded rigorous understanding of their immunoregulatory role in the tumor microenvironment.We performed high-dimensional single-cell RNA sequencing (scRNA-seq) on four patient tumors pretreatment and posttreatment from a neoadjuvant trial of patients with advanced-stage head and neck squamous cell carcinoma that were treated with the αPD-1 therapy, nivolumab. The head and neck CAF (HNCAF) protein activity profiles, derived from this cohort of paired scRNA-seq, were used to perform protein activity enrichment analysis on the 28-patient parental cohort of clinically annotated bulk transcriptomic profiles. Ex vivo coculture assays were used to test functional relevance of HNCAF subtypes.Fourteen distinct cell types were identified with the fibroblast population showing significant changes in abundance following nivolumab treatment. Among the fibroblast subtypes, HNCAF-0/3 emerged as predictive of nivolumab response, while HNCAF-1 was associated with immunosuppression. Functionally, HNCAF-0/3 were found to reduce TGFβ-dependent PD-1+TIM-3+ exhaustion of CD8 T cells, increase CD103+NKG2A+ resident memory phenotypes, and enhance the overall cytolytic profile of T cells.Our findings demonstrate the functional importance of distinct HNCAF subsets in modulating the immunoregulatory milieu of human HNSCC. In addition, we have identified clinically actionable HNCAF subtypes that can be used as a biomarker of response and resistance in future clinical trials.

31 citations


Journal ArticleDOI
TL;DR: Redding et al. as discussed by the authors tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system.
Abstract: Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies.Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247.

27 citations


Journal ArticleDOI
TL;DR: Itch pathogenesis is broadly characterized into histaminergic and nonhistaminergic pathways and transmitted via 2 main receptor families: G protein-coupled receptors and transient receptor potential channels as discussed by the authors .
Abstract: Itch pathogenesis is broadly characterized into histaminergic and nonhistaminergic pathways and transmitted via 2 main receptor families: G protein–coupled receptors and transient receptor potential channels. In the skin, itch is primarily transmitted by unmyelinated type C and thinly myelinated type Aδ nerve fibers. Crosstalk between the immune and neural systems modulates itch transmission at the skin, spinal cord, and brain. Among the many known pruritogens, Th2 cytokines, such as interleukin-4, interleukin-13, interleukin-31, and thymic stromal lymphopoietin, are particularly important mediators that signal through shared Janus kinase pathways, representing novel targets for novel itch therapeutics. Emerging evidence has also revealed that the opioidergic system is a potent modulator of itch transmission, with increased μ-opioid activity and decreased κ-opioid activity contributing to itch pathogenesis. Optimal management of itch requires that treatment approaches be tailored to specific etiologic itch subtypes. When the etiology is unknown and patients are given a diagnosis of chronic pruritus of unknown origin, treatment should be guided by the presence of Th2 polarization, often reflected by increased blood eosinophils. In the second article of this 2-part series, we outline our current understanding of itch pathogenesis and discuss available and emerging treatments for itch. Itch pathogenesis is broadly characterized into histaminergic and nonhistaminergic pathways and transmitted via 2 main receptor families: G protein–coupled receptors and transient receptor potential channels. In the skin, itch is primarily transmitted by unmyelinated type C and thinly myelinated type Aδ nerve fibers. Crosstalk between the immune and neural systems modulates itch transmission at the skin, spinal cord, and brain. Among the many known pruritogens, Th2 cytokines, such as interleukin-4, interleukin-13, interleukin-31, and thymic stromal lymphopoietin, are particularly important mediators that signal through shared Janus kinase pathways, representing novel targets for novel itch therapeutics. Emerging evidence has also revealed that the opioidergic system is a potent modulator of itch transmission, with increased μ-opioid activity and decreased κ-opioid activity contributing to itch pathogenesis. Optimal management of itch requires that treatment approaches be tailored to specific etiologic itch subtypes. When the etiology is unknown and patients are given a diagnosis of chronic pruritus of unknown origin, treatment should be guided by the presence of Th2 polarization, often reflected by increased blood eosinophils. In the second article of this 2-part series, we outline our current understanding of itch pathogenesis and discuss available and emerging treatments for itch. Journal Based CME Instructions and InformationJournal of the American Academy of DermatologyVol. 86Issue 1Preview Full-Text PDF CME examinationJournal of the American Academy of DermatologyVol. 86Issue 1Preview Full-Text PDF

26 citations


Journal ArticleDOI
TL;DR: In this article , the authors evaluated the safety and tolerability of preoperative administration of three doses of the immune checkpoint inhibitor nivolumab in patients with clinically localized high-risk renal cell carcinoma.

22 citations


Journal ArticleDOI
TL;DR: In this article , the authors summarize the body of evidence implicating each of these risk factors in residual coronary heart disease risk, including systemic inflammation, diabetes mellitus, high-density lipoprotein, plasma triglycerides (TG), residual lipoproteins (RLP), and vascular endothelial dysfunction (ED).

22 citations


Journal ArticleDOI
TL;DR: In this article, the TGF-β superfamily member GDF-15 was identified as a component of the regeneration-promoting program (RPP), which is essential for proper repair.
Abstract: Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte-derived macrophages. Pro-inflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed regeneration-promoting program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage-derived factors coordinate tissue repair. Gene expression kinetics-based clustering of blood circulating Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow macrophages, isolated from injured muscle, identified the TGF-β superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and on muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARγ. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration-associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (growth factor-expressing macrophages [GFEMs]).

20 citations


Journal ArticleDOI
TL;DR: In this article , the authors used rational engineering and cross-species screening to develop an NTR variant, NTR 2.0, which exhibits ~100-fold improvement in MTZ-mediated cell-specific ablation efficacy, eliminating the need for near-toxic prodrug treatment regimens.
Abstract: Transgenic expression of bacterial nitroreductase (NTR) enzymes sensitizes eukaryotic cells to prodrugs such as metronidazole (MTZ), enabling selective cell-ablation paradigms that have expanded studies of cell function and regeneration in vertebrates. However, first-generation NTRs required confoundingly toxic prodrug treatments to achieve effective cell ablation, and some cell types have proven resistant. Here we used rational engineering and cross-species screening to develop an NTR variant, NTR 2.0, which exhibits ~100-fold improvement in MTZ-mediated cell-specific ablation efficacy, eliminating the need for near-toxic prodrug treatment regimens. NTR 2.0 therefore enables sustained cell-loss paradigms and ablation of previously resistant cell types. These properties permit enhanced interrogations of cell function, extended challenges to the regenerative capacities of discrete stem cell niches, and novel modeling of chronic degenerative diseases. Accordingly, we have created a series of bipartite transgenic reporter/effector resources to facilitate dissemination of NTR 2.0 to the research community.

19 citations


Journal ArticleDOI
TL;DR: The first part of a 2-part continuing medical education series as discussed by the authors describes the broader epidemiology and specific conditions associated with itch and the clinical presentation and diagnostic workup for patients with itch.
Abstract: Itch, or pruritus, is the uncomfortable sensation underlying the desire to scratch. Itch is a very common complaint in the general population that can result from dermatologic, systemic (eg, renal, hepatobiliary, endocrine), paraneoplastic, neuropathic, and psychogenic etiologies. Chronic itch is associated with significant sleep disturbances and profoundly reduces overall quality of life. Certain populations, including elderly and African Americans, are at increased risk of experiencing heightened burden of itch. Because of the variable clinical presentation and wide-ranging etiologies, itch presents a challenge for clinicians. The initial evaluation should include a complete blood count, with differential, hepatic, renal, and thyroid function testing along with diabetes screening. Further testing should be guided by history and physical examination findings. There should be a heightened concern for underlying malignancy in individuals older than 60 years of age who have a history of liver disease and diffuse itch less than 12 months of duration. For individuals with chronic pruritus of unknown origin, increased blood eosinophils may serve as a biomarker of T helper cell type 2 polarization and response to immunomodulator therapies. In this first part of a 2-part continuing medical education series, we describe the broader epidemiology and specific conditions associated with itch and the clinical presentation and diagnostic workup for patients with itch.

Journal ArticleDOI
TL;DR: In this article , the authors describe antibody responses in a cohort of patients with rheumatic and musculoskeletal diseases on immunosuppression 6 months after completing the two-dose SARS-CoV-2 mRNA vaccine series.

Journal ArticleDOI
TL;DR: In this paper , the authors discuss the recent advancements in immune-mediated kidney disease via the lens of direct and indirect immune mediated mechanisms, which has culminated in the development of multiple therapeutic agents that consistently improved renal and patient outcomes.

Journal ArticleDOI
01 Sep 2022-Neuron
TL;DR: In this article , the authors demonstrate that Dynamin 1 is pre-recruited to endocytic sites for ultra-fast endocytosis, where the condensates do not form.

Journal ArticleDOI
TL;DR: In this article , a review focused on pediatric gliomas, ependymomas, and medulloblastomas is presented. But the classification includes genetic changes, which have prognostic significance and may lead to therapeutic targets.
Abstract: Childhood brain tumors were previously classified by histologic appearance and location. A new classification includes genetic changes, which have prognostic significance and may lead to therapeutic targets. This review focuses on pediatric gliomas, ependymomas, and medulloblastomas.

Journal ArticleDOI
TL;DR: In this paper , the prototypical GAGA pioneer factor (GAF) was shown to be chromatin bound with nucleosome-like confinement for more than 2 min, far longer than the dynamic range of most transcription factors.
Abstract: How pioneer factors interface with chromatin to promote accessibility for transcription control is poorly understood in vivo. Here, we directly visualize chromatin association by the prototypical GAGA pioneer factor (GAF) in live Drosophila hemocytes. Single-particle tracking reveals that most GAF is chromatin bound, with a stable-binding fraction showing nucleosome-like confinement residing on chromatin for more than 2 min, far longer than the dynamic range of most transcription factors. These kinetic properties require the full complement of GAF’s DNA-binding, multimerization and intrinsically disordered domains, and are autonomous from recruited chromatin remodelers NURF and PBAP, whose activities primarily benefit GAF’s neighbors such as Heat Shock Factor. Evaluation of GAF kinetics together with its endogenous abundance indicates that, despite on–off dynamics, GAF constitutively and fully occupies major chromatin targets, thereby providing a temporal mechanism that sustains open chromatin for transcriptional responses to homeostatic, environmental and developmental signals. Here authors visualize dynamics GAGA pioneer factor (GAF) association with chromatin in vivo in Drosophila hemocytes. The characterization of GAF kinetics provides a temporal mechanism for maintenance of open chromatin for transcriptional responses to homeostatic, environmental and developmental signals.

Journal ArticleDOI
TL;DR: In this paper , the authors describe the selection and validation of a genetically and antigenically diverse reference panel of 15 HCV pseudoparticles (HCVpps) for neutralization assays, and propose that this multitier reference panel could be adopted as a standard for the measurement of neutralizing antibody potency and breadth, facilitating meaningful comparisons of neutralization results from vaccine studies in different laboratories.

Journal ArticleDOI
TL;DR: In this paper , a prospective multicenter pilot study comparing HIV D+/R+ to donors without-HIV to recipients with HIV D−/R+) LT was performed.

Journal ArticleDOI
TL;DR: The authors found that Prurigo nodularis (PN) is associated with significant quality-of-life impairment, similar to the level of other chronic systemic conditions, and that PN is also associated with substantial individual economic burden, emphasizing the necessity of research on effective treatment options.
Abstract: Prurigo nodularis (PN) is an understudied, pruritic inflammatory skin disease. Little is known about the effect of PN on quality of life and its associated economic burden.To quantify the impact of PN on quality of life and its economic implications.A cohort study of PN patients (n = 36) was conducted using the Health Utilities Index Mark 3 questionnaire. Control data from US adults (n = 4187) were obtained from the 2002-2003 Joint Canada/United States Survey of Health. Quality-adjusted life year loss and economic costs were estimated by comparing the Health Utilities Index Mark 3 scores of the PN patients with those of the controls.The PN patients had lower overall health performance compared to the controls, (mean ± SE, 0.52 ± 0.06 vs 0.86 ± 0.003, respectively, P < .001). In multivariable regression, PN was found to be associated with worse health performance (coefficient -0.34, 95% CI [-0.46 to -0.23]), most prominent in the pain subdomain (coefficient -0.24, 95% CI [-0.35 to -0.13]). This correlated to an average of 6.5 lifetime quality-adjusted life years lost per patient, translating to an individual lifetime economic burden of $323,292 and a societal burden of $38.8 billion.These results demonstrate that PN is associated with significant quality-of-life impairment, similar to the level of other chronic systemic conditions. PN is also associated with a substantial individual economic burden, emphasizing the necessity of research on effective treatment options.

Journal ArticleDOI
TL;DR: In this article , the potential effects of climate change and its consequences on agricultural yield and micronutrient quality, primarily zinc, iron, and vitamin A, of plant foods and upon the availability of animal foods, are summarized.

Journal ArticleDOI
TL;DR: In this article, the effects of cortical anatomical parameters (volumes, dimension, and torque) on simulated tDCS current density in healthy young, middle-aged, and older males and females were investigated.

Journal ArticleDOI
TL;DR: In this paper , the authors discuss key factors that influence blood culture performance, with a focus on the preanalytical phase, including technical aspects of the blood culture collection process and blood culture indications.
Abstract: There has been significant progress in detection of bloodstream pathogens in recent decades with the development of more sensitive automated blood culture detection systems and the availability of rapid molecular tests for faster organism identification and detection of resistance genes. However, most blood cultures in clinical practice do not grow organisms, suggesting that suboptimal blood culture collection practices (e.g., suboptimal blood volume) or suboptimal selection of patients to culture (i.e., blood cultures ordered for patients with low likelihood of bacteremia) may be occurring. A national blood culture utilization benchmark does not exist, nor do specific guidelines on when blood cultures are appropriate or when blood cultures are of low value and waste resources. Studies evaluating the potential harm associated with excessive blood cultures have focused on blood culture contamination, which has been associated with significant increases in health care costs and negative consequences for patients related to exposure to unnecessary antibiotics and additional testing. Optimizing blood culture performance is important to ensure bloodstream infections (BSIs) are diagnosed while minimizing adverse events from overuse. In this review, we discuss key factors that influence blood culture performance, with a focus on the preanalytical phase, including technical aspects of the blood culture collection process and blood culture indications. We highlight areas for improvement and make recommendations to improve current blood culture practices among hospitalized patients.

Journal ArticleDOI
TL;DR: In this article , the effects of cortical anatomical parameters (volumes, dimension, and torque) on simulated tDCS current density in healthy young, middle-aged, and older males and females were investigated.

Journal ArticleDOI
TL;DR: Based on the largest ethnographic study to date, undertaken with 150 women who froze their eggs for nonmedical reasons in the United States and Israel, this work examines egg freezing at the end of romance.
Abstract: The newest innovation in assisted reproduction is oocyte cryopreservation, more commonly known as egg freezing, which has been developed as a method of fertility preservation. Studies emerging from...

Journal ArticleDOI
22 Feb 2022-Energies
TL;DR: Nickel-based electrocatalysts are a fitting alternative for large-scale hydrogen production, as they are economically accessible and can be used to produce green hydrogen from water electrolysis using intermittent sources as discussed by the authors .
Abstract: Currently, hydrogen production is based on the reforming process, leading to the emission of pollutants; therefore, a substitute production method is imminently required. Water electrolysis is an ideal alternative for large-scale hydrogen production, as it does not produce any carbon-based pollutant byproducts. The production of green hydrogen from water electrolysis using intermittent sources (e.g., solar and eolic sources) would facilitate clean energy storage. However, the electrocatalysts currently required for water electrolysis are noble metals, making this potential option expensive and inaccessible for industrial applications. Therefore, there is a need to develop electrocatalysts based on earth-abundant and low-cost metals. Nickel-based electrocatalysts are a fitting alternative because they are economically accessible. Extensive research has focused on developing nickel-based electrocatalysts for hydrogen and oxygen evolution. Theoretical and experimental work have addressed the elucidation of these electrochemical processes and the role of heteroatoms, structure, and morphology. Even though some works tend to be contradictory, they have lit up the path for the development of efficient nickel-based electrocatalysts. For these reasons, a review of recent progress is presented herein.

Journal ArticleDOI
TL;DR: In this paper , the authors performed multivariable logistic regressions to compare comorbidities in adult patients with atopic dermatitis versus age-and sex-matched controls and found increased odds of psychiatric conditions, including anxiety (odds ratio [OR] 1.44] and mood disorders (OR 1.31), were observed in patients with AD.
Abstract: Atopic dermatitis (AD) is a pruritic, inflammatory skin disease associated with various comorbidities. However, comprehensive analyses of real-world comorbidities in adult patients with AD are limited.To characterize the real-world comorbidities associated with adult AD in an ambulatory population.We queried the MarketScan Commercial Claims and Encounters database from January 1, 2017 to December 31, 2017. Multivariable logistic regressions were performed to compare comorbidities in adult patients with AD versus age- and sex-matched controls.A total of 39,779 patients with AD and 353,743 controls were identified. Increased odds of psychiatric conditions, including anxiety (odds ratio [OR] 1.44) and mood disorders (OR 1.31), were observed in patients with AD. Patients with AD had higher likelihoods of autoimmune diseases, including vitiligo (OR 4.44) and alopecia areata (OR 6.01). Adult AD was also associated with infections, including impetigo (OR 9.72), methicillin-resistant Staphylococcus aureus (OR 3.92), and cellulitis (OR 2.52). Patients with AD were more likely to have systemic conditions, including lymphoid/hematopoietic malignancy (OR 1.91), atherosclerosis (OR 1.69), and metabolic syndrome (OR 1.47). For all the above, P < .001.Retrospective analysis of health care claims data.Adult AD is associated with various psychiatric and systemic comorbidities, emphasizing the systemic nature of AD and the need for the collaborative management of these patients.


Journal ArticleDOI
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) as mentioned in this paper measured the Healthcare Access and Quality (HAQ) Index overall and for select age groups in 204 locations from 1990 to 2019, using the arithmetic mean of scaled mortality-to-incidence ratios (MIRs) and riskstandardised death rates (RSDRs) for 32 causes of death that should not occur in the presence of timely, quality health care.

Journal ArticleDOI
01 Apr 2022-iScience
TL;DR: In this article , gene knockout of OPA1, a mitochondrial dynamin-related GTPase that mediates mitochondrial fusion, prevents megamitochondria formation and liver damage in a NASH mouse model induced by a methionine-choline-deficient (MCD) diet.

Journal ArticleDOI
TL;DR: Boyarsky et al. as discussed by the authors evaluated the safety and immunogenicity of a third dose of a SARS-CoV-2 vaccine in solid organ transplant recipients, with 5 of 7 patients having a discernable antibody response to a booster dose.