Vitiligo is a cutaneous autoimmune disorder characterized by progressive depigmentation due to melanocyte destruction by cytotoxic T cells. Genetic factors predispose patients to the disease, supported by environmental factors often initiating new disease episodes. We questioned whether disease outcomes are partially defined by pathogenic microbes driving nutrient deficiencies and inflammation.
View Article and Find Full Text PDFForkhead box P3 (Foxp3) regulatory T cells (Tregs) resolve acute inflammation and repair the injured lung after viral pneumonia. Vimentin is a critical protein in the distal pole complex (DPC) of Tregs. This study reveals the inhibitory effect of vimentin on the suppressive and reparative capacity of Tregs.
View Article and Find Full Text PDFMelanoma arises from transformation of melanocytes in the basal layer of epidermis where they are surrounded by keratinocytes, with which they interact through cell contact and paracrine communication. Although research focuses on how the accumulation of oncogene and tumor suppressor gene mutations in melanocytes drive melanomagenesis, how alterations in keratinocytes serve as extrinsic drivers of melanoma initiation and progression is poorly understood. We recently identified keratinocyte desmoglein 1 (DSG1) as an mediator of keratinocyte:melanoma crosstalk.
View Article and Find Full Text PDFA major limitation of immunotherapy is the development of resistance resulting from cancer-mediated inhibition of host lymphocytes. Cancer cells release CCL2 to recruit classical monocytes expressing its receptor CCR2 for the promotion of metastasis and resistance to immunosurveillance. In the circulation, some CCR2-expressing classical monocytes lose CCR2 and differentiate into intravascular nonclassical monocytes that have anticancer properties but are unable to access extravascular tumor sites.
View Article and Find Full Text PDFBackground: No standardized, evidence-based surveillance practices exist to guide and optimize recurrence detection in patients with cutaneous melanoma.
Objective: To determine the most high-yield positive review of systems for signaling recurrence in patients with cutaneous melanoma.
Methods: This retrospective cohort study assessed patients with a history of cutaneous melanoma and compared demographic and clinical characteristics, including a comprehensive review of systems, among those who experienced recurrence and those who did not.
The evolution of T cell molecular signatures in the distal lung of patients with severe pneumonia is understudied. Here, we analyzed T cell subsets in longitudinal bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia, including unvaccinated patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with respiratory failure not linked to pneumonia. In patients with SARS-CoV-2 pneumonia, activation of interferon signaling pathways, low activation of the NF-κB pathway and preferential targeting of spike and nucleocapsid proteins early after intubation were associated with favorable outcomes, whereas loss of interferon signaling, activation of NF-κB-driven programs and specificity for the ORF1ab complex late in disease were associated with mortality.
View Article and Find Full Text PDFBackground: Dystrophic epidermolysis bullosa (DEB) describes a rare genetic blistering disorder characterized by fragile skin. This study aimed to classify the frequency, demographics, cost, and comorbidities associated with emergency department (ED) visits due to DEB.
Methods: The Nationwide Emergency Department Sample (NEDS) was analyzed for pediatric (age <18) ED visits from 2015 to 2019.
Cutaneous T-cell lymphomas (CTCL) are a rare group of T-cell neoplasms which infiltrate the skin and can result in substantial morbidity and mortality. Risk factors for CTCL are still poorly understood though recent studies suggest chemical exposures may play a role in its development. To further characterize patient-centered risk factors for CTCL, especially compared with matched controls, we performed one of the largest prospective cohort survey studies to date to examine patient-reported exposures and health-related quality of life (HRQoL) in association with concurrent clinical disease characteristics.
View Article and Find Full Text PDFPBRM1 is frequently mutated in cancers of epithelial origin. How PBRM1 regulates normal epithelial homeostasis, prior to cancer initiation, remains unclear. Here, we show that PBRM1's gene regulatory roles differ drastically between cell states, leveraging human skin epithelium (epidermis) as a research platform.
View Article and Find Full Text PDFPathogen clearance and resolution of inflammation in patients with pneumonia require an effective local T cell response. Nevertheless, local T cell activation may drive lung injury, particularly during prolonged episodes of respiratory failure characteristic of severe SARS-CoV-2 pneumonia. While T cell responses in the peripheral blood are well described, the evolution of T cell phenotypes and molecular signatures in the distal lung of patients with severe pneumonia caused by SARS-CoV-2 or other pathogens is understudied.
View Article and Find Full Text PDFMelanoma is an aggressive cancer typically arising from transformation of melanocytes residing in the basal layer of the epidermis, where they are in direct contact with surrounding keratinocytes. The role of keratinocytes in shaping the melanoma tumor microenvironment remains understudied. We previously showed that temporary loss of the keratinocyte-specific cadherin, Desmoglein 1 (Dsg1), controls paracrine signaling between normal melanocytes and keratinocytes to stimulate the protective tanning response.
View Article and Find Full Text PDFKeloids are benign, fibroproliferative dermal tumors that typically form owing to abnormal wound healing. The current standard of care is generally ineffective and does not prevent recurrence. To characterize keloid scars and better understand the mechanism of their formation, we performed transcriptomic profiling of keloid biopsies from a total of 25 subjects of diverse racial and ethnic origins, 15 of whom provided a paired nonlesional sample, a longitudinal sample, or both.
View Article and Find Full Text PDFSelf-renewing somatic tissues rely on progenitors to support the continuous tissue regeneration. The gene regulatory network maintaining progenitor function remains incompletely understood. Here we show that NUP98 and RAE1 are highly expressed in epidermal progenitors, forming a separate complex in the nucleoplasm.
View Article and Find Full Text PDFBackground/objectives: Healthcare transition (HCT) refers to movement from pediatric to adult healthcare models. Lack of HCT preparation contributes to poor health outcomes. This study measures readiness to transition in individuals with genetic skin conditions.
View Article and Find Full Text PDFMelanoma arises from transformation of melanocytes in the basal layer of the epidermis where they are surrounded by keratinocytes, with which they interact through cell contact and paracrine communication. Considerable effort has been devoted to determining how the accumulation of oncogene and tumor suppressor gene mutations in melanocytes drive melanoma development. However, the extent to which alterations in keratinocytes that occur in the developing tumor niche serve as extrinsic drivers of melanoma initiation and progression is poorly understood.
View Article and Find Full Text PDFPersistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 pneumonia, low tidal volumes to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood.
View Article and Find Full Text PDFPulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy, we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells.
View Article and Find Full Text PDFPrimary graft dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular nonclassical monocytes (NCM) initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) permeabilize the vascular endothelium to allow neutrophil extravasation necessary for PGD.
View Article and Find Full Text PDFAlveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice.
View Article and Find Full Text PDFBackground: Little is known about the use and burden of emergency department (ED) visits for cellulitis/erysipelas in the United States.
Objective: To determine the prevalence, risk factors, complications, and cost of emergency care for cellulitis/erysipelas in the United States.
Methods: Cross-sectional study of the 2006 to 2016 National Emergency Department Sample, including a 20% sample of US ED visits (N = 320,080,467).
Despite the widespread use of antibiotics, bacterial pneumonias in donors strongly predispose to the fatal syndrome of primary graft dysfunction (PGD) following lung transplantation. We report that bacterial endotoxin persists in human donor lungs after pathogen is cleared with antibiotics and is associated with neutrophil infiltration and PGD. In mouse models, depletion of tissue-resident alveolar macrophages (TRAMs) attenuated neutrophil recruitment in response to endotoxin as shown by compartmental staining and intravital imaging.
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