Marginated Neutrophils in the Lungs Effectively Compete for Nanoparticles Targeted to the Endothelium, Serving as a Part of the Reticuloendothelial System.

Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but has yet to achieve this goal with the vast majority of targets. One rare example of success in this pursuit has been the 25+ years of studies targeting the lung endothelium using nanoparticles conjugated to antibodies against endothelial surface molecules. However, here we show that such "endothelial-targeted" nanocarriers also effectively target the lungs' numerous marginated neutrophils, which reside in the pulmonary capillaries and patrol for pathogens.

Activation of alveolar epithelial ER stress by β-coronavirus infection disrupts surfactant homeostasis in mice: implications for COVID-19 respiratory failure.

COVID-19 syndrome is characterized by acute lung injury, hypoxemic respiratory failure, and high mortality. Alveolar type 2 (AT2) cells are essential for gas exchange, repair, and regeneration of distal lung epithelium. We have shown that the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and other members of the β-coronavirus genus induce an endoplasmic reticulum (ER) stress response in vitro; however, the consequences for host AT2 cell function in vivo are less understood.

Impaired AMPK Control of Alveolar Epithelial Cell Metabolism Promotes Pulmonary Fibrosis.

Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously described that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells.

PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptgfr) are implicated as a TGF-β1-independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene.

Disruption of Prostaglandin F Receptor Signaling Attenuates Fibrotic Remodeling and Alters Fibroblast Population Dynamics in A Preclinical Murine Model of Idiopathic Pulmonary Fibrosis.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2, and its cognate receptor FPr () are implicated as a TGF1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (I - ) expressing a disease-associated missense mutation in the surfactant protein C () gene.

Chronic Expression of a Clinical Mutation Causes Murine Lung Fibrosis with Idiopathic Pulmonary Fibrosis Features.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial lung disease. A barrier to developing more effective therapies for IPF is the dearth of preclinical models that recapitulate the early pathobiology of this disease. Intratracheal bleomycin, the conventional preclinical murine model of IPF, fails to reproduce the intrinsic dysfunction to the alveolar epithelial type 2 cell (AEC2) that is believed to be a proximal event in the pathogenesis of IPF.

Culture impact on the transcriptomic programs of primary and iPSC-derived human alveolar type 2 cells.

Dysfunction of alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of lung alveoli, is implicated in pulmonary disease pathogenesis, highlighting the importance of human in vitro models. However, AEC2-like cells in culture have yet to be directly compared to their in vivo counterparts at single-cell resolution. Here, we performed head-to-head comparisons among the transcriptomes of primary (1°) adult human AEC2s, their cultured progeny, and human induced pluripotent stem cell-derived AEC2s (iAEC2s).

Disruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells.

Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury.

Safety of dupilumab in a 5-month-old infant with severe atopic dermatitis.

Dupilumab is a fully humanized monoclonal antibody that suppresses Th2-mediated inflammation by inhibiting signaling of interleukin-4 and interleukin-13 through the interleukin-4 alpha receptor subunit, and is approved by the FDA for the treatment of moderate to severe atopic dermatitis (AD) in children 6 years of age and older. While initial data from phase 2 trials in children less than 6 years are promising, dupilumab use in children less than 6 months of age is not well studied. Here we present a case of a 5-month-old boy with severe primary AD, eosinophilia, hypogammaglobulinemia, and poor weight gain, who was successfully treated with dupilumab and experienced no serious adverse effects.

The common ABCA3 variant disrupts AT2 cell quality control and increases susceptibility to lung injury and aberrant remodeling.

ATP-binding cassette class A3 (ABCA3) is a lipid transporter that plays a critical role in pulmonary surfactant function. The substitution of valine for glutamic acid at codon 292 (E292V) produces a hypomorphic variant that accounts for a significant portion of mutations associated with lung disorders spanning from neonatal respiratory distress syndrome and childhood interstitial lung disease to diffuse parenchymal lung disease (DPLD) in adults including pulmonary fibrosis. The mechanisms by which this and similar mutations disrupt alveolar type 2 (AT2) cell homeostasis and cause DPLD are largely unclear.

Implementation of a pediatric provider-to-provider store-and-forward teledermatology system: Effectiveness, feasibility, and acceptability in a pilot study.

Background/objectives: Long wait times for in-person appointments in pediatric dermatology can lead to delays in specialty care, additional health system touchpoints, patient and family dissatisfaction, poorer outcomes, and increased overall health care costs. Store-and-forward teledermatology may address these challenges and improve access to care in pediatric dermatology.

Methods: We describe a prospective, non-blinded cohort study with follow-up surveys conducted from March 1, 2018, to September 20, 2018.

Stereotactic Body Radiation and Interleukin-12 Combination Therapy Eradicates Pancreatic Tumors by Repolarizing the Immune Microenvironment.

Over 80% of pancreatic ductal adenocarcinoma (PDA) patients are diagnosed with non-resectable late-stage disease that lacks effective neoadjuvant therapies. Stereotactic body radiation therapy (SBRT) has shown promise as an emerging neoadjuvant approach for treating PDA, and here, we report that its combination with local interleukin-12 (IL-12) microsphere (MS) immunotherapy results in marked tumor reduction and cures in multiple preclinical mouse models of PDA. Our findings demonstrate an increase of intratumoral interferon gamma (IFNγ) production following SBRT/IL-12 MS administration that initiates suppressor cell reprogramming and a subsequent increase in CD8 T cell activation.

Wait times, health care touchpoints, and nonattendance in an academic pediatric dermatology clinic.

Background And Objectives: Timely access to pediatric dermatology care remains a challenge. While awaiting appointments, many patients and families utilize so-called health care touchpoints outside of the dermatology clinic such as primary care or emergency department visits to address dermatologic concerns. Long waiting periods also factor into nonattendance rates at pediatric dermatology appointments.

Intratumoral Hypoxia Reduces IFN-γ-Mediated Immunity and MHC Class I Induction in a Preclinical Tumor Model.

Tumor hypoxia occurs because of an increased demand for oxygen by the rapidly growing tumor cells, together with reduction in the oxygen supply due to malformed and nonfunctional tumor vasculature. The effects of tumor hypoxia on radiotherapy (RT) are well known; however, recent findings suggest it may also suppress immunotherapy, although the mechanisms governing this observation remain undetermined. Our laboratory and others have shown that IFN-γ conditions the tumor milieu and is important for the efficacy of RT.

Environmental cues received during development shape dendritic cell responses later in life.

Environmental signals mediated via the aryl hydrocarbon receptor (AHR) shape the developing immune system and influence immune function. Developmental exposure to AHR binding chemicals causes persistent changes in CD4+ and CD8+ T cell responses later in life, including dampened clonal expansion and differentiation during influenza A virus (IAV) infection. Naïve T cells require activation by dendritic cells (DCs), and AHR ligands modulate the function of DCs from adult organisms.

A slime of the times: Two cases of acute irritant contact dermatitis from homemade slime.

We describe two cases of acute-onset erythema, peeling, and pruritus or tenderness isolated to the palmar surface of the hands. A detailed exposure history revealed significant periods of contact with homemade slime; given the clinical findings and timing of exposure, acute contact dermatitis of the hands was suspected. Symptoms and clinical findings resolved after avoidance of the suspected causative contactants.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

Background: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).

Methods: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency.

Utility and tolerability of the long-pulsed 1064-nm neodymium:yttrium-aluminum-garnet (LP Nd:YAG) laser for treatment of symptomatic or disfiguring vascular malformations in children and adolescents.

Background: Vascular malformations manifest with pain, bleeding, disability, and disfigurement in a subset of children. There are scant data available on the utility and tolerability of laser surgery for symptomatic or disfiguring non-port-wine stain vascular malformations in children.

Objective: The objective of this study was to determine the utility and tolerability of the 1064-nm long-pulsed neodymium:yttrium-aluminum-garnet (LP Nd:YAG) laser for treatment of symptomatic or disfiguring vascular malformations in children.

Autoinflammatory Skin Disease: A Review of Concepts and Applications to General Dermatology.

We provide an up-to-date summary of important concepts of autoinflammation as well as describe important but rare monogenic autoinflammatory disorders that may present with cutaneous findings. Finally, of particular interest to a practicing general dermatology audience, we review concepts of autoinflammation as they apply to understanding the disease pathogenesis of common skin disorders.

Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes.

Although radiotherapy (RT) is widely used to control tumor growth across many cancer types, there is a relatively high incidence of RT failure exhibited by tumor recurrence, therefore a clear need exists to achieve improved effectiveness of RT. The RT-elicited immune response largely impacts the efficacy of RT and includes immune cells that kill tumor cells, but also immunosuppressive cells, which dampen anti-tumor immunity. Using murine models in which syngeneic tumor cell lines (Colon38, Glioma261, Line1) are grown intramuscularly and treated with 15 Gy local RT, we assessed the effects of RT on both the systemic and intratumoral immune response.

GM-CSF modulates pulmonary resistance to influenza A infection.

Alveolar type II epithelial or other pulmonary cells secrete GM-CSF that regulates surfactant catabolism and mucosal host defense through its capacity to modulate the maturation and activation of alveolar macrophages. GM-CSF enhances expression of scavenger receptors MARCO and SR-A. The alveolar macrophage SP-R210 receptor binds the surfactant collectin SP-A mediating clearance of respiratory pathogens.