Interplay between aging, lung inflammation/remodeling, and fibronectin EDA in lung cancer progression.

Lung cancer remains the leading cause of cancer death in the United States. Since most lung cancers occur in aged individuals with chronic lung disorders characterized by inflammation and/or fibrosis, we hypothesized that aging and tissue inflammation/remodeling act in concert to promote lung cancer progression. To test this, we engaged in studies using young and aged C57BL/6 mice in conjunction with bleomycin treatment in a syngeneic model of lung cancer.

Rod photoreceptor clearance due to misfolded rhodopsin is linked to a DAMP-immune checkpoint switch.

Chronic endoplasmic reticulum stress resulting from misfolding of the visual pigment rhodopsin (RHO) can lead to loss of rod photoreceptors, which initiates retinitis pigmentosa, characterized initially by diminished nighttime and peripheral vision. Cone photoreceptors depend on rods for glucose transport, which the neurons use for assembly of visual pigment-rich structures; as such, loss of rods also leads to a secondary loss of cone function, diminishing high-resolution color vision utilized for tasks including reading, driving, and facial recognition. If dysfunctional rods could be maintained to continue to serve this secondary cone preservation function, it might benefit patients with retinitis pigmentosa, but the mechanisms by which rods are removed are not fully established.

The Integrin Inhibitor Cilengitide and Bleomycin-Induced Pulmonary Fibrosis : Cilengitide and Bleomycin-Induced Pulmonary Fibrosis.

Purpose: Fibroproliferation and excess deposition of extracellular matrix (ECM) are the pathologic hallmarks of idiopathic pulmonary fibrosis (IPF), a chronic progressive disorder with high mortality and suboptimal treatment options. Although the etiologic mechanisms responsible for the development and progression of IPF remain unclear, cell-ECM interactions and growth factors are considered important. Cilengitide is a cyclic RGD pentapeptide with anti-angiogenic activity that targets αvβ3, αvβ5 and α5β1, integrins known to mediate cell-ECM interactions and activate the pro-fibrotic growth factor Transforming Growth Factor beta (TGF-β).

Acetylation of putative arylamine and alkylaniline carcinogens in immortalized human fibroblasts transfected with rapid and slow acetylator N-acetyltransferase 2 haplotypes.

Exposure to alkylanilines found in tobacco smoke and indoor air is associated with risk of bladder cancer. Genetic factors significantly influence the metabolism of arylamine carcinogens and the toxicological outcomes that result from exposure. We utilized nucleotide excision repair (NER)-deficient immortalized human fibroblasts to examine the effects of human N-acetyltransferase 1 (NAT1), CYP1A2, and common rapid (NAT2*4) and slow (NAT2*5B or NAT2*7B) acetylator human N-acetyltransferase 2 (NAT2) haplotypes on environmental arylamine and alkylaniline metabolism.

MicroRNA-135a Protects Against Ethanol-Induced Apoptosis in Neural Crest Cells and Craniofacial Defects in Zebrafish by Modulating the Siah1/p38/p53 Pathway.

MicroRNAs (miRNAs) are small non-coding RNAs that are involved in various biological processes, including apoptosis, by regulating gene expression. This study was designed to test the hypothesis that ethanol-induced downregulation of miR-135a contributes to ethanol-induced apoptosis in neural crest cells (NCCs) by upregulating Siah1 and activating the p38 mitogen-activated protein kinase (MAPK)/p53 pathway. We found that treatment with ethanol resulted in a significant decrease in miR-135a expression in both NCCs and zebrafish embryos.

International Perspective on the New 2019 American Thoracic Society/Infectious Diseases Society of America Community-Acquired Pneumonia Guideline: A Critical Appraisal by a Global Expert Panel.

In 2019, the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) issued a substantial revision of the 2007 guideline on community-acquired pneumonia (CAP). Despite the fact that generalization of infectious disease guidelines is limited because of substantial geographic differences in microbiologic etiology and antimicrobial resistance, the ATS/IDSA guideline is frequently applied outside the United States. Therefore, this project aimed to give a perspective on the ATS/IDSA CAP recommendations related to the management of CAP outside the United States.

Oxysophocarpine reduces oxidative stress and inflammation in tuberculosis-infected neutrophils and mouse lungs.

Tuberculosis (TB) is a chronic inflammatory infectious disease caused by (Mtb), which induces irreversible pulmonary damage. Oxysophocarpine (OSC) is a natural alkaloid that exhibits multiple pharmacological activities, including anti-inflammation; however, the protective effects of OSC against TB and the mechanisms involved are unknown. Here, we established murine and cellular models of TB with C3HeB/FeJ mice and neutrophils infected with H37Rv to investigate the biological functions of OSC in TB.

The Matrisome, Inflammation, and Liver Disease.

Chronic fatty liver disease is common worldwide. This disease is a spectrum of disease states, ranging from simple steatosis (fat accumulation) to inflammation, and eventually to fibrosis and cirrhosis if untreated. The fibrotic stage of chronic liver disease is primarily characterized by robust accumulation of extracellular matrix (ECM) proteins (collagens) that ultimately impairs the function of the organ.

The elevated systemic cytokine levels in HIV patients are not associated with an elevated pulmonary cytokine environment.

Background: HIV-positive patients on anti-retroviral therapy (ART) are at higher risk of developing many non-AIDS related chronic diseases, including chronic obstructive pulmonary disease (COPD), compared to HIV-negative individuals. While the mechanisms are not clear, a persistent pro-inflammatory state appears to be a key contributing factor. The aims of this study were to investigate whether HIV-positive patients without COPD present evidence of potentially predisposing abnormal pulmonary cytokine/chemokine environment and to explore the relationship between pulmonary and systemic cytokine levels.

Metabolic Deregulation of the Blood-Outer Retinal Barrier in Retinitis Pigmentosa.

Retinitis pigmentosa (RP) initiates with diminished rod photoreceptor function, causing peripheral and night-time vision loss. However, subsequent loss of cone function and high-resolution daylight and color vision is most debilitating. Visual pigment-rich photoreceptor outer segments (OS) undergo phagocytosis by the retinal pigment epithelium (RPE), and the RPE also acts as a blood-outer retinal barrier transporting nutrients, including glucose, to photoreceptors.

High Thymic Output of Effector CD4 Cells May Lead to a Treg : T Effector Imbalance in the Periphery in NOD Mice.

Regulatory T cells (Tregs) play a critical role in controlling autoreactive T cells, and quantitative and/or qualitative deficiencies in Tregs are associated with autoimmune diseases, including type 1 diabetes (T1D), in both humans and mice. Both the incidence of T1D and percentages of peripheral Tregs in NOD mice vary considerably between animal facilities. In our animal facility, the incidence of T1D in NOD mice is high at 90-100% and the percentages of peripheral CD4Foxp3 cells in ~9-10-week-old female NOD mice are decreased compared to control (B6) mice shortly before high glucose is first detected (~12 weeks).

Exposure to Nitro-PAHs interfere with germination and early growth of Hordeum vulgare via oxidative stress.

Nitrated polycyclic aromatic hydrocarbons (Nitro-PAHs) as important organic pollutants are ubiquitous in the atmospheric environment, agricultural soils and aquatic environments to pose a severe polluting risk. However, little is known about the mechanism of Nitro-PAHs genotoxicity in plants. We analyzed seeds germination, seedlings growth, and toxicity mechanism following 1-Nitropyrene treatment in Hordeum vulgare.

Vinyl chloride-induced interaction of nonalcoholic and toxicant-associated steatohepatitis: Protection by the ALDH2 activator Alda-1.

Vinyl chloride (VC), an abundant environmental contaminant causes steatohepatitis at high levels, but is considered safe at lower (i.e., sub-OSHA) levels.

Culturally Effective Care for Refugee Populations: Interprofessional, Interactive Case Studies.

Introduction: Within health sciences education literature, the majority of reported student experiences with refugee populations are limited to traditional, professionally independent, elective courses and extracurricular volunteer opportunities. A simulated patient exercise is a learning opportunity that helps participants engage with material in real time in a realistic environment, demanding higher levels of learning. This session utilized a simulated patient facilitator in interprofessional small groups to explore common health needs and barriers to care among refugee populations.

Embryonic exposure to oxy-polycyclic aromatic hydrocarbon interfere with pancreatic β-cell development in zebrafish via altering DNA methylation and gene expression.

Oxygenated polycyclic aromatic hydrocarbons (OPAHs) are a class of anthropogenic, persistent and very toxic PAH contaminant associated with developmental toxicity. Abnormal glucose metabolism disturbs energy balances that impair the early development of vertebrates, but the mechanisms by which maternal OPAH exposure alters glucose homeostasis in offspring are not well understood. Studies have suggested that epigenetic changes, particularly in DNA methylation, provide a memory of plastic developmental responses to the environment, leading to the generation of novel offspring phenotypes.

Attenuated Replication of Lassa Virus Vaccine Candidate ML29 in STAT-1 Mice.

Lassa virus (LASV), a highly prevalent mammalian arenavirus endemic in West Africa, can cause Lassa fever (LF), which is responsible for thousands of deaths annually. LASV is transmitted to humans from naturally infected rodents. At present, there is not an effective vaccine nor treatment.

Role of SOD3 in silica-related lung fibrosis and pulmonary vascular remodeling.

Background: Work-place exposure to silica dust may lead to progressive lung inflammation culminating in the development of silicosis, an irreversible condition that can be complicated by onset of pulmonary hypertension (PH). The molecular mechanisms leading to the development of PH and lung fibrosis in response to silica are not well understood. Oxidant/antioxidant imbalance in the lung may promote fibroproliferation and vascular smooth muscle proliferation, ultimately leading to the development of PH.

Epigenetically distinct sister chromatids and asymmetric generation of tumor initiating cells.

Cancer stem cells (CSC) are thought to be an important source of cancer cells in tumors of different origins. Mounting evidence suggests they are generated reversibly from existing cancer cells, and supply new cancer cells during tumor progression and following therapy. Elegant lineage mapping stud(ies are identifying progenitors, and in some cases differentiated cells, as targets of transformation in a variety of tumors.

Functional expression of human arylamine N-acetyltransferase NAT1*10 and NAT1*11 alleles: a mini review.

The arylamine N-acetyltransferase (NAT) nomenclature committee assigns functional phenotypes for human arylamine N-acetyltransferase 1 (NAT1) alleles in those instances in which the committee determined a consensus has been achieved in the scientific literature. In the most recent nomenclature update, the committee announced that functional phenotypes for NAT1*10 and NAT1*11 alleles were not provided owing to a lack of consensus. Phenotypic inconsistencies observed among various studies for NAT1*10 and NAT1*11 may be owing to variable allelic expression among different tissues, the limitations of the genotyping assays (which mostly relied on techniques not involving direct DNA sequencing), the differences in recombinant protein expression systems used (bacteria, yeast, and mammalian cell lines) and/or the known inherent instability of human NAT1 protein, which requires very careful handling of native and recombinant cell lysates.

Mitotic polarization of transcription factors during asymmetric division establishes fate of forming cancer cells.

A model of K-Ras-initiated lung cancer was used to follow the transition of precancerous adenoma to adenocarcinoma. In hypoxic, Tgf-β1-rich interiors of adenomas, we show that adenoma cells divide asymmetrically to produce cancer-generating cells highlighted by epithelial mesenchymal transition and a CD44/Zeb1 loop. In these cells, Zeb1 represses the Smad inhibitor Zeb2/Sip1, causing Pten loss and launching Tgf-β1 signaling that drives nuclear translocation of Yap1.

Interaction of volatile organic compounds and underlying liver disease: a new paradigm for risk.

Occupational and environmental exposures to industrial chemicals are known to cause hepatotoxicity and liver injury, in humans and in animal models. Historically, research has focused on severe acute liver injury (e.g.

Manipulation of MicroRNAs in Cultured Mouse Embryos: Applications for Developmental Toxicology.

MicroRNAs (miRNAs) are a class of small noncoding RNAs that modulate the expression of virtually all genes. miRNAs have been implicated in the regulation of a broad range of cellular and physiologic processes. Dysregulation of miRNAs has been found to be associated with a variety of diseases and disorders, including teratogenesis.

Inflammasome-Independent Leukotriene B Production Drives Crystalline Silica-Induced Sterile Inflammation.

Silicosis is a lung inflammatory disease caused by chronic exposure to crystalline silica (CS). Leukotriene B (LTB) plays an important role in neutrophilic inflammation, which drives silicosis and promotes lung cancer. In this study, we examined the mechanisms involved in CS-induced inflammatory pathways.

Vinyl chloride dysregulates metabolic homeostasis and enhances diet-induced liver injury in mice.

Vinyl chloride (VC), a common industrial organochlorine and environmental pollutant, has been shown to directly cause hepatic angiosarcoma and toxicant-associated steatohepatitis at high exposure levels. However, the impact of lower concentrations of VC on the progression of underlying liver diseases (e.g.