Pulmonary Cell News Volume 6.19 | May 18 2017

TOP STORY

Clonal History and Genetic Predictors of Transformation into Small-Cell Carcinomas from Lung Adenocarcinomas

Researchers identified that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)–resistant lung adenocarcinoma (LADC) and small-cell lung cancer (SCLC) share a common clonal origin and undergo branched evolutionary trajectories. The clonal divergence of SCLC ancestors from the LADC cells occurred before the first EGFR TKI treatments, and the complete inactivation of both RB1 and TP53 were observed from the early LADC stages in sequenced tumors. [J Clin Oncol] Abstract

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Human Asthmatic Bronchial Cells Are More Susceptible to Sub-Chronic Repeated Exposures of Aerosolized Carbon Nanotubes at Occupationally-Relevant Doses than Healthy Cells

Scientists aimed to realistically mimic sub-chronic inhalation of multi-walled carbon nanotubes in vitro, using the air-liquid interface cell exposure system for aerosol exposures onto reconstituted human bronchial tissue from healthy and asthmatic donors. The reliability and sensitivity of the system was validated using crystalline quartz, which elicited an increased (pro-)inflammatory response, as reported in vivo. [ACS Nano] Abstract

Effect of Surface Functionalizations of Multi-Walled Carbon Nanotubes on Neoplastic Transformation Potential in Primary Human Lung Epithelial Cells

The authors hypothesized that different plasma coating functional groups determine multi-walled carbon nanotube (MWCNT) neoplastic transformation potential. Using their established model, human primary small airway epithelial cells were continuously exposed for 8 and 12 weeks at 0.06 µg/cm² to three month aged as prepared-MWCNT, carboxylated-MW, and aminated-MWCNTs. [Nanotoxicology] Abstract

An Innate Defense Peptide BPIFA1/SPLUNC1 Restricts Influenza a Virus Infection

To determine a role in host defense against influenza A virus infection and to find the underlying defense mechanism, scientists developed transgenic mouse models that are deficient in bactericidal/permeability-increasing fold-containing family member A1 (BPIFA1) and used these, in combination with in vitro three-dimensional mouse tracheal epithelial cell cultures, to investigate its antiviral properties. [Mucosal Immunol] Abstract

Activation of Eosinophils Interacting with Bronchial Epithelial Cells by Antimicrobial Peptide LL-37: Implications in Allergic Asthma

Researchers found that co-culture of eosinophils and bronchial epithelial cell line BEAS-2B significantly enhanced intercellular adhesion molecule-1 on both cells and CD18 expression on eosinophils upon LL-37 stimulation. IL-6, CXCL8 and CCL4 were substantially released in co-culture in the presence of LL-37. [Sci Rep] Full Article

Nanoencapsulation of a Glucocorticoid Improves Barrier Function and Anti-Inflammatory Effect on Monolayers of Pulmonary Epithelial Cell Lines

The anti-inflammatory effect of polymeric deflazacort nanocapsules was investigated, and possible improvement of epithelial barrier function using filter grown monolayers of A549 and Calu-3 using as models was assessed. [Eur J Pharm Biopharm] Abstract

LUNG CANCER

A Clinical Drug Library Screen Identifies Clobetasol Propionate as an NRF2 Inhibitor with Potential Therapeutic Efficacy in KEAP1 Mutant Lung Cancer

To develop potent nuclear factor E2-related factor 2 (NRF2) inhibitors for therapeutic purpose, investigators screened ~4000 clinical compounds and determined clobetasol propionate (CP) as the most potent NRF2 inhibitor. Mechanistically, CP prevented nuclear accumulation and promoted β-TrCP-dependent degradation of NRF2 in a glucocorticoid receptor- and a glycogen synthase kinase 3-dependent manner. [Oncogene] Abstract

Resistance to RET-Inhibition in RET-Rearranged NSCLC Is Mediated by Reactivation of RAS/MAPK Signaling

Using distinct dose-escalation strategies, two ponatinib-resistant LC-2/ad cell lines, PR1 and PR2, were derived. PR1 and PR2 cell lines retained expression, but not phosphorylation of the RET fusion and lacked evidence of a resistance mutation in the RET kinase domain. Both resistant lines retained activation of the MAPK pathway. Next-generation RNA sequencing revealed an oncogenic NRAS p.Q61K mutation in the PR1 cell. [Mol Cancer Ther] Abstract

Cytoplasmic RAP1 Mediates Cisplatin Resistance of Non-Small Cell Lung Cancer

Investigators found that the expression of cytoplasmic RAP1 was significantly higher in high-grade non-small cell lung cancer (NSCLC) tissues than in low-grade NSCLC. Compared with a normal pulmonary epithelial cell line, the A549 NSCLC cells exhibited more cytoplasmic RAP1 expression as well as increased NF-κB activity. Cisplatin treatment resulted in a further increase of cytoplasmic RAP1 in A549 cells. [Cell Death Dis] Full Article

Disruption of SHH Signaling Cascade by SBE Attenuates Lung Cancer Progression and Sensitizes DDP Treatment

The authors revealed that Scutellariabarbata D. Don extraction (SBE) specifically repressed sonic hedgehog (SHH) signaling pathway to interfere the SHH-mediated non-small cell lung cancer progression and metastasis via arresting cell cycle progression. They also found that SBE significantly sensitized lung cancer cells to chemotherapeutic agent DDP via repressing SHH components in vitro and in vivo. [Sci Rep] Full Article

Adiponectin Down-Regulates CREB and Inhibits Proliferation of A549 Lung Cancer Cells

Scientists analyzed cell proliferation, cell cycle of A549 cells treated with adiponectin as well as cyclic AMP response element binding transcription factor activation status in human lung adenocarcinoma A549 cells and in non-small cell lung cancer samples. [Pulm Pharmacol Ther] Abstract

A Tumor Suppressor Role for C/EBPα in Solid Tumors: More Than Fat and Blood

The authors review the function of transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) in solid tumors and focus on the molecular mechanisms underlying its tumor suppressive role. [Oncogene] Abstract

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Aduro Biotech Announces Clinical Collaboration with Merck to Evaluate the Combination of Aduro’s CRS-207 with Merck’s KEYTRUDA^® (Pembrolizumab) for the Treatment of Mesothelioma

Aduro Biotech, Inc. announced the expansion of its clinical collaboration with Merck to include an additional Phase II clinical trial. The companies will investigate the combination of CRS-207, Aduro’s live, attenuated double-deleted based immunotherapy, with KEYTRUDA^®, Merck’s anti-PD-1 therapy, for the treatment of patients with malignant pleural mesothelioma whose disease progressed following prior treatment. [Aduro Biotech, Inc.] Press Release

FDA Expands Approved Use of Kalydeco to Treat Additional Mutations of Cystic Fibrosis

The U.S. Food and Drug Administration (FDA) expanded the approved use of Kalydeco for treating cystic fibrosis. The approval triples the number of rare gene mutations that the drug can now treat, expanding the indication from the treatment of 10 mutations, to 33. The agency based its decision, in part, on the results of laboratory testing, which it used in conjunction with evidence from earlier human clinical trials. [U.S. Food and Drug Administration] Press Release

Lawmakers Decry Trump Plan to Slash NIH 2018 Budget

Lawmakers from both sides of the aisle in the U.S. House of Representatives voiced their displeasure with the Trump administration’s proposed $5.8 billion cut to the budget of the National Institutes of Health in Bethesda, Maryland. [Science Insider] Editorial

China’s Belt and Road Infrastructure Plan Also Includes Science

China’s plan to make massive investments in land and sea links with global trading partners also includes a little noticed commitment to support science and engineering, including the creation of dozens of new laboratories. [ScienceInsider] Editorial

Trump Officials Act to Tilt Federal Science Boards toward Industry

Critics say that changes to advisory groups at the Environmental Protection Agency and Department of Interior could restrict or paralyze them. [Nature News] Editorial

NEW Tumor Immunology and Immunotherapy
October 1-4, 2017
Boston, United States

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NEW Postdoctoral Research Scientist – miRNAs in Differentiation of Lung Progenitor Cells (Columbia University)

Postdoctoral Research Associate I – In Vitro and In Vivo Mechanisms of Pulmonary Hypertension (University of Arizona)

Postdoctoral Researcher – Inhalation & Developmental Toxicology (Louisiana State University)

Postdoctoral Scientist – Macrophage and Lung Fibrosis (University of Oxford)

PhD Studentship – Border and Regions Airways Training Hub (Dundalk Institute of Technology)

Faculty – Immunology of Lung Diseases (National Jewish Health)

Research Administrator IV – Early Detection of Lung Cancer (Fred Hutchinson Cancer Research Center)

Postdoctoral Research Fellow – Lung Cancer Genetics and Genomics (Fred Hutchinson Cancer Research Center)

Tenure Track Positions – Translational Asthma Research Program (Perelman School of Medicine)

Assistant, Associate or Full Professor Position(s) – Asthma Research (University of Pennsylvania)

NIH Training Grant – Pediatric Pulmonary Medicine (University of Pittsburgh)

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