Pulmonary Cell News Volume 7.37 | Sep 20 2018

TOP STORY

mRNA Circularization by METTL3-eIF3h Enhances Translation and Promotes Oncogenesis

METTL3 promoted translation of a large subset of oncogenic mRNAs—including bromodomain-containing protein 4 (BRD4)—that is also N⁶-methyladenosine-modified in human primary lung tumors. METTL3 depletion inhibited tumorigenicity and sensitized lung cancer cells to BRD4 inhibition. [Nature] Abstract

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Lung Colonization by Aspergillus fumigatus Is Controlled by ZNF77

Scientists used genome-edited epithelial cells to show that the genetic variant rs35699176 in ZNF77 caused loss of integrity of the bronchial epithelium and increased levels of extracellular matrix proteins. These changes promoted Aspergillus fumigatus conidial adhesion, germination and growth. [Nat Commun] Full Article | Press Release

Effects of Ghrelin on iNOS-Derived NO Promoted LPS-Induced Pulmonary Alveolar Epithelial A549 Cells Apoptosis

Lipopolysaccharide (LPS) increased the apoptosis rate of A549 accompanied by increased Bax levels and decreased Bcl-2 levels through activating JNK signaling, which was reversed when the scientists diminished the inducible nitric oxide synthase (iNOS) expression in A549 cells using lentiviral vectors encoding iNOS shRNA in the presence of LPS. [Cell Physiol Biochem] Full Article

IL-17A Attenuates IFN-λ Expression by Inducing Suppressor of Cytokine Signaling Expression in Airway Epithelium

The authors showed that polyinosinic:polycytidylic acid (polyI:C) and influenza A virus (IAV) infection increased IFN-λ expression at mRNA and protein levels in primary cultures of normal human bronchial epithelial cells, whereas IL-17A attenuated polyI:C- or IAV-induced IFN-λ expression. [J Immunol] Abstract

Differential Effects of Nintedanib and Pirfenidone on Lung Alveolar Epithelial Cell Function in Ex Vivo Murine and Human Lung Tissue Cultures of Pulmonary Fibrosis

Low μM concentrations of Nintedanib and mM concentrations of Pirfenidone reduced fibrotic gene expression including collagen 1a1 and fibronectin in murine and human 3D ex vivo lung tissue cultures (3D-LTCs) as well as primary murine alveolar epithelial type II cells (pmATII). Nintedanib stabilized expression of distal lung epithelial cell markers, especially surfactant protein C in pmATII cells as well as in murine and human 3D-LTCs. [Respir Res] Full Article

LUNG CANCER

Recurrent WNT Pathway Alterations Are Frequent in Relapsed Small Cell Lung Cancer

Researchers showed enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human small cell lung cancer cell lines through APC knockdown induced chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrated increased WNT activity. [Nat Commun] Full Article

Functional Proteomics and Deep Network Interrogation Reveal a Complex Mechanism of Action of Midostaurin in Lung Cancer Cells

Investigators showed that simultaneous inhibition of TBK1, PDPK1 and AURKA was required to elicit midostaurin’s cellular effects. They showed that combined inhibition of these targets altered PI3K/AKT and cell cycle signaling pathways that in part converged on PLK1. Rational combination of midostaurin with the potent PLK1 inhibitor BI2536 elicited strong synergy. [Mol Cell Proteomics] Abstract | Full Article

VAOS, a Novel Vanadyl Complexes of Alginate Saccharides, Inducing Apoptosis via Activation of AKT-Dependent ROS Production in NSCLC

Vanadyl alginate oligosaccharides (VAOS) exhibited effective inhibitory effects in non-small cell lung cancer (NSCLC) both in cultured cells and in a xenograft mouse model. VAOS was further identified to induce NSCLC cell apoptosis through activating protein kinase B (AKT) to elevate intracellular reactive oxygen species (ROS) levels by increasing in oxygen consumption and impairing the ROS-scavenging system. [Free Radic Biol Med] Abstract | Graphical Abstract

RIF1 Promotes Tumor Growth and Cancer Stem Cell-Like Traits in NSCLC by Protein Phosphatase 1-Mediated Activation of Wnt/β-Catenin Signaling

RIF1 knockdown inhibited non-small-cell lung carcinoma (NSCLC) cell growth in vitro and in vivo, whereas overexpression of RIF1 in NSCLC cell lines promoted cell growth, cell cycle progression and cancer stem cell-like properties via promoting PP1–AXIN interaction and thereby activating Wnt/β-catenin signaling. [Cell Death Dis] Full Article

Arsenic Circumvents the Gefitinib Resistance by Binding to P62 and Mediating Autophagic Degradation of EGFR in Non-Small Cell Lung Cancer

Arsenic trioxide (ATO) promoted autophagic degradation of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) cells by directly binding to P62, which interacted with EGFR, preferentially the L858R/T790M mutant providing a plausible explanation for a more favorable effect of ATO on NCI-H1975 cells. [Cell Death Dis] Full Article

Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells

Atractylenolide 1 (ATL-1) inhibited the protein expression and the promoter activity of zeste homolog 2 (EZH2), which was reversed in cells with 3-phosphoinositide dependent protein kinase-1 (PDK1) overexpression. ATL-1 inhibited the expression levels of HOTAIR. While silencing HOTAIR inhibited the expressions of PDK1 and EZH2, overexpression of HOTAIR reduced the ATL-1-reduced PDK1 and EZH2 protein expressions and EZH2 promoter activity. [Cell Physiol Biochem] Full Article

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New and Emerging Therapies for Pulmonary Arterial Hypertension

Both novel and repurposed compounds with rationale from preclinical experimental models and human cells are now in clinical trials in patients with pulmonary arterial hypertension (PAH). Findings from these studies will elucidate the pathobiology of PAH and may result in clinically important improvements in outcome. [Annu Rev Med] Abstract

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Large European Real-World Study Reports Effects of Spiolto^® Respimat^® for People Living with COPD in Daily Clinical Practice

Boehringer Ingelheim announced results from the OTIVACTO study, an observational European real-world study of 7,443 COPD patients treated with Spiolto^&reg Respimat^&reg, which were presented. [Press release from Boehringer Ingelheim (Business Wire, Inc.) discussing research presented at the European Respiratory Society (ERS) International Congress 2018, Paris] Press Release

RejuvenAir^® Metered Cryospray^™ Shows Promise as Treatment for COPD Patients with Chronic Bronchitis

CSA Medical Inc. presented positive results of its feasibility study of the RejuvenAir^® Metered Cryospray^™ system. [Press release from CSA Medical Inc. (PR Newswire Association LLC.) discussing research presented at the European Respiratory Society (ERS) International Congress 2018, Paris] Press Release

Pulmatrix to Present Pre-Clinical Data on PUR1800 (RV1162)

Pulmatrix, Inc. presented preclinical data on the anti-inflammatory activity of PUR1800 (RV1162). [Press release from Pulmatrix, Inc. discussing research presented at the European Respiratory Society (ERS) International Congress 2018, Paris] Press Release

Innovent Presents Clinical Data of Anti-PD-1 Antibody Sintilimab as the First-line Treatment for Patients with NSCLC

Innovent Biologics presented clinical trial data on cohort D of sintilimab clinical studies. [Press release from Innovent Biologics, Inc. discussing research presented at the 2018 Annual Meeting of Chinese Society of Clinical Oncology (CSCO), Xiamen] Press Release

Samumed And United Therapeutics Announce North American License Agreement For Samumed’s IPF Drug Candidate

Samumed LLC has entered an exclusive license agreement with United Therapeutics Corporation for North American rights to Samumed’s SM04646, being developed for the treatment of idiopathic pulmonary fibrosis (IPF). Deal terms include $10 million up-front, plus up to $340 million in developmental milestones and up to low double-digit royalties. [Samumed, LLC.] Press Release

Fasenra Shows Consistent Safety and Sustained Efficacy in Long-Term Phase III BORA Trial in Severe Eosinophilic Asthma

AstraZeneca announced results from the BORA Phase III extension trial evaluating the long-term safety and efficacy of Fasenra as an add-on maintenance treatment in patients with severe eosinophilic asthma who had previously completed one of the two pivotal SIROCCO or CALIMA Phase III trials. [AstraZeneca] Press Release

First Randomized Controlled Trial in Portopulmonary Hypertension Shows OPSUMIT^® (Macitentan) Significantly Improved Pulmonary Vascular Resistance Compared with Placebo

Actelion Pharmaceuticals Ltd announced the results of the first randomized controlled trial in portopulmonary hypertension, which showed OPSUMIT^® significantly improved pulmonary vascular resistance compared with placebo, meeting the primary endpoint of the study. [Actelion Pharmaceuticals Ltd (Business Wire, Inc.)] Press Release

Cedars-Sinai Awarded $12 Million to Study Deadly Lung Conditions

A scientific team led by Cedars-Sinai has been awarded $12 million from the National Institutes of Health to investigate two deadly lung conditions: idiopathic pulmonary fibrosis and chronic lung allograft dysfunction. [Cedars-Sinai] Press Release

Roivant Launches Respivant Sciences to Develop Innovative Therapeutics for Respiratory Diseases

Roivant Sciences announced the launch of Respivant Sciences, a biopharmaceutical company focused on improving the lives of patients suffering from serious respiratory diseases. Respivant’s pipeline is anchored by RVT-1601, an inhaled therapeutic being developed for the treatment of chronic cough in patients with idiopathic pulmonary fibrosis. [ROIVANT SCIENCES LTD.] Press Release

NSF Spells Out New Sexual Harassment Policy: Talk to Us

Starting next month, universities must tell the National Science Foundation (NSF) in Alexandria, Virginia, if any faculty members with NSF grants have been found guilty of sexual and other forms of harassment, or if they have suspended them for any reason. But NSF won’t pull its funding if institutions can assure the agency that another faculty member can take over the research project. [ScienceInsider] Editorial

Huge Peer-Review Study Reveals Lack of Women and Non-Westerners

The study looked at all submissions made to the open-access title eLife from its launch in 2012 to 2017 — nearly 24,000 in total. It found that women worldwide, and researchers outside North America and Europe, were less likely to be peer reviewers, editors and last authors. [Nature News] Editorial

NEW AACR: Targeting RAS-Driven Cancers
December 9-12, 2018
San Diego, California, United States

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NEW Postdoctoral Fellow – Vascular and/or Lung Biology (Yale University)

Postdoctoral Research Fellow – Respiratory Epithelial Cell Biology (STEMCELL Technologies Inc.)

Postdoctoral Fellow – Sepsis and Pulmonary Injury Research (University of Maryland)

Research Fellow – Development of Occupational Diseases (CDC/National Institute for Occupational Safety and Health)

Postdoctoral Scientist – Cancer Biology and Immunology (Technical University of Munich)

PhD Students – Lung Disease Research (Justus-Liebig-Universität Gießen)

Faculty Investigators – Cancer Research (The University of Alabama at Birmingham)

Postdoctoral Position – Lung Diseases (German Research Center for Environmental Health)

Postdoctoral Position – Acute Lung Injury (University of Kentucky)

Cancer Research Scholar – Lung Cancer (University of California, San Francisco)

Principal Investigators – Cancer (University of Alabama Birmingham)

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