Pulmonary Cell News Volume 8.17 | May 9 2019

TOP STORY

Endothelial Sash1 Is Required for Lung Maturation Through Nitric Oxide Signaling

Constitutive or endothelial-restricted sterile alpha motif and SRC homology 3 domain containing protein 1 (Sash1) loss led to a delay in maturation of alveolar epithelial cells causing reduced surfactant-associated protein synthesis. Researchers showed that Sash1 interacted with β-arrestin 1 downstream of the TLR4 pathway to activate Akt and endothelial nitric oxide synthase in microvascular endothelial cells. [Cell Rep] Full Article | Graphical Abstract

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Authentic Modeling of Human Respiratory Virus Infection in Human Pluripotent Stem Cell-Derived Lung Organoids

The authors modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids derived from human pluripotent stem cells contained mesoderm and pulmonary endoderm and developed into branching airway and alveolar structures. [MBio] Full Article

FGF10-FGFR2B Signaling Generates Basal Cells and Drives Alveolar Epithelial Regeneration by Bronchial Epithelial Stem Cells after Lung Injury

Investigators report that inactivation of Fgfr2b in bronchial epithelial stem cells (BESCs) impaired their contribution to both alveolar epithelial regeneration and honeycomb cysts after bleomycin injury. By contrast overexpression of Fgf10 in BESCs enhanced fibrosis resolution by favoring the more desirable outcome of alveolar epithelial regeneration over the development of pathologic honeycomb cysts. [Stem Cell Reports] Full Article

Nascent Lung Organoids Reveal Epithelium- and BMP-Mediated Suppression of Fibroblast Activation

Researchers utilized nascent organoids composed of human and mouse lung epithelial and mesenchymal cells to demonstrate that healthy lung epithelium dramatically repressed transcriptional, contractile and matrix synthetic functions of lung fibroblasts. Repression of fibroblast activation required signaling via the bone morphogenetic protein pathway. [Am J Respir Cell Mol Biol] Abstract

miR-21 Upregulation Increases IL-8 Expression and Tumorigenesis Program in Airway Epithelial Cells Exposed to Cigarette Smoke

It was demonstrated that: A549 cells constitutively expressed higher levels of miR-21 and IL-8; cigarette smoke extracts (CSE) increased STAT3 nuclear expression in 16HBE; in both cell lines, CSE and agomiR-21 increased: miR‐21 expression; ERK1/2 activation and IL-8 gene expression and protein release; TLR4 inhibition counteracted the effects of CSE on miR-21 in A549; apigenin reduced miR-21 and IL-8 gene expression in both cell lines. [J Cell Physiol] Abstract

The cullin4A Is Up-Regulated in Chronic Obstructive Pulmonary Disease Patient and Contributes to Epithelial-Mesenchymal Transition in Small Airway Epithelium

The expression of cullin4A (CUL4A) was assessed by immunohistochemistry in lung epithelium specimens from smokers, non-smokers and patients with chronic obstructive pulmonary disease. The role of CUL4A on cigarette smoke extract-induced epithelial-mesenchymal transition in human small airway epithelial cells was assessed by silencing or overexpression CUL4A in vitro. [Respir Res] Full Article

LUNG CANCER

MicroRNA-130b Functions as an oncomiRNA in Non-Small Cell Lung Cancer by Targeting Tissue Inhibitor of Metalloproteinase-2

The authors examined the role of miR-130b in non-small cell lung cancer (NSCLC). Their results showed that high expression of miR-130b in clinical specimens was significantly associated with poor overall survival in patients with NSCLC. Moreover, miR-130b expression was significantly increased in NSCLC clinical specimens from patients with vascular and lymphatic invasion. [Sci Rep] Full Article

SOX9 Drives the Epithelial-Mesenchymal Transition in Non-Small-Cell Lung Cancer Through the Wnt/β-Catenin Pathway

Scientists generated SOX9-overexpression and SOX9-knockdown cells lines and their corresponding control cell lines by transfection with lentiviral constructs. SOX9-overexpressing and SOX9-knockdown non-small cell lung cancer cells were injected in zebrafish to examine distance metastasis. Gene set enrichment analysis was applied to analyze the correlation between SOX9 overexpression and the Wnt/β-catenin pathway. [J Transl Med] Full Article

Preferential Sensitivity to HDAC Inhibitors in Tumors With CREBBP Mutation

Researchers used human cell lines from small cell lung cancer (SCLC) as well as primary mouse tumor cells and genetically engineered mouse models for sonic hedgehog medulloblastoma to test treatment options with histone deacetylase inhibitors (HDACi) in CREBBP wild-type and mutated tumors. In contrast to CREBBP wild-type SCLC cells, CREBBP-mutated SCLC cells showed significantly lower IC₅₀ values after treatment with HDACi. [Cancer Gene Ther] Abstract

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Microbiota-Dependent Regulation of Antimicrobial Immunity in the Lung

The authors summarize current understanding of how the microbiota affects antimicrobial immunity and disease tolerance during viral and bacterial pulmonary infections. A better understanding of these mechanisms could help to refine clinical approaches in order to preserve or rescue the microbiota-immune system interplay and protect patients against lung infections. [Am J Respir Cell Mol Biol] Abstract

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AIT Therapeutics to Present Data

AIT Therapeutics, Inc. announced it would present its study, entitled: “Synergistic Effect of Nitric Oxide with Antibiotics Against Mycobacterium Abscessus in Vitro”. The study will be presented as part of a mini-symposium on “Advances in the Treatment of NTM.” [Press release from AIT Therapeutics, Inc. (GlobeNewswire, Inc.) discussing research to be presented at the 2019 American Thoracic Society (ATS) Conference, Dallas] Press Release

resTORbio Announces Initiation of Phase III Clinical Program of RTB101 in Clinically Symptomatic Respiratory Illness

resTORbio, Inc. announced the initiation of PROTECTOR 1, the first Phase III trial of RTB101, an orally administered, small molecule, potent inhibitor of target of rapamycin complex 1. The two PROTECTOR Phase III trials are designed to evaluate the safety and efficacy of RTB101 for decreasing the percent of elderly subjects with clinically symptomatic respiratory illness, defined as illness associated with a respiratory tract infection based on prespecified diagnostic criteria, with or without laboratory-confirmation of a pathogen. [resTORbio, Inc.] Press Release

BerGenBio Completes Recruitment Into Second Stage of Phase II Trial With Selective AXL Inhibitor Bemcentinib in Combination With KEYTRUDA^® in Patients With Advanced NSCLC

BerGenBio ASA announced that it has completed enrollment into the second stage of its Phase II trial evaluating the company’s selective AXL inhibitor bemcentinib in combination with MSD’s anti-PD-1 therapy, KEYTRUDA, in patients with previously treated advanced adenocarcinoma of the lung (non-small cell lung cancer, NSCLC) whose disease is progressing on or after prior systemic chemotherapy. [BerGenBio ASA] Press Release

Verona Pharma Initiates Additional Phase IIb Clinical Trial With Nebulized Ensifentrine to Inform Dose Selection for Phase III Trials

Verona Pharma plc announced the initiation of a Phase IIb dose-ranging study evaluating nebulized ensifentrine added on to a long acting bronchodilator in patients with moderate-to-severe COPD. The company anticipates reporting data around year end and commencing Phase III clinical trials for this indication in 2020. [Verona Pharma plc] Press Release

Cotinga Pharmaceuticals Releases Early Interim Data of Phase Ib/IIa Combination Trial of COTI-2 in Solid Tumors

Cotinga Pharmaceuticals Inc. announced that the company has released early interim data of its ongoing Phase Ib/IIa clinical trial of COTI-2 plus cisplatin in solid tumors. The primary objective of the second cohort is to continue to evaluate the safety and tolerability of COTI-2 in combination with standard-of-care cisplatin. Secondary objectives include determination of efficacy and pharmacokinetics profiling. [Cotinga Pharmaceuticals Inc. (GlobeNewswire, Inc.)] Press Release

Onxeo Announces Treatment of First Patient in DRIIV-1b, a Phase Ib Clinical Trial of AsiDNA™ in Combination with Chemotherapy

Onxeo S.A. announced a new milestone in the clinical development of AsiDNA™ with the treatment of the first patient in DRIIV-1b, a Phase Ib clinical study of AsiDNA™, a first-in-class tumor DNA repair inhibitor, in combination with carboplatin and with carboplatin plus paclitaxel, in patients with solid tumors eligible to such treatments. [Onxeo S.A.] Press Release

European Commission Approves LORVIQUA^® (Lorlatinib) for Certain Adult Patients With Previously-Treated ALK-Positive Advanced Non-Small Cell Lung Cancer

Pfizer Inc. announced that the European Commission granted conditional marketing authorization for LORVIQUA^®, as a monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer whose disease has progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy, or crizotinib and at least one other ALK TKI. [Pfizer Inc. (Business Wire, Inc.)] Press Release

Sanofi : Dupixent^® (Dupilumab) Approved for Severe Asthma by European Commission

The European Commission has approved Dupixent^® for use in adults and adolescents 12 years and older as an add-on maintenance treatment for severe asthma with type 2 inflammation characterized by raised blood eosinophils and/or raised fractional exhaled nitric oxide, who are inadequately controlled with high dose inhaled corticosteroid plus another medicinal product for maintenance treatment. [Sanofi (GlobeNewswire, Inc.)] Press Release

Savara Announces Molgradex Received Fast Track Designation by FDA for Treatment of Autoimmune Pulmonary Alveolar Proteinosis

Savara Inc. announced that the FDA granted Fast Track designation for Molgradex, an inhaled formulation of recombinant human granulocyte-macrophage colony-stimulating factor. Molgradex, the company’s lead product candidate, is being investigated in a pivotal Phase III study, called IMPALA, for the treatment of autoimmune pulmonary alveolar proteinosis. [Savara Inc.] Press Release

White House to Convene Committee to Address Research Obstacles

The leaders of the White House Office of Science and Technology, National Institutes of Health, National Science Foundation, National Institute of Standards and Technology, and the Department of Energy’s science division have formed a committee “to address issues facing the US research community,” President Donald Trump’s administration announced. [The Scientist] Editorial

Black Academics Publish One-Fifth of South Africa’s Research

The proportion of scientific articles published by academics in South Africa who are black, colored or of Indian origin has risen almost tenfold since the end of apartheid, to about one-third, finds a report on scholarly publishing in the country. [Nature News] Editorial

NEW IASLC 2019 World Conference on Lung Cancer
September 7-10, 2019
Barcelona, Spain

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NEW Postdoctoral Researcher – Stem Cell Biology of the Lung and Intestines (Standford School of Medicine)

Scientist – Pulmonary (STEMCELL Technologies Inc.)

Postdoctoral Fellow – Inflammation Suppression & Lung Disease (National University of Singapore)

Postdoctoral Professor – Basal Allergy and Immunology (Aarhus University)

Postdoctoral Fellowship – Redox Systems in Lung and Breast Cancer (The Held Laboratory)

Postdoctoral Studentship – Lung Adenocarcinoma Research (Max Delbrück Centrum for Molecular Medicine)

Postdoctoral Fellow – Machine Learning in Cancer Treatment (Institute of Cancer Research)

Postdoctoral Fellow – Bioinformatics of Chronic Respiratory Diseases (University of Technology Sydney)

Postdoctoral Fellow – Vascular & Lung Biology (Ann & Robert H. Lurie Children’s Hospital of Chicago)

Postdoctoral Researcher – Regenerative Medicine for Lung Conditions (United Therapeutics)

Postdoctoral Researcher – Causes of Allergies and Asthma (Stanford University)

Postdoctoral Position – Pulmonary/Lung Carcinogenesis Translational Research (Albert Einstein College of Medicine)

Postdoctoral Position – Lung Research (Columbia University)

Postdoctoral Scholar – Acute Respiratory Distress Syndrome (University of California, San Francisco)

Associate Professor – Oncology (University of California, Davis)

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