Pulmonary Cell News Volume 8.23 | Jun 20 2019

TOP STORY

A Cellular Census of Human Lungs Identifies Novel Cell States in Health and in Asthma

Researchers used single-cell transcriptomics to chart the cellular landscape of upper and lower airways and lung parenchyma in healthy lungs, and lower airways in asthmatic lungs. They report location-dependent airway epithelial cell states and a novel subset of tissue-resident memory T cells. [Nat Med] Abstract | Press Release

(Ranked by impact factor of the journal)

Modeling of Fibrotic Lung Disease Using 3D Organoids Derived from Human Pluripotent Stem Cells

Investigators showed that the introduction of all Hermansky-Pudlak syndrome (HPS) mutations associated with HPS-associated interstitial pneumonia promoted fibrotic changes in lung organoids, while the deletion of HPS8, which is not associated with HPSIP, did not. Genome-wide expression analysis revealed the upregulation of interleukin-11 in epithelial cells from HPS mutant fibrotic organoids. [Cell Rep] Full Article | Graphical Abstract

USP9X Promotes LPS-Induced Pulmonary Epithelial Barrier Breakdown and Hyperpermeability by Activating NF-kBp65 Feedback Loop

Human pulmonary alveolar epithelial cells were treated with LPS to establish an acute lung injury model in vitro, in which LPS stimulation resulted in pulmonary epithelial barrier breakdown and hyperpermeability. Cell viability was measured by CCK-8, and the transepithelial permeability was examined by measurement of transepithelial electrical resistance and the transepithelial flux. [Am J Physiol Cell Physiol] Abstract

Junín Virus Induces Autophagy in Human A549 Cells

Researchers investigated the role of autophagy during Junín virus (JUNV) multiplication using human A549 cells. They found that JUNV infection induced an increment of the LC3-II/LC3-I ratio, an accumulation of punctate pattern in RFP-LC3-transfected cells and the colocalisation of viral nucleoprotein and LC3 protein, suggesting autophagosome formation. [PLoS One] Full Article

LUNG CANCER

Dysregulated Tgfbr2/ERK-Smad4/SOX2 Signaling Promotes Lung Squamous Cell Carcinoma Formation

Mechanistically, inhibition of phosphorylated ERK1/2 significantly upregulated the expression of SOX2, an oncogenic driver of lung squamous cell carcinoma, and cooperated with SMAD4 repression to elevate SOX2. Inhibition of ERK1/2 in Smad4fl/fl;KrasG12D mice led to extensive lung squamous cell carcinoma (SCC) formation that resembled the SCC phenotype of TGF-β type II receptor (Tgfbr2)-deficient mice. [Cancer Res] Abstract

Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity

The authors describe a poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor-sensitive phenotype that was conferred by tyrosine kinase inhibitor (TKI) treatment in vitro and in vivo and appeared independent of any particular TKI resistance mechanism. They found that PARP-1 protected cells against cytotoxic reactive oxygen species produced by nicotinamide adenine dinucleotide phosphate oxidase. [Cell Rep] Full Article | Graphical Abstract

Antitumor Activity of Dual Blockade of PD-L1 and MEK in NSCLC Patients Derived Three-Dimensional Spheroid Cultures

Scientists studied the effects of MEK inhibitors (MEK-I) on PD-L1 and MCH-I protein expression and cytokine production in vitro in NSCLC cell lines and in PBMCs from healthy donors and NSCLC patients, the efficacy of combining MEK-I with anti-PD-L1 antibody in ex-vivo human spheroid cultures obtained from fresh biopsies from NSCLC patients in terms of cell growth arrest, cytokine production and T-cell activation by flow cytometry. [J Exp Clin Cancer Res] Full Article

Validation of NEDD8-Conjugating Enzyme UBC12 as a New Therapeutic Target in Lung Cancer

The expression of NEDD8-conjugating enzyme UBC12/UBE2M and NEDD8 were estimated by bioinformatics analysis and western blot in human lung cancer cell lines. The malignant phenotypes of lung cancer cells were evaluated both in vitro and in vivo upon UBC12 knockdown. [EBioMedicine] Full Article

FBXO22 Mediates Polyubiquitination and Inactivation of LKB1 to Promote Lung Cancer Cell Growth

Researchers present evidence that FBXO22 interacted with and promoted polyubiquitination of liver kinase B1 (LKB1). More intriguingly, FBXO22 mediated Lys-63-linked LKB1 polyubiquitination and inhibited kinase activity of LKB1. [Cell Death Dis] Full Article

A Chimeric Poxvirus with J2R (Thymidine Kinase) Deletion Shows Safety and Anti-Tumor Activity in Lung Cancer Models

Investigators report the sequence analysis of chimeric poxvirus (CF33) and oncolytic potential of a GFP-encoding CF33 virus (CF33-GFP) with a J2R deletion in lung cancer models. Replication of CF33-GFP and the resulting cytotoxicity were higher in cancer cell lines compared to a normal cell line, in vitro. [Cancer Gene Ther] Full Article

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Cellular Crosstalk in the Development and Regeneration of the Respiratory System

The authors explore the cellular crosstalk that coordinates the development and regeneration of the respiratory system. They discuss both the classic cell and developmental biology studies and recent single-cell analyses to provide an integrated understanding of the cellular niches that control how the respiratory system develops, interacts with the external environment and responds to injury. [Nat Rev Mol Cell Biol] Abstract

Immune Checkpoint Inhibitors in Small Cell Lung Cancer: A Partially Realized Potential

Small cell lung cancer (SCLC) is a highly lethal subtype of lung cancer that has seen few therapeutic advances, despite ongoing concerted efforts. Immunotherapy has been an effective option in other carcinogen-related cancers and has shown modest activity in SCLC. [Adv Ther] Full Article

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EffRx Pharmaceuticals Signs Exclusive License Agreement with Pharmaxis for the Registration and Commercialization of Bronchitol^® in Switzerland

EffRx Pharmaceuticals SA announced it has entered into an exclusive license agreement with Pharmaxis Ltd for the registration and commercialization of Bronchitol^® for cystic fibrosis in Switzerland. [EffRx Pharmaceuticals SA (Business Wire, Inc.)] Press Release

Spero Therapeutics Announces Collaboration with Bill & Melinda Gates Medical Research Institute to Develop SPR720 for Tuberculosis

Spero Therapeutics, Inc. announced that it entered into a collaboration with the Bill & Melinda Gates Medical Research Institute to develop SPR720 for the treatment of lung infections caused by Mycobacterium tuberculosis, an indication that is designated as a critical concern by the World Health Organization. [Spero Therapeutics] Press Release

Continuation of “Atalante 1” Phase III Clinical Trial of Tedopi^® in NSCLC Patients Post Checkpoint Inhibitor Failure Following IDMC Recommendation

OSE Immunotherapeutics announced that, after reviewing global study data, the Independent Data Monitoring Committee (IDMC) saw no safety concerns and recommended the continuation of patient recruitment, without any modifications, of its ongoing international pivotal Phase III trial, called Atalante 1, evaluating Tedopi^® in HLA-A2 positive non-small cell lung cancer (NSCLC) patients post immune checkpoint inhibitor failure. [OSE Immunotherapeutics] Press Release

Turning Point Therapeutics Initiates Phase II Registrational Portion of TRIDENT-1 Clinical Study

Turning Point Therapeutics, Inc. announced initiation of the registrational Phase II portion of its TRIDENT-1 clinical study of patients with ROS1⁺ advanced non-small cell lung cancer and TRK⁺ advanced solid tumors. [Turning Point Therapeutics, Inc.] Press Release

Jounce Therapeutics Initiates Phase II EMERGE Study of Vopratelimab in Combination with Ipilimumab in Patients with Non-Small Cell Lung Cancer or Urothelial Cancer

Jounce Therapeutics, Inc. announced that it has initiated dosing in the Phase II EMERGE clinical trial of its lead product candidate, vopratelimab, in combination with ipilimumab in patients with non-small cell lung cancer or urothelial cancer who have progressed on or after PD-1/PD-L1 inhibitor therapies. [Jounce Therapeutics, Inc.] Press Release

Enanta Pharmaceuticals Announces Topline Results Showing EDP-938 Achieved Its Primary and Secondary Endpoints in Its Phase IIa Human Challenge Study in Healthy Adults Infected with Respiratory Syncytial Virus (RSV)

Enanta Pharmaceuticals, Inc. announced topline results that demonstrated that EDP-938 achieved highly statistically significant reductions in viral load and in resolution of clinical symptoms compared to placebo in its Phase IIa human challenge study of EDP-938 in healthy adults infected with respiratory syncytial virus. [Enanta Pharmaceuticals, Inc.] Press Release

Immutep Completes Recruitment of Initial Cohort in 1^st Line NSCLC Patients for TACTI-002 Trial

Immutep Limited announced that 17 patients have been enrolled into the first cohort of the first line non-small cell lung cancer (NSCLC) arm (Part A) of the Phase II TACTI-002 clinical trial. This completed patient recruitment of the initial cohort of the study Part A. [Immutep Limited] Press Release

FDA Approves Merck’s KEYTRUDA^® (Pembrolizumab) as Monotherapy for Patients with Metastatic Small Cell Lung Cancer (SCLC) with Disease Progression on or after Platinum-Based Chemotherapy and at Least One Other Prior Line of Therapy

Merck announced that the FDA has approved KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for the treatment of patients with SCLC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. [Merck] Press Release

Japan Becomes the First Country to Approve Roche’s Personalized Medicine Rozlytrek

Roche announced that Japan’s Ministry of Health, Labour and Welfare has approved Rozlytrek^® for the treatment of adult and pediatric patients with neurotrophic tyrosine receptor kinase fusion-positive, advanced recurrent solid tumors. [Roche] Press Release

Millennial Lung Health Will Get Its First Focus with $24.8 Million Grant

The long term impact on someone’s lungs due to vaping or air quality will be examined in a large, first-of-its-kind longitudinal study of lung health led by Northwestern Medicine scientists in partnership with the American Lung Association. The study, titled ‘The American Lung Association Lung Health Cohort,’ is funded by a $24.8 million grant awarded June 16 by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. [Northwestern University] Press Release

UIC’s Institute for Tuberculosis Research Tapped to Support $28 Million Drug Discovery Project

The University of Illinois at Chicago will work with TB Alliance to help find new drug treatments for tuberculosis, a bacterial infection considered to be one of the leading causes of death worldwide. TB Alliance is a nonprofit organization dedicated to the discovery, development and delivery of new TB cures. [The University of Illinois at Chicago] Press Release

Academics Join Outcry Sparked by Hong Kong’s Contentious Extradition Bill

Since the bill that would legalize the extradition of people from Hong Kong to mainland China to stand trial or serve criminal sentences was announced, more than a thousand academics from around the world have signed a petition against the proposed law, saying it would restrict free speech and academic debate as well as eroding personal freedoms. [Nature News] Editorial

Men Need Not Apply: University Set to Open Jobs Just to Women

A Dutch engineering university is taking radical action to increase its share of female academics by opening job vacancies to women only. Starting on 1 July, the Eindhoven University of Technology in the Netherlands will not allow men to apply for permanent academic jobs for the first six months of the recruitment process under a new fellowship program. [Science Magazine] Editorial

Infant Monkeys Died in Accidental Poisoning at UC Davis Lab

News of the latest deaths comes as Congress moves forward with plans to increase its scrutiny of the use of nonhuman primates in research. Earlier this year, lawmakers ordered the National Institutes of Health and the US FDA to compile reports on their use of the animals. [The Scientist] Editorial

NEW Physiology 2019
July 8-10, 2019
Aberdeen, United Kingdom

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NEW Postdoctoral Fellow – Pluripotent Stem Cell-Derived Human Lung Organoids (Columbia University Irving Medical Center)

Scientist – Pulmonary (STEMCELL Technologies Inc.)

Researcher Position – Translational Cancer Research (University of Tromsø)

Postdoctoral Researcher – Cystic Fibrosis Stem Cell Models (The University of Alabama at Birmingham)

Postdoctoral Researcher – Lung Lineage Development (Hospital for Sick Children)

Assistant Professor – Lung Disease Research (University of McGill)

Senior Scientific Officer – Lung Cancer Liquid Biopsy Biomarker Research (Cancer Research UK Manchester Institute)

Postdoctoral Fellowship – RNA in Lung Sepsis and Inflammation (Boston University)

Postdoctoral Fellowship – Respiratory and Ophthalmic Diseases (Queen’s University Belfast)

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

Associate Professor – Oncology (University of California, Davis)

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