Pulmonary Cell News Volume 5.48 | Dec 8 2016

TOP STORY

MEK Inhibitors Block Growth of Lung Tumors with Mutations in Ataxia–Telangiectasia Mutated

Investigators reported that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. [Nat Commun] Full Article | Press Release

(Ranked by impact factor of the journal)

Modulation of Apical Constriction by Wnt Signaling Is Required for Lung Epithelial Shape Transition

The impact of cell shapes on tissue morphogenesis remains unclear. Scientists showed that expression of Wnt components were decreased in the canalicular-saccular stages, and genetically constitutive activation of Wnt signaling impaired air sac formation by inducing apical constriction in the epithelium as seen in the pseudoglandular stage. Organ culture models also demonstrated that Wnt signaling induces apical constriction through the apical actomyosin cytoskeletal organization. [Development] Abstract

Intermittent Hypoxia during Recovery from Neonatal Hyperoxic Lung Injury Causes Long-Term Impairment of Alveolar Development: A New Rat Model of BPD

Rat models of bronchopulmonary dysplasia (BPD) using varying degrees of hyperoxia to produce injury either cause early mortality or spontaneously recover following removal of the inciting stimulus, thus limiting clinical relevance. Researchers sought to refine an established rat model induced by exposure to 60% O₂ from birth by following hyperoxia with intermittent hypoxia (IH). [Am J Physiol Lung Cell Mol Physiol] Abstract

Effects of Carbocysteine and Beclomethasone on Histone Acetylation/Deacetylation Processes in Cigarette Smoke Exposed Bronchial Epithelial Cells

The authors aimed to assess the effects of cigarette smoke, carbocysteine, and beclomethasone dipropionate on histone deacetylase 3 expression/activity, N-CoR expression, histone acetyltransferases expression, p-CREB and IL-1 m-RNA expression, neutrophil chemotaxis. Increased p-CREB expression was observed in the bronchial epithelium of smokers. [J Cell Physiol] Abstract

The Cellular Kinetics of Lung Alveolar Epithelial Cells and Its Relationship with Lung Tissue Repair after Acute Lung Injury

Researchers showed that alveolar epithelium type 2 cells (AEC2s) are damage resistant during acute lung injury. Then they observed the relationship between the expression of HGF, c-Met following acute lung injury (ALI) in rat lung and proliferation of AEC2s. The proliferation of AEC2s was inhibited when isolated primary AEC2s were co-cultured with c-Met inhibitor SU11274. [Respir Res] Full Article

Responses of A549 Human Lung Epithelial Cells to Cristobalite and α-Quartz Exposures Assessed by Toxicoproteomics and Gene Expression Analysis

Scientists used cytotoxicity assays, proteomic and gene expression analyses to examine the difference in response of A549 cells to two silica particles that differ in physical properties, namely cristobalite and α-quartz. Cytotoxicity assays such as lactate dehydrogenase release, 5-bromo-2′-deoxyuridine incorporation and cellular ATP showed that both silica particles could cause cell death, decreased cell proliferation and metabolism in the A549 human lung epithelial cells. [J Appl Toxicol] Full Article

LUNG CANCER

Characterization of EGFR T790M, L792F, and C797S Mutations as Mechanisms of Acquired Resistance to Afatinib in Lung Cancer

Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors. The authors established afatinib-resistant cells by transfecting Ba/F3 cells with common or exon 18 mutations and subjecting them to chronic exposure to increasing concentrations of afatinib. Afatinib-resistant clones were separately established through N-ethyl-N-nitrosourea mutagenesis and exposure to fixed concentrations of afatinib. [Mol Cancer Ther] Abstract

Dual Targeting of Glutaminase 1 and Thymidylate Synthase Elicits Death Synergistically in NSCLC

Scientists showed Glutaminase 1 (GLS1) inhibition induced cell cycle arrest with ATP depletion by glutamate reduction. Dual inhibition with bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and thymidylate synthase inhibitor, 5-fluorouracil (5-FU), elicits cell death synergistically through cell cycle arrest in non-small cell lung cancer (NSCLC). A preclinical xenograft model of NSCLC showed remarkable anti-tumor effect synergistically in the BPTES and 5-FU dual therapy group. [Cell Death Dis] Full Article

Cancer-Associated Fibroblasts Treated with Cisplatin Facilitates Chemoresistance of Lung Adenocarcinoma through IL-11/IL-11R/STAT3 Signaling Pathway

The authors showed cancer associated fibroblasts treated with cisplatin conferred chemoresistance to lung cancer cells. Meanwhile, Interleukin-11 (IL-11) was significantly up-regulated in the cancer-associated fibroblasts stimulated by cisplatin. As confirmed in lung adenocarcinoma cells in vivo and in vitro, IL-11 could protect cancer cells from cisplatin-induced apoptosis and thus promote their chemoresistance. [Sci Rep] Full Article

rpL3 Promotes the Apoptosis of p53 Mutated Lung Cancer Cells by Down-Regulating CBS and NFκB upon 5-FU Treatment

Researchers reported that rpL3 induced by 5-FU treatment in Calu-6 cells represses CBS transcription and reduces CBS protein stability leading to a decrease of CBS protein levels. rpL3 also regulates negatively the activation of NFκB by preventing NFκB nuclear translocation through IκB-α up-regulation. [Sci Rep] Full Article

Cancer Cell Plasticity: Rapid Reversal of Chemosensitivity and Expression of Stemness Markers in Lung and Breast Cancer Tumorspheres

The authors have simulated on cycle of environmental conditions to study the reversible nature of the stemness status in terms of chemoresistance. They first generated floating tumorspheres from lung and breast cancer cells by culturing them in serum-free media without the addition of any external mitogenic stimulation, and subsequently re-incubating them back in serum-containing media to simulate routine culture conditions. [J Cell Physiol] Abstract

Dose-Biomarker-Response Modeling of the Anticancer Effect of Ethaselen in a Human Non-Small Cell Lung Cancer Xenograft Mouse Model

Investigators explored the relationship between the ethaselen dose and thioredoxin reductase (TrxR) activity level and the relationship between TrxR degradation and tumor apoptosis in a human lung carcinoma A549 xenograft model. [Acta Pharmacol Sin] Abstract

New Horizons for Cystic Fibrosis Treatment

The authors discuss how CFTR mutations translate to disturbed synthesis or function of the CFTR protein and how its understanding has opened the way to ‘personalized’ treatments to correct the basic defect. The first two drugs have reached the clinic: a CFTR potentiator to augment CFTR channel function, and the combination of this potentiator with a corrector to increase CFTR expression at the cell membrane. [Pharmacol Ther] Abstract

Visit our reviews page to see a complete list of reviews in the pulmonary cell research field.

Updated KEYTRUDA^® (Pembrolizumab) Data in Small Cell Lung Cancer and Mesothelioma Presented

Merck announced that updated findings from the Phase Ib KEYNOTE-028 study investigating the use of KEYTRUDA^® (pembrolizumab), the company’s anti-PD-1 therapy, in previously treated patients with advanced small cell lung cancer and malignant pleural mesothelioma, showed clinical activity and durable responses in some patients. [Press release from Merck discussing research presented at 17^th World Conference on Lung Cancer, Vienna] Press Release

Opdivo (Nivolumab) Alone or Combined with Yervoy (Ipilimumab) Shows Encouraging Response and Survival Rates in Recurrent Small Cell Lung Cancer, from Phase I/II Study CheckMate

Bristol-Myers Squibb Company announced updated results for Opdivo monotherapy and in combination with Yervoy in previously treated small cell lung cancer patients, a cohort of the Phase I/II open-label CheckMate -032 trial. [Bristol-Myers Squibb Company] Press Release

Novartis Announces Zykadia^® First-Line Study Results Showing 16.6 Month Progression-Free Survival in Patients with ALK+ Advanced NSCLC

Novartis announced results from its Phase III open-label, randomized, active-controlled, multi-center ASCEND-4 study, which found that patients with anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer (NSCLC) treated with first-line Zykadia^® (ceritinib) had a median progression-free survival of 16.6 months, compared to 8.1 months in patients treated with standard first-line chemotherapy with maintenance. [Novartis] Press Release

Breakthrough Prize Marks 5^th Anniversary Celebrating Top Achievements in Science and Awards More than $25 Million in Prizes at Gala Ceremony in Silicon Valley

The Breakthrough Prize and founders Sergey Brin and Anne Wojcicki, Yuri and Julia Milner, and Mark Zuckerberg and Priscilla Chan, announced the recipients of the 2017 Breakthrough Prizes, marking the organization’s fifth anniversary recognizing top achievements in Life Sciences, Fundamental Physics and Mathematics. A combined total of $25 million was awarded at the gala ceremony in Silicon Valley, hosted by Morgan Freeman. Each of the Breakthrough Prizes is worth $3 million, the largest individual monetary prize in science. [Breakthrough Prize] Press Release

Senate Sends Massive Biomedical Innovation Bill to Obama for Signing

By a 94-to-five vote, the Senate approved the 21^st Century Cures Act, clearing the way for President Barack Obama to sign the measure into law. The massive bill dedicates $4.8 billion over the next decade to research initiatives at the National Institutes of Health and makes an array of changes at the Food and Drug Administration designed to speed the approval of new drugs and medical devices. [ScienceInsider] Editorial

Controversial Impact Factor Gets a Heavyweight Rival

One of science’s most contentious metrics has a flashy new rival. Publishing giant Elsevier launched the CiteScore index to assess the quality of academic journals. Although the index ranks journals with a formula that largely mimics the influential Journal Impact Factor (JIF), it covers twice as many journals and its formula includes tweaks that produce some notably different results, including lower scores for some high-JIF journals. [Nature News] Editorial

Mexico Proposal to Ban Human-Embryo Research Would Stifle Science

Researchers are waiting to see whether Mexico’s legislature will approve an amendment to the national health law that would ban experiments with human embryos. The amendment is intended to regulate assisted reproduction, including the payment of surrogate mothers, donations to egg and sperm banks and the fertilization of more than three eggs at a time. But it would also ban the creation of human embryos for any purpose except reproduction and any research with existing human embryos. [Nature News] Editorial

CRISPR Heavyweights Battle in US Patent Court

Berkeley and its rival, the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, are each vying for the intellectual property underlying CRISPR–Cas9, which is adapted from a system that bacteria use to fend off viruses. During the hearing the US Patent and Trademark Office judges challenged Berkeley’s central claim: that once its researchers demonstrated that CRISPR–Cas9 could be used to edit DNA in bacteria, any reasonably skilled person could have adapted the technique for use in more complex cells. [Nature News] Editorial

NEW 19^th International Conference on Clinical Application of Adult Stem Cells
February 14-15, 2017
Havana, Cuba

Visit our events page to see a complete list of events in the community.

NEW Postdoctoral Position – Targeted Approaches to Lung Cancers (University of California San Francisco)

Post-Doctoral Research Fellow – Neurobiology (Institut of Molecular Biology)

Assistant Professor – Molecular Therapeutics of Cancer (Dartmouth College)

Postdoctoral Research Assistant/Associate(s) (University of Cambridge)

Postdoctoral Position – Heart, Lung and Blood Vascular Medicine (University of Pittsburgh)

Postdoctoral Fellow – System Genetics and Genomics of Lung Diseases (Brigham & Women’s Hospital – Harvard Medical School)

Scientists/Physicians – Laboratory/Translational/Clinical Research in Lung Cancers (University of New Mexico Comprehensive Cancer Center)

Postdoctoral Research Fellow – Cancer GeneticsEpigenetics (Fred Hutchinson Cancer Research Center)

Postdoctoral Researcher – Lung Cancer (Northwestern University)

Postdoctoral Fellow – Lung Biology (Boston University)

Cell Biologist – Pulmonary Vascular Signaling (University of Maryland)

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