Citations

Platelets have an emerging and incompletely understood role in a myriad of host immune responses, extending their role well beyond regulating thrombosis. Acute respiratory distress syndrome is a complex disease process characterized by a range of pathophysiologic processes including oxidative stress, lung deformation, inflammation, and intravascular coagulation. The objective of this review is to summarize existing knowledge on platelets and their putative role in the development and resolution of lung injury.

AbstractMicroRNA‐200 (miR‐200) has emerged as a regulator of the PI3K/AKT pathway and cancer cell growth. It was reported that miR‐200 can activate PI3K/AKT by targeting FOG2 (friend of GATA 2), which directly binds to the p85α regulatory subunit of PI3K. We found that miR‐200 was elevated in early stage lung adenocarcinomas when compared with normal lung tissues, and the expression of miR‐200 promoted the tumor spheroid growth of lung adenocarcinoma cells. We show that AKT activation was essential for such oncogenic action of miR‐200. However, depletion of FOG2 had little effect on AKT activation. By performing a reverse‐phase protein array, we found that miR‐200 not only activated AKT but also concomitantly inactivated S6K and increased IRS‐1, an S6K substrate that is increased on S6K inactivation. Depletion of IRS‐1 partially inhibited the miR‐200‐dependent AKT activation. Taken together, our results suggest that miR‐200 may activate AKT in lung adenocarcinoma cells through a FOG2‐independent mechanism involving IRS‐1. Our findings also provide evidence that increased miR‐200 expression may contribute to early lung tumorigenesis and that AKT inhibitors may be useful for the treatment of miR‐200‐dependent tumor cell growth. © 2015 IUBMB Life, 67(9):720–725, 2015

On March 25 and 26, 2015, the National Heart, Lung, and Blood Institute sponsored a meeting on the State of the Science in Transfusion Medicine on the National Institutes of Health (NIH) campus in Bethesda, Maryland, which was attended by a diverse group of 330 registrants. The meeting's goal was to identify important research questions that could be answered in the next 5 to 10 years and which would have the potential to transform the clinical practice of transfusion medicine. These questions could be addressed by basic, translational, and/or clinical research studies and were focused on four areas: the three “classical” transfusion products (i.e., red blood cells, platelets, and plasma) and blood donor issues. Before the meeting, four working groups, one for each area, prepared five major questions for discussion along with a list of five to 10 additional questions for consideration. At the meeting itself, all of these questions, and others, were discussed in keynote lectures, small‐group breakout sessions, and large‐group sessions with open discourse involving all meeting attendees. In addition to the final lists of questions, provided herein, the meeting attendees identified multiple overarching, cross‐cutting themes that addressed issues common to all four areas; the latter are also provided. It is anticipated that addressing these scientific priorities, with careful attention to the overarching themes, will inform funding priorities developed by the NIH and provide a solid research platform for transforming the future practice of transfusion medicine.

Exposure to moderate hyperoxia in prematurity contributes to subsequent airway dysfunction and increases the risk of developing recurrent wheeze and asthma. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) axis modulates airway tone by regulating airway smooth muscle (ASM) intracellular Ca2+([Ca2+]i) and contractility. However, the effects of hyperoxia on this axis in the context of Ca2+/contractility are not known. In developing human ASM, we explored the effects of novel drugs that activate sGC independent of NO on alleviating hyperoxia (50% oxygen)-induced enhancement of Ca2+responses to bronchoconstrictor agonists. Treatment with BAY 41–2272 (sGC stimulator) and BAY 60-2770 (sGC activator) increased cGMP levels during exposure to 50% O2. Although 50% O2did not alter sGCα1or sGCβ1expression, BAY 60-2770 did increase sGCβ1expression. BAY 41-2272 and BAY 60-2770 blunted Ca2+responses to histamine in cells exposed to 50% O2. The effects of BAY 41-2272 and BAY 60-2770 were reversed by protein kinase G inhibition. These novel data demonstrate that BAY 41-2272 and BAY 60-2770 stimulate production of cGMP and blunt hyperoxia-induced increases in Ca2+responses in developing ASM. Accordingly, sGC stimulators/activators may be a useful therapeutic strategy in improving bronchodilation in preterm infants.

Lung diseases such as emphysema, interstitial fibrosis, and pulmonary vascular diseases cause significant morbidity and mortality, but despite substantial mechanistic understanding, clinical management options for them are limited, with lung transplantation being implemented at end stages. However, limited donor lung availability, graft rejection, and long-term problems after transplantation are major hurdles to lung transplantation being a panacea. Bioengineering the lung is an exciting and emerging solution that has the ultimate aim of generating lung tissues and organs for transplantation. In this article we capture and review the current state of the art in lung bioengineering, from the multimodal approaches, to creating anatomically appropriate lung scaffolds that can be recellularized to eventually yield functioning, transplant-ready lungs. Strategies for decellularizing mammalian lungs to create scaffolds with native extracellular matrix components vs. de novo generation of scaffolds using biocompatible materials are discussed. Strengths vs. limitations of recellularization using different cell types of various pluripotency such as embryonic, mesenchymal, and induced pluripotent stem cells are highlighted. Current hurdles to guide future research toward achieving the clinical goal of transplantation of a bioengineered lung are discussed.

Abstract Several studies have identified common genetic factors that influence susceptibility to lung cancer but no large studies have systematically studied familial lung cancers. The Genetic Epidemiology of Lung Cancer Consortium completed a genome-wide association study (GWAS) using samples from 757 cases and 796 controls, all of European American ancestry, and frequency matched on age and sex. Genotyping was performed by the Center for Inherited Disease Research (CIDR) using an Illumina Human OmniExpressExome-8v1 array. The most significantly associated SNPs were identified in the cases as a whole, and were also stratified by histology (adenocarcinoma and squamous cell carcinoma) and family history (0-1 and 2-5 affected family members). Analysis of all cases and controls identified a large number of SNPs around the CFTR gene that are strongly associated with lung cancer risk. Upon imputation with European Ancestry 1000 genomes data, the most significant SNP in this region is rs43034 (p = 3.89E-07, OR = 0.657) in the promoter region. In addition, an exonic missense SNP, rs213950 (p = 6.32E-07, OR = 0.663), and an intronic SNP with a possible splicing effect, rs213935 (p = 5.20E-07, OR = 0.660) were also identified as possible protective alleles. Analysis by histological subtype identified several rare and exonic SNPs that were specific by histology. We highlight two SNPs, rs114719990 (p = 1.194E-04, OR = 336.8, SETD2, c.3229A>G, p.Thr1077Ala) and rs199710487 (p = 1.124E-04, OR = 366, NTN5, c.656G>A, p.Arg219Gln), that were identified as strongly associated SNPs in cases with histologically confirmed adenocarcinoma, and two SNPs, rs144465058 (p = 1.029E-04, OR = 484.6, ANK3, c.6555G>T, p.Gln2185His) and rs140216112 (p = 1.087E-04, OR = 476, GRIK4, c.1013C>G, p.Ala338Gly), that were identified as top SNPs in cases with histologically confirmed squamous cell carcinoma. The SETD2 gene is thought to be a tumor suppressor gene and variants in this gene have previously been associated with leukemia and glioma (Zhu X et al. 2014, Fontebasso AM et al. 2013), and may now have implications in lung cancer, specifically adenocarcinoma development. In conclusion, we identified SNPs in the CFTR gene that may have a protective effect on lung cancer and several rare and exonic variants that were specific to histology subtype. SNPChrPositionGeneGenomic/ Nucleotide/ Amino acid changeOdds Ratiop-valueCFTR Protective Allelesrs430347117108449CFTRg.117108449T>C; 2.4kb upstream0.6573.89×10−7rs2139507117199533CFTRc.1408G>A; p.Val470Met0.6636.32×10−7rs2139357117178208CFTRc.869+1481A>G0.6605.20×10−7 Citation Format: Diana M. Toledo, Susan M. Pinney, Diptasri Mandal, Mariza de Andrade, Elena Kupert, Jennifer Franks, Colette Gaba, Claire L. Simpson, Ming You, Marshall W. Anderson, Joan E. Bailey-Wilson, Christopher I. Amos, Ann Schwartz. Genetic Epidemiology of Lung Cancer Consortium: genome-wide association study of familial lung cancer cases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-189. doi:10.1158/1538-7445.AM2015-LB-189

Abstract Background: Recent genome-wide association studies (GWAS) have identified 28 susceptibility loci for Lung cancer (LC), 32 loci for smoking behavior, 10 loci for chronic obstructive pulmonary disease (COPD), 63 loci for pulmonary function and related phenotypes, totaling 107 GWAS susceptibility loci (as of November 2014). Given the common variants that have been found to be associated with LC in GWAS, targeted-region exome sequencing provides a cost-effective approach for further investigation of high-priority regions of the genome and has the great potential to identify rare causal variants in GWAS loci. Patients and Methods: Using an extreme phenotype approach, we selected 48 sporadic LC patients reporting heavy smoking histories with the presence of severe COPD in whom environmental factors are considered overwhelming, and 54 familial LC cases from families with at least three first-degree relatives with LC who are likely enriched for genomic signal, to search for the disease-causing rare mutations within the target 107 GWAS loci using exome sequencing data. Results: By focusing on exome profiles of these target 107 loci, we identified two disease-causing rare mutations on 6p21.32 TNXB p. Arg504His and 10q25.1 CCDC147 p.Arg696Cys. The homozygous Arg504His mutation presented in four familial and one sporadic LC cases. Notably, the minor allele frequency (MAF) of this variant in Caucasians from 1000 Genomes is very rare (<0.001). The heterozygous CCDC147 Arg696Cys variant were identified in two familial cases and one sporadic case. The MAF for this variant in the Caucasians from 1000 Genomes is 0.004. Both deleterious changes lead to truncation of the putative proteins, which disrupts the predicted domain and alters the cellular localization. We also observed several other suggestive rare mutations on G7C, TNS1, DBH1, and CHRNA5. Conclusion: Our target exome sequencing results demonstrate novel highly disruptive LC risk-conferring TNXB and CCDC147 mutations. Since the rare variants have appreciable effects on disease risk prediction, families and patients may warrant screening for mutations in TNXB and CCDC147 (if validated) to assess their potential LC risk. Citation Format: Yanhong Liu, Farrah Kheradmand, Michael Scheurer, Caleb Davis, David Wheeler, Edwin Silverman, Shete Sanjay, Spiridon Tsavachidis, Georgina Armstrong, Elena Kupert, Marshall Anderson, Yafang Li, Claudio Pikielny, Joan E. Bailey-Wilson, Ming You, Colette Gaba, Mariza DeAndrade, Diptasri Mandal, Claire Simpson, Susan Pinney, Christopher Amos, Margaret Spitz. Target exome sequencing for disease-causing rare mutations in familial and sporadic lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4600. doi:10.1158/1538-7445.AM2015-4600

Abstract Recently, Wilson et al. (doi:10.1038/onc.2013.396) found that EYA4 was frequently inactivated biallelically in sporadic lung cancer, displays tumor suppressor gene-like properties and affects DNA repair, and that 5 of 17 common SNPs in this 0.3Mb region showed nominal association to familial lung cancer (FLC, p<0.05) although these associations are not genome-wide significant after correction for multiple testing.. However, this is an interesting candidate gene for FLC risk because it is located on chromosome 6q in a region where we previously showed evidence of linkage to FLC (PMID: 15272417, 20215501). Here, we sequenced 75 individuals from our 9 most strongly 6q-linked families, using Illumina technology and a custom Agilent kit to capture 37Mb of chromosome 6 from 130Mb to 167Mb. We closely examined a region around EYA4, between 133Mb and 135Mb. This region contains a number of other genes in addition to EYA4, including the Vanin cluster; ribosomal protein S12; the tumor suppressor gene TCF21 and its antisense RNA TARID which directs methylation and activation of TCF21; solute carriers SLC18B1 and SLC2A12 and the serum/glucocorticoid regulated kinase SGK1. To detect sharing of variants among affecteds in each family while allowing for phenocopies, singlepoint affected-only linkage analysis was performed on lung cancer affection status for all sequence variants using the Elston-Stewart algorithm implemented in the R package paramlink assuming penetrance of 0.01, 0.1 and 0.1 for dd/Dd/DD and a disease allele (D) frequency of 0.01, at a recombination fraction (theta) of 0. The highest total LOD score (summed over all 9 families) in the entire 37Mb targeted region was not near EYA4. In only one family was there any variant in EYA4 that appeared on the linked haplotype with close to the highest family-specific LOD score: Family 30 had a LOD of 0.6514 at several EYA4 variants (max LOD across region 0.6519). However, many variants across the region had similar LODs. In the remaining families, all EYA4 variants had LODs much lower than the maximum family-specific LOD score in the region. Thus, EYA4 variants are unlikely to explain our 6q linkage peak in these 6q-linked families. The second highest total LOD score for the entire 37Mb targeted region was found near EYA4 at 133.9Mb (LOD = 3.82), in the middle of the TARID antisense RNA gene. This variant appears to be entirely novel, as it is not present in any of the online variant databases, such as NHLBI's ESP or 1000 Genomes. In two families, the family LOD score at this locus was at or close to the highest in the region: in Family 44 the LOD score was 1.206 (max LOD across entire region 1.207) and in Family 35 the LOD score was 0.3958 (max LOD across region 0.3959). Therefore this variant in the TARID antisense RNA is a candidate in some of our families most strongly linked to chromosome 6q. Citation Format: Joan E. Bailey-Wilson, Claire L. Simpson, Susan M. Pinney, Mariza de Andrade, Colette Gaba, Ping Yang, Ming You, Elena Y. Kupert, Ann G. Schwartz, Diptasri Mandal, Christopher I. Amos, Marshall W. Anderson. Evaluation of EYA4 as a candidate risk locus in familial lung cancer families linked to 6q. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2757. doi:10.1158/1538-7445.AM2015-2757

Abstract Background: Squamous cell carcinoma is a common type of lung cancer and accounts for about 25-30% of all non-small cell lung cancers. Metformin is a drug commonly prescribed as first-line treatment for type-2 diabetes, with some evidence showing that the drug can also act directly on cancer cells. One of the mechanisms of action is through activation of the AMP-activated protein kinase (AMPK) which is involved in control of energy homeostasis in cells. The goal of this study was to determine metformin response in different cell lines and different cellular contexts, and to use that information to work towards the generation of a metformin “sensitivity index” that could be used guide individualized chemoprevention. Methods: We performed cell survival analysis on squamous cell carcinoma lines, skin fibroblast lines and differentiated IPS cell lines to identify differences in metformin response both for different cell lines and for cells in different cell context. Microarray profiling was used to determine differentially expressed genes that are regulated by metformin treatment in order to generate signatures of metformin response. Results: Cell survival analysis showed that different cell lines respond differently to metformin, and cells of identical genotypes in a variety of differentiated states or cellular contexts also show differential response to metformin. Gene expression profiling of metformin treated cells identified differentially expressed genes that may mediate metformin response. Conclusion: Differences in response to metformin treatment across a variety of cell lines and cellular contexts suggest heterogeneity that may be patient-specific. Using genes that are differentially expressed following metformin treatment, we identified a 55-gene set that can be used as a metformin “sensitivity index” to stratify patients into metformin responders and non-responders and guide individualized chemoprevention. Citation Format: Michael K. Asiedu, Matthew R. Barron, Marie Christine Aubry, Dennis Wigle. Metformin as a chemoprevention agent for lung squamous cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1897. doi:10.1158/1538-7445.AM2015-1897