Adam C. Gower

• Boston University

Objectives: Examination of bronchial epithelium-derived gene expression signature of bronchiectasis (BE) in nasal epithelium. Methods: We studied 220 participants from the Detection of Early Lung Cancer Among Military Personnel study with bulk RNA-seq of nasal epithelium brushings. Gene set enrichment analysis (GSEA) was used to examine whether gen...

Introduction: The biology of early human hypertensive heart disease (HHD) is largely unexplored due to limited cardiac tissue access. Site-specific transcriptomics of human cardiac tissue before development of overt HHD offers a unique vantage to understand the biology of HHD in human cardiac tissue. Hypothesis: We hypothesize that transcriptomic s...

Neutrophils were once considered a homogenous population of transcriptionally static, pathogen-killing cells, however, recent models have demonstrated neutrophil functional and transcriptional plasticity. We performed transcriptomic analyses in a murine model of pneumococcal pneumonia to investigate neutrophil plasticity and demonstrate that neutro...

The coordinate regulation of metabolism and epigenetics to establish cell state-specific gene expression patterns during lineage progression is a central aspect of cell differentiation, but the factors that regulate this elaborate interplay are not well-defined. The imprinted Dlk1-Dio3 noncoding RNA (ncRNA) cluster has been associated with metaboli...

A greater understanding of molecular, cellular, and immunological changes during the early stages of lung adenocarcinoma development could improve diagnostic and therapeutic approaches in patients with pulmonary nodules at risk for lung cancer. To elucidate the immunopathogenesis of early lung tumorigenesis, we evaluated surgically resected pulmona...

Introduction: We developed a rigorous, systematic protocol for the dissection and preservation of human hearts for biobanking to advance our understanding of cardiovascular diseases (CVDs). Existing cardiac biobanks consist largely of biopsy tissue in select diseases and are insufficient for correlating whole organ phenotype with clinical data. Met...

Objectives We sought to develop a rigorous, systematic protocol for the dissection and preservation of human hearts for biobanking that expands previous success in postmortem transcriptomics to multiomics from paired tissue. Background Existing cardiac biobanks consist largely of biopsy tissue or explanted hearts in select diseases and are insuffi...

SARS-CoV-2 infection and disease severity are influenced by viral entry (VE) gene expression patterns in the airway epithelium. The similarities and differences of VE gene expression (ACE2, TMPRSS2, and CTSL) across nasal and bronchial compartments have not been fully characterized using matched samples from large cohorts. Gene expression data from...

Objectives: Discovering airway gene expression alterations associated with radiographic bronchiectasis (BE) may improve the understanding of the pathobiology of early-stage BE. Methods: Presence of radiographic BE in 173 individuals without a clinical diagnosis of BE was evaluated. Bronchial brushings from these individuals were transcriptomical...

Liver fibrosis is a sign of non-alcoholic fatty liver disease progression towards steatohepatitis (NASH) and cirrhosis and is accelerated by aging. Glutaredoxin-1 (Glrx) controls redox signaling by reversing protein S-glutathionylation, induced by oxidative stress, and its deletion causes fatty liver in mice. Although Glrx regulates various pathway...

Time is a central element of the sexual dimorphic patterns of development, pathology and aging of the skeleton. Since the transcriptome is a representation of the phenome, we hypothesized that both sex and sex specific temporal, transcriptomic differences in bone tissues over an 18‐month period would be informative to the underlying molecular proce...

Objective The immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical,...

Background: SARS-CoV-2 infection and disease severity are influenced by viral entry (VE) gene expression patterns in airway epithelium. The similarities and differences of VE gene expression (ACE2, TMPRSS2, and CTSL) across nasal and bronchial compartments has not been fully characterized using matched samples from large cohorts. Results: Gene exp...

Introduction: The Lung Precancer Atlas (PCA) is developing bulk and single cell RNA-seq pipelines to process Lung PCA sequencing data collected across our multi-institutional consortium. The pipelines will be publicly available to run using the Terra Cloud platform so that they can be used by other members of the NCI Human Tumor Atlas Network (HTAN...

Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infects host cells with help from the Viral Entry (VE) proteins ACE2, TMPRSS2, and CTSL. Proposed risk factors for viral infection, as well as the rate of disease progression, include age, sex, chronic obstructive pulmonary disease,...

Objective: The immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical...

Determining the clinical significance of CT scan-detected subsolid pulmonary nodules requires an understanding of the molecular and cellular features that may foreshadow disease progression. We studied the alterations at the transcriptome level in both immune and non-immune cells, utilizing single-cell RNA sequencing, to compare the microenvironmen...

The function of most long noncoding RNAs (lncRNAs) is unknown. However, recent studies reveal important roles of lncRNAs in regulating cancer-related pathways. Human antisense lncRNA-NKX2-1-AS1 partially overlaps the NKX2-1/TTF1 gene within chromosomal region 14q13.3. Amplification of this region and/or differential expression of genes therein are...

Background: The emergence of fully antimicrobial resistant Neisseria gonorrhoeae has led global public health agencies to identify a critical need for next generation anti-gonococcal pharmaceuticals. The development and success of these compounds will rely upon valid pre-clinical models of gonorrhoeae infection. We recently developed and reported...

Background The potential utility of microRNA as biomarkers for early detection of cancer and other diseases is being investigated with genome-scale profiling of differentially expressed microRNA. Processes for measurement assurance are critical components of genome-scale measurements. Here, we evaluated the utility of a set of total RNA samples, de...

OBJECTIVES/SPECIFIC AIMS: Microarray technology has produced large volumes of gene expression data profiling differences in gene expression in a vast array of conditions, much of which is publicly available. Methods to query these data for similarities in patterns of gene regulation are limited to comparisons between preannotated groups. In respons...

Alveolar macrophages orchestrate pulmonary innate immunity and are essential for early immune surveillance and clearance of microorganisms in the airways. Inflammatory signaling must be sufficiently robust to promote host defense but limited enough to prevent excessive tissue injury. Macrophages in the lungs utilize multiple transcriptional and pos...

Airway epithelial cell responses are critical to the outcome of lung infection. In this study, we aimed to identify unique contributions of epithelial cells during lung infection. In order to differentiate genes induced selectively in epithelial cells during pneumonia, we compared genome-wide expression profiles from 3 sorted cell populations: epit...

The gene expression profile of cytologically-normal bronchial airway epithelial cells has previously been shown to be altered in patients with lung cancer. Although bronchoscopy is often used for the diagnosis of lung cancer, its sensitivity is imperfect, especially for small and peripheral suspicious lesions. In this study, we derived a gene expre...

Induced pluripotent stem cells (iPSCs) provide an inexhaustible source of cells for modeling disease and testing drugs. Here we develop a bioinformatic approach to detect differences between the genomic programs of iPSCs derived from diseased versus normal human cohorts as they emerge during in vitro directed differentiation. Using iPSCs generated...

Increasing our understanding of early events in the pathogenesis of lung cancer is crucial for identification of new targets for prevention and treatment of this malignancy. Earlier work has shown that seemingly normal cells adjacent to the tumor carry specific molecular alterations that are characteristic of the tumor itself suggestive of a field...

Lung squamous cell carcinoma (SCC) is thought to arise from premalignant lesions in the airway epithelium; therefore studying these lesions is critical for understanding lung carcinogenesis. Previous microarray and sequencing studies designed to discover early biomarkers and therapeutic targets for lung SCC had limited success identifying key drive...

Earlier work identified specific tumor-promoting abnormalities that are shared between lung cancers and adjacent normal bronchial epithelia. We sought to characterize the yet unknown global molecular and adjacent airway field cancerization (FC) in early-stage non-small cell lung cancer (NSCLC). Whole-transcriptome expression profiling of resected e...

Significance MicroRNAs are small noncoding RNAs that negatively regulate gene expression and have been implicated in a variety of cellular processes. Using small RNA sequencing, we identified microRNA 4423 (miR-4423) as a primate-specific microRNA whose expression is largely restricted to airway epithelium and which functions as a regulator of airw...

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Little is known about the mechanisms involved in the initiation and progression of lung cancer, even though lung cancer contributes to the most cancer-related deaths in the world. Lung squamous cell carcinoma (SCC) is the second most common histological subtype, and often...

Earlier work has identified in lung cancer a field cancerization (FC) phenomenon in which tumors and adjacent normal appearing tissues share specific molecular abnormalities (e.g., loss of heterozygosity) that may be highly pertinent to cancer pathogenesis. We sought to characterize the global molecular airway FC adjacent to early-stage non-small c...

Induced pluripotent stem cells (iPSCs) hold great promise for modeling human hematopoietic diseases. However, intrinsic variability in the capacities of different iPSC lines for hematopoietic development complicates comparative studies and is currently unexplained. We created and analyzed 3 separate iPSC clones from fibroblasts of 3 different norma...

Caveolae are cell membrane invaginations that are highly abundant in adipose tissue, endothelial cells and the lung. The formation of caveolae is dependent on the expression of various structural proteins that serve as scaffolding for these membrane invaginations. Cavin1 is a newly identified structural protein whose deficiency in mice leads to los...

Gene sets with significant enrichment in genes whose expression is altered in Cavin 1−/− macrophages. Gene Set Enrichment Analysis (GSEA) was performed on 1,625 gene sets from Gene Ontology, KEGG, Reactome, and Biocarta, and 14 of these gene sets were found to be significantly enriched (FDR q <0.05) among genes whose expression was up- or down-regu...

Smoking is a significant risk factor for lung cancer, the leading cause of cancer-related deaths worldwide. Our group has previously shown that epithelial gene expression is altered throughout the airway of smokers and that some of these changes are regulated by microRNAs. Moreover, we have previously identified gene expression differences in cytol...

Smoking, the main risk factor leading to lung cancer, causes both genetic and epigenetic changes resulting in aberrant gene expression. UTX is a histone demethylase that has been implicated in many cancers and has been shown to regulate both cell cycle and differentiation genes. However, the role of UTX has not been elucidated in lung cancer. We hy...

The homeodomain transcription factor Nkx2-1 is essential for normal lung development and homeostasis. In lung tumors, it is considered a lineage survival oncogene and prognostic factor depending on its expression levels. The target genes directly bound by Nkx2-1, that could be the primary effectors of its functions in the different cellular context...

(a). Target genes at E11.5 (log(2) >0.75, p≤0.001). (b) Target genes at E19.5 (log(2) >0.75, p≤0.001). (DOC)

Nkx2-1 target genes expressed in lung development and correlated to NKX2-1 levels in human lung tumor datasets. (DOC)

Relative expression of selected Nkx2-1 target genes in E12 and E18 developing mouse lung extracted from the expression microarray dataset GEO series GSE 10889 (27). (TIF)

Comparison of three commercial Nkx2-1 antibodies. Western blot experiments were performed using MLE15 lung epithelial cell protein extracts. Nkx2-1 rabbit polyclonal antibody (EMD-Millipore-Upstate), rabbit monoclonal antibody (Abcam) and mouse monoclonal antibody (LabVision, Fisher Scientific) detect a strong band between 40–45 kD (upper black arr...

Genes bound and regulated by Nkx2-1 in human fetal lung epithelial cells. (DOC)

PCR and qPCR Oligonucleotide sequences. (DOC)

Genome-wide patterns of Nkx2-1 binding. Location of Nkx2-1 binding in all mouse chromosomes in E11.5 (red) and E19.5 (green) lungs. X axis (chromosomal location), y axis (binding signal intensity). (TIF)

Nkx2-1 binding patterns to selected target genes in lung development. Binding profiles of Nkx2-1 to newly identified target genes (left panel). Chromatin immunoprecipitation-qPCR validation of Nkx2-1 binding to target genes (right panel). IP DNA from E11.5 and E19.5 lungs, input and IgG immunoprecipitated control were used in qPCR analyses. Oligonu...

Nkx2-1 levels in human lung tumors significantly correlate with expression of developmental Nkx2-1 target genes. Additional heatmaps of human lung tumor genes identified in GSE 12667 dataset showing gene expression levels of the human homologues of Nkx2-1 target genes identified in mouse lung development at E11.5 (upper panel) and E19.5 (lower pane...

Nkx2-1 target genes genes included in Cancer pathways identified by IPA. (DOC)

(a) E11.5 overrepresented biological processes identified by EASE analysis p<0.05. (b) E19.5 overrepresented biological processes identified by EASE analysis (p<0.05). (DOC)

Overrepresented canonical pathways identified by Ingenuity Pathway Analysis Software. (DOC)

Dysregulation of TNF-α in lamina propria macrophages (LPM) is a feature of inflammatory bowel diseases (IBD). LPS-Induced-TNF-Alpha-Factor (LITAF) is a transcription factor that mediates TNF-α expression. To determine whether LITAF participates in the mediation of TNF-α expression in acutely inflamed colonic tissues, we first established the TNBS-i...

A gene expression signature of E2 treatment. The expression of these 111 genes was previously reported to be increased or decreased > 2.5-fold by the treatment of MCF7 cells with 10 nM 17-β-estradiol (E2) for either 8 or 48 hours (or both) relative to treatment with vehicle[20].

A gene expression signature of p63 silencing. The expression of these 77 genes was previously reported to be increased or decreased > 2-fold in at least three of five cell lines treated with an shRNA targeting p63, relative to the same cell lines treated with an shRNA targeting GFP[28].

Variation of openSESAME p values with sample size in GEO series GSE2225 and GSE21653. A, B. For each sample size, 1000 subsets of each GEO series were obtained by permutation and SA scores were computed. Fisher's exact test or a two-sided Kolmogorov-Smirnov (K-S) test were used to compute p values for each permutation. C, D. The expression values o...

Variation of openSESAME p values with signature size in GEO series GSE2225 and GSE21653. A, B. For each subset size, 1000 subsets of the signature genes were obtained by permutation, maintaining the same proportion of up- and down-regulated genes in the original signature, and SA scores were computed using each GEO series. Fisher's exact test or a...

Variation of openSESAME p values with signature composition in GEO series GSE2225 and GSE21653. A, B. For each subset size, 1000 subsets of the up-and down-regulated genes in the signature were obtained by permutation, maintaining a constant signature size, and SA scores were computed using each GEO series. Fisher's exact test or a two-sided Kolmog...

Comparison of MARQ and openSESAME query results using the E2 treatment signature. In queries using the E2 treatment signature, these GEO series were assigned an FDR q < 0.05 by openSESAME with either the K-S or Fisher's exact tests or contained an experimental comparison to which MARQ assigned an FDR-corrected p < 0.05. Series are sorted in ascendi...

Comparison of MARQ and openSESAME query results using the p63 silencing signature. In queries using the p63 silencing signature, these GEO series were assigned an FDR q < 0.05 by openSESAME with either the K-S or Fisher's exact tests or contained an experimental comparison to which MARQ assigned an FDR-corrected p < 0.05. Series are sorted in ascen...

Results of openSESAME query using E2 treatment signature. In an openSESAME query using the signature of E2 treatment, these 56 GEO series were assigned an FDR q < 0.25 with either the K-S or Fisher's exact tests. Series are sorted in ascending order by K-S q value.

Results of openSESAME query using p63 silencing signature. In an openSESAME query using the signature of p63 silencing, these 123 GEO series were assigned an FDR q < 0.25 with either the K-S or Fisher's exact tests. Series are sorted in ascending order by K-S q value.

Receiver Operating Curves (ROCs) using E2 treatment signature in Connectivity Map (CMap) MCF7 dataset. An openSESAME query was performed using the original 189-Affymetrix-probeset E2 treatment signature on the ranked fold changes from all instances of treatment of MCF7 cells in the CMap build 2.0 dataset. A ROC was constructed (orange) in which ins...

Background Identifying similarities between patterns of differential gene expression provides an opportunity to identify similarities between the experimental and biological conditions that give rise to these gene expression alterations. The growing volume of gene expression data in open data repositories such as the NCBI Gene Expression Omnibus (G...

Cigarette smoke creates a molecular field of injury in epithelial cells that line the respiratory tract. We hypothesized that transcriptome sequencing (RNA-Seq) will enhance our understanding of the field of molecular injury in response to tobacco smoke exposure and lung cancer pathogenesis by identifying gene expression differences not interrogate...

The "field of injury" hypothesis proposes that exposure to an inhaled insult such as cigarette smoke elicits a common molecular response throughout the respiratory tract. This response can therefore be quantified in any airway tissue, including readily accessible epithelial cells in the bronchus, nose, and mouth. High-throughput technologies, such...

The goal of this study was to characterize the small RNA transcriptome and discover novel microRNAs (miRNAs) associated with lung cancer in human bronchial epithelial cells using massively parallel sequencing. To this end, small RNA (10-40 nts) was isolated from bronchial brushings obtained via bronchoscopy. Samples pooled from healthy non-smokers,...

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Cigarette smoking is the most significant risk factor for the initiation and development of lung cancer. Tobacco exposure often results in chronic inflammation, tissue injury, and airway repair. A recent hypothesis demonstrates the presence of a stem/progenitor cell popu...

Smoking is the most important known risk factor for the development of lung cancer. Tobacco exposure results in chronic inflammation, tissue injury, and repair. A recent hypothesis argues for a stem/progenitor cell involved in airway epithelial repair that may be a tumor-initiating cell in lung cancer and which may be associated with recurrence and...

This study compared adhesion reformation after open and laparoscopic adhesiolysis in a rat model. Adhesions were induced by surgically creating ischaemic buttons on the peritoneal side wall. After 7 days the animals underwent laparoscopy with carbon dioxide insufflation or laparotomy to score and lyse adhesions. Peritoneal tissue and fluid were col...

While restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the definitive surgical treatment for patients suffering from chronic ulcerative colitis (CUC), pouchitis still remains a major late complication. Fecal stasis has been implicated in the etiology of ileal inflammation; however, the mechanism(s) remain unclear, in...

Introduction Postoperative adhesions pose a continued healthcare problem. We previously demonstrated that intraperitoneal (IP) administration of a neurokinin-1 receptor antagonist (NK-1RA) at surgery reduces intraabdominal adhesions in rats. The NK-1RA aprepitant (Emend™, Merck) is clinically approved for preventing postoperative nausea and vomitin...

Intra-abdominal adhesions are a significant source of postoperative morbidity. Bioresorbable barriers composed of hyaluronic acid and carboxymethylcellulose (HA/CMC) reduce adhesion formation by physically separating injured or healing peritoneal surfaces. To assess whether the efficacy of a physical barrier can extend beyond the site of applicatio...

Introduction: Postoperative adhesions pose a continued healthcare problem. We previously demonstrated that intraperitoneal (i.p.) administration of a neurokinin-1 receptor antagonist (NK-1RA) at surgery reduces intraabdominal adhesions in rats. The NK-1RA aprepitant (Emend, Merck) is clinically approved for preventing postoperative nausea and vomi...

Genetic variants in embryonic lethal, abnormal vision, Drosophila-like 4 (ELAVL4) have been reported to be associated with onset age of Parkinson disease (PD) or risk for PD affection in Caucasian populations. In the current study we genotyped three single nucleotide polymorphisms in ELAVL4 in a Caucasian study sample consisting of 712 PD patients...

Peritoneal adhesions, a major complication of abdominal surgery, are due, in part, to reduced levels of postoperative peritoneal tPA, an enzyme that facilitates degradation of fibrinous adhesions. Mesothelial cells lining the peritoneum are a primary source of tPA. Since the antioxidants vitamin E and methylene blue (MB) reduce adhesion formation i...

Dysregulation of TNF‐α secretion by lamina propria macrophages (LPM) is a hallmark of the inflammatory bowel disease Crohn's Disease (CD). LITAF has been shown to regulate TNF expression in macrophages and macrophage‐specific LITAF mac −/− mice (KO) are resistant to LPS induced sepsis. LITAF protein is increased by 30% in LPM isolated from C57BL/6...

Mounting evidence indicates that postoperative oxidative stress may be linked to decreased fibrinolytic activity and, subsequently, the development of intraabdominal adhesions. The goal of this study was to determine if methylene blue, a highly redox active dye that has been shown to inhibit adhesion formation (1) acts as an antioxidant in the post...

Adhesions remain a significant complication of abdominal surgery. There is a growing body of evidence suggesting that remodeling of peritoneal extracellular matrix by matrix metalloproteinases (MMPs) is involved in adhesion formation. We have shown that administration of a specific neurokinin-1 receptor (NK-1R) antagonist (CJ-12,255, Pfizer) to rat...

Oxidative stress has been implicated in intra-abdominal adhesion formation. Substance P, a neurokinin-1 receptor (NK-1R) ligand, facilitates leukocyte recruitment and reactive oxygen species (ROS) generation. We have shown in a rat model of adhesion formation that intraperitoneal administration of a NK-1R antagonist at the time of abdominal operati...

Up to 94% of patients experience fibrous adhesions after abdominal surgery, and a significant number of these patients require a second operation for open or laparoscopic lysis of adhesions (LOA). The authors have previously shown that inhibition of the binding of tachykinin ligands to the neurokinin 1 receptor (NK-1R) using the neurokinin 1 recept...

Current methods to prevent intraabdominal adhesions are not uniformly effective. We recently showed in rats that a neurokinin-1 receptor (NK-1R) antagonist is capable of reducing adhesion formation. To determine the clinical feasibility of using an NK-1R antagonist to reduce adhesions, this study examined the time dependence for the effectiveness o...

The aims of this study were to determine if statins reduce adhesion formation in vivo and to identify the mechanism of action in vitro. : Intraperitoneal adhesions develop in up to 95% of patients following laparotomy. Adhesions are reduced by mechanisms that up-regulate fibrinolysis within the peritoneum. Statins promote fibrinolysis in the cardio...

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) plays a key role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). Recently, a new transcription factor termed LITAF (lipopolysaccharide-induced TNF-alpha factor) was shown to mediate TNF-alpha expression in human macrophages by direct binding to specific se...

Nuclear factor kappa B (NF-κ B) plays a key role in initiating inflammation associated with colitis. A systematic study was conducted in the rat DSS colitis model to determine the temporal relationship between NF-κ B activation and expression of substance P (SP), neurokinin-1 receptor (NK-1R), proinflammatory cytokines, and adhesion molecules. Rats...

OBJECTIVES: The aims of this study were to determine if statins reduce adhesion formation in vivo and to identify the mechanism of action in vitro. BACKGROUND: Intraperitoneal adhesions develop in up to 95% of patients following laparotomy. Adhesions are reduced by mechanisms that up-regulate fibrinolysis within the peritoneum. Statins promote fibr...