Building a vertically integrated genomic learning health system: The biobank at the Colorado Center for Personalized Medicine.

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine.

HLA homozygosity is associated with Non-Hodgkin lymphoma.

The "heterozygote advantage" hypothesis has been postulated regarding the role of human leukocyte antigen (HLA) in non-Hodgkin lymphoma (NHL), where homozygous loci are associated with an increased risk of disease. In this retrospective study, we analyzed the HLA homozygosity of 3789 patients with aplastic anemia (AA), acute lymphocytic leukemia (ALL), acute myeloblastic leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL) at HLA-A, B, C, DRB1 and DQB1 loci compared to 169,964 normal controls. HLA homozygosity at one or more loci was only associated with an increased risk in NHL patients (OR = 1.

Low-Coverage Whole Genome Sequencing Using Laser Capture Microscopy with Combined Digital Droplet PCR: An Effective Tool to Study Copy Number and Kras Mutations in Early Lung Adenocarcinoma Development.

Defining detailed genomic characterization of early tumor progression is critical to identifying key regulators and pathways in carcinogenesis as potentially druggable targets. In human lung cancer, work to characterize early cancer development has mainly focused on squamous cancer, as the earliest lesions are more proximal in the airways and often accessible by repeated bronchoscopy. Adenocarcinomas are typically located distally in the lung, limiting accessibility for biopsy of pre-malignant and early stages.

Glucocorticoid Receptor ChIP-Seq Identifies PLCD1 as a KLF15 Target that Represses Airway Smooth Muscle Hypertrophy.

Glucocorticoids exert important therapeutic effects on airway smooth muscle (ASM), yet few direct targets of glucocorticoid signaling in ASM have been definitively identified. Here, we show that the transcription factor, Krüppel-like factor 15 (KLF15), is directly induced by glucocorticoids in primary human ASM, and that KLF15 represses ASM hypertrophy. We integrated transcriptome data from KLF15 overexpression with genome-wide analysis of RNA polymerase (RNAP) II and glucocorticoid receptor (GR) occupancy to identify phospholipase C delta 1 as both a KLF15-regulated gene and a novel repressor of ASM hypertrophy.

Cistrome-based Cooperation between Airway Epithelial Glucocorticoid Receptor and NF-κB Orchestrates Anti-inflammatory Effects.

Antagonism of pro-inflammatory transcription factors by monomeric glucocorticoid receptor (GR) has long been viewed as central to glucocorticoid (GC) efficacy. However, the mechanisms and targets through which GCs exert therapeutic effects in diseases such as asthma remain incompletely understood. We previously defined a surprising cooperative interaction between GR and NF-κB that enhanced expression of A20 (TNFAIP3), a potent inhibitor of NF-κB.

Response Element Composition Governs Correlations between Binding Site Affinity and Transcription in Glucocorticoid Receptor Feed-forward Loops.

Combinatorial gene regulation through feed-forward loops (FFLs) can bestow specificity and temporal control to client gene expression; however, characteristics of binding sites that mediate these effects are not established. We previously showed that the glucocorticoid receptor (GR) and KLF15 form coherent FFLs that cooperatively induce targets such as the amino acid-metabolizing enzymes AASS and PRODH and incoherent FFLs exemplified by repression of MT2A by KLF15. Here, we demonstrate that GR and KLF15 physically interact and identify low affinity GR binding sites within glucocorticoid response elements (GREs) for PRODH and AASS that contribute to combinatorial regulation with KLF15.

Context-dependent cooperation between nuclear factor κB (NF-κB) and the glucocorticoid receptor at a TNFAIP3 intronic enhancer: a mechanism to maintain negative feedback control of inflammation.

TNF expression is elevated in asthma and other inflammatory airway diseases that are commonly treated with glucocorticoid-based therapies, but the impact of glucocorticoids on negative feedback control of TNF is not well understood. We analyzed the effect of dexamethasone, a potent synthetic glucocorticoid, on TNF-regulated gene expression in cultured airway epithelial cells. Although dexamethasone-mediated activation of the glucocorticoid receptor (GR) potently repressed expression of IL1β, IL8, and several other pro-inflammatory TNF targets, the expression of anti-inflammatory TNF targets such as TNFAIP3 (A20) and NFKBIA was selectively spared or augmented by dexamethasone treatment.

Hands-on workshops as an effective means of learning advanced technologies including genomics, proteomics and bioinformatics.

Genomics and proteomics have emerged as key technologies in biomedical research, resulting in a surge of interest in training by investigators keen to incorporate these technologies into their research. At least two types of training can be envisioned in order to produce meaningful results, quality publications and successful grant applications: (1) immediate short-term training workshops and (2) long-term graduate education or visiting scientist programs. We aimed to fill the former need by providing a comprehensive hands-on training course in genomics, proteomics and informatics in a coherent, experimentally-based framework.

Pregnancy amelioration of arthritis in SKG mice corresponds with alterations in serum amyloid A3 levels.

OBJECTIVES: Pregnancy leads to rheumatoid arthritis remission in humans. The objective of this study was to determine if the SKG mouse could serve as a model for pregnancy-associated inflammatory arthritis amelioration. In addition, the maternal peripheral blood mononuclear cell (PBMC) transcriptome was assessed to define a biomarker associated with remission.

Clinical implications of growth hormone-secreting tumor subtypes.

Growth hormone (GH) pituitary tumors are almost always benign adenomas, yet are associated with significant morbidity and mortality. Surgical and medical responses of GH tumors are often incomplete, and therefore predictors of residual or recurrent disease are needed. Clinical features, including patient gender, age or size of adenoma, have proven to be unreliable predictors of recurrence.

Elevated DISC1 transcript levels in PBMCs during acute psychosis in patients with schizophrenia.

BACKGROUND: Severe mental disorders like schizophrenia are a leading cause of disability in people in the prime years of their lives (aged 15 to 44 years). Relapse is a primary contributor to schizophrenia disease burden and is frequently attributed to medication noncompliance and inadequate doses. Currently, a patient's neuroleptic dose is titrated to clinical response within recommended dose ranges.

Significant downregulation of platelet gene expression in metastatic lung cancer.

Platelets play a major role in the metastatic dissemination of tumor cells in vivo . Recent evidence reveals megakaryocyte-derived platelet pre-mRNA is spliced to mRNA and then translated into functional proteins in response to external stimulation. Employing a human lung cancer model, we hypothesized a subset of megakaryocyte/platelet genes exists that are significantly over or underexpressed in metastasis compared with noncancer.

A short survey of computational analysis methods in analysing ChIP-seq data.

Chromatin immunoprecipitation followed by massively parallel next-generation sequencing (ChIP-seq) is a valuable experimental strategy for assaying protein-DNA interaction over the whole genome. Many computational tools have been designed to find the peaks of the signals corresponding to protein binding sites. In this paper, three computational methods, ChIP-seq processing pipeline (spp), PeakSeq and CisGenome, used in ChIP-seq data analysis are reviewed.

Alveolar macrophage gene expression is altered in the setting of alcohol use disorders.

Background: Alcohol use disorders (AUDs) are associated with an increased susceptibility to a variety of common and devastating pulmonary diseases including community- and hospital-acquired pneumonias, as well as the acute respiratory distress syndrome (ARDS). Alveolar macrophages play an important role in preventing the development of these disorders through maintaining lung sterility and resolving lung inflammation. Although alcohol exposure has been associated with aberrant alveolar macrophage function in animal models, the clinical relevance of these observations in humans is not established.

A survey of statistical software for analysing RNA-seq data.

High-throughput RNA sequencing is rapidly emerging as a favourite method for gene expression studies. We review three software packages - edgeR, DEGseq and baySeq - from Bioconductor http://bioconductor.org for analysing RNA-sequencing data.

Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma.

Background: The etiology of hemangiosarcoma remains incompletely understood. Its common occurrence in dogs suggests predisposing factors favor its development in this species. These factors could represent a constellation of heritable characteristics that promote transformation events and/or facilitate the establishment of a microenvironment that is conducive for survival of malignant blood vessel-forming cells.

Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl.

Although Bcr-Abl kinase inhibitors have proven effective in the treatment of chronic myeloid leukemia (CML), they generally fail to eradicate Bcr-Abl(+) leukemia cells. To identify genes whose inhibition sensitizes Bcr-Abl(+) leukemias to killing by Bcr-Abl inhibitors, we performed an RNAi-based synthetic lethal screen with imatinib mesylate in CML cells. This screen identified numerous components of a Wnt/Ca(2+)/NFAT signaling pathway.

Gene expression in the brain during reovirus encephalitis.

Viral encephalitis remains a significant cause of morbidity and mortality throughout the world. We performed microarray analysis to identify genes and pathways that are differentially regulated during reovirus encephalitis and that may provide novel therapeutic targets for virus-induced diseases of the central nervous system (CNS). An increase in the expression of 130 cellular genes was found in the brains of reovirus-infected mice at early times post infection, compared to mock-infected controls.

Gene expression profiles of sporadic canine hemangiosarcoma are uniquely associated with breed.

The role an individual's genetic background plays on phenotype and biological behavior of sporadic tumors remains incompletely understood. We showed previously that lymphomas from Golden Retrievers harbor defined, recurrent chromosomal aberrations that occur less frequently in lymphomas from other dog breeds, suggesting spontaneous canine tumors provide suitable models to define how heritable traits influence cancer genotypes. Here, we report a complementary approach using gene expression profiling in a naturally occurring endothelial sarcoma of dogs (hemangiosarcoma).

Statistical identification of gene association by CID in application of constructing ER regulatory network.

Background: A variety of high-throughput techniques are now available for constructing comprehensive gene regulatory networks in systems biology. In this study, we report a new statistical approach for facilitating in silico inference of regulatory network structure. The new measure of association, coefficient of intrinsic dependence (CID), is model-free and can be applied to both continuous and categorical distributions.

Multiple pathways of mitochondrial-nuclear communication in yeast: intergenomic signaling involves ABF1 and affects a different set of genes than retrograde regulation.

Mitochondrial-nuclear communication is taking on increased importance in models of oxygen sensing, oxidative stress, aging, and disease. The deletion of the mitochondrial genome (mtDNA) and, hence, the ability to respire, affects expression of several nuclear genes through at least two different mitochondrial-nuclear communication pathways. One of the pathways, retrograde regulation, is activated by a reduction in respiration, while another, intergenomic signaling, is unaffected by respiration but requires mtDNA.

The PhenoGen informatics website: tools for analyses of complex traits.

Background: With the advent of "omics" (e.g. genomics, transcriptomics, proteomics and phenomics), studies can produce enormous amounts of data.

Identification of genes controlled by the pregnane X receptor by microarray analysis of mRNAs from pregnenolone 16alpha-carbonitrile-treated rats.

Mammalian liver contains a pregnane X receptor (PXR, NR1I2), which binds drugs and other xenobiotics, and stimulates (or suppresses) expression of numerous genes involved in the metabolic elimination of foreign compounds and some toxic endogenous substances. In the present study, we used microarray analysis to identify genes whose expression in rat liver was significantly altered by pregnenolone 16alpha-carbonitrile (PCN) treatment. PCN is a synthetic steroid that induces cytochrome P4503A expression and is hepatoprotective by increasing resistance to subsequent stressful insults.