Metabolism and response to stress gene signatures reveal ulcerative colitis heterogeneity and identify patients with increased response to therapy.

Background And Aims: Ulcerative colitis (UC) therapies lead to variable remission and response rates in patients participating in clinical trials, likely due to interindividual target variability, differences in active biological pathways, feedback, and/or resistance mechanisms. Here, we stratified patients into subtypes by characterizing heterogeneity using mucosal biopsy transcriptomics data.

Methods: Transcriptomics data from an andecaliximab phase 2/3 study in patients with UC were scored for gene signature enrichment.

Expert recommendations to standardize transcriptomic analysis in inflammatory bowel disease clinical trials.

Background And Aims: Substantial methodological and reporting heterogeneity confounds the interpretation and generalizability of transcriptomic data for inflammatory bowel disease (IBD) studies. We aimed to develop recommendations to standardize transcriptomic research in clinical trials.

Methods: A 2-part study was undertaken.

Identification of immune cell markers associated with ulcerative colitis histological disease activity in colonic biopsies.

Aims: Accurate determination of histological activity in ulcerative colitis (UC) is essential given its diagnostic and prognostic importance. Data on the relationship between histology and immune cell markers are limited. We aimed to evaluate the association between histological disease activity and immune cell marker concentration in colonic biopsies from patients with UC.

Effect of storage time on peripheral blood mononuclear cell isolation from blood collected in vacutainer CPT™ tubes.

Background: Clinical trials of novel therapies for the treatment of ulcerative colitis (UC) may benefit from immune cell profiling, however implementation of this methodology is limited in the multicenter trial setting by necessity of timely (within 6 to 8 h) isolation and processing of peripheral blood mononuclear cells (PBMC) from whole blood samples. Becton Dickinson Vacutainer CPT™ Cell Preparation Tubes (CPT™) limit required processing prior to shipping to a central lab to an initial centrifugation step within 24 h of sample collection. As shipping may delay final processing beyond 24 h, we analyzed cell viability and T cell composition in whole blood stored in CPT™ to determine if their use may accommodate processing delays typical for multicenter clinical trials.

Meta-analysis of gene expression disease signatures in colonic biopsy tissue from patients with ulcerative colitis.

Publicly available ulcerative colitis (UC) gene expression datasets from observational studies and clinical trials include inherently heterogeneous disease characteristics and methodology. We used meta-analysis to identify a robust UC gene signature from inflamed biopsies. Eight gene expression datasets derived from biopsy tissue samples from noninflammatory bowel disease (IBD) controls and areas of active inflammation from patients with UC were publicly available.

Pharmacological Interventions for the Prevention and Treatment of Immune Checkpoint Inhibitor-Associated Enterocolitis: A Systematic Review.

Background: Patients treated with immune checkpoint inhibitors (ICIs) may develop ICI-associated enterocolitis, for which there is no approved treatment.

Aims: We aimed to systematically review the efficacy and safety of medical interventions for the prevention and treatment of ICI-associated enterocolitis.

Methods: MEDLINE, EMBASE, and the Cochrane Library were searched to identify randomized controlled trials (RCTs), cohort and case-control studies, and case series/reports, evaluating interventions (including corticosteroids, biologics, aminosalicylates, immunosuppressants, and fecal transplantation) for ICI-associated enterocolitis.

Biomarkers of Crohn's Disease to Support the Development of New Therapeutic Interventions.

Background: Currently, 2 coprimary end points are used by health authorities to determine the effectiveness of therapeutic interventions in patients with Crohn's disease (CD): symptomatic remission (patient-reported outcome assessment) and endoscopic remission (ileocolonoscopy). However, there is lack of accepted biomarkers to facilitate regulatory decision-making in the development of novel therapeutics for the treatment of CD.

Methods: With support from the Helmsley Charitable Trust, Critical Path Institute formed the Crohn's Disease Biomarkers preconsortium (CDBpC) with members from the pharmaceutical industry, academia, and nonprofit organizations to evaluate the CD biomarker landscape.

Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority.

CO2 exposure at pressure impacts metabolism and stress responses in the model sulfate-reducing bacterium Desulfovibrio vulgaris strain Hildenborough.

Geologic carbon dioxide (CO2) sequestration drives physical and geochemical changes in deep subsurface environments that impact indigenous microbial activities. The combined effects of pressurized CO2 on a model sulfate-reducing microorganism, Desulfovibrio vulgaris, have been assessed using a suite of genomic and kinetic measurements. Novel high-pressure NMR time-series measurements using (13)C-lactate were used to track D.

Inference of interactions in cyanobacterial-heterotrophic co-cultures via transcriptome sequencing.

We used deep sequencing technology to identify transcriptional adaptation of the euryhaline unicellular cyanobacterium Synechococcus sp. PCC 7002 and the marine facultative aerobe Shewanella putrefaciens W3-18-1 to growth in a co-culture and infer the effect of carbon flux distributions on photoautotroph-heterotroph interactions. The overall transcriptome response of both organisms to co-cultivation was shaped by their respective physiologies and growth constraints.

DNA methylation as a biomarker for preeclampsia.

Background: Preeclampsia contributes significantly to pregnancy-associated morbidity and mortality as well as future risk of cardiovascular disease in mother and offspring, and preeclampsia in offspring. The lack of reliable methods for early detection limits the opportunities for prevention, diagnosis, and timely treatment.

Purpose: The purpose of this study was to explore distinct DNA methylation patterns associated with preeclampsia in both maternal cells and fetal-derived tissue that represent potential biomarkers to predict future preeclampsia and inheritance in children.

Changes in translational efficiency is a dominant regulatory mechanism in the environmental response of bacteria.

To understand how cell physiological state affects mRNA translation, we used Shewanella oneidensis MR-1 grown under steady state conditions at either 20% or 8.5% O2. Using a combination of quantitative proteomics and RNA-Seq, we generated high-confidence data on >1000 mRNA and protein pairs.

Coregulation of Terpenoid Pathway Genes and Prediction of Isoprene Production in Bacillus subtilis Using Transcriptomics.

The isoprenoid pathway converts pyruvate to isoprene and related isoprenoid compounds in plants and some bacteria. Currently, this pathway is of great interest because of the critical role that isoprenoids play in basic cellular processes, as well as the industrial value of metabolites such as isoprene. Although the regulation of several pathway genes has been described, there is a paucity of information regarding system level regulation and control of the pathway.

Improving RNA-Seq Precision with MapAl.

With currently available RNA-Seq pipelines, expression estimates for most genes are very noisy. We here introduce MapAl, a tool for RNA-Seq expression profiling that builds on the established programs Bowtie and Cufflinks. In the post-processing of RNA-Seq reads, it incorporates gene models already at the stage of read alignment, increasing the number of reliably measured known transcripts consistently by 50%.

Characterization and improvement of RNA-Seq precision in quantitative transcript expression profiling.

Motivation: Measurement precision determines the power of any analysis to reliably identify significant signals, such as in screens for differential expression, independent of whether the experimental design incorporates replicates or not. With the compilation of large-scale RNA-Seq datasets with technical replicate samples, however, we can now, for the first time, perform a systematic analysis of the precision of expression level estimates from massively parallel sequencing technology. This then allows considerations for its improvement by computational or experimental means.

Therapeutically targeting ErbB3: a key node in ligand-induced activation of the ErbB receptor-PI3K axis.

The signaling network downstream of the ErbB family of receptors has been extensively targeted by cancer therapeutics; however, understanding the relative importance of the different components of the ErbB network is nontrivial. To explore the optimal way to therapeutically inhibit combinatorial, ligand-induced activation of the ErbB-phosphatidylinositol 3-kinase (PI3K) axis, we built a computational model of the ErbB signaling network that describes the most effective ErbB ligands, as well as known and previously unidentified ErbB inhibitors. Sensitivity analysis identified ErbB3 as the key node in response to ligands that can bind either ErbB3 or EGFR (epidermal growth factor receptor).

ErbB receptors: new insights on mechanisms and biology.

The ErbB family of four receptor tyrosine kinases occupies a central role in a wide variety of biological processes from neuronal development to breast cancer. New information continues to expand their biologic significance and to unravel the molecular mechanisms that underlie the signaling capacity of these receptors. Here, we review several aspects of ErbB receptor physiology for which new and significant information is available.

ErbB-4 s80 intracellular domain abrogates ETO2-dependent transcriptional repression.

ErbB-4 is cleaved by alpha- and gamma-secretases to release a soluble 80-kDa intracellular domain, termed s80, which translocates to the nucleus. s80 is present in the nucleus of normal and cancerous mammary cells and is predicted to have a role in cell differentiation. To further investigate the mechanism by which s80 may mediate differentiation, we tested whether s80 regulates Eto2, a transcriptional corepressor that is involved in erythrocyte differentiation and is also implicated in human breast cancer.

Translating the histone code into leukemia.

The "histone code" is comprised of the covalent modifications of histone tails that function to regulate gene transcription. The post-translational modifications that occur in histones within the regulatory regions of genes include acetylation, methylation, phosphorylation, ubiquitination, sumoylation, and ADP-ribosylation. These modifications serve to alter chromatin structure and accessibility, and to act as docking sites for transcription factors or other histone modifying enzymes.

Specific protein redirection as a transcriptional therapy approach for t(8;21) leukemia.

Important progress has been achieved in the knowledge about the pathogenesis of cancer. However, despite these advances, the therapeutic strategies are still limited. Leukemias are often characterized by specific balanced translocations, with the t(8;21) balanced translocation being the most frequent chromosomal aberration in acute myeloid leukemia (AML).

The t(8;21) fusion protein contacts co-repressors and histone deacetylases to repress the transcription of the p14ARF tumor suppressor.

The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. The translocation fuses the DNA binding domain of AML1 to nearly all of the ETO co-repressor. ETO associates with the mSin3 and N-CoR co-repressors as well as histone deacetylases 1, 2, and 3.

The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia.

The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. This translocation creates a fusion protein consisting of the acute myeloid leukemia-1 transcription factor and the eight-twenty-one corepressor (AML1 ETO), which represses transcription through AML1 (RUNX1) DNA binding sites and immortalizes hematopoietic progenitor cells. We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO.