The State of the Region: Hampton Roads 2001

This is Old Dominion University\u27s second annual State of the Region Report. While it represents the work of many individuals connected in various ways to the university, the Report does not constitute an official viewpoint of the University, or it\u27s president, Dr. Roseann Runte. This year\u27s Report was produced with the goal of making Hampton Roads an even better place to live. Those who know and love the region of Hampton Roads frequently boast of its numerous strengths and successes, but we do so with the understanding that it would be possible for us to improve the region\u27s performance in certain areas. However, in order to improve our situation, we must have accurate knowledge about where we are, and what the policy implications are of the various choices in front of us. This year\u27s Report should be quite helpful in supplying such information. At the end of the day, we hope to have stimulated thought and discussion about things that matter.https://digitalcommons.odu.edu/economics_books/1017/thumbnail.jp

Cancer associated fibroblasts predict for poor outcome and promote periostin-dependent invasion in oesophageal adenocarcinoma

Interactions between cancer cells and cancer-associated fibroblasts (CAF) play an important role in tumour development and progression. In this study we investigated the functional role of CAF in oesophageal adenocarcinoma (EAC). We used immunochemistry to analyse a cohort of EAC patients (183 patients) for CAF markers related to disease mortality. We characterized CAF and normal oesophageal fibroblasts (NOF) using western blotting, immunofluorescence and gel contraction. Transwell assays, 3-D organotypic culture and xenograft models were used to examine effects on EAC cell function, and dissect molecular mechanisms regulating invasion. Most EAC (93%) contained CAF with a myofibroblastic (?-SMA-positive) phenotype, which correlated significantly with poor survival (p?=?0.016; HR 7. 1 (1.7-29.4). Primary CAF, isolated from EAC, have a contractile, myofibroblastic phenotype, and promote EAC cell invasion in vitro (Transwell assays, p?=?<0.05; organotypic culture, p?<?0.001) and in vivo (p?=?<0.05). In vitro, this pro-invasive effect is modulated through the matricellular protein periostin. Periostin is secreted by CAF, and acts as a ligand for EAC cell integrins ?v?3 and ?v?5, promoting activation of the PI3kinase/Akt pathway. In patient samples, periostin expression at the tumour cell/stromal interface correlates with poor overall and disease-free survival. Our study highlights the importance of the tumour stroma in EAC progression. Paracrine interaction between CAF-secreted periostin and EAC-expressed integrins results in PI3 kinase/Akt activation and increased tumour cell invasion. Most EAC contain a myofibroblastic CAF-rich stroma; this may explain the aggressive, highly infiltrative nature of the disease, and suggests that stromal targeting may produce therapeutic benefit in EAC patient

The State of the Region: Hampton Roads 2004

This is Old Dominion University\u27s fifth annual State of the Region report. While it represents the work of many people connected in various ways to the university, the report does not constitute an official viewpoint of Old Dominion, or it\u27s president, Dr. Roseann Runte. The report maintains the goal of stimulating thought and discussion that ultimately will make Hampton Roads an even better place to live. We are proud of our region\u27s many successes, but realize that it is possible to improve our performance. In order to do so, we must have accurate information about where we are and a sound understanding of the policy options open to us.https://digitalcommons.odu.edu/economics_books/1014/thumbnail.jp

Human Genetics in Rheumatoid Arthritis Guides a High-Throughput Drug Screen of the CD40 Signaling Pathway

Although genetic and non-genetic studies in mouse and human implicate the CD40 pathway in rheumatoid arthritis (RA), there are no approved drugs that inhibit CD40 signaling for clinical care in RA or any other disease. Here, we sought to understand the biological consequences of a CD40 risk variant in RA discovered by a previous genome-wide association study (GWAS) and to perform a high-throughput drug screen for modulators of CD40 signaling based on human genetic findings. First, we fine-map the CD40 risk locus in 7,222 seropositive RA patients and 15,870 controls, together with deep sequencing of CD40 coding exons in 500 RA cases and 650 controls, to identify a single SNP that explains the entire signal of association (rs4810485, P = 1.4×10(−9)). Second, we demonstrate that subjects homozygous for the RA risk allele have ∼33% more CD40 on the surface of primary human CD19+ B lymphocytes than subjects homozygous for the non-risk allele (P = 10(−9)), a finding corroborated by expression quantitative trait loci (eQTL) analysis in peripheral blood mononuclear cells from 1,469 healthy control individuals. Third, we use retroviral shRNA infection to perturb the amount of CD40 on the surface of a human B lymphocyte cell line (BL2) and observe a direct correlation between amount of CD40 protein and phosphorylation of RelA (p65), a subunit of the NF-κB transcription factor. Finally, we develop a high-throughput NF-κB luciferase reporter assay in BL2 cells activated with trimerized CD40 ligand (tCD40L) and conduct an HTS of 1,982 chemical compounds and FDA–approved drugs. After a series of counter-screens and testing in primary human CD19+ B cells, we identify 2 novel chemical inhibitors not previously implicated in inflammation or CD40-mediated NF-κB signaling. Our study demonstrates proof-of-concept that human genetics can be used to guide the development of phenotype-based, high-throughput small-molecule screens to identify potential novel therapies in complex traits such as RA

Using age compositions derived from spatio-temporal models and acoustic data collected by uncrewed surface vessels to estimate Pacific hake (Merluccius productus) biomass-at-age

Generating biomass-at-age indices for fisheries stock assessments with acoustic data collected by uncrewed surface vessels (USVs) has been hampered by the need to resolve acoustic backscatter with contemporaneous biological (e.g., age) composition data. To address this limitation, Pacific hake (Merluccius productus; “hake”) acoustic data were gathered from a USV survey (in 2019) and acoustic-trawl survey (ATS; 2019 and eight previous years), and biological data were gathered from fishery-dependent and non-target (i.e., not specifically targeting hake) fishery-independent sources (2019 and eight previous years). To overcome the lack of contemporaneous biological sampling in the USV survey, age class compositions were estimated from a generalized linear mixed spatio-temporal model (STM) fit to the fishery-dependent and non-target fishery-independent data. The validity of the STM age composition estimation procedure was assessed by comparing estimates to age compositions from the ATS in each year. Hake biomass-at-age was estimated from all combinations of acoustics (USV or ATS in 2019, ATS only in other years) and age composition information (STM or ATS in all years). Across the survey area, proportional age class compositions derived from the best STM differed from ATS observations by 0.09 on average in 2019 (median relative error (MRE): 19.45%) and 0.14 across all years (MRE: 79.03%). In data-rich areas (i.e., areas with regular fishery operations), proportional age class compositions from the STM differed from ATS observations by 0.03 on average in 2019 (MRE: 11.46%) and 0.09 across years (MRE: 54.96%). On average, total biomass estimates derived using STM age compositions differed from ATS age composition-based estimates by approximately 7% across the study period (~ 3% in 2019) given the same source of acoustic data. When biomass estimates from different sources of acoustic data (USV or ATS) were compared given the same source of age composition data, differences were nearly ten-fold greater (22% or 27%, depending on if ATS or STM age compositions were used). STMs fit to non-contemporaneous data may provide suitable information for assigning population structure to acoustic backscatter in data-rich areas, but advancements in acoustic data processing (e.g., automated echo classification) may be needed to generate viable USV-based estimates of biomass-at-age

Evolving BioAssay Ontology (BAO): modularization, integration and applications

The lack of established standards to describe and annotate biological assays and screening outcomes in the domain of drug and chemical probe discovery is a severe limitation to utilize public and proprietary drug screening data to their maximum potential. We have created the BioAssay Ontology (BAO) project ( http://bioassayontology.org ) to develop common reference metadata terms and definitions required for describing relevant information of low-and high-throughput drug and probe screening assays and results. The main objectives of BAO are to enable effective integration, aggregation, retrieval, and analyses of drug screening data. Since we first released BAO on the BioPortal in 2010 we have considerably expanded and enhanced BAO and we have applied the ontology in several internal and external collaborative projects, for example the BioAssay Research Database (BARD). We describe the evolution of BAO with a design that enables modeling complex assays including profile and panel assays such as those in the Library of Integrated Network-based Cellular Signatures (LINCS). One of the critical questions in evolving BAO is the following: how can we provide a way to efficiently reuse and share among various research projects specific parts of our ontologies without violating the integrity of the ontology and without creating redundancies. This paper provides a comprehensive answer to this question with a description of a methodology for ontology modularization using a layered architecture. Our modularization approach defines several distinct BAO components and separates internal from external modules and domain-level from structural components. This approach facilitates the generation/extraction of derived ontologies (or perspectives) that can suit particular use cases or software applications. We describe the evolution of BAO related to its formal structures, engineering approaches, and content to enable modeling of complex assays and integration with other ontologies and datasets