Volume 07

Introduction from Interim Dean Dr. Jennifer Apperson Spatial Analysis of Potential Risk Factors Associated with Addition of Atlantic Coast Pipeline Through Virginia by Rachel C. Lombardi Delicate Matters with No Speaking, Hope and Nothing, Mono Duality by Ben Osterhout Connect Graphic Design Senior Project by Lindsay Graybill Phenolic Acids in Brassicaceae Plants: Ovipositional Stimulants or Deterrents for Cabbage White Butterfly, Pieris Rapae? by Rebecca E. Dey And Skyler T. Carpenter Abecedarian Cards by Emma Beckett, Jason Ware, And Mollie Andrews Helvetica: A Type Specimen Book by James Bates, Landon Cooper, Tiffani Jeffries, And Maria Wheaton “Things Left Behind” by Dallas Price Heretic Adornment by Laura Kahler Photography by Sarah Charlton Revisiting Longfellow: Expressing Universality through Accessibility by Anna Bultrowicz Magazine Spreads from “What Dreams May Come: Marriage Across Cultures” by Emily Spittle Magazine Spreads From “Live on The Street: A Naked Look at Human Sex Trafficking” by Erin Godwin Lasting Light by Eamon Brokenbroug

Coronary 18F-Fluoride Uptake and Progression of Coronary Artery Calcification

Background Positron emission tomography (PET) using 18F-sodium fluoride (18F-fluoride) to detect microcalcification may provide insight into disease activity in coronary atherosclerosis. This study aimed to investigate the relationship between 18F-fluoride uptake and progression of coronary calcification in patients with clinically stable coronary artery disease. Methods Patients with established multivessel coronary atherosclerosis underwent 18F-fluoride PET-computed tomography angiography and computed tomography calcium scoring, with repeat computed tomography angiography and calcium scoring at one year. Coronary PET uptake was analyzed qualitatively and semiquantitatively in diseased vessels by measuring maximum tissue-to-background ratio. Coronary calcification was quantified by measuring calcium score, mass, and volume. Results In a total of 183 participants (median age 66 years, 80% male), 116 (63%) patients had increased 18F-fluoride uptake in at least one vessel. Individuals with increased 18F-fluoride uptake demonstrated more rapid progression of calcification compared with those without uptake (change in calcium score, 97 [39-166] versus 35 [7-93] AU; P<0.0001). Indeed, the calcium score only increased in coronary segments with 18F-fluoride uptake (from 95 [30-209] to 148 [61-289] AU; P<0.001) and remained unchanged in segments without 18F-fluoride uptake (from 46 [16-113] to 49 [20-115] AU; P=0.329). Baseline coronary 18F-fluoride maximum tissue-to-background ratio correlated with 1-year change in calcium score, calcium volume, and calcium mass (Spearman ρ=0.37, 0.38, and 0.46, respectively; P<0.0001 for all). At the segmental level, baseline 18F-fluoride activity was an independent predictor of calcium score at 12 months (P<0.001). However, at the patient level, this was not independent of age, sex, and baseline calcium score (P=0.50). Conclusions Coronary 18F-fluoride uptake identifies both patients and individual coronary segments with more rapid progression of coronary calcification, providing important insights into disease activity within the coronary circulation. At the individual patient level, total calcium score remains an important marker of disease burden and progression. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02110303

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

A Large Sample of Extremely Metal-poor Galaxies at z<1z<1 Identified from the DESI Early Data

Extremely metal-poor galaxies (XMPGs) at relatively low redshift are excellent laboratories for studying galaxy formation and evolution in the early universe. Much effort has been spent on identifying them from large-scale spectroscopic surveys or spectroscopic follow-up observations. Previous work has identified a few hundred XMPGs. In this work, we obtain a large sample of 223 XMPGs at $z<1$ from the early data of the Dark Energy Spectroscopic Instrument (DESI). The oxygen abundance is determined using the direct $T_{\rm e}$ method based on the detection of the [O III]$\lambda$4363 line. The sample includes 95 confirmed XMPGs based on the oxygen abundance uncertainty; remaining 128 galaxies are regarded as XMPG candidates. These XMPGs are only 0.01% of the total DESI observed galaxies. Their coordinates and other proprieties are provided in the paper. The most XMPG has an oxygen abundance of $\sim 1/34 Z_{\odot}$, stellar mass of about $1.5\times10^7 M_{\odot}$ and star formation rate of 0.22 $M_{\odot}$ yr$^{-1}$. The two most XMPGs present distinct morphologies suggesting different formation mechanisms. The local environmental investigation shows that XMPGs preferentially reside in relatively low-density regions. Many of them fall below the stellar mass-metallicity relations (MZRs) of normal star-forming galaxies. From a comparison of the MZR with theoretical simulations, it appears that XMPGs are good analogs to high-redshift star-forming galaxies. The nature of these XMPG populations will be further investigated in detail with larger and more complete samples from the on-going DESI survey.Comment: accepted for publication in Ap

A Large Sample of Extremely Metal-poor Galaxies at z < 1 Identified from the DESI Early Data

Extremely metal-poor galaxies (XMPGs) at relatively low redshift are excellent laboratories for studying galaxy formation and evolution in the early universe. Much effort has been spent on identifying them from large-scale spectroscopic surveys or spectroscopic follow-up observations. Previous work has identified a few hundred XMPGs. In this work, we obtain a large sample of 223 XMPGs at z &lt; 1 from the early data of the Dark Energy Spectroscopic Instrument (DESI). The oxygen abundance is determined using the direct T e method based on the detection of the [O iii]λ4363 line. The sample includes 95 confirmed XMPGs based on the oxygen abundance uncertainty; the remaining 128 galaxies are regarded as XMPG candidates. These XMPGs are only 0.01% of the total DESI observed galaxies. Their coordinates and other properties are provided in the paper. The most XMPGs have an oxygen abundance of ∼1/34 Z ⊙, a stellar mass of about 1.5 × 107 M ⊙, and a star formation rate of 0.22 M ⊙ yr−1. The two most XMPGs present distinct morphologies suggesting different formation mechanisms. The local environmental investigation shows that XMPGs preferentially reside in relatively low-density regions. Many of them fall below the stellar mass–metallicity relations (MZRs) of normal star-forming galaxies. From a comparison of the MZR with theoretical simulations, it appears that XMPGs are good analogs to high-redshift star-forming galaxies. The nature of these XMPG populations will be further investigated in detail with larger and more complete samples from the ongoing DESI survey

Phosphatidylinositol 3-kinase (PI3K) pathway activation in bladder cancer

The phosphatidylinositol 3-kinase (PI3K) pathway is a critical signal transduction pathway that regulates multiple cellular functions. Aberrant activation of this pathway has been identified in a wide range of cancers. Several pathway components including AKT, PI3K and mTOR represent potential therapeutic targets and many small molecule inhibitors are in development or early clinical trials. The complex regulation of the pathway, together with the multiple mechanisms by which it can be activated, make this a highly challenging pathway to target. For successful inhibition, detailed molecular information on individual tumours will be required and it is already clear that different tumour types show distinct combinations of alterations. Recent results have identified alterations in pathway components PIK3CA, PTEN, AKT1 and TSC1 in bladder cancer, some of which are significantly related to tumour phenotype and clinical behaviour. Co-existence of alterations to several PI3K pathway genes in some bladder tumours indicates that these proteins may have functions that are not related solely to the known canonical pathway

Long-distance migratory shorebirds travel faster towards their breeding grounds, but fly faster post-breeding

Long-distance migrants are assumed to be more time-limited during the pre-breeding season compared to the post-breeding season. Although breeding-related time constraints may be absent post-breeding, additional factors such as predation risk could lead to time constraints that were previously underestimated. By using an automated radio telemetry system, we compared pre- and post-breeding movements of long-distance migrant shorebirds on a continent-wide scale. From 2014 to 2016, we deployed radio transmitters on 1,937 individuals of 4 shorebird species at 13 sites distributed across North America. Following theoretical predictions, all species migrated faster during the pre-breeding season, compared to the post-breeding season. These differences in migration speed between seasons were attributable primarily to longer stopover durations in the post-breeding season. In contrast, and counter to our expectations, all species had higher airspeeds during the post-breeding season, even after accounting for seasonal differences in wind. Arriving at the breeding grounds in good body condition is beneficial for survival and reproductive success and this energetic constraint might explain why airspeeds are not maximised in the pre-breeding season. We show that the higher airspeeds in the post-breeding season precede a wave of avian predators, which could suggest that migrant shorebirds show predation-minimizing behaviour during the post-breeding season. Our results reaffirm the important role of time constraints during northward migration and suggest that both energy and predation-risk constrain migratory behaviour during the post-breeding season

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Study of Z boson production in pPb collisions at √sNN=5.02 TeV

The production of Z bosons in pPb collisions at root S-NN = 5.02 TeV is studied by the CMS experiment via the electron and muon decay channels. The inclusive cross section is compared to pp collision predictions, and found to scale with the number of elementary nucleon-nucleon collisions. The differential cross sections as a function of the Z boson rapidity and transverse momentum are measured. Though they are found to be consistent within uncertainty with theoretical predictions both with and without nuclear effects, the forward-backward asymmetry suggests the presence of nuclear effects at large rapidities. These results provide new data for constraining nuclear parton distribution functions

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes