tbuckley/cabot-search huggingface dataset:
BETs Need Greens: Folate Deficiency and Resistance to MYC-Targeted Therapies
Authors: Ludovica Marando, Brian J.P. Huntly
Journal: Cancer Discovery (2020)

Recently, small-molecule inhibitors of general transcriptional regulators such as BET proteins and the RNA-PolII-regulating kinase CDK7 have been shown to have efficacy in multiple solid and liquid tumors. An article in this issue of Cancer Discovery identifies a nongenetic mechanism of resistance related to deficiency of folate that leads, via increased S-adenosylhomocysteine and reduced repressive histone methylation, to reactivation of a transcriptional program which promotes AML cell survival under the pressure of BET inhibition.See related article by Su et al., p. 1894.
THU0220 An estimation of the prevalence of hypermobility
Authors: M Gumà, J Roca, S Holgado, M Valls-Roc, E Casado, J Forcada, JC Duro, A Olive, X Tena
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Hypermobility is associated with several rheumatic manifestations. The association with SLE is controversial. <h3>Objectives</h3> To determine the prevalence of hypermobility in two different populations: a general practitioner (GP) office and out-patients clinic of a referral rheumatology hospital. <h3>Methods</h3> 280 patients (193 females, 87 males); mean age 44.7 ± 11.2 were consecutively reviewed in a GP office. 370 patients (233 females, 84 males); mean age 50.5 ± 16.8 were consecutively visited at the out-patients rheumatology clinic. Hypermobility was evaluated following the criteria of Carter-Beighton (hypermobility &gt; 4 points). <h3>Results</h3> Hypermobility was present in 42/280 (15%) at the GP office and in 81/317 (25%) in the out patients rheumatology clinic. <h3>Conclusion</h3> The prevalence of hypermobility at the GP office and a rheumatology clinic is high. Furthermore it is close to the prevalence of hypermobility in the general population.
Mean and visit-to-visit variability of glycemia and left ventricular diastolic dysfunction: A longitudinal analysis of 3025 adults with serial echocardiography
Authors: Jiyeon Ahn, Janghyun Koh, Darae Kim, Gyuri Kim, Kyu Yeon Hur, Sang Won Seo, Kyunga Kim, Jae Hyeon Kim, Jeong Hoon Yang, Sang-Man Jin
Journal: Metabolism (2020)
Abstract 10893: Mechanism of Chronic Urotensin II Receptor Blockade Causes Regression in Murine Heart Failure: Beneficial Effects on Neurohormonal Activation, Cardiomyocyte Contractile Function, [Ca2+]i Regulation and Beta-Adrenergic Modulation
Authors: Yixi Liu, Che Ping Cheng, Peng Zhou, Zhe Chen, Satoshi Masutani, Nobuyuki Ohte, Michael F Callanhan, David Zhao, Heng-Jie Cheng
Journal: Circulation (2018)

Background: Heart failure (HF) is associated with increased levels of urotensin-II (UII) and upregulation of UII-mediated cardiac inhibitory pathway. This suggests that cardiac UII activation contr...
Abstract PO-003: Adaptation of colorectal cancer cells to the brain microenvironment: The role of IRS2
Authors: Inbal Greenberg, Anat Klein, Rachel Grossman, Ethan Sokol, Eilam Yeini, Paula Ofek, Ronit Satchi-Fainaro, Hadas Reuveni, Tami Rubinek, Ido Wolf
Journal: Cancer Research (2020)

Abstract Brain metastases (BMs) from colorectal cancer (CRC) are currently the fourths leading cause of BMs, and their incidence is on the rise. Yet, mechanisms mediating the formation of BMs from CRC are unknown. We aimed to explore genomic drivers enabling tropism and adaptation of CRC cells to the brain environment and decipher mechanisms facilitating the process. We analyzed FoundationOne database, which contains genomic alterations data of cancer-related genes in over 16,000 human CRC primary and metastasis samples. Increased prevalence was noted in the insulin receptor substrate 2 (IRS2) gene, which was significantly amplified in BMs relative to primary tumors and other metastatic sites. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is known to be involved in more aggressive behavior of different cancer types. In agreement with the genomic data, immunohistochemistry of human clinical samples showed increased expression of IRS2 protein in BMs. Next, we created an in-vitro system mimicking the brain microenvironment using human astrocytes or their conditioned media (CM). Under these conditions, IRS2-overexpressed CRC cells survived better and formed larger 3D spheres. IRS2-silenced CRC cells showed a mirror image. Furthermore, IRS2-overexpressed CRC cells generated larger brain lesions in an intracranial CRC BMs mice model. Interestingly, a transcriptomic analysis revealed significant enrichment of the AKT and β-catenin pathways by IRS2. Indeed, IRS2-amplified cells showed enhanced AKT phosphorylation and inhibition of PI3K or AKT using Alpelisib or Akt1/2 kinase inhibitor, respectively, effectively decreased their proliferation in CM. Importantly, IRS2-amplified cells had increased expression and transcriptional activity of the β-catenin, and AKT pathway inhibitors or IRS2 inhibitor (NT-219) had a more pronounced effect on the activity of β-catenin on those cells. These data indicate, for the first time, the unique genomic profile of CRC BMs and imply the IRS2 role in promoting CRC BMs. These effects may be mediated, at least in part, by modulation of the AKT and β-catenin pathway. These findings may pave the way for the development of novel therapeutic strategies to prevent BMs formation. Citation Format: Inbal Greenberg, Anat Klein, Rachel Grossman, Ethan Sokol, Eilam Yeini, Paula Ofek, Ronit Satchi-Fainaro, Hadas Reuveni, Tami Rubinek, Ido Wolf. Adaptation of colorectal cancer cells to the brain microenvironment: The role of IRS2 [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-003.
309P Improved diagnostic accuracy in MRI breast lesions using a classification system and multilayer perceptron neural network
Authors: V.P.B. Koyyala, A. Jajodia, G. Sindhwani, A. Chaturvedi, A. Mehta, S. Pasricha, R. Kapur, A. Dewan, D.C. Doval, S. Joga, B. Amrith
Journal: Annals of Oncology (2020)
Frequent Assembly of Chimeric Complexes in the Protein Interaction Network of an Interspecies Yeast Hybrid
Authors: Rohan Dandage, Caroline M Berger, Isabelle Gagnon-Arsenault, Kyung-Mee Moon, Richard Greg Stacey, Leonard J Foster, Christian R Landry
Journal: Molecular Biology and Evolution (2020)

Abstract Hybrids between species often show extreme phenotypes, including some that take place at the molecular level. In this study, we investigated the phenotypes of an interspecies diploid hybrid in terms of protein–protein interactions inferred from protein correlation profiling. We used two yeast species, Saccharomyces cerevisiae and Saccharomyces uvarum, which are interfertile, but yet have proteins diverged enough to be differentiated using mass spectrometry. Most of the protein–protein interactions are similar between hybrid and parents, and are consistent with the assembly of chimeric complexes, which we validated using an orthogonal approach for the prefoldin complex. We also identified instances of altered protein–protein interactions in the hybrid, for instance, in complexes related to proteostasis and in mitochondrial protein complexes. Overall, this study uncovers the likely frequent occurrence of chimeric protein complexes with few exceptions, which may result from incompatibilities or imbalances between the parental proteomes.
AB0222 HEALTH STATE UTILITY VALUES IN RHEUMATOID ARTHRITIS BY SEX, AGE AND DISEASE ACTIVITY: REFERENCE DATA FROM A COLOMBIAN COHORT OF 1,545 PATIENTS
Authors: D. Rojas-Gualdrón, J. C. Diaz-Coronado, D. Hernandez-Parra, Y. Durango-Durango, R. Pined, a Tamayo
Journal: Annals of the Rheumatic Diseases (2020)

Background: As the basis for quality-adjusted life years (QALYs) calculation, health state utilities are essential for health technology assessment and economic evaluation. Objectives: To provide a reference value set of health state utility for patients with rheumatoid arthritis. Methods: A cross-sectional study was conducted in 1,545 patients diagnosed with rheumatoid arthritis. Disease activity was evaluated with the DAS-28 score. Health state utility (HSU) was estimated with the EUROQOL-5D-3L, using as reference the Spanish-speaking Hispanic predicted preference weights for 243 EQ-5D health states. Mean HSU differences were analyzed with the generalized linear model. A p-value &lt;0.05 was considered statistically significant. Results: Patients mean age was 58.2 years (SD = 12.5), 82.4% were female. Disease activity was high in 137 (8.9%), moderate in 305 (19.7%) and low in 231 (56.4%) patients; 872 (56.4%) patients were in remission. HSU differed significantly by sex age and disease activity. Figures 1a (women) and 1b (men) shows the HSU by age and disease activity. Figure 1. Health State utilities by sex, age and disease activity Conclusion: The way patients value different health states according to their sex, age and disease activity must be considered in health technology assessment and economic evaluations of interventions for rheumatoid arthritis patients. We provide a reference set for Latin-American patients. References: [1]Zarate V, Kind P, Chuang L-H. Hispanic Valuation of the EQ-5D Health States: A Social Value Set for Latin Americans. Value in Health. 2008;11(7):1170-7. Disclosure of Interests: None declared
Disproportionate Incidence of COVID-19 Infection, Hospitalizations, and Deaths Among Persons Identifying as Hispanic or Latino — Denver, Colorado March–October 2020
Authors: Laura Jean Podewils, Tori L. Burket, Christie Mettenbrink, Abigail Steiner, Allison Seidel, Kenneth Scott, Lilia Cervantes, Romana Hasnain-Wynia
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Persons identifying as Hispanic or Latino (Hispanic) represent the second largest racial/ethnic group in the United States (1), yet understanding of the impact of coronavirus disease 2019 (COVID-19) in this population is limited. To evaluate COVID-19 health disparities in the community and inform public health, health system, and community-based interventions, local public health authorities analyzed the sociodemographic characteristics of persons who were diagnosed, hospitalized, and who died with COVID-19 in Denver, Colorado. During the first 7 months of the COVID-19 epidemic in Denver (March 6-October 6, 2020) the majority of adult COVID-19 cases (54.8%), hospitalizations (62.1%), and deaths (51.2%) were among persons identifying as Hispanic, more than double the proportion of Hispanic adults in the Denver community (24.9%) (1). Systemic drivers that influence how Hispanic persons live and work increase their exposure risks: compared with non-Hispanic persons, Hispanic persons with COVID-19 in Denver reported larger household sizes and were more likely to report known exposures to household and close contacts with COVID-19, working in an essential industry, and working while ill. Reducing the disproportionate incidence of COVID-19 morbidity and mortality among Hispanic persons will require implementation of strategies that address upstream social and environmental factors that contribute to an increased risk for both infection and transmission and that facilitate improved access to culturally congruent care.
Abstract 13373: Exercise Improves Angiogenic Function of Circulating Exosomes in Type 2 Diabetes: Role of Extracellular SOD
Authors: Kareem Abdelsaid, Sudhahar Varadarajan, Archita Das, Yutao Liu, Xuexiu Fang, Malgorzata McMenamin, Yaoliang Tang, Tohru Fukai, Masuko Ushio-fukai
Journal: Circulation (2020)

Background: Exosomes, key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) have detrimental effects. Exercise not only improves endothelial dysfunction and angiogenesis in T2DM but also induces secretion of exosomes into circulation. Extracellular superoxide dismutase (ecSOD) is a major secretory Cu containing antioxidant enzyme that catalyzes dismutation of O 2 •- to H 2 O 2 and its full activity requires Cu transporter ATP7A. We reported that ecSOD-derived H 2 O 2 in endothelial cells (ECs) enhances angiogenesis while impaired ATP7A-ecSOD axis in diabetes induces endothelial dysfunction. Here we examined whether exercise-derived exosomes (Exe-Exo) may have pro-angiogenic effects via regulating ATP7A-ecSOD axis in T2DM. Results: Two weeks of voluntary wheel exercise of control C57Bl6 mice increased plasma exosome levels (6.2-fold) characterized by Nanosight, TEM and exosome markers (CD63, CD81, Tsg101). Treatment of HUVECs with equal number of exosomes revealed that angiogenic responses such as EC migration (1.8-fold) and tube formation (1.7-fold) were significantly enhanced by Exe-Exo compared to sedentary-derived exosomes (Sed-Exo). This was associated with increased ATP7A (2.9-fold) and ecSOD (1.4-fold) expression in Exe-Exo. Sed-Exo from high fat-induced T2DM mice significantly decreased EC migration (40%) and tube formation (10%) as well as ATP7A expression (28%) compared to Sed-Exo from control mice, which were restored by T2DM Exe-Exo, but not by T2DM/ecSOD KO Exe-Exo. Furthermore, exosomes overexpressing ecSOD (ecSOD-Exo) which mimic exercise increased angiogenesis and H2O2 levels in ECs, which were inhibited by overexpression of catalase. In vivo, skin wound healing model showed that direct application of T2DM Sed-Exo delayed while T2DM Exe-Exo enhanced wound healing of control mice. Furthermore, defective wound healing in T2DM mice or ecSOD KO mice were rescued by ecSOD-Exo application. Conclusion: Exercise training improves pro-angiogenic function of circulating exosomes in T2DM via increasing ATP7A-ecSOD axis, which may provide an effective therapy for promoting angiogenesis and wound repair in metabolic and cardiovascular diseases.
Structural and Functional Characterization of a Single Chain Î²3 Integrin in Solution and on the Cell Surface and the Implications on Integrin Activation and Pathogenesis of Anti-HPA-1a Alloantibodies
Authors: Aye Myat Myat Thinn, Zhengli Wang, Dongwen Zhou, Yan Zhao, Brian R. Curtis, Jieqing Zhu
Journal: Blood (2017)
Abstract PO-020: Targeting metabolism to improve response to immune-checkpoint inhibition in melanoma
Authors: Jiske F. Tiersma, Bernard Evers, Barbara M. Bakker, Steven de Jong, Mathilde Jalving
Journal: Cancer Research (2020)

Abstract Immune checkpoint inhibitors improve long term survival of advanced melanoma patients, however, 40-50% of patients do not benefit. Reprogrammed tumor metabolism may hinder immune cell function. We aimed to reverse metabolic reprogramming in melanoma cells by inhibiting pyruvate dehydrogenase (PDK), thereby reducing lactate secretion, while preserving or enhancing immune cell activity. In addition, we strived to elucidate metabolic vulnerabilities arising during PDK inhibitor treatment by co-treating cells with other metabolically targeted inhibitors. We treated a panel of melanoma cell lines with genetic backgrounds similar to those most frequently found in the clinic with PDK inhibitor dichloroacetate (DCA) to determine effects on viability, expression of metabolic proteins and oxygen consumption/lactate secretion. IC50 values for DCA were 14.9 ± 1.0 for A375, 13.3 ± 0.6 for MeWo, 20.0 ± 1.4 for SK-MEL-28 and 27.3 ± 1.7 mM for SK-MEL-2 cells. PDK inhibition decreased expression of the phosphorylated (inactive) form of PDH (pPDH) in melanoma cells. DCA treatment led to an up to threefold increase in the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio in melanoma cells. Growth inhibition of DCA synergized with other metabolic inhibitors CB-839 (glutaminase inhibitor) and metformin. The combination index (CI) was less than 0.5, indicating strong synergy, for DCA with CB-839 or DCA with metformin in several models. DCA at concentrations affecting OCR:ECAR ratio of melanoma cells (7 mM) had only minimal effects on proliferation of activated T cells and peripheral blood mononuclear cells (PBMCs). Interestingly, the interferon-γ level as a marker of cytotoxicity was increased by DCA in culture media of both T cells and PBMCs. We conclude that PDK inhibition through DCA reverses metabolic programming in melanoma cells. Also, DCA toxicity was enhanced by other metabolic inhibitors, showing that DCA treatment leads to dependency on other metabolic pathways. DCA treatment was non-toxic to immune cells and even enhanced cytotoxicity. Therefore, DCA may be a valuable tool in improving response to immunotherapy in melanoma patients. Citation Format: Jiske F. Tiersma, Bernard Evers, Barbara M. Bakker, Steven de Jong, Mathilde Jalving. Targeting metabolism to improve response to immune-checkpoint inhibition in melanoma [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-020.
Genotype imputation and variability in polygenic risk score estimation
Authors: Shang-Fu Chen, Raquel Dias, Doug Evans, Elias L. Salfati, Shuchen Liu, Nathan E. Wineinger, Ali Torkamani
Journal: Genome Medicine (2020)

Polygenic risk scores (PRSs) are a summarization of an individual's genetic risk for a disease or trait. These scores are being generated in research and commercial settings to study how they may be used to guide healthcare decisions. PRSs should be updated as genetic knowledgebases improve; however, no guidelines exist for their generation or updating.
James Finbarr (Barry) Cullen
Authors: Hector Bryson Chawla
Journal: BMJ (2020)

James Finbarr Cullen (“Barry”) was one of the great names in ophthalmology, although he would never have thought that of himself. He qualified at University College Dublin in1952. After the obligatory registration year, he moved into his chosen specialty at the Dublin Eye and Ear Hospital, then on to the Royal Victoria Infirmary and General Hospital in Newcastle. From there he successfully appeared for the fellowship of the Royal College of Surgeons of England, six months short of actually being eligible to sit it—an honour that merely confirmed his practice of doing everything in double quick time.

He spent a year at the Wilmer Institute at Johns Hopkins University in Baltimore with Frank Walsh, a pioneer in neuro-ophthalmology. This not only drew him into the mysteries of the eye-brain nexus but also gave him an interest that would absorb him for the following 60 years.

On his return to the UK, his new skill made him the chosen candidate, despite strong local opposition, for the post of senior lecturer with Professor George Scott in Edinburgh. With the new Eye Pavilion due to open in 1969, the timing was perfect for the professor to entrust Barry with executive freedom to plan and select the equipment.

This he did, but in his view, there was more to a first class unit than instruments. The junior doctors were of even greater importance; he wanted them to be trained and not just left to absorb the subject by simply being there. The most junior doctor in the professorial unit was therefore relieved of commitments in the clinics for six months in the first year. Friday afternoons were given over to teaching sessions, which are still a sacrosanct end to the hospital week.

For the nurses, he realised that by promoting Edinburgh as the centre …
Abstract 11430: Transplantation of an Antigenically-defined MSC Subpopulation Induces Superior Cardiac Repair After a Reperfused Myocardial Infarction
Authors: Guangming Cheng, Lin Zhao, Magdy Girgis, Arash Davani, Yanjuan Yang, Jeryl Hauptman, Robert J Vincent, Ewa K Zuba-Surma, Buddhadeb Dawn
Journal: Circulation (2019)

Introduction: The outcomes of cardiac repair with bone marrow mesenchymal stem cells (MSCs) have been variable and generally suboptimal. Bone marrow MSCs are quite heterogeneous in nature. Hypothes...
Solving Population-wide Obesity — Progress and Future Prospects
Authors: Shiriki Kumanyika, William H. Dietz
Journal: New England Journal of Medicine (2020)

Interview with Dr. Shiriki Kumanyika on U.S. and global strategies for addressing obesity and related health threats. (11:15)Download The global obesity rate has tripled since the mid-1970s. Major investments have been made in this area, and there have been some legislative and regulatory successes. But addressing obesity and other major health threats in concert could enable more effective solutions.
Topical corticosteroids normalize both skin and systemic inflammatory markers in infant atopic dermatitis
Authors: M. A. McAleer, I. Jakasa, N. Stefanovic, W. H. I. McLean, S. Kezic, A. D. Irvine
Journal: British Journal of Dermatology (2020)

Background Atopic dermatitis (AD) is the most common inflammatory skin disease. It is highly heterogeneous in clinical presentation, treatment response, disease trajectory and associated atopic comorbidities. Immune biomarkers are dysregulated in skin and peripheral blood. Aims We used noninvasive skin and peripheral biomarkers to observe the effects of real-world topical corticosteroid (TCS) treatment in infants with AD, by measuring skin and blood biomarkers before and after therapy. Methods Seventy-four treatment-naïve infants with AD underwent 6 weeks of TCS treatment. Stratum corneum (SC) and plasma blood biomarkers as well as SC natural moisturizing factor (NMF) were measured before and after TCS therapy. Immune markers included innate, T helper (Th)1 and Th2 immunity, angiogenesis, and vascular factors. AD severity was assessed by the Scoring Atopic Dermatitis index, and skin barrier function by transepidermal water loss (TEWL). Twenty healthy infants were recruited as controls. Results TCS therapy predictably led to improvement in disease severity. Levels of immune markers in the skin and in the peripheral blood showed significant change from baseline, though most did not reach healthy control levels. The most prominent change from baseline in the SC was in markers of innate immune activation, interleukin (IL)-18, IL-8 and IL-1α, and the Th2 chemokines C-C motif chemokine (CCL)17 and CCL22. In blood, the largest changes were in Th2-skewed biomarkers: CCL17, IL-13, CCL22, IL-5, and CCL26. TEWL decreased after therapy; no significant changes from baseline were found for NMF. Conclusions The profound impact of topical therapy on systemic biomarkers suggests that the skin compartment generates a major component of dysregulated systemic cytokines in infant AD. There may be long-term beneficial effects of correcting systemic immune dysregulation through topical therapy.
Assessing Risk of Progression of Low-Risk Branch-Duct Intraductal Papillary Mucinous Neoplasms
Authors: J.-Matthias Löhr, Marco Del Chiaro
Journal: JAMA Network Open (2020)

Gabriele Capurso, PhD; Stefano Crippa, MD; Giuseppe Vanella, MD; Mariaemilia Traini, MD; Giulia Zerboni, MD; Piera Zaccari, MD; Giulio Belfiori, MD; Manuel Gentiluomo, PhD; Tommaso Pessarelli, MD; Maria Chiara Petrone, MD; Daniele Campa, PhD; Massimo Falconi, MD; Paolo Giorgio Arcidiacono, MD
Respiratory function in patients post-infection by COVID-19: a systematic review and meta-analysis
Authors: R. Torres-Castro, L. Vasconcello-Castillo, X. Alsina-Restoy, L. Solis-Navarro, F. Burgos, H. Puppo, J. Vilaró
Journal: Pulmonology (2020)

Evidence suggests lungs as the organ most affected by coronavirus disease 2019 (COVID-19). The literature on previous coronavirus infections reports that patients may experience persistent impairment in respiratory function after being discharged. Our objective was to determine the prevalence of restrictive pattern, obstructive pattern and altered diffusion in patients post-COVID-19 infection and to describe the different evaluations of respiratory function used with these patients.