tbuckley/cabot-search huggingface dataset:
Tap Water Contributions to Plasma Concentrations of Poly- and Perfluoroalkyl Substances (PFAS) in a Nationwide Prospective Cohort of U.S. Women
Authors: Xindi C. Hu, Andrea K. Tokranov, Jahred Liddie, Xianming Zhang, Philippe Grandjean, Jaime E. Hart, Francine Laden, Qi Sun, Leo W. Y. Yeung, Elsie M. Sunderland
Journal: Environmental Health Perspectives (2019)

Between 2013 and 2015, concentrations of poly- and perfluoroalkyl substances (PFAS) in public drinking water supplies serving at least six million individuals exceeded the level set forth in the health advisory established by the U.S. Environmental Protection Agency. Other than data reported for contaminated sites, no systematic or prospective data exist on the relative source contribution (RSC) of drinking water to human PFAS exposures.This study estimates the RSC of tap water to overall PFAS exposure among members of the general U.S.We measured concentrations of 15 PFAS in home tap water samples collected in 1989-1990 from 225 participants in a nationwide prospective cohort of U.S. women: the Nurses' Health Study (NHS). We used a one-compartment toxicokinetic model to estimate plasma concentrations corresponding to tap water intake of PFAS. We compared modeled results with measured plasma PFAS concentrations among a subset of 110 NHS participants.Tap water perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) were statistically significant predictors of plasma concentrations among individuals who consumed [Formula: see text] cups of tap water per day. Modeled median contributions of tap water to measured plasma concentrations were: PFOA 12% (95% probability interval 11%-14%), PFNA 13% (8.7%-21%), linear perfluorooctanesulfonic acid (nPFOS) 2.2% (2.0%-2.5%), branched perfluorooctanesulfonic acid (brPFOS) 3.0% (2.5%-3.2%), and perfluorohexanesulfonic acid (PFHxS) 34% (29%-39%). In five locations, comparisons of PFASs in community tap water collected in the period 2013-2016 with samples from 1989-1990 indicated increases in quantifiable PFAS and extractable organic fluorine (a proxy for unquantified PFAS).Our results for 1989-1990 compare well with the default RSC of 20% used in risk assessments for legacy PFAS by many agencies. Future evaluation of drinking water exposures should incorporate emerging PFAS. https://doi.org/10.1289/EHP4093.
Abstract 12091: 3-Vessel Spontaneous Coronary Artery Dissection After Triptan Exposure
Authors: Ahmed Abu-Haniyeh, Amit Goyal, Michael Faulx
Journal: Circulation (2018)

Spontaneous Coronary Artery Dissection (SCAD) is a rare and potentially fatal condition characterized by spontaneous disruption of the coronary artery wall that is not iatrogenic, traumatic, or ath...
Low High-Density Lipoprotein Cholesterol (HDL) Is a Significant Poor Prognostic Factor in Malignant Lymphoma
Authors: Takuji Matsuo, Haruko Tashiro, Ritsu Sumiyoshi, Tadashi Yamamoto, Yoko Oka-Miura, Kensuke Matsumoto, Jun Ooi, Naoki Shirafuji
Journal: Blood (2017)
Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): Phase III POLO trial.
Authors: Hedy L. Kindler, Pascal Hammel, Michele Reni, Eric Van Cutsem, Teresa Macarulla Mercade, Michael J. Hall, Joon Oh Park, Daniel Hochhauser, Dirk Arnold, Do-Youn Oh, Anke C. Reinacher-Schick, Giampaolo Tortora, Hana Algül, Eileen Mary O'Reilly, David McGuinness, Karen Cui, Katia Schlienger, Gershon Y. Locker, Talia Golan
Journal: Journal of Clinical Oncology (2019)

LBA4 Background: Pancreatic cancer (PC) pts with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) have shown response to the PARP inhibitor olaparib (Kaufman 2015). POLO is the first phase III trial to evaluate efficacy of maintenance treatment with a PARP inhibitor in PC. Methods: POLO is an international, randomized, double-blind, placebo-controlled trial of pts with a gBRCAm and pancreatic adenocarcinoma who had received ≥16 weeks of first-line PBC for metastatic disease without progression. Pts were randomized 3:2 to maintenance olaparib (O) tablets (300 mg bid) or placebo (P). Treatment began 4–8 weeks after last PBC dose, continuing until investigator-assessed progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) by blinded independent central review (modified RECIST 1.1). Results: We screened 3315 pts, identified 247 with a gBRCAm, randomized 154 (O 92, P 62), and treated 151 (O 90, P 61). Pt characteristics (O/P): age, median (range) 57 (37–84)/57 (36–75); male, 58%/50%; ECOG performance status 0, 71%/61%. With 104 events, PFS was significantly improved with O vs. P (hazard ratio [HR] 0.53; 95% CI 0.35, 0.82; p = 0.0038; median PFS was 7.4 vs. 3.8 months [mo], respectively) and consistent irrespective of response to prior PBC (complete/partial HR 0.62; stable disease HR 0.50). From 6 mo, the % of pts progression-free in the O arm was more than twice that in the P arm (Table). At the interim overall survival analysis (46% maturity), HR was 0.91 (95% CI 0.56, 1.46; p = 0.68). Grade ≥3 adverse events (AE) occurred in 40% of O- and 23% of P-treated pts; 5.5% and 1.7% of pts, respectively, discontinued treatment due to an AE. Conclusions: Maintenance olaparib provided a statistically significant and clinically meaningful improvement in PFS in mPC pts with a gBRCAm who had not progressed on PBC. Safety was consistent with the known profile for olaparib. POLO is the first phase III trial to validate a biomarker-driven treatment in PC. Clinical trial information: NCT02184195. [Table: see text]
Interleukin-17 receptor D: An orphan receptor finds a home in the skin
Authors: Allison C. Billi, Johann E. Gudjonsson
Journal: Science Immunology (2019)

Interleukin-17 receptor D (IL-17RD) heterodimerizes with IL-17RA to form a receptor selective for the cytokine IL-17A. (See the related Research Article by Su et al. )
Abstract 14231: Effectiveness and Safety of Statin Therapy in Children: A Multi-Center, Real-World Clinical Practice Experience
Authors: Rae Ellen W Kavey, Cedric Manlhiot, Tanveer Collins, Samuel S Gidding, Matthew Demczko, Sarah Clauss, Ruth Phillippi, Ashraf Harahsheh, Michele Mietus-Snyder, Brian McCrindle
Journal: Circulation (2015)

Results of statin use in clinical practice in children are very limited, with effectiveness and safety data based on short-term clinical trials. To address this, we reviewed the results of all children with primary hypercholesterolemia treated with statins for more than 6 months from 4 Pediatric Lipid Clinics. Expert Panel guidelines recommend statin if LDL-cholesterol (LDL-C) exceeds 4.9 mmol/L (190 mg/dL), or 4.1 mmol/L (160 mg/dL) with additional risk factors, after 6 months of lifestyle modification, with hepatic enzyme monitoring plus clinical surveillance and CK measurement for myositis. Patients at all study sites were managed using these guidelines. Results: There were 246 pts (59% male) who had 1488 clinical assessments. Mean age at statin initiation was 12.5±0.5 yrs. Mean duration of therapy was 2.9 yrs (IQR: 1.9_4.7) with 48% more than 3 yrs. Initial statin prescribed varied over time but 61% of pts were started on atorvastatin and 70% remained on the first statin prescribed. Mean compliance was assessed at 92% and 234 pts (94%) remained on statin therapy at the end of the review. Baseline and follow-up lab values and anthropometry (mean + SD) appear below. While 13 pts (5%) had transient AST or ALT &gt; 3xULN, or CK &gt;10xULN at some time during follow-up, no pt was diagnosed with myositis. In regression analysis adjusted for repeated measures over time, statin treatment was associated with significant reductions in total cholesterol, LDL-C and non-HDL-C with no change in HDL-C, TG, safety labs or anthropometry. Despite statin, 51% and 70% of pts had LDL-C levels above minimal (&lt;3.35mmol/L; 130 mg/dL) and ideal (&lt;2.85mmol/L; 110 mg/dL) targets at last follow-up. Conclusions: These findings in a large series of pts from real-world clinical practice show that statin therapy in children with primary hypercholesterolemia is safe and effectively lowers LDL-C on mid-term follow-up. Side effects are rare and discontinuation of treatment is uncommon.
Adenylyl cyclase 5–generated cAMP controls cerebral vascular reactivity during diabetic hyperglycemia
Authors: Arsalan U. Syed, Gopireddy R. Reddy, Debapriya Ghosh, Maria Paz Prada, Matthew A. Nystoriak, Stefano Morotti, Eleonora Grandi, Padmini Sirish, Nipavan Chiamvimonvat, Johannes W. Hell, Luis F. Santana, Yang K. Xiang, Madeline Nieves-Cintrón, Manuel F. Navedo
Journal: Journal of Clinical Investigation (2019)

Elevated blood glucose (hyperglycemia) is a hallmark metabolic abnormality in diabetes. Hyperglycemia is associated with protein kinase A (PKA)-mediated stimulation of L-type Ca2+ channels in arterial myocytes resulting in increased vasoconstriction. However, the mechanisms by which glucose activates PKA remain unclear. Here, we showed that elevating extracellular glucose stimulates cAMP production in arterial myocytes, and that this was specifically dependent on adenylyl cyclase 5 (AC5) activity. Super-resolution imaging suggested nanometer proximity between subpopulations of AC5 and the L-type Ca2+ channel pore-forming subunit CaV1.2. In vitro, in silico, ex vivo and in vivo experiments revealed that this close association is critical for stimulation of L-type Ca2+ channels in arterial myocytes and increased myogenic tone upon acute hyperglycemia. This pathway supported the increase in L-type Ca2+ channel activity and myogenic tone in two animal models of diabetes. Our collective findings demonstrate a unique role for AC5 in PKA-dependent modulation of L-type Ca2+ channel activity and vascular reactivity during acute hyperglycemia and diabetes.
Large-Scale Comparative Analysis of Codon Models Accounting for Protein and Nucleotide Selection
Authors: Iakov I Davydov, Nicolas Salamin, Marc Robinson-Rechavi
Journal: Molecular Biology and Evolution (2019)

There are numerous sources of variation in the rate of synonymous substitutions inside genes, such as direct selection on the nucleotide sequence, or mutation rate variation. Yet scans for positive selection rely on codon models which incorporate an assumption of effectively neutral synonymous substitution rate, constant between sites of each gene. Here we perform a large-scale comparison of approaches which incorporate codon substitution rate variation and propose our own simple yet effective modification of existing models. We find strong effects of substitution rate variation on positive selection inference. More than 70% of the genes detected by the classical branch-site model are presumably false positives caused by the incorrect assumption of uniform synonymous substitution rate. We propose a new model which is strongly favored by the data while remaining computationally tractable. With the new model we can capture signatures of nucleotide level selection acting on translation initiation and on splicing sites within the coding region. Finally, we show that rate variation is highest in the highly recombining regions, and we propose that recombination and mutation rate variation, such as high CpG mutation rate, are the two main sources of nucleotide rate variation. Although we detect fewer genes under positive selection in Drosophila than without rate variation, the genes which we detect contain a stronger signal of adaptation of dynein, which could be associated with Wolbachia infection. We provide software to perform positive selection analysis using the new model.
OP0277 RNA SEQUENCING AND MACHINE LEARNING TECHNIQUES PREDICT MAJOR ORGAN INVOLVEMENT IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: Anastasia Filia, George Bertsias, Nikolaos Panousis, Dionisis Nikolopoulos, Emmanouil Dermitzakis, Dimitrios Boumpas
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Both clinically and molecularly, Systemic Lupus Erythematosus (SLE) is a heterogeneous disease with non-synchronous multi-organ involvement of varying severity, and alternating periods of remission and flares. There is an unmet need for a blood-based- "liquid biopsy" to predict prognosis of the disease. <h3>Objectives</h3> To detect the smallest set of genes predicting SLE organ involvement and disease activity using RNA-sequencing data derived from whole blood cells from 150 SLE patients and machine learning techniques. <h3>Methods</h3> Disease activity was measured by the SLE disease activity index-2000 (SLEDAI-2K) and by organ involvement (treated as binary outcomes). SLEDAI-2K: mild-moderate disease (SLEDAI 0-8), severe (SLEDAI ≥8). Organ involvement: major (renal, heart, lung, central nervous system &amp; SLEDAI-2K≥6) and minor (all others). The RNA-sequencing dataset was pre-processed to assemble 20,368 genes and then split in training/validation data. Two feature selection steps (edgeR and recursive feature elimination) were used to remove noise and keep the smallest set of genes which best predicts each outcome. Different prediction models were fit to identify which one performs best using the gene signature selected in the previous step. <h3>Results</h3> Two gene signatures were kept after feature selection to predict each of the two outcomes (25 genes for organ involvement; 50 genes for SLEDAI-2K). Organ involvement was predicted with high accuracy (accuracy=0.89, sensitivity=0.89, specificity=0.88 in the validation data) using the elastic net generalised linear model. Among the 25 best predictors were <i>MPO, ITGA3</i> and<i> CD38</i>. SLEDAI-2K could not be predicted with high accuracy (accuracy 0.75, sensitivity=0.79, specificity=0.67) using the neural network model. Performance was still the same even when 1648 genes (after first feature selection step) were used as predictors of SLEDAI-2K. The performance of these models will also be tested in an independent test dataset once available (currently undergoing sequencing). <h3>Conclusion</h3> The model predicting organ involvement performed better compared to the model predicting SLEDAI-2K. This could be attributed to the fact that certain disease manifestations are not currently included in SLEDAI-2K. Further analysis and functional laboratory experiments of those genes will help to identify biomarkers for more accurate assessment of disease activity and prognosis in the clinic. <h3>Acknowledgement</h3> This work was supported by FOREUM, SYSCID and ERC-Advanced Grant. <h3>Disclosure of Interests</h3> None declared
Trends in Mortality Due to Cancer in the United States by Age and County-Level Income, 1999–2015
Authors: Diana R Withrow, Amy Berrington de González, Susan Spillane, Neal D Freedman, Ana F Best, Yingxi Chen, Meredith S Shiels
Journal: JNCI Journal of the National Cancer Institute (2019)

Disparities in cancer mortality by county-level income have increased. It is unclear whether these widening disparities have affected older and younger adults equally. National death certificate data were utilized to ascertain cancer deaths during 1999-2015. Average annual percent changes in mortality rates and mortality rate ratios (RRs) were estimated by county-level income quintile and age (25-64 vs ≥65 years). Among 25- to 64-year-olds, cancer mortality rates were 30% higher (RR = 1.30, 95% confidence interval [CI] = 1.29 to 1.31) in the lowest-vs the highest-income counties in 1999-2001 and 56% higher (RR = 1.56, 95% CI = 1.55 to 1.57) in 2013-2015; the disparities among those 65 years and older were smaller but also widened over time (RR1999-2001 = 1.04, 95% CI = 1.03 to 1.05; RR2013-2015 = 1.14, 95% CI = 1.13 to 1.14). Widening disparities occurred across cancer sites. If all counties had the mortality rates of the highest-income counties, 21.5% of cancer deaths among 25- to 64-year-olds and 7.3% of cancer deaths in those 65 years and older would have been avoided in 2015. These results highlight an ongoing need for equity-focused interventions, particularly among younger adults.
AB1119 THE PRESENCE OF SYNOVITIS IS THE MAIN FACTOR INFLUENCING THE DEVELOPMENT OF PAIN SYNDROME IN ARTHRITIS OF THE KNEE JOINT
Authors: Ninel Aleksandrova, Natalia Nikitina, Vladislav Aleksandrov, Ludmila Shilova, Andrey Aleksandrov
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Dysfunctions and pain syndrome in lesions of the knee joint can significantly discomfort a sick person and lead to a persistent decrease in physical activity and disability. Often pain syndrome precedes radiographic appearance of the structural changes in the joint and is accompanied by an increase in number of different changes in the synovium according to ultrasound investigation. <h3>Objectives</h3> To investigate the clinical significance of ultrasound criteria of changes in the synovial membrane of the knee joint cavity and its role in the assessment of pain in gonarthrosis. <h3>Methods</h3> 30 people aged 30 to 50 years with osteoarthritis of the knee joint were under observation; assessment of the severity of pain in the knee when walking was at least 40 mm on a visual analogue scale (VAS). Ultrasound examination of the knee joint was carried out according to standard procedure using a linear sensor with a frequency of 05.12 MHz in an ultrasonic diagnosis system Accuvix V10 (Samsung Medison, Korea). <h3>Results</h3> The evaluation of ultrasound changes was performed in the upper inversion of the knee joint according to the following criteria: the severity of intraarticular effusion (1), synovial proliferation (2), local vascularization of the synovial membrane by power doppler (3). All patients were divided into three groups, according to the severity of pain in the knee joint: group I (12 people) - 41–59 mm, group II (10 people) - 60–79 mm, group III (8 people) - 80-100 mm on the VAS scale. By comparing changes in the knee joint by ultrasound data in patients of different groups, the following results were obtained: group I: severity of intraarticular effusion - 10 people (minimal changes in 60%, moderate in 20%, expressed in 20%), synovial proliferation - 4 people (moderate changes in 50%, expressed in 50%), local vascularization of synovium - 6 people (minimal changes in 66.7%, moderate in 16.7%, expressed in 16.6%); Group II: severity of intraarticular effusion - 9 people (55.6%, 22.2% and 22.2%), synovial proliferation - 3 people (0%, 33.3% and 66.7%,), local vascularization of the synovial membrane - 4 people (25%, 25% and 50%, respectively); group III: severity of intraarticular effusion - 8 people (62.5%, 12.5% and 25%), synovial proliferation - 5 people (20%, 40% and 40%), local vascularization of the synovial membrane - 3 people (per 33.3%, respectively). <h3>Conclusion</h3> The use of ultrasound in the diagnosis of diseases of the knee joints allows to reliably determine the structural and functional changes in all components of the knee joint. The severity of pain in gonarthrosis is most associated with the presence of synovitis in the joint. <h3>Disclosure of Interests</h3> None declared
PB2422 INHERITED THROMBOPHILIA BY WOMEN WITH THROMBOSIS AND REPRODUCTIVE FAILURES IN ANAMNESIS
Authors: A. Kiseleva, E. Butina, E. Poponina, I. Paramonov
Journal: HemaSphere (2019)

Background: Thrombosis or thrombotic syndrome is a pathological condition caused by the formation of blood clots in the arteries, veins and cavities of a heart ‐ blood clots. As known. pregnancy is a period of increased risk of thrombotic complications due to hypercoagulation, venous stasis and damage to the vessel wall (Virchow triad). Hereditary predisposition to thrombophilia is a risk factor for thrombosis during pregnancy, affecting its course. Aims: To assess the distribution of polymorphic genes associated with thrombophilia and prothrombotic conditions (F2, F5, F7, F13, FGB, ITGA2, ITGB3, PAI‐1) by women with thrombosis and reproductive failures in anamnesis. Methods: Typing of thrombophilia and prothrombotic conditions genes was carried out by polymerase chain reaction in real time on the detecting amplifier DT‐96 (DNA Technology, Russia). The criterion χ 2 was used for statistical data processing. Polymorphism of genes was studied in 123 women: 39 ‐ women with thrombosis of the upper and lower extremities, pulmonary embolism and reproductive failures (from 1 to 5 missed abortions), 84 ‐ healthy women without pathology of pregnancy (control group). Results: The following frequency of occurrence of polymorphic alleles: F2, F5, F7, F13, FGB, ITGA2, ITGB3, PAI‐1 in the studied group and the control group was established. The presence of ”non‐mutant“ alleles: F2 ‐ 92.3% and 98.8% (p = 0.059); F5 ‐ 94.9% and 95.2% (p = 0.931); F7 ‐ 97.4% and 73.8% (p = 0.002); F13 ‐ 59.0% and 50.0% (p = 0.354); FGB ‐ 53.8% and 48.8% (p = 0.604); ITGA2 ‐ 51.3 and 44.6% (p = 0.489); ITGB3 ‐ 61.5% and 82.1% (p = 0.014); PAI‐1 ‐ 15.4% and 16.7% (p = 0.885). The presence of ”mutant“ heterozygous alleles: F2 ‐ 7.7% and 1.2% (p = 0.059); F5 ‐ 5.1% and 3.6% (p = 0.685); F7 ‐ 2.6% and 25.0% (p = 0.003); F13 ‐ 28.2% and 41.7% (p = 0.152); FGB ‐ 43.6% and 44.0% (p = 0.963); ITGA2 ‐ 38.5 and 47.0% (p = 0.372); ITGB3 ‐ 33.3% and 16.7% (p = 0.038); PAI‐1 ‐ 46.2% and 52.4% (p = 0.52). Based on the results of the study, it was established that the T/C polymorphism of the ITGB3 gene is more common by women with thrombosis and reproductive failure, and T/T polymorphism ‐ by women from the control group. The heterozygous form of the F7 gene was less frequently detected by women from the studied group than in the control group (p &lt;0.05). The non‐mutant form of the F7 gene was found significantly more often in women from the studied group than from the control group (p &lt;0.05). Summary/Conclusion: The presence of the T/C polymorphism of the ITGB3 gene and the absence of the G/A polymorphism of the F7 gene are associated with reproductive failure by women with thrombosis in anamnesis.
Abstract 19866: Investigating Lipidomics of Patient Specific iPSC Derived Hepatocytes
Authors: Mostafa Kiamehr, Anna Alexanova, Leena E Viiri, Terhi Vihervaara, Kaisa M Koistinen, Mika Hilvo, Kim Ekroos, Reijo Käkelä, Katriina Aalto-Setälä
Journal: Circulation (2017)

Introduction: Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem cells (hiPSCs) offer an alternative model for primary human hepatocytes (PHHs) when analyzing the funct...
Rapid Evolution of Gained Essential Developmental Functions of a Young Gene via Interactions with Other Essential Genes
Authors: Yuh Chwen G Lee, Iuri M Ventura, Gavin R Rice, Dong-Yuan Chen, Serafin U Colmenares, Manyuan Long
Journal: Molecular Biology and Evolution (2019)

New genes are of recent origin and only present in a subset of species in a phylogeny. Accumulated evidence suggests that new genes, like old genes that are conserved across species, can also take on important functions and be essential for the survival and reproductive success of organisms. Although there are detailed analyses of the mechanisms underlying new genes' gaining fertility functions, how new genes rapidly become essential for viability remains unclear. We focused on a young retro-duplicated gene (CG7804, which we named Cocoon) in Drosophila that originated between 4 and 10 Ma. We found that, unlike its evolutionarily conserved parental gene, Cocoon has evolved under positive selection and accumulated many amino acid differences at functional sites from the parental gene. Despite its young age, Cocoon is essential for the survival of Drosophila melanogaster at multiple developmental stages, including the critical embryonic stage, and its expression is essential in different tissues from those of its parental gene. Functional genomic analyses found that Cocoon acquired unique DNA-binding sites and has a contrasting effect on gene expression to that of its parental gene. Importantly, Cocoon binding predominantly locates at genes that have other essential functions and/or have multiple gene-gene interactions, suggesting that Cocoon acquired novel essential function to survival through forming interactions that have large impacts on the gene interaction network. Our study is an important step toward deciphering the evolutionary trajectory by which new genes functionally diverge from parental genes and become essential.