tbuckley/cabot-search huggingface dataset:
Beyond the RfD: Broad Application of a Probabilistic Approach to Improve Chemical Dose–Response Assessments for Noncancer Effects
Authors: Weihsueh A. Chiu, Daniel A. Axelrad, Chimeddulam Dalaijamts, Chris Dockins, Kan Shao, Andrew J. Shapiro, Greg Paoli
Journal: Environmental Health Perspectives (2018)

Background: The National Academies recommended risk assessments redefine the traditional noncancer Reference Dose (RfD) as a probabilistically derived risk-specific dose, a framework for which was recently developed by the World Health Organization (WHO). Objectives: Our aim was to assess the feasibility and implications of replacing traditional RfDs with probabilistic estimates of the human dose associated with an effect magnitude M and population incidence I (HDMI). Methods: We created a comprehensive, curated database of RfDs derived from animal data and developed a standardized, automated, web-accessible probabilistic dose–response workflow implementing the WHO framework. Results: We identified 1,464 RfDs and associated endpoints, representing 608 chemicals across many types of effects. Applying our standardized workflow resulted in 1,522 HDMI values. Traditional RfDs are generally within an order of magnitude of the HDMI lower confidence bound for I=1% and M values commonly used for benchmark doses. The greatest contributor to uncertainty was lack of benchmark dose estimates, followed by uncertainty in the extent of human variability. Exposure at the traditional RfD frequently implies an upper 95% confidence bound of several percent of the population affected. Whether such incidences are considered acceptable is likely to vary by chemical and risk context, especially given the wide range of severity of the associated effects, from clinical chemistry to mortality. Conclusions: Overall, replacing RfDs with HDMI estimates can provide a more consistent, scientifically rigorous, and transparent basis for risk management decisions, as well as support additional decision contexts such as economic benefit–cost analysis, risk–risk tradeoffs, life-cycle impact analysis, and emergency response. https://doi.org/10.1289/EHP3368
SRC-3 is involved in maintaining hematopoietic stem cell quiescence by regulation of mitochondrial metabolism in mice
Authors: Mengjia Hu, Hao Zeng, Shilei Chen, Yang Xu, Song Wang, Yong Tang, Xinmiao Wang, Changhong Du, Mingqiang Shen, Fang Chen, Mo Chen, Cheng Wang, Jining Gao, Fengchao Wang, Yongping Su, Junping Wang
Journal: Blood (2018)
Risk of meticillin resistant <i>Staphylococcus aureus</i> and <i>Clostridium difficile</i> in patients with a documented penicillin allergy: population based matched cohort study
Authors: Kimberly G Blumenthal, Na Lu, Yuqing Zhang, Yu Li, Rochelle P Walensky, Hyon K Choi
Journal: BMJ (2018)

To evaluate the relation between penicillin allergy and development of meticillin resistant Staphylococcus aureus (MRSA) and C difficile.Population based matched cohort study.United Kingdom general practice (1995-2015).301 399 adults without previous MRSA or C difficile enrolled in the Health Improvement Network database: 64 141 had a penicillin allergy and 237 258 comparators matched on age, sex, and study entry time.The primary outcome was risk of incident MRSA and C difficile. Secondary outcomes were use of β lactam antibiotics and β lactam alternative antibiotics.Among 64 141 adults with penicillin allergy and 237 258 matched comparators, 1365 developed MRSA (442 participants with penicillin allergy and 923 comparators) and 1688 developed C difficile (442 participants with penicillin allergy and 1246 comparators) during a mean 6.0 years of follow-up. Among patients with penicillin allergy the adjusted hazard ratio for MRSA was 1.69 (95% confidence interval 1.51 to 1.90) and for C difficile was 1.26 (1.12 to 1.40). The adjusted incidence rate ratios for antibiotic use among patients with penicillin allergy were 4.15 (95% confidence interval 4.12 to 4.17) for macrolides, 3.89 (3.66 to 4.12) for clindamycin, and 2.10 (2.08 to 2.13) for fluoroquinolones. Increased use of β lactam alternative antibiotics accounted for 55% of the increased risk of MRSA and 35% of the increased risk of C difficile.Documented penicillin allergy was associated with an increased risk of MRSA and C difficile that was mediated by the increased use of β lactam alternative antibiotics. Systematically addressing penicillin allergies may be an important public health strategy to reduce the incidence of MRSA and C difficile among patients with a penicillin allergy label.
It Is Time to Invest in the Prevention of Depression
Authors: David Daniel Ebert, Pim Cuijpers
Journal: JAMA Network Open (2018)

Michael Silverstein, MD, MPH; Howard Cabral, PhD, MPH; Mark Hegel, PhD; Yaminette Diaz-Linhart, MSW, MPH; William Beardslee, MD; Caroline J. Kistin, MD, MSc; Emily Feinberg, ScD
Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis
Authors: Kevin R. Flaherty, Charlene D. Fell, J. Terrill Huggins, Hilario Nunes, Robert Sussman, Claudia Valenzuela, Ute Petzinger, John L. Stauffer, Frank Gilberg, Monica Bengus, Marlies Wijsenbeek
Journal: European Respiratory Journal (2018)

We assessed safety and tolerability of treatment with pirfenidone (1602–2403 mg·day −1 ) and nintedanib (200–300 mg·day −1 ) in patients with idiopathic pulmonary fibrosis (IPF). This 24-week, single-arm, open-label, phase IV study ( ClinicalTrials.gov identifier NCT02598193 ) enrolled patients with IPF with forced vital capacity % pred ≥50% and diffusing capacity of the lung for carbon monoxide % pred ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg·day −1 for ≥28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602–2403 mg·day −1 ) and nintedanib (200–300 mg·day −1 ). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither. 89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatment-related TEAEs. Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF.
Intravenous immunoglobulin vs observation in childhood immune thrombocytopenia: a randomized controlled trial
Authors: Katja M. J. Heitink-Pollé, Cuno S. P. M. Uiterwaal, Leendert Porcelijn, Rienk Y. J. Tamminga, Frans J. Smiers, Nicole L. van Woerden, Judit Wesseling, Gestur Vidarsson, Annemieke G. Laarhoven, Masja de Haas, Marrie C. A. Bruin
Journal: Blood (2018)
Darwinian Positive Selection on the Pleiotropic Effects of KITLG Explain Skin Pigmentation and Winter Temperature Adaptation in Eurasians
Authors: Zhaohui Yang, Hong Shi, Pengcheng Ma, Shilei Zhao, Qinghong Kong, Tianhao Bian, Chao Gong, Qi Zhao, Yuan Liu, Xuebin Qi, Xiaoming Zhang, Yinglun Han, Jiewei Liu, Qingwei Li, Hua Chen, Bing Su
Journal: Molecular Biology and Evolution (2018)

Human skin color diversity is considered an adaptation to environmental conditions such as UV radiation. Investigations into the genetic bases of such adaptation have identified a group of pigmentation genes contributing to skin color diversity in African and non-African populations. Here, we present a population analysis of the pigmentation gene KITLG with previously reported signal of Darwinian positive selection in both European and East Asian populations. We demonstrated that there had been recurrent selective events in the upstream and the downstream regions of KITLG in Eurasian populations. More importantly, besides the expected selection on the KITLG variants favoring light skin in coping with the weak UV radiation at high latitude, we observed a KITLG variant showing adaptation to winter temperature. In particular, compared with UV radiation, winter temperature showed a much stronger correlation with the prevalence of the presumably adaptive KITLG allele in Asian populations. This observation was further supported by the in vitro functional test at low temperature. Consequently, the pleiotropic effects of KITLG, that is, pigmentation and thermogenesis were both targeted by natural selection that acted on different KITLG sequence variants, contributing to the adaptation of Eurasians to both UV radiation and winter temperature at high latitude areas.
The Anticancer Activity of a First-in-class Small-molecule Targeting PCNA
Authors: Long Gu, Robert Lingeman, Fumiko Yakushijin, Emily Sun, Qi Cui, Jianfei Chao, Weidong Hu, Hongzhi Li, Robert J. Hickey, Jeremy M. Stark, Yate-Ching Yuan, Yuan Chen, Steven L. Vonderfecht, Timothy W. Synold, Yanhong Shi, Karen L. Reckamp, David Horne, Linda H. Malkas
Journal: Clinical Cancer Research (2018)

Proliferating cell nuclear antigen (PCNA) plays an essential role in regulating DNA synthesis and repair and is indispensable to cancer cell growth and survival. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was ubiquitously expressed in a broad range of cancer cells and tumor tissues, but not significantly in nonmalignant cells. We found the L126-Y133 region of caPCNA is structurally altered and more accessible to protein-protein interaction. A cell-permeable peptide harboring the L126-Y133 sequence blocked PCNA interaction in cancer cells and selectively kills cancer cells and xenograft tumors. On the basis of these findings, we sought small molecules targeting this peptide region as potential broad-spectrum anticancer agents.By computer modeling and medicinal chemistry targeting a surface pocket partly delineated by the L126-Y133 region of PCNA, we identified a potent PCNA inhibitor (AOH1160) and characterized its therapeutic properties and potential toxicity.AOH1160 selectively kills many types of cancer cells at below micromolar concentrations without causing significant toxicity to a broad range of nonmalignant cells. Mechanistically, AOH1160 interferes with DNA replication, blocks homologous recombination-mediated DNA repair, and causes cell-cycle arrest. It induces apoptosis in cancer cells and sensitizes them to cisplatin treatment. AOH1160 is orally available to animals and suppresses tumor growth in a dosage form compatible to clinical applications. Importantly, it does not cause significant toxicity at 2.5 times of an effective dose.These results demonstrated the favorable therapeutic properties and the potential of AOH1160 as a broad-spectrum therapeutic agent for cancer treatment.
Abstract 322: High EMSY expression defines a BRCA-like subgroup of high-grade serous ovarian carcinoma with superior survival and platinum sensitivity
Authors: Robert L. Hollis, Michael Churchman, Tzyvia Rye, Andrena M. McCavigan, Laura A. Knight, Richard Kennedy, C. Simon Herrington, Charlie Gourley
Journal: Cancer Research (2018)

Abstract EMSY, encoding a BRCA2-binding protein, is reportedly amplified in 6-18% of high grade serous ovarian carcinomas (HGSOCs). As a negative regulator of BRCA2, HGSOCs with EMSY overexpression may mimic BRCA-mutant patients, who experience superior clinical outcome and hypersensitivity to platinum chemotherapy and PARP inhibition by virtue of homologous recombination deficiency (HRD). Here we investigate the impact of EMSY expression, extracted from local and publicly available transcriptomic data, on the outcome and platinum sensitivity of HGSOCs. Platinum response data were collected from the Edinburgh Ovarian Cancer Database. Overall survival (OS) and progression-free survival (PFS) differences were assessed using multivariate cox regression accounting for age, stage at diagnosis and debulking status. Within the Edinburgh cohort, high EMSY expression was associated with superior OS and PFS (table 1). Datasets from the MRC ICON7 trial control arm, Tothill et al, Mateescu et al, Pils et al, and TCGA cohorts demonstrated similar benefit for high-EMSY patients. Within the Edinburgh cohort, high-EMSY patients displayed significantly superior complete response (CR) rate to platinum at second (radio CR 44.4% vs 12.5%, P = 0.035; CA125 CR 88.0% vs 55.0%, P = 0.002) and third exposure (radio CR 50.0% vs 5.9%, P = 0.080; CA125 CR 53.3% vs 21.3%, P = 0.021), with prolonged time to progression (median 127 vs 83.5 days from second platinum, P = 0.084; median 151.5 vs 60.5 days from third platinum, P = 0.004). Within high-risk (advanced stage suboptimally debulked) HGSOCs, more high-EMSY patients remained recurrence-free 5 and 10 years from diagnosis (17.6% vs 2.7%, P = 0.031; 12.5% vs 0.9%, P = 0.041). Together these data demonstrate a subgroup of HGSOCs defined by high EMSY expression experience superior clinical outcome and platinum sensitivity, consistent with HRD. This subgroup may therefore represent HGSOCs that are also sensitive to PARP inhibition. DatasetEventMulti HR95% CIPEdinburghOS0.590.39 – 0.900.013PFS0.600.38 – 0.930.022MRC ICON7 control armOS0.210.07 – 0.680.009Tothill (primary tumour masses)OS0.280.09 – 0.900.032MateescuOS0.430.18 – 0.990.048PilsOS0.270.08 – 0.870.028TCGA advanced stage patientsPFS0.690.45 – 1.050.081 Citation Format: Robert L. Hollis, Michael Churchman, Tzyvia Rye, Andrena M. McCavigan, Laura A. Knight, Richard Kennedy, C. Simon Herrington, Charlie Gourley. High EMSY expression defines a BRCA-like subgroup of high-grade serous ovarian carcinoma with superior survival and platinum sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 322.
Abstract 16502: Defiency of Purinergic Receptor P2X7 Reduces Atherosclerosis in Mice
Authors: Peter Stachon, Adrian Heidenreich, Julian Merz, Natalie Hoppe, Christoph Bode, Marco Idzko, Andreas Zirlik
Journal: Circulation (2016)

Introduction:  As shown in different previous studies, extracellular nucleotides such as ATP or UDP play an important role in chronic inflammatory diseases like COPD, Asthma, and atherosclerosis. These extracellular nucleotides bind to purinergic receptors, e. g. P2X7, promoting a danger signal and lead to inflammatory cell recruitment.   Hypothesis:  We hypothesized a role of the signal axis ATP - P2X7 in the chronic disease of atherosclerosis.   Methods:  LDL-receptor deficient mice (LDLR  -/- ) or P2X7-defcient mice were fed for 16 weeks with High Cholesterol or chow Diet (HCD). P2X7 expression and atherosclerosis was assessed by qPCR and immunohistochemistry. Intravital microscopy was performed in P2X7 competent and deficient mice after stimulation with ATP. Leukocyte migration was assessed by Boyden Chamber Assay.   Results:  We found significant more expression of P2X7 mostly in lesional macrophages in atherosclerotic vessels . In a next step, we crossed LDLR -/-  mice with P2X7 -/-  mice. The P2X7 -/-  LDLR -/-  mice were fed with HCD for 16 weeks. P2X7-competent LDLR -/-  mice served as control group. P2X7-knockout mice contained smaller atherosclerotic lesions in the aortic arches than P2X7-competent mice (lesions mean P2X7 -/-  LDLR -/-  = 0.084cm 2 , lesions mean LDLR -/-  = 0.162cm 2 ; n=20, p=0.004). To gain into the role of P2X7 in leukocyte recruitment, P2X7 competent or deficient mice were stimulated with 100nmol ATP. More leukocytes role and adhere on the vessel wall of P2X7 competent compared to P2X7 deficient mice as shown by intravital microscopy. Moreover the leukocyte migration in the Boyden Chamber Assay is reduced in P2RX7 -/-  LDLR -/-  mice comparing to LDLR -/-  mice after ATP-stimulation.   Conclusions:  We could show that P2X7 is overexpressed in atherosclerosis. P2X7 deficiency leads to less plaque formation in the aortic arches. Mechanistically the leukocyte recruitment is decreased in P2X7 deficient mice after ATP-Stimulation.
Acute Effect of Empagliflozin on Fractional Excretion of Sodium and eGFR in Youth With Type 2 Diabetes
Authors: Petter Bjornstad, Lori Laffel, William V. Tamborlane, Gudrun Simons, Stefan Hantel, Maximilian von Eynatten, Jyothis George, Jan Marquard, David Z.I. Cherney
Journal: Diabetes Care (2018)

Early markers of diabetic kidney disease (DKD), including hyperfiltration and elevated albumin excretion, are common in youth with type 2 diabetes (T2D) (1). Despite the morbidity associated with the development of future DKD in youth-onset T2D, pharmacotherapeutic options to lower hyperglycemia are limited to metformin and insulin, the only drugs approved for use in pediatric patients.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce blood pressure, weight, and hyperglycemia in adults with T2D. Furthermore, a 38% reduction in cardiovascular death and a 39% reduction in incident or worsening nephropathy have been demonstrated with the selective SGLT2 inhibitor empagliflozin in patients with established cardiovascular disease (2,3). In young adults with type 1 diabetes, treatment with the SGLT2 inhibitor empagliflozin for 8 weeks was associated with natriuresis, increased renal vascular resistance, and reductions in glomerular filtration rate (GFR) (using inulin clearances) and renal blood flow (assessed by p -aminohippuric acid clearance) in those with baseline hyperfiltration (4). This renal hemodynamic profile suggested that the 20% reduction in hyperfiltration observed in this trial was due to afferent vasoconstriction and a decline in intraglomerular hypertension (4). In adults with T2D, the reduction in intraglomerular hypertension is typically reflected by a mean reduction in estimated GFR (eGFR) of 2–4 mL/min/1.73 m2 after treatment initiation, followed by a stabilization of eGFR decline compared …
Adrenal Calcifications in an Infant
Authors: Irit Krause, Hila Gavrieli
Journal: New England Journal of Medicine (2018)

A 4-month-old girl was hospitalized with failure to thrive, hepatosplenomegaly, anemia, and hyperlipidemia. Radiography revealed calcification of both adrenal glands. A diagnosis of lysosomal acid lipase deficiency was made.
Stratification of Systemic Lupus Erythematosus Patients Into Three Groups of Disease Activity Progression According to Longitudinal Gene Expression
Authors: Daniel Toro‐Domínguez, Jordi Martorell‐Marugán, Daniel Goldman, Michelle Petri, Pedro Carmona‐Sáez, Marta E. Alarcón‐Riquelme
Journal: Arthritis & Rheumatology (2018)

Objective The highly heterogeneous clinical presentation of systemic lupus erythematosus ( SLE ) is characterized by the unpredictable occurrence of disease flares and organ damage. Attempts to stratify lupus patients have been limited to classification based on clinical information, leading to unsuccessful clinical trials and controversial research results. This study was undertaken to develop and validate a robust method to stratify patients with lupus according to longitudinal disease activity and whole‐genome gene expression data in order to establish subgroups of patients who share disease progression mechanisms. Methods We used a cluster‐based approach to stratify SLE patients based on the correlation between disease activity scores and longitudinal gene expression information. Clustering robustness was evaluated by the bootstrap method, and the clusters were characterized in terms of clinical and functional features. Results We observed a clear partition into 3 different disease clusters in 2 independent sets of patients, one pediatric and one adult, which was not influenced by treatment, race, or other source of bias. Two of the clusters differentiated into a group showing a correlation between the percentage of neutrophils and disease activity progression and a group showing a correlation between the percentage of lymphocytes and disease activity progression. The third cluster, in which the percentage of neutrophils correlated to a lesser degree with disease activity, was functionally more heterogeneous. Patients in the neutrophil‐driven clusters had an increased risk of developing proliferative nephritis. Conclusion Our findings indicate that SLE patients can be stratified into 3 subgroups of patients who show different mechanisms of disease progression and are clinically differentiated. Our results have important implications for treatment options, the design of clinical trials, our understanding of the etiology of the disease, and the prediction of severe glomerulonephritis.
Platelet Counts during Pregnancy
Authors: Jessica A. Reese, Jennifer D. Peck, David R. Deschamps, Jennifer J. McIntosh, Eric J. Knudtson, Deirdra R. Terrell, Sara K. Vesely, James N. George
Journal: New England Journal of Medicine (2018)

Platelet counts of less than 150,000 per cubic millimeter during uncomplicated pregnancies are described as gestational thrombocytopenia if no alternative cause is identified. Platelet counts may be even lower in women with pregnancy-related complications. However, the occurrence and severity of thrombocytopenia throughout pregnancy are not defined.
Abstract 3539: Establishing ubiquitylation patterns in cells: Efficient monitoring of oncogenic ubiquitylation activity
Authors: Peter K. Foote, Xiaolong Lu, Rajesh Singh
Journal: Cancer Research (2018)

Abstract Cells regulate their internal functions by the ubiquitylation of many key proteins, especially onco-proteins and tumor suppressors. As a result, ubiquitin proteasome system (UPS) substrates and the relevant UPS enzymes have been identified as attractive anti-cancer targets. However, traditional methods for monitoring ubiquitylation patterns, including by immunoprecipitation coupled with immunoblot analysis (IP/IB) or by mass spectrometry methods, are either insensitive, low throughput, or highly intensive. Here, we describe three Tandem Ubiquitin Binding Entity (TUBE)-based assays, UbiTest, HT-UbiTest, and UbiQuant S, which provide a platform to efficiently detect ubiquitylation of anti-cancer targets. UbiTest is an immunoblot-based assay, which can be used to easily identify ubiquitlyated proteins. Compared to traditional ubiquitin IP/IB, this assay avoids epitope masking of antibodies caused by ubiquitin modification. HT-UbiTest extends this concept using a TUBE pulldown followed by two-antibody detection in a 96-well plate, and allows high-throughput absolute quantification of a target of interest. UbiQuant S is a high-throughput assay to quantify ubiquitylation status in cells or tissue. Ubiquitylated proteins are identified by energy transfer between AlphaLISA bead-labeled TUBE and antibody against the endogenous protein of interest in a homogenous plate-based assay. Furthermore, we have extended these technologies to identify K63- and K48-linked poly-ubiquitylated proteins using poly-ubiquitin linkage-selective TUBEs. Several prominent therapeutic targets in oncology and immuno-oncology have been used to verify these assays, including Cbl-b and its substrates, p53, and USP7. The efficiency and sensitivity of these assays have wide applications in drug discovery targeting ubiquitylation-dependent signaling pathways. Examples using DUB and ubiquitin ligase inhibitors illustrate the power of this system. These novel assays are versatile tools for understanding the role of ubiquitylation in cancer treatment, and provide platforms to monitor disease biomarkers in response to drug action. Citation Format: Peter K. Foote, Xiaolong Lu, Rajesh Singh. Establishing ubiquitylation patterns in cells: Efficient monitoring of oncogenic ubiquitylation activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3539.