tbuckley/cabot-search huggingface dataset:
Comprehensive Analyses and Prioritization of Tox21 10K Chemicals Affecting Mitochondrial Function by in-Depth Mechanistic Studies
Authors: Menghang Xia, Ruili Huang, Qiang Shi, Windy A. Boyd, Jinghua Zhao, Nuo Sun, Julie R. Rice, Paul E. Dunlap, Amber J. Hackstadt, Matt F. Bridge, Marjolein V. Smith, Sheng Dai, Wei Zheng, Pei-Hsuan Chu, David Gerhold, Kristine L. Witt, Michael DeVito, Jonathan H. Freedman, Christopher P. Austin, Keith A. Houck, Russell S. Thomas, Richard S. Paules, Raymond R. Tice, Anton Simeonov
Journal: Environmental Health Perspectives (2018)

Background: A central challenge in toxicity testing is the large number of chemicals in commerce that lack toxicological assessment. In response, the Tox21 program is re-focusing toxicity testing from animal studies to less expensive and higher throughput in vitro methods using target/pathway-specific, mechanism-driven assays. Objectives: Our objective was to use an in-depth mechanistic study approach to prioritize and characterize the chemicals affecting mitochondrial function. Methods: We used a tiered testing approach to prioritize for more extensive testing 622 compounds identified from a primary, quantitative high-throughput screen of 8,300 unique small molecules, including drugs and industrial chemicals, as potential mitochondrial toxicants by their ability to significantly decrease the mitochondrial membrane potential (MMP). Based on results from secondary MMP assays in HepG2 cells and rat hepatocytes, 34 compounds were selected for testing in tertiary assays that included formation of reactive oxygen species (ROS), upregulation of p53 and nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), mitochondrial oxygen consumption, cellular Parkin translocation, and larval development and ATP status in the nematode Caenorhabditis elegans. Results: A group of known mitochondrial complex inhibitors (e.g., rotenone) and uncouplers (e.g., chlorfenapyr), as well as potential novel complex inhibitors and uncouplers, were detected. From this study, we identified four not well-characterized potential mitochondrial toxicants (lasalocid, picoxystrobin, pinacyanol, and triclocarban) that merit additional in vivo characterization. Conclusions: The tier-based approach for identifying and mechanistically characterizing mitochondrial toxicants can potentially reduce animal use in toxicological testing. https://doi.org/10.1289/EHP2589
Screening for Urinary Incontinence in Women: A Recommendation From the Women's Preventive Services Initiative
Authors: Nancy O'Reilly, Heidi D. Nelson, Jeanne M. Conry, Jennifer Frost, Kimberly D. Gregory, Susan M. Kendig, Maureen Phipps, Alina Salganicoff, Diana Ramos, Christopher Zahn, Amir Qaseem
Journal: Annals of Internal Medicine (2018)

Recommendation on screening for urinary incontinence in women by the Women's Preventive Services Initiative (WPSI), a national coalition of women's health professional organizations and patient representatives. The WPSI's recommendations are intended to guide clinical practice and coverage of services for the Health Resources and Services Administration and other stakeholders. The target audience for this recommendation includes all clinicians providing preventive health care for women, particularly in primary care settings. This recommendation applies to women of all ages, as well as adolescents.The WPSI developed this recommendation after evaluating evidence regarding the benefits and harms of screening for urinary incontinence in women. The evaluation included a systematic review of the accuracy of screening instruments and the benefits and harms of treatments. Indirect evidence was used to link screening and health outcomes in the chain of evidence that might support screening in the absence of direct evidence. The WPSI also considered the effect of screening on symptom progression and avoidance of costly and complex treatments, as well as implementation factors.The WPSI recommends screening women for urinary incontinence annually. Screening ideally should assess whether women experience urinary incontinence and whether it affects their activities and quality of life. The WPSI recommends referring women for further evaluation and treatment if indicated.
Abstract LB-049: Cancer stem cell-produced lysophosphatidic acid reprograms surrounding tumor cells to a stem-like state
Authors: Taha Rakhshandehroo, Jiali Tan, Brandon Grosshart, David Cheresh
Journal: Cancer Research (2018)

Abstract Within a tumor, cancer stem cells (CSCs) represent a small yet highly aggressive, metastatic population that enhances the progression of the surrounding non-CSCs. Here we define lysophosphatidic acid (LPA) as a primary factor produced by pancreatic CSCs that converts non-CSCs to a stem-like fate. LPA promotes increased anchorage independence, drug resistance, self-renewal and stem gene expression including Oct4 and Nanog. Cancer stem cells were found to express high levels of the LPA producing enzyme cPLA2 explaining their production of LPA. Pancreatic cancer cells exposed to the drug Gemcitabine showed a dramatic upregulation of the LPA receptor 4 enabling the cells to become drug resistant and tolerant to a range of microenvironmental stresses. These finding indicate that LPA is a bioactive lipid produced by CSCs that converts surround pancreatic tumor cells to a highly aggressive state. Therapeutic intervention and/or microenvironmental stress will induce non-CSCs to express LPA Receptor 4, thereby making them stress tolerant and drug resistant. Evidence is provided that targeting the LPA receptor pathway may reverse this paracrine effect and thereby reverse cancer progression and drug resistance. Citation Format: Taha Rakhshandehroo, Jiali Tan, Brandon Grosshart, David Cheresh. Cancer stem cell-produced lysophosphatidic acid reprograms surrounding tumor cells to a stem-like state [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 LB-049.
Does Racial Bias Affect NCI-Funded PIs' Willingness to Mentor Prospective Graduate Students?
Authors: Jeffrey D. Robinson, Nathan Dieckmann, Elizabeth Withers, Dena Hassouneh, Charles R. Thomas
Journal: Cancer Research (2018)

Audit studies suggest that racial discrimination disadvantages black individuals in educational/professional advancement. We hypothesized that prospective black male doctoral students would experience greater disparity in responses when seeking access to National Cancer Institute (NCI)-funded principal investigators (PI) compared with prospective white males. Primary aim was to explore response and acceptance rates for black versus white men seeking cancer research mentorship. Identical e-mails were sent to 1,028 randomly selected PIs affiliated with 65 NCI-designated cancer centers from "Lamar Washington" (black; n = 515) or "Brad Anderson" (white; n = 513). Primary outcomes: (i) responses within one week; and (ii) type of response. We used logistic regression to examine effects of condition (black/white) on primary outcomes. Approximately 48.3% and 50.0% of the sample responded to "Lamar" and "Brad," respectively. For responders, 40.9% and 43.7% and "agreed" to meet with Lamar and Brad, respectively. This design did not detect bias by PIs against black prospective male students. Cancer Res; 78(17); 4809-11. ©2018 AACR.
Abstract 3222: Evaluation of associations between circulating proteins and breast cancer risk using genetic variants
Authors: Xiang Shu, Jiandong Bao, Lang Wu, Jirong Long, Xingyi Guo, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Jacques Simard, Douglas F. Easton
Journal: Cancer Research (2018)

Abstract Breast cancer is the most commonly diagnosed cancer in women in many countries. Several circulating protein biomarkers have been identified in relation to breast cancer risk. However, previous studies either had small sample sizes or employed low-throughput techniques. To search for novel biomarkers, we utilized genetic variants as instruments and evaluated over 1,400 proteins in relation to breast cancer risk using data from the Breast Cancer Association Consortium (BCAC). We extracted beta coefficients from reported protein quantitative trait loci (pQTL) derived from genome-wide association studies of circulating proteins. Summary statistics of these pQTL variants associated with breast cancer risk were obtained from 122,977 cases and 105,974 controls of European descent in the BCAC. Associations of genetically predicted protein levels with breast cancer risk were evaluated using the inverse-variance weighted method. For proteins with a significant association, expression levels of the corresponding gene were predicted using genotyping and transcriptomic data from the Genotype-Tissue Expression project and then evaluated for their associations with breast cancer risk. We identified 56 protein biomarkers showing a significant association with breast cancer risk after accounting for multiple comparisons (false discovery rate &amp;lt; 0.05). Among them, levels of 32 proteins were influenced by variants close to a newly reported breast cancer susceptibility locus (9q34.2, ABO). Inverse associations of breast cancer risk were found with membrane proteins such as insulin receptor, insulin-like growth factor receptor 1, hepatocyte growth factor receptor, neurogenic locus notch homolog protein 1, and vascular endothelial growth factor receptor 2, with odds ratios ranging from 0.82 to 0.97 per unit increase in genetic risk scores (p-values ranging from 6.53x10-4 to 3.28x10-8). Genetically predicted expression of five genes, CPNE1, CTSF, TFPI, SCG3, and QSOX2, was found to be associated with breast cancer risk at p &amp;lt;0.05 in the same direction as the associations observed for the corresponding proteins. Results from our study suggest that multiple membrane proteins related to insulin resistance may be linked to breast cancer risk through genetic variants at 9q34.2. Citation Format: Xiang Shu, Jiandong Bao, Lang Wu, Jirong Long, Xingyi Guo, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Jacques Simard, Douglas F. Easton. Evaluation of associations between circulating proteins and breast cancer risk using genetic variants [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 3222.
Healthcare-associated pneumonia in acute care hospitals in European Union/European Economic Area countries: an analysis of data from a point prevalence survey, 2011 to 2012
Authors: Jan Walter, Sebastian Haller, Chantal Quinten, Tommi Kärki, Benedikt Zacher, Tim Eckmanns, Muna Abu Sin, Diamantis Plachouras, Pete Kinross, Carl Suetens
Journal: Eurosurveillance (2018)

An aim of the ECDC point prevalence survey (PPS) in European Union/European Economic Area acute care hospitals was to acquire standardised healthcare-associated infections (HAI) data. We analysed one of the most common HAIs in the ECDC PPS, healthcare-associated pneumonia (HAP). Standardised HAI case definitions were provided and countries were advised to recruit nationally representative subsets of hospitals. We calculated 95% confidence intervals (CIs) around prevalence estimates and adjusted for clustering at hospital level. Of 231,459 patients in the survey, 2,902 (1.3%; 95% CI: 1.2-1.3) fulfilled the case definition for a HAP. HAPs were most frequent in intensive care units (8.1%; 95% CI: 7.4-8.9) and among patients intubated on the day of the survey (15%; 95% CI: 14-17; n = 737 with HAP). The most frequently reported microorganism was Pseudomonas aeruginosa (17% of 1,403 isolates), followed by Staphylococcus aureus (12%) and Klebsiella spp. (12%). Antimicrobial resistance was common among isolated microorganisms. The most frequently prescribed antimicrobial group was penicillins, including combinations with beta-lactamase inhibitors. HAPs occur regularly among intubated and non-intubated patients, with marked differences between medical specialities. HAPs remain a priority for preventive interventions, including surveillance. Our data provide a reference for future prevalence of HAPs at various settings.
Abstract 2491: Nuclear exporter protein XPO1 a novel prognostic and therapeutic target in gastric cancer
Authors: Irfana Muqbil, Zaid Mahdi, Rahman Choudhary, Erkan Baloglu, William Senapedis, Yosef Landesman, Sharon Shacham, Michael Kauffman, Steve Kim, Rafic Beydoun, Richard N. Berri, Anthony Shields, Ramzi M. Mohammad, Asfar S. Azmi
Journal: Cancer Research (2018)

Abstract The high mortality rate associated with Gastric Cancer (GC) indicates the urgent need for actionable therapeutic targets. The nuclear exporter protein exportin 1 (XPO1/CRM1) is the exclusive exporter of many tumor suppressor proteins (TPSs) and growth regulators. XPO1 is often over-expressed in different malignancies leading to aberrant cytoplasmic localization of TSPs and subsequent inactivation. A detailed analysis on the correlation of XPO1 with inflammation-metaplasia-dysplasia-carcinoma sequence progression was performed using immunohistochemistry in 70 GC cases: (a) 10 cases from normal gastric mucosa, (b) 10 cases of stomach with intestinal metaplasia with and without inflammation, (c) 10 cases of mucosa with low-grade dysplasia (d) 10 cases of mucosa with high-grade dysplasia, (e) 10 cases of gastric adenocarcinoma and (f) 20 cases of metastatic gastric carcinoma. A correlation between XPO1 expression, the pathological and clinical features of the disease as well as survival were analyzed. Gastric cancer cell lines were exposed to the Selective Inhibitors of Nuclear Export (SINE) compounds (selinexor, KPT-8602, KPT-185, or the natural agent, leptomycin B (LMB), then analyzed using cytotoxicity and molecular assays. In addition, the activity of selinexor was evaluated in a sub-cutaneous xenograft of gastric cancer cell line NCI-N87. XPO1 served as a prognostic marker for poor outcome as positive staining of XPO1 in GC correlated with aggressive behavior of the disease. Targeting XPO1 using SINE compounds or LMB resulted in inhibition of GC cellular growth (IC50&amp;lt;200 nM), induction of apoptosis and suppression of colony formation (p&amp;lt;0.01). Molecular analysis revealed nuclear retention of several important TSPs, induction of pro-apoptotic proteins and suppression of pro-survival factor Bcl-2. Selinexor given orally at doses of 15 mg/kg twice a week for three weeks caused statistically significant reduction of NCI-N87 tumors in mice (p&amp;lt;0.05). Efficacy studies of SINE compounds in patient derived models of GC are ongoing. Our findings strongly demonstrate the potential of XPO1 to serve not only as a prognostic marker but also as a therapeutic marker in GC that warrants further clinical investigations. Citation Format: Irfana Muqbil, Zaid Mahdi, Rahman Choudhary, Erkan Baloglu, William Senapedis, Yosef Landesman, Sharon Shacham, Michael Kauffman, Steve Kim, Rafic Beydoun, Richard N. Berri, Anthony Shields, Ramzi M. Mohammad, Asfar S. Azmi. Nuclear exporter protein XPO1 a novel prognostic and therapeutic target in gastric cancer [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 2491.
Abstract 2450: The importance of a family of long noncoding RNAs from the Y chromosome in radiotherapy and chemotherapy response of male non-small cell lung cancer
Authors: Tayvia Brownmiller, Jamie Barr, Abby Harold, Erik Bey, Ivan Martinez
Journal: Cancer Research (2018)

Abstract Lung cancer is the number one cause of cancer-related deaths in the United States. The 5-year overall survival rate for patients with non-small cell lung cancer (NSCLC) stands at 18%, with women having a twice better overall survival rate than men. Currently, there is no solid evidence to explain the disparity between gender survival rates. The protein coding genes of the X and Y chromosomes have been relatively well characterized, and previous studies have implicated phenomena such as the dysregulation of X inactivation and the loss of the Y chromosome in a number of cancers. However, the regions of these chromosomes responsible for producing noncoding RNAs (ncRNAs) are not well understood. One such class of ncRNAs are long noncoding RNAs (lncRNAs), which are primarily classified as larger than 200 nucleotides and carry out functions in nearly every cellular process via a variety of mechanisms. In this study, we have identified a novel family of Y chromosome-linked lncRNAs that we hypothesize play a role in NSCLC cell survival. Our preliminary data show a time- and dose-dependent response in expression of the Y chromosome lncRNA family after radiation in radiosensitive NSCLC cell lines but not in radioresistant NSCLC cell lines, and we see a similar trend in response to cisplatin. Additionally, upon knockdown of this family in a sensitive cell line using two different shRNAs, we immediately observed an increase in proliferation of the knockdown cells when compared to shCtrl as well as increased cell viability and resistance to apoptosis in response to radiation, and increased resistance to cisplatin. We plan to further characterize these lncRNAs using methods such as qRT-PCR, virtual Northern blotting, traditional Northern blotting, direct RNA sequencing, cellular fractionation, and fluorescent in situ hybridization and determine their function by shRNA knockdown and subsequent assays to measure cellular processes in response to radiation and chemotherapy. The Identification of a male-specific component of lung cancer would fill a knowledge gap that could provide potential therapeutic targets and new prognostic factors, thereby improving the response rate of men with NSCLC. Citation Format: Tayvia Brownmiller, Jamie Barr, Abby Harold, Erik Bey, Ivan Martinez. The importance of a family of long noncoding RNAs from the Y chromosome in radiotherapy and chemotherapy response of male non-small cell lung cancer [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 2450.
Abstract P188: Preterm Birth is a Predictor of Future Maternal Intima Medial Thickness: The CARDIA Study
Authors: Janet M Catov, Cora E Lewis, Minjae Lee, Patrick R Ramsey, Melissa F Wellons, Erica P Gunderson
Journal: Circulation (2012)

Introduction: Preterm birth (PTB, delivery &lt;37 weeks) may be a marker of a chronic pro- inflammatory response associated with excess risk of coronary artery disease. Hypothesis: We hypothesized that women with PTB would have elevated blood pressure, markers of inflammation (C-reactive protein [CRP], Interleukin-6 [IL-6]) as well as higher intima medial thickness (IMT) in the years following pregnancy. Further, we considered that these differences would persist after removing PTB cases due to self-reported hypertensive disorders of pregnancy (primary reason for indicated PTB). Methods: We studied 916 women (46% Black) who delivered 1,181 live births between enrollment in the Coronary Artery Risk Development in Young Adults (CARDIA) study (age 18-30 years) and 20 years later (age 38-50 years). CRP was measured at years 7, 15 and 20; IL-6 and common carotid IMT (average of the maximum wall thickness of the respective carotid artery segment based on 4 ultrasonic measurements for the common carotid arteries) were measured at year 20. Blood pressure, lipids, and anthropometrics were measured at baseline and 6 follow-up visits. Median concentrations of inflammatory markers and mean IMT were compared in women with and without a history of PTB. Change in blood pressure, lipids, body size and CRP concentrations according to PTB status was also evaluated using generalized estimating equations (GEE). Results: A total of 226 women (24.7%) reported at least one PTB. Women with PTBs had modestly higher pre-pregnancy systolic blood pressure (SBP) compared to women who delivered term births (106.3 vs. 104.9 mmHg, p=0.02); SBP was higher across follow-up (p=0.03 for group differences) and increased more rapidly over 20 years compared to women with term births (p&lt;0.01 for group*time interaction). These differences remained significant after removal of women with hypertension in pregnancy. Women with PTB had modestly higher mean body mass index (BMI) at baseline, and differences were more robust beginning in year 7 of follow up. Compared to women with term births, women with PTB had borderline higher mean IMT at year 20, adjusted for age and BMI (difference=0.016 mm, p=0.06). Adjustment for blood pressure change from baseline to year 20 did not affect the estimate. Adjustment for race attenuated this difference (p=0.33), and after excluding women with self-reported hypertension in pregnancy IMT no longer differed by PTB status. CRP, IL-6 and lipids did not differ according to PTB status. Conclusion: Women with PTBs, regardless of hypertension during pregnancy, had higher blood pressure before pregnancy and in the two decades after pregnancy compared to women with term births. They also higher mean IMTs, explained in part by race. Differences in IMT may be limited to women who reported hypertension in pregnancy, and were not related to inflammatory markers. PTB may mark women at excess risk of atherosclerosis.
Abstract 5429: Targeting Nrf2 anti-oxidative pathway as a novel strategy to suppress IDH1-mutated cancer
Authors: Yang Liu
Journal: Cancer Research (2018)

Abstract Background: Reactive oxygen species are recently recognized as a second messenger that affects many aspects in cell biology. In cancer cells, ROS has been proof closely related to metabolic reprogramming, tumor proliferation, progression and metastasis. In tumors with isocitrate dehydrogenase (IDH) mutations, the neomorphic enzyme results in unusual accumulation of ROS in cancer cells, suggesting distinctive vulnerabilities may be established in these types of cancer. However, the biologic function of ROS in IDH1-mutated cancers remains elusive. Methods: In this study, we explored the ROS homeostasis in IDH1 mutated glioma. We investigated the correlation between ROS scavenging genes and overall survival in 530 IDH1-mutated glioma cases. Mechanistically, we focused on nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway and seek for novel therapeutic strategy by targeting ROS burden in cancer cells. We further investigated the therapeutic value of Nrf2 inhibitor, Brusatol, in IDH1 mutated cancer in vitro and in vivo. Results: We found IDH1 mutation leads to substantial reprogramming in ROS homeostasis, highlighted with prompted ROS generation and detoxification. Stronger expression of ROS scavenging gene predicts drug resistance and poor disease outcome. Enhanced Nrf2-associated scavenging pathway was found essential to maintain reasonable intracellular ROS level during cancer progression. Targeting Nrf2 scavenging pathway not only led to ROS overload, DNA/protein oxidative damage, but also reduced tumor cell proliferation and xenograft growth in vivo. Conclusions: IDH1 mutant glioma highly depend on Nrf2 scavenging pathway to maintain ROS homeostasis. Targeting ROS scavenging might be a novel approach to treat gliomas with IDH1 mutation. Citation Format: Yang Liu. Targeting Nrf2 anti-oxidative pathway as a novel strategy to suppress IDH1-mutated cancer [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 5429.
Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials
Authors: Kenneth B Gordon, Bruce Strober, Mark Lebwohl, Matthias Augustin, Andrew Blauvelt, Yves Poulin, Kim A Papp, Howard Sofen, Lluís Puig, Peter Foley, Mamitaro Ohtsuki, Mary Flack, Ziqian Geng, Yihua Gu, Joaquin M Valdes, Elizabeth H Z Thompson, Hervé Bachelez
Journal: The Lancet (2018)