tbuckley/cabot-search huggingface dataset:
Abstract 3688: Akt pathway genes classify GBM into 6 prognostic subgroups with different clinical and molecular features
Authors: Anna M. Joy, Archana Ramesh, Ivan Smirnov, Anjan Misra, William Shapiro, Heidi Phillips, Ken Aldape, Gordon Mills, Seungchan Kim, Burt Feuerstein
Journal: Cancer Research (2012)

Abstract The Akt pathway is a therapeutic target in Glioblastoma Multiforme (GBM) and an important determinant of patient outcome. However, it is not known if akt pathway variations exist in GBM tumors. To investigate we developed a list of Akt pathway genes and investigated expression subgroups in a set of human GBM. Akt classification divides GBM into 6 subgroups with differing survivals and clinical/molecular features. Median survival of patients in the longest surviving subgroup (subgroup 5) was 3.9 yr vs 0.75 yr for patients in the shortest surviving subgroup (p &amp;lt; 0.01 Bonferroni corrected log rank). Patients in the long surviving subgroup were younger than the rest (median age = 38 vs 49 respectively; p = 0.05 corrected for multiple comparisons), but survival differences were independent of age (p = 0.027; subgroup 5 vs the rest). Tumors in short surviving subgroups were characterized by chr7 gain, chr10 loss and high ser473 phosphorylated-akt (p-akt) staining. The long surviving subgroup tumors were enriched for chr19q loss, low p-akt staining, elevated Notch staining and had no DNA copy number alterations in chr7 or chr10. Previously described subgroups (Phillips et.al.) were enriched in akt subgroups (all with p&amp;lt;0.001). These results suggest that tumors with a pathological diagnosis of GBM are a collection of molecular subgroups with fundamental differences in biology and clinical behavior. We hypothesize that Akt subgroups will enhance drug discovery and help personalize treatment for GBM therapeutics. Supported by Barrow Neurological Foundation (BGF and AMJ), Halle Family Foundation (BGF), and NIH 1 K01 NS064952-01A1 (AMJ). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3688. doi:1538-7445.AM2012-3688
Abstract 2497: ET-743 interferes with EWS-FLI1 driven WRN expression in Ewing sarcoma cells and sensitizes to topoisomerase I inhibitors
Authors: Laura E. Segars, Arnulfo Mendoza, Lee J. Helman, Patrick J. Grohar
Journal: Cancer Research (2012)

Abstract The hallmark of Ewing sarcoma is the EWS-FLI1 transcription factor believed to be responsible for oncogenesis and tumor progression. ET-743 (Trabectedin, Yondelis™) is a natural product recently identified as a particularly active agent for Ewing sarcoma cells in vitro. We have recently demonstrated that ET-743 interferes with the activity of the oncogenic transcription factor EWS-FLI1. In this report, we examine the link between EWS-FLI1 suppression and the DNA damage response. We hypothesize that blocking the EWS-FLI1 associated DNA damage response may confer additional sensitivity to specific cytotoxic agents. DNA repair pathways and EWS-FLI1 targets were evaluated by microarray expression, western blot analysis and siRNA interference. Microarray expression and western blot analysis revealed that ET-743 suppresses WRN and XRCC4 expression, critical proteins in the Non-Homologous End Joining Pathway (NHEJ) repair pathway. Further siRNA data showed that the EWS-FLI1 transcription factor drives the expression of WRN. These results suggest that WRN suppression by ET-743 is occurring through an EWS-FLI1 dependent mechanism. Since the NHEJ pathway is associated with resistance to specific chemotherapeutic agents, several combination therapies were investigated in vitro. ESFT cells show heightened sensitivity to the combination of ET-743 and the topoisomerase I inhibitor, SN-38. This result was unique to topoisomerase I inhibitors and further restricted to ESFT cell lines. Consistent with these results, previous reports have established that WRN deficient cells are hypersensitive to topoisomerase I but not topoisomerase II inhibitors. Additionally, we found that irinotecan augments the ET-743 mediated transcriptional inhibition of EWS-FLI1. Taken together these mechanisms account for the heightened sensitivity of the combination of ET-743 and irinotecan observed both in vitro and in vivo in two different ESFT xenograft models. In summary, by employing a mechanism based approach, we have identified a novel combination therapy of ET-743 and irinotecan. By linking the EWS-FLI1 transcriptional program to the DNA damage response in ESFT cells, we expose an inherent weakness to topoisomerase I inhibitors thus creating a cell type specific sensitivity to the drug. This report provides a novel method of oncogenic transcription factor targeting that involves direct suppression of downstream targets and exploitation of the resulting changes in gene expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2497. doi:1538-7445.AM2012-2497
Uses of NHANES Biomarker Data for Chemical Risk Assessment: Trends, Challenges, and Opportunities
Authors: Jon R. Sobus, Robert S. DeWoskin, Yu-Mei Tan, Joachim D. Pleil, Martin Blake Phillips, Barbara Jane George, Krista Christensen, Dina M. Schreinemachers, Marc A. Williams, Elaine A. Cohen Hubal, Stephen W. Edwards
Journal: Environmental Health Perspectives (2015)

Each year, the U.S. NHANES measures hundreds of chemical biomarkers in samples from thousands of study participants. These biomarker measurements are used to establish population reference ranges, track exposure trends, identify population subsets with elevated exposures, and prioritize research needs. There is now interest in further utilizing the NHANES data to inform chemical risk assessments.This article highlights a) the extent to which U.S. NHANES chemical biomarker data have been evaluated, b) groups of chemicals that have been studied, c) data analysis approaches and challenges, and d) opportunities for using these data to inform risk assessments.A literature search (1999-2013) was performed to identify publications in which U.S. NHANES data were reported. Manual curation identified only the subset of publications that clearly utilized chemical biomarker data. This subset was evaluated for chemical groupings, data analysis approaches, and overall trends.A small percentage of the sampled NHANES-related publications reported on chemical biomarkers (8% yearly average). Of 11 chemical groups, metals/metalloids were most frequently evaluated (49%), followed by pesticides (9%) and environmental phenols (7%). Studies of multiple chemical groups were also common (8%). Publications linking chemical biomarkers to health metrics have increased dramatically in recent years. New studies are addressing challenges related to NHANES data interpretation in health risk contexts.This article demonstrates growing use of NHANES chemical biomarker data in studies that can impact risk assessments. Best practices for analysis and interpretation must be defined and adopted to allow the full potential of NHANES to be realized.
Randomized Clinical Trial of Diethylstilbestrol versus Tamoxifen in Postmenopausal Women with Advanced Breast Cancer
Authors: James N. Ingle, David L. Ahmann, Stephanie J. Green, John H. Edmonson, Harry F. Bisel, Larry K. Kvols, William C. Nichols, Edward T. Creagan, Richard G. Hahn, Joseph Rubin, Stephen Frytak
Journal: New England Journal of Medicine (1981)

Before the introduction of tamoxifen, diethylstilbestrol (DES) was widely considered to be the hormonal treatment of choice in postmenopausal women with advanced breast cancer. We performed a randomized clinical trial of these two agents to determine their relative efficacy and toxicity. The trial involved 143 evaluable patients, of whom 99 had received no prior systemic therapy and 44 had received previous chemotherapy. The regression rates (complete plus partial) were higher in patients receiving DES (41 per cent) than in those receiving tamoxifen (33 per cent), but not significantly so (P = 0.37). In patients who had had no prior systemic therapy, the rates were 44 per cent and 38 per cent, respectively (P = 0.55), and in those who had had previous chemotherapy, 32 per cent vs. 23 per cent (P = 0.50). Analysis of the time until treatment failure for the two treatment groups showed no significant difference (medians: DES, 142 days; tamoxifen, 171 days). Toxicity was greater in patients receiving DES; nine of 74 patients (12 per cent) discontinued therapy solely because of adverse reactions. Since there was no statistically significant difference in efficacy and since tamoxifen was less toxic, tamoxifen appears to be the preferred agent. (N Engl J Med. 1981; 304:16–21.)
Abstract 545: Autocrine growth regulation by PEDF is mediated by ovarian steroid hormones: Implications in the pathogenesis of endometrial carcinoma
Authors: Kuang-Tzu Huang, Savvas C. Pavlides, Khushbakhat Mittal, Stephanie V. Blank, Susan E. Crawford, Leslie I. Gold
Journal: Cancer Research (2012)

Abstract The angiogenic inhibitor and neurotrophic factor, pigment epithelium-derived factor (PEDF) was first shown in the eye and is now shown to be expressed in a number of tissues and to function in apoptosis and growth inhibition. The importance of PEDF in growth regulation of the endometrium is reflected in PEDF null mice, which develop endometrial hyperplasia. Therefore, we hypothesized that PEDF is decreased in human endometrial carcinoma with loss of growth inhibition. We show by immunostaining (n=44) that PEDF expression is decreased in both stromal and epithelial cells in atypical endometrial hyperplasia (AEH), the precursor to type I endometrial carcinoma (ECA; 80% of all ECAs) and ECA. Whereas PEDF is highly expressed by primary endometrial epithelial cells (EECs) and stromal cells, ECA cells synthesize less protein and stromal cells isolated from malignant endometrium (cancer associated fibroblasts; CAFs) synthesize 80% less PEDF mRNA (n=35) by quantitative real time PCR and less PEDF protein. In addition, whereas exogenous recombinant PEDF inhibits proliferation of ECA cell lines (e.g. HEC-1B by 40%; peak response at 4nM), PEDF antibodies and PEDF siRNA stimulate proliferation suggesting PEDF inhibits cell proliferation in an autocrine manner in the endometrium. Estrogen (E2) stimulates and progesterone (Pg) inhibits proliferation of the endometrium in a cyclical manner. Due to these hormonal growth regulatory effects, E2 induces AEH and Type I ECA and Pg is a successful therapeutic agent for these diseases. Therefore, we further hypothesized that E2 decreases PEDF causing dysreglated growth and conversely, that Pg might inhibit growth by increasing PEDF. Indeed, we show that treatment of the ECA cell lines, HEC-1A, HEC-1B, KLE and primary EECs with E2 decreased PEDF mRNA and protein expression, which was blocked by the estrogen receptor (ER) antagonist, ICI 182,780. In direct contrast, Pg increased PEDF mRNA and protein, which was blocked by the antagonist, RU486. It is notable that the PEDF promoter contains two putative PREs and one ERE thereby justifying these responses. Taken together, our data implicate PEDF as an autocrine hormone-regulated inhibitor of endometrial growth and suggest that the E2-driven decrease in PEDF leads to dysregulated endometrial growth as an important molecular target in the pathogenesis of type I ECA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 545. doi:1538-7445.AM2012-545
AB0718 Relationship between Disease Activity and Cardiovascular Comorbidities in Ankylosing Spondylitis
Authors: R. Balabanova, M. Podryadnova, M. Urumova, S. Erdes
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> In ankylosing spondylitis hart and vascular involvement mainly due to systemic process. <h3>Objectives</h3> To assess prevalence and specification of cardiovascular comorbidities, its relationship with disease activity in AS patients. <h3>Methods</h3> We studied 200 AS pts (m:f 146:54): mean age 34,9±9,5, disease duration 49 [5-396] month, mean age of disease onset 30,1±9,7, 72% were with axial involvement. ECG, echocardiography, metabolic syndrome characteristics were accessed. <h3>Results</h3> Mean body mass index was 25±4,4, including 53% pts wit overweight. 78 (39%) from the 200 pts performed dislipidemiya: higher cholesterol level (18%), LDL (38%), decrease of HDL (2%). Pathological changes on the ECG were detected in 40% cases: hypertrophy of the left ventricular myocardium (11, 2%), incomplete bundle-branch block (11,2%), and atrioventricular block (5%). Echocardiography present in 24 pts. Pericarditis with a small effusion detected in 17% pts, 46% pts had induration/dilatation of aorta, valve apparatus deficiency mostly 1 stage -mitral (63%), tricuspid (50%), pulmonary (21%), aortic (8%). Arterial hypertension (AH) were performed in 48 pts (24%), mean age 44,0±7,7, other 52 pts have no AH (middle age 33,0±6,6 years). In AH pts 75% were with high level of BASDAI (&gt;4) (p=0,0017). <h3>Conclusions</h3> Pathological changes on the ECG and Echocardiography have no significant clinical manifestations. AH developed significantly more frequently in AS patients with high disease activity. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3643
Abstract 3193: NPV-LDE-225 (Erismodegib) inhibits human prostate cancer stem cell growth in NOD/SCID IL2Rγ null mice by regulating Bmi-1 and microRNA-128.
Authors: Rajesh Nanta, Sharmila Shankar, Rakesh K. Srivastava
Journal: Cancer Research (2013)

Abstract Prostate cancer stem cells (CSCs) are defined by their extensive self-renewal, differentiation, and tumor initiation properties. It is now clear that CSCs are involved in tumor growth and recurrence, and resistance to conventional treatments. Thus, the strategy that suppresses stemness and consequently tumorigenic potential of CSCs could be considered for the management of prostate cancer. The objectives of this study were to examine the molecular mechanisms by which NPV-LDE-225 / Erismodegib (smoothened inhibitor) regulates stem cell characteristics in prostate cancer. Effects of NPV-LDE-225 on CSC's viability, sphere formation, apoptosis, transcriptional activity, and epithelial-mesenchymal transition (EMT) were measured. NPV-LDE-225 inhibited cell viability and spheroid formation, and induced apoptosis by activation of caspase-3 and cleavage of PARP. NPV-LDE-225 induced expression of Bax and Bak, and inhibited the expression of Bcl-2, Bcl-XL, XIAP, cIAP1, cIAP2 and survivin. NPV-LDE-225 inhibited Gli transcriptional activity, Gli-DNA interaction, and the expression of Gli1, Gli2, Patched1 and Patched 2 in prostate CSCs. Interestingly, NPV-LDE-225 induced PDCD4 and apoptosis and inhibited cell viability by suppressing miR-21. Furthermore, NPV-LDE-225 inhibited pluripotency maintaining factors Nanog, Oct4, cMyc and Sox-2. The inhibition of Bmi-1 by NPV-LDE-225 was regulated by up-regulation of miR-128. NPV-LDE-225 suppressed EMT by up-regulating E-cadherin and inhibiting N-cadherin, Snail, Slug and Zeb1 through regulating miR-200 family. Finally, NPV-LDE-225 inhibited CSC tumor growth which was associated with the suppression of Gli1, Gli2, Patched-1, Patched-2, Cyclin D1 and PCNA, and cleaved caspase-3 and PARP in tumor tissues derived from NOD/SCID IL2Rγ null mice. Overall, our findings suggest that inhibition of the Shh signaling pathway in CSCs is a potential therapeutic strategy for prostate cancer. Citation Format: Rajesh Nanta, Sharmila Shankar, Rakesh K. Srivastava. NPV-LDE-225 (Erismodegib) inhibits human prostate cancer stem cell growth in NOD/SCID IL2Rγ null mice by regulating Bmi-1 and microRNA-128. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3193. doi:10.1158/1538-7445.AM2013-3193
Abstract 1956: High-throughput screens identify microRNAs essential for HER2-positive breast cancer cell growth.
Authors: Suvi-Katri Leivonen, Kristine Kleivi Sahlberg, Rami Makela, Olli Kallioniemi, Anne-Lise Borresen-Dale, Merja Perala
Journal: Cancer Research (2013)

Abstract MicroRNAs (miRNAs) are small non-coding RNAs regulating gene expression post-transcriptionally. Due to their capability to target multiple genes, often in a same pathway, miRNAs would be ideal candidates for therapeutic targeting. Here, our aim was to characterize the role of miRNAs in the regulation of HER2-signaling in breast cancer. HER2 is a receptor tyrosine kinase amplified in over 20% of human breast cancers and it regulates many important cellular processes, including cell growth and survival. HER2 mediates its signals by activating downstream pathways, such as phosphatidyl-inositol-3 kinase (PI3K)/AKT and the mitogen-activated protein kinases. We performed miRNA gain-of-function assays by screening two HER2-positive cell lines (KPL-4 and JIMT-1) with a miRNA mimic library consisting of 810 human miRNAs. The levels of HER2, phospho-AKT, phospho-ERK1/2, cell proliferation (Ki67) and apoptosis (cleaved PARP) were detected with specific antibodies using protein lysate microarrays. In order to find the miRNAs most efficiently inhibiting HER2 signaling and proliferation as well as inducing apoptosis, we did rank product analyses through the whole data matrix. These analyses resulted in 38 miRNAs (q≤0.05). Among them were miR-491-5p, miR-342-5p and miR-744*, which were significantly (p≤0.05) down-regulated in HER2-positive breast tumors as compared to HER2-negative tumors. miR-342-5p appeared to specifically inhibit HER2-positive cell growth, as it had no effect on the growth of HER2-negative control cell line. Furthermore, higher expression of miR-342-5p was associated with better survival in breast cancer patients. We characterized also miRNAs directly targeting HER2 and identified eight novel miRNAs (miR-552, miR-541, miR-193a-5p, miR-453, miR-134, miR-498, miR-449b, and miR-449a) as direct regulators of the HER2 3’UTR. Taken together, the miRNAs identified here are potent negative regulators of HER2 function and they may also play a role in vivo during breast cancer progression. These results suggest mechanistic insights in HER2 regulation in breast cancer and open potential new strategies towards prevention and therapeutic inhibition of HER2-positive breast cancer. Citation Format: Suvi-Katri Leivonen, Kristine Kleivi Sahlberg, Rami Makela, Olli Kallioniemi, Anne-Lise Borresen-Dale, Merja Perala. High-throughput screens identify microRNAs essential for HER2-positive breast cancer cell growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1956. doi:10.1158/1538-7445.AM2013-1956
Abstract 3651: Parity-related molecular signatures and breast cancer heterogeneity.
Authors: Melissa Rotunno, Xuezheng Sun, Jonine Figueroa, Mark Sherman, Montserrat Garcia-Closas, Paul Meltzer, Tyisha Williams, Sallie Smith Schneider, Joseph Jerry, Rose Yang, Melissa Troester
Journal: Cancer Research (2013)

Abstract Background. Parity is an established protective factor for ER-positive but not ER-negative breast cancer and it may increase the risk of triple-negative (negative for ER, PR, and HER2) tumors. Characterizing parity-related gene expression patterns in normal breast and breast tumor tissues may improve our understanding of the biological mechanisms underlying the subtype-specific associations between parity and breast cancer risk. Method. Gene expression changes associated with parity were identified in microarray data (4x44 K Agilent) from breast tissue of 74 non-diseased reduction mammoplasty (RM) patients. This parity signature, together with published parity signatures, were compared by GSEA method with gene expression (4x44 K Agilent and Illumina arrays) from both normal (N=150) and tumor (N=208) tissues of breast cancer patients from the Polish Breast Cancer Study (PBCS), overall and by tumor ER status. Results. We identified 908 genes significantly up-regulated by parity status (parous vs. nulliparous, FDR = 0.047), including genes in inflammatory pathways. Parity-related signatures identified by us and by previously published studies were significantly enriched in normal and tumor tissue of parous PBCS patients, specifically in ER-positive tumors (FWER&amp;lt;0.1). Conclusions. Our analysis identified a novel parity-related gene signature in normal breast tissue from healthy women, which is also detected in normal and tumor tissues in breast cancer patients with ER-positive tumors. The lack of parity-associated signatures in ER-negative tumors may reflect the disruption of parity-associated pathways (pro-inflammatory) in ER-negative tumors. Citation Format: Melissa Rotunno, Xuezheng Sun, Jonine Figueroa, Mark Sherman, Montserrat Garcia-Closas, Paul Meltzer, Tyisha Williams, Sallie Smith Schneider, Joseph Jerry, Rose Yang, Melissa Troester. Parity-related molecular signatures and breast cancer heterogeneity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3651. doi:10.1158/1538-7445.AM2013-3651
β-Adrenergic Bronchodilators
Authors: Harold S. Nelson
Journal: New England Journal of Medicine (1995)

Of the three classes of bronchodilators (β2-adrenergic–receptor agonists, methylxanthines, and anticholinergic agents), the β2-adrenergic–receptor agonists produce the greatest bronchodilation in patients with bronchial asthma.1 β2-Adrenergic agonists are generally preferred both for the relief of acute symptoms2,3 and for the prevention of exercise-induced bronchospasm.4 The recent introduction of long-acting inhaled β2-adrenergic agonists has overcome the principal shortcoming of the previously available drugs of this class, their limited duration of action. However, the possibility of adverse effects with regular use of β2-adrenergic agonists has been raised.57 In this article I . . .