tbuckley/cabot-search huggingface dataset:
Abstract 11676: Left Ventricular Property in Hypertensive Patients Assessed by the Novel Automated One-Beat Real-Time Three-dimensional Speckle Tracking Echocardiography With High Volume Rates
Authors: NoriakiSato, MasanoriKawasaki, RyuheiTanaka, ShingoMinatoguchi, HeleneHoule, TomokoFujii, YoshiakiGoto, KojiOno, KazuoAmano, HidemaroSato, KoshiGoto, MayumiKaneda, MasafumiKawade, ShunichiroWarita, TakeshiHirose, MakotoIwama, ToshiyukiNoda, SachiroWatanabe, ShinyaMinatoguchi
Journal: Circulation (2014)

Background: Left ventricular (LV) systolic and diastolic properties in patients with hypertension (HTN) are deteriorated by pressure overload, resulting in heart failure with reduced or preserved ejection fraction (EF). We developed novel one-beat real-time 3-dimensional speckle tracking echocardiography (3D-STE) with high volume rates to measure LV contractility and relaxation. Thus, we examined LV systolic properties such as LVEF, LV stroke work (SW) and contractility and LV diastolic properties such as LV relaxation and stiffness in HTN with or without LV hypertrophy (LVH) using novel 3D-STE. Methods: We examined HTN patients without LVH (n=45, age: 70±8), HTN patients with LVH (n=45, age: 70±5) and controls (n=60, age: 69±10). LV contractility and relaxation were assessed by LV strain rate (SR) during systole and isovolumic relaxation (IVR) using novel 3D-STE. Pulmonary capillary wedge pressure (PCWP) was estimated as 10.7 - 12.4 x log {left atrial (LA) active emptying function / minimum LA volume} as...
Medications for Alcohol and Opioid Use Disorders and Risk of Suicidal Behavior, Accidental Overdoses, and Crime
Authors: Yasmina Molero, Johan Zetterqvist, Ingrid A. Binswanger, Clara Hellner, Henrik Larsson, Seena Fazel
Journal: American Journal of Psychiatry (2018)

Objective: The authors examined associations between medications for alcohol and opioid use disorders (acamprosate, naltrexone, methadone, and buprenorphine) and suicidal behavior, accidental overdoses, and crime. Method: In this total population cohort study, 21,281 individuals who received treatment with at least one of the four medications between 2005 and 2013 were identified. Data on medication use and outcomes were collected from Swedish population-based registers. A within-individual design (using stratified Cox proportional hazards regression models) was used to compare rates of suicidal behavior, accidental overdoses, and crime for the same individuals during the period when they were receiving the medication compared with the period when they were not. Results: No significant associations with any of the primary outcomes were found for acamprosate. For naltrexone, there was a reduction in the hazard ratio for accidental overdoses during periods when individuals received treatment compared with periods when they did not (hazard ratio=0.82, 95% CI=0.70, 0.96). Buprenorphine was associated with reduced arrest rates for all crime categories (i.e., violent, nonviolent, and substance-related) as well as reduction in accidental overdoses (hazard ratio=0.75, 95% CI=0.60, 0.93). For methadone, there were significant reductions in the rate of suicidal behaviors (hazard ratio=0.60, 95% CI=0.40–0.88) as well as reductions in all crime categories. However, there was an increased risk for accidental overdoses among individuals taking methadone (hazard ratio=1.25, 95% CI=1.13, 1.38). Conclusions: Medications currently used to treat alcohol and opioid use disorders also appear to reduce suicidality and crime during treatment.
Identification of anti-Gram-negative bacteria agents targeting the interaction between ribosomal proteins L12 and L10
Authors: Weiwei Wang, Chao Liu, Ningyu Zhu, Yuan Lin, Jiandong Jiang, Yanchang Wang, Yan Li, Shuyi Si
Journal: Acta Pharmaceutica Sinica B (2018)

Gram-negative bacteria have become the main pathogens and cause serious clinical problems with increased morbidity and mortality. However, the slow discovery of new antimicrobial agents is unable to meet the need for the treatment of bacterial infections caused by drug-resistant strains. The interaction of L12 and L10 is essential for ribosomal function and protein synthesis. In this study, a yeast two-hybrid system was established to successfully detect the interaction between L12 and L10 proteins from gram-negative bacteria Escherichia coli, which allows us to screen compounds that specifically disrupt this interaction. With this system, we identified two compounds IMB-84 and IMB-87 that block L12-L10 interaction and show bactericidal activity against E. coli. We used glutathione-S-transferase (GST) pull-down and surface plasmon resonance (SPR) assays to demonstrate that these compounds disrupt L12-L10 interaction in vitro and the target of compounds was further confirmed by the overexpression of target proteins. Moreover, protein synthesis and elongation factor G-dependent GTPase activities are inhibited by two compounds. Therefore, we have identified two antibacterial agents that disrupt L12-L10 interaction by using yeast two-hybrid system.
Abstract 567: The lysosomal transporter SLC46A3 is a potential predictive biomarker for antibody-drug conjugates bearing the non-cleavable warheads SG3376 and DM1
Authors: Krista Kinneer, Yu-Tzu Tai, Sriram Sridhar, John Meekin, Sandrina Phipps, Ben Ruddle, Ryan Fleming, Nazzareno Dimasi, Ronald Herbst, Arnaud Tiberghien, Luke Masterson, Philip Howard, Kenneth Anderson, David Tice
Journal: Cancer Research (2018)

Abstract Antibody drug conjugates (ADCs) combine a monoclonal antibody with a potent cytotoxic drug to preferentially eliminate antigen-positive cells for the treatment of cancer. ADCs bearing non-cleavable drug-linkers such as the pyrrolobenzodiazepine (PBD) SG3376 or the maytansinoid DM1 rely upon lysosomal degradation of the antibody for release of the cytotoxic warheads, which must then escape the lysosome and bind to their intracellular targets. We sought to identify the mechanism of lysosomal transport of these membrane-insoluble warheads and have recently reported that the lysosomal transporter SLC46A3 is required for cytotoxic activity of ADCs bearing SG3376 and DM1, and that loss of SLC46A3 is a mechanism of acquired resistance to Trastuzumab-DM1 (T-DM1). Here we explore the potential translational relevance of SLC46A3. Analysis of SLC46A3 mRNA expression across several tumors showed that breast cancer cell lines and primary tumor samples have relatively high levels of SLC46A3 compared to samples derived from multiple myeloma (MM), esophageal, and upper aerodigestive tract malignancies, all of which are being targeted in clinical trials with non-cleavable DM1 ADCs. Deeper analysis indicates that levels of SLC46A3 are decreased in MM patients compared to healthy donors, and levels are further decreased in the relapsed/refractory setting compared to samples taken at diagnosis. We measured the expression of SLC46A3 in a panel of MM cell lines by RT-PCR and found that 5 of 9 (56%) had undetectable levels of SLC46A3. In vitro cytotoxicity assays demonstrate that SLC46A3-negative cells are resistant to B-cell maturation antigen (BCMA)-targeted ADCs prepared with non-cleavable DM1 and SG3376 warheads, but remain sensitive to the cleavable payload PBD SG3249 (Tesirine). Taken together, our results suggest that SLC46A3 may be a predictive response marker for ADCs bearing the non-cleavable warheads SG3376 and DM1, and this marker may be particularly useful in trials involving MM. Citation Format: Krista Kinneer, Yu-Tzu Tai, Sriram Sridhar, John Meekin, Sandrina Phipps, Ben Ruddle, Ryan Fleming, Nazzareno Dimasi, Ronald Herbst, Arnaud Tiberghien, Luke Masterson, Philip Howard, Kenneth Anderson, David Tice. The lysosomal transporter SLC46A3 is a potential predictive biomarker for antibody-drug conjugates bearing the non-cleavable warheads SG3376 and DM1 [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 567.
Abstract 15988: Worsening Somatic Depressive Symptoms Are Associated With Increased Mortality in Patients With Heart Failure
Authors: Boyoung Hwang, Debra K Moser, Michele M Pelter, Kathleen Dracup
Journal: Circulation (2013)

Background: Depression is prevalent in patients with heart failure (HF) and is associated with poor prognosis. However, the effect of changes in specific symptoms over time on mortality of HF patients is not known. Objective: To examine whether changes in cognitive and somatic symptoms of depression over time predict mortality of HF patients. Methods: In this secondary analysis of data from the REMOTE-HF clinical trial, we analyzed data from 451 HF patients who survived at least 1 year and completed the 9-item Patient Health Questionnaire (PHQ-9) at 1 year (40% female, age 65.7 ± 12.8 years, ejection fraction [EF] = 39.0 ± 15.1%, 87.3% NYHA class II or III). Depressive symptoms were assessed with the PHQ-9 at baseline and at 1 year. Based on published PHQ-9 factor models, cognitive and somatic scores were calculated, respectively. Medical records were reviewed for clinical data. Controlling for baseline depressive symptoms and demographic and clinical characteristics, Cox proportional-hazards regression a...
Comparison of Exercise Performance in Patients With Chronic Severe Heart Failure Versus Left Ventricular Assist Devices
Authors: DonnaMancini, RochelleGoldsmith, HowardLevin, AinatBeniaminovitz, EricRose, KatharineCatanese, MargaretFlannery, MehmetOz
Journal: Circulation (1998)

Background—Left ventricular assist devices (LVADs) are frequently used as a bridge to cardiac transplantation and may be useful as long-term therapy. The purpose of this study was to compare the exercise performance of LVAD patients with that of ambulatory heart failure patients. Methods and Results—Exercise testing with hemodynamic and respiratory gas measurements was performed in 65 congestive heart failure (CHF) patients (age 53±10 years) and 20 LVAD patients (age 49±8 years). Peak Vo2 was significantly higher in the LVAD than the CHF patients (CHF, 12±3; LVAD, 15.9±3.8 mL · kg−1 · min−1; P<0.001), as was the Vo2 at the anaerobic threshold (CHF, 8.1±2.1; LVAD, 12.2±2.9 mL · kg−1 · min−1; P<0.001). At rest, mean arterial blood pressure (CHF, 87±11; LVAD, 94±9 mm Hg) and cardiac output (CHF, 4±1; LVAD, 4.9±0.9 L/min) were increased, whereas mean pulmonary artery pressure (CHF, 28±11; LVAD, 18±4 mm Hg) and pulmonary artery wedge pressure (CHF, 16±10; LVAD 5±3 mm Hg) were reduced (all P<0.01). At peak ex...
Role of Asymmetric Dimethylarginine in Vascular Injury in Transgenic Mice Overexpressing Dimethylarginie Dimethylaminohydrolase 2
Authors: KazuhiroHasegawa, ShuWakino, SatoruTatematsu, KyokoYoshioka, KoichiroHomma, NaokiSugano, MasumiKimoto, KoichiHayashi, HiroshiItoh
Journal: Circulation Research (2007)

Dimethylarginie dimethylaminohydrolase (DDAH) degrades asymmetric dimethylarginine (ADMA), an endogenous nitric oxide (NO) synthase inhibitor, and comprises 2 isoforms, DDAH1 and DDAH2. To investigate the in vivo role of DDAH2, we generated trangenic mice overexpressing DDAH2. The transgenic mice manifested reductions in plasma ADMA and elevations in cardiac NO levels but no changes in systemic blood pressure (SBP), compared with the wild-type mice. When infused into wild-type mice for 4 weeks, ADMA elevated SBP and caused marked medial thickening and perivascular fibrosis in coronary microvessels, which were accompanied by ACE protein upregulation and cardiac oxidative stress. The treatment with amlodipine reduced SBP but failed to ameliorate the ADMA-induced histological changes. In contrast, these changes were abolished in transgenic mice, with a reduction in plasma ADMA. In coronary artery endothelial cells, ADMA activated p38 MAP kinase and the ADMA-induced ACE upregulation was suppressed by p38 MAP ...
Cellular Effects of β-Particle Delivery on Vascular Smooth Muscle Cells and Endothelial Cells
Authors: JeannetteFareh, RémiMartel, PounehKermani, GuyLeclerc
Journal: Circulation (1999)

Background—Although endovascular radiotherapy inhibits neointimal hyperplasia, the exact cellular alterations induced by β irradiation remain to be elucidated. Methods and Results—We investigated in vitro the ability of 32P-labeled oligonucleotides to alter (1) proliferation of human and porcine vascular smooth muscle cells (VSMCs) and human coronary artery endothelial cells (ECs), (2) cell cycle progression, (3) cell viability and apoptosis, (4) cell migration, and (5) cell phenotype and morphological features. β radiation significantly reduced proliferation of VSMCs (ED50 1.10 Gy) and ECs (ED50 2.15 Gy) in a dose-dependent manner. Exposure to β emission interfered with cell cycle progression, with induction of G0/G1 arrest in VSMCs, without evidence of cell viability alteration, apoptosis, or ultrastructural changes. This strategy also proved to efficiently inhibit VSMC migration by 80% and induce contractile phenotype appearance, as shown by the predominance of α-actin immunostaining in β-irradiated ce...
Abstract 4258: Magnesium intake and mortality due to liver cancer and other liver diseases: Results from the Third National Health and Nutrition Examination Survey Cohort
Authors: Zhu Xiangzhu, Lijun Wu, Lei Fan, Edmond K Kabagambe, Yiqing Song, Menghua Tao, Xiaosong Zhong, Lifang Hou, Martha J. Shrubsole, Jie Liu, Qi Dai
Journal: Cancer Research (2018)

Abstract People with fatty liver disease are at high risk of magnesium deficiency. Meanwhile, low magnesium status is linked to both chronic inflammation and insulin resistance. However, no study has investigated the association between intake of magnesium and risk of mortality due to liver cancer and other liver diseases. We evaluated the association between total magnesium intake and mortality due to liver cancer and other liver diseases in the Third National Health and Nutrition Examination Study (NHANES III) cohort, which included 13,504 participants who completed liver ultrasound examination for hepatic steatosis. Overall magnesium intake was associated with a reduced risk of mortality due to liver cancer and other liver disease at borderline significance (P=0.05). In multi-variable adjusted models, every 100 mg increase in intake of magnesium was associated with a 49% reduction in the risk for mortality due to liver cancer and other liver diseases. Although interactions between magnesium intake and alcohol use and hepatic steatosis at baseline were not significant (P&amp;gt;0.05), inverse associations between magnesium intake with liver cancer and other liver disease mortality were stronger among alcohol drinkers and those with hepatic steatosis. Our novel findings suggest higher intakes of magnesium may be associated with a reduced risk of mortality due to liver cancer and other liver disease particularly among alcohol drinkers and those with hepatic steatosis. Further studies are warranted to confirm the findings. Citation Format: Zhu Xiangzhu, Lijun Wu, Lei Fan, Edmond K Kabagambe, Yiqing Song, Menghua Tao, Xiaosong Zhong, Lifang Hou, Martha J. Shrubsole, Jie Liu, Qi Dai. Magnesium intake and mortality due to liver cancer and other liver diseases: Results from the Third National Health and Nutrition Examination Survey Cohort [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 4258.
Abstract 35: Triple-negative breast cancer cells alter the pulmonary landscape to favor metastasis via exosome-mediated release of NM23
Authors: Suzann Duan, Senny Nordmeier, Aidan E. Byrnes, Miles A. Brown, Iain L. Buxton
Journal: Cancer Research (2018)

Abstract There is strong evidence implicating exosomes, cell-derived nanoscale vesicles, and their protein cargo in facilitating dialogue between primary tumor cells and the premetastatic niche. Identified by our lab as one such protein, secreted nucleoside diphosphate kinase (NM23/NDPK) has been shown to activate endothelial remodeling in support of proangiogenic and prometastatic events. We have previously demonstrated that triple-negative breast cancer (MDA-MB-231) cells elaborate exosomes enriched with NDPK transphosphorylase activity and target the lung as a future site of metastasis. Using in vitro and in vivo approaches, we interrogate the functional role of NDPK in exosome-mediated lung remodeling. In cell-based assays, we demonstrate that MDA-MB-231 exosomes stimulate migration of pulmonary vascular endothelial cells and enhance monolayer permeability. These effects are reversed following treatment with an inhibitor of NDPK activity or an antagonist to the purinergic P2Y1 receptor. Further, we show that immune-compromised mice receiving intravenous injections of MDA-MB-231 exosomes exhibit enhanced pulmonary vascular leakage, whereas treatment with an inhibitor of NDPK attenuates this effect. Using tandem mass tag labeling and mass spectrometry, we profiled proteomic changes to the lung and identified the purinergic signaling pathway as among those significantly affected by exosome treatment. These results elucidate the functional role of exosomal NDPK in compromising vascular integrity and transforming the pulmonary landscape to support colonization by circulating breast cancer cells. Citation Format: Suzann Duan, Senny Nordmeier, Aidan E. Byrnes, Miles A. Brown, Iain L. Buxton. Triple-negative breast cancer cells alter the pulmonary landscape to favor metastasis via exosome-mediated release of NM23 [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 35.
Abstract 1663: Identification and characterization of a small-molecule inhibitor of the human uracil-DNA glycosylase for use in combination with DNA damage-based anticancer therapies
Authors: Mya T. Nguyen, Yan Yan, Yuriy Fedorvo, John Pink, Drew Adams, Stanton Gerson
Journal: Cancer Research (2018)

Abstract Our research aims to develop therapeutically active inhibitors of the human uracil-DNA glycosylase (UNG). UNG, a highly conserved enzyme, plays a pivotal role in preventing abnormal bases, uracil and 5-fluorouracil, from incorporation into DNA as a result of treatment with chemotherapeutic drugs, floxuridine (5-FdU) and pemetrexed (PEM). Our previous publication reports that the depletion of UNG by shRNA causes uracil and 5-FU incorporation into DNA following 5-FdU or PEM exposure, and highly sensitizes certain human cancer cells to these chemotherapeutic drugs. These data suggest that UNG specific inhibitors could improve the anticancer effect of 5-FdU or PEM. However, a few known inhibitors have not been shown to function at therapeutic concentrations in human cells. Therefore, in order to identify a novel, small-molecule compound targeting the human UNG enzymatic activity, we have previously optimized a biochemically high-throughput screening (HTS) assay that measures the removal of uracil from a DNA hairpin based on the un-quenching of fluorescence. This assay has been successfully employed in a pharmacologically active compound collection screen (&amp;gt;3,000 small-molecules+ approved drugs). In 384-well plate runs using control wells in which enzyme is not added, the average assay provides signal to background ratios of 3.0 to 4.0. Typical Z factors range from 0.6-0.7, indicating a robust assay. We have identified five bioactive compounds with IC50 values &amp;lt; 1uM and have selected a nanoMolar inhibitor of the human UNG enzyme termed, UNGi-A. By using an in vitro DNA glycosylase activity assay, this compound displays a significant inhibitory activity towards the purified human UNG enzyme over time, in a dose-dependent manner. Further characterization shows a significant effect of this inhibitor on UNG activity in cellular extract that expresses endogenous UNG from DLD1 human colon cancer cell line. The result suggests that UNGi-A compound diminishes UNG activity in cell extracts. In addition, thermal shift assay (TSA) data suggest that UNGi-A binds directly to the human UNG enzyme. Together, this compound shows potential activity that blocks the human UNG activity and we are currently evaluating the effect of UNGi-A in combination with 5-FdU on UNG activity in human cancer cells. Citation Format: Mya T. Nguyen, Yan Yan, Yuriy Fedorvo, John Pink, Drew Adams, Stanton Gerson. Identification and characterization of a small-molecule inhibitor of the human uracil-DNA glycosylase for use in combination with DNA damage-based anticancer therapies [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 1663.
Abstract 4850: The minor groove binding agent quinacrine inhibits growth and increases apoptotic death in diffuse intrinsic pontine glioma tumor cells
Authors: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G. Eberhart, Eric H. Raabe
Journal: Cancer Research (2018)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an invasive, incurable and aggressive pediatric brain tumor found in the brainstem. Improved understanding of the biology of DIPG tumors is urgently needed to develop novel treatments. Our previous studies have shown that DIPG tumors and cell lines express high levels of the DNA-binding stem cell factor high mobility group AT-hook 2 (HMGA2).. Targeting HMGA2 using lentiviral shRNA decreased DIPG cell invasion, proliferation and increased apoptosis in our studies. We hypothesized that inhibiting HMGA2 using DNA minor groove binding drugs like quinacrine would decrease DIPG proliferation and increase apoptotic cell death. We used three DIPG cell lines (JHHDIPG1, JHHDIPG16A, and SUDIPG13) to test the effect of quinacrine. Quinacrine has traditionally been used as an anti-malarial drug and is known to strongly bind to DNA. We used BrdU incorporation as a measure of proliferation and expression of cleaved caspase-3 (CC-3) as a measure of apoptosis. Treatment of DIPG cells with quinacrine showed a dose dependent increase in cell death (CC-3 expression) from 3uM to 20uM, with the most effective doses being from 3uM to 5uM. In all three DIPG cell lines, treatment with 1uM to 5uM quinacrine showed a significant reduction in cell proliferation (BrdU) from 3uM to 5uM compared to vehicle-treated cells (P&amp;lt;0.0001). Additionally, treatment of DIPG cell lines with 1uM to 5uM quinacrine showed a significant increase in apoptotic cell death (CC-3 expression) compared to vehicle control cells from 3uM to 5uM (P&amp;lt;0.001). Our data suggests that minor groove binding agents like quinacrine could be effective therapies for this lethal brain tumor. Our future studies are aimed at testing the efficacy of quinacrine in inhibiting DIPG tumorigenicity and elucidating the mechanism of action. Citation Format: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G. Eberhart, Eric H. Raabe. The minor groove binding agent quinacrine inhibits growth and increases apoptotic death in diffuse intrinsic pontine glioma tumor cells [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 4850.