tbuckley/cabot-search huggingface dataset:
Abstract 16974: Comparison of Low-density Lipoprotein Cholesterol Threshold Attainment With Alirocumab versus Ezetimibe Treatment in the ODYSSEY Program
Authors: Christopher PCannon, BertrandCariou, VelichkaValcheva, SophieGuillonneau, Serban RIorga, Michael HDavidson
Journal: Circulation (2016)

Introduction: Recent guidelines and treatment pathways recommend PCSK9 inhibitors (e.g., alirocumab [ALI]) or ezetimibe (EZE) on background statin therapy for patients not reaching LDL-C thresholds despite treatment with maximally-tolerated statin (MTS) doses ± other lipid-lowering therapies. This analysis compares LDL-C threshold attainment with ALI 75/150 mg Q2W vs EZE 10 mg treatment following moderate to MTS dose therapy in a pool of 3 randomized, EZE-controlled Phase III ODYSSEY studies (COMBO II, OPTIONS I, OPTIONS II). Methods: Patients were randomized to ALI or EZE in a double-blind fashion. Patients were stratified based on their calculated baseline LDL-C levels, and the percent of patients reaching an LDL-C threshold of <70 mg/dL at week (W)12 and W24 was assessed. Results: A higher percent of patients achieved the LDL-C threshold of <70 mg/dL on ALI treatment than on EZE, regardless of baseline LDL-C level (Figure). The difference between ALI and EZE in percent of patients reaching this LDL-C t...
Activity of Afatinib in Heavily Pretreated Patients With ERBB2 Mutation–Positive Advanced NSCLC: Findings From a Global Named Patient Use Program
Authors: Solange Peters, Alessandra Curioni-Fontecedro, Hovav Nechushtan, Jin-Yuan Shih, Wei-Yu Liao, Oliver Gautschi, Vito Spataro, Mojca Unk, James Chih-Hsin Yang, Robert M. Lorence, Philippe Carrière, Agnieszka Cseh, Gee-Chen Chang
Journal: Journal of Thoracic Oncology (2018)

Approximately 1% to 4% of NSCLC tumors harbor erb-b2 receptor tyrosine kinase 2 (ERBB2) mutation; there is no approved targeted treatment for this subgroup.Patients with stage IV NSCLC that progressed after clinical benefit on erlotinib/gefitinib and/or had activating EGFR or ERBB2 mutations, had exhausted other treatments, and were ineligible for afatinib trials were enrolled in a named patient use program, receiving afatinib 30 to 50 mg/d on a compassionate basis within routine clinical practice. Efficacy and safety were retrospectively assessed in the subgroup with ERBB2 mutation-positive NSCLC.Twenty-eight heavily pretreated patients in the named patient use program had a documented ERBB2 mutation by local testing. Median time-to-treatment failure (TTF; time from treatment initiation to discontinuation for any reason) was 2.9 months; eight patients (29%) had TTF greater than 1 year. Objective response rate was 19% (3 of 16 patients with response data achieved partial response) and disease control rate (DCR) was 69% (11 of 16). Among 12 patients for whom type of ERBB2 mutation was specified, 10 had a p.A775_G776insYVMA insertion in exon 20, four of whom (40%) remained on afatinib for more than 1 year. This subgroup had median TTF of 9.6 months, objective response rate of 33% (two of six), and disease control rate of 100% (six of six).This analysis of patients treated in clinical practice provides further evidence of the activity of afatinib in ERBB2 mutation-positive NSCLC, and suggests that identification of specific subgroups with certain mutations, such as p.A775_G776ins/YVMA insertion in exon 20, could help optimize outcomes with ErbB2-targeted treatment.
Abstract 3552: Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ
Authors: Zhijun Liu
Journal: Cancer Research (2018)

Abstract Glioblastomas (GBM) are the most aggressive brain cancers without effective therapeutics. The Hippo pathway transcriptional coactivators YAP/TAZ were implicated as drivers in GBM progression and could be therapeutic targets. Here, we found in an unbiased screen of 1650 compounds that amlodipine is able to inhibit survival of GBM cells by suppressing YAP/TAZ activities. Instead of its known function as an L-type calcium channel blocker, we found that amlodipine is able to activate Ca2+ entry by enhancing store-operated Ca2+ entry (SOCE). Amlodipine as well as approaches that cause store depletion and activate SOCE trigger phosphorylation and activation of Lats1/2, which in turn phosphorylate YAP/TAZ and prevent their accumulation in the cell nucleus. Furthermore, we identified that protein kinase C (PKC) beta II is a major mediator of Ca2+-induced Lats1/2 activation. Ca2+ induces accumulation of PKC beta II in an actin cytoskeletal compartment. Such translocation depends on inverted formin-2 (INF2). Depletion of INF2 disrupts both PKC beta II translocation and Lats1/2 activation. Functionally, we found that elevation of cytosolic Ca2+ or PKC beta II expression inhibits YAP/TAZ-mediated gene transcription. In vivo PKC beta II expression inhibits GBM tumor growth and prolongs mouse survival through inhibition of YAP/TAZ in an orthotopic mouse xenograft model. Our studies indicate that Ca2+ is a crucial intracellular cue that regulates the Hippo pathway, and that triggering SOCE could be a strategy to target YAP/TAZ in GBM. Citation Format: Zhijun Liu. Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ [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 3552.
Abstract 2386: Identification of SIK1 as a potential therapeutic target for desmoplastic small round cell tumor
Authors: Alifiani B. Hartono, Sean B. Lee
Journal: Cancer Research (2018)

Abstract Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive malignant cancer caused by the chromosomal translocation of t(11;22)(p13;q12) that produces a novel, aberrant transcription factor, EWS-WT1. EWS-WT1 is essential in the formation of DSRCT as well as for maintaining DSRCT cell growth. However, current research has not elucidated how EWS-WT1 leads to the oncogenesis of DSRCT. Through our integrative gene expression data, we identified Salt Inducible Kinase 1 (SIK1) as one of direct target genes of EWS-WT1 in JN-DSRCT-1 cell line. SIK1 is a member of the AMPK related kinases and is involved in gluconeogenesis and lipogenesis regulation, skeletal myocytes development, p53 dependent anoikis, and cell cycle regulation. Through our ChIP analysis, we showed that EWS-WT1 directly binds to a 2kb proximal promoter region of SIK1. Following SIK1 depletion, JN-DSRCT-1 cell proliferation sharply decreased, similar to the growth inhibition observed when EWS-WT1 is depleted. We further showed that cells do not transit to S phase when SIK1 is depleted, suggesting a critical role of SIK1 in cell cycle regulation in DSRCT. Taken together, we have established that EWS-WT1 directly activates SIK1 expression and promotes cell proliferation through SIK1. Therefore, our work identified SIK1 as a new potential therapeutic target in DSRCT. Citation Format: Alifiani B. Hartono, Sean B. Lee. Identification of SIK1 as a potential therapeutic target for desmoplastic small round cell tumor [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 2386.
Abstract 2731: Checkpoint inhibitor therapy in combination with the implantation of agarose encapsulated cancer cells inhibits tumor growth in a mouse model of osteosarcoma
Authors: Pradeep R. Dumpala, Prithy C. Martis, Melissa A. Bemrose, Atira Dudley, Barry H. Smith, Lawrence S. Gazda
Journal: Cancer Research (2018)

Abstract We have previously shown that murine renal adenocarcinoma (RENCA) cells encapsulated in agarose macrobeads (MB) secrete factors that inhibit the proliferation of freely growing tumor cells outside the MB, both in vitro and in vivo. This effect is being investigated in ongoing clinical trials with colorectal patients who underwent laparoscopic intraperitoneal implantations of RENCA MBs (NCT01053013, NCT02046174). In the current study, we report the effect of immune checkpoint inhibitors (anti-PD-1 and anti-PD-L1 monoclonal antibodies) in combination with RENCA MBs on tumor burden in BALB/cJ mice induced with K7M2 murine osteosarcoma tumors. Mice that developed tumors (2-5 mm) on subcutaneous injection of K7M2 cells were randomly enrolled in the following study groups: sham, RENCA MBs only, anti-PD-1 only, RENCA MBs + anti-PD-1, anti-PD-L1 only, RENCA MBs + anti-PD-L1. Anti-PD-1 and anti-PD-L1 antibodies were administered ip bi-weekly for 3-6 weeks. RENCA MBs were implanted in the peritoneal cavity on the day of enrollment. Mean tumor volumes (mm3) throughout days 0-24 were: RENCA MB (199.17 ± 125.57), anti-PD-1 only (278.87 ± 180.34), anti-PD-L1 only (332.46 ± 185.13) and sham treated mice (512.61 ± 230.12). RENCA MB and anti-PD-L1 combination therapy did not inhibit tumor growth (375.00 ± 511.61). PD-L1 expression was absent in primary tumors as observed by immunostaining. Treatment with RENCA MBs plus anti-PD-1 treatment demonstrated an additive effect (116.94 ± 83.77) compared to RENCA MB only or anti-PD-1 alone. Moreover, tumors in 4 out of 16 mice from the RENCA MB plus anti-PD-1 group receded and were undetectable (3 in less than 1 week and 1 at 39 days) following treatment. Tumors also regressed and were not palpable in 1 mouse each in the anti-PD-1 and RENCA MB plus anti-PD-L1 groups at day 14 and 9, respectively. Discontinuation of anti-PD-1 and anti-PD-L1 treatment after 3 weeks of treatment resulted in loss of tumor growth regulation. Preliminary data suggests that continued treatment with these immune checkpoint inhibitors beyond 3 weeks prolongs the regulation of tumor growth in this model. These data support the use of anti-PD-1 in combination with the implantation of RENCA macrobeads in this mouse model of osteosarcoma, and the possibility of similar approaches in the clinic. Citation Format: Pradeep R. Dumpala, Prithy C. Martis, Melissa A. Bemrose, Atira Dudley, Barry H. Smith, Lawrence S. Gazda. Checkpoint inhibitor therapy in combination with the implantation of agarose encapsulated cancer cells inhibits tumor growth in a mouse model of osteosarcoma [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 2731.
Serotonin-Induced Hypercontraction Through 5-Hydroxytryptamine 1B Receptors in Atherosclerotic Rabbit Coronary Arteries
Authors: TatsuroIshida, SeinosukeKawashima, Ken-ichiHirata, TsuyoshiSakoda, YasushiShimokawa, YoichiMiwa, NobutakaInoue, TomomiUeyama, MasashiShiomi, HozukaAkita, MitsuhiroYokoyama
Journal: Circulation (2001)

Background—Augmented vasoconstriction to serotonin (5-hydroxytryptamine [5-HT]) in atherosclerotic vessels plays a crucial role in the development of myocardial ischemia. We investigated mechanisms for serotonin-evoked hypercontraction in atherosclerotic rabbit coronary arteries. Methods and Results—Contractile responses to serotonergic agents of endothelium-denuded coronary arteries from control and Watanabe heritable hyperlipidemic rabbits (WHHL) were examined. WHHL coronary arteries exhibited hypercontraction to 5-HT1–receptor agonists; the constrictor threshold concentrations and ED50 to serotonin, 5-carboxamidotryptamine, and sumatriptan in WHHL were significantly lower, and the Emax in WHHL to these agents were increased 55% to 59% above those of the control. Serotonin-evoked contractions in both groups were inhibited by GR127935 (5-HT1B/1D antagonist; 0.1 to 1 nmol/L) and pertussis toxin but not by ketanserin (5-HT2 antagonist; 0.01 to 1 μmol/L), suggesting that the hypercontraction is most likely ...
Caveolin Plays a Central Role in Endothelial Progenitor Cell Mobilization and Homing in SDF-1–Driven Postischemic Vasculogenesis
Authors: ElhemSbaa, JulieDeWever, PhilippeMartinive, CarolineBouzin, FrançoiseFrérart, Jean-LucBalligand, ChantalDessy, OlivierFeron
Journal: Circulation Research (2006)

When neovascularization is triggered in ischemic tissues, angiogenesis but also (postnatal) vasculogenesis is induced, the latter requiring the mobilization of endothelial progenitor cells (EPC) from the bone marrow. Caveolin, the structural protein of caveolae, was recently reported to directly influence the angiogenic process through the regulation of the vascular endothelial growth factor (VEGF)/nitric oxide pathway. In this study, using caveolin-1 null mice (Cav−/−), we examined whether caveolin was also involved in the EPC recruitment in a model of ischemic hindlimb. Intravenous infusion of Sca-1+ Lin− progenitor cells, but not bone marrow transplantation, rescued the defective neovascularization in Cav−/− mice, suggesting a defect in progenitor mobilization. The adhesion of Cav−/− EPC to bone marrow stromal cells indeed appeared to be resistant to the otherwise mobilizing SDF-1 (Stromal cell–Derived Factor-1) exposure because of a defect in the internalization of the SDF-1 cognate receptor CXCR4. Sy...
Plasticity of Human Adipose Lineage Cells Toward Endothelial Cells
Authors: ValériePlanat-Benard, Jean-SébastienSilvestre, BéatriceCousin, MireilleAndré, MaryseNibbelink, RadiaTamarat, MichelClergue, CaroleManneville, CorinneSaillan-Barreau, MichelineDuriez, AlainTedgui, BernardLevy, LucPénicaud, LouisCasteilla
Journal: Circulation (2004)

Background— Adipose tissue development and remodeling are closely associated with the growth of vascular network. We hypothesized that adipose tissue may contain progenitor cells with angiogenic potential and that therapy based on adipose tissue-derived progenitor cells administration may constitute a promising cell therapy in patients with ischemic disease. Methods and Results— In mice, cultured stromal-vascular fraction (SVF) cells from adipose tissue have a great proangiogenic potential, comparable to that of bone marrow mononuclear cells in the mouse ischemic hindlimb model. Similarly, cultured human SVF cells differentiate into endothelial cells, incorporate into vessels, and promote both postischemic neovascularization in nude mice and vessel-like structure formation in Matrigel plug. In vitro, these cells represent a homogeneous population of CD34- and CD13-positive cells, which can spontaneously express the endothelial cell markers CD31 and von Willebrand factor when cultured in semisolid medium. ...
Relapsed and refractory nodular lymphocyte-predominant Hodgkin lymphoma: an analysis from the German Hodgkin Study Group
Authors: Dennis A. Eichenauer, Annette Plütschow, Lena Schröder, Michael Fuchs, Boris Böll, Bastian von Tresckow, Volker Diehl, Peter Borchmann, Andreas Engert
Journal: Blood (2018)
Abstract 13253: Pattern of Cardiac Output vs O2 Uptake Ratio During Maximal Exercise in Heart Failure With Reduced Ejection Fraction: Pathophysiological Insights
Authors: Greta Generati, Francesco Bandera, Marta Pellegrino, Valentina Labate, Francesco Carbone, Eleonora Alfonzetti, Marco Guazzi
Journal: Circulation (2015)

Background: the oxygen uptake (VO2) response to exercise, measured during cardiopulmonary exercise testing (CPET), has prognostic value in heart failure (HF). The increase in VO2 is due to the increase in cardiac output (CO) and arterial-mixed venous oxygen content difference (C(a-v)O2). How much (C(a-v)O2) contribute to VO2 increase may be estimated by the CO/VO2 ratio. Aim: To study the cardiac and functional phenotype associated with CO/VO2 ratio at peak exercise in HF with reduced ejection fraction (HFrEF). Methods: 104 HFrEF patients (mean age 64±11 y, male %, ischemic etiology 68%, mean LVEF 34±9%) underwent a maximal CPET (incremental ramp protocol) combined with exercise-echo. Results: Study population was divided into 2 groups according to the peak exercise CO/VO2 (cutoff 0.49, CO/VO2 median value) Group A (n=52) with CO/VO2 &lt;049 and B (n=52) with CO/VO2 ≥0.49. Despite similar peak VO2 (13.8 vs 12.6 mL/min/kg p=ns) patients with impaired CO exercise response (Group A) showed worse cardiac remodeling (LVEDV indexed 101±33 vs 91±23 mL/m2 p=0.09, E/e’28±15 vs 22±11 p=0.02) and more severe mitral regurgitation at rest and peak exercise (ERO rest 22±10 16±9 mm2 p=0.02, peak 33±13 vs 25±12 mm2 p=0.03). Group A patients exhibited also more impaired right ventricular function (TAPSE rest 17±5 vs 19±4 mm p=0.0001, peak 19±5 vs 21±4 p=0.04) associated with ventilatory inefficiency (VE/VCO2 slope 36±11 vs 31±7 p=0.01). The two Groups presented with similar average Hb levels. Conclusions: In advanced HF population, the worse exercise performance is associated witha reduced CO /VO2 ratio during maximal exercise, that for a similar peak VO2 as compared to the population with a high CO/VO2 ratio, is suggestive of "optimal" peripheral O2 extraction as compensation to a reduced O2 delivery.
Activation of Human Neutrophil by Cytokine-Activated Endothelial Cells
Authors: TatsujiTakahashi, FumihikoHato, TakahisaYamane, HiroshiFukumasu, KenichiSuzuki, SachioOgita, YoshikiNishizawa, SeiichiKitagawa
Journal: Circulation Research (2001)

Abstract—Cytokine activation of vascular endothelial cells renders the hyperadhesiveness for neutrophils. During the processes of inflammation and atherosclerosis, the production of reactive oxygen species by neutrophils contributes to endothelial cell (EC) damage and injury. However, the precise mechanisms for neutrophil activation by ECs remain unknown. Thus, we investigated what kinds of pathophysiological factors synthesized by inflammatory cytokine-activated ECs potentiated the activity of neutrophil functions. The magnitude of O2− release from neutrophils, which is one of pivotal neutrophil functions, was measured as an indicator potentiated by activated ECs. Neutrophils release massive amounts of O2− on coculture with activated ECs. Anti–granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody (Ab) or specific platelet-activating factor (PAF)-receptor antagonist suppressed the O2− release from neutrophils on coculture with the activated ECs by 50% to 70%. The supernatants from activated E...
Abstract 19252: Ideal Cardiovascular Health and Employee Productivity
Authors: Steven Driver, Anita Panjwani, Bonnie Spring, Donald M Lloyd-Jones, Norrina Allen
Journal: Circulation (2015)

Introduction: The AHA has defined ideal cardiovascular health (CVH) as the simultaneous presence of 4 optimal health behaviors (not smoking, eating a healthy diet, meeting physical activity goals, and maintaining a healthy weight) and 3 optimal health factors (lower blood pressure, blood sugar, and cholesterol). An association between ideal CVH and employee productivity has not yet been established. Objectives: In this study, we sought to investigate whether employees with high CVH are more productive than employees with moderate or low CVH. Methods: In fiscal year 2015, an academic medical center offered health risk appraisal surveys (HRAs) to its 6,500 employees. Completion rates have been &gt;90% to date (n=6,144). Ideal, intermediate, and poor levels for each of the 7 components listed above were calculated from HRA responses according to standard AHA definitions and assigned values of 2, 1, and 0 respectively. An overall CVH score was calculated for each respondent from the sum of individual component scores with a range of 0-14 (low 0-7 points, moderate 8-10, and high 11-14). Productivity was measured by responses related to missed work days due to illness (absenteeism) and days employees came to work but did not feel at their best (presenteeism). In this cross-sectional analysis, we used logistic regression to compare productivity responses between employees with high, moderate, and low CVH adjusting for race and sex (age was unavailable due to employee privacy concerns). Results: Overall, 35% of employees were in high CVH, 58% moderate, and 6% low. The odds of missing at least one workday due to illness during a two-week period were 67% lower among employees with high CVH compared to employees with low CVH (adjusted OR 0.33; 95% CI, 0.20-0.56). The odds of reporting that physical or emotional health problems made it difficult to concentrate on work at least half the time were 85% lower among employees with high CVH compared with low CVH (adjusted OR 0.15; 95% CI, 0.07-0.33). Conclusions: Self-reported higher CVH was strongly associated with better employee productivity as measured by fewer sick days and better concentration at work. These results support the notion that helping employees stay healthy may represent a valuable near-term strategy for employers.
Physical activity as a moderator for obstructive sleep apnoea and cardiometabolic risk in the EPISONO study
Authors: Marcos Mônico-Neto, Hanna Karen Moreira Antunes, Ronaldo Vagner Thomatieli dos Santos, Vânia D'Almeida, Altay Alves Lino de Souza, Lia Rita Azeredo Bittencourt, Sergio Tufik
Journal: European Respiratory Journal (2018)

Obstructive sleep apnoea (OSA) is positively associated with cardiometabolic diseases; however, high levels of physical activity could decrease the incidence of OSA and associated comorbidities. In this study we aimed to examine the incidence of OSA in relation to physical activity, and its role as a protective factor in individuals with OSA on the incidence of cardiometabolic diseases, in an 8–9-year follow-up study. We analysed data of 658 volunteers from the São Paulo Epidemiologic Sleep Study (EPISONO), a cohort study of individuals aged 20–80 years, collected through polysomnography, the International Physical Activity Questionnaire and an assessment of cardiometabolic profile. Active subjects had a lower risk of developing OSA compared with nonactive subjects (relative risk 0.877, 95% CI 0.296–0.855) and there was a reduced risk of developing type 2 diabetes mellitus in active/apnoeic subjects (relative risk 0.493, 95% CI 0.252–0.961) compared with nonactive subjects. Metabolic equivalent was negatively associated to cardiometabolic markers, such as C-reactive protein (exp( B )=0.720; p=0.001), interleukin-6 (exp( B )=0.991; p=0.03), insulin (exp( B )=0.982; p=0.03), triglycerides (exp( B )=0.997; p&lt;0.001), homeostasis model assessment for insulin resistance (exp( B )≤0.946; p&lt;0.024), quantitative insulin sensitivity check index (exp( B )=992.4; p&lt;0.001) and mean arterial pressure (exp( B )=0.987; p=0.001). Physical activity was a protective factor against type 2 diabetes mellitus in apnoeic individuals; moreover, being active reduced the risk of developing OSA and was associated with a better cardiometabolic profile.
Modulation of Antioxidant Enzyme Expression and Function by Estrogen
Authors: KerstinStrehlow, SimoneRotter, SvenWassmann, OliverAdam, ChristianGrohé, KerstinLaufs, MichaelBöhm, GeorgNickenig
Journal: Circulation Research (2003)

Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and can be effectively influenced by radical scavenging enzyme activity and expression. The vasoprotective effects of estrogens may be related to antioxidative properties. Therefore, effects of 17β-estradiol on production of reactive oxygen species and radical scavenging enzymes were investigated. 17β-estradiol diminished angiotensin II–induced free radical production in vascular smooth muscle cells (DCF fluorescence laser microscopy). 17β-estradiol time- and concentration-dependently upregulated manganese (MnSOD) and extracellular superoxide dismutase (ecSOD) expression (Northern and Western blotting) and enzyme activity (photometric assay). Nuclear run-on assays demonstrated that 17β-estradiol increases MnSOD and ecSOD transcription rate. Half-life of MnSOD mRNA was not influenced, whereas ecSOD mRNA was stabilized by estrogen. Copper-zinc SOD, glutathione-peroxidase, and catalase were not affected by estrogen. Estrogen deficie...