tbuckley/cabot-search huggingface dataset:
Factors Affecting Vaccination in Children and Their Siblings After Autism Spectrum Disorder Diagnosis
Authors: Scott S. Field
Journal: JAMA Pediatrics (2018)

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Abstract A16: COL11A1 confers cisplatin resistance through fatty acid oxidation in ovarian cancer cells
Authors: Miran Rada, Jennifer Cha, Jessica Sage, Bo Zhou, Wei Yang, Sandra Orsulic, Dong-Joo Cheon
Journal: Clinical Cancer Research (2018)

Abstract Cisplatin resistance is the major challenge in the treatment of ovarian cancer, and it is crucial to develop novel therapeutic strategies to block cisplatin resistance. The purpose of this study was to identify new therapeutic targets for the treatment of cisplatin-resistant ovarian cancer. We previously identified collagen type XI alpha 1 (COL11A1) as a novel biomarker associated with cisplatin resistance in ovarian cancer. COL11A1 is expressed by cancer-associated fibroblasts (CAFs) adjacent to cancer cells as well as cisplatin-resistant ovarian cancer cell lines. Our data indicate that COL11A1 inhibits cisplatin-induced apoptosis in ovarian cancer cells, but not through altered gene expression of many of the well-established mechanisms of cisplatin resistance (i.e., transport, inactivation, DNA repair pathways). Rather, our proteomics data revealed that mitochondrial fatty acid beta-oxidation (FAO) was the most upregulated pathway by COL11A1 in ovarian cancer cells. To determine a link between COL11A1-driven cisplatin resistance and FAO, we knocked down COL11A1 in A2780CIS cisplatin-resistant ovarian cancer cells, a cell line expressing high endogenous levels of COL11A1. COL11A1 knockdown not only decreased the expression of genes involved in fatty acid beta-oxidation, such as CD36, CPT1A, ACAA2, HADHA, but also decreased fatty acid oxidation rate and increased cisplatin-induced apoptosis in A2780CIS ovarian cancer cells. In contrast, ovarian cancer cells became resistant to cisplatin-induced apoptosis and increased fatty acid beta-oxidation when exposed to COL11A1 protein or cocultured with COL11A1-overexpressing CAFs. Importantly, these cancer cells became more sensitive to the FAO inhibitor etomoxir. Collectively, our results suggest that COL11A1 confers cisplatin resistance by increasing FAO in ovarian cancer cells. Our study uncovers FAO as a promising therapeutic target to reduce cisplatin resistance in ovarian cancer, particularly in recurrent ovarian cancers that typically express high levels of COL11A1. Citation Format: Miran Rada, Jennifer Cha, Jessica Sage, Bo Zhou, Wei Yang, Sandra Orsulic, Dong-Joo Cheon. COL11A1 confers cisplatin resistance through fatty acid oxidation in ovarian cancer cells. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A16.
Left Ventricular Thrombus Enhancement After Intravenous Injection of Echogenic Immunoliposomes
Authors: AndrewHamilton, Shao-LingHuang, DrewWarnick, AdamStein, MarkRabbat, TarunaMadhav, BonnieKane, AshwinNagaraj, MelvinKlegerman, RobertMacDonald, DavidMcPherson
Journal: Circulation (2002)

Background— Targeted echogenic immunoliposomes (ELIPs) for ultrasound enhancement of atheroma components have been developed. To date, ELIP delivery has been intra-arterial. To determine whether ELIPs can be given intravenously with enhancement of systemic structures, a left ventricular thrombus (LVT) model was developed. Methods and Results— In 6 animals plus 1 dose-ranging animal, the apical coronary arteries were ligated, and an LVT was produced by injecting Hemaseel fibrin adhesive through the apical myocardium. The thrombus was imaged epicardially and transthoracically at 0, 1, 5, and 10 minutes after anti-fibrinogen ELIP injections. The dose of ELIPs was varied. PBS and unconjugated ELIPs were controls. The apical thrombi were easily reproduced and clearly visible with epicardial and transthoracic ultrasound. Enhancement occurred with 2 mg anti-fibrinogen ELIPs and increased with dose. With 8 mg ELIPs, enhancement was different from control within 10 minutes (P<0.05). Rhodamine-labeled anti-fibrinog...
Abstract 12042: Heart Rate Variability After Cardiac Arrest is Preserved by Whole Body Periodic Acceleration (pGz)
Authors: Jose A Adams, Arkady Uryash, Peter Pastuszko, Ann Pastuszko, Vinay Nadkarni, Paul Kurlansky
Journal: Circulation (2014)

Predicting neurological outcome after brain injury or cardiac arrest (CA) is difficult. Heart Rate Variability (HRV) and lack thereof are markers for poor neurological outcome, and decreased HRV af...
Abstract 1458: TRPM2 modulates neuroblastoma cell survival through Pyk2, CREB and MCU activation
Authors: Iwona Malgorzata Hirschler-Laszkiewicz, Shu-jen Chen, Lei Bao, JuFang Wang, Xue-Qian Zhang, Santhanam Shanmughapriya, Kerry Keefer, Muniswamy Madesh, Joseph Y. Cheung, Barbara A. Miller
Journal: Cancer Research (2018)

Abstract Transient Receptor Potential Melastatin subfamily member 2 (TRPM2) is highly expressed in many cancers including neuroblastoma. Proline-rich tyrosine kinase 2 (Pyk2) is calcium-sensitive non-receptor tyrosine kinase which enhances cell survival and is activated by calcium influx through TRPM2. Pyk2 also modulates mitochondrial calcium uptake through phosphorylation of the mitochondrial calcium uniporter (MCU), impacting mitochondrial function, and through its effects on CREB, which regulates transcription of MCU. The purpose of this work was to investigate the mechanisms by which TRPM2 regulates cancer cell survival in order to develop new therapeutic strategies based on inhibition of TRPM2. Two models of TRPM2 inhibition were utilized: 1) reducing TRPM2 function in SH-SY5Y cells by expression of the dominant negative construct TRPM2-S, a short isoform of TRPM2, and 2) depletion of TRPM2 expression with CRISPR/Cas9 technology. Treatment with Doxorubicin (Doxo) was used as a model of oxidative stress. Doxorubicin reduced growth of cells in which TRPM2 was inhibited significantly more than control cells. Inhibition of TRPM2 also reduced Pyk2 and CREB expression and activation. Using shRNA technology we showed that Pyk2 mediated reduced expression and activation of CREB and activation of STAT3 in TRPM2 expressing cells. Fractionation experiments showed that depletion of TRPM2 reduced phosphorylation of whole cell and mitochondrial Src and Pyk2 and expression of mitochondrial CREB and MCU. Src has an important role in Pyk2 phosphorylation. In TRPM2 depleted cells, mitochondrial Ca uptake was significantly reduced since both peak mitochondrial calcium uniporter currents and amount of calcium transported (current-time integral) measured in mitoplasts were lower. Wt Pyk2 but not the phospho-deficient mutant Y402F and wt TRPM2 but not the TRPM2 Ca-impermeant mutant E960D, restored viability after Doxo treatment of SH-SY5Y cells in which TRPM2 was inhibited. In conclusion, these results suggest that TRPM2 inhibition leads to reduced viability in neuroblastoma through the Src-Pyk2-CREB-MCU pathway, which plays a key role in regulating mitochondrial function and cellular bioenergetics. Citation Format: Iwona Malgorzata Hirschler-Laszkiewicz, Shu-jen Chen, Lei Bao, JuFang Wang, Xue-Qian Zhang, Santhanam Shanmughapriya, Kerry Keefer, Muniswamy Madesh, Joseph Y. Cheung, Barbara A. Miller. TRPM2 modulates neuroblastoma cell survival through Pyk2, CREB and MCU activation [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 1458.
Abstract 17958: A Novel Method of Reducing Hypoxic Injury by Perfluorocarbon Nanobubbles in Cardiomyocytes During Hypoxia Treatment - miRNA Reflections
Authors: Mark C Arokiaraj, Eric Mennesson
Journal: Circulation (2017)

Introduction: To identify the role of perfluorocarbon nanobubbles in cardioprotection after hypoxic injury. Hypothesis: PFC nano-bubbles could have a potential role in myocardial salvage during acute ischaemia. Methods: Perfluorocarbon nanobubbles were synthesised by a standard protocol. Cardiomyocytes were seeded in cell culture wells and were subjected to hypoxia treatment (5% O2). The cells were treated with PFC nanobubbles or Phosphate buffered saline which served as a control. PFC's were added to the hypoxia treatment cells as well as to control cells without hypoxia treatment. Serial additions of PFC’s were made for 4 hours during hypoxia treatment. At the end of the procedure the cells were analysed by microscopy and mi RNA was extracted by a standard protocol. The complete panel of mi RNA was quantitatively and qualitatively assessed. The concentration of total RNA measured by nano drop was >475 ng/microL (RNA Integrity Number >9.8, for each). Results: Compared to the controls there was a signific...
Abstract 1696: Glycogen synthase kinase (GSK-3) inactivation downregulates PD-1 and synergizes with PD-1/PL1 and CTLA-4 blockade in cancer immunotherapy
Authors: Christopher E. Rudd
Journal: Cancer Research (2018)

Abstract Immune checkpoint blockade (ICB) of negative co-receptors on T-cells such as cytotoxic T-cell antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) is a promising approach for the treatment of cancer. Despite this success, the poor prognosis for most patients continues to highlight a need for developing novel clinical interventions. In this context, we identified the enzyme glycogen synthase kinase-3 (GSK-3) as the major regulator of PD-1 expression on T-cells (Taylor et al., 2016 Immunity). We have shown that small molecule inhibitors (SMIs) of GSK-3 are as effective as anti-PD-1 in controlling the growth of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings (Taylor et al., 2017 Can Res; Krueger and Rudd, Immunity 2017). At the same time, the fact that GSK-3 inactivation up-regulates transcription factor T-bet which upregulates interferon gamma (IFNγ) and granzyme B (GZMB) suggested that GSK-3 inactivation might provide extra value beyond of its down-regulation of PD-1. Here, we show that GSK-3 SMIs can synergize with anti-PD-1 and anti-CTLA-4 to eliminate B16 solid tumors that are otherwise resistant to anti-PD-1, or anti-CTLA-4 inhibition alone. At a cellular level, GSK-3 inactivation preferentially down-regulated PD-1 on CD8+ tumor infiltrating T-cells, while at a molecular level, GSK-3 SMIs inhibited PD-1 transcription, increased granzyme B (GZMB)/ interferon-gamma1 (IFNγ) transcription and directly acted upon glycogen synthase to skew metabolism towards greater glycolysis. We further showed that the inactivation of GSK-3α/β through siRNA or by SMIs substituted for CD28 co-stimulation in the potentiation of cytotoxic CD8+ CTL function. This data supports a model where GSK-3 mediates the dependency of anti-PD-1 immunotherapy on the expression of CD28. Overall, our data show that GSK-3 inactivation is an immune-sensitizer which assists the immune system to overcome tumor resistance to immune check-point blockade. Citation Format: Christopher E. Rudd. Glycogen synthase kinase (GSK-3) inactivation downregulates PD-1 and synergizes with PD-1/PL1 and CTLA-4 blockade in cancer immunotherapy [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 1696.
Synthetic Inhibitors of Platelet Glycoprotein IIb/IIIa in Clinical Development
Authors: MarcVerstraete
Journal: Circulation (2000)

Abstract—Activation of the platelet glycoprotein (GP IIb/IIIa) receptor on the platelet surface is the final pathway of platelet aggregation, regardless of the initiating stimulus. Inhibitors of GP IIb/IIIa receptors include monoclonal antibodies (abciximab) against this receptor and peptidic and nonpeptidic synthetic specific receptor blockers. Abciximab exchanges between and binds to platelets for as long as 2 weeks, whereas synthetic GP IIb/IIIa inhibitors inhibit ex vivo platelet aggregation for only a few hours after the end of infusion, but some have the advantage of also being orally active. In the secondary prevention of atherothrombosis, large-scale trials were successfully conducted with aspirin, dipyridamole, ticlopidine, and clopidogrel. In the first large-scale trials with GP IIb/IIIa inhibitors, abciximab was investigated. In aggregate, synthetic GP IIb/IIIa inhibitors, combined with aspirin and heparin, were shown to reduce ischemic events in patients with high- and low-risk coronary interv...
THU0327 Real world (RW) experience with an anti-il-17a inhibitor in biologic naÏve and biologic experienced psoriatic arthritis (PSA) patients
Authors: R. Moon, J. Hill, N. Booth, S. Lobosco
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Two IL-17A inhibitors are approved for the treatment of PsA, ixekizumab and secukinumab. At the time of this survey, real world evidence was only available for secukinumab, which was approved for PsA in 2016 in EU, Australia and Switzerland. Secukinumab label dose for PsA patients with either concomitant moderate to severe plaque psoriasis or anti-TNFα inadequate responders is 300 mg. For other patients, the recommended dose is 150 mg. All patients receive a loading dose regimen by S.C. injection at Weeks 0, 1, 2, 3 and 4, followed by monthly maintenance dose. Little data are published on the RW utilisation of secukinumab in PsA. <h3>Objectives</h3> Describe RW dose utilisation of an anti-IL-17A inhibitor, among biologic naïve and biologic experienced PsA patients. <h3>Methods</h3> Data from a chart review study conducted in 2017 across France, Germany, Italy, Spain, UK, Australia and Switzerland where secukinumab is reimbursed were used. Specialists were recruited by field-based interviewers, and provided information on demographics, Body Surface Area (BSA), time since diagnosis and treatment for their adult PsA patients currently receiving secukinumab. <h3>Results</h3> 212 rheumatologists, 89 dermatologists, 1 orthopedist provided data for 1451 patients. Mean age 50.6 years, 47% female, mean time since PsA diagnosis 5.9 years and 86% had concomitant psoriasis. 96% received prior csDMARD(s) and 8% prior apremilast. 29% (425) were biologic naïve and 71% (1024) biologic experienced (limited differences between specialists: 74% rheumatologists; 63% dermatologists). 34%, 24%, and 13% received, 1, 2, and 3+prior biologics respectively. Among biologic naïve patients on 150 mg, 36% (52/145) had a BSA ≥10%, where the recommended dose is 300 mg at secukinumab initiation. 29% (274/930) of biologic experienced patients received secukinumab at 150 mg, not the recommended 300 mg dose (figure 1) <h3>Conclusions</h3> In the RW, secukinumab is prescribed mainly in biologic experienced patients (71%) and is not universally prescribed at the recommended dose for PsA. Specifically, of those who are biologic naïve (29%), 36% of patients on 150 mg had moderate to severe psoriasis, which is outside the recommended dose. Further RW experience is needed for ixekizumab. <h3>Acknowledgements</h3> Acknowledgements: This chart review study was designed and run by Adelphi Real World. The study was supported by a number of pharmaceutical companies, including Eli Lilly and Company. This specific analysis and abstract was supported by Eli Lilly and Company. <h3>Disclosure of Interest</h3> R. Moon: None declared, J. Hill Grant/research support from: Eli Lilly and Company, Employee of: Eli Lilly and Company, N. Booth: None declared, S. Lobosco: None declared
Abstract LB-074: Examining SENP Localization In HEK-293 Cells Using MG-132 And Cycloheximide
Authors: Michael Robinson, Charles S. Umbaugh, Marxa L. Figueiredo
Journal: Cancer Research (2018)

Abstract Post translational modifications are changes to proteins that occur during or after synthesis by the ribosome. Often these modifications are necessary to form mature proteins. SUMOylation (Small Ubiquitin-like Modifier, SUMO) is a type of post translational modification that has a connection to a protein, Laminin Receptor, that contributes to the aggressiveness and proliferation of cancer. SUMO proteases, called SENPs, remove SUMO groups from SUMOylated proteins. Because Laminin Receptor may be a SUMOylated protein and is in the nucleus, we wanted to first explore how SENP-2 and SENP-3 localize under various cellular conditions. To understand the behavior of SENPs under cellular stress, we transfected human embryonic kidney cells, called HEK-293 cells, with SENP-2 or SENP-3 tagged to the fluorescent protein EGFP. We treated the cells with MG-132, a proteasome inhibitor, or with cycloheximide, a protein synthesis inhibitor. We used live imaging to qualitatively understand how SENP-2 and SENP-3 localize in the cell in normal conditions and under cell stress. Then, we looked for differences in cytosolic and nuclear partitioning of SENP-2 and SENP-3 by western blot. The exposure of SENPs to the two inhibitors helped us to understand the behavior of the SUMO proteases between the nucleus and cytoplasm. Citation Format: Michael Robinson, Charles S. Umbaugh, Marxa L. Figueiredo. Examining SENP Localization In HEK-293 Cells Using MG-132 And Cycloheximide [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-074.
Abstract 10885: Age Independent Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction
Authors: Selma F Mohammed, Sultan A Mirzoyev, Margaret M Redfield
Journal: Circulation (2012)

Background: The prevalence of heart failure (HF) with preserved ejection fraction (HFpEF) increases dramatically with age. Studies conflict as to whether myocardial fibrosis increases with age in persons without HF and while fibrosis is postulated to play a key role in HFpEF pathophysiology, few studies have assessed fibrosis in HFpEF hearts. We hypothesized that myocardial fibrosis increases with age in persons without HF but that patients with HFpEF have more fibrosis than non-HF hearts independent of age. Methods: HFpEF subjects were identified using Mayo Clinic HF databases and crossed to the Mayo Clinic Autopsy Tissue Registry (EF > 40% at HF diagnosis; n=110; age range 40-103 at death). Controls were those ≥40 years of age at death without ante-mortem HF diagnosis who died of non-cardiovascular causes and had undergone cardiac autopsy (≥ 20 pts per age at death decade ≥ 4th decade; n=130 total). Fibrosis was quantified on whole field digital microscopy of full thickness LV sections using a custom de...
Abstract 3162: Endothelin-1 receptor/beta-arrestin-1 pathway promotes invadopodia and metastatic process by integration with hMENA in human serous ovarian cancer
Authors: Valentina Caprara, Francesca Di Modugno, Lidia Chellini, Piera Tocci, Francesca Spadaro, Andrea Sacconi, Giovanni Blandino, Paola Nisticò, Anna Bagnato, Laura Rosanò
Journal: Cancer Research (2018)

Abstract Aberrant activation of the endothelin-1 receptor (ET-1R) elicits pleiotropic effects relevant for serous ovarian cancer (SOC) cell invasion. The network activated by this receptor might be finely, spatially and temporary orchestrated by β-arrestin1 (β-arr1)-driven interactome. Recently, we uncovered a novel role for ET-1R/β-arr1 as regulator of cytoskeletal remodelling and invasive protrusions, invadopodia. Emerging evidence demonstrated that hMENA protein, an Ena/Vasp family member, is a key invadopodia component. In this study, we set out to molecularly dissect whether hMENA might represent a novel interacting partner of β-arr1 necessary for invadopodial function downstream of ET-1R in SOC cells. ENAH mRNA is significantly upregulated in OC tissues, and in particular in high-grade (HG)-SOC tumors, compared with normal tissues. In a panel of SOC cells, the expression hMENA, along with the spliced isoform hMENAΔv6, is upregulated by ET-1, at mRNA and protein levels, through β-arr1, restricted to mesenchymal phenotype. This effect is inhibited by treatment with the dual ETAR/ETBR antagonist macitentan. As shown by biochemical and imaging assays, ET-1 promotes a physical association between hMENA and β-arr1 as well PDZ-RhoGEF, which in turn activate RhoC. Most importantly, ET-1 induces localization of hMENA in F-actin-containing puncta, which co-localize with cortactin, and extracellular matrix degradation sites, thus promoting invadopodia maturation. Silencing of hMENA, as well as of β-arr1, or treatment with macitentan, impairs ET-1-dependent invadopodia activity, MMP secretion and activation, invasion, transendothelial migration and cell plasticity. In vivo, macitentan is able to inhibit SOC metastatic dissemination and hMENA expression along with other invadopodia markers. Finally, high ETAR/ARRB1/ENAH gene expression is associated with a poor prognosis in SOC patients. Collectively, these data define a pivotal function of hMENA/ hMENAΔv6, which is required for ET-1/β-arr1-induced invadopodial function and metastatic spreading of SOC. Citation Format: Valentina Caprara, Francesca Di Modugno, Lidia Chellini, Piera Tocci, Francesca Spadaro, Andrea Sacconi, Giovanni Blandino, Paola Nisticò, Anna Bagnato, Laura Rosanò. Endothelin-1 receptor/beta-arrestin-1 pathway promotes invadopodia and metastatic process by integration with hMENA in human serous ovarian 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 3162.
Inhibition of Neointima Formation After Experimental Coronary Artery Stenting
Authors: EckhardAlt, IrisHaehnel, ChristineBeilharz, KlausPrietzel, DanielPreter, AxelStemberger, ThiloFliedner, WolfErhardt, AlbertSchömig
Journal: Circulation (2000)

Background—To minimize acute stent thrombosis and development of restenosis, stents coated with biodegradable and nonbiodegradable polymers have been proposed to serve as sustained-release drug carriers. Methods and Results—In both a sheep and a pig model, we examined the vascular response to standard and high-pressure implantation of coronary Palmaz-Schatz stents coated with a 10-μm layer of polylactic acid (MW 30 kDa) releasing recombinant polyethylene glycol (r-PEG)–hirudin and the prostacyclin analogue iloprost, both drugs with antithrombotic and potentially antiproliferative effects. Study observation time was 28 days. Between the corresponding stent groups, no differences were observed with regard to preplacement and postplacement implantation parameters. The morphometric analysis demonstrated that the coating was associated with a greater lumen diameter through a reduction in the mean restenosis area by 22.9% (P<0.02) in the standard-pressure model (sheep) and by 24.8% (P<0.02) in the overstretch p...