tbuckley/cabot-search huggingface dataset:
Abstract 16755: Association Between Achievement of Risk Factor Standard of Care Goals and Major Adverse Cardiovascular Events in Patients With Stable Coronary Artery Disease in the STABILITY Trial
Authors: Harvey D White, Ralph A Stewart, Anthony J Dalby, Amanda Stebbins, Christopher P Cannon, Andrzej Budaj, Ales Linhart, Steen Husted, Emile R Mohler, Prem Pais, Rafael Diaz, Philippe Gabriel Steg, Sue Krug-Gourley, Christopher B Granger, Judith S Hochman, Wolfgang Koenig, Robert A Harrington, Claes Held, Lars Wallentin
Journal: Circulation (2015)

Introduction: Clinical practice guidelines have recommended evidence based medicine (EBM) and treatment targets for optimal management of BP, LDL Cholesterol (LDLc) and of HbA1c in diabetic patients with stable coronary heart disease [CHD]. However the importance of achieving these goals is uncertain. Hypothesis: In patients with stable CHD achievement of goals for blood pressure, LDLc, and HbA1c in diabetics, and use of EBM are associated with a lower risk of major adverse cardiovascular events [MACE]. Methods: In 13,624 patients with stable CHD, who participated in the STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial, BP, LDLc and HbA1c in diabetes were assessed at baseline, and at 3, 6 and 12 month follow-up visits; BP and medication use were additionally assessed at 1 month. EBM; aspirin, beta blockers, ACE / ARB, and statins, were recommended for patients without contraindications. Standard of care (SOC) targets were BP&lt;140/90 mmHg, LDLc &lt;70mg/dl and &lt;100mg/dl, and HbA1c&lt;7% in 4711 diabetics. Achievement of each of these targets was defined as meeting the target on ≥4 of 5 visits for BP and EBM, and ≥3 of 4 biochemical measurements. A landmark analysis assessed the association between achievement of EBM and of each SOC target during the first year of the study and MACE, defined as cardiovascular death, MI, or stroke, during a further 2.7 years follow-up, after adjusting for baseline predictors of MACE in a Cox proportional hazards model. Results: See Table. Conclusions: High rates of evidence based medicine use were achieved. MACE was related to LDLc. After one year the risk of subsequent MACE was reduced for patients who met target LDLc levels and for diabetic patients who achieved target HbA1c.
Abstract 5466: CXCL14 suppresses the aggressive phenotype in triple-negative breast cancer (TNBC) through CXCR4
Authors: Carla R. Gibbs, Rosa Mistica C. Ignacio, Ann Richmond, Deok-Soo Son
Journal: Cancer Research (2018)

Abstract The chemokine network is involved in cancer metastasis by modulating cell migration and angiogenesis. CXCL12-CXCR4 is a common signaling axis that is associated with cancer metastasis. Metastatic breast cancers often overexpress the CXCR4 receptor, whereas lung tissues express high levels of CXCL12; consequently, this is a proposed mechanism for breast cancer metastasis to the lung. CXCL14, an anti-inflammatory chemokine, has been postulated to be an alternative ligand for CXCR4, though a formal assignment of CXCR4 as the receptor for CXCL14 has not been made. Interestingly, CXCL14 competes with CXCL12, a main ligand for CXCR4, to modulate CXCL12-CXCR4 downstream activation of ERK. CXCL14 expression is downregulated in oral, colon, prostate, lung, pancreatic, cervical, kidney cancers, and in TNBC when compared to other subtypes of breast cancer. Overexpression of CXCL14 in cancer cell lines in vivo and in vitro leads to decrease in tumor metastasis. CXCL14 overexpression in the MDA-MB-231 breast cancer cell line leads to a decrease in cell growth, invasion and migration. To further explore a role for CXCL14 in breast cancer aggressiveness, we examined the effects of CXCL14 on the cell migration and metastasis of additional breast cancer cell lines. Here we performed cell migration and MTT cytotoxicity assays using MDA-MB-231 and BT-549 TNBC cell lines and the MCF-7 estrogen receptor+ cell line. Our results demonstrate TNBC cells are significantly more sensitive to CXCL14 compared to non-TNBC MCF7 cells (in Boyden chamber migration assay). Also, in our experiments CXCL14 did not alter proliferation in either TNBC cells or non-TNBC cells. However, when we generated CXCR4-overexpressing breast cancer cell lines using parental BT-549, MDA-MB-231, and MCF-7 cells, we observed the changes in the phosphorylation of ERK1/2 (MAPK targets) and pAKT (PI3K downstream effector protein). Based on these data, we propose CXCL14 as a negative modifier of the CXCL12-CXCR4 axis in TNBC. Based on these data, we propose a negative role for CXCL14 in the modulation of TNBC aggressiveness. Citation Format: Carla R. Gibbs, Rosa Mistica C. Ignacio, Ann Richmond, Deok-Soo Son. CXCL14 suppresses the aggressive phenotype in triple-negative breast cancer (TNBC) through CXCR4 [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 5466.
Response to Letter Regarding Article, “Annual Rate of Transvenous Defibrillation Lead Defects in Cardioverter-Defibrillators Over a Period of >10 Years”
Authors: ThomasKleemann, TorstenBecker, KlausDoenges, MargitVater, JochenSenges, SteffenSchneider, WernerSaggau, UdoWeisse, KarlheinzSeidl
Journal: Circulation (2007)
Heat Shock Transcription Factor 1 Protects Cardiomyocytes From Ischemia/Reperfusion Injury
Authors: YunzengZou, WeidongZhu, MasayaSakamoto, YingjieQin, HiroshiAkazawa, HaruhiroToko, MihoMizukami, NorihikoTakeda, TohruMinamino, HiroyukiTakano, ToshioNagai, AkiraNakai, IsseiKomuro
Journal: Circulation (2003)

Background— Because cardiomyocyte death causes heart failure, it is important to find the molecules that protect cardiomyocytes from death. The death trap is a useful method to identify cell-protective genes. Methods and Results— In this study, we isolated the heat shock transcription factor 1 (HSF1) as a protective molecule by the death trap method. Cell death induced by hydrogen peroxide was prevented by overexpression of HSF1 in COS7 cells. Thermal preconditioning at 42°C for 60 minutes activated HSF1, which played a critical role in survival of cardiomyocytes from oxidative stress. In the heart of transgenic mice overexpressing a constitutively active form of HSF1, ischemia followed by reperfusion-induced ST-segment elevation in ECG was recovered faster, infarct size was smaller, and cardiomyocyte death was less than wild-type mice. Protein kinase B/Akt was more strongly activated, whereas Jun N-terminal kinase and caspase 3 were less activated in transgenic hearts than wild-type ones. Conclusions— Th...
Novel Effect of Oxidized Low-Density Lipoprotein
Authors: SergiySukhanov, YusukeHigashi, Shaw-YungShai, HiroyukiItabe, KoichiOno, SampathParthasarathy, PatrickDelafontaine
Journal: Circulation Research (2006)

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classical glycolytic enzyme that is involved in cellular energy production and has important housekeeping functions. We used the natural prooxidant and proatherogenic molecule oxidized low-density lipoprotein (OxLDL) to determine a potential link between OxLDL-promoted oxidative stress, GAPDH expression, and smooth muscle cell energy metabolism. OxLDL but not native LDL (nLDL) produced a 60% to 100% dose- and time-dependent reduction of GAPDH protein. OxLDL increased reactive oxygen species (ROS) formation, including rapid elevation of H2O2 levels. OxLDL decreased intracellular catalase expression, likely contributing to the increase in H2O2. Antioxidants, anti-CD36 receptor antibody, NADPH oxidase, or lipoxygenase blockers decreased OxLDL-specific ROS and prevented GAPDH downregulation. 12/15-Lipoxygenase or p47phox deficiency resulted in attenuation of GAPDH downregulation, but 5-lipoxygenase suppression had no effect. OxLDL or exogenous H2O2 oxidize...
Abstract 1854: Treatment of head and neck squamous cell carcinoma cells with BMS754807 and Dasatinib induce synergistic cytotoxicity through altered focal adhesion signaling
Authors: Christine E. Lehman, Rolando MEndez, Mark Axelrod, Julia Wulfkuhle, Emanuel Petricoin, Daniel Gioeli, Mark Jameson
Journal: Cancer Research (2018)

Abstract Head and neck cancer (HNC) is the 6th most common cancer worldwide and the 9th most common cancer in the United States. Singular, targeted cancer therapies rarely produce a robust, complete and durable response and often do not substantially prolong patient survival. Adaptive survival responses often blunt the cytotoxic effects of drugs resulting in resistance. Therefore, targeting compensatory signaling pathways may provide improved therapeutic responses. Even with the current best treatment, 5-year survival for all patients with head and neck squamous cell carcinomas (HNSCC) is only approximately 65%, further highlighting the need for improved combinatorial treatments. Previous work in our laboratory has shown that inhibitors of Insulin Like Growth Factor 1 Receptor (IGF1R) and Src family kinases, when used in combination, synergistically inhibit HNSCC growth in vitro. Therefore, to explore the mechanisms which may contribute to this synergistic cytotoxicity, we utilized reverse phase protein arrays to assess the proteome of HNSCC lines treated with BMS754807 and Dasatinib to inhibit IGF1R and Src, respectively. We identified focal adhesion signaling as a potentially vital node in the cell signaling network of synergistic cytotoxicity upon treatment of HNSCC with BMS754807 and Dasatinib. Focal Adhesion Kinase (FAK) and Paxillin phosphorylation was decreased synergistically with the combination of BMS754807 and Dasatinib. Using western blot analysis, we confirmed a decrease in phosphorylation of FAK Y576/577 and Paxillin Y118 upon combined treatment with BMS754807 and Dasatinib. Interestingly, FAK is upregulated in radioresistant HNSCC patients and, metastases have increased phosphorylation of FAK compared to normal tissues. FAK is amplified in up to 26% of HNSCC and overexpression of Paxillin is associated with unfavorable prognosis, highlighting the importance of focal adhesion signaling in head and neck cancers. Our data suggests that interactions between integrins, receptor tyrosine kinase, and non-receptor kinase signaling regulate cell survival in HNSCC. Disruption of IGFR and Src activity leads to convergent inhibition of focal adhesion signaling and synergistic cytotoxicity in a variety of HNSCC cell lines. Citation Format: Christine E. Lehman, Rolando MEndez, Mark Axelrod, Julia Wulfkuhle, Emanuel Petricoin, Daniel Gioeli, Mark Jameson. Treatment of head and neck squamous cell carcinoma cells with BMS754807 and Dasatinib induce synergistic cytotoxicity through altered focal adhesion signaling [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 1854.
Abstract 2648: Prognostic significance of thyroid hormone receptor-alpha-2 (THRα2) expression in triple-negative breast cancer: A TCGA study
Authors: Katarzyna J. Jerzak, Anna Dvorkin-Gheva, Jessica G. Cockburn, Anita Bane, John A. Hassell
Journal: Cancer Research (2018)

Abstract Background: Thyroid hormones promote breast cancer cell proliferation and expression of their cognate nuclear receptors has shown prognostic potential in small cohort studies. Among two isoforms of thyroid hormone receptor alpha (THRα), the alpha1 splice variant (THRα1) promotes thyroid hormone mediated cell proliferation whereas the alpha2 variant (THRα2) opposes it. Hence, THRα2 expression may be a favorable prognostic biomarker in breast cancer. Methods: A publicly available database of breast tumors archived by The Cancer Genome Atlas (TCGA) was employed for this study. We analyzed RNA expression of THRα1 and THRα2 in 106 triple negative breast cancers (TNBCs) and correlated it with tumor stage (I vs II vs III) and nodal involvement (positive vs negative). Tumor grade was not uniformly reported. Univariate Cox proportional hazards regression models were fitted to determine the prognostic impact of THRα1 and THRα2 expression on overall survival (OS) and multivariate models were adjusted for age, tumor stage and radiation treatment. Results: The median age of women was 54 (range 29-90) and 12.3% died. The majority (62.3%) of patients presented with stage II disease; 16.0% were stage III and 17.9% were stage I at diagnosis. There was no significant correlation between THRα1 or THRα2 expression and tumor stage or nodal involvement. Expression of THRα2 was associated with improved OS in both uni- and multi-variate models (Table). Conclusions: In this study, THRα2 expression was independently prognostic for improved OS in TNBC. We previously demonstrated similar results in 158 TNBCs via immunohistochemistry but differentiation between RNA (as opposed to protein) splice variants is more precise. These results support investigation of THRα2 up-regulation or THRα1 inhibition as therapeutic strategies. Table. Prognostic associations of THRα2 expression in TNBCVariableUnivariate HR (95%CI)p valueMultivariate HR (95%CI)p valueLog (THRα2)0.46 (0.26-0.81)&amp;lt;0.010.28 (0.09-0.84)0.02Log (THRα1)0.54 (0.31-0.94)0.031.38 (0.53-3.62)0.51Age (years)0.98 (0.94-1.02)0.370.92 (0.84-1.01)0.10Stage (I vs II vs III vs IV)6.14 (2.19-17.22)&amp;lt;0.0126.03 (4.05-167.14)&amp;lt;0.01Radiation therapy (yes vs no)0.23 (0.04-1.22)0.080.10 (0.02-0.73)0.02 Citation Format: Katarzyna J. Jerzak, Anna Dvorkin-Gheva, Jessica G. Cockburn, Anita Bane, John A. Hassell. Prognostic significance of thyroid hormone receptor-alpha-2 (THRα2) expression in triple-negative breast cancer: A TCGA study [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 2648.
Abstract 712: Immune checkpoint inhibitor induced tumor gene expression changes in murine syngeneic colon cancer models
Authors: Patrick Fadden, Douglas Weitzel, Kelli Davis, Thi Bui, David Hurtado, Hannah Haines, Rhiannon Roark, Ashleigh Derrick, Beverly Godfrey, Ian Belle, Katherine Krontz, Cristina Sokolowski, Aidan Synnott, Edgar Wood
Journal: Cancer Research (2018)

Abstract The success of immune checkpoint therapy with anti-PD-1 and anti-CTLA-4 antibodies has generated broad interest in immuno-based interventions for oncology. Preclinical efficacy assessment of these novel immune-oncology therapies requires a functional immune system and therefore is frequently performed in murine syngeneic tumor models. In addition to tumor growth inhibition, syngeneic tumor models provide a platform to investigate the mechanism of action for a given novel therapeutic target. Characterization and mechanism of action for immune-based cancer therapies in murine syngeneic tumor models is often assessed by flow cytometry; measuring changes in tumor infiltrating leukocyte (TIL) populations following treatment induction. We assessed whether transcriptomic gene expression analysis could identify additional relevant biomarkers for immunotherapy response. Mice bearing subcutaneous syngeneic colon cancer tumors were dosed intraperitoneally with either vehicle alone, anti-CTLA-4, anti-PD-1, or a combination of the two immune checkpoint inhibitors on days 1, 4, and 8. Tumors were harvested on day 9 and half from each group were assessed for TIL population composition by flow cytometry and half by Clariom D mouse transcriptome array analysis. We identified a number of immune cell-related genes with differential expression that correlated to the therapeutic response and were consistent with changes identified in TIL populations by flow cytometry. These results provide an additional metric for assessing immunotherapy response in vivo. In addition, these data suggest that a smaller, defined panel of gene targets may be developed as biomarkers for specific immune system responses to immune checkpoint therapies in murine syngeneic models. Citation Format: Patrick Fadden, Douglas Weitzel, Kelli Davis, Thi Bui, David Hurtado, Hannah Haines, Rhiannon Roark, Ashleigh Derrick, Beverly Godfrey, Ian Belle, Katherine Krontz, Cristina Sokolowski, Aidan Synnott, Edgar Wood. Immune checkpoint inhibitor induced tumor gene expression changes in murine syngeneic colon cancer models [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 712.
Efficacy of an Empowerment-Based, Group-Delivered HIV Prevention Intervention for Young Transgender Women
Authors: Robert Garofalo, Lisa M. Kuhns, Sari L. Reisner, Katie Biello, Matthew J. Mimiaga
Journal: JAMA Pediatrics (2018)

The incidence of HIV infection among transgender women in the United States is extremely high, with young transgender women (YTW) at highest risk; condomless sex is the primary risk behavior for transmission. However, there are no published randomized clinical trials to date examining interventions to reduce sexual risk for HIV acquisition and transmission within this group. To determine the efficacy of a culturally specific, empowerment-based, and group-delivered behavioral prevention intervention to reduce sexual risk for HIV acquisition and transmission in sexually active YTW aged 16 to 29 years. Randomized clinical efficacy trial of Project LifeSkills, a group-delivered, behavioral HIV prevention intervention, vs standard of care conducted among 190 sexually active YTW between March 26, 2012, and August 15, 2016, at community-based locations in Boston, Massachusetts, and Chicago, Illinois, to reduce sexual risk for HIV acquisition or transmission. Data analysis was by a modified intention-to-treat approach. Participants were randomized (approximately 2:2:1) to the LifeSkills intervention (n = 116), standard of care only (n = 74), or a diet and nutrition time- and attention-matched control (attention control) arm (n = 43). The attention control arm was dropped during active enrollment per the Data Safety and Monitoring Board's recommendation. The LifeSkills intervention was delivered in six 2-hour sessions spanning a 3-week period. Primary outcome was change in the number of self-reported condomless anal or vaginal sex acts in the 4 months before the baseline assessment and that reported at the 4-, 8-, and 12-month visits. Of the 190 study participants, the mean (SD) age was 23.4 (3.4) years (range, 16-29 years); 47 (24.7%) were white, 83 (43.7%) were black or African American, 25 (13.2%) were Hispanic or Latina, and 35 (18.4%) were another race/ethnicity. From baseline to 4 months, the LifeSkills group had a 30.8% greater mean (SE) reduction in condomless sex acts (2.26 [0.40] at baseline vs 1.22 [0.22] at 4 months) compared with the standard of care group (2.69 [0.59] at baseline vs 2.10 [0.47] at 4 months) (risk ratio [RR], 0.69; 95% CI, 0.60-0.80; P < .001). Similarly, the LifeSkills group had a 39.8% greater mean (SE) reduction in condomless sex acts at the 12-month follow-up visit compared with the standard of care group (0.71 [0.13] vs 1.40 [0.32]; RR, 0.60; 95% CI, 0.50-0.72; P < .001). Among YTW at sexual risk of HIV acquisition or transmission, the LifeSkills intervention resulted in a 39.8% greater mean reduction in condomless sex acts during the 12-month follow-up in comparison to the standard of care group. This trial is the first to date to demonstrate evidence of efficacy for a behavioral intervention to reduce sexual risk in YTW. ClinicalTrials.gov Identifier: NCT01575938.
Long-Term Survival of Xenografted Neonatal Cardiomyocytes by Adenovirus-Mediated CTLA4-Ig Expression and CD40 Blockade
Authors: Tao-ShengLi, HiroshiIto, KojiKajiwara, KimikazuHamano
Journal: Circulation (2003)

Background— Prolonged survival of xenografted neonatal cardiomyocytes was achieved by blocking the CD28/B7 costimulatory pathway via CTLA4-Ig gene transfer. We examined the long-term survival of xenografted neonatal cardiomyocytes by adenovirus-mediated CTLA4-Ig expression and transient CD40 blockade with anti-CD40L monoclonal antibody (MR1). Methods and Results— Neonatal cardiomyocytes derived from Dark Agouti rats were infected with CTLA4-Ig-expressing adenovirus vectors and injected directly into the normal myocardium of C3H/He mice. Mice were also given an intraperitoneal injection of 500 μg MR1 (CTLA+MR group, n=30) or control immunoglobulin (CTLA group, n=30) 1 hour before and 1, 3, and 7 days after cardiomyocyte implantation. As a control, cells infected with β-Gal-expressing adenovirus vector (RL group, n=15) and cells without infection (control group, n=15) were injected into additional mice. Mice from all groups were killed 2, 4, and 8 weeks after xenotransplantation, and mice from the CTLA+MR a...
Abstract 3143: A novel approach to deplete Treg cells using non-IL-2 blocking anti-CD25-targeting antibodies leads to complete rejection of established tumors
Authors: Isabelle Solomon, Frederick Arce Vargas, Dimitrios Zervas, Chen Qing, Josephine Salimu, Mark Brown, Pascal Merchiers, Aghiles Boughetane, Karl S. Peggs, Anne Goubier, Sergio A. Quezada
Journal: Cancer Research (2018)

Abstract The accumulation of regulatory T cells (Tregs) in the tumor hampers effector anti-tumor activity and correlates with a bad prognosis in several human cancers. Increasing the effector T cell (Teff) to regulatory T cell (Treg) ratio is known to result in improved control of established tumors. Studies demonstrating high levels of CD25 expression on Tregs but not Teff in human tumors have underscored its relevance as a target for Treg depletion. This supported the development of anti-CD25 depleting monoclonal antibodies (mAbs) as a promising monotherapy as well as combination partner in cancer immunotherapies. To date, anti-CD25 antibodies for clinical use have been designed to deplete CD25 positive cells but also to block IL-2 binding and signaling. Since IL-2 is a critical cytokine involved in T cell activation and proliferation, we hypothesized that a depleting antibody targeting CD25 on Treg cells but not blocking IL-2 signaling on Teff cells would induce a more potent anti-tumor response by depleting Tregs whilst still allowing IL-2 to stimulate effector T cells. We therefore compared the functional activity of anti-mouse CD25 depleting mAbs with and without IL-2 blocking activity. After having confirmed their differential impact on IL-2 signaling, we evaluated the therapeutic activity of these mAbs in various syngeneic tumor models. While both the IL-2 blocking and non-IL-2 blocking mAbs showed equivalent Treg-depleting activity, the antibody sparing IL-2 signaling promoted stronger anti-tumor effect than the IL-2 blocking mAb, with complete tumor regression observed in 70-100% of the mice after a single administration of the antibody. Our data demonstrates that targeting CD25 with ADCC enabled antibodies preserving IL-2 signaling is a novel and powerful strategy for rejection of established tumors via depletion of Treg cells and enhanced, cell intrinsic, IL-2-driven effector T cell activation. Citation Format: Isabelle Solomon, Frederick Arce Vargas, Dimitrios Zervas, Chen Qing, Josephine Salimu, Mark Brown, Pascal Merchiers, Aghiles Boughetane, Karl S. Peggs, Anne Goubier, Sergio A. Quezada. A novel approach to deplete Treg cells using non-IL-2 blocking anti-CD25-targeting antibodies leads to complete rejection of established tumors [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 3143.