tbuckley/cabot-search huggingface dataset:
Abstract 948: Preventing estrogen receptor alpha-positive breast cancer outgrowth with the use of hormone replacement therapy
Authors: Anna G. Dembo, Emily S. Aledort, Geoffrey L. Greene
Journal: Cancer Research (2018)

Abstract Menopause occurs in all women, usually between the ages of 45 and 55. As a result of menopause, women often experience undesirable vasomotor symptoms, which can be alleviated by hormone replacement therapy (HRT). The Women's Health Initiative (WHI) trial concluded that PremPro, a HRT formulation that combines conjugated equine estrogens (CE) with medroxyprogesterone acetate, increases the risk of breast cancer. Over the years, the number of women taking HRT has dramatically decreased due to the perceived risk based largely on the results of the WHI trial. Follow-up sudies suggest that breast cancer cases from PremPro treatment were primarily due to the outgrowth of occult tumors, not the formation of new disease. Duavee, a more recent form of HRT that combines CE and bazedoxifene (BZA), a selective estrogen receptor modulator (SERM) and degrader (SERD), has been approved by the FDA for treatment of moderate to severe hot flashes and to reduce the risk of osteoporosis. More importantly, this CE+BZA mixture not only relieves symptoms associated with menopause, but it also does not stimulate the breast or uterus. Several preclinical studies suggest that CE+BZA might be protective in the breast, however the mechanism of action of this new combination therapy is not known. Our goal, therefore, is to elucidate the underlying molecular mechanisms by which CE+BZA differentially affects estrogen receptor alpha (ERα) action in the mammary gland, using transcriptome and whole genome occupancy analysis in breast cancer cell lines. RNA-Seq and ChIP-Seq studies suggest that CE+BZA decreases pathways related to S-phase entry, cell cycle regulation and BRCA1. We are also studying the effects of CE+BZA on early mammary cancer progression in the estrogen-sensitive polyoma middle T antigen (PyMT) transgenic mouse model and have observed that treatment with CE+BZA delayed the onset of tumors and decreased their rate of growth. Mice treated with CE+BZA also survived longer. In addition, CE+BZA was able to decrease the rate of tumor growth in an ERα-positive patient-derived xenograft (PDX) mouse model. An improved understanding of the molecular mechanisms of CE+BZA action in hormone sensitive breast cancer cell and animal models should have important implications for women considering HRT. Citation Format: Anna G. Dembo, Emily S. Aledort, Geoffrey L. Greene. Preventing estrogen receptor alpha-positive breast cancer outgrowth with the use of hormone replacement therapy [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 948.
Assessment of Fetal Compromise by Doppler Ultrasound Investigation of the Fetal Circulation
Authors: KurtHecher, StuartCampbell, PatDoyle, KevinHarrington, KyprosNicolaides
Journal: Circulation (1995)

Background Doppler studies of the fetal circulation in intrauterine growth retardation and hypoxia have demonstrated a compensatory redistribution of arterial blood flow with increased flow to the cerebrum and myocardium and decreased flow to the periphery. The aim of this study was to evaluate the significance of changes in fetal venous blood flow waveforms in high-risk pregnancies and to investigate the time relation between alterations in venous and arterial Doppler waveform indices in compromised fetuses. Methods and Results The cross-sectional study consisted of 108 high-risk singleton pregnancies between 23 and 42 weeks’ gestation without fetal chromosomal abnormalities or major malformations. Blood flow velocity waveforms were recorded from the umbilical arteries, descending thoracic aorta, middle cerebral artery, tricuspid and mitral ventricular inflow, ductus venosus, inferior vena cava, and the right hepatic vein. The mean velocity and pulsatility index were calculated for arterial vessels, the ...
Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response
Authors: Peng Jiang, Shengqing Gu, Deng Pan, Jingxin Fu, Avinash Sahu, Xihao Hu, Ziyi Li, Nicole Traugh, Xia Bu, Bo Li, Jun Liu, Gordon J. Freeman, Myles A. Brown, Kai W. Wucherpfennig, X. Shirley Liu
Journal: Nature Medicine (2018)
CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma
Authors: Long‐Zi Liu, Zhao Zhang, Bo‐Hao Zheng, Yang Shi, Men Duan, Li‐Jie Ma, Zhi‐Chao Wang, Liang‐Qing Dong, Ping‐Ping Dong, Jie‐Yi Shi, Shu Zhang, Zhen‐Bin Ding, Ai‐Wu Ke, Ya Cao, Xiao‐Ming Zhang, Ruibin Xi, Jian Zhou, Jia Fan, Xiao‐Ying Wang, Qiang Gao
Journal: Hepatology (2018)

Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within the tumor microenvironment. However, the tropism regulation and functions of these cells in hepatocellular carcinoma (HCC) are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic, and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1+ cells toward HCC invasive margin, approximately 80% of which were CD14+ monocytes. Clinically, a high density of marginal CCR1+CD14+ monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor‐educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro‐tumor factors and activating signal transducer and activator of transcription 1/3, extracellular signal‐regulated kinase 1/2, and v‐akt murine thymoma viral oncogene homolog signaling in HCC cells. Meanwhile, tumor‐derived CCR1+CD14+ monocytes expressed significantly higher levels of programmed cell death‐ligand 1, B7‐H3, and T‐cell immunoglobulin domain and mucin domain‐3 that may lead to immune suppression. Transcriptome sequencing confirmed that tumor‐infiltrating CCR1+CD14+ monocytes were reprogrammed to upregulate immune checkpoints, immune tolerogenic metabolic enzymes (indoleamine and arginase), inflammatory/pro‐angiogenic cytokines, matrix remodeling proteases, and inflammatory chemokines. Orthotopic animal models confirmed that CCL15‐CCR1 axis forested an inflammatory microenvironment enriched with CCR1+ monocytes and led to increased metastatic potential of HCC cells. Conclusion: A complex tumor‐promoting inflammatory microenvironment was shaped by CCL15‐CCR1 axis in human HCC. Blockade of CCL15‐CCR1 axis in HCC could be an effective anticancer therapy.
Abstract 17199: Impact of Mean Arterial Pressure on Clinical Outcomes in Comatose Survivors of Out-of-hospital Cardiac Arrest
Authors: Juan J Russo, Tyler E James, Christina Osborne, Benjamin Hibbert, Altayyeb Yousef, Michael Froeschl, Derek Y So, Marino Labinaz, Aun-Yeong Chong, Chris Glover, Jean-Francois Marquis, Michel R Le May, Alexander Dick
Journal: Circulation (2016)

Background: Comatose survivors of out-of-hospital cardiac arrest (OHCA) are subject to significant morbidity and mortality. Adequate cerebral oxygen delivery is crucial during the early post-arrest period and often compromised by hypotension, cerebrovascular dysregulation, and myocardial dysfunction characterizing the post-cardiac arrest syndrome. Although cerebral perfusion has been hypothesized to be highly dependent on mean arterial pressure (MAP) during the early post-cardiac arrest period, optimal blood pressure targets have not been established. Methods: We identified consecutive patients undergoing targeted temperature management following OHCA secondary to a shockable rhythm (ventricular tachycardia or fibrillation) between August 2010 and July 2013. We then examined the incidence of death and severe neurologic dysfunction (defined as a cerebral performance category (CPC) ≥3) in relation to mean MAP during the first 96 hours of hospitalization. Multivariable logistic regression analyses were used ...
Abstract 11762: Left Atrial Inflammation and Platelet Reactivity: A Comparison of Atrial Arrhythmia and an Underlying Substrate
Authors: Carlee D Schultz, Scott R Willoughby, Sathesh Kumar, Priya Shenbanga, Sukesh C Nair, Alok Srivastava, David Chase, Sunil T Chandy, Bobby John, Prashanthan Sanders
Journal: Circulation (2012)

Introduction: Atrial fibrillation (AF) is associated with increased risk of thromboembolic events, which occur as a consequence of left atrial thrombus formation. Rheumatic mitral disease is a potent substrate for AF. Inflammation and platelet hyperactivity are a key process involved in thrombus formation. This study investigated the left atrial specific inflammatory and platelet response in patients with AF and in a chronically remodelled substrate for AF (rheumatic mitral stenosis [MS]) Methods: This study involved 12 patients with AF (CHADS ≤1) undergoing catheter ablation, 19 patients with severe MS (no AF) undergoing balloon mitral valvuloplasty and 6 reference patients with supraventricular tachycardia (SVT) undergoing a electrophysiology study. Blood samples were collected from the left atria (LA) in all patients groups (start of procedure). Plasma levels of vascular cell (VCAM-1) and intracellular (I CAM-1) adhesion molecule were measured as markers of inflammation, with soluble CD40 Ligand (CD40L...
Unique Cardioprotective Action of the New Calcium Antagonist Mibefradil
Authors: RainerSchulz, HeinerPost, AndreasJalowy, UlrichBackenköhler, HilmarDörge, ChristianVahlhaus, GerdHeusch
Journal: Circulation (1999)

Background—Mibefradil is a calcium antagonist with few negative inotropic effects at therapeutic concentrations. Methods and Results—The effect of mibefradil on infarct size (IS) was compared with those of placebo, amlodipine, and verapamil in 64 anesthetized pigs. In placebo pigs, after 90 minutes of ischemia and 120 minutes of reperfusion, IS (by triphenyl tetrazolium chloride staining) was 15.3±10.8% (SD) of the area at risk. Mibefradil (0.60 mg/kg IV) reduced heart rate and left ventricular (LV) pressure, and IS was 1.9±3.9% (P<0.05 versus placebo). Verapamil (0.15 mg/kg IV) also decreased heart rate, LV pressure, and IS (6.1±4.2%, P<0.05 versus placebo). Amlodipine (0.20 mg/kg IV) did not alter heart rate, LV pressure, or IS (9.9±5.4%, P=NS versus placebo). When heart rate was maintained constant by left atrial pacing and LV pressure was adjusted to that of the placebo group by an intra-aortic balloon, mibefradil still decreased IS (3.8±3.0%, P<0.05 versus placebo), but verapamil did not (11.6±8.3%, ...
JAK-STAT signaling is activated in the kidney and peripheral blood cells of patients with focal segmental glomerulosclerosis
Authors: Jianling Tao, Laura Mariani, Sean Eddy, Holden Maecker, Neeraja Kambham, Kshama Mehta, John Hartman, Weiqi Wang, Matthias Kretzler, Richard A. Lafayette
Journal: Kidney International (2018)
Abstract 3761: Histone deacetylase inhibitor, Entinostat enhances the tumor specific immune response by generating T-cell central memory in the TME
Authors: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Peter Ordentlich, Lei Wang, Seema Gupta, Samir N. Khleif
Journal: Cancer Research (2018)

Abstract The epigenetic deregulation of T-cells and enhanced numbers of immunosuppressive cells in the tumor microenvironment (TME) are associated with decreased anti-tumor effects. Hence, targeting the epigenetic modifications using modulators such as histone deacetylase inhibitors (HDACi) provides the basis for a potential role for these agents in cancer-immunotherapy. In this context, Entinostat, an oral HDACi has been shown to reprogram the TME by impacting the numbers and activity of the immunosuppressive cell populations resulting in enhanced anti-tumor activity when combined with immune checkpoint blockade. However, the effect of this inhibitor on anti-tumor activity of effector T-cells is not well understood. Here, using animal tumor-models that require antigen-vaccine for T cell priming, we showed that Entinostat significantly synergized with tumor antigen-specific vaccine in delaying the tumor growth and prolonging mice survival. Further, we found that administering Entinostat in combination with antigen-priming resulted in sustainable long-term anti-tumor effects. Immunologically, Entinostat significantly enhanced the total CD8+, antigen-specific CD8+, granzyme B+ (GB+) CD8+, and antigen-specific GB+CD8+ T-cells in the TME when combined with the vaccine. Interestingly, we found that Entinostat led to a significant increase in the number of central memory T-cells (TCM; CD62L+CD44+) and decrease in the effector memory cells (TEM; CD62L-CD44+) in the TME. Notably, we did not find significant immune modulation in the periphery following the combination treatment indicating that the immune modulatory effects of Entinostat were localized to TME and hence may be associated with less systemic toxicity. Taken together these results highlight the ability of Entinostat to significantly enhance anti-tumor responses partly through the generation of central-memory which may translate to durable responses. These data provide further support on the potential of utilizing Entinostat in combinatorial immunotherapeutic strategies. Citation Format: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Peter Ordentlich, Lei Wang, Seema Gupta, Samir N. Khleif. Histone deacetylase inhibitor, Entinostat enhances the tumor specific immune response by generating T-cell central memory in the TME [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 3761.
Abstract 20924: Liver Fibrosis Increases Inferior Vena Caval Flow and Power Output of the Heart in Single Ventricle Patients After Fontan
Authors: Phillip M Trusty, Zhenglun Wei, Pierre A Russo, Lea F Surrey, David Goldberg, Jack Rychik, Mark A Fogel, Ajit P Yoganathan
Journal: Circulation (2016)

Introduction: The staged Fontan procedure has shown promising short term outcomes in single ventricle patients. However, Fontan-associated liver disease is a marked problem seen in this population ...
Abstract 12916: Elevation of Fatty Acid-Binding Protein 4 is Predisposed by Family History of Hypertension and Contributes to Blood Pressure Elevation
Authors: Takahiro Fuseya, Masato Furuhashi, Hideki Ota, Shutaro Ishimura, Tomohiro Mita, Hiroshi Akasaka, Hirofumi Ohnishi, Hideaki Yoshida, Shigeyuki Saitoh, Tetsuji Miura
Journal: Circulation (2012)

[Background] Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), a lipid chaperone, is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and association of elevated serum FABP4 level with obesity, insulin resistance, and atherosclerosis. However, little is known about the role of FABP4 in essential hypertension. [Methods] First, using blood samples in 296 subjects on no medication of our cohort, the Tanno-Sobetsu study cohort, correlation between serum FABP4 level and blood pressure was examined. Second, we next examined difference between serum FABP4 concentrations in 18 normotensives (NT) and 30 non-treated essential hypertensives (EHT). The EHT were divided into 18 insulin-sensitive EHT (EHT-S) and 12 insulin-resistant EHT (EHT-R) based on their insulin sensitivity index, the M value, determined by the hyperinsulinemic-euglycemic clamp technique. We lastly determined FABP4 levels in 30 young normotensive men with or without a family history of hyper...
Abstract 2496: YY1 regulates the germinal center reaction by inhibiting apoptosis
Authors: Sally E. Trabucco, Hong Zhang
Journal: Cancer Research (2018)

Abstract The germinal center (GC) reaction produces high-affinity antibodies for a robust adaptive immune response. If dysregulated, the same processes cause GC B cells to become susceptible to lymphomagenesis. It is important to understand how the GC reaction is regulated. In this study, we show that transcription factor YY1 is required to maintain a robust GC reaction in mice. Selective ablation of YY1 significantly decreased in the frequency and number of GC B cells during the GC reaction. This decrease of GC B cells was accompanied by increased apoptosis in these cells. Further, we found that loss of YY1 disrupted the balance between dark zones and light zones, leading to a preferential decrease in dark zone cells. Collectively, these results indicate that YY1 plays an important role in regulating the balance between dark zone and light zone cells in GCs and between survival and death of GC B cells. Citation Format: Sally E. Trabucco, Hong Zhang. YY1 regulates the germinal center reaction by inhibiting apoptosis [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 2496.
Salt-Sensitive Hypertension Induced by Decoy of Transcription Factor Hypoxia-Inducible Factor-1α in the Renal Medulla
Authors: NingjunLi, FanYi, MinXia, Pin-LanLi
Journal: Circulation Research (2008)

Hypoxia inducible factor (HIF)-1α, a transcription factor, is abundantly expressed in the renal medulla and regulates many oxygen-sensitive genes such as nitric oxide synthase, cyclooxygenase-2, and heme oxygenase-1. Given the important roles of these genes in the control of arterial pressure, the present study was to test the hypothesis that HIF-1α–mediated gene activation serves as an antihypertensive pathway by regulating renal medullary function and sodium excretion. HIF-1α decoy oligodeoxynucleotides (ODNs) or scrambled ODNs were transfected into the renal medulla in uninephrectomized Sprague–Dawley rats. Two weeks after ODN transfection, the HIF-1α binding activities were significantly inhibited by 45%, and high salt–induced increases of nitric oxide synthase-2 and heme oxygenase-1 transcriptions were also inhibited by 70% and 61% in the renal medulla from decoy rats. The natriuretic responses and increases of renal medullary blood flow responding to the elevations of renal perfusion pressure were s...
Burden of Comorbid Diseases in Patients with Hemophilia: The Cross-Sectional Analysis of the Patient Reported Outcomes, Burden and Experiences (PROBE) Study
Authors: Mark Skinner, Chatree Chai-Adisaksopha, Randall Curtis, Neil Frick, Declan Noone, Brian O'Mahony, David Page, Jeffrey Stonebraker, Alfonso Iorio
Journal: Blood (2017)
Abstract 2385: Evaluation of GCN2 chemical probes: Activity in leukemia
Authors: Lea Lough, Dan Sherman, Eric Ni, Palaniraja Thandapani, Ioannis Aifantis, Timothy Cardozo
Journal: Cancer Research (2018)

Abstract Cellular stress signals activate adaptive signaling pathways of the mammalian integrated stress response (ISR), which converge at the phosporylation of eIF2α. Drug-like chemical inhibitors targeting major ISR kinases have been identified, with the exception of GCN2. We synthesized and evaluated a series of GCN2 inhibitors based on a triazolo[4,5-d]pyrimidine scaffold. Several compounds potently inhibited GCN2 in vitro in orthogonal assays and displayed good selectivity over the related kinases PERK, HRI, and IRE1. The compounds had low solubility at pH 7.4, but sufficient permeability to inhibit phosporylation of eIF2α in HEK293T cells with an IC50 &amp;lt; 150 nM. In a screen of the NCI-60 cancer cell line panel, the leukemia cells were the only group of cancer cell lines to uniformly exhibit growth inhibition. Given the previously reported genetic association of Gcn2 with resistance to asparaginase, which is a first line clinical leukemia therapy, pharmacologic inhibition of Gcn2 may overcome resistance to asparaginase treatment in leukemia. Citation Format: Lea Lough, Dan Sherman, Eric Ni, Palaniraja Thandapani, Ioannis Aifantis, Timothy Cardozo. Evaluation of GCN2 chemical probes: Activity in leukemia [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 2385.
Abstract B04: Functional characterization of IGF-IR/PI3K/Akt signaling in myxoid liposarcoma
Authors: Marcel Trautmann, Magdalene Alice Cyra, Christian Bertling, Ilka Isfort, Jasmin Menzel, Konrad Steinestel, Inga Grünewald, Bianca Altvater, Claudia Rossig, Pierre Åman, Eva Wardelmann, Sebastian Huss, Wolfgang Hartmann
Journal: Clinical Cancer Research (2018)

Abstract Introduction: Myxoid liposarcoma (MLS) is the second most common type of liposarcoma and an aggressive disease with particular propensity to develop hematogenic metastases. Ninety percent of MLS are characterized by a reciprocal translocation t(12;16) (q13;p11), leading to the pathogenic gene fusion of FUS and DDIT3. The resulting chimeric FUS-DDIT3 fusion protein is suggested to play a crucial role in MLS pathogenesis, although the specific mechanism of action remains to be substantiated. Aiming at the preclinical identification of novel therapeutic options, we here investigate the functional relevance of FUS-DDIT3 in IGF-IR/PI3K/Akt signal transduction. Experimental Procedures: Immunohistochemical analyses of IGF-IR/PI3K/Akt signaling effectors and modulators were performed in a comprehensive cohort of clinical MLS specimens. FUS-DDIT3-dependent activation of the IGF-IR/PI3K/Akt signaling cascade was analyzed by siRNA and immunoblotting in vitro. Cell proliferation and FACS assays were performed in multiple tumor-derived MLS cell lines. An established MLS chorioallantoic membrane model (CAM) was employed for in vivo confirmation of the preclinical in vitro data. Results: In a significant subset of MLS specimens, immunohistochemical staining revealed elevated phosphorylation levels of various signaling components, representing a strong indication of activated IGF-IR/PI3K/Akt signaling to be a frequent feature in MLS. IGF-IR inhibition significantly suppressed the IGF-IR/PI3K/Akt signaling cascade, associated with impairment of MLS cell viability and induction of apoptosis in vitro and in vivo. Furthermore, siRNA-mediated knockdown of FUS-DDIT3 led to dephosphorylation of IGF-IR/PI3K/Akt signaling components, implying that the FUS-DDIT3 fusion protein is involved in the IGF-IR regulated signaling cascade. Conclusions: Our preclinical study emphasizes the pivotal role of the IGF-IR/PI3K/Akt signaling pathway in MLS pathogenesis and indicates its functional dependence on the MLS-specific FUS-DDIT3 fusion protein. Furthermore, our in vitro and in vivo results demonstrate that targeting the IGF-IR/PI3K/Akt signaling pathway provides a rational, molecularly founded therapeutic strategy in the treatment of MLS. Citation Format: Marcel Trautmann, Magdalene Alice Cyra, Christian Bertling, Ilka Isfort, Jasmin Menzel, Konrad Steinestel, Inga Grünewald, Bianca Altvater, Claudia Rossig, Pierre Åman, Eva Wardelmann, Sebastian Huss, Wolfgang Hartmann. Functional characterization of IGF-IR/PI3K/Akt signaling in myxoid liposarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B04.