tbuckley/cabot-search huggingface dataset:
Angiotensin-Converting Enzyme Inhibitor Ramiprilat Interferes With the Sequestration of the B2 Kinin Receptor Within the Plasma Membrane of Native Endothelial Cells
Authors: ThomasBenzing, IngridFleming, AndreeBlaukat, WernerMüller-Esterl, RudiBusse
Journal: Circulation (1999)

Background—ACE (kininase II) inhibitors have been shown to exert their beneficial cardiovascular effects via the inhibition of both angiotensin II formation and bradykinin breakdown. Because recent evidence suggests that ACE inhibitors may also interfere with B2 kinin receptor signaling and thus enhance the vascular response to bradykinin, we examined whether the distribution of B2 kinin receptors within the plasma membrane of native endothelial cells is affected by an ACE inhibitor. Methods and Results—Localization of the B2 kinin receptor in membranes prepared from native porcine aortic endothelial cells was evaluated by means of specific [3H]bradykinin binding and immunoprecipitation of the B2 receptor from isolated membranes. Effects of bradykinin and ramiprilat on intracellular signaling were determined by monitoring the activation of the extracellularly regulated kinases Erk1 and Erk2 as well as [Ca2+]i increases in fura 2–loaded endothelial cells. Stimulation of native endothelial cells with bradyk...
Abstract 16146: Clinical Significant of the Ratio of Eicosapentaenoic Acid to Arachidonic Acid as a Risk Marker for Coronary Artery Disease
Authors: MasashiSakuma, YoshiyukiKitagawa, ShichiroAbe, ShigeruToyoda, ShintaroWatanabe, KatsutoEbisawa, YoshiakiMurakami, ToashiakiAndo, HiroyukiSugimura, IsaoTaguchi, TeruoInoue
Journal: Circulation (2014)

Introduction: The plasma eicosapentaenoic acid to arachidonic acid ratio (EPA/AA), which is determined only by dietary intake, has been attracting attention as a new risk marker for coronary artery disease (CAD). A Japanese inland prefecture, Tochigi, ranks higher mortality rate from CAD and lower seafood consumption, compared to other prefectures. The aim of this study was to investigate the EPA/AA ratio in residents of Tochigi prefecture. Methods and Results: We measured the EPA/AA ratio in patients undergoing diagnostic coronary angiography, because of suspicion for having CAD. In all of the patients, statins but not EPA agents were given. A total of 816 patients were enrolled in 7 centers around Tochigi prefecture. In overall patients, low-density lipoprotein cholesterol level was well controlled as 88±33 mg/dl. The median value of the EPA/AA ratio in all patients was 0.37. The EPA/AA ratio was lower in younger patients (<60 yrs), compared to elderly patients (≥60 yrs) (P<0.01). When subjects were div...
Abstract 4387: Triplet nucleotide repeat-based siRNAs are highly toxic to cancer cells
Authors: Andrea E. Murmann, Will Putzbach, Quan Gao, Monal Patel, Elizabeth T. Bartom, Calvin Law, Bryan Bridgeman, Siquan Chen, Kaylin M. McMahon, Shad C. Thaxton, Marcus E. Peter
Journal: Cancer Research (2018)

Abstract Triplet nucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington's disease (HD). Pathology is caused by both protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR can be used to kill cancer cells by targeting genes containing reverse complimentary long TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the 6 members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG-induced cell death occurs in vitro in all tested cancer cell lines and in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR-based siRNAs as a novel form of anticancer reagents. Citation Format: Andrea E. Murmann, Will Putzbach, Quan Gao, Monal Patel, Elizabeth T. Bartom, Calvin Law, Bryan Bridgeman, Siquan Chen, Kaylin M. McMahon, Shad C. Thaxton, Marcus E. Peter. Triplet nucleotide repeat-based siRNAs are highly toxic to cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4387.
Author Correction: Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer
Authors: Yonathan Lissanu Deribe, Yuting Sun, Christopher Terranova, Fatima Khan, Juan Martinez-Ledesma, Jason Gay, Guang Gao, Robert A. Mullinax, Tin Khor, Ningping Feng, Yu-Hsi Lin, Chia-Chin Wu, Claudia Reyes, Qian Peng, Frederick Robinson, Akira Inoue, Veena Kochat, Chang-Gong Liu, John M. Asara, Cesar Moran, Florian Muller, Jing Wang, Bingliang Fang, Vali Papadimitrakopoulou, Ignacio I. Wistuba, Kunal Rai, Joseph Marszalek, P. Andrew Futreal
Journal: Nature Medicine (2018)
Abstract 3104: Establishment of an oral tongue squamous cell carcinoma cell line from a never-smoking patient
Authors: Steven J. Wang, Saurabh Asthana, Annemieke van Zante, Adam B. Olshen, Frank McCormick, Osamu Tetsu
Journal: Cancer Research (2018)

Abstract (Objective) The rising incidence of oral tongue squamous cell carcinoma (OTSCC) in patients who have never smoked and the paucity of knowledge of its biological behavior prompted us to develop a new cell line originating from a never-smoker. (Materials and methods) Fresh tumor tissue of keratinizing OTSCC was collected from a 44-year-old woman who had never smoked. Serum-free media with a low calcium concentration were used in cell culture, and a multifaceted approach was taken to verify and characterize the cell line, designated UCSF-OT-1109.(Results) UCSF-OT-1109 was authenticated by STR DNA fingerprint analysis, presence of an epithelial marker EpCAM, absence of human papilloma virus (HPV) DNA, and SCC-specific microscopic appearance. Sphere-forming assays and mouse xenografts supported its tumorigenic potential. Spectral karyotype (SKY) analysis revealed numerical and structural chromosomal abnormalities. Whole-exome sequencing (WES) identified 46 non-synonymous and 13 synonymous somatic single-nucleotide polymorphisms (SNPs) and one frameshift deletion in the coding regions. Specifically, mutations of CDKN2A, TP53, SPTBN5, NOTCH2, and FAM136A were found in the databases. Copy number aberration (CNA) analysis revealed that the cell line loses chromosome 3p and 9p, but lacks amplification of 3q and 11q (as does HPV-negative, smoking-unrelated OTSCC). It also exhibits four distinctive focal amplifications in chromosome 19p, containing 131 genes without SNPs. Particularly, 52 genes showed &amp;gt;3- to 4-fold amplification and could be potential oncogenic drivers.(Conclusion) We have successfully established a novel OTSCC cell line from a never-smoking patient. UCSF-OT-1109 is potentially a robust experimental model of OTSCC in never-smokers. Citation Format: Steven J. Wang, Saurabh Asthana, Annemieke van Zante, Adam B. Olshen, Frank McCormick, Osamu Tetsu. Establishment of an oral tongue squamous cell carcinoma cell line from a never-smoking patient [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 3104.
Impaired Motion Processing in Schizophrenia and the Attenuated Psychosis Syndrome: Etiological and Clinical Implications
Authors: Antígona Martínez, Pablo A. Gaspar, Steven A. Hillyard, Søren K. Andersen, Javier Lopez-Calderon, Cheryl M. Corcoran, Daniel C. Javitt
Journal: American Journal of Psychiatry (2018)

Objective: The ability to perceive the motion of biological objects, such as faces, is a critical component of daily function and correlates with the ability to successfully navigate social situations (social cognition). Deficits in motion perception in schizophrenia were first demonstrated about 20 years ago but remain understudied, especially in the early, potentially prodromal, stages of the illness. The authors examined the neural bases of visual sensory processing impairments, including motion, in patients with schizophrenia (N=63) and attenuated psychosis (clinical high risk) (N=32) compared with age-matched healthy control subjects (N=67). Method: Electrophysiological recordings during stimulus and motion processing were analyzed using oscillatory (time frequency) approaches that differentiated motion-onset-evoked activity from stimulus-onset sensory-evoked responses. These were compared with functional MRI (fMRI) measures of motion processing. Results: Significant deficits in motion processing were observed across the two patient groups, and these deficits predicted impairments in both face-emotion recognition and cognitive function. In contrast to motion processing, sensory-evoked stimulus-onset responses were intact in patients with attenuated psychosis, and, further, the relative deficit in motion-onset responses compared with stimulus-onset responses predicted transition to schizophrenia. In patients with schizophrenia, motion detection deficits mapped to impaired activation in motion-sensitive visual cortex during fMRI. Additional visual impairments in patients with schizophrenia, not present in patients with attenuated psychosis, implicated other visual regions, including the middle occipital gyrus and pulvinar thalamic nucleus. Conclusions: The study findings emphasize the importance of sensory-level visual dysfunction in the etiology of schizophrenia and in the personal experience of individuals with the disorder and demonstrate that motion-processing deficits may predate illness onset and contribute to impaired function even in patients with attenuated psychosis.
Abstract LB-145: Enhancement of checkpoint inhibitor therapy by beta-alethine
Authors: Floyd Taub, Suzin Wright, Amanda Guth
Journal: Cancer Research (2018)

Abstract Beta-alethine (BA) is a small molecule drug that has demonstrated impressive anti-tumor immune responses against melanoma, particularly when combine with low dose anti-PD1. Here we report on the dose of BA that optimally enhances anti-PD1, the efficacy of BA combined with various immune checkpoint inhibitors (ICIs) in a murine bladder cancer and we propose a potential mechanism of action of BA to explain its synergistic effect. We tested 3 different doses of BA that were logs apart (30 mg/kg, 30 ug/kg, and 600 ng/kg) either alone or in combination with low dose (10 ug per mouse for a total of 3 doses 3 days apart) anti-PD1 in the DBA mouse Cloudman melanoma mouse model. The lowest dose of BA (600 ng/kg) in combination with anti-PD1 resulted in cures in 33% of the mice when treatment was initiated when tumors were of substantial size (average size of 30 mm2). Previous work starting with smaller tumor sizes (average 20 mm2) resulted in an 80% cure rate when a low dose of BA was used in combination with low dose anti-PD1. Analysis of blood from treated animals demonstrated that the combination led to decreased expression of multiple checkpoint molecules on both T cells and myeloid cells and to a decrease in tumor promoting inflammatory macrophages. We further demonstrated efficacy of combining BA with other ICI therapies in a s.c. MBT2 murine bladder cancer study in C3H mice. In these studies, we saw that BA was synergistic with a-PD1 at all doses tested (30 mg/kg, 30 ug/kg and 600 ng/kg weekly s.c.). The effect was seen even when only 4 weekly doses of BA were given. Interestingly, tumor growth increased when BA was discontinued, a phenomenon observed in previous compassionate use veterinary studies. Synergy with OX40 and CTLA4, were also seen, but further studies of dose and schedule are required for optimization. Our results demonstrate that a low dose of BA is optimal to enhance the efficacy of anti-PD1 and that this observed combinatorial effect is conserved in at least two different tumor types in different mouse strains. Based on analysis of T and myeloid cells in treated mice, we hypothesize that BA works via inducing pleiotropic changes that result in downregulation of multiple immune checkpoint molecules on T cells and on myeloid cells making it less feasible for these cells to use other pathways of immune suppression as compared to single agent anti-PD1 therapy and thus increase potential for cures. Citation Format: Floyd Taub, Suzin Wright, Amanda Guth. Enhancement of checkpoint inhibitor therapy by beta-alethine [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-145.
Abstract 1245: Identification of germline variants in cancer susceptibility genes in patients with hereditary breast and ovarian cancer syndrome by massive parallel sequencing in Argentinean population
Authors: Alejandra Franco, Fernando Orti, Sandra Perdomo, Cecilia Riggi, Cecilia Frecha, Javier Oliver
Journal: Cancer Research (2018)

Abstract Breast cancer is the most frequent cancer and ovarian cancer the seventh most frequent cancer among females worldwide, representing approximately 25% and 4% of all cancers. In Argentina, breast cancer and Ovarian cancer cause 6163 and 1332 deaths per year, respectively. Both breast and ovarian cancers are heterogeneous diseases composed of different tumor types with distinctive features and behaviors. The main risk factors for breast and ovarian cancer include age, family history, and genetics.The genetic components of both of the diseases have been well established, contributing to up to 10% of all breast cancer cases and 15% of all ovarian cancer cases.The two major susceptibility genes for both diseases are BRCA1 and BRCA2, and several other susceptibility genes have been identified. However, in the majority of high-risk breast and/or ovarian cancer (HBOC) families, the genetic predisposition factors remain unidentified, making the genetic counseling of these families challenging. The aim of the current study is to utilize an NGS approach to identify genetic factors that predispose individuals to hereditary breast and/or ovarian cancer (HBOC) in the high-risk Argentinian BRCA1/2 mutation-negative HBOC patients.16 patients were analyzed, the DNA was extracted from a blood samples and was subjected to a targeted massively parallel sequencing platform comprising 141 cancer predisposition genes. We detected in these patient 6 pathogenic variants in SBDS, FANCA, MC1R, WRN, MSR1 and SDHD genes. The effect of these variants are of type: non-synonymous (67%) and stop codon gains (33%). We also found 6 variants of uncertain significance (VUS) in APC, RAD50, SDHB, FANCD2, MLH1 and CDH1 genes.In conclusion, the identification of new variants could help to discover new genes associated to HBOC in the population of Argentina.These findings provide an excellent premise for further studies and could be utilized in the design of more efficient clinical management strategies for HBOC. Citation Format: Alejandra Franco, Fernando Orti, Sandra Perdomo, Cecilia Riggi, Cecilia Frecha, Javier Oliver. Identification of germline variants in cancer susceptibility genes in patients with hereditary breast and ovarian cancer syndrome by massive parallel sequencing in Argentinean population [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 1245.
Angiotensin II Signaling Pathways Mediate Expression of Cardiac T-Type Calcium Channels
Authors: LaurentFerron, VéroniqueCapuano, YannRuchon, EdithDeroubaix, AlainCoulombe, Jean-FrançoisRenaud
Journal: Circulation Research (2003)

Recent studies indicate that cardiac T-type Ca2+ current (ICaT) reappears in hypertrophied ventricular cells. The aim of this study was to investigate the role of angiotensin II (Ang II), a major inducer of cardiac hypertrophy, in the reexpression of T-type channel in left ventricular hypertrophied myocytes. We induced cardiac hypertrophy in rats by abdominal aorta stenosis for 12 weeks and thereafter animals were treated for 2 weeks with losartan (12 mg/kg per day), an antagonist of type 1 Ang II receptors (AT1). In hypertrophied myocytes, we showed that the reexpressed ICaT is generated by the CaV3.1 and CaV3.2 subunits. After losartan treatment, ICaT density decreased from 0.40±0.05 pA/pF (n=26) to 0.20±0.03 pA/pF (n=27, P<0.01), affecting CaV3.1- and CaV3.2-related currents. The amount of CaV3.1 mRNA increased during hypertrophy and retrieved its nonhypertrophic level after losartan treatment, whereas the amount of CaV3.2 mRNA was unaffected by stenosis. In cultured newborn ventricular cells, chronic ...
Serum Digitalis and Arrhythmia in Patients Undergoing Cardiopulmonary Bypass
Authors: Johnmorrison, Thomaskillip
Journal: Circulation (1973)

To assess the possible role of digitalis in the etiology of arrhythmia following cardiopulmonary bypass, serum digoxin or digitoxin was determined serially by radioimmunoassay in 24 chronically digitalized patients undergoing open-heart surgery. After an initial fall during bypass probably secondary to intraoperative fluid, serum digitalis rebounded, rising to or surpassing the preoperative value in 21 of the 24 patients studied. Peak rebound serum digitalis occurred an average of 13 hours following onset of bypass. Eight patients receiving maintenance digoxin developed arrhythmia postbypass at or near the peak of the rebound. The arrhythmia subsided as the peak was passed. Mean serum digoxin at the time of arrhythmia was 1.3 ± 0.2 (sd) ng/ml. A significantly higher (P < 0.001) value than the value of 0.07 ± 0.03 ng/ml found in patients without arrhythmia. Occurrence of arrhythmia could not be correlated with diagnosis, clinical status, cardiac size, blood gas, or serum electrolyte values. In 77 control s...
SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity
Authors: Gunther Boysen, Daniel N. Rodrigues, Pasquale Rescigno, George Seed, David Dolling, Ruth Riisnaes, Mateus Crespo, Zafeiris Zafeiriou, Semini Sumanasuriya, Diletta Bianchini, Joanne Hunt, Deirdre Moloney, Raquel Perez-Lopez, Nina Tunariu, Susana Miranda, Inês Figueiredo, Ana Ferreira, Rossitza Christova, Veronica Gil, Sara Aziz, Claudia Bertan, Flavia M. de Oliveira, Mark Atkin, Matthew Clarke, Jane Goodall, Adam Sharp, Theresa MacDonald, Mark A. Rubin, Wei Yuan, Christopher E. Barbieri, Suzanne Carreira, Joaquin Mateo, Johann S. de Bono
Journal: Clinical Cancer Research (2018)

Abstract Purpose: CHD1 deletions and SPOP mutations frequently cooccur in prostate cancer with lower frequencies reported in castration-resistant prostate cancer (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of CHD1-deleted/SPOP-mutated metastatic CRPC (mCRPC). Experimental Design: We identified 89 patients with mCRPC who had hormone-naive and castration-resistant tumor samples available: These were analyzed for CHD1, PTEN, and ERG expression by IHC. SPOP status was determined by targeted next-generation sequencing (NGS). We studied the correlations between these biomarkers and (i) overall survival from diagnosis; (ii) overall survival from CRPC; (iii) duration of abiraterone treatment; and (iv) response to abiraterone. Relationship with outcome was analyzed using Cox regression and log-rank analyses. Results: CHD1 protein loss was detected in 11 (15%) and 13 (17%) of hormone-sensitive prostate cancer (HSPC) and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic SPOP mutations, with six of these mutations not reported previously in prostate cancer. SPOP mutations and/or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR, 14.50 P = 0.001; CHD1: OR, 7.30, P = 0.08) and a longer time on abiraterone (SPOP: HR, 0.37, P = 0.002, CHD1: HR, 0.50, P = 0.06). Conclusions: SPOP-mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment. Clin Cancer Res; 24(22); 5585–93. ©2018 AACR.
Myocardial Contractile Function and Heart Rate in Mice With Myocyte-Specific Overexpression of Endothelial Nitric Oxide Synthase
Authors: FriedrichBrunner, PenelopeAndrew, GeraldWölkart, RudolfZechner, BerndMayer
Journal: Circulation (2001)

Background— The major source of nitric oxide (NO) in the heart is the constitutive form of NO synthases (eNOS, NOS III) that is expressed in vascular endothelium and cardiac myocytes. NO mediates endothelium-dependent vasodilation and may modulate cardiac function. We examined the role of NO in hearts from transgenic (TG) mice overexpressing eNOS exclusively in cardiac myocytes. Methods and Results— Three independent TG lines with varying levels of NOS activity were selected, and the hearts were isolated and retrogradely perfused at constant flow. We found that NO is positively inotropic in spontaneously beating hearts from wild-type (WT) mice, whereas hearts overexpressing eNOS had reduced basal contractility that was partially reversed by NOS blockade. Heart rate was not altered. Acetylcholine (10 to 1000 nmol/L) increased contractility in unstimulated hearts and decreased contractility after β-adrenergic stimulation with norepinephrine, and these responses were identical in WT and TG hearts. Finally, r...
Abstract 19530: Functional Assessment of Coronary Artery Disease Using Low-dose Dynamic Computed Tomography Perfusion
Authors: Logan Hubbard, Benjamin Ziemer, Jerry Lipinski, Bahman Sadeghi, Hanna Javan, E M Groves, Sabee Molloi
Journal: Circulation (2015)

Introduction: Computed tomographic angiography (CTA) is, despite its limitations, a powerful modality for noninvasive assessment of coronary artery disease (CAD). Current dynamic CT perfusion (CTP) techniques aim to improve CAD assessment, but deliver high radiation doses, limiting their clinical feasibility. Therefore, we propose a low-dose, dynamic CTP technique that allows for vessel-specific, functional assessment of CAD. Methods: A coronary angioplasty balloon was advanced into the proximal left anterior descending (LAD) coronary artery of seven swine (35-45 kg) to induce several levels of stenosis at maximal hyperemia (IC adenosine, 240 μg/min). Reference fluorescence microspheres and IV contrast (370 mg/mL iodine, 25 mL, 7 mL/s) were injected and prospective, ECG-gated dynamic CTP was performed using a 320-slice CT scanner at 100 kVp and 200 mA. Twenty volume scans were acquired per stenosis level for dose comparison to current techniques, but only two volume scans, denoted as V 1 and V 5 , were used for CTP measurement. V 1 was the first volume scan after the aortic input function exceeded a triggering threshold of 180 HU, and V 5 was the fifth volume scan post aortic triggering. All CTP measurements were compared to reference microsphere perfusion measurements using linear regression. Results: The result of dynamic CTP measurement was in good agreement with reference microsphere perfusion measurement (P CTP = 0.91 P MICRO + 0.37, R 2 = 0.85), as shown in the figure. Additionally, the effective dose of the proposed technique using a two-volume scan acquisition protocol was 2.6 mSv; much lower than the ~10 mSv effective dose of current dynamic CTP techniques. Conclusions: The results indicate the potential for substantial dose reduction in dynamic CTP while maintaining measurement accuracy. By reducing the number of volume scans necessary for accurate perfusion measurement, vessel-specific functional assessment of CAD by dynamic CTP is clinically feasible.