tbuckley/cabot-search huggingface dataset:
Abstract 4237: Differences in the frequencies of tumor <i>VHL</i> mutation and HIF-2α expression between black and white patients with clear cell renal carcinoma
Authors: Catherine L. Callahan, Lee E. Moore, Petra Lenz, Kendra Schwartz, Julie Ruterbusch, Faith Davis, Wong-Ho Chow, W. Marston Linehan, Maria J. Merino, Stephen M. Hewitt, Nathaniel Rothman, Jonathan N. Hofmann, Michael L. Nickerson, Mark P. Purdue
Journal: Cancer Research (2018)

Abstract Background: Black Americans have a poorer prognosis for clear cell renal cell carcinoma (ccRCC) than white Americans, potentially due in part to differences in tumor biology. In a recent analysis of The Cancer Genome Atlas (TCGA), tumors from black ccRCC patients had a lower rate of mutation in the VHL tumor suppressor gene and lower expression of hypoxia inducible factors (HIF) than tumors from white ccRCC patients. However, as this study was based on a small number of black patients (N=19) and had limited information on patients' medical histories and risk factors profiles, further investigation is needed. Objective: We evaluated differences in the frequencies of somatic VHL gene mutations and HIF-1α and -2α protein expression between tumors from black and white ccRCC patients. Methods: The investigation utilized formalin-fixed tissue and data collected from patients participating in a case-control study conducted in Chicago and Detroit. We sequenced VHL using the Ion Torrent platform for tumors from 69 black and 98 white patients, and measured tumor HIF-1α and -2α protein expression for 88 black and 240 white patients using immunohistochemistry. Results: Black patients' tumors had a lower frequency of VHL mutation than those of white patients (32% vs. 49%; P = 0.03) as well as a lower frequency of above-median HIF-2α expression (33% vs. 56%; P=0.002). HIF-1α expression did not differ by race (P=0.14). These racial differences persisted after multivariable model adjustment for age, sex, hypertension, chronic kidney disease, body mass index, smoking status, stage, grade, and tumor size [VHL mutation: odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.19, 0.98; HIF-2α expression: OR = 0.33, 95% CI = 0.18, 0.61]. Conclusions: Our observation that VHL mutation and high HIF-2α expression are less frequent in ccRCC tumors of black vs. white patients confirms the earlier TCGA finding. These findings suggest that ccRCC in black patients is a fundamentally different disease than ccRCC in white patients. Citation Format: Catherine L. Callahan, Lee E. Moore, Petra Lenz, Kendra Schwartz, Julie Ruterbusch, Faith Davis, Wong-Ho Chow, W. Marston Linehan, Maria J. Merino, Stephen M. Hewitt, Nathaniel Rothman, Jonathan N. Hofmann, Michael L. Nickerson, Mark P. Purdue. Differences in the frequencies of tumor VHL mutation and HIF-2α expression between black and white patients with clear cell renal carcinoma [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 4237.
Abstract 628: Immunometabolic signature of papillary thyroid carcinoma
Authors: Vivian L. Weiss, Naira Baregamian
Journal: Cancer Research (2018)

Abstract Introduction: Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer with rapidly rising incidence. The interface between PTC tumor metabolic reprogramming and metabolic immunomodulation remains poorly understood. Experimental Procedures: We sought to investigate the immunometabolic interaction patterns of PTC tumors and to determine whether a correlative relationship exists between tumor-infiltrating immune cell phenotypes and the expression of tumor metabolic enzymes. We performed a computational immunogenomic analysis to calculate leukocyte fractions within 496 PTC tumors from The Cancer Genome Atlas (TCGA). Immunogenomic analysis was performed using CIBERSORT (Newman AM et al., Nature Methods2015), a deconvolution method to calculate leukocyte fractions using RNA gene expression signatures. The PTC immune cell fractions were then compared to the RNA expression of tumor metabolic enzymes within the TCGA data using regression analysis. Matching targeted metabolomic analysis (Metabolon, Inc.) of 20 human PTC tumors was performed to determine tumor metabolite profiles associated with perturbed tumor cellular metabolic pathways based on the TCGA data analysis. Results: The immunogenomic and PTC metabolic pathway enzyme expression analysis demonstrated significant correlation between immune cell types and major metabolic pathway enzymes. Specifically, tumor glycolytic enzymes upstream of the TCA cycle correlated with CD8 (hexokinase-1, p&amp;lt;0.0001) and T regulatory (enolase, p&amp;lt;0.0001) cell infiltrates. Enhanced pyruvate cycling into the TCA cycle correlated with the presence of several immune cell types (malic enzyme 2 vs. follicular helper T cells, p&amp;lt;0.0001; pyruvate carboxylase vs CD8 T cells, p&amp;lt;0.0001). The expression of TCA cycle enzymes correlated with the fraction of macrophages (aconitase, p&amp;lt;0.0001; IDH1, p&amp;lt;0.05). Significant differences in PTC tumor and normal thyroid tissue metabolite profiles were observed in glycolysis and TCA cycle, further supporting our findings of immunometabolic plasticity it PTC. Together, these findings highlight the central role TCA cycle activity plays in PTC tumor immunometabolism. Conclusion: We demonstrate, for the first time, a distinct immunometabolic tumor signature supported by tumor metabolic reprogramming in PTC tumors. This novel characterization approach provides an important foundation for future functional metabolic studies within the tumor and immunologic microenvironment. A mechanistic understanding of the complex integration of immune networks and cellular metabolism can be harnessed for future therapeutic immunometabolic modulation in PTC. Citation Format: Vivian L. Weiss, Naira Baregamian. Immunometabolic signature of papillary thyroid carcinoma [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 628.
Abstract 16395: Multipoint Left Ventricular Pacing Improves Acute Hemodynamics and Short-Term Outcomes in Cardiac Resynchronization Therapy: A Systematic Review
Authors: Rodrigo Mendirichaga, Litsa K Lambrakos, Rhanderson Cardoso, Alexis Rodriguez, Chris Healy, Juan F Viles-Gonzalez, Raul D Mitrani, Jeffrey J Goldberger
Journal: Circulation (2016)

Introduction: One third of patients who meet criteria for cardiac resynchronization therapy fail to respond. Multipoint pacing of the left ventricle (MPP) has emerged as an alternative to reduce ra...
Voxel-wise radiogenomic mapping of tumor location with key molecular alterations in patients with glioma
Authors: Miguel Angel Tejada Neyra, Ulf Neuberger, Annekathrin Reinhardt, Gianluca Brugnara, David Bonekamp, Martin Sill, Antje Wick, David T W Jones, Alexander Radbruch, Andreas Unterberg, Jürgen Debus, Sabine Heiland, Heinz-Peter Schlemmer, Christel Herold-Mende, Stefan Pfister, Andreas von Deimling, Wolfgang Wick, David Capper, Martin Bendszus, Philipp Kickingereder
Journal: Neuro-Oncology (2018)

This study aims to evaluate the impact of tumor location on key molecular alterations on a single voxel level in patients with newly diagnosed glioma.A consecutive series of n = 237 patients with newly diagnosed glioblastoma and n = 131 patients with lower-grade glioma was analyzed. Volumetric tumor segmentation was performed on preoperative MRI with a semi-automated approach and images were registered to the standard Montreal Neurological Institute 152 space. Using a voxel-based lesion symptom mapping (VLSM) analysis, we identified specific brain regions that were associated with tumor-specific molecular alterations. We assessed a predefined set of n = 17 molecular characteristics in the glioblastoma cohort and n = 2 molecular characteristics in the lower-grade glioma cohort. Permutation adjustment (n = 1000 iterations) was used to correct for multiple testing, and voxel t-values that were greater than the t-value in >95% of the permutations were retained in the VLSM results (α = 0.05, power > 0.8).Tumor location predilection for isocitrate dehydrogenase (IDH) mutant tumors was found in both glioblastoma and lower-grade glioma cohorts, each showing a concordant predominance in the frontal lobe adjacent to the rostral extension of the lateral ventricles (permutation-adjusted P = 0.021 for the glioblastoma and 0.013 for the lower-grade glioma cohort). Apart from that, the VLSM analysis did not reveal a significant association of the tumor location with any other key molecular alteration in both cohorts (permutation-adjusted P > 0.05 each).Our study highlights the unique properties of IDH mutations and underpins the hypothesis that the rostral extension of the lateral ventricles is a potential location for the cell of origin in IDH-mutant gliomas.
Significance of Morphological Abnormalities Detected by MRI in Patients Undergoing Successful Ablation of Right Ventricular Outflow Tract Tachycardia
Authors: SebastianGlobits, GerhardKreiner, HerbertFrank, GottfriedHeinz, UrsulaKlaar, BernhardFrey, HeinzGössinger
Journal: Circulation (1997)

Background MRI can demonstrate subtle morphological changes of the right ventricle in patients with idiopathic right ventricular outflow tract tachycardia (RVOT). The present study examines the incidence and significance of right ventricular (RV) abnormalities detected by MRI with respect to the site of successful radiofrequency catheter ablation of the clinical tachycardia. Methods and Results The study population comprised 20 patients (mean age, 40±12 years) undergoing elimination of recurrent RVOT by radiofrequency catheter ablation. MRI studies were performed before ablation to assess RV volumes and function, as well as structural abnormalities of the RV myocardium. Ten healthy age- and sex-matched subjects served as control subjects. The successful ablation sites, as documented by radiographs of the catheter position, were compared with MRI findings. Patients with RVOT showed no difference in respect to RV volumes and ejection fractions compared with control subjects. Whereas RV abnormalities were li...
The Impact of Macrophage Insulin Resistance on Advanced Atherosclerotic Plaque Progression
Authors: IraTabas, AlanTall, DomenicoAccili
Journal: Circulation Research (2010)

Abstract: Atherothrombotic vascular disease is the major cause of death and disability in obese and diabetic subjects with insulin resistance. Although increased systemic risk factors in the setting of insulin resistance contribute to this problem, it is likely exacerbated by direct effects of insulin resistance on the arterial wall cells that participate in atherosclerosis. A critical process in the progression of subclinical atherosclerotic lesions to clinically relevant lesions is necrotic breakdown of plaques. Plaque necrosis, which is particularly prominent in the lesions of diabetics, is caused by the combination of macrophage apoptosis and defective phagocytic clearance, or efferocytosis, of the apoptotic macrophages. One cause of macrophage apoptosis in advanced plaques is activation of a proapoptotic branch of the unfolded protein response, which is an endoplasmic reticulum stress pathway. Macrophages have a functional insulin receptor signaling pathway, and downregulation of this pathway in the ...
Decoding the Right Ventricle in 3 Dimensions
Authors: Karima Addetia, Roberto M. Lang
Journal: JAMA Cardiology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Abstract 11587: Excessive NaCl Intake Aggravates Aortic Dissection Through IL-17 Pathway
Authors: Norifumi Nishida, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Makiko Hayashi, Sohei Ito, Hideo Yasukawa, Yoshihiro Fukumoto
Journal: Circulation (2015)

Excessive NaCl intake is an established risk factor of cardiovascular events, although the molecular mechanism has not been fully understood. Aortic dissection (AD) is one of the fatal cardiovascular events, in which proinflammatory response is proposed to be important. In this study, we investigated the effect of excessive NaCl intake on a mouse AD model that was induced by continuous infusion of beta-aminopropionitrile (BAPN), a collagen/elastin crosslink inhibitor, and angiotensin II (AngII). BAPN+AngII caused thoracic and suprarenal AD in most of the mice within 2 weeks. Excessive NaCl intake was achieved by giving 1% NaCl as drinking water (Hi-Na) 1 week prior to and during the BAPN+AngII infusion. The lesion length of AD was significantly longer in Hi-Na group than in normal water group, even though systolic blood pressure or pulse rate showed no significant changes. Because recent studies have demonstrated that excessive NaCl activates TH17/IL-17 pathway that is central to the inflammatory response, we examined the involvement of IL-17 in AD using IL-17 knockout mice (IL17-KO). Deletion of IL-17 gene abolished the exacerbating effect of NaCl on the severity of AD. Transcriptome analysis of aortae before AD onset showed that strong induction of proinflammatory genes and suppression of extracellular matrix (ECM) genes precede the AD development in this model. Although IL-17 is central to inflammatory response in general, alteration of inflammatory response was not prominent in IL17-KO aorta. Instead, genes of ECM was upregulated in IL17-KO at the baseline. With BAPN+AngII and excessive NaCl intake, expression of ECM genes were higher in IL17-KO compared to wild type aorta. Picrosirius red staining showed that the amount of medial collagen fibers, the major ECM to support the physical strength of aorta, was increased in IL17-KO compared to wild type mice without NaCl overload or BAPN+AngII administration. These data uncovered the unexpected role of IL-17 to suppress the ECM deposition in aorta. Because ECM is essential to maintain the physical strength of aortic walls, the increase of ECM would explains why IL17-KO aorta is protected from dissection. NaCl intake and IL-17 may represent important therapeutic targets for AD.
HSP90 Inhibition Drives Degradation of FGFR2 Fusion Proteins: Implications for Treatment of Cholangiocarcinoma
Authors: Dante Lamberti, Giulia Cristinziano, Manuela Porru, Carlo Leonetti, Jan B. Egan, Chang‐Xin Shi, Simonetta Buglioni, Carla A. Amoreo, Loriana Castellani, Mitesh J. Borad, Stefano Alemà, Sergio Anastasi, Oreste Segatto
Journal: Hepatology (2018)

About 15% of intrahepatic cholangiocarcinomas (ICCs) express constitutively active fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs) generated by chromosomal translocations. FFs have been nominated as oncogenic drivers because administration of FGFR tyrosine kinase inhibitors (F-TKIs) can elicit meaningful objective clinical responses in patients carrying FF-positive ICC. Thus, optimization of FF targeting is a pressing clinical need. Herein, we report that three different FFs, previously isolated from ICC samples, are heat shock protein 90 (HSP90) clients and undergo rapid degradation upon HSP90 pharmacological blockade by the clinically advanced HSP90 inhibitor ganetespib. Combining catalytic suppression by the F-TKI BGJ398 with HSP90 blockade by ganetespib suppressed FGFR2-TACC3 (transforming acidic coiled-coil containing protein 3) signaling in cultured cells more effectively than either BGJ398 or ganetespib in isolation. The BGJ398 + ganetespib combo was also superior to single agents when tested in mice carrying subcutaneous tumors generated by transplantation of FGFR2-TACC3 NIH3T3 transformants. Of note, FF mutants known to enforce clinical resistance to BGJ398 in ICC patients retained full sensitivity to ganetespib in cultured cells. Conclusion: Our data provide a proof of principle that upfront treatment with the BGJ398 + ganetespib combo improves therapeutic targeting of FGFR2 fusions in an experimental setting, which may be relevant to precision medicine approaches to FF-driven ICC.
Gender-Based Differences in Cardiac Repolarization in Mouse Ventricle
Authors: VéroniqueTrépanier-Boulay, ChantaleSt-Michel, AnnieTremblay, CélineFiset
Journal: Circulation Research (2001)

The mouse heart has become a widely used model for genetic studies of heart diseases. Thus, understanding gender differences in mouse cardiac repolarization is crucial to the interpretation of such studies. The objective of this study was to evaluate whether there are gender differences in cardiac repolarization in mouse ventricle and to gain insights into the ionic and molecular mechanisms underlying these differences. Action potential durations (APDs) and K+ currents in male and female ventricular myocytes were compared using a patch-clamp technique. APD20, APD50, and APD90 were found to be significantly longer in females than males. Examination of the different K+ currents revealed that a significantly lower current density exists in female ventricular myocytes compared with male myocytes for the ultrarapid delayed rectifier K+ current, IKur (at +30 mV, male, 33.2±2.9 pA/pF [n= 22]; female, 20.9±1.73 pA/pF [n= 19], P<0.001). Consistent with these findings were the results of the ribonuclease protection...
Oral Memantine for the Treatment of Glaucoma
Authors: Robert N. Weinreb, Jeffrey M. Liebmann, George A. Cioffi, Ivan Goldberg, James D. Brandt, Chris A. Johnson, Linda M. Zangwill, Susan Schneider, Hanh Badger, Marina Bejanian
Journal: Ophthalmology (2018)

To evaluate the effectiveness and safety of oral memantine as a potential neuroprotective agent in open-angle glaucoma (OAG) at risk for progression.Two randomized, double-masked, placebo-controlled, parallel-group, multicenter, 48-month studies identically designed, initiated 1 year apart, and completed in 2006. Protocol amendments included a 1-year extension (first study) and change in primary endpoint and analysis (second study).Patients (2298 total) with bilateral OAG; glaucomatous optic disc damage and visual field loss in 1 eye; glaucomatous optic disc damage and/or visual field loss in the contralateral eye (at screening), topically treated or untreated intraocular pressure (IOP) of 21 mmHg or less (at baseline); and at risk of glaucomatous progression (per prespecified criteria).Patients were randomized 3:2:2 to receive memantine 20 mg, memantine 10 mg, or placebo tablets daily. Glaucomatous progression was assessed in the intent-to-treat population by full-threshold standard automated perimetry (SAP), frequency doubling technology (FDT), and stereoscopic optic disc photographs, standardized by quality control assessment at centralized reading centers. Safety evaluations included adverse events (AEs), best-corrected visual acuity, biomicroscopy, IOP, and ophthalmoscopy. Efficacy data from each study were analyzed per protocol. Pooled analyses of efficacy and safety data were also performed.The predefined primary efficacy measure was glaucomatous visual field progression, as measured by SAP. Additional efficacy measures included glaucomatous progression of visual field (FDT) and optic nerve damage (stereoscopic optic disc photographs).The proportion of patients who completed the studies was similar among groups (80%-83%). Compared with placebo, daily treatment with memantine 10 mg or 20 mg for 48 months did not delay glaucomatous progression significantly in the individual studies and pooled analyses. The pooled risk reduction ratio (95% confidence interval) assessed by SAP was -0.13 (-0.40, 0.09) and -0.17 (-0.46, 0.07) for memantine 10 mg and 20 mg, respectively. Results were similar per FDT and stereoscopic optic disc photographs. The most common AEs leading to treatment discontinuations were dizziness, headache, fatigue, and nausea.With technologies available when the studies were conducted, daily treatment with memantine over 48 months was not shown to prevent glaucomatous progression in this patient population.
Spread of Excitation from the Sinus Node
Authors: Toyomisano, Shunichiyamagishi
Journal: Circulation Research (1965)

Microelectrodes were employed to determine the mode of propagation of excitation from the sinus node in the rabbit heart. The excitation starts from the sinus node radially, at first, but then proceeds to the crista terminalis, often obliquely. This is because some special tissue having a slow conduction velocity lies behind the sinus node, and also because there is a zone of relatively faster conduction at the basal wall of the superior vena cava. Once the excitation wave enters the crista terminalis, it travels rapidly in two opposite directions through two branches of the ring-like structure which is formed by the crista terminalis and its extension. The excitation wave traveling through the branch encircling the inferior vena cava reached the atrioventricular node earlier in most instances. In the caval region inside the ring-like structure there is a zone of relatively faster conduction. The conduction to the atrioventricular node through this route is latent in the normal state, because conduction t...
Reduction of Infarct Size and Prevention of Cardiac Rupture in Transgenic Mice Overexpressing FrzA
Authors: LaurentBarandon, ThierryCouffinhal, JéromeEzan, PascaleDufourcq, PierreCostet, PhilippeAlzieu, LionelLeroux, CatherineMoreau, DanièleDare, CécileDuplàa
Journal: Circulation (2003)

Background— FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled pathway, is expressed in the heart and vessels during mouse embryogenesis and adulthood. FrzA is involved in cell cycle control of vascular cells and angiogenesis. We assessed the hypothesis that FrzA could control the healing process after myocardial infarction (MI). Methods and Results— We demonstrated an upregulation of sFRP-1 and distinct wnt and fz member expression after MI. We established transgenic (Tg) mice that overexpress FrzA under a cytomegalovirus promoter and developed a model of MI by coronary artery ligation. FrzA reduced cardiac rupture after MI in Tg (6.5% versus 26.4% in controls; n=165, P<0.01). MI was smaller in Tg at each time point (18±10.8% of left ventricular circumference versus 30±14.2% in controls at day 30; P<0.001). Similar results were found in cryolesion-induced MI. Cardiac function was improved in Tg mice (3800±370 mm Hg/s dP/dtmax versus 2800±840 in controls; −2800±440 dP/dt...