tbuckley/cabot-search huggingface dataset:
Abstract 2577: Predictive value of multigene assay for chemotherapy benefit in patients with HR+/HER2- early breast cancer
Authors: Mi Jeong Kwon
Journal: Cancer Research (2018)

Abstract Our risk score based on a combination of multigene expression and clinical variables was validated to predict the risk of distant metastasis in hormone receptor-positive and human epidermal growth factor 2-negative (HR+/HER2-) early breast cancer in our previous study. In addition to its prognostic value, we investigated the predictive value of the risk score for adjuvant chemotherapy benefit in lymph node-negative (LN-), HR+/HER2- breast cancer. 346 patients who treated with hormone therapy (n = 203) alone or hormone therapy plus chemotherapy (n = 143) were classified as low-risk and high-risk group according to the risk score. There was a significant improvement in 10-year distant metastasis-free survival (DMFS) by the addition of adjuvant chemotherapy to hormone therapy in patients with a high risk score (26.5%, P = 0.003), whereas no benefit of chemotherapy was observed in those with a low risk score. The test for interaction between chemotherapy treatment and risk score was significant. The risk score also identified patients who will not benefit from chemotherapy among clinical high-risk group. Our study suggests that the risk score predicts the benefit of adjuvant chemotherapy in LN-, HR+/HER2- breast cancer and the addition of the risk score in the traditional cliniopathological factors may aid the improved treatment decisions. Citation Format: Mi Jeong Kwon. Predictive value of multigene assay for chemotherapy benefit in patients with HR+/HER2- early breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2577.
Opening of Mitochondrial KATP Channels Attenuates the Ouabain-Induced Calcium Overload in Mitochondria
Authors: HideyukiIshida, YukiHirota, ChokohGenka, HiroeNakazawa, HaruakiNakaya, ToshiakiSato
Journal: Circulation Research (2001)

We tested whether opening of mitochondrial ATP-sensitive K+ (mitoKATP) channels depolarizes mitochondrial membrane potential (ΔΨm) and thereby prevents the mitochondrial Ca2+ overload. With the use of a Nipkow disk confocal system, the mitochondrial Ca2+ concentration ([Ca2+]m) and ΔΨm in rat ventricular myocytes were measured by loading cells with Rhod-2 and JC-1, respectively. Exposure to ouabain (1 mmol/L) for 30 minutes produced mitochondrial Ca2+ overload, and the intensity of Rhod-2 fluorescence significantly increased to 173±16% of baseline (P<0.001). Treatment of myocytes with the mitoKATP channel opener diazoxide (100 μmol/L) blunted the ouabain-induced mitochondrial Ca2+ overload (131±10% of baseline; P<0.001 versus ouabain). Moreover, diazoxide significantly depolarized the ΔΨm and reduced the intensity of JC-1 fluorescence during application of ouabain to 89±2% of baseline (P<0.05). These effects of diazoxide were blocked by the mitoKATP channel blocker 5-hydroxydecanoate (500 μmol/L). These r...
Hexokinase 2 as a novel selective metabolic target for rheumatoid arthritis
Authors: Marta F Bustamante, Patricia G Oliveira, Ricard Garcia-Carbonell, Adam P Croft, Jeff M Smith, Ramon L Serrano, Elsa Sanchez-Lopez, Xiao Liu, Tatiana Kisseleva, Nissim Hay, Christopher D Buckley, Gary S Firestein, Anne N Murphy, Shigeki Miyamoto, Monica Guma
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Recent studies indicate that glucose metabolism is altered in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). Hexokinases (HKs) catalyse the first step in glucose metabolism, and HK2 constitutes the principal HK inducible isoform. We hypothesise that HK2 contributes to the synovial lining hypertrophy and plays a critical role in bone and cartilage damage. Methods HK1 and HK2 expression were determined in RA and osteoarthritis (OA) synovial tissue by immunohistochemistry. RA FLS were transfected with either HK1 or HK2 siRNA, or infected with either adenovirus (ad)-GFP, ad-HK1 or ad-HK2. FLS migration and invasion were assessed. To study the role of HK2 in vivo, 10 8 particles of ad-HK2 or ad-GFP were injected into the knee of wild-type mice. K/BxN serum transfer arthritis was induced in HK2 F/F mice harbouring Col1a1-Cre (HK2 Col1 ), to delete HK2 in non-haematopoietic cells. Results HK2 is particular of RA histopathology (9/9 RA; 1/8 OA) and colocalises with FLS markers. Silencing HK2 in RA FLS resulted in a less invasive and migratory phenotype. Consistently, overexpression of HK2 resulted in an increased ability to migrate and invade. It also increased extracellular lactate production. Intra-articular injection of ad-HK2 in normal knees dramatically increased synovial lining thickness, FLS activation and proliferation. HK2 was highly expressed in the synovial lining after K/BxN serum transfer arthritis. HK2 Col1 mice significantly showed decreased arthritis severity, bone and cartilage damage. Conclusion HK2 is specifically expressed in RA synovial lining and regulates FLS aggressive functions. HK2 might be an attractive selective metabolic target safer than global glycolysis for RA treatment.
Feeding Artery of a Left Atrial Myxoma Demonstrated by Three-Dimensional Volume-Rendering Images With Multislice Computed Tomography
Authors: NobusadaFunabashi, NobuyukiKomiyama, HiroshiHasegawa, HideyukiKato, YutakaYamamoto, KatsuyaYoshida, IsseiKomuro
Journal: Circulation (2002)
Abstract 14976: Foxo3a Modulates Mitochondrial and Myocardial Function by Regulating Bnip3 Gene Expression in the Heart
Authors: Antoine H Chaanine, Erik Kohlbrenner, Scott Gamb, Adam Guenzel, Katherine Klaus, Ahmad Fayyaz, Sreekumaran Nair, Roger J Hajjar, Margaret M Redfield
Journal: Circulation (2016)

Introduction: FOXO3a is a transcription factor which regulates glucose metabolism, muscle atrophy and cell death in post-mitotic cells. Its role in regulating mitochondrial and myocardial function is not well studied. Hypothesis: We hypothesized that FOXO3a through BNIP3 modulates mitochondrial function and myocardial energetics, remodeling and function in cardiac stress. Methods and Results: We utilized a rat model of pressure overload hypertrophy due to ascending aortic banding (AAB) with preserved ejection fraction (EF≊80%), left ventricular (LV) remodeling (LVEDV≥600 μl and LVESV≥120 μl) and diastolic dysfunction as well as studies in adult cardiomyocytes (ACM). Sprague Dawley rats (200 g) underwent AAB. Eight weeks after AAB, rats meeting the above echo criteria, were randomized to receive a tail vein injection of control adeno-associated virus containing GFP without a promoter (AAV9.GNP, n=8) or a dominant-negative FOXO3a mutant (AAV9.dn-FX3a, n=8). At 6 weeks post-injection, echo showed smaller LVE...
Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome
Authors: Xiaoyan Yu, Xiao-Lu Teng, Feixiang Wang, Yuhan Zheng, Guojun Qu, Yan Zhou, Zhilin Hu, Zhongqiu Wu, Yuzhou Chang, Lei Chen, Hua-Bing Li, Bing Su, Liming Lu, Zhiduo Liu, Shao-Cong Sun, Qiang Zou
Journal: The Journal of Experimental Medicine (2018)

Metabolic programs are crucial for regulatory T (T reg) cell stability and function, but the underlying mechanisms that regulate T reg cell metabolism are elusive. Here, we report that lysosomal TRAF3IP3 acts as a pivotal regulator in the maintenance of T reg cell metabolic fitness. T reg–specific deletion of Traf3ip3 impairs T reg cell function, causing the development of inflammatory disorders and stronger antitumor T cell responses in mice. Excessive mechanistic target of rapamycin complex 1 (mTORC1)–mediated hyper-glycolytic metabolism is responsible for the instability of TRAF3IP3-deficient T reg cells. Mechanistically, TRAF3IP3 restricts mTORC1 signaling by recruiting the serine-threonine phosphatase catalytic subunit (PP2Ac) to the lysosome, thereby facilitating the interaction of PP2Ac with the mTORC1 component Raptor. Our results define TRAF3IP3 as a metabolic regulator in T reg cell stability and function and suggest a lysosome-specific mTORC1 signaling mechanism that regulates T reg cell metabolism.
Characteristics of Cavotricuspid Isthmus–Dependent Atrial Flutter After Left Atrial Ablation of Atrial Fibrillation
Authors: AmanChugh, RakeshLatchamsetty, HakanOral, DarrylElmouchi, DavidTschopp, ScottReich, PetarIgic, TammyLemerand, EricGood, FrankBogun, FrankPelosi, FredMorady
Journal: Circulation (2006)

Background— Patients who have previously undergone ablation of atrial fibrillation may experience cavotricuspid isthmus (CTI)-dependent atrial flutter during follow-up. The effects of left atrial (LA) ablation on the characteristics of CTI-dependent flutter have not been described. Methods and Results— Fifteen patients underwent ablation of CTI-dependent flutter late after LA ablation of AF. The ECG, biatrial activation patterns, and LA voltage maps during flutter were analyzed. Thirty age- and gender-matched patients who underwent ablation of CTI-dependent flutter without prior LA ablation served as control subjects. Among the patients with prior LA ablation, mapping revealed counterclockwise activation around the tricuspid annulus in 12 of 15 patients (80%) and clockwise activation in 3 of 15 patients (20%). The flutter waves in the inferior leads were upright in 9 of the 15 patients (60%) with prior LA ablation and in none of the control subjects (P<0.001). The upright flutter waves in the inferior lea...
Distribution of Heart Potentials on Dog's Thoracic Surface
Authors: BrunoTaccardi
Journal: Circulation Research (1962)

The distribution of equipotential lines on the surface of the trunk has been determined experimentally in the dog at 8 to 15 instants of time during ventricular depolarization. Multiple potential maxima and minima are simultaneously present on the explored area during a large part of the activation time: their number, shape, and location vary continuously during ventricular excitation, following the same general scheme in all the animals studied. The single dipole theory does not account for the experimental data, reported in this paper. As far as surface potentials are concerned, the dog heart behaves as a multipolar generator. Complete exploration of the chest surface yields much more information about the electrical activity of the heart than is obtainable from routine limb and chest electrocardiograms. The relationships between the location of the potential maxima and minima on the body surface and the probable situation of the excitation waves in the heart are tentatively discussed.
Vesicle-Cloaked Virus Clusters Are Optimal Units for Inter-organismal Viral Transmission
Authors: Marianita Santiana, Sourish Ghosh, Brian A. Ho, Vignesh Rajasekaran, Wen-Li Du, Yael Mutsafi, Dennise A. De Jésus-Diaz, Stanislav V. Sosnovtsev, Eric A. Levenson, Gabriel I. Parra, Peter M. Takvorian, Ann Cali, Christopher Bleck, Anastasia N. Vlasova, Linda J. Saif, John T. Patton, Patrizia Lopalco, Angela Corcelli, Kim Y. Green, Nihal Altan-Bonnet
Journal: Cell Host & Microbe (2018)
Stem Cell Factor in Mast Cells and Increased Mast Cell Density in Idiopathic and Ischemic Cardiomyopathy
Authors: VincenzoPatella, IsabellaMarinò, EloisaArbustini, BärbelLamparter-Schummert, LauraVerga, MonikaAdt, GianniMarone
Journal: Circulation (1998)

Background—We compared cardiac mast cell (HHMC) density and the immunological and nonimmunological release of mediators from mast cells isolated from heart tissue of patients with idiopathic dilated (DCM) (n=24) and ischemic cardiomyopathy (ICM) (n=10) undergoing heart transplantation and from control subjects (n=10) without cardiovascular disease. Methods and Results—HHMC density in DCM (18.4±1.6 cells/mm2) and ICM (18.4±1.5 cells/mm2) was higher than that in control hearts (5.3±0.7 cells/mm2; P<.01). The histamine and tryptase contents of DCM and ICM hearts were higher than those of control hearts. The histamine content of the hearts was correlated with mast cell density (rs=.91; P<.001). Protein A/gold staining of heart tissue revealed stem cell factor (SCF), the principal growth, differentiating, and activating factor of human mast cells, in HHMC secretory granules. Histamine release from cardiac mast cells caused by immunological (anti-IgE and rhSCF) and nonimmunological stimuli (Ca2+ ionophore A2318...
Actin Cytoskeleton Remodeling Drives Breast Cancer Cell Escape from Natural Killer–Mediated Cytotoxicity
Authors: Antoun Al Absi, Hannah Wurzer, Coralie Guerin, Celine Hoffmann, Flora Moreau, Xianqing Mao, Joshua Brown-Clay, Rémi Petrolli, Carla Pou Casellas, Monika Dieterle, Jean-Paul Thiery, Salem Chouaib, Guy Berchem, Bassam Janji, Clément Thomas
Journal: Cancer Research (2018)

Elucidation of the underlying molecular mechanisms of immune evasion in cancer is critical for the development of immunotherapies aimed to restore and stimulate effective antitumor immunity. Here, we evaluate the role of the actin cytoskeleton in breast cancer cell resistance to cytotoxic natural killer (NK) cells. A significant fraction of breast cancer cells responded to NK-cell attack via a surprisingly rapid and massive accumulation of F-actin near the immunologic synapse, a process we termed "actin response." Live-cell imaging provided direct evidence that the actin response is associated with tumor cell resistance to NK-cell-mediated cell death. High-throughput imaging flow cytometry analyses showed that breast cancer cell lines highly resistant to NK cells were significantly enriched in actin response-competent cells as compared with susceptible cell lines. The actin response was not associated with a defect in NK-cell activation but correlated with reduced intracellular levels of the cytotoxic protease granzyme B and a lower rate of apoptosis in target cells. Inhibition of the actin response by knocking down CDC42 or N-WASP led to a significant increase in granzyme B levels in target cells and was sufficient to convert resistant breast cancer cell lines into a highly susceptible phenotype. The actin response and its protective effects were fully recapitulated using donor-derived primary NK cells as effector cells. Together, these findings establish the pivotal role of actin remodeling in breast cancer cell resistance to NK-cell-mediated killing.Significance: These findings establish the pivotal role of the actin cytoskeleton in driving breast cancer cell resistance to natural killer cells, a subset of cytotoxic lymphocytes with important roles in innate antitumor immunity. Cancer Res; 78(19); 5631-43. ©2018 AACR.
Amelioration by Quinapril of Myocardial Infarction Induced by Coronary Occlusion/Reperfusion in a Rabbit Model of Atherosclerosis
Authors: ShiroHoshida, NobushigeYamashita, KiminoriKawahara, TsunehikoKuzuya, MasatsuguHori
Journal: Circulation (1999)

Background—The increased severity of the myocardial injury produced by coronary occlusion-reperfusion in models of atherosclerosis is associated with an increase in leukocyte accumulation in the ischemic myocardium. Expression of P-selectin, an adhesion molecule involved in the interaction between leukocytes and endothelium, is increased in atherosclerotic vessels. Long-term angiotensin-converting enzyme (ACE) inhibition has been shown to reduce atherosclerotic vascular change in experimental models. Methods and Results—We examined changes in the size of the infarct resulting from coronary occlusion/reperfusion in normally fed and cholesterol-fed rabbits that were chronically treated with quinapril. Infarct size was significantly larger in the cholesterol-fed versus normally fed rabbits. ACE activity in the ischemic and nonischemic myocardium was significantly reduced by quinapril. Chronic quinapril administration significantly ameliorated the increased myocardial injury in cholesterol-fed rabbits. Quinap...
Abstract 5806: Combination of the miniature drug conjugate PEN-866 with PARP inhibitors as a rational approach to overcoming limitations of PARP inhibitor monotherapy
Authors: Samantha Perino, James M. Quinn, Marrissa Callahan, Gitanjali Sharma, Brian White, Mark Bilodeau, Leila Alland, Kerry Whalen, Richard Wooster
Journal: Cancer Research (2018)

Abstract PEN-866 is a novel miniature drug conjugate comprised of a Heat Shock Protein 90 (HSP90) targeting ligand attached through a cleavable linker to SN-38, the active metabolite of the approved topoisomerase I inhibitor, irinotecan. The conjugate accumulates and is retained in tumor cells through the HSP90 targeting ligand. PEN-866 linker cleavage provides sustained release of SN-38 at a high local tumor concentration leading to DNA damage and apoptosis of tumor cells resulting in broad preclinical antitumor activity. Reducing the DNA repair activity in tumor cells is an opportunity to significantly potentiate the efficacy of PEN-866. Poly ADP ribose polymerase (PARP) has an important role in the repair of DNA. PARP inhibitors have shown activity in the clinical setting, both in patients whose cancers harbor mutations in BRCA1 and BRCA2, and in those that are BRCA1/2 wildtype, and are approved as monotherapy for use in treatment of patients with advanced ovarian cancers. Combining PARP inhibitors with other therapeutics has been challenging due to dose limiting toxicities. Combining PARP inhibitors with PEN-866 is mechanistically appealing with the potential for greater efficacy as compared to these agents used alone and the potential to mitigate the toxicity of the combination of a PARP inhibitor with conventional cytotoxic therapy due to the high levels of accumulation and retention of PEN-866 in xenograft tumors. To evaluate these hypotheses, we have combined PEN-866 and PARP inhibitors in preclinical models of human cancer. Efficacy studies were carried out in both BRCA mutant and BRCA wildtype tumor xenografts combining PEN-866 and PARP inhibitors, and the combinations resulted in greater efficacy than that of the single agent in tumors with both genetic backgrounds. In addition, a pharmacodynamic assessment of DNA damage was performed in tumors responsive to the combination treatment. These data demonstrate that combination of PEN-866 and PARP inhibitors provide greater efficacy than single agent activity alone, including BRCA wildtype tumors, and support the evaluation of such combinations in the clinical setting. The authors acknowledge David Proia, Weiwen Ying and others from Synta Pharmaceuticals who contributed to this work. Citation Format: Samantha Perino, James M. Quinn, Marrissa Callahan, Gitanjali Sharma, Brian White, Mark Bilodeau, Leila Alland, Kerry Whalen, Richard Wooster. Combination of the miniature drug conjugate PEN-866 with PARP inhibitors as a rational approach to overcoming limitations of PARP inhibitor monotherapy [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 5806.
Free-Floating Thrombus in Right Heart and Massive Pulmonary Embolism Migrating Into Pulmonary Artery
Authors: YoshihiroNoji, TohruKojima, TakahikoAoyama, MasatoYamaguchi, TsutomuAraki, SusumuFujino, KatsuakiYokota, NorikoKumamoto, TakakiyoNakaya, KeiichiroTakase, MasamiShimizu, HiroshiMabuchi
Journal: Circulation (2005)
Activation of Platelet Function Through G Protein–Coupled Receptors
Authors: StefanOffermanns
Journal: Circulation Research (2006)

Because of their ability to become rapidly activated at places of vascular injury, platelets are important players in primary hemostasis as well as in arterial thrombosis. In addition, they are also involved in chronic pathological processes including the atherosclerotic remodeling of the vascular system. Although primary adhesion of platelets to the vessel wall is largely independent of G protein–mediated signaling, the subsequent recruitment of additional platelets into a growing platelet thrombus requires mediators such as ADP, thromboxane A2, or thrombin, which act through G protein–coupled receptors. Platelet activation via G protein–coupled receptors involves 3 major G protein–mediated signaling pathways that are initiated by the activation of the G proteins Gq, G13, and Gi. This review summarizes recent progress in understanding the mechanisms underlying platelet activation and thrombus extension via G protein–mediated signaling pathways.
Coronary Arteriography in the Intact Dog
Authors: Felixpearl, Meyerfriedman, Normangray, Brucefriedman
Journal: Circulation (1950)

A method is described whereby the coronary arteries of dogs with intact chests can be regularly demonstrated roentgenologically by the use of small amounts of Diodrast injected through a specially devised catheter which is passed to the aortic sinus through a peripheral artery. The artery is preserved by suture. Electrocardiograms taken during the procedure were normal. The aortic valves of two excised hearts previously subjected to forceful trauma by the catheter, showed no abnormality. Characteristic arteriograms are reproduced, showing coronary arteries, separate cusps of the aortic valves, and the proximal aorta.
The Exposome: Molecules to Populations
Authors: Megan M. Niedzwiecki, Douglas I. Walker, Roel Vermeulen, Marc Chadeau-Hyam, Dean P. Jones, Gary W. Miller
Journal: The Annual Review of Pharmacology and Toxicology (2018)

Derived from the term exposure, the exposome is an omic-scale characterization of the nongenetic drivers of health and disease. With the genome, it defines the phenome of an individual. The measurement of complex environmental factors that exert pressure on our health has not kept pace with genomics and historically has not provided a similar level of resolution. Emerging technologies make it possible to obtain detailed information on drugs, toxicants, pollutants, nutrients, and physical and psychological stressors on an omic scale. These forces can also be assessed at systems and network levels, providing a framework for advances in pharmacology and toxicology. The exposome paradigm can improve the analysis of drug interactions and detection of adverse effects of drugs and toxicants and provide data on biological responses to exposures. The comprehensive model can provide data at the individual level for precision medicine, group level for clinical trials, and population level for public health.