tbuckley/cabot-search huggingface dataset:
Genomic prediction of relapse in recipients of allogeneic haematopoietic stem cell transplantation
Authors: J. Ritari, K. Hyvärinen, S. Koskela, M. Itälä-Remes, R. Niittyvuopio, A. Nihtinen, U. Salmenniemi, M. Putkonen, L. Volin, T. Kwan, T. Pastinen, J. Partanen
Journal: Leukemia (2018)

Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the most informative variants while controlling against overfitting. Our results show that germline genetic polymorphisms in patients entail a significant contribution to relapse risk, as judged by the predictive performance of the model (AUC = 0.72 [95% CI: 0.63–0.81]). Furthermore, the top contributing variants were predictive in two independent replication cohorts (n = 258 and n = 125) from the same population. The results can help elucidate relapse mechanisms and suggest novel therapeutic targets. A computational genomic model could provide a step toward individualized prognostic risk assessment, particularly when accompanied by other data modalities.
l-Methionine Augments Mammalian Myocardial Contraction by Sensitizing the Myofilament to Ca2+
Authors: YasukiKihara, MoriakiInoko, ShigetakeSasayama
Journal: Circulation Research (1995)

Abstract l-Methionine is an essential amino acid that has been reported to have a potent positive inotropic effect on the mammalian myocardium. We studied the mechanisms of the inotropic effect in ventricular myocardium from the rabbit. In the isolated coronary-perfused whole heart, l-methionine in a millimolar range exerted concentration-dependent positive inotropic effects on the isovolumic left ventricle, which were associated with negative lusitropic effects (prolonged time course of relaxation). The chronotropic state and the coronary perfusion pressure were not affected. These complex effects on the isolated whole heart were not blocked by pretreatment with (μmol/L) propranolol 1, prazosin 1, carbachol 3, staurosporine 1, or [Ser1,Ile8]angiotensin II 0.1. To further study the subcellular mechanisms, isolated ventricular papillary muscles from the same species were loaded with a bioluminescent indicator, aequorin, to monitor [Ca2+]i. In the presence of 3 mmol/L l-methionine, the isometric tension sho...
Abstract 15733: Long-Term Follow-Up of Patients With Paroxysmal Atrial Fibrillation and Severe Left Atrial Scarring: Comparison Between Pulmonary Vein Antrum Isolation Only or PVAI Combined With Either Scar Homogenization or Trigger Ablation
Authors: Sanghamitra Mohanty, Prasant Mohanty, Luigi Di Biase, Chintan Trivedi, Rong Bai, Pasquale Santangeli, Javier Sanchez, Patrick Hranitzky, G. J Gallinghouse, Amin Al-Ahmad, Rodney Horton, Richard Hongo, Steven Hao, Salwa Beheiry, Claude S Elayi, Dhanunjay Lakkireddy, Y. Madhu Reddy, Juan F Viles Gonzales, John David Burkhardt, Andrea Natale
Journal: Circulation (2015)

Background: Left atrial (LA) scarring, a consequence of cardiac fibrosis is a powerful predictor of procedure-outcome in atrial fibrillation (AF) patients undergoing catheter ablation. We sought to compare the long-term outcome in patients with paroxysmal AF and severe LA scarring/fibrosis identified by 3D mapping undergoing ablation of the pulmonary veins (PVAI) only or PVAI and the entire scar areas (scar homogenization) or PVAI plus ablation of the non-PV triggers. Methods: One-hundred seventy seven consecutive patients with paroxysmal atrial fibrillation and severe left atrial scarring were included in this study. LA scarring was diagnosed by 3D voltage mapping. The degree of scar was described as severe when &gt;60% of the LA area was involved. Non-PV triggers were defined as ectopic triggers originating from sites other than pulmonary veins such as interatrial septum, superior vena cava, left atrial appendage, ligament of Marshall, crista terminalis and coronary sinus. Patients underwent ablation of the pulmonary vein antrum (PVAI) only (n=45, group 1), PVAI extended to the entire scar areas (scar homogenization [n=66, group 2]) or PVAI plus ablation of non-PV triggers (n=66, group 3). Choice of ablation strategy was determined by the operator. Patients were followed up for arrhythmia recurrence with event recorders, ECG and Holter monitoring. Results: Baseline characteristics were not different between the groups (age 63±9 vs 58±10 vs. 60±11 years, p=0.23; male 71%, vs. 72% vs. 73% p= 0.91). After a single procedure, all patients were followed-up for a minimum of two years. The long-term success rate at the end of the follow up was 19% (12 pts) in group 1, 21% (14 pts) in group 2, and 61% (40 pts) in group 3. Kaplan-Meier log-rank test indicated that the cumulative probability of AF-free survival was significantly higher in group 3 (overall log-rank p &lt;0.001, pairwise comparison 1 vs. 3 and 2 vs. 3 was significant at p&lt;0.01). Conclusions: In patients with paroxysmal atrial fibrillation and severe left atrial scarring, PVAI plus ablation of non-PV triggers is associated with significantly better long-term outcome than PVAI alone or when PVAI is combined with scar homogenization.
Inducible Nitric Oxide Synthase Deficiency Does Not Affect the Susceptibility of Mice to Atherosclerosis but Increases Collagen Content in Lesions
Authors: Xi-LinNiu, XiaYang, KiyotakaHoshiai, KazuoTanaka, SadaakiSawamura, YasuhiroKoga, HiroeNakazawa
Journal: Circulation (2001)

Background—Although endothelial nitric oxide synthase (NOS) is antiatherogenic, the role of inducible NOS (iNOS) in the development of atherosclerosis is not established. Methods and Results—We compared the susceptibility of iNOS knockout (iNOS−/−) and wild-type (iNOS+/+) mice to the development of atherosclerosis induced by feeding an atherogenic diet for 15 weeks. Plasma lipid level, atherosclerotic lesion size, and cellular density in the lesions were all similar in the 2 strains (lesion size: iNOS+/+ 285±73×103 μm2, iNOS−/− 293±82×103 μm2, n=10). iNOS mRNA was detected in the lesions of iNOS+/+ but not iNOS−/− mice through RT-PCR. Immunohistochemically, iNOS+/+ mice showed iNOS staining in macrophages and medial smooth muscle cells in the lesions. Nitrotyrosine staining showed a similar distribution, whereas it was absent in iNOS−/− mice. There was no apparent difference in the intensity or distribution of vascular cell adhesion molecule-1 staining in the lesions of the 2 strains. However, the lesions...
Selective Effects of Oxygen Free Radicals on Excitation-Contraction Coupling in Ventricular Muscle
Authors: Wei DongGao, YonggeLiu, EduardoMarban
Journal: Circulation (1996)

Background Oxygen free radicals (OFRs) have been implicated in the pathogenesis of myocardial stunning, but the precise mechanism by which OFRs foster stunning remains unclear. We investigated the pathophysiology of the contractile dysfunction that occurs after direct exposure of OFRs to cardiac muscle and compared the results with the pathophysiology of stunned myocardium. Methods and Results Trabeculae from the right ventricles of rat hearts were loaded iontophoretically with fura-2 to determine [Ca2+]i. Steady-state force-[Ca2+]i relations were obtained by rapid electrical stimulation in the presence of ryanodine. Two exogenous OFR-generating systems were used: H2O2+Fe3+-nitrilotriacetic acid (H2O2+Fe3+) to produce hydroxyl radical, and xanthine oxidase+purine (XO+P) to produce superoxide. In muscles exposed to H2O2+Fe3+ for 10 minutes, both twitch force and Ca2+ transients were decreased (eg, in 1.5 mmol/L external [Ca2+], force decreased from 41±7 to 23±4 mN/mm2, P<.05, and Ca2+ transient amplitude f...
Abstract 1040: Patient derived xenografts of hematologic malignancies for translational research
Authors: Antje Siegert, Bernadette Brzezicha, Stephan Fuhrmann, Leonid Karawajew, Martin Janz, Clemens Schmitt, Iduna Fichtner, Jens Hoffmann
Journal: Cancer Research (2018)

Abstract Acute leukemias and lymphomas represent a very heterogeneous group of hematologic malignancies and pose an important challenge in the clinical routine. They frequently develop resistance to the treatment with standard-of-care (SoC) drugs and have a high incidence of disease recurrence. Recent progress in molecular profiling has helped to identify new potential drivers for the different leukemia and lymphoma subtypes, with some of them being potential therapeutic targets. Further target validation and drug development projects are highly dependent on corresponding preclinical models representing the different clinical subtypes. Therefore, we started to establish and characterize new patient derived xenografts (PDX) of AML, ALL and lymphomas for drug development and translational research. AML- and ALL-PDX were derived from bone marrow aspirates or peripheral blood samples, from primary or relapsed acute leukemia patients. Purified cells were transplanted either intravenously (i.v.) and/or subcutaneously (s.c.) into immunodeficient mice. Some mice developed a systemic AML, which was monitored by flow cytometric analysis of blood samples. Non-Hodgkin- or Hodgkin lymphoma-PDX were derived from peripheral blood, lymph node extirpations or core needle biopsies, and were usually transplanted subcutaneously into immunodeficient mice. For further characterization, established PDX models were treated with SoC and investigational drugs. In parallel, gene expression profiles as well as mutations were analyzed within the first in vivo passages. More than 20 new PDX models from AML, ALL, NHL and HL have been successfully established and characterized. Highly individual response to the treatments were observed, correlation analyses with mutations and gene expression are ongoing. Our newly and extensively characterized PDX models from hematologic malignancies are suitable tools for preclinical drug development. They provide an exceptional platform for the identification and validation of new targets and allow the preclinical screening of new compounds and combinations for translational research projects. Citation Format: Antje Siegert, Bernadette Brzezicha, Stephan Fuhrmann, Leonid Karawajew, Martin Janz, Clemens Schmitt, Iduna Fichtner, Jens Hoffmann. Patient derived xenografts of hematologic malignancies for translational research [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 1040.
Abstract 5890: Aurora-A potentiates chemoresistance via regulating the microRNA biogenesis pathway
Authors: Li Jyuan Lin
Journal: Cancer Research (2018)

Abstract Chemotherapy has a good success rate in colorectal cancer; however, recurrence of colorectal cancer is still frequent due to the development of drug resistance. MicroRNA (miRNA) is a type of non-coding RNA with a size of around 19-22 nucleotides and plays an important role in regulating many biological functions, the onset of diseases, as well as drug response. It was reported that Dicer, one of the key enzymes of the miRNA biogenesis pathway, may be involved in the chemoresistance through regulating the expression of miRNAs. Aurora-A, a cell cycle-regulated kinase, plays a vital role in cancer development and chemoresistance. According to the TCGA database, the expression levels of Dicer and Aurora-A are both increased in colorectal cancer. Here, we demonstrated that overexpressed Aurora-A can regulate the chemodrug response by influencing the miRNA biogenesis pathway via Dicer in colorectal cancer. Our results showed that the protein level, but not the mRNA expression, of Dicer was decreased upon 5-FU or oxaliplatin treatment in drug sensitive cells; whereas, the expression level of Dicer was increased in oxaliplatin resistant cell lines. Knockdown expression of Dicer in oxaliplatin resistant cell lines could reverse the resistance of oxaliplatin. The expression levels of several potential miRNAs changed upon chemodrugs treatment. Interestingly, we found that overexpressed Aurora-A could increase the expression of Dicer and potentiate drug resistance in colorectal cancer cells. In contrast, knockdown expression of Aurora-A decreased Dicer protein expression and led to enhanced drug sensitivity. Taken together, our results suggested that Aurora-A and Dicer can collaborate to regulate drug response through influencing the miRNA biogenesis pathway in colorectal cancer. The further mechanism of Dicer and Aurora-A in chemoresistance is currently under our investigation. Citation Format: Li Jyuan Lin. Aurora-A potentiates chemoresistance via regulating the microRNA biogenesis pathway [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 5890.
Aldosterone Upregulates Ca2+ Current in Adult Rat Cardiomyocytes
Authors: Jean-PierreBénitah, GuyVassort
Journal: Circulation Research (1999)

Abstract—Aldosterone is associated with the pathogenesis and progression of left ventricular hypertrophy and heart failure, independent of its relation with arterial blood pressure. However, little information exists about the possible influence of this mineralocorticoisteroid on cardiomyocyte electrical activity. The present study was designed to determine the role of aldosterone on whole-cell Ca2+ current (ICa) in isolated adult rat ventricular myocytes using the patch-clamp technique. We found that incubation of cells with 1 μmol/L aldosterone for 24 hours increases the density of ICa significantly. This “long-term” aldosterone treatment had no significant effects on the kinetics and voltage dependence of ICa inactivation. Moreover, no demonstrable influence of aldosterone on ICa could be detected during short-term exposure (up to 6 hours), under our experimental conditions. The classical aldosterone intracellular receptor antagonist spironolactone (250-fold excess) was able to blunt the aldosterone-in...
Abstract 18914: Comparison of Statin Eligibility Using the Pooled Cohort Equations, ATP-III Framingham and Reynolds Risk Scores Among Adults Who Experienced ASCVD Events: The Atherosclerosis Risk in Communities Study
Authors: Tamar Polonsky, David Couper, Amy Yang, Philip Greenland, Salim Virani, Brad C Astor, Ervin Fox, Ron C Hoogeveen, Thomas H Mosley, Scott D Solomon, Christie M Ballantyne, Vijay Nambi
Journal: Circulation (2015)

Background: The 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol recommended initiating statin therapy when an individual’s 10-year estimated ASCVD risk ≥7.5% We sought to determine whether adults who eventually experienced ASCVD events were more likely to be identified as having ≥7.5% risk using the ACC/AHA’s Pooled Cohort Equations (PCE) compared to the ATP III-Framingham (FRS) and Reynolds risk scores (RRS). Methods: We used data from the biracial Atherosclerosis Risk in Communities Study (ARIC) visit 4 (1996-1998) because hsCRP was measured at this exam. We excluded participants with an ASCVD event prior to visit 4, diabetes, statin use at visit 4, age&gt;74, LDL-C &gt;190 mg/dl, or missing data. Published models for the PCE, ATP III-FRS, and RRS estimated risk. We defined statin eligibility as an estimated 10-year risk ≥7.5% for the PCE and RRS, and ≥10% for the ATP III-FRS. The primary outcome for each score was based on the outcomes originally used to derive the scores: ATP III-FRS (MI or CHD death), PCE (MI, CHD death, stroke) and RRS (MI, CHD death, stroke and revascularization). Results: Using the PCE, 2592 participants had an estimated risk ≥7.5% and 2760 &lt;7.5%. The median age among those with estimated risk ≥7.5% was 66; 19% were black and 35% were women. Over a median of 11 years 304 CHD events, 201 strokes and 432 revascularizations occurred. With all 3 risk scores &gt;80% of men who experienced events had an estimated risk ≥7.5% (see Table). In contrast, a much smaller proportion of women who experienced events had an estimated risk ≥7.5%, although the PCE yielded the highest proportion (52%). Conclusions: A cutoff of ≥7.5% 10-year ASCVD risk identified the majority of male participants in ARIC who experienced subsequent ASCVD events regardless of the risk score used. Substantially fewer women who experienced events were identified. Lower risk cutoffs or additional markers of ASCVD risk may be required when making decisions about statin therapy for women.
Leukemia in gastrointestinal organs as cause of treatment failure: 378 cases analyzed
Authors: Isabel Cunningham, Daniel Worthley
Journal: American Journal of Hematology (2018)

Abstract Leukemia growing as tumors in gastrointestinal organs is an under‐investigated cause of treatment failure and death. These present with symptoms often mistaken for common toxicities but may grow large before symptoms. To synthesize experience available only in case reports, 378 were analyzed. Invasive and metastatic behavior typical of solid GI tumors was revealed even when marrow was uninvolved. Within 3 months of diagnosis, 33% had died, 47% within 1 year. Survivals of 4 to 18 years after involvement suggest cure is possible. Evidence is presented that combined local and systemic therapy has successfully treated GI leukemic tumors when identified early.
Innocent Spectators, Helping Hands or a Fifth Column? Acute Hepatitis A Infection Reveals Important Insights Into Bystander T Cells
Authors: Ruben C. Hoogeveen, Georg M. Lauer
Journal: Hepatology (2018)

Hoogeveen, Ruben C. M.D.; Lauer, Georg M. M.D., Ph.D.Editor(s): Corey, Kathleen E.2; Malhi, Harmeet3 Author Information
Abstract 16326: Is the Novel Algorithm for Estimating Left Ventricular Diastolic Dysfunction in ASE/EACVI Guideline of 2016 Applicable in Patients With Coronary Artery Disease?
Authors: Junki Yamamoto, Kazuaki Wakami, Shohei Kikuchi, Syunsuke Murai, Hiroshi Fujita, Tomonori Sugiura, Toshihiko Goto, Nobuyuki Ohte
Journal: Circulation (2017)

Background: Using multiple parameter for assessing left ventricular (LV) diastolic function is recommended in the novel algorithm of ASE/EACVI guideline of 2016. Although this algorithm is based on...
Gene Transfer of Heterologous G Protein–Coupled Receptors to Cardiomyocytes
Authors: Karl-LudwigLaugwitz, Hans-JörgWeig, AlessandraMoretti, EvaHoffmann, PeterUeblacker, IngoPragst, KaiRosport, AlbertSchömig, MartinUngerer
Journal: Circulation Research (2001)

Abstract—In heart failure, reduced cardiac contractility is accompanied by blunted cAMP responses to β-adrenergic stimulation. Parathyroid hormone (PTH)–related peptide and arginine vasopressin are released from the myocardium in response to increased wall stress but do not stimulate contractility or adenylyl cyclase at physiological concentrations. To bypass the defective β-adrenergic signaling cascade, recombinant P1 PTH/PTH-related peptide receptors (rPTH1-Rs) and V2 vasopressin receptors (rV2-Rs), which are normally not expressed in the myocardium and which are both strongly coupled to adenylyl cyclase, and recombinant β2-adrenergic receptors (rβ2-ARs) were overexpressed in cardiomyocytes by viral gene transfer. The capacity of endogenous hormones to increase contractility via the heterologous, recombinant receptors was compared. Whereas V2-Rs are uniquely coupled to Gs, PTH1-Rs and β2-ARs are also coupled to other G proteins. Gene transfer of rPTH1-Rs or rβ2-ARs to adult cardiomyocytes resulted in ma...
Abstract 17581: Evidence for Circulating Stem Cells Derived from the Human Heart and Their Therapeutic Potential
Authors: Han-MoYang, Ju-YoungKim, Hyun-JaiCho, Joo-EunLee, So-JungLim, SooryeonhwaJin, Kyung-WooPark, SahminLee, Hae-YoungLee, Hyun-JaeKang, Byung-HeeOh, Young-BaePark, Hyo-SooKim
Journal: Circulation (2014)

Introduction and Hypothesis: Many studies have shown resident cardiac stem cells in myocardium as well as epicardial progenitor cells in epicardium. However, the presence of stem cells in the endocardium has not been elucidated. In this study, we identified circulating multipotent stem cells from human peripheral blood. Furthermore, we investigated the origin and the therapeutic potential of these cells. Methods and Results: We identified a new population of cells from human peripheral blood mononuclear cells, which were quite different from previously reported stem cells. Newly identified cells expressed genes such as Oct3/4, KLF4, Nanog, and c-Myc. Moreover, FACS analysis precluded the possibility that these cells might be hematopoietic stem cells. To investigate the origin of these cells, we collected peripheral blood from patients undergoing bone marrow, liver, heart, or kidney transplantation. After culturing these cells, we could confirm that these stem cells were derived from the human heart by ide...
Endoscopic dual therapy for giant peptic ulcer hemorrhage
Authors: Igor Braga Ribeiro, Daniel Tavares Rezende, Antonio Coutinho Madruga Neto, Edson Ide, Carlos Kiyoshi Furuya, Diogo Turiani Hourneaux De Moura, Eduardo Guimarães Hourneaux De Moura
Journal: Endoscopy (2018)

Upper gastrointestinal bleeding (UGIB) is a common condition with an incidence of 40 − 150 cases per 100 000 inhabitants per year [1] [2]. Peptic ulcer represents the most common cause of UGIB and dual therapy seems to be the best treatment [3].
Left Ventricular Dysfunction on Exercise Long Term After Total Repair of Tetralogy of Fallot
Authors: ChisatoKondo, MakotoNakazawa, KiyokoKusakabe, KazuoMomma
Journal: Circulation (1995)

Background Excellent results regarding mortality are well recognized in the long-term period after intracardiac repair of tetralogy of Fallot. However, it is still unclear how postoperative sequelae affect cardiac performance during exercise. Methods and Results Twenty-nine patients with tetralogy of Fallot were studied 16±2 years after intracardiac repair by use of radionuclide first-pass ventriculography with an ultra-high-sensitive gamma camera at rest and at peak exercise on a semi-upright bicycle ergometer. The results were compared with those from 10 age- and sex-matched control subjects. Left and right ventricular ejection fraction and absolute ventricular volume were measured at rest and peak exercise. Regional right ventricular wall motion and diastolic function of the left ventricle were also assessed. Cardiac output of tetralogy was normally preserved both at rest and during exercise. Nevertheless, the incremental response of left ventricular ejection fraction during exercise was depressed in t...
Atrial Fibrillation After Isolated Coronary Surgery Affects Late Survival
Authors: GiovanniMariscalco, CatherineKlersy, MarcoZanobini, MaciejBanach, SandroFerrarese, PaoloBorsani, CristianoCantore, PaoloBiglioli, AndreaSala
Journal: Circulation (2008)

Background— Atrial fibrillation (AF) after coronary artery bypass graft surgery is a difficult problem and a continuing source of morbidity and mortality. However, the prognostic implications of postoperative AF are still in dispute. Our aim was to ascertain the impact of AF after coronary artery bypass graft on postoperative survival and to assess its prognostic role in cause-specific mortality. Methods and Results— We conducted a prospective observational study of 1832 patients undergoing isolated coronary artery bypass graft between January 2000 and December 2005 at 2 cardiac surgery centers in northern Italy. Patients affected by postoperative AF were identified and followed up until death or study end (April 30, 2007). A total of 570 patients (31%) developed AF after coronary surgery. Patients affected by postoperative AF experienced a longer hospital stay (7 days [25th to 75th percentile, 7 to 10 days] versus 7 days [25th to 75th percentile, 6 to 8 days]; P<0.001). Hospital mortality also was higher...