tbuckley/cabot-search huggingface dataset:
ASCO Quality Training Program: Five-year review.
Authors: Michael Kenneth Keng, Gene Cunningham, Terry Gilmore, Timothy D. Gilligan, Doris Quinn, Laura Kaufman, John Bingham, Vedner Guerrier, Anne C. Chiang, Ashraf Mahmoud Mohamed, Jordan Hagemann
Journal: Journal of Clinical Oncology (2019)

7 Background: ASCO introduced a Quality Training Program (QTP) in 2013 with an aim: train oncology professionals to design, implement and lead successful quality improvement (QI) activities and assume leadership positions to champion culture change in their practices. Methods: The QTP is a formal 6-month program taught by QI faculty and mentored by QI coaches over five days of in-person learning across three sessions, and hands-on learning at the participants’ practices. Sessions include seminars, case examples, and small group exercises. Participants attend in multi-disciplinary teams and focus on a problem they wish to solve in their practice. Scheduled conference calls with QI coaches were held between sessions. Participants complete pre and post QTP surveys (10 point Likert scale; 1 - no knowledge/competence to 10 - complete knowledge/competence) and provide direct written feedback. Results: Since its inception, QTP has had 15 courses (10 domestic and 5 international) with 120 teams and 544 total participants. QTP is led by an 8-member steering group with 16 faculty and coaches. All post-survey items had an increase in knowledge and competence. Each item’s score was calculated as the mean difference between ‘before’ and ‘after’ score. Participants stated increase of 46% to 84%: overall mean increase for knowledge 38% and competence 37%. The greatest increase were: methodology and practical tools to make changes in practice (writing an aim statement, implementing rapid improvement, process analysis tools, and flowcharting the process). Most common suggestion for improvement was allowing more time for the project. Participants are encouraged to write articles and present work in poster and plenary sessions. QTP have led to 7 manuscripts and 21 abstract presentations to national meetings. Six QTP alumni currently are now QI coaches and faculty. Conclusions: The QTP is a successful QI course for oncology professionals who need to measure performance, investigate quality and safety issues, and implement change. It is the only oncology-focused QI training, as all faculty and coaches are providers and QI specialists with oncology experience, making this a unique opportunity. The success will provide further momentum to offer QTP domestically and around the world.
Allogeneic Stem Cell Transplantation For Cytogenetically Normal Acute Myeloid Leukemia: Impact Of FLT3 and NPM1 Mutational Status
Authors: Philipp Hemmati, Theis H. Terwey, Lam G. Vuong, Philipp D le Coutre, Bernd Dörken, Renate Arnold
Journal: Blood (2013)
Abstract 17017: Risk Prediction of Death and Failure in Patients With Atrio-pulmonary Connections: 40 Years Experience in Australia and New Zealand
Authors: Chin L Poh, Diana Zannino, Robert G Weintraub, David S Winlaw, Dorothy J Radford, Leeanne E Grigg, Gavin R Wheaton, Andrew Bullock, Robert N Justo, Thomas L Gentles, David S Celermajer, Yves d'Udekem
Journal: Circulation (2015)

Objective: To identify parameters predictive of death and failure in patients with an atrio-pulmonary connection Fontan. Methods: Retrospective analysis of long-term follow-up data using the Australia and New Zealand Fontan Registry Results: There were 245 patients surviving hospital discharge after an atriopulmonary Fontan from 1975 to 1994. At latest follow-up, 54 pts died, 29 underwent heart transplantation and 93 had Fontan failure (death, transplantation, Fontan conversion, protein losing enteropathy, severe left ventricular dysfunction on echocardiography or NYHA3). Twenty-eight years survival, freedom from death and transplantation and freedom from Fontan failure were respectively 62% (95%CI 55-71%), 58% (95% CI 50-67%) and 40% (95% CI 33-50%). Predictors of death and transplantation were dextrocardia (HR 1.8;p= 0.05), longer Fontan bypass time (HR= 1.01, p=0.05) and moderate or more late atrioventricular valve regurgitation (HR 3.97; p=0.02). One hundred and seven patients developed atrial arrhythmias, with first documented event at 15.7 years (IQR 10.5-19.3) post Fontan completion. Development of arrhythmia increased the likelihood of death or transplantation (HR 3.05, p&lt;0.001) and Fontan failure (HR 4.7, p&lt;0.001). Thromboembolic events occurred in 42 patients, 30 (71%) of whom were on warfarin but less than half (12/30) within therapeutic range. Thirty-nine patients underwent Fontan conversion. Threshold for conversion was lower in one center in which patients were operated earlier with better functional status, shorter history of arrhythmias and less antiarrhythmic medications. Conversion resulted in a reduced risk of Fontan failure (HR 0.48) in patients cared for by the center with lower conversion threshold but an increased risk in the remaining centres (HR 5.65) (p=0.023). Conclusions: Arrhythmias is an early sign predicting failure of the Fontan circulation of those with an atrio-pulmonary Fontan. Fontan conversion is only associated with improved outcomes when timely performed.
Abstract 851: NCLX Expression Attenuates Pathological Remodeling in Experimental Cardiac Hypertrophy and Non-ischemic Heart Failure
Authors: Joanne F Garbincius, Timothy S Luongo, Devin W Kolmetzky, Alycia N Hildebrand, John W Elrod
Journal: Circulation Research (2019)

Mitochondrial calcium ( m Ca 2+ ) uptake couples acute changes in cardiomyocyte bioenergetic demand to ATP production, but in excess triggers mitochondrial permeability transition and cardiomyocyte necrosis, as occurs during cardiac injury. Despite established roles for m Ca 2+ flux in response to acute stress, the role of m Ca 2+ signaling in chronic stress is poorly defined. As m Ca 2+ regulates the TCA cycle with the potential to affect mitochondrial signaling and/or metabolite pools required for biosynthesis, we reasoned that altered m Ca 2+ homeostasis may be an essential mechanism underlying hypertrophic growth and remodeling of the myocardium. Here, we used mice with cardiac-specific overexpression (OE) of the mitochondrial Na + /Ca 2+ exchanger (NCLX), the primary mediator of m Ca 2+ efflux in the heart, to test the hypothesis that m Ca 2+ signaling contributes to cardiac remodeling during sustained hemodynamic stress. We subjected NCLX OE (TRE-NCLX x α-MHC-tTA) and control (αMHC-tTA) mice to 12-wk transverse aortic constriction (TAC) or 4-wk infusion with angiotensin II + phenylephrine (AngII/PE) as experimental models of cardiac hypertrophy and non-ischemic heart failure. Cardiac function of NCLX OE and control mice was monitored throughout these studies via echocardiography and remodeling was assessed via tissue gravimetrics, histology, and qPCR gene expression analysis. Cardiac NCLX OE preserved ejection fraction, prevented afterload-induced hypertrophy and fibrosis, and attenuated the induction of both hypertrophic ( Nppa , Nppb , Acta1 ) and fibrotic ( Postn1 , Spp1 ) gene programs in mice subjected to 12-wk TAC. Examination at 2-wk post-TAC revealed attenuated hypertrophy and blunted hypertrophic and fibrotic gene expression in NCLX OE mice. These data indicate that increased capacity for m Ca 2+ efflux mitigates TAC-induced remodeling, prior to the development of contractile dysfunction. NCLX OE similarly attenuated atrial hypertrophy and the induction of hypertrophic and fibrotic gene programs in mice infused with AngII/PE. Together, these findings support a critical role for m Ca 2+ in driving pathological remodeling in non-ischemic heart disease and point to NCLX as a potent therapeutic target for cardiovascular disease.
Abstract 900: Troponin I Tyrosine 26 Phosphorylation Accelerates i <i>n vivo</i> Myocardial Relaxation
Authors: Elizabeth A Brundage, Vikram Shettigar, Ying H Lin, Brendan Agatisa-Boyle, Mark Y Jeong, Mark T Ziolo, Brandon J Biesiadecki
Journal: Circulation Research (2019)

Heart failure results in depressed cardiac systolic contraction and diastolic relaxation, both of which limit the heart’s ability to pump blood. Currently there is no therapy to accelerate the detrimental slowed relaxation in heart failure. A fundamental mechanism of the heart to modulate cardiac relaxation is through serine/threonine kinase-mediated phosphorylation of the contractile regulatory protein troponin I (TnI). Non-receptor tyrosine-specific kinases are expressed in the heart and their activity is altered in disease; yet, the role of tyrosine kinase-mediated phosphorylation to directly modulate cardiac relaxation has not been described. TnI is phosphorylated at tyrosine 26 (Tyr26) in the heart and we previously demonstrated TnI Tyr26 phosphorylation accelerates myofilament deactivation. TnI Tyr26 phosphorylation is therefore the first tyrosine phosphorylation identified to directly modulate cardiac myofilament function, however the effects of tyrosine phosphorylation on in vivo function of the heart are unknown. To determine the effect of tyrosine phosphorylation on heart function, we generated a TnI Tyr26 phosphorylation (Tg Y26E) mouse. At the muscle level, myofibrils from Tg Y26E mice exhibit accelerated myofibril relaxation. Echocardiography and pressure-volume hemodynamic measurements demonstrate Tg Y26E mice have enhanced diastolic function evident in accelerated myocardial relaxation, without depressed systolic function or altered morphology. As a whole these data support the phosphorylation of TnI at Tyr26 as a novel tyrosine signaling mechanism to accelerate in vivo diastolic function without depressing systolic contraction.
Improved Survival After Allogeneic Hematopoietic Stem Cell Transplantation for Metastatic Renal Cancer Associated with Homozygosity for the HLA-G 14 Base-Pair Deletion Polymorphism: An EBMT STWP Study
Authors: Benedetta Mazzi, Roberto Crocchiolo, Didier Blaise, Lisbeth Barkholt, Jacques-Olivier Bay, Rocco Pastano, Margherita Torchio, Stefania Trinca, Jacopo Peccatori, Fabio Ciceri, Katharina Fleischhauer, Marco Bregni
Journal: Blood (2012)
Re: Gaëtan Devos, Gert De Meerleer, Steven Joniau. Have We Entered the Era of Imaging Before Salvage Treatment for Recurrent Prostate Cancer? Eur Urol 2019;76:265–7
Authors: Aurélie De Bruycker, Valérie Fonteyne, Piet Ost
Journal: European Urology (2019)
Chronic myeloid leukemia stem cells require cell-autonomous pleiotrophin signaling
Authors: Heather A. Himburg, Martina Roos, Tiancheng Fang, Yurun Zhang, Christina M. Termini, Lauren Schlussel, Mindy Kim, Amara Pang, Jenny Kan, Liman Zhao, Hyung Suh, Joshua P. Sasine, Gopal Sapparapu, Peter M. Bowers, Gary Schiller, John P. Chute
Journal: Journal of Clinical Investigation (2019)

Tyrosine kinase inhibitors (TKIs) induce molecular remission in the majority of patients with chronic myelogenous leukemia (CML), but the persistence of CML stem cells hinders cure and necessitates indefinite TKI therapy. We report that CML stem cells upregulate the expression of pleiotrophin (PTN) and require cell-autonomous PTN signaling for CML pathogenesis in BCR/ABL+ mice. Constitutive PTN deletion substantially reduced the numbers of CML stem cells capable of initiating CML in vivo. Hematopoietic cell-specific deletion of PTN suppressed CML development in BCR/ABL+ mice, suggesting that cell-autonomous PTN signaling was necessary for CML disease evolution. Mechanistically, PTN promoted CML stem cell survival and TKI resistance via induction of Jun and the unfolded protein response. Human CML cells were also dependent on cell-autonomous PTN signaling, and anti-PTN antibody suppressed human CML colony formation and CML repopulation in vivo. Our results suggest that targeted inhibition of PTN has therapeutic potential to eradicate CML stem cells.
Cy7-Tocilizumab/Fab(Tocilizumab): Near Infrared Fluorescence In Vivo Imaging of Multiple Myeloma
Authors: Ximena Camacho, Carolina Perroni, Mara de Souza Junqueira, Marcelo Fernandez, Roger Chammas, Carlos Buchpiguel, Juan Pablo Gambini, Pablo Cabral, Eloisa Riva
Journal: Blood (2018)
Ajuba Functions as An HDAC-Dependent Co-Repressor for Autoregulation of the Growth Factor Independent-1 Transcription Factor
Authors: Meghan E. B. Rojas, Chinavenmeni S. Velu, Diego E. Montoya-Durango, Avedis Kazanjian, Chris M. Jay, Gregory D. Longmore, H. Leighton Grimes
Journal: Blood (2008)
Smoking Confers Poor Survival in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Treated with the Combination of Intensive Therapy with Tyrosine Kinase Inhibitor (TKI)
Authors: Elias J. Jabbour, Koji Sasaki, Farhad Ravandi, Nicholas J Short, Guillermo Garcia-Manero, Naval G. Daver, Tapan M. Kadia, Marina Y. Konopleva, Nitin Jain, Ghayas C. Issa, Zeev E. Estrov, Rebecca E. Garris, Maria Khouri, Patrice Nasnas, Naveen Pemmaraju, Jorge E. Cortes, Susan M. O'Brien, Hagop M. Kantarjian
Journal: Blood (2018)
Interrogation of the Coagulation Cascade Acute Coronary Syndrome Using Novel Elisa-Based Assays for Single Protease Quantification
Authors: Jens Posma, Rene van Oerle, Diane Fens, Jose govers Riemslag, Julia Mueller, Stefan Heitmeier, Hugo ten Cate, Henri M.H. Spronk
Journal: Blood (2018)
Abstract 783: Epicardial Contribution to Arrhythmogenic Cardiomyopathy
Authors: Arwa Kohela, Sebastiaan van Kampen, Tara Moens, Jantine Monshouwer-Kloots, Bas Molenaar, Martijn Wehrens, Arjan Vink, Huei-Sheng Vincent Chen, Eva van Rooij
Journal: Circulation Research (2019)

Arrhythmogenic cardiomyopathy (ACM) is an inherited disease mainly caused by desmosomal gene mutations and characterized by myocardial loss, replacement with fibro-fatty tissue, arrhythmias and sudden cardiac death. To date, it is unclear which cell type and molecular mechanisms contribute to the fibro-fatty phenotype. The epicardium is the outer mesothelial layer of the heart which has the capacity to undergo epithelial-to-mesenchymal transition (EMT) and differentiate into various cardiac cell types. The aim of this study is to investigate whether epicardial cells contribute to the excess fibro-fatty infiltration seen in ACM patients. To this end, we differentiated induced pluripotent stem cells (iPSCs) from an ACM patient with a haploinsufficiency-causing mutation in the desmosomal gene plakophilin-2 (PKP2) (c.2013delC), and an isogenic control into epicardial cells. While Western blot, flow cytometry, qPCR and immunofluorescence imaging indicated comparable epicardial differentiation efficiencies, RNA-sequencing revealed a profound increased expression of fibroblast and lipid markers only in mutant epicardial cells. These data were corroborated by the spontaneous accumulation of lipid droplets and adipogenic markers in the PKP2 mutant epicardial cells. Single cell sequencing analysis revealed a significant induction of Activating Enhancer-Binding Protein 2 (AP2) family of transcription factors in a subset of PKP2 mutant epicardial cells, which are known to play roles in EMT and lipid biogenesis. siRNA-mediated knock down of AP2 members in mutant epicardial cells significantly reduced the expression of fat and fibroblast markers, suggesting an AP2-mediated fibro-fatty signalling in epicardial cells. The PKP2-dependence of these findings was further validated in healthy iPSC-epicardial cells treated with siRNAs targeting PKP2 which recapitulated the observations made in the mutant cells. Using this human in vitro model system, we were able to show the epicardial role during fibro-fatty tissue replacement upon PKP2 suppression. Ongoing experiments, including studies on explanted ACM hearts and a PKP2 c.2013delC knock-in mouse model, aim at further elucidating the molecular mechanisms of ACM pathogenesis.
Abstract 414: Postnatal Cardiac Tissue Harbors Progenitor Cells With Unique Metabolic Profile
Authors: Justin Kurian, Antonia Yuko, Kelsey Busch, Daria Harlamova, Nicole Kasatkin, Marcus Wagner, Sadia Mohsin, Steven Houser, Hong Wang, Mohsin Khan
Journal: Circulation Research (2019)

Rationale: The developmental cardiac tissue is a proliferative organ capable of regeneration that extends briefly into the postnatal period. Studies show that the heart undergoes alterations in metabolism that coincide with cessation of regenerative processes during postnatal development. Whether cardiac cells in the early postnatal heart exhibit metabolic properties that favor regeneration remains unknown. Objective: To determine whether postnatal cardiac tissue harbors CPCs with unique metabolic profile. Methods and Results: CPCs were isolated from C57BL/6 mice aged 2-day (NCPC), 2-month (adult CPC) and 2-year old (ACPC). Morphological assessment showed NCPCs were smaller and rounded compared to CPCs and ACPCs and expressed putative stem cell markers and were negative for hematopoietic marker CD45. Interestingly, NCPCs expressed elevated levels of pluripotency markers such as LIN28 compared to ACPCs and CPCs. Increased viability, proliferation rate, metabolic activity and reduced doubling times were observed in NCPCs compared to CPCs and ACPCs measured by CyQuant, MTT, and Resazurin assays. NCPCs demonstrated a youthful phenotype and were resistant to H2O2 induced stress compared to ACPCs and CPCs as measured by β-Galactosidase and TUNEL labeling respectively together with a unique expression of paracrine factors as assessed by proteome profiler array. Interestingly, NCPCs demonstrated increased ATP generation, glycolytic activity and reduced oxidative phosphorylation compared to CPCs and ACPCs measured by seahorse assay parallel with enhanced expression of glycolytic enzymes measured by qRT-PCR and western blot. NCPCs showed increased lactate production and pyruvate kinase activity and low mitochondrial membrane potential. Interestingly, mitochondrial fuel dependency assay showed increased glutamine dependency as the fuel for mitochondrial oxidative phosphorylation. RNA-sequencing analysis demonstrated increased expression of metabolic signaling in NCPCs compared to CPCs and ACPCs. Conclusions: Postnatal cardiac tissue possesses progenitor cell population with unique metabolic profile that coincides with enhanced functional properties of NCPCs suggesting their potential therapeutic value for cardiac repair.
Run for your life: tweaking the weekly physical activity volume for longevity
Authors: Johannes Burtscher, Martin Burtscher
Journal: British Journal of Sports Medicine (2019)

> There is nothing better than exercise but more exercise.

Regular physical activity (PA) and high cardiorespiratory fitness (CRF: aerobic capacity, VO2 max) reduce all-cause mortality even after adjusting for relevant confounders.1 2 Large-scale studies indicate an almost linear relationship between increasing CRF and longevity, with no signs of an upper limit.3 It remains less clear which PA volumes are optimal for a long life. Public health guidelines recommend a minimum of 150–300 min moderate intensity aerobic PA or 75–150 min vigorous intensity aerobic PA per week to induce general health benefits.4 

Dr Hannah Arem and colleagues, using pooled data from six studies in the USA and Europe (including 661 137 adults), showed that meeting PA guidelines was associated with a large longevity benefit.5 And there were even further improvements until the benefit for longevity reached a threshold at a level 3–5 times higher (450–750 min/week) than the minimum recommendations, without adverse effects in those performing PA at ≥10 times that minimum. The maximum all-cause mortality reduction was almost 40% without relevant differences between …
Abstract 310: Time-Dependent Changes in Myocardial Edema Overestimate the Ischemic Area-at-Risk Up to One Week After Reperfused Myocardial Infarction in Swine
Authors: Brian R Weil, George Techiryan, John M Canty
Journal: Circulation Research (2019)

Objective: Assessment of tissue salvage after myocardial infarction (MI) requires accurate quantification of the ischemic area at risk (AAR). Although the AAR is typically measured retrospectively within one week after reperfusion, dynamic changes in tissue composition may affect the precision of this approach. Given recent cardiac MRI data demonstrating a transient reduction in myocardial edema 24 hours after reperfused MI, we tested the hypothesis that this is an optimal timepoint for accurate retrospective AAR assessment. Methods: Swine (n=27) were subjected to a 1 hour LAD occlusion, during which the AAR was assessed by contrast enhanced CT-derived quantification of the myocardial perfusion defect. Phthalocyanine blue was administered at the end of occlusion (n=7) or during re-occlusion of the LAD 3 hours (n=5), 24 hours (n=5) or 7 days (n=10) after reperfusion for pathologic determination of the AAR. Serial echocardiography was performed in the 24 hour reperfusion group to assess end diastolic wall thickness (EDWT) as a surrogate index of post-MI edema. Results: When assessed before reperfusion, the AAR was similar by CT and postmortem pathology ( Table ). However, AAR measurements 3 hours, 24 hours, and 7 days after reperfusion overestimated CT AAR mass by 38±7 %, 31±10 %, and 37±5%, respectively. Echocardiography showed a marked increase in EDWT 1 and 3 hours after reperfusion, followed by a decrease at 24 hours that remained significantly higher than pre-ischemia values. Conclusion: Despite partial resolution of edema 24 hours after reperfusion, AAR measurement at this time does not provide an accurate assessment of the AAR obtained during the initial coronary occlusion.
Abstract 945: A Novel Role of Cardiac DNA Methylation as a Regulator of Fibrosis in Human Diabetic Heart Failure
Authors: Luke A Potter, Mark E Pepin, Adam R Wende
Journal: Circulation Research (2019)

Human heart failure (HF) is accompanied by changes in cardiac gene expression; however, the impact of diabetes mellitus on this transcriptional regulation remains unclear. Our laboratory studies the role of epigenetics in HF and focuses on DNA methylation, commonly accepted as a negative regulator of gene expression when present in a gene’s promoter. In the current study, we hypothesized that diabetes alters cardiac DNA methylation and the transcriptome. We performed an integrated analysis of RNA-sequencing and DNA methylation using human left ventricle biopsies from HF patients to determine the effect of diabetes on this reprogramming. Our analysis identified global changes in cardiac DNA methylation as well as mRNA expression sufficient to distinguish diabetic from non-diabetic patients. Specifically, we identified significant regulation of 1,133 genes (|1.5| fold-change, P&lt;0.05) and 9,302 methylation sites (|5%| methylation, P&lt;0.05). Within the 391 co-regulated genes, only 174 genes had altered promoter-associated methylation. Consistent with the accepted dogma that promoter methylation inversely regulates gene expression, we found that 119 of those 174 genes displayed this inverse relationship; of these, an overwhelming majority (102) were hypomethylated in diabetic relative to non-diabetic hearts. These findings contrast the cardiac hypermethylation we have reported for ischemic HF. Gene set enrichment of the 119 inversely-regulated genes identified numerous pathways involved in fibrosis, including extracellular matrix organization (FDR&lt;0.05, 3.9% enriched) and collagen biosynthesis (FDR&lt;0.05, 6.3% enriched), which suggest that DNA methylation contributes to the adverse cardiac remodeling associated with diabetic heart failure. To identify putative regulators of these transcriptional and epigenetic differences, a candidate gene approach was used to reveal induction (2.5-fold, Q&lt;0.05) and demethylation (20.5%, P&lt;0.05) of EGR2, a known regulator of fibrosis. Furthermore, we found induction of GADD45beta (2.6-fold, Q &lt; 0.05) a known regulator of DNA demethylation. Taken together, these observations suggest that epigenetic mechanisms underlie an etiology-specific reprogramming of cardiac fibrosis in diabetic HF.