tbuckley/cabot-search huggingface dataset:
Abstract 404: Deterministic Paracrine Repair of Injured Myocardium using Microfluidic Cocooning of Heart Explant-Derived Cells
Authors: Pusphinder Kanda, Ainara Benavente-Babace, Michel Godin, Darryl R Davis
Journal: Circulation Research (2019)

Previous work has shown that cocooning heart explant-derived cells (EDCs) within protective nanoporous gel capsules before intra-myocardial injection increases the retention of transplanted cells and the paracrine production of nanoparticles to improve post infarct cardiac function. In this study, we investigated the influence of cocoon size and intracapsular cell number on cell-treatment outcomes using a newly developed microfluidic-based (MF) cellular cocooning platform. Methods/Results: Traditional vortex-based encapsulation (Vx) inherently provides cocoons of varying diameters (30-100 μm; 68±5 μm). By altering the flow pressure ratios and the nozzle diameters within the MF chip, we encapsulated human EDCs within small (51±1 μm, MF50) and large (90±1 μm, MF90) diameter nanoporous gel cocoons for comparison with standard Vx-defined capsules (71±1 μm, MF70). MF cocooning mirrored the expected Poisson distribution with smaller cocoons having a greater proportion of single cells while larger diameter cocoons contained greater proportions of multicellular aggregates. Immunodeficient mice underwent left coronary artery ligation 1 week before randomization to echocardiographic guided intra-myocardial injection of EDCs (suspended or variable diameter cocoons) or vehicle. Increasing cocoon diameter stimulated progressive salutary effects on post-infarct function (ejection fraction), scar burden and newly generated peri-infarct blood vessels (isolectin B4+) and cardiomyocytes (BrdU+/TNT+) 4 weeks after treatment. Bioluminescent imaging of luciferase tagged cells revealed increasing cocoon diameter reduced the rate of cell clearance from injured tissues. Disrupting cell-cell contact within the capsules (using a custom antibody cocktail to block E/P-selectin and N-cadherin) reduced the amount and profile of pro-healing cytokines + nanoparticles delivered to injured myocardium. Conclusions: Increasing cocoon diameter and cell occupancy within protective nanoporous gel cocoons boosts paracrine-mediated repair of damaged myocardium by slowing clearance of cells from injured tissues and the number of cytokines + nanoparticles secreted by micro-encapsulated cells.
Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of Mitochondrial Vulnerability in Acute Myeloid Leukemia
Authors: Irene Baccelli, Yves Gareau, Bernhard Lehnertz, Gingras Stephane, Jean-Francois Spinella, Alexandre Beautrait, Sophie Corneau, Nadine Mayotte, Isabel Boivin, Simon Girard, Tara MacRae, Melanie Frechette, Koryne Leveille, Jana Krosl, Clarisse Thiollier, Evgeny Kanshin, Thierry Bertomeu, Jasmin Coulombe-Huntington, Corinne St-Denis, Marie-Eve Bordeleau, Geneviève Boucher, Philippe P Roux, Sébastien Lemieux, Mike Tyers, Pierre Thibault, Anne Marinier, Josée Hébert, Guy Sauvageau
Journal: Blood (2018)
Abstract 462: High Speed Imaging of Single Cardiomyocyte Action Potentials Using a Far-red Genetically Encoded Voltage Sensor
Authors: Shoshana Das, Sanaya Shroff, Hua-an Tseng, Anant Chopra, Xue Han, Christopher Chen
Journal: Circulation Research (2019)

The ability to image cardiac membrane potentials allows for the observation of cellular communication and electrical activity, both of which are important to maintain cardiac syncytium; these can be altered in diseases (e.g. Long QT Syndrome). Traditionally voltage dyes such as Di-8-ANEPPS have been used to optically measure action potentials (APs). However, these dyes express transiently, have poor signal to noise ratios, and are toxic. More recently, genetically encoded voltage indicators (GEVIs) have been developed to replace state-of-the-art voltage dyes, but sensors currently used within the cardiac field exhibit poor kinetics and/or low signal to noise ratios (SNR). Recently, Archon1, a new genetically encoded voltage sensor, was developed in the neuroscience field; this sensor exhibits excellent membrane localization, temporal sensitivity, and SNR, enabling the optical detection of individual spikes in neurons. Here we use Archon1 for the first time in cardiac cells, to monitor single cell cardiac APs in 2D and 3D in vitro systems in response to different environmental stimuli. Human induced pluripotent stem cell-derived cardiomyocytes were infected with Archon1 and imaged using a one-photon fluorescence microscope equipped with a high speed sCMOS camera to demonstrate cardiac AP tracings. The kinetics and SNR of Archon1 are compared to traditional electrophysiology and Di-8-ANEPPS measurements. Additionally, E-4031 (K+ Channel Blocker) and Nifedipine (Ca2+ Channel Blocker) were used to demonstrate the sensitivity of this sensor in a drug dosage study. To study the APs of single cells within a 3D engineered microtissue, cardiomyocytes expressing Archon1 were seeded into a force transducing micro-pillar device and the APs for optically isolated cells were recorded. Demonstration of this new genetically encoded voltage sensor in cardiac cells enables the monitoring of single and multi-cell APs in 2D and 3D applications and can be extended to in vivo. This tool, newly applied to cardiac biology and tissue engineering will allow for better and more accurate observation of cardiac electrical activity to probe human cardiovascular disease.
Abstract 936: Entropyx of Cardiac Rhythm Uniquely Predicts Mortality in a Multi-site Polysomnography (psg) Study of Ambulatory Asymptomatic Community Adults With Heart Failure
Authors: Priya Umapathi, Mackenzie Samson, Negin Hajizadeh, Tracie Lin, Ginger A Conway, Elliseo Gullar, Brian O'Rourke, Thomas McGinn, Steven R Jones, Deeptankar DeMazumder
Journal: Circulation Research (2019)

Introduction: Heart failure (HF) is associated with high rates of mortality and hospital readmission. Current strategies for risk stratification are limited. Recently, we introduced EntropyX, a novel measure of non-linear patterns underlying physiological variability using newer concepts of entropy estimation and machine learning. EntropyX of cardiac repolarization (EntropyX QT ) enhanced the predictive value of all established risk factors in a multicenter study of HF patients (PMID: 27044982). Herein, we test the hypothesis that EntropyX of ventricular activation (EntropyX RR ) during sleep enhances the performance of established mortality risk factors in asymptomatic community adults with HF. We interpret our results in context of fundamental mechanistic studies in animal models and modern theories of systems biology. Methods &amp; Results: We followed 96 NYHA class I HF adults in sinus rhythm for 6.5±3.0 years (1994-2011; SHHS NCT#00005275). Baseline exposures included demographics, history, medications, labs, PSG metrics [e.g., sleep disordered breathing (SDB)], ECG analyses [e.g., heart rate (HRV), QT variability (QTV)], and EntropyX RR . The cohort had mean age of 70±10 years, 49% women, 11% African Americans, and 46 deaths (48%; N=35 from cardiovascular events) over 4.6±2.6 years. After adjusting for exposures, the adjusted hazard ratios (4th to 1st quartile) for mortality for EntropyX RR was 2.3 (95% CI, 1.1-4.6) and age was 4.5 (1.9-10.3), consistent with machine learning-based classification and regression tree analysis. Addition of EntropyX RR to a multivariate model (comprised of age, diabetes, myocardial infarction, SDB) improved continuous net reclassification by 43% (37-48). Conclusions: EntropyX RR during sleep predicts mortality over follow-up of asymptomatic community adults with HF, independent of conventional risk factors and linear/deterministic measures (e.g., HRV, QTV, SDB). Unlike simpler concepts of RR variability, EntropyX RR is a fundamentally different measure, reflecting the complexity of multi-directional physiological network properties that regulate homeostatic function under changing conditions. This new paradigm complements conventional measures of risk and has potential for broad application.
Abstract 324: Translation Determines the Acute Cardiac Response to Ischemia/Reperfusion
Authors: Christoph Hofmann, Fereshteh S Younesi, Ole M Schwerdt, Etienne Bioleau, Hugo A Katus, Christoph Dieterich, Mirko Völkers
Journal: Circulation Research (2019)

Introduction: Since transcription is a relatively slow process, translation of preexisting mRNA networks might affect cardiac gene expression thereby rapidly adapting the myocardium to stress before changes in transcription take place. The mTOR kinase links nutrient and energy levels to protein synthesis by regulation of mRNA translation. Inhibition of mTOR complex 1, the responsible pathway for translational regulation, protects against reperfusion injury, however the underlying mechanisms are unknown. Through rapid restoration of myocardial energy levels upon reperfusion an mTOR-dependent translatome could adapt early changes in gene expression inducing a maladaptive gene network, independent from transcription, which mediates reperfusion injury. Hypothesis: Reperfusion induces an mTOR-mediated overshooting protein synthesis response that contributes to reperfusion injury by rapidly and selectively translating preexisting mRNAs. Methods and Results: To induce reperfusion injury mice were subjected to 60 minutes of LAD ligation and increasing times of reperfusion. Puromycin incorporation showed an overshooting protein synthesis response of cardiac myocytes upon reperfusion that was especially prevalent in the peri-infarct region. Protein synthesis was induced by increased formation of the eIF4F translation initiation complex through the mTORC1-4EBP1 signaling axis. Cardiac myocyte specific ribosome profiling combined with RNA-seq of hearts 2 days after reperfusion showed that the acute cardiac response to reperfusion was mediated by translation of specific mRNAs encoding proteins which determine early events of reperfusion such as leukocyte infiltration and inflammation. Inhibition of the mTORC1-4EBP1-eIF4F axis attenuated this specific protein synthesis response. Importantly, 4EGI-1, a specific inhibitor of eIF4F complex formation, bypassed off-target effects of previously used mTOR inhibitors and protected cardiac myocytes from cell death upon reperfusion. Conclusions: During reperfusion protein synthesis is strongly induced in the peri-infarct region by mTORC1 and contributes to reperfusion injury by rapidly translating specific mRNAs that mediate the early gene expression response to reperfusion.
Meeting lung cancer value based care requirements with documentation of patient goals and preferences.
Authors: Avnish K Bhatia, Devika Govind Das, Debra Wujcik, Susie Owenby, Wanda D. Hall, Tasha Smith, Ralph Zinner
Journal: Journal of Clinical Oncology (2019)

222 Background: Non-small cell lung cancer (NSCLC) accounts for 25% of all cancer deaths with 5-year survival of 6%. Recent scientific advances in molecular based treatments and immunotherapy and insurers’ emphasis on patient-centered care is changing patient care. This study sought to incorporate patients’ perceptions, goals, and preferences into treatment planning. Methods: After provider education and using electronic care planning software (CPS), a pilot of 50 patients with advanced NSCLC from two academic centers completed tablet-based surveys addressing treatment goals, decision-making preferences, and interest in clinical trials. Results were shared with the provider during the visit. Once treatment was selected, the CPS generated a personalized care management plan. Results: Participants were mean age 65 (range 41-86), 52% female, and 78% white. 60% (12/20) Stage IV patients believed that their cancer was curable. 62% (31/50) were not interested in clinical trial participation. 48% (24/50) wanted to share treatment decision making; 34% (12/50) wanted to make the final decision after seriously considering the doctor’s opinion; 6% (3/ 50) wanted the provider to make the final decision but consider their opinion, and 10% (5/50) wanted to leave all decisions to the provider. Conclusions: Patient perception of curability and decision-making preferences were important domains identified by personalized-care management planning in this Lung Cancer pilot study. Pre-visit CPS use provided the opportunity for the provider to address treatment intent and decision-making at the point-of-care. Academic centers generally expect their patients to have strong interest in clinical trials; Investigation for the reasons for disinterest warrants further exploration.
Abstract 619: Cardiac Function in Electronic Cigarette-Exposed Adolescent Mice
Authors: Evan W Neczypor, Vineeta Tanwar, Jeremy M Adelstein, Michael D Muffler, Chadi Pellegrini Anaruma, Loren E Wold
Journal: Circulation Research (2019)

Objective: Electronic cigarettes (e-cigs) are the most commonly used tobacco product by teens and young adults. The aim of the present study was to determine the potential effects of e-cig vapor exposure on cardiac function in adolescent mice. Materials and Methods: Adult FVB/NJ male and female mice were bred in our housing facility. Following birth, male offspring were raised in room air until weaning. At 3 weeks of age, mice were separated into two exposure groups: 1) E-cigarette exposure with nicotine (EC(+), N=5) (10.1 mg nicotine/1mL 50:50 propylene glycol:vegetable glycerin), or 2) E-cigarette exposure without nicotine (EC(-), N=4) and exposed for two months. A puff profile consisting of one 70-mL vapor puff per minute of exposure was administered for 4 h/day, 5 days/week over the course of two months. Cotinine concentration in the urine of mice from either group was determined using a cotinine ELISA kit. Echocardiography was used to examine global cardiac function after 1 and 2 months of exposure. Results: The average cotinine concentration in the urine of the EC(+) group after two months of exposure was 113.33 ng/mL, while there was not a detectable concentration of cotinine in the urine of EC(-) mice. Echocardiography showed no significant alterations in ejection fraction (%EF), fractional shortening (%FS), left ventricular end systolic diameter (LVES d ), or posterior wall thickness (PWT) between the EC(+) and EC(-) groups, nor any significant alterations between the first month and the second month timepoints for either group. Future Directions: Exposures will continue for longer durations until a cardiac phenotype becomes apparent. Once in vivo cardiac dysfunction becomes evident, we will investigate in vitro cardiomyocyte function.
Abstract 516: GRK5 Regulates Cardiac Fibroblast Differentiation and Fibrosis
Authors: Akito Eguchi, Walter J Koch
Journal: Circulation Research (2019)

Pathological remodeling of the heart is a hallmark of heart failure (HF) and these structural changes further perpetuate the disease. Cardiac fibroblasts are the critical cell type that is responsible for maintaining the structural integrity of the heart. Stress conditions, such as a myocardial infarction (MI), can activate and induce the transdifferentiation of quiescent fibroblasts into synthetic and contractile myofibroblasts. G protein-coupled receptor (GPCR) kinases (GRKs) are important mediators of cardiovascular homeostasis through dampening of GPCR signaling. GRK5 is one isoform of these kinases that is expressed in the heart and has been shown to be up-regulated in human HF. Of note, GRK5 has been demonstrated to translocate to the nucleus in cardiomyocytes in a calcium-calmodulin (Ca 2+ -CAM)-dependent manner, promoting hypertrophic gene transcription through activation of NFAT and NFκB. Interestingly, these transcription factors are also involved in fibroblast activation. GRK5 is highly expressed and active in cardiac fibroblasts (CFs), however its pathophysiological role in these crucial cardiac cells is unknown. Utilizing adult mouse CFs in vitro , our preliminary data suggests a relevant role for GRK5 in the activation of fibroblasts. We observed that genetic deletion of GRK5 (GRK5KO) in CFs attenuated α-smooth muscle actin (α-SMA) expression, a myofibroblast marker, after stimulation with Angiotensin II (AngII). In addition, deletion of GRK5 diminished the expression of myofibroblast genes and proteins such as Collagen I and III after AngII stimulation. GRK5KO CF’s were also refractory to AngII mediated collagen gel contraction and protein translation. In vivo , mice with fibroblast-specific deletion of GRK5 were protected against cardiac fibrosis and hypertrophy after AngII infusion and post-MI compared to wild type mice. Mechanistically, GRK5 translocates to the nucleus after AngII stimulation and pharmacological inhibition of this event (via inhibition of Ca 2+ -CAM) prevented AngII mediated fibroblast transdifferentiation. These data support the hypothesis that GRK5 is an essential regulator of fibroblast activation and could be a novel therapeutic target to decrease adverse myocardial remodeling after injury.
Abstract 185: Role of Substance P in Pathogenesis of Chemotherapy Associated Cardiotoxicity.
Authors: Ashiq Legi, Prema Robinson
Journal: Circulation Research (2019)

Doxorubicin (DOX), is broadly considered the most active single agent available for many cancers. Doxorubicin has been known to induce, cardiotoxicity and life-threatening heart failure or acute coronary syndromes in some patients. There is an urgent need to develop new non-cardiotoxic therapies in cancer. Substance P (SP) is a neuropeptide involved in pain transmission. We had previously determined that aprepitant, an antagonist of SP receptor (neurokinin1 receptor (NK-1R)), that is routinely used to treat chemotherapy associated nausea, prevents DOX induced cardiomyocyte death in vitro. In the current studies, we determined if SP receptor antagonism could prevent chemotherapy induced cardiotoxicity in vivo. Six week old, male C57BL/6 mice were administered DOX (5 mg/kg of body weight, intraperitoneally (IP) once a week for 5 wks. In the aprepitant treated group, five days before the first injection of DOX, aprepitant (0.5 mg/kg) was administered in the drinking water, and then consequently every day until the end of the experiment. The control groups were treated with vehicle alone (1X PBS) instead of DOX without or with aprepitant pretreatment. Mice were euthanized 6 weeks after the first dose of DOX. We determined heart functions by echocardiogram in all mice. The mean ejection fraction (EF) and fractional shortening (FS), percentage, following treatment with DOX respectively decreased significantly by 25.85% and 30.73% compared to that in the control vehicle group (EF: 40.428 ± 6.68 (DOX; n = 4) vs 54.526 ± 11.15% (Control Vehicle group; n = 4) (FS: 19.51 ± 3.66% (DOX; n = 4) vs. 28.16 ± 7.38% (Control Vehicle group; n = 4) (both, P &lt; 0.05, ANOVA). Importantly, treatment with aprepitant in DOX treated mice normalized the EF and FS values to that present in the control vehicle group (EF; 56.80 ± 6.81 (DOX+aprepitant; n = 4) vs 54.526 ± 11.15% (Control Vehicle group; n = 4) (FS; 29.64 ± 4.46% (DOX+aprepitant; n = 4) v 28.16 ± 7.38% (Control Vehicle group; n = 4) (both, P &lt; 0.05, ANOVA). These findings indicate that SP contributes to chemotherapy associated cardiac-dysfunction via interaction with its high affinity receptor, NK1R. These studies suggest that SP-receptor antagonism may be a novel option to prevent chemotherapy associated cardiotoxicity in cancer.
RADIATION ONCOLOGY
Authors: B. Kunheri, A. Arjunan, P. Krishnan, B. Pillai, S. Prasad, V. Bernier-Chastagner, E. Desandes, C. Carrie, C. Alapetite, T. Hankinson, D. Jones, M. Handler, N. Foreman, A. Liu, N. P. Smiley, T. Alden, W. Hartsell, J. Fangusaro, C. E. Hill-Kayser, R. A. Lustig, J. E. Minturn, S. Both, A. J. Waanders, J. B. Belasco, C. Armstrong, P. C. Phillips, M. J. Fisher, C. E. Hill-Kayser, I. Paltin, R. A. Lustig, M. J. Fisher, S. Both, J. B. Belasco, K. A. Cole, A. J. Waanders, P. C. Phillips, J. E. Minturn, E. Wells, G. Vezina, L. Kilburn, B. Rood, F. Crozier, E. Hwang, R. Packer, G. O. Janssens, S. van den Bosch, P. G. van Kollenburg, C. E. Gidding, J. H. Schieving, J. H. Kaanders, E. J. van Lindert, K. Kramer, N. Pandit-Taskar, M. M. Souweidane, S. Wolden, C. DeSelm, N.-K. V. Cheung, Y. Lassen-Ramshad, J. Hansen, K. Seiersen, J. B. B. Petersen, A. Mahajan, D. Grosshans, D. Ris, M. Chintagumpala, F. Okcu, M. F. McAleer, B. Moore, H. Stancel, C. Minard, D. Guffey, L. Kahalley, K. Blomgren, K. Zhou, C. Xie, C. Zhu, M. F. McAleer, Z. Zhao, J. Weinberg, D. Sandberg, D. Hughes, A. Mahajan, P. Anderson, N. Guha-Thakurta, K. Muller, M. Hoffmann, C. Seidel, M. Warmuth-Metz, T. Pietsch, U. Kordes, A. Sander, J. Rossler, N. Graf, H. Scheithauer, R.-D. Kortmann, C. M. Kramm, A. O. von Bueren, J. Gunther, M. Sato, M. Chintagumpala, E. Jo, A. Paulino, A. Adesina, L. Ketonen, J. Jones, J. Su, F. Okcu, S. Khatua, R. Dauser, W. Whitehead, J. Weinberg, A. Mahajan, L. Gandola, E. Pecori, V. Biassoni, C. Chiruzzi, E. Schiavello, S. Meroni, F. Spreafico, E. Pignoli, M. Massimino, R. Jalali, U. Krishna, T. Gupta, S. Goswami, J. Deodhar, D. Dutta, S. Kannan, A. Goel, R. Sarin, J. Sastry, M. Ronghe, D. Murphy, K. Forbes, R. Jones, F. Cowie, J. Brown, D. Indelicato, E. O. Goksel, E. Tezcanli, H. Bilge, None Yasemin, Y. Yarar, M. Sato, J. Gunther, A. Mahajan, E. Jo, A. Paulino, A. Adesina, J. Jones, L. Ketonen, J. Su, M. Okcu, S. Khatua, R. Dauser, W. Whitehead, J. Weinberg, M. Chintagumpala, A. Paulino, E. Jo, M. Sato, J. Su, M. F. Okcu, A. Mahajan, R. Dauser, W. Whitehead, A. Adesina, M. Chintagumpala, A. Danielsson, M. Tisell, B. Rydenhag, H. Caren
Journal: Neuro-Oncology (2014)
The Prognosis of Transformed DLBCL Were Superior to De Novo DLBL after the Relapsed/Refractory Status Related to the MYC Translocation
Authors: Yuko Mishima, Masahiro Yokoyama, Noriko Nishimura, Yoshiharu Kusano, Hideki Uryu, Norihito Inoue, Anna Nishihara, Takanori Fukuta, Yuko Shirouchi, Naoko Tsuyama, Kengo Takeuchi, Yasuhito Terui
Journal: Blood (2018)
Abstract 14450: Challenging Hypertension: M-Atrial Natriuretic Peptide Enhances Antihypertensive Actions of Furosemide and Attenuates the Activation of Aldosterone
Authors: Nina A Dzhoyashvili, Seetha R Iyer, Yang Chen, Gerald E Harders, S. J Sangaralingham, Horng H Chen, John C Burnett
Journal: Circulation (2018)

Introduction: Hypertension is becoming increasingly resistant (RH) in spite of treatment with antihypertensive drugs. Furosemide (Fs) increases the effectiveness of antihypertensive agents, but act...
Incidence and Risk Factors for Second Malignancies after Transplant in Long Term Survivors of Allogeneic Haematopoietic Stem Cell Transplant: A Single Centre Experience
Authors: Mohammed Snober, Richard Syzdlo, Jane Apperley, Aristeidis Chaidos, Edward Kanfer, Dragana Milojkovic, Eduardo Olavarria, Renuka Palanicawandar, Jiri Pavlu, Jeannie F Todd, Nina Salooja
Journal: Blood (2018)
Imatinib-Treated CML Patients With Discordant Response Between Cytogenetic and Molecular Tests At 3 and 6 Month Timepoints Have a Reduced Probability Of Subsequent Optimal Response: A Study From The “Gruppo Triveneto LMC”
Authors: Massimiliano Bonifacio, Gianni Binotto, Mario Tiribelli, Elisabetta Calistri, Elena Maino, Roberta Zanotti, Luca Frison, Luciana Marin, Renato Fanin, Gianpietro Semenzato, Giovanni Pizzolo
Journal: Blood (2013)