tbuckley/cabot-search huggingface dataset:
Abstract 786: A Novel Desmoplakin Mutation Contributes to Arrhythmogenic Cardiomyopathy
Authors: Sebastiaan J van Kampen, Eirini Kyriakopoulou, Su Ji Han, Birgit Goversen, Jantine Monshouwer-Kloots, Joep Eding, Teun de Boer, Toon van Veen, Eva van Rooij
Journal: Circulation Research (2019)

Genetic alterations in desmosomal genes are associated with arrhythmogenic cardiomyopathy (ACM). This condition is characterized by sudden cardiac death, severe arrhythmias, and the presence of fibro-fatty patches within the myocardium. Despite the fact that the pathophysiology of ACM is well described, the molecular mechanisms underlying disease onset and progression are poorly understood. In an effort to identify disease-driving mechanisms we obtained induced pluripotent stem cells (hIPS) from a patient harboring a novel heterozygous mutation in desmoplakin ( DSP p.Tyr1188His/WT ), which we corrected to yield an isogenic control. hIPS cells carrying a known pathogenic mutation in desmoplakin ( DSP p.Arg1113X/WT ) served as a positive control. Gene expression analyses of DSP p.Tyr1188His/WT hIPS-derived cardiomyocytes revealed a dysregulation of desmosomal and ion channel-related genes. At the functional level we observed a prolonged action potential duration in DSP p.Tyr1188His/WT cardiomyocytes. Importantly, we validated these findings in an independent knock-in line carrying the same heterozygous ( DSP p.Tyr1188His/WT ) mutation. To study the in vivo relevance we additionally generated two corresponding mouse models harboring the mouse equivalent of the human desmoplakin mutations in the endogenous locus ( Dsp p.Tyr1200His/WT and Dsp p.Arg1125X/WT ). Both lines show altered connexin 43, phospholamban and Na V 1.5 expression levels under baseline conditions, recapitulating the changes observed in the hIPS-derived cardiomyocytes. Moreover, Fos- and RhoA-signaling pathways are enriched in these mice compared with wildtype littermates. Since exercise can be a trigger for the development of ACM, we are currently in the process of examining the effect of intense swimming exercise in the models. We show that the DSP p.Tyr1188His/WT mutation causes cellular changes linked to ACM pathogenesis, indicating this mutation to be disease-driving. Moreover, our novel mouse models of ACM recapitulate the findings observed in our human models and show key hallmarks of ACM disease progression. Future studies will focus on the underlying pathogenic mechanisms in the presented models.
Abstract 472: Smyd1 Variants Regulate Distinct Areas of Chromatin in the Cardiomyocyte
Authors: Marta Szulik, Mickey Miller, Christopher Conley, Timothy Parnell, Sarah Franklin
Journal: Circulation Research (2019)

Heart failure is one of the most devastating conditions that contributes to 25% of all deaths in the USA every year. The development of heart failure, which is often preceded by cardiac hypertrophy resulting from an increased workload, is accompanied by global changes in gene expression that resemble a more fetal-like transcriptome. Although many epigenetic factors have been identified, which influence these underlying changes in transcription during disease, we still know very little about how this process is regulated on a molecular level. Smyd1 is a unique histone methyltransferase that modifies lysine residues to regulate gene expression in the cardiomyocyte. Originally, Smyd1 was identified as a necessary regulator of cardiac development, but recently we have shown that Smyd1 is differentially expressed during cardiac hypertrophy and failure and that loss of Smyd1 (in conditional, cardiomyocyte-specific knockout mice) leads to hypertrophic growth, metabolic dysfunction and ultimately heart failure. In mice, the smyd1 gene produces two variants, Smyd1a and Smyd1b, which differ only by a 13 amino acid deletion. In addition, we have shown that overexpression of Smyd1a (but not Smyd1b) can prevent phenylephrine-induced hypertrophy, however, both variants are capable of suppressing ANF expression. Despite this interesting data, the specific genomic regions bound by these variants and the unique genes they regulate are unknown. Therefore, to identify the genes regulated by Smyd1 variants we performed ChIP-Seq in cardiomyocytes under normal and hypertrophic conditions. Interestingly, our analyses show that Smyd1a binds DNA more frequently than Smyd1b under basal conditions (2,392 vs 1,004 binding events, respectively) but that Smyd1b exhibits greater binding in hypertrophic conditions (2,414 vs 5,045 binding events). Moreover, bioinformatics analysis of these sites confirmed both conserved and unique binding preferences and showed that while both variants are most abundant in distal intergenic regions (32-57%), Smyd1a is uniquely enriched (24%) at gene promoters (&lt;1kb). These exciting results suggest novel and distinct regulatory functions of Smyd1 isoforms and begin to inform us how Smyd1 regulates cardiac morphology and physiology.
Impact of early release of oral investigational prescriptions on safety and efficiency at a comprehensive cancer center.
Authors: Alan H. Breaud, Audrea H Szabatura, Laura Cedro, Anna Shanedling, Hakim Lakhani, Caryn Caparrotta, Teresa Mazeika, Garrett Rompelman, Amy Gallant, Khanh Tu Do, Sylvia Bartel
Journal: Journal of Clinical Oncology (2019)

257 Background: At Dana-Farber Cancer Institute (DFCI), timing of order release to the pharmacy is a contributing factor to safety and processing concerns for oral investigational medications. Day-of release can lead to delayed delivery to the patient, creating a risk of missing timed specific protocol data collection, and rushed critical pharmacy safety checks, an issue raised in a comprehensive proactive systems safety risk assessment. We conducted a pilot project aimed at improving the safety and efficiency of oral investigational medication processing within the pharmacy by releasing prescription orders at least 24 hours in advance of a patient’s appointment. Methods: A team of pharmacists, nurses, process improvement professionals, and a physician designed a pilot project where the prescriber released oral investigational prescriptions, from 9 selected research protocols, at least 24 hours before a patient’s appointment. From 11/2/2018-3/1/2019, we used manual timestamp data to compare prescription processing times for prescriptions released at least 24 hours in advance (“released early”) to prescriptions released less than 24-hours in advance (“not released early”). Qualitative feedback was obtained to assess pilot impact on prescription processing safety. Results: As shown in the table below, prescription processing time on day of patient appointment for prescriptions released early was shorter, on average, compared to those not released early (p &lt; 0.05). Due to orders being released early, pharmacy staff noted feeling less pressure during prescription checks and a better ability to proactively assess inventory and prescription issues. Conclusions: Releasing oral investigational prescriptions early reduced the prescription processing time and increased time available for safety checks. Expanding this workflow change to all investigational medication orders can increase the safety and efficiency of prescription processing at DFCI. [Table: see text]
RNA Expression Profile Using Targeted NGS As a Potential Predictor of Early Molecular Response and Relapse in Core-Binding Factor Acute Myeloid Leukemia
Authors: Mahesh Swaminathan, Nicholas Stavrou, Spiraggelos Antzoulatos, Maher Albitar, Keyur Patel, Jorge E. Cortes, Courtney D. DiNardo, Tapan M. Kadia, Elias J. Jabbour, Guillermo Garcia-Manero, Hagop M. Kantarjian, Gautam Borthakur
Journal: Blood (2018)
Abstract 488: Overexpression of the Prostaglandin E2 EP3 Receptor Reduces Cardiac Function in an Angiotensin II Model of Hypertension
Authors: Timothy D Bryson, Jiang Xu, David Taube, Edward Peterson, Pamela HARDING
Journal: Circulation Research (2019)

Prostaglandin E2 (PGE2) EP receptor subtypes EP3 and EP4 are present in the heart and signal via decreased and increased cAMP production, respectively. Previously we reported that cardiomyocyte-specific EP4 KO mice develop a phenotype of dilated cardiomyopathy with reduced ejection fraction, that PGE2 decreases contractility via EP3 in vivo, in vitro and ex vivo; and that EP3 expression in the heart increases when mice are subjected to Angiotensin (Ang) II-hypertension (HTN). We therefore hypothesized that overexpression of EP3 in the heart would exacerbate Ang II-HTN. To test this hypothesis, we used 10-12 week old male EP3 transgenic (Tg) mice with EP3 overexpression in cardiomyocytes and their wild type (WT) controls infused with either vehicle or 1.4 mg/kg/d Ang II for 2 weeks. Echocardiography was performed on conscious mice at the end of the experiment and systolic blood pressure (SBP) was measured every 2 days by tail cuff. Results: Table 1. All data are reported as means ± SEM. N= 3-6 mice per group. Statistical significance: * and *** p &lt; 0.05 and p &lt; 0.005 vs WT + vehicle, ++ p &lt; 0.01 vs WT + Ang II, §§§ p &lt; 0.005 vs Tg + vehicle. As shown in the table, cardiac function was unaffected in WT mice after Ang II infusion. Baseline cardiac function was reduced in EP3 Tg mice receiving vehicle and in contrast to WT mice, was further diminished after Ang II infusion. These differences were not due to altered systolic blood pressure. In conclusion, EP3 Tg mice present with reduced cardiac function at baseline and in support of our hypothesis, exhibit an enhanced response to Ang II. Antagonism of the EP3 receptor may be a novel treatment for heart failure associated with hypertension.
Current gaps in sepsis immunology: new opportunities for translational research
Authors: Ignacio Rubio, Marcin F Osuchowski, Manu Shankar-Hari, Tomasz Skirecki, Martin Sebastian Winkler, Gunnar Lachmann, Paul La Rosée, Guillaume Monneret, Fabienne Venet, Michael Bauer, Frank M Brunkhorst, Matthijs Kox, Jean-Marc Cavaillon, Florian Uhle, Markus A Weigand, Stefanie B Flohé, W Joost Wiersinga, Marta Martin-Fernandez, Raquel Almansa, Ignacio Martin-Loeches, Antoni Torres, Evangelos J Giamarellos-Bourboulis, Massimo Girardis, Andrea Cossarizza, Mihai G Netea, Tom van der Poll, André Scherag, Christian Meisel, Joerg C Schefold, Jesús F Bermejo-Martín
Journal: The Lancet Infectious Diseases (2019)
CRM1/XPO1 Represents a Promising Therapeutic Target for Treatment of Chronic Lymphocytic Leukemia
Authors: Rosa Lapalombella, Caroline Berglund, Emilia Mahoney, Katie Williams, Shruti Jha, Asha Ramanunni, Vincent Sandanayaka, Sharon Shechter, Dilara McCauley, Sharon Shacham, Michael Kauffman, John C. Byrd
Journal: Blood (2011)
The impact of interdisciplinary shared medical appointments in newly diagnosed early-stage melanoma patients: The Cleveland Clinic experience.
Authors: Benjamin Switzer, David J Savage, Rujul Parikh, Jung Min Song, Carolyn Stanek, Ann Yurco, Pauline Funchain, Joel Daniel Marcus
Journal: Journal of Clinical Oncology (2019)

230 Background: Shared Medical Appointments (SMA) serve as a unique means of improving outcomes and patient satisfaction while reducing clinic wait times and healthcare costs. Early-stage melanoma survivors may benefit from a targeted SMA. This cohort exhibits high rates of psychosocial distress, with up to 30% warranting clinical intervention (Kasparian, 2013). Additionally,numerically more melanoma deaths are related to thin ( &lt; 1mm) melanomas than those with thick ( &gt; 4mm) on presentation (Whitehall et al, 2015). We hypothesized that an SMA targeting early-stage melanoma patients may reducepsychologic fear and stress, as well as improve patients’ melanoma-related knowledge and adherence to their individualized care plans. Methods: The Cleveland Clinic’s Early Stage Melanoma Survivorship SMA interdisciplinary care team focused on crucial survivorship and prevention techniques, in addition to targeting modifiable behaviors for patients to collaboratively explore (format introduced ASCO Quality 2018, abst 69). A retrospective chart review assessed for demographics, participation rates, changes in depression scores, follow-up show-rates, and post-SMA survey results. Results: Of 477 early stage melanoma patients seen during the time of SMA implementation (6/2018-4/2019), only 91 (19.1%) attended oncology follow-up appointments, and 34 (7.1%) participated in an SMA. Participants expressed high rates of satisfaction and improvement in melanoma-related knowledge, whileexhibiting a &gt; 92% show rate in subsequent oncologic and dermatologic medical appointments compared to 74% and 73%, respectively, in the non-SMA group. No significant improvement in depression and anxiety scoring was noted in SMA vs. non-SMA groups. SMA attendance was notably higher in younger (mean age 56 vs 61) and female (56% vs 30%) patient cohorts without appreciable differences in social history, marital status, or socioeconomic region. Conclusions: Survivorship SMAs for early stage melanoma patients appear to exhibit high rates of patient satisfaction, improvement in clinical knowledge, and adherence to routine dermatology and oncology follow-up appointments.
Pericardial effusion under nivolumab: case-reports and review of the literature
Authors: Anastasia Saade, Audrey Mansuet-Lupo, Jennifer Arrondeau, Constance Thibault, Mariana Mirabel, François Goldwasser, Stéphane Oudard, Laurence Weiss
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Nivolumab, a programmed death-1 (PD-1) inhibitor, is an immune checkpoint inhibitor particularly used in the treatment of malignant melanoma, non-small cell lung cancer and renal cell carcinoma. Immune-related adverse events are frequent under immunotherapies. Cardiotoxic side effects, initially thought to be rare, are more often encountered paralleling the expanding use of immune checkpoint blockade. Among them, pericardial effusion and tamponade deserve attention as they may present with unusual symptomatology. <h3>Case presentation</h3> We report three cases of pericardial effusion under nivolumab for lung adenocarcinoma. Two cases of early and late-onset pericardial effusion were symptomatic with tamponade and one case occurred without any symptoms. Pericardiocentesis with pericardial biopsy was performed in symptomatic pericardial effusion followed by the administration of a corticotherapy. Pericardial biopsies showed infiltration of T-lymphocytes, mostly CD4<sup>+</sup>. Nivolumab was stopped in two cases and resumed for one patient. Pericardial effusion evolved positively in all cases with or without treatment. <h3>Conclusions</h3> We review the literature on pericardial effusion under nivolumab to further discuss the hallmarks of pericardial effusion under nivolumab and the management of nivolumab therapy in this situation. In conclusion, pericardial effusion as an immune-related adverse event under nivolumab appears less rare than initially thought and may require particular attention.
Platelet lamellipodium formation is not required for thrombus formation and stability
Authors: Yvonne Schurr, Andreas Sperr, Julia Volz, Sarah Beck, Lucy Reil, Charly Kusch, Patrick Eiring, Sheila Bryson, Markus Sauer, Bernhard Nieswandt, Laura Machesky, Markus Bender
Journal: Blood (2019)
Treatment patterns and barriers involving the use of CDK4/6 inhibitors for women with HR+, HER2- breast cancer.
Authors: Sara M. Tolaney, Joyce O'Shaughnessy, Tariqa Ackbarali, Rebecca Crawford, Jeffrey D. Carter, Laurence Greene, Tamar Sapir
Journal: Journal of Clinical Oncology (2019)

27 Background: For women with HR+, HER2- breast cancer, cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) can significantly improve outcomes. However, the most effective uses of CDK4/6i may be limited by barriers including a lack of systems-based pathways and education to guide individualized treatment. In a quality improvement program in 2 healthcare systems, we assessed baseline treatment patterns and barriers involving CDK4/6i use. Methods: Participants were 34 oncologists and team members. At baseline, we administered surveys to assess barriers to prescribing CDK4/6i and audited the EMRs of 100 women with HR+, HER2- breast cancer in each system. EMRs were audited for demographics; disease characteristics; and treatment history, monitoring, and shared decision-making (SDM) involving CDK4/6i. The teams participated in an audit-feedback session and developed action plans for resolving gaps. Results: Overall, 31% of the 200 women received a CDK4/6i, and 13% received a CDK4/6i as second-line therapy. More than 30% of women treated with a CDK4/6i had documentation of only Stage I/II disease. EMR audits revealed low rates of recommended electrolyte monitoring and ECGs (0%), liver function tests (LFT; 44%), and SDM (Table). Surveys were completed by 20 participants. Whereas 80% indicated being likely to recommend a CDK4/6i, they reported barriers of identifying eligible patients (35%) and monitoring for disease progression (45%). A moderate proportion of oncologists reported considering menopausal status (60%) and patient preferences (50%) in CDK4/6i decision-making. Participants developed action plans for improving EMR documentation for disease stage and protocols for monitoring progression. Conclusions: These baseline findings reveal gaps that may inform QI initiatives for promoting the appropriate use of CDK4/6i for women with HR+, HER2- breast cancer. Findings from baseline EMR audits (n = 200). [Table: see text]
Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy
Authors: Yuting Liu, Jon Zugazagoitia, Fahad Shabbir Ahmed, Brian S. Henick, Scott N. Gettinger, Roy S. Herbst, Kurt A. Schalper, David L. Rimm
Journal: Clinical Cancer Research (2019)

Programmed death ligand 1 (PD-L1) is expressed in tumor cells and immune cells, and both have been associated with response to anti-PD-1 axis immunotherapy. Here, we examine the expression of PD-L1 to determine which cell type carries the predictive value of the test.We measured the expression of PD-L1 in multiple immune cells with two platforms and confocal microscopy on three retrospective Yale NSCLC cohorts (425 nonimmunotherapy-treated cases and 62 pembrolizumab/nivolumab/atezolizumab-treated cases). The PD-L1 level was selectively measured in different immune cell subsets using two multiplexed quantitative immunofluorescence panels, including CD56 for natural killer cells, CD68 for macrophages, and CD8 for cytotoxic T cells.PD-L1 was significantly higher in macrophages in both tumor and stromal compartment compared with other immune cells. Elevated PD-L1 in macrophages was correlated with high PD-L1 level in tumor as well as CD8 and CD68 level (P < 0.0001). High PD-L1 expression in macrophages was correlated with better overall survival (OS; P = 0.036 by cell count/P = 0.019 by molecular colocalization), while high PD-L1 expression in tumor cells was not.In nearly 500 non-small cell lung cancer (NSCLC) cases, the predominant immune cell type that expresses PD-L1 is CD68+ macrophages. The level of PD-L1 in macrophages is significantly associated with the level of PD-L1 in tumor cells and infiltration by CD8+ T cells, suggesting a connection between high PD-L1 and "hot" tumors. In anti-PD-1 axis therapy-treated patients, high levels of PD-L1 expression in macrophages are associated with longer OS and may be responsible for the predictive effect of the marker.
Graft-Versus-Leukemia Effect after Haplo-Identical Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Patients with AML- No Association with Graft-Versus-Host Disease: A Study on Behalf of the Acute Leukemia Working Party of EBMT
Authors: Avichai Shimoni, Myriam Labopin, Emanuele Angelucci, Didier Blaise, Fabio Ciceri, Yener Koc, Zafer Gülbas, Jose L. Diez-Martin, Benedetto Bruno, Luca Castagna, Massimo Martino, Montserrat Rovira, Mohamad Mohty, Arnon Nagler
Journal: Blood (2018)
Responsiveness of quality‐of‐life measures in patients with peripheral vascular malformations: the OVAMA project
Authors: M.M. Lokhorst, S.E.R. Horbach, M. Waner, T.M. O, C.J.M. Vleuten, L.B. Mokkink, C.M.A.M. Horst, P.I. Spuls
Journal: British Journal of Dermatology (2019)

The OVAMA (Outcome Measures for Vascular Malformations) project determined quality of life (QoL) as a core outcome domain for patients with vascular malformations. In order to measure how current therapeutic strategies alter QoL in these patients, a patient‐reported outcome measurement (PROM) responsive to changes in QoL is required. To assess the responsiveness of two widely used generic QoL PROMs, the Medical Outcomes Study Short Form 36 (SF‐36) and Skindex‐29, in adult patients with vascular malformations. In an international multicentre prospective study, treated and untreated patients completed the SF‐36 and Skindex‐29 at baseline and after a follow‐up period of 6–8 weeks. Global rating of change (GRC) scales assessing various QoL‐related outcome domains were additionally completed. Per subscale, responsiveness was assessed using two methods: by testing hypotheses on expected correlation strength between change scores of the questionnaires and the GRC scales, and by calculating the area under the receiver operating characteristics curve (AUC). The questionnaires were considered responsive if ≥ 75% of the hypotheses were confirmed or if the AUC was ≥ 0·7. Eighty‐nine participants were recruited in three centres in the Netherlands and the U.S.A., of whom 67 completed all baseline and follow‐up questionnaires. For all subscales of the SF‐36 and Skindex‐29, < 75% of the hypotheses were confirmed and the AUC was < 0·7. Our findings suggest that the SF‐36 and Skindex‐29 seemed unresponsive to change in QoL. This suggests that alternative PROMs are needed to measure – and ultimately improve – QoL in patients with vascular malformations. What's already known about this topic? Quality of life is often impaired in patients with vascular malformations. Quality of life is considered a core outcome domain for evaluating treatment of vascular malformations. To measure the effect of treatment on quality of life, a patient‐reported outcome measure is required that is responsive to changes in quality of life. What does this study add? This is the first study assessing the responsiveness of quality‐of‐life measures in patients with vascular malformations. The results seem to indicate that the Medical Outcomes Study Short Form 36 (SF‐36) and Skindex‐29 are not responsive to changes in quality of life in patients with vascular malformations. What are the clinical implications of this work? Medical Outcomes Study Short Form 36 (SF‐36) and Skindex‐29 are not ideal to assess the effect on quality of life over time, of treatment strategies for peripheral vascular malformations.