tbuckley/cabot-search huggingface dataset:
Abstract 105: MCL-1 Promotes Drp1-Mediated Mitochondrial Fission as an Adaptive Response to Stress
Authors: Alexandra G Moyzis, Navraj S Lally, Rita A Najor, Leonardo J Leon, Åsa B Gustafsson
Journal: Circulation Research (2019)

The anti-apoptotic BCL-2 family member, Myeloid Cell Leukemia-1 (MCl-1), is highly expressed in myocardium and plays a critical role in maintaining mitochondrial homeostasis. We have previously found that cardiomyocyte-specific MCL-1 knockout mice develop rapid cardiac dysfunction and cardiomyopathy but show little activation of apoptotic cell death. Instead, loss of MCL-1 resulted in atypical mitochondrial morphology and function. This suggests that besides its anti-apoptotic role, MCL-1 may have broader functions in regulating mitochondrial dynamics and function. MCL-1 localizes to two different mitochondrial locations in myocytes. One form exists on the outer mitochondrial membrane (MCL-1 OM ) and a shorter cleaved form resides in the mitochondrial matrix (MCL-1 Matrix ). We found that overexpression of MCL-1 WT or MCL-1 OM , but not MCL-1 Matrix , induces fragmentation and perinuclear aggregation of the mitochondria in a Drp1-dependent manner. Mutating MCL-1’s BH3 domain (G198E D199A), which is required for MCL-1’s anti-apoptotic function, completely abrogates its ability to induce perinuclear aggregation. Interestingly, a MCL-1-BCL-2 chimera, in which MCL-1’s BH domains are replaced with those of BCL-2, is still able to induce perinuclear aggregation. This suggests that the presence of a functional BH3 domain is sufficient for induction of perinuclear aggregation. We confirmed that there is increased interaction between endogenous MCL-1 and Drp1 in response to a variety of fission-promoting stimuli, including glucose deprivation, hypoxia, and treatment with rotenone or FCCP. MCL-1 overexpression also protects against cell death in response to these stimuli, but this protection is abrogated when Drp1 is knocked down using siRNA. Additionally, Drp1 levels are significantly increased at the mitochondria in the hearts of MCL-1 OM transgenic mice, and this increase corresponds to an increased interaction between MCL-1 and Drp1 in these transgenic mice. Consistent with these findings, many of the mitochondria in these transgenic mice appear to be smaller than those from the WT mice, indicative of enhanced mitochondrial fission. Thus, our data suggests that MCL-1 functions as a positive regulator of Drp1-mediated mitochondrial fission.
Abstract 433: Hydrogen Sulfide Protects the Heart Against Homocysteine-Induced Remodeling by Regulating Autophagy and Pyroptosis
Authors: Sumit Kar, Santosh K Yadav, Ravi Goyal, David J Lefer, Paras K Mishra
Journal: Circulation Research (2019)

Hydrogen sulfide (H 2 S), a byproduct of homocysteine (Hcy) transsulfuration, protects against adverse cardiac remodeling in diabetic cardiomyopathy, hyperhomocysteinemia (HHcy), and other cardiomyopathies. However, the underlying molecular mechanisms are unclear. Pyroptosis is a caspase 1-mediated cell death mechanism that promotes remodeling. It is inhibited by autophagy, a lysosomal degradation process that maintains cellular homeostasis. We hypothesized that H 2 S supplementation inhibits Hcy-induced pyroptosis by increasing autophagy in the heart. We treated CBS +/- mice (a model of HHcy) and WT mice with SG1002 (slow-releasing H 2 S donor) or control diet for 14 weeks and performed deep sequencing of their hearts (LV tissue). Ingenuity Pathway Analysis revealed SG1002 downregulated cardiac hypertrophy genes, plausibly by altering upstream regulators involved in pyroptosis and autophagy (IL-1β and mTOR). Western blot results showed that SG1002 suppresses mTOR in CBS +/- hearts (WT: 2.1±0.83, CBS: 10±2.4, CBS+SG: 3.8±2.3, WT+SG: 0.96±0.39) to induce autophagy. SG1002 decreases IL-1β (WT: 0.61±0.08, CBS: 0.88±0.07, CBS+SG: 0.32±0.01, WT+SG: 0.38±0.03) and inhibits caspase-1 activity to suppress Hcy-induced pyroptosis. NF-kB p65, which activates pyroptosis, is also downregulated by SG1002. We conclude that H 2 S could alleviate cardiac remodeling by inducing autophagy and inhibiting NF-kB-mediated pyroptosis. This is the first report that H 2 S controls cross-talk of cardiac pyroptosis and autophagy.
Impact of in-house specialty pharmacy on access to novel androgen axis inhibitors in men with advanced prostate cancer.
Authors: Nathan Handley, Siobhan Kirk, Anna Driscoll, Adam Binder, William Kevin Kelly
Journal: Journal of Clinical Oncology (2019)

132 Background: Novel androgen axis inhibitors are standard of care treatments in advanced prostate cancer. The billed amounts for these medications are often very high, which may create significant financial toxicity for patients and lead to delays in treatment. Our institution implemented an in-house specialty pharmacy in 2014, that provides these medications and evaluates copay assistance options for all patients. We evaluated the program’s impact on out of pocket cost (OOP) and turnaround time (TAT). Methods: We reviewed available internal specialty pharmacy records to identify prescriptions for abiraterone or enzalutamide filled between 1/1/17 and 12/31/18. Payments were stratified by primary payment (amount reimbursed by the patient’s prescription plan based on the benefit’s design) and copayment assistance. Turnaround times (TAT) in business days were stratified by prescriptions requiring intervention (prior authorization, copayment assistance, or insufficient inventory) and clean prescriptions (those requiring no intervention). Results: One thousand for hundred seventeen prescriptions for 175 unique patients requiring abiraterone (n = 869, 61.3%) or enzalutamide (n = 548, 38.7%) were filled through the institution’s specialty pharmacy. The average amount paid by primary payer was $9,492.96 for a 30 day supply (range: $3,382.48-$12,939.84). Average quoted copay was $577.53 (range $3.08-$10,560.39). 64% of patients received copayment assistance. Average OOP cost per prescription after co-pay assistance was $100.83 (range $0-$8556.64). Three patients declined treatment due to cost (1.7% of overall). Average TAT was 2.98 days for clean prescriptions and 3.36 days for prescriptions needing intervention (p = 0.055). Conclusions: OOP cost varied significantly based on plan design and copayment assistance eligibility. The majority of patients received copayment assistance, which markedly reduced OOP cost. Cost rarely precluded access to treatment. TAT was not significantly prolonged for prescriptions requiring intervention. Further studies to determine impact of pharmacy type on access to specialty medications are indicated.
Impact of brain metastases on end-of-life health care utilization.
Authors: Emily Miller Ray, Lisette Dunham, Katherine Elizabeth Reeder-Hayes, Hanna Kelly Sanoff
Journal: Journal of Clinical Oncology (2019)

116 Background: Patients with brain metastases (BMets) represent a subset of cancer patients who may experience high costs and frequent healthcare utilization. This study aims to assess whether patients with BMets have higher likelihood of healthcare utilization at the end of life (EOL) compared to other patients with metastatic cancer. Methods: Using the Cancer Information and Population Health Resource, linking North Carolina Medicare, Medicaid, and private payer claims with state cancer registry data, we conducted an observational cohort study of decedents with metastatic melanoma, renal cell carcinoma, breast cancer, or lung cancer (diagnosed 2003-2014) with or without BMets. Multivariate logistic regression, adjusting for demographics, cancer type, systemic treatment, comorbidity, frailty, and hospice use, was used to examine the impact of BMets on use of the emergency department (ED), hospital, and intensive care unit (ICU) in the 30 days prior to death. Results: Patients with BMets are hospitalized at EOL more often than patients without BMets (44% vs 38%, p &lt; 0.001), but experience no difference in ED or ICU use. BMets patients receiving systemic treatment were particularly high risk for hospital and ICU use (odds ratios in Table). Black race and Charlson comorbidity score 3+ increased risk of hospitalization and ICU use. Utilization did not vary by cancer type. Hospice care significantly reduced all utilization. Conclusions: Patients with BMets are high risk for hospitalization at the end of life. Further study is needed to determine if targeted health system interventions can decrease hospitalizations in this patient group. [Table: see text]
Safety and Efficacy of Primary Prophylaxis with Voriconazole in Adult Patients with Acute Leukemia.
Authors: Jose F. Tomas, Pilar Delgado, Juan C. Garcia-Zueco, Raquel de Oña, Monica Estevez, A. Rezusta, D. Yague, Jose I. Garcia-Cia, Rebeca Iglesias, Daniel Rubio-Felix
Journal: Blood (2007)
A Pilot Study of Central Venous Catheter Survival in Cancer Patients Using Low Molecular Weight Heparin (Dalteparin) for the Treatment of Deep Vein Thrombois of the Upper Extremity (UEDVT).
Authors: Michael J. Kovacs, Roseann Andreou, Marc Rodger, David R. Anderson, Susan R. Kahn, Joy E. Mangel, Beverly Morrow, Anne Marie Clement, Philip S. Wells
Journal: Blood (2006)
Hepatic Artery Embolization Induces the Local Overexpression of Transforming Growth Factor β1 in a Rat Hepatoma Model
Authors: Eisuke Ueshima, Hideyuki Nishiofuku, Haruyuki Takaki, Yutaka Hirata, Hiroshi Kodama, Toshihiro Tanaka, Kimihiko Kichikawa, Koichiro Yamakado, Takuya Okada, Keitaro Sofue, Masato Yamaguchi, Koji Sugimoto, Takamichi Murakami
Journal: Liver Cancer (2019)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; The underlying mechanism involved in the recurrence of hepatoma after hepatic arterial embolization (HAE) is not adequately examined. An immunosuppressive cytokine, transforming growth factor β1 (TGF-β1), can lead to tumor progression and is affected by hypoxia in various cancers. The study aimed to assess the effect of HAE on the expression of TGF-β1 in a rat hepatoma model. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Sprague-Dawley rats bearing N1S1 hepatoma cells underwent HAE (HAE group, &lt;i&gt;n&lt;/i&gt; = 5) or sham treatment (sham group, &lt;i&gt;n&lt;/i&gt; = 4). The animals were euthanized at 48 h, and liver tissues were harvested. Immunohistochemistry (IHC) and quantitative polymerase chain reaction (qPCR) were performed to compare the expression of TGF-β1 and hypoxia-inducible factor 1α (HIF-1α) between the HAE and sham groups. In vitro experiments with the N1S1 cell line were also performed under normoxic (21% O&lt;sub&gt;2&lt;/sub&gt;) or hypoxic (1% O&lt;sub&gt;2&lt;/sub&gt;) conditions for 48 h, and the expression of TGF-β1 and HIF-1α was assessed with western blotting and enzyme-linked immunosorbent assay. Statistical data comparisons were performed by Student &lt;i&gt;t&lt;/i&gt; test. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; IHC showed that both the TGF-β1-positive and HIF-1α-positive tumor peripheral areas were larger in the HAE group (6.59 ± 2.49 and 10.26 ± 4.14%; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.001, respectively) than in the sham group (0.34 ± 0.41 and 0.40 ± 0.84% respectively). Similarly, qPCR showed that the mRNA expression levels of TGF-β1 and HIF-1α were higher (1.95 ± 0.38-fold and 1.62 ± 0.37-fold; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.001 and &lt;i&gt;p&lt;/i&gt; = 0.002, respectively) in the HAE group than those in the sham group. TGF-β1 expression was suppressed when HIF-1α inhibitors were added (&lt;i&gt;p&lt;/i&gt; = 0.001), and HIF-1α expression was upregulated when exogenous TGF-β1 was added (&lt;i&gt;p&lt;/i&gt; = 0.033) in N1S1 cells. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; HAE enhanced local TGF-β1 expression in a rat hepatoma model. In vitro experiments suggest that HAE-induced hypoxic stress may trigger the interdependent expression of TGF-β1 and HIF-1α.
Efficacy of Nilotinib in EARLY Chronic PHASE CML Patients WHO Have Suboptimal Cytogenetic or Molecular Response to Imatinib. A Multicentric Retrospective Study
Authors: Luigia Luciano, Elisa Seneca, Mario Annunziata, Luca Pezzullo, Paolo Danise, Ursula Sessa, Fausto Palmieri, Mariolina Iovine, Roberto Vallone, Fabrizio Pane
Journal: Blood (2012)
Abstract 111: Wnt Signaling Inhibition Rescues Voltage-Gated Na <sup>+</sup> Current in Brugada Syndrome Patient Cardiomyocytes
Authors: Wenbin Liang, Aizhu Lu, Cencen Chu, Jerry Wang
Journal: Circulation Research (2019)

Aims: Both inherited arrhythmogenic diseases (such as Brugada Syndrome) and heart failure are associated with reduced voltage-gated Na + current (I Na ) which promotes lethal arrhythmias and sudden deaths. We and others have shown that Wnt/β-catenin signaling (Wnt signaling), which is active in heart disease, inhibits I Na in rat and mouse cardiomyocytes. But whether Wnt signaling regulates I Na in human cardiomyocytes and represents a novel therapeutic target is unknown. This study aims to investigate if Wnt signaling inhibits I Na in human cardiomyocytes, to elucidate the underlying mechanisms, and to test if blocking Wnt signaling can rescue I Na in Brugada Syndrome patient cardiomyocytes. Methods and Results: Cardiomyocytes were differentiated from human induced pluripotent stem cells (hiPSC-CMs) that were derived from healthy volunteers or a Brugada Syndrome patient. Whole-cell patch-clamp technique was used for I Na measurement. Activation of Wnt signaling in healthy hiPSC-CMs led to a 69% reduction in I Na amplitude (peak current at -20 mV: -10.5±2.8 pA/pF, n=9 cells vs. control -33.6±4.1 pA/pF, n=6 cells, p&lt;0.01) by reducing SCN5A mRNA (encoding the pore-forming α subunit of I Na , Na v 1.5). In addition, Wnt signaling also reduced Na v 1.5 glycosylation causing a depolarizing shift of I Na activation curve (a mechanism found in human, but not in rodent, cardiomyocytes). Blocking Wnt signaling in Brugada hiPSC-CMs with shRNA-mediated β-catenin knockdown led to a 13-fold increase in I Na amplitude (p&lt;0.01, n=9 cells), offsetting the fundamental genetic defect. Consistent with increased I Na, blocking Wnt signaling also upregulated SCN5A mRNA and Na v 1.5 protein, without affecting expression of other cardiac ion channels in Brugada hiPSC-CMs. Conclusions: This study demonstrated Wnt-inhibition of human cardiac I Na and, using Brugada Syndrome as an example, demonstrated that blocking Wnt signaling is a novel therapeutic strategy to rescue I Na in heart disease.
Treatment of Bleeding in Severely Thrombocytopenic Patients with Transfusion of Dimethyl Sulfoxide (DMSO) Cryopreserved Platelets (CPP) Is Safe - Report of a Phase 1 Dose Escalation Safety Trial
Authors: Sherrill J. Slichter, Larry J. Dumont, Jose A. Cancelas, Terry Gernsheimer, Zbigniew Szczepiorkowski, Nancy M. Dunbar, Stephen Medlin, MeLinh Jones, Neeta Rugg, Gautham Prakash, Greggory J. Housler, Victor W. MacDonald, Peter Hmel, Janet H. Ransom
Journal: Blood (2016)
Abstract 11250: Bone Marrow Mononuclear Cell Transplantation Improves Cardiac Function in Ischemic Cardiomyopathy via High Mobility Group Box 1 Released from Dead Donor Cells
Authors: Masahiro Kaneko, Yasunori Shintani, Takuya Narita, Chiho Ikebe, Niall Campbell, Vinit Sawhney, Nobuko Tano, Steven Coppen, Kenta Yashiro, Ken Suzuki
Journal: Circulation (2012)

Injection of bone marrow mononuclear cells (BMCs) improves cardiac function in ischemic cardiomyopathy allegedly due to the “paracrine effect” mediated by secretion from surviving BMCs. However, do...
Patients enrolled in clinical trials with Medicaid or no insurance and overall survival benefits from new interventions.
Authors: Joseph M. Unger, Charles David Blanke, Michael Leo LeBlanc, William E. Barlow, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2019)

119 Background: Very few new treatments tested in randomized phase III cancer clinical trials show an overall survival (OS) benefit. Understanding whether the benefits are consistent among all patient groups is critical for informing guideline care. However, within trials, there is limited power to examine demographic or insurance subsets, especially in under-represented groups. Here we systematically examine whether positive treatment effects apply to all demographic and insurance groups. Methods: We examined all SWOG treatment trials completed from 1985-2014, and pooled data from trials with a statistically significant (p &lt; .05) OS benefit for the experimental treatment. We conducted multivariable Cox regression analyses adjusting for clinical risk level and stratifying by study-specific 2-year OS probability ( &lt; 25% vs. 25-75% vs. &gt; 75%). Interaction tests determined whether OS hazard ratios (HRs) differed by 5 prespecified factors including age ( &lt; 65 vs. ≥65), race (black vs. other), sex, ethnicity (Hispanic vs. non-Hispanic), and insurance status in patients &lt; 65 years (private insurance vs. Medicaid/no insurance). Results: We identified 16 trials, containing 9,328 patients, with statistically significantly better OS in the experimental arm. The OS HR did not differ by sex (p = .60), race (p = .68), or ethnicity (p = .66). However, patients ≥65 years had a smaller treatment benefit than patients &lt; 65 (HR = 1.24 vs HR = 1.37, p = .03), and patients with Medicaid/no insurance had a smaller treatment benefit than private insurance patients (HR = 1.22 vs. HR = 1.70, p = .03). Conclusions: The magnitude of the OS benefit from experimental treatments may not be uniform among demographic and insurance status groups. Older age patients and those with suboptimal insurance are at greater risk of experiencing competing risks of death, which can reduce power to identify the benefits of new experimental therapies. Trial designs should account for the risk of non-cancer deaths in important patient groups. Future research should examine whether reduced treatment impact is due to a higher comorbid burden in older patients, and to worse adherence to protocol care in those with limited financial resources.
Abstract 339: Biomechanics and Calcium Handling of Thin Filament Hypertrophic Cardiomyopathy Variants
Authors: Giuliana G Repetti, Christopher N Toepfer, Amanda C Garfinkel, Gabriela Venturini, Jonathan G Seidman, Christine E Seidman
Journal: Circulation Research (2019)

The mechanism by which genetic variants of the thin filament cause hypertrophic cardiomyopathy (HCM) has not been fully elucidated. Induced pluripotent stem cell (iPSC)-derived cardiomyocytes can provide a rapidly generatable disease modeling tool to study HCM in these variants. While variants in the thick and thin filament both cause HCM, cardiomyocytes that harbor pathogenic variants in the thin filament genes troponin I ( TNNI3 ) and troponin T ( TNNT2 ) display a distinct molecular phenotype, which we hypothesize differs from the thick filament HCM phenotype. Both thin and thick filament mutant cardiomyocytes display increased measured oxygen consumption rate assessed by metabolic assays, however we hypothesize that the mechanism that drives metabolic change is not common between thick and thin filament variants. Mutations in the thick filament typically shift myosin conformations during relaxion towards a higher energy utilizing a disordered relaxed state (DRX) that enables ATP hydrolysis with more free myosin heads, and this likely accounts for their increased oxygen consumption. However thin filament mutations cause myosin heads to preferentially adopt a conformation in which the myosin heads are sequestered and unable to bind actin. This super relaxed state (SRX) is associated with energy conservation, which would predict reduced contractility. Yet contractility data from thin filament mutants replicate the classic HCM phenotype of hypercontractility and disturbed sarcomere relaxation. To further probe the mechanism by which thin filament variants drive HCM pathophysiology we have employed methodologies to assess calcium transients in iPSC-derived cardiomyocytes harboring thin filament variants. TNNT2 variants recapitulate this disrupted calcium handling.
Metabolic Reprogramming Overcomes T Cell Inhibition By AML Cells
Authors: Franziska Maria Uhl, Sophia Chen, David O'Sullivan, Michael Buck, Jörg Büscher, Dietmar Pfeifer, Jürgen Finke, Justus Duyster, Hartmut Bertz, Khalid Shoumariyeh, Melanie Börries, Gesa Richter, Tobias Madl, Erika L. Pearce, Robert Zeiser
Journal: Blood (2018)
Abstract 651: Single-nucleus Transcriptome Analysis of Patients’ Heart Tissue Reveals Disease-specific Transcriptional Signatures in Heart Failure
Authors: Kanna Fujita, Seitaro Nomura, Takanori Fujita, Masahiro Satoh, Toshiyuki Ko, Shintaro Yamada, Masamichi Ito, Manami Katoh, Masaru Hatano, Hiroyuki Aburatani, Issei Komuro
Journal: Circulation Research (2019)

Single-cell transcriptome analysis is a powerful strategy uncovering heterogeneities of cells and their responses and molecular mechanism in developmental, physiological, and pathological processes. We have applied this technology to cardiac tissue, single-cardiomyocyte RNA- seq analysis of heart failure model mice and human failing heart, and we have uncovered heterogeneous stress response during cardiomyocyte remodeling, showing distinct transcriptional dynamics of the cardiomyocyte gene programs. However, it is difficult to simultaneously analyze transcriptomes of cardiomyocytes and non-cardiomyocytes in the archival heart tissue because of its highly interconnected feature and significant differences in cellular characteristics. We established single-nucleus RNA- seq analysis pipeline to overcome such problems and comprehensively analyze cells consist of heart tissue, to elucidate molecular mechanism in the pathogenesis of heart failure, combining the data with clinical phenotype of the disease.Single-nucleus analysis of the frozen mouse heart successfully reclassified cardiac cells by their transcriptomic features. By comparing single-nucleus RNA- seq profiles with single-cell RNA- seq profiles, we found a significant difference of mRNA localization between the cytosol and nucleus. mRNA of nuclear mitochondrial genes is preferentially localized in the cytosol, whereas that of extracellular matrix genes is in the nucleus. We also conducted single-nucleus RNA- seq analysis of the heart from patients with heart failure, again successfully reclassified cell types, and found disease specific transcriptomic landscape in heart failure. We are going to integrate single-nucleus gene expression profiles with the phenotypic characteristics such as treatment response and clinical prognosis, to reveal the molecular characteristics useful for cardiovascular precision medicine.
Autologous Stem Cell Transplantation In Immunoglobulin Light Chain Amyloidosis With Factor X Deficien
Authors: Stefan F Cordes, Morie A Gertz, Francis K Buadi, Yi Lin, Martha Q Lacy, Prashant Kapoor, Shaji K Kumar, Arleigh McCurdy, Angela Dispenzieri, David Dingli, Suzanne R Hayman, William J. Hogan, Rajiv K Pruthi
Journal: Blood (2013)