tbuckley/cabot-search huggingface dataset:
Purkinje-Muscle Reentry as a Mechanism of Polymorphic Ventricular Arrhythmias in a 3-Dimensional Model of the Ventricles
Authors: OmerBerenfeld, JoséJalife
Journal: Circulation Research (1998)

Abstract—Multiple electrode mapping of the ventricles during complex tachyarrhythmias has revealed focal subendocardial activation whose mechanism remains unexplained. We hypothesized that reentry involving the Purkinje-muscle junctions (PMJs) may be a mechanism for such focal excitations. We have constructed an anatomically appropriate computerized 3-dimensional model of the mammalian ventricles that includes the Purkinje conduction system and 214 PMJs distributed throughout the endocardium. Isochronal maps during normal excitation, as well as during right or left bundle branch block, resembled experimental measurements and compared well with isochronal maps of propagation in the human heart. Activity observed at both sides of a PMJ in the model showed that propagation from Purkinje fibers to muscle was slower than in the opposite direction. Under these realistic and normal conditions, the evolution of reentrant activity involving muscle and the Purkinje network was simulated. The reentry pattern was ind...
Association of Immunologic Markers With Survival in Upfront Resectable Pancreatic Cancer
Authors: Ephraim S. Tang, Philippa H. Newell, Ronald F. Wolf, Paul Daniel Hansen, Benjamin Cottam, Carmen Ballesteros-Merino, Michael J. Gough
Journal: JAMA Surgery (2018)

Although previous studies have hypothesized increased risk in agricultural areas because of atrazine exposure, 4,5 one of the most common herbicides used in the United States, this herbicide is rarely used in forested areas and is more commonly used for corn in the Midwest.A previous study in the San Joaquin Valley in California from 1997 to 2006 also did not find evidence of this association. 6 The primary limitation of this study is that it was retrospective and observational, using an administrative database, and thus relied on accurate coding.The rising risk of gastroschisis in rural counties in California is not clearly owing to agricultural exposures.
Abstract 5095: Concurrent <i>Dnmt3a</i> haploinsufficiency partially abrogates competitive disadvantage in <i>Smc3</i> haploinsufficient myeloid cells
Authors: Tianjiao Wang, John S. Welch
Journal: Cancer Research (2018)

Abstract SMC3 encodes a subunit of cohesin associated with recurrent heterozygous mutations in acute myeloid leukemia (AML) and other myeloid malignancies. About one-third of these mutations are predicted loss-of-function (nonsense and splice-site mutations) and the rest are missense with unclear function. To understand whether these missense mutations might have dominant-negative effects or phenocopy loss-of-function effects, we compared the consequences of Smc3 deficient and haploinsufficient mouse models. We found that both embryonic and somatic deletion of homozygous Smc3 alleles led to complete hematopoietic failure. Furthermore, in competitive transplantation, following engraftment and subsequent tamoxifen treatment, the Smc3fl/fl/ERT2-Cre+/- BM cells were rapidly outcompeted, with earliest cell loss in the Gr1+ myeloid compartment. Hence, Smc3 is indispensable for hematopoiesis and AML-associated SMC3 missense mutations are unlikely to have dominant-negative effects. We examined the consequences of somatic Smc3 haploinsufficiency using Smc3fl/+/ERT2-Cre+/-. We found that Smc3 haploinsufficiency did not lead to increased number of initial methylcellulose colonies, nor did these cells replate beyond two weeks. In competitive transplantations, we again observed a significant competitive disadvantage in the Smc3fl/+/ERT2-Cre+/- BM cells, most pronounced in the Gr1+ myeloid cells. Competitive disadvantage is counter-intuitive for a leukemia-associated mutation. SMC3 mutations frequently co-occur with DNMT3A mutations. We, therefore, asked whether Smc3 haploinsufficiency might lead to a competitive advantage if it occurred in the background of Dnmt3a haploinsufficiency. With the addition of Dnmt3a haploinsufficiency, the severe myeloid competitive disadvantage was partially ameliorated, but the significant competitive disadvantage in other lineages remained intact. In summary, our data demonstrate that homozygous Smc3 deletion was incompatible with embryonic or adult hematopoiesis, with the greatest defects noted within myeloid compartment, indicating that AML-associated SMC3 mutations are unlikely to have dominant-negative effects. Smc3 haploinsufficiency resulted in a myeloid competitive disadvantage, which was partially abrogated in the presence of concurrent Dnmt3a haploinsufficiency, suggesting lineage-specific interactions between the mutations. Citation Format: Tianjiao Wang, John S. Welch. Concurrent Dnmt3a haploinsufficiency partially abrogates competitive disadvantage in Smc3 haploinsufficient myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5095.
A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus
Authors: Bronwyn M. Gunn, Wen-Han Yu, Marcus M. Karim, Jennifer M. Brannan, Andrew S. Herbert, Anna Z. Wec, Peter J. Halfmann, Marnie L. Fusco, Sharon L. Schendel, Karthik Gangavarapu, Tyler Krause, Xiangguo Qiu, Shinhua He, Jishnu Das, Todd J. Suscovich, Jonathan Lai, Kartik Chandran, Larry Zeitlin, James E. Crowe, Douglas Lauffenburger, Yoshihiro Kawaoka, Gary P. Kobinger, Kristian G. Andersen, John M. Dye, Erica Ollmann Saphire, Galit Alter
Journal: Cell Host & Microbe (2018)
Abstract 15566: Induced Pluripotent Stem Cell-Derived Cardiomyocytes Recapitulate Clinically Observed Refractoriness to Therapeutic β-Blockade in a Patient-Specific Model of Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Marcela K Preininger, Rajneesh Jha, Qingling Wu, Monalisa Singh, Joshua T Maxwell, Bo Wang, Peter S Fischbach, Aarti Dalal, Mary B Wagner, Chunhui Xu
Journal: Circulation (2015)

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by diastolic store overload-induced Ca2+ waves during β-adrenergic receptor (β-AR) stimulation. Mysteriously, β-blockers are ineffective at abolishing stress-induced ventricular arrhythmias in ~25% of patients. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from these CPVT patients offer an attractive system for investigating the phenomenon, but it remains unknown whether iPSC-CMs can recapitulate clinically observed patient-specific drug responses. Hypothesis: This study assessed the hypothesis that patient-specific refractoriness to β-blocker therapy can be observed in vitro using CPVT iPSC-CMs. Methods: We generated iPSC-CMs from a control individual and a CPVT patient insensitive to the widely prescribed β-blocker nadolol, but responsive to flecainide, and compared the efficacy of the two drugs in vitro in diminishing diastolic Ca2+ waves and restoring Ca2+ spark parameters during β-AR stimulation. Results: In CPVT hiPSC-CMs (n = 34), β-AR agonism elicited intense diastolic Ca2+ waves and potentiated unduly frequent, large, and prolonged Ca2+ sparks compared to control iPSC-CMs (n = 12). Pursuant to the patient’s in vivo responses, nadolol-treated CPVT iPSC-CMs (n = 27) demonstrated inadequate improvement of Ca2+ handling defects during β-AR stimulation relative to flecainide-treated CPVT iPSC-CMs (n = 25). Nadolol showed no significant effect on the frequency of diastolic Ca2+ waves, but reduced mean amplitude by 50% (p &lt; 0.0001). In contrast, flecainide reduced both frequency and amplitude by 83% (p &lt; 0.001) and 72% (p &lt; 0.0001), respectively. During nadolol treatment, Ca2+ spark frequency, width, and duration remained significantly altered, while flecainide restored all Ca2+ spark parameters to baseline levels. Conclusions: Clinically observed recalcitrance to β-blocker therapy in individuals with CPVT can be modeled in vitro using patient-derived iPSC-CMs. Furthermore, the efficacy of other drugs such as flecainide can be comparatively evaluated, supporting the use of patient-specific iPSC-CMs as a clinically-relevant implement of precision medicine.
Reperfusion Causes Significant Activation of Heat Shock Transcription Factor 1 in Ischemic Rat Heart
Authors: JunichiroNishizawa, AkiraNakai, ToshioHigashi, MasakoTanabe, ShinichiNomoto, KatsuhikoMatsuda, ToshihikoBan, KazuhiroNagata
Journal: Circulation (1996)

Background The myocardial protective role of heat shock protein (HSP) has been demonstrated, and there has been increasing interest in stress response in the heart. We examined the DNA-binding activity of heat shock transcription factor (HSF), by which the transcription of heat shock genes is mainly regulated, during heat shock or ischemia/reperfusion in isolated rat heart. Methods and Results Rat hearts were isolated and perfused with Krebs-Henseleit buffer by the Langendorff method. Whole-cell extracts were prepared for gel mobility shift assay using oligonucleotides containing the heat shock element, which is present upstream of all heat shock genes. Induction of mRNAs for HSP70, HSP90, and GRP78 (glucose-regulated protein) was examined by Northern blot analysis. Although the activation of HSF during global ischemia was weak and rapidly attenuated, postischemic reperfusion induced a significant activation of HSF. In addition, although HSP70 mRNA was hardly induced during ischemia, its burst induction w...
Abstract 5142: Elevated glycolysis in pre-malignant ovarian cancer
Authors: Anna E. Lokshin, Mounia Alaoui El Azher, Liudmila Velikokhatnaya, Denise Prosser
Journal: Cancer Research (2018)

Abstract Ovarian cancer is the fifth leading cause of cancer death in women and the most lethal gynecologic malignancy. High-grade serous ovarian carcinoma (HGSC) originates mainly from the fallopian tube epithelium, and is characterized by TP53 mutation identified in all HGSCs as well as the fallopian tubal precursor of serous tubal intraepithelial carcinomas (STICs). The loss of a functional TP53 is an early event in the malignant transformation of fallopian tube epithelium. We have established 4 primary cell cultures of normal fallopian tube epithelial (FTE) cells, and further generated immortalized FTE cells using SV40 large plus small T antigens (FTE-TAg) to disrupt TP53 function. This model mimics the primary lesions of ovarian cancer and is suitable to identify biomarkers and molecular targets of ovarian cancer. Therefore, we compared the secretomes of primary FTE cells with that of their parental isogenic pairs FTE-TAg cells using mass spectrometry analysis. We identified 813 proteins, 228 of which were differentially expressed. Ingenuity Pathway Analysis (IPA) core analysis revealed glycolysis as a major canonical pathway. Overexpression of key enzymes of glycolytic pathway was confirmed by IHC in human STIC lesions. Molecular mechanisms of glycolysis regulation in premalignant lesion of ovarian cancer were determined. Role of glycolysis in the establishment of premalignant ovarian cancer microenvironment (PME) was characterized. Prevention approaches targeting glycolysis were tested in transgenic animal model of ovarian cancer. Citation Format: Anna E. Lokshin, Mounia Alaoui El Azher, Liudmila Velikokhatnaya, Denise Prosser. Elevated glycolysis in pre-malignant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5142.
Abstract 19943: International Variation in 30-day Unscheduled Cardiovascular Rehospitalization Rates Following Acute Myocardial Infarction in the Global Registry of Acute Coronary Events (GRACE)
Authors: Prashant Vaishnava, Wei Huang, Fred Anderson, David Brieger, Philippe Gabriel Steg, Joel Gore, Keith Fox, Kim Eagle
Journal: Circulation (2014)

Background: Readmission after AMI is common and costly. There is paucity of data to define international rates of 30-day readmission. We performed an analysis of the GRACE registry to characterize predictors of and international variation in readmission rates after AMI. Methods: Data were evaluated from 26,268 patients with AMI enrolled in GRACE from 14 countries between 1999 and 2007. Patients who had an unscheduled hospitalization for cardiovascular disease within 1 month of discharge were identified. Stepwise logistic regression analysis was performed to evaluate for independent predictors of 30-day readmission. In analyses adjusted for individual predictors of GRACE score and patient-level length of stay (LOS), odds ratios for readmission for each country vs. the United States were calculated. Results: 1856 patients (7.1%) were readmitted for a cardiovascular cause within 30 days. There was significant variation in unadjusted readmission rates across countries (P<0.001). There was a trend toward highe...
Abstract 1712: Assessing tumor mutation load using an NGS-based, routine-friendly target gene panel
Authors: Jose Costa, Joana Reis, Margarida Fernandes, Rafaela Silva, Luis Cirnes, Ruchi Chaudhary, Fatima Carneiro, Jose C. Machado
Journal: Cancer Research (2018)

Abstract In several cancer models, it was shown that tumor mutation load correlates with response to immune checkpoint blockade therapy. However, whole exome sequencing of FFPE samples is not ideal for implementation on molecular pathology laboratories. In colorectal cancer (CRC), mutation load is correlated with microsatellite instability (MSI), which can therefore be used as surrogate marker for mutation load. In this study, we aimed at determining whether a target NGS-based mutation panel can be used for routine testing of mutation load in cancer, by assessing its performance in identifying MSI+ and MSI- CRC samples. The Oncomine Tumor Mutation Load Assay, which targets 409 genes corresponding to 1.7Mb of sequencing data, was used. It is a two-pool panel, optimized for FFPE samples, and only requires 20 ng of DNA in total. A cohort of 16 CRC samples was used. These included six cases MSI+, known to present a hypermutable phenotype caused by the loss of DNA mismatch repair activity, and 10 MSI- samples, which typically have a lower rate of somatic mutation. DNA was isolated from 10 uM slide cuts using the MagMAX FFPE DNA/RNA Ultra Kit. A multiplex of eight samples per 540 sequencing chip was sequenced using an Ion S5 XL system. In our data set, we observed an average of 67.2 mutations per Mb for the MSI+ samples and an average of 29.7 mutations per Mb for the MSI- samples (p=0.004). Using a cut-off of 40.0 mutations per Mb, we were able to classify correctly every sample as MSI+ or MSI-. Interestingly, we observed a tri-modal distribution of the samples, suggesting there might be a sub-group of MSI+ CRC cases that show a level of mutation load comparable to that of MSI- CRC cases. It remains to be seen whether these MSI+, low mutation load CRC cases are non-responders to treatment with immunotherapy. A validation cohort of CRC cases is currently being analyzed to validate our findings. In this study, we demonstrate it is viable to use a target and routine-amenable NGS-based sequencing gene panel to identify CRC samples with different levels of mutation load. It remains to be seen whether mutation load is a better predictor of response to immunotherapy than MSI status in CRC. This approach also needs to be validated in different tumor types. Citation Format: Jose Costa, Joana Reis, Margarida Fernandes, Rafaela Silva, Luis Cirnes, Ruchi Chaudhary, Fatima Carneiro, Jose C. Machado. Assessing tumor mutation load using an NGS-based, routine-friendly target gene panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1712.
Abstract 19203: A Case of New Supraventricular Tachycardia During Pregnancy, With the Development of Post-partum Eclampsia, Torsades De Pointes, and Long Qt Syndrome: Is There a Connection?
Authors: TarakRambhatla, ArberKodra, EvanLevine, StavrosMountantonakis, KabirBhasin, NicholasSkipitaris
Journal: Circulation (2014)

Background: There is a mechanistic link between QT prolongation and the development of TdP. Women with LQTS have an increased risk of serious cardiac arrhythmias during the postpartum period,however,there is limited data on the effects of pregnancy on those without a prolonged QT prior to delivery. Case Description: The patient is a 22 y/o female with no history of arrhythmia.During pregnancy she had three episodes of SVT,each prompting hospital admissions.ECG showed a heart rate of 148-163bpm,a QTc of 390 to 410ms,and laboratory data a magnesium level of 1.6.On day 3 after a scheduled cesarean section, she suffered a eclamptic seizure and then a Tdp induced cardiac arrest.Magnesium was immediately given.CPR was performed for 31 minutes until return of spontaneous circulation was achieved.The patient had an extended ICU course but was eventually discharged home with her newborn twins,a subcutaneous implantable cardiac defibrillator (S-ICD),multiple postpartum ECGs showing QTc of 493 to 524ms,and a diagnos...
Abstract 14608: Non-Invasive Derivation of Resting Coronary Artery Flow Directly From CT Angiography (CTA) via the Transluminal Attenuation Gradient (TAG) in Left- versus Right-Dominant Circulation
Authors: DImitrios Mitsouras, Rani Sewatkar, Andreas A Giannopoulos, Mukta Agrawal, Elizabeth George, Michael K Cheezum, Sujata Shanbhag, Ron Blankstein, Marcus Y Chen, Frank J Rybicki
Journal: Circulation (2015)

Introduction: The TAG characterizes the dropoff in CTA contrast enhancement along the length of a vessel. It can detect functionally significant CAD without additional CTA radiation or computation. However, its relationship to flow is not established. Hypothesis: We sought to establish how TAG relates to previously-reported values of coronary flow. Materials and Methods: TAG was measured in the 3 major coronary arteries (LAD,LCX,RCA) of 42 patients (35 right- [RD], 7 left/co-dominant [LD]) with &lt;25% stenosis imaged with single heart-beat 320-row CT. TAG was adjusted for scan kVp based on the relationship of iodine concentration vs blood HU. First, the ratio of TAG in each artery for RD vs LD arteries was compared to that of invasively-measured flow reported in n=496 patients (PREDICTION trial, Sakamoto et al, Am J Cardiol 2013;111:1420). Second, in 34 patients with CTA bolus tracking images available, the rate at which contrast was increasing at CTA (ie, HU increase/sec) was measured as a linear fit of descending aortic attenuation in the tracking images vs time to calculate flow via the following theoretical relationship we derived for TAG and flow (Figure): Q[ml/sec]~Lumen Area[cm^2]*Contrast inflow slope[HU/sec]/TAG[HU/cm]. Lumen area was determined for the arterial length used for TAG measurement. Results: TAG LD-to-RD ratios were within 2%, 6% and 30% of flow ratios in the LAD, LCX and RCA respectively (Table). LAD and LCX flow derived from TAG was within 4-16% of reported flow; RCA flow was over-/underestimated by 51%/20% in RD/LD patients, respectively (Table). Conclusion: TAG in non-stenotic coronaries is related to resting coronary flow. Knowledge of the temporal change of inflowing contrast concentration enables derivation of reasonable values of coronary flow from CTA using the TAG. This is a critical step toward obtaining the flow boundary conditions for FFR-CT techniques to non-invasively detect functionally significant CAD.
Abstract 3844: TAK-659, a SYK kinase inhibitor, demonstrates preclinical antitumor activity in solid tumor models
Authors: Jessica J. Sappal, Matthew Theisen, Zhongmin Xiang, Stephen Tirrell, Rudy Christmas, Jie Yu, Mengkun Zhang, Karuppiah Kannan
Journal: Cancer Research (2018)

Abstract TAK-659 is a highly potent, reversible inhibitor of spleen tyrosine kinase (SYK) and fms related tyrosine kinase 3 (FLT3) that is currently being investigated in Phase I and II clinical trials. SYK is expressed ubiquitously in hematopoietic cells, and abnormal function of SYK has been implicated in several types of hematopoietic malignancies, including diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and peripheral T-cell lymphoma (PTCL). Although there are considerable data supporting a role for SYK signaling in hematological cancers, data on the relevance of SYK in solid tumors are emerging. The literature suggests that SYK expression plays a role in the growth of breast and ovarian cancers, and the pancreatic adenocarcinoma microenvironment has been shown to be B-cell rich, giving us a basis to explore the activity of TAK-659 in these indications. Furthermore, ovarian cancer patients with recurrent disease have been shown to have an increase in pSYK at the time of relapse versus at diagnosis, suggesting a role for SYK in chemoresistance. The ability of TAK-659 to inhibit ex vivo colony formation of cells with the ability to grow anchorage independently in semi-solid medium was examined in 31 different human tumor xenografts. TAK-659 showed concentration-dependent inhibition of tumor colony growth in 5/31 tumor models tested, including gastric, breast, and ovarian cancers. Pre-clinically, TAK-659 has exhibited significant antitumor activity in a number of mouse xenograft models of solid tumors. We demonstrate here that daily oral administration of TAK-659 at 60mg/kg over 21 days leads to significant antitumor activity in primary human tumor models of gastric, pancreatic, triple negative breast (TNBC), and ovarian cancers, all of which express pSYK. Significant anti-tumor activity was also observed in the HCC70 TNBC xenograft model which does not express total SYK, demonstrating that TAK-659 may have anti-tumor effects beyond the inhibition of pSYK signaling. A decrease in myeloid derived suppressor cells was seen following TAK-659 treatment in this xenograft model, suggesting an immunomodulatory response may be driving the antitumor activity. Taken together, these data along with published information support the rationale for the investigation of TAK-659 in solid tumor cancer indications. Citation Format: Jessica J. Sappal, Matthew Theisen, Zhongmin Xiang, Stephen Tirrell, Rudy Christmas, Jie Yu, Mengkun Zhang, Karuppiah Kannan. TAK-659, a SYK kinase inhibitor, demonstrates preclinical antitumor activity in solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3844.