tbuckley/cabot-search huggingface dataset:
Abstract 12086: Relationship of Cardiac Rhythm and Other Electrocardiogram Findings with Sites of Wall Thickening and Abnormal Late Enhancement in Patients with Confirmed Cardiac Amyloidosis
Authors: Nobusada Funabashi, Kohki Nakamura, takehio sasaki, Shigeto Naito, Yoshio Kobayashi
Journal: Circulation (2021)

Introduction: Left ventricular (LV) wall thickening and diastolic dysfunction on TTE without high voltage R wave on ECG to a diagnosis of cardiac amyloidosis (CA). However, amyloid sometimes invade right ventricle (RV), and left (LA) and right (RA) atria to cause ECG changes such as sick sinus syndrome (SSS), arrhythmia, and QRS axis deviation. Hypothesis: We hypothesized that sites of wall thickening and abnormal late enhancement (LE) on cardiac CT and MRI, suggesting amyloid invasion, correlated with cardiac rhythm and other ECG findings in patients with CA confirmed by biopsy. Methods: 26 patients (11 females) with suspected CA, showing LV wall thickening by TTE without a high voltage R wave, underwent cardiac CT. 5 patients (3 females, mean 73 years) were diagnosed with CA: complicated multiple myeloma, 2; senile ATTR (transthyretin) amyloidosis, 1; immunoglobulin light chain amyloidosis 1; and transthyretin mutation, 1. 4 patients underwent cardiac MRI. Results: 2 patients (cases 1 and 2) had SSS (junctional rhythm), 1 had atrial tachycardia, and the remaining 2 (cases 4 and 5) had a normal sinus rhythm. In case 1, ECG showed a left QRS axis deviation, no low voltage R wave and a mild LA load. Wall thickening in basal interventricular septum (IVS), LV inferior-posterior wall, LA on CT, LE in endocardium in whole LV, RV, and RA on CT, and LE in endocardium in whole LV, RV, LA, and IVS on MRI were observed. In case 2, ECG showed a normal QRS axis, no low voltage R wave, no LA load, wall thickening in whole LV, RV, LA, and IVS on CT, and unclear (CT) or no (MRI) LE. In case 3, ECG showed a normal QRS axis, with low voltage R wave, no LA load, wall thickening in LA and basal IVS on CT, LE in LA and basal IVS on CT, and LE in LA only on MRI. In case 4, ECG showed left QRS axis deviation, a low voltage R wave, and no LA load, wall thickening in LA and RV on CT, unclear LE on CT, and LE in whole LV, endocardium in RV, and whole IVS on MRI. In case 5, ECG showed a right QRS axis deviation, low voltage R wave, and a mild LA load, wall thickening in IVS, LV lateral wall, LV anterior wall, RA, RV outflow tract, and RA appendage, and no LE on CT (MRI not performed). Conclusions: The presence of wall thickening and abnormal LE in RV, LA, and RA in addition to LV on CT or MRI would be important which may influence ECG changes in patients with CA.
Abstract 11568: The Role of the Microbiome in the Improved Exercise Performance in the Regulator of G Protein Signaling 14 (rgs14) Knock Out (KO) Mice
Authors: Sara C Campbell, Marko Oydanich, Jie Zhang, Candace R Longoria, Olufunmilola Ibironke, Dorothy E Vatner, David P Siderovski, Stephen F Vatner
Journal: Circulation (2021)

The Regulator of G Protein Signaling 14 knockout (RGS14 KO) mouse strain has a unique brown adipose tissue (BAT) mechanism mediating its phenotype of healthful longevity and improved exercise performance. RGS14 KO mice demonstrated a 51 ± 8% increase in treadmill running distance before exhaustion and a 44 ± 7% increase in work to exhaustion compared to their wild type littermates (WTLs). Three days after BAT transplantation from RGS14 KO mice to WTL mice, the RGS14 KO BAT donor mice lost their enhanced exercise capacity, whereas it was gained in the WTL BAT recipients: their running distance and work to exhaustion rose by 46 ± 5% and 52 ± 7%, respectively. In contrast, when BAT was transplanted to WTL mice from other WTL mice, exercise capacity did not increase at 3 days after transplantation, but was only seen after 2 months post-transplantation. Based on these observations, our hypothesis was that the unique characteristics of RGS14 KO BAT, in inducing enhanced exercise capacity upon transplantation, are mediated by novel gene upregulation within the BAT, as well as potential interactions between the BAT and the microbiome. We found that RGS14 KO mice harbor two unique, health-beneficial strains of Akkermansia muciniphilia ( A. muciniphilia BIOML-A22 and A. muciniphilia AN78) in their gut and their BAT has a number of novel genes upregulated, including Lnpep (leucyl/cystinyl aminopeptidase), TFAM (transcription factor A, mitochondrial), and Lncbate10, the latter being a critical regulator of BAT differentiation. To address directly the role of the microbiome, the mice were treated with antibiotics for 1 week. Although WTL exercise capacity was not significantly different before and after antibiotic-induced microbiota clearance, the RGS14 KO mice lost their enhanced exercise capacity after antibiotic treatment: RGS14 KO running distance fell by 35 ± 7%, and work to exhaustion fell by 41 ± 7%. Thus, RGS14 KO BAT engages changes to resident commensal microbiota that are beneficial to exercise capacity and therefore represents a potential (and novel) therapeutic modality for improving exercise performance and for creating healthful longevity.
Abstract 13937: The Association Between Left Ventricular End-Diastolic Diameter and Long-Term Mortality in Patients With Coronary Artery Disease
Authors: Qiang Li, Jin Liu, Haozhang Huang, Weihua Chen, Shanshan Shi, Shiqun Chen, Yong Liu
Journal: Circulation (2021)

Background: Left ventricular end-diastolic diameter (LVEDD) is a common indicator in echocardiogram, and increased LVEDD is correlated with left ventricular (LV) insufficiency. However, the relationship between LVEDD and mortality in patients with coronary artery disease (CAD) is uncertain. Methods: This study enrolled 33,147 patients with CAD who had undergone transthoracic echocardiography between January 2007 and December 2018 in Cardiorenal Improvement (CIN) study (ClinicalTrials.gov NCT04407936). These patients were divided into four groups according to the quartile of LVEDD (Quartile 1: LVEDD≤43 mm, Quartile 2: 43&lt;LVEDD≤46 mm, Quartile 3: 46&lt;LVEDD≤51 mm, Quartile 4: LVEDD&gt;51 mm) and were categorized into two groups (Quartile 1-3 versus Quartile 4). Survival curves were generated with the Kaplan-Meier method. The restricted cubic splines and cox proportional hazards models were used to investigate the association with LVEDD and all-cause mortality. Results: In our study, there were a total of 33,147 patients, whose average age was 63.0±10.6 years and 24.01% of them were female. In the average follow-up period of 5.2 years, a totally of 4,288 patients died. After adjusting for confounding factors, patients with the larger LVEDD (Quartile 4) remain had a 1.19-fold risk for all-cause mortality (95% confidence interval: 1.09 to 1.30) compared with the lower quartile (Quartile 1-3). Conclusions: Enlarged LVEDD was an independent predictor of all-cause mortality in patients with CAD. LVEDD measurements may be helpful for risk stratification and providing therapeutic direction for the management of CAD patients.
CBIO-06. CELL INTRINSIC HFE DRIVES SEX-SPECIFIC GLIOBLASTOMA GROWTH
Authors: Katie M Troike, Erin E Mulkearns-Hubert, Daniel J Silver, James Connor, Justin Lathia
Journal: Neuro-Oncology (2021)

Abstract Iron is an essential element required for a number of cellular processes and can contribute to malignant transformation and tumor expansion. In glioblastoma (GBM), tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving proliferation and tumor growth. The homeostatic iron regulatory (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by modulating iron uptake and release. HFE is upregulated in GBM tumors compared to non-tumor brain and expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. However, it is unclear how HFE impacts sex-specific GBM growth. To interrogate the underlying mechanism of HFE-mediated sex differences, we employed genetic loss and gain of function approaches using syngeneic mouse glioma models. We observed significant alterations in the expression of several iron-associated genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. We found that knockdown of Hfe decreased cell number and increased apoptosis in vitro and led to a significant impairment of tumor growth in vivo, with a more pronounced effect seen in female mice. Conversely, overexpression of Hfe increased cell number and significantly decreased survival only in female animals. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression in a sex-dependent manner. These data also suggest an unexplored link between cell intrinsic iron signaling and sex-specific microenvironmental and immune responses, which is the focus of ongoing studies.
Tolinapant (ASTX660), a Non-Peptidomimetic Antagonist of cIAP1/2 and XIAP, and the HDAC Inhibitor Romidepsin Are Synergistic in <i>in Vitro</i> Models of T Cell Lymphoma
Authors: John S Manavalan, Ipsita Pal, Aidan Pursley, George A. Ward, Tomoko Smyth, Martin Sims, David J Feith, Thomas P. Loughran, Owen A. O'Connor, Enrica Marchi
Journal: Blood (2021)
Abstract 11766: Late Gestation Fetal Oxygenation is Associated With Birthweight and Head Circumference in Patients With Cyanotic Congenital Heart Disease
Authors: Liqun Sun, Fu-tsuen Lee, Joshua F van Ameron, Sharon Portnoy, Jessie M Lim, Brahmdeep S Saini, Edgar Jaeggi, John C Kingdom, Christopher K Macgowan, Steven P Miller, Mike Seed
Journal: Circulation (2021)

Introduction: Abnormal fetal growth and development are evident in patients with cyanotic congenital heart disease (cCHD). However, the relationship between growth and fetal oxygenation is unknown. We sought to investigate the relationship between fetal hemodynamics and fetal growth in cCHD using fetal cardiovascular Magnetic Resonance Imaging (MRI). Hypothesis: The impaired fetal oxygenation would be associated with diminished fetal brain and body growth in cCHD. Methods: We performed a prospective observational study in fetuses diagnosed with cCHD at our institution from June 2010 to January 2020. Late-gestational fetal cardiovascular MRI was performed in 152 fetuses with cCHD to assess fetal blood flow (phase-contrast MRI) and oxygen saturation (T2 oximetry) in the major fetal vessels to calculate oxygen delivery to the brain and body according to our previously published techniques. Results are provided as medians with IQR and compared with 30 gestational age-matched normal controls using Mann-Whitney U test. A Pearson’s correlation was used to examine the relationships between variables. Results: Compared with normal controls, fetuses with cCHD had significantly reduced birth weight Z-scores [-0.41 (-0.29, 0.84) vs. -0.19 (-0.46, 0.37), p = 0.03], and neonatal head circumference Z-scores [0.1 (-1.75, 0.95) vs. 0.69 (0.1, 1.79), p = 0.003]. As a combined cohort, birthweight Z-score was correlated with fetal oxygen delivery (r = 0.33, p = 0.003), umbilical vein flow (r = 0.2, p = 0.006) and oxygen saturation (r = 0.25, p = 0.02). Birth head circumference Z-score was correlated with fetal cerebral oxygen delivery (r = 0.33, p = 0.01) and ascending aorta oxygen saturation (r = 0.33, p = 0.009). We also found an inverse relationship between ascending aorta oxygen saturation and superior vena cava flow (r = -0.24, p = 0.036). Conclusions: In conclusion, we observed associations between placental function in late gestation and birthweight, as well as cerebral oxygen delivery in utero and head circumference at birth. Our findings are in keeping with the concept that cCHD impacts fetal development through abnormal circulatory physiology and placental function.
Quantitative Trait of Neutrophil Count Is Influenced By Variants in the Region of <i>Gsdma</i> and <i>PSMD3-CSF3, a</i>ging, Cardiometabolic Comorbidities but Not By Chip
Authors: Marie-France Gagnon, Sylvie Provost, Sami Ayachi, Manuel Buscarlet, Luigina Mollica, Marie-Pierre Dubé, Lambert Busque
Journal: Blood (2021)
Single-Agent Rituximab and Ultra-Low-Dose Adaptive Radiotherapy for the Treatment of Indolent Non-Hodgkin Lymphoma
Authors: Meredith Jackson, Sean All, Samantha Brocklehurst, Neil B Desai, Jennifer L Shah, Syed M Rizvi, Farrukh T. Awan, Praveen Ramakrishnan Geethakumari, Kiran A Kumar
Journal: Blood (2021)
Errors in Relative Risks Reported in Figure 3 in a Network Meta-analysis of Cognitive Behavior Therapy Delivery Formats in Adults With Depression
Authors: Pim Cuijpers, Hisashi Noma, Toshi A. Furukawa
Journal: JAMA Psychiatry (2021)

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Abstract 10501: Clinical Outcomes After Transcatheter Edge-to-Edge Repair of the Mitral Valve with the Mitraclip <sup>TM</sup> System in Cancer Survivors
Authors: Nikhil Agrawal, Kevin Lin, Lucas Battel, Enrique Garcia-Sayan, Juan Lopez-Mattei, Salman A Arain, Konstantinos Charitakis, Cezar Iliescu, Richard W Smalling, Abhijeet Dhoble
Journal: Circulation (2021)

Introduction: Valvular diseases, especially Mitral regurgitation (MR) confer a high cardiovascular burden in cancer survivors. Transcatheter Edge-to-Edge Repair (TEER) with the MitraClip TM system has shown promising results in the management of severe MR regardless of etiology. However, little is known about the impact of cancer history on patient outcomes. Methods: We studied 456 consecutive patients (cancer: 86; non-cancer: 370) with severe mitral regurgitation who underwent mitral valve TEER at our institution from 2005 to 2020. In addition to pre-and post-procedural characteristics, we examined imaging parameters and outcome data including all-cause mortality. We used Cox regression analysis to identify factors associated with mortality. Results: Patients were followed for a mean of 9.2 months (SD 19). Table 1 shows the baseline and follow-up characteristics for both groups. At 1-year follow-up, only 4 (5%) cancer survivors and 23 (6%) non-cancer patients had died. In a Cox regression analysis, short-term (&lt;90 days) and long-term (1 year) mortality were similar in both cohorts (HR 0.8 and 1.2, respectively; p&gt;0.05). Age and sex were also not significantly associated with mortality (p&gt;0.05). In subgroup analyses, at 1-year follow-up, cancer survivors who had received prior radiation therapy were more likely to have died (11% vs 0; X2=5.07, p=0.024) and cancer survivors with solid tumors were more likely to have an NYHA functional class III-IV at 1-year follow-up than those with hematologic malignancies (X2=4.75, p=0.029). Conclusions: In this large retrospective study, short- and long-term all-cause mortality after mitral valve TEER were similar in both cancer survivors and non-cancer patients. Prior radiation therapy and history of solid tumors may be poor prognostic markers.
Abstract 10838: Impact of Diabetes on Soluble Fms-Like Tyrosine Kinase-1 and Cardiovascular Events in Patients with Suspected or Known Coronary Artery Disease: The EXCEED-J Study
Authors: Hiromichi Wada, Tsuyoshi Shinozaki, Masahiro Suzuki, Satoru Sakagami, Junichi Funada, Morihiro Matsuda, Masatoshi Shimizu, Takashi Takenaka, Yukiko Morita, Kazuya Yonezawa, Hiromi Matsubara, Yujiro Ono, Toshihiro Nakamura, Kazuteru Fujimoto, Akiyo Ninomiya, Toru Kato, Takashi Unoki, Daisuke Takagi, Kyohma Wada, Moritake Iguchi, Kazuhiko Kotani, Mitsuru Abe, Masaharu Akao, Koji Hasegawa
Journal: Circulation (2021)

Background: Whether diabetes mellitus (DM) modifies the relationship between soluble fms-like tyrosine kinase-1 (sFlt-1), a vascular endothelial growth factor (VEGF) antagonist, and cardiovascular (CV) events in patients with suspected or known coronary artery disease (CAD) are unclear. Methods: Using data from a multicenter, prospective cohort of 3255 patients with suspected or known CAD undergoing elective coronary angiography, we assessed the impact of DM on the prognostic values of sFlt-1 and other biomarkers. Heparin-free fasting serum levels of sFlt-1, VEGF, placental growth factor, cystatin C, N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), and high-sensitivity C-reactive protein (hs-CRP) were measured in 1281 DM and 1974 non-DM patients enrolled in the EXCEED-J study. The primary outcome was 3-point major adverse CV events (3P-MACE) defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, CV death, and 5P-MACE defined as a composite of 3P-MACE, heart failure hospitalization, and coronary/peripheral artery revascularization. Results: After adjusting for potential clinical confounders, serum levels of sFlt-1, NT-proBNP, hs-cTnI and cystatin C, but not other biomarkers, were significantly associated with 3P-MACE in the entire cohort. These associations were still significant for sFlt-1, NT-proBNP, and hs-cTnI, but not for cystatin C, in non-DM patients. In contrast, NT-proBNP, hs-cTnI and cystatin C, but not sFlt-1, were significantly associated with 3P-MACE in DM patients. The sFlt-1 level was also significantly associated with all-cause death and CV death in the entire cohort and in non-DM patients, but not in DM patients. It was not significantly associated with 5P-MACE in the entire cohort, non-DM patients, or DM patients. Furthermore, sFlt-1 provided an incremental prognostic information for 3P-MACE and CV death to the model with potential clinical confounders in non-DM patients, but not in DM patients. Conclusions: Serum levels of sFlt-1 were independently associated with 3P-MACE and CV death in patients with suspected or known CAD. These associations were attenuated in DM patients.
Expression of CD20 Affects Early MRD Response to Rituximab in Adult B Cell Precursor Lymphoblastic Leukemia of the GMALL 08/2013 Trial
Authors: Monika Szczepanowski, Johanna Richter, Miriam Kelm, Heiko Trautmann, Britta Kehden, Matthias Ritgen, Christoph Faul, Kathrin Nachtkamp, Björn Steffen, Andreas Viardot, Johannes Gärtner, Johannes Duell, Claudia D. Baldus, Stefan Schwartz, Nicola Goekbuget, Monika Brüggemann
Journal: Blood (2021)
Abstract 10392: Association of Frailty with Incident Heart Failure with Preserved and Reduced Ejection Fraction in Late Life: The Aric Study
Authors: Diego Ramonfaur, Hicham Skali, Dalane W Kitzman, Priya Palta, Chiadi E Ndumele, Brian Claggett, Suma H Konety, Amil M Shah
Journal: Circulation (2021)

Introduction: The incidence and prevalence of both frailty and heart failure (HF) are greatest in late life, and both have been associated with inflammation and markers of myocardial injury. While frailty is cross-sectionally associated with HF, the association of frailty with incident HF, and HF with preserved (HFpEF) or reduced ejection fraction (HFrEF) is unclear. Methods: Among 5,517 participants in the Atherosclerosis Risk in Communities study with frailty assessment and free of HF at Visit 5 (2011-2013), frailty was ascertained using information on weight loss, low grip strength, exhaustion, low energy expenditure and slow gait. Frail was defined as the presence of &gt; 3 frailty components, pre-frail as 1-2 components, and robust as 0 components. HF was ascertained through adjudication of hospitalizations with related ICD codes. Multivariable Cox proportional hazard models were used to evaluate the association of frailty status at Visit 5 with incident HF overall, HFpEF (LVEF ≥50%), and HFrEF (LVEF &lt;50%). Models were adjusted for age, race, gender, BMI, GFR, and history of stroke, MI, atrial fibrillation, hypertension and diabetes mellitus. Results: Mean age was 75 +/- 5 years, 58% were female, and 22% were Black. Forty-six percent were classified as robust, 48% as pre-frail, and 6% frail. Frail participants were older and had a higher prevalence of cardiovascular co-morbidities. Over a median follow-up of 7.1 (IQR 5.5-7.8) years, 525 participants developed incident HF (249 HFpEF, 209 HFrEF, 67 HF with unknown LVEF). Both pre-frailty and frailty were associated with heightened risk of incident HF compared to robust participants (Figure). The magnitude of risk associated with frailty status was similar for both HFpEF and HFrEF. Conclusions: Pre-frailty and frailty are both associated with heightened risk of incident HF in late life, independent of traditional cardiovascular risk factors. These associations are similar in magnitude for HFpEF and HFrEF.
DDRE-14. OPTIMIZING MDM2 INHIBITION FOR THE TREATMENT OF HIGH-GRADE GLIOMA
Authors: Veronica Rendo, Leslie Lupien, Nicholas Khuu, Kristine Pelton, Lara Elcavage, Sophie Lu, Prasidda Khadka, Jaldeep Langhnoja, Tim Phoenix, Keith Ligon, Pratiti Bandopadhayay, Rameen Beroukhim
Journal: Neuro-Oncology (2021)

Abstract A majority of high grade gliomas retain a wild-type TP53 gene and are amenable to strategies for activation of the pathway to inhibit tumor growth. The interaction between p53 and MDM2 has served as target for such strategies currently in clinical trials for glioblastoma. As the effects and resistance mechanisms of MDM2 inhibition (MDM2i) remain poorly understood in glioma, we performed genomic and transcriptomic analyses in patient-derived models to better characterize sensitive tumors and identify putative biomarkers of drug response. Treatment with an MDM2 inhibitor (KRT232/AMG232) impaired the growth of cell lines with wild-type TP53 status, particularly in tumors with amplification of MDM2/4 or PPM1D activating mutations. Treatment with KRT232 upregulated both cell cycle arrest and apoptotic cellular responses, with unique temporal and transcriptional differences correlated with MDM2/4 or PPM1D status. In other tumors resistance to MDM2i is mainly mediated by TP53 mutations, but in a subset of chronic KRT232-treated glioma models we noted lack of TP53 mutations and identified cell state and transcriptional changes as potentially more treatable mediators of resistance.