tbuckley/cabot-search huggingface dataset:
Abstract 13810: Diabetes versus Cardiovascular Mortality in the Context of Food Insecurity Among United States Adults
Authors: Srikanta K Banerjee, Patrick Dunn
Journal: Circulation (2021)

Food insecurity has become an important global concern with close associations with cardiovascular disease. However, how food insecurity affects individuals with long-term diabetes is currently unknown. In this study, we assessed the hypothesis that positive diabetes history modifies the effect of food insecurity on cardiovascular disease (CVD) mortality. We analyzed data on adults (≥ 20 years) from the 1999-2010 National Health and Nutrition Examination Survey, with mortality data obtained through 2015. The causes of death for adults (N=4037) were defined using the International Classification of Disease coding (ICD-10). Complex Samples Cox regression was used to assess if diabetes status modified the relationship between food insecurity and CVD-mortality. During a 11.1-year follow-up, among adults with diabetes, 184 individuals died (15%). The hazard ratio (HR) for CVD-mortality among adults with food insecurity compared with adults without food insecurity, with adjustment for age and gender only, was 1.66; 95% confidence interval [CI: 1.26, 2.20]. The adjusted HR was elevated, 2.13 (CI 1.30-3.48, p &lt; 0.05), among adults with diabetes and food insecurity but close to 1.0 (1.57 CI 0.97-2.54, p = 0.07) among adults with only food insecurity after the results were controlled for medical risk factors (chronic kidney disease (CKD) and obesity) and demographic risk factors (age, gender, ethnicity, education). In conclusion, individuals who are food-insecure and have diabetes have a higher probability of death from cardiovascular disease in long-term follow-up than those individuals without diabetes. Risk scoring and CVD prevention strategies should include screening and surveillance for food insecurity status. Comprehensive and interdisciplinary approaches to reducing cardiovascular disease-related disparities and health risks should be implemented through equity research.
Updates in HER2-Positive and Triple-Negative Breast Cancers
Authors: Melinda L. Telli, William J. Gradishar
Journal: Journal of the National Comprehensive Cancer Network (2021)

The recent approval of 4 agents for the treatment of patients with metastatic HER2-positive breast cancer has led to expanded recommendations in the NCCN Guidelines for treatment of this disease. For triple-negative disease, immunotherapy continues to gain traction in this challenging subtype, both in the preoperative and metastatic settings, though not yet as adjuvant treatment. Sacituzumab govitecan is another new agent with strong utility in triple-negative disease, and PARP inhibitors are recommended options in BRCA -mutated disease.
Abstract 13974: Mitochondrial Chaperonin CLPB Determines MICU1 Protein Turnover and Mitochondrial Calcium Overload in Ischemia-Reperfusion Injury
Authors: Dhanendra Tomar, Ryan McGregor, pooja jadiya, Alycia Hildebrand, John W Elrod
Journal: Circulation (2021)

Background: Mitochondrial calcium uptake 1 protein (MICU1) fine-tunes mitochondrial calcium ( m Ca 2+ ) uptake across the inner mitochondrial membrane (IMM) by regulating the open probability of the mitochondrial calcium uniporter channel complex (mtCU). The loss of MICU1 is associated with numerous chronic disease states and contributes to mitochondrial calcium overload. Here we report that in response to hypoxia, MICU1 protein turnover is higher compared to all other mtCU components, suggesting a dynamically regulated post-translational system controls MICU1 expression. Methods: Biotin-based proximity labeling and liquid chromatography- mass spectrometry proteomics, protein biochemistry, live-cell Ca 2+ imaging, confocal and super-resolution imaging, CRISPR/Cas9 based gene editing, AAV9 based gene delivery, and mouse left coronary artery ligation for myocardial ischemia-reperfusion (IR) injury were utilized to discern the role of CLPB in MICU1 turnover, m Ca 2+ overload, and IR injury. Results and Conclusions: To identify the components regulating MICU1 protein turnover, we performed an unbiased proteomics screen utilizing MICU1 fused to BioID2, a biotinylation proximity labeling strategy combined with avidin-based isolation and mass spectrometry. We identified caseinolytic peptidase B protein homolog (CLPB), a mitochondrial chaperonin/disaggregase, as a potential determinant of the MICU1 protein turnover. We confirmed that CLPB lacks proteolytic activity using in vitro protein degradation assays. Next, to identify the CLPB partner protease, we performed a subsequent BIOID2 screen of the CLPB interactome. We identified that in response to hypoxia, the intermembrane space (IMS) localized protease YME1L was necessary for MICU1 protein turnover. Subsequent experiments suggest that CLPB regulated MICU1 protein turnover is a critical molecular event in the onset of cell death in the context of cardiac injury. As knockdown of CLPB is sufficient to decrease infarct size and protect against cardiac ischemia reperfusion injury in mice. In conclusion, we detail a previously unknown protein-quality control system regulating MICU1 and influencing mitochondrial calcium uptake and downstream cellular events.
Multivalent network modifier upregulates bioactivity of multispecies biofilm-resistant polyalkenoate cement
Authors: Ji-Yeong Kim, Woojin Choi, Utkarsh Mangal, Ji-Young Seo, Tae-Yun Kang, Joohee Lee, Taeho Kim, Jung-Yul Cha, Kee-Joon Lee, Kwang-Mahn Kim, Jin-Man Kim, Dohyun Kim, Jae-Sung Kwon, Jinkee Hong, Sung-Hwan Choi
Journal: Bioactive Materials (2021)

Polyalkenoate cement (PAC) is a promising material for regenerative hard tissue therapy. The ionically rich glass component of PAC encourages bioactive interaction via. the release of essential ions. However, PAC bioactivity is restricted owing to (i) structurally inherent cationic network formers and (ii) surface bacterial biofilm formation. These two factors cause a deficiency in ion release, further complicated by secondary infections and premature therapeutic failure. Here, a multivalent zwitterionic network modifier (mZM) is presented for upregulation of ionic exchange and bioactivity enhancement. By introducing a non-zero charged mZM into PACs, an increase in the proportion of non-bridging oxygen occurs. The network modification promotes ion channel formation, causing a multiple-fold increase in ion release and surface deposition of hydroxy-carbonate apatite (ca. 74%). Experiments ex vivo and animal models also demonstrate the efficient remineralization ability of the mZM. Furthermore, divalent cationic interaction results in bacterial biofilm reduction (ca. 68%) while also influencing a shift in the biofilm species composition, which favors commensal growth. Therefore, PAC modification with mZM offers a promising solution for upregulation of bioactivity, even aiding in customization by targeting site-specific regenerative therapy in future applications.
Abstract 12204: Factor Xa Inhibitors but Not Vitamin K Antagonists Are Associated With Lower Risk of Mortality After Index Peripheral Endovascular Intervention
Authors: Stanislav Henkin, Barbara Gladders, Michael Young, Philip P Goodney
Journal: Circulation (2021)

Introduction: Peripheral endovascular intervention (PVI) has become more common than surgical bypass for patients with peripheral artery disease (PAD). While low-dose rivaroxaban is associated with lower risk of major adverse limb events, full-dose anticoagulation may be necessary for other indications. Hypothesis: We hypothesized that, compared to Vitamin K antagonists, Factor Xa inhibitors are associated with lower risk of adverse events after PVI. Methods: We analyzed patients who underwent index PVI in the Vascular Quality Initiative (2010-2016) and linked outcomes to Medicare claims data. Using multivariable regression modeling, we then examined the association between discharge anticoagulation and prespecified outcomes (all-cause mortality, re-intervention, lower limb amputation). Results: Among 10,165 patients undergoing PVI, 1497 (14.7%: 11.7% Vitamin K antagonist, 1.3% Factor Xa inhibitors, 1.7% other anticoagulant) were discharged on an anticoagulant. Patients on an anticoagulant were older and more medically complex (e.g. coronary artery disease, congestive heart failure, diabetes); more likely to undergo urgent/emergent procedure with infrapopliteal treatment; and more likely to be discharged without an antiplatelet agent. Anticoagulation was associated with significantly higher risk of mortality (OR 1.8, 95% CI 1.2-2.1, p&lt;0.001) and amputation (OR 1.4, 95% CI 1.2-1.6). In multivariate regression modeling, Factor Xa inhibitors were associated with lower risk of death (OR 0.61, 95% 0.39-0.95), while Vitamin K antagonists were associated with higher risk of death (OR 1.28, 95% CI 1.1-1.5). Similar trends were observed for re-intervention and lower limb amputation, although not statistically significant. Conclusions: Compared to Vitamin K antagonists, the use of Factor Xa inhibitors post-PVI is associated with lower risk of death. Further studies are necessary to evaluate the mechanism of this effect.
Abstract 13548: Ventricular Tachycardia: National Trends Among Young: A Public Health Alert
Authors: Harsh P Patel, Samarthkumar J Thakkar, Rezwan Munshi, Mohammed Faisaluddin, Ashish Kumar, Tikal Kansara, Sarju Ganatra, Mohan Rao, Christopher V Desimone, Abhishek Deshmukh, Sourbha Dani
Journal: Circulation (2021)

Introduction: In the last two decades, risk factors, prevalence, and mortality due to coronary artery disease in young adults is on the rise. Hypothesis: Assess the prevalence, trends, and economic burden of ventricular tachycardia (VT) in young adults (18-44 years). Methods: The Nationwide Inpatient Sample was explored for hospitalizations with VT in patients (Age 19-44) between 2005-2018 and divided among 3 groups of the quadrennial period using validated ICD-9 and ICD-10 CM codes. The Pearson chi-square test and Student’s t-test were used for categorical and continuous variables, respectively. We assessed the temporal trends of mortality in VT as well as trends of VT stratified by age, sex, and race by the linear-by-linear association test (Figure 1). Results: Out of 5,156,326 patients were admitted with VT between 2005-2018, 309,636 were in young adults. Among them, 102,433 were admitted between 2005-2009 (mean age 36.1±6.99; 61% male, 58.5% white), 109,591 between 2010-2014 (mean age 35.5±7.16; 59% male, 54.2% white), and 97,495 between 2015-2018 (mean age 35.4±7.00; 60% male, 52.3% white) (p&lt;0.0001). In the young adults with VT, all-cause mortality was 7.37% from 2005-2009, 7.85% from 2010-2014 (6.5% relative increase from 2005-2009), and 8.98% from 2015-2018 (relative increase of 14.4% from 2010-2014) (p&lt;0.0001). Inflation adjusted cost increased over the years [$12,177 in 2005-2009; $13,249 in 2010-2014; $15,807 in 2015-2018; p&lt;0.0001)]. Conclusions: The prevalence of VT in young individuals is rising. VT-related mortality and healthcare utilization costs are on the rise in the study period. VT burden and poor outcomes were notable for Black males. Further studies are required for targeted screening and preventative measures in young adults.
Abstract 10052: Trends and Outcomes of Ischemic Stroke After Transcatheter Aortic Valve Implantation, a US National Propensity Matched Analysis
Authors: Salman Zahid, Muhammad Atif Khan, Arslan Inayat, AAMER UBAID, Hamza Zahid Ullah Muhammadzai, Devesh Rai, Mian Tanveer Ud Din, Fnu Salman, Chadi Alraies, Mahboob Alam, David L Fischman, Mohan Rao, bipul baibhav, Jeremiah Depta, Sudarshan balla
Journal: Circulation (2021)

Introduction: Contemporary data on stroke predictors and outcomes in patients undergoing transcatheter aortic valve implantation (TAVI) remains limited. Hypothesis: Patients who develop a stroke while undergoing TAVI have increased in-hospital mortality and adverse events. Methods: We analyzed National Inpatient Sample (NIS) data from the year 2011 to 2018. Results: A total of 215,938 patients underwent TAVI. Of the patients who underwent TAVI, 4579 (2.2%) suffered from stroke and 211359 (97.8%) did not have a stroke. Adjusted mortality was higher in patients who had a stroke (10.9%) as compared to patients who did not have a stroke (3.1%). Patients with stroke were more likely to be discharged to nursing home compared to patients without a stroke (89.8% vs 47.7%). Multivariate logistic regression analysis showed that at baseline, age, female sex, atrial fibrillation, chronic kidney disease and peripheral vascular disease were significant predictors of stroke. Median Cost of care ($63367 vs $48070) and length of stay (8 vs 4 days) were considerably higher for patients with stroke when compared to the comparison group (p&lt;0.01 for all). Conclusions: In conclusion we report that stroke is associated with increased mortality, morbidity, and resource utilization in patients undergoing TAVI. Baseline characteristics like age, gender, atrial fibrillation, chronic kidney disease and peripheral vascular disease are significant predictors of this adverse event.
Clinicopathologic Characteristics and Genomic Profiling of De Novo CD5 Positive Diffuse Large B-Cell Lymphoma: A Multicenter Retrospective Study in China
Authors: Wei Sang, Yuhan Ma, Xiangmin Wang, Ziyuan Shen, Linyan Xu, Jianlin Qiao, Kailin Xu, Hui Liu
Journal: Blood (2021)
Hemichorea in non-ketotic hyperglycaemia
Authors: Bingjun Zhang, Zhengqi Lu
Journal: BMJ (2021)

This is a brain magnetic resonance image (MRI) of a woman in her 70s with hemichorea associated non-ketotic hyperglycaemia (HC-NKH) because of poorly controlled diabetes (white arrowhead, fig 1).



Fig 1 

The patient had experienced involuntary choreatic movements on …
Abstract 6950: Precision Quantification of Cardiac Biomarkers Using Reagent-Free Electrochemical Aptasensors
Authors: Alam Mahmud, Jagotamoy Das, Dingran Chang, Surath Gomis, Jenise Chen, Hanie Yousefi, Edward H Sargent, Shana O Kelley
Journal: Circulation (2021)

Introduction: Precision quantification of cardiac biomarkers in unprocessed patient samples could reveal critical information in the event of acute myocardial infarction and chronic heart failure. Consequential research efforts have been made in recent years to develop self-contained analytical devices for accurate and rapid quantification of molecular analytes in unprocessed biological fluids, however, their poor sensitivity and compromised robustness in complex biofluids greatly limit their clinical usability. We aimed to investigate the utility of a new biomolecular analysis technique for accurately quantifying BNP and NT-pro BNP directly in whole blood using only a sensor-modified electrode chip. Methods and Results: Recently, we have developed a new class of reagentless biosensors using a molecular pendulum (MP) for monitoring physiologically relevant proteins directly in unprocessed body fluids. The sensing strategy is based on the kinetics of a MP tethered to an electrode surface where the motion of the MP is modulated by the presence of target analyte. Using an antibody as the bioreceptor unit, our MP sensors demonstrated to detect 1 pg/mL of cardiac troponin I in several bio-fluids. Since aptamers hold great promise for developing next-generation of diagnostics and therapeutic tools, we employed them to develop reagent-free MP aptasensors that quantify different heart failure biomarkers including BNP and NT-pro BNP directly in whole human blood. Our MP aptasensors show excellent performance matrices, such as a wide dynamic range (10 fg/mL to 10 ng/mL of BNP), a limit of quantification of 93.5 fg/mL, excellent specificity, and long-term stability, measured directly in whole human blood. Moreover, the analytical resolving capability of the sensors can distinguish samples that differ by only 20 pg/mL of BNP, which is critical for the BNP guided therapy for heart failure. We were also able to quantify BNP and NT-pro BNP simultaneously from the same sample by multiplexing the sensors on the same electronic chip. Conclusion: The analytical strength of our reagent-free MP aptasensors warrants their accelerated development as they could play crucial roles for earlier identification and better risk stratification of heart failure patients.
Abstract 13406: Psychosocial Stress, Life Satisfaction, And Hypertension: A Mediation Analysis
Authors: Liying Zhang, Rhonda Dailey, Robert D Brook, Phillip Levy
Journal: Circulation (2021)

Background: Disparities in hypertension control remain an important issue in public health. Evidence indicates that psychosocial factors are associated with onset and trajectory of hypertension. However, mediators of the association between psychosocial factors and hypertension are understudied. The objective of this study is to explore the mediating effect of life satisfaction on the link between psychosocial stress and hypertension. Method: This is a secondary analysis of data from the Panel Study of Income Dynamics (PSID) with the 2019 wave of 26,084 adults. Hypertension was assessed with the question: “Has a doctor or other health professional ever told you that you had high blood pressure or hypertension?” Psychosocial stress was assessed by using the K-6 Non-Specific Psychological Distress Scale developed by Dr. Ronald Kessler with 6 items. Participants were asked to rate their life satisfaction with a Likert-type question. Multiple logistic regression and mediation analysis were performed. Results: The mean age of this sample was 45 years and 27.5% were female. Results showed that participants with a higher level of psychosocial stress had a lower proportion of life satisfaction (26.3% vs. 70.7%, p&lt;0.01) and a higher proportion of hypertension (42.5% vs. 28.6%, p&lt;0.01) compared to those with a lower level of psychosocial stress. Participants who rated their life satisfied had a lower proportion of hypertension (27.4% vs. 32.9%, p&lt;0.01) compared to those who rated their life not satisfied. After controlling for covariates, regression results showed that psychosocial stress and life satisfaction were associated with hypertension independently. The indirect effect of psychosocial stress on hypertension through life satisfaction was significant (p&lt;0.01). Conclusions: Psychosocial stress was significantly associated with hypertension and this effect was partially mediated by life satisfaction. Interventions to decrease psychosocial stress that also emphasize improvements in life satisfaction may be needed to reduce the impact on hypertension.
The High Affinity CXCR4 Inhibitor, BL-8040, Impairs the Infiltration, Migration, Viability, and Differentiation of Regulatory T Cells
Authors: Michal Abraham, Inbal Mishalian, Abi Vainstein, Liron Shemesh-Darvish, Ella Sorani, Orly Eizenberg, Amnon Peled
Journal: Blood (2021)
Abstract 9686: Stroke and Thrombosis Risk in Left Ventricular Non-Compaction
Authors: Matthew Collins, Matthew Laubham, Cara Joyce, Mingxi Yu, MAX LIEBO
Journal: Circulation (2021)

Introduction: Left ventricular non-compaction (LVNC) is a rare genetic condition affecting 1 in 5000 people in which the myocardium of the left ventricle fails to adequately compact, forming deep recesses within the muscle wall. These recesses have been theorized to contribute to thrombus formation and embolic stroke, though the association has never been firmly established in the limited literature over the last 20 years. Hypothesis: We assessed the hypothesis that patients with LVNC, as well as those with hypertrabeculation not meeting LVNC criteria, would have increased rates of lifetime incidence of CVA, LV thrombus diagnosis, and distal arterial embolic events. Methods: We performed a retrospective control-matched cohort study assessing patients at Loyola University Medical Center diagnosed with LVNC, as well as those with hypertrabeculated left ventricles not meeting LVNC criteria, assembling the largest cohort of adult patients in the literature to date. We matched our study patients to controls based on age, HTN, DM, smoking status, history of atrial fibrillation, and history of DVT/PE. Results: Compared to matched controls, neither the LVNC group (n=98) nor the hypertrabeculation group (n=119) showed an increased risk of CVA, but both were associated with an increase in diagnosis of LV thrombus by TTE, TEE, or cMRI (p=0.045, p=0.003, respectively). Furthermore, in the LVNC group, each 10% increase in EF was found to reduce the risk of a composite endpoint of arterial thromboembolism (CVA, LV thrombus, distal arterial embolus) by 50%, while in the hypertrabeculation group, each 10% increase in EF reduced total arterial thromboembolism by 37%. Conclusions: These findings suggest that patients with hypertrabeculated left ventricles are either more likely to have LV thrombi that do not result in CVA events, or that due to the ventricle morphology, LV thrombi are being diagnosed when none are actually present. Furthermore, our study supports the existing literature that more severe systolic dysfunction increases risk for CVA and thromboembolic events, though that association seems largely multifactorial. Based on these results we cannot advocate for or against a particular anticoagulation strategy in patients with LVNC.
CSIG-14. PTEN AS A SIGNATURE OF VULNERABILITY OF GBM TO NEDDYLATION INHIBITION
Authors: Brett Taylor, Shayesteh Ferdosi, Matthew Lee, Nanyun Tang, Sen Peng, Rita Bybee, Lauren Hartman, George Reid, Krystine Garcia-Mansfield, Ritin Sharma, Patrick Pirrotte, Jianhui Ma, Alison Parisian, Frank Furnari, Harshil Dhruv, Michael Berens
Journal: Neuro-Oncology (2021)

Abstract Neddylation is a specific pathway within the ubiquitin/proteasome system that is overactive in GBM, and whose upregulation has been associated with glioma progression and worse survival. Pevonedistat (MLN4924) is a first-in-class small-molecule neddylation inhibitor shown to inhibit growth of GBM cells by impacting protein degradation in culture and orthotopic xenografts. However, the determinants of vulnerability are not fully understood. Because the molecular heterogeneity within and across GBM patients obscures therapeutic targets and obfuscates signals of efficacy in clinical trials, we pursue the use of molecular “signatures of vulnerability” to targeted agents in subsets of preclinical models. Selective vulnerability to pevonedistat was shown in a subset of GBM; notably, models with mutations or copy number deletions of PTEN are associated with de novo resistance to pevonedistat. Time-course studies of sensitive and non-sensitive GBM cells using transcriptomics and proteomics/phosphoproteomics uncovered additional determinants of response to pevonedistat. Our results demonstrate that in GBM, resistance to pevonedistat is driven by reduced PTEN-chromatin binding (loss-of-function or lower expression) that is also independent of PTEN’s lipid phosphatase activity (i.e., PI3K/AKT signaling). Across 25 glioma cell lines, we found that PTEN signaling, DNA replication, and chromatin instability pathways are the most significant differentiators between pevonedistat sensitive vs. non-sensitive models. In GBM models with modest to low sensitivity to pevonedistat, TOP2A expression was elevated. Combination treatment with the TOP2A inhibitor, etoposide, proved synergistic with pevonedistat. We report that PTEN status both serves as a novel biomarker for GBM sensitivity to pevonedistat and reveals a synergistic vulnerability to TOP2A inhibitors in combination with pevonedistat. Paired use of GBM PDX models of varying sensitivity with drug development testing allows the advancement of a promising agent as well as a patient-enrollment “signature of vulnerability” likely to increase the likelihood of demonstrating therapeutic efficacy in early stage clinical trials.