tbuckley/cabot-search huggingface dataset:
Abstract 9910: Effect of Renal Denervation in Resistant Hypertension: A Meta-Analysis of Randomized Controlled Trials
Authors: Vijairam Selvaraj, Affan Ansari, Ajay K Mishra
Journal: Circulation (2021)

Introduction: Resistant hypertension is defined as blood pressure that remains ≥ 140/90 mm Hg despite adherence to at least three maximally tolerated doses of antihypertensive medications, including a diuretic. Catheter based renal denervation has been studied as one of the interventions for blood pressure control in such patients. Data comparing renal denervation versus sham procedure have shown disparate results. This meta-analysis summarizes the current evidence on the effect of sham controlled renal denervation on the treatment of resistant hypertension. Methods: Embase, Pubmed and Cochrane Central databases were searched from inception until May 30, 2021. RCTs comparing catheter based renal denervation with a sham control were included. Outcomes assessed were change in 24h ambulatory systolic blood pressure, change in 24h ambulatory diastolic blood pressure, change in office systolic blood pressure, and change in office diastolic blood pressure. Weighted mean differences (WMD) were calculated and pooled into a random effects model meta-analysis. Results: Seven studies with 1,264 participants were included in the analysis. Catheter based renal denervation was associated with significant decrease in ambulatory systolic blood pressure (WMD: -3.76; 95% CI: -2.44 to -5.09, p value &lt;.00001) and ambulatory diastolic blood pressure (WMD: -1.78; 95% CI: -0.84 to -2.72, p value=0.0002) compared with sham. The reduction in office systolic and office diastolic blood pressure was also significantly greater with catheter renal denervation than sham control (WMD: -5.95; 95% CI: -3.93 to -7.97; p value&lt;0.00001 and WMD: -3.54; 95% CI: -2.35 to -4.72; p value&lt;0.00001). Conclusions: There was significant benefit of renal denervation for resistant hypertension for all the studied outcomes. Based on this data, compliant patients with resistant hypertension who are maxed on lifestyle and pharmacological management may benefit from catheter based renal denervation.
CTIM-26. PHASE I/II STUDY OF THE COMBINATION OF PEMBROLIZUMAB (MK-3475) AND LASER INTERSTITIAL THERMAL THERAPY (LITT) IN RECURRENT GLIOBLASTOMA
Authors: Jian Campian, Omar Butt, Ashley Ghinaseddin, Maryam Rahman, Milan Chheda, Tanner Johanns, George Ansstas, Jiayi Huang, Jingxia Liu, Grayson Talcott, Ruth Katumba, Alice Zhou, William Leidig, Gavin Dunn, Albert Kim, Eric Leuthardt, David Tran
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The blood brain barrier (BBB) remains a potential barrier to central nervous system (CNS) penetration of novel immunotherapies in recurrent glioblastoma (rGBM). Laser interstitial thermal therapy (LITT) was recently demonstrated to induce BBB disruption. When combined with anti-PD1 blockade, LITT may therefore potentiate host T-cell mediated cytotoxicity. This phase I/II study aims to evaluate the safety and efficacy of combining LITT and the PD-1 inhibitor pembrolizumab for rGBM. METHODS Phase I treated eligible bevacizumab-naïve high grade glioma patients with LITT and the anti-PD1 inhibitor pembrolizumab at 3 dose levels (100, 150, and 200 mg IV Q3W; 3 patients at each level), while phase II was restricted to rGBM patients only with the recommended phase II dose (RP2D) of pembrolizumab. Phase II was initially designed to randomize rGBM to either pembrolizumab or pembrolizumab+LITT but was later amended to receive only pembrolizumab+LITT after 16 patients were randomized (10 pembrolizumab+LITT arm, 6 pembrolizumab-alone arm). Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan Meier method, and adverse events (AE) documented. RESULTS Phase I enrolled 9 patients (7 rGBM and 2 anaplastic astrocytomas, 33% IDH-mut, 44% MGMTp-methylated) with no dose limiting toxicities (DLT), prompting selection of 200mg Q3W as the RP2D. Phase II interim analysis included 34 rGBM patients (9% IDH-mut, 50% MGMTp-methylated; 6 receiving pembrolizumab alone and 28 pembrolizumab+LITT) plus two Phase I rGBM patients who received RP2D. On per-protocol analysis, pembrolizumab+LITT cohort had improved PFS (median PFS 10.5 months vs 2.1 months) and OS (median OS 11.4 months vs 5.2 months) than pembrolizumab alone. A single treatment-related grade 3 AE was noted (respiratory infection). CONCLUSION: LITT may be safely combined with pembrolizumab for rGBM with promising clinical outcomes on interim analysis. Enrollment for Phase II, correlative studies, and continued AE documentation are ongoing. Clinical Trial ID NCT02311582.
Quantification and prognostic significance of interferon-γ secreting SARS-CoV-2 responsive T cells in hospitalized patients with acute COVID-19
Authors: Daniel Pan, Jee Whang Kim, Joshua Nazareth, Sara Assadi, Adam Bellass, Jack Leach, James G Brosnan, Adam Ahmed, Fleur Starcevic, Shirley Sze, Christopher A Martin, Caroline M Williams, Michael R Barer, Amandip Sahota, Prashanth Patel, Andrea Tattersall, Andrea Cooper, Manish Pareek, Pranabashis Haldar
Journal: Journal of Infection (2021)
Abstract 11452: Full 3D Single Heartbeat Electromechanical Wave Imaging of the Heart in Vivo with Coherent Compounding of Diverging Waves
Authors: Julien Grondin, Rachel Weber, Elisa E Konofagou
Journal: Circulation (2021)

Introduction: Electromechanical wave imaging (EWI) is a new ultrasound-based technique that can noninvasively map myocardial activation of all four chambers at high temporal resolution (500-2000 frames per second). Localization of atrial and ventricular arrhythmias with 3D-rendered EWI maps has been demonstrated and validated in heart rhythm disorders using multiple 2D echocardiographic views at different heartbeats. Objective: The objective of this study was to assess the in vivo performance of single heartbeat 3D EWI using coherent compounding of high volume-rate 3D anatomical echocardiography. Methods: A 32x32-element matrix array (Vermon, France) was connected to four synchronized research ultrasound scanners (Vantage 256, Verasonics, WA). High volume rate acquisitions were performed with diverging wave imaging at a compounded imaging rate of 840 volumes per second. Three healthy volunteers were imaged during normal sinus rhythm and one open chest canine was imaged during left ventricular pacing. Timing of zero-crossing of temporal inter-volume axial strain curves, corresponding to local onset of contraction, was determined for EWI activation. Results: A normal activation sequence was consistently observed in all volunteers (Figure 1). Early activation was mapped in the right atrium, followed by the left atrium, followed by the ventricles. Epicardial ventricular pacing was performed alternatively in the basal anterior-lateral region and in the apical anterior-septal region. The earliest activated region with 3D EWI was observed in the same location as the pacing electrode (Figure 1). Good agreement between 3D EWI and electro-anatomical mapping was obtained. Conclusions: Ultrasound-based full 3D EWI is capable of consistently mapping myocardial activation of the full heart in a single heartbeat in healthy volunteers noninvasively and is capable of identifying early activation during epicardial ventricular pacing in an open-chest canine.
Abstract 9567: Association Between Parity and Markers of Inflammation: The Multi-Ethnic Study of Atherosclerosis
Authors: Angelica K Ezeigwe, Oluseye Ogunmoroti, Anum Minhas, Carla Rodriguez, Brigitte Kazzi, Oluwaseun E Fashanu, Olatokunbo I Osibogun, Lara Kovell, Colleen Harrington, Erin Michos
Journal: Circulation (2021)

Introduction: Grand multiparity (≥5 live births) is associated with a future risk of cardiovascular disease (CVD). Inflammation also increases the risk for adverse CV outcomes and may be a mechanism linking parity to CVD. We aimed to investigate the association between parity and several markers of inflammation. Methods: We studied 3,454 female MESA participants (age 45-84 and free of CVD) who had data on parity and inflammatory markers measured at baseline. Parity (live births) was categorized as 0 (reference), 1-2, 3-4, or ≥5. Progressively adjusted linear regression models were used to evaluate the association between parity and natural log-transformed levels of fibrinogen, D-dimer, GlycA, high sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6). Results: Mean age at the baseline visit was 62±10 yrs. The proportion of women with nulliparity (0), 1-2, 3-4, and ≥5 live births were 620 (18%), 1357 (39%), 1004 (29%) and 473 (14%), respectively. There was no association between parity and fibrinogen. Women with grand multiparity had 28%, 10% and 18% higher levels of hsCRP, IL-6 and D-dimer, respectively, compared to nulliparous women, after adjustment for demographic factors (Model 1). Additionally, women with 1-2 and 3-4 live births had higher hsCRP and women with 1-2 live births had higher GlycA compared to nulliparous women in the fully adjusted model (Table). Conclusion: In this diverse cohort of mid-life women free from clinical CVD, we found a history of higher parity was positively associated with specific inflammatory markers; however, these associations were largely attenuated after adjustment for lifestyle and CVD risk factors. There was no clear dose-response relationship between higher parity status and higher inflammatory levels. Future studies are needed to evaluate how inflammation may influence the link between parity and CVD, and whether lifestyle/pharmacotherapy targeting inflammation can reduce CVD risk among multiparous women.
Abstract 14309: Clinical Outcomes of Acute Myocardial Infarction in Hematological Cancers
Authors: MUHAMMAD ZUBAIR KHAN, Joshua Weinstock, Kirtenkumar Patel, Sona Franklin, Jason Naftulin, Ayesha Jamil, Aida Abraham, Steven Kutalek
Journal: Circulation (2021)

The purpose of our study is to determine hospital outcomes of acute myocardial infarction (MI) with hematological cancers and their subtypes. Method: Patient data was obtained from the Nationwide Inpatient Sample (NIS) database between years 2009-2015. Patients with a diagnosis of acute MI [non-ST segment elevation myocardial infarction and ST segment elevation myocardial infarction (NSTEMI/STEMI)] and hematological cancer subtypes were identified using validated International Classification of Diseases, 9th revision, and Clinical Modification (ICD-9-CM) codes. Statistical analysis using Pearson chi-squared test was performed to determine hospital outcomes between acute MI and hematological cancer subtypes. Results: The prevalence of NSTEMI was 1.2%, and STEMI was 0.2% in hematological cancers, n=3,027,800. Among hematological cancer subtypes, the highest prevalence of NSTEMI and STEMI was seen in lymphocytic leukemia (2.4% and 0.25%, respectively). Mortality (16.8% vs. 8.8%), hospitalization cost (25469$ ± 36763$ vs. 20534$ ± 24767$) and length of stay (8.3 days ± 10 days vs. 6.3 ± 7.8 days) were higher in the acute MI patients with hematological cancers compared to acute MI patients without cancer. Among hematological cancer patients with acute MI, the highest mortality was found in patients with myeloid leukemia (23%) followed by multiple myeloma (MM) (17.9%), lymphocytic leukemia (15.9%) and lymphoma (14.4%). The length of stay and hospitalization cost was highest in those with myeloid leukemia followed by MM, lymphocytic leukemia and lymphoma. Conclusion: This study showed that hematological cancer patients with acute MI had a higher mortality, hospitalization cost and length of stay. Among the hematological cancer subtypes, the highest mortality, length of stay and hospitalization cost was found in myeloid leukemia.
Integrated genome and tissue engineering enables screening of cancer vulnerabilities in physiologically relevant perfusable ex vivo cultures
Authors: Michael Hu, Xin Yi Lei, Jon D. Larson, Melissa McAlonis, Kyle Ford, Daniella McDonald, Krystal Mach, Jessica M. Rusert, Robert J. Wechsler-Reya, Prashant Mali
Journal: Biomaterials (2021)
Daratumumab Versus Lenalidomide Maintenance Therapy for Multiple Myeloma: A Randomized Pilot Study Comparing Patient-Reported Health Related Quality of Life Measures
Authors: Urvi A Shah, Maria Malik, Kelly Werner, Miranda Burge, Sean M Devlin, Sham Mailankody, Neha Korde, Malin Hultcrantz, Hani Hassoun, Carlyn Tan, Kylee H Maclachlan, Sydney X. Lu, Dhwani Patel, Audrey Hamilton, Michael Scordo, Parastoo B. Dahi, Oscar B Lahoud, David J. Chung, Heather J Landau, Gunjan L. Shah, Sergio A Giralt, Alexander Lesokhin, Ola Landgren
Journal: Blood (2021)
A record 100 000 people in the US died from overdoses in 12 months of the pandemic, says CDC
Authors: Owen Dyer
Journal: BMJ (2021)

The United States’ opioid epidemic worsened significantly during the pandemic, with overdose deaths recorded in the 12 months leading up to April 2021 up 28.5% from the year before, show data from the Centers for Disease Control and Prevention.1

Health systems across the country reported 97 990 overdose deaths during that period. Accounting for reporting delays, the CDC estimated that the final figure will be 100 306 lives lost to overdoses, of which 75 673 were opioid overdoses.

Of these, 64 178 deaths involved synthetic opioids such as fentanyl, a drug which has flooded the country in recent years. China cracked down on producers who would …
TAMI-70. METABOLIC VULNERABILITY TO GPX4 INHIBITION AND FERROPTOSIS OF QUIESCENT ASTROCYTE-LIKE GLIOMA CELL POPULATIONS
Authors: Matei Banu, Athanassios Dovas, Michael Argenziano, Wenting Zhao, Dominique Higgins, Pavan Upadhyayula, Aayushi Mahajan, Nelson Humala, Trang Nguyen, Fereshteh Zandkarimi, Markus D Siegelin, Stockwell Brent, Peter Sims, Jeffrey N Bruce, Peter Canoll
Journal: Neuro-Oncology (2021)

Abstract Diversity is a key feature in the glioma ecosystem. Adaptation to a changing tumor microenvironment is achieved through cellular and metabolic plasticity. Here we show that slow-cycling, astrocyte-like glioma cell subpopulations activate distinct metabolic programs, rendering them susceptible to novel treatments. We performed multi-omics analysis on transgenic murine glioma models to characterize cellular heterogeneity. Bulk RNAseq on targeted time-dependent biopsies combined with scRNAseq uncovered distinct tumor cell populations, including a quiescent, astrocyte-like population relatively insensitive to conventional chemotherapy targeting proliferating cells. Using scRNAseq, we identified a persistently conserved astrocytic population in human IDH1-mt/wt high-grade gliomas. This astrocytic tumor population was more abundant in mouse models with constitutive Notch activation, however it was associated with alterations in several other transcriptional programs, suggesting that targeted therapies would likely be ineffective at eradicating it. Gene ontology analysis revealed enrichment in mitochondrial genes specifically regulating oxidative phosphorylation and tricarboxylic acid cycle. Energetic, lipidomic and metabolomic analyses revealed significant mitochondrial β-fatty acid oxidation and lipid catabolism, with less effective oxygen consumption rate and higher basal oxidative stress. Furthermore, this astrocytic tumor population had depleted levels of basal GSH and was more sensitive to reactive oxygen species. Leveraging this metabolic vulnerability, we performed drug screens and found that therapeutic inhibition of complex I or GPX4 was highly effective and synergistic. GPX4 inhibition induced ferroptosis, a newly-discovered form of programmed non-necroptotic cell death mediated by iron-driven lipid peroxidation. Using scRNAseq and RNAscope on ex vivo slice cultures from murine and human gliomas, we found that GPX4 inhibition and ferroptosis induction in the glioma microenvironment selectively eradicated the quiescent astrocytic subpopulation whereas proliferating glioma were less sensitive. Our data therefore supports a novel treatment paradigm, employing metabolic strategies, such as ferroptosis, in conjunction with chemotherapy and RT to target distinct tumor cell populations with different therapeutic vulnerabilities.
Abstract 9933: Determinants of High-Risk Featured Coronary Plaque Burden for the Prediction of Patient Outcomes in Suspected Coronary Artery Disease: A Coronary Ct Angiography Study
Authors: Hiroki Yamaura, Kenichiro Otsuka, Hirotoshi Ishikawa, Kuniyuki Shirasawa, Noriaki Kasayuki
Journal: Circulation (2021)

Background: Computed tomography (CT) coronary angiography (CCTA) is a non-invasive imaging modality that provides quantitative assessment of disease burden of coronary atherosclerosis and epicardial adipose tissue (EAT). This study aimed to investigate the prognostic implication of low-attenuation non-calcified plaque (LAP) burden and its association with EAT in patients with suspected coronary artery disease (CAD). Methods: This study consists of 400 symptomatic patients (58% male, 65 years) with suspected CAD undergoing CCTA. Coronary artery calcium score (CACS) was measured with Agatston method. LAP was defined as an atherosclerotic plaque with CT attenuation value of &lt;30 Hounsfield Units (HU). The %LAP was calculated as LAP volume divided by vessel volume(%). EAT volume was defined as adipose tissues having CT attenuation value ranging from -250 to -30 HU within pericardial sac. The primary endpoint was a composite event of death and coronary revascularization. Results: Among the study patients, quartiles for %LAP for 3-vessel coronary arteries were as follow; Q1 0.06-0.72%, Q2 0.72-1.11%, Q3 1.11-1.71%, and Q4&gt;1.74%. During the follow-up period (median 552 days), the primary endpoint was observed in 52 patients (13%). In the Cox hazard model, %LAP (Q4) [HR 2.16, p&lt;0.05], obstructive CAD &gt;50% diameter stenosis [HR 9.44, p&lt;0.05], and diabetes mellitus [HR 1.78, p&lt;0.05] were independent predictors of the primary endpoint. Kaplan-Meier curves analysis demonstrated that patients with %LAP (Q4) had a worse prognosis compared to those with Q1-Q3 (p&lt;0.001, Figure 1). In logistic regression analysis adjusting for age, gender, and clinical variables, the determinants of %LAP (Q4) were a greater CACS and EAT volume (p&lt;0.05). Conclusions: This study demonstrates that CACS and EAT volume provide noninvasive stratification of patients who exhibit a greater high-risk coronary plaque burden that may contribute to acute coronary events.
Abstract P481: Short-term Synbiotic, B420 And Oligofructose, Treatment Reverse High-fat-diet Related Pathologies In Ischemic Reperfusion Mouse Models
Authors: Christina H Hoyer-Kimura, Christine Behm, Joshua P Fricks, Frank Duca, John P Konhilas
Journal: Circulation Research (2021)

The gut microbiome impacts metabolic homeostasis, and several inflammatory pathologies including obesity, glucose intolerance, and worsened cardiovascular disease outcomes are associated with an altered gut microbiome. We have previously demonstrated Bifidobacterium animalis lactis 420 ([B420], a probiotic) attenuates myocardial infarct injury in mice following ischemic reperfusion (IR) injury. Further, Oligofructose ([OFS], a prebiotic) improves glucose tolerance, and reduces weight gain in high-fat-diet (HFD) mice. However, the combined ability of B420 and OFS (a synbiotic) on cardiovascular and metabolic disease is unknown. We hypothesized that short-term (2 weeks) synbiotic treatment improves adiposity and glucose tolerance and reduces IR infarct size in HFD fed male mice more than prebiotic or probiotic treatments alone. Adult male mice were fed HFD (45% fat) for 2 weeks and were then treated with OFS (10microliters/gram weight, 200miligram OFS/ 300microliters saline), B420 (10microliters/gram weight, 10 9 CFU/ 300microliters saline), or B420+OFS (synbiotic treatment) via daily gavage for 2 weeks. Following treatment mice underwent an IR protocol, (45-minute ligation followed by reperfusion). Oral glucose tolerance tests were conducted prior to and after treatment to determine blood glucose. Fasted mice were gavaged with glucose (2.5g/kg glucose) and blood glucose was measured over 120 minutes. Body weight, and kcal intake were measured weekly. Upon sacrifice epididymal fat mas was weighed to determine adiposity. Data were analyzed by one-way ANOVA or T-test. We found that short-term synbiotic treatment with B420+OFS during HFD-feeding reduced adiposity and improved glucose tolerance, while probiotic or prebiotic treatment alone had no effect. However, short-term treatment, including synbiotic, did not significantly reduce heart infarct size as previously demonstrated with longer treatment periods. Taken together, these results suggest that synbiotic treatment improves metabolic impairments more rapidly than B420 or OFS alone, and precedes improvements in infarct size.
BIOM-17. DIFFERENCES IN THE IMMUNE MICROENVIRONMENT OF GLIOMAS HARBORING IDH2 VERSUS IDH1 MUTATIONS
Authors: Quinn Ostrom, Joanne Xiu, Giselle lopez, Ashley Sumrall, Sonikpreet Aulakh, Michael Glantz, Edward Pan, Mustafa Khasraw, David M Ashley, Kyle Walsh
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION IDH mutations are a defining feature of lower-grade glioma and secondary glioblastoma. Approximately 95% of glioma-associated IDH mutations are in codon 132 of IDH1, but a small proportion are in IDH2. IDH mutations produce the oncometabolite 2-hydroxyglutarate, which induces global DNA hypermethylation and is associated with an immunosuppressive tumor microenvironment. IDH1 is localized in the cytosol while IDH2 is found in the mitochondrial matrix, and mutations in these genes may have differing effects on the tumor microenvironment. METHODS Formalin-fixed, paraffin-embedded tissue from 633 IDH-mutant gliomas (615 IDH1-mutant, 18 IDH2-mutant) underwent whole-exome and whole-transcriptome sequencing at Caris Life Sciences (236 grade 2/3 astrocytoma, 158 grade 2/3 oligodendroglioma, 202 IDH-mutant glioblastoma, 37 glioma, NOS). QuantiSEQ was used to infer tumor-infiltrating immune cell populations from RNAseq data, and gene-set enrichment analyses (GSEA) were performed using Wikipathway. RESULTS IDH1-mutant gliomas had higher levels of pro-inflammatory M1 macrophages (P=0.04), modestly higher levels of monocytes (P=0.08), and lower levels of neutrophils (P=0.04) – typically considered immunosuppressive – compared with IDH2-mutant gliomas. No differences were observed in levels of B cells, dendritic cells, NK cells, or T cell subsets (Treg, CD4+, CD8+). IDH2-mutant gliomas were enriched for hallmark oligodendroglioma mutations (TERT promoter, CIC, FUBP1), while IDH1-mutant gliomas were enriched for hallmark astrocytoma mutations (ATRX, TP53). However, associations with tumor-infiltrating immune cells persisted after excluding 1p/19q co-deleted oligodendroglioma from analyses. GSEA revealed upregulation of the microglial TYROBP signaling pathway, the microglial phagocytic pathway, and of Type II Interferon signaling in IDH1-mutant gliomas versus IDH2-mutant gliomas. CONCLUSIONS Although IDH2 mutations are generally thought to function similarly to IDH1 mutations, we observe differences in tumor-infiltrating immune cells across groups. IDH2-mutant gliomas appeared to have a more immunosuppressive tumor microenvironment than their IDH1-mutant counterparts. Early-phase immunotherapy trials should consider covariate-adaptive randomization approaches to equally allocate IDH2-mutant gliomas across treatment arms.