tbuckley/cabot-search huggingface dataset:
Abstract PO-032: Targeting the KRAS dimerization interface enhances T-cell mediated anti-tumor response in vivo
Authors: Imran Khan, Julia Lefler, Catherine Marelia, Mariyam Zuberi, Eric Denbaum, Akiko Koide, Cynthia Timmers, Michael Ostrowski, Shohei Koide, John O’Bryan
Journal: Cancer Research (2020)

Abstract RAS is the most frequently mutated human oncogene and about 20% of all human cancers harbor mutations in one of three RAS oncogenes (K, N and H-RAS) with pancreatic cancers harboring RAS mutations in &amp;gt;90% of tumors. Therapeutically targeting RAS has been highly challenging and other than allele specific KRAS (G12C) inhibitors, no direct RAS inhibitor has been approved for clinical trial. However, KRAS (G12C) mutations are less abundant in some cancers like pancreatic cancer, thus there remains an unmet need for inhibitors that target the more common RAS mutants. This demand devising novel strategies to identify new approaches to inhibit RAS. Previously, we developed the H/KRAS-specific monobody called NS1 that allosterically inhibit RAS-mediated signaling by targeting the α4-α5 dimerization interface. When used as a genetically encoded intracellular reagent, NS1 inhibited the growth of H/KRAS-mutant human tumor lines both in vitro and in xenograft tumor models. However, these tumor models lack a functional immune system. Here, we evaluated the potency of targeting KRAS dimerization interface with NS1 in an immune-competent murine model of pancreatic cancer. Although human and murine KRAS differ by a single amino acid [Asp (D) to Glu (E)] at position 132 in the NS1 binding region of the allosteric lobe, NS1 bound similarly to human and murine KRAS both in vitro and in vivo. Furthermore, NS1 expression inhibited ERK-MAPK activation, proliferation and anchorage-independent growth of engineered KPC cells derived from pancreatic tumor in the KPC genetic mouse model. Finally, when these engineered KPC cells were injected orthotopically in immune-competent C57/B6 mice, we observed a dramatic decrease in tumor growth kinetics and tumor burden in NS1 expressing cohorts. Similarly, NS1 expression resulted in decreased ERK-MAPK activation and increased apoptosis. NS1 expressing tumors were characterized by increased infiltration of helper CD4+ T cells and macrophage. Thus, inhibition of mutant KRAS by NS1 results in an enhanced anti-tumor immune response in a syngeneic model for pancreatic cancer. These results establish that targeting α4-α5 dimerization interface of RAS can be a viable therapeutic option for targeting KRAS-mutant pancreatic cancer. Citation Format: Imran Khan, Julia Lefler, Catherine Marelia, Mariyam Zuberi, Eric Denbaum, Akiko Koide, Cynthia Timmers, Michael Ostrowski, Shohei Koide, John O’Bryan. Targeting the KRAS dimerization interface enhances T-cell mediated anti-tumor response in vivo [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-032.
Abstract 245: Dispatcher Assisted Cardiopulmonary Resuscitation in Patients Not in Cardiac Arrest: A Multi-Center, Observation Study
Authors: Julia YX Ng, Zariel J Sim, Fahad J Siddiqui, Nur Shahidah, Benjamin SH Leong, Ling Tiah, Yih Yng Ng, Shalini Arulanandam, Andrew FW Ho, Marcus E Ong
Journal: Circulation (2020)

Background: Dispatcher-assisted cardiopulmonary resuscitation (DA-CPR) can increase bystander CPR rates and improve outcomes in out-of-hospital cardiac arrest (OHCA). Protocols used by dispatchers are designed to provide a quick assessment for prompt initiation of CPR. However, there are instances where non-cardiac arrest cases are falsely recognised by dispatchers to be in cardiac arrest. These patients may go on to receive chest compressions and potentially suffer from complications of unnecessary CPR, though the clinical implications of starting DA-CPR on these non-cardiac arrest cases have not been studied. Hence, the objectives of this study are to find the prevalence and clinical outcomes of DA-CPR in patients not in cardiac arrest in the Singapore population. Methods: This was a multi-center, observational study of all dispatcher-recognized cardiac arrests cases between January to December 2017 involving three tertiary hospitals in Singapore. Data was collected through audio review of dispatch calls from the national emergency ambulance service and information about patients’ clinical outcomes were prospectively collected from health records. Results: During the study period, dispatchers recognised 821 patients as having cardiac arrest. Of these, 40.0% (328/ 821) were not in cardiac arrest. 52.7% (173/ 328) of the non-cardiac arrest patients had chest compressions initiated under dispatcher assistance. No complications from chest compressions were reported. The top diagnoses of non-cardiac arrest patients found were cerebrovascular accidents (CVA), syncope and infection. A multiple logistic regression model with estimates adjusted for the presence or absence of chest compressions revealed that only final diagnoses of CVA (OR 20.68), infection (OR 17.34) and myocardial infarction (OR 32.19) were associated with in-hospital mortality. Conclusion: In this study, chest compressions initiated due to false recognition of cardiac arrest by dispatchers did not result in any reported complications and was not associated with in-hospital mortality. This provides reassurance for the continued implementation of DA-CPR.
Abstract 13691: Factors Affecting Extubation Time Post-Cardiac Surgery
Authors: Quynh Nguyen, Kevin Coghlan, Yongzhe Hong, Jeevan Nagendran, Roderick MacArthur, Wing Lam
Journal: Circulation (2020)

Introduction: Early extubation, defined as extubation within 6 hours post-operation, was found to be safe and associated with decreased complications and costs. Recent enhanced recovery after surgery guidelines recommend early extubation for cardiac surgery patients. This retrospective study aimed to assess our institution’s extubation strategy and identify predictive factors of early extubation in our cardiac surgery patients. Methods: Our study included 13,807 adult patients who underwent cardiothoracic surgery from 2010-2019 at our institution. Forward stepwise multivariable logistic regression analysis was used on patients with complete data (n=10,783) to identify predictors of early extubation. Results: Of the 10,783 patients, 3740 (35%) were extubated within 6 hours post-operation. Early extubated patients were younger, had higher BMI and more likely to be fast track designated. These patients more frequently underwent isolated coronary artery bypass graft (CABG), isolated valve or adult congenital surgery than late extubated patients. Early extubated patients had higher incidence of coronary artery disease (CAD) and anxiety, and were less likely to have difficult intubation or require circulatory support post-surgery. Analysis of 10,783 patients showed BMI &gt;30 (OR=1.840, 95% CI=1.624-2.083), fast track designation (OR=1.338, 95% CI=1.12-1.598) and having CAD (OR=1.107, 95% CI=1.007-1.217) to be predictive of early extubation. Data on patient transfer to the ICU were only available from 2014-2018. Within this sub-group of 7296 patients, variables predictive of early extubation included BMI &gt;30 (OR=1.364, 95% CI=1.195-1.557), dayshift transfer to the ICU (OR=1.680, 95% CI=1.516-1.862), fast track designation (OR=1.397, 95% CI=1.115-1.751) and having isolated procedures such as CABG (OR=1.630, 95% CI=1.413-1.880) and valve surgery (OR=1.506, 95% CI=1.300-1.745). Conclusions: BMI &gt;30, having fast track designation, and having CAD are associated with early extubation. When taking into account patient transfer to the ICU, BMI &gt;30, having fast track designation, dayshift transfer to the ICU, and having isolated procedures such as CABG and valve surgery are associated with early extubation.
Butyrate-Rich Diets Improve Redox Status and Fibrin Lysis in Behçet’s Syndrome
Authors: Giacomo Emmi, Alessandra Bettiol, Elena Niccolai, Matteo Ramazzotti, Amedeo Amedei, Giuditta Pagliai, Niccolò Taddei, Francesco Sofi, Claudia Fiorillo, Domenico Prisco, Matteo Becatti
Journal: Circulation Research (2020)
Abstract 13911: Interleukin-5-induced Eosinophil Population Improves Cardiac Function After Myocardial Infarction
Authors: Jun-Yan Xu, Wen-Yang Jiang, Yu-Yan Xiong, Rui-Jie Tang, Yu Ning, Yue-Jin Yang
Journal: Circulation (2020)

Background: Eosinophils have been commonly recognized as one of the major participants in helminth infection and allergic diseases. Recent studies suggest that these innate immune cells mediate tissue repairs after muscle, hepatic, or endometrial injuries. Yet, the precise role of eosinophils in myocardial infarction (MI) remains unclear. Interleukin (IL)-5 is the most important cytokines that are responsible for the development, activation, and survival of eosinophils. Here, we report a role of IL-5 in infarcted heart. Methods and Results: MI was induced by permanent ligation of left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot show that infarcted heart IL-5 expression is increased by 2.35-fold (P&lt;0.01) higher than their expression in the heart of sham mice at day 5 after surgery. External supply of recombinant mouse IL-5 (100 μg/kg/day for 3 days) reduces the infarct size (by 13.38%, P&lt;0.01), increases ejection fraction (from 32.41% to 43.93%, P&lt;0.01), and increases angiogenesis (CD31 area from 3.35% to 4.14%, P=0.03) in the peri-infarct zone. An expansion of eosinophils is observed in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of eosinophils by TRFK5 pretreatment mutes the beneficial effects of IL-5 in MI mice. Mechanistic studies also demonstrate that IL-5 increases the accumulation of M2 macrophages in infarcted myocardium at day 7 post-MI. In vitro co-culture experiments reveal that eosinophils shift bone marrow-derived macrophage polarization towards the M2 phenotypes. This effect is abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses show that eosinophils promote the macrophage downstream STAT6 phosphorylation. Conclusions: We demonstrate here that IL-5 facilitates the recovery of post-MI cardiac function by promoting eosinophils accumulation and subsequent polarization of M2 macrophages via the IL-4/STAT6 axis.
Abstract 13660: Initial Revascularization in Chronic Coronary Syndromes With Myocardial Ischemia
Authors: Andrea Soares, William E Boden, Whady Hueb, Maria M Brooks, Helen A Vlachos, Angela Hardi, David L Brown
Journal: Circulation (2020)

Introduction: Ischemic heart disease is the leading cause of death worldwide. It is unknown whether initial revascularization using percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) plus optimal medical therapy (OMT) in patients with chronic coronary syndromes (CCS), obstructive coronary artery disease (CAD) and myocardial ischemia improves hard clinical outcomes compared to OMT alone. Hypothesis: In CCS patients with obstructive CAD and documented myocardial ischemia, initial revascularization plus OMT does not reduce death or nonfatal myocardial infarction (MI) compared to OMT alone. Methods: We searched Ovid Medline, Embase, Scopus, and Cochrane Library databases from inception to March 2020 for randomized controlled trials (RCTs) of PCI or CABG and OMT vs OMT alone for CCS patients in whom stents and statins were used in more than 50% of patients. Random-effects models were used to estimate average treatment effects across trials. The co-primary outcomes were all-cause death and nonfatal MI at 5 years. Results: Six RCTs were identified that randomized 10,020 CCS patients. At 5 years, among 5,025 CCS patients assigned to revascularization plus OMT, there were 492 deaths (9.8%) compared to 482 deaths among 4,995 patients (9.6%) assigned to OMT (OR, 1.01, 95% CI: 0.88-1.16; P=0.87). There were 521 nonfatal MIs (10.3%) in those assigned to revascularization plus OMT compared with 593 MIs (11.9%) in those assigned to OMT arms (OR, 0.78, 95% CI: 0.58-1.05; P=0.10). In subgroup analysis, nonfatal MI was not reduced by PCI plus OMT (OR, 0.95, 95% CI: 0.74-1.23, P=0.71) but was significantly reduced in studies of CABG plus OMT compared to OMT alone (OR, 0.38, 95% CI: 0.23-0.64, P&lt;0.001). The overall effect of CABG on reducing nonfatal MI was significantly greater than that of PCI (P=0.002). Conclusions: In patients with CCS and myocardial ischemia, initial revascularization with PCI or CABG plus OMT was not associated with a reduction in death at 5 years compared to OMT alone. CABG plus OMT reduced nonfatal MI compared to OMT alone whereas PCI did not. These findings suggest important differences in MI outcomes between those who undergo CABG vs. PCI, but no overall difference in mortality compared with OMT alone.
Abstract 125: Capital Do-Re-Mi: A Randomized Trial of Dobutamine Compared to Milrinone in Cardiogenic Shock
Authors: Rebecca Mathew, Pietro Di Santo, Jeffrey Marbach, Jordan Hutson, Trevor Simard, Richard Jung, Anas Merdad, Aws Almufleh, Willy Weng, Omar Abdel-Razek, Shannon Fernando, Kwadwo Kyeremanteng, Jordan Bernick, George Wells, Michael Froeschl, Marino Labinaz, Michel R Le May, Juan J Russo, Benjamin M Hibbert
Journal: Circulation (2020)

Introduction: Cardiogenic shock (CS) is associated with significant morbidity and mortality. Although inotropic support is a mainstay of medical therapy for CS, little evidence exists to guide the selection of inotropic agents in clinical practice. Methods: In this double blind randomized controlled trial, we assigned patients with SCAI class B to E shock to either milrinone or dobutamine for inotropic support. Therapy was titrated based on clinical, biochemical and hemodynamic response as evaluated by the treating physician. The primary outcome was a combined endpoint of in hospital mortality, non-fatal MI, stroke, new initiation of renal replacement therapy (RRT), need for MCS or cardiac transplant, or cardiac arrest with successful resuscitation. Secondary outcomes included individual components of the primary outcome. Results: Among 192 participants, there was no significant difference in the primary outcome, occurring in 49% (47 of 96) of patients in the milrinone arm and 54% (52 of 96) patients in the dobutamine group (RR 0.90, 95% CI of 0.69-1.19, p-value = 0.47). There were also no differences in important secondary outcomes between milrinone and dobutamine, including in-hospital mortality 37% (35 of 96) vs 43% (41 of 96) (RR 0.85, 95% CI 0.60-1.21, p-value = 0.38) or need for RRT 22% (21 of 96) vs 17% (16 of 96) (RR 1.31, 95% CI 0.73-2.36, p-value = 0.36). Conclusions: In this randomized clinical trial of milrinone and dobutamine in CS, there was no difference in the primary composite outcome or in important secondary outcomes. The selection of inotropic agent could reasonably be based on physician comfort, cost and individual response to therapy.
Abstract 316: Younger Age Increases Risk of Self-reported Affective and Cognitive Sequelae Six Months Post Cardiac Arrest
Authors: Lars Evald, Kolbjorn Bronnick, Christophe Henri Valdemar Duez, Anni Jeppesen, Anders Morten Grejs, Eldar Søreide, Hans Kirkegaard, Jørgen Feldbæk Nielsen
Journal: Circulation (2020)

Introduction: Self-reported affective and cognitive sequelae are frequently reported in cardiac arrest survivors; however, little is known about the risk factors. Hypothesis: We assessed the hypothesis that self-reported (subjective) affective and cognitive outcomes six months after OHCA may be associated with demography, acute care and cerebral outcome. Methods: This is a sub study of the multicenter “Target Temperature Management for 48 vs. 24 hours and Neurologic Outcome after Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial” (the TTH48 trial) investigating the effect of prolonged TTM (24h vs 48h) at 33±1°C. Patients with good outcome on the Cerebral Performances Categories (CPC score≤2) were invited to answer questionnaires on anxiety, depression, emotional distress, perceived stress and cognitive failures six months after OHCA. Multivariate regression analyses were used to test the possible predictors of self-reported outcomes six months follow-up added successively in three blocks: [1] demography (age and gender), [2] acute care (time to ROSC and allocated treatment (24h vs 48h TTM)) and [3] cerebral outcome (objective cognitive impairment and CPC score). Results: A total of 79 out of 107 eligible patients were included in the analysis. There were no significant differences in baseline characteristics between the included group and the group lost to follow-up. [1] Younger age was a significant predictor across all self-reported outcomes, even when controlling for gender, ROSC time, treatment allocation, cognitive impairment and global outcome (CPC). Female gender was a predictor of anxiety, though this should be interpreted cautiously as only eight women participated. [2] ROSC time predicted self-reported cognitive failures, when not controlling for block 3. Treatment allocation had no predictive value. [3] Objective cognitive impairment was not a predictor of self-reported affective or cognitive sequelae. The CPC score was a significant predictor of self-reported affective outcomes, albeit not for self-reported cognitive failures. Conclusion: Younger age was a significant risk factor for self-reported affective and cognitive sequelae six months post OHCA. The CPC score may be a proxy for self-reported affective outcomes.
Abstract 15867: Flexibility Modifies the Age-related Arterial Stiffness in Women With Systemic Lupus Erythematosus
Authors: Alba Hernandez Martinez, Sergio Sola-Rodriguez, Jose A Vargas-Hitos, Blanca Gavilan-Carrera, Antonio Rosales-Castillo, Alberto Soriano-Maldonado
Journal: Circulation (2020)

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune multisystemic disease associated with premature cardiovascular disease morbidity and mortality. Arterial stiffness is an age-dependent powerful cardiovascular risk predictor, which is elevated in SLE. The elasticity of the vascular wall and muscle flexibility are both partially determined by elastin-collagen composition, and whereas cardiorespiratory fitness seems to delay the age-related arterial stiffening in SLE, it might be speculated that flexibility (another component of physical fitness) could reduce the sympathetic nervous system dysfunction observed in patients with SLE and thus reduce arterial stiffness. However, whether higher flexibility is related to lower age-related arterial stiffness in SLE is unknown. Hypothesis: We assessed the hypothesis that flexibilitymay attenuate the negative effect of age on arterial stiffness in women with SLE. Methods: This cross-sectional study included 76 women with SLE (age 43.2, SD 13.8) with mild disease activity. Arterial stiffness was assessed with pulse wave velocity (PWV), flexibility by the back-scratch test, disease activity through SLEDAI, and cumulative organ damage with SDI, blood pressure by standardized methods and menopause status by questionnaire. Quantile regression tested the association of age, flexibility, and their interaction, with PWV (controlling for mean blood pressure, menopause, SLEDAI, SDI and corticosteroids exposure). Sample size was determined for a two-tailed test with a power of 0.8, significance p &lt; 0.05 and effect size &gt; 0.7 (n=34). Results: There was a back-scratchхage interaction effect on PWV ( p &lt;0.001). For women with -20 cm in the back-scratch test (i.e. short to touch her middle fingers behind the back), PWV was 0.107 m/s higher for 1-year increase in age, whereas for women with 15 cm, PVW was 0.064 m/s higher for 1-year increase in age. Conclusion: In conclusion, higher flexibility is associated with a lower increase in age-related arterial stiffness in SLE women. Further research is needed to determine whether improving flexibility through stretching exercises reduces the arterial stiffness associated with aging.
Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study
Authors: Solmaz Sahebjam, Peter A Forsyth, Nam D Tran, John A Arrington, Robert Macaulay, Arnold B Etame, Christine M Walko, Theresa Boyle, Edwin N Peguero, Michael Jaglal, Sepideh Mokhtari, Heiko Enderling, Natarajan Raghunand, Tyra Gatewood, Wendy Long, Jennifer L Dzierzeski, Brittany Evernden, Timothy Robinson, Melissa C Wicklund, Sungjune Kim, Zachary J Thompson, Dung-Tsa Chen, Prakash Chinnaiyan, Hsiang-Hsuan Michael Yu
Journal: Neuro-Oncology (2020)

Radiotherapy may synergize with programmed cell death 1 (PD1)/PD1 ligand (PD-L1) blockade. The purpose of this study was to determine the recommended phase II dose, safety/tolerability, and preliminary efficacy of combining pembrolizumab, an anti-PD1 monoclonal antibody, with hypofractionated stereotactic irradiation (HFSRT) and bevacizumab in patients with recurrent high-grade gliomas (HGGs).Eligible subjects with recurrent glioblastoma or anaplastic astrocytoma were treated with pembrolizumab (100 or 200 mg based on dose level Q3W) concurrently with HFSRT (30 Gy in 5 fractions) and bevacizumab 10 mg/kg Q2W.Thirty-two patients were enrolled (bevacizumab-naïve, n = 24; bevacizumab-resistant, n = 8). The most common treatment-related adverse events (TRAEs) were proteinuria (40.6%), fatigue (25%), increased alanine aminotransferase (25%), and hypertension (25%). TRAEs leading to discontinuation occurred in 1 patient who experienced a grade 3 elevation of aspartate aminotransferase. In the bevacizumab-naïve cohort, 20 patients (83%) had a complete response or partial response. The median overall survival (OS) and progression-free survival (PFS) were 13.45 months (95% CI: 9.46-18.46) and 7.92 months (95% CI: 6.31-12.45), respectively. In the bevacizumab-resistant cohort, PR was achieved in 5 patients (62%). Median OS was 9.3 months (95% CI: 8.97-18.86) with a median PFS of 6.54 months (95% CI: 5.95-18.86). The majority of patients (n = 20/26; 77%) had tumor-cell/tumor-microenvironment PD-L1 expression <1%.The combination of HFSRT with pembrolizumab and bevacizumab in patients with recurrent HGG is generally safe and well tolerated. These findings merit further investigation of HFSRT with immunotherapy in HGGs.