tbuckley/cabot-search huggingface dataset:
CTNI-35. UPDATE ON THE FEASIBILITY STUDY OF OKN-007 IN COMBINATION WITH TEMOZOLOMIDE AND RADIATION IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: James Battiste, Deborah Wright, Chad Glenn, Ian Dunn, Ozer Algan, Tyler Gunter, Daniel Zhao, Andrew Cohoon, Sarah Sung, Rheal Towner, Hyon sook Kim
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Temozolomide (TMZ) with concurrent radiation is the traditional standard of care for newly diagnosed glioblastoma. Unfortunately, this combination has limited efficacy and resistance can render TMZ ineffective. The novel anti-cancer agent OKN-007 plus TMZ increased survival in preclinical studies. Therefore, we initiated a phase Ib/feasibility clinical trial (NCT03587038) of OKN-007 in combination with TMZ and radiation therapy (RT). We report the safety and tolerability findings of this trial in-progress. METHODS Adults with newly-diagnosed GBM were eligible. OKN-007 was administered by IV at 60 mg/kg. There were three treatment phases: Concomitant, Pre-Maintenance, and Maintenance. In the Concomitant Phase, patients received OKN-007 three times per week (Cohort A) or five times per week (Cohort B); all patients receive TMZ at 75 mg/m2 daily and RT at 60 Gy over 30 fractions. In the 28-day Pre-Maintenance Phase, all patients receive OKN-007 thrice weekly. In the Maintenance Phase (MP), comprising up to eighteen 28-day cycles, TMZ was dosed at 150-200 mg/m2 on days 1-5 of each cycle for six cycles. OKN-007 was administered thrice weekly for six cycles, then twice weekly for three cycles, then once weekly for nine cycles. Each cohort was evaluated for safety with 3-6 patients followed by an expansion of cohorts if safety parameters were met. RESULTS Three patients completed Cohort A without dose-limiting toxicity (DLT). In Cohort B, two DLT’s (hematologic toxicities deemed to be related to TMZ) occurred, and this cohort was stopped. Currently, median PFS and OS have not been reached due to lack of events, but preliminary data indicate improved median PFS and OS compared to standard of care. CONCLUSIONS The treatment plan appears safe and well-tolerated at the Cohort A combination dosing level and may increase favorable treatment outcomes suggesting that the OKN-007 warrants further study.
IMMU-35. INDUCTION OF ANTI-TUMOR IMMUNITY BY TUMOR TREATING FIELDS (TTFIELDS) IN GLIOBLASTOMA
Authors: Dongjiang Chen, Son Le, Tarun Hutchinson, Dan Jin, Mathew Sebastian, Tianyi Liu, Ashley Ghinaseddin, Maryam Rahman, David Tran
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION The novel approved GBM treatment TTFields employs alternating, intermediate-frequency (200kHz) electric fields to disrupt mitotic macromolecules leading to chromosome mis-segregation and apoptosis. Emerging evidence indicates that TTFields may also induce inflammation; however, the mechanism and whether this can be harnessed as cancer immunotherapy remain unclear. METHODS Multiple GBM cell lines were treated with TTFields using Inovitro, an in vitro TTFields system and integrity of the nuclear envelope and content and activation of key DNA sensor inflammatory pathways analyzed by immunostaining, expression profiling, and protein assays. In a syngeneic orthotopic murine model, TTFields-treated GBM cells were used to provide an in-situ vaccination platform. For validation, we performed bulk and single-cell RNAseq of PBMCs from 12 newly diagnosed GBM patients treated with TTFields. RESULTS TTFields induce focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that recruit and intensely activate the 2 major DNA sensors – cGAS and AIM2, and their cognate inflammasomes, thereby releasing pro-inflammatory cytokines and type-1 interferons (T1IFNs) that promote development and maturation of DCs and cytotoxic T cells. In murine model, TTFields-treated GBM cells induce anti-tumor memory immunity both intratumorally and systemically, producing a cure rate of 40% and partial immunity in an additional 25% in a STING- and AIM2-dependent manner. In patients with newly diagnosed GBM patients, we sequenced a total of 193,760 PBMCs and detected robust post-TTFields activation of adaptive immunity via the T1IFN trajectory anchored by plasmacytoid DCs, which was strongly correlated with the TCRαβ clonal expansion index observed in 11 of 12 patients (Spearman coefficient r=-0.8, P=0.014). Importantly, we also defined a T cell-based gene signature predictive of TTFields effects on T cell activation and TCRαβ clonal expansion. CONCLUSION Collectively, these studies define a novel strategy using TTFields to improve immunotherapy in GBM and potentially other solid tumors.
Abstract 12338: Promotion of Arteriolar Differentiation of Vascular Endothelial Cells by PKD-1/CD36 Signaling-Mediated Chromatin Remodeling
Authors: Ana K Gutierrez-Garcia, Emily Spangler, Adam Beck, Bin Ren
Journal: Circulation (2021)

Vessel narrowing and occlusions reduce blood supply to end tissues, leading to myocardial infarction in the heart or tissue loss in the peripheral vasculature. Effective approaches are needed to establish de novo arteriogenesis to treat these conditions. An essential first step is to understand mechanisms of arteriolar differentiation, in which transcriptional reprogramming of vascular endothelial cells (ECs) may be critical. Our previous studies indicate that protein kinase D (PKD-1) is required for arterial differentiation and plays an essential role in proarteriogenic reprogramming via transcriptional inhibition of antiangiogenic receptor CD36 via histone deacetylase HDAC7. We hypothesize that PKD-1/CD36 signaling initiates an epigenetic reprogramming of ECs for arteriolar differentiation via chromatin remodeling. To test this hypothesis, we isolated primary heart and lung ECs from wild-type control, EC-specific cd36 KO or pkd-1 KO mice. Total RNA was extracted for expression of arteriogenic genes by RT-qPCR. The proteins were collected for Western blotting and ChIP assays. Our results showed that when CD36 was downregulated in primary ECs from hearts and lungs, the expression levels of PKD-1 and arteriogenic genes EphB2 and DLL4 were significantly elevated compared to controls (p &lt; 0.05). Intriguingly, we observed a significant increase in protein expression of neuropilin1. In contrast, in heart ECs from the EC-specific pkd-1 KO mice, arteriogenic gene expressions were downregulated whereas CD36 expression was significantly upregulated. Using the ChIP assay, we measured the interactions between H3K9 on the CD36, DLL4, or EphB2 promoters using ECs from EC-specific cd36 and pkd-1 KO mice. In conclusion, our results indicate that an epigenetic reprogramming regulates arteriolar differentiation at a transcriptional level by chromatin remodeling. PKD-1 signaling may dictate CD36 transcriptional levels, thereby reprogramming ECs for arteriolar differentiation by inducing an arteriogenic gene signature, which may contribute to de novo arteriogenesis under ischemic conditions.
IMMU-20. HYDROGEL-CXCL9 VACCINE RESULTS IN MRNA DELIVERY TO DENDRITIC CELLS AND POTENT ANTI-TUMOR RESPONSES IN GBM
Authors: Farhad Dastmalchi, Aida Karachi, Yusuf Mehkri, Ashley O’Malley, Vignesh Subramaniam, Thomas Angelini, Duane Mitchell, Maryam Rahman
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Our group and others have shown mRNA-vaccines have significant anti-tumor efficacy in the treatment of brain tumors and are currently being tested in first-in-human trials. To further enhance mRNA delivery, a hydrogel platform was developed with the addition of CXCL9 to promote immune cell trafficking. METHODS We generated the vaccine by utilizing a hydrogel platform. CXCL9 and Nano-mRNA were loaded into the hydrogel. In vitro recruitment of DCs and NK was evaluated by fluorescence microscopy. In vivo recruitment of immune cells was analyzed by flowcytometry after collecting the fat pad, spleen, and tumor samples from KR158b-luc and Gl261-gp100 tumor-bearing animals 3, 5 and 10 days after vaccine delivery. The efficacy of the vaccine was evaluated by measuring overall survival, and tumor growth was measured by IVIS live-imaging. RESULTS Dendritic cells(DCs) and natural killer(NK) cells were able to efficiently migrate within the hydrogel-CXCL9 platform and uptake and express mRNA in vivo. In vitro, the hydrogel-CXCL9 was combined with nanoparticles loaded with total tumor RNA, and the vaccine was delivered to KR-158-luc and GL261-gp100 tumor-bearing animals via mammary fat pad SQ injection. Flow cytometry of the fat pad and draining lymph nodes demonstrated showed significant recruitment of endogenous DCs including inflammatory-DC(P= 0.0035), conventional-DC1(P= 0.0076), pDC(P=0.0028), NK(p= 0.0025 compared to the control group. In two different tumor models, a single dose of the vaccine resulted in significant survival benefits compared to control animals (n=10,P&amp;lt; 0.0001). SQ injection was superior to intracranial injection of the vaccine. Vaccinated animals showed an increased number of antigen-specific CD8 T cells in spleen(P= 0.0001) and tumor-microenvironment(P= 0.0070). CONCLUSION The hydrogel-CXCL9 platform results in efficient delivery of mRNA loaded nanoparticles to endogenous DCs and also causes an upregulation of NK cells with resultant improved survival in murine GBM models including the highly resistant KR158 model with a single dose. Further studies are ongoing.
Abstract 13126: Sudden Cardiac Arrest in Asian Americans: Prospective Evaluation in Two US Communities
Authors: Harpriya Chugh, Arayik Sargsyan, Audrey Uy-Evanado, Damon Klebe, Chad Sorenson, Bernadine Dizon, Kotoka NAKAMURA, Faye L Norby, Angelo Salvucci, Jonathan Jui, Sumeet S Chugh, Kyndaron Reinier
Journal: Circulation (2021)

Background: There is a lack of data on epidemiology of sudden cardiac arrest (SCA) in the Asian-American community. We have recently reported lower annual incidence of SCA in Asian compared to White non-Hispanic residents of Ventura County, CA. However, the generalizability of these findings has not been evaluated. Hypothesis: We hypothesized that these trends are observed in other US communities. Methods: An epidemiologic assessment of SCA was performed and compared in Ventura County, CA (2018 Pop 848,112; study period 2015-2021) and Multnomah County, OR (2010 Pop 712,036; study period 2002-2014). All out-of-hospital SCA cases with likely cardiac etiology and resuscitation attempted by emergency medical services (EMS) were prospectively ascertained. We calculated race-specific annual age-adjusted SCA incidence using the US standard population and compared incidence and resuscitation outcomes between Asians and Whites in both counties. Results: A total of 2084 SCA cases were identified in VC (65% male; mean age 71 ± 16 y) and 4149 in MC (69% male; mean age 63 ±18 y). Asian and White SCA cases were similar by age and sex in both counties (p=0.08). In VC, annual age adjusted incidence per 100,000 was 29.4 in Asians and 36.8 in Whites (p=0.02). In MC, annual age adjusted incidence per 100,000 was 22.8 in Asians and 31.1 in Whites (p=0.002). No significant differences were observed in bystander CPR provision or 911 call response time (p&gt;0.23), but Asians were less likely than Whites to present with shockable rhythm (VF/VT) in both locations (VC 10% vs 26%, p&lt;0.001; MC 36% vs 44%, p=0.07). Survival to hospital discharge following SCA was similar in Asian and White residents in VC (Asians 8.4%, Whites 12%, p=0.25) and MC (Asians 11.9%, Whites 14.1%, p=0.52). Conclusion: We observed lower annual incidence of SCA among Asians compared to Whites in these two separate and geographically distinct US communities. Emergency response and outcomes of arrest were similar in Asians and Whites, despite a lower presentation with a shockable rhythm among Asians. Further study is required to determine whether lower SCA incidence in Asians is explained by a lower risk factor burden or other factors.
Abstract P309: Particulate Matter Increases Oxidative Stress And Shortens The Action Potential In IPS-derived Cardiomyocytes
Authors: Mariana Argenziano, jiajia yang, Mariana Burgos Angulo, Thomas V McDonald
Journal: Circulation Research (2021)

Introduction: Air particulate matter (PM) represents one of the most critical environmental issues worldwide, causing more than 3 million deaths a year. In the US, hospital admissions due to heart failure (HF) increase by 0.8% for every 10 μg/m3 elevation in PM. However, the biological mechanisms behind the effects of PM on cardiovascular disease (CVD) remain poorly defined. Recent studies showed that PM 2.5 can translocate into the circulation, causing cumulative toxicity. With air pollution increasing due to human activity and the growing prevalence of HF, there is a critical need to understand PM's contributions to CVD to develop preventive treatments and novel therapeutic approaches. Hypothesis: We hypothesize that PM can exert its toxic effect by increasing oxidative stress and apoptosis and affecting cardiac electrophysiology. Methods: Three independent induced pluripotent stem cell lines (IPSC) were differentiated into cardiomyocytes (iCMs) and cultured for 30 days before treatment with 100 μg/ml of PM 2.5 for 48h. Experiments including immunostaining, qPCR, RNAseq and Multielectrode Array (MEA) were performed in control (CT) and PM-treated iCMs (PM). Results: Treatment with PM increased ROS and decreased ATP production (CT 9.9±1.2pmol vs PM 6.6±0.8pmol, p&lt;0.01, n=20). Immunostaining showed mitochondrial fragmentation and increased expression of cleaved caspase3 without structural changes. Moreover, PM caused upregulation of the apoptotic markers P53 , PARP1 and CASP3, oxidative stress markers CYP1A1, CYP1B1 and MT2A, and cardiac markers CACNA1C together with downregulation of GJA1 . RNAseq analysis showed upregulation of Gene Ontology terms related to detoxification, response to toxic substances and oxidative stress. Upregulated KEGG pathways included oxidative phosphorylation, hypertrophic cardiomyopathy and dilated cardiomyopathy. MEA experiments revealed a decrease in the spike amplitude and conduction velocity, along with shortening of the action potential (APD90: CT 577±20ms vs. PM 489±16ms, p&lt;0.05, n=20) and increased beat period irregularity (CT 3.2±0.7% vs. PM 13.1±1.6%, p&lt;0.001, n=20). These electrophysiological changes were reversed by treatment with the antioxidant N-acetylcysteine. Conclusions: We conclude that PM plays a direct role in the development of CVD, causing an increase in oxidative stress and affecting the electrophysiology of the heart. Further functional studies in iCMs from HF patients will provide evidence of the effects of these changes on the phenotype of the disease.
Abstract 13445: Precise Score Validation in Buenos Aires 1 Registry
Authors: Florencia Munoz, Cristian M Garmendia, Marcos Viruel, Juan Costabel, Rosina Arbucci, Ernesto Duronto, Horacio E Fernandez
Journal: Circulation (2021)

Introduction: The PRECICE DAPT Score predicts the bleeding risk in patients treated with dual antiplatelet treatment after primary percutaneous coronary intervention (pPCI). Hypothesis: We sought to assess and compare the prediction power of the PRECISE-DAPT score with regards to bleeding events in patients suffering from non-ST elevation acute coronary syndromes (NSTEACS) and undergoing invasive management in a real- world scenario from Argentina. Methods: Our external validation cohort included 862 patients from Buenos Aires 1 registry. The PRECISE DAPT score was calculated upon admission and the characteristics and evolution of the patients were analyzed in a period of 15 months. The ability of PRECISE-DAPT to predict BARC type 2, 3 or 5 bleeding and BARC type 3 or 5 bleeding and ischemic events (MACE: myocardial infarction, stent thrombosis, or ischemic stroke) during follow up was evaluated. Results: PRECISE-DAPT score was low effective at predicting bleeding events type 2, 3 or 5 (c-statistics 0.58 [95% CI, 0.52-0.61]) moderate at BARC 3 or 5 (c-statistics 0.72 [95% CI, 0.64-0.78]), and poor for MACE (c-statistics 0.49 [95% CI, 0.,45-0.51]). Calibration was accurate (χ2 &gt; 0.05) in all scenarios. High PRECISE-DAPT score (≥25, n= [%]) was associated with very high risk of bleeding (HR 2.1) and ischemic events (HR 1.9) Conclusions: In real-world study, PRECISE DAPT was moderately accurate in predicting bleeding and ischemic events. PRECISE DAPT score ≥25 was able to identify a subgroup of patients with high bleeding and thrombotic events.
Abstract 12549: Population Patterns of Clustering in Cardiovascular Health Metrics and Associations With Cardiovacular Disease: A Latent Classpopulation Patterns of Clustering in Cardiovascular Health Metrics and Associations With Cardiovacular Disease: A Latent Class Analysis
Authors: Hongyan Ning, Juned Siddique, Sadiya Khan, Amanda M Perak, Norrina Allen, John T Wilkins, Don Lloyd-jones
Journal: Circulation (2021)

Background: Cardiovascular health (CVH) is defined by 7 health behaviors (smoking, diet, physical activity) and factors (body mass index, blood pressure, total cholesterol, glucose). we sought to explore how CVH components cluster in individuals and examine associations of clusters with cardiovascular disease (CVD). Methods: Participants aged 20-79 years were included from four longitudinal cohorts. Levels of each CVH metric were classified as ideal, intermediate, or poor using AHA definitions. Among sex and race subgroup, we applied latent class analysis (LCA) models on CVH metrics and individuals were assigned to a class based on the highest posterior probability of membership. Cox regression model was conducted to estimate the association of cluster and the CVD events. Results: Among 9270 White and 3913 Black women, and 7773 White and 2875 Black men, 6004 CVD events occurred during 19.5 years’ follow-up. Three common classes were observed (Figure 1): Suboptimal (unfavorable behaviors and factors), Mixed (diverse levels of behaviors and factors), and Favorable factors. One additional class of Unfavorable Behaviors (with relatively favorable factors) was identified in Whites. Compared with Favorable factors, other classes had significantly higher risk for CVD (Figure 2), except in Black women. Conclusions: We observed three common clusters of CVH component, with an additional class of Unfavorable Behaviors (only) in White participants, that were significantly associated with incident CVD across subgroups. Given that 27-47% of participants were in the Suboptimal group, multifaceted primordial prevention strategies will be needed to bend the CVD epidemic curve.
Abstract 8881: Comprehensive Assessment of Systemic Atherosclerosis in Relation to the Ocular Resistive Index in Acute Coronary Syndrome Patients
Authors: Yasunari Ebuchi, daisuke fukamachi, Keisuke Kojima, Taiji Nagaoka, Nobuhiro Murata, Akihito Ohgaku, Yutaka Koyama, Hidesato Fujito, Riku Arai, Masaki Monden, Takehiro Tamaki, Daisuke Kitano, Yasuo Okumura, Satoru Yamagami
Journal: Circulation (2021)

Introduction: It remains unclear how systemic atherosclerosis can affect ocular microvessels. The abnormality of the ocular microvasculatures can be non-invasively detected by measuring ocular arterial blood flow velocity using laser speckle flowgraphy (LSFG). Among the ocular blood flow parameters obtained by LFSG, the ocular blowout time (BOT) and the ocular resistivity index (RI) are used as the index of retinal vascular resistance. The purpose of this study was to investigate the relationship between ocular vascular resistance evaluated by LSFG and cardiac function evaluated by transthoracic echocardiography in patients with acute coronary syndrome (ACS). Methods: We evaluated 53 patients with ACS who were taken to Coronary Care Unit between April 2019 and September 2020. The mean blur rate (MBR), the ocular blowout time (BOT) and the ocular resistivity index (RI) were measured by LSFG. In addition, the age-matched normal subjects were also evaluated the measurement of LSFG in 20 healthy subjects with no ocular disease and no history of cardiovascular disease. Results: Among all ACS patients, there were significant positive correlations between ocular RI and systemic parameters, i.e., IMT(r = 0.34, P = 0.01), PWV(r = 0.41, P &lt; 0.01), BUN(r = 0.27, P = 0.047), cystatin C(r = 0.32, P = 0.020), urinary β2 microglobulin(r = 0.30, P = 0.029), L-FABP(r = 0.28, P = 0.046), and E/e’(r = 0.34, P = 0.013). There was also significant negative correlation between ocular BOT and PWV(r = -0.44, P &lt; 0.01). Age-matched comparing the selective ACS (n=20) with healthy group (n=20), the ocular RI was significantly higher in the ACS group (0.34 ± 0.04 vs 0.38 ± 0.07, P = 0.03). Conclusions: We found that the ocular resistivity index, which was non-invasively obtained by LSFG, was associated with systemic atherosclerosis, early renal dysfunction and cardiac diastolic dysfunction in ACS patients, suggesting that it might be useful index as an non-invasive comprehensive arteriosclerotic markers.
Abstract 13788: Systematic Review: Utility of Human Immune Responses to Group A Streptococcus Antigens as a Diagnostic Indicator for Acute Rheumatic Fever
Authors: Taariq M Salie, Kimona Rampersadh, Babu Muhamed, Kelin Engel, Liesl Zuhlke, James Dale, Mark E Engel
Journal: Circulation (2021)

Introduction: Previous studies have established that group A streptococcus (GAS) antibody titre is correlated with a diagnosis of acute rheumatic fever (ARF). However, results vary in the usefulness of GAS antibodies, particularly anti-Streptolysin-O (ASO) and anti-DNase B, in confirming a recent GAS infection. Therefore, we sought to provide, from published studies, an evidence-based synthesis of the correlation of streptococcal serology to establish the usefulness of immunological data in aiding the diagnosis of ARF. These findings are anticipated to have implications where echocardiography is not freely available, especially where ARF is rampant. Methods: We conducted a comprehensive search across a number of databases. Applying a priori criteria, we selected articles reporting on studies, regardless of study design, that evaluate the levels of antibodies against GAS-specific antigens in ARF subjects against control values or a published standard. Data were extracted onto data extraction forms, captured electronically and analysed using STATA software. Risk of bias was assessed in included studies using the Newcastle-Ottawa Scale . Results: The search strategy yielded 534 studies, from which 24 met the inclusion criteria, reporting on evaluation of titres for SLO (n=10), DNase B (n=9), anti-streptokinase (ASK) (n=3) amongst others. Elevation in titres was determined by comparison with controls and upper limit of normal (ULN) antibody values as determined in healthy individuals. Meta-analysis of case-controlled studies revealed moderate odds ratio (OR) correlations between ARF diagnosis and elevated titres for SLO (OR=10.57; 95% CI, 3.36 to 33.29; 10 studies) and DNase B (OR=6.97; 95% CI, 2.99 to 16.27; 7 studies). Conclusions: While providing support for incorporating SLO and DNase B in the diagnosis of ARF, we present the following reflections: an elevation in SLO and DNase B levels are not consistently associated with an ARF diagnosis; increasing the number of GAS proteins in the test is warranted to improve sensitivity; paired (acute and convalescent) samples could provide a more accurate indication of a rising titre. Use of community-based controls as a standard is not a reliable marker by which to gauge recent GAS infection
Helminths make themselves at home
Authors: Elia D. Tait Wojno
Journal: The Journal of Experimental Medicine (2021)

Drurey et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20211140) show that excretory/secretory products from the parasitic helminth Heligmosomoides polygyrus suppress the host-protective small intestinal epithelial response. These findings establish that helminths directly modulate the tissue in which they live, shining new light on the host–parasite interaction.