tbuckley/cabot-search huggingface dataset:
Abstract 11265: Sex-Specific Response to Endothelin-1 Overexpression Mediates Thoracic Aortic Aneurysm Development
Authors: Vivian Lee-Kim, Deepak Atri, Shamsudheen Vellarikkal, Pierre Paradis, Ernesto L Schiffrin, Rajat Gupta
Journal: Circulation (2021)

Introduction: Thoracic aortic aneurysms (TAAs) are common diseases associated with high morbidity and mortality. Although TAAs are more common in men, women have worse outcomes and dissect at smaller aortic diameters. Endothelin-1 (ET-1) is the most potent vasoconstrictor in humans, and an important mediator of vascular stiffness and tone. ET-1 levels are increased in patients with TAA, and genetic variants that affect ET-1 production and receptor expression are associated with vascular diseases. Though ET-1 levels do not differ between men and women with TAA, it is unknown if response to ET-1 mediates sex-specific differences. Hypothesis: ET-1 has different effects on vascular stiffness and aortic dissection risk in men and women. Methods: Angiotensin-II (AngII) was delivered subcutaneously at 1 ug/kg/min dose and rate using osmotic pumps for 28 days in endothelial cell-specific ET-1 transgenic (eET-1) and matched WT control mice. We measured blood pressure, aortic stiffness, and aortic size at the end of the study. Results: We observed marked sex-specific ET-1 effects on TAA. Despite elevated blood pressure in all animals that received AngII (Fig1A), we observed increased aortic stiffness in male eET-1 mice (+1.5 m/s eET-1 vs. +0.74 m/s WT) but decreased aortic stiffness in female eET-1 mice (-1.9 m/s eET-1 vs. +0.69 m/s WT), measured by pulse wave velocity (Fig1B). Consistent with these results, aortic diameter was only increased in male eET-1 mice (+0.61 mm eET-1 vs. +0.11 mm WT) but not in female eET-1 mice (+0.06 mm eET-1 vs. +0.11 mm WT) (Fig1C). Significantly, 2 of 3 male eET-1 animals died before 28 days from dissected TAAs, whereas all females survived the length of the study. Conclusions: In the AngII-TAA model, there is a sex dimorphic effect of ET-1 overexpression. Male mice have greater vascular stiffness and develop TAA in response to the same level of ET-1 as in matched female mice. This difference may explain the increased incidence of TAA in men.
Abstract 11395: Randomized Feasibility Study of Problem-Solving Therapy Compared to Stroke Education for Depressive Symptoms and Quality of Life in Stroke Survivor-Care Partner Dyads
Authors: Meghan Tierney, Niloufar N Hadidi
Journal: Circulation (2021)

Introduction: Stroke survivors often face multiple physical and/or cognitive disabilities requiring ongoing assistance with activities of daily living. Family members often step in to provide this care. Both stroke survivors and care partners commonly report depressive symptoms impacting health and QOL. Poststroke depression is well-studied in survivors, but care partner depression is less understood. Symptoms shared by stroke survivors and their care partners present opportunities for dyad-focused interventions. Problem-Solving Therapy (PST) is a psychosocial intervention that has been effective for managing depression. We adapted this therapy in a novel way for use with stroke survivor-care partner dyads for reduction of depressive symptoms and improvement in QOL. Our primary aim was to address the feasibility and acceptability of PST with secondary aims measuring changes in PHQ-9 and EQ-5D pre/post intervention. Methods: A convenience sample of 14 adult stroke survivor-care partner dyads were randomized 1:1 to either 6 weekly sessions of PST or 6 matched weekly sessions of stroke-related health education as an attention control group. Participants completed PHQ-9 and EQ-5D at baseline, mid-point, and post-intervention. Survivor functional status and caregiver burden were also assessed at these points. Results: The PST intervention was well-received by dyads with 100% of post-intervention ratings indicating satisfaction or great satisfaction with the experience. Participants reported being challenged to think differently (55.6%), improved dyad communication (44.4%) and feeling a sense of accomplishment (33.3%). Analysis focused on feasibility measures, identifying recruitment challenges and design considerations for subsequent studies. No significant changes in outcome measures were noted in this small sample. Conclusion: A dyad approach to behavioral interventions may promote a sense of well-being by providing an opportunity to address challenges that are faced by both individuals. Feasibility and acceptability were established in this small sample; future studies should focus on a larger, diverse sample. Participant feedback suggests booster sessions may also be helpful in sustaining the impact of this novel approach.
Meteorin-β/Meteorin like/IL-41 attenuates airway inflammation in house dust mite-induced allergic asthma
Authors: Xun Gao, Ting-Fan Leung, Gary Wing-Kin Wong, Wing-Hung Ko, Mengyun Cai, Ellie Jiayi He, Ida Miu-Ting Chu, Miranda Sin-Man Tsang, Ben Chung-Lap Chan, Jiawei Ling, Xiao Fan, Liwei Lu, Christopher Wai-Kei Lam, Chun-Kwok Wong
Journal: Cellular and Molecular Immunology (2021)
SURG-06. THE SAFETY PROFILE OF TUMOR TREATING FIELDS (TTFIELDS; 200 KHZ) CONCOMITANT WITH VENTRICULO-PERITONEAL SHUNTS IN PATIENTS WITH GLIOBLASTOMA AND HYDROCEPHALUS
Authors: Nancy Ann Oberheim-Bush, Wenyin Shi, Michael McDermott, Alexander Grote, Julia Stindl, Leonardo Lustgarten
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Hydrocephalus is a common development in patients with glioblastoma (GBM) requiring treatment with ventriculo-peritoneal (VP)-shunts (programmable/non-programmable). To maximize outcomes in this high-risk population, evaluation of VP-shunt usage concomitant with GBM treatments is necessary. Tumor Treating Fields (TTFields; 200 kHz; anti-mitotic, loco-regional cancer modality) non-invasively delivers continuous, alternating electrical fields per scalp-placed arrays. TTFields treatment has obtained FDA-approval/CE-mark in adult patients with newly-diagnosed GBM (ndGBM) and recurrent GBM (rGBM). Due to insufficient TTFields/VP-shunt usage data, label does not currently advise concurrent use. We report on safety data from adult patients utilizing TTFields/VP-shunts in the real-world, clinical-setting. METHODS This retrospective, post-marketing, safety surveillance analysis evaluated unsolicited data from adult patients with GBM/hydrocephalus who were TTFields-treated in the presence of a VP-shunt. Available data from &amp;gt;18,000 patients with GBM prescribed TTFields (November 1, 2012 to April 15, 2021 [cut-off date]) were screened for eligibility. Included were 156 adult patients (≥ 18 years of age) with confirmed GBM/hydrocephalus and TTFields/VP-shunt (46 programmable; 110 non-programmable/unknown) usage. Patients were further analyzed by diagnosis (ndGBM, n=92; rGBM, n=64). RESULTS Of 156 TTFields/VP-shunt-treated patients (median age 52), 66% were male and 81% from the United States (19%; Europe/Middle-east/Africa). Overall, no TTFields-related shunt-failures or differences by GBM diagnosis in shunt-type and TTFields-related AEs were observed. Commonly-reported TTFields-related adverse events (AEs) &amp;gt;10% were beneath-array skin reactions (∼43%), electric sensations (∼14%; tingling), headache (∼13%), fatigue/malaise (∼12%), and heat sensation (∼11%; warmth); headache and fatigue/malaise are also associated with other concomitant treatments/disease burden. There were 5 serious AEs (all skin AEs) potentially-related to TTFields at the shunt-site (2 events, wound dehiscence; 3 events, skin erosion). CONCLUSIONS Adult patients with GBM/hydrocephalus treated with TTFields (200 kHz)/VP-shunts in the real-world, clinical-setting suggests feasibility and a tolerable safety profile; with no evidence of disrupted VP-shunt effectiveness. TTFields safety profile was consistent with prior-studies.
Abstract 12665: BCL6B is a Putative Endothelial-Specific Master Regulator
Authors: Nicole M Valenzuela
Journal: Circulation (2021)

Introduction: BCL6B (ZBTB28) is highly enriched transcription factor in endothelial cells. Yet, the function and gene targets of BCL6B in vascular endothelial cells (EC) are almost completely unknown. Hypothesis: BCL6B expression is specified in EC by master regulators, and it regulates vascular specific programming. Methods: Using bioinformatics approaches we examined the putative mechanisms of BCL6B regulation in quiescent and activated EC. We examined murine and human endothelial expression and ChIP-Seq datasets; and BCL6B ChIP-Seq data [ENCODE]; and knockdown of Ets family transcription factors. Results: BCL6B was specifically enriched in EC compared with all other lineages in both mouse and human. Its expression did not differ in HUVEC that were freshly isolated or long-term cultured. The chromatin landscape surrounding the BCL6B gene was distinctively accessible in EC but not in 6 other cell types in Encode (high H3K27Ac, H3K4me1, H3K4me3, low H3K9me3), indicative of an active promoter and strong enhancer. Among EC, BCL6B expression was particularly high in heart and lung and further enriched within a pro-angiogenic subset of EC. In EC, BCL6B expression highly correlated with SOX17, ERG and FLI1 expression. Moreover, Erg, Ets1, Jun and Fos transcription factor binding to the BCL6B gene could be demonstrated in endothelium. Knockdown of Erg/Fli1 in EC resulted in significant reduction in BCL6B expression. BCL6 consensus DNA binding motifs are predicted within a number of endothelial immune response genes, intersecting with ETS, NFκB and STAT targets. BCL6B ChIP-Seq data in HEK293T demonstrated nearly 8,500 non-redundant peaks. BCL6B bound PROX1 , LDLR , JAM2 , ETS1 , MECOM , HOXA9/A10 , SPRY2, CD36, CDH5, VWA8, GATA6 CD59, as well as endothelial inflammatory genes CXCL2, IL8, STAT1, CSF1, and CCL20 . Conclusions: BCL6B is constitutively expressed by EC, and is predicted to bind endothelial specification and inflammatory genes. We postulate that BCL6B is critical for maintenance of vascular homeostasis as well as for tuning of endothelial inflammatory responses.
Poziotinib in Non–Small-Cell Lung Cancer Harboring <i>HER2</i> Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial
Authors: Xiuning Le, Robin Cornelissen, Marina Garassino, Jeffrey M. Clarke, Nishan Tchekmedyian, Jonathan W. Goldman, Szu-Yun Leu, Gajanan Bhat, Francois Lebel, John V. Heymach, Mark A. Socinski
Journal: Journal of Clinical Oncology (2021)

Insertion mutations in Erb-b2 receptor tyrosine kinase 2 gene (ERBB2 or HER2) exon 20 occur in 2%-5% of non-small-cell lung cancers (NSCLCs) and function as an oncogenic driver. Poziotinib, a tyrosine kinase inhibitor, was evaluated in previously treated patients with NSCLC with HER2 exon 20 insertions.ZENITH20, a multicenter, multicohort, open-label phase II study, evaluated poziotinib in patients with advanced or metastatic NSCLC. In cohort 2, patients received poziotinib (16 mg) once daily. The primary end point was objective response rate evaluated by independent review committee (RECIST v1.1); secondary outcome measures were disease control rate, duration of response, progression-free survival, and safety and tolerability. Quality of life was assessed.Between October 2017 and March 2021, 90 patients with a median of two prior lines of therapy (range, 1-6) were treated. With a median follow-up of 9.0 months, objective response rate was 27.8% (95% CI, 18.9 to 38.2); 25 of 90 patients achieved a partial response. Disease control rate was 70.0% (95% CI, 59.4 to 79.2). Most patients (74%) had tumor reduction (median reduction 22%). Median progression-free survival was 5.5 months (95% CI, 3.9 to 5.8); median duration of response was 5.1 months (95% CI, 4.2 to 5.5). Clinical benefit was seen regardless of lines and types of prior therapy, presence of central nervous system metastasis, and types of HER2 mutations. Grade 3 or higher treatment-related adverse events included rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). Most patients had poziotinib dose reductions (76.7%), with median relative dose intensity of 71.5%. Permanent treatment discontinuation because of treatment-related adverse events occurred in 13.3% of patients.Poziotinib demonstrates antitumor activity in previously treated patients with HER2 exon 20 insertion NSCLC.
Prediction of lipid nanoparticles for mRNA vaccines by the machine learning algorithm
Authors: Wei Wang, Shuo Feng, Zhuyifan Ye, Hanlu Gao, Jinzhong Lin, Defang Ouyang
Journal: Acta Pharmaceutica Sinica B (2021)

Lipid nanoparticle (LNP) is commonly used to deliver mRNA vaccines. Currently, LNP optimization primarily relies on screening ionizable lipids by traditional experiments which consumes intensive cost and time. Current study attempts to apply computational methods to accelerate the LNP development for mRNA vaccines. Firstly, 325 data samples of mRNA vaccine LNP formulations with IgG titer were collected. The machine learning algorithm, lightGBM, was used to build a prediction model with good performance (R2 > 0.87). More importantly, the critical substructures of ionizable lipids in LNPs were identified by the algorithm, which well agreed with published results. The animal experimental results showed that LNP using DLin-MC3-DMA (MC3) as ionizable lipid with an N/P ratio at 6:1 induced higher efficiency in mice than LNP with SM-102, which was consistent with the model prediction. Molecular dynamic modeling further investigated the molecular mechanism of LNPs used in the experiment. The result showed that the lipid molecules aggregated to form LNPs, and mRNA molecules twined around the LNPs. In summary, the machine learning predictive model for LNP-based mRNA vaccines was first developed, validated by experiments, and further integrated with molecular modeling. The prediction model can be used for virtual screening of LNP formulations in the future.
Abstract 14024: High-Field MRI Advanced Neuroimaging Characterization of Cerebrovascular Damage in a Mouse Model of Hypertension-Induced Cognitive Impairment
Authors: Lorenzo Carnevale, Raimondo Carnevale, Francesco Mastroiacovo, Marialuisa Perrotta, Daniela Carnevale, Giuseppe Lembo
Journal: Circulation (2021)

Introduction: Hypertension in one of the main risk factors for vascular cognitive impairment (VCI) and neurodegenerative pathologies as Alzheimer’s Disease (AD). To identify the underlying mechanisms it is important to use experimental models that present the pathophysiological characteristics of AD and VCI, hence allowing the investigation of molecular processes not explorable in humans. To ease the translational potential of these findings it is fundamental to characterize the brain damage with techniques easily applicable to the cognitive-declining patient, like MRI. Methods: Transverse aortic constriction (TAC) was performed in C57Bl/6J mice to induce severe hypertension to the cerebral vasculature and long term VCI. The cognitive performance at the Morris Water Maze (MWM) and Novel Object Recognition (NOR), the cerebrovascular injury by macro and microstructural MRI and cerebral blood flow (CBF) were analyzed. T2w volumetric images, diffusion tensor imaging, CBF sequences were performed on a small-animal dedicated 7 Tesla MRI. Results: TAC-hypertensive mice displayed significantly reduced learning capabilities, evidenced in the acquisition phase of MWM, and a marked impairment in spatial and short-term memory shown by probe trial in MWM and NOR test. At the structural MRI, TAC mice showed white matter microstructural degradation in the Fimbria, evidenced by a reduction of Fractional Anisotropy (SHAM vs TAC: 0.52±0.01 vs 0.44±0.02, p=0.047), coupled with a hypothalamic swelling (Right: SHAM vs TAC: 7.14±0.09 vs 7.50±0.11mm 3 , p=0.035; Left: SHAM vs TAC: 7.18±0.20 vs 7.91±0.17mm 3 , p=0.019). Hemodynamic alterations resulted in reduced cortical and hypothalamic CBF (Cortex: SHAM vs TAC: 96.6±3.4 vs 77.1±6.8 mL/100mg/min, p=0.046; Hypothalamus: SHAM vs TAC: 140±6 vs 122±4 mL/100mg/min, p=0.025). Furthermore the histological analysis evidenced a capillary rarefaction and reduced capillary-pericyte coverage in the prefrontal cortex, suggestive of a severe impact of the elevated blood pressure on the brain vasculature. Conclusions: In conclusion we have developed a mouse model of hypertension that reproduces typical tracts of the human pathology and a pipeline of analysis that will ease translate findings from bench to bedside.
Low Programmed Death-Ligand 1–Expressing Subgroup Outcomes of First-Line Immune Checkpoint Inhibitors in Gastric or Esophageal Adenocarcinoma
Authors: Joseph J. Zhao, Dominic Wei Ting Yap, Yiong Huak Chan, Benjamin Kye Jyn Tan, Chong Boon Teo, Nicholas L. Syn, Elizabeth C. Smyth, Yu Yang Soon, Raghav Sundar
Journal: Journal of Clinical Oncology (2021)

PURPOSE The US Food and Drug Administration has granted regulatory approval for the use of nivolumab—an immune checkpoint inhibitor (ICI)—in the first-line treatment of advanced gastric or esophageal adenocarcinoma (GEAC), regardless of programmed death-ligand 1 (PD-L1) expression. However, the efficacy of ICIs in low PD-L1–expressing tumors remains unclear. MATERIALS AND METHODS This study aims to reconstruct unreported Kaplan-Meier (KM) plots of PD-L1 combined positive score (CPS) subgroups of randomized phase III trials comparing the addition of ICIs with conventional chemotherapy in the first-line treatment of GEAC. A graphical reconstructive algorithm was adopted to estimate time-to-event outcomes from reported overall survival and progression-free survival (OS and PFS) KM plots describing overall or subgroup cohorts. Using reconstructed time-to-event outcomes, KMSubtraction conducts bipartite matching of patients from the reported subgroup among the overall cohort. By excluding matched patients, KM plots and survival analyses of the unreported subgroups were retrieved. RESULTS CheckMate-649, KEYNOTE-062, and KEYNOTE-590 were included. Two PD-L1 subgroups were identified with data unreported in the primary manuscripts: PD-L1 CPS 1-4 from CheckMate-649 and PD-L1 CPS 1-9 from KEYNOTE-062. No significant differences in OS and PFS were demonstrated in ICI-chemotherapy combinations when compared with chemotherapy among CheckMate-649 PD-L1 CPS 1-4 (OS: hazard ratio [HR] = 0.950, 95% CI, 0.747 to 1.209, P = .678; PFS: HR = 0.958, 95% CI, 0.743 to 1.236, P = .743) and KEYNOTE-062 PD-L1 CPS 1-9 subgroups. In the KEYNOTE-062 PD-L1 CPS 1-9 subgroup, patients treated with pembrolizumab had an increased hazard of tumor progression (HR = 2.092, 95% CI, 1.661 to 2.635, P &lt; .001). CONCLUSION Using KMSubtraction, data of PD-L1 subgroups previously unreported by primary manuscripts of pivotal clinical trials were retrieved. These data suggest the lack of benefit in the addition of ICI to chemotherapy in low PD-L1–expressing GEAC tumors.
Abstract 11842: Graft Flushing Solution Applies Myocardial Protection Properties in Coronary Artery Bypass Grafting
Authors: Philipp Szalkiewicz, Maximilian Y Emmert, Paul Heinisch, Zsuzsanna Arnold, Crailsheim Ingo, Mach Markus, Martin Grabenwöger, Bernhard Winkler
Journal: Circulation (2021)

Introduction: In on-pump coronary artery bypass grafting (CABG) procedures testing of the distal anastomoses via repeated flushing of graft storage solution perfuses at a certain extent the downstream myocardium. This study evaluated the impact of specific solutions on myocardial protection during CABG procedures. Hypothesis: Duragraft® (Somaluthion, Jupiter FL,USA) storage solution exhibits beneficial myocardial protection compared to 0.9% Saline/Biseko® (Biotest Pharma GmbH, Dreieich, Germany). Methods: Between 7/2019 - 3/2020 either Duragraft® (Group A) or 0.9% Saline/Biseko (Group B) was applied during 272 CABG procedures. After propensity matching 166 patients of identical group size (male: 86.7%; 68.1 ± 9.3 years) were analyzed in this single center retrospective study. Cardiac enzymes were evaluated after CABG during hospital stay and compared between both groups. Results: The mean count of venous and overall grafts was 1.5 (± 0.5) and 2.6 (±0.7). No clear difference in the distribution pattern of Creatine Kinase was observed, while high sensitive Troponin I (in nanogram per liter) were significantly lower in Group A at 12-24 hours (4384.9 (± 5509.6) vs. 11566.9 (± 31505,1); p= 0.042), two days (1931.9 (± 3079.8) vs. 4978.5 (± 9145.6); p= 0.05), three days (1473.3 (± 3207.4) vs. 2939.8 (±5564.5); p= 0.046) four days (992.4 (± 1957.3) vs. 1995 (± 3404.8); p= 0.037) and at the sixth day (716.3 (± 1056,2) vs. 1573.9 (±3013.1); p= 0.046) after surgery. Conclusions: Downstream myocardium perfusion with graft solution could provide enhanced myocardial protection in on-pump procedures, with Duragraft® being superior to Saline/Biseko® in terms of Troponin release.
Abstract 10984: The Novel Curcumin Formulation, ASD-Cur Suppressed Myocardial Infarction Induced Heart Failure in Rats
Authors: Hidemichi Takai, Tatsuya Morimoto
Journal: Circulation (2021)

Introduction: Curcumin prevents the development of heart failure, demonstrating that the compound is a potential treatment for the disease. Although curcumin is known to be safe, its therapeutic efficiency is limited due to its low bioavailability. To overcome this problem, we developed ASD-Cur, an amorphous formulation of curcumin. Hypothesis: ASD-Cur have greater therapeutic potency than Theracurmin ® , a colloidal submicron dispersion of curcumin. Methods: Male SD rats were orally administrated with ASD-Cur or Theracurmin ® (10 mg/kg curcumin). The plasma levels of curcumin were measured at 0.25, 0.5, 1, 2, 4 and 6 hours after administration. Twelve healthy volunteers, who had provided written informed consent, were administrated with ASD-Cur or Theracurmin ® containing 30 mg curcumin, and plasma curcumin concentrations were determined at 0.5, 1, 2, 4 and 8 hours. Next, the rats were subjected to MI or sham surgery. One week after surgery, the MI rats were randomly assigned to 4 groups: vehicle, ASD-Cur (0.2 mg/kg curcumin), or Theracurmin ® (0.2 or 0.5 mg/kg curcumin). Daily oral administration of these compounds was repeated for 6 weeks. After echocardiographic examination, myocardial cell diameter, perivascular fibrosis, mRNA levels, and the acetylation of histone H3K9 were measured. Results: After administration, the area under the plasma concentration-time curve (AUC 0-6h ) and the maximum plasma concentration (C max ) of ASD-Cur were 3.7-fold and 9.6-fold higher than those of Theracurmin ® , respectively. The AUC 0-8h and C max of ASD-Cur in humans were 3.4-fold and 5.4-fold higher than those of Theracurmin ® , respectively. Echocardiographic analysis showed that 0.2 mg/kg ASD-Cur and 0.5 mg/kg Theracurmin ® significantly improved both MI-induced reduction in FS and left ventricular hypertrophy to the same extent. Both treatments significantly suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, mRNA levels of hypertrophic markers and cardiac fibrosis, and the acetylation of histone H3K9 to the same extent. Conclusions: These findings indicated that ASD-Cur has greater bioavailability than Theracurmin ® , and could have greater therapeutic potency towards MI-induced heart failure at a lower dose.