tbuckley/cabot-search huggingface dataset:
Abstract 11572: Plasma Proteomic Signature Implicates Impaired Calcium Handling and Cell-Matrix Adhesion in Repaired Tetralogy of Fallot with Right Ventricular Volume and Pressure Overload
Authors: Ingrid Lan, Aihua Zhu, Jennifer E Van Eyk, Sushma Reddy
Journal: Circulation (2021)

Introduction: Patients with repaired tetralogy of Fallot (TOF) are subject to chronic volume and pressure loading leading to a 40% probability of right ventricular (RV) failure by the 3 rd decade of life. We sought to identify a non-invasive, circulating signature of the systemic response to right heart stress to better understand the mechanisms of RV failure and to develop novel therapies. Methods: High throughput mass spectroscopy was used to assess circulating plasma proteins in controls with structurally normal hearts (N=14) and in TOF s/p repair (N=74): no residual lesion (N=4), severe right heart volume overload (N=28), severe right heart pressure overload (N=20), and moderate right heart volume and pressure overload (N=22). Ingenuity pathway analysis was used to identify enriched biological processes using proteins with log2 fold change&gt;0.6, and q value &lt;0.05. Results: Mean age in controls was 15±2yrs, 50% male and in TOF s/p repair 17±14yrs, 34% male. The RV was moderately dilated with normal function in those with volume and/or pressure overload. We identified (i) excellent proteomic coverage identifying &gt;1500 proteins/sample; (ii) unique subset of proteins distinguishing control from tetralogy of Fallot with residual defects (Fig 1); (iii) upregulated pathways involved signal transduction (CREBBP), catabolic processes (NT5M), cell death and aging (FUCOA 2-fold); (iv) downregulated pathways involved immune response (IGHV4), complement and coagulation activation (VWF), regulation of calcium handling (S100A 12-fold) and cell-extracellular matrix adhesion. Conclusion: Patients with TOF s/p repair with RV volume and pressure overload have a distinct proteomic profile implicating heightened cell death pathways and impaired calcium handling which may predispose to heart failure and arrhythmias. These data suggest peripheral blood proteins can provide insight into the mechanisms of RV failure and can be used for monitoring disease progression.
Housing interventions for women experiencing intimate partner violence: a systematic review
Authors: Alexa R Yakubovich, Alysha Bartsch, Nicholas Metheny, Dionne Gesink, Patricia O'Campo
Journal: The Lancet Public Health (2021)

BackgroundIntimate partner violence (IPV) is the leading cause of women's homelessness. However, what works best to respond to the needs of women experiencing IPV and homelessness remains unclear. We aimed to systematically review the effects of housing interventions on the physical, psychosocial, and economic wellbeing of women experiencing IPV.MethodsIn this systematic review, we searched 15 electronic databases and conducted an extensive grey literature and hand reference search between Jan 29, 2020, and May 31, 2021. We included controlled quantitative studies of housing interventions (from emergency shelter to permanent supportive housing) that were reported in English, without time restrictions, and examined any physical, psychosocial, or economic outcomes among women experiencing IPV. We critically appraised included studies using the Cochrane Effective Practice and Organisation of Care criteria and extracted data using a piloted extraction form. We synthesised our results using harvest plots to summarise whether the weight of the evidence suggested benefits, disadvantages, or null effects; patterns by study quality; and evidence gaps. This study is registered with PROSPERO, CRD42020176705.FindingsWe screened 23 902 unique records and identified 34 eligible studies with quantitative data on the outcomes of housing interventions among women experiencing IPV. Most studies evaluated the outcomes of either shelter interventions (18 studies [53%]) or shelter plus some other programming (eight [24%]). The remaining eight studies evaluated longer-term housing solutions, including supportive housing (five studies [15%]), critical time interventions (one [3%]), transitional housing (one [3%]), and stay-at-home models (one [3%]). There was no cumulative evidence of disadvantages following any IPV-housing intervention. Evidence of benefits was strongest for mental health outcomes, intent to leave partner, perceived safety, and housing and partner-related stress. Included studies were at high risk of bias across most domains (eg, confounding).InterpretationThere is promising evidence on the continuum of IPV-housing services for women, especially in terms of proximal outcomes, such as mental health, intent to leave partner, safety, and housing stress. However, more research of higher quality is needed, particularly on long-term housing solutions and from outside of the USA.FundingThe Social Sciences and Humanities Research Council (430-2021-01176) and Canadian Institutes of Health Research (HSI-166388).
EXTH-20. SINGLE-CELL DRUG ACTIVITY MAPPING IN GLIOBLASTOMA IDENTIFIES EXTENDED DRUG RESPONSE HETEROGENEITY AND THERAPY-INDUCED CELLULAR PLASTICITY
Authors: Dena Panovska, Asier Antoranz, Pieter-Jan Creemers, Marleen Derweduwe, Pouya Nasari, Gabriele Orlando, Sofie Van Gassen, Annelies Claeys, Tatjana Verbeke, Lien Solie, Raf Sciot, Paul Clement, David Van der Planken, Michiel Verfaillie, Frederic Rousseau, Joost Schymkowitz, Yvan Saeys, Keith Ligon, Steven De Vleeschouwer, Frederik De Smet
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) remains a highly malignant and incurable brain tumour. The inability to achieve clinical improvements in GBM treatment can be attributed to the excessive heterogeneity and plasticity of GBM cells, which is reflected by the presence of various cellular states within each tumour. How each of these tumour cell subtypes respond to therapy remains largely unknown. In this work, we developed a functional diagnostic analysis pipeline to measure therapeutic activity in GBM tumour cells at single-cell resolution using mass cytometry by time-of-flight (CyTOF). By applying an optimised GBM-specific and therapy-tailored antibody panel, we measured therapeutic activity upon exposure to ionising radiation (RT) or a small molecule MDM2 inhibitor (AMG232) in a cohort of patient-derived GBM cell lines (n=14). As such, extended heterogeneity in drug responsiveness was reflected by diverse degrees of alterations in cell cycle progression and apoptotic signalling, in addition to shifts in tumoral phenotypic states implying therapy-induced plasticity. A similar approach was used to measure drug activity in freshly resected tumour samples (n=18) harvested from different tumour regions (core or invasive front) within hours following surgery. Accordingly, we identified highly variable fractions of responsive tumour and microenvironmental cell populations in a patient-specific way. The ability to measure drug activity at single-cell resolution in a patient-tailored manner by applying a genotype-agnostic method, paves the way for advanced precision cancer medicine in GBM by offering a novel approach to more precisely select eligible patients for prospective clinical trials.
Updates in the Management of Early-Stage Diffuse Large B-Cell Lymphoma
Authors: Thomas M. Habermann
Journal: Journal of the National Comprehensive Cancer Network (2021)

Several important updates have emerged in the management of early-stage diffuse large B-cell lymphoma. Three trials resulted in the approval of rituximab + cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) for use in these patients internationally. Furthermore, studies have been initiated to determine whether 4 or 6 cycles of this regimen should be administered without radiation therapy (RT). Six cycles of R-CHOP plus central nervous system (CNS) prophylaxis and prophylactic testicular RT are recommended for patients with extranodal disease occupying the testicles. Although controversial, there is a reasonable consensus in the literature to consider 6 cycles of R-CHOP plus involved-site RT and CNS prophylaxis for patients with extranodal disease of the breast. Patients with primary bone and gastric extranodal disease do not seem to derive a significant survival benefit from RT. Molecular subtype evaluations may change treatment approaches.
NCOG-21. PREDICTORS OF SURVIVAL IN ELDERLY PATIENTS UNDERGOING SURGERY FOR GBM
Authors: Mathew Voisin, Sanskriti Sasikumar, Gelareh Zadeh
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND An increasing number of elderly patients are being diagnosed with GBM and undergoing surgery. These patients often present with multiple medical comorbidities and have significantly worse outcomes compared to adult patients. The goal of this study was to determine clinical predictors of survival in elderly patients undergoing surgery for GBM. METHODS A retrospective chart review of all consecutive patients 65 years of age and older that underwent surgery for newly diagnosed GBM from 2005-2018 was performed. A total of 150 patients were included, and subdivided into two age categories; 65-74 and 75 or older. RESULTS Advanced age and medical comorbidities were not associated with decreased survival (p = 0.07 and p = 0.09, respectively). Postoperative complication was associated with worse survival for all patients (HR = 2.34, p = 0.01) and occurred in patients with longer lengths of stay (p &amp;lt; 0.0001) and discharge destination other than home (p = 0.001). CONCLUSIONS The presence of medical comorbidities and advanced age are not reasons to exclude patients with GBM from surgical consideration. Postoperative complication is the most significant predictor of survival in elderly patients and can be avoided by a short length of stay and discharge home.
Abstract 12261: Access to Care among Hispanic Patients Hospitalized for Lower Extremity Peripheral Artery Disease
Authors: Kristie M Harris, Paulina Luna, Yulanka Castro-Dominguez, Carolina Severiche, Kim G Smolderen, Carlos Mena-hurtado
Journal: Circulation (2021)

Introduction: Compared to other racial/ethnic groups, Hispanics are less likely to access regular primary care, which can delay detection and management of PAD. It is unknown whether in admissions for PAD, a trend towards more burden is observed for Hispanic vs. non-Hispanic White (NHW) patients. We therefore examined emergency department (ED) and elective admissions, length of stay (LOS), and costs accrued by ethnicity in patients hospitalized for primary PAD. Methods: The 2011-2017 National Inpatient Sample data were used to identify admissions in Hispanics and NHWs and whether the patient sought care via the ED and if the admission was elective. Yearly and overall percentages for each were determined, and temporal trends evaluated with the Cochran-Mantel-Haenszel test, stratified by ethnicity. Differences in median LOS and cost by ethnicity were evaluated with the Wilcoxon rank sum test. Results: From 2011-2017, there were 1,018,220 PAD hospitalizations (39% female, 14% Hispanic) and the percentage of patients who accessed inpatient care via the ED increased in Hispanics and NHWs, but was consistently higher in Hispanics (Fig. 1, all P trend &lt;0.0001). Across all years, 58.0% (82,047 of 141,551) of admissions in Hispanics were via the ED compared to 36.7% (321,932 of 876,669) in NHWs ( d =0.48) and elective admissions were higher in NHWs (396,294; 45.2%) than in Hispanics (38,661; 27.3%, d =0.43). Median LOS (4.5 vs. 3.7 days) and cost ($63,813 vs. $52,368) were higher in Hispanics than NHWs ( p &lt;.0001). Conclusions: Hispanic patients are more likely than NHWs to seek emergent, non-elective inpatient PAD care and to be admitted for longer and accrue greater costs. They are also increasingly more likely to access this care via the ED which may provide fewer barriers than other settings, especially for uninsured patients or those without legal immigration status. More accessible outpatient care may potentially reduce ED burden and improve PAD management for this population.
Abstract 13459: Human iPS-Derived Pre-Epicardial Cells Direct Cardiomyocyte Aggregation Expansion and Organization <i>in vitro</i>
Authors: Jacques P Guyette, Jun Jie Tan, Harald C Ott
Journal: Circulation (2021)

During heart maturation, epicardial-derived cells emanating from the pro-epicardial organ envelope the developing heart, then integrate within the myocardium and undergo epithelial-mesenchymal transition (EMT) to become fibroblasts, smooth muscle cells, and endothelial cells that enable several processes of healthy heart morphogenesis (i.e., ventricular thickening, compaction, and angiogenesis). Directed cardiac differentiation of human induced-pluripotent stem cells (hiPSCs) holds great potential for generating several cardiovascular cell types, which can theoretically be combined to model cardiac development more completely and engineer sophisticated myocardial grafts. Here, we show that differentiating hiPSC-derived lateral plate mesoderm (LPM) with BMP4, RA and VEGF (BVR) for 96 hours can generate a premature form of epicardial cells (termed pre-epicardial cells, PECs) with high efficiency (86.8 ± 4.1% WT1 + by FACS), that also show significant increases in WT1, TBX18, SEMA3D , TBX5, BNC, and SCX transcript expression within 7 days. This protocol was successfully reproduced in three commercial lines of hiPSCs. BVR stimulation after Wnt inhibition of LPM demonstrated efficient co-differentiation and spatial organization of PECs and cardiomyocytes (CMs) in a single 2D culture. Co-culture consolidated CMs into dense aggregates, which then formed a connected beating syncytium with significantly enhanced contractility (0.029 ± 0.002 mN/mm 2 ; p&lt;0.05 vs. CMs-alone and co-culture controls), improved calcium handling (i.e. amplitude, upstroke, and decay), sarcomere length (1.82 ± 0.02 μm vs. 1.72 ± 0.03 μm, p=0.00264) and mitochondrial density (79.4 ± 3% vs. 54.9 ± 6%, p=0.0029). Co-cultured PECs demonstrated enhanced maturity to epicardial cells with significant upregulation of UPK1B, ITGA4, and ALDH1A2 transcript expressions. Our study also demonstrated that PECs secrete IGF2 and stimulate CM proliferation in co-culture (37.2 ± 2.1% vs. 28.1 ± 1%, p=0.016). These characteristics suggest PECs could play a key role in enhancing cell-cell signaling and tissue organization, which may help to recapitulate important aspects of cardiac morphogenesis in vitro and advance the maturation of bioengineered cardiac constructs.
Abstract 14011: Myomegalin, a 250 Kilodalton Phosphodiesterase Interacting Protein (PDE4DIP), Shows a Novel Protein Interaction With Cardiac Myosin Binding Protein C
Authors: Emily T Farrell, Wenxuan Cai, Willem J De Lange, Ying Ge, John C Ralphe
Journal: Circulation (2021)

Cardiac myosin binding protein C (cMyBP-C) is a sarcomeric protein important in the regulation of cardiac contraction through its phosphorylation-dependent interactions with myosin heavy chain and actin. MYBPC3, the gene encoding cMyBP-C, contains the largest number of hypertrophic cardiomyopathy (HCM)-causing mutations. Interestingly, the region of MYBPC3 containing the greatest number of HCM-causing missense mutations, the central domains, have an unknown physiological relevance to the overall function of the protein. Intriguingly, central domain C3 contains a positively charged, putative surface binding interface for an as-yet unidentified ligand. Two of the most common HCM-causing mutations, R495Q and R502W, located in C3, appear to alter this charged interface. We have previously shown that these two mutations lead to altered contractile kinetics and hypophosphorylation of cMyBP-C. We hypothesize that this region of C3 contains an important binding region that is disrupted by both the R495Q and R502W mutations. To reveal candidate binding proteins, we performed a pull-down assay using mouse cardiac homogenate and a GST-tagged C2-C4 fragment of cMyBP-C, with or without the R495Q mutation. Mass spectrometry revealed that myomegalin, a 250 kDa phosphodiesterase-4D-interacting protein (PDE4DIP), bound the WT, but not the R495Q C2-C4 fragment. To confirm the interaction between cMyBP-C and myomegalin in situ , we performed Duolink proximity ligase assay (PLA) in cultured neonatal mouse cardiomyocytes which revealed a positive interaction in cMyBP-C +/+ but not in cMyBP-C -/- cells (n&gt;20) (Figure). Our data strongly suggest that a large isoform of myomegalin, separately known to form a protein complex with PKA/AKAP, forms a novel interaction with cMyBP-C. We hypothesize that perturbations in this interaction lead to altered PKA localization and the observed changes in R495Q and R502W cMyBP-C phosphorylation, and may contribute to the HCM phenotype.
CD38 Down-Regulation on <i>Ex Vivo</i> Activated and Expanded NK Cells for Cell Therapy Persists after Infusion
Authors: Hareth Nahi, Michael Chrobook, Stephan Meinke, Charlotte Gran, Nicole Marquardt, Gabriel Afram, Tolga Sutlu, Mari Gilljam, Birgitta Stellan, Arnika Kathleen Wagner, Lilian Walther-Jallow, Johan Liwing, Monika Klimkowska, Goesta Gahrton, Per Ljungman, Hans-Gustaf Ljunggren, Evren Alici
Journal: Blood (2021)
Abstract 10535: Tissue-Incubation-Chamber Provides Enhanced Viability of Porcine Aortic Valve Tissue in Dynamic Long-Term Culture
Authors: Claudia Dittfeld, Maximilian Winkelkotte, Florian Schmieder, Stephan Behrens, Anett Jannasch, Klaus Matschke, Frank Sonntag, Sems-Malte Tugtekin
Journal: Circulation (2021)

Introduction: Aortic valve (AV) stenosis is caused by fibrosis and calcification of the three-layered valve tissue. Current in vitro and in vivo models are insufficient to reflect cell-cell or cell-matrix interaction and pathophysiological processes. Therefore a novel tissue incubation chamber (TIC) enabling dynamic AV-tissue culture in micro-physiological systems (MPS) was designed to improve emulation of the extreme in vivo conditions of the cardiac cycle. This pilot study aims to verify tissue viability to ensure applicability of the TIC in conjunction with a MPS in AV research. Methods: Porcine AV tissue of 3x5 mm is maintained in the TIC for 14 days within a conventional cell incubator under sterile conditions. A pump-chip able to generate a pulsatile flow rate of 13.4 μl/s (150 bpm) accomplishes average shear forces of 0.017 dyn/cm 2 . Two viability assays were performed to compare dynamic and static setups. AV samples were snap frozen, cryo sectioned and intracellular LDH activity in central tissue regions was visualized using a Tetrazolium-based dye. In addition, a Resazurin reduction assay (50-300 μM) was applied. Results: The LDH-viability stain reveals no significant reduction of viable tissue sections in dynamically incubated AV tissues (96.4 ± 1.3 %) but a significant decrease in the static counterparts (67.8 ± 4.7 %, n=3). The Resazurin assay on the other hand showed significant viability reduction in dynamic setup after 12 days (57 ± 5.4 %), whereas significant reduction was already detected in static culture after 8 days (57.5 ± 15.1 %, n=4). Due to the discrepancy of both viability assays, an inadequate diffusion rate based on structural AV tissue integrity was hypothesized with the need to adapt Resazurin assay concentration. A saturation curve conducted consecutively determined an optimal Resazurin concentration of 300μM to be used in upcoming AV tissue culture (n=4). Conclusion: Enhanced viability of porcine AV tissue following dynamic incubation in the TIC was achieved but further adaptation in terms of higher shear forces and a more physiological sample fixation is envisioned. Dynamically cultured AV tissue cultures in the novel TICs offer a relevant improvement for investigation of AV pathophysiology.
Nanoparticle delivery of recombinant IL-2 (BALLkine-2) achieves durable tumor control with less systemic adverse effects in cancer immunotherapy
Authors: Jun Kim, Seounghun Kang, Kyoung Won Kim, Myeong-Gang Heo, Dae-In Park, Joon-Hyung Lee, Nam Ju Lim, Dal-Hee Min, Cheolhee Won
Journal: Biomaterials (2021)

Recent strategies in cancer immunotherapy based on interleukin-2 (IL-2) are generally focused on reducing regulatory T cell (Treg) development by modifying IL-2 receptor alpha (IL-2Rα) domain. However, the clinical utility of high-dose IL-2 treatment is mainly limited by severe systemic toxicity. We find that peritumorally injectable 'BALLkine-2', recombinant human IL-2 (rIL-2) loaded porous nanoparticle, dramatically reduces systemic side effects of rIL-2 by minimizing systemic IL-2 exposure. Notably, in cynomolgus monkeys, subcutaneous (SC)-injection of BALLkine-2 not only dramatically reduces systemic circulation of rIL-2 in the blood, but also increases half-life of IL-2 compared to IV- or SC-injection of free rIL-2. Peritumorally-injected BALLkine-2 enhances intratumoral lymphocyte infiltration without inducing Treg development and more effectively synergizes with PD-1 blockade than high-dose rIL-2 administration in B16F10 melanoma model. BALLkine-2 could be a highly potent therapeutic option due to higher anti-tumor efficacy with lower and fewer doses and reduced systemic toxicity compared to systemic rIL-2.
Abstract 12777: Bmi1 Mediates Chromatin Remodeling and Redox Homeostasis for Cardiac Repair After Myocardial Injury
Authors: Lindsay Kraus, Marcus J Wagner, Tabito Kino, Sadia Mohsin
Journal: Circulation (2021)

Introduction: Myocardial injury leads to oxidative stress that has a significant impact on the development and progression of disease. Increasing evidence suggests that oxidative stress globally influences chromatin landscape of the cells. Effects of oxidative stress on these chromatin alterations mediate a number of cellular changes, including DNA damage, cell death, and accelerated senescence which are all disease-driving mechanisms during the failing heart. Targeting oxidative stress-dependent pathways is thus a promising strategy for the prevention and treatment after myocardial injury. The Polycomb complex protein BMI-1 (Bmi1) an epigenetic regulator, is associated with numerous biological functions including, mediating DNA damage control, ROS signaling and senescence. However, there is currently a lack of understanding on how Bmi1 mediates epigenetic modifications affecting heart function during injury and is a focus of this study. Hypothesis: The epigenetic regulation by Bmi1 mediates reparative process after myocardial injury by regulating ROS production. Specifically, Bmi1 modulates the epigenetic landscape of cardiac cells that mediates various molecular processes during development and stress conditions. Methods and Results: Using a Bmi1 knockout (KO) model through the induction of a tamoxifen Cre recombinase system, cardiac function is determined through echocardiography using adult mice following myocardial infarction. The Bmi1 KO has a significant decrease in heart function after myocardial infarction, which has been associated with increased cellular ROS production, fibrosis, and apoptotic mechanisms which are measured by fluorescent ROS assays, TUNEL assays, western blotting, PCR, and immunohistochemistry. To date, we have found that cardiac cells, including adult cardiomyocytes and adult cardiac fibroblasts, isolated from the Bmi1 KO model have increased cellular ROS production, increased expression of fibrotic genes including Acta2, Vimentin, Collagen, and increased expression of apoptotic pathway regulators including Aldo1, Eno1, NFkB, Ap-1, and HIF1-a. Conclusions: Bmi-1 regulation mediates repair during pathological challenge by regulating ROS production after myocardial injury.