tbuckley/cabot-search huggingface dataset:
Abstract 12359: Measuring Continuous Changes in Individual Cardiovascular Risk for People With Diabetes and Pre-Diabetes
Authors: Lindsay Sears, Jorge Guerra, Veena Patel, Lindsay Sears, Dan Goldner, Jeff Dachis
Journal: Circulation (2021)

Objective: For people attempting to lower cardiovascular disease (CV) risk through self-care, feedback on progress can be a strong motivator. Many CV risk scores, however, are based on binary inputs (e.g., whether the subject is diagnosed with diabetes or hypertension). In such cases, incremental improvements in health metrics (e.g., blood glucose, BG; blood pressure, BP), though known to reduce CV risk, will not necessarily reduce the risk score. We modified a well-known risk score to accept continuous inputs and used the modified score to estimate CV risk variability over time for a large sample of people with diabetes. Method: One Drop has collected over 25 billion data points from members in all 195 countries, including BP, BG, weight, medication, food, physical activity, heart rate, sleep, comorbidities and demographics. The INTERHEART risk score (IRS) uses CV risk factor information to compute a score ranging from 0 to 40, each point representing a 12% increase in risk. We transformed the risk ratios from published studies of CV risk factors (i.e., BG, BP, BMI, BP medications) to align with the IRS scale, interpolating among reported values by fitting functions via constrained optimization. We applied the modified risk assessment retrospectively to data collected between 2016-2021. Results: Among the 2,150 One Drop members included, the majority did not report gender (43%; 32% male) and had type 1 diabetes (78%; 14% type 2; 1% prediabetes; 7% other) with BMI of 28.8±6.9. CV risk scores varied from 2 to 23 IRS points, with six-month standard deviations ranging from 0.008 to 6.379 IRS points. Variations over time for individuals were driven by changes in BG (r = 0.89) more than BP (r = 0.70). Conclusion: Established CV risk scores can be modified to replace binary inputs with continuous inputs. This provides a more granular measure of risk to enable more specific intervention personalization and detect smaller changes in risk over time when evaluating interventions. Moreover, people working to lower their CV risk could benefit from seeing that even small changes in their BG, BP, weight and use of medications lead to a reduction of CV risk.
Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro
Authors: Luz Garcia-Alonso, Louis-François Handfield, Kenny Roberts, Konstantina Nikolakopoulou, Ridma C. Fernando, Lucy Gardner, Benjamin Woodhams, Anna Arutyunyan, Krzysztof Polanski, Regina Hoo, Carmen Sancho-Serra, Tong Li, Kwasi Kwakwa, Elizabeth Tuck, Valentina Lorenzi, Hassan Massalha, Martin Prete, Vitalii Kleshchevnikov, Aleksandra Tarkowska, Tarryn Porter, Cecilia Icoresi Mazzeo, Stijn van Dongen, Monika Dabrowska, Vasyl Vaskivskyi, Krishnaa T. Mahbubani, Jong-eun Park, Mercedes Jimenez-Linan, Lia Campos, Vladimir Yu. Kiselev, Cecilia Lindskog, Paul Ayuk, Elena Prigmore, Michael R. Stratton, Kourosh Saeb-Parsy, Ashley Moffett, Luiza Moore, Omer A. Bayraktar, Sarah A. Teichmann, Margherita Y. Turco, Roser Vento-Tormo
Journal: Nature Genetics (2021)

Abstract The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma.
Abstract 11689: Among Patients Hospitalized for Infective Endocarditis, There is No Association Between Solid Organ Transplant Recipient Status and In-Hospital Mortality: A Retrospective Cohort Study From National Inpatient Sample 2016-2017
Authors: Nischit Baral, Olga Santiago-Rivera, Tripti Gupta, Mahin Khan, Hafiz Khan, Abhijeet Ghatol, Sagar Mallikethi Lepakshi Reddy, Basel Abdelazeem, Govinda Adhikari, Arvind Kunadi, parul sud, Hameem U Changezi
Journal: Circulation (2021)

Introduction: Infective endocarditis (IE) is a serious complication following solid organ transplant (SOT) including heart or lung transplant, however, we only have few outcome based studies on this topic. Hypothesis: SOT recipients hospitalized for IE have higher in-hospital mortality compared to non-SOT. Methods: This is a retrospective cohort study from IE hospitalizations using 2016-2017 National Inpatient Sample (NIS) in patients 18 years or older. The primary outcome was in-hospital mortality. Secondary outcomes were length of stay (LOS), and total charges. We performed multivariable logistic regression (in-hospital mortality) and negative binomial regression models (LOS and total charges) to test our hypothesis. Model were adjusted for potential confounders including age, sex, race, insurance, income level, and comorbidities. STATA 17.0 (Stata-Corp LP, College Station, TX) was used for data analysis. Results: There were 14,294,784 hospitalizations in 2016 and 2017. Our final study sample consisted of 5,477 IE discharges with the mean age of 52.1 years old (SD= ±19.12; range 18 to 90 yrs), 0.60 % (n=33) were SOT recipients, 41% were female (p=1.00), and 76.4% were White (p=0.12). Weighted bivariate group (SOT vs non-SOT) analyses suggested that SOT recipients had statistically higher proportion of Charlson comorbidity index of three or more (90.91% vs 33.13%; p&lt;001). SOT IE patients had a higher prevalence for the following co-morbidities: diabetes mellitus (24.24% vs 12.67%; p=0.05) and kidney disease (90.91% vs 21.6%; p&lt;0.001). SOT recipient status did not have statistically significant association with in-hospital mortality (aOR 0.50; 95% CI: 0.07, 3.83; p = 0.508) after controlling for confounders. Similarly, there were not statistically significant difference in length of stay (β= -0.167; linearized SE ±0.17; 95% CI: -0.50, 0.17; p=0.323) or total healthcare cost (β = -0.29; linearized SE ±0.27; 95% CI -0.82, 0.24; p= 0.284). Conclusions: Among IE patients, SOT recipient status is not associated with higher or lower in-hospital mortality compared to non-SOT. Moreover, SOT status is not associated with significant differences in resource utilization (hospital LOS and total hospitalization charges).
Incidence, Risk Factors and Outcomes of Pancytopenia Following Chimeric Antigen Receptor (CAR)-T Cell Therapy in Relapsed Refractory Diffuse Large B Cell Lymphoma
Authors: Malini Surapaneni, Samer Alkassis, Seongho Kim, Abhinav Deol, Lois Ayash, Asif Alavi, Andrew Kin, Voravit Ratanatharathorn, Joseph P. Uberti, Dipenkumar Modi
Journal: Blood (2021)
Abstract 252: Accurate ECG Interpretation With Use of the Analysis During Compressions With Fast Reconfirmation (ADC-FR) Technology
Authors: Qing Tan, Annemarie Silver, Frederick J Geheb
Journal: Circulation (2013)

Background: Use of Analysis during Compressions with Fast Reconfirmation (ADC-FR) technology, which features automated rhythm analysis and charging during chest compressions (CCs) with a brief reconfirmation analysis during CC pause, has been shown to reduce CC interruptions compared with standard AED operation. The purpose of this study was to determine the accuracy of the ADC-FR algorithm. Methods: A retrospective analysis was conducted of AED Pro and AED Plus defibrillator records (ZOLL Medical) containing ECG and CC acceleration data, collected as part of a registry, from the treatment of 624 out-of-hospital cardiac arrest patients. With ADC-FR, the ECG rhythm is interpreted during CCs using an advanced algorithm and the defibrillator is charged the last 10 seconds of the CC interval. A quick reconfirmation analysis is initiated after the rescuer stands clear to confirm the shock/no-shock result of the analysis performed during CCs. If the analysis during CC and reconfirmation analysis agree, the defibrillator is immediately armed (if shockable) or disarmed (if non-shockable). If the reconfirmation analysis and analysis during CCs differ, an additional analysis is conducted. For ADC-FR testing, the CC acceleration signal was used to identify CC intervals followed by a CC-free period of at least 6 seconds (for reconfirmation analysis) and the ADC-FR algorithm was applied. The analysis results were saved in text files, which were used to calculate algorithm accuracy. Results: A total of 2059 advisories were generated by the ADC-FR algorithm. As shown in the table, the ADC-FR advisory algorithm accuracy exceeded the AHA performance goals for all rhythms. Conclusions: The ADC-FR algorithm produces accuracies better than performance goals recommended by AHA even though the performance goals are for algorithm tests with artifact-free ECG signal. Therefore, the ADC-FR can be used to reduce CC pauses while preserving shock decision accuracy.
Abstract 11062: The δC Isoform of Ca2+/Calmodulin-Dependent Protein Kinase II (camk2) Regulates Cardiac Metabolic Substrate Switching in Mice
Authors: Alireza Saadatmand, Mark E Pepin, Matthias Dewenter, Uwe Haberkorn, Johannes Backs
Journal: Circulation (2021)

Introduction: Ca2+/calmodulin-dependent protein kinase II (CaMK2) is a recognized driver of pathological cardiac remodeling and heart failure, but its role in the metabolic reprogramming of heart f...
Exploring sentinel conditions and the accrual sequence of multiple long-term condition multimorbidity using birth cohort and primary care data: an exploratory retrospective cohort study
Authors: Emilia Holland, Sebastian Stannard, Nisreen Alwan, Michael Boniface, Rebecca Hoyle, Zlatko Zlatev, Sarah Crozier, Mazen Ahmed, James McMahon, William Ware, Simon D S Fraser
Journal: The Lancet (2021)
IDH1/2 Mutations Are Maintained in a Subset of Patients with Acute Myeloid Leukemia in Complete Remission and Do Not Correlate with Residual Disease
Authors: Giovanni Marconi, Lorenza Bandini, Agnese Patuelli, Chiara Sartor, Sarah Parisi, Jacopo Nanni, Gianluca Cristiano, Letizia Zannoni, Giorgia Simonetti, Maria Teresa Bochicchio, Emanuela Ottaviani, Giovanni Martinelli, Stefania Paolini, Cristina Papayannidis, Michele Cavo, Antonio Curti
Journal: Blood (2021)
Positive and negative selection shape the human naive B cell repertoire
Authors: Jeff W. Chen, Jean-Nicolas Schickel, Nikolaos Tsakiris, Joel Sng, Florent Arbogast, Delphine Bouis, Daniele Parisi, Ruchi Gera, Joshua M. Boeckers, Fabien R. Delmotte, Margaret Veselits, Catharina Schuetz, Eva-Maria Jacobsen, Carsten Posovszky, Ansgar S. Schulz, Klaus Schwarz, Marcus R. Clark, Laurence Menard, Eric Meffre
Journal: Journal of Clinical Investigation (2021)

Although negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naive B cell positive selection remains elusive. Using 2 humanized mouse models, we demonstrate that there was strong skewing of the expressed immunoglobulin repertoire upon transit into the peripheral naive B cell pool. This positive selection of expanded naive B cells in humanized mice resembled that observed in healthy human donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymus-derived Tregs and MHC class II–restricted self-antigen presentation by B cells. Indeed, both defective MHC class II expression on B cells of patients with rare bare lymphocyte syndrome and prevention of self-antigen presentation via HLA-DM inhibition in humanized mice resulted in the production of autoreactive naive B cells. These latter observations suggest that Tregs repressed autoreactive naive B cells continuously produced by the bone marrow. Thus, a model emerged, in which both positive and negative selection shaped the human naive B cell repertoire and that each process was mediated by fundamentally different molecular and cellular mechanisms.
Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma
Authors: Takashi Ishio, Sarvesh Kumar, Joji Shimono, Anusara Daenthanasanmak, Sigrid Dubois, Yuquan Lin, Bonita Bryant, Michael N. Petrus, Emmanuel Bachy, Da Wei Huang, Yandan Yang, Patrick L. Green, Hiroo Hasegawa, Michiyuki Maeda, Hideki Goto, Tomoyuki Endo, Takashi Yokota, Kanako C. Hatanaka, Yutaka Hatanaka, Shinya Tanaka, Yoshihiro Matsuno, Yibin Yang, Satoshi Hashino, Takanori Teshima, Thomas A. Waldmann, Louis M. Staudt, Masao Nakagawa
Journal: Blood (2021)

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild-type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.
Assessing Bone Marrow Activity in Patients with Essential Thrombocythemia and Prefibrotic Myelofibrosis: Results of a Pilot Study of [<i>18F</i>]FLT PET
Authors: Mohamed A Yassin, Sadek A Nehmeh, Abdulqadir Jeprel Nashwan, Samah Kohla, Shehab Fareed Mohamed, Omer Ismail, Ahmad Al Sabbagh, Lajos Szabados, Dina Sameh Soliman, Hadi Fayad
Journal: Blood (2021)
TAMI-11. INCREASED M1 MACROPHAGE INFILTRATION CORRELATED WITH POOR PROGNOSIS OF WHO IV GLIOMAS
Authors: zhaoming Zhou, Mingyao Lai, Jiangfen Zhou, Qingjun Hu, Ruyu Ai, shaoqun Li, Cheng Zhou, Linbo Cai
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Gliomas are the malignancy with a poor prognosis. Our previous database mining study demonstrated that M1 macrophage infiltration predicted the survival of GBM patients. Here in this study, we further explored the findings. METHODS RNA-seq was performed on 90 WHO IV glioma tissue samples. The sequencing data was investigated with xCell for the cell infiltration levels, and the M1 macrophage infiltration was further analyzed for the prognostic prediction effect with overall survival (OS) data. Differentially expressed genes (DEGs) were calculated between groups and the hub genes were determined by the MCC models in Cytoscape. The survival risk score (SRS) calculating models were established by several machine learning methods, including the least absolute shrinkage and selection operator (LASSO), generalized linear model (GLM), and linear discriminant analysis (LDA). RESULTS Compared with M1 macrophages none infiltration, WHO IV gliomas with M1 macrophages infiltration was associated with poor prognosis, and this result remained significant in multivariate analyses (hazard ratio [HR], 0.219; 95% CI, 0.047–0.723; P = 0.035). Protein-to-protein (PPI) network analysis of top 200 up-regulated DEGs determined 10 hub genes (P4HB, PDIA6, LAMB1, PRKCSH, CSF1, LAMB2, LGALS1, RCN1, CALU, and TNC). Further analysis determined that the 10 hub genes were enriched in the ECM-receptor interaction signaling pathway, and six out of the ten gene expressions were confirmed by immunohistochemistry staining. Based on the 6 genes, a survival risk score (SRS) was established by machine learning methods. SRS was able to distinguish the high-risk and low-risk WHO IV gliomas with an AUC = 0.80 [95% CI: 0.74 – 0.86, P &amp;lt; 0.01]. CONCLUSIONS M1 macrophage infiltration was an unfavorable prognostic biomarker for WHO IV gliomas. ECM-receptor interaction signaling pathway was involved in M1 macrophage infiltration. Hub genes in the signaling pathway could be the potential therapeutic targets for WHO IV gliomas.
TAMI-75. LIPID METABOLISM AS A THERAPEUTIC VULNERABILITY IN BET INHIBITOR-RESISTANT MEDULLOBLASTOMA
Authors: Leslie Lupien, Adam Boynton, Rushil Kumbhani, Gabrielle Gionet, Amy Goodale, David Root, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2021)

Abstract MYC-driven medulloblastomas are a particularly devastating group of pediatric brain tumors that exhibit resistance and continued progression despite standard of care treatments. Our preclinical work identified BET-bromodomain inhibitors as a potentially promising new class of drugs for children with medulloblastoma and other MYC-driven cancers, providing rationale to evaluate these agents in clinical trials. However, treatment with BET inhibitor (BETi) alone is unlikely to be sufficient for a cure, with most tumors evolving to acquire resistance to single-agent targeted therapies. We applied an integrative genomics approach to identify genes and pathways mediating BETi response in medulloblastoma. These studies revealed that MYC-driven medulloblastoma cells with acquired resistance to BETi reinstate transcription of essential genes suppressed by drug, and exhibit changes in cell state and new vulnerabilities not present in drug-sensitive cells. We now have a growing body of evidence showing that BET inhibition downregulates the expression of key lipid metabolism genes and metabolism-related signaling pathways, and that medulloblastoma cells with adaptive resistance to drug differentially express and exhibit preferential dependency on specific lipid metabolic genes and transcriptional regulators. Our studies explore the possibility of exploiting these novel metabolic vulnerabilities in order to overcome BETi resistance and provide a more efficacious upfront therapy.
Abstract P378: Metabolic Dysregulation Of Endothelial Sk Channels Via Protein Kinase C
Authors: Hang Xing, Guangbin Shi, Yuhong Liu, Frank W Sellke, Jun Feng
Journal: Circulation Research (2021)

Introduction: Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease, which predisposes to ischemic cardiovascular events. Small conductance calcium-activated-potassium (SK) channels are largely responsible for coronary arteriolar relaxation mediated by endothelium-dependent hyperpolarizing factors. Diabetic inactivation/inhibition of endothelial SK channels contributes to endothelial dysfunction. Endothelial dysfunction during diabetes (DM) is also associated with increases in metabolites NADH, and PKC. The pyridine nucleotide NADH has been recently found to inactivate endothelial SK channels. The overexpressed and activated PKC has been shown to play an important role in diabetes-induced endothelial dysfunction. However, it is undefined if PKC is involved in the metabolite NADH dysregulation of endothelial SK channels. Hypothesis: We hypothesized that PKC in a signaling cascade whereby NADH dysregulates endothelial SK channels. Methods: SK channels currents of human coronary artery endothelial cells were measured by whole cell patch clamp method in the presence or absence of NADH, and/or PKC activator PMA, PKC inhibitors or endothelial PKC α /PKCβ knock-down by using short interfering RNA. Results: NADH (30-300μM, n=7-9) or PKC activator PMA (30-300μM, n=6-12) reduced endothelial SK current density (p&lt;0.05 vs. control (n=15), Fig. A-D), whereas the selective PKC α inhibitor LY333531 (50nM, n=12) significantly reversed the NADH-induced SK channel inhibition (p&gt;0.05 vs. control (n=15), Fig. E). PKC α knock-down failed to affect NADH (n=13) and PMA (n=10) inhibition of endothelial SK currents (Fig. F). In contrast, PKCβ knock-down significantly prevented NADH (n=12) and PMA (n=6)-induced SK inhibition (p&gt;0.05, vs. control, Fig. G). Conclusions: The metabolite NADH dysregulation of endothelial SK channels was via PKCβ activation.
TAMI-45. MICROGLIAL CYTOKINES INDUCE INVASIVENESS AND PROLIFERATION THROUGH PYK2 AND FAK ACTIVATION IN HUMAN GLIOBLASTOMA CELL
Authors: Rebeca Nunez, Miguel Mayol-Del Valle, Luis Almodovar, Lilia Kucheryavykh
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most aggressive and highly invasive primary brain tumor in adults. Evidence suggests that microglia create a microenvironment favoring glioma invasion and proliferation. Indeed, previous reports indicate the involvement of focal adhesion kinase (FAK) signaling cascades in glioma cell proliferation. Besides, studies from our laboratory support a critical role of Pyk2, a relative of FAK, in glioma invasion by tumor-infiltrating microglia. However, the microglial-released factors modulating Pyk2 and FAK signaling pathways are unknown. In this study, 20 human GBM specimens were evaluated to identify the cytokine expression patterns in purified microglia and FAK and Pyk2 phosphorylation in glioma cell fraction by RT-PCR and western blot. A Pierson correlation test demonstrated a high correlation (0.8-1.0) of gene expression for PDGFα, PDGFβ, SDF-1α, IL-6, IL-8, and EGF in percoll-purified microglia, and pPyk2(Y579/580) and pFAK(Y925) levels in glioma cell fraction. The role of cytokines in cell invasion and proliferation by Pyk2/FAK activation was further investigated in primary cell lines from three patients. Thirty percent up-regulation of pPyk2 and pFAK was detected in glioma cells treated (2 hrs.) with microglia conditioned media (MCM) compared to control cells. siPyk2 or siFAK knockdown identified IL-6 (100 μM) and EGF (1 μM) as key factors of Pyk2- and FAK-dependent activation in all glioma cell lines. Similar results with siPyk2 or siFAK were observed for matrix degradation, invadopodia formation, cell viability, and mitosis. Indeed, Tocilizumab (IL-6R blocker, 100 ng/mL) and Gefitinib (EGFR blocker, 1 μM) reversed the effect of MCM on glioma cell proliferation and invasion in all cell lines evaluated. These findings support a pivotal role of Pyk2 and FAK in enhancing proliferation and invasion of glioma tumors through IL-6 and EGF-dependent pathways. The latter could be of clinical relevance for new therapeutic developments in GBM patients.