tbuckley/cabot-search huggingface dataset:
Abstract P400: Treatment With The AMPK Agonist AICAR Alleviates Age-associated Cardiac Defects In The Mouse By Distinct Sex-specific Mechanisms
Authors: Aude Angelini, Jesus Ortiz-Urbina, JoAnn Trial, Mark L Entman, George E Taffet, Katarzyna A Cieslik
Journal: Circulation Research (2021)

Heart failure is a major cause of mortality in the elderly. Features of cardiac aging include diastolic dysfunction and interstitial fibrosis with sex-specific differences. We treated old male and female mice (21 months-old) 3 times a week for 3 months with the AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR, 0.166 mg/g BW). We previously reported that AICAR normalizes the aged fibroblast phenotype. In a longitudinal study, we found that AICAR attenuates the age-associated increase in left atrial volume, an indirect indicator of diastolic dysfunction, in female AICAR-treated mice (-29% ±5%) but not in males (-7% ±6%). Cardiac fibroblasts from AICAR-treated mice expressed decreased pro-collagen levels by 42% (mean fluorescence intensity, P=0.0003 for females, and P=0.05 for males). Cardiac fibroblasts cultured on decellularized cardiac matrices also had a reduced expression of pro-collagen when treated with AICAR (0.5mM, 7 days). Myocardial hydroxyproline level (an indicator of total collagen content) was reduced in female hearts (from 0.83 ± 0.07 in controls to 0.48 ± 0.05 in AICAR-treated, P=0.006). Female cells also exhibited a reduced expression of periostin after treatment (by 65%, P=0.02). By contrast, age-matched control males had a lower cardiac level of hydroxyproline (-65%, P=0.0002) and periostin (-45%, P=0.0004) than females, and were not affected by the treatment. Accumulation of defective mitochondria is a hallmark of aging. Since AICAR can favor mitophagy, we isolated mitochondrial fractions from the hearts of old mice undergoing treatment. We found that AICAR decreased Parkin level in the small mitochondria fraction (0.75±0.09, P=0.028) in males, but no significant change was found between the groups of females. The reduction of Parkin may suggest improved clearance of defective mitochondria.For all experiments, we used 4-10 animals per group. One-way Anova or student’s T-test evaluated statistical significance. In conclusion, age-associated cardiac remodeling leads to distinct patterns between male and female mice. AICAR treatment can have sex-specific effects: it reduces fibrosis in females but may promote mitophagy in males, translating into an improvement of heart function via distinct mechanisms.
EPID-17. COMPARATIVE EPIDEMIOLOGY OF PRIMARY BRAIN TUMORS AMONG ADOLESCENTS AND YOUNG ADULTS (AYA)
Authors: Nayan Lamba, Bryan Iorgulescu
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION We utilized national registry data to evaluate the unique epidemiology of primary adolescent and young adult (AYA) brain tumors according to the WHO2016 classification. METHODS AYA patients (15≤age≤39) presenting between 2004-2017 with a brain tumor were identified by ICD-O-3 coding from the National Cancer Database (comprising &amp;gt;70% of newly-diagnosed cancers in the U.S.), and compared to pediatric and adult populations. Epidemiology and overall survival (estimated by Kaplan-Meier techniques and multivariable Cox regression) were assessed by WHO2016 tumor type. RESULTS 108,705 AYA brain tumor patients were identified (56.9% female), compared to 23,928 pediatric (46.8% female) and 748,272 adult (55.6% female) patients. Among the 69.4% of AYA brain tumors with pathological diagnosis, diffuse gliomas (31.4%), sellar tumors (19.2%), and meningiomas (15.3%) predominated in both sexes. Diffuse glioma (31.4%), sellar (19.2%), cranial nerve (7.3%), and mesenchymal non-meningothelial (4.1%) tumors represented a greater proportion of AYA brain tumors than in either pediatric or adult populations. A majority of all intracranial GCTs (59.2%) and neuronal &amp; mixed neuronal-glial tumors (51.6%) presented during AYA. Although the prevalence of diffuse gliomas was similar between AYAs and adults, AYA gliomas were more likely to be grade 2-3 astrocytomas (38.9% vs 14.3%) and oligodendrogliomas (19.3% vs 4.3%) than in adults. GBMs represented 76.0% of adult diffuse gliomas vs. only 25.7% of AYA diffuse gliomas, but with a similar prevalence of MGMT promoter methylation (40.8% vs 38.4%). Notably, 50.7% of AYA PCNSLs were associated with HIV/AIDS, vs only 7.1% in adults (p&amp;lt; 0.001). CONCLUSIONS The distribution, epidemiology, and survival outcomes of primary brain tumors in the AYA population are distinct from their pediatric and adult counterparts. Notably, AYA infiltrative gliomas were more often of lower grade than adults and AYA PCNSL were far more likely to be associated with HIV/AIDS. Primary brain tumors in AYA patients require specialized management.
Genetic Screening of Patients with Evans Syndrome: A Single Centre Analysis
Authors: Maurizio Miano, Daniela Guardo, Alice Grossi, Elena Palmisani, Francesca Fioredda, Paola Terranova, Michela Lupia, Enrico Cappelli, Gianluca Dell'Orso, Marina Lanciotti, Isabella Ceccherini, Carlo Dufour
Journal: Blood (2021)
STEM-18. STROMAL EXTRACELLULAR VESICLES DRIVE GLIOMA STEM CELL REPROGRAMMING
Authors: Lata Adnani, Brian Meehan, Jordan Kassouf, Cristiana Spinelli, Nadim Tawil, Janusz Rak
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma multiforme (GBM) represents the most frequent and lethal form of brain tumors originating from glioma stem cells (GSCs). GBM remains lethal because the rate limiting patho-mechanisms remain poorly understood. In this regard, few limitations involve the diversity 'between' cellular states and the molecular/cellular complexity 'within' the tumour mass. Using cell based- and mouse- models, we explored extracellular vesicle (EV) mediated interactions between cancer and stromal cells impacting phenotypes of GSCs as a function of their molecular subtype. EVs are spherical membrane structures that cells release to expel different molecular cargo (lipids, proteins, RNA, DNA), which can be transported across a distance in the brain and taken up by various ‘recipient’ cells resulting in reprogramming of the recipient cell's content and function. In vivo, GSCs altered their pattern of NOTCH signalling and molecular phenotype as a function of proximity to non-transformed host cells in the brain. In vitro stromal EVs altered GSC sphere forming capacity, proteome and expression of mesenchymal markers. Thus, EV mediated tumour-stromal interactions could represent a biological switch and a novel targeting point in the biology of GBM.
Abstract 12675: Intravenous Iron Decreases Rehospitalizations but Doesn’t Change Mortality in Patients Admitted With Acute Heart Failure and Iron Deficiency: A Systematic Review and Meta-Analysis
Authors: Nischit Baral, Nabin R Karki, Rohit Rauniyar, Pramod Savarapu, Basel Abdelazeem, ASHIYA KHAN, Joshua Christy, Emad Kandah, Govinda Adhikari, santosh dhungana, Anish C Paudel, Bandana Ranabhat, Kamal Rikabi, Trailokya Pandit, Arvind Kunadi
Journal: Circulation (2021)

Introduction: The role of intravenous (IV) iron in chronic heart failure has been well studied, however, its role in acute heart failure (AHF) is lesser well-known. Including the recent late breaking AFFIRM-HF trial, we performed a systematic review and meta-analysis to highlight the role of IV iron in AHF in iron deficiency. Hypothesis: We hypothesized that IV iron doesn’t change mortality or heart failure re-hospitalization rates in patients with AHF with iron deficiency. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and cohort studies published from inception till May 8, 2021. We searched PubMed, MEDLINE, EMBASE (embase.com), and Cochrane database including only RCTs and Cohort studies. We included one prospective and one retrospective Cohort studies and two RCT in our meta-analysis. Eligible studies included adults with AHF, LVEF less than 40%-50%, and able to receive iv iron therapy. Outcomes included re-hospitalization rates and overall mortality from 30 days to 52 weeks post randomization (in one RCT). We used random-effects model calculating Risk Ratio (RR) with 95% confidence interval (95%CI) using Review Manger 5.4 software. I 2 statistics was used to assess heterogeneity. Results: There were total 1561 participants in both groups (iv iron and placebo/control) of four studies. The controls were comparable in both cohort studies and both the RCTs were well matched. Our results showed re-hospitalization in 278 of 833 (33.37%) patients in the IV iron/exposure group and 337 of 728 (0.46%) patients in the placebo/control group. The pooled result showed that the risk of rehospitalization was comparable across both groups (RR 0.85, 95%CI 0.62-1.17; I 2 =45%, P=0.14). However, subgroup analysis, including RCTs only showed that iv iron decreases re-hospitalization rate by 28% compared to placebo (RR 0.72, 95% CI: 0.64, 0.82, I 2 =0%, P&lt;0.00001) but didn’t improve mortality when compared to placebo (RR 0.97, 95% CI: 0.73, 1.30, I 2 =0%). Conclusions: IV iron showed significant improvement in re-hospitalization rate for AHF hospitalizations in iron deficient patients but didn’t improve overall mortality. We need larger RCTs to further validate its effect on mortality.
Progression of patients with Raynaud's phenomenon to systemic sclerosis: a five-year analysis of the European Scleroderma Trial and Research group multicentre, longitudinal registry study for Very Early Diagnosis of Systemic Sclerosis (VEDOSS)
Authors: Silvia Bellando-Randone, Francesco Del Galdo, Gemma Lepri, Tunde Minier, Dörte Huscher, Daniel E Furst, Yannick Allanore, Oliver Distler, László Czirják, Cosimo Bruni, Serena Guiducci, Jerome Avouac, Maurizio Cutolo, Vanessa Smith, Marco Matucci-Cerinic
Journal: The Lancet Rheumatology (2021)
When I use a word . . . . Taking therapeutic care
Authors: Jeffrey K Aronson
Journal: BMJ (2021)

In healthcare there are different forms of taking care or taking precautions. When using a therapeutic intervention, one takes care by implementing it appropriately. When the appropriate intervention is pharmacological that means giving an appropriate formulation of a medication in an appropriate dosage regimen. If the intervention might cause harm, but the benefit:harm balance is favourable, one might do nothing apart from monitoring or one might introduce a preventive strategy, such as the use of mesna when giving an oxazaphosphorine such as cyclophosphamide. Vaccination and contraception are both examples of precautionary measures that have an excellent benefit:harm balance. But when the benefit:harm balance of an intervention is unfavourable the precaution to be taken is avoidance of the intervention. That, and only that, form of precaution, avoidance to avoid harm, is a defining feature of the precautionary principle.
Factor VIII Level Comparison in Patients with Severe Hemophilia a on Emicizumab with Inhibitors with One Stage, Bovine and Human Chromogenic Assays and the Factor VIII Equivalency of Emicizumab Using <i>In Vivo G</i>lobal Hemostasis Assays
Authors: Hande Kizilocak, Elizabeth Marquez-Casas, Joshua Brown, Jemily Malvar, Guy Young
Journal: Blood (2021)
Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms
Authors: Shutao Zhang, Xinhua Qu, Juyang Jiao, Haozheng Tang, Minqi Wang, You Wang, Hongtao Yang, Weien Yuan, Bing Yue
Journal: Bioactive Materials (2021)

Methicillin-resistant Staphylococcus aureus (MRSA), biofilms, and persisters are three major factors leading to recurrent and recalcitrant implant infections. Although antibiotics are still the primary treatment for chronic implant infections in clinical, only few drugs are effective in clearing persisters and formed biofilms. Here, felodipine, a dihydropyridine calcium channel blocker, was reported for the first time to have antibacterial effects against MRSA, biofilm, and persisters. Even after continuous exposure to sub-lethal concentrations of felodipine, bacteria are less likely to develop resistance. Besides, low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance (aacA-aphD). Next, biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters. Furthermore, the result of protein profiling, and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence (agrABC), biofilm formation and TCA cycle. Then, molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease, which could lead to substantial protein degradation. Furthermore, murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response. In conclusion, low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA, biofilm, and persisters.
Abstract 12899: CMR Derived Intraventricular Pressure Gradients Analysis Shows Impaired Left Ventricular Function in Precapillary Pulmonary Hypertension
Authors: Jacqueline L Vos, Tim Leiner, Arie P van Dijk, Gianni Pedrizzetti, Fawaz Alenezi, Constantijn T van der Wegen, Mieke M Driessen, Robin Nijveldt
Journal: Circulation (2021)

Introduction: Precapillary pulmonary hypertension (pPH) predominantly harms the right ventricle. Still, due to ventricular interdependence, it also affects left ventricular (LV) function. Since LV ejection fraction (EF) is often preserved, more sensitive techniques may be better suited to detect LV dysfunction, such as LA strain or estimation of LV intraventricular pressure gradients (IVPG). However, the value of these techniques in pPH is still unknown. Hypothesis: Cardiovascular magnetic resonance (CMR) derived LA phasic function and LV-IVPG can detect LV dysfunction in pPH patients. Methods: pPH patients (n=31) and healthy controls (n=10), age- and sex-matched, underwent CMR imaging. LA phasic function and the LV-IVPG, calculating the pressure gradient between apex and base throughout the cardiac cycle, were analyzed using standard long-axis cines. Results: LV systolic function, both LVEF as well as the IVPG positive systolic ejection force, was preserved in pPH patients compared to healthy controls (p=0.90, p=0.08 resp.). However, diastolic function in pPH patients was impaired, depicted by 1. lower LA reservoir (patients vs. controls 26% ±9 vs. 37% ±7, p=0.001) and conduit strain (15% ±8 vs. 26% ±7, p=0.001), and 2. an impaired diastolic suction force, and decreased E-wave decelerative force, indicating a weaker passive filling in early to mid-diastole ( see Table ). Also, 11 pPH patients (35%) showed reversal of IVPG at systolic-diastolic transition, meaning that LV pressure temporarily exceeds LA pressure, whereas none of the healthy controls showed this pattern (p=0.04). Conclusions: pPH impacts LV function by altering diastolic function, demonstrated by an impairment of LA phasic function and LV-IVPG analysis. These parameters could therefore potentially be used as early markers for LV functional decline in pPH patients.
Abstract 11947: Evaluating Critical Values in Predicting Cardiomyopathy With Coronary Artery Disease Using Features Decided by Machine Learning Algorithms
Authors: Sairamvinay Vijayaraghavan, Carter W English, Jeffrey Flack, Prasant Mohapatra, Uma N Srivatsa
Journal: Circulation (2021)

Introduction: Cardiomyopathy in coronary artery disease (CAD) is associated with increased mortality. Identification of strong predictors related to cardiomyopathy in coronary artery disease can assist in appropriate ICD candidacy. Hypothesis: Identify critical values for predictors of reduced left ventricular ejection fraction (LVEF ≤ 40%) aside from baseline LVEF. Methods: We identified 2116 patients hospitalized with CAD and the top 10 predictors to predict follow-up were regressed separately against the follow-up LVEF to identify their critical values, where the fitted regression line meets the predicted follow-up LVEF at 40%. Each predictor is binarized based on the identified critical values and correlation with LVEF. We trained various classifiers to predict the follow-up LVEF ≤ 40%. Hazard ratios were used to compare the efficiency between all variables versus one predictor (baseline LVEF) based on the strong (at least 1 predictor ensures a low follow-up EF) and weak samples. Results: Using critical values and correlation trends for each predictor influences follow-up LVEF prediction(Table 1). Using all the variables outperformed the baseline LVEF alone in predicting follow-up EF class(Table 2). Clearly, decision-based algorithms did better because they were able to classify easily based on the binary values of the predictors. Conclusions: We identified strong variables and their critical values which aspire to improve the timing and efficiency of appropriate ICD implantation in patients just based on merely looking at any one of the predictor values and the critical value for each predictor. It simplifies the classification of follow-up LVEF for a clinician.
INNV-37. XCELSIOR: A REAL-TIME, REAL-WORLD LEARNING PLATFORM FOR PATIENTS WITH ADVANCED CANCER
Authors: Timothy Stuhlmiller, Mark Shapiro, Asher Wasserman, Zachary Osking, Jeff Shrager, Bryan Federowicz, Matthew Warner, Julie Friedland, Al Musella, Nicholas Blondin, Ekokobe Fonkem, Eric Wong, Santosh Kesari
Journal: Neuro-Oncology (2021)

Abstract xCures operates a direct-to-patient, real-world evidence platform for decentralized clinical research. The platform leverages a nationwide observational research protocol (XCELSIOR, NCT03793088) to aggregate, normalize, and analyze N-of-1 clinical outcomes to continuously learn from and inform treatment decisions. Individual data elements are extracted directly from medical documents such as clinic notes, and radiology, genomics, and pathology reports. The data elements are standardized to established biomedical ontologies and stored in a validated and part 11 compliant electronic database, suitable for statistical analyses and regulatory filings. This permits comparison of patient outcomes across institutions and removes the burden of data entry from oncologists and their staff. As an extremely efficient real-world data solution, we have utilized this platform to accelerate both academic- and commercial-sponsored clinical research, prospectively integrating diagnostics and algorithms with interventional treatments. For each patient that participates in XCELSIOR, artificial intelligence-powered clinical decision support algorithms suggest testing and treatment options. These options and supporting treatment rationales are sourced from key opinion leaders, tumor boards, clinical researchers, practicing oncologists, and published literature, and ranked using the real-world outcomes data from the registry. At the conference, we will present an overview of this real-time learning infrastructure and report on clinical case studies for pharma and non-profit groups including over 75 virtual tumor boards and real-world evidence generated from over 150 patients with CNS cancers that we have helped in partnership with Cancer Commons and The Musella Foundation for Brain Tumor Research and Education. Outcomes analyses stratified by therapeutic interventions and biomarkers will be reported, including frequency of adverse events, time to treatment failure, time to disease progression, and overall survival. Interventions include standard-of-care chemotherapies as well as therapies accessed by clinical trial, expanded access, and off-label prescription.
CTIM-07. A PHASE I/II STUDY EVALUATING THE SAFETY AND EFFICACY OF A NOVEL LONG-ACTING INTERLEUKIN-7, NT-I7, FOR PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMAS AFTER CHEMORADIOTHERAPY
Authors: Jian Campian, Omar Butt, Jingqin Luo, Chandini Avvaru, Ruth Katumba, Alice Zhou, Albert Kim, Gavin Dunn, Christopher Abraham, Se Hwan Yang, Jean Fan, Byung Ha Lee, Sunita Ranjitkar, NgocDiep Le, George Ansstas, Tanner Johanns, Michael Rettig, Milan Chheda, Jiayi Huang
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Lymphopenia is common after standard radiation therapy (RT) and temozolomide (TMZ) in high-grade gliomas (HGG) and correlates with shorter survival. Interleukin-7 (IL-7), a T-cell proliferation cytokine, is inappropriately low in HGG patients. Our previous preclinical studies demonstrated that NT-I7 (efineptakin alfa), a recombinant human IL-7, corrects lymphopenia and improves survival in murine glioma models. This study examines the safety and absolute lymphocyte counts (ALCs) following administration of NT-I7 patients with newly diagnosed HGG. METHODS Patients with HGG receiving RT/TMZ with ALC ≥600 were eligible. NT-I7 was administered intramuscularly within 1 week after completion of concurrent RT/TMZ and then every 12 weeks, for up to 4 total doses. Phase I examined 6 dose levels (60, 120, 240, 540, 720, and 960 mcg/kg) using the accelerated-titration design for the first 2 doses and 3 + 3 design thereafter to identify the maximum tolerated dose (MTD). Phase II is a double-blinded, placebo-controlled study with 10 HGG patients per arm comparing changes in ALC. Immune profiling will be performed with CyTOF and cytokine analysis. RESULTS Phase I is complete, with 19 patients (89% GBM, median age: 58 (range: 25-78), median baseline ALC: 1000 cells/mm3, median dexamethasone: 0 mg/day (range: 0-12)). The median number of NT-I7 doses administered was 2 (range: 2-4). The most common treatment-related adverse event was grade 1 or 2 injection site reactions (42%). Two patients had dose-limiting toxicities at 960 mcg/kg (grade 3 elevated alanine aminotransferase and grade 3 back pain), prompting selection of 720 mcg/kg for phase II. Dose-dependent increases in ALC were observed at 4 weeks ranging from 1.3x to 4.1x. Phase II enrollment is ongoing. CONCLUSIONS NT-I7 is well tolerated when administered after chemoradiotherapy for HGG patients with MTD of 720 mcg/kg and demonstrates dose-dependent increase of ALC. Phase II and immune profiling are ongoing. Clinical Trial ID: NCT03687957.