tbuckley/cabot-search huggingface dataset:
Abstract P139: The Association of Cardiorespiratory Fitness With Cardiometabolic Risk Factors and Markers of Endothelial Function in the Study of Latino Youth (SOL Youth)
Authors: Carmen R Isasi, Garrett Strizich, Christina M Parrinello, Robert Kaplan, Martha L Daviglus, Daniela Sotres-Alvarez, Denise C Vidot, Maria M LLabre, Gregory Talavera, Mercedes R Carnethon
Journal: Circulation (2017)

Background: Adult cardiorespiratory fitness (CRF) is associated with lower risk of cardiovascular disease and mortality. However, there is scarce information in youth about the role of CRF in subclinical measures of CVD, such as endothelial function. In this study we tested associations of cardiometabolic factors (CMF) and biomarkers of endothelial function (e-selectin; PAI-1). Methods: We included 1,380 participants (699 girls and 681 boys) aged 8-16 years from SOL Youth. CRF was assessed by a step test and VO2 max was estimated. CMF included fasting glucose, lipids, blood pressure. Inflammatory markers included hs-CRP and adiponectin. Associations of CRF with e-selectin and PAI-1 were assessed with multiple linear regression models, adjusting for potential confounders: actigraphy derived physical activity (PA) and sedentary time (SED), adiposity, and socio-demographic factors. Odds ratios were derived for the association of CRF and having ≥3 CVD risk factors (RF)(defined by elevated age/sex appropriate BP, lipids, glucose, and obesity), adjusted for confounders. Analyses accounted for complex survey design. Results: Boys and US-born youth were more likely to have higher CRF. CRF was positively correlated with PA (r=.23, p&lt;.0001) but inversely correlated with SED (r=-.10, p=.001), BMIz-score (r=-.37, p&lt;.0001), waist circumference (WC)(r=-.38, p&lt;.0001), and %body fat (r=-.43, p&lt;.0001). In multivariate models adjusting for socio-demographic factors, PA and SED (model 1), CRF was strongly and inversely associated with markers of endothelial function, inflammation, and CMF, which were attenuated when adjusting for WC (model 2)(Table 1). The odds of having ≥3 CVD RF was significantly lower at highest quartiles of fitness (ORs Q2=.47, Q3=.68, Q4=.35, p-trend=.001) after adjusting for confounders and WC. Conclusions: Among Latino youth, CRF appears to be a strong protective factor for endothelial dysfunction and CMF. Strategies to improve CRF may be a useful approach for improving cardiovascular health in youth.
Serotonin‐release assay‐positive but platelet factor 4‐dependent enzyme‐immunoassay negative: <scp>HIT</scp> or not <scp>HIT</scp>?
Authors: Theodore E. Warkentin, Maureen A. Smythe, Mona A. Ali, Naveed Aslam, Jo‐Ann I. Sheppard, James W. Smith, Jane C. Moore, Donald M. Arnold, Ishac Nazy
Journal: American Journal of Hematology (2020)

IgG-specific and polyspecific PF4-dependent enzyme-immunoassays (EIAs) have exceptionally high sensitivity (≥99%) for diagnosis of heparin-induced thrombocytopenia (HIT), a drug reaction caused by platelet-activating antibodies detectable by serotonin-release assay (SRA). The IgG-specific EIAs are recommended for screening, as their high sensitivity is accompanied by relatively high specificity vis-à-vis polyspecific EIAs. We investigated the frequency of SRA-positive/EIA-negative (SRA+/EIA-) HIT, prompted by referral to our reference HIT laboratory of serial blood samples from a patient ("index case") with false-negative IgG-specific EIAs. Despite initial clinical suspicion for HIT, repeat negative IgG-specific EIAs prompted heparin resumption, which triggered recurrent thrombocytopenia and near-fatal cardiac arrest, indicating likely post-heparin HIT-associated anaphylactoid reaction. Further investigations revealed a strong-positive SRA, whether performed with heparin alone, PF4 alone, or PF4/heparin, with inhibition by Fc receptor-blocking monoclonal antibody (indicating IgG-mediated platelet activation); however, five different IgG-specific immunoassays yielded primarily negative (or weak-positive) results. To investigate the frequency of SRA+/EIA- HIT, we reviewed the laboratory and clinical features of patients with this serological profile during a 6-year period in which our reference laboratory investigated for HIT using both SRA and IgG-specific EIA. Although ~0.2% of 8546 patients had an SRA+/EIA- profile, further review of 15 such cases indicated clerical/laboratory misclassification or false-positive SRA in all, with no SRA+/EIA- HIT case identified. We conclude that while SRA+/EIA- HIT is possible-as shown by our index case-this clinical picture is exceptionally uncommon. Moreover, the requirement for a positive EIA is a useful quality control maneuver that reduces risk of reporting a false-positive SRA result.
Kidney Function After Initiation and Discontinuation of Empagliflozin in Patients With Heart Failure With and Without Type 2 Diabetes: Insights From the EMPERIAL Trials
Authors: Stefan D. Anker, Piotr Ponikowski, Christoph Wanner, Egon Pfarr, Sibylle Hauske, Barbara Peil, Afshin Salsali, Ivana Ritter, Audrey Koitka-Weber, Martina Brueckmann, JoAnn Lindenfeld, William T. Abraham
Journal: Circulation (2021)
Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis
Authors: Jennifer Cautela, Sarah Zeriouh, Melanie Gaubert, Laurent Bonello, Marc Laine, Michael Peyrol, Franck Paganelli, Nathalie Lalevee, Fabrice Barlesi, Franck Thuny
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Myocarditis is a rare but life-threatening adverse event of cancer treatments with immune checkpoint inhibitors (ICIs). Recent guidelines recommend the use of high doses of corticosteroids as a first-line treatment, followed by intensified immunosuppressive therapy (IIST) in the case of unfavorable evolution. However, this strategy is empirical, and no studies have specifically addressed this issue. Therefore, we aimed to investigate and compare the clinical course, management and outcome of ICI-induced myocarditis patients requiring or not requiring IIST. Methods This case–control study included all patients consecutively admitted to The Mediterranean University Center of Cardio-Oncology (Aix-Marseille University, France) for the diagnosis of ICI-induced myocarditis according to Bonaca’s criteria and treated with or without IIST. In addition, we searched PubMed and included patients from previously published case reports treated with IIST in the analysis. The clinical, biological, imaging, treatment, all-cause death and cardiovascular death data of patients who required IIST were compared with those of patients who did not. Results A total of 60 patients (69±12 years) were included (36 were treated with IIST and 24 were not). Patients requiring IIST were more likely to have received a combination of ICIs (39% vs 8%, p=0.01), and developed the first symptoms/signs of myocarditis earlier after the onset of ICI therapy (median, 18 days vs 60 days, p=0.002). They had a significantly higher prevalence of sustained ventricular arrhythmia, complete atrioventricular block, cardiogenic shock and troponin elevation. Moreover, they were more likely to have other immune-related adverse events simultaneously (p&lt;0.0001), especially myositis (p=0.0002) and myasthenia gravis (p=0.009). Patients who required IIST were more likely to die from any cause (50% vs 21%, p=0.02). Among them, patients who received infliximab were more likely to die from cardiovascular causes (OR, 12.0; 95% CI 2.1 to 67.1; p=0.005). Conclusion The need for IIST was more common in patients who developed myocarditis very early after the start of ICI therapy, as well as when hemodynamic/electrical instability or neuromuscular adverse events occurred. Treatment with infliximab might be associated with an increased risk of cardiovascular death.
DIPG-14. TARGETING POLO-LIKE KINASE 1 IN COMBINATION WITH KEY ONCOGENIC DRIVERS IN DIPG: FROM SINGLE AGENT TO COMBINATION STRATEGIES
Authors: Laura Franshaw, Elisha Hayden, Swapna Joshi, Jie Liu, Anahid Ehteda, Chi Nam Ignatius Pang, Maria Tsoli, David S Ziegler
Journal: Neuro-Oncology (2020)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) are devastating paediatric brainstem tumours. Loss of function mutations in DIPG decrease genetic stability and impair DNA damage response pathways promoting tumourigenesis. Polo-like Kinase 1 (PLK1) is a pivotal controller of cell growth, regulating key intermediaries of DNA replication, homologous repair, the cell cycle and cell division. We have found DIPG cultures consistently overexpress PLK1 with inhibition resulting in decreased tumour cell growth, heightened cell cycle arrest and apoptosis. Single agent treatment using PLK1 inhibitors unprecedentedly doubled the median survival of animals harbouring DIPG tumours. Through gene expression analysis, we’ve showed PLK1 inhibition affected multiple pathways which control the cell cycle, cell death regulation, microtubule organization and regulation of cell migration. We found these pathways of differentially expressed genes were significantly enriched for known targets of both E2F1 and E2F4. Analysis of gene expression and proteomic studies also revealed PLK1 inhibition decreased the activation and expression of key tumour promoting mediators within multiple phases of the cell cycle, decreased expression of tumour promoters including MYC and the PI3K/mTOR pathway and reactivated tumour suppressors p53 and PTEN. Assessing these changes in the treated transcriptome and proteome, we aim to develop multiple potentially translatable combination treatment strategies for DIPG. We have performed mechanistic studies and identified synergism with PLK1 inhibitors and the epigenetic regulator panobinostat, bet/bromodomain inhibitor JQ1, dual PI3K/mTOR inhibitor bimiralisib and PI3K inhibitor BKM120. Finally, we found PLK1 inhibitors act as potent radiosensitizers, enhancing the therapeutic effects of radiotherapy in vitro and in vivo.
Predicting Long-Term Survival in Pulmonary Arterial Hypertension: More Than Just Pulmonary Vascular Resistance⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Reda E. Girgis
Journal: Journal of the American College of Cardiology (2011)
Acute Liver Injury With Therapeutic Doses of Acetaminophen: A Prospective Study
Authors: Alexandre Louvet, Line Carolle Ntandja Wandji, Elise Lemaître, Marion Khaldi, Claire Lafforgue, Florent Artru, Benoît Quesnel, Guillaume Lassailly, Sébastien Dharancy, Philippe Mathurin
Journal: Hepatology (2020)

Because of the extensive use of this drug, further evaluation of acute liver injury (ALI) with therapeutic doses of acetaminophen (APAP; ≤6 g/d) is required. We characterize ALI with therapeutic doses of APAP and determine the host factors associated with disease severity and the predictors of outcome.All patients admitted with severe APAP-related ALI in our center were included from 2002 to 2019, either attributable to therapeutic doses or overdose. ALI with therapeutic doses (ALITD) was defined as APAP intake <6 g/d. Overall, 311 of 400 patients with APAP-related ALI had overdose and 89 had taken therapeutic doses. The host factors associated with ALITD were fasting ≥1 day (47.5% of ALITD patients vs. 26% in overdose; P = 0.001), excess drinking (93.3% vs. 48.5%; P < 0.0001), and repeated APAP use (4 vs. 1 day; P < 0.0001). Patients with ALITD were older (44 vs. 30.7 years; P < 0.0001) and had more severe liver injury. In the overall population, the independent predictors of disease severity were older age, longer duration of APAP, and excess drinking. Thirty-day survival was lower in ALITD than in overdose (87.2 ± 3.6% vs. 94.6 ± 1.3%; P = 0.02). Age and the presence of at least one of the King's College Hospital criteria were independent predictors of 30-day survival whereas the pattern of drug intoxication, excess drinking, and bilirubin were not.ALI with therapeutic doses of APAP is associated with more severe liver injury than overdose. It only occurs in patients with excess drinking and/or fasting. A warning should be issued about the repeated use of nontoxic doses of APAP in patients with those risk factors.
DDRE-05. DECREASED EXPRESSION OF DNA DAMAGE RESPONSE PATHWAYS CORRELATES WITH SYNERGISTIC ACTIVITY OF TEMOZOLOMIDE WITH ATR INHIBITORS IN GLIOBLASTOMA
Authors: Shaofang Wu, Xiaolong Li, Sanjay Singh, Dimpy Koul, W K Alfred Yung
Journal: Neuro-Oncology (2020)

Abstract The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most important gaps in enabling the development of effective targeted cancer therapies. Increasing evidence supports the notion that DNA damage response (DDR) signaling plays an important role in inducing radiation and temozolomide (TMZ) resistance in glioblastoma (GBM) and hence, it has emerged as a molecular target for therapeutic development. The cellular response to TMZ therapy is critically mediated by MGMT and DDR signaling networks that are regulated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia and Rad3-related protein (ATR). ATR is a primary sensor of DNA damage initiating subsequent repair leading to cell survival. Here, we show that three clinical grade ATR inhibitors (Bay1895344, AZD6738 and VE-822) had similar selective sensitivity pattern across eight glioma-like stem cells (GSC) lines tested with three (GSC28, GSC11, GSC274) being the most sensitive, and three (GSC300, GSC272, and GSC20) being the most resistant cell lines. Interestingly, all three ATR inhibitors showed a significant synergism with TMZ (Combination index and Bliss model) in GSC300, GSC272, and GSC20, and antagonism in GSC28, GSC11, and GSC274. Further analysis showed that the synergistic group was resistant to single agent ATR inhibitor, whereas antagonistic group was inherently sensitive to ATR inhibitor. The synergistic response was not associated with any major genetic alterations such as MGMT status, EGFR amplification, PTEN deletion/mutation, or p53 deletion/mutation. However, GSEA analysis of baseline RNA-seq data of the 6 cell lines showed an enhanced expression of six DNA damage/repair/response pathways in the antagonistic group. It suggests that a low level of DNA damage/repair/response pathways could be a marker of synergy for TMZ with ATR inhibitors in GBM. Further studies are underway to validate this observation in more GSC lines in vitro and in vivo.
STEM-21. CLINICAL RELEVANCE OF CANCER STEM CELL CYTOTOXICITY ASSAY IN GUIDING TREATMENT FOR GLIOBLASTOMA
Authors: Claudio Pier Paolo, Tulika Ranjan, Candace Howard, Alexander Yu, Linda Xu, Khaled Aziz, David Jho, Jodi Leonardo, Krista Denning, Jagan Valluri
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND. The prognosis of glioblastoma (GBM) treated with standard-of-care regimens remains very poor with a median time to recurrence of 7-9 months, and a median survival of 15-18 months. GBMs contain a small, but resilient population of cancer stem cells (CSCs) that contribute to tumor initiation, maintenance, and therapy resistance. For these reasons, its is extremely important to determine the sensitivity of CSCs to chemotherapeutic agents, with the intent of identifying more effective treatment protocols which would then translate into improved clinical survival. METHODS. We have used a novel CLIA and CAP-accredited Cancer Stem Cell Cytotoxicity Assay (ChemoID) to guide treatment for 55 Grade III and Grade IV glioma patients with the most efficacious chemotherapy treatments from a panel of FDA approved drugs or their combinations. Patients were evaluated by MRI scans and response was assessed according to RANO criteria. RESULTS: We report here a prospective clinical investigation using the ChemoID assay to measure the sensitivity and resistance of CSCs and bulk of tumor cells cultured from 55 GBM clinical specimens challenged with several chemotherapy agents, which were also correlated to the clinical response of the treated patients, independently of other biomarkers. The median recurrence time was 15 months for patients with a sensitive (&amp;gt;40% cell kill) CSCs test versus only 6 months for patients with a resistant CSCs test. CONCLUSIONS. The data suggests that GBM patients treated with CSC Cytotoxicity Assay-guided responsive drugs have delayed time to recurrence and the assay has the potential to help tailor chemotherapy choices to improve clinical outcomes.
A Case to Optimize Medications in Children With Severe Neurological Impairment
Authors: Abigail Musial, Joanna E. Thomson
Journal: JAMA Network Open (2020)

James A. Feinstein, MD, MPH; Chris Feudtner, MD, PhD, MPH; Allison B. Blackmer, PharmD; Robert J. Valuck, PhD; Diane L. Fairclough, DrPH; Jacqueline Holstein, BA; LiseAnne Gregoire, BS; Sadaf Samay, MPH; Allison Kempe, MD, MPH
PATH-36. SYNCHRONOUS TTF-1-POSITIVE TUMORS AND PITUITARY ADENOMAS. ARE WE SENDING INSUFFICIENT TUMOR TISSUE FOR PATHOLOGY?
Authors: Franco Rubino, Daniel Eichberg, Ashish shah, Evan Luther, Victor Lu, Ali Saad, Ricardo Komotar, Michael Ivan
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Tumors of the posterior pituitary are a distinct group of low-grade neoplasms arising from the sellar region. According to the most recent World Health Organization (WHO) guidelines, these tumors are grouped based on TTF-1 immunostain positivity. The coexistence of a posterior and anterior pituitary tumors is statistically extremely unlikely. OBJECTIVE In this study, we present a case of a 41-year-old woman suffering from Cushing syndrome with the presence of two pituitary masses on MRI. Also, the relevant literature is systematically reviewed. METHODS Two databases (PubMed and Google Scholar) and crossed references were systematically reviewed for TTF-1 pituitary tumors with coexisting pituitary adenoma or increased pituitary serum hormone levels. A literature review was performed according to PRISMA guidelines. Also, one patient from our institution is reported. Data regarding demographic features, type of anterior and posterior pituitary tumor, clinical features of the patients and lab results, MRI findings, and pathology results were extracted. RESULTS Seventeen retrospective case reports and case series were identified and included. Twenty-four patients were analyzed (including the reported case). The mean age was 46 ± 16 years, with a male-to-female ratio of 0.33:1. Pituicytomas and granular cell tumors were the only posterior pituitary tumors reported in 19 (79%) and 5 (21%) cases, respectively. There are only eight cases reported (including our patient) with a confirmed pituitary adenoma and a TTF-1 pituitary tumor (one GCT with GH-secreting adenoma, five pituicytoma with ACTH-secreting adenoma, one with GH-secreting adenoma and one with a null type adenoma). CONCLUSION We presented the eighth reported case of a TTF-1 pituitary tumor coexisting with a pituitary adenoma. We think that improving the amount of the tissue specimen available for pathology evaluation could increase the incidence of these very rare tumors.
Abstract 15195: Causes and Predictors of 30-Day Post-PCI Readmission Rate in Patients With Pulmonary Hypertension- A Nationwide Readmission Database Analysis
Authors: Neel Patel, Birendra Amgai, Sandipan Chakraborty, Soniya Koirala, Aneeta Kumari, Dhrubajyoti Bandyopadhyay, Adrija Hajra, Eyal Herzog, Wilbert S Aronow
Journal: Circulation (2019)

Introduction: Readmission after percutaneous coronary intervention (PCI) is common, costly, and could be accounted for Medicare penalties. Our study is aimed to explore various causes and predictor...
Abstract 13576: Anti-senescent Drug Screening by Deep Learning-based Morphology Senescence Scoring
Authors: Dai Kusumoto, Tomohisa Seki, Hiromune Sawada, Toshiomi Katsuki, Mai Kimura, Shogo Ito, Jin Komuro, Hisayuki Hashimoto, Keiichi Fukuda, Shinsuke Yuasa
Journal: Circulation (2020)

Backgrounds: Deep learning is currently being applied to many complex tasks. The accuracy of image classification, in particular, has improved with the development of convolutional neural networks (CNNs). Cellular senescence is a hallmark of ageing and is highly important for the pathogenesis of aging-related diseases. Furthermore, cellular senescence has been identified as a potential therapeutic target. Specific molecular markers are widely used to identify senescent cells, but senescent cells also show unique morphology, which can be identified by CNN. Objective: We develop a strong-performing, morphology-based CNN system called Deep-SeSMo to identify senescent cells, and establish a novel quantitative scoring system to evaluate the probability that an endothelial cell is senescent. Methods and results: We induced cellular senescence in human umbilical vein endothelial cells (HUVECs) using three different stressors: ROS; an anti-cancer reagent; and replication stress, and demonstrated that CNN performed with high accuracy and generalizability. Then, we developed a “senescence score” based on the output of the pre-trained CNN, optimized it for the classification problem, and defined the overall average output probability calculated by the pre-trained CNN as the quantitative senescence score, namely Deep-SeSMo. Deep-SeSMo correctly evaluates the effects of well-known anti-senescent reagents; nicotinamide mononucleotide (NMN) and metrofmin. We screened for drugs that control cellular senescence using a kinase inhibitor library by Deep-SeSMo-based drug-screening and discovered four novel anti-senescent drugs. RNA sequence analysis revealed that those compounds commonly suppress senescent phenotypes through inhibition of the inflammatory response pathway. Conclusions: Using Deep-SeSMo, we demonstrated that the morphology-based CNN system can be a powerful tool for anti-senescent drug screening.
Precise Tumor Photothermal Therapy Guided and Monitored by Magnetic Resonance/Photoacoustic Imaging using A Safe and pH‐Responsive Fe(III) Complex
Authors: Guohai Liang, Jiamei Han, Da Xing
Journal: Advanced Healthcare Materials (2020)

Abstract Photothermal agents with strong near infrared (NIR) optical absorbance and excellent biocompatibility and traceability are highly desired for precise photothermal therapy. This study reports the development of a dual‐functional Fe 3+ complex (Fe‐ZDS) for imaging‐guided, precise photothermal therapy of tumors. The complex has stable structure and obvious zwitterionic features, resulting in excellent biocompatibility and efficient renal clearance. The iron‐dopa core structure renders the complex capable of generating magnetic resonance imaging (MRI) contrast, while synergistically exhibiting optical absorption in the red and NIR regions. Interestingly, the optical absorption of the complex is pH‐sensitive, with significantly higher absorption intensity in a weakly acidic environment than in a neutral environment. Thus the complex can respond to acidic tumor stimuli and confine the energy of the laser to the tumor tissue. The MRI contrast and photoacoustic signal of the complex is taken advantage of to monitor the probe injection process and optimize the injection position and dosage for maximally covering the tumor tissue and assessing the activation of the complex in tumor tissues. The evolution of temperature inside the tissue during the laser irradiation is also monitored. Using Fe‐ZDS as the theranostic probe, satisfactory treatment outcomes are achieved for photothermal therapy of tumors.