tbuckley/cabot-search huggingface dataset:
CTIM-02. PHASE II STUDY OF IPILIMUMAB AND NIVOLUMAB IN LEPTOMENINGEAL CARCINOMATOSIS
Authors: Matthew Strickland, Eudocia Quant Lee, Nancy Wang, Justine Cohen, Ugonma Chukwueke, Deborah Forst, April Eichler, Beth Overmoyer, Nancy Lin, Wendy Chen, Aditya Bardia, Dejan Juric, Ibiayi Dagogo-Jack, Michael White, Jorg Dietrich, Naema Nayyar, Albert Kim, Christopher Alvarez-Breckenridge, Maura Mahar, Joana Mora, Brian Nahed, Pamela Jones, Helen Shih, Elizabeth Gerstner, Anita Giobbie-Hurder, Scott Carter, Kevin Oh, Daniel Cahill, Ryan Sullivan, Priscilla Brastianos
Journal: Neuro-Oncology (2021)

Abstract Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.
Abstract 9355: Home Monitoring to Detect Emergent Anti-Ro/SSA Antibody Mediated Fetal Av Block: Preliminary Results of the STOP BLOQ Study
Authors: Bailey M Drewes, Colin K Phoon, Elena S Sinkoveskaya, Lisa W Howley, Ruben J Acherman, Majd Makhoul, Nelangi M Pinto, Mala Masson, D W Benson, Alfred Abuhamad, Jill P Buyon, Bettina F Cuneo
Journal: Circulation (2021)

Introduction: Fetal complete AV block (CAVB), complicates 2% of anti-Ro antibody positive pregnancies and carries substantial perinatal morbidity and mortality. Anti-inflammatory treatment of 1° and 2° (emergent) AVB may prevent progression to CAVB, yet the optimal surveillance strategy to detect emergent CAVB is unknown. Methods: We examined participants in a multicenter, open label clinical trial of pregnancies risk stratified by anti-Ro antibodies into high (≥1000 IU) or low (&lt;1000 IU) titers. Low titer mothers were followed by echocardiograms or routine OB care; high titer mothers underwent 3x/day fetal heart rate monitoring (FHRM) and weekly or biweekly fetal echocardiograms from 17-26 weeks. If mothers suspected abnormal FHRM, they texted fetal heart sounds to cardiologist, who assessed FHRM and reassured or referred for emergency fetal echocardiogram (performed in &lt; 6 hours). Postnatal electrocardiograms (ECG) were evaluated. Results: Sixty-five subjects from 7 centers were recruited and 60 (92%) enrolled at 14 (5-19) weeks. There were 24 (40%) low titer and 36 (60%) high titer mothers. High titer mothers underwent FHRM; 92% completed FHRM and 100% completed surveillance echocardiograms. Of 3,360 FHRM recordings, mothers texted 39 (1%) recordings of concern; cardiologist deemed 2/39 (5%) as abnormal and emergency echocardiograms revealed atrial ectopy. No fetus developed emergent or CAVB. Postnatal ECGs demonstrated normal AV conduction in all neonates: 2 miscarried at &lt;12 weeks and 48 are in utero. Conclusion: These data support FHRM in the surveillance of anti-Ro antibody positive pregnancies because of high enrollment, feasibility, and accuracy in arrhythmia detection.
Abstract 11737: Higher Frequency of Ventricular Ectopy is Associated With Incident Dementia in Older Adults Without Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Romil R Parikh, Wendy Wang, Faye L Norby, Michael J Zhang, Kuni Matsushita, Elsayed Z Soliman, B Gwen Windham, Thomas Mosley, James R Pike, Bruce A Wasserman, Michelle C Johansen, Rebecca F Gottesman, Alvaro Alonso, Lin Y Chen
Journal: Circulation (2021)

Introduction: Excessive ventricular ectopy (VE) is a risk factor for stroke. It is unclear whether higher frequency of VE is associated with the risk of dementia. Hypothesis: Higher frequency of VE, including ventricular tachycardias (VT) and premature ventricular contractions (PVC), are associated with a higher risk of dementia. Methods: We included 2167 participants without adjudicated dementia, stroke or atrial fibrillation (mean age, 79 years, 60% female, 26% Black). We measured burden of VT and PVC over 2 weeks at baseline (2016-17) with Zio XT patch: an ambulatory ECG recorder (iRhythm Technologies, Inc.). We quantified PVC burden as: 1) natural log of frequency in episodes/day (due to skewed distribution) and 2) dichotomously, split at the median level of frequency. We quantified VT burden as: 1) presence of any VT, 2) frequency of VT (episodes/day) split at the median, and 3) duration of the longest VT episode split at the median, using ‘no VT’ group as the referent in each case. We adjudicated dementia events through 2019 using cognitive testing at study visits, telephone cognitive interviews, and medical records. We calculated relative risk of incident dementia by Poisson regression with robust error variance. Results: At baseline, PVC and VT were present in 99% and 27% of participants, respectively. Over 2 years of follow-up, 66 (3.0%) participants developed dementia. Higher frequency of PVCs and VTs (≥ median vs none), and longer duration of the longest VT episode (≥ median vs none) were associated with a higher risk of dementia independent of cardiovascular (CV) disease and risk factors (Table). These associations were attenuated after adjusting for incident stroke. Conclusions: In older adults, higher VE frequency is associated with a higher dementia risk independent of CV risk factors. Our novel findings broaden the scope of “vascular contribution to cognitive impairment and dementia” to include ventricular arrhythmias as novel risk factors for dementia.
Higher exhaled nitric oxide at 6 weeks of age is associated with less bronchiolitis and wheeze in the first 12 months of age
Authors: Carla Rebeca Da Silva Sena, Ediane de Queiroz Andrade, Patricia de Gouveia Belinelo, Elizabeth Percival, Benjamin Prangemeier, Christopher O'Donoghue, Sandrine Terry, Tanya Burke, William Gunning, Vanessa E Murphy, Paul D Robinson, Peter D Sly, Peter G Gibson, Adam M Collison, Joerg Mattes
Journal: Thorax (2021)

Background Nitric oxide in exhaled air (eNO) is used as a marker of type 2 immune response-induced airway inflammation. We aimed to investigate the association between eNO and bronchiolitis incidence and respiratory symptoms in infancy, and its correlation with eosinophil protein X (EPX). Methods We followed up infants at 6 weeks of age born to mothers with asthma in pregnancy and measured eNO during natural sleep using a rapid response chemiluminescense analyser (CLD88; EcoMedics), collecting at least 100 breaths, interpolated for an expiratory flow of 50 mL/s. EPX normalised to creatinine was measured in urine samples (uEPX/c). A standardised questionnaire was used to measure symptoms in first year of life. Associations were investigated using multiple linear regression and robust Poisson regression models. Results eNO levels were obtained in 184 infants, of whom 125/184 (68%) had 12 months questionnaire data available and 51/184 (28%) had uEPX/c measured. Higher eNO was associated with less respiratory symptoms during the first 6 weeks of life (n=184, ß-coefficient: –0.49, 95% CI –0.95 to –0.04, p=0.035). eNO was negatively associated with uEPX/c (ß-coefficient: –0.004, 95% CI –0.008 to –0.001, p=0.021). Risk incidence of bronchiolitis, wheeze, cold or influenza illness and short-acting beta-agonist use significantly decreased by 18%–24% for every unit increase in eNO ppb. Conclusion Higher eNO levels at 6 weeks of age may be a surrogate for an altered immune response that is associated with less respiratory symptoms in the first year of life.
Abstract 9127: The Impact of Iron Deficiency on Long-Term Outcomes in Patients with Acute Decompensated Heart Failure
Authors: Norihisa Miyawaki, Masahiro Ishikura, Ryosuke Murai, Taiji Okada, Toshiaki Toyota, Yasuhiro Sasaki, Tomohiko Taniguchi, Kitae Kim, Atsushi Kobori, Natsuhiko Ehara, Makoto Kinoshita, Yutaka Furukawa
Journal: Circulation (2021)

Introduction: Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF). However, the significance of ID as a prognostic factor has not been fully elucidated in patients with acute decompensated heart failure (ADHF). Hypothesis: ID is associated with a high cardiovascular event risk in ADHF. Methods: We retrospectively reviewed the ADHF patients who admitted to our hospital between December 2014 and March 2018. ID was defined as TSAT (transferrin saturation) &lt; 20% at discharge. Primary outcome measure was a composite of all-cause death and HF rehospitalization. Patients who died or underwent transfusion during index hospitalization were excluded from the analysis. Results: Among 256 patients who enrolled in the analysis, 119 patients (46.5%) had ID and 137 patients (53.5%) did not. Patients with ID had significantly lower hemoglobin levels (11.0 vs 12.1g/dl; p&lt;0.01) and estimated glomerular filtration rates (42.3 vs 48.1 ml/min/m2; p&lt;0.01) than non-ID patients. During the median follow-up period of 2.8 years, patients (30.1%) died and 96 patients (37.5%) re-hospitalized for HF. Although HF rehospitalization was numerically higher in ID patients than in non-ID patients (44.5% vs 31.4%, p = 0.03), Kaplan-Meier analysis showed comparable risks for all-cause death (log-rank p=0.67) and HF rehospitalization (log-rank p=0.90) between ID and non-ID patients. Conclusions: ID in patients with ADHF were common and associated with anemia and renal impairment. However, ID might not be a significant prognostic factor in ADHF patients.
Targeting the P2Y<sub>13</sub> Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma
Authors: Rhiannon B. Werder, Md Ashik Ullah, Muhammed Mahfuzur Rahman, Jennifer Simpson, Jason P. Lynch, Natasha Collinson, Sonja Rittchen, Ridwan B. Rashid, Md Al Amin Sikder, Herlina Y. Handoko, Bodie F. Curren, Ismail Sebina, Gunter Hartel, Alec Bissell, Sylvia Ngo, Tejasri Yarlagadda, Sumaira Z. Hasnain, Wenying Lu, Sukhwinder S. Sohal, Megan Martin, Simon Bowler, Lucy D. Burr, Laurent O. Martinez, Bernard Robaye, Kirsten Spann, Manuel A. R. Ferreira, Simon Phipps
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type 2 inflammation and asthma pathogenesis. Objectives: To determine whether P2Y13-R (P2Y13 receptor), a purinergic GPCR (G protein–coupled receptor) and risk allele for asthma, regulates the release of IL-33 and HMGB1. Methods: Bronchial biopsy specimens were obtained from healthy subjects and subjects with asthma. Primary human airway epithelial cells (AECs), primary mouse AECs, or C57Bl/6 mice were inoculated with various aeroallergens or respiratory viruses, and the nuclear-to-cytoplasmic translocation and release of alarmins was measured by using immunohistochemistry and an ELISA. The role of P2Y13-R in AEC function and in the onset, progression, and exacerbation of experimental asthma was assessed by using pharmacological antagonists and mice with P2Y13-R gene deletion. Measurements and Main Results: Aeroallergen exposure induced the extracellular release of ADP and ATP, nucleotides that activate P2Y13-R. ATP, ADP, and aeroallergen (house dust mite, cockroach, or Alternaria antigen) or virus exposure induced the nuclear-to-cytoplasmic translocation and subsequent release of IL-33 and HMGB1, and this response was ablated by genetic deletion or pharmacological antagonism of P2Y13. In mice, prophylactic or therapeutic P2Y13-R blockade attenuated asthma onset and, critically, ablated the severity of a rhinovirus-associated exacerbation in a high-fidelity experimental model of chronic asthma. Moreover, P2Y13-R antagonism derepressed antiviral immunity, increasing IFN-λ production and decreasing viral copies in the lung. Conclusions: We identify P2Y13-R as a novel gatekeeper of the nuclear alarmins IL-33 and HMGB1 and demonstrate that the targeting of this GPCR via genetic deletion or treatment with a small-molecule antagonist protects against the onset and exacerbations of experimental asthma.
Abstract 13661: Low Organ Perfusion Pressure Indexed To Body Surface Area Predicts Poor Survival Even After Heart Transplantation If The Right Atrial Pressure Is High
Authors: Ravikumar Ratnagiri, Komarakshi R Balakrishnan, Suresh Rao K G, T Muralikrishna, Ramanan Veena
Journal: Circulation (2021)

Introduction: Increased Right Atrial pressure (RAP) is associated with impaired renal function and mortality in patients with heart failure. Reduced renal perfusion pressure is associated with dera...
Benefit–harm analysis of azithromycin for the prevention of acute exacerbations of chronic obstructive pulmonary disease
Authors: Safa Ahmadian, Don D Sin, Larry Lynd, Mark Harrison, Mohsen Sadatsafavi
Journal: Thorax (2021)

Background Low-dose oral azithromycin therapy is recommended as a preventive treatment for acute exacerbations of COPD. However, the overall benefit–harm balance of this treatment has not been well studied. Methods A probabilistic Markov model of COPD was created to simulate the course of COPD over 20 years. The model was populated with evidence from the literature and dedicated data analysis. The benefit of azithromycin was modelled as a reduction in exacerbation rates. Adverse events, including cardiovascular events, hearing loss, gastrointestinal symptoms and antimicrobial resistance (leading to a gradual decline in the effectiveness of azithromycin), were considered. All outcomes were assigned a health-related utility weight to estimate the overall net change in the quality-adjusted life year (QALY) associated with the use of azithromycin. Results In patients with a positive exacerbation history, azithromycin resulted in a net QALY gain of 17.9 per 100 patients (99.8% probability of expected QALY gain) over 20 years. The net benefit increased to 21.8 QALYs per 100 patients (99.9% probability of expected QALY gain) among the ‘frequent exacerbator’ subgroup. Azithromycin was not net beneficial among those without any moderate/severe exacerbations in the previous year. Findings were robust against series of sensitivity, scenario and threshold analyses. Conclusions Long-term therapy with azithromycin confers a net benefit to ex-smoker patients with COPD with a recent history of exacerbations and an even larger benefit to those who are frequent exacerbators.
<i>Microenvironment Profiling in Myelodysplastic Syndromes and Its Relationship to Clonal Hematopoiesis and Disease Progression</i>
Authors: Antonieta Molero Yordi, Bárbara Tazón, Laura Gallur, Silvia Saumell, Tamara Jimenez, Teresa Ezponda, Maria Julia Montoro, Félix López Cadenas, Lídia Altimiras, Carla Sánchez Ruiz, Ana Alfonso, Olga Salamero, Ana Pérez, Soraya Peralta, Maria Diez-Campelo, Felipe Prosper, Francesc Bosch, David Valcarcel
Journal: Blood (2021)
Abstract 12868: Normal Values and Reference Ranges for Left Atrial Strain by Speckle Tracking Echocardiography: The Copenhagen City Heart Study
Authors: Anne B Nielsen, Kristoffer G Skaarup, Raphael Hauser, Niklas D Johansen, Mats H Lassen, Gorm B Jensen, Peter Schnohr, Rasmus Mogelvang, Tor Biering-Sørensen
Journal: Circulation (2021)

Background: In current literature, left atrial (LA) function assessed by 2D speckle tracking echocardiography (2DSTE) has shown increasing clinical and prognostic significance. We sought to establish age- and sex-based normative values of LA strain measures in the general population and to assess the diagnostic and prognostic yield of the prediction intervals (PI) in relation to baseline and future atrial fibrillation (AF). Methods: We performed 2DSTE in members of the general population included in the 5 th round of the Copenhagen City Heart Study. We determined normative values of peak atrial longitudinal strain (PALS), peak atrial contraction strain (PACS), and left atrial conduit strain (LACS) based on age and sex in 1,757 healthy participants. In a secondary analysis, 3,657 participants, regardless of health status, were included to assess the diagnostic and prognostic value of the established reference values. Results: In the healthy cohort, median age was 46 years (IQR: 33, 57), 62% were female. Median normative values of PALS, PACS, and LACS in the healthy participants were 39.1% (PI: 22.7-67.4%), 15.5% (PI: 6.3-28.0%), and 23.5% (PI: 8.6-44.8%), respectively. We observed higher values and reference limits of PALS and LACS in females compared to males, while no differences were observed for PACS. Across four different age categories, all three LA strain parameters differed significantly in both females and males. PALS and LACS decreased, while PACS increased with advancing age (Figure 1). The lower reference limits of all three LA strain parameters showed high specificity (range 96-98%) in relation to baseline and future AF, implying a low risk of AF in participants with LA strain above the lower prediction interval in their respective sex and age group. Conclusion: We report normal values for LA strain measures stratified by sex and age. The established lower reference limits showed high specificity regarding baseline and future AF diagnosis.
CSIG-08. ABT-414 RESISTANT GBM TUMORS HARBOR THE TEK S466I MUTATION AND EXHIBIT INCREASED STEMNESS
Authors: Mylan Blomquist, Teresa Noviello, Fulvio D'Angelo, Christopher Sereduk, Benjamin Rabichow, Aunay Miller, Bianca-Maria Marin, Forest White, Jann Sarkaria, Anna Lasorella, Antonio Iavarone, Michele Ceccarelli, Nhan Tran
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM), the most common primary brain tumor in adults, remains uniformly fatal due to the lack of effective targeted therapies for this aggressive malignancy. Genomic amplification of epidermal growth factor receptor (EGFR) occurs in 40-60% of primary GBM. Half of all EGFR-amplified cases of GBM also harbor EGFRvIII, a constitutively active, truncated variant of EGFR. The incidence of EGFR alterations in GBM makes inhibition of EGFR/EGFRvIII an attractive therapeutic approach. Depatuxizumab mafodotin (ABT-414) is an antibody-drug conjugate comprised of ABT-806, a mAB against EGFR, and a cytotoxic payload (monomethyl auristatin F). ABT-414 therapy initially showed promising results as an EGFRvIII therapy in vivo and in vitro; however, ABT414 failed to provide a survival benefit in phase I/II clinical trials, potentially due to therapeutic resistance. In this study, we seek to investigate the mechanisms of resistance to ABT-414 by performing whole exome, transcriptome and single cell RNA seq on ABT-414 resistant GBM PDX tumors. Our data showed an enrichment of mutations unique to the ABT-414 resistant tumors, including a point mutation (S466I) in TEK/TIE2 transmembrane angiopoietin receptor. In vitro expression of TEK S466I in GBM cells showed an increase in activation of ERK and STAT3 and increased TEK/TIE2 immunoprecipitation with EGFR compared to the wild-type TEK receptor. Furthermore, gene ontology analysis reveals that ABT-414-treated flank tumors exhibit increased activation of extracellular matrix organization and CNS developmental processes compared to flank tumors in the control treatment groups. ABT-414-treated tumors also demonstrate increased expression of inhibitor of differentiation (ID)1 and ID3, associated with stem-like phenotype in glioblastoma. Taken together, our data indicate that resistance to ABT-414 is mediated by both de novo mutations not detected in the parent tumor and adaptive dysregulation of pathways which may lead to dedifferentiation and therapeutic resistance.
Abstract 10574: Living with Sexual Partner Slowed Klotho Deficiency-Induced Heart Aging <i>via</i> Suppressing Renal Sodium-Phosphate Co-Transporters
Authors: Kai Chen, Zhongjie Sun
Journal: Circulation (2021)

Background: Staying young at heart is a dream of many aged people. Sexuality is now generally considered beneficial for the overall health. It reduces the risk of a heart attack. However, while the concept of “sex improves health” has been demonstrated, the underlying mechanism remains poorly understood. Methods &amp; Results: Klotho mutant homozygous (KL-/-) mice and age- and sex-matched wild-type (WT) mice were used. One male and one female mouse were co-housed from weaning and fed with low-phosphorus diet to reduce serum phosphate level. And the mice co-housing with the same gender were used as control. Body weight was measured weekly and lifespan was recorded. Heart function was measured by magnetic resonance imaging (MRI). Mice were sacrificed just before dying. Klotho-deficient mice demonstrated heart aging phenotype, as evidenced by cardiac remodeling and cardiac dysfunction. The compromised cardiac function was associated with increased oxidative stress, mitochondrial damage and myocyte apoptosis. We showed that hyperphosphatemia contributes to Klotho deficiency-induced cardiac damages. Interestingly, sexuality attenuated cardiac aging. Mechanistically, sex increased estrogen secretion, which decreased hyperphosphatemia through inhibition of renal tubular sodium-dependent phosphate (NaPi) co-transporters. Co-housing sexual partners also attenuated oxidative stress and myocyte apoptosis and improved mitochondrial function. Moreover, living with sexual partners extends the lifespan by 86.8% in KL(-/-) female mice and 38.7% in male mice. Conclusion: In the Klotho deficiency-induced aging model, sexuality improves heart aging and extends lifespan. This study demonstrated for the first time that living with sexual partners increases estrogen secretion which inhibits renal NaPi co-transporters leading to attenuation Klotho deficiency-induced hyperphosphatemia and heart aging.