tbuckley/cabot-search huggingface dataset:
Abstract 11038: One Year Prognosis After Coronary Intervention in Hemodialysis Patients Accompanied with Triglyceride Deposit Cardiomyovasculopathy, a Novel Type Atherosclerosis with Triglyceride Deposition
Authors: Yusuke Nakano, Hirohiko Ando, Tomohiro Onishi, Hirofumi Ohashi, Wataru Suzuki, Hiroaki Takashima, Ken-ichi Hirano, Tetsuya Amano
Journal: Circulation (2021)

Introduction: Triglyceride deposit cardiomyovasculopathy (TGCV) patients presents the massive accumulation of triglyceride in smooth muscle cells characterized by a novel diffuse narrowing atherosclerosis. There are reported prognostic data on hemodialysis cases accompanied with TGCV, however, little prognostic data after coronary intervention are known. Hypothesis: There might be poor prognosis after coronary intervention in hemodialysis patients accompanied with TGCV. Methods: This retrospective single-center observational study included data from the cardiac catheter database at the study institution between April 2011 and March 2017. Among 654 consecutive patients on hemodialysis, the data for 36 patients implanted DES who could be collated the diagnostic criteria for TGCV using both 123I-β-methyl-iodophenyl- pentadecanoic acid scintigraphy and coronary angiography were analysed. Patients were divided into two groups (TGCV or non-TGCV control group). One-year prognosis after coronary intervention in patients accompanied with and without TGCV were studied. Results: The cohort included 13 and 23 patients accompanied with and without TGCV, respectively. Figure showed one-year prognosis, composite of cardiovascular death or non-fatal myocardial infarction or urgent revascularization, between two groups. Incidence of composite events after coronary intervention was higher in the TGCV group than in the control group (log-rank p=0.036). TGCV was a significantly and independently associated with one-year prognosis after coronary intervention even after adjusted confounding factors. Conclusions: These results demonstrated that TGCV comorbidity is associated with poor prognosis after coronary intervention in hemodialysis patients, and contributes to the novel risk factor for coronary intervention.
EXTH-63. A NOVEL MOUSE MODEL OF DIFFUSE MIDLINE GLIOMA FOR TARGETED IMMUNOTHERAPY
Authors: Maggie Seblani, Markella Zannikou, Joseph Duffy, Rebecca Levine, Qianli Liu, Craig Horbinski, Oren Becher, Irina Balyasnikova
Journal: Neuro-Oncology (2021)

Abstract In children, diffuse midline gliomas retain poor outcomes, failing to have a durable response to conventional therapies. Immunotherapies hold promise, with the integration of the host's immune system fundamental to their design. Here, we describe a novel genetically engineered immunocompetent model that incorporates interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen, to evaluate the antitumor activity of IL13Rα2-CAR T cell and bispecific T cell engager (BiTE) therapies in preclinical studies. The RCAS-Tva delivery system was utilized to induce gliomagenesis through p53 loss and the constitutive expression of PDGFB and human IL13Rα2 in Nestin-Tva;p53fl/fl mice. Pups were injected with virus-producing DF1 cells, encoding either for RCAS-Cre and PDGFB+IL13Rα2 or RCAS-Cre and PDGFB. Kaplan-Meier survival curves established and compared tumor growth dynamics in both models. Tumor tissue was characterized through immunohistochemistry and H&amp;E staining. Cell lines generated from tumor-bearing tissue were used for orthotopic injection and in vitro studies. Expression of PDGFB and IL13Rα2 was confirmed by flow cytometry and western blot. In both groups, de novo tumors developed without significant difference in median survival between RCAS:PDGFB (n=25, 40 days) and RCAS:PDGB+IL13Rα2 (n=32, 39 days). Tumors demonstrated characteristics of high-grade glioma such as infiltration, pseudopalisading necrosis, microvascular proliferation, high Ki-67 index, heterogenous IL13Rα2 expression, with notable presence of CD11b+ macrophages and low count of CD3+ T cells. Orthotopic tumors from developed cell lines were histologically similar to de novo tumors. Treatment of generated cell lines with IL13Rα2-targeting BiTE protein resulted in a loss of glioma cell viability and target-specific activation of T cells. Engineered de novo tumors possess histopathologic features common to diffused midline gliomas. IL13Rα2-positive cell lines derived from de novo tumors were responsive to targeted treatment, opening the opportunity for preclinical assessment of IL13Rα2-directed immunotherapies, with the potential for clinical translation.
BIOM-22. RELEVANCE OF TUMOR MUTATION BURDEN (TMB) IN HIGH-GRADE GLIOMAS
Authors: Hagai Ligumsky, Deborah Blumenthal, Felix Bokstein
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Efforts have been directed toward searching for molecular biomarkers predicting response to immunotherapy in glial tumors. Recently, FDA granted accelerated approval of pembrolizumab for treatment patients with solid tumors with high mutational burden (TMB-H; ≥ 10 mut/Mb). There are conflicting results regarding the use of this parameter in glial tumors. OBJECTIVE to review NGS examinations of patients with glial tumors and high TMB and to analyze their response to immunotherapy. METHODS we retrospectively reviewed NGS examinations from patients with glial tumors treated in Tel-Aviv Medical Center from 2016-2021. Cases with TMB-H were retrieved and analyzed. RESULTS We identified nine high-grade glioma patients with TMB-H. The median age was 38 (19-65). There were 4 patients with glioblastoma; three with anaplastic oligodendroglioma; and two with anaplastic astrocytoma. All but one received radiation prior to the biopsy used for NGS examination, and all were treated with temozolomide. The median TMB was 54 (19-252). Only one glioblastoma patient with a family history of Lynch syndrome had microsatellite instability (MSI)-high; all other patients were MSI stable (MSS). Nevertheless, in all cases, mutated mismatch repair (MMR) genes were detected (MSH6 in 3 patients, MSH2 in one patient, MLH1 in one patient, PMS 2 in one patient, and both MSH2 and 6 in one patient). Six patients received immunotherapy. Only one patient with recurrent glioblastoma and the highest TMB in the group (252) demonstrated a near complete response to pembrolizumab and remains on treatment more than three years. All other patients did not respond to immunotherapy. CONCLUSION TMB-H in primary glioma is associated with mutations of MMR genes. It is typically associated with MSS in these patients (MSI-high was seen in only one syndromic patient). In contrast to systemic neoplasms with TMB-H, the majority of our patients did not respond to immunotherapy.
Abstract 14420: STIM and Orai Spatial Distribution in the Infarcted Mouse Heart Reveals Their Role in Fibroblast Activation
Authors: Jesse Gammons, Janith Halpage, Salvatore Mancarella
Journal: Circulation (2021)

Introduction: Heart failure (HF) remains a major source of late morbidity and mortality after myocardial infarction (MI). Calcium handling and the signaling pathways that govern the functional remodeling associated with HF are unclear. Store-operated calcium entry (SOCE) is a key factor in modulating Ca2+ signals. SOCE is mediated by the STIM protein and Orai channels. Monitoring STIM and Orai distribution is of great interest for studying cardiac remodeling after MI. This study investigated the spatial distribution of STIM and Orai in the heart after MI injury. Methods: The myocardial injury was induced in adult mice via ligation of the left anterior descending artery. MI- and sham-operated animals were euthanized, and hearts were harvested for ex-vivo analyses at 3, 7, 14, and 28 days after MI. We used western blot coupled with immunostaining to detect temporal and spatial profiling of specific STIM and Orai isoforms in different physiological zones and timepoints of MI to generate an integrative high-resolution map of STIM-Orai expression during cardiac remodeling. Results: We found that STIM1 and Orai1 proteins were upregulated from 3-day post-MI throughout day 28 post-MI, (3-4 fold times higher than controls, p&lt;0.001). STIM1 and Orai1 were the most abundant isoforms present in the injured heart. In contrast, Orai3 expression was found to transiently increase at 3- and 7-day post-MI (1.5 fold, p&gt;0.01), STIM2 and Orai2 expression did not change. Spatial pattern analysis revealed a marked gradient of STIM1 and Orai1 expression (decreasing from the border zone, the infarcted area, and the distal area). Co-labeling with cell-specific markers revealed that cardiac fibroblasts exhibited a high level of STIM1 and Orai1 expression. In vitro activation of cardiac fibroblasts showed a marked increase of STIM1 and Orai1 protein expression. Conclusions: Taken together, these data demonstrate that STIM1 and Orai1 expression is associated with fibroblast activation during fibrotic remodeling in the MI. Ca2+ signaling pathways that drive the expansion of fibrosis may rely on sustained STIM1 and Orai1 expression in scar formation and fibroblast activation, of which could provide future targets to exploit for treatment to prevent HF.
Abstract 11334: Metabolic Labeling and Systemic Tracking of Cardiomyocyte-Derived Exosomal MiRNAs
Authors: Chaoshan Han, Junjie Yang, qinkun zhang, Hind Lal, Jianyi Zhang, Gangjian Qin
Journal: Circulation (2021)

Background &amp; Hypothesis: Following acute myocardial infarction (AMI), cardiac exosomes are released into circulation ( PB Exo), thereby transferring cargo miRNAs (miRs) to remote organs to trigger systemic responses. However, the scope and impact of cardiac miR transfer is largely unknown. Since T. gondii uracil phosphoribosyltransferase (UPRT) can convert 4-thiouracil into 4-thiouridine (4TU), then incorporating into nascent RNAs, and the 4TU-labeled RNAs can be identified by thio-linked-biotinylation and streptavidin-affinity isolation, we hypothesize that cardiomyocyte (CM)-specific expression of UPRT ( CM UPRT) allows labeling and tracking of CM-derived miRs in PB Exo and peripheral organs. Methods &amp; Results: We generated CM UPRT mice by crossing αMHC-Cre and CA-GFPstop flox - UPRT mice. Six hours after 4-thiouracil injection, RNAs were isolated from the heart and PB Exo and found to be labeled with high specificity and sensitivity. Then we attempted to isolate representative miRs of different tissue specificities from PB Exo and multiple organs; only CM specific miR-208a, but not other-tissue specific miRs, was 4TU labeled, thus isolated, abundantly in PB Exo and lung. Among FACS-sorted lung cells, endothelial cells (ECs) have the highest CM miR-208a level. Next, we monitored CM miR-208a levels after AMI, which peaked in PB Exo at 12 h and in the lung at 24 h. Since miR-208a is from the intron 29 of the cardiac α-MHC, we measured α-MHC transcript in the lung, which was barely detectable. To determine the biological effect of PB Exo-mediated CM miR-208a transfer, we i.v. injected PB Exo obtained from Sham and AMI mice to intact mice; Sham-Exo and to a greater extent, AMI-Exo, but not Exo from LNA-anti-miR-208a pre-treated mice, downregulated the protein expression of miR-208a target genes (Glyr1, Tmbim6, and NLK) in the lung. Since all the three proteins suppress key effectors in the NF-kB pathway, we examined NF-kB’s classic targets (ICAM-1, VCAM-1 and E-selectin); PB Exo-mediated Glyr1, Tmbim6, and NLK downregulation was associated with ICAM-1, VCAM-1 and E-selectin upregulation. Conclusion: CM UPRT expression permits labeling and tracking of CM miRs in PB Exo and organs; cardiac Exo and CM miR-208a may contribute to AMI-associated lung inflammation.
Abstract MP262: Endogenous Smad7 Restrains Myofibroblast Activation And Protects From Post-infarction Heart Failure By Suppressing Tgf-beta Signaling And By Directly Inhibiting Erbb2
Authors: Claudio Humeres, Arti V Shinde, Anis Hanna, Linda Alex, Simon Conway, Nikolaos G Frangogiannis
Journal: Circulation Research (2021)

Repair of the infarcted heart requires TGF-β/Smad3 signaling in cardiac myofibroblasts and formation of an organized myofibroblast-populated scar. However, TGF-β-driven myofibroblast activation needs to be tightly regulated to prevent excessive fibrosis and adverse remodeling that may precipitate heart failure. We hypothesized that induction of endogenous suppressive signals, such as the inhibitory Smad7; may restrain infarct myofibroblast activation, protecting from adverse remodeling and fibrosis, and we examined the molecular mechanisms of Smad7 actions. In a mouse model of non-reperfused infarction, Smad3 activation triggered Smad7 synthesis in α-SMA+ infarct myofibroblasts, but not in α-SMA-negative fibroblasts. Mice with myofibroblast-specific Smad7 loss had increased heart failure-related mortality, worse dysfunction, and accentuated fibrosis in the infarct border zone and papillary muscles. In isolated cardiac fibroblasts, Smad7 overexpression attenuated myofibroblast conversion and reduced synthesis of structural and extracellular matrix proteins, whereas Smad7 knockdown promoted a matrix-synthetic phenotype. Smad7 actions on TGF-β cascades involved de-activation of Smad2/3 and non-Smad Erk/Akt pathways, without affecting TGF-β receptor activity. Unbiased transcriptomic analysis identified receptor tyrosine kinase (RTK) signaling as a major target of Smad7. Proteomic arrays demonstrated that the RTK Erbb2 is a target of Smad7 in cardiac fibroblasts. Western blots and co-immunoprecipitation assays showed that Smad7 interacts with Erbb2 in a TGF-independent manner and restrains Erbb1/Erbb2 activation, suppressing expression of fibrogenic proteases, integrins and CD44. In conclusion, Smad7 induction in infarct myofibroblasts serves as an endogenous TGF-β-induced negative feedback mechanism that inhibits post-infarction fibrosis by restraining Smad- dependent and Smad-independent TGF-β responses, and by suppressing TGF-independent fibrogenic actions of Erbb2. Protective effects of Smad7 in cardiac remodeling may have important therapeutic implications for heart failure patients.
Veliparib monotherapy following carboplatin/paclitaxel plus veliparib combination therapy in patients with germline BRCA-associated advanced breast cancer: results of exploratory analyses from the phase III BROCADE3 trial
Authors: H.S. Han, B.K. Arun, B. Kaufman, H. Wildiers, M. Friedlander, J.P. Ayoub, S.L. Puhalla, B.A. Bach, M.G. Kundu, N. Khandelwal, D. Feng, S. Bhattacharya, D. Maag, C.K. Ratajczak, V. Diéras
Journal: Annals of Oncology (2021)

In the BROCADE3 trial, addition of the poly(ADP-ribose) polymerase inhibitor, veliparib, to carboplatin/paclitaxel improved progression-free survival (PFS) (hazard ratio 0.71, 95% confidence interval 0.57-0.88; P = 0.002) in patients with advanced human epidermal growth factor receptor 2-negative, germline BRCA1/2-mutated breast cancer. A subset of patients discontinued both carboplatin and paclitaxel before progression and continued on veliparib/placebo maintenance monotherapy until progression. Analyses in this patient subgroup are reported.Patients were randomized 2 : 1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Veliparib (120 mg twice daily) or placebo was given on days -2 to 5, carboplatin (area under the curve 6 mg/ml) on day 1, and paclitaxel (80 mg/m2) on days 1, 8, and 15 of 21-day cycles. Patients who discontinued both carboplatin and paclitaxel before progression received blinded study drug monotherapy at an increased dose of 300-400 mg twice daily continuously. PFS was the primary endpoint. Exploratory analyses were carried out in the subgroup of patients who received blinded study drug as monotherapy. A time-varying Cox model including data from all patients was also used to evaluate treatment effect in the combination and monotherapy phases.A total of 136 of 337 patients randomized to veliparib plus carboplatin/paclitaxel and 58/172 patients randomized to placebo plus carboplatin/paclitaxel discontinued both carboplatin and paclitaxel before progression and continued on blinded veliparib or placebo monotherapy. In this blinded monotherapy subgroup, investigator-assessed median PFS from randomization was 25.7 months with veliparib versus 14.6 months with placebo. Hazard ratios from a time-varying Cox model favored veliparib during both combination therapy and monotherapy. Any-grade adverse events occurring in the monotherapy phase were primarily gastrointestinal. The most common grade ≥3 adverse events were neutropenia and anemia (4% each with veliparib; 5% and 2%, respectively, with placebo).Veliparib maintenance monotherapy had a tolerable safety profile and may extend PFS following combination chemotherapy.
Incidence of Thrombotic Microangiopathies in Quebec: An 8-Year Overview from a Laboratory Centralizing Adamts-13 Testing
Authors: Clémence Merlen, Emmanuelle Pépin, Ousmane Barry, Anik Cormier, Caroline Dubois, Anne-Laure Lapeyraque, Stephan Troyanov, Georges-Etienne Rivard, Arnaud Bonnefoy
Journal: Blood (2021)
Occupational IgE-mediated rhinitis caused by ninhydrin
Authors: M. Hytönen, K. P. Martimo, T. Estlander, O. Tupasela
Journal: Allergy (1996)

Ninhydrin is a laboratory chemical used as a reagent in the detection of free amino and carboxyl groups in proteins and peptides. We present the case of a laboratory technician who developed symptoms of rhinitis when handling papers immersed in a solution containing ninhydrin. Prick tests for ninhydrin and ninhydrin RAST were positive. The inhalation provocation test in an exposure chamber gave an immediate nasal response. A positive prick test to ninhydrin, an elevated level of specific IgE antibodies to ninhydrin, and the RAST inhibition test confirmed an IgE-mediated type I allergic reaction. We are not aware of any other report of ninhydrin as a cause of IgE-mediated allergy.
Abstract 10890: Clinical Significance of Proteinuria and Hematuria in Chronic Heart Failure
Authors: Takamasa Sato, Akiomi Yoshihisa, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2018)

Introduction: Proteinuria (PU) and hematuria (HU) are easily detected by dipstick test and useful markers in the screening for chronic kidney disease. However, the clinical significance of PU or HU...
Abstract 13159: Subclinical Cardiac Magnetic Resonance Imaging Reveals Subtle Myocardial Tissue Abnormalities in Individuals With Arrhythmogenic Cardiomyopathy-Associated Genetic Variants
Authors: Eric D Carruth, Sam Fielden, Amro Alsaid, Brandon Fornwalt, Christopher M Haggerty
Journal: Circulation (2021)

Introduction: With expanding genomic sequencing, incidental identification of patients with disease-causing variants who do not have overt disease is increasingly common. For example, secondary findings of desmosome gene variants associated with arrhythmogenic cardiomyopathy (ACM) are recommended for clinical return but exhibit low penetrance. Additional biomarkers, such as myocardial tissue characteristics, are needed to uncover early disease in patients with genetic risk. Hypothesis: Patients with desmosome variants (G + ) but no clinical phenotype have abnormal ventricular volumes, left ventricular (LV) mass, native T1, T2, post-contrast T1, synthetic extracellular volume (sECV), and late gadolinium enhancement (LGE) via cardiac MRI. Methods: G + individuals were ascertained after clinical confirmation of likely pathogenic/pathogenic desmosome variants from 64548 sequenced Geisinger MyCode patients. MRI studies with myocardial mapping from a single scanner were included. Controls were identified from clinical MRI studies read as having normal biventricular structure and function. Patients who met diagnostic criteria for any cardiomyopathy were excluded from both groups. Ventricular volumes, mass, and tissue properties were defined by manual segmentation. Results: Qualifying studies were identified for 18 G + and 19 genotype unknown (G + ) controls, with similar age and sex. Biventricular volumes and function, as well as LV mass, were similar (Figure). Native T1 was elevated (mean±SEM 1027±9 ms G + vs. 979±15 ms G + ; p = 0.04). No significant differences were found in post-contrast T1, sECV, or native T2. Atypical LGE patterns were noted in 5/18 G + vs. 0/19 G + (p = 0.02). Conclusion: Elevated native T1 and atypical LGE, perhaps due to subclinical fibrosis, were detected in G + patients with normal mass and volume and no overt clinical cardiomyopathy. Longitudinal follow up with larger cohorts will help assess the prognostic significance of these findings.
Abstract 10889: Impact of the COVID-19 Pandemic on Ambulatory Pediatric Cardiology Care by Race/Ethnicity
Authors: Larissa M Wenren, Emily M Bucholz, Maria Perez, Francis Fynn-Thompson, Kathy J Jenkins, Jean Connor, Sarah D De Ferranti, Susan F Saleeb
Journal: Circulation (2021)

Introduction: Racial/ethnic disparities in congenital heart disease outcomes are well documented. The impact of COVID-19 on race/ethnicity in access to ambulatory pediatric cardiology care is unknown. Methods: To examine differences in ambulatory care visits by race/ethnicity and whether differences were exacerbated by the COVID pandemic (March 2020), we examined number of visits scheduled (0-18 years old) and visit completion (as scheduled, delayed completion within 6 months, incomplete) by race/ethnicity. We focused on early pandemic, April 2020 (vs April 2019) and later pandemic, July 2020 (vs April 2020), using chi-square and logistic regression. Results: Annual clinic volume fell by 4.5% during the pandemic (18,725 to 17,866). Race/ethnicity shifted slightly towards white compared to non-white minority (NWM) 30% vs 28%, p &lt;0.001. Public insurance was constant at 33%, p =0.83. Telehealth visits accounted for 46% of visits during the pandemic (0.8% pre-pandemic), with different utility by white than NWM patients (49% vs 43%, p &lt;0.001). Visits in April 2020 fell by 57% from April 2019 and percent of visits completed without delay declined from 69% to 39%, p &lt;0.001. Visits in July were similar from 2019 to 2020 but visits completed without delay declined from 71% to 62%, p &lt;0.001. Visit completion rates varied by race/ethnicity (Figure 1), with differences between white vs NWM early in the pandemic ( p =0.01). Differences in visit completion rates by race/ethnicity were not significantly different from the year prior ( p for interaction=0.74) or from April to July 2020 ( p for interaction=0.48). Conclusions: NWM have higher rates of incomplete/delayed visits compared to whites, though the difference was not statistically heightened by the pandemic. Telehealth visits have become a prominent part of ambulatory care, with higher completion rates by white patients. Efforts to reduce lapses in care are needed across demographics to ensure equitable care delivery.