tbuckley/cabot-search huggingface dataset:
CSIG-24. TARGETED INHIBITION OF CDK5-MEDIATED REGULATION OF HUMAN ENDOGENOUS RETROVIRUS K (HML-2) ENVELOPE PROTEIN IN ATYPICAL TERATOID RHABDOID TUMOR
Authors: Tara Doucet-O'Hare, Jared Rosenblum, Brianna DiSanza, Catherine DeMarino, Abigail Atkinson, Nasir Malik, Joe Steiner, Harish Pant, Avindra Nath, Zhengping Zhuang
Journal: Neuro-Oncology (2021)

Abstract Atypical teratoid rhabdoid tumor (ATRT) is a pediatric brain tumor with a high mortality rate characterized by mutations in/ deletions of SWI/SNF matrix-associated actin-dependent regulator of chromatin sub-family B member 1 (SMARCB1). We previously showed that loss of SMARCB1 causes up-regulation and release of HML-2 subfamily of human endogenous retrovirus K envelope protein (HML-2 ENV), resulting in maintenance of pluripotency. Here, we investigated intracellular trafficking and release of HML-2 ENV. Further, we demonstrate two potential therapeutic strategies to decrease intracellular HML-2 ENV: 1) inhibition of calcium influx by ouabain, a cardiac glycoside toxic to neural stem cells, and 2) targeted inhibition of cyclin-dependent kinase 5 (CDK5), which is restricted to neurons by p35, its activator protein, by TP5. ATRT cell lines and tumor tissue obtained from patients were confirmed for SMARCB1 loss and increased HML-2 ENV. Cell viability and intracellular HML-2 ENV concentration were measured after treatment with ouabain and TP5 (CDK5 antagonist). We evaluated the calcium-mediated effect of ouabain on HML-2 intracellular concentration by treating the cells with ouabain, the calcium chelators calcimycin and EGTA, and calpeptin, a calpain inhibitor, which activates CDK5, and measuring HML-2 ENV and p35. We evaluated HML-2 ENV for a CDK5 consensus phosphorylation site and performed co-immunoprecipitation to evaluate direct interaction. We evaluated activity of CDK5 in ATRT cell lines by autoradiography. Both Ouabain and TP5 caused a decrease in cell viability in a dose-dependent manner. Further, ouabain treatment decreased HML-2 ENV intracellular concentration. We found that HML-2 ENV contains a consensus phosphorylation site for CDK5. We discovered that HML-2 ENV was bound to CDK5. We established that ATRT cell lines had hyperactive CDK5. Finally, we established that the effect of ouabain on HML-2 ENV was due to indirect inhibition of calcium-mediated activation of calpain and thus CDK5.
Abstract 13243: Integrin Linked Kinase Expression in Human Valvular Endothelial Cells Plays a Protective Role in Calcific Aortic Valve Disease
Authors: Sandra Sanchez, Paula Reventun, Mercedes Castro, Alberto Cook-Calvete, Lucía Benito, Ignacio Hernandez Navarro, Jose Lopez Menedez, Carlos Zaragoza, Marta Saura
Journal: Circulation (2021)

Introduction: Calcific aortic valve disease (CAVD) is the most common valvular heart disease in the aging population. CAVD is a highly active ossification process originated in valvular interstitial cells which differentiate towards an osteoblastic phenotype. However, the role of valvular endothelial cells in CAVD has not been fully explored. We previously demonstrated that ILK expression in vascular endothelium plays an essential cardioprotective role. Hypothesis: Endothelial ILK plays a protective role in human valvular endothelial cells osteogenesis. Methods and Results: Human aortic valves were obtained from 52 patients with calcific aortic stenosis compared with 16 non-calcified aortic valves and ILK levels were analyzed. Our study showed a significant relationship between the degree of AV calcification and decreased ILK expression detected by IHQ and qPCR (p&lt; 0,013). Moreover, decreased ILK expression correlated with BMP2 and Runx2, two markers of valvular calcification (p&lt;0.01). Human valvular endothelial cells (hVECs) isolated from non-calcified controls display the ability to calcify when cultured in pro-calcifiying conditions and ILK levels were unaffected by the pro-calcifiying conditions. However, silencing ILK expression in hVECs resulted in decreased NO production, increased expression of calcific disease markers Runx2, BMP2, and osteopontin. ILK silencing in hVECs induced calcium deposition, determined by alizarin red staining, when cultured in pro-calcifiying conditions. Thus, our results suggest that decreased ILK expression could promote endothelial to osteogenic phenotype transition. Restoring nitric oxide levels by DETA-NONOate treatment in ILK silenced hVEC was able to reverse those effects partially. Conclusions: Collectively, our results point to a crucial role of ILK in maintaining human valve endothelial cell function preventing valvular calcification.
EPCO-01. MOLECULAR PROFILING OF SPINAL CORD EPENDYMOMA
Authors: Erika Yamazawa, Shota Tanaka, Genta Nagae, Takayoshi Umeda, Taijun Hana, Phyo Kim, Fumi Higuchi, Toshihiro Takami, Yuta Nakanishi, Keisuke Takai, Takashi Komori, Hirokazu Takami, Masashi Nomura, Akitake Mukasa, Shunsaku Takayanagi, Kazuhiko Ishii, Hideaki Imai, Reiko Matsuura, Tsukasa Koike, Yoshihiro Kushihara, Shohei Nambu, Kazuha Kugasawa, Hiroyuki Aburatani, Nobuhito Saito
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Ependymomas are currently classified into 9 subgroups by DNA methylation profiles. Although spinal cord ependymoma (SP-EPN) is distinct from other tumors, diversity within SP-EPN is still unclear. Here, we used transcriptomic and epigenomic profiles to investigate the diversity among Japanese SP-EPN cases. MATERIALS AND METHODS We analyzed 57 SP-EPN patients (32 males and 25 females, aged from 18 to 78 years, median: 52), including two cases of neurofibromatosis type 2, five cases of grade 3 (WHO grade). We obtained transcriptome (RNA-seq) and DNA methylation (Infinium Methylation EPIC array) data from fresh frozen specimens of SP-EPN resected at the University of Tokyo Hospital and our collaborative groups. RESULTS Three cases had a previous intracranial ependymoma operation. Hierarchical clustering of the DNA methylation data showed that these three cases of intracranial origin as a different cluster from spinal origin. The 45 grade 2 spinal ependymoma showed a relatively homogenous methylation pattern. However, the methylation status of HOX gene cluster regions is compatible with the segment of origin, which reflects the cells of origins are derived after the determination of segment identity. RNA sequencing of 57 cases revealed two subgroups within grade 2. Gene ontology analysis of differentially expressed genes suggested the difference in metabolic state such as rRNA translation and mitochondrial respiration between the two expression subgroups. CONCLUSION Epigenetic analysis indicated the accurate body segment origin of SP-EPN. We observed that metabolic states could divide grade 2 spinal cord ependymoma into 2 subgroups and will present the relationship to clinicopathological information.
General Patient-Reported Outcome Measure Tools Non-Reflective of AL Amyloidosis Quality of Life (QoL): A Systematic Literature Review
Authors: Sotirios Bristogiannis, Charalampia Kyriakou, Ashutosh Wechelaker, Brendan Wisniowski, Shameem Mahmood, Sajitha Sachchithanantham
Journal: Blood (2021)
Abstract 13976: Upstroke Time per Cardiac Cycle: Screening Index for Severe Aortic Stenosis
Authors: Tasuku Higashihara, Takayuki Nakano, ATSUSHI TAKEDA, Yuichi Morita, Noriaki Watanabe, Yoshiharu Sada, Hiroki Ikenaga, Hiroto Utsunomiya, Yukihiro Fukuda, Yukiko Nakano
Journal: Circulation (2021)

Introduction: AS is one of the most common valvular heart diseases in the elderly population. Since the TAVR era, the indications for AS invasive treatment have expanded to patients at high risk of surgery and even those at moderate risk. Therefore, a simplified screening test is needed to extract patients with severe AS. Hypothesis: Brachial-ankle pulse wave analysis, which is a non-invasive well-established test, is useful for screening patients with severe AS in routine clinical practice. Methods: We recruited patients who were admitted to Hiroshima University Hospital for scrutiny of AS. Severe AS was defined as an aortic valve area (AVA) of &lt;1.0 cm 2 or peak transaortic velocity &gt;4 m/s or a mean pressure gradient of &gt;40 mmHg. Pulse wave measurement was performed with the VP-1000 device (Omron, Kyoto, Japan), and upstroke time per cardiac cycle (UTCC; [upstroke time/cardiac cycle] x 100%) was calculated. We excluded patients with peripheral artery disease (ABI &lt;0.9) or lack of UTCC data. Results: A total of 235 patients with AVA and UTCC available data were analyzed. In these patients, UTCC was correlated with AVA (r = -0.279; p &lt;0.001, Figure). In 121 patients who underwent TAVR and had available data of UTCC before and after TAVR, UTCC was significantly shortened after TAVR (from 20.7% [IQR; 18.6, 23.3] to 18.7% [16.7, 21.0]; p &lt;0.001). After adjustment by LVEF, LVEDV, BSA, and AF, UTCC was still correlated with AVA (β= -0.012, p = 0.001). Conclusions: UTCC from brachial-ankle pulse wave analysis might help identify severe AS patients in routine clinical practice.
Abstract 12057: GDF15 and CHI3L1 Are Associated With a High-Risk Phenotype in Heart Failure Patients - Results From the Harvest-Malmö and Media-DHF Cohorts
Authors: Anna Dieden, Nicolas Girerd, John Molvin, Johan Korduner, Petri Gudmundsson, Erasmus Bachus, Hannes Holmes, Kevin Duarte, Faiez ZANNAD, Amra Jujic, Martin Magnusson
Journal: Circulation (2021)

Introduction: Even though treatment for heart failure (HF) has improved over recent decades, the mortality is still high, and the high re-hospitalization rate poses a huge economic burden to the society. Hypothesis: Here, we explored if proteomic profiles differed between high mortality risk/multiple hospitalized HF patients versus HF patients that survived without multiple hospitalizations. Methods: A multiplex protein panel was analysed in patients hospitalized for HF (The Swedish heart failure cohort (HARVEST-Malmö) discovery cohort: n=296; mean age 74.6 years; 30% women) and a replication cohort, the European MEDIA-DHF cohort (n=430). We characterized three mutually exclusive phenotypes of HF based on vital and hospitalization status (survivors without multiple hospitalizations (≥2; n=50); deceased without multiple hospitalizations (n=46) and multiply hospitalized but not dead (n=86), and explored associations between proteins and phenotype in multivariate logistic regressions. Results: In the discovery cohort, SCGB3A2 (OR 2.51 (1.14-5.52; p=0.023); elafin (OR 2.50 (1.01-6.14; p=0.047), GDF15 (OR 2.82 (1.07-7.42); p=0.036) and CHI3L1 (3.09 (1.42-6.72); p=0.004) presented with significant associations with death without multiple hospitalizations. GDF15 and CHI3L1 also presented with associations with multiple hospitalizations. SCGB3A2, elafin, In the replication cohort GDF15 and CHI3L1 were both associated with death without multiple hospitalizations (n=9) a model adjusted for age and sex. When associations between GDF15 and CHI3L1 and multiple hospitalizations were explored in the replication cohort, GDF15but not CHI3L1 presented with significant associations in a model adjusted for age and sex (p=0.005 and p=0.900, respectively), but the association was attenuated upon further adjustment (p=0.80). Conclusions: In two European hospitalized HF populations, we could show associations between GDF15 and CHI3L1 and a high-risk phenotype of HF in both the discovery and replication cohorts.
Abstract 12546: Artificial Neural Network Models for Lipid Profile Prediction in the US General Population
Authors: Juwel RANA, Townim Faisal Chowdhury, Shafin Rahman, John Oldroyd, Rakibul Islam
Journal: Circulation (2021)

Introduction: Hyperlipidemia is a major risk factor for cardiovascular disease. Tests of blood lipid concentrations require a blood sample to be taken in a clinical setting, which is costly, time-consuming, and may preclude measurements in a large number of people at risk. Hypothesis/Objective: This study aimed to develop artificial neural network (ANN) models to predict lipid profiles of the US general population using noninvasive and low-cost diagnostic features. Methods: We used the most recent cycle of the National Health and Nutrition Examination Survey (NHANES) 2017-2018. The participants with missing values in outcomes: total cholesterol (TCH), triglycerides (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL), and aged&lt;18 years were excluded. We developed ANN-based prediction models using various combinations of eight features: age, gender, race/ethnicity, body mass index, waist to hip ratio, waist to height ratio, systolic and diastolic blood pressure with three to thirty hidden neurons in one layered feed-forward ANN. We trained ANN models 100 times for seven different input combinations. The performances of these prediction models were evaluated by mean accuracy (ACC), R-squared (R 2 ), mean square error (MSE), root mean square error (RMSE), and mean absolute error (MAE). Results: Of 5176 participants, 51.8% were females with a mean (range) age of 52 (18-80) years. Results show that the ANN models can predict these outcomes with high mean ACC, (TCH 96.69%, HDL 95.11%, LDL 93.47%, TG 91.35%), average R2 (TCH 0.022, HDL 0.186, LDL -0.019, TG 0.158), average MSE (TCH 0.048, HDL 0.056, LDL 0.152, TG 0.268), average RMSE (TCH 0.220, HDL 0.237, LDL 0.389, TG 0.518), and average MAE (TCH 0.171, HDL 0.192, LDL 0.287, TG 0.410). Conclusions: ANN is an effective diagnostic tool for predicting lipid profiles for the US general population, and can be used to predict lipid profiles for clinical diagnosis using noninvasive and low-cost features.
Abstract 10328: Eicosapentaenoic Acid versus Mixed Eicosapentaenoic/Docosahexaenoic Acid Added to Statin Therapy for Reducing Plaque Volume in Coronary Atherosclerosis: A Systematic Review and Meta-Analysis of Prospective Randomized Trials
Authors: John P Sheppard, Suvasini Lakshmanan, Suraj Dahal, April Kinninger, Sion K Roy, Deepak L Bhatt, Matthew J Budoff, John R Nelson
Journal: Circulation (2021)

Introduction: Multiple trials demonstrate efficacy of eicosapentaenoic acid (EPA) for lowering cardiovascular risk. Imaging studies suggest this benefit may relate to measurable effects on coronary plaque. Interestingly, EPA mixed with docosahexaenoic acid (DHA) has largely failed to show clinical benefit. The differential effects of EPA and EPA/DHA on coronary plaque burden and characteristics, including prognostically significant features such as lipid volume, remain unclear. Methods: We performed a systematic review of clinical trials that longitudinally measured coronary plaque volume in patients randomized to statin+EPA or statin+EPA/DHA versus statin alone, and performed network meta-analysis to estimate the standardized mean difference (SMD) of these treatments in percent change of total plaque volume and plaque lipid volume. Results: Ten trials comprising 860 patients met inclusion criteria among 535 articles. Four studies used intravascular ultrasound, three used coronary CTA, and three used optical coherence tomography. Among statin, statin+EPA, and statin+EPA/DHA treatments, random effects analysis yielded changes of +1.7% [-2.8%, +6.3%], -11.0% [-20.7%, -1.3%], and -3.4% [-14.5%, +7.8%] in total plaque volume and +3.1% [-1.6%, +7.8%], -19.8% [-27.5%, -12.1%], and -6.4% [-20.3%, +7.5%] in plaque lipid volume. Compared with statin, statin+EPA achieved greater percent reduction in coronary plaque volume (total volume: SMD = 0.92, P = 0.002; lipid volume: SMD = 1.04, P = 0.003) but statin+EPA/DHA showed no difference (total volume: SMD = 0.19, P = 0.58; lipid volume: SMD = 0.42, P = 0.38). Conclusions: In this most up-to-date meta-analysis, EPA as an adjunct to statins is associated with significant reductions in coronary plaque burden, including plaque lipid volume - unlike EPA/DHA combinations. These differential effects on coronary atherosclerosis offer mechanistic insights to observed clinical benefits of statin+EPA therapy.
The First Real-World Evidence Prospective Registry of Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm Treated with Tagraxofusp, a CD123-Targeted Therapy, in Europe
Authors: Uwe Platzbecker, Emanuele Angelucci, Pau Montesinos, Roberto M. Lemoni, Alexandros Spyridonidis, Joaquín Casariego, Tariq I. Mughal, Mohamad Mohty
Journal: Blood (2021)
Abstract 12129: Vascular Endothelial Barrier Protection May Prevent Arrhythmias in Atrial Fibrillation and Myocardial Infarction
Authors: Louisa Mezache, Gerard Nuovo, Rengasayee Veeraraghavan
Journal: Circulation (2021)

Vascular leak is a major sequela of inflammation, which is associated with arrhythmic pathologies such as atrial fibrillation (AF) and myocardial infarction (MI). We recently demonstrated that the vascular leak-inducing cytokine vascular endothelial growth factor (VEGF; 90-580 pg/ml - levels found in AF patients) induces acute remodeling (30-60 minutes) of sodium channel (Na V 1.5) -rich intercalated disk (ID) nanodomains, disrupting their ultrastructure and prompting translocation of Na V 1.5 from these sites. This in turn disrupted impulse propagation and promoted arrhythmias in murine atria. Here, we tested the hypotheses that i) similar acute pro-arrhythmic remodeling occurs in the ventricles of MI patients, and ii) protecting the vascular barrier may prevent arrhythmias following an acute inflammatory insult. First, we examined myocardial samples from five human MI patients. VEGF was overexpressed in both cardiomyocytes and vascular endothelium in the border zone surrounding &lt;6 month-old infarcts. Notably, co-localization analysis showed significantly reduced Na V 1.5 near both connexin43 and N-cadherin within the border zone in 1-, 3-, and 9-day-old infarcts, paralleling our observations in mouse atria. Next, we returned to our murine model of AF induced by acute inflammatory insult (100 pg/ml VEGF for 60 minutes) to test the antiarrhythmic efficacy of protecting the vascular endothelial barrier. Overall, median in vivo arrhythmia burden was higher in VEGF-treated mice relative to vehicle controls (7.5±11 vs. 0±6 s/hr). We tested two strategies shown to prevent vascular barrier breakdown: Blocking connexin43 hemichannels (αCT11 peptide) decreased in vivo arrhythmia burden to 0 ± 6.07 s/hr. Panx1-IL2 (a peptide inhibitor of Panx1 channels) treatment decreased also in vivo arrhythmia burden (0 ± 15.57 s/hr with 1.6 μM Panx1-IL2). Similar antiarrhythmic efficacy was also achieved with small molecule inhibitors of Cx43 and Panx1. These results highlight VEGF-induced vascular leak as a novel mechanism for acute arrhythmias both in the early stage AF and following MI. Indeed, this mechanism may contribute to post-MI AF. Importantly, vascular-barrier protection may be a viable strategy to prevent these arrhythmias.
Small-molecule inhibitors that disrupt the MTDH–SND1 complex suppress breast cancer progression and metastasis
Authors: Minhong Shen, Yong Wei, Hahn Kim, Liling Wan, Yi-Zhou Jiang, Xiang Hang, Michael Raba, Stacy Remiszewski, Michelle Rowicki, Cheng-Guo Wu, Songyang Wu, Lanjing Zhang, Xin Lu, Min Yuan, Heath A. Smith, Aiping Zheng, Joseph Bertino, John F. Jin, Yongna Xing, Zhi-Ming Shao, Yibin Kang
Journal: Nature Cancer (2021)
A Flash of Gold and Glitter
Authors: Wendy Tong
Journal: JAMA Oncology (2021)

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E14a2 and e14a2+e13a2 BCR-ABL Transcripts Are Associated with Earlier Cytogenetic and Molecular Response Rates in CML-CP Treated with Imatinib
Authors: Katia B Pagnano, Eliana C Miranda, Fernanda S Seguro, Gustavo Hr Magalhaes, Nelma D Clementino, Arthur Moellmann-Coelho, Maryanna N Da Silva, Renato Centrone, Monika Conchon, Jaisson Bortolini, Teresa Cristina Bortolheiro, Valquiria Povoa, Luciana Nardinelli, Carmino Antonio De Souza, Israel Bendit
Journal: Blood (2017)
Abstract 10851: Statin Shows Significant Antiatherosclerosis and Anti-Inflammatory Effect in Kawasaki Disease Model Mouse
Authors: Yusuke Motoji, Ryuji Fukazawa, MAKOTO WATANABE, Kanae Tsuno, Miyagi Yasuo, Yasuhiko Itoh, Yosuke Ishii
Journal: Circulation (2021)

Introduction: Kawasaki disease (KD) is an acute systemic vasculitis, which might promote atherosclerosis in adulthood. The purpose of this study is to verify long-term effect of HMG-CoA inhibitor (statin) for the vasculitis. Hypothesis: Statins suppressed inflammatory cell infiltration and plaque arteriosclerosis in KD, and might have a preventive effect on the onset of cardiovascular events in the chronic phase. Methods: Candida albicans water-soluble fraction (CAWS) was injected intraperitoneally in 5-week-old male apoE -/- mice to create KD-like vasculitis. All mice were fed a high-fat diet 2 weeks after the first injection. Divided into 3 groups, PBS (P), CAWS (C), and CAWS with statin (CS) (orally administered atorvastatin 10mg/kg/day), and sacrificed 6 or 10 weeks after injection and obtained the aorta with the heart (from root to iliac bifurcation). The lipid plaque lesion on the aorta was stained with Oil Red O and the inflammatory cells in aortic root sections were stained with hematoxylin and eosin. These area ratios were quantified and compared. Results: Both atherosclerosis and inflammatory cell infiltration were significantly promoted by CAWS (p&lt;0.01). Statin significantly suppressed plaque area after 10 weeks (C 33±1.5%, CS 18±1.7%) and inflammatory cell infiltration after 6, 10 weeks (C 16±0.6%, CS 7.8±0.9% after 6 weeks, and C 20±2.1%, CS 10±1.0 after 10 weeks, respectively). We examined the statistical correlation between the plaque lesion and the inflammatory cell area, so it revealed the trend between the two groups (r=0.97, P&lt;0.001). Conclusions: CAWS vasculitis, KD-like vasculitis, promoted the development of atherosclerosis in apoE -/- mice. It was newly revealed that long-term oral administration of statin significantly suppressed not only atherosclerosis but also inflammatory cell infiltration. Statin treatment might be expected for secondary prevention of the onset of cardiovascular events in the chronic phase of KD.