tbuckley/cabot-search huggingface dataset:
Treatment of Portal, Mesenteric, and Splenic Vein Thrombosis with Rivaroxaban: A Pilot, Prospective Cohort Study
Authors: Nicoletta Riva, Jan Beyer-Westendorf, Laura Contino, Eugenio Bucherini, Maria Teresa Sartori, Elvira Grandone, Rita Carlotta Santoro, Marc Carrier, Aurelien Delluc, Valerio De Stefano, Fulvio Pomero, Alberto Tosetto, Cecilia Becattini, Ida Martinelli, Barbara Nardo, Laurent Bertoletti, Marcello Di Nisio, Alejandro Lazo-Langner, Alessandro Schenone, Walter Ageno
Journal: Blood (2021)
CTNI-24. A PHASE 1/2 STUDY OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING
Authors: Susan Chi, Antony Hsieh, Megan Foley, Hongliang Shi, Preethi Swamy, Jill Rodstrom, Marc Rudoltz
Journal: Neuro-Oncology (2021)

Abstract Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor; response rates are only ~15% with targeted therapies. Germ cell tumors and high-grade glioma (HGG) are the most common with KIT alterations; sarcoma and HGG are the most common tumors with platelet-derived growth factor receptor alpha (PDGFRA) alterations. H3K27M gliomas are dependent on PDGFRA signaling and patients have an overall survival of ~1 year. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid or CNS tumors, or H3K27M gliomas. The selective KIT and PDGFRA inhibitor, avapritinib, demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50 &amp;lt; 2 nM), and PDGFRA activation-loop (D842V) mutants (IC50 = 0.24 nM); cellular IC50 of PDGFRA wild-type was 95 nM. CNS penetration in preclinical models (brain-to-plasma ratios at steady-state ranging from 0.74–1.00) demonstrated potential for CNS antitumor activity. Avapritinib is approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V) in the USA, and in the EU for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. Objectives of this 2-part phase 1/2, multicenter, open-label study are to assess avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients aged 2 to &amp;lt; 18 years with solid R/R tumors dependent on KIT or PDGFRA signaling, including H3K27M gliomas and no alternative treatment options. Part 1 will enroll ≥ 6 patients; primary endpoint is confirmed age and body surface area physiologically-based pharmacokinetic modeling dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥ 25 patients at the recommended avapritinib dose from Part 1; primary endpoint is objective response rate. Avapritinib once-daily will be administered in continuous 28-day cycles.
Abstract 12305: Cardiomyocyte Alignment Control Promotes the Electrical Integration and Improve the Contractile Function of Human Cardiac Tissue
Authors: Takuma Takada, Daisuke Sasaki, Katsuhisa Matsuura, Koichiro Miura, Satoru Sakamoto, Hiroshi Goto, Jun Homma, Tatsuya Shimizu, Nobuhisa Hagiwara
Journal: Circulation (2021)

Introduction: Alignment, as seen in the native myocardium, is crucial for maintaining the functional cardiac tissue. However, it remains unclear how cardiomyocyte alignment control influences cardiac function and the underlying mechanisms. The aims of our study were to fabricate aligned human cardiac tissue using a micro-processed fibrin gel and elucidated the effect of alignment control on contractile properties. Methods: We fabricated aligned human cardiac tissue through cultivating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) on a micro-processed fibrin gel with inverted V-shaped ridges (MFG). The orientation index was calculated based on the Fourier analysis using Phalloidin staining images. The cardiac tissue function was evaluated with a contractile force measurement system. Results: The orientation index of hiPSC-CMs on MFG was significantly higher than that on the control fibrin gel (1.5±0.1 vs. 1.2±0.1, p&lt;0.001, n=4) and that was close to the orientation index of an adult rat heart tissue (1.6±0.1), suggesting hiPSC-CMs on MFG were aligned more uniformly than the control. The contractile force, maximum contractile velocity, and relaxation velocity were significantly increased in aligned cardiac tissue compared with non-aligned cardiac tissue [contractile force (75bpm): 0.9±0.5 mN vs. 0.5±0.3 mN, p=0.02, n=11]. Motion capture analysis revealed cardiomyocytes in the aligned cardiac tissues showed more unidirectional contraction than the non-aligned cardiac tissues. Furthermore, the timing of contraction at five designated points in the tissues was significantly closed in the aligned tissue, suggesting cardiomyocyte alignment control might improve the systolic and relaxation function of cardiac tissue by promoting synchronous cardiomyocyte contraction. Conclusion: Cardiomyocyte alignment control promoted the electrical integration of cardiomyocytes and contributed to generate the strong contractile force. Understanding the molecular mechanisms of alignment control-mediated synchronous contraction of cardiomyocytes might provide us the new insights on electrophysiological properties of heart tissue.
Abstract 9401: Relationship Between Circulating Levels of Angiotensinogen and Hypertension—The Multi-Ethnic Study of Atherosclerosis
Authors: Patrick J Trainor, Michela Brambatti, Samantha M Carlisle, Adam E Mullick, Tanvir Kahlon, Diana Otero, Hossein Mousavi, Erin Michos, Pamela Ouyang, Erin Morgan, Yvonne Tami, Sotirios Tsimikas, Andrew P Defilippis
Journal: Circulation (2021)

Introduction: Angiotensinogen (AGT) is a critical component of the renin-angiotensin-aldosterone system (RAAS) that regulates blood pressure (BP), volume, and electrolyte levels. While physiological effects of AGT are primarily mediated by AGT-derived peptide hormones, effects of AGT independent of these peptides have been described recently in animal models. We sought to determine the relationship between AGT levels, sex, ethnicity, and hypertension (HTN). Methods: We measured baseline plasma AGT levels using an enzyme-linked immunoassay in 5,786 Multiethnic Study of Atherosclerosis (MESA) participants, aged 45 to 84 yrs. We determined the associations between AGT levels and clinical and demographic variables, medication usage, and BP at the first exam. The relationship between prevalent HTN was then determined using adjusted models. Results: Mean AGT levels (log-transformed) were significantly higher in females than males and differed across race/ethnicities with the ordering (from highest to lowest): White, Black, Hispanic, and Chinese adults. The difference between the sexes was greatest in White adults with females having 1.44 times greater levels than males (95% CI: 1.40, 1.48), and lowest in Chinese adults. In males not taking medications targeting RAAS, one SD higher log-AGT was associated with a 2.61 mmHg higher SBP (95% CI: 1.49, 3.80), in females it was associated with 0.97 mmHg higher SBP (95% CI: 0.30, 1.65). Use of RAAS-blocking medications attenuated these associations. In risk factor-adjusted models, higher levels of AGT were associated with higher odds of prevalent HTN. Conclusions: AGT levels differ between race/ethnicities and between the sexes. Higher levels of AGT are associated with higher BP and odds of prevalent HTN. Despite lower levels in males, the association between levels and BP was greater in males. Taken together, the difference in levels and in the association with BP suggests sex-specific regulation and effects of AGT.
Abstract 10088: Atrial Fibrillation/Atrial Flutter Related Mortality Rates Among the Young Population; Data from CDC Wonder 1999-2019
Authors: Abdul Minhas, Shakeel Jamal, Safi U Khan, Waqas Ullah, Muhammad Osama Muslim, Marat Fudim
Journal: Circulation (2021)

Introduction: Atrial fibrillation (AF) majorly effects the elderly, but it can also affect the younger population. The aim of this study was to examine the trends in AF related deaths in the young population in the United States from 1999 to 2019. Methods: We used CDC Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) to access National Vital Statistics System data from 1999 to 2019. AF associated deaths, age 15- 44 years were identified from multiple causes of death and were represented as age-adjusted mortality rates (AAMR) per 1,000,000 population. Joinpoint regression was used to examine changes in trend and annual percentage change (APC) overall and stratified by sex and racial/ethnic groups. Results: AAMR related to AF decreased from 1.3 in 1999 to 3.7 in 2019 (APC 5.4 [95% CI, 4.8 to 6.0]). AAMR was higher in men (3.1) than women (1.3). AAMR was highest in blacks (4.4) followed by whites (1.9) and others (1.5) (includes Asian or Pacific Islanders; and American Indian or Alaska Natives). AAMR was highest in Black males (6.4). APC in AAMR increased in men (5.4) during the entire study period. In women, APC increased till 2010 (2.5) and then further accelerated till 2019 (8.4). APC in AAMR increased in Whites (5.6) and Blacks (5.3) during the entire study period. Conclusion: AF associated mortality has been consistently increasing in the younger population across all sexes and races. Further research is needed to understand the underlying factors to help develop preventative strategies.
Abstract 12850: The Effect of Regionalization on End-of-Life Hospitalizations for Adult Congenital Cardiology Patients
Authors: Christine M Bui, Olga Saynina, lisa chamberlain, Paul Wise, Susan M Fernandes
Journal: Circulation (2021)

Introduction: Adult congenital heart disease (ACHD) patients may have shortened life expectancy due to complications of interventions and accrued comorbidities. Specialized ACHD care has become standard of care. The effect of regionalization on ACHD patient death is not known. Methods: The Office of Statewide Health Planning and Development database identified ACHD patients ≥ 18 years who died in California hospitals from 1995 - 2018. Specialized ACHD centers were self-designated, so high and low ACHD surgical volume centers were also compared. Results: Of 3,724 patients, when comparing by volume, more deaths occurred at low (85.2%) than high volume centers (14.8%); when comparing by specialization, more deaths occurred at non-ACHD (78.8%) than ACHD centers (21.2%). Moderate (9.4%) and high complexity (4.4%) lesions were rare. Common causes of death were sepsis (14.6%), myocardial infarction (9.3%), stroke (7.5%), and heart failure (7.1%). High volume centers were more likely the location of death than low volume centers for patients aged 18-64, with private insurance, and who lived &gt;20 miles away (p &lt;0.0001 for all). These held true for ACHD vs non-ACHD centers (p &lt;0.0001 for all). Low volume centers were more likely the location of death than high volume centers for patients from zip codes with relative poverty (p 0.0243). This held true for non-ACHD vs ACHD centers (p 0.0182). Over 24 years, the proportion of patients dying at ACHD centers increased (Figure 1), while the proportion of patients dying at high volume centers decreased. Conclusion: ACHD patients who die at high surgical volume and ACHD self-designated centers are more likely to be young, have private insurance, be referred to centers far from home, and have higher socioeconomic status. These likely reflect disparities in access to specialized ACHD care. Despite regionalization with an increase in specialized ACHD centers over time, the majority of ACHD patients continue to die at non-specialized centers.
Siglec-15 Is a Novel Immunomodulatory Protein and Therapeutic Target in Acute Lymphoblastic Leukemia
Authors: Claire E. Pillsbury, Jairo A. Fonseca, Jodi Dougan, Hasan Abukharma, Gloria Gonzalez-Flamenco, Sunita I. Park, Linda N. Liu, Christopher C. Porter
Journal: Blood (2021)
Abstract 10084: Acute Myocardial Infarction Related Mortality Stratified by State and Region; 1999-2019
Authors: Abdul Minhas, Abu Baker Sheikh, Muhammmad Khan, Muhammad Hisham Khan Wazir, Sachin S Goel, Marat Fudim
Journal: Circulation (2021)

Introduction: Acute myocardial infarction (AMI) accounts for significant morbidity and mortality and the mortality may vary across regions and states. The aim of this study was to examine the trends in AMI related deaths stratified by regions in the United States from 1999 to 2019. Methods: We used CDC Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) to access National Vital Statistics System data from 1999 to 2019. AMI related deaths, age &gt;/=25 years were identified from multiple causes of death and were represented as age-adjusted mortality rates (AAMR) per 100,000 population. Joinpoint regression was used to examine changes in trend and annual percentage change (APC) overall and stratified by regions. Results: AAMR was highest in South (91.7) followed by Midwest (88.2), Northeast (77.3), and West (64.6). APC in AAMR decreased across all the regions at variable pace. After initial decline, the decrease in APC in AAMR decelerated in South (-2.7) since 2012, Midwest (-3.0) and Northeast (-4.0) since 2009 and West (-2.7) since 2010. States with AAMRs &gt;90th percentile included Arkansas (180.8), Kentucky (136.3), Mississippi (129.7), Tennessee (123.2), Missouri (121.2) and South Dakota (117.9) and &lt;10th percentile included Alaska (44.0), Nevada (48.0), Minnesota (48.8), Hawaii (53.4), Colorado (54.0) and Montana (54.6). Conclusion: AMI related mortality in elderly has been decreasing at a variable pace in various regions. Significant disparities exist across various regions and states. Further research is needed to examine the underlying causes of these disparities and targeted interventions are required to address these disparities.
Abstract 11122: Understanding Patients’ Experience in an Outpatient IV Diuretic Clinic
Authors: Margaret Emmons, Susan D'Anna, Deborah Cantlin, Carolyn DeMark, Kim Ambrose, Lauren Gilstrap
Journal: Circulation (2021)

Introduction: Nurse led, outpatient IV diuretic clinics are being established with the goal of improving heart failure (HF) care and reducing hospitalizations. To date, limited data exists regarding what is most important to the patients who receive care in this novel setting. In order to better understand patients’ priorities and to improve the quality of care delivered in the multidisciplinary, IV diuretic clinic, a qualitative study was undertaken. Methods: We conducted semi-structured interviews with 19 patients within 24-72 hours after they received care in the IV diuretic clinic to explore their expectations and experience in clinic as well as their care goals. The interview was recorded and transcribed. The recording was listened to while reviewing the transcript. The interviews were then analyzed and coded for thematic analysis. Based on the results of these qualitative interviews, changes to clinic operations were made and the patients’ clinic experience evolved over time ( Figure 1 ). Results: In terms of care goals, almost all patients stated they wanted the clinic visit to “improve” or “relieve” their HF symptoms. Specifically, patients expressed wanting “fluid off” and a desire to be able to “breathe better.” Many expressed a desire to return to a “normal life.” In terms of expectations, patients expected the staff to be competent and were appreciative that the staff was available to them to answer questions. In terms of their experiences, patients were very satisfied with their clinic experience and appreciated that they did not have to be admitted to the hospital to receive care. Conclusions: An ongoing understanding of patients’ goals, expectations and experiences will enable us to continually refine the clinic processes and enhance the clinic experience to provide competent out of hospital care to HF patients.
Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion
Authors: Valeria Fumagalli, Micol Ravà, Davide Marotta, Pietro Di Lucia, Chiara Laura, Eleonora Sala, Marta Grillo, Elisa Bono, Leonardo Giustini, Chiara Perucchini, Marta Mainetti, Alessandro Sessa, José M. Garcia-Manteiga, Lorena Donnici, Lara Manganaro, Serena Delbue, Vania Broccoli, Raffaele De Francesco, Patrizia D’Adamo, Mirela Kuka, Luca G. Guidotti, Matteo Iannacone
Journal: Science Immunology (2022)

The development of a tractable small animal model faithfully reproducing human coronavirus disease 2019 pathogenesis would arguably meet a pressing need in biomedical research. Thus far, most investigators have used transgenic mice expressing the human ACE2 in epithelial cells (K18-hACE2 transgenic mice) that are intranasally instilled with a liquid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suspension under deep anesthesia. Unfortunately, this experimental approach results in disproportionate high central nervous system infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model’s usefulness. Here, we describe the use of an inhalation tower system that allows exposure of unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction but did not lead to fatal viral neuroinvasion. When compared with intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition, and a transcriptional signature comparable to that observed in SARS-CoV-2–infected patients. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection), and therapeutic interventions.
Quality of Life and Karnofsky Performance Status in Patients with Relapse or Refractory Primary Central Nervous System Lymphoma during Phase I/II Study of Tirabrutinib
Authors: Yasuhito Terui, Yoshitaka Narita, Motoo Nagane, Kazuhiko Mishima, Yoshiki Arakawa, Hajime Yonezawa, Katsunori Asai, Noriko Fukuhara, Kazuhiko Sugiyama, Naoki Shinojima, Arata Aoi, Ryo Nishikawa
Journal: Blood (2021)
GSK3-beta as a candidate therapeutic target in soft tissue sarcomas
Authors: S. Verbeke, R. Perret, V. Chaire, E. Richard, V. Velasco, F. Giles, L. Cavalcante, A. Italiano
Journal: Journal of Hematology & Oncology (2021)

Soft tissue sarcoma (STS) is a predominantly fatal rare malignancy with inadequate treatment options. Glycogen synthase kinase 3β (GSK-3β) is an emerging target in human malignancies. Its therapeutic relevance in STS is unknown. We analyzed the prognostic impact of GSK-3β gene and protein expression in two independent cohorts of patients with STS. We then treated STS cell lines and mice xenografts with a novel GSK-3 inhibitor 9-ING-41 alone or in combination with chemotherapy. We demonstrated that 9-ING-41 treatment induced significant STS cells apoptosis and was synergistic in vivo when combined with chemotherapy. Mechanistically, 9-ING-41 induces significant apoptosis of STS cells via suppression of NF-κB-mediated X-linked inhibitor of apoptosis protein (XIAP) expression. These data support the inclusion of patients with STS in clinical studies of 9-ING-41 alone and in combination with chemotherapy.
Abstract P401: The Anti-arrhythmic Effects Of VDAC Isoforms Are Mediated By Glutamate 73 Through Regulation Of Mitochondrial Calcium Transport
Authors: Lauren Crisman, Hirohito Shimizu, Adam Langenbacher, Jie Huang, Kevin Wang, Johann Schredelseker, Jau-Nian Chen
Journal: Circulation Research (2021)

Mitochondria critically regulate cellular processes such as bioenergetics, metabolism, calcium homeostasis and apoptosis. VDAC proteins are abundant proteins that control the passage of ions and metabolites across the outer mitochondrial membrane. We have previously shown that activation of VDAC2, is able to buffer excess calcium and thereby suppress calcium overload induced arrhythmogenic events in vitro and in vivo. However, the mechanism by which VDAC2 regulates calcium transport and cardiac contractions remained unclear. It is also unclear whether all three VDAC isoforms (VDAC1,2 and 3) possess similar cardioprotective activity. The zebrafish tremblor/ncx1 mutant lacks functional NCX1 in cardiomyocytes leading to calcium overload, and the manifestation of fibrillation-like phenotypes. Using the tremblor/ncx1 mutant as a model, we observed isoform-specific differences between the VDAC family members. VDAC1 and VDAC2 enhanced mitochondrial calcium trafficking and restore rhythmic contraction in tremblor mutants, whereas, VDAC3 did not. We found that the differing rescue capabilities of VDAC proteins were dependent upon residues in their N-terminal halves. Phylogenetic analysis further revealed the presence of an evolutionarily conserved glutamate at position 73 (E73) within VDAC1 and VDAC2, but a glutamine (Q73) in VDAC3. Excitingly, we showed that replacing VDAC2 E73 with Q73 ablated its calcium transporting activity. Conversely, substituting the Q73 with E73 allows VDAC3 to gain calcium trafficking and cardioprotective abilities. Overall, our study demonstrates an essential role for the evolutionarily conserved glutamate-73 in determining the anti-arrhythmic effect of VDAC isoforms through their regulation of mitochondrial calcium uptake.
Central Venous Access for Peripheral Stem Cell Collection in Autologous Donors: Safety within an Outpatient Transplantation Program
Authors: Andrés A. León-Peña, José M. Priego-Aguilar, Erick Linares-Padilla, Michelle Rosas-Tellez, José Manuel Priesca-Marin, Martin Ojeda-Laguna, Elizabeth García-Villaseñor, Lorena Bojalil-Álvarez, Óscar A. Reyes-Cisneros, José Antonio Fernández-Gutiérrez, Iván Murrieta-Álvarez, Andres Gomez-De Leon, Guillermo J. Ruiz-Delgado, David Gomez-Almaguer, Guillermo J. Ruiz-Argüelles
Journal: Blood (2021)