tbuckley/cabot-search huggingface dataset:
Abstract 15923: A Combined <i>In Silico</i> and <i>In Vitr</i> o Approach for Surgical Planning of Pediatric Coarctation Repair
Authors: Fanette Chassagne, Sujatha Buddhe, Lester C Permut, David MCMULLAN, Stephen P Seslar, Alberto Aliseda
Journal: Circulation (2020)

Introduction: Coarctation of the aorta is a congenital malformation of the proximal descending aorta that results in severe narrowing of the vessel lumen. It causes significant changes in the aortic hemodynamics, including reduced blood flow and an increased pressure gradient in this area of the vasculature. When this congenital cardiac malformation is associated with aortic arch hypoplasia, a two step-surgery is proposed: first, an end-to-end anastomosis in performed to remove all the ductal tissue surrounding the coarctation, and then the aorta is longitudinally incised and patched to increase its diameter. The design of the patch, based on the surgeon’s experience, is done in the OR. A combined in silico and in vitro approach is proposed to test the possibility of a priori design of the patch. This approach would also open the door to optimization of the patch to restore physiological hemodynamics in the aorta. Methods &amp; Results: CFD simulations of the hemodynamics in the pre-treatment aortic arch were created from the segmentation of patients’ images who received surgical treatment at Seattle Children’s Hospital. In vivo hemodynamics data were used as boundary conditions for the simulation. The design of the patch was created via an in-house code and was based on surgeons’ input: the locations of the start and the end of the lumen enlargement and the length of the aortic segment to be resected. The optimization of the patch design was performed by comparing the simulated hemodynamics (pressure drop, endothelial shear stress, size of the recirculation region, ...) before and after the patch repair. The optimized patch design was then used by the surgeon to perform the in vitro surgical treatment on a physical model of the patient’s anatomy, made in a translucent silicon rubber. The repaired anatomical model was scanned by X-ray microtomography and cast in an optically clear silicone. Time-resolved particle image velocimetry measurements were performed to characterize the post-treatment hemodynamics, and compared to the results of the CFD simulation. Conclusions: This unique in silico and in vitro approach allows surgeons to perform different repairs on patient-specific physical in vitro models and to optimize the design of the patch prior to starting the surgery.
TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons
Authors: Daxing Gao, Michael J. Ciancanelli, Peng Zhang, Oliver Harschnitz, Vincent Bondet, Mary Hasek, Jie Chen, Xin Mu, Yuval Itan, Aurélie Cobat, Vanessa Sancho-Shimizu, Benedetta Bigio, Lazaro Lorenzo, Gabriele Ciceri, Jessica McAlpine, Esperanza Anguiano, Emmanuelle Jouanguy, Damien Chaussabel, Isabelle Meyts, Michael S. Diamond, Laurent Abel, Sun Hur, Gregory A. Smith, Luigi Notarangelo, Darragh Duffy, Lorenz Studer, Jean-Laurent Casanova, Shen-Ying Zhang
Journal: Journal of Clinical Investigation (2021)

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3–/– mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-β secretion and ISG mRNA in induced pluripotent stem cell–derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-β immunity.
Abstract 15023: Junctophilin-2 (JPH2) Interactome in Ventricular Myocytes is Subcellular Compartment-dependent and Subject to Remodeling During Hypertrophy Leading to Heart Failure
Authors: Tytus Bernas, Rengasayee Veeraraghavan, Wilson T Zachary, Soltisz Andrew, Min Jiang, Gea-ny Tseng
Journal: Circulation (2020)

Introduction: Junctions between sarco/endoplasmic reticulum (SR/ER) and sarcolemma (SL), where Ca-induced Ca release (CICR) takes place, are important for myocardial contractility. JPH2 is the major SR/SL tether in cardiomyocytes. Hypothesis: JPH2 interacts with diverse proteins depending on its subcellular location. Furthermore, JPH2's distribution and relations with its interactors are subject to remodeling in diseased state. Methods: We studied spontaneously hypertensive rats: 2-3 months (SY, healthy) and ≥ 20 months (SO, in heart failure). We used immunoprecipitation (IP) and global unbiased search (proteomics) to identify JPH2's interactors in cardiomyocytes. We used high-resolution structured illumination microscopy (SIM) followed by deconvolution and object-based segmentation in 3 dimension (OBS3D) to quantify spatial relationships between JPH2 and interactors. Results: Based on proteomics JPH2's interactors are involved in: SR/ER function, vesicular transport, sub-sarcolemma scaffold, ion transporters/channels, intercalated disc (ICD) organization and mitochondrial function. We quantified spatial relationships between JPH2 and 6 interactors representing distinct subcellular compartments: RyR2 (junctional SR), Cav1.2 (t-tubules), dystrophin (peripheral SL), caveolin-3 (caveolae), connexin-43 (ICD), and prohibitin-1 (mitochondria). In SY myocytes, JPH2 clusters are organized along the z-lines and peripheral SL, consistent with close and reciprocal association in JPH2/RyR2 and JPH2/dystrophin. In SO myocytes, JPH2 is dispersed from z-lines but stays close to peripheral SL and clusters to ICD. This leads to reduced proximity between JPH2 and Cav1.2 or RyR2, but closer proximity to connexin-43. Conclusions: In failing heart, a portion of JPH2 shifts from t-tubule/SR junctions (where CICR occurs) to ICDs (where store-operated Ca entry 'SOCE' occurs), likely contributing to dysregulation of intracellular Ca handling.
Emergence of the EGFR T790M mutation in a lung adenocarcinoma cell line after vandetanib treatment
Authors: Eiki Ichihara, Kadoaki Ohashi, Nagio Takigawa, Hiromi Kashihara, Hiromasa Takeda, Toshio Kubo, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura
Journal: Cancer Research (2008)

678  Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor (EGFR), and RET tyrosine kinases. Vandetanib has demonstrated antitumor activity as a single agent in patients with refractory or recurrent non-small-cell lung cancer. To investigate the mechanisms of acquired resistance to vandetanib, we established a PC-9/VanR cell line by continuously exposing parent PC-9 cells that carried an in-frame deletion in EGFR exon 19 (delE746-A750; derived from a Japanese patient with adenocarcinoma of the lung) to increasing concentrations of vandetanib. The 50% inhibition concentrations (IC50) were determined using a modified 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The IC50 of parental PC-9 cells and PC-9/VanR to vandetanib were 0.086 and 4.6 μM, respectively (relative resistance 53.3). The IC50 of parent PC-9 cells and PC-9/VanR cells to gefitinib were 0.047 and 8.0 μM, respectively (relative resistance 167). PC-9/VanR cells acquired complete cross-resistance to gefitinib. Oral administration of 5 mg/kg vandetanib and 5 mg/kg gefitinib for 6 weeks delayed the tumor growth to the same extent (53% and 55% of the control tumor volume, respectively) in an in vivo xenograft model using PC-9/VanR cells. A direct sequencing assay showed a secondary T790M mutation in the vandetanib-resistant PC-9/VanR cells. Western blotting revealed that vandetanib did not inhibit p-EGFR, p-MAPK, or p-AKT in PC-9/VanR cells. These findings are compatible with those observed in gefitinib resistance due to the T790M mutation. The expression levels of all other ErbB family proteins, c-Met, and PTEN in vandetanib-resistant PC-9/VanR cells were the same as those in parent PC-9 cells. Taken together, T790M seems to be closely associated with resistance to vandetanib. We demonstrated the emergence of a secondary T790M mutation in vandetanib-resistant cells that showed cross resistance to gefitinib ex vivo.
IMPACT OF REPORTED LEVEL OF EXPOSURE TO COVID-19 PATIENTS ON PHYSICIANS IN RESIDENCY AND FELLOWSHIP TRAINING PROGRAMS
Authors: A. Cravero, N. J. Kim, L. D. Feld, K. Berry, A. Rabiee, N. Bazarbashi, S. Bassin, T. H. Lee, A. Moon, X. Qi, P. S. Liang, E. S. Aby, M. Q. Khan, K. J. Young, A. A. Patel, K. Wijarnpreecha, A. Kobeissy, A. Moutaz Hashim, A. Houser, G. Ioannou
Journal: Hepatology (2020)

Background: During the novel coronavirus-2019 (COVID-19) pandemic, physicians in residency and fellowship training programs are serving as essential healthcare workers while also attempting to continue their preparation for eventual independent practice in their field  We aimed to determine how level of exposure patients with COVID-19 affected the experience of graduate medical trainees in terms of their safety, professional development, and well-being during March and April 2020 Methods: We administered an anonymous, voluntary, web-based survey to physicians enrolled in residency or fellowship training programs in any specialty worldwide A convenience sampling of trainees was obtained through distribution of the survey by email and social media posts from April 20th to May 11th, 2020 To investigate the impact of burden of exposure to COVID-19 the trainee experience, we categorized respondents according to their self-reported estimate of the number of patients with COVID-19 that they provided care for in March and April 2020 (0, 1-30, 31-60, >60)  Descriptive statistics were performed and the chi square test was used to evaluate for statistical significance  A multivariable logistic regression analysis was conducted to determine independent predictors of physician burnout Results: Surveys were completed by 1420 trainees, of whom 1031 (73%) were residents Most of the fellows who responded to the survey were training in gastroenterology/ hepatology (27%, 85/280) Trainees who cared for a greater number of COVID-19 patients were more likely to report limited access to PPE and COVID-19 testing and more likely to report testing positive for COVID-19 (Figure 1A) Compared to trainees who did not take care of COVID-19 patients, those who took care of 1-30 patients (adjusted odds ratio [AOR] 1 80, 95% CI 1 29-2 51), 31-60 patients (AOR 3 30, 95% CI 1 86-5 88) and >60 patients (AOR 4 03, 95% CI 2 12-7 63) were increasingly more likely to report burnout More than half (835, 58%) of trainees reported concern about their future preparedness for independent practice Trainees who cared for >60 COVID-19 patients compared to those who did not care for any COVID-19 patients reported similar levels of concern about their preparedness for independent practice (56%, 372/636 vs 58%, 71/125 respectively, p-value 0 57, Figure 1B) Conclusion: Physician trainees who were involved in the care of patients with COVID-19 were more likely to report unsafe working conditions and suffered from higher rates of physician burnout Trainees were concerned about the effects of lost training opportunities on their professional development irrespective of the number of COVID-19 patients they cared for
Duodenal Adenocarcinoma Mimicking Metastasis of Prostate Cancer on 18F–Prostate-Specific Membrane Antigen–1007 PET/CT
Authors: Fumihiko Soeda, Tadashi Watabe, Hiroki Kato, Motohide Uemura, Norio Nonomura
Journal: Clinical Nuclear Medicine (2020)

A 76-year-old man with dyspnea (initial prostate-specific antigen [PSA]: 216 ng/mL) underwent F-FDG PET/CT, with uptake in the prostate, lymph nodes, fifth thoracic vertebra (T5), and cricoid cartilage. A biopsy revealed prostate adenocarcinoma (Gleason score 4 + 5, cT4 N1 M1). On initiation of combined androgen blockade therapy, PSA value decreased. However, 4 years later, in a castration-resistant state (PSA 2.14 ng/mL), CT and bone scintigraphy revealed a duodenal tumor and T5 metastasis. F-prostate-specific membrane antigen-1007 PET/CT showed uptake in the already known T5 metastasis (SUVmax, 33.55) and even in the duodenal tumor (16.55). The latter was histologically diagnosed as duodenal adenocarcinoma.
Abstract 112: Short- and Long-term Survival of Patients Supported on Venoarterial and Veno-venous Extracorporeal Membrane Oxygenation
Authors: Ioana Florea, Kunal Kotkar, Ralph Damiano, Marc R Moon, Akinobu Itoh, Muhammad Masood
Journal: Circulation (2020)

Introduction: Use of both venoarterial (VA) and veno-venous (VV) extracorporeal membrane oxygenation (ECMO) has broadened to an expanded set of indications for supporting patients in shock, but outcome data by these indications remains limited. This study examines survival of VA and VV ECMO patients by indication. Methods: A retrospective review of adults supported by ECMO at a single center for cardiogenic shock between January 2010 - November 2018 was conducted. VA ECMO patients (n=449) and VV ECMO patients (n=91) were classified according to indication for ECMO support. Kaplan-Meier analysis was used to construct survival curves at 30 days and 1 year and compared using log-rank test. Post-hoc Tukey test was used to adjust for multiple comparisons. Results: The subgroups of indication for VA-ECMO support were Acute Pulmonary Embolism (PE, n=14), Ischemic Cardiomyopathy or Myocardial Infarction (ICM or MI, n=108), Non-Ischemic Cardiomyopathy (NICM, n=82), Post-Cardiotomy (n=129), Transplant (Tx, n=32), and Other (n=84). Kaplan-Meier estimates of survival stratified by indication at 30 days and 1 year were significant (30d: p=0.006, 1y: p=0.009, Figure 1). Multiple comparisons at 30 days and 1 year were significant for Acute PE v Post-Cardiotomy (30d: p=0.044, 1y: p=0.029), NICM v Post-Cardiotomy (30d: p=0.016, 1y: p=0.025), and Tx v Post-Cardiotomy (30d: p=0.01, 1y: p=0.022). Among VV-ECMO patients, the subgroups of indication were ARDS: Influenza (n=25), ARDS: Other Infection (n=24), and ARDS: Non-Infectious (n=42). No statistically significant difference in survival was appreciated between these indications either at 30 days (p=0.742) or 1 year (p=7.82). Conclusions: Patients who require Post-Cardiotomy VA-ECMO support have worse short- and long-term survival compared to patients who require support for Acute PE, NICM, or Transplant indications. Among VV-ECMO patients, however, no survival difference is appreciated by indication.
Abstract 15479: Adherence to Healthy Lifestyles Among Chinese Adults
Authors: Xingyi Zhang, Jiapeng Lu, Chaoqun Wu, Jianlan Cui, Yue Wu, Anyi Hu, Jing Li, Xi Li
Journal: Circulation (2020)

Introduction: Healthy lifestyles are effective means to reduce premature deaths. However, comprehensive knowledge about adherence to multiple healthy lifestyles in Chinese adults is still lacking. Methods: We interviewed 938,545 adults aged 35-75 years from 248 counties/districts of China in a national population-based epidemiological project, the China PEACE-MPP. We defined four healthy lifestyles as non-smoking, none or moderate alcohol use, sufficient leisure-time physical activity (LTPA), and healthy diet. We established multi-level logistic regression models to explore the factors associated with the adherence. Multivariable Cox proportional hazard models were fitted to assess the impact of adherence to healthy lifestyles on all-cause and cardiovascular mortality. Results: Among the participants, 78.6% were non-smokers, 98.0% had none or moderate alcohol use, 25.7% had sufficient LTPA, 19.7% had healthy diet, and only 5.8% adhered to all four heathy lifestyles. The overall adherence varied substantially across seven regions (P&lt;0.01, median odds ratio=3.2), which was highest in the North China (7.5%), and lowest in the Southwest (3.4%). Participants who were female, elder, non-farmers, with higher education, with higher household income, married, hypertensive or diabetic, having cardiovascular disease history, or living in urban areas were more likely to adhere to all four healthy lifestyles in general. Adherence to none or moderate alcohol use, however, was associated with lower education and income. During a median follow-up of 1.66 years (IQR 0.66-2.63), those adhered to all four healthy lifestyles had lower risk of all-cause mortality (HR 0.43, 95% CI 0.30-0.60) and cardiovascular mortality (HR 0.38, 95% CI 0.21-0.68), compared with participants who did not adhere to any healthy lifestyle. Conclusions: The adherence to healthy lifestyles in Chinese adults was far from ideal. Targeted health promotion strategies were urgently in need.
Abstract 13704: Simulation-based Uptraining Improves Provider Comfort in the Management of Critically Ill Patients With Covid-19
Authors: James M Horowitz, Eugene Yuriditsky, Sunil Nair, Brian S Kaufman
Journal: Circulation (2020)

Introduction: The COVID-19 surge at our institution required deployment of large numbers of non-intensive care unit (ICU) physicians and advanced practice providers to assist in the management of the critically ill. A 3-hour “uptraining” simulation session was offered to these providers that focused on various aspects of ICU care. Hypothesis: We hypothesized that following a 3-hour simulation session, providers would feel more comfortable in managing critically-ill patients with COVID-19. Methods: One hundred and seventy-five providers underwent a 3-hour simulation-based session focused on management of shock, acute respiratory distress syndrome, and critical care ultrasound. All participants were sent surveys to assess their comfort with various aspects of ICU care following return to their usual work environments. Results: One hundred and eight providers of 175 (62%) completed the surveys. Cardiology fellows and faculty accounted for 36% of the responders, acute care nurse practitioners (NPs) accounted for 16%, while other NPs, residents, and fellows accounted for the remainder. Prior to simulation training, 31% regularly managed patients in the ICU and 28% occasionally managed ICU patients. Following training, 71% of participants were deployed to a COVID-19 ICU as part of their workflow. Overall, 104/108 responders (96%) felt training either significantly or somewhat improved their knowledge in the management of ICU patients. Ninety-four participants (91%) felt training impacted their care of critically ill patients with COVID-19. Table 1 is a display of specific ICU skillsets taught in the session and if the participants felt better equipped to utilize what was covered post deployment. Conclusions: Simulation-based training improved provider comfort in the management of critically ill patients with COVID-19. Table 1: Participants response to “if they felt better equipped to utilize ICU skills following simulation training”
Abstract #1771: Anti-tumor effects of nitrosylcobalamin (NO-Cbl) against spontaneous tumors in dogs
Authors: Joseph Bauer, Gerald Frye, Anne Bahr, Jennifer Gieg, Daniel Lindner
Journal: Cancer Research (2009)

Background: Given the limited options available to treat canine cancers, the use of companion animals (pets) for evaluating new drugs may identify better therapies for veterinary and human oncology. Objective: The anti-tumor effects of nitrosylcobalamin (NO-Cbl), an apoptosis-inducing, vitamin B12 based carrier of nitric oxide (NO), was evaluated in three dogs with spontaneous carcinomas. Animals: (1) A 13 year-old female spayed Giant Schnauzer was diagnosed with inoperable thyroid carcinoma and hypercalcemia. (2) A 6 yr-old male neutered Golden Retriever presented malignant peripheral nerve sheath tumor (MPNST). (3) A ten yr-old castrated male Bichon Frise presented with apocrine gland anal sac adenocarcinoma (AGACA) after previously failing multiple therapies. Methods: The dogs were administered single agent NO-Cbl 28 mg/kg s.c. b.i.d. In addition the Bichon Frise received 6 cycles of carboplatin during week 42 - 56 of treatment. Tumor regression was measured by physical exam and verified using ultrasound and MRI. Serum chemistries and hematologic parameters were monitored throughout the studies. Results: (1) The Giant Schnauzer demonstrated a 77% reduction in tumor volume compared to baseline after ten months of daily NO-Cbl treatment. (2) The Golden Retriever demonstrated a 39% reduction in tumor volume compared to pre-treatment after 9 months of daily NO-Cbl therapy. (3) The Bichon Frise demonstrated a 43% regression of the primary tumor and a 90% regression of the iliac lymph node measured by MRI after 15 months of treatment. After 53 months, the dog currently has stable disease, normal liver enzymes, CBC analysis, and no evidence of toxicity. Clinical Significance: The use of vitamin B12 to deliver nitric oxide to tumors is novel. We have shown previously that NO-Cbl is endocytosed by malignant cells, resulting in intra-tumoral NO release. In this study, we have shown that daily long-term use of NO-Cbl induced partial responses in all dogs without any signs of toxicity. The use of NO-Cbl capitalizes on the tumor specific properties of the vitamin B12 receptor and represents a promising anti-cancer therapy.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1771.