tbuckley/cabot-search huggingface dataset:
Inhibition of von Willebrand Factor Binding to Platelet GP Ib by a Fractionated Aurintricarboxylic Acid Prevents Restenosis After Vascular Injury in Hamster Carotid Artery
Authors: HiroyukiMatsuno, OsamuKozawa, MasayukiNiwa, ToshihikoUematsu
Journal: Circulation (1997)

Background Aurintricarboxylic acid (ATA) prevents von Willebrand factor binding to platelet glycoprotein (GP) Ib, with higher-molecular-weight ATA more effective than the lower-molecular-weight compound. We investigated the effects of high-molecular-weight ATA (Mr=7500), obtained by fractionating commercial ATA, in the injured hamster carotid artery. Methods and Results Platelet aggregation was induced in vitro with ADP (2.5 μmol/L) or botrocetin (5 μg/mL) in hamster platelet-rich plasma. IC50 values were 348.6±22.4 and 8.2±3.2 μg/mL, respectively. The endothelium of hamster carotid artery was denuded with a modified catheter. Continuous administration of high-molecular-weight ATA (10, 30, and 100 μg·kg−1·h−1) with an infusion pump produced antithrombotic effects in a dose-dependent manner, as evaluated by prolongation of time to occlusion. Neointima formation was observed 2 weeks after catheterization, and proliferating smooth muscle cells (SMCs) were identified by the thymidine analogue 5-bromo-2-deoxy-...
Abstract 1541: Directed, unbiased mapping of lentiviral integrations with next generation sequencing in CAR-T cells
Authors: Timothy G. Johnstone, Rajagopal Chari, David Koppstein, Ronald J. Hause, Rafael Ponce, Adrian W. Briggs, Francois Vigneault
Journal: Cancer Research (2018)

Abstract During manufacturing of an exemplary CD19-directed CAR-T cell product, patient T cells were transduced with a viral vector encoding the CD19-directed, 41BBζ endodomain-containing chimeric antigen receptor (CAR) construct, enabling permanent genetic modification of the target T cells. Lentiviral transduction with a self-inactivating (SIN) vector can offer certain advantages in safety and consistency over other DNA delivery methods. Although the integration patterns of wildtype HIV-1 have been well-characterized and shown to have a low risk of insertional transformation, the addition of an artificial construct may have the potential to affect integration patterns. Existing techniques for viral integration mapping, such as ligation-mediated polymerase chain reaction (LM-PCR), have limitations precluding comprehensive, unbiased, high-throughput insertion site mapping. To characterize insertional events in engineered CAR-T cells, we developed an unbiased NGS assay and computational pipeline capable of characterizing viral integration events genome-wide. The method leverages Tn5 transposase, coupled with a long terminal repeat-specific PCR, to map integration events down to nulceotide resolution. This assay identified over 150,000 high-confidence integration events across 23 patient-derived CAR-T cell products. Analysis of these sites revealed a similar integration preference to lentiviruses described in the literature: driven by GC content, local nucleotide content, chromatin status, and transcriptional activity, with no indication of preferential integration at oncogenic loci. In conclusion, in this assay a CD19-directed, CAR-containing lentivirus exhibited a low risk integration profile with no significant evidence of construct-specific risk factors. Furthermore, the findings suggest that the NGS assay may be useful for more efficient, cost-effective, and sensitive measurement of CAR-T integration events for a range of constructs. Citation Format: Timothy G. Johnstone, Rajagopal Chari, David Koppstein, Ronald J. Hause, Rafael Ponce, Adrian W. Briggs, Francois Vigneault. Directed, unbiased mapping of lentiviral integrations with next generation sequencing in CAR-T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1541.
Effects of Interrupting Sedentary Behavior With Short Bouts of Moderate Physical Activity on Glucose Tolerance in Children With Overweight and Obesity: A Randomized Crossover Trial
Authors: Miranda M. Broadney, Britni R. Belcher, David A. Berrigan, Robert J. Brychta, Ira L. Tigner, Faizah Shareef, Alexia Papachristopoulou, Jacob D. Hattenbach, Elisabeth K. Davis, Sheila M. Brady, Shanna B. Bernstein, Amber B. Courville, Bart E. Drinkard, Kevin P. Smith, Douglas R. Rosing, Pamela L. Wolters, Kong Y. Chen, Jack A. Yanovski
Journal: Diabetes Care (2018)

OBJECTIVE Sedentary children have greater risk of developing abnormalities in glucose homeostasis. We investigated whether interrupting sedentary behavior (sitting) with very short periods of walking would improve glucose metabolism without affecting dietary intake in children with overweight or obesity. We hypothesized that interrupting sitting with short bouts of moderate-intensity walking would decrease insulin area under the curve (AUC) during an oral glucose tolerance test (OGTT) compared with uninterrupted sitting. RESEARCH DESIGN AND METHODS Overweight/obese (BMI ≥85th percentile) children 7–11 years of age underwent two experimental conditions in random order: prolonged sitting (3 h of continuous sitting) and interrupted sitting (3 min of moderate-intensity walking at 80% of ventilatory threshold every 30 min for 3 h). Insulin, C-peptide, and glucose were measured every 30 min for 3 h during an OGTT. Each session was followed by a buffet meal. Primary outcomes were differences in OGTT hormones and substrates and in buffet meal intake by condition. RESULTS Among 35 children with complete data, mixed-model results identified lower insulin and C-peptide in the interrupted condition (P = 0.007 and P = 0.029, respectively); the intervention reduced insulin AUC by 21% (P &amp;lt; 0.001) and C-peptide AUC 18% (P = 0.001) and improved estimated insulin sensitivity (P = 0.013). Neither buffet total energy intake (1,262 ± 480 vs. 1,260 ± 475 kcal; P = 0.89) nor macronutrient composition of the meal (P values &amp;gt;0.38) differed between conditions significantly. CONCLUSIONS Interrupting sitting with brief moderate-intensity walking improved glucose metabolism without significantly increasing energy intake in children with overweight or obesity. Interrupting sedentary behavior may be a promising intervention strategy for reducing metabolic risk in such children.
Lose appetite, lose control: integrins and noncanonical autophagy regulate germinal center reactions
Authors: Jeremy S. Leventhal
Journal: Journal of Clinical Investigation (2018)

T cell-dependent germinal center (GC) reactions are the pinnacle of adaptive immune responses, with profound effects on human health and disease. It has long been known that ligands of an innate immune pattern recognition receptor subgroup, TLRs, amplify antibody responses; however, the mechanisms regulating this phenomenon are poorly understood. In this issue of the JCI, Raso et al. demonstrate that αvβ3 integrins regulate the magnitude and speed of TLR-augmented GC reactions, limiting both short- and long-term humoral immunity. This phenomenon is dependent on a noncanonical form of the autophagy pathway and Rubicon, a noncanonical autophagy-associated protein. B cell-specific deletion of the gene encoding αvβ3 integrin enhanced GC responses in mice and conferred a dramatic survival advantage compared with controls after influenza infection, confirming that B cell integrin manipulation represents a potential and exciting target for augmenting or inhibiting GC reactions.
Production and transplantation of bioengineered lung into a large-animal model
Authors: Joan E. Nichols, Saverio La Francesca, Jean A. Niles, Stephanie P. Vega, Lissenya B. Argueta, Luba Frank, David C. Christiani, Richard B. Pyles, Blanca E. Himes, Ruyang Zhang, Su Li, Jason Sakamoto, Jessica Rhudy, Greg Hendricks, Filippo Begarani, Xuewu Liu, Igor Patrikeev, Rahul Pal, Emiliya Usheva, Grace Vargas, Aaron Miller, Lee Woodson, Adam Wacher, Maria Grimaldo, Daniil Weaver, Ron Mlcak, Joaquin Cortiella
Journal: Science Translational Medicine (2018)

The inability to produce perfusable microvasculature networks capable of supporting tissue survival and of withstanding physiological pressures without leakage is a fundamental problem facing the field of tissue engineering. Microvasculature is critically important for production of bioengineered lung (BEL), which requires systemic circulation to support tissue survival and coordination of circulatory and respiratory systems to ensure proper gas exchange. To advance our understanding of vascularization after bioengineered organ transplantation, we produced and transplanted BEL without creation of a pulmonary artery anastomosis in a porcine model. A single pneumonectomy, performed 1 month before BEL implantation, provided the source of autologous cells used to bioengineer the organ on an acellular lung scaffold. During 30 days of bioreactor culture, we facilitated systemic vessel development using growth factor-loaded microparticles. We evaluated recipient survival, autograft (BEL) vascular and parenchymal tissue development, graft rejection, and microbiome reestablishment in autografted animals 10 hours, 2 weeks, 1 month, and 2 months after transplant. BEL became well vascularized as early as 2 weeks after transplant, and formation of alveolar tissue was observed in all animals (n = 4). There was no indication of transplant rejection. BEL continued to develop after transplant and did not require addition of exogenous growth factors to drive cell proliferation or lung and vascular tissue development. The sterile BEL was seeded and colonized by the bacterial community of the native lung.
Abstract 1819: Acquired T790M mutation after first generation EGFR tyrosine kinase retreatment
Authors: Sung Yong Lee, Jee Youn OH, Jae Jeong Shim, Kyung Ho Kang, Kyung Hoon Min
Journal: Cancer Research (2018)

Abstract Introduction The first or second generation EGFR TKI drugs showed good overall response and progression free survival rates in EGFR mutation positive patients. However, most of them progress within 12 months from treatment start due to acquired resistance. In clinical practice, many physicians frequently offer these patients retreatment with EGFR TKIs after a chemotherapy break, because EGFR TKI retreatment can reduce the regrowing EGFR TKI sensitive clones. We evaluated induction of T790M mutation in previously sensitive EGFR mutation positive cancer patients that repeatedly treated EGFR TKIs. Method We reviewed the medical records of patients who were rechallenged with first generation EGFR TKIs. Those patients were previously responded to gefitinib or erlotinib and progressed after several chemotherapies. We analyzed the clincopathological characteristics, treatment modality and their outcome, and development of T790M mutation. EGFR mutations in exons 18, 19, 20, and 21 were evaluated with PNA mediated PCR clamping method. Results Three patients showed acquired T790M mutation after first generation EGFR TKIs retreatment. The acquired T790M mutation was detected in the tumor tissue in two patients and in the bronchoalveolar lavage fluid in the other patient. Three patients were taking osimertinib or olmutinib, two patients showed good clinical efficacy and low adverse events, however the other patient showed serious adverse event (interstitial lung disease). Conclusions Re-treatment with first generation EGFR TKIs after drug holiday in sensitizing EGFR mutant patients are considered to be an effective option, because EGFR TKI retreatment can reduce the regrowing EGFR TKI sensitive clones. Moreover, retreatment of first generation EGFR TKI may also induce or expand EGFR TKI resistance by T790M mutation and it could be treated with third generation EGFR TKI. Citation Format: Sung Yong Lee, Jee Youn OH, Jae Jeong Shim, Kyung Ho Kang, Kyung Hoon Min. Acquired T790M mutation after first generation EGFR tyrosine kinase retreatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1819.
Reduction of Serum Cholesterol and Hypercholesterolemic Atherosclerosis in Rabbits by Secoisolariciresinol Diglucoside Isolated From Flaxseed
Authors: KailashPrasad
Journal: Circulation (1999)

Background—Secoisolariciresinol diglucoside (SDG) is a plant lignan isolated from flaxseed. Lignans are platelet-activating factor–receptor antagonists that would inhibit the production of oxygen radicals by polymorphonuclear leukocytes. SDG is an antioxidant. Antioxidants studied thus far are known to reduce hypercholesterolemic atherosclerosis. The objective of this study was to determine the effect of SDG on various blood lipid and aortic tissue oxidative stress parameters and on the development of atherosclerosis in rabbits fed a high-cholesterol diet. Methods and Results—Rabbits were assigned to 4 groups: group 1, control; group 2, SDG control (15 mg · kg body wt−1 · d−1 PO); group 3, 1% cholesterol diet; and group 4, same as group 3 but with added SDG (15 mg · kg body wt−1 · d−1 PO). Blood samples were collected before (time 0) and after 4 and 8 weeks of experimental diets for measurement of serum triglycerides, total cholesterol (TC), and LDL, HDL, and VLDL cholesterol (LDL-C, HDL-C, and VLDL-C). T...
Abstract P189: Prevalence of Lifestyle Factors for Hypertension Control in the United States
Authors: Angela M Thompson-Paul, Cathleen Gillespie, Soyoun Park, Jennifer L Foltz, Fleetwood Loustalot
Journal: Circulation (2016)

Background: While most adults require antihypertensive medications for blood pressure control, some are able to achieve control through lifestyle modifications alone. The objective of this study was to examine whether a higher prevalence of persons with untreated, controlled HTN are meeting recommendations for five modifiable factors for cardiovascular (CV) health more than persons with treated HTN and secondly whether this has changed over time. Methods: Using data from non-pregnant adults 20-79 years of age with a history of or currently treated HTN, from the National Health and Nutrition Examination Survey, 1999-2004 (n=3,526) and 2005-2012 (n=6,344), we calculated the age-standardized (10-year age groups), weighted prevalence of five modifiable factors for CV health: recommended physical activity levels (≥150 minutes per week at moderate intensity, ≥75 min/week or more at vigorous intensity, or an equivalent combination); recommended sodium intake (&lt;2,300 mg/day), healthy weight (body mass index 18.5 to &lt;25 kg/m2); not a current smoker; and no/moderate alcohol consumption (up to 1 drink/day for women or 2 drinks/day for men). Results: Among eligible adults, few have untreated but controlled HTN (5.8% [n=206] in 1999-2004, and 6.2% [n=394] in 2005-2012, P for trend=0.65). The proportion of persons meeting physical activity recommendations declined significantly between the time periods for all three groups. A higher proportion of adults with untreated, controlled HTN met recommendations for 3 or more modifiable factors (43.9% and 33.6% for 1999-2004 and 2005-2012, respectively; versus 41.2% and 26.0% in persons with controlled, treated HTN; and 39.4% and 25.2% in persons with uncontrolled HTN). Conclusions: Fewer than 1 in 10 adults had untreated but controlled HTN. Among them, more than 1 in 3 are meeting recommendations for 3 or more modifiable factors for CV health; however, it is unclear why the remainder of untreated persons have controlled HTN if they are not adherent to lifestyle recommendations.
How Disruptive Innovation by Business and Technology Firms Could Improve Population Health
Authors: Anne Stey, Hemal Kanzaria, Robert Brook
Journal: JAMA (2018)

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Abstract 5856: Identification and validation of Nrf2 inhibitors in esophageal squamous cell carcinoma
Authors: Seth Weir, Xiaoxin Chen, Chorlada Paiboonrungruan
Journal: Cancer Research (2018)

Abstract Background: The Nrf2/Keap1 pathway is critical for human cells to respond to oxidative stress. In basal conditions the Keap1 homodimer is bound to Nrf2 in the cytoplasm. When stressed, Keap1 releases Nrf2 which translocates into the nucleus, binds the antioxidant response element, and activate antioxidative genes. Somatic mutations of Nrf2 or Keap1 gene can cause constitutive activation of this pathway, and thus results in chemoradioresistance and poor survival in patients with esophageal squamous cell carcinoma (ESCC). Our goal is to identify chemical Nrf2 inhibitors for targeted therapy of Nrf2high ESCC in the future. Methods: Possible Nrf2 inhibitors were identified using high throughput screening of 1,280 compounds in the Prestwick library, and 35,000 compounds in the Asinex library with Nqo1-EGFP H1299 cells stimulated by an Nrf2 activator (CDDO). Nrf2 activity was monitored via Incucyte by measuring the total normalized green fluorescence divided by the total normalized red fluorescence (tagged nuclear cherry marker). The red channel assessed cell viability and cytotoxicity of compounds. Inhibitors were identified if they met a threshold of &amp;gt;50% inhibition. Lead compounds will be further validated in vitro with KYSE 450 (Nrf2low+Keap1 knockdown) and KYSE 70 (Nrf2high) by examining their effects on expression of nuclear Nrf2 and its downstream target gene (Nqo1). These compounds will also be validated in vivo using Sox2CreER;Nrf2Ki/Ki mice. Results: We successfully established the in vitro assay with Nqo1-EGFP H1299 cells for high throughput screening of Nrf2 inhibitors. Eight lead compounds were identified from the Prestwick library and validated as Nrf2 inhibitors via a dose-response experiment (IC50&amp;lt;1μM). Screening of the Asinex library and further validations are still ongoing. Conclusion: We have identified Nrf2 inhibitors through high-throughput screening and will test them in vitro and finally in vivo. Citation Format: Seth Weir, Xiaoxin Chen, Chorlada Paiboonrungruan. Identification and validation of Nrf2 inhibitors in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5856.
Abstract 4576: Combination of a label independent CTC enrichment platform with fluorescence <i>in situ</i> hybridization for the molecular characterization of CTCs in non-small cell lung cancer patients
Authors: Aliki Ntzifa, Martha Zavridou, Pavlos Pollakis, Georgia Bardi, Vasilis Georgoulias, Athanasios Kotsakis, Evi Lianidou
Journal: Cancer Research (2018)

Abstract Background: Patients with EGFRmt non-small cell lung cancer (NSCLC) develop resistance to first (erlotinib/ gefitinib) and second (afatinib) generation EGFR tyrosine kinase inhibitors (EGFR TKIs). Circulating tumor cells (CTCs) may be used as a potential biological material to monitor genetic alterations during the clinical course of the disease. We used the ParsortixTM (ANGLE) system, a label-independent microfluidic-based technology platform, to enrich CTCs from whole blood of NSCLC patients to evaluate the presence of HER-2 and c-MET amplification using fluorescence in situ hybridization (FISH). Materials and methods: Peripheral blood (PB) (15mL) from 42 patients with EGFRmt and resistant to 1st and 2nd generation EGFR TKIs NSCLC was obtained before, during and after treatment with osimertinib. CTCs were isolated using the ParsortixTM system and were further analyzed for HER-2 and c-MET amplification by FISH. Results: PB samples were obtained before (n=42), after one cycle (n=12) and at PD (n=7) during treatment with Osimertinib. One patient had HER-2 amplified CTCs whereas in total, 5 patients had marginally HER-2-positive CTCs; HER-2-positive CTCs were observed in 1/42 baseline sample but in none post-1st cycle and PD samples. Similarly, c-MET amplification was detected in 3/42 patients at baseline whereas in total 4 patients had marginally c-MET-positive CTCs. Treatment with Osimertinib resulted in a decrease of the number of c-MET amplified CTCs in these patients. In all c-MET and HER-2 amplified CTCs there was no HER-2 or c-MET amplification in the primary tumor. c-MET amplification in the primary tumor was detected only in one patient, however this patient had no detectable CTCs. Conclusions: Our preliminary results indicate that in selected patients with EGFRmt NSCLC, detection of HER-2 or c-MET amplified CTCs may be correlated with tumor resistance to EGFR TKIs. The ParsortixTM system can be successfully combined with downstream FISH analysis for the molecular characterization of CTCs in NSCLC patients. More samples are currently being analyzed in order to reveal the implication of HER-2 and c-MET amplification in resistance to therapy with first, second and third generation EGFR TKIs. Citation Format: Aliki Ntzifa, Martha Zavridou, Pavlos Pollakis, Georgia Bardi, Vasilis Georgoulias, Athanasios Kotsakis, Evi Lianidou. Combination of a label independent CTC enrichment platform with fluorescence in situ hybridization for the molecular characterization of CTCs in non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4576.
Parasystole with Fixed Coupling
Authors: Richardlangendorf, Alfredpick
Journal: Circulation (1967)

Four examples of spontaneous and six of artificial ventricular parasystole exhibiting fixed coupling of the premature beats were presented. In five cases, one of the pacemakers was located in the S-A node, in four in the A-V junction, and in one at first in the A-V junction and later in the ventricles. The material was divided according to the presence either of mutual protection of the two pacemakers (group I, four cases) or of unilateral protection of the parasystolic pacemaker (group II, five cases). When the rates of both pacemakers are regular and the conditions for impulse propagation remain stable, fixed (forced) coupling of parasystolic beats develops under the following conditions: in group I (with mutual protection) (a) if there is-by chance or by experimental adjustment-a simple numerical relation between the two pacemaker rates, or (b) if subthreshold stimuli become effective only during a short super-normal period of excitability in the early portion of the ventricular cycle; and in group II ...