tbuckley/cabot-search huggingface dataset:
Radiation-induced mitochondria-associated adaptive responses in tumorigenic human prostate cell lines
Authors: Danupon Nantajit, Kazi Ahmed, Ming Fan, Ning Cao, Jeffrey Murley, David Grdina, Jian Jian Li
Journal: Cancer Research (2008)

5763  Although accumulated data suggest that exposure of mammalian cells to different doses of ionizing radiation can induce adaptive responses to subsequent radiation exposures, the mechanism underlying such results still remains unclear. We have reported that cultured normal and tumor cells surviving long-term fractionated radiation exposure express radioresistant phenotypes. The purpose of this research is to identify the functional shift in mitochondrial oxidative phosphorylation complexes in response to fractionated radiation exposure. The cell lines have been established from human neonatal prostate epithelium by transfection with SV40 (named 267B1) or co-transfection with SV40 and vKi-Ras. Clonogenic survival and animal xenograft experiments demonstrate that Ki cells are tumorigenic and radioresistant. A profile of clones has been established with the radiation regimen of long-term exposure with different daily doses. We are currently measuring the expression level and phosphorylation activities of nuclear encoded oxidative phosphorylation proteins, particularly cytochrome c oxidase (complex IV). We aim to identify if any components of cytochrome c oxidase are responsible for retaining mitochondria stability and result in tumor radioresistance which can lead to generating specific targets to enhance the therapy of prostate cancer.
Dynamic clonal hematopoiesis and functional T-cell immunity in a supercentenarian
Authors: Erik B. van den Akker, Stavros Makrodimitris, Marc Hulsman, Martijn H. Brugman, Tatjana Nikolic, Ted Bradley, Quinten Waisfisz, Frank Baas, Marja E. Jakobs, Daphne de Jong, P. Eline Slagboom, Frank J. T. Staal, Marcel J. T. Reinders, Henne Holstege
Journal: Leukemia (2020)
High hopes: lower risk of death due to mental disorders and self-harm in a century-long US Olympian cohort compared with the general population
Authors: Stephanie L. Duncombe, Hirofumi Tanaka, Quentin De Larochelambert, Julien Schipman, Jean-François Toussaint, Juliana Antero
Journal: British Journal of Sports Medicine (2020)

Objective To determine the risk of death due to prominent mental disorders, substance abuse, and self-harm among US Olympians compared with the general population. Methods All female (n=2301) and male (n=5823) US Olympians who participated in the summer or winter Games between 1912 and 2012 were followed until 2016. The National Death Index certified their vital statuses and causes of death. We performed a Standard Mortality Ratio (SMR) analysis for all causes studied and applied the years-saved (YS) method to quantify differences in the risk of death for (1) anxiety, depression and self-harm and (2) substance abuse and eating disorders. Additionally, we examined the YS across sports with greater than 100 total deaths and between medalists and non-medalists. Results US Olympians had a 32% (SMR=0.68, 95% CI 0.49 to 0.91) lower risk of death compared with the general population, resulting in a longevity advantage of 0.21 YS (95% CI 0.14 to 0.29) for deaths by depression, anxiety and self-harm and 0.12 years (95% CI 0.08 to 0.15) for substance abuse and eating disorders. There were no significant differences between medalists and non-medalists, but findings varied by sports. Most sports (eg, athletics, swimming, rowing) had significantly lower risks of deaths than the general population with the exceptions of fencing and shooting. Shooting showed a trend towards a higher risk through suicide by firearm. Conclusion Olympians have a lower risk of death, favouring an increased longevity compared with the general population for mental disorders, substance abuse and suicides.
Abstract 13273: Treatment of Sleep Apnea With Positive Airway Pressure and Its Effect on Diastolic Dysfunction: A Systematic Review and Meta-analysis
Authors: Mohammed AlSadawi, Farzane Saeidifard, violeta capric, Patricia J Erwin, Adam Budzikowski
Journal: Circulation (2020)

Introduction: This meta-analysis assessed the effect of chronic non-invasive positive airway pressure (&gt; 6 weeks) on moderate to severe OSA with diastolic dysfunction based on echocardiographic parameters. Hypothesis: chronic use of non-invasive positive airway pressure (&gt; 6 weeks) on moderate to severe OSA improves diastolic dysfunction based on echocardiographic parameters. Methods: We searched the databases for randomized clinical trials including Ovid MEDLINE, Ovid Embase Scopus, Web of Science, Google Scholar, and EBSCO CINAHL from inception up to December 20th, 2019. The search was not restricted to time, publication status or language. Two independent investigators screened the identified studies and extracted the data, in duplicate. Risk of bias was assessed using Cochrane collaboration tools. Results: A total of 2753 results were identified. A total of 9 studies including 808 participants were included. Results showed improvement in deceleration time (-39.49ms CI[-57.24,-21.74]; p=0.000), isovolumic relaxation time (-9.32 ms CI[-17.08, -1.57]; p=0.02) and the ratio of early mitral inflow velocity to mitral annular early diastolic velocity (E/E’) (-1.38 CI[-2.6, -0.16]; p=0.03). However, improvement in left atrial volume index, the ratio of early to late mitral inflow velocities (E/A) was not statistically significant. The risk of bias is mild to moderate. Conclusions: Our results suggest that chronic treatment of moderate to severe OSA with non-invasive positive airway pressure is associated with improvement in diastolic dysfunction.
Skin cancer awareness and prevention behaviour in Wales
Authors: S. Ziaj, F. Tseliou, D. Datta, R. A. Abbott
Journal: British Journal of Dermatology (2020)

DEAR EDITOR, Skin cancer incidence is increasing worldwide, with higher incidence rates in Wales than in other UK countries. 1,2The majority of skin cancers are caused by overexposure to ultraviolet radiation, and prevention measures are recommended at government level and by individuals. 3,4In Wales, the Sunbeds Act was passed in 2010 prohibiting people under the age of 18 years from using sunbeds.This study aimed to assess skin cancer awareness, preventive behaviour and knowledge of vitamin D to inform skin cancer prevention strategies in Wales.A questionnaire was developed in conjunction with HealthWise Wales, a population-based online study of individuals over 16 years old and residing or accessing healthcare in Wales.6][7] Participants registered with HealthWise Wales were invited to complete the questionnaire, either online or over the phone, between October 2017 and October 2018.Responders were analysed by demographics and socioeconomic factors, with differences tested using z-tests.In total 6386 participants responded (4476 female, 70Á1%), with the following age distribution: 6Á4% age < 25 years, 26Á4% age 25-44 years, 41Á4% age 45-64 years and 25Á8% age ≥ 65 years.The majority (91Á3%) reported Fitzpatrick type skin I-III.Participants reported that they check their skin daily (6Á2%), weekly (11Á3%), monthly (10Á0%), every 2-
Abstract 15294: 24-hour Levosimendan Infusion Decreases Biventricular Filling Pressures and Increases Cardiac Output at Rest and Exercise in PH-HFpEF
Authors: Daniel Burkhoff, Barry A Borlaug, Sanjiv J Shah, Stuart Rich
Journal: Circulation (2020)

Background: There are no specific treatments for patients with HFpEF and pulmonary hypertension (PH-HFpEF). Increased central and pulmonary venous pressures (CVP, PCWP) are believed to contribute importantly to symptoms at rest and during exercise. Levosimendan (LEVO), a calcium sensitizer/KATP channel activator, is known to reduce CVP and PCWP in patients with reduced LVEF. We hypothesized that LEVO would have similar effects in PH-HFpEF. Methods: 44 PH-HFpEF patients with mean pulmonary artery (mPAP) ≥35 mmHg, PCWP ≥20 mmHg, LVEF ≥40% and NYHA II or III symptoms underwent hemodynamic measurements at rest, during passive leg raise (PLR) and during supine bicycle exercise for 3 minutes at 25 Watts (EX) at baseline and following a continuous 24-hour infusion of LEVO (0.1 μg/kg/min) as part of a multicenter clinical trial. Measurements included CVP, mPAP, PCWP, mean arterial pressure (MAP) and cardiac index (CI); pulmonary and systemic vascular resistances (PVR, SVR) were calculated. Hemodynamic tracings were analyzed in a core lab blinded to condition and timepoint. The primary endpoint was the change of PCWP at 25 Watts. Results: Patients averaged 69±9.1 years old, 61.4% were female and had a mPAP of 41.0±9.3 mmHg at rest. LEVO decreased mPAP at rest, CVP and PCWP at rest and EX, and increased CI with EX; there were no significant changes in mPAP, PVR or SVR. Resting and EX hemodynamic data are summarized in the Table. 37 of the 44 patients (84%) were considered hemodynamic “responders” based on a pre-specified ≥4 mmHg decrease of EX PCWP. Conclusions: In patients with PH-HFpEF, a 24 hour levosimendan infusion at 0.1 μg/kg/min decreased CVP and PCWP and increased CI at rest and EX, despite no significant effect on SVR or PVR. A majority of patients exhibited acute hemodynamic response. While the underlying mechanism(s) remain to be clarified, LEVO’s effects on CVP and PCWP warrant further study of this drug as a treatment for PH-HFpEF.
Abstract IA-18: Epithelial cell plasticity in pancreatic cancer: The function and fate of metaplastic tuft cells
Authors: Howard C. Crawford
Journal: Cancer Research (2020)

Abstract The pancreas is a notoriously plastic organ. In pancreatitis and early in the transformation process, pancreatic acinar cells give rise to a relatively homogeneous metaplastic duct phenotype. By modulating developmental transcription factor networks metaplastic duct cells then transdifferentiate to other epithelial derivatives including chemosensory tuft cells and neuroendocrine-like adenocarcinoma. To determine the function of metaplastic tuft cells (MTCs), we ablated the taste receptor associated G-protein GNAT3 in the context of pancreatic neoplasia. We found an accelerated progression of benign pancreatic neoplasia to pancreatic cancer, a phenotype attributable to a reactive upregulation of CXCL1 and CXCL2, and a resulting influx of immunosuppressive granulocytic MDSCs. To determine the fate of MTCs, we used a novel dual recombinase system to lineage trace their fate through pancreatic cancer progression, finding that they give rise to a unique subset of cells within invasive adenocarcinoma. Citation Format: Howard C. Crawford. Epithelial cell plasticity in pancreatic cancer: The function and fate of metaplastic tuft cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-18.
Overcoming Adaptive Resistance to KRAS and MEK Inhibitors by Co-targeting mTORC1/2 Complexes in Pancreatic Cancer
Authors: Wells S. Brown, Paul C. McDonald, Oksana Nemirovsky, Shannon Awrey, Shawn C. Chafe, David F. Schaeffer, Jinyang Li, Daniel J. Renouf, Ben Z. Stanger, Shoukat Dedhar
Journal: Cell Reports Medicine (2020)

Activating KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDACs), yet KRAS has remained a difficult target to inhibit pharmacologically. Here, we demonstrate, using several human and mouse models of PDACs, rapid acquisition of tumor resistance in response to targeting KRAS or MEK, associated with integrin-linked kinase (ILK)-mediated increased phosphorylation of the mTORC2 component Rictor, and AKT. Although inhibition of mTORC1/2 results in a compensatory increase in ERK phosphorylation, combinatorial treatment of PDAC cells with either KRAS (G12C) or MEK inhibitors, together with mTORC1/2 inhibitors, results in synergistic cytotoxicity and cell death reflected by inhibition of pERK and pRictor/pAKT and of downstream regulators of protein synthesis and cell survival. Relative to single agents alone, this combination leads to durable inhibition of tumor growth and metastatic progression in vivo and increased survival. We have identified an effective combinatorial treatment strategy using clinically viable inhibitors, which can be applied to PDAC tumors with different KRAS mutations.
Abstract 17155: Is Aortic Annular Calcium Burden a Predictor of Post TAVR Right Ventricular Pacing?
Authors: Sagar Ranka, Tarun Dalia, Nikhil Parimi, NACHIKET MADHAV APTE, Amit Shrestha, Tauseef Akhtar, Raghuveer Dendi, Seth Sheldon, Madhu Reddy, Thomas Rosamond, Rhea C Pimentel
Journal: Circulation (2020)

Background: Preliminary reports have suggested the role of annular calcium in independently predicting pacemaker implantation after transcatheter aortic valve replacement (TAVR). Data regarding role of calcium in the aortic-valvular complex on pacemaker dependency is lacking. Hypothesis: Calcium volume and score in the aortic annular region predicts RV (right ventricle) pacing burden. Methods: We conducted a retrospective single-center study at our tertiary care center including patients who had new pacemaker implantation after TAVR procedure (n=47). Standard calcium scoring software was used to demarcate and quantify the calcium along the aortic cusps and subvalvular region and dichotomized into septal and non-septal based on proximity to the interventricular septum. Standard statistical tests were used for analysis with two-sided p-value &lt;0.05 considered significant. Results: The mean age was 78.6 ± 10.3 years and females were 42.6%. At baseline, 44.7% had narrow QRS complex, with 31.9% had right bundle branch block (RBBB), 8.5% had left bundle branch block (LBBB). Median Pre-TAVR QRS duration was 112 ms. Median septal and non-septal calcium score were 646 and 474 with a volume of 441 mm 3 and 327.2 mm 3 , respectively. Patients with progression to complete heart block (CHB) during index admission had significantly higher non-septal volume (650 mm 3 vs 344 mm 3 ;p=0.01) and score (892 vs 485;p=0.01) when compared to progression after discharge. Similarly, the high burden of RV pacing (&gt;40%) was associated with lower septal calcium score (989 vs 552, p= 0.03) and volume (717 mm 3 vs 385 mm 3 , p=0.03) within 3 months of TAVR. No septal or non-septal parameters were predictive of pacing burden for mid-term (3-12 months) and long-term (&gt;12 months) follow up. Septal calcium parameters were not predictive of RV pacing burden or progression to CHB. Conclusion: Quantitative calcium in the non-septal and septal regions were predictive of early progression to CHB and a higher burden of RV pacing, respectively. Larger scale studies on calcium distribution and the burden should be performed to validate our findings.
Tumor-targeted delivery of siRNA to silence Sox2 gene expression enhances therapeutic response in hepatocellular carcinoma
Authors: Yu Xia, Guoyi Tang, Yi Chen, Changbing Wang, Min Guo, Tiantian Xu, Mingqi Zhao, Yongjian Zhou
Journal: Bioactive Materials (2020)

RNA interference (RNAi) is one of the most promising methods for the treatment of malignant tumors. However, developing an efficient biocompatible delivery vector for small interfering RNA (siRNA) remains a challenging issue. This study aimed to prepare a non-viral tumor-targeted carrier, named RGDfC-modified functionalized selenium nanoparticles (RGDfC-SeNPs). RGDfC-SeNPs were used to selectively deliver siSox2 to HepG2 liver cancer cells and tissues for the treatment of hepatocellular carcinoma (HCC). In the current study, RGDfC-SeNPs were successfully synthesized and characterized. It was shown that RGDfC-SeNPs could effectively load siSox2 to prepare an antitumor prodrug [email protected] [email protected] exhibited selective uptake in HepG2 liver cancer cells and LO2 normal liver cells, indicating RGDfC-SeNPs could effectively deliver siSox2 to HepG2 liver cancer cells. [email protected] entered HepG2 cells via clathrin-mediated endocytosis by firstly encircling the cytoplasm and then releasing siSox2 in the lysosomes. [email protected] could effectively silence Sox2 and inhibit the proliferation, migration and invasion of HepG2 cells. [email protected] induced HepG2 cells apoptosis most likely via overproduction of reactive oxygen species and disruption of the mitochondrial membrane potentials. Most importantly, [email protected] significantly inhibited the tumor growth in HepG2 tumor-bearing mice without obvious toxic side effects. These studies indicated that RGDfC-SeNPs may be an ideal gene carrier for delivering siSox2 to HepG2 cells and that [email protected] may be a novel and highly specific gene-targeted prodrug therapy for HCC.
Abstract 14134: The Impact of Ablation for Atrial Fibrillation on Dementia Incidence in Patients With and Without Depression
Authors: Heidi T May, Tami L Bair, Stacey Knight, Jeffrey L Anderson, Joseph B Muhlestein, Kirk U Knowlton, Benjamin D Horne, T Jared J Bunch
Journal: Circulation (2020)

Introduction: Studies have previously shown that atrial fibrillation (AF) is associated with dementia. The mechanisms are likely multifactorial, but may involve treatment strategies that include anticoagulation use and rhythm management, particularly when used early. Patients that have earlier-life depression are at risk of dementia. However, depression diagnosis in AF patients may indicate a patient at higher risk of developing dementia and whether treatments ameliorate that risk is unknown. Methods: A total of 132,703 AF patients without a history of dementia were studied. History of depression was determined at the time of AF diagnosis. Patients were deemed as having a follow-up ablation if it occurred prior to a dementia diagnosis. Patients were stratified into 4 groups based on depression history and follow-up ablation status: no depression, ablation (n=5,960); no depression, no ablation (n=106,986); depression, ablation (n=923); and depression, no ablation (n=18,834). Patients were followed for 5-year incidence of dementia. Results: A total of 14.9% (n=19,757) pts had a history of depression at the time of AF diagnosis. The mean time between depression and AF diagnoses was 4.9±4.8 years. Patients with depression were younger (68±15 vs. 71±14 years), more likely to be female (62% vs. 44%), and had more cardiovascular comorbidities. Mean time to ablation was 1.3±1.4 days (median: 7.7 months) from AF diagnosis. Frequencies of 5-year dementia were: no depression, ablation=1.6%; no depression, no ablation=5.2%; depression, ablation=4.7%; and depression, no ablation=9.7%, p&lt;0.0001. Multivariable comparisons between the groups are shown in the Figure. Conclusion: In AF patients with and without depression, ablation was associated with a lower risk of incident dementia. Rhythm control approaches that improve long-term brain perfusion may represent a means to impact cognitive declines in patients at higher risk because of earlier-life depression.
Mechanical Allodynia Circuitry in the Dorsal Horn Is Defined by the Nature of the Injury
Authors: Cedric Peirs, Sean-Paul G. Williams, Xinyi Zhao, Cynthia M. Arokiaraj, David W. Ferreira, Myung-chul Noh, Kelly M. Smith, Priyabrata Halder, Kelly A. Corrigan, Jeremy Y. Gedeon, Suh Jin Lee, Graziana Gatto, David Chi, Sarah E. Ross, Martyn Goulding, Rebecca P. Seal
Journal: Neuron (2020)
Abstract 14472: Indications for ICD Implantation Differ Between Women and Men
Authors: Sebastian Ingelaere, Ruben Hoffmann, Georges Mairesse, Yves R Vandekerckhove, Jean-Benoît le Polain de Waroux, Johan Vijgen, Ivan Blankoff, Rik Willems
Journal: Circulation (2020)

Introduction: The impact of gender on ICD implantation practice and survival remain a topic of controversy. We analysed differences between men and women in patients implanted with an ICD in Belgium. Methods: The Belgian governmental health care institution (RIZIV/INAMI) keeps track of every ICD implantation by a digital registry. Participation is mandatory for reimbursement. From this registry, we analysed all new ICD implantations between 01/02/2010 and 31/01/2019 in Belgian patients. We compared men with women for baseline patient characteristics. We used a Chi 2 test for categorical variables (NYHA class, primary vs secondary prevention, underlying heart disease, type of device, QRS duration, presence of atrial fibrillation, diabetes and other comorbidity, center volume, population density and average income of the area of residency) and a Mann-Whitney U test for continuous variables [age and ejection fraction(EF)]. We used the Bonferroni method to correct for multiple testing. Secondly, we performed a Kaplan-Meier analysis. At last, we performed a multivariate logistic regression for 3-year and total mortality. Results: Only 3146 (20.8%) on 14747 implantations were in women. Women were significantly younger and had a better EF compared to men. Except for oncological history, women had less comorbidities (table 1). More women functioned in NYHA class &gt; II and had a QRS &gt; 150ms, which was consistent with a higher CRT-D vs VVI/DDD ratio. Kaplan-Meier showed a survival benefit in women (log-rank, p=&lt;0.001). Further exploration with multivariate logistic regression showed that female gender was significant protective for long-term total mortality, but not for short-term 3-year mortality. Conclusions: Only a minority of patients implanted with a new ICD in Belgium are women. Their clinical profile differs from men. Their long-term survival is better, which can in part be explained by differences in indications and comorbidities.
Abstract 12363: First of Its Kind, Cuff-Less, Standalone, Wearable Technology for Continuous, Non-invasive Blood Pressure Monitoring
Authors: Mohan Thanikachalam, Abhijit Biswas
Journal: Circulation (2019)

Introduction: The current arm cuff-based blood pressure (BP) technologies only provide single-point BP measurements, which lead to 30% misdiagnosis and are inadequate for management of hypertension...