tbuckley/cabot-search huggingface dataset:
Abstract 18533: Walking on Eggshells: Patient Narratives of Recovery After Atrial Fibrillation Ablation
Authors: Kathryn Wood, Angel Barnes, Kristina Hines
Journal: Circulation (2015)

Introduction: Atrial Fibrillation (AF), the most common irregular heart rhythm worldwide, is now considered an epidemic. Ablation is a highly successful, curative procedure in most arrhythmias except AF. The first six months after an AF ablation can be wrought with more arrhythmias and symptoms than before the procedure. This study explored the patient’s perspective of the challenges faced during the first six months following an AF ablation. Methods: Our longitudinal mixed methods study used interviews and questionnaires at baseline and at 1, 3, and 6 months following AF ablation treatment in 20 AF patients. Subjects were recruited from an online AF patient website to obtain geographic diversity. Subjects also wore a Zio®Patch monitor at each of the measurement points to correlate symptoms with underlying cardiac rhythm. Grounded theory analysis was used for the qualitative data. A repeated measure ANOVA was used to compare changes in quantitative scores over time. Results: Mean age = 64 ± 14 years and the sample was 55% female. Qualitative analysis themes included: (1) seeking reassurance and meaning of symptoms were constant throughout the six months; (2) struggling with feelings of isolation, fatigue, and anxiety were common yet varied across the six months; (3) patient expectations of treatment outcome varied greatly from provider expectations; (4) managing symptoms and drug changes was very challenging work for patients. Patterns of fatigue and anxiety expressed during the interviews correlated with the quantitative scores. Patients felt that standard educational preparation was inadequate in both content and timing. Many patients were using smart phone apps and websites for information and reassurance that the providers were not aware of. Conclusions: Despite the AF epidemic, patients struggled in perceived isolation with little direction from providers. Quicker recognition by health care providers of the most common challenges patients face in following AF ablation could lead to earlier diagnosis and more targeted interventions based on their needs. By obtaining these insights into patients’ perspectives on AF and treatment, providers learn to develop interventions specifically aimed at the challenges patients feel are most difficult.
Abstract 2671: 17beta-hydroxywithanolides inhibit the proliferation of castration-resistant prostate cancer cells by reducing levels of cFLIP
Authors: Alan D. Brooks, Nicola E. Wright, Ya-ming Xu, Kithsiri Wijeratne, Poonam Tewary, Neil Cross, A. A. Leslie Gunatilaka, Thomas J. Sayers
Journal: Cancer Research (2018)

Abstract Using a high throughput gene expression profiling assay directly targeting genes of the androgen receptor pathway, we previously identified the 17beta-hydroxywithanolide (17-BHW), physachenolide C (PCC), as a potent inhibitor of prostate cancer cell growth. Using a panel of prostate cancer cell lines, PCC at low concentrations (IC50 20-50 nM) reduced prostate cancer cell numbers under both standard and 3D in vitro growth conditions. This reduction in cell number was due to growth inhibition and not apoptosis, with PCC causing reductions in the levels of cyclin D, an increase in p21 and arrest of cells in the G1 phase of the cell cycle. Subsequently over 150 natural and semi-synthetic withanolides were evaluated for their ability to inhibit prostate cancer cell growth. All highly active withanolides were 17-BHWs, and some were up to 4-fold more active than PCC. Preliminary structure-activity relationship (SAR) studies suggested that the enone moiety in ring A was essential for activity. In addition, acetoxylation at C-18, an alpha orientation of the side-chain lactone group and the double bond at C-24(25) of the lactone ring played important roles in determining the activity of 17-BHWs as inhibitors of prostate cancer cell growth. Interestingly highly active 17-BHWs rapidly reduced levels of both antiapoptotic cFLIPL and cFLIPS proteins in 22Rv1 prostate cancer cells. However, this reduction did not sensitize 22Rv1 cells to apoptosis. Nonetheless specific reduction of cFLIPL in the castration-resistant 22Rv1 cells using siRNA significantly inhibited their proliferation. This suggests that cFLIPL plays a critical role in the proliferation of some castration-resistant prostate cancer cells. Since the 17-BHW scaffold is amenable to optimization by a medicinal chemistry approach, this could lead to the identification of highly active natural product-based inhibitors of castration-resistant prostate cancer cell proliferation. The cellular molecular target(s) of active 17-BHWs that promote cFLIP reduction are currently under further investigation. Funded by FNLCR Contract HHSN261200800001E and the University of Arizona. Citation Format: Alan D. Brooks, Nicola E. Wright, Ya-ming Xu, Kithsiri Wijeratne, Poonam Tewary, Neil Cross, A. A. Leslie Gunatilaka, Thomas J. Sayers. 17beta-hydroxywithanolides inhibit the proliferation of castration-resistant prostate cancer cells by reducing levels of cFLIP [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 2671.
Effect of Oxygen on Growth of Cultured Myocardial Cells
Authors: Miltonhollenberg
Journal: Circulation Research (1971)

The present study was designed to explore the effects of environmental oxygen as a possible regulator of cardiac cell division and growth. Trypsindispersed heart cells from the ventricles of chick embryos 8 to 12 days old were grown in culture at 37°C in a nutrient medium (NCI) with 10% fetal calf serum. They were exposed to constant 5% CO2 gas environments in which the percent of O2 was varied. Net protein synthesis increased progressively as O2 was reduced from 80% to 2 to 5%. After the first 24 hours, little further protein synthesis occurred in plates grown in 80% O2. The rates of cellular incorporation of 14C-amino acids and uridine-2-14C increased progressively as the fraction of O2 was reduced. In cells grown at 80% O2, incorporation of uridine-2-14C into RNA was impaired before that of 14C-amino acid into protein. After actinomycin-D (5 µg/ml) (which quickly halted uridine incorporation into the rapidly labeled fraction of RNA), the rate of incorporation of 14C-amino acid into protein declined exp...
Abstract 34: Identification of a phosphorylation cascade triggering Wnt/planar cell polarity signaling in breast cancer cells
Authors: Jean-Paul Borg
Journal: Cancer Research (2018)

Abstract The developmental Wnt/planar cell polarity (PCP) pathway is the most recently described branch of Wnt signaling strongly implicated in cancer development at early and late stages. Upregulation of Wnt/PCP components and signaling is indeed observed in many cancers, this event being mostly associated with cancer progression. However, how the function of this signaling is remains presently an open question. Recent work in our laboratory found that Prickle1 and Vangl2, two core Wnt/PCP components, are overexpressed in triple negative breast cancers and associated with poor prognosis. Prickle1 is a cytoplasmic PET/LIM-containing protein phosphorylated by the serine/threonine kinase Mink1 which triggers Prickle1 localization at the plasma membrane and regulates its activity. Activation of the Prickle1-Mink1 axis promotes breast cancer cell motility and metastatic spreading in the mouse by promoting β1-integrin turn-over, focal adhesion dynamics and cytoskeleton remodeling. However, Prickle1 is probably not the unique substrate of Mink1 in breast cancer cells. Through a combination of protein purification and mass spectrometry analysis, we identified novel partners of the Prickle1-Mink1 complex which includes LL5β, a PH domain containing protein involved in β1-integrin turn-over. In parallel, by an independent approach looking for Mink1 substrates in breast cancer cells, we identified LL5β as a potential substrate for this poorly described protein kinase. Using recombinant LL5β and Prickle1, we confirmed that Mink1 can directly phosphorylate both proteins in in vitro kinase assays. We also defined that, in breast cancer cells, Mink1 associates with and phosphorylates LL5β, controlling its subcellular localization, a key step for cancer cell motility. Our data provide novel insights on the regulation of the prometastatic Wnt/PCP pathway by characterizing an yet unknown multi-step phosphorylation cascade with promising targeting potential. Citation Format: Jean-Paul Borg. Identification of a phosphorylation cascade triggering Wnt/planar cell polarity signaling in breast cancer 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 34.
Abstract 15323: How Often Should Chest Compressions be Paused to Assess the Cardiac Rhythm? A Systematic Review and Meta-analysis
Authors: Joshua C Reynolds, Violetta Raffay, Eddy Lang, Peter T Morley, Kevin Nation
Journal: Circulation (2015)

Objectives: Most guidelines recommend pausing chest compressions at 2-min intervals to analyze the cardiac rhythm. We assessed the literature on the optimal interval at which to pause chest compressions in adults for cardiac rhythm analysis in any setting. Methods: To conduct this systematic review and meta-analysis, we searched PubMed, Embase, and Cochrane databases through January 2, 2015, including human studies addressing any two different intervals of rhythm analysis. We excluded animal studies, manikin studies, case reports, editorials, and studies published only in abstract form. We assessed for bias per the Cochrane Handbook criteria for randomized controlled trials (RCT) and observational studies, then used GRADE methodology to evaluate the quality of evidence for functional outcome, survival, and return of spontaneous circulation. Two reviewers independently screened titles/abstracts, and resolved disagreement by consensus. We summarized study results using RR for RCTs and OR for observational studies. Meta-analyses were performed with Mantel-Haenszel random effects model. Results: Of 1,135 papers identified, 8 were included (3 RCT and 5 observational studies) encompassing 15,242 subjects. Quality of evidence was very low or low (downgraded for risk of bias and indirectness). RCT comparing specific time intervals (3-minutes vs. immediate analysis; 1-minute vs. 2-minutes; 3-minutes vs. 1-minute) demonstrated no benefit in either arm. Meta-analyses of 5 observational studies demonstrated moderate pooled benefit of a bundled ‘minimally interrupted chest compression’ protocol dictating 200-compression intervals over historical controls treated with 1- or 3-minute intervals per the 2000 guidelines (ROSC: OR 1.9, 95% CI 1.3, 2.7; survival to discharge: OR 2.9, 95% CI 2.1, 3.8; good functional outcome: OR 2.9, 95% CI 1.6, 5.4). No pooled estimate had significant heterogeneity. Conclusion: We found no quality evidence to support pausing chest compressions at any singular interval to assess the cardiac rhythm in adults in cardiac arrest in any setting. Very low quality evidence suggests improved outcomes in patients receiving a bundled 200-compression interval protocol compared to 1- or 3-minute intervals.
Quality Of Life (qol) Trajectory In Patients With Idiopathic Pulmonary Fibrosis (ipf): Longitudinal Qol Assessment Of The Insights-Ipf Registry
Authors: M. Kreuter, J. J. Swigris, D. Pittrow, A. Prasse, J. Klotsche, S. Geier, H. Wirtz, D. Koschel, S. Andreas, C. Grohe, M. Claussen, J. Behr
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Abstract 18462: Hickam's Dictum Revisited: A Multifactorial Etiology of Stroke in a Patient With Rheumatic Mitral Stenosis and Atrial Septal Aneurysm
Authors: Shashank S Sinha, Peter G Hagan, Daniel T Eitzman
Journal: Circulation (2015)

A 64-year-old gentleman with rheumatic mitral stenosis (MS), coronary artery disease, and active tobacco abuse was admitted with a left posterior cerebral artery (PCA) territory ischemic cerebrovascular accident (CVA). He presented with confusion, headaches, and alexia with stable vital signs. He denied rest or exertional dyspnea. Physical exam revealed right homonymous hemianopia, mild right upper extremity dysmetria, decreased right facial sensation, and mild prosopagnosia. Initial neuroimaging confirmed an evolving left hemispheric infarct. Laboratory testing showed unremarkable inflammatory markers. Computed tomographic (CTA) and magnetic resonance angiography (MRA) of the head and neck confirmed left PCA territory acute or subacute infarction with occlusion of the left P2 segment. 12-lead electrocardiogram demonstrated normal sinus rhythm. Occult atrial fibrillation was not seen. Transthoracic echocardiogram (TTE) showed no evidence of right-to-left interatrial shunt. Moderate left atrial (LA) dilation, posterior mitral leaflet tip calcification, and a resting mean mitral gradient of 20 millimeters of mercury (mmHg) suggested severe mitral stenosis. Given the discrepancy between the patient’s symptoms and the TTE findings, transesophageal echocardiogram (TEE) was performed (Figure). The patient’s left PCA territory infarct was ascribed to multifactorial cardioembolic etiologies: 1) Atrial septal aneurysm (ASA) 2) Rheumatic MS and 3) Aortic arch atheroma. Anticoagulation was recommended and initiated 14 days after his CVA to minimize risk of hemorrhagic transformation. High-dose atorvastatin and aspirin were instituted. He progressed well through rehabilitation, demonstrating steady neurological improvement. The case underscores the importance of pursuing further investigation when discrepancies exist between clinical and objective data. ASA is an uncommon but under-recognized risk factor for cardioembolic stroke.
Abstract 2808: Simultaneous inhibition of SHP2 phosphatase at two allosteric sites
Authors: Michelle Fodor, Edmund Price, Ping Wang, Hengyu Lu, Andreea Argintaru, Zhouliang Chen, Meir Glick, Huai-Xiang Hao, Mitsunori Kato, Robert Koenig, Jonathan R. LaRochelle, Gang Liu, Eric McNeill, Dyuti Majumdar, Gisele Nishiguchi, Lawrence Perez, Greg Paris, Christopher Quinn, Timothy Ramsey, Martin Sendzik, Michael Shultz, Sarah Williams, Travis Stams, Stephen C. Blacklow, Matthew J. LaMarche, Michael G. Acker
Journal: Cancer Research (2018)

Abstract SHP2 is a cytoplasmic non-receptor tyrosine phosphatase involved in the propagation of extracellular signaling through receptor tyrosine kinases. Aberrant SHP2 activity has been identified as a driver in multiple cancers and SHP2 has also been implicated in the PD-1/PD-L1-mediated exhaustion of effector T-cells, leading to immune system evasion of tumors. Recently, we reported the identification of SHP099, an allosteric inhibitor of SHP2 with in in vivo efficacy against multiple RTK-driven tumor xenograft models. Here we report the use of alternate screening paradigms to identify a novel allosteric inhibitor which binds to a previously uncharacterized pocket on SHP2. Like SHP099, the second allosteric inhibitor stabilizes a closed conformation of SHP2, which blocks access to the phosphatase active site. Structure based drug design led to improvements in potency, and combination studies in biochemical, biophysical and cellular assays confirm dual occupation of SHP099 and the second allosteric molecule, resulting in improved potency. This work highlights a rare opportunity for dual occupation of inhibitors for a single target and provides additional tools for the exploration of SHP2 biology. Citation Format: Michelle Fodor, Edmund Price, Ping Wang, Hengyu Lu, Andreea Argintaru, Zhouliang Chen, Meir Glick, Huai-Xiang Hao, Mitsunori Kato, Robert Koenig, Jonathan R. LaRochelle, Gang Liu, Eric McNeill, Dyuti Majumdar, Gisele Nishiguchi, Lawrence Perez, Greg Paris, Christopher Quinn, Timothy Ramsey, Martin Sendzik, Michael Shultz, Sarah Williams, Travis Stams, Stephen C. Blacklow, Matthew J. LaMarche, Michael G. Acker. Simultaneous inhibition of SHP2 phosphatase at two allosteric sites [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 2808.
해설논문(Review Article) : 윌슨병: 진단과 치료의 최근 동향
Authors: 서정기 ( Jeong Kee Seo )
Journal: Clinical and Molecular Hepatology (2006)

Wilson disease (WD) is an autosomal recessive disorder of copper transport that results in accumulation of copper primarily in the liver, the brain and the cornea. WD is the most common inherited liver disease with the prevalence of 1: 37,000 in the pediatric population in Korea. Mutations in the ATP7B gene cause failure of copper excretion into the bile and a defective incorporation of copper into ceruloplasmin. More than 300 mutations in the ATP7B gene have been described so far. Mutations differ between ethnic groups. The p.R778L (an allele frequency of 37%), p.A874V (13%), p.L1083F (8%) and p.N1270S (6%) are the common major mutations in Korea. Conflicting results on genotype/phenotype correlations of the most common mutations have been reported in various countries. There seems to be no correlation between the R778L mutation and age of onset or clinical manifestations in Korean patients. None of the laboratory parameters alone allows a definite diagnosis of WD. In a nation-wide survey of WD, low serum ceruloplasmin ( 100 ?g), high hepatic copper content (>250 ?g/g of dry liver) and Kayser-Fleischer rings were found in 96%, 86%, 88%, and 73% of the 550 Korean patients respectively. A combination of any two of the above 4 laboratory findings is strong support for a diagnosis of WD. For the last couple of years, genetic testing has been playing an increasingly important role in diagnosing WD. Direct DNA sequencing did confirm WD in 98% of the Korean patients. Two mutations were detected in 70% and one mutation in 28% of the patients who showed characteristic biochemical and clinical findings of WD. Genetic testing, either by haplotype analysis or by mutation analysis, is the only reliable tool for differentiating heterozygote carriers from affected asymptomatic patients. The agents of the first choice among chelators and zinc in specific clinical situations of WD is still a matter of debate. Because of frequent side effects and initial neurologic deterioration of penicillamine therapy, less toxic trientine or zinc has gradually replaced penicillamine over the past few years. Trientine or tetrathiomolybdate has been increasingly recommended as the first-line treatment for neurologic WD. Currently, liver transplantation is not recommended as primary treatment for neurologic WD. Recently published data show that initial zinc therapy for asymptomatic/presymptomatic patients and maintenance zinc therapy in patients after long term chelation are safe and effective. Further researches and the new guidelines on the proper management of patients with WD are needed.
Abstract 1301: Using the evolutionary ages of genes to understand hallmark features of cancer
Authors: David L. Goode, Anna S. Trigos, Anthony T. Papenfuss, Richard B. Pearson
Journal: Cancer Research (2018)

Abstract The evolutionary age of a gene is closely tied to its role in cancer. As organisms evolved into multicellular forms, new pathways emerged to control core cellular processes formed in unicellular ancestors such as cell division, DNA replication and energy metabolism. Tumors rely on many of these core processes, at the same time as they suppress key pathways linked to the emergence of multicellularity. This suggests the guiding principles behind many hallmarks of cancer could be better understood in an evolutionary context, by investigating interactions between unicellular and multicellular genes and how they are disrupted in cancer. We have found the evolutionary histories of genes are associated with their expression and regulation (Trigos et al., PNAS 2017), the selection and response to genetic alterations, as well as the rewiring of transcriptional networks across 7 tumor types. Our results reveal different transcriptional and mutational patterns in cancer between genes with different evolutionary ages, with selection for genetic alterations in early metazoan genes leading to the transcriptional rewiring of the regulation between unicellular and multicellular genes, driving carcinogenesis. Examples of how this approach can help prioritize genes for drug treatment and inform novel treatment strategies will be given. Citation Format: David L. Goode, Anna S. Trigos, Anthony T. Papenfuss, Richard B. Pearson. Using the evolutionary ages of genes to understand hallmark features of cancer [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 1301.
Risk of benign meningioma after childhood cancer in the DCOG-LATER cohort: contributions of radiation dose, exposed cranial volume, and age
Authors: Judith L Kok, Jop C Teepen, Flora E van Leeuwen, Wim J E Tissing, Sebastian J C M M Neggers, Helena J van der Pal, Jacqueline J Loonen, Dorine Bresters, Birgitta Versluys, Marry M van den Heuvel-Eibrink, Eline van Dulmen-den Broeder, Margriet van der Heiden-van der Loo, Berthe M P Aleman, Laurien A Daniels, Cornelis J A Haasbeek, Bianca Hoeben, Geert O Janssens, John H Maduro, Foppe Oldenburger, Caroline van Rij, Robbert J H A Tersteeg, Michael Hauptmann, M H van den Berg, A H Bruggink, H N Caron, W V Dolsma, M A Grootenhuis, J G den Hartogh, N Hollema, M C Jongmans, M W M Jaspers, A Postma, M J van de Vijver, Leontien C M Kremer, Cécile M Ronckers
Journal: Neuro-Oncology (2018)

Pediatric cranial radiotherapy (CrRT) markedly increases risk of meningiomas. We studied meningioma risk factors with emphasis on independent and joint effects of CrRT dose, exposed cranial volume, exposure age, and chemotherapy.The Dutch Cancer Oncology Group-Long-Term Effects after Childhood Cancer (DCOG-LATER) cohort includes 5-year childhood cancer survivors (CCSs) whose cancers were diagnosed in 1963-2001. Histologically confirmed benign meningiomas were identified from the population-based Dutch Pathology Registry (PALGA; 1990-2015). We calculated cumulative meningioma incidence and used multivariable Cox regression and linear excess relative risk (ERR) modeling.Among 5843 CCSs (median follow-up: 23.3 y, range: 5.0-52.2 y), 97 developed a benign meningioma, including 80 after full- and 14 after partial-volume CrRT. Compared with CrRT doses of 1-19 Gy, no CrRT was associated with a low meningioma risk (hazard ratio [HR] = 0.04, 95% CI: 0.01-0.15), while increased risks were observed for CrRT doses of 20-39 Gy (HR = 1.66, 95% CI: 0.83-3.33) and 40+ Gy (HR = 2.81, 95% CI: 1.30-6.08). CCSs whose cancers were diagnosed before age 5 versus 10-17 years showed significantly increased risks (HR = 2.38, 95% CI: 1.39-4.07). In this dose-adjusted model, volume was not significantly associated with increased risk (HR full vs partial = 1.66, 95% CI: 0.86-3.22). Overall, the ERR/Gy was 0.30 (95% CI: 0.03-unknown). Dose effects did not vary significantly according to exposure age or CrRT volume. Cumulative incidence after any CrRT was 12.4% (95% CI: 9.8%-15.2%) 40 years after primary cancer diagnosis. Among chemotherapy agents (including methotrexate and cisplatin), only carboplatin (HR = 3.55, 95% CI: 1.62-7.78) appeared associated with meningioma risk. However, we saw no carboplatin dose-response and all 9 exposed cases had high-dose CrRT.After CrRT 1 in 8 survivors developed late meningioma by age 40 years, associated with radiation dose and exposure age, relevant for future treatment protocols and awareness among survivors and physicians.