tbuckley/cabot-search huggingface dataset:
Abstract 20669: LRRC10 and Dilated Cardiomyopathy-Associated I195T LRRC10 Mutation Differentially Regulate Cav1.2 L-Type Ca2+ Channels
Authors: Marites T Woon, Pamela Long, Louise Reilly, Jared M Evans, Alexis M Keefe, Martin R Lea, Ravi C Balijepalli, Timothy M Olson, Youngsook Lee, Timothy J Kamp
Journal: Circulation (2016)

Leucine-rich repeat containing protein 10 (LRRC10) is a cardiac-specific protein and loss of LRRC10 in LRRC10-/- mice results in dilated cardiomyopathy (DCM). Here we describe a novel mutation in h...
Abstract 19918: Early High-dose Atorvastatin versus Rosuvastatin on Contrast Induced Nephropathy in Acute Coronary Syndromes
Authors: Anna Toso, Mario Leoncini, Mauro Maioli, Francesco Tropeano, Simona Villani, Francesco Bellandi
Journal: Circulation (2017)

Introduction: The PRATO-ACS trial showed that early on-admission high-dose rosuvastatin reduced contrast induced-acute kidney injury (CI-AKI) occurrence and improved clinical outcome in statin-naiv...
Abstract 15067: Catheter Ablation Improves Cardiac Function in Both Patients With Paroxysmal and Persistent Atrial Fibrillation
Authors: Yosuke Nakatani, Tamotsu Sakamoto, Yoshiaki Yamaguchi, Yasushi Tsujino, Kunihiro Nishida, Koichiro Kinugawa
Journal: Circulation (2017)

Introduction: Atrial fibrillation (AF) causes loss of atrial kick and induces tachycardia induced cardiomyopathy, and consequently leads to a decrease in cardiac function. However, time-course chan...
EGFR Exon 20 Insertion Mutations Display Sensitivity to Hsp90 Inhibition in Preclinical Models and Lung Adenocarcinomas
Authors: Susan E. Jorge, Antonio R. Lucena-Araujo, Hiroyuki Yasuda, Zofia Piotrowska, Geoffrey R. Oxnard, Deepa Rangachari, Mark S. Huberman, Lecia V. Sequist, Susumu S. Kobayashi, Daniel B. Costa
Journal: Clinical Cancer Research (2018)

Purpose:. EGFR exon 20 insertions account for up to 10% of all EGFR mutations in lung adenocarcinomas, representing the third most common cluster of mutations. The management of advanced cancers with these mutations remains elusive, without an approved inhibitor.Experimental Design:. Preclinical models of a representative set of EGFR exon 20 insertion mutations to evaluate the efficacy of different inhibitors and description of the clinical outcome of an advanced lung cancer.Results:. We show that select first-, second-, and third-generation EGFR inhibitors are unable to deter common EGFR exon 20 insertion mutants in concentrations that spare the wild-type kinase. Nonetheless, EGFR exon 20 insertion mutants associate with the Hsp90 chaperone system. We exploit this vulnerability to show that the nongeldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets, and induces apoptosis. In addition, a patient whose EGFR inhibitor–insensitive lung adenocarcinoma harbored an EGFR exon 20 insertion mutation had a confirmed radiographic response to luminespib.Conclusions:. The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.
Systematic Analysis of Compounds Specifically Targeting Telomeres and Telomerase for Clinical Implications in Cancer Therapy
Authors: Hee-Sheung Lee, Mar Carmena, Mikhail Liskovykh, Emma Peat, Jung-Hyun Kim, Mitsuo Oshimura, Hiroshi Masumoto, Marie-Paule Teulade-Fichou, Yves Pommier, William C. Earnshaw, Vladimir Larionov, Natalay Kouprina
Journal: Cancer Research (2018)

Abstract The targeting of telomerase and telomere maintenance mechanisms represents a promising therapeutic approach for various types of cancer. In this work, we designed a new protocol to screen for and rank the efficacy of compounds specifically targeting telomeres and telomerase. This approach used two isogenic cell lines containing a circular human artificial chromosome (HAC, lacking telomeres) and a linear HAC (containing telomeres) marked with the EGFP transgene; compounds that target telomerase or telomeres should preferentially induce loss of the linear HAC but not the circular HAC. Our assay allowed quantification of chromosome loss by routine flow cytometry. We applied this dual-HAC assay to rank a set of known and newly developed compounds, including G-quadruplex (G4) ligands. Among the latter group, two compounds, Cu-ttpy and Pt-ttpy, induced a high rate of linear HAC loss with no significant effect on the mitotic stability of a circular HAC. Analysis of the mitotic phenotypes induced by these drugs revealed an elevated rate of chromatin bridges in late mitosis and cytokinesis as well as UFB (ultrafine bridges). Chromosome loss after Pt-ttpy or Cu-ttpy treatment correlated with the induction of telomere-associated DNA damage. Overall, this platform enables identification and ranking of compounds that greatly increase chromosome mis-segregation rates as a result of telomere dysfunction and may expedite the development of new therapeutic strategies for cancer treatment. Significance: An assay provides a unique opportunity to screen thousands of chemical compounds for their ability to inactivate replication of telomeric ends in cancer cells and holds potential to lay the foundation for the discovery of new treatments for cancer. Cancer Res; 78(21); 6282–96. ©2018 AACR.
The Supreme Court’s Crisis Pregnancy Center Case — Implications for Health Law
Authors: Wendy E. Parmet, Micah L. Berman, Jason A. Smith
Journal: New England Journal of Medicine (2018)

Interview with Prof. Wendy Parmet on the Supreme Court decision on the constitutionality of a California law about information provided by crisis pregnancy centers. (06:11)Download The decision in National Institute of Family and Life Advocates v. Becerra has created new uncertainty, and invited new litigation, regarding numerous health laws that were once assumed to be constitutional.
Drug-coated balloons for small coronary artery disease (BASKET-SMALL 2): an open-label randomised non-inferiority trial
Authors: Raban V Jeger, Ahmed Farah, Marc-Alexander Ohlow, Norman Mangner, Sven Möbius-Winkler, Gregor Leibundgut, Daniel Weilenmann, Jochen Wöhrle, Stefan Richter, Matthias Schreiber, Felix Mahfoud, Axel Linke, Frank-Peter Stephan, Christian Mueller, Peter Rickenbacher, Michael Coslovsky, Nicole Gilgen, Stefan Osswald, Christoph Kaiser, Bruno Scheller, Peter Buser, Michael Kühne, Michael Zellweger, Christian Sticherling, Bastian Wein, Raphael Twerenbold, Gregor Fahrni, Björn Plicht, Berthold Struck, Ismet Önal, Bodo Cremers, Yvonne Clever, Sebastian Ewen, Stephan Schirmer, Michael Böhm, Andreas Wagner, Bernward Lauer, Georg Stachel, Robert Höllriegel, Ephraim Winzer, Hans Rickli, Peter Ammann, Philipp Haager, Lukas Trachsel, Lucas Joerg, Dominique Nüssli, Hans Roelli, Micha Maeder, Franziska Rohner, Sinisa Markovic, Rima Paliskyte, Dominik Buckert, Belal Awad, Paul Erne, Peiman Jamshidi, Florim Cuculi, Ioannis Kapos, Stefan Toggweiler, Florian Riede, Tudor Pörner, Karsten Lenk, Michel Noutsias, Ralf Surber, Gudrun Dannberg, Markus Franz, Sylvia Otto, Robert Zweiker, Ella NIederl, Sabine Perl, Burkert Pieske, Albrecht Schmidt, Olev Luha, Dirk Von Lewinski, Florian Krackhardt, Behrouz Kherad, Timo Jerichow, Christian Butter, Michael Neuss, Grit Tambor, Frank Hölschermann, Leonhard Bruch, Sebastian Winkler, Corinna Lenz, Mirko Seidel, Boris Keweloh, Alexandra Röttgen, Steffen Bohl, Alexander Wolf, Andreas Hoffmann
Journal: The Lancet (2018)
The Pattern of Striatal Dopamine Depletion as a Prognostic Marker in De Novo Parkinson Disease
Authors: Seok Jong Chung, Han Soo Yoo, Hye Sun Lee, Jungsu S. Oh, Jae Seung Kim, Young H. Sohn, Phil Hyu Lee
Journal: Clinical Nuclear Medicine (2018)

Purpose To investigate whether the patterns of striatal dopamine depletion could provide prognostic information on the clinical profiles of early-stage Parkinson disease (PD). Methods Approximately 634 patients with drug-naive PD who underwent 18 F-FP-CIT PET scans were followed up for at least 2 years. After quantifying dopamine transporter (DAT) availability in each striatal subregion, the patterns of striatal dopamine depletion of each patient were assessed based on (1) the degree of dopamine loss in the other striatal subregions compared to the posterior putamen (inter-subregional ratio [ISR]) and (2) the interhemispheric asymmetry of dopamine loss in the posterior putamen (asymmetry index [AI]). According to their patterns, we assessed the longitudinal changes in l -dopa-equivalent doses and l -dopa-induced dyskinesia (LID)-free times using the linear mixed model and Cox regression model, respectively. Results There was no significant correlation between the ISR and AI values (Pearson correlation coefficient, 0.150). The linear mixed model showed that higher AI values were associated with slower longitudinal increases in l -dopa-equivalent dose across time ( P = 0.003), whereas ISR values were not ( P = 0.154). The Cox regression model demonstrated that higher ISR values were associated with early development of LID (hazard ratio, 1.693; P = 0.010), whereas AI values were not ( P = 0.269). Conclusions The present study demonstrated that the pattern of anterior-to-posterior gradient and right-to-left asymmetry of striatal DAT availability predicted the development of LID and increasing doses of dopaminergic medications.
CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated <i>EGFR</i>-Mutated Advanced Non–Small-Cell Lung Cancer
Authors: Thanyanan Reungwetwattana, Kazuhiko Nakagawa, Byoung Chul Cho, Manuel Cobo, Eun Kyung Cho, Alessandro Bertolini, Sabine Bohnet, Caicun Zhou, Ki Hyeong Lee, Naoyuki Nogami, Isamu Okamoto, Natasha Leighl, Rachel Hodge, Astrid McKeown, Andrew P. Brown, Yuri Rukazenkov, Suresh S. Ramalingam, Johan Vansteenkiste
Journal: Journal of Clinical Oncology (2018)

Purpose We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) in patients with untreated EGFR-mutated advanced non–small-cell lung cancer from the phase III FLAURA study. Patients and Methods Patients (N = 556) were randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib); brain scans were not mandated unless clinically indicated. Patients with asymptomatic or stable CNS metastases were included. In patients with symptomatic CNS metastases, neurologic status was required to be stable for ≥ 2 weeks after completion of definitive therapy and corticosteroids. A preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiologic review. The CNS evaluable-for-response set included patients with ≥ one measurable CNS lesion. Results Of 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n = 67) had measurable and/or nonmeasurable CNS lesions, including 41 patients (osimertinib, n = 22; standard EGFR-TKIs, n = 19) with ≥ one measurable CNS lesion. Median CNS progression-free survival in patients with measurable and/or nonmeasurable CNS lesions was not reached with osimertinib (95% CI, 16.5 months to not calculable) and 13.9 months (95% CI, 8.3 months to not calculable) with standard EGFR-TKIs (hazard ratio, 0.48; 95% CI, 0.26 to 0.86; P = .014 [nominally statistically significant]). CNS objective response rates were 91% and 68% in patients with ≥ one measurable CNS lesion (odds ratio, 4.6; 95% CI, 0.9 to 34.9; P = .066) and 66% and 43% in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 2.5; 95% CI, 1.2 to 5.2; P = .011) treated with osimertinib and standard EGFR-TKIs, respectively. Probability of experiencing a CNS progression event was consistently lower with osimertinib versus standard EGFR-TKIs. Conclusion Osimertinib has CNS efficacy in patients with untreated EGFR-mutated non–small-cell lung cancer. These results suggest a reduced risk of CNS progression with osimertinib versus standard EGFR-TKIs.
Aortic ulceration in a tocilizumab-treated patient with Takayasu arteritis
Authors: Emily J Liebling, Rosemary Peterson, Teresa Victoria, Jon M Burnham
Journal: Annals of the Rheumatic Diseases (2018)

In the first randomised, placebo-controlled trial evaluating the efficacy and safety of tocilizumab in patients with Takayasu arteritis, Nakaoka et al ’s1 findings favour tocilizumab over placebo regarding time to relapse, as measured by clinical, laboratory and imaging metrics; infection served as the most common adverse event. In contrast, we report a patient with Takayasu arteritis disease progression that culminated in aortic ulceration while on tocilizumab therapy.

A 16-year-old girl presented with constitutional symptoms, anaemia of chronic inflammation, elevated erythrocyte sedimentation rate and C reactive protein levels, and imaging evidence of large vessel vasculitis in the chest and abdomen. CT and MR angiography showed vessel wall thickening, oedema and enhancement of the main pulmonary arteries, abdominal aorta and its branches, as well as luminal narrowing of the superior mesenteric artery (SMA). Initial treatment with high-dose steroids, methotrexate and infliximab, a chimeric monoclonal antibody to tumour necrosis factor-alpha (TNF-α), resulted in rapid improvement of …
Abstract 13897: Serum Irisin Levels and Cardiovascular Outcomes in Patients With Acute Myocardial Infarction
Authors: Ming Yun Ho, Chao-Yung Wang
Journal: Circulation (2017)

Introduction: Irisin, a recently identified myokine, regulates mitochondrial function and energy expenditure. The concentration of irisin is significantly altered after ST-elevation myocardial infa...
Abstract P165: Future Burden of Morbidity and Disability in England and Wales: A Modelling Study
Authors: Maria Guzman Castillo, Sara Ahmadi-Abhari, Piotr Bandosz, Martin Shipley, Simon Capewell, Archana Singh-Manoux, Mika Kivimaki, Eric Brunner, Martin O’Flaherty
Journal: Circulation (2016)

Background: Cardiovascular disease (CVD) and dementia have profound impacts on the morbidity and disability burden in older people. Uncertainty remains regarding the future incidence of these conditions. We forecast future levels of morbidity and disability in England and Wales up to 2040 under two scenarios regarding CVD and dementia future trends. Methods: We developed a probabilistic Markov model (IMPACT-BAM) which follows the transitions of the England and Wales population into health states characterised by the presence or absence of CVD, dementia and disability to 2040. Data sources include national health registers (ONS) and cohort studies (HSE, Whitehall II and ELSA). Modelled CVD and Non-CVD mortality and prevalence trends for disability and morbidity were used to estimate trends in life expectancy (LE), morbidity-free life expectancy (MFLE) and disability-free life expectancy (DFLE). We assumed that CVD incidence and mortality will continue their current trends and modelled two scenarios: Scenario A assumes constant dementia incidence, a common assumption when projecting future burden of dementia; Scenario B assumes 2% annual decline in dementia incidence, as suggested in UK population-based cohorts. Results: In 2011, LE at age 65 was 18.4 years for men and 21.0 years for women. In Scenario A, LE at 65 in 2040 will increase to 26.7 and 24.8 years in men and women. DFLE at 65 will increase (by 5.5 years in men and 2.8 years in women, to 21.7 and 20.7 years respectively). MFLE at 65 will increase slightly (by 1.5 years in men and 1.4 in women, to 10.7 and 13.2 years respectively). Disability prevalence would increase by 3.1% to 14.4% ( 1,081,483 of 7,510,299) in men and decrease slightly (by 0.6% to 14% (1,214,754 of 8,676,813)) in women. In Scenario B, LE at 65 in 2040 will increase to a similar degree as in Scenario A, but DFLE and MFLE will increase faster (DFLE: by 7.5 years in men and 4.6 in women, to 23.7 and 22.5 years respectively; MFLE: by 4.5 years for both genders to 13.8 years in men and 16.3 in women). Disability prevalence will slightly increase (by 0.8% to 12.1% (908,746 of 7,510,299)) in men and decrease by 3.0% to 11.4% (989,157 of 8,676,813) in women. Conclusions: The future disability burden crucially depends on assumptions about future dementia incidence trends. If the dementia incidence continues unchanged, the duration of morbidity and disability will be prolonged. However, if dementia incidence decreases (as suggested in the UK and mirroring CVD declines) we could live more years in good health, with morbidity compressed into a shorter period before death.
Transcription Factor PROX1 Suppresses Notch Pathway Activation via the Nucleosome Remodeling and Deacetylase Complex in Colorectal Cancer Stem–like Cells
Authors: Jenny Högström, Sarika Heino, Pauliina Kallio, Marianne Lähde, Veli-Matti Leppänen, Diego Balboa, Zoltán Wiener, Kari Alitalo
Journal: Cancer Research (2018)

Abstract The homeobox transcription factor PROX1 is induced by high Wnt/β-catenin activity in intestinal adenomas and colorectal cancer, where it promotes tumor progression. Here we report that in LGR5+ colorectal cancer cells, PROX1 suppresses the Notch pathway, which is essential for cell fate in intestinal stem cells. Pharmacologic inhibition of Notch in ex vivo 3D organoid cultures from transgenic mouse intestinal adenoma models increased Prox1 expression and the number of PROX1-positive cells. Notch inhibition led to increased proliferation of the PROX1-positive colorectal cancer cells, but did not affect their ability to give rise to PROX1-negative secretory cells. Conversely, PROX1 deletion increased Notch target gene expression and NOTCH1 promoter activity, indicating reciprocal regulation between PROX1 and the Notch pathway in colorectal cancer. PROX1 interacted with the nucleosome remodeling and deacetylase (NuRD) complex to suppress the Notch pathway. Thus, our data suggests that PROX1 and Notch suppress each other and that PROX1-mediated suppression of Notch mediates its stem cell function in colorectal cancer. Significance: These findings address the role of the PROX1 homeobox factor as a downstream effector of Wnt/β-catenin singling in colorectal cancer stem cells and show that PROX1 inhibits the Notch pathway and helps to enforce the stem cell phenotype and inhibit differentiation. Cancer Res; 78(20); 5820–32. ©2018 AACR.
Effective reporting of key performance indicators is essential for balancing the benefits and drawbacks of colonoscopy
Authors: Evelien Dekker, Maxime Bronzwaer
Journal: Endoscopy (2018)

See also: Endoscopy assistants influence the quality of colonoscopyEndoscopy 2018; 50(09): 871-877DOI: 10.1055/s-0044-101706 See also: Colonoscopic perforations in the English National Health Service Bowel Cancer Screening ProgrammeEndoscopy 2018; 50(09): 861-870DOI: 10.1055/a-0584-7138
Persistent Marburg Virus Infection in the Testes of Nonhuman Primate Survivors
Authors: Kayla M. Coffin, Jun Liu, Travis K. Warren, Candace D. Blancett, Kathleen A. Kuehl, Donald K. Nichols, Jeremy J. Bearss, Christopher W. Schellhase, Cary J. Retterer, Jessica M. Weidner, Sheli R. Radoshitzky, Jennifer M. Brannan, Anthony P. Cardile, John M. Dye, Gustavo Palacios, Mei G. Sun, Jens H. Kuhn, Sina Bavari, Xiankun Zeng
Journal: Cell Host & Microbe (2018)
Association of Fundamentals of Laparoscopic Surgery Certification With Outcomes of Laparoscopic Cholecystectomy Performed by Surgical Residents
Authors: Emily D. Dubina, Xuan-Binh D. Pham, Alexander C. Schwed, Hoover Wu, Imani McElroy, Amy H. Kaji, Christian de Virgilio
Journal: JAMA Surgery (2018)

This study examines outcomes of laparoscopic cholecystectomies performed by surgical residents before and after mandatory implementation of Fundamentals of Laparoscopic Surgery certification to assess whether certification is associated with residence performance or patient outcome.
<i>Primum non nocere</i>: is faecal microbiota transplantation doing harm to patients with IBS?
Authors: Paul Enck
Journal: Gut (2018)

A recent paper in this journal1 caught my attention: In a well-designed placebo-controlled trial of faecal microbiota transplantation (FMT) in patients with IBS, 12 days of blinded provision of the transplant or placebo in capsules improved symptoms in patients randomised to placebo significantly better than in patients receiving FMT, for IBS symptom severity at 3 and 6 months, and for IBS quality of life at 1, 3 and 6 months of follow-up. Patients receiving FMT showed sustained alterations of their microbiota, obviously unrelated to the symptom burden.

Taking the effect of FMT on the gut microbiota in IBS aside (that has a scientific value by itself), these results not only imply that improvements seen with FMT in IBS in controlled2 …
Abstract P181: Blood Pressure and All-cause Mortality Among Patients with Type 2 Diabetes
Authors: Weiqi Li, Peter T Katzmarzyk, Ronald Horswell, Yujie Wang, Gang Hu
Journal: Circulation (2016)

Background: The recommended goal for blood pressure (BP) control has recently been adjusted for people with diabetes, but the optimal BP control range for the diabetic population is still uncertain. Aims: To investigate the association between blood pressure and the risk of mortality among patients with type 2 diabetes. Methods: We performed a prospective cohort study of 35,261 patients with type 2 diabetes. Cox proportional hazards regression models were used to estimate the association of BP with all-cause mortality. Results: During a mean follow-up period of 8.7 years, 4,199 deaths were identified. The multivariable-adjusted hazard ratios of all-cause mortality associated with different levels of systolic/diastolic BP (&lt;110/65, 110-119/65-69, 120-129/70-80, 130-139/80-90 [reference group], 140-159/90-100, and ≥160/100 mmHg) were 1.70 (95% confidence interval [CI] 1.42-2.04), 1.26 (95% CI 1.07-1.50), 0.99 (95% CI 0.86-1.12), 1.00, 0.92 (95% CI 0.82-1.03), and 1.10 (95% CI 0.98-1.23) using baseline BP measurements, and 2.62 (95% CI 2.00-3.44), 1.77 (95% CI 1.51-2.09), 1.22 (95% CI 1.09-1.36), 1.00, 0.90 (95% CI 0.82-1.00), and 0.98 (95% CI 0.86-1.12) using an updated mean value of BP during follow-up, respectively. The U-shaped associations were confirmed in both African American and white patients, in both men and women, in those who were or were not taking antihypertensive drugs; and in patients aged 30-49 years and 50-59 years. Conclusion: The current study found a U-shaped association between BP at baseline and during follow-up and the risk of all-cause mortality among patients with type 2 diabetes.
Abstract 16956: Trends in Lipid Screening Among Adults in an Integrated Health Care Delivery System, 2009 to 2015
Authors: Kristi Reynolds, Teresa N Harrison, Shen-Chih Chang, Jin-Wen Y Hsu, Deborah S Ling-Grant, T. C Cheetham, Rong Wei, Susan H Boklage, Victoria Romo-LeTourneau, Ronald D Scott
Journal: Circulation (2016)

Background: Lipid screening (LS) is needed to determine eligibility for statins and other cardiovascular (CV) risk reduction interventions. Currently, there are no publicly reported metrics on LS in the general population. Trends in LS overall and in those with atherosclerotic CV disease (ASCVD) and diabetes mellitus (DM) were investigated in a large, integrated health care delivery system. Methods: Individuals aged ≥20 years from 10/1/09 through 09/30/15 were identified and temporal trends in LS were examined. LS was reported for each year as a proportion of the eligible members aged 20-39 years who had ever been screened and those aged ≥40 years who had been screened in the preceding 6 years. Baseline characteristics including demographics, comorbid conditions, and health care utilization were extracted from electronic health records. Trends in LS were analyzed by age group, gender, and ASCVD and DM status. Cochran-Armitage tests were used to assess temporal trends. Results: Over 2 million individuals w...