tbuckley/cabot-search huggingface dataset:
Associations of Combined Genetic and Lifestyle Risks With Incident Cardiovascular Disease and Diabetes in the UK Biobank Study
Authors: M. Abdullah Said, Niek Verweij, Pim van der Harst
Journal: JAMA Cardiology (2018)

Genetic and lifestyle factors both contribute to the risk of developing cardiovascular disease, but whether poor health behaviors are associated with similar increases in risk among individuals with low, intermediate, or high genetic risk is unknown.To investigate the association of combined health behaviors and factors within genetic risk groups with coronary artery disease, atrial fibrillation, stroke, hypertension, and type 2 diabetes as well as to investigate the interactions between genetic risk and lifestyle.The UK Biobank cohort study includes more than 500 000 participants aged 40 to 70 years who were recruited from 22 assessment centers across the United Kingdom from 2006 to 2010. A total of 339 003 unrelated individuals of white British descent with available genotype and matching genetic data and reported sex were included in this study from the UK Biobank population-based sample. Individuals were included in the analyses of 1 or more new-onset diseases. Data were analyzed from April 2006 to March 2015.Risks of new-onset cardiovascular disease and diabetes associated with genetic risk and combined health behaviors and factors. Genetic risk was categorized as low (quintile 1), intermediate (quintiles 2-4), or high (quintile 5). Within each genetic risk group, the risks of incident events associated with ideal, intermediate, or poor combined health behaviors and factors were investigated and compared with low genetic risk and ideal lifestyle.Of 339 003 individuals, 181 702 (53.6%) were female, and the mean (SD) age was 56.86 (7.99) years. During follow-up, 9771 of 325 133 participants (3.0%) developed coronary artery disease, 7095 of 333 637 (2.1%) developed atrial fibrillation, 3145 of 332 971 (0.9%) developed stroke, 11 358 of 234 651 (4.8%) developed hypertension, and 4379 of 322 014 (1.4%) developed diabetes. Genetic risk and lifestyle were independent predictors of incident events, and there were no interactions for any outcome. Compared with ideal lifestyle in the low genetic risk group, poor lifestyle was associated with a hazard ratio of up to 4.54 (95% CI, 3.72-5.54) for coronary artery disease, 5.41 (95% CI, 4.29-6.81) for atrial fibrillation, 4.68 (95% CI, 3.85-5.69) for hypertension, 2.26 (95% CI, 1.63-3.14) for stroke, and 15.46 (95% CI, 10.82-22.08) for diabetes in the high genetic risk group.In this large contemporary population, genetic composition and combined health behaviors and factors had a log-additive effect on the risk of developing cardiovascular disease. The relative effects of poor lifestyle were comparable between genetic risk groups. Behavioral lifestyle changes should be encouraged for all through comprehensive, multifactorial approaches, although high-risk individuals may be selected based on the genetic risk.
Leukotriene biosynthetic enzymes as therapeutic targets
Authors: Jesper Z. Haeggström
Journal: Journal of Clinical Investigation (2018)

Leukotrienes are powerful immune-regulating lipid mediators with established pathogenic roles in inflammatory allergic diseases of the respiratory tract - in particular, asthma and hay fever. More recent work indicates that these lipids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, and metabolic diseases as well as cancer. Biosynthesis of leukotrienes involves oxidative metabolism of arachidonic acid and proceeds via a set of soluble and membrane enzymes that are primarily expressed by cells of myeloid origin. In activated immune cells, these enzymes assemble at the endoplasmic and perinuclear membrane, constituting a biosynthetic complex. This Review describes recent advances in our understanding of the components of the leukotriene-synthesizing enzyme machinery, emerging opportunities for pharmacological intervention, and the development of new medicines exploiting both antiinflammatory and pro-resolving mechanisms.
Evolution of LOH patterns on chromosome 9 in recurrent bladder tumors in relation to a FGFR3 mutation
Authors: Lucie C. Kompier, Madelon N. Van der Aa, Latifa Qoubbane, Irene Lurkin, Antoine Van Exsel, Theo H. Van der Kwast, Ellen C. Zwarthoff
Journal: Cancer Research (2005)

5733  4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lung tumors and is a suspected human carcinogen. Our previous study demonstrated that high corn oil and olive oil diets inhibited NNK lung tumorigenesis at the post-initiation stage. Furthermore, diets high in corn oil or olive oil significantly decreased cyclooxygenase (COX) activity on day 7 after NNK treatment, a time point when COX activity was maximally induced by NNK. The purpose of the present study was to further elucidate the effect of high corn oil and olive oil diets on COX expression and NNK-induced cell proliferation. Female A/J mice were treated with a single dose of NNK (103mg/kg; i.p) or saline and fed control (AIN-93), high corn oil or olive oil diets starting two days after NNK treatment. Groups of mice were sacrificed at 2, 5, 7, 15, and 35 days after NNK. The cell proliferation index was measured by incorporation of bromodeoxyuridine (Brdu) immunohistochemically. In NNK control mice, there was approximately 2.3-fold increase in the number of Brdu-labelled cells in bronchiolar epithelium from day 5 to day 7, as compared to control mice. By day 35, cell proliferation index returned to the level of control mice. Dietary corn oil or olive oil treatment significantly lowered the cell proliferation index by 43-60% on day 5 and 7. Intense immunostaining for COX-2 protein was observed in NNK-treated mouse bronchiolar epithelium on day 5 and 7. By day 35, COX-2 immunostaining intensity in NNK-treated mouse lung returned to control levels. Administration of high corn oil or olive oil diets resulted in decreased COX-2 immunostaining, from day 2 to day 35. Western blotting analysis demonstrated that NNK induced the protein level of COX-2 and had no effect on COX-1 in lung microsomes on day 7. Whereas, the high-fat diet decreased COX-2 protein levels and had no effect on COX-1. Furthermore, the lung cytosolic 12-lipoxygenase protein level was increased in NNK control animals and was further induced in mice fed high olive oil diet. Immunostaining of lung tissue sections from our previous NNK tumorigenesis study revealed elevated COX-2 expression in NNK control mice compared to those of control and high-fat diet fed animals, when the experimental diets were administered 2 days after NNK. However, when mice were fed high olive oil diet starting 1wk or 5wk after NNK, there was no significant difference in pulmonary COX-2 levels between high olive oil-fed mice and NNK control mice. The present study suggests that the suppression of NNK-induced early pulmonary cell proliferation by high corn oil and olive oil diets may be partially due to the inhibition of COX-2 expression and thereby may contribute to the inhibition of NNK-induced lung tumorigenesis by dietary corn oil and olive oil.
Atopic dermatitis in Chinese patients shows TH2/TH17 skewing with psoriasiform features
Authors: Tom C. Chan, Riana D. Sanyal, Ana B. Pavel, Jacob Glickman, Xiuzhong Zheng, Hui Xu, Yung-Tsu Cho, Tsen-Feng Tsai, Huei-Chi Wen, Xiangyu Peng, Inna Cueto, James G. Krueger, Emma Guttman-Yassky
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 12905: Chronic Effect of Cibenzoline on Left Ventricular Pressure Gradient, Left Ventricular Diastolic Function and Left Ventricular Hypertrophy in Patients with Hypertrophic Obstructive Cardiomyopathy
Authors: Mareomi Hamada, Kiyotaka Ohshima, Shuntaro Ikeda
Journal: Circulation (2012)

Aim:  We examined the chronic effect of antiarrhythmic drug, cibenzoline on left ventricular pressure gradient (LVPG), left ventricular diastolic function and left ventricular hypertrophy in patients with hypertrophic obstructive cardiomyopathy (HOCM).   Methods:  Forty-eight patients with HOCM participated (mean age:58±12 years). Mean dose of cibenzoline was 293±40mg/day, and mean follow-up period was 56.0±28.4 months. In addition to cibenzoline, β-blocker was administered to 40 patients and Ca-antagonist was administered to 29 patients. Before administration of cibenzoline and at the chronic stage of the treatment, LVPG and E-velocity/A-velocity ratio (E/A ratio) was measured in echocardiogram, and in electrocardiogram heart rate (HR), SV1+RV5, depth in negative T wave and HR corrected QT interval (QTc) were measured.   Results:  [[Unable to Display Character: ①]]HR decreased from 74±14/min to 63±9/min. [[Unable to Display Character: ②]]LVPG decreased from 93.8±49.9 mmHg to 19.0±18.8 mmHg.[[Unable to Display Character: ③]]E/A ratio increased from 0.75±0.42 to 1.52±0.62. [[Unable to Display Character: ④]] SV1+RV5 decreased from 49.8±19.3 mm to 35.3±15.7 mm. [[Unable to Display Character: ⑤]] depth in negative T wave decreased from 8.0±7.3 mm to 5.1±5.7 mm. Negative T wave in 7 patients with HOCM changed to positive. [[Unable to Display Character: ⑥]] QTc shortened from 0.486±0.051 msec to 0.455±0.050 msec. These changes were all significant.   Conclusion:  These results indicate that the treatment with cibenzoline can decrease LVPG, improve left ventricular diastolic dysfunction and bring about left ventricular regression to patients with HOCM without any serious side effects.
Association of Retinal Nerve Fiber Layer Thinning With Current and Future Cognitive Decline
Authors: Fang Ko, Zaynah A. Muthy, John Gallacher, Cathie Sudlow, Geraint Rees, Qi Yang, Pearse A. Keane, Axel Petzold, Peng T. Khaw, Charles Reisman, Nicholas G. Strouthidis, Paul J. Foster, Praveen J. Patel
Journal: JAMA Neurology (2018)

Identifing potential screening tests for future cognitive decline is a priority for developing treatments for and the prevention of dementia.To examine the potential of retinal nerve fiber layer (RNFL) thickness measurement in identifying those at greater risk of cognitive decline in a large community cohort of healthy people.UK Biobank is a prospective, multicenter, community-based study of UK residents aged 40 to 69 years at enrollment who underwent baseline retinal optical coherence tomography imaging, a physical examination, and a questionnaire. The pilot study phase was conducted from March 2006 to June 2006, and the main cohort underwent examination for baseline measures from April 2007 to October 2010. Four basic cognitive tests were performed at baseline, which were then repeated in a subset of participants approximately 3 years later. We analyzed eyes with high-quality optical coherence tomography images, excluding those with eye disease or vision loss, a history of ocular or neurological disease, or diabetes. We explored associations between RNFL thickness and cognitive function using multivariable logistic regression modeling to control for demographic as well as physiologic and ocular variation.Odds ratios (ORs) for cognitive performance in the lowest fifth percentile in at least 2 of 4 cognitive tests at baseline, or worsening results on at least 1 cognitive test at follow-up. These analyses were adjusted for age, sex, race/ethnicity, height, refraction, intraocular pressure, education, and socioeconomic status.A total of 32 038 people were included at baseline testing, for whom the mean age was 56.0 years and of whom 17 172 (53.6%) were women. A thinner RNFL was associated with worse cognitive performance on baseline assessment. A multivariable regression controlling for potential confounders showed that those in the thinnest quintile of RNFL were 11% more likely to fail at least 1 cognitive test (95% CI, 2.0%-2.1%; P = .01). Follow-up cognitive tests were performed for 1251 participants (3.9%). Participants with an RNFL thickness in the 2 thinnest quintiles were almost twice as likely to have at least 1 test score be worse at follow-up cognitive testing (quintile 1: OR, 1.92; 95% CI, 1.29-2.85; P < .001; quintile 2: OR, 2.08; 95% CI, 1.40-3.08; P < .001).A thinner RNFL is associated with worse cognitive function in individuals without a neurodegenerative disease as well as greater likelihood of future cognitive decline. This preclinical observation has implications for future research, prevention, and treatment of dementia.
Association of Retinal Neurodegeneration on Optical Coherence Tomography With Dementia
Authors: Unal Mutlu, Johanna M. Colijn, M. Arfan Ikram, Pieter W. M. Bonnemaijer, Silvan Licher, Frank J. Wolters, Henning Tiemeier, Peter J. Koudstaal, Caroline C. W. Klaver, M. Kamran Ikram
Journal: JAMA Neurology (2018)

<h3>Importance</h3> Retinal structures may serve as a biomarker for dementia, but longitudinal studies examining this link are lacking. <h3>Objective</h3> To investigate the association of inner retinal layer thickness with prevalent and incident dementia in a general population of Dutch adults. <h3>Design, Setting, and Participants</h3> From September 2007 to June 2012, participants from the prospective population-based Rotterdam Study who were 45 years and older and had gradable retinal optical coherence tomography images and at baseline were free from stroke, Parkinson disease, multiple sclerosis, glaucoma, macular degeneration, retinopathy, myopia, hyperopia, and optic disc pathology were included. They were followed up until January 1, 2015, for the onset of dementia. <h3>Exposures</h3> Inner retinal layer thicknesses (ie, retinal nerve fiber layer [RNFL]) and ganglion cell–inner plexiform layer (GC-IPL) thicknesses measured on optical coherence tomography images. <h3>Main Outcomes and Measures</h3> Odds ratios and hazard ratios for incident dementia per SD decrease in retinal layer thickness adjusted for age, sex, education, and cardiovascular risk factors. <h3>Results</h3> Of 5065 individuals eligible for optical coherence tomography scanning, 3289 (64.9%) (mean [SD] age 68.9 [9.9] years, 1879 [57%] women) were included in the analysis. Of these 3289 individuals, 41 (1.2%) already had dementia. Thinner GC-IPL was associated with prevalent dementia (odds ratio per SD decrease in GC-IPL, 1.37 [95% CI, 0.99-1.90]). No association was found of RNFL with prevalent dementia. During 14 674 person-years of follow-up (mean [SD], 4.5 [1.6] years), 86 individuals (2.6%) developed dementia of whom 68 (2.1%) had Alzheimer disease. Thinner RNFL at baseline was associated with an increased risk of developing dementia (hazard ratio per SD decrease in RNFL, 1.44 [95% CI, 1.19-1.75]), which was similar for Alzheimer disease (hazard ratio, 1.43 [95% CI, 1.15-1.78]). No association was found between GC-IPL thickness and incident dementia (hazard ratio, 1.13 [95% CI, 0.90-1.43]). <h3>Conclusions and Relevance</h3> Thinner RNFL is associated with an increased risk of dementia, including Alzheimer disease, suggesting that retinal neurodegeneration may serve as a preclinical biomarker for dementia.
Specificity of the DNA Mismatch Repair System (MMR) and Mutagenesis Bias in Bacteria
Authors: Hongan Long, Samuel F Miller, Emily Williams, Michael Lynch
Journal: Molecular Biology and Evolution (2018)

The mutation rate of an organism is influenced by the interaction of evolutionary forces such as natural selection and genetic drift. However, the mutation spectrum (i.e., the frequency distribution of different types of mutations) can be heavily influenced by DNA repair. Using mutation-accumulation lines of the extremophile bacterium Deinococcus radiodurans ΔmutS1 and the model soil bacterium Pseudomonas fluorescens wild-type and MMR- (Methyl-dependent Mismatch Repair-deficient) strains, we report the mutational features of these two important bacteria. We find that P. fluorescens has one of the highest MMR repair efficiencies among tested bacteria. We also discover that MMR of D. radiodurans preferentially repairs deletions, contrary to all other bacteria examined. We then, for the first time, quantify genome-wide efficiency and specificity of MMR in repairing different genomic regions and mutation types, by evaluating the P. fluorescens and D. radiodurans mutation data sets, along with previously reported ones of Bacillus subtilis subsp. subtilis, Escherichia coli, Vibrio cholerae, and V. fischeri. MMR in all six bacteria shares two general features: 1) repair efficiency is influenced by the neighboring base composition for both transitions and transversions, not limited to transversions as previously reported; and 2) MMR only recognizes indels <4 bp in length. This study demonstrates the power of mutation accumulation lines in quantifying DNA repair and mutagenesis patterns.
Abstract 15619: Periprocedural Ischemic Events After TAVI Performed With or Without Prior Balloon Aortic Valvuloplasty
Authors: Florence Leclercq, Jessica Labour, Myriam Akodad, Jean Christophe Macia, Benoit Lattuca, Thomas Gandet, Nicolas de Champfleur, Audrey Agullo, Hélène Vernhet, Laurent Schmutz, Bernard Albat, Guillaume Cayla
Journal: Circulation (2016)

Introduction: Direct implantation of the transcather heart valve (THV) without prior balloon valvuloplasty (BAV) is commonly done with new generation devices but we lack of prospective data related...
Contribution of BKCa channels to vascular tone regulation by PDE3 and PDE4 is lost in heart failure
Authors: Sarah Idres, Germain Perrin, Valérie Domergue, Florence Lefebvre, Susana Gomez, Audrey Varin, Rodolphe Fischmeister, Véronique Leblais, Boris Manoury
Journal: Cardiovascular Research (2018)

Regulation of vascular tone by 3',5'-cyclic adenosine monophosphate (cAMP) involves many effectors including the large conductance, Ca2+-activated, K+ (BKCa) channels. In arteries, cAMP is mainly hydrolyzed by type 3 and 4 phosphodiesterases (PDE3, PDE4). Here, we examined the specific contribution of BKCa channels to tone regulation by these PDEs in rat coronary arteries, and how this is altered in heart failure (HF).Concomitant application of PDE3 (cilostamide) and PDE4 (Ro-20-1724) inhibitors increased BKCa unitary channel activity in isolated myocytes from rat coronary arteries. Myography was conducted in isolated, U46619-contracted coronary arteries. Cilostamide (Cil) or Ro-20-1724 induced a vasorelaxation that was greatly reduced by iberiotoxin (IBTX), a BKCa channel blocker. Ro-20-1724 and Cil potentiated the relaxation induced by the β-adrenergic agonist isoprenaline (ISO) or the adenylyl cyclase activator L-858051 (L85). IBTX abolished the effect of PDE inhibitors on ISO but did not on L85. In coronary arteries from rats with HF induced by aortic stenosis, contractility and response to acetylcholine were dramatically reduced compared with arteries from sham rats, but relaxation to PDE inhibitors was retained. Interestingly, however, IBTX had no effect on Ro-20-1724- and Cil-induced vasorelaxations in HF. Expression of the BKCa channel α-subunit, of a 98 kDa PDE3A and of a 80 kDa PDE4D were lower in HF compared with sham coronary arteries, while that of a 70 kDa PDE4B was increased. Proximity ligation assays demonstrated that PDE3 and PDE4 were localized in the vicinity of the channel.BKCa channels mediate the relaxation of coronary artery induced by PDE3 and PDE4 inhibition. This is achieved by co-localization of both PDEs with BKCa channels, enabling tight control of cAMP available for channel opening. Contribution of the channel is prominent at rest and on β-adrenergic stimulation. This coupling is lost in HF.
CNS relapse in patients with DLBCL treated with lenalidomide plus R-CHOP (R2CHOP): analysis from two phase 2 studies
Authors: Ayed O. Ayed, Annalisa Chiappella, Levi Pederson, Betsy R. Laplant, Angela Giovanna Congiu, Gianluca Gaidano, Michele Spina, Alessandro Re, Federica Cavallo, Gerardo Musuraca, William R. Macon, Thomas Witzig, Umberto Vitolo, Grzegorz S. Nowakowski
Journal: Blood Cancer Journal (2018)

Abstract Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a devastating event occurring in ~ 5% of patients treated with R-CHOP. We hypothesized that adding lenalidomide to R-CHOP (R2CHOP) may decrease the risk of CNS relapse. We analyzed records for patients with DLBCL from two R2CHOP trials. We assessed variables pertinent to the CNS-International Prognostic Index (CNS-IPI) scoring system and classified patients into groups of low, intermediate, and high risk of CNS relapse. The 2-year CNS relapse rate for each risk group was estimated using the Kaplan–Meier method and compared with reported rates in cohorts treated with contemporary chemoimmunotherapy. A total of 136 patients were included. Mean age was 65 and median follow-up was 48.2 months. 10.3, 71.3, and 18.4% of patients were classified into low, intermediate, and high-risk CNS-IPI groups, respectively. Only one of 136 patients developed CNS relapse, corresponding to an incidence of 0.7% and an estimated 2-year CNS relapse rate of 0.9% for the entire R2CHOP cohort. The estimated 2-year CNS relapse rates for the low, intermediate, and high-risk groups were 0, 0, and 5.0%, respectively. Frontline therapy with R2CHOP in patients with DLBCL is associated with a lower-than-expected rate of CNS relapse.
Abstract 669: The regulation of ALOX15 expression in colorectal cancer to overcome the resistance to radiation therapy
Authors: Yoo Jin Na, Dae-Hee Lee, Bo Ram Kim, Jung Lim Kim, So Yeon Jeong, Seong Hye Park, Min Jee Jo, Yoon A Jeong, Hye Kyeong Yun, Sang Cheul Oh
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is the third most common cancer and the third leading cause of 'cancer related death' world-wide. In case of CRC patients who have large sized tumor, radiation therapy is essential to decrease tumor size without having to eliminate the anus. However, radiation effects vary according to patients. Also, the association between genes and radiation sensitivity is still rarely researched. In this study, we elucidated that the expression level of ALOX15 regulates radiation sensitivity by TNFα signaling pathway in CRC cells. ALOX15 is known as the main metabolic enzyme for linoleic acid and arachidonic acid. Interestingly, stable cells which express low ALOX15 inhibit radiation-induced apoptosis. Mechanistically, inhibition of ALOX15 increases NF-kB under radiation therapy condition. NF-kB that plays a key role in the cellular response to DNA damage is a reason for ALOX15 to act as a radiation sensitizer. Taken together, our results indicate that ALOX15 is suggested as a prediction marker for radiation therapy. In addition, screening natural compound for elevating ALOX15 would be used for the purpose of combination therapy in radiation-resistant CRC cells. Citation Format: Yoo Jin Na, Dae-Hee Lee, Bo Ram Kim, Jung Lim Kim, So Yeon Jeong, Seong Hye Park, Min Jee Jo, Yoon A Jeong, Hye Kyeong Yun, Sang Cheul Oh. The regulation of ALOX15 expression in colorectal cancer to overcome the resistance to radiation therapy [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 669.