tbuckley/cabot-search huggingface dataset:
FKBP5 and Attention Bias for Threat
Authors: Negar Fani, David Gutman, Erin B. Tone, Lynn Almli, Kristina B. Mercer, Jennifer Davis, Ebony Glover, Tanja Jovanovic, Bekh Bradley, Ivo D. Dinov, Alen Zamanyan, Arthur W. Toga, Elisabeth B. Binder, Kerry J. Ressler
Journal: JAMA Psychiatry (2013)

<h3>Importance</h3>The FKBP5 gene product regulates glucocorticoid receptor (GR) sensitivity and hypothalamic-pituitary-adrenal axis functioning and has been associated with many stress-related psychiatric disorders. The study of intermediate phenotypes, such as emotion-processing biases and their neural substrates, provides a way to clarify the mechanisms by which FKBP5 dysregulation mediates risk for psychiatric disorders.<h3>Objective</h3>To examine whether allelic variations for a putatively functional single-nucleotide polymorphism associated with FKBP5 gene regulation (rs1360780) would relate differentially to attention bias for threat. this was measured through behavioral response on a dot probe task and hippocampal activation during task performance. Morphologic substrates of differential hippocampal response were also measured.<h3>Design</h3>Cross-sectional study conducted from 2010 to 2012 examining associations between genotype, behavioral response, and neural response (using functional magnetic resonance imaging [fMRI]) on the dot probe; voxel-based morphometry and global and local shape analyses were used to measure structural differences in hippocampi between genotype groups.<h3>Setting</h3>Participants were recruited from primary care clinics of a publicly funded hospital in Atlanta, Georgia.<h3>Participants</h3>An African American cohort of adults (N = 103) was separated into 2 groups by genotype: one genotype group included carriers of the rs1360780 T allele, which has been associated with increased risk for posttraumatic stress disorder and affective disorders; the other group did not carry this allele. Behavioral data included both sexes (N = 103); the MRI cohort (n = 36) included only women.<h3>Main Outcome Measures</h3>Behavioral and fMRI (blood oxygen level–dependent) response, voxel-based morphometry, and shape analyses.<h3>Results</h3>Carriers of the rs1360780 T allele showed an attention bias toward threat compared with individuals without this allele (F<sub>1,90</sub> = 5.19, P = .02). Carriers of this allele demonstrated corresponding increases in hippocampal activation and differences in morphology; global and local shape analyses revealed alterations in hippocampal shape for TT/TC compared with CC genotype groups.<h3>Conclusion</h3>Genetic variants of FKBP5 may be associated with risk for stress-related psychiatric disorders via differential effects on hippocampal structure and function, resulting in altered attention response to perceived threat.
Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells.
Authors: A D'Andrea, M Aste-Amezaga, N M Valiante, X Ma, M Kubin, G Trinchieri
Journal: The Journal of Experimental Medicine (1993)

Natural killer cell stimulatory factor or interleukin 12 (NKSF/IL-12) is a heterodimeric cytokine produced by monocytes/macrophages, B cells, and possibly other accessory cell types primarily in response to bacteria or bacterial products. NKSF/IL-12 mediates pleiomorphic biological activity on T and NK cells and, alone or in synergy with other inducers, is a powerful stimulator of interferon gamma (IFN-gamma) production. IL-10 is a potent inhibitor of monocyte-macrophage activation, that inhibits production of tumor necrosis factor alpha (TNF-alpha), IL-1 and also IFN-gamma from lymphocytes acting at the level of accessory cells. Because TNF-alpha and IL-1 are not efficient inducers of IFN-gamma, the mechanism by which IL-10 inhibits IFN-gamma production is not clear. In this paper, we show that IL-10 is a potent inhibitor of NKSF/IL-12 production from human peripheral blood mononuclear cells activated with Staphylococcus aureus or lipopolysaccharide (LPS). Both the production of the free NKSF/IL-12 p40 chain and the biologically active p70 heterodimer are blocked by IL-10. NKSF/IL-12 p40 chain mRNA accumulation is strongly induced by S. aureus or LPS and downregulated by IL-10, whereas the p35 mRNA is constitutively expressed and only minimally regulated by S. aureus, LPS, or IL-10. Although IL-10 is able to block the production of NKSF/IL-12, a powerful inducer of IFN-gamma both in vitro and in vivo, the mechanism of inhibition of IFN-gamma by IL-10 cannot be explained only on the basis of inhibition of NKSF/IL-12 because IL-10 can partially inhibit IFN-gamma production induced by NKSF/IL-12, and also, the IFN-gamma production in response to various stimuli in the presence of neutralizing antibodies to NKSF/IL-12. Our findings that antibodies against NKSF/IL-12, TNF-alpha, or IL-1 beta can significantly inhibit IFN-gamma production in response to various stimuli and that NKSF/IL-12 and IL-1 beta can overcome the IL-10-mediated inhibition of IFN-gamma, suggest that IL-10 inhibition of IFN-gamma production is primarily due to its blocking production from accessory cells of the IFN-gamma-inducer NKSF/IL-12, as well as the costimulating molecule IL-1 beta.
Growth-rate regulated genes have profound impact on interpretation of transcriptome profiling in Saccharomyces cerevisiae
Authors: Birgitte Regenberg, Thomas Grotkjær, Ole Winther, Anders Fausbøll, Mats Åkesson, Christoffer Bro, Lars Kai Hansen, Søren Brunak, Jens Nielsen
Journal: Genome biology (2006)

Abstract Background Growth rate is central to the development of cells in all organisms. However, little is known about the impact of changing growth rates. We used continuous cultures to control growth rate and studied the transcriptional program of the model eukaryote Saccharomyces cerevisiae , with generation times varying between 2 and 35 hours. Results A total of 5930 transcripts were identified at the different growth rates studied. Consensus clustering of these revealed that half of all yeast genes are affected by the specific growth rate, and that the changes are similar to those found when cells are exposed to different types of stress (&gt;80% overlap). Genes with decreased transcript levels in response to faster growth are largely of unknown function (&gt;50%) whereas genes with increased transcript levels are involved in macromolecular biosynthesis such as those that encode ribosomal proteins. This group also covers most targets of the transcriptional activator RAP1, which is also known to be involved in replication. A positive correlation between the location of replication origins and the location of growth-regulated genes suggests a role for replication in growth rate regulation. Conclusion Our data show that the cellular growth rate has great influence on transcriptional regulation. This, in turn, implies that one should be cautious when comparing mutants with different growth rates. Our findings also indicate that much of the regulation is coordinated via the chromosomal location of the affected genes, which may be valuable information for the control of heterologous gene expression in metabolic engineering.
Antiproliferative Effect of Liver X Receptor Agonists on LNCaP Human Prostate Cancer Cells
Authors: Junichi Fukuchi, John M. Kokontis, Richard A. Hiipakka, Chih-pin Chuu, Shutsung Liao
Journal: Cancer Research (2004)

Abstract Liver X receptors function as central transcriptional regulators for lipid homeostasis, for which agonists have been developed as potential drugs for treatment of cardiovascular diseases and metabolic syndromes. Because dysregulation of lipid metabolism has been implicated in sex hormone-dependent cancers, we investigated the effect of liver X receptor agonists on prostate and breast cancer cell proliferation. Treatment of human prostate cancer LNCaP cell lines with the synthetic liver X receptor agonist T0901317 decreased the percentage of S-phase cells in a dose-dependent manner and increased the expression of cyclin-dependent kinase inhibitor p27Kip-1 (p27). Knockdown of p27 by RNA interference blocks T0901317-induced growth inhibition, suggesting that p27 expression plays a crucial role in this signaling. Liver X receptor agonists also inhibited the proliferation of other prostate and breast cancer cell lines. The level of liver X receptor α expression correlated directly with sensitivity to growth inhibition by liver X receptor agonists. Retroviral expression of liver X receptor α in human breast cancer MDA-MB435S cells, which express low levels of endogenous liver X receptors and are insensitive to T0901317, sensitized these cells to T0901317. Consistent with our observations in LNCaP cells, T0901317 induces dramatic up-regulation of p27 in liver X receptor α–overexpressing MDA-MB435S cells. Furthermore, oral administration of T0901317 inhibited the growth of LNCaP tumors in athymic nude mice. Based on these results, modulation of the liver X receptor signaling pathway is a new target for controlling tumor cell proliferation; therefore, liver X receptor agonists may have utility as antitumorigenic agents.
Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors
Authors: Timothy Kottke, Fiona Errington, Jose Pulido, Feorillo Galivo, Jill Thompson, Phonphimon Wongthida, Rosa Maria Diaz, Heung Chong, Elizabeth Ilett, John D. Chester, Hardev Pandha, Kevin Harrington, Peter Selby, Alan Melcher, Richard Vile
Journal: Nature Medicine (2011)
Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis
Authors: Robert G. Knodell, Kamal G. Ishak, William C. Black, Thomas S. Chen, Robert Craig, Neil Kaplowitz, Thomas W. Kiernan, Jerome Wollman
Journal: Hepatology (1981)

A Histology Activity Index has been developed which generates a numerical score for liver biopsy specimens obtained from patients with asymptomatic chronic active hepatitis. Biopsies are graded in four categories: periportal necrosis, intralobular necrosis, portal inflammation, and fibrosis. Under code, three pathologists and three hepatologists evaluated 14 liver biopsy specimens obtained from five patients with asymptomatic chronic active hepatitis. Good correlation was seen between severity of liver biopsy lesions as judged by conventional histological descriptions and Histology Activity Index scores. Significant differences in Histology Activity Index score occurred in only 2 or 28 duplicate scorings of biopsy specimens by two observers. This system provides definitive endpoints for statistical analysis of serial changes in liver histology and offers an alternative to the use of conventional pathological descriptions in following the natural history and treatment responses of asymptomatic chronic active hepatitis.
Genetic association between obstructive bronchitis and enzymes of oxidative stress
Authors: Mario Bauer, Carolin Gräbsch, Uwe Schlink, Norman Klopp, Thomas Illig, Ursula Krämer, Andrea von Berg, Beate Schaaf, Michael Borte, Joachim Heinrich, Olf Herbarth, Irina Lehmann, Stefan Röder
Journal: Metabolism (2012)
Increase in Physical Activity Energy Expenditure Is Associated With Reduced Metabolic Risk Independent of Change in Fatness and Fitness
Authors: Ulf Ekelund, Paul W. Franks, Stephen Sharp, Søren Brage, Nicholas J. Wareham
Journal: Diabetes Care (2007)

OBJECTIVE—We sought to examine whether change in physical activity energy expenditure (PAEE) is associated with change in metabolic risk factors and whether this association is independent of change in fat mass and aerobic fitness. RESEARCH DESIGN AND METHODS—In a population-based sample of 176 men and 217 women followed prospectively for 5.6 years, we measured PAEE by individually calibrated heart rate monitoring, aerobic fitness, total body fat (fat mass), and metabolic risk factors (blood pressure, fasting triglycerides, HDL cholesterol, insulin, and 2-h glucose) at baseline and follow-up. RESULTS—A 100 J · kg fat-free mass (FFM)−1 · min−1 increase in PAEE from baseline to follow-up reduced triglycerides by 3.5% (95% CI 0.03–5.7) in men and 3.2% (0.02–5.4) in women, fasting insulin by 5.3% (1.0–7.5) in men and women, and 2-h glucose by 3.2% (0.3–5.3) in men and 3.1% (0.3–5.2) in women, after adjustment for sex, age, smoking status, aerobic fitness, baseline phenotype, and change in fat mass. In general, the magnitudes of association for change in fat mass with metabolic risk factors were two to three times stronger than for PAEE. CONCLUSIONS—Increasing levels of physical activity may protect against metabolic disease even in the absence of improved aerobic fitness and reduced body fatness. Therefore, the combination of increasing levels of physical activity and avoidance of gain in fat mass is likely to be the most successful approach for preventing cardiovascular and metabolic disease.
Routine Use of the Confusion Assessment Method for the Intensive Care Unit
Authors: Maarten M. van Eijk, Mark van den Boogaard, Rob J. van Marum, Paul Benner, Piet Eikelenboom, Marina L. Honing, Ben van der Hoven, Janneke Horn, Gerbrand J. Izaks, Annette Kalf, Attila Karakus, Ine A. Klijn, Michael A. Kuiper, Frank-Erik de Leeuw, Tjarda de Man, Roos C. van der Mast, Robert-Jan Osse, Sophia E. de Rooij, Peter E. Spronk, Peter H. van der Voort, Willem A. van Gool, Arjen J. Slooter
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Delirium is often unrecognized in ICU patients and associated with poor outcome. Screening for ICU delirium is recommended by several medical organizations to improve early diagnosis and treatment. The Confusion Assessment Method for the ICU (CAM-ICU) has high sensitivity and specificity for delirium when administered by research nurses. However, test characteristics of the CAM-ICU as performed in routine practice are unclear.To investigate the diagnostic value of the CAM-ICU in daily practice.Teams of three delirium experts including psychiatrists, geriatricians, and neurologists visited 10 ICUs twice. Based on cognitive examination, inspection of medical files, and Diagnostic and Statistic Manual of Mental Disorders, 4th edition, Text Revision criteria for delirium, the expert teams classified patients as awake and not delirious, delirious, or comatose. This served as a gold standard to which the CAM-ICU as performed by the bedside ICU-nurses was compared. Assessors were unaware of each other's conclusions.Fifteen delirium experts assessed 282 patients of whom 101 (36%) were comatose and excluded. In the remaining 181 (64%) patients, the CAM-ICU had a sensitivity of 47% (95% confidence interval [CI], 35%-58%); specificity of 98% (95% CI, 93%-100%); positive predictive value of 95% (95% CI, 80%-99%); and negative predictive value of 72% (95% CI, 64%-79%). The positive likelihood ratio was 24.7 (95% CI, 6.1-100) and the negative likelihood ratio was 0.5 (95% CI, 0.4-0.8).Specificity of the CAM-ICU as performed in routine practice seems to be high but sensitivity is low. This hampers early detection of delirium by the CAM-ICU.
BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients
Authors: Anne Petrij-Bosch, Tamara Peelen, Margreethe van Vliet, Ronald van Eijk, Renske Olmer, Marion Drüsedau, Frans B.L. Hogervorst, Sandra Hageman, Petronella J.W. Arts, Marjolijn J.L. Ligtenberg, Hanne Meijers-Heijboer, Jan G.M. Klijn, Hans R.A. Vasen, Cees J. Cornelisse, Laura J. van't Veer, Egbert Bakker, Gert-Jan B. van Ommen, Peter Devilee
Journal: Nature Genetics (1997)
β-Arrestins Regulate Atherosclerosis and Neointimal Hyperplasia by Controlling Smooth Muscle Cell Proliferation and Migration
Authors: Jihee Kim, Lisheng Zhang, Karsten Peppel, Jiao-Hui Wu, David A. Zidar, Leigh Brian, Scott M. DeWire, Sabrina T. Exum, Robert J. Lefkowitz, Neil J. Freedman
Journal: Circulation Research (2008)

Atherosclerosis and arterial injury-induced neointimal hyperplasia involve medial smooth muscle cell (SMC) proliferation and migration into the arterial intima. Because many 7-transmembrane and growth factor receptors promote atherosclerosis, we hypothesized that the multifunctional adaptor proteins beta-arrestin1 and -2 might regulate this pathological process. Deficiency of beta-arrestin2 in ldlr(-/-) mice reduced aortic atherosclerosis by 40% and decreased the prevalence of atheroma SMCs by 35%, suggesting that beta-arrestin2 promotes atherosclerosis through effects on SMCs. To test this potential atherogenic mechanism more specifically, we performed carotid endothelial denudation in congenic wild-type, beta-arrestin1(-/-), and beta-arrestin2(-/-) mice. Neointimal hyperplasia was enhanced in beta-arrestin1(-/-) mice, and diminished in beta-arrestin2(-/-) mice. Neointimal cells expressed SMC markers and did not derive from bone marrow progenitors, as demonstrated by bone marrow transplantation with green fluorescent protein-transgenic cells. Moreover, the reduction in neointimal hyperplasia seen in beta-arrestin2(-/-) mice was not altered by transplantation with either wild-type or beta-arrestin2(-/-) bone marrow cells. After carotid injury, medial SMC extracellular signal-regulated kinase activation and proliferation were increased in beta-arrestin1(-/-) and decreased in beta-arrestin2(-/-) mice. Concordantly, thymidine incorporation and extracellular signal-regulated kinase activation and migration evoked by 7-transmembrane receptors were greater than wild type in beta-arrestin1(-/-) SMCs and less in beta-arrestin2(-/-) SMCs. Proliferation was less than wild type in beta-arrestin2(-/-) SMCs but not in beta-arrestin2(-/-) endothelial cells. We conclude that beta-arrestin2 aggravates atherosclerosis through mechanisms involving SMC proliferation and migration and that these SMC activities are regulated reciprocally by beta-arrestin2 and beta-arrestin1. These findings identify inhibition of beta-arrestin2 as a novel therapeutic strategy for combating atherosclerosis and arterial restenosis after angioplasty.
Smoking and overweight determine the likelihood of developing rheumatoid arthritis
Authors: Maria J H de Hair, Robert B M Landewé, Marleen G H van de Sande, Dirkjan van Schaardenburg, Lisa G M van Baarsen, Danielle M Gerlag, Paul P Tak
Journal: Annals of the Rheumatic Diseases (2012)

Rheumatoid arthritis (RA) is a prototypic chronic inflammatory disease with a debilitating course if untreated. A genetic predisposition for RA is known, and its occurrence is associated with the presence of autoantibodies in the serum and with environmental factors. It is unknown if smoking and overweight are contributory factors for developing RA in individuals with RA-specific autoantibodies in the serum.Fifty-five individuals at risk for developing RA, based on the presence of RA-specific autoantibodies in the serum, who never had any evidence of arthritis upon physical examination, were followed over time. Smoking was assessed as being never or ever smoker and body mass index as <25 (normal) or ≥25 kg/m² (overweight). Clinical endpoint was the occurrence of arthritis. Proportional hazard regression analysis was performed to investigate the potential of (combinations of) variables in predicting the onset of arthritis over time.After a median follow up time of 13 (IQR 6-27) months, 15 individuals (27%) developed arthritis. Smoking was associated with the development of arthritis (HR (95% CI): 9.6 (1.3 to 73.0); p=0.029). Overweight was, independently of smoking, associated with arthritis (HR (95% CI): 5.6 (1.3 to 25.0); p=0.023). The overall arthritis risk of 28% after a median of 27 months follow up increased to 60% in individuals with a smoking history combined with overweight.This is the first prospective study showing that smoking and overweight increase the risk of development of arthritis in a cohort of autoantibody-positive individuals at risk for developing RA. These results show the importance of life style factors in development of RA and should be critically evaluated in future clinical research aimed at disease prevention.
Do big athletes have big hearts? Impact of extreme anthropometry upon cardiac hypertrophy in professional male athletes
Authors: Nathan R Riding, Othman Salah, Sanjay Sharma, François Carré, Rory O'Hanlon, Keith P George, Bruce Hamilton, Hakim Chalabi, Gregory P Whyte, Mathew G Wilson
Journal: British Journal of Sports Medicine (2012)

Aim Differentiating physiological cardiac hypertrophy from pathology is challenging when the athlete presents with extreme anthropometry. While upper normal limits exist for maximal left ventricular (LV) wall thickness (14 mm) and LV internal diameter in diastole (LVIDd, 65 mm), it is unknown if these limits are applicable to athletes with a body surface area (BSA) &gt;2.3 m 2 . Purpose To investigate cardiac structure in professional male athletes with a BSA&gt;2.3 m 2 , and to assess the validity of established upper normal limits for physiological cardiac hypertrophy. Methods 836 asymptomatic athletes without a family history of sudden death underwent ECG and echocardiographic screening. Athletes were grouped according to BSA (Group 1, BSA&gt;2.3 m 2 , n=100; Group 2, 2–2.29 m 2 , n=244; Group 3, &lt;1.99 m 2 , n=492). Results There was strong linear relationship between BSA and LV dimensions; yet no athlete with a normal ECG presented a maximal wall thickness and LVIDd greater than 13 and 65 mm, respectively. In Group 3 athletes, Black African ethnicity was associated with larger cardiac dimensions than either Caucasian or West Asian ethnicity. Three athletes were diagnosed with a cardiomyopathy (0.4% prevalence); with two athletes presenting a maximal wall thickness &gt;13 mm, but in combination with an abnormal ECG suspicious of an inherited cardiac disease. Conclusion Regardless of extreme anthropometry, established upper limits for physiological cardiac hypertrophy of 14 mm for maximal wall thickness and 65 mm for LVIDd are clinically appropriate for all athletes. However, the abnormal ECG is key to diagnosis and guides follow-up, particularly when cardiac dimensions are within accepted limits.
Transcriptional Regulation of Human <i>Protease-Activated Receptor 1</i>: A Role for the Early Growth Response-1 Protein in Prostate Cancer
Authors: Zaidoun Salah, Myriam Maoz, Gallina Pizov, Rachel Bar-Shavit
Journal: Cancer Research (2007)

Abstract Transcriptional regulation plays a central role in the molecular pathways underlying preferential cancer growth and metastasis. In the present study, we investigated the regulation of human protease-activated receptor 1 (hPar1) gene overexpression in the malignant androgen hormone-resistant phase. We found increased hPar1 RNA chain elongation and no change in message stability in cells with high levels of PAR1 expression, indicating that increased transcription is largely responsible for the overexpression of hPar1 in prostate tumor progression. Enforced expression of early growth response-1 (Egr-1) plasmid markedly enhanced luciferase activity driven by the hPar1 promoter. The neuroendocrine peptide bombesin significantly induced hPar1 expression and increased the ability of the cells to invade Matrigel, an effect abolished by expression of hPar1 small interfering RNA, showing the importance of hPAR1 in invasion. Bombesin also markedly enhanced Egr-1 binding to the hPar1 promoter in vivo and in vitro. These data suggest that bombesin enhances Egr-1 expression leading to increased hPar1 transcription, thereby increasing PAR1 expression and function. Immunohistostaining of prostate tissue biopsy specimens revealed a direct correlation between the degree of prostate cancer malignancy, PAR1 expression, and EGR-1 expression. Altogether, we show that transcriptional regulation of hPar1 in the aggressive hormone-resistant prostate cancer stage is controlled in part by the transcription factor Egr-1 and may play a central role in invasiveness, an important indicator of malignancy. [Cancer Res 2007;67(20):9835–43]