tbuckley/cabot-search huggingface dataset:
Characterization of Common UGT1A8, UGT1A9, and UGT2B7 Variants with Different Capacities to Inactivate Mutagenic 4-Hydroxylated Metabolites of Estradiol and Estrone
Authors: Jean Thibaudeau, Johanie Lépine, Jelena Tojcic, Yannick Duguay, Georges Pelletier, Marie Plante, Jacques Brisson, Bernard Têtu, Simon Jacob, Louis Perusse, Alain Bélanger, Chantal Guillemette
Journal: Cancer Research (2006)

Abstract The oxidative metabolism of estrone (E1) and estradiol (E2) to form carcinogenic 4-hydroxy-catecholestrogens (4-OHCE) is associated with uterine and breast carcinogenesis. In this study, we conducted functional analyses of genetic variants in the UDP-glucuronosyltransferase UGT1A8, UGT1A9, and UGT2B7 enzymes primarily involved in the inactivation of 4-OHCEs. Compared with UGT2B7*2 (H268Y), UGT2B7*1 exhibited a 2-fold lower efficiency (intrinsic clearance) at conjugating 4-hydroxyestrone and 4-hydroxyestradiol at positions 3 and 4 caused by altered capacities (Vmax) and affinities (Km). The −79 G&amp;gt;A promoter variation, characterizing the UGT2B7*2g haplotype, leads to a 50% reduction of transcription (P &amp;lt; 0.001) in human endometrial carcinoma-1B cells. Furthermore, a &amp;gt;12-fold decreased intrinsic clearance of the *1 proteins was induced by selected amino acid substitutions in UGT1A8 (*3 C277Y) and UGT1A9 (*3 M33T). Frequencies of the low-activity alleles in Caucasians were 45% for UGT2B7*1, 5% for the −79A promoter variant, 1.2% for UGT1A8*3, and 2.2% for UGT1A9*3. Supporting a protective role in two organs sensitive to 4-OHCE–induced damages, the expression of UGT enzymes was shown by immunohistochemistry in normal breast and endometrial tissues and confirmed by Western blotting in a subset of samples. Altogether, findings suggest that specific polymorphisms in UGT genes may modulate the exposure to carcinogenic metabolites of E2 and potentially lead to an altered risk of breast and endometrial cancers in women carrying the variant alleles. (Cancer Res 2006; 66(1): 125-33)
Aberrant Expression of OX1 Receptors for Orexins in Colon Cancers and Liver Metastases: an Openable Gate to Apoptosis
Authors: Thierry Voisin, Aadil El Firar, Magali Fasseu, Christiane Rouyer-Fessard, Véronique Descatoire, Francine Walker, Valérie Paradis, Pierre Bedossa, Dominique Henin, Thérèse Lehy, Marc Laburthe
Journal: Cancer Research (2011)

Abstract Resistance to apoptosis is a recurrent theme in colon cancer. We have shown previously that the 7-transmembrane spanning receptor OX1R for orexins promotes robust apoptosis in the human colon cancer cell line HT29 through an entirely novel mechanism involving phosphorylation of tyrosine-based motifs in OX1R. Here, we investigated the status of OX1R in a large series of human colorectal tumors and hepatic metastases. All primary colorectal tumors regardless of their localization and Duke's stages and all hepatic metastases tested expressed OX1R mRNA and/or protein. In sharp contrast, adjacent normal colonocytes or hepatocytes as well as control normal tissues were negative. Next, we showed that nine human colon cancer cell lines established from primary tumors or metastases expressed OX1R mRNA and underwent important apoptosis on orexin-A challenge. Most interestingly, orexin-A also promoted robust apoptosis in cells that are resistant to the most commonly used drug in colon cancer chemotherapy, 5-fluorouracil. When human colon cancer cells were xenografted in nude mice, orexin-A administered at day 0 strongly slowed the tumor growth and even reversed the development of established tumors when administered 7 days after cell inoculation. Orexin-A also acts by promoting tumor apoptosis in vivo because caspase-3 is activated in tumors on orexin treatment of nude mice. These findings support that OX1R is an Achilles heel of colon cancers, even after metastasis or chemoresistance. They suggest that OX1R agonists might be novel candidates for colon cancer therapy. Cancer Res; 71(9); 3341–51. ©2011 AACR.
UK scientific adviser criticises UK planning for flu pandemic
Authors: A. O'Dowd
Journal: BMJ (2009)

The government’s chief scientific adviser is not convinced that the United Kingdom has the right plans in place to cope with avian flu.

John Beddington, who also chairs the Science Advisory Group in Emergencies, which reports directly to the ministerial committee that deals with the swine flu outbreak, chaired by the health secretary, Alan Johnson, said that he had doubts about how well prepared the government was to deal with an outbreak of H5N1 flu (avian flu).

But the current swine flu (A/H1N1) outbreak was rightly taking precedence, he said, and plans to deal with that were appropriate for now. 

Professor Beddington was speaking before the House of …
Microfluidics Expands the Zebrafish Potentials in Pharmaceutically Relevant Screening
Authors: Chia‐Yuan Chen, Chao‐Min Cheng
Journal: Advanced Healthcare Materials (2014)

The objective of this study is to enlarge the impact of microfluidics on the pharmaceutical industry by highlighting the reported scientific work on the synergistic relationship between zebrafish and microfluidics, and furthering that effort to shed light on how microfluidics can facilitate the use of zebrafish as a gene screening tool. Zebrafish is ranked the third most important animal model after rats and mice, according to a National Institutes of Health (NIH) announcement in 2003. It has become a staple for scientists to examine and subsequently begin to unravel the mystery of human diseases, and is increasingly used in toxicological studies for new drug development. The unique characteristics that this tiny fish possesses, including rapid growth rate, prodigious numbers of offspring, and eggs that develop outside the body, make it an invaluable genetic tool. Evidently, these advantages can be broadened with the addition of a properly designed microfluidic circuit. By means of the presented illustrations and demonstrated applications, the goal is to spark interest in the development of more novel microfluidic platform designs that can leverage the attributes of zebrafish and quickly come to commercial fruition.
Fluorescence optical imaging as a novel technique for the visualisation of inflammation in patients with systemic sclerosis with Raynaud’s phenomenon: a pilot study
Authors: Alexander Pfeil, Karl F Drummer, Peter Oelzner, Joachim Böttcher, Christian Jung, Gunter Wolf
Journal: Annals of the Rheumatic Diseases (2014)

Systemic sclerosis (SSc) is a connective tissue disease affecting various organs including the peripheral vessels and resulting in Raynaud`s phenomenon. For treatment of Raynaud's phenomenon, the vasodilator Prostaglandin I2 analogue iloprost is widely used. Fluorescence optical imaging (FOI) is an in vivo technique to visualise inflammation based on the accumulation of fluorescence optical contrast media (indocyanine green, ICG) which is proved in patients with rheumatoid arthritis.1 The aim of this prospective pilot-study was to visualise inflammation before and after treatment with iloprost using FOI in patients with SSc and associated Raynaud`s phenomenon (figure 1).



Figure 1 
(A) Normal fluorescence optical imaging of a healthy control. (B) Initial imaging of the enhancement of indocyanine green by fluorescence optical imaging as a marker of inflammatory activity in patients with systemic sclerosis (SSc) and associated Raynaud`s phenomenon before the application of iloprost (day 0). (C) …
The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium
Authors: Yuqing Huo, Christian Weber, S.B. Forlow, Markus Sperandio, Jayant Thatte, Matthias Mack, Steffen Jung, Dan R. Littman, Klaus Ley
Journal: Journal of Clinical Investigation (2001)

In a reconstituted flow chamber system, preincubation with chemokines can trigger the arrest of rolling monocytes, suggesting that this interaction could help recruit these cells to early atherosclerotic lesions. To date, however, the contribution of endothelium–derived chemokines found in these lesion to monocyte arrests has not been investigated. The endothelium of lesion-prone carotid arteries from apolipoprotein E–deficient (ApoE–/–) mice, but not control mice, presents the chemokines KC (mouse GRO-α) and JE (mouse monocyte chemoattractant protein-1 [MCP-1]). Arrest of a monocytic cell line or mouse blood monocytes perfused through carotid arteries of ApoE–/– mice was reduced by treating with either pertussis toxin, an antagonist of CXCR2, or an antibody to KC, but this process was insensitive to agents that blocked CCR-2 or JE. Conversely, monocyte accumulation more than doubled upon pre-perfusion of the carotid artery with KC but not with mouse MCP-1. Blockade of α4β1 integrin (VLA-4) or vascular cell adhesion molecule-1, but not CD18 or intercellular adhesion molecule-1, almost completely inhibited the arrest of monocytes. We conclude that when presented by early atherosclerotic lesions, KC but not murine MCP-1 triggers VLA-4–dependent monocyte recruitment.
Exercise and smoking habits among Swedish postmenopausal women.
Authors: J Frisk, J Brynhildsen, T Ivarsson, P Persson, M Hammar
Journal: British Journal of Sports Medicine (1997)

OBJECTIVE: To assess exercise habits and their relation to smoking habits and social and medical factors in postmenopausal women. METHODS: A cross-sectional study with a questionnaire to all 1324 55-56 year old women in Linköping, Sweden. RESULTS: Response rate was 85%. About a third of the women took part in some kind of quite strenuous exercise for at least one hour a week. After a quarter worked out once a week; fewer did swimming and jogging. One in four women smoked. Women who used hormone replacement therapy, who were not smoking and who had a physically light occupation more often took part in strenuous sports. Women who had been treated for malignancies or with back problems exercised to the same extent as women in the general population. CONCLUSION: About a third of the post-menopausal women exercised on a regular basis, if exercise involved in getting to and from work was not counted. Since regular physical exercise has many health benefits, more women should be encouraged to take part in regular physical exercise. Factors probably associated with level of education and general awareness of the importance of a healthy lifestyle positively influenced the likelihood of these women to be physically active on a regular basis. A previous malignant disease or current back problems did not prevent women from taking part in exercise on a regular basis.
Clinical presentation and outcome by age categories in acute heart failure: results from an international observational cohort
Authors: Antonio Teixeira, Jiri Parenica, Jin Joo Park, Shiro Ishihara, Khalid F. AlHabib, Said Laribi, Aldo Maggioni, Òscar Miró, Naoki Sato, Katsuya Kajimoto, Alain Cohen‐Solal, Enrique Fairman, Johan Lassus, Christian Mueller, William F. Peacock, James L. Januzzi, Dong‐Ju Choi, Patrick Plaisance, Jindrich Spinar, Alexandre Mebazaa, Etienne Gayat
Journal: European Journal of Heart Failure (2015)
A1C Variability as an Independent Risk Factor for Microalbuminuria in Young People With Type 1 Diabetes
Authors: M. Loredana Marcovecchio, R. Neil Dalton, Francesco Chiarelli, David B. Dunger
Journal: Diabetes Care (2011)

To assess the potential association between A1C variability (A1C-SD) and microalbuminuria in young people with type 1 diabetes.Serially collected samples for A1C measurement were available for 1,232 subjects with childhood-onset type 1 diabetes recruited to the Oxford Regional Prospective Study and the Nephropathy Family Study.The median (range) number of A1C assessments was 4 (2-16). Mean intrapersonal A1C was 9.5% and A1C-SD was 0.91. Mean A1C and A1C-SD values were higher in subjects with microalbuminuria (n = 227) than in those with normoalbuminuria (10.3 vs. 9.4%; 1.12 vs. 0.86, P < 0.001). In a Cox regression model, A1C-SD was independently associated with microalbuminuria (hazard ratio 1.31 [95% CI 1.01-1.35]).In the current study, A1C variability was an independent variable that added to the effect of A1C on the risk for microalbuminuria in youth with type 1 diabetes, a population highly vulnerable to vascular complications.
PGH synthase and lipoxygenase generate superoxide in the presence of NADH or NADPH.
Authors: R C Kukreja, H A Kontos, M L Hess, E F Ellis
Journal: Circulation Research (1986)

Purified PGH synthase when acting on arachidonic acid in the presence of reduced nicotinamide-adenine dinucleotide or reduced nicotinamide-adenine dinucleotide 3'-phosphate generated superoxide in burst-like fashion. In eight experiments using different batches of enzyme, the mean +/- SE rate of superoxide generation from 100 U of enzyme measured as the superoxide dismutase-inhibitable reduction of cytochrome c was 5.06 +/- 0.19 nmol/min in the first minute and 0.35 +/- 0.03 nmol/min subsequently. Optimum rates of superoxide were seen at concentrations of reduced nicotinamide-adenine dinucleotide in excess of 80 microM and reduced nicotinamide-adenine dinucleotide 3'-phosphate in excess of 100 microM. Using prostaglandin G2 or linoleic acid as substrate rather than arachidonate also resulted in superoxide generation. When prostaglandin H2 was used as substrate, no superoxide was generated. The rate of superoxide generation was markedly inhibited by cyclooxygenase inhibitors. Superoxide generation was also observed during the action of lipoxygenase on either linoleic or arachidonic acid in the presence of reduced nicotinamide-adenine dinucleotide or reduced nicotinamide-adenine dinucleotide 3'-phosphate but not in their absence. Indomethacin had no effect on superoxide generation from lipoxygenase. We conclude that PGH synthase and lipoxygenase produce superoxide via a side-chain reaction dependent on the presence of suitable reducing cosubstrate. This mechanism is analogous to that described for peroxidases in general.
SU5416 is a potent inhibitor of hepatocyte growth factor receptor (c-Met) and blocks HGF-induced invasiveness of human HepG2 hepatoma cells
Authors: Si Y. Wang, Bing Chen, Yi Q. Zhan, Wang X. Xu, Chang Y. Li, Ri F. Yang, Hong Zheng, Pei B. Yue, Steven H. Larsen, Hui B. Sun, Xiaoming Yang
Journal: Journal of Hepatology (2004)
Test a Clade in Phylogenetic Trees
Authors: Xiaofei Shi, Hong Gu, Chris Field
Journal: Molecular Biology and Evolution (2006)

We develop a new method for testing a portion of a tree (called a clade) based on multiple tests of many 4-taxon trees in this paper. This is particularly useful when the phylogenetic tree constructed by other methods have a clade that is difficult to explain from a biological point of view. The statement about the test of the clade can be made through the multiple P values from these individual tests. By controlling the familywise error rate or the false discovery rate (FDR), 4 different tree test methods are evaluated through simulation methods. It shows that the combination of the approximately unbiased (AU) test and the FDR-controlling procedure provides strong power along with reasonable type I error rate and less heavy computation.
Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis
Authors: Jamie M J Weaver, Caryn S Ross-Innes, Nicholas Shannon, Andy G Lynch, Tim Forshew, Mariagnese Barbera, Muhammed Murtaza, Chin-Ann J Ong, Pierre Lao-Sirieix, Mark J Dunning, Laura Smith, Mike L Smith, Charlotte L Anderson, Benilton Carvalho, Maria O'Donovan, Timothy J Underwood, Andrew P May, Nicola Grehan, Richard Hardwick, Jim Davies, Arusha Oloumi, Sam Aparicio, Carlos Caldas, Matthew D Eldridge, Paul A W Edwards, Nitzan Rosenfeld, Simon Tavaré, Rebecca C Fitzgerald
Journal: Nature Genetics (2014)
Prognostic score systems and community-acquired bacteraemic pneumococcal pneumonia
Authors: C. Spindler, Å. Örtqvist
Journal: European Respiratory Journal (2006)

The aim of this study was to evaluate the accuracy of three score systems: the pneumonia severity index (PSI); CURB-65 (confusion; urea &gt;7 mM; respiratory rate ≥30 breaths·min -1 ; blood pressure &lt;90 mmHg systolic or ≤60 mmHg diastolic; aged ≥65 yrs old); and modified American Thoracic Society rule for predicting intensive care unit (ICU) need and mortality due to bacteraemic pneumococcal pneumonia. All adult patients (n = 114) with invasive pneumococcal pneumonia at the Karolinska University Hospital, Sweden, 1999–2000, were included in the study. Severity scores were calculated and the independent prognostic importance of different variables was analysed by multiple regression analyses. PSI ≥IV, CURB-65 ≥2, and the presence of one major or more than one minor risk factor in mATS all had a high sensitivity, but somewhat lower specificity for predicting death and ICU need. The death rate was 12% (13 out of 114). Severity score and treatment in departments other than the Dept of Infectious Diseases were the only factors independently correlated to death. Patients treated in other departments more often had severe underlying illnesses and were more severely ill on admission. However, a significant difference in death rates remained after adjustment for severity between the two groups. In conclusion, all score systems were useful for predicting the need for intensive care unit treatment and death due to bacteremic pneumococcal pneumonia. The pneumonia severity index was the most sensitive, but CURB-65 was easier to use.
Fc receptor γ-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils
Authors: Shigeaki Hida, Sho Yamasaki, Yuzuru Sakamoto, Masaya Takamoto, Kazushige Obata, Toshiyuki Takai, Hajime Karasuyama, Kazuo Sugane, Takashi Saito, Shinsuke Taki
Journal: Nature Immunology (2008)
The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin
Authors: Alexander V. Birk, Shaoyi Liu, Yi Soong, William Mills, Pradeep Singh, J. David Warren, Surya V. Seshan, Joel D. Pardee, Hazel H. Szeto
Journal: Journal of the American Society of Nephrology (2013)

Ischemia causes AKI as a result of ATP depletion, and rapid recovery of ATP on reperfusion is important to minimize tissue damage. ATP recovery is often delayed, however, because ischemia destroys the mitochondrial cristae membranes required for mitochondrial ATP synthesis. The mitochondria-targeted compound SS-31 accelerates ATP recovery after ischemia and reduces AKI, but its mechanism of action remains unclear. Here, we used a polarity-sensitive fluorescent analog of SS-31 to demonstrate that SS-31 binds with high affinity to cardiolipin, an anionic phospholipid expressed on the inner mitochondrial membrane that is required for cristae formation. In addition, the SS-31/cardiolipin complex inhibited cytochrome c peroxidase activity, which catalyzes cardiolipin peroxidation and results in mitochondrial damage during ischemia, by protecting its heme iron. Pretreatment of rats with SS-31 protected cristae membranes during renal ischemia and prevented mitochondrial swelling. Prompt recovery of ATP on reperfusion led to rapid repair of ATP-dependent processes, such as restoration of the actin cytoskeleton and cell polarity. Rapid recovery of ATP also inhibited apoptosis, protected tubular barrier function, and mitigated renal dysfunction. In conclusion, SS-31, which is currently in clinical trials for ischemia-reperfusion injury, protects mitochondrial cristae by interacting with cardiolipin on the inner mitochondrial membrane.
In vitro growth rate of fibroblast-like synovial cells is reduced by methotrexate treatment
Authors: R J U Lories
Journal: Annals of the Rheumatic Diseases (2003)

<b>Background:</b> Fibroblast-like synovial cells (FLS) can be cultured and expanded in vitro in monolayer. Little is known about the growth characteristics of FLS derived from different patients. <b>Objective:</b> To study FLS cultures, with particular attention to differences in growth rate of FLS from patients with rheumatoid arthritis (RA) and from other arthritic patients. Additionally, to analyse the influence of methotrexate (MTX) treatment, patient age, and disease duration on FLS growth characteristics. <b>Materials and methods:</b> FLS were isolated from needle arthroscopy biopsy specimens. Twenty four patients (11 RA, 8 spondyloarthropathy, 1 osteoarthritis, and 4 undifferentiated arthritis) were studied. FLS population doubling time was determined between passage 2 and passage 5. Differences in population doubling time between RA and non-RA FLS and between FLS from patients receiving MTX and those not receiving this drug were analysed. In addition, possible correlations between FLS population doubling time and patient age or disease duration were examined. <b>Results:</b> In vitro monolayer FLS cultures from needle arthroscopy biopsy specimens showed linear growth characteristics. Cell growth rate was not correlated with type of disease. Cells from patients undergoing treatment with MTX showed a longer population doubling time than FLS from patients not receiving this drug (Mann-Whitney test, p&lt;0.05). No correlation was found with patient age or disease duration. <b>Conclusion:</b> The results suggest that FLS growth in monolayer is not dependent on the disease affecting the joint. MTX treatment, however, was more relevant in determining FLS growth rate.
The Quality of Periconception Medical Care in Women With Diabetes Needs Improvement
Authors: Shlomit Riskin-Mashiah, Ron Auslander, Ronit Almog
Journal: Diabetes Care (2013)

We evaluated the quality of periconception medical care in pregnant women with diabetes and assessed the influence of sociodemographic characteristics.The study was based on retrospective data collection from electronic database on cohort of Israeli women at Clalit Health Services (CHS) with pre-existing diabetes who gave birth in 2008-2011. It included data on A1C and other laboratory test results, prescription fillings, diet and ophthalmology consultations, and sociodemographics extracted from CHS computerized systems. The performance of each of nine recommended measures in the periconception period and a composite quality score was evaluated; the score ranged from 0-8. Multivariate logistic regression was used to examine independent sociodemographic predictors of low-quality overall scores.A total of 166 women gave birth to 180 infants; the performance of the different quality parameters ranged from 81% for A1C and kidney function tests to only 30% for dietary consultation and 41.1% for ophthalmology exam. Forty-nine percent of women had A1C <7.0% (53 mmol/mol). Only 45% took folic acid, whereas 13.9% continued the use of potentially teratogenic drugs in the first trimester. One-third of women were in the low-quality (0-3) overall score. In the multiple logistic regression analysis, the only significant variables to predict lower composite quality scores were multiparity odds ratio of 3.43 (95% CI 1.66-7.10; P = 0.001), Arabian ethnicity 3.76 (1.78-7.92; P = 0.001), and immigrant 3.73 (1.25-11.16; P = 0.018).The periconception medical care of diabetic women is suboptimal. More intensive and targeted care is needed in order to optimize periconception care of diabetic patients, especially in the high-risk subpopulations.