tbuckley/cabot-search huggingface dataset:
Short telomere length, lung function and chronic obstructive pulmonary disease in 46 396 individuals
Authors: Line Rode, Stig E Bojesen, Maren Weischer, Jørgen Vestbo, Børge G Nordestgaard
Journal: Thorax (2012)

<h3>Background</h3> A previous case–control study of 100 individuals found that short telomere length was associated with a 28-fold increased risk of chronic obstructive pulmonary disease (COPD). <h3>Objectives</h3> To test the hypothesis that short telomere length is associated with reduced lung function and an increased risk of COPD. <h3>Methods</h3> Observational study of 46 396 individuals from the Danish general population. <h3>Measurements</h3> Leucocyte telomere length and spirometry were measured. COPD was defined using either fixed forced expiratory volume in 1 s (FEV<sub>1</sub>)/forced vital capacity (FVC) ratio &lt;0.70 as suggested by the Global initiative for chronic Obstructive Lung Disease (GOLD) or FEV<sub>1</sub>/FVC below the lower limit of normal (LLN). <h3>Results</h3> Telomere length decreased significantly with increasing age (p&lt;10<sup>−300</sup>). FEV<sub>1</sub>, FVC and FEV<sub>1</sub>/FVC decreased with decreasing telomere length quartiles (p trend: 5×10<sup>−51</sup>, 5×10<sup>−35</sup> and 6×10<sup>−137</sup>, respectively), but the associations attenuated after age and multivariable adjustment. The risk of COPD increased with decreasing telomere length quartile (p trend: p=7×10<sup>−92</sup> for GOLD; p=8×10<sup>−44</sup> for FEV<sub>1</sub>/FVC below LLN), but associations also attenuated after adjustment. Unadjusted and multivariable adjusted OR for shortest versus longest telomere length quartiles were 2.06 (95% CI 1.91 to 2.22) and 1.15 (95% CI 1.06 to 1.25) for GOLD and 1.73 (95% CI 1.60 to 1.88) and 1.19 (95% CI 1.09 to 1.30) for FEV<sub>1</sub>/FVC below LLN, respectively. Per 1000 base pairs decrease in telomere length, the multivariable adjusted OR was 1.07 (95% CI 1.03 to 1.10) for GOLD and 1.07 (95% CI 1.03 to 1.11) for FEV<sub>1</sub>/FVC below LLN. <h3>Conclusions</h3> Short telomere length is associated with decreased lung function and with increased risk of COPD, but the associations are markedly attenuated after adjustment. Our data support a modest correlation between telomere length and the lung function indices examined.
Lateral gene transfer and parallel evolution in the history of glutathione biosynthesis genes
Authors: Shelley D Copley, Jasvinder K Dhillon
Journal: Genome biology (2002)

Glutathione is found primarily in eukaryotes and in Gram-negative bacteria. It has been proposed that eukaryotes acquired the genes for glutathione biosynthesis from the alpha-proteobacterial progenitor of mitochondria. To evaluate this, we have used bioinformatics to analyze sequences of the biosynthetic enzymes γ-glutamylcysteine ligase and glutathione synthetase. γ-Glutamylcysteine ligase sequences fall into three groups: sequences primarily from gamma-proteobacteria; sequences from non-plant eukaryotes; and sequences primarily from alpha-proteobacteria and plants. Although pairwise sequence identities between groups are insignificant, conserved sequence motifs are found, suggesting that the proteins are distantly related. The data suggest numerous examples of lateral gene transfer, including a transfer from an alpha-proteobacterium to a plant. Glutathione synthetase sequences fall into two distinct groups: bacterial and eukaryotic. Proteins in both groups have a common structural fold, but the sequences are so divergent that it is uncertain whether these proteins are homologous or arose by convergent evolution. The evolutionary history of the glutathione biosynthesis genes is more complex than anticipated. Our analysis suggests that the two genes in the pathway were acquired independently. The gene for γ-glutamylcysteine ligase most probably arose in cyanobacteria and was transferred to other bacteria, eukaryotes and at least one archaeon, although other scenarios cannot be ruled out. Because of high divergence in the sequences, the data neither support nor refute the hypothesis that the eukaryotic gene comes from a mitochondrial progenitor. After acquiring γ-glutamylcysteine ligase, eukaryotes and most bacteria apparently recruited a protein with the ATP-grasp superfamily structural fold to catalyze synthesis of glutathione from γ-glutamylcysteine and glycine. The eukaryotic glutathione synthetase did not evolve directly from the bacterial glutathione synthetase.
Clinical spectral characterisation of colonic mucosal lesions using autofluorescence and δ aminolevulinic acid sensitisation
Authors: C Eker, S Montán, E Jaramillo, K Koizumi, C Rubio, S Andersson-Engels, K Svanberg, S Svanberg, P Slezak
Journal: Gut (1999)

BACKGROUND AND AIMS Laser induced fluorescence (LIF) from colonic mucosa was measured in vivo with and without δ aminolevulinic acid (ALA) in an attempt to differentiate between neoplasia and non-neoplasia in real time during colonoscopy. METHODS Spectra from 32 adenomas, 68 normal sites, and 14 hyperplastic polyps in 41 patients were obtained with a point monitoring system. Twenty one of the patients had been given a low dose of ALA as a photosensitiser before the examination. Light of 337, 405, or 436 nm wavelength was used as excitation. Stepwise multivariate linear regression analysis was performed. RESULTS With 337 nm excitation, 100% sensitivity and 96% specificity was obtained between normal mucosa and adenomas. Seventy seven per cent of the hyperplastic polyps were classified as non-neoplastic. When exciting with 405 and 436 nm, the possibility of distinguishing different types of tissue was considerably better in the ALA patients than in the non-ALA patients. CONCLUSIONS The in vivo point measurements imply that a good discrimination between normal tissue and adenomatous polyps can be obtained using the LIF technique. Excitation at 337 nm and at 405 nm or 436 nm using ALA gives good results. LIF also shows potential for distinguishing adenomatous from hyperplastic polyps. The number of detection wavelengths could be reduced if chosen properly.
The Role of SATB1 in Breast Cancer Pathogenesis
Authors: Elizabeth Iorns, H. James Hnatyszyn, Pearl Seo, Jennifer Clarke, Toby Ward, Marc Lippman
Journal: JNCI Journal of the National Cancer Institute (2010)

SATB1 has been previously proposed as a key protein that controls the development and progression of breast cancer. We explored the potential of the SATB1 protein as a therapeutic target and prognostic marker for human breast cancer.We used aggressive (MDA-MB-231 and BT549) and nonaggressive (SKBR3 and MCF7) breast cancer cell lines to investigate the potential of SATB1 as a therapeutic target. SATB1 mRNA expression was silenced in aggressive cells by use of short hairpin RNAs against SATB1. SATB1 was overexpressed in nonaggressive cells by use of SATB1 expression vectors. We assessed the effect of modifying SATB1 expression on the transformed phenotype by examining anchorage-independent cell proliferation, acinar morphology on matrigel, and migration by wound healing in cultured cells. We examined tumor formation and metastasis, respectively, by use of orthotopic mammary fat pad and tail vein xenograft mouse models (mice were used in groups of six, and in total, 96 mice were used). SATB1 mRNA expression was compared with outcome for patients with primary breast cancer from six previous microarray studies that included a total of 1170 patients. All statistical tests were two-sided.The transformed phenotype was not suppressed by SATB1 silencing in aggressive cells and was not enhanced by ectopic expression of SATB1 in nonaggressive cells. Modifying SATB1 expression did not alter anchorage-independent cell proliferation, invasive acinar morphology, or cell migration in cultured cells and did not affect tumor formation or metastasis in xenograft mouse models. In addition, SATB1 expression was not associated with decreased overall survival of patients with primary breast cancer in six previous independent microarray studies (overall odds ratio = 0.80, 95% confidence interval = 0.62 to 1.03, P = .10).In contrast to previous studies, we found that SATB1 expression did not promote breast cancer progression and was not associated with breast cancer outcome.
Tumor Promotion by Dietary Fat in Azoxymethane-Induced Colon Carcinogenesis in Female F344 Rats: Influence of Amount and Source of Dietary Fat&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: B S Reddy, Y Maeura
Journal: JNCI Journal of the National Cancer Institute (1984)

The promoting effect of dietary corn oil (CO), safflower oil (SO), olive oil (OO), coconut oil (CC), and medium-chain triglycerides (MCT) on azoxymethane (AOM)-induced colon tumors was studied in female F344 rats. The animals were fed low-fat diets containing 5% CO, 5% SO, or 5% OO 2 weeks before, during, and 1 week after sc injection of 20 mg AOM/kg body weight. One week after the AOM treatment, groups of animals were transferred to high-fat diets containing 23.52% CO, 23.52% SO, 23.52% OO, and 23.52% CC, or 5.88% CO + 17.64% MCT; the remaining animals were continued on 5% fat diets. All animals were fed these diets until the termination of the experiment. Body weights and intakes of calories, protein, and micronutrients were comparable among the various dietary groups. The incidence of colon tumors was increased in rats fed diets containing high-CO and high-SO compared to those fed low-CO and low-SO diets, whereas the diets containing high OO, CC, or MCT had no promoting effect on colon tumor incidence. There was a significant increase in the excretion of fecal deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid in animals fed the high-CO and high-SO diets and no difference in these secondary bile acids excretion in animals fed the high-OO and high-CC diets compared to those animals fed their respective 5% fat diets. This study thus indicates that not only the amount of dietary fat but also the fatty acid composition (type) of fat are important factors in the determination of the promoting effect in colon carcinogenesis.
Review: In rheumatoid arthritis, adding rituximab to methotrexate improves clinical outcomes
Authors: Ami Schattner
Journal: Annals of Internal Medicine (2015)

ACP Journal Club16 June 2015Review: In rheumatoid arthritis, adding rituximab to methotrexate improves clinical outcomesAmi Schattner, MDAmi Schattner, MDHebrew University Hadassah, Jerusalem, Israel (A.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2015-162-12-009 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationLopez-Olivo MA, Amezaga Urruela M, McGahan L, Pollono EN, Suarez-Almazor ME. Rituximab for rheumatoid arthritis. Cochrane Database Syst Rev. 2015;1:CD007356. https://pubmed.ncbi.nlm.nih.gov/25603545Clinical Impact RatingsGIM/FP/GP: Allerg & Immunol: Rheumatology: References1. Listing J, Kekow J, Manger B, et al. Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNFα inhibitors and rituximab. Ann Rheum Dis. 2015;74:415-21. [PMID: 24291654] Google Scholar2. Finckh A, Ciurea A, Brulhart L, et al; Physicians of the Swiss Clinical Quality Management Program for Rheumatoid Arthritis. B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum. 2007;56:1417-23. [PMID: 17469098] Google Scholar Author, Article, and Disclosure InformationAuthors: Ami Schattner, MDAffiliations: Hebrew University Hadassah, Jerusalem, Israel (A.S.)This article was published at Annals.org on 2 June 2015. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byCancer chemotherapeutics in rheumatoid arthritis: A convoluted connection 16 June 2015Volume 162, Issue 12Page: JC9KeywordsBiologicsClinical trial reportingDisease modifying antirheumatic drugsMethotrexatePhysical functioningQuality of lifeRheumatoid arthritisRheumatologySafetySerious adverse events ePublished: 16 June 2015 Issue Published: 16 June 2015 Copyright & PermissionsCopyright © 2015 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Hypoperfusion of the myocardium relative to myocardial metabolism during delayed coronary constriction
Authors: A. H Huang, B. D Nearing, R. L Verrier
Journal: Cardiovascular Research (1993)

Objective: The aim was to test the hypothesis that the myocardium becomes hypoperfused, relative to its metabolic demands, during the delayed coronary constriction which is observed following termination of a period of sympathetic stimulation. Methods: This was tested by beat by beat analysis of the ratio of coronary blood flow to the product of heart rate and systolic blood pressure (HR×SBP), an index of myocardial metabolism, in acutely instrumented open chest canine preparations, before, during, and after direct electrical stimulation of the left stellate ganglion. Results: Myocardial metabolism increased in response to stellate stimulation, as evidenced by increases in heart rate, aortic blood pressure, and HR×SBP. These were accompanied by increased blood flow and decreased vascular resistance in the left anterior descending coronary artery. Delayed coronary constriction, defined as the period with the lowest coronary blood flow observed after the end of the stimulation, occurred 1 to 3 min after stimulation was terminated and was characterised by recovery of heart rate, blood pressure, HR×SBP, and coronary blood flow toward control levels, while coronary vascular resistance overshot to above control levels. The ratio of coronary blood flow to HR×SBP fell progressively in the poststimulation period to significantly less (mean 0.715, range of ± 1 SEM 0.638 to 0.800, p<0.05) than control (1.0, by definition) in experiments performed with partial prestenosis of the left anterior descending coronary artery. In a selected subgroup of observations with a mean reduction in coronary blood flow during delayed coronary constriction comparable to that reported previously, the flow/metabolism ratio was even lower (mean 0.239, range of ± 1 SEM 0.202 to 0.284). Conclusions: The phenomenon of delayed coronary constriction clearly involves a mismatch between myocardial supply and demand: coronary blood flow becomes inappropriately low for the prevailing level of myocardial metabolism. Cardiovascular Research 1993;27:435-441
Tetrahydrobiopterin and eNOS dimer/monomer ratio?a clue to eNOS uncoupling in diabetes?
Authors: J BAUERSACHS, A SCHAFER
Journal: Cardiovascular Research (2005)

See article by Cai et al.  [14]  (pages 823–831) in this issue. 

Nitric oxide (NO) generated by the endothelial NO synthase (eNOS) critically determines vascular tone as well as vascular wall homeostasis [1]. Reduced NO bioavailability, which is associated with an increase in the formation of reactive oxygen species within the vascular wall, is the key determinant of endothelial dysfunction. The paradoxical finding of a concomitant increase in eNOS expression and reduced endothelium-dependent vasodilatation/relaxation [2–4] has drawn attention to the fact that eNOS itself in pathological states may be the source of superoxide anions, a so-called “eNOS uncoupling” (for review, see [5]). eNOS uncoupling has been linked to a reduced tetrahydrobiopterin (BH4) availability, and supplementation of BH4 is generally able to restore eNOS-mediated NO formation and endothelial function in hypertension, hypercholesterolemia … 

*Corresponding author. Medizinische Universitatsklinik, Josef-Schneider-Str. 2, D-97080 Wurzburg, Germany. Tel.: +49 931 201 1; fax: +49 931 201 36302. Email address: j.bauersachs{at}medizin.uni-wuerzburg.de
Attitudes Toward Psychiatry as a Prospective Career Among Students Entering Medical School
Authors: David Feifel, Christine Yu Moutier, Neal R. Swerdlow
Journal: American Journal of Psychiatry (1999)

The number of U.S. medical graduates choosing careers in psychiatry is in decline. In order to determine whether this disinclination toward psychiatry occurs before versus during medical school, this study surveyed medical students at the start of their freshman year.Within the first 2 weeks of medical training, 223 freshman medical students from three Southwestern medical schools were surveyed with a questionnaire designed to assess their perceptions of careers in various specialties.Responses suggest that new medical students most strongly value aspects of doctoring that seem to comport well with the actual practice of psychiatry: desire for interpersonal contact, helping patients, attractive lifestyle, and challenging work. However, these students begin their medical training viewing a career in psychiatry as distinctly and consistently less attractive than other specialties surveyed. More than one-quarter of the new medical students had already definitively ruled out a career in psychiatry. New medical students rated psychiatry significantly lower than each of the other specialties in regard to the degree to which it was a satisfying job, financially rewarding, enjoyable work, prestigious, helpful to patients, dealing with an interesting subject matter, intellectually challenging, drawing on all aspects of medical training, based on a reliable scientific foundation, expected to have a bright and interesting future, and a rapidly advancing field of understanding and treatment.Contrasting these results with previous studies suggests that an erosion has occurred over the past two decades in the attitudes that new medical students hold toward psychiatry. The authors suggest that some of the negative attitudes are based on objectifiably false beliefs that should be actively targeted for remediation within the medical school curriculum.
CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice.
Authors: S Cardell, S Tangri, S Chan, M Kronenberg, C Benoist, D Mathis
Journal: The Journal of Experimental Medicine (1995)

Rather unexpectedly, major histocompatibility complex class II-deficient mice have a significant population of peripheral CD4+ T lymphocytes. We have investigated these cells at the population and clonal levels. CD4+ T lymphocytes from class II-deficient animals are thymically derived, appear early in ontogeny, exhibit the phenotype of resting memory cells, are potentially functional by several criteria, and have a diverse T cell receptor repertoire. They do not include substantially elevated numbers of NK1.1+ cells. Hybridomas derived after polyclonal stimulation of the CD4+ lymphocytes from class II-deficient animals include a subset with an unusual reactivity pattern, responding to splenocytes from many mouse strains including the strain of origin. Most members of this subset recognize the major histocompatibility complex class Ib molecule CD1; their heterogeneous reactivities and T cell receptor usage further suggest the involvement of peptides and/or highly variable posttranslational modifications.
A quantitative estimate of melanoma mortality from ultraviolet A sunbed use in the U.K.
Authors: B.L. Diffey
Journal: British Journal of Dermatology (2003)

Concern has been expressed for many years in the medical and regulatory literature about the adverse health effects, especially melanoma, from the use of sunbeds for cosmetic tanning.To estimate the mortality from melanoma as a result of the use of sunbeds for cosmetic tanning in the U.K.A model using a Monte Carlo random sampling technique was developed to estimate human ultraviolet exposure to both sunlight and sunbeds, and these data were used to predict the contribution of sunbeds to melanoma mortality in the U.K.The mortality from melanoma due to sunbed use each year in the U.K. is estimated to be about 100 deaths.Sunbed use could be regarded as a relatively minor self-imposed detriment to public health compared with other voluntary 'pleasurable' activities associated with significant mortality, such as smoking and drinking alcohol. While cosmetic tanning using sunbeds should be discouraged, prohibition is not warranted especially as exposure to the sun, which cannot be regulated, remains the major contributory factor to the risk of melanoma.
DNA Diversity in Sex-Linked and Autosomal Genes of the Plant Species Silene latifolia and Silene dioica
Authors: Dmitry A. Filatov, Valerie Laporte, Clementine Vitte, Deborah Charlesworth
Journal: Molecular Biology and Evolution (2001)

The relatively recent origin of sex chromosomes in the plant genus Silene provides an opportunity to study the early stages of sex chromosome evolution and, potentially, to test between the different population genetic processes likely to operate in nonrecombining chromosomes such as Y chromosomes. We previously reported much lower nucleotide polymorphism in a Y-linked gene (SlY1) of the plant Silene latifolia than in the homologous X-linked gene (SlX1). Here, we report a more extensive study of nucleotide diversity in these sex-linked genes, including a larger S. latifolia sample and a sample from the closely related species Silene dioica, and we also study the diversity of an autosomal gene, CCLS37.1. We demonstrate that nucleotide diversity in the Y-linked genes of both S. latifolia and S. dioica is very low compared with that of the X-linked gene. However, the autosomal gene also has low DNA polymorphism, which may be due to a selective sweep. We use a single individual of the related hermaphrodite species Silene conica, as an outgroup to show that the low SlY1 diversity is not due to a lower mutation rate than that for the X-linked gene. We also investigate several other possibilities for the low SlY1 diversity, including differential gene flow between the two species for Y-linked, X-linked, and autosomal genes. The frequency spectrum of nucleotide polymorphism on the Y chromosome deviates significantly from that expected under a selective-sweep model. However, we detect population subdivision in both S. latifolia and S. dioica, so it is not simple to test for selective sweeps. We also discuss the possibility that Y-linked diversity is reduced due to highly variable male reproductive success, and we conclude that this explanation is unlikely.
Chaperone Hsp47 Drives Malignant Growth and Invasion by Modulating an ECM Gene Network
Authors: Jieqing Zhu, Gaofeng Xiong, Hanjiang Fu, B. Mark Evers, Binhua P. Zhou, Ren Xu
Journal: Cancer Research (2015)

The extracellular matrix (ECM) is a determining factor in the tumor microenvironment that restrains or promotes malignant growth. In this report, we show how the molecular chaperone protein Hsp47 functions as a nodal hub in regulating an ECM gene transcription network. A transcription network analysis showed that Hsp47 expression was activated during breast cancer development and progression. Hsp47 silencing reprogrammed human breast cancer cells to form growth-arrested and/or noninvasive structures in 3D cultures, and to limit tumor growth in xenograft assays by reducing deposition of collagen and fibronectin. Coexpression network analysis also showed that levels of microRNA(miR)-29b and -29c were inversely correlated with expression of Hsp47 and ECM network genes in human breast cancer tissues. We found that miR-29 repressed expression of Hsp47 along with multiple ECM network genes. Ectopic expression of miR-29b suppressed malignant phenotypes of breast cancer cells in 3D culture. Clinically, increased expression of Hsp47 and reduced levels of miR-29b and -29c were associated with poor survival outcomes in breast cancer patients. Our results show that Hsp47 is regulated by miR-29 during breast cancer development and progression, and that increased Hsp47 expression promotes cancer progression in part by enhancing deposition of ECM proteins.