tbuckley/cabot-search huggingface dataset:
Association of a Serotonin Transporter Polymorphism (5-HTTLPR) With Depression, Perceived Stress, and Norepinephrine in Patients With Coronary Disease: The Heart and Soul Study
Authors: Christian Otte, Jeanne McCaffery, Sadia Ali, Mary A. Whooley
Journal: American Journal of Psychiatry (2007)

Objective: The short allele of a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to interact with stressful life events to predict depression in otherwise healthy individuals. Whether the short allele increases risk for depression associated with the stress of a chronic illness has not been established. Method: In a cross-sectional genetic association study, the authors examined the association of 5-HTTLPR with current depression (measured by the Computerized Diagnostic Interview Schedule), perceived stress (measured by the Perceived Stress Scale), and 24-hour urinary norepinephrine excretion in 557 outpatients with chronic coronary disease. Results: Among individuals carrying an s allele, 25% (97 of 383) had current depression, compared with 17% (29 of 174) of l/l homozygotes. The unadjusted odds ratio was 1.6, with a 95% confidence interval (CI) of 1.0–2.6; the age- and gender-adjusted odds ratio was also 1.6 (95% CI=1.0–2.5). Participants carrying an s allele had a higher mean score for perceived stress than l/l homozygotes (5.4 versus 4.7) and a higher rate of moderate or high perceived stress (adjusted odds ratio=1.6, 95% CI=1.1–2.3). Mean 24-hour norepinephrine excretion was higher in s allele carriers (55.6 versus 50.2 mg/day), who were more likely to have norepinephrine values in the highest quartile (adjusted odds ratio=1.7, 95% CI=1.0–3.0). Conclusions: Among patients with chronic illness, carriers of the s allele of 5-HTTLPR are more vulnerable to depression, perceived stress, and high norepinephrine secretion. These factors may contribute to worse cardiovascular outcomes in these patients.
A phase I dose escalation study of AT9283, a small molecule inhibitor of aurora kinases, in patients with advanced solid malignancies
Authors: H.-T. Arkenau, R. Plummer, L.R. Molife, D. Olmos, T.A. Yap, M. Squires, S. Lewis, V. Lock, M. Yule, J. Lyons, H. Calvert, I. Judson
Journal: Annals of Oncology (2011)
Prenatal Exposure to Fluoxetine Induces Fetal Pulmonary Hypertension in the Rat
Authors: Enrica Fornaro, Dongge Li, Jingyi Pan, Jaques Belik
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Fluoxetine is a selective serotonin reuptake inhibitor antidepressant widely used by pregnant women. Epidemiological data suggest that fluoxetine exposure prenatally increases the prevalence of persistent pulmonary hypertension syndrome of the newborn. The mechanism responsible for this effect is unclear and paradoxical, considering the current evidence of a pulmonary hypertension protective fluoxetine effect in adult rodents.To evaluate the fluoxetine effect on fetal rat pulmonary vascular smooth muscle mechanical properties and cell proliferation rate.Pregnant rats were treated with fluoxetine (10 mg/kg) from Day 11 through Day 21 of gestation.Fetuses were delivered by cesarean section. As compared with controls, fluoxetine exposure resulted in fetal pulmonary hypertension as evidenced by an increase in the weight ratio of the right ventricle to the left ventricle plus septum (P = 0.02) and by an increase in pulmonary arterial medial thickness (P < 0.01). Postnatal mortality was increased among experimental animals, and arterial oxygen saturation was 96 +/- 1% in 1-day-old control animals and significantly lower (P < 0.01) in fluoxetine-exposed pups (79 +/- 2%). In vitro, fluoxetine induced pulmonary arterial muscle contraction in fetal, but not adult, animals (P < 0.01) and reduced serotonin-induced contraction at both ages (P < 0.01). After in utero exposure to a low fluoxetine concentration the pulmonary arterial smooth muscle cell proliferation rate was significantly increased in fetal, but not adult, cells (P < 0.01).In contrast to the adult, fluoxetine exposure in utero induces pulmonary hypertension in the fetal rat as a result of a developmentally regulated increase in pulmonary vascular smooth muscle proliferation.
Blood mRNA biomarkers for detection of treatment response in acute pulmonary exacerbations of cystic fibrosis
Authors: J A Nick, L A Sanders, B Ickes, N J Briones, S M Caceres, K C Malcolm, S J Brayshaw, C S Chacon, C M Barboa, M C Jones, C St Clair, J L Taylor-Cousar, D P Nichols, S D Sagel, M Strand, M T Saavedra
Journal: Thorax (2013)

Acute pulmonary exacerbations accelerate pulmonary decline in cystic fibrosis (CF). There is a critical need for better predictors of treatment response.To test whether expression of a panel of leucocyte genes directly measured from whole blood predicts reductions in sputum bacterial density.A previously validated 10-gene peripheral blood mononuclear cell (PBMC) signature was prospectively tested in PBMC and whole blood leucocyte RNA isolated from adult subjects with CF at the beginning and end of treatment for an acute pulmonary exacerbation. Gene expression was simultaneously quantified from PBMCs and whole blood RNA using real-time PCR amplification. Test characteristics including sensitivity, specificity, positive and negative predictive values were calculated and receiver operating characteristic curves determined the best cut-off to diagnose a microbiological response. The findings were then validated in a smaller independent sample.Whole blood transcript measurements are more accurate than forced expiratory volume in 1 s (FEV(1)) or C reactive protein (CRP) alone in identifying reduction of airway infection. When added to FEV(1), the whole blood gene panel improved diagnostic accuracy from 64% to 82%. The specificity of the test to detect reduced infection was 88% and the positive predictive value for the presence of persistent infection was 86%. The area under the curve for detecting treatment response was 0.81. Six genes were the most significant predictors for identifying reduction in airway bacterial load beyond FEV(1) or CRP alone. The high specificity of the test was replicated in the validation cohort.The addition of blood leucocyte gene expression to FEV(1) and CRP enhances specificity in predicting reduced pulmonary infection and may bolster the assessment of CF treatment outcomes.
Natriuretic peptide measurements as part of the diagnostic work-up in pleural effusions: an emerging concept?
Authors: T. Mueller, M. Haltmayer
Journal: European Respiratory Journal (2006)

In the 1950s and 60s, the possible role of the heart in the control of renal excretion of salt and water, and thereby of the extra cellular fluid volume, as well as the presence of specific granules within atrial muscle cells was recognised 1,2. Nevertheless, little attention was paid to the possibility of the existence of an endocrine cardiac natriuretic hormone system until the landmark experiments in the late 1970s by de Bold et al. 3, which led to the discovery of atrial natriuretic peptide (A-type natriuretic peptide; ANP) having potent natriuretic, diuretic and vasodilatator actions.

This initiated intense research characterising a family of structurally similar but genetically distinct natriuretic peptides, including B-type natriuretic peptide (BNP, formerly named brain natriuretic peptide), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide and urodilatin. ANP and BNP are synthesised by cardiac myocytes (so-called cardiac natriuretic peptides). It is now generally accepted that their release into the blood is increased by factors that raise intra-cardiac pressure and volume overload 4. Unlike ANP, the primary source of BNP is considered to be the cardiac ventricles. Other natriuretic peptides, such as CNP and urodilatin, are not secreted by cardiomyocytes but by other tissues.

Cardiac natriuretic peptides are derived from pre-prohormones 4. In particular, BNP is derived from the precursor pre-proBNP, which contains 134 amino acids including a signal peptide of 26 amino acids. The prohormone containing 108 amino acids (proBNP), produced by cleavage of the signal peptide, is further split into BNP, which is considered to be the biologically active hormone, and an inactive amino terminal fragment (NT-proBNP). BNP and NT-proBNP are secreted on an equimolar basis, but their molar ratio in plasma is not 1:1 because BNP has a shorter plasma half-life than NT-proBNP.

As indicated, the natriuretic peptide hormones …
Compensatory role of Langerhans cells and langerin-positive dermal dendritic cells in the sensitization phase of murine contact hypersensitivity
Authors: Tetsuya Honda, Saeko Nakajima, Gyohei Egawa, Kouetsu Ogasawara, Bernard Malissen, Yoshiki Miyachi, Kenji Kabashima
Journal: Journal of Allergy and Clinical Immunology (2010)
Identification of RASAL1 as a Major Tumor Suppressor Gene in Thyroid Cancer
Authors: D. Liu, C. Yang, E. Bojdani, A. K. Murugan, M. Xing
Journal: JNCI Journal of the National Cancer Institute (2013)

RAS-coupled MAPK and PI3K pathways play a fundamental role in thyroid tumorigenesis, and classical genetic alterations upregulating these pathways are well characterized. We hypothesized that gene abnormality of negative modulators of these signaling pathways might be an important alternative genetic background for thyroid cancer.By examining gene expression patterns of negative modulators of RAS signaling, we attempted to identify potential tumor suppressor genes. We then analyzed the methylation and mutation patterns of the identified gene in 101 thyroid tumors and tested its functions in vitro and in vivo to establish the tumor suppressor role in thyroid cancer.Among 13 negative modulators of the RAS pathway screened, RASAL1, encoding a RAS GTPase-activating protein, was frequently hypermethylated in thyroid cancers, which was coupled to its silencing in thyroid cancer cells. We also, for the first time, identified the presence of RASAL1 mutations, with a prevalence of 4.88% (n = 2 of 41) in follicular thyroid cancer (FTC) and 16.67% (n = 5 of 30) in anaplastic thyroid cancer (ATC). RASAL1 displayed MAPK- and PI3K-suppressing and thyroid tumor-suppressing activities, which were all impaired by the mutations. Hypermethylation and mutations of RASAL1 were mutually exclusive and collectively found in zero of 20 benign thyroid tumors, 3.22% (n = 1 of 31) of papillary thyroid cancers, 31.70% (n = 13 of 41) of FTCs, and 33.33% (n = 10 of 30) of ATCs. A rate of 20.83% (n = 5 of 24) of tumors carrying RASAL1 mutation or methylation at high levels (>50%) vs 44.16% (n = 34 of 77) of tumors carrying no RASAL1 mutation or methylation at low levels (< 50%) harbored any of the classical mutations (two-sided P = .02, Fisher exact test) in RAS, BRAF, PTEN, and PIK3CA genes in the MAPK and PI3K pathways, revealing a largely mutually exclusive relationship.We identified RASAL1 as a major tumor suppressor gene that is frequently inactivated by hypermethylation and mutations, providing a new alternative genetic background for thyroid cancer, particularly FTC and ATC.
Association Between Smoking, Hematological Parameters, and Metabolic Syndrome in Japanese Men
Authors: Nobukazu Ishizaka, Yuko Ishizaka, Ei-Ichi Toda, Ryozo Nagai, Minoru Yamakado
Journal: Diabetes Care (2006)

Cigarette smoking increases the risk for metabolic syndrome (1), and it may also affect hematological parameters (2). Because certain hematological parameters may be associated with metabolic syndrome (3), we have investigated whether the mode of association between smoking and metabolic syndrome varies according to hematological parameters.

Among individuals who had undergone a general heath screening test between 1994 and 2003, 27,972 subjects (9,729 never smokers [52.8 ± 10.7 years], 7,242 former smokers [54.8 ± 9.9 years], and 11,001 current …
IMPAIRED TWIST RATE IN PATIENTS WITH SEVERE AORTIC STENOSIS DESPITE NORMAL EJECTION FRACTION IDENTIFIED BY THREE-DIMENSIONAL SPECKLE TRACKING ECHOCARDIOGRAPHY
Authors: Hamid Reza Salehi, Wajih Syed, Maryam Esmaeilzadeh, Lissa Sugeng, Natesa Pandian
Journal: Journal of the American College of Cardiology (2014)
Targeting von Hippel-Lindau Pathway in Renal Cell Carcinoma
Authors: Premal H. Patel, Rajendrakumar S.V. Chadalavada, R.S.K. Chaganti, Robert J. Motzer
Journal: Clinical Cancer Research (2006)

Abstract Inheritance of a defective copy of the von Hippel-Lindau (VHL) gene leads to the most common cause of inherited renal cell carcinoma (RCC). In addition, most patients with sporadic RCC have aberrant VHL. In the absence of VHL, hypoxia-inducible factor α accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. We review here the biology of RCC and how a combination of proximal and distal block of VHL/hypoxia-inducible factor α pathway by novel targeted agents, including sunitinib, sorafenib, bevacizumab, everolimus, and temsirolimus, has led to significant improvements in progression-free survival.
Long-term survival outcomes after definitive chemoradiation versus surgery in patients with resectable squamous carcinoma of the esophagus: results from a randomized controlled trial
Authors: A.Y.B. Teoh, P.W.Y. Chiu, W.K. Yeung, S.Y.W. Liu, S.K.H. Wong, E.K.W. Ng
Journal: Annals of Oncology (2012)
A Combined Analysis of the Cystic Fibrosis Transmembrane Conductance Regulator: Implications for Structure and Disease Models
Authors: Jian-Min Chen, Chris Cutler, Caroline Jacques, Gilles Bœuf, Erick Denamur, Guillaume Lecointre, Bernard Mercier, Gordon Cramb, Claude Férec
Journal: Molecular Biology and Evolution (2001)

Over the past decade, nearly 1,000 variants have been identified in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in classic and atypical cystic fibrosis (CF) patients worldwide, and an enormous wealth of information concerning the structure and function of the protein has also been accumulated. These data, if evaluated together in a sequence comparison of all currently available CFTR homologs, are likely to refine the global structure-function relationship of the protein, which will, in turn, facilitate interpretation of the identified mutations in the gene. Based on such a combined analysis, we had recently defined a "functional R domain" of the CFTR protein. First, presenting two full-length cDNA sequences (termed sCFTR-I and sCFTR-II) from the Atlantic salmon (Salmo salar) and an additional partial coding sequence from the eastern gray kangaroo (Macropus giganteus), this study went further to refine the boundaries of the two nucleotide-binding domains (NBDs) and the COOH-terminal tail (C-tail), wherein NBD1 was defined as going from P439 to G646, NBD2 as going from A1225 to E1417, and the C-tail as going from E1418 to L1480. This approach also provided further insights into the differential roles of the two halves of CFTR and highlighted several well-conserved motifs that may be involved in inter- or intramolecular interactions. Moreover, a serious concern that a certain fraction of missense mutations identified in the CFTR gene may not have functional consequences was raised. Finally, phylogenetic analysis of all the full-length CFTR amino acid sequences and an extended set of exon 13–coding nucleotide sequences reinforced the idea that the rabbit may represent a better CF model than the mouse and strengthened the assertion that a long-branch attraction artifact separates the murine rodents from the rabbit and the guinea pig, the other Glires.
Leadership development for early career doctors
Authors: Cordelia EM Coltart, Ronny Cheung, Antonella Ardolino, Ben Bray, Brett Rocos, Alex Bailey, Rob Bethune, John Butler, Mary Docherty, Kate Drysdale, Alan Fayaz, Felix Greaves, Jonathan Hafferty, Aeesha NJ Malik, Ahmad Moolla, Louise Morganstein, Fiona Pathiraja, Aditi Shah, Graham Sleat, Vivian Tang, Iain Yardley, Liam Donaldson
Journal: The Lancet (2012)
Improving Melanoma Classification by Integrating Genetic and Morphologic Features
Authors: Amaya Viros, Jane Fridlyand, Juergen Bauer, Konstantin Lasithiotakis, Claus Garbe, Daniel Pinkel, Boris C Bastian
Journal: PLoS Medicine (2008)

In melanoma, morphology-based classification systems have not been able to provide relevant information for selecting treatments for patients whose tumors have metastasized. The recent identification of causative genetic alterations has revealed mutations in signaling pathways that offer targets for therapy. Identifying morphologic surrogates that can identify patients whose tumors express such alterations (or functionally equivalent alterations) would be clinically useful for therapy stratification and for retrospective analysis of clinical trial data.
Effectiveness of an intervention to reduce house dust mite allergen levels in children's beds
Authors: S. Mihrshahi, G. B. Marks, S. Criss, E. R. Tovey, C. H. Vanlaar, J. K. Peat
Journal: Allergy (2003)

Background: In temperate climates, exposure to house dust mite (HDM) allergens is the strongest environmental risk factor for childhood asthma. Environmental modifications to limit exposure have the potential to reduce the prevalence of asthma. The aim of this study was to reduce allergen exposure for children at high risk of developing asthma. Methods: A total of 616 pregnant women were randomized to HDM intervention and control groups. The control group had no special recommendations whereas the intervention group was given allergen impermeable mattress covers and an acaricidal washing detergent for bedding. Children were visited regularly until 18 months of age to have dust collected from their bed. Results: Der p 1 concentrations in the control group increased from 5.20 μ g/g at 1 month to 22.18 μ g/g at 18 months but remained low in the intervention group, ranging from 3.27 μ g/g at 1 month to 6.12 μ g/g at 18 months. Conclusions: In a high HDM allergen environment, a combined approach using physical barriers and an acaricidal wash, is effective in reducing HDM allergen concentrations in bedding. However, even with these control measures in place, HDM allergen levels remained high by international standards.
Increased Clearance and Degradation of [3H]Insulin in Streptozotocin Diabetic Rats
Authors: Jacques Philippe, Philippe A. Halban, Asllan Gjinovci, William C. Duckworth, Jurek Estreicher, Albert E. Renold
Journal: Journal of Clinical Investigation (1981)

The role of the insulin-receptor compartment in the pharmacokinetics of intravenously injected insulin in rats was studied. Since streptozotocin-diabetes in rats results in increased insulin binding to tissues in vitro, insulin pharmacokinetics in streptozotocin-diabetic rats were compared to controls, using semisynthetic [3H]insulin as the tracer. The initial distribution volume for [3H]insulin was elevated by 60% in diabetic rats. By contrast, no difference in initial distribution volume for [14C]inulin was observed, and the absolute values were lower than those found for [3H]insulin. The metabolic clearance rate of [3H]insulin was elevated by 44% in diabetic rats. That these differences were the result of increased binding of insulin to a specific receptor compartment in diabetic rats was shown by three additional experiments. The first involved receptor saturation by injection of 10 U native insulin 2 min before the tracer injection, resulting in identical [3H]insulin disappearance rates in the two groups of rats. The second consisted of displacing [3H]insulin from receptors by injecting 10 U unlabeled insulin 6 min after the tracer injection. Displacement of intact [3H]insulin from receptors and subsequent reappearance in the circulation occurred in both control and diabetic animals; however, such displacement was 25% greater in the diabetic rats. Finally, treatment of diabetic rats with insulin for 8 d normalized [3H]insulin clearance even though the tracer was injected at a time when the animals were again hyperglycemic and hypoinsulinemic. This suggests that down-regulation of insulin receptors had occurred during insulin therapy. These results confirm that a specific compartment for insulin exists (the insulin-receptor compartment) and that this compartment plays an important role in insulin clearance.
IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H)
Authors: Joanne L. Jones, Chia-Ling Phuah, Amanda L. Cox, Sara A. Thompson, Maria Ban, Jacqueline Shawcross, Amie Walton, Stephen J. Sawcer, Alastair Compston, Alasdair J. Coles
Journal: Journal of Clinical Investigation (2009)

Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity.
Inhibition of anastomotic intimal hyperplasia using a chimeric decoy strategy against NF B and E2F in a rabbit model
Authors: T. Miyake, M. Aoki, R. Morishita
Journal: Cardiovascular Research (2008)

Neointimal formation remains a major limitation after arterial reconstruction. To overcome this problem, we focused on two important transcription factors, nuclear factor-kappaB (NFκB) and E2F. The purpose of this study was to determine the effects of simultaneous inhibition of these transcription factors on the formation of neointimal hyperplasia. We employed chimeric decoy oligodeoxynucleotides (ODN) to inhibit both NFκB and E2F simultaneously, and examined the effects of chimeric decoy ODN on the proliferation and migration of cultured vascular cells and on the formation of neointimal hyperplasia using prosthetic graft placement in a rabbit hypercholesterolemia model. Our in vitro study demonstrated that transfection of chimeric decoy ODN inhibited platelet-derived growth factor (PDGF)-induced proliferation and migration of vascular smooth muscle cells, whereas endothelial cell proliferation was not inhibited. In an in vivo study, treatment with chimeric decoy ODN significantly inhibited proximal and distal anastomotic intimal hyperplasia, and accelerated re-endothelialization. α-Smooth muscle actin (α-SMA)-positive cell proliferation was inhibited at the anastomotic sites. Expression of PDGF-BB and PDGF receptor-β was also suppressed by chimeric decoy ODN, resulting in a reduction of α-SMA-positive cell accumulation. In addition, chimeric decoy ODN treatment inhibited macrophage accumulation, which was accompanied by a reduction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 gene expression. The present study demonstrates the feasibility of chimeric decoy ODN treatment for preventing neointimal formation. This strategy might be useful to improve the clinical outcome after arterial reconstruction.