tbuckley/cabot-search huggingface dataset:
Genetic variation in glutathione metabolism and DNA repair genes predicts survival of small-cell lung cancer patients
Authors: Z. Sun, J. Chen, J. Aakre, R.S. Marks, Y.Y. Garces, R. Jiang, O. Idowu, J.M. Cunningham, Y. Liu, V.S. Pankratz, P. Yang
Journal: Annals of Oncology (2010)
Insulin-like growth factor-I induces reactive oxygen species production and cell migration through Nox4 and Rac1 in vascular smooth muscle cells
Authors: D. Meng, D.-D. Lv, J. Fang
Journal: Cardiovascular Research (2008)

We showed previously that insulin-like growth factor-I (IGF-I)-induced vascular smooth muscle cells (VSMCs) proliferation through the production of reactive oxygen species (ROS). However, how IGF-I-induced ROS was unknown. The aim of this study is to investigate the mechanisms by which IGF-I induces ROS production in VSMCs. Methods results Reverse transcription-PCR, real-time PCR, immunoblotting, and confocal microscopic image analysis were employed to determine protein expression, small Rho-GTPase Rac1 activation, and ROS production. Inhibition of NADPH oxidase 4 (Nox4) or Rac1 was performed by means of siRNA technology. Inhibition of Rac1 activity was accomplished using dominant-negative form of Rac1 (N17Rac1) plasmid. VSMCs from Sprague-Dawley rat thoracic aortas were used in this work.IGF-I enhanced ROS production in rat VSMCs. IGF-I increased the protein level of Nox4 but had little effect on its mRNA level. IGF-I induced the activation of Rac1. Either knockdown of Nox4 or inactivation of Rac1 impaired IGF-I-induced ROS. Over-expression of Nox4 increased NADPH oxidase activity, which was not influenced by inactivation of Rac1. Neither over-expression nor knockdown of Rac1 influenced Nox4 expression. Knockdown of Nox4 did not affect IGF-I-induced activation of Rac1. IGF-I increased matrix metalloproteinase (MMP)-2 and 9 activity and promoted VSMC migration, which was inhibited by knockdown of Nox4 and inactivation of Rac1.Our results suggest that Nox4 and Rac1 mediate IGF-I-induced ROS production and cell migration in VSMCs and that Nox4 is not regulated by Rac1.
Hypoxia Decreases Exhaled Nitric Oxide in Mountaineers Susceptible to High-Altitude Pulmonary Edema
Authors: THILO BUSCH, PETER BÄRTSCH, DIRK PAPPERT, EKKEHARD GRÜNIG, WULF HILDEBRANDT, HUBERT ELSER, KONRAD J. FALKE, ERIK R. SWENSON
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

An exaggerated hypoxic pulmonary vasoconstriction is essential for development of high-altitude pulmonary edema (HAPE). We hypothesized that susceptibility to HAPE may be related to decreased production of nitric oxide (NO), an endogenous modulator of pulmonary vascular resistance, and that a decrease in exhaled NO could be detected during hypoxic exposure. Therefore, we investigated respiratory tract NO excretion by chemiluminescence and pulmonary artery systolic pressure (Ppa,s) by echocardiography in nine HAPE-susceptible mountaineers and nine HAPE-resistant control subjects during normoxia and acute hypoxia (fraction of inspired oxygen [Fi O2 ] = 0.12). The subjects performed oral breathing. Nasally excreted NO was separated from respiratory gas by suction via a nasal mask. In HAPE-susceptible subjects, NO excretion in expired gas significantly decreased (p < 0.05) during hypoxia of 2 h in comparison with normoxia (28 ± 4 versus 21 ± 2 nl/min, mean ± SEM). In contrast, the NO excretion rate of control subjects remained unchanged (31 ± 6 versus 33 ± 6 nl/ min, NS). Nasal NO excretion did not differ significantly between groups during normoxia (HAPE-susceptible group, 183 ± 16 nl/ min; control subjects, 297 ± 55 nl/min, NS) and was not influenced by hypoxia. The changes in Ppa,s with hypoxia correlated with the percent changes in lower respiratory tract NO excretion (R = − 0.49, p = 0.04). Our data provide the first evidence of decreased pulmonary NO production in HAPE-susceptible subjects during acute hypoxia that may contribute among other factors to their enhanced hypoxic pulmonary vascular response.
Epigenetic Inactivation of the Circadian Clock Gene <i>BMAL1</i> in Hematologic Malignancies
Authors: Hiroaki Taniguchi, Agustin F. Fernández, Fernando Setién, Santiago Ropero, Esteban Ballestar, Alberto Villanueva, Hiroyuki Yamamoto, Kohzoh Imai, Yasuhisa Shinomura, Manel Esteller
Journal: Cancer Research (2009)

Abstract Disruption of circadian rhythms, daily oscillations in biological processes that are regulated by an endogenous clock, has been linked to tumorigenesis. Normal and malignant tissues often show asynchronies in cell proliferation and metabolic rhythms. Cancer chronotherapy takes biological time into account to improve the therapy. However, alterations of the circadian clock machinery genes have rarely been reported in human cancer. Herein, we show that the BMAL1 gene, a core component of the circadian clock, is transcriptionally silenced by promoter CpG island hypermethylation in hematologic malignancies, such as diffuse large B-cell lymphoma and acute lymphocytic and myeloid leukemias. We also describe how BMAL1 reintroduction in hypermethylated leukemia/lymphoma cells causes growth inhibition in colony assays and nude mice, whereas BMAL1 depletion by RNA interference in unmethylated cells enhances tumor growth. We also show that BMAL1 epigenetic inactivation impairs the characteristic circadian clock expression pattern of genes such as C-MYC, catalase, and p300 in association with a loss of BMAL1 occupancy in their respective promoters. Furthermore, the DNA hypermethylation–associated loss of BMAL1 also prevents the recruitment of its natural partner, the CLOCK protein, to their common targets, further enhancing the perturbed circadian rhythm of the malignant cells. These findings suggest that BMAL1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting the cellular circadian clock. [Cancer Res 2009;69(21):8447–54]
Vascular Matrix Metalloproteinase-2 Cleaves Big Endothelin-1 Yielding a Novel Vasoconstrictor
Authors: Carlos Fernandez-Patron, Marek W. Radomski, Sandra T. Davidge
Journal: Circulation Research (1999)

Abstract —Matrix metalloproteinase-2 (MMP-2, gelatinase A) and its tissue inhibitor (TIMP-2) are mainly known for their roles in the (patho)physiological remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. A mechanism of action of MMP-2 is the proteolytic breakdown of specific extracellular matrix proteins. The amino acid sequences in interstitial collagen (Gly-Leu/Ile) and laminin-5 (Ala-Leu) that are cleaved by MMP-2 are homologous to a region (Gly 32 -Leu 33 ) within human big endothelin-1[1 to 38] (big ET-1). Big ET-1 requires cleavage to an active form to produce vasoconstriction. We tested the hypothesis that vascular MMP-2 can cleave big ET-1, thus generating a vasoconstrictor peptide. In perfused rat mesenteric arteries with an intact endothelium, inhibition of vascular MMP-2 with TIMP-2 reduced (by 16.2±4.2%) the vasoconstrictor effects of big ET-1 (50 pmol). However, when the endothelium was mechanically removed, TIMP-2 abolished (&gt;90%) the vasoconstriction of big ET-1, and this effect was mimicked by an anti–MMP-2 antibody. Incubation of big ET-1 with recombinant human MMP-2 resulted in the specific cleavage of the Gly 32 -Leu 33 bond of big ET-1. Moreover, the resultant peptide ET-1[1 to 32] exerted greater vasoconstrictor effects than big ET-1. We conclude that vascular MMP-2 contributes to the vasoconstrictor effects of big ET-1 by cleaving big ET-1 to yield a novel and potent vasoconstrictor, ET-1[1 to 32]. These data implicate, for the first time, the endogenous MMP-2/TIMP-2 system in the regulation of vascular reactivity.
Influence of Patients’ Requests for Direct-to-Consumer Advertised Antidepressants
Authors: Richard L Kravitz, Ronald M Epstein, Mitchell D Feldman, Carol E Franz, Rahman Azari, Michael S Wilkes, Ladson Hinton, Peter Franks
Journal: JAMA (2005)

Direct-to-consumer (DTC) advertising of prescription drugs in the United States is both ubiquitous and controversial. Critics charge that it leads to overprescribing, while proponents counter that it helps avert underuse of effective treatments, especially for conditions that are poorly recognized or stigmatized.To ascertain the effects of patients' DTC-related requests on physicians' initial treatment decisions in patients with depressive symptoms.Randomized trial using standardized patients (SPs). Six SP roles were created by crossing 2 conditions (major depression or adjustment disorder with depressed mood) with 3 request types (brand-specific, general, or none).Offices of primary care physicians in Sacramento, Calif; San Francisco, Calif; and Rochester, NY, between May 2003 and May 2004.One hundred fifty-two family physicians and general internists recruited from solo and group practices and health maintenance organizations; cooperation rates ranged from 53% to 61%.The SPs were randomly assigned to make 298 unannounced visits, with assignments constrained so physicians saw 1 SP with major depression and 1 with adjustment disorder. The SPs made a brand-specific drug request, a general drug request, or no request (control condition) in approximately one third of visits.Data on prescribing, mental health referral, and primary care follow-up obtained from SP written reports, visit audiorecordings, chart review, and analysis of written prescriptions and drug samples. The effects of request type on prescribing were evaluated using contingency tables and confirmed in generalized linear mixed models that accounted for clustering and adjusted for site, physician, and visit characteristics.Standardized patient role fidelity was excellent, and the suspicion rate that physicians had seen an SP was 13%. In major depression, rates of antidepressant prescribing were 53%, 76%, and 31% for SPs making brand-specific, general, and no requests, respectively (P<.001). In adjustment disorder, antidepressant prescribing rates were 55%, 39%, and 10%, respectively (P<.001). The results were confirmed in multivariate models. Minimally acceptable initial care (any combination of an antidepressant, mental health referral, or follow-up within 2 weeks) was offered to 98% of SPs in the major depression role making a general request, 90% of those making a brand-specific request, and 56% of those making no request (P<.001).Patients' requests have a profound effect on physician prescribing in major depression and adjustment disorder. Direct-to-consumer advertising may have competing effects on quality, potentially both averting underuse and promoting overuse.
Molecular Mechanisms Involved in the Growth Stimulation of Breast Cancer Cells by Leptin
Authors: Na Yin, Dan Wang, Hua Zhang, Xia Yi, Xiaojing Sun, Bin Shi, Huijian Wu, Ge Wu, Xinjuan Wang, Yongfeng Shang
Journal: Cancer Research (2004)

Abstract Obesity is a risk factor for breast cancer in postmenopausal women. Leptin, an adipocyte-derived cytokine, elicits proliferative effects in some cell types and potentially stimulates the growth of mammary epithelium. Here we show that leptin induced time- and dose-dependent signal transducer and activator of transcription 3 (STAT3) phosphorylation and extracellular signal-regulated kinase (ERK) 1/2 kinase activation in breast carcinoma cells. Blocking STAT3 phosphorylation with a specific inhibitor, AG490, abolished leptin-induced proliferation of MCF-7 cells, whereas blocking ERK1/2 activation by a specific ERK1/2 kinase inhibitor, U0126, did not result in any significant changes in leptin-induced cell proliferation. Our experiments also showed that one member of the p160 family of steroid receptor coactivators, steroid receptor coactivator (SRC)-1, but not glucocorticoid receptor interacting protein 1 (GRIP1) or amplified in breast cancer 1 (AIB1), also functioned in gene transactivation in response to leptin treatment. Glutathione S-transferase pull-down experiments showed that SRC-1 physically interacted with the activation domain of STAT3 and that chromatin immunoprecipitation experiments detected the occupancy of SRC-1, but not GRIP1 or AIB1, on the promoter of STAT3 target genes. Our experiments collectively showed that SRC-1 is involved in STAT3 signaling pathway that is implicated in leptin-stimulated cell growth.
Systemic inflammation and progression of COPD
Authors: J. Vestbo
Journal: Thorax (2007)

The role of C-reactive protein

C-reactive protein (CRP) is considered one of the key markers of systemic inflammation in chronic obstructive pulmonary disease (COPD) and currently receives a lot of attention. In their systematic review of systemic inflammation in COPD, Gan et al showed that CRP was associated with the level of forced expiratory volume in 1 s (FEV1) in the five studies included in the review,1 and two recent studies using fairly large populations of well-characterised patients with COPD have shown a strong association between increased CRP levels and prognosis.2,3 Sin and Man have previously shown that raised levels of CRP were associated with cardiac injury in COPD4 but, in the two recent studies, the association between CRP and mortality was not merely driven by an associated risk of cardiovascular deaths.2,3

In this issue of Thorax ( see p 515 ) Fogarty et al examine the association between CRP and FEV1 in more detail.5 Using data on 2633 randomly selected adults …
Novel phage display-derived neuroblastoma-targeting peptides potentiate the effect of drug nanocarriers in preclinical settings
Authors: Monica Loi, Daniela Di Paolo, Marco Soster, Chiara Brignole, Alice Bartolini, Laura Emionite, Jessica Sun, Pamela Becherini, Flavio Curnis, Andrea Petretto, Monica Sani, Alessandro Gori, Marco Milanese, Claudio Gambini, Renato Longhi, Michele Cilli, Theresa M. Allen, Federico Bussolino, Wadih Arap, Renata Pasqualini, Angelo Corti, Mirco Ponzoni, Serena Marchiò, Fabio Pastorino
Journal: Journal of Controlled Release (2013)

Molecular targeting of drug delivery nanocarriers is expected to improve their therapeutic index while decreasing their toxicity. Here we report the identification and characterization of novel peptide ligands specific for cells present in high-risk neuroblastoma (NB), a childhood tumor mostly refractory to current therapies. To isolate such targeting moieties, we performed combined in vitro/ex-vivo phage display screenings on NB cell lines and on tumors derived from orthotopic mouse models of human NB. By designing proper subtractive protocols, we identified phage clones specific either for the primary tumor, its metastases, or for their respective stromal components. Globally, we isolated 121 phage-displayed NB-binding peptides: 26 bound the primary tumor, 15 the metastatic mass, 57 and 23 their respective microenvironments. Of these, five phage clones were further validated for their specific binding ex-vivo to biopsies from stage IV NB patients and to NB tumors derived from mice. All five clones also targeted tumor cells and vasculature in vivo when injected into NB-bearing mice. Coupling of the corresponding targeting peptides with doxorubicin-loaded liposomes led to a significant inhibition in tumor volume and enhanced survival in preclinical NB models, thereby paving the way to their clinical development.
Reference genomes and transcriptomes of Nicotiana sylvestris and Nicotiana tomentosiformis
Authors: Nicolas Sierro, James ND Battey, Sonia Ouadi, Lucien Bovet, Simon Goepfert, Nicolas Bakaher, Manuel C Peitsch, Nikolai V Ivanov
Journal: Genome biology (2013)

Nicotiana sylvestris and Nicotiana tomentosiformis are members of the Solanaceae family that includes tomato, potato, eggplant and pepper. These two Nicotiana species originate from South America and exhibit different alkaloid and diterpenoid production. N. sylvestris is cultivated largely as an ornamental plant and it has been used as a diploid model system for studies of terpenoid production, plastid engineering, and resistance to biotic and abiotic stress. N. sylvestris and N. tomentosiformis are considered to be modern descendants of the maternal and paternal donors that formed Nicotiana tabacum about 200,000 years ago through interspecific hybridization. Here we report the first genome-wide analysis of these two Nicotiana species.Draft genomes of N. sylvestris and N. tomentosiformis were assembled to 82.9% and 71.6% of their expected size respectively, with N50 sizes of about 80 kb. The repeat content was 72-75%, with a higher proportion of retrotransposons and copia-like long terminal repeats in N. tomentosiformis. The transcriptome assemblies showed that 44,000-53,000 transcripts were expressed in the roots, leaves or flowers. The key genes involved in terpenoid metabolism, alkaloid metabolism and heavy metal transport showed differential expression in the leaves, roots and flowers of N. sylvestris and N. tomentosiformis.The reference genomes of N. sylvestris and N. tomentosiformis represent a significant contribution to the SOL100 initiative because, as members of the Nicotiana genus of Solanaceae, they strengthen the value of the already existing resources by providing additional comparative information, thereby helping to improve our understanding of plant metabolism and evolution.
Shoulder injuries in tennis players
Authors: H van der Hoeven, W B Kibler
Journal: British Journal of Sports Medicine (2006)

The mechanism of the overhead action in throwing sports has been studied extensively. This motion is unnatural and highly dynamic, often exceeding the physiological limits of the joint. Owing to overload of various anatomical structures, the shoulder is susceptible to injury. Optimal shoulder function requires good kinetic chain function, optimal stability, and coordination of the scapula in the overhead action. A well balanced action of the rotator cuff muscles and capsular structures is necessary to obtain a stable centre of rotation during the overhead action. This review concerns shoulder injuries, related to the overhead motion in tennis players, which can be explained by the same mechanism as thrower's shoulder.
Cellular Physiology of Cholesterol Efflux in Vascular Endothelial Cells
Authors: Brian J. O’Connell, Maxime Denis, Jacques Genest
Journal: Circulation (2004)

Of the cells that compose the atherosclerotic plaque, vascular endothelial cells are the most resistant to cholesterol accumulation. Cholesterol efflux pathways may play an important role in endothelial cholesterol homeostasis.We examined the global genetic response of endothelial cells to cholesterol and in particular the contribution of the cholesterol efflux proteins ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor B-I (SR-BI) to endothelial cell cholesterol efflux. The ABCG1 gene is induced in endothelial cells by cholesterol, whereas ABCA1 is not. Using specific chemical inhibitors of ABC transporters and SR-BI, we have shown that neither ABC transporters nor SR-BI is required for apolipoprotein A-1-mediated endothelial cholesterol efflux.Endothelial cells may use nontraditional pathways for cholesterol efflux.
Fifth of coalition MPs have links to private healthcare firms
Authors: A. O'Dowd
Journal: BMJ (2014)

A trade union has accused 71 MPs in the United Kingdom’s coalition government of benefiting from a growing role for the private sector in providing NHS services.

The union Unite published a report on 18 November in which it listed 64 Conservative and seven Liberal Democrat MPs as having links to private healthcare interests, including the prime minister, David Cameron, and the health secretary for England, Jeremy Hunt.1

Unite said that this showed that these MPs were linked to companies or individuals who were seeking to profit from the reorganisation of the NHS brought about by the Health and Social Care Act, which came into force last year and which created a legal mechanism to force healthcare commissioners to put NHS services out to tender from any source, including the private and independent sectors.

The report does not say that any politicians or donors acted illegally, and the Conservative and Liberal …
Is parent–child bed-sharing a risk for wheezing and asthma in early childhood?
Authors: Maartje P.C.M. Luijk, Agnes M.M. Sonnenschein-van der Voort, Viara R. Mileva-Seitz, Pauline W. Jansen, Frank C. Verhulst, Albert Hofman, Vincent W.V. Jaddoe, Johan C. de Jongste, Marinus H. van IJzendoorn, Liesbeth Duijts, Henning Tiemeier
Journal: European Respiratory Journal (2014)

Household crowding can place young children at risk for respiratory infections which subsequently provoke asthma symptoms. However, crowding might also protect against asthma, in accordance with the hygiene hypothesis. We tested if parent–infant bed-sharing, an important dimension of household crowding, increases or decreases the risk for asthma. In a population-based prospective cohort (N = 6160) we assessed bed-sharing at 2 and 24 months; wheezing between 1 and 6 years of age; and asthma at 6 years of age. Generalised estimating equation models were used to assess repeated measures of wheezing and asthma. We found no association between bed-sharing in early infancy and wheezing or diagnosis of asthma. By contrast, we found a positive association between bed-sharing in toddlerhood and both wheezing (OR 1.42, 95% CI 1.15–1.74) and asthma (OR 1.57, 95% CI 1.03–2.38). Wheezing was not associated with bed-sharing when using cross-lagged modelling. This study suggests that bed-sharing in toddlerhood is associated with an increased risk of asthma at later ages, and not vice versa . Further studies are needed to explore the underlying causal mechanisms.
NOD2/CARD15 Polymorphisms in Allogeneic Stem-Cell Transplantation From Unrelated Donors: T Depletion Matters
Authors: Ernst Holler, Joachim Hahn, Reinhard Andreesen, Gerhard Rogler, Julia Brenmoehl, Hildegard Greinix, Anne Marie Dickinson, Gerard Socie, Daniel Wolff, Juergen Finke
Journal: Journal of Clinical Oncology (2008)
A UK-based resource to support the monitoring and safe use of anti-TB drugs and second-line treatment of multidrug-resistant TB
Authors: J. L. Potter, T. Capstick, W. M. Ricketts, N. Whitehead, O. M. Kon
Journal: Thorax (2014)

Using the best available evidence and expert consensus, this document provides guidance for adverse effect monitoring in multidrug-resistant TB (MDR-TB). It includes recommendations for baseline tests, routine drug and toxicity monitoring guides as well as individual drug monographs for all drugs currently available in the UK to treat TB. These recommendations provide a structure through which healthcare professionals can better manage the complex drug regimens required for the treatment of MDR-TB; minimising the risk of adverse incidents and helping to improve patients' tolerance, compliance and treatment completion.