tbuckley/cabot-search huggingface dataset:
Hepatocyte growth factor-induced endothelial cell motility is mediated by the upregulation of inducible nitric oxide synthase expression
Authors: K Purdie
Journal: Cardiovascular Research (2002)

Hepatocyte growth factor (HGF) is an angiogenic mitogen which stimulates migration in various cell types and has been shown to induce the production of nitric oxide (NO) in epithelial cells. Conflicting data exist on the effect of NO on endothelial cell migration. The aim of this study was to investigate a possible role for NO in HGF-stimulated endothelial cell motility.The study was performed primarily using an endothelial cell line derived from adult human saphenous vein. Transient transfection experiments were additionally performed using an adult human coronary artery endothelial cell line. Nitric oxide synthase expression was examined by western blot analysis. Time-lapse digital image microscopy was used to measure cell motility. A DNA construct was used in transient transfections to over-express inducible nitric oxide synthase (iNOS) as an N-terminal fusion to enhanced green fluorescent protein (EGFP).HGF upregulated the expression of iNOS but not constitutive endothelial nitric oxide synthase (eNOS). Treatment of cells with the specific iNOS inhibitor 1400 W revealed that functional iNOS was required for HGF-stimulated endothelial cell motility. HGF-induced iNOS expression was partially abrogated in the presence of the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY294002, but not the Src kinase inhibitor, PP1. Endothelial cell motility increased significantly (P<0.0001) in the presence of the exogenous NO donor spermine-NO and cells expressing the iNOS-EGFP fusion protein exhibited significantly greater (P=0.0038) motility than those expressing EGFP alone.These combined data show that elevated NO production is sufficient to stimulate endothelial cell motility and link HGF and NO, both previously implicated in modulating motility, in a common signalling pathway.
Quantitative Analysis of the T Cell Repertoire Selected by a Single Peptide–Major Histocompatibility Complex
Authors: Laurent Gapin, Yoshinori Fukui, Jean Kanellopoulos, Tetsuro Sano, Armanda Casrouge, Vanessa Malier, Emmanuel Beaudoing, Daniel Gautheret, Jean-Michel Claverie, Takehiko Sasazuki, Philippe Kourilsky
Journal: The Journal of Experimental Medicine (1998)

The positive selection of CD4+ T cells requires the expression of major histocompatibility complex (MHC) class II molecules in the thymus, but the role of self-peptides complexed to class II molecules is still a matter of debate. Recently, it was observed that transgenic mice expressing a single peptide–MHC class II complex positively select significant numbers of diverse CD4+ T cells in the thymus. However, the number of selected T cell specificities has not been evaluated so far. Here, we have sequenced 700 junctional complementarity determining regions 3 (CDR3) from T cell receptors (TCRs) carrying Vβ11-Jβ1.1 or Vβ12-Jβ1.1 rearrangements. We found that a single peptide–MHC class II complex positively selects at least 105 different Vβ rearrangements. Our data yield a first evaluation of the size of the T cell repertoire. In addition, they provide evidence that the single Eα52-68–I-Ab complex skews the amino acid frequency in the TCR CDR3 loop of positively selected T cells. A detailed analysis of CDR3 sequences indicates that a fraction of the β chain repertoire bears the imprint of the selecting self-peptide.
Overexpression of the Aldo-Keto Reductase Family Protein AKR1B10 Is Highly Correlated with Smokers' Non–Small Cell Lung Carcinomas
Authors: Shin-ichi Fukumoto, Naoko Yamauchi, Hisashi Moriguchi, Yoshitaka Hippo, Akira Watanabe, Junji Shibahara, Hirokazu Taniguchi, Shumpei Ishikawa, Hirotaka Ito, Shogo Yamamoto, Hiroko Iwanari, Mitsugu Hironaka, Yuichi Ishikawa, Toshiro Niki, Yasunori Sohara, Tatsuhiko Kodama, Masaharu Nishimura, Masashi Fukayama, Hirotoshi Dosaka-Akita, Hiroyuki Aburatani
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Squamous cell carcinoma (SCC) and adenocarcinoma of the lung are currently subject to similar treatment regimens despite distinct differences in histology and epidemiology. The aim of this study is to identify a molecular target with diagnostic and therapeutic values for SCC. Experimental Design: Genes specifically up-regulated in SCC were explored through microarray analysis of 5 SCCs, 5 adenocarcinomas, 10 small cell lung carcinomas, 27 normal tissues, and 40 cancer cell lines. Clinical usefulness of these genes was subsequently examined mainly by immunohistochemical analysis. Results: Seven genes, including aldo-keto reductase family 1, member B10 (AKR1B10), were identified as SCC-specific genes. AKR1B10 was further examined by immunohistochemical analysis of 101 non–small cell lung carcinomas (NSCLC) and its overexpression was observed in 27 of 32 (84.4%) SCCs and 19 of 65 (29.2%) adenocarcinomas. Multiple regression analysis showed that smoking was an independent variable responsible for AKR1B10 overexpression in NSCLCs (P &amp;lt; 0.01) and adenocarcinomas (P &amp;lt; 0.01). AKR1B10 staining was occasionally observed even in squamous metaplasia, a precancerous lesion of SCC. Conclusion: AKR1B10 was overexpressed in most cases with SCC, which is closely associated with smoking, and many adenocarcinoma cases of smokers. These results suggest that AKR1B10 is a potential diagnostic marker specific to smokers' NSCLCs and might be involved in tobacco-related carcinogenesis.
Effect of different forms of information produced for cancer patients on their use of the information, social support, and anxiety: randomised trial
Authors: R B Jones, J Pearson, A J Cawsey, D Bental, A Barrett, J White, C A White, W H Gilmour
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To explore the hypothesis that different methods of selecting and printing information for cancer patients could improve emotional support by affecting interaction with others, and so lead to improved psychological wellbeing. <b>Design</b> Randomised trial with eight groups (three factors, 2′2′2). Data collected at recruitment and three month follow-up. <b>Participants</b> 400 patients starting radiotherapy, of whom 325 with breast or prostate cancer and complete anxiety and depression data were included in the analysis. <b>Interventions</b> Printed booklets: half had only general information from CancerBACUP about each patient9s cancer and half had personalised information from the patient9s medical record plus selected general information; half were composed of information chosen interactively by the patient and half were produced automatically with a larger volume of material; and half had additional advice on anxiety management and half did not. <b>Main outcome measures</b> Patients9 views of the information, use of their booklets with others; change in reported social support; change in anxiety and depression. <b>Results</b> The larger booklets produced automatically were more likely to be found useful and to tell patients something new and less likely to be seen as too limited than the booklets produced interactively, but they were also more likely to overwhelm some patients. Personalised booklets were more likely than general booklets to tell patients something new. There was no difference in patients9 perceived understanding of their cancer by any of the intervention factors. Patients with personalised information were more likely to show their booklets to others and to think it helped in discussing their cancer or its treatment. There were no major differences in social support, anxiety, or depression by any intervention factors. <b>Conclusions</b> Patients were more likely to show personalised information to their confidants than general information. Further research is needed into the effects of sharing information on patients9 social support and anxiety. <b>Trial registration</b> US Government Clinical Trials Database NCT00127465
Reply to J.-H. Choi et al
Authors: Thomas Bachelot, Claire Cropet, Isabelle Ray-Coquard, Eric Pujade-Lauraine
Journal: Journal of Clinical Oncology (2012)

as the response rate), and Wieand et al 5 proposed multistage designs for the comparison of a time to event end point (such as progression-free survival and overall survival) between randomly assigned arms.The strength of clinical trials is well-controlled and unbiased study results.However, this is true only when clinical trials satisfy the conditions of prospective studies (ie, they are conducted and the final data analyses are performed as planned by the study protocols).
Depression: A Decision-Theoretic Analysis
Authors: Quentin J.M. Huys, Nathaniel D. Daw, Peter Dayan
Journal: Annual Review of Neuroscience (2015)

The manifold symptoms of depression are common and often transient features of healthy life that are likely to be adaptive in difficult circumstances. It is when these symptoms enter a seemingly self-propelling spiral that the maladaptive features of a disorder emerge. We examine this malignant transformation from the perspective of the computational neuroscience of decision making, investigating how dysfunction of the brain's mechanisms of evaluation might lie at its heart. We start by considering the behavioral implications of pessimistic evaluations of decision variables. We then provide a selective review of work suggesting how such pessimism might arise via specific failures of the mechanisms of evaluation or state estimation. Finally, we analyze ways that miscalibration between the subject and environment may be self-perpetuating. We employ the formal framework of Bayesian decision theory as a foundation for this study, showing how most of the problems arise from one of its broad algorithmic facets, namely model-based reasoning.
The Unforgettable Dr Farrell
Authors: L. Farrell
Journal: BMJ (2009)

“You’re a marvellous doctor,” she said. I shuffled my feet uneasily. We Irish are a modest race, but this is a veneer only; as La Rochefoucald observed, “To refuse praise is to wish to be praised twice.” And “You’re a marvellous doctor” was, I felt, quite inadequate to describe the wonder that is me; I wanted a parade, a brass band, Mickey Mouse, stars climbing the dew dropping sky just to light my passing feet, Angelina (Jolie) weeping by the phone the next day because I …
Antisense Therapy for Angioplasty Restenosis
Authors: Martin R. Bennett, Stephen M. Schwartz
Journal: Circulation (1995)

The high affinity of even relatively short sequences of DNA for their target mRNA suggests that antisense agents represent an ideal method of suppressing specific gene products both in vitro and in vivo. In experiments performed thus far, an effect on the target mRNA in cultured vascular cells and in the vessel wall can be documented. The in vitro activity, toxicity, and pharmacokinetic data of antisense oligonucleotides are encouraging, and the in vivo animal experiments demonstrating suppression of neointimal formation are very promising. If animals trials presently under way show continued suppression not only of intimal formation but also of loss of lumen caliber after a single application, then effective delivery of antisense oligonucleotides is a realistic possibility. Nevertheless, some words of caution regarding the use of antisense oligonucleotides are warranted. Potential nonspecific effects of antisense oligonucleotides should be carefully considered in studies in which antisense agents are used to define biological functions of specific genes. In particular, demonstration that the target mRNA has been suppressed does not prove that other sequences within the mRNA pool have not also been suppressed. Critical control measures include adding back the target mRNA or protein and demonstrating similar biological effects with antisense sequences, which also suppress target gene expression directed at different regions of the target mRNA. At the clinical level, the systemic effects of antisense oligonucleotides, the dosage required, the timing of administration compared with mechanical intervention, and the toxicity of breakdown products all need to be established. In addition, the most appropriate targets for antisense use in restenosis remain largely obscure. Indiscriminate suppression of cell-cycle genes or proto-oncogenes may be as acutely toxic as current anticancer chemotherapy if the site delivery is not completely localized. Furthermore, much of the clinical evidence suggests that restenosis is a chronic process, continuing to develop weeks to months after the procedure. If this is the case, then the current approaches that rely on a transient, local application of an antisense agent may fail. If, however, a target gene is identified that is specific to vascular tissue, then repeated administration of an antisense agent may be tolerated via a systemic route. This approach has proved successful in targeting mutated genes with little suppression of closely related genes and with minimal systemic toxicity. An alternative approach is to transfect the target tissue with a gene that makes it susceptible to systemic delivery of a drug that is not normally toxic to mammalian cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Differential Notch Signaling in the Epicardium Is Required for Cardiac Inflow Development and Coronary Vessel Morphogenesis
Authors: Gonzalo del Monte, Jesús C. Casanova, Juan Antonio Guadix, Donal MacGrogan, John B.E. Burch, José María Pérez-Pomares, José Luis de la Pompa
Journal: Circulation Research (2011)

The proepicardium is a transient structure comprising epicardial progenitor cells located at the posterior limit of the embryonic cardiac inflow. A network of signals regulates proepicardial cell fate and defines myocardial and nonmyocardial domains at the venous pole of the heart. During cardiac development, epicardial-derived cells also contribute to coronary vessel morphogenesis.To study Notch function during proepicardium development and coronary vessel formation in the mouse.Using in situ hybridization, RT-PCR, and immunohistochemistry, we find that Notch pathway elements are differentially activated throughout the proepicardial-epicardial-coronary transition. Analysis of RBPJk-targeted embryos indicates that Notch ablation causes ectopic procardiogenic signaling in the proepicardium that in turn promotes myocardial differentiation in adjacent mesodermal progenitors, resulting in a premature muscularization of the sinus venosus horns. Epicardium-specific Notch1 ablation using a Wt1-Cre driver line disrupts coronary artery differentiation, reduces myocardium wall thickness and myocyte proliferation, and reduces Raldh2 expression. Ectopic Notch1 activation disrupts epicardium development and causes thinning of ventricular walls.Epicardial Notch modulates cell differentiation in the proepicardium and adjacent pericardial mesoderm. Notch1 is later required for arterial endothelium commitment and differentiation and for vessel wall maturation during coronary vessel development and myocardium growth.
Angiogenesis by gene therapy: a new horizon for myocardial revascularization?
Authors: B Lewis
Journal: Cardiovascular Research (1997)

The concept of therapeutic angiogenesis is based on the premise that the potential for vascular growth inherent in vascular tissue can be utilized to promote the development of new blood vessels under the influence of the appropriate growth factors. Direct application of growth factors of the fibroblast (acidic, basic fibroblast growth factor, FGF-5), endothelial (vascular endothelial growth factor) and other series has been effective in preliminary studies. Angiogenesis by gene transfer provides an attractive alternative, with the advantage that the protein may continue to be secreted for a longer period of time and that the gene may be targeted to specific tissues to enhance efficacy and reduce systemic side effects. Angiogenesis by gene transfer is currently under investigation using a variety of growth factors and a wide array of potential delivery systems. These include application of the gene as naked DNA or by viral vector in the proximal vessel by direct intravascular injection, interventional cardiologic techniques (hydrogel coating on balloon, double balloon system, stent implantation) or by direct application to adventitia, pericardium or ischemic tissue distal to the site of arterial obstruction. As our understanding of the molecular and genetic processes underlying angiogenesis increases, and as we examine the results of preliminary animal and human protocols, we hope to develop the potential of angiogenesis by gene transfer for therapeutic use.
Immigrants' perceptions of the quality of their cancer care: an Australian comparative study, identifying potentially modifiable factors
Authors: D. Goldstein, M.L. Bell, P. Butow, M. Sze, L. Vaccaro, S. Dong, W. Liauw, R. Hui, M. Tattersall, W. Ng, R. Asghari, C. Steer, J. Vardy, P. Parente, M. Harris, N.V. Karanth, M. King, A. Girgis, M. Eisenbruch, M. Jefford
Journal: Annals of Oncology (2014)
Genome-Wide Allelic Imbalance Analysis of Pediatric Gliomas by Single Nucleotide Polymorphic Allele Array
Authors: Kwong-Kwok Wong, Yvonne T.M. Tsang, Yi-Mieng Chang, Jack Su, Angela M. Di Francesco, Daniela Meco, Riccardo Riccardi, Laszlo Perlaky, Robert C. Dauser, Adekunle Adesina, Meenakshi Bhattacharjee, Murali Chintagumpala, Ching C. Lau
Journal: Cancer Research (2006)

Abstract Using single nucleotide polymorphic (SNP) allele arrays, we analyzed 28 pediatric gliomas consisting of 14 high-grade gliomas and 14 low-grade gliomas. Most of the low-grade gliomas had no detectable loss of heterozygosity (LOH) in any of the 11,562 SNP loci; exceptions were two gangliogliomas (3q and 9p), one astrocytoma (6q), and two subependymal giant cell astrocytomas (16p and 21q). On the other hand, all high-grade gliomas had various degrees of LOH affecting 52 to 2,168 SNP loci on various chromosomes. LOH occurred most frequently in regions located at 4q (54%), 6q (46%), 9p (38%), 10q (38%), 11p (38%), 12 (38%), 13q (69%), 14q (54%), 17 (38%), 18p (46%), and 19q (38%). We also detected amplifications of epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor α (PDGFRα) in a few of the 13 cases of glioblastoma multiforme analyzed. Interestingly, the amplified EGFR and PDGFRα were located within regions of LOH. SNP loci with LOH and copy number changes were validated by sequencing and quantitative PCR, respectively. Our results indicate that, in some pediatric glioblastoma multiforme, one allele each of EGFR and PDGFRα was lost but the remaining allele was amplified. This may represent a new molecular mechanism underlying tumor progression. (Cancer Res 2006; 66(23): 11172-8)
Mechanisms of exertional dyspnoea in pulmonary veno-occlusive disease with <i>EIF2AK4</i> mutations
Authors: Pierantonio Laveneziana, David Montani, Peter Dorfmüller, Barbara Girerd, Olivier Sitbon, Xavier Jaïs, Laurent Savale, Mélanie Eyries, Florent Soubrier, Thomas Similowski, Gérald Simonneau, Marc Humbert, Gilles Garcia
Journal: European Respiratory Journal (2014)

Mechanisms of exertional dyspnoea in pulmonary veno-occlusive disease with EIF2AK4 mutationsTo the Editor:Dyspnoea curtails daily-living activities in patients with pulmonary veno-occlusive disease (PVOD) [1,2] and pulmonary arterial hypertension (PAH) [3][4][5].It is a common clinical observation that PVOD patients may experience greater dyspnoea than PAH patients during daily activities [1,2].However, this clinical feature and its putative underlying mechanisms have not yet been explored.Cardiopulmonary exercise testing (CPET) is well suited for understanding mechanisms underlying dyspnoea during exercise both in research and clinical settings [4,5].In the present study, we hypothesised that the perceived clinical difference between PVOD and PAH regarding exertional dyspnoea would be reflected by a different physiological response to CPET.Building on recent advances obtained with CPET in PAH patients [4], we set out to evaluate the relationship between exertional dyspnoea and the physiological response to CPET in eight PVOD patients presenting with recessive mutations in EIF2AK4, compared with 16 idiopathic or heritable PAH patients.We studied eight clinically stable patients referred to the French Reference Center for Pulmonary Hypertension (Le Kremlin-Bice ˆtre, France) for management of PAH [6,7].Using whole-exome sequencing, we detected recessive mutations in the major gene linked to PVOD development, EIF2AK4 (also called GCN2), that co-segregated with PVOD in eight patients studied, as recently described [8].16 clinically stable patients with diagnosed idiopathic or heritable PAH [9] and without other concomitant diseases were also evaluated.Pulmonary function tests, cycle ergometer symptom-limited incremental CPET, and measurements at rest and at peak exercise of arterial oxygen tension (PaO 2 ) and arterial carbon dioxide tension (PaCO 2 ), the physiological dead space (VD)/tidal volume (VT) ratio, and the alveolar-arterial oxygen tension gradient (PA-aO 2 ) and arterial-end-tidal carbon dioxide tension gradient (Pa-ETCO 2 ) were evaluated as previously described [4].The intensity of dyspnoea was rated using the modified 10-point Borg scale [10] at rest and at peak exercise.
Endobronchial ultrasound in therapeutic bronchoscopy
Authors: F. Herth, H.D. Becker, J. LoCicero, A. Ernst
Journal: European Respiratory Journal (2002)

Endobronchial ultrasound (EBUS) has been introduced as an adjunct to diagnostic bronchoscopy as it allows evaluation of the submucosal and parabronchial structures. Its use in therapeutic bronchoscopy has not been assessed. A large observational study of the value of EBUS in therapeutic bronchoscopy is presented here. From January 1998–January 2001 all patients undergoing therapeutic bronchoscopy and EBUS were evaluated prospectively. Patient demographics, indication for bronchoscopy, interventional treatments used and changes in therapy as influenced by the use of EBUS were documented. A total 2,446 therapeutic bronchoscopies were performed. In 1,174 cases EBUS was used (29% mechanical tumour debridement, 20% airway stenting, 13% Neodymium:yttrium aluminium garnet (Nd:YAG) laser use, 23% argon plasma coagulation, 11% brachytherapy, 2% foreign body removal and 2% endoscopic abscess drainage). EBUS guided or changed therapy significantly in 43% of cases. Changes included adjustment of stent dimensions, termination of tumour debridement when nearing vessels, and referral for surgical interventions rather than endoscopic treatment. Complications associated with EBUS use were minimal. No patient undergoing EBUS guided tumour destruction experienced severe bleeding or fistula formation. In summary, endobronchial ultrasound was easily performed and changed or guided therapeutic decisions during therapeutic bronchoscopic procedures in a substantial number of cases. As this may result in better outcomes, it has become a standard adjunct in the authors practice.
Plasticity and Primary Motor Cortex
Authors: Jerome N. Sanes, John P. Donoghue
Journal: Annual Review of Neuroscience (2000)

One fundamental function of primary motor cortex (MI) is to control voluntary movements. Recent evidence suggests that this role emerges from distributed networks rather than discrete representations and that in adult mammals these networks are capable of modification. Neuronal recordings and activation patterns revealed with neuroimaging methods have shown considerable plasticity of MI representations and cell properties following pathological or traumatic changes and in relation to everyday experience, including motor-skill learning and cognitive motor actions. The intrinsic horizontal neuronal connections in MI are a strong candidate substrate for map reorganization: They interconnect large regions of MI, they show activity-dependent plasticity, and they modify in association with skill learning. These findings suggest that MI cortex is not simply a static motor control structure. It also contains a dynamic substrate that participates in motor learning and possibly in cognitive events as well.