tbuckley/cabot-search huggingface dataset:
Independent Prognostic Value of Screen Detection in Invasive Breast Cancer
Authors: Stella Mook, Laura J. Van ’t Veer, Emiel J. Rutgers, Peter M. Ravdin, Anthonie O. van de Velde, Flora E. van Leeuwen, Otto Visser, Marjanka K. Schmidt
Journal: JNCI Journal of the National Cancer Institute (2011)

BackgroundMammographic screening has led to a proportional shift toward earlier-stage breast cancers at presentation. We assessed whether the method of detection provides prognostic information above and beyond standard prognostic factors and investigated the accuracy of predicted overall and breast cancer–specific survival by the computer tool Adjuvant! among patients with screen-detected, interval, and nonscreening-related carcinomas.
Mutation in pre-mRNA adenosine deaminase markedly attenuates neuronal tolerance to O2 deprivation in Drosophila melanogaster
Authors: Enbo Ma, Xiang-Qun Gu, Xiaohui Wu, Tian Xu, Gabriel G. Haddad
Journal: Journal of Clinical Investigation (2001)

O2 deprivation can produce many devastating clinical conditions such as myocardial infarct and stroke. The molecular mechanisms underlying the inherent tissue susceptibility or tolerance to O2 lack are, however, not well defined. Since the fruit fly, Drosophila melanogaster, is extraordinarily tolerant to O2 deprivation, we have performed a genetic screen in the Drosophila to search for loss-of-function mutants that are sensitive to low O2. Here we report on the genetic and molecular characterization of one of the genes identified from this screen, named hypnos-2. This gene encodes a Drosophila pre-mRNA adenosine deaminase (dADAR) and is expressed almost exclusively in the adult central nervous system. Disruption of the dADAR gene results in totally unedited sodium (Para), calcium (Dmca1A), and chloride (DrosGluCl-α) channels, a very prolonged recovery from anoxic stupor, a vulnerability to heat shock and increased O2 demands, and neuronal degeneration in aged flies. These data clearly demonstrate that, through the editing of ion channels as targets, dADAR, for which there are mammalian homologues, is essential for adaptation to altered environmental stresses such as O2 deprivation and for the prevention of premature neuronal degeneration.
Juvenile onset spondyloarthropathies: therapeutic aspects
Authors: R Burgos-Vargas
Journal: Annals of the Rheumatic Diseases (2002)

Juvenile onset spondyloarthropathy (SpA) is a term that refers to a group of human leucocyte antigen (HLA)-B27 associated inflammatory disorders affecting children under the age of 16 years, producing a continuum of clinical symptoms through adulthood. This disease is characterised by enthesopathy and arthropathy affecting the joints of the lower extremities and seronegativity for IgM rheumatoid factor and antinuclear antibodies. Children usually present with undifferentiated SpA and progress to differentiated forms over time. Except for the prevalence of some clinical features at onset, the pathogenic and clinical aspects of juvenile onset SpAs resemble those of the adult disease. Thus application of the same or similar therapeutic measures for both juvenile and adult onset SpAs seems logical. Current treatments for juvenile onset SpA provide symptomatic improvement, but do not alter disease progression. The increased expression of tumour necrosis factor alpha (TNFα) in synovial tissue of patients with adult and juvenile onset SpA and its correlation with infiltration of inflammatory mediators into the synovia suggest a significant pathogenic role of this cytokine. Clinical trials of anti-TNFα antibody (infliximab) therapy in patients with adult onset SpA have demonstrated significant clinical improvement in inflammatory pain, function, disease activity, and quality of life in correlation with histological and immunohistochemical evidence of modulation of synovial inflammatory processes. These promising findings suggest that anti-TNFα therapy may confer similar benefits in patients with juvenile onset SpA.
Therapeutic implications of the pathophysiology of COPD
Authors: P. T. Macklem
Journal: European Respiratory Journal (2010)

This review examines 18 studies published ≥30 yrs ago. They show that the earliest manifestation of chronic obstructive pulmonary disease (COPD) is an increase in residual volume suggesting that the natural history of COPD is a progressive increase in gas trapping with a decreasing vital capacity (VC). The reduction in VC forces the forced expiratory volume in 1 s to decline with it. This is aggravated by rapid shallow breathing leading to dynamic hyperinflation. The earlier studies show that this is energetically opposite to a minimal work or force pattern and is responsible for dyspnoea and exercise limitation. This information, available for &gt;30 yrs leads to three virtually untested hypotheses: 1) training patients to breathe slowly and deeply transiently during exercise should decrease the work of breathing, dynamic hyperinflation and improve exercise performance; 2) rapid shallow breathing is caused by alveolar and bronchial inflammation that stimulates non-myelinated vagal C-fibre afferents, which are known to cause this breathing pattern; and 3) if so, therapeutic efforts to block these afferents might restore a slow-deep pattern and be beneficial, particularly in COPD exacerbations.
Expression of specific cytolytic activity by H-2I region-restricted, influenza virus-specific T lymphocyte clones.
Authors: A E Lukacher, L A Morrison, V L Braciale, B Malissen, T J Braciale
Journal: The Journal of Experimental Medicine (1985)

Among murine class II major histocompatibility complex (MHC)-restricted cytotoxic T lymphocyte (CTL) clones specific for type A influenza virus, we have identified both noncytolytic clones and clones exhibiting H-2 I region-restricted cytolytic activity. After appropriate antigenic stimulation, both cytolytic and noncytolytic clones proliferated in the absence of exogenous interleukin 2. All of the clones possess the Thy-1.2+, Lyt-1+2-, L3T4+ phenotype. The class II MHC restriction of viral recognition by the CTL clones was mapped by proliferation using recombinant mouse strains and by inhibition of cytotoxic activity with monoclonal antibodies directed to class II MHC products and L3T4a. The restriction specificity of two CTL clones was unambiguously assigned to the E beta d chain by using L cell transfectant lines expressing E alpha kE beta d or E alpha kE beta k gene products. Analysis of the viral specificity of the cloned lines revealed subtype-specific and crossreactive patterns of viral antigen recognition; the pattern of viral antigen specificity exhibited by each clone in proliferation and cell-mediated cytotoxicity was identical. Each CTL clone also demonstrated antigen-dependent release of helper factor(s) that promoted in vitro primary anti-SRBC responses. Finally, the cytotoxic effector function of the class II MHC-restricted CTL clones was mediated by direct lysis of virus-infected cells, and not by secretion of a cytolytic lymphokine.
Kinome expression profiling and prognosis of basal breast cancers
Authors: Renaud Sabatier, Pascal Finetti, Emilie Mamessier, Stéphane Raynaud, Nathalie Cervera, Eric Lambaudie, Jocelyne Jacquemier, Patrice Viens, Daniel Birnbaum, François Bertucci
Journal: Molecular Cancer (2011)

Abstract Background Basal breast cancers (BCs) represent ~15% of BCs. Although overall poor, prognosis is heterogeneous. Identification of good- versus poor-prognosis patients is difficult or impossible using the standard histoclinical features and the recently defined prognostic gene expression signatures (GES). Kinases are often activated or overexpressed in cancers, and constitute targets for successful therapies. We sought to define a prognostic model of basal BCs based on kinome expression profiling. Methods DNA microarray-based gene expression and histoclinical data of 2515 early BCs from thirteen datasets were collected. We searched for a kinome-based GES associated with disease-free survival (DFS) in basal BCs of the learning set using a metagene-based approach. The signature was then tested in basal tumors of the independent validation set. Results A total of 591 samples were basal. We identified a 28-kinase metagene associated with DFS in the learning set (N = 73). This metagene was associated with immune response and particularly cytotoxic T-cell response. On multivariate analysis, a metagene-based predictor outperformed the classical prognostic factors, both in the learning and the validation (N = 518) sets, independently of the lymphocyte infiltrate. In the validation set, patients whose tumors overexpressed the metagene had a 78% 5-year DFS versus 54% for other patients (p = 1.62E-4, log-rank test). Conclusions Based on kinome expression, we identified a predictor that separated basal BCs into two subgroups of different prognosis. Tumors associated with higher activation of cytotoxic tumor-infiltrative lymphocytes harbored a better prognosis. Such classification should help tailor the treatment and develop new therapies based on immune response manipulation.
Preoperative Dual-Phase Parathyroid Imaging With Tc-99m-Sestamibi
Authors: Anne K. Arveschoug, Henrik Bertelsen, Birthe Vammen, Jens Brøchner-Mortensen
Journal: Clinical Nuclear Medicine (2006)

Previously, we have found that the additional use of a pinhole collimator in parathyroid scintigraphy resulted in a decrease in the number of incorrect side localizations and an increase in reproducibility compared with that of using a parallel-hole collimator alone.The aim was to investigate whether the addition of anterior oblique views to parathyroid scintigraphy (PS) with a pinhole collimator could further enhance the diagnostic ability and reproducibility. The level of preoperative parathyroid hormone (PTH) as a potential predictor of the usefulness of the supplementary views was also studied.Forty-seven patients with primary hyperparathyroidism (HPT) underwent dual-phase PS using a combined protocol with parallel-hole and pinhole collimators. The pinhole collimator was used in the anterior as well as right and left anterior oblique positions. Thyroid pertechnetate scans were undertaken in the same positions. Two observers assessed the images independently.By adding oblique views, the gain in correct side localization occurred in all cases but one was seen in patients with rapid washout. The level of PTH could not predict these patients. The observer agreement on correct side localizations rose significantly from 81% to 94%.The addition of oblique views to the imaging protocol using the pinhole collimator for parathyroid and thyroid scintigraphy in primary HPT results in an increase in observer agreement and the number of correct side localizations in patients with rapid washout of MIBI. The preoperative level of PTH cannot, however, predict these patients.
Cardiac-Specific Overexpression of GLUT1 Prevents the Development of Heart Failure Attributable to Pressure Overload in Mice
Authors: Ronglih Liao, Mohit Jain, Lei Cui, Jessica D’Agostino, Francesco Aiello, Ivan Luptak, Soeun Ngoy, Richard M. Mortensen, Rong Tian
Journal: Circulation (2002)

Background— Increased rates of glucose uptake and glycolysis have been repeatedly observed in cardiac hypertrophy and failure. Although these changes have been considered part of the fetal gene reactivation program, the functional significance of increased glucose utilization in hypertrophied and failing myocardium is poorly understood. Methods and Results— We generated transgenic (TG) mice with cardiac-specific overexpression of insulin-independent glucose transporter GLUT1 to recapitulate the increases in basal glucose uptake rate observed in hypertrophied hearts. Isolated perfused TG hearts showed a greater rate of basal glucose uptake and glycolysis than hearts isolated from wild-type littermates, which persisted after pressure overload by ascending aortic constriction (AAC). The in vivo cardiac function in TG mice, assessed by echocardiography, was unaltered. When subjected to AAC, wild-type mice exhibited a progressive decline in left ventricular (LV) fractional shortening accompanied by ventricular dilation and decreased phosphocreatine to ATP ratio and reached a mortality rate of 40% at 8 weeks. In contrast, TG-AAC mice maintained LV function and phosphocreatine to ATP ratio and had &lt;10% mortality. Conclusions— We found that increasing insulin-independent glucose uptake and glycolysis in adult hearts does not compromise cardiac function. Furthermore, we demonstrate that increasing glucose utilization in hypertrophied hearts protects against contractile dysfunction and LV dilation after chronic pressure overload.
End-of-life decisions in neonatal intensive care: physicians' self-reported practices in seven European countries
Authors: M Cuttini, M Nadai, M Kaminski, G Hansen, R de Leeuw, S Lenoir, J Persson, M Rebagliato, M Reid, U de Vonderweid, HG Lenard, M Orzalesi, R Saracci
Journal: The Lancet (2000)
Trastuzumab-Resistant Cells Rely on a HER2-PI3K-FoxO-Survivin Axis and Are Sensitive to PI3K Inhibitors
Authors: Anindita Chakrabarty, Neil E. Bhola, Cammie Sutton, Ritwik Ghosh, María Gabriela Kuba, Bhuvanesh Dave, Jenny C. Chang, Carlos L. Arteaga
Journal: Cancer Research (2012)

Abstract The antibody trastuzumab is approved for treatment of patients with HER2 (ERBB2)-overexpressing breast cancer. A significant fraction of these tumors are either intrinsically resistant or acquire resistance rendering the drug ineffective. The development of resistance has been attributed to failure of the antibody to inhibit phosphoinositide 3-kinase (PI3K), which is activated by the HER2 network. Herein, we examined the effects of PI3K blockade in trastuzumab-resistant breast cancer cell lines. Treatment with the pan-PI3K inhibitor XL147 and trastuzumab reduced proliferation and pAKT levels, triggering apoptosis of trastuzumab-resistant cells. Compared with XL147 alone, the combination exhibited a superior antitumor effect against trastuzumab-resistant tumor xenografts. Furthermore, treatment with XL147 and trastuzumab reduced the cancer stem-cell (CSC) fraction within trastuzumab-resistant cells both in vitro and in vivo. These effects were associated with FoxO-mediated inhibition of transcription of the antiapoptosis gene survivin (BIRC5) and the CSC-associated cytokine interleukin-8. RNA interference–mediated or pharmacologic inhibition of survivin restored sensitivity to trastuzumab in resistant cells. In a cohort of patients with HER2-overexpressing breast cancer treated with trastuzumab, higher pretreatment tumor levels of survivin RNA correlated with poor response to therapy. Together, our results suggest that survivin blockade is required for therapeutic responses to trastuzumab and that by combining trastuzumab and PI3K inhibitors, CSCs can be reduced within HER2+ tumors, potentially preventing acquired resistance to anti-HER2 therapy. Cancer Res; 73(3); 1190–200. ©2012 AACR.
A Comparison Study of Multiple Measures of Adherence to HIV Protease Inhibitors
Authors: Honghu Liu, Carol E. Golin, Loren G. Miller, Ron D. Hays, C. Keith Beck, Sam Sanandaji, Judith Christian, Tomasa Maldonado, Dena Duran, Andrew H. Kaplan, Neil S. Wenger
Journal: Annals of Internal Medicine (2001)

Background: Poor adherence to HIV protease inhibitors may compromise the effectiveness of treatment. Few studies have compared methods for measuring adherence or have related adherence measures to a clinical outcome. Objective: To examine the relationship among a composite score of adherence, the three primary measures of adherence, and HIV virologic response. Design: Longitudinal cohort study. Setting: Public HIV clinic. Patients: 108 HIV-infected adults receiving protease inhibitors or non-nucleoside reverse transcriptase inhibitors who were monitored for 666 monthly intervals. Measurements: Medication Event Monitoring System (MEMS), pill count, and interview combined into a composite adherence score (CAS), and HIV viral load. Results: Mean antiretroviral adherence differed by adherence measure (MEMS, 0.63; pill count, 0.83; interview, 0.93; and CAS, 0.76). Composite adherence score decreased significantly over time. Composite adherence score, MEMS values, pill values, and interview values were statistically significantly associated with achievement of an undetectable viral load within 6 months of initiating therapy. Composite adherence score showed the strongest predictive relationship (odds ratios for a 10% increase in adherence for CAS, MEMS, pill count, and interview, respectively, were 1.26 [95% CI, 1.16 to 1.37], 1.13 [CI, 1.06 to 1.21], 1.10 [CI, 1.02 to 1.19], and 1.35 [CI, 0.94 to 1.94]). Conclusions: Different measures applied to the same patient suggest different levels of adherence. Adherence may be underestimated by MEMS and overestimated by pill count and interview. A summary measure combining several measures is more strongly related to a clinical response, but more practical measurement methods are needed for clinical use.
Efficacy of Bilateral Prophylactic Mastectomy in BRCA1 and BRCA2 Gene Mutation Carriers
Authors: L. C. Hartmann, T. A. Sellers, D. J. Schaid, T. S. Frank, C. L. Soderberg, D. L. Sitta, M. H. Frost, C. S. Grant, J. H. Donohue, J. E. Woods, S. K. McDonnell, C. W. Vockley, A. Deffenbaugh, F. J. Couch, R. B. Jenkins
Journal: JNCI Journal of the National Cancer Institute (2001)

In women with a family history of breast cancer, bilateral prophylactic mastectomy is associated with a decreased risk of subsequent breast cancer of approximately 90%. We examined the association between bilateral prophylactic mastectomy and breast cancer risk in women at high risk for breast cancer who also had mutations in BRCA1 and BRCA2 genes.We obtained blood samples from 176 of the 214 high-risk women who participated in our previous retrospective cohort study of bilateral prophylactic mastectomy. We used conformation-sensitive gel electrophoresis and direct sequence analysis of the blood specimens to identify women with mutations in BRCA1 and BRCA2. The carriers' probabilities of developing breast cancer were estimated from two different penetrance models.We identified 26 women with an alteration in BRCA1 or BRCA2. Eighteen of the mutations were considered to be deleterious and eight to be of uncertain clinical significance. None of the 26 women has developed breast cancer after a median of 13.4 years of follow-up (range, 5.8-28.5 years). Three of the 214 women are known to have developed a breast cancer after prophylactic mastectomy. For two of these women, BRCA1 and BRCA2 screening was negative, and no blood specimen was available for the third. Estimations of the effectiveness of prophylactic mastectomy were performed, considering this woman as both a mutation carrier and a noncarrier. These calculations predicted that six to nine breast cancers should have developed among the mutation carriers, which translates into a risk reduction, after bilateral prophylactic mastectomy, of 89.5%-100% (95% confidence interval = 41.4% to 100%).Prophylactic mastectomy is associated with a substantial reduction in the incidence of subsequent breast cancer not only in women identified as being at high risk on the basis of a family history of breast cancer but also in known BRCA1 or BRCA2 mutation carriers.
Cartilage oligomeric matrix protein expression in systemic sclerosis reveals heterogeneity of dermal fibroblast responses to transforming growth factor β
Authors: G Farina, R Lemaire, P Pancari, J Bayle, R L Widom, R Lafyatis
Journal: Annals of the Rheumatic Diseases (2008)

Objective: Cartilage oligomeric matrix protein (COMP) accumulates in systemic sclerosis (SSc) skin and is upregulated by transforming growth factor (TGF)β. To further characterise the response to TGFβ in SSc, we investigated TGFβ1 and COMP expression and myofibroblast staining in SSc skin. Methods: Skin biopsies from patients with diffuse cutaneous SSc (dSSc), limited cutaneous SSc (lSSc) and healthy controls were evaluated for COMP mRNA expression using real-time PCR. COMP, α-smooth muscle actin (SMA) and TGFβ were assessed in skin sections and in cultured fibroblasts by immunohistochemistry. Clinical disease status was assessed by the modified Rodnan skin score (mRSS). Results: Myofibroblasts expressing SMA and COMP were found coexpressed in many cells in dSSc dermis, but each also stained distinct cells in the dermis. Cultured SSc dermal fibroblasts also showed heterogeneity for COMP and SMA expression, with cells expressing SMA, COMP, both or neither. TGFβ treatment increased COMP and SMA-expressing cells. COMP mRNA expression in lesional skin from patients with dSSc correlated with the mRSS and TGFβ1 staining. Conclusion: These findings suggest that TGFβ upregulation of COMP and/or SMA expression in subpopulations of fibroblasts contributes to different pathways of fibrosis and that multiple TGFβ regulated genes may serve as biomarkers for the degree of SSc skin involvement.
Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2-inhibitory analog, dimethyl-celecoxib (DMC), in tumor cells in vitro and in vivo
Authors: Peter Pyrko, Nathaniel Soriano, Adel Kardosh, Yen-Ting Liu, Jasim Uddin, Nicos A Petasis, Florence M Hofman, Ching-Shih Chen, Thomas C Chen, Axel H Schönthal
Journal: Molecular Cancer (2006)

Abstract Background 2,5-Dimethyl-celecoxib (DMC) is a close structural analog of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex ® ) that lacks COX-2-inhibitory function. However, despite its inability to block COX-2 activity, DMC is able to potently mimic the anti-tumor effects of celecoxib in vitro and in vivo, indicating that both of these drugs are able to involve targets other than COX-2 to exert their recognized cytotoxic effects. However, the molecular components that are involved in mediating these drugs' apoptosis-stimulatory consequences are incompletely understood. Results We present evidence that celecoxib and DMC are able to down-regulate the expression of survivin, an anti-apoptotic protein that is highly expressed in tumor cells and known to confer resistance of such cells to anti-cancer treatments. Suppression of survivin is specific to these two drugs, as other coxibs (valdecoxib, rofecoxib) or traditional NSAIDs (flurbiprofen, indomethacin, sulindac) do not affect survivin expression at similar concentrations. The extent of survivin down-regulation by celecoxib and DMC in different tumor cell lines is somewhat variable, but closely correlates with the degree of drug-induced growth inhibition and apoptosis. When combined with irinotecan, a widely used anticancer drug, celecoxib and DMC greatly enhance the cytotoxic effects of this drug, in keeping with a model that suppression of survivin may be beneficial to sensitize cancer cells to chemotherapy. Remarkably, these effects are not restricted to in vitro conditions, but also take place in tumors from drug-treated animals, where both drugs similarly repress survivin, induce apoptosis, and inhibit tumor growth in vivo. Conclusion In consideration of survivin's recognized role as a custodian of tumor cell survival, our results suggest that celecoxib and DMC might exert their cytotoxic anti-tumor effects at least in part via the down-regulation of survivin – in a manner that does not require the inhibition of cyclooxygenase-2. Because inhibition of COX-2 appears to be negligible, it might be worthwhile to further evaluate DMC's potential as a non-coxib alternative to celecoxib for anti-cancer purposes.
Clinical Usefulness Of Bronchial Mannitol Provocation Test In Children With Asthma Symptoms
Authors: Young A. Park, Hyun Bin Park, Yoon Hee Kim, Hee Seon Lee, Yoon Ki Han, Min Jung Kim, Hye Mi Jee, Kyung Won Kim, Myung Hyun Sohn, Kyu-Earn Kim
Journal: Journal of Allergy and Clinical Immunology (2014)