tbuckley/cabot-search huggingface dataset:
Nitric oxide but not carbon monoxide is continuously released in the human nasal airways
Authors: J.O.N. Lundberg, J. Palm, K. Alving
Journal: European Respiratory Journal (2002)

Results from different laboratories indicate that nitric oxide (NO) and carbon monoxide (CO) coexist in the human airways both in health and disease. These gases are present in exhaled human breath and high concentrations of NO as well as CO have been reported in the nasal airways. In addition, exhaled CO and NO are increased in patients with airways inflammation. NO and CO were measured simultaneously in orally exhaled air and in air sampled from the nose in 18 healthy subjects using chemiluminescence (for NO) and infrared (for CO) techniques at different fixed flow rates. The acute effects of smoking on airway release of NO and CO were also studied. Nasal NO was detected in all subjects and the concentrations were highly flow-dependent (mean±sem: 236±23 and 527±49 parts per billion (ppb), at 2 and 0.5 L·min −1 , respectively). In contrast, no evidence of CO release in the nasal airways regardless of sample flow rate was found. In fact, additional experiments indicated a net absorption of CO when low levels of this gas were flushed through the nasal cavity. Nasal CO also remained undetectable after smoking. Both NO (22±2 ppb) and CO (1.1±0.1 parts per million) were consistently found in orally exhaled air. CO, but not NO, levels increased acutely after smoking a cigarette. The authors conclude that the patterns of nitric oxide and carbon monoxide release in the airways seem to differ profoundly in healthy subjects. Orally exhaled air contains both nitric oxide and carbon dioxide whereas nasal air contains nitric oxide only.
South African Indians Show a High Prevalence of NIDDM and Bimodality in Plasma Glucose Distribution Patterns
Authors: Mahomed A K Omar, Mahomed A Seedat, Robin B Dyer, Ayesha A Motala, Lucinda T Knight, Peter J Becker
Journal: Diabetes Care (1994)

OBJECTIVE To determine the prevalence of diabetes mellitus and impaired glucose tolerance (IGT) and to test for bimodality in the plasma glucose distribution in South African Indians. RESEARCH DESIGN AND METHODS Subjects were selected by systematic cluster sampling in various areas of Durban. They underwent a modified glucose tolerance test whereby fasting and 2-h postglucose (75 g) plasma glucose levels were measured. The program MIX was used to test for bimodality in the plasma glucose distribution. RESULTS We tested 2,479 subjects (1,441 women and 1,038 men). Based on the revised World Health Organization criteria, the crude prevalence of diabetes mellitus was 9.8%, and the crude prevalence of IGT was 5.8%; the age- and sex-adjusted prevalence was 13.0 and 6.9%, respectively. IGT was significantly more common in men (7.6%) than in women (4.4%). Obesity was a feature of both diabetes mellitus and IGT, particularly in women. Both fasting and 2-h plasma glucose values did not conform to a single normal distribution pattern in any age-group, whereas unequivocal evidence of bimodality was seen in the 55- to 74-year age-group of both sexes for fasting and 2-h glucose and also in the 2-h levels of men in the 25- to 34-year age-group. CONCLUSIONS This study has highlighted a high prevalence of non-insulindependent diabetes mellitus in South African Indians and bimodality in the plasma glucose distribution.
Lack of Apoptotic Protease Activating Factor-1 Expression and Resistance to Hypoxia-Induced Apoptosis in Cervical Cancer
Authors: Cornelia Leo, Lars-Christian Horn, Cora Rauscher, Bettina Hentschel, Christine E. Richter, Alexander Schütz, Chandra Paul Leo, Michael Höckel
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Clinical observations suggest that intratumoral hypoxia increases the aggressiveness of tumors through clonal selection of cancer cells that have lost their apoptotic potential. The aim of this study, therefore, was to investigate the expression of the proapoptotic protein apoptotic protease activating factor-1 (Apaf-1) in cervical cancers and to analyze its relation to intratumoral hypoxia and apoptosis. Furthermore, the effect of hypoxia and apoptosis on survival was examined. Experimental Design: In 56 patients, intratumoral oxygenation measurements and subsequent needle biopsies were done. The obtained tissue was analyzed by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assays and by immunohistochemistry with an Apaf-1 antibody. Results: Apaf-1 was expressed in 86% of cancers. The median apoptosis rate was 1.0%. There was no correlation between Apaf-1 expression and intratumoral hypoxia. However, Apaf-1 expression was negative in 37.5% of hypoxic cervical cancers (pO2 ≤ 10 mmHg) with low apoptosis rates (≤1.0%) compared with only 5.0% in nonhypoxic cancers and hypoxic cancers with high apoptosis (P = 0.005; Fisher's exact test). With a median follow-up period of 44 months, there was a nonsignificant trend toward worse prognosis in the hypoxic low-apoptotic group (P = 0.08). Conclusions: Although Apaf-1 is expressed in the vast majority of cervical cancers, a significant proportion of tumors with low apoptosis rates despite intratumoral hypoxia showed a lack of Apaf-1 expression. This finding suggests that loss of Apaf-1 expression is a mechanism by which hypoxic cervical cancers acquire resistance to apoptosis. Thus, low Apaf-1 expression in hypoxic tumors may be an unfavorable prognostic factor.
Haemodynamics and gas exchange before and after coil embolization of pulmonary arteriovenous malformations
Authors: P Andrivet, F Lofaso, MF Carette, J Allegrini, S Adnot
Journal: European Respiratory Journal (1995)

A complete description of haemodynamics and gas exchange before and after percutaneous coil embolization of multiple pulmonary arteriovenous malformations is reported in a 45 year old woman with hereditary haemorrhagic telangiectasis (HHT). Before treatment, whilst the patient complained of severe dyspnoea during daily activities, an intrapulmonary shunt of 31% was measured (inert gas elimination technique), together with a cardiac output (thermodilution technique) of 12.4 L.min-1, resulting in a resting arterial oxygen tension (PaO2) of 8.53 kPa. Effective occlusion of all visible pulmonary malformations resulted in a rapid and major improvement in exercise tolerance, whilst resting PaO2 remained almost unchanged. A second investigation performed 4 months after treatment revealed a persistent intrapulmonary shunt of 19%, a cardiac output of 7.35 L.min-1, and a resting PaO2 of 10.53 kPa. We conclude that major increases in cardiac output largely contribute to the maintenance of PaO2 in patients with multiple pulmonary arteriovenous malformations and intrapulmonary shunt. The benefit of coil embolization is due both to an improvement in arterial oxygenation and a normalization of cardiac output.
Functional Expression and Mutations of c-Met and Its Therapeutic Inhibition with SU11274 and Small Interfering RNA in Non–Small Cell Lung Cancer
Authors: Patrick C. Ma, Ramasamy Jagadeeswaran, Simha Jagadeesh, Maria S. Tretiakova, Vidya Nallasura, Edward A. Fox, Mark Hansen, Erik Schaefer, Katsuhiko Naoki, Alan Lader, William Richards, David Sugarbaker, Aliya N. Husain, James G. Christensen, Ravi Salgia
Journal: Cancer Research (2005)

Abstract Non–small cell lung cancer (NSCLC) is a difficult disease to treat. The c-Met receptor is an attractive potential target for novel therapeutic inhibition in human cancers. We provide strong evidence that c-Met is overexpressed, activated, and sometimes mutated in NSCLC cell lines and tumor tissues. Expression of c-Met was found in all (100%) of the NSCLC tumor tissues examined (n = 23) and most (89%) of the cell lines (n = 9). Sixty-one percent of tumor tissues strongly expressed total c-Met, especially adenocarcinoma (67%). Specific expression of phospho-Met (p-Met) [Y1003] and [Y1230/1234/1235] was seen by immunohistochemistry. p-Met expression was preferentially observed at the NSCLC tumor invasive fronts. c-Met alterations were identified within the semaphorin domain (E168D, L299F, S323G, and N375S) and the juxtamembrane domain (R988C, R988C + T1010I, S1058P, and alternative splice product skipping entire juxtamembrane domain) of a NSCLC cell line and adenocarcinoma tissues. We validated c-Met as potential therapeutic target using small interfering RNA down-regulation of the receptor expression by 50% to 60% in NSCLC cells. This led to inhibition of p-Met and phospho-AKT and up to 57.1 ± 7.2% cell viability inhibition at 72 hours. The selective small molecule inhibitor of c-Met SU11274 inhibited cell viability in c-Met-expressing NSCLC cells. SU11274 also abrogated hepatocyte growth factor–induced phosphorylation of c-Met and its downstream signaling. Here, we provide first direct evidence by small interfering RNA targeting and small molecule inhibitor that c-Met is important in NSCLC biology and biochemistry. These results indicate that c-Met inhibition will be an important therapeutic strategy against NSCLC to improve its clinical outcome.
Altered Striatal Activation Predicting Real-World Positive Affect in Adolescent Major Depressive Disorder
Authors: Erika E. Forbes, Ahmad R. Hariri, Samantha L. Martin, Jennifer S. Silk, Donna L. Moyles, Patrick M. Fisher, Sarah M. Brown, Neal D. Ryan, Boris Birmaher, David A. Axelson, Ronald E. Dahl
Journal: American Journal of Psychiatry (2008)

Objective: Alterations in reward-related brain function and phenomenological aspects of positive affect are increasingly examined in the development of major depressive disorder. The authors tested differences in reward-related brain function in healthy and depressed adolescents, and the authors examined direct links between reward-related brain function and positive mood that occurred in real-world contexts. Method: Fifteen adolescents with major depressive disorder and 28 adolescents with no history of psychiatric disorder, ages 8–17 years, completed a functional magnetic resonance imaging guessing task involving monetary reward. Participants also reported their subjective positive affect in natural environments during a 4-day cell-phone-based ecological momentary assessment. Results: Adolescents with major depressive disorder exhibited less striatal response than healthy comparison adolescents during reward anticipation and reward outcome, but more response in dorsolateral and medial prefrontal cortex. Diminished activation in a caudate region associated with this depression group difference was correlated with lower subjective positive affect in natural environments, particularly within the depressed group. Conclusions: Results support models of altered reward processing and related positive affect in young people with major depressive disorder and indicate that depressed adolescents’ brain response to monetary reward is related to their affective experience in natural environments. Additionally, these results suggest that reward-processing paradigms capture brain function relevant to real-world positive affect.
Impact of age and medical comorbidity on adjuvant treatment outcomes for stage III colon cancer: a pooled analysis of individual patient data from four randomized, controlled trials
Authors: D.G. Haller, M.J. O'Connell, T.H. Cartwright, C.J. Twelves, E.F. McKenna, W. Sun, M.W. Saif, S. Lee, G. Yothers, H.-J. Schmoll
Journal: Annals of Oncology (2015)
A synthetic PPAR-γ agonist triterpenoid ameliorates experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses
Authors: Jun Wei, Hongyan Zhu, Kazuhiro Komura, Gabriel Lord, Michal Tomcik, Wenxia Wang, Sruthi Doniparthi, Zenshiro Tamaki, Monique Hinchcliff, Joerg H W Distler, John Varga
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Persistent fibroblast activation initiated by transforming growth factor β (TGF-β) is a fundamental event in the pathogenesis of systemic sclerosis, and its pharmacological inhibition represents a potential therapeutic strategy. The nuclear receptor, peroxisome proliferator-activated receptor γ (PPAR-γ), exerts potent fibrotic activity. The synthetic oleanane triterpenoid, 2-cyano-3,12-dioxo-olean-1,9-dien-28-oic acid (CDDO), is a PPAR-γ agonist with potential effects on TGF-β signalling and dermal fibrosis. <h3>Objective</h3> To examine the modulation of fibrogenesis by CDDO in explanted fibroblasts, skin organ cultures and murine models of scleroderma. <h3>Material and methods</h3> The effects of CDDO on experimental fibrosis induced by bleomycin injection or by overexpression of constitutively active type I TGF-β receptor (TgfbR1ca) were evaluated. Modulation of fibrotic gene expression was examined in human skin organ cultures. To delineate the mechanisms underlying the antifibrotic effects of CDDO, explanted skin fibroblasts cultured in two-dimensional monolayers or in three-dimensional full-thickness human skin equivalents were studied. <h3>Results</h3> CDDO significantly ameliorated dermal fibrosis in two complementary mouse models of scleroderma, as well as in human skin organ cultures and in three-dimensional human skin equivalents. In two-dimensional monolayer cultures of explanted normal fibroblasts, CDDO abrogated fibrogenic responses induced by TGF-β. These CDDO effects occurred via disruption of Smad-dependent transcription and were associated with inhibition of Akt activation. In scleroderma fibroblasts, CDDO attenuated the elevated synthesis of collagen. Remarkably, the in vitro antifibrotic effects of CDDO were independent of PPAR-γ. <h3>Conclusions</h3> The PPAR-γ agonist triterpenoid CDDO attenuates fibrogenesis by antagonistically targeting canonical TGF-β/Smad and Akt signalling in a PPAR-γ-independent manner. These findings identify this synthetic triterpenoid as a potential new therapy for the control of fibrosis.
A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer
Authors: M.N. Fornier, P.G. Morris, A. Abbruzzi, G. D'Andrea, T. Gilewski, J. Bromberg, C. Dang, M. Dickler, S. Modi, A.D. Seidman, N. Sklarin, J. Chang, L. Norton, C.A. Hudis
Journal: Annals of Oncology (2011)
Zardaverine and aerosolised iloprost in a model of acute respiratoryfailure
Authors: R.T. Schermuly, H. Leuchte, H.A. Ghofrani, N. Weissmann, F. Rose, M. Kohstall, H. Olschewski, C. Schudt, F. Grimminger, W. Seeger, D. Walmrath
Journal: European Respiratory Journal (2003)

In this study, the impact of aerosolised prostacyclin (PGI 2 ) and iloprost in the absence or presence of subthreshold intravascular doses of the dual-selective phosphodiesterase-3/4 inhibitor zardaverine was investigated in an experimental model of acute respiratory failure. In perfused rabbit lungs, continuous infusion of the thromboxane‐A 2 ‐mimetic U46619 provoked pulmonary hypertension, accompanied by progressive lung oedema formation and severe ventilation-perfusion mismatch with predominance of shunt flow (increasing from ∼2 to 58%, as assessed by the multiple inert gas elimination technique). Aerosolisation of PGI 2 (in total 1.05 µg·kg −1 ) for 15 min caused a decrease in pulmonary artery pressure ( P pa ) and a limitation of maximum shunt flow to ∼37%. When nebulised PGI 2 was combined with subthreshold intravascular zardaverine, which did not affect pulmonary haemodynamics per se , the duration of the PGI 2 effect was increased. Aerosolisation of 3 µg·kg −1 PGI 2 resulted in a transient decrease in P pa and a reduction in shunt flow. In the presence of subthreshold zardaverine, the effects of this PGI 2 dose were only marginally increased. Aerosolisation of iloprost (in total 0.7 µg·kg −1 ) for 15 min caused a more sustained decrease in P pa , some enhanced reduction of oedema formation as compared with PGI 2 and a decrease in shunt flow to ∼32%. Most impressively, when combined with subthreshold zardaverine, iloprost suppressed oedema formation to &lt;15% and shunt flow to ∼8%. In conclusion, combined use of aerosolised iloprost and subthreshold systemic phosphodiesterase-3/4 inhibitor may result in selective intrapulmonary vasodilation, a reduction in oedema formation and an improvement in ventilation-perfusion matching in acute respiratory failure.
Fossil Calibration of Molecular Divergence Infers a Moderate Mutation Rate and Recent Radiations for Pinus
Authors: Ann Willyard, John Syring, David S. Gernandt, Aaron Liston, Richard Cronn
Journal: Molecular Biology and Evolution (2006)

Silent mutation rate estimates for Pinus vary 50-fold, ranging from angiosperm-like to among the slowest reported for plants. These differences either reflect extraordinary genomic processes or inconsistent fossil calibration, and they have important consequences for population and biogeographical inferences. Here we estimate mutation rates from 4 Pinus species that represent the major lineages using 11 nuclear and 4 chloroplast loci. Calibration was tested at the divergence of Pinus subgenera with the oldest leaf fossil from subg. Strobus (Eocene; 45 MYA) or a recently published subg. Strobus wood fossil (Cretaceous; 85 MYA). These calibrations place the origin of Pinus 190–102 MYA and give absolute silent rate estimates of 0.70–1.31 × 10−9 and 0.22–0.42 × 10−9·site−1·year−1 for the nuclear and chloroplast genomes, respectively. These rates are approximately 4- to 20-fold slower than angiosperms, but unlike many previous estimates, they are more consistent with the high per-generation deleterious mutation rates observed in pines. Chronograms from nuclear and chloroplast genomes show that the divergence of subgenera accounts for about half of the time since Pinus diverged from Picea, with subsequent radiations occurring more recently. By extending the sampling to encompass the phylogenetic diversity of Pinus, we predict that most extant subsections diverged during the Miocene. Moreover, subsect. Australes, Ponderosae, and Contortae, containing over 50 extant species, radiated within a 5 Myr time span starting as recently as 18 MYA. An Eocene divergence of pine subgenera (using leaf fossils) does not conflict with fossil-based estimates of the Pinus–Picea split, but a Cretaceous divergence using wood fossils accommodates Oligocene fossils that may represent modern subsections. Because homoplasy and polarity of character states have not been tested for fossil pine assignments, the choice of fossil and calibration node represents a significant source of uncertainty. Based on several lines of evidence (including agreement with ages inferred using calibrations outside of Pinus), we conclude that the 85 MYA calibration at the divergence of pine subgenera provides a reasonable lower bound and that further refinements in age and mutation rate estimates will require a synthetic examination of pine fossil history.
Radiotherapy Alone Versus Combined Chemotherapy and Radiotherapy in Nonresectable Non-Small-Cell Lung Cancer: First Analysis of a Randomized Trial in 353 Patients
Authors: T. Le Chevalier, R. Arriagada, E. Quoix, P. Ruffle, M. Martin, M. Tarayre, L.-T. Marie-Jose, J.-Y. Douillard, A. Laplanche
Journal: JNCI Journal of the National Cancer Institute (1991)

We report the results observed in a large, randomized study that compared the effects of radiotherapy alone (the standard therapy) with those of a combination of radiotherapy and chemotherapy in nonresectable squamous cell and large-cell lung carcinoma. The radiation dose was 65 Gy in each group, and chemotherapy included vindesine, cyclophosphamide, cisplatin, and lomustine. In this study, 177 patients received radiotherapy alone (group A), and 176 patients received the combined treatment (group B). The 2-year survival rate was 14% in group A and 21% in group B (P = .08). The distant metastasis rate was significantly lower in group B (P less than .001). Local control was poor in both groups (17% and 15%, respectively) and remained the major problem.
Carbamoylphosphonate Matrix Metalloproteinase Inhibitors 3: <i>In vivo</i> Evaluation of Cyclopentylcarbamoylphosphonic Acid in Experimental Metastasis and Angiogenesis
Authors: Reuven Reich, Yiffat Katz, Rivka Hadar, Eli Breuer
Journal: Clinical Cancer Research (2005)

Abstract The spread of malignant tumor cells from a primary neoplasm to distant organs where they multiply and form new foci is the major cause of death from cancer. Despite the different modalities of cancer treatment, no effective curative therapy of metastatic lesions is available. To possess metastatic potential, a cell has to be able to invade the surrounding tissue, spread via lymphatics and/or the bloodstream, extravasate, and multiply at secondary sites. There is increasing evidence for a positive correlation between matrix metalloproteinase-2 (MMP-2) activity and tumor cell invasion. Agents blocking MMP-2 have been shown to prevent tumor cell invasion in vitro and in vivo. Inhibition of MMPs has, therefore, become the focus of considerable interest in connection with a variety of potential therapeutic applications. We have discovered a nontoxic MMP-2–selective inhibitor effective at nanomolar range on recombinant MMP. This compound, cyclopentylcarbamoylphosphonic acid, significantly inhibited cellular invasion and capillary formation in vitro. Further, i.p. or oral administration of the compound significantly reduced lung metastasis formation and s.c. tumor growth in a murine melanoma model. The effect of this novel compound on lung colonization, capillary formation, and s.c. tumor growth indicates that the compound might also be effective in treatment of primary tumor growth in reduction, or at least in prevention, of further tumor growth, thereby reducing the tumor burden of the patient by a nontoxic approach.
A Rapid and Sensitive Enzymatic Method for Epidermal Growth Factor Receptor Mutation Screening
Authors: Pasi A. Jänne, Ana M. Borras, Yanan Kuang, Andrew M. Rogers, Victoria A. Joshi, Hema Liyanage, Neal Lindeman, Jeffrey C. Lee, Balazs Halmos, Elizabeth A. Maher, Robert J. Distel, Matthew Meyerson, Bruce E. Johnson
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Mutations in the epidermal growth factor receptor (EGFR) are associated with clinical and radiographic responses to EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Currently available methods of EGFR mutation detection rely on direct DNA sequencing, which requires isolation of DNA from a relatively pure population of tumor cells, cannot be done on small diagnostic specimens, and lack sensitivity. Here we describe the use of a sensitive screening method that overcomes many of these limitations. Experimental Design: We screened 178 non–small cell lung cancer specimens for mutations in exons 18 to 21 of EGFR using a DNA endonuclease, SURVEYOR, which cleaves mismatched heteroduplexed DNA. Samples were analyzed by high-performance liquid chromatography on the Transgenomic WAVE HS system. Selected specimens that produced digestion products using SURVEYOR were subsequently reanalyzed by size separation or under partially denaturing conditions, followed by fractionation and sequencing. The specimens included DNA isolated from frozen tumor specimens, dissected formalin-fixed, paraffin-embedded tumor specimens undergoing clinical sequencing, and undissected formalin-fixed, paraffin-embedded specimens. One hundred sixty specimens were independently analyzed using direct DNA sequencing in a blinded fashion. Results: EGFR mutations were detected in 16 of 61 fresh frozen tumor specimens, 24 of 91 dissected formalin-fixed, paraffin-embedded tumor specimens, and 11 of 26 undissected formalin-fixed, paraffin-embedded tumor specimens. Compared with sequencing, the sensitivity and specificity of the present method were 100% and 87%. The positive and negative predictive values were 74% and 100%, respectively. SURVEYOR analysis detected 7 (4%) mutations that were not previously detected by direct sequencing. Conclusions: SURVEYOR analysis provides a rapid method for EGFR mutation screening with 100% sensitivity and negative predictive value. This unbiased scanning technique is superior to direct sequencing when used with undissected formalin-fixed, paraffin-embedded specimens.