tbuckley/cabot-search huggingface dataset:
Gefitinib Maintenance in Stage III Non–Small-Cell Lung Cancer
Authors: David J. Stewart
Journal: Journal of Clinical Oncology (2008)

■■■ TOTHEEDITOR:Kellyetal 1 recentlyreportedinJournalofClinical Oncology that gefitinib maintenance after chemoradiotherapy and consolidation chemotherapy was associated with a significant decreaseinoverallsurvival(butonlyaslightdecreaseinprogression-free survival)comparedwithplaceboinstageIIInon‐small-celllungcancer(NSCLC).Theyofferpotentialexplanationsforthis,asdoKeedyet al 2 in an accompanying editorial. We would like to suggest an additional possible reason for this outcome. The flattening of the NSCLC dose-response curve at higher chemotherapy doses suggests that the most important factor in chemotherapy resistance is deficiency of factors required for efficacy. 3 Platinum-resistant cell lines may have decreased expression of a range of transporters that are important for cellular uptake of chemotherapy and nutrients. 4 In patients with a variety of resistant tumor types, we assessed tumor expression (by immunohistochemistry) of the copper transporter CTR1, which is also important in platinum uptake. CTR1 expression was significantly lower in tumors of patients who had received either chemotherapy or targeted therapies withintheprevious3monthsthanintumorsofpatientswithalonger interval off therapy. 5 The correlation with time from last chemotherapy or targeted therapy was stronger than the correlation with time from last cytotoxic therapy alone. This leads us to hypothesize that either chemotherapy or targeted therapy may result in a broad reduction in membrane transporters and that this, in turn, may generate broad cross resistance. This could, in part, explain why adding tyrosine kinase inhibitors to chemotherapy did not improve outcome in chemotherapy-naive advanced NSCLC patients 6 and might also predict that monoclonal antibodies (that do not require uptake across membranes) might add to chemotherapy even if small molecules did not. If correct, this would also predict that most other currentlyavailablesmallmoleculestargetingtumorcellswilladdlittle
Analysis of BAL fluid in M. avium-intracellulare infection in individuals without predisposing lung disease
Authors: Y Yamazaki, K Kubo, M Sekiguchi, T Honda
Journal: European Respiratory Journal (1998)

The purpose of this study was to investigate the characteristics of pulmonary inflammation caused by Mycobacterium avium-intracellulare (MAI) in individuals with neither predisposing lung disease nor immunodeficiency. We reviewed the records of 20 patients with pulmonary MAI infection (including 19 female patients) whose past history and previous chest radiographs revealed no predisposing lung disease. We analysed the bronchoalveolar lavage fluid (BALF) from these 20 patients and from six normal female controls. The BALF was recovered directly from the relevant segment that was identified with chest-computed tomography. The BALF cell profiles showed significantly elevated counts for total cells, lymphocytes and neutrophils, but the macrophage cell count was not elevated. The CD4+ lymphocyte count and CD4+/CD8+ ratio were significantly increased compared with those in the controls. The lymphocytes demonstrated phenotypical evidence of activation, with increased expression of human leukocyte antigen-D-related antigen (HLA-DR). The tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and IL-8 concentrations were significantly increased. The neutrophil elastase concentration was also increased, and it was significantly correlated with the neutrophil cell count in the BALF. These findings suggest that the increased counts of activated CD4+ lymphocytes and neutrophils and the elevated concentrations of proinflammatory cytokines and neutrophil elastase appear to be common characteristics in Mycobacterium avium-intracellulare infection.
Rat cardiac muscle single cell automaticity responses to alpha- and beta-adrenergic agonists and antagonists.
Authors: K Hermsmeyer, R Mason, S H Griffen, P Becker
Journal: Circulation Research (1982)

Isolated cardiac muscle cells from neonatal rat ventricular myocardium have both alpha- and beta-adrenergic, positive chronotropic responses, with sensitivity to applied adrenergic agents more than 100 times greater than the intact neonatal heart. These highly sensitive isolated single cells and small groups of cells also reveal partial agonist activity of the alpha-adrenergic antagonist, phentolamine, and the beta-adrenergic antagonist, propranolol. The most likely explanation for the high sensitivity is the lack of a desensitization process that could involve both a desensitization substance and changes in receptors. These experiments suggest that all adrenergic antagonists could possibly show partial agonist activity.
Influence of diet with different lipid composition on neutrophil chemiluminescence and disease activity in patients with rheumatoid arthritis.
Authors: M Magaro, L Altomonte, A Zoli, L Mirone, P De Sole, G Di Mario, S Lippa, A Oradei
Journal: Annals of the Rheumatic Diseases (1988)

Neutrophil chemiluminescence was determined in patients with active rheumatoid arthritis. Twelve patients were randomly assigned either to a diet high in polyunsaturated fatty acids supplemented with eicosapentaenoic and docosahexaenoic acids or to a diet high in saturated fatty acids. A correlation with clinical and laboratory parameters is also reported. No statistical difference was observed in neutrophil chemiluminescence and in clinical parameters in the group of patients treated with a diet high in saturated fatty acids. Fish oil ingestion resulted in subjective alleviation of active rheumatoid arthritis and reduction of neutrophil chemiluminescence. This study corroborates the hypothesis of an anti-inflammatory role for polyunsaturated fatty acids in patients with chronic inflammatory diseases.
Cardiac Progenitor Cell Commitment Is Inhibited by Nuclear Akt Expression
Authors: Kimberlee M. Fischer, Shabana Din, Natalie Gude, Mathias H. Konstandin, Weitao Wu, Pearl Quijada, Mark A. Sussman
Journal: Circulation Research (2011)

Stem cell therapies to regenerate damaged cardiac tissue represent a novel approach to treat heart disease. However, the majority of adoptively transferred stem cells delivered to damaged myocardium do not survive long enough to impart protective benefits, resulting in modest functional improvements. Strategies to improve survival and proliferation of stem cells show promise for significantly enhancing cardiac function and regeneration.To determine whether injected cardiac progenitor cells (CPCs) genetically modified to overexpress nuclear Akt (CPCeA) increase structural and functional benefits to infarcted myocardium relative to control CPCs.CPCeA exhibit significantly increased proliferation and secretion of paracrine factors compared with CPCs. However, CPCeA exhibit impaired capacity for lineage commitment in vitro. Infarcted hearts receiving intramyocardial injection of CPCeA have increased recruitment of endogenous c-kit cells compared with CPCs, but neither population provides long-term functional and structural improvements compared with saline-injected controls. Pharmacological inhibition of Akt alleviated blockade of lineage commitment in CPCeA.Although overexpression of nuclear Akt promotes rapid proliferation and secretion of protective paracrine factors, the inability of CPCeA to undergo lineage commitment hinders their capacity to provide functional or structural benefits to infarcted hearts. Despite enhanced recruitment of endogenous CPCs, lack of functional improvement in CPCeA-treated hearts demonstrates CPC lineage commitment is essential to the regenerative response. Effective stem cell therapies must promote cellular survival and proliferation without inhibiting lineage commitment. Because CPCeA exhibit remarkable proliferative potential, an inducible system mediating nuclear Akt expression could be useful to augment cell therapy approaches.
Oral Human Brain Natriuretic Peptide Activates Cyclic Guanosine 3′,5′-Monophosphate and Decreases Mean Arterial Pressure
Authors: Alessandro Cataliotti, John A. Schirger, Fernando L. Martin, Horng H. Chen, Paul M. McKie, Guido Boerrigter, Lisa C. Costello-Boerrigter, Gail Harty, Denise M. Heublein, Sharon M. Sandberg, Kenneth D. James, Mark A. Miller, Navdeep B. Malkar, Karen Polowy, John C. Burnett
Journal: Circulation (2005)

The objective of this study was to address the feasibility and the biological activity of orally administered human brain natriuretic peptide (hBNP). Proprietary technology has been developed in which short, amphiphilic oligomers are covalently attached to peptides. The conjugated peptides are intended to have an improved pharmacokinetic profile and to enable oral administration. We hypothesized that novel oral conjugated hBNP (CONJ-hBNP) increases plasma hBNP, activates cGMP, and reduces mean arterial pressure (MAP).This randomized crossover-designed study tested the biological activity of oral CONJ-hBNP compared with oral native hBNP in normal conscious dogs. Measurements of MAP, plasma hBNP, and cGMP were made at baseline (BL) and repeated at 10, 30, 60, 120, 180, and 240 minutes after oral administration. Plasma hBNP was not detectable in dogs at BL. Plasma hBNP was detected after native hBNP and CONJ-HBNP administration. However, plasma hBNP concentration was significantly higher after CONJ-hBNP than after native hBNP administration (P=0.0374 between groups). Plasma cGMP increased after CONJ-hBNP for 60 minutes (from 10.8+/-3 to 36.8+/-26 pmol/mL; P<0.05), whereas it did not change after native hBNP (P=0.001 between groups). MAP decreased at 10 minutes and remained decreased for 60 minutes after CONJ-hBNP (from 113+/-8 to 101+/-12 mm Hg after 10 minutes to 97.5+/-10 mm Hg after 30 minutes to 99+/-13 mm Hg after 60 minutes) while remaining unchanged after native hBNP (P=0.0387 between groups).This study reports for the first time that novel conjugated oral BNP activates cGMP and significantly reduces MAP, thus implying an efficacious coupling of CONJ-hBNP to the natriuretic receptor-A. These data advance a new concept of orally administered chronic BNP therapy for cardiovascular diseases.
Induction of Centrosome Amplification and Chromosome Instability in Human Bladder Cancer Cells by p53 Mutation and Cyclin E Overexpression
Authors: Kenji Kawamura, Hideki Izumi, Zhiyong Ma, Ryosuke Ikeda, Manabu Moriyama, Tatsuro Tanaka, Takayuki Nojima, Linda S. Levin, Kohzaburo Fujikawa-Yamamoto, Koji Suzuki, Kenji Fukasawa
Journal: Cancer Research (2004)

Abstract Centrosome amplification frequently occurs in human cancers and is a major cause of chromosome instability (CIN). In mouse cells, centrosome amplification can be readily induced by loss or mutational inactivation of p53. In human cells, however, silencing of endogenous p53 alone does not induce centrosome amplification or CIN, although high degrees of correlation between p53 mutation and CIN/centrosome amplification in human cancer can be detected, suggesting the presence of additional regulatory mechanism(s) in human cells that ensures the numeral integrity of centrosomes and genomic integrity. Cyclin E, a regulatory subunit for CDK2 that plays a key role in centrosome duplication, frequently is overexpressed in human cancers. We found that cyclin E overexpression, together with loss of p53, efficiently induces centrosome amplification and CIN in human bladder cancer cells but not by either cyclin E overexpression or loss of p53 alone. We extended these findings to bladder cancer specimens and found that centrosome amplification is strongly correlated with concomitant occurrence of cyclin E overexpression and p53 inactivation but not with either cyclin E overexpression or p53 inactivation alone. Because cyclin E expression is strictly controlled in human cells compared with mouse cells, our findings suggest that this stringent regulation of cyclin E expression plays an additional role underlying numeral homeostasis of centrosomes in human cells and that deregulation of cyclin E expression, together with inactivation of p53, results in centrosome amplification.
Magnetic resonance angiography isequivalent to X-Ray coronary angiography for the evaluation of coronary arteries in kawasaki disease
Authors: Sophie Mavrogeni, George Papadopoulos, Marouso Douskou, Savas Kaklis, Ioannis Seimenis, Panagiotis Baras, Polixeni Nikolaidou, Chryssa Bakoula, Evangelos Karanasios, Athanasios Manginas, Dennis V Cokkinos
Journal: Journal of the American College of Cardiology (2004)
Endothelial Nitric Oxide Synthase Plays an Obligatory Role in the Late Phase of Ischemic Preconditioning by Activating the Protein Kinase Cε–p44/42 Mitogen-Activated Protein Kinase–pSer-Signal Transducers and Activators of Transcription1/3 Pathway
Authors: Yu-Ting Xuan, Yiru Guo, Yanqing Zhu, Ou-Li Wang, Gregg Rokosh, Roberto Bolli
Journal: Circulation (2007)

The role of endothelial nitric oxide synthase (eNOS) in ischemic preconditioning (PC) and cardioprotection is poorly understood. We addressed this issue using a genetic, rather than pharmacological, approach.In the nonpreconditioned state, eNOS-/- mice exhibited infarct sizes similar to those of wild-type mice. A sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles (ischemic PC) induced late PC in wild-type mice; genetic deletion of eNOS abrogated the cardioprotection induced by late PC. In wild-type mice, ischemic PC induced membranous translocation of protein kinase C (PKC) epsilon and an increase in pSer-MEK-1/2 and pTyr-p44/42 mitogen-activated protein kinase, nuclear pSer-signal transducers and activators of transcription (STAT)1 and pSer-STAT3, and nuclear STAT1/3 DNA binding activity, followed by upregulation of cyclooxygenase-2 protein and activity 24 hours later. All of these changes were abrogated in eNOS-/- mice. The NO donor diethylenetriamine/NO recapitulated the effects of ischemic PC.In contrast to previous reports, we found that basal eNOS activity does not modulate infarct size in the nonpreconditioned state. However, eNOS is obligatorily required for the development of the cardioprotective effects of late PC and acts as the trigger of this process by activating the PKC epsilon-MEK-1/2-p44/42 mitogen-activated protein kinase pathway, leading to Ser-727 phosphorylation of STAT1 and STAT3 and consequent upregulation of STAT-dependent genes such as cyclooxygenase-2. The effects of eNOS-derived NO are reproduced by exogenous NO (NO donors), implying that nitrates can upregulate cardiac cyclooxygenase-2.
Comparison of chemical-activated luciferase gene expression bioassay and gas chromatography for PCB determination in human serum and follicular fluid.
Authors: A Pauwels, P H Cenijn, P J Schepens, A Brouwer
Journal: Environmental Health Perspectives (2000)

We assessed exposure to dioxin-like compounds using chemical and bioassay analysis in different matrices in a female population. A total of 106 serum and 9 follicular fluid samples were collected from infertile women attending Centers for Reproductive Medicine in Belgium from 1996 to 1998. Major polychlorinated biphenyl (PCB) congeners were quantified by chemical analysis using gas chromatography with electron-capture detection, and the chemical-activated luciferase gene expression (CALUX) bioassay was used to determine the total dioxin-like toxic equivalence (TEQ) of mixtures of polyhalogenated aromatic hydrocarbons present in body fluids, such as serum and follicular fluid. To the best of our knowledge, this is the first investigation to determine TEQ values by the CALUX bioassay in follicular fluid. The TEQ levels in both matrices are well correlated (r = 0.83, p = 0.02). As the chemical and bioassay analysis executed in this study do not cover the same span of polyhalogenated aromatic hydrocarbons, we did not expect totally correlated results. Moreover, the sample workup and quantification of the analytes differed completely. Nonetheless, the TEQ values in human extracts correlated well with the sum of four major PCB congeners chemically determined in both serum and follicular fluid. These results indicate that the CALUX bioassay may serve as a simple, relatively inexpensive prescreening tool for exposure assessment in epidemiologic surveys.
PI3K/PTEN/Akt pathway status affects the sensitivity of high-grade glioma cell cultures to the insulin-like growth factor-1 receptor inhibitor NVP-AEW541
Authors: Daniel Hägerstrand, Maja Bradic Lindh, Cristina Peña, Carlos Garcia-Echeverria, Monica Nistér, Francesco Hofmann, Arne Östman
Journal: Neuro-Oncology (2010)

IGF-1 receptor signaling contributes to the growth of many solid tumors, including glioblastoma. This study analyzed the sensitivity of 8 glioblastoma cultures to the IGF-1 receptor inhibitor NVP-AEW541. Growth reduction, caused by a combination of antiproliferative and proapoptotic effects, varied between 20% and 100%. Growth-inhibitory effects of IGF-1 receptor siRNA were also demonstrated in 2 of the cultures. Activating mutations in PIK3CA were found in 2 cultures, and 2 other cultures displayed ligand-independent Akt phosphorylation. Growth inhibition was significantly reduced in cultures with PIK3CA mutations or ligand-independent Akt phosphorylation. PTEN siRNA experiments supported the notion that the status of the PI3K/PTEN/Akt pathway is involved in determining NVP-AEW541 sensitivity. Combination treatments with either PI3 kinase or mTOR inhibitors together with NVP-AEW541 were performed. These experiments demonstrated the effects of NVP-AEW541 in cells not responding to mono-treatment with the IGF-1 receptor inhibitor, when used together with either of the 2 other inhibitors. Together, the studies support continued clinical development of IGF-1 receptor antagonists for glioblastomas and identify links between PI3K/PTEN/Akt status and sensitivity to mono-treatment with NVP-AEW541. Furthermore, the studies suggest that NVP-AEW541 is also active together with PI3 kinase and mTOR inhibitors in cultures with a dysregulated PI3K/PTEN/Akt pathway. These studies should assist in future clinical development of IGF-1 receptor antagonists for glioblastoma and other tumors.
Acarbose Improves Glycemic Control in Overweight Type 2 Diabetic Patients Insufficiently Treated With Metformin
Authors: Patrick Phillips, Jeff Karrasch, Russell Scott, Dennis Wilson, Robert Moses
Journal: Diabetes Care (2003)

OBJECTIVE—To investigate the efficacy and safety of acarbose as add-on therapy in overweight type 2 patients with diabetes inadequately controlled by metformin. RESEARCH DESIGN AND METHODS—This study adopted a multicenter, randomized, double-blind, placebo-controlled, parallel group design. After a 4-week placebo run-in period, subjects were randomized to either acarbose (titrated up to 100 mg b.i.d.) or placebo. The primary efficacy variable was the change in HbA1c from baseline to the end of the 24-week treatment period. Change in fasting blood glucose was assessed as a secondary efficacy parameter. RESULTS—The intention-to-treat analysis from baseline to week 24 (81 patients for HbA1c and 82 for fasting blood glucose) showed statistically significant differences between acarbose and placebo treatment in HbA1c (1.02%; 95% CI 0.543–1.497; P = 0.0001) and fasting blood glucose (1.132 mmol/l; 95% CI 0.056–2.208; P = 0.0395) (adjusted least square means). In all, 18 patients (47%) in the acarbose group were classified as responders with a ≥5% reduction in HbA1c (relative to baseline) at the end point compared to 6 (14%) in the placebo group (P = 0.001). The safety profiles were similar for both treatment groups except for the higher incidence of gastrointestinal side effects during acarbose therapy. CONCLUSIONS—The addition of acarbose to metformin monotherapy provides an efficacious and safe alternative for glycemic improvement in overweight type 2 patients inadequately controlled by metformin alone.
Effects of Dietary Manipulation on Vascular Status of Patients With Peripheral Vascular Disease
Authors: Kenneth Hutchison
Journal: JAMA (1983)

In a one-year, double-blind clinical trial, 45 patients with peripheral vascular disease (PVD) were randomly assigned to either the American Heart Association Hyperlipidemia Diet C (n=20) or a low-fat, high-fiber, complex carbohydrate diet similar to the Pritikin Maintenance Diet (n=25). Vascular status and blood lipid levels were monitored at 0, 2, 4, 6, and 12 months. Walking distance increased significantly in both groups, with no difference between groups. No vascular parameters changed significantly, suggesting that increased walking distance was due to improved metabolic capacity of the muscle. A trend toward lower blood lipid values was observed, with no significant differences within or between groups. We conclude that while patients with PVD benefit from a program of diet and exercise, there is no apparent advantage to the more difficult complex carbohydrate diet. (<i>JAMA</i>1983;249:3326-3330)
Estimating Total Body Water in Children on the Basis of Height and Weight
Authors: Bruce Z. Morgenstern, Douglas W. Mahoney, Bradley A. Warady
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. An estimate of total body water (TBW) has important implications in clinical practice. For patients on peritoneal dialysis (PD), the estimate is critical when determining the delivered dialysis dose. The formulas of Mellits and Cheek have been recommended to estimate TBW in children on PD. These formulas were derived from healthy children, and very few infants were included. To assess the accuracy of these formulas, the original data were obtained and additional data from a broad literature review were compiled. The majority of the new data points were in the infant age range. Data were fitted using least-squares methodology and backward elimination to obtain a parsimonious model. Best fits were obtained using age, gender, and weight or a height × weight term. The results of the curves are as follows: Infants 0 to 3 mo (<i>n</i>= 71): TBW = 0.887 × (Wt)<sup>0.83</sup> Children 3 mo to 13 yr(<i>n</i> = 167): TBW = 0.0846 × 0.95<sup>[if female]</sup> × (Ht ×Wt)<sup>0.65</sup> Children &gt; 13 yr (<i>n</i> = 99): TBW = 0.0758 × 0.84<sup>[if female]</sup> × (Ht × Wt)<sup>0.69</sup> When compared with the previous Mellits and Cheek formulas, the new formula fits better for infants (comparison of prediction errors, <i>P</i> &lt; 0.0004). These newer formulas do not perform significantly better for the older two groups. Actual TBW measurement in children on PD must still be determined to verify the use of these formulas and to accurately assess dialysis delivery and adequacy.