tbuckley/cabot-search huggingface dataset:
C/EBPα and HNF6 protein complex formation stimulates HNF6-dependent transcription by CBP coactivator recruitment in HepG2 cells
Authors: Yuichi Yoshida, Douglas E. Hughes, Francisco M. Rausa, Il-Man Kim, Yongjun Tan, Gretchen J. Darlington, Robert H. Costa
Journal: Hepatology (2006)

We previously demonstrated that formation of complexes between the DNA-binding domains of hepatocyte nuclear factor 6 (HNF6) and forkhead box a2 (Foxa2) proteins stimulated Foxa2 transcriptional activity. Here, we used HepG2 cell cotransfection assays to demonstrate that HNF6 transcriptional activity was stimulated by CCAAT/enhancer-binding protein α (C/EBPα), but not by the related C/EBPβ or C/EBPδ proteins. Formation of the C/EBPα–HNF6 protein complex required the HNF6 cut domain and the C/EBPα activation domain (AD) 1/AD2 sequences. This C/EBPα–HNF6 transcriptional synergy required both the N -terminal HNF6 polyhistidine and serine/threonine/proline box sequences, as well as the C/EBPα AD1/AD2 sequences, the latter of which are known to recruit the CREB binding protein (CBP) transcriptional coactivator. Consistent with these findings, adenovirus E1A–mediated inhibition of p300/CBP histone acetyltransferase activity abrogated C/EBPα–HNF6 transcriptional synergy in cotransfection assays. Co-immunoprecipitation assays with liver protein extracts demonstrate an association between the HNF6 and C/EBPα transcription factors and the CBP coactivator protein in vivo . Furthermore, chromatin immunoprecipitation assays with hepatoma cells demonstrated that increased levels of both C/EBPα and HNF6 proteins were required to stimulate association of these transcription factors and the CBP coactivator protein with the endogenous mouse Foxa2 promoter region. In conclusion , formation of the C/EBPα–HNF6 protein complex stimulates recruitment of the CBP coactivator protein for expression of Foxa2, a transcription factor critical for regulating expression of hepatic gluconeogenic genes during fasting. (Hepatology 2006;43:276–286.)
Solitary pulmonary nodule uncovered
Authors: Eloísa Silva, Marta Sousa, Jorge Vale, Vitor Melo, António Reis, António Simões Torres
Journal: European Respiratory Journal (2013)

Introduction: The approach to the solitary pulmonary nodule (SPN), pursuing a premature diagnosis of malignancy, remains a challenge in critical practice.  Objectives: to evaluate the clinical and imaging characteristics of the nodule and determine the variables associated with malignancy.  Methods: retrospective study, through review of clinical files of patients with SPN.  Results: 47 patients were included, 51.1% female, with an average age of 63.4 years. On 66% of the patients lesion was seen on chest X-ray. Most nodules were located in the right inferior lobe (27.7%).The most prevalent etiologies were malignancy (36.2%), hamartoma (17%) and tuberculoma (6.4%). Malignant nodules were predominantly located in the right inferior lobe (35.3%), were > 2cm (70.6%) with solid attenuation (76.5%) and irregular/spiculated borders (76.5%); 47.1% had pleural tail and 17.6% had air bronchograms; no calcification or cavitation were seen on these nodules. 93.3% showed contrast enhancement on CT, mostly heterogeneous, and 84.6% FDG enhancement on PET-CT. Older age, nodule size, pleural tail, heterogeneous enhancement on CT and FDG enhancement on PET were statistically related to malignancy.  Conclusion: Malignancy showed a prevalence of 36.2%. Older age, nodule size, pleural tail, heterogeneous enhancement on CT and enhancement on PET were statistically related to malignancy.
Effects of dietary carbohydrate on delayed onset muscle soreness and reactive oxygen species after contraction induced muscle damage
Authors: G L Close, T Ashton, T Cable, D Doran, C Noyes, F McArdle, D P M MacLaren
Journal: British Journal of Sports Medicine (2005)

Delayed onset muscle soreness (DOMS) occurs after unaccustomed exercise and has been suggested to be attributable to reactive oxygen species (ROS). Previous studies have shown increased ROS after lengthening contractions, attributable to invading phagocytes. Plasma glucose is a vital fuel for phagocytes, therefore carbohydrate (CHO) status before exercise may influence ROS production and DOMS.To examine the effect of pre-exercise CHO status on DOMS, ROS production, and muscle function after contraction induced muscle damage.Twelve subjects performed two downhill runs, one after a high CHO diet and one after a low CHO diet. Blood samples were drawn for analysis of malondialdehyde, total glutathione, creatine kinase, non-esterified fatty acids, lactate, glucose, and leucocytes. DOMS and muscle function were assessed daily.The high CHO diet resulted in higher respiratory exchange ratio and lactate concentrations than the low CHO diet before exercise. The low CHO diet resulted in higher non-esterified fatty acid concentrations before exercise. DOMS developed after exercise and remained for up to 96 hours, after both diets. A biphasic response in creatine kinase occurred after both diets at 24 and 96 hours after exercise. Malondialdehyde had increased 72 hours after exercise after both diets, and muscle function was attenuated up to this time.Downhill running resulted in increased ROS production and ratings of DOMS and secondary increases in muscle damage. CHO status before exercise had no effect.
Intestinal transit, deoxycholic acid and the cholesterol saturation of bile--three inter-related factors.
Authors: S N Marcus, K W Heaton
Journal: Gut (1986)

There is considerable evidence that the level of deoxycholic acid in the bile influences biliary cholesterol saturation. Deoxycholic acid is formed in the colon and absorbed slowly. Hence changes in colonic transit rate might influence biliary deoxycholic acid and the cholesterol saturation of bile. When 14 constipated subjects took standardised senna tablets for six weeks in a dose sufficient to lower mean whole gut transit time from 134 to 54 hours, deoxycholic acid as a proportion of biliary bile acids fell from 25.9 +/- 8.6 to 17.2 +/- 8.3% (p less than 0.0001) and deoxycholic acid pool measured by isotope dilution fell from 0.64 +/- 0.34 to 0.45 +/- 0.29 g (p less than 0.0001). In those subjects (n = 8) whose bile was initially supersaturated with cholesterol, the saturation index fell from 1.40 +/- 0.22 to 1.20 +/- 0.19 (p = 0.02). Conversely, when 12 normal volunteers took loperamide capsules sufficient to cause symptomatic constipation and to prolong mean transit-time from 48 to 103 hours, the deoxycholic acid pool increased from 0.40 +/- 0.24 to 0.57 +/- 0.17 g (p = 0.008). The percentage deoxycholic acid did not alter significantly, because the estimated total bile acid pool expanded (from 1.98 +/- 0.61 to 2.81 +/- 0.48 g; p less than 0.001), presumably because of loperamide slowing down small bowel transit. Despite this expansion of the bile acid pool, loperamide increased the cholesterol saturation index from 1.10 +/- 0.31 to 1.20 +/- 0.32 (p = 0.01). Changes in colonic transit rate alter the size of the deoxycholic acid pool and bile cholesterol saturation. These findings suggest that constipation or slow colonic transit might increase the chance of supersaturated bile and hence of gall stones.
Impact of<i>ABCB1</i>Allelic Variants on QTc Interval Prolongation
Authors: Tristan M. Sissung, Erin R. Gardner, Richard L. Piekarz, Reuben Howden, Xiaohong Chen, Sukyung Woo, Ryan Franke, James A. Clark, Laura Miller-DeGraff, Seth M. Steinberg, David Venzon, David Liewehr, Steven R. Kleeberger, Susan E. Bates, Douglas K. Price, Douglas R. Rosing, Christopher Cabell, Alex Sparreboom, William D. Figg
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Although the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood–tissue barriers (i.e., blood–brain and blood–nerve), its participation in a putative blood–heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT prolongation and cardiotoxicity. Experimental Design: ABCB1-related romidepsin transport kinetics were explored in LLC-PK1 cells transfected with different ABCB1 genetic variants. ABCB1 plasma and intracardiac concentrations were determined in Abcb1a/1b (−/−) mice and wild-type FVB controls. These same mice were used to evaluate romidepsin-induced heart rate-corrected QT interval (QTc) prolongation over time. Finally, a cohort of 83 individuals with available QTcB and ABCB1 genotyping data were used to compare allelic variation in ABCB1 versus QTc-prolongation phenotype. Results: Here, we show that mice lacking the ABCB1-type P-glycoprotein have higher intracardiac concentrations of a model ABCB1 substrate, romidepsin, that correspond to changes in QT prolongation from baseline (ΔQTc) over time. Consistent with this observation, we also show that patients carrying genetic variants that could raise ABCB1 expression in the cardiac endothelium have lower ΔQTc following a single dose of romidepsin. Conclusions: To our knowledge, this is the first evidence that Abcb1-type P-glycoprotein can limit intracardiac exposure to a drug that mediates QT prolongation and suggests that certain commonly inherited polymorphisms in ABCB1 may serve as markers for QT prolongation following the administration of ABCB1-substrate drugs. Clin Cancer Res; 17(4); 937–46. ©2010 AACR.
Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.
Authors: G Boden, X Chen
Journal: Journal of Clinical Investigation (1995)

It was the aim of this study to determine whether FFA inhibit insulin-stimulated whole body glucose uptake and utilization in patients with non-insulin-dependent diabetes. We performed five types of isoglycemic (approximately 11mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin; (c) with insulin plus glycerol; (d) with saline; (e) with saline plus fat/heparin and two types of euglycemic (approximately 5mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin. During these studies, we determined rates of glucose uptake, glycolysis (both with 3[3H] glucose), glycogen synthesis (determined as glucose uptake minus glycolysis), carbohydrate oxidation (by indirect calorimetry) and nonoxidative glycolysis (determined as glycolysis minus carbohydrate oxidation). Fat/heparin infusion did not affect basal glucose uptake, but inhibited total stimulated (insulin stimulated plus basal) glucose uptake by 40-50% in isoglycemic and in euglycemic patients at plasma FFA concentration of approximately 950 and approximately 550 microM, respectively. In isoglycemic patients, the 40-50% inhibition of total stimulated glucose uptake was due to near complete inhibition of the insulin-stimulated part of glucose uptake. Proportional inhibition of glucose uptake, glycogen synthesis, and glycolysis suggested a major FFA-mediated defect involving glucose transport and/or phosphorylation. In summary, fat produced proportional inhibitions of insulin-stimulated glucose uptake and of intracellular glucose utilization. We conclude, that physiologically elevated levels of FFa could potentially be responsible for a large part of the peripheral insulin resistance in patients with non-insulin-dependent diabetes mellitus.
Phase I and pharmacokinetic study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f ), using a weekly 30-minute intravenous infusion, in patients with advanced solid malignancies
Authors: J.P. Braybrooke, E. Boven, N.P. Bates, R. Ruijter, N. Dobbs, P.D. Cheverton, H.M. Pinedo, D.C. Talbot
Journal: Annals of Oncology (2003)
Streptococcal impetigo induces Th1‐preponderant activation of T lymphocytes with subsequent anergy to superantigenic exotoxins in patients with atopic dermatitis
Authors: None Tokura, None Ishii‐Ginoza, None Seo, None Ito, None Sakurai, None Furukawa, None Takigawa
Journal: British Journal of Dermatology (1998)
Radiation Improves the Distribution and Uptake of Liposomal Doxorubicin (Caelyx) in Human Osteosarcoma Xenografts
Authors: Catharina de L. Davies, Lisa M. Lundstrøm, Jomar Frengen, Live Eikenes, Øyvind S. Bruland, Olav Kaalhus, Mari H. B. Hjelstuen, Christian Brekken
Journal: Cancer Research (2004)

Abstract Liposomal drug delivery appears to improve the antitumor effect and reduce toxicity compared with the free drug. The therapeutic index may be improved further by combining cytotoxic drugs and radiotherapy. Successful therapy requires that the cytotoxic agents reach the tumor cells. Therefore, we studied tumor growth and the microdistribution of liposomal doxorubicin (Caelyx) with and without additional ionizing radiation in human osteosarcoma xenografts in athymic mice. Caelyx was injected i.v. 1 day before single or fractionated radiotherapy. Both chemoirradiation regimens induced significant tumor growth delays and worked synergistically. Confocal laser scanning microscopy showed that intact liposomes were located in close proximity to endothelial cells, and the distribution of released doxorubicin was heterogeneous. Before radiotherapy, hardly any doxorubicin was localized in the central parts of the tumor. Radiotherapy increased the tumor uptake of doxorubicin by a factor of two to four, with drug being redistributed farther from the vessels in the tumor periphery and located around vessels in the central parts of the tumor. Colocalization of doxorubicin and hypoxic cells showed no distribution of drug into hypoxic areas. Dynamic contrast-enhanced magnetic resonance imaging (MRI) 1 day before the injection of Caelyx and 2 days after treatment start showed that the combined treatment reduced the vascular volume and the vascular transfer rate of the MRI tracer. The results show that chemoirradiation with Caelyx induces synergistic treatment effects. Improved intratumoral drug uptake and distribution are responsible to some extent for the enhanced antitumor effect.
Studies on Mechanisms of Hypocalcemia of Magnesium Depletion
Authors: Chilumula R. Reddy, Jack W. Coburn, David L. Hartenbower, Robert M. Friedler, Arnold S. Brickman, Shaul G. Massry, Jenifer Jowsey
Journal: Journal of Clinical Investigation (1973)

Studies were carried out to evaluate the mechanism of hypocalcemia in magnesium depletion. Day old chicks fed a magnesium deficient diet developed marked hypocalcemia, with a direct relation between serum calcium (y) and magnesium (x): y = 2.68 x + 4.24, r = 0.84 (both in mg/100 ml). Injections of parathyroid extract that increased serum calcium 2-3 mg/100 ml in normals had no effect in Mg-depleted birds. Very large dietary supplements of calcium or vitamin D(3) increased mean serum calcium only from 5.3 to 7.7 and 7.8 mg/100 ml, respectively, while a normal magnesium diet for 3 days increased calcium from 5.3 to 9.9 mg/100 ml despite absence of dietary calcium. Intestinal calcium transport, studied in vitro, and the calcium concentration of the carcass was significantly increased in magnesium-depleted chicks, making it unlikely that reduced intestinal absorption of calcium caused the hypocalcemia. In magnesium-deficient chicks, the bone content of magnesium was decreased by 74%, the calcium content was unchanged, and the cortical thickness of bone was markedly increased. After 3 days of magnesium-repletion, cortical thickness was reduced with increased endosteal resorption. There was an increase in unmineralized osteoid tissue in the magnesium-depleted chicks. Parathyroid gland size and histology did not differ in magnesium-depleted and control birds. The results suggest that hypocalcemia develops due to altered equilibrium of calcium between extracellular fluid and bone, favoring increased net movement into the latter. Failure of parathyroid gland function could also exist, and unresponsiveness to parathyroid hormone (PTH) may also contribute to the hypocalcemia. However, failure of PTH action is probably due to the presence of excess osteoid tissue rather than a primary event leading to hypocalcemia.
Early Postoperative Paclitaxel Followed by Concurrent Paclitaxel and Cisplatin With Radiation Therapy for Patients With Resected High-Risk Head and Neck Squamous Cell Carcinoma: Report of the Phase II Trial RTOG 0024
Authors: David I. Rosenthal, Jonathan Harris, Arlene A. Forastiere, Randal S. Weber, John A. Ridge, Jeffrey N. Myers, Adam S. Garden, Michael R. Kuettel, Kulbir Sidhu, Christopher J. Schultz, Andy Trotti, K. Kian Ang
Journal: Journal of Clinical Oncology (2009)

We sought to improve outcomes for patients with high-risk head and neck squamous cell cancer (HNSCC) after surgical resection by testing the feasibility and safety of early postoperative chemotherapy followed by concurrent chemoradiotherapy.Eligible patients had resected, stages III to IV HNSCC with positive margins, extracapsular nodal extension, or multiple positive nodes. Paclitaxel (80 mg/m(2)) was given once weekly during postoperative weeks 2, 3, and 4 and was given before radiation therapy (RT). Paclitaxel (30 mg/m(2)) and cisplatin (20 mg/m(2)) were given once weekly during the last 3 weeks of RT (60 Gy over 6 weeks, beginning 4 to 5 weeks after surgery). The primary end points were treatment safety and tolerability compared with concurrent cisplatin (100 mg/m(2) every 3 weeks) and RT, as tested in Radiation Therapy Oncology Group trial RTOG 9501.The median follow-up time for the 70 patients enrolled was 3.3 years (range, 0.6 to 4.4 years) for surviving patients. Tolerability of all treatment components was comparable to that of RTOG 9501 treatment, which is the current standard of care (compliance rate, 75%; 95% CI, 63% to 85%). One patient died, and seven patients experienced grade 4 nonhematologic toxicities. Rates of locoregional control, disease-free survival, and overall survival exceeded those of RTOG 9501 after adjustment for important prognostic variables (ie, positive margins, extracapsular extension, primary site, and performance status).Chemotherapy soon after surgery followed by concurrent chemoradiotherapy therapy was feasible; tolerance was in line with standard postoperative chemoradiotherapy; and this regimen led to excellent rates of locoregional control and disease-free survival.
Guideline for the Management of Fever and Neutropenia in Children With Cancer and/or Undergoing Hematopoietic Stem-Cell Transplantation
Authors: Thomas Lehrnbecher, Robert Phillips, Sarah Alexander, Frank Alvaro, Fabianne Carlesse, Brian Fisher, Hana Hakim, Maria Santolaya, Elio Castagnola, Bonnie L. Davis, L. Lee Dupuis, Faith Gibson, Andreas H. Groll, Aditya Gaur, Ajay Gupta, Rejin Kebudi, Sérgio Petrilli, William J. Steinbach, Milena Villarroel, Theoklis Zaoutis, Lillian Sung
Journal: Journal of Clinical Oncology (2012)

Purpose To develop an evidence-based guideline for the empiric management of pediatric fever and neutropenia (FN). Methods The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary and multinational group composed of experts in pediatric oncology and infectious disease as well as a patient advocate. The Panel was convened for the purpose of creating this guideline. We followed previously validated procedures for creating evidence-based guidelines. Working groups focused on initial presentation, ongoing management, and empiric antifungal therapy. Each working group developed key clinical questions, conducted systematic reviews of the published literature, and compiled evidence summaries. The Grades of Recommendation Assessment, Development, and Evaluation approach was used to generate summaries, and evidence was classified as high, moderate, low, or very low based on methodologic considerations. Results Recommendations were made related to initial presentation (risk stratification, initial evaluation, and treatment), ongoing management (modification and cessation of empiric antibiotics), and empiric antifungal treatment (risk stratification, evaluation, and treatment) of pediatric FN. For each recommendation, the strength of the recommendation and level of evidence are presented. Conclusion This guideline represents an evidence-based approach to FN specific to children with cancer. Although some recommendations are similar to adult-based guidelines, there are key distinctions in multiple areas. Implementation will require adaptation to the local context.
Serum Anticholinergicity in Elderly Depressed Patients Treated With Paroxetine or Nortriptyline
Authors: Bruce G. Pollock, Benoit H. Mulsant, Robert Nebes, Margaret A. Kirshner, Amy E. Begley, Sati Mazumdar, Charles F. Reynolds
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: The authors' goal was to compare serum anticholinergicity of 61 elderly depressed patients randomly assigned to double-blind treatment with paroxetine (N=31) or nortriptyline (N=30). METHOD: Both antidepressants were titrated in a standardized manner, and plasma was sampled weekly for measurement of paroxetine and nortriptyline and its hydroxy metabolite concentrations. Serum anticholinergicity was measured at baseline and after 1, 4, and 6 weeks of treatment. Side effects were assessed by using a validated scale. RESULTS: After correcting for pretreatment anticholinergicity, the authors found that mean serum anticholinergicity for the nortriptyline-treated patients was significantly greater than that for the paroxetine group at all weeks assessed. Serum anticholinergicity was significantly correlated with nortriptyline but not with paroxetine plasma levels. Complaints of dry mouth and tachycardia were significantly more frequent and severe in the nortriptyline group. CONCLUSIONS: These findings suggest that, at therapeutic plasma concentrations, paroxetine has approximately one-fifth the anticholinergic potential of nortriptyline in older patients. (Am J Psychiatry 1998; 155:1110–1112)