tbuckley/cabot-search huggingface dataset:
Histone deacetylase inhibition decreases proliferation and potentiates the effect of ionizing radiation in atypical teratoid/rhabdoid tumor cells
Authors: J. A. Knipstein, D. K. Birks, A. M. Donson, I. Alimova, N. K. Foreman, R. Vibhakar
Journal: Neuro-Oncology (2011)

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant central nervous system neoplasm that primarily occurs in children less than 3 years of age. Because of poor outcomes with intense and toxic multimodality treatment, new therapies are urgently needed. Histone deacetylase inhibitors (HDIs) have been evaluated as novel agents for multiple malignancies and have been shown to function as radiosensitizers. They act as epigenetic modifiers and lead to re-expression of inappropriately repressed genes, proteins, and cellular functions. Because of the underlying chromatin remodeling gene mutation in ATRT, HDIs are ideal candidates for therapeutic evaluation. To evaluate the role of HDIs against ATRT in vitro, we assessed the effect of drug treatment on proliferation, apoptosis, and gene expression. In addition, we examined HDI pretreatment as a radiosensitization strategy for ATRT. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium with phenazine methosulfate electron coupling reagent (MTS) and clonogenic assays demonstrated that HDI treatment significantly reduces the proliferative capacity of BT-12 and BT-16 ATRT cells. In addition, the HDI SNDX-275 was able to induce apoptosis in both cell lines and induced p21Waf1/Cip1 protein expression as measured by Western blot. Evaluation of differential gene expression by microarray and pathway analysis after HDI treatment demonstrated alterations of several key ATRT cellular functions. Finally, we showed that HDI pretreatment effectively potentiates the effect of ionizing radiation on ATRT cells as measured by clonogenic assay. Our findings suggest that the addition of HDIs to ATRT therapy may prove to be beneficial, especially when administered in combination with current treatment modalities, such as radiation.
High Levels of Phosphorylated Form of Akt-1 in Prostate Cancer and Non-Neoplastic Prostate Tissues Are Strong Predictors of Biochemical Recurrence
Authors: Gustavo Ayala, Timothy Thompson, Guang Yang, Anna Frolov, Rile Li, Peter Scardino, Makoto Ohori, Thomas Wheeler, Wade Harper
Journal: Clinical Cancer Research (2004)

Abstract Akt is a serine-threonine-kinase that phosphorylates proteins in several pathways regulating aspects of metabolism, apoptosis, and proliferation. Akt signaling promotes proliferation and increased cell survival and is thought to play an important role in prostate cancer progression. Tissue microarrays (640 patients) with triplicate cores of non-neoplastic prostate, BPH, and index tumor were immunostained with antibody to Phospho-Akt (Ser473), digitized, and quantified. The expression index (Intensity*Percentage) was used for statistical analysis. P-Akt-1 staining was found in both the non-neoplastic and cancer tissues, predominantly in cytoplasmic locations. High level P-Akt-1 is expressed almost exclusively in cancer. By Kaplan-Meier actuarial model, high expression of P-Akt-1 in prostate cancer was predictive of a higher probability of recurrence on univariate and multivariate analysis. Akt-1 expression was an independent prognostic indicator of biochemical recurrence-free survival when Gleason 6 and 7 patients were analyzed separately. Surprisingly, a high level of P-Akt-1 expression in non-neoplastic tissues is also an independent predictor of biochemical recurrence. This suggests that some patients might have an inherent predisposition to express a high level of P-Akt-1 and, therefore, to have an adverse prognosis. We conclude that P-Akt-1 is most likely involved in the progression of prostate cancer and is an excellent biomarker for biochemical recurrence.
Magnetic Resonance Imaging Detects Changes in Structure and Perfusion, and Response to Therapy in Early Cystic Fibrosis Lung Disease
Authors: Mark O. Wielpütz, Michael Puderbach, Annette Kopp-Schneider, Mirjam Stahl, Eva Fritzsching, Olaf Sommerburg, Sebastian Ley, Migle Sumkauskaite, Jürgen Biederer, Hans-Ulrich Kauczor, Monika Eichinger, Marcus A. Mall
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Studies demonstrating early structural lung damage in infants and preschool children with cystic fibrosis (CF) suggest that noninvasive monitoring will be important to identify patients who may benefit from early therapeutic intervention. Previous studies demonstrated that magnetic resonance imaging (MRI) detects structural and functional abnormalities in lungs from older patients with CF without radiation exposure.To evaluate the potential of MRI to detect abnormal lung structure and perfusion in infants and preschool children with CF, and to monitor the response to therapy for pulmonary exacerbation.MRI studies were performed in 50 children with CF (age, 3.1 ± 2.1 yr; range, 0-6 yr) in stable clinical condition (n = 40) or pulmonary exacerbation before and after antibiotic treatment (n = 10), and in 26 non-CF control subjects (age, 2.9 ± 1.9 yr). T1- and T2-weighted sequences before and after intravenous contrast and first-pass perfusion imaging were acquired, and assessed on the basis of a dedicated morphofunctional score.MRI demonstrated bronchial wall thickening/bronchiectasis, mucus plugging, and perfusion deficits from the first year of life in most stable patients with CF (global score, 10.0 ± 4.0), but not in non-CF control subjects (score, 0.0 ± 0.0; P < 0.001). In patients with exacerbations, the global MRI score was increased to 18.0 ± 2.0 (P < 0.001), and was significantly reduced to 12.0 ± 3.0 (P < 0.05) after antibiotic therapy.MRI detected abnormalities in lung structure and perfusion, and response to therapy for exacerbations in infants and preschool children with CF. These results support the development of MRI for noninvasive monitoring and as an end point in interventional trials for early CF lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT00760071).
Ultrasound and Microbubble-Targeted Delivery of Macromolecules Is Regulated by Induction of Endocytosis and Pore Formation
Authors: Bernadet D.M. Meijering, Lynda J.M. Juffermans, Annemieke van Wamel, Rob H. Henning, Inge S. Zuhorn, Marcia Emmer, Amanda M.G. Versteilen, Walter J. Paulus, Wiek H. van Gilst, Klazina Kooiman, Nico de Jong, René J.P. Musters, Leo E. Deelman, Otto Kamp
Journal: Circulation Research (2009)

Contrast microbubbles in combination with ultrasound (US) are promising vehicles for local drug and gene delivery. However, the exact mechanisms behind intracellular delivery of therapeutic compounds remain to be resolved. We hypothesized that endocytosis and pore formation are involved during US and microbubble targeted delivery (UMTD) of therapeutic compounds. Therefore, primary endothelial cells were subjected to UMTD of fluorescent dextrans (4.4 to 500 kDa) using 1 MHz pulsed US with 0.22-MPa peak-negative pressure, during 30 seconds. Fluorescence microscopy showed homogeneous distribution of 4.4- and 70-kDa dextrans through the cytosol, and localization of 155- and 500-kDa dextrans in distinct vesicles after UMTD. After ATP depletion, reduced uptake of 4.4-kDa dextran and no uptake of 500-kDa dextran was observed after UMTD. Independently inhibiting clathrin- and caveolae-mediated endocytosis, as well as macropinocytosis significantly decreased intracellular delivery of 4.4- to 500-kDa dextrans. Furthermore, 3D fluorescence microscopy demonstrated dextran vesicles (500 kDa) to colocalize with caveolin-1 and especially clathrin. Finally, after UMTD of dextran (500 kDa) into rat femoral artery endothelium in vivo, dextran molecules were again localized in vesicles that partially colocalized with caveolin-1 and clathrin. Together, these data indicated uptake of molecules via endocytosis after UMTD. In addition to triggering endocytosis, UMTD also evoked transient pore formation, as demonstrated by the influx of calcium ions and cellular release of preloaded dextrans after US and microbubble exposure. In conclusion, these data demonstrate that endocytosis is a key mechanism in UMTD besides transient pore formation, with the contribution of endocytosis being dependent on molecular size.
Kinetics of gentamicin uptake and release in the rat. Comparison of inner ear tissues and fluids with other organs.
Authors: P Tran Ba Huy, P Bernard, J Schacht
Journal: Journal of Clinical Investigation (1986)

The kinetics of entry and release of gentamicin was investigated in fluids and tissues of the inner ear of the rat, as well as in renal cortex, and in organs that do not share susceptibility to the toxic effects of aminoglycosides. Various modes of administration were used to achieve different patterns of drug plasma concentrations. Electrophysiological and histological examinations were performed to correlate pharmacokinetics and ototoxicity. Results show that: the uptake of the drug by the inner ear tissues is dose dependent and manifests a rapid saturation kinetics with a concentration plateau of about 1 micrograms/mg of protein. The low ratio of the perilymph and endolymph to plasma concentrations argues against the concept of an accumulation of the drug in the inner ear over drug levels in plasma, which has been considered as the basic mechanism of ototoxicity. In renal cortex, the kinetics appears similar to that of the inner ear but the concentrations achieved are 10-fold higher than in cochlear tissues. In other organs (liver, heart, lung, and spleen), no saturation could be demonstrated within the duration of the experiment. Ototoxicity seems to be related to the penetration of the drug into compartment(s) from which the half-life of disappearance is extremely slow. Rapid uptake, early saturation, and long exposure of the tissues to the drug may account for the development of toxicity in inner ear and kidney.
Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based cohort study in the five Nordic countries. Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology.
Authors: R Sankila, S Garwicz, J H Olsen, H Döllner, H Hertz, A Kreuger, F Langmark, M Lanning, T Möller, H Tulinius
Journal: Journal of Clinical Oncology (1996)

PURPOSE To assess the risk of subsequent malignant neoplasms among Hodgkin's disease patients diagnosed before 20 years of age in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). PATIENTS AND METHODS There were 1,641 Hodgkin's disease patients identified through the national cancer registries since the 1940s or 1950s. The patients were monitored for 17,000 person-years until the end of 1991. Expected figures were derived from the age-specific incidence rates in each country and standardized incidence ratios (SIR) were calculated. RESULTS A total of 62 subsequent neoplasms were diagnosed (SIR, 7.7; 95% confidence interval [CI], 5.9 to 9.9). The overall cumulative risk of subsequent neoplasms was 1.9% at the 10-year follow-up point, 6.9% at 20 years, and 18% at 30 years. There were 26 subsequent neoplasms among males (SIR, 6.5; 95% CI, 4.3 to 9.6) and 36 among females (SIR, 8.9; 95% CI, 6.2 to 12), of which 16 were breast cancers (SIR, 17; 95% CI, 9.9 to 28). High risks were seen for thyroid cancer (SIR, 33; 95% CI, 15 to 62), for secondary leukemia (SIR, 17; 95% CI, 6.9 to 35), and for non-Hodgkin's lymphoma (SIR, 15; 95% CI, 4.9 to 35). The relative risk increased from 3.3 (95% CI, 1.2 to 7.1) for Hodgkin's disease patients diagnosed in the 1940s and 1950s to 15 (95% CI, 7.4 to 27) in the 1980s. The highest risk of secondary leukemia (SIR, 68; 95% CI, 18 to 174) was seen among those diagnosed with Hodgkin's disease in the 1980s. CONCLUSION Patients who survive Hodgkin's disease at a young age are at very high relative risk of subsequent malignant neoplasms throughout their lives. In particular, the high relative risk of breast cancer following Hodgkin's disease in the teenage years calls for enhanced activity for early diagnosis.
Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired pulmonary alveolar proteinosis
Authors: JF Seymour, CG Begley, U Dirksen, JJ Presneill, NA Nicola, PE Moore, OD Schoch, P van Asperen, B Roth, S Burdach, AR Dunn
Journal: Blood (1998)
ONO-4059—a Potent and Selective Reversible Bruton’s Tyrosine Kinase (Btk) Inhibitor: Single Agent, Twice Daily (BD) Dosing and Dosing with Food Results in Sustained, High Trough Levels of ONO-4059, Translating into 100% Tumour Remission in a TMD-8 Xenograft Model
Authors: Toshio Yoshizawa, Tomoko Yasuhiro, Hideyuki Honda, Kazuhito Kawabata
Journal: Blood (2014)
Prognostic Relevance of Fragile Histidine Triad Protein Expression in Patients with Small Cell Lung Cancer
Authors: Ulrich-Peter Rohr, Nina Rehfeld, Helene Geddert, Lucy Pflugfelder, Ingmar Bruns, Judith Neukirch, Astrid Rohrbeck, Hans J. Grote, Ulrich Steidl, Roland Fenk, Bertram Opalka, Helmut E. Gabbert, Ralf Kronenwett, Rainer Haas
Journal: Clinical Cancer Research (2005)

The fragile histidine triad protein (FHIT) is a putative tumor suppressor in patients with lung cancer. In this study, we examined the prognostic value of FHIT expression for survival in patients with small cell lung cancer (SCLC).As assessed by immunohistochemistry using formalin-fixed, paraffin-embedded tissue sections, tumors of 225 patients with SCLC were retrospectively evaluated for FHIT expression. The influence of FHIT staining intensities as well as the proportion of FHIT-positive cells within a tumor was taken into consideration for univariate and multivariate survival analysis.FHIT expression was observed in 61.8% of the SCLC tumors. Lack of FHIT was significantly associated with a shorter survival time for the patients with a median of 157 +/- 18 days compared with 210 +/- 18 days for those patients with FHIT-positive tumors (P = 0.0061). Furthermore, the proportion of FHIT-positive cells within the tumor was related to survival. Patients with tumors of <25% FHIT-positive cells had the worst survival of 155 +/- 21 days compared with 217 +/- 19 days for patients with a proportion of > or =25% of FHIT-expressing tumor cells (P = 0.0016). In contrast to the proportion of FHIT-positive cells within the tumor, no significant difference in survival was observed when different FHIT staining intensities (weak versus strong) were considered (median survival of 208 +/- 17 versus 234 +/- 34 days, P=0.665). Multivariate analysis using Cox regression including 11 variables confirmed the prognostic significance of FHIT expression next to performance status, tumor stage, and lactate dehydrogenase.The presence of FHIT was correlated with a better prognosis for patients with SCLC.
Predicting Human Drug Glucuronidation Parameters: Application of In Vitro and In Silico Modeling Approaches
Authors: John O. Miners, Paul A. Smith, Michael J. Sorich, Ross A. McKinnon, Peter I. Mackenzie
Journal: The Annual Review of Pharmacology and Toxicology (2004)

Cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which both exist as enzyme "superfamilies," are together responsible for the metabolism of most hepatically cleared drugs. There is currently intense interest in the development of techniques that permit identification of the CYP and UGT isoform(s) involved in the metabolism of a newly discovered drug, and hence prediction of factors likely to alter elimination in vivo. In addition, the quantitative scaling of kinetic parameters for a metabolic pathway assumes importance for identifying newly discovered drugs with undesirable in vivo pharmacokinetic properties. Although qualitative and quantitative in vitro-in vivo correlation based on data generated using human liver tissue or recombinant enzymes have been applied successfully to many drugs eliminated by CYP, these strategies have proved less definitive for glucuronidated compounds. Computational (in silico) modeling techniques that potentially provide a facile and economic alternative to the in vitro methods are now emerging. This review assesses the utility of in vitro and in silico approaches for the qualitative and quantitative prediction of drug glucuronidation parameters and the challenges facing the development of generalizable models.
Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling: Biophase Distribution, Receptor Theory, and Dynamical Systems Analysis
Authors: Meindert Danhof, Joost de Jongh, Elizabeth C.M. De Lange, Oscar Della Pasqua, Bart A. Ploeger, Rob A. Voskuyl
Journal: The Annual Review of Pharmacology and Toxicology (2006)

Mechanism-based PK-PD models differ from conventional PK-PD models in that they contain specific expressions to characterize, in a quantitative manner, processes on the causal path between drug administration and effect. This includes target site distribution, target binding and activation, pharmacodynamic interactions, transduction, and homeostatic feedback mechanisms. As the final step, the effects on disease processes and disease progression are considered. Particularly through the incorporation of concepts from receptor theory and dynamical systems analysis, important progress has been made in the field of mechanism-based PK-PD modeling. This has yielded models with much-improved properties for extrapolation and prediction. These models constitute a theoretical basis for rational drug discovery and development.
HOW BNP AND BODY WEIGHT CHANGES VARY IN HEART FAILURE WITH PRESERVED EJECTION FRACTION COMPARED TO REDUCED EJECTION FRACTION: SECONDARY RESULTS OF THE HABIT (HF ASSESSMENT WITH BNP IN THE HOME) TRIAL
Authors: Kevin Shah, Denise Barnard, Brian Jaski, Geir Frivold, H. John Marais, Maged Azer, Michael Miyamoto, Dawn Lombardo, Damon Kelsay, Navaid Iqbal, Pam Taub, Paul Clopton, Barry Greenberg, Michael Zile, Alan Maisel
Journal: Journal of the American College of Cardiology (2014)
<i>LIN28</i>Expression in Malignant Germ Cell Tumors Downregulates<i>let-7</i>and Increases Oncogene Levels
Authors: Matthew J. Murray, Harpreet K. Saini, Charlotte A. Siegler, Jennifer E. Hanning, Emily M. Barker, Stijn van Dongen, Dawn M. Ward, Katie L. Raby, Ian J. Groves, Cinzia G. Scarpini, Mark R. Pett, Claire M. Thornton, Anton J. Enright, James C. Nicholson, Nicholas Coleman
Journal: Cancer Research (2013)

Abstract Despite their clinicopathologic heterogeneity, malignant germ cell tumors (GCT) share molecular abnormalities that are likely to be functionally important. In this study, we investigated the potential significance of downregulation of the let-7 family of tumor suppressor microRNAs in malignant GCTs. Microarray results from pediatric and adult samples (n = 45) showed that LIN28, the negative regulator of let-7 biogenesis, was abundant in malignant GCTs, regardless of patient age, tumor site, or histologic subtype. Indeed, a strong negative correlation existed between LIN28 and let-7 levels in specimens with matched datasets. Low let-7 levels were biologically significant, as the sequence complementary to the 2 to 7 nt common let-7 seed “GAGGUA” was enriched in the 3′ untranslated regions of mRNAs upregulated in pediatric and adult malignant GCTs, compared with normal gonads (a mixture of germ cells and somatic cells). We identified 27 mRNA targets of let-7 that were upregulated in malignant GCT cells, confirming significant negative correlations with let-7 levels. Among 16 mRNAs examined in a largely independent set of specimens by quantitative reverse transcription PCR, we defined negative-associations with let-7e levels for six oncogenes, including MYCN, AURKB, CCNF, RRM2, MKI67, and C12orf5 (when including normal control tissues). Importantly, LIN28 depletion in malignant GCT cells restored let-7 levels and repressed all of these oncogenic let-7 mRNA targets, with LIN28 levels correlating with cell proliferation and MYCN levels. Conversely, ectopic expression of let-7e was sufficient to reduce proliferation and downregulate MYCN, AURKB, and LIN28, the latter via a double-negative feedback loop. We conclude that the LIN28/let-7 pathway has a critical pathobiologic role in malignant GCTs and therefore offers a promising target for therapeutic intervention. Cancer Res; 73(15); 4872–84. ©2013 AACR.
Diagnostic utility of a novel thin bronchoscope
Authors: G. L. Casoni, V. Poletti
Journal: European Respiratory Journal (2008)

To the Editors: 

In a recent issue of the European Respiratory Journal ( ERJ ), Oki et al. 1 evaluated the diagnostic utility of a novel thin bronchoscope with a 1.7-mm working channel for peripheral pulmonary lesions. We have a few comments we would like to make about this article.

First, all bronchoscopists know that bleeding occurs to some degree in virtually all transbronchial lung biopsy (TBLB) procedures and, in some …
A 10 year follow up of 180 adults with bronchial asthma: factors important for the decline in lung function.
Authors: C S Ulrik, V Backer, A Dirksen
Journal: Thorax (1992)

Little is known about the factors that determine outcome in asthma. The purpose of this study was to describe the relation of various factors of potential importance to the rate of decline in lung function in adults with intrinsic and extrinsic asthma.Of 180 asthmatic patients, 143 (79%) participated in a 10 year follow up examination. At the time of enrollment all patients underwent certain tests for asthma (case history, total IgE, skinprick tests, the radioallergosorbent test (RAST), histamine release from basophil leucocytes, and specific bronchial provocations). On the basis of these tests 94 patients had intrinsic asthma and 49 extrinsic asthma.Patients with intrinsic asthma had an annual decline in FEV1 of 50 ml, whereas those with extrinsic asthma had a decline of 22.5 ml; the rate of decline of lung function increased with increasing age in both groups. An inverse relation between initial FEV1 and decline in FEV1 (the "horse racing effect") was found for the patients with extrinsic asthma but not for the patients with intrinsic asthma. There was no relation between rate of decline in lung function and number of cigarettes smoked. A high degree of airway variability--that is, reversibility in FEV1--at the time of enrollment was found to be associated with a steeper decline in lung function in patients with intrinsic asthma, whereas increasing degrees of obstruction (decreasing FEV1/VC ratio at enrollment) and need for treatment with corticosteroids were associated with a more pronounced decline in FEV1 in patients with extrinsic asthma.The rate of decline in lung function is greater in patients with intrinsic asthma than in patients with extrinsic asthma; the prognosis for intrinsic and extrinsic asthma is to some extent influenced by different factors, which suggests that the pathogenetic mechanisms underlying intrinsic and extrinsic asthma may differ.