bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coadministration of Ritonavir Strongly Enhances the Apparent Oral Bioavailability of Docetaxel in Patients with Solid Tumors
Authors: Oostendorp Roos L. , Huitema Alwin , Rosing Hilde , Jansen Robert S. , ter Heine Rob , Keessen Marianne , Beijnen Jos H. , Schellens Jan H.M. 
Published: June 2009

Abstract
Purpose: To enhance the systemic exposure to oral docetaxel by coadministration of ritonavir, an efficacious inhibitor of CYP 3A4 with minor P-glycoprotein inhibiting effects, in patients with cancer.
Experimental Design: A proof-of-concept study was carried out in 12 patients with solid tumors. The first cohort of patients (n = 4) received 10 mg and the subsequent cohort (n = 8) 100 mg of oral docetaxel, coadministered with 100 mg oral ritonavir randomized simultaneously or ritonavir given 60 minutes before docetaxel on days 1 and 8. On day 15 or 22, patients received 100 mg i.v. docetaxel.
Results: The area under the plasma concentration-time curve in patients who received 10 mg oral docetaxel in combination with ritonavir was low, and the dose could safely be increased to 100 mg. The area under the plasma concentration-time curve in patients who received 100 mg oral docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 2.4 ± 1.5 and 2.8 ± 1.4 mg/h/L, respectively, compared with 1.9 ± 0.4 mg/h/L after i.v. docetaxel. The apparent oral bioavailability of docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 131% ± 90% and 161% ± 91%, respectively. The oral combination of docetaxel and ritonavir was well tolerated.
Conclusion: Coadministration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. These data are promising and form the basis for further development of a clinically applicable oral formulation of docetaxel combined with ritonavir.
Phase I Pharmacokinetic and Pharmacodynamic Study of Carboplatin and Topotecan Administered Intravenously Every 28 Days to Patients with Malignant Solid Tumors
Authors: Boss David S. , Siegel-Lakhai Wandena S. , van Egmond-Schoemaker Nadja E. , Pluim Dick , Rosing Hilde , ten Bokkel Huinink Wim W. , Beijnen Jos H. , Schellens Jan H.M. 
Published: June 2009

AbstractPurpose: Preclinical studies have shown that the combination of topotecan and carboplatin is synergistic. To evaluate the schedule dependency of this interaction, the following phase I trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carboplatin and topotecan in patients with malignant solid tumors.Experimental Design: In part 1, patients received carboplatin on day 1 and topotecan on days 1, 2, and 3 (C→T schedule). In part 2, topotecan was administered on days 1, 2, and 3, followed by carboplatin on day 3 (T→C schedule). Pharmacokinetics were determined in plasma and DNA topoisomerase I catalytic activity and Pt-DNA adducts in WBC and tumor tissue.Results: Forty-one patients were included. Dose-limiting toxicities during the C→T schedule were grade 4 thrombocytopenia and febrile neutropenia (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 4 min mg/mL; topotecan, 0.5 mg/m2/d). Dose-limiting toxicities during the T→C schedule included grade 4 neutropenia, thrombocytopenia, neutropenic fever, and grade 4 nausea and vomiting (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 6 min mg/mL; topotecan, 0.9 mg/m2/d). One complete response and five partial responses were observed. The clearance of and exposure to carboplatin and topotecan did not depend on the sequence of drug administration. No schedule-dependent effects were seen in Pt-DNA levels and DNA topoisomerase I catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C→T schedule.Conclusion: The T→C schedule was better tolerated because both hematologic and nonhematologic toxicities were milder. Other pharmacodynamic factors than the ones investigated must explain the schedule-dependent differences in toxicities.
Cell Cycle/Apoptosis Molecule Expression Correlates with Imatinib Response in Patients with Advanced Gastrointestinal Stromal Tumors
Authors: Romeo Salvatore , Debiec-Rychter Maria , Van Glabbeke Martine , Van Paassen Heidi , Comite Paola , Van Eijk Ronald , Oosting Jan , Verweij Jaap , Terrier Philippe , Schneider Ulrike , Sciot Raf , Blay Jean Yves , Hogendoorn Pancras C.W. ,   on behalf of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group
Published: June 2009

AbstractPurpose: Altered expression of cell cycle/apoptosis key regulators may promote tumor progression, reflect secondary genetic/epigenetic events, and impair the effectiveness of therapy. Their expression pattern might then identify gastrointestinal stromal tumor (GIST) patient subgroups with different response to imatinib and elucidate novel therapeutic targets.Experimental Design: Immunohistochemical evaluation of expression of p53, p16, p21, CHK2, CCND1, BCL2, CDK4, and MDM2 was done on 353 histologically validated GIST patients enrolled into a European/Australasian phase III trial. TP53 was screened for mutations in cases with presumptive nonfunctional protein; that is, high p53 and low expression of the two downstream molecules p21 and MDM2. Results were correlated with clinicopathologic data, KIT/PDGFRA mutation status, and imatinib dosage.Results: Frequent impaired expression was found for BCL2 (78%), CHK2 (53%), p53 (50%), and p16 (47%). Stomach-originating GISTs showed significantly lower expression of p21, p16, and BCL2. KIT/PDGFRA wild-type GISTs had significant lower expression of CDK4. Eighty-eight percent of the high p53 expressers show low downstream target activation, indicating a nonfunctional p53 route. Of these high p53 expressers, 16.4% harbor a detectable TP53 mutation. Multivariate analysis, including previously identified markers, showed an independent effect of p53 and p16 on progression-free survival (PFS). Patients with high level of CHK2 and p21 showed significantly better PFS upon a high-dose regimen.Conclusions: Impaired p53, p16, BCL2, and CHK2 expression is common in advanced GISTs. Distinct patterns of expression correlate with tumor site, genotype, and PFS. Cell cycle/apoptosis maintenance is instrumental for optimal response to imatinib.
Combined Survival Analysis of Prospective Clinical Trials of Gefitinib for Non–Small Cell Lung Cancer with EGFR Mutations
Authors: Morita Satoshi , Okamoto Isamu , Kobayashi Kunihiko , Yamazaki Koichi , Asahina Hajime , Inoue Akira , Hagiwara Koichi , Sunaga Noriaki , Yanagitani Noriko , Hida Toyoaki , Yoshida Kimihide , Hirashima Tomonori , Yasumoto Kosei , Sugio Kenji , Mitsudomi Tetsuya , Fukuoka Masahiro , Nukiwa Toshihiro 
Published: June 2009

Abstract
Purpose: Somatic mutations of the epidermal growth factor receptor (EGFR) gene are associated with an increased response to gefitinib in patients with non–small cell lung cancer. We have examined the impact of gefitinib on progression-free survival and overall survival in patients with EGFR mutation–positive non–small cell lung cancer.
Experimental Design: We searched for all clinical trials that prospectively evaluated the efficacy of gefitinib for advanced non–small cell lung cancer with EGFR mutations in Japan. We did a combined analysis based on individual patient data from the identified trials.
Results: Seven eligible trials were identified for a total of 148 non–small cell lung cancer patients with EGFR mutations. The overall response rate to gefitinib was 76.4% [95% confidence interval (95% CI), 69.5-83.2]. The median progression-free survival and overall survival were 9.7 months (95% CI, 8.2-11.1) and 24.3 months (95% CI, 19.8-28.2), respectively. Good performance status and chemotherapy-naïve status were significantly associated with a longer progression-free survival or overall survival. Of the 148 patients, 87 received gefitinib as a first-line therapy, whereas 61 received systemic chemotherapy before gefitinib treatment. The median progression-free survival after the start of first-line therapy was significantly longer in the gefitinib-first group than in the chemotherapy-first group (10.7 versus 6.0 months; P &lt; 0.001), whereas no significant difference in median overall survival was apparent between the two groups (27.7 versus 25.7 months; P = 0.782).
Conclusions: Gefitinib monotherapy confers substantial clinical benefit in terms of progression-free survival and overall survival in non–small cell lung cancer patients with EGFR mutations. Randomized trials comparing chemotherapy with gefitinib as a first-line treatment are warranted in such patients.
Epigenetic mechanisms of irinotecan sensitivity in colorectal cancer cell lines
Authors: Crea Francesco , Giovannetti Elisa , Cortesi Filippo , Mey Valentina , Nannizzi Sara , Gallegos Ruiz Marielle I. , Ricciardi Simona , Del Tacca Mario , Peters Godefridus J. , Danesi Romano 
Published: June 2009

Abstract
Irinotecan is a topoisomerase-I (Top-I) inhibitor used for the treatment of colorectal cancer. DNA demethylating agents, including 5-azacytidine (5-aza), display synergistic antitumor activity with several chemotherapy drugs. 5-Aza may enhance irinotecan cytotoxicity by at least one of the following mechanisms: (a) Top-I promoter demethylation, (b) activation of genes involved in Top-I transcriptional regulation (p16 or Sp1), and (c) modulation of the cell cycle and apoptosis after DNA damage. The growth-inhibitory effects of SN38, the active metabolite of irinotecan, 5-aza, and their combinations, were studied in four colorectal cancer cell lines. The effects of treatments on cell cycle were analyzed by flow cytometry, and apoptosis was measured by fluorescence microscopy. Top-I, Sp1, and p53 expression modulated by 5-aza were measured by real-time PCR. Methylation of Top-I, p16, 14-3-3σ, and hMLH1 promoters before and after 5-aza treatment were measured by MethyLight PCR and DNA bisulfite sequencing. Low-dose 5-aza significantly enhanced the apoptotic effect of irinotecan in all colorectal cancer cells, whereas a synergistic cytotoxic effect was observed only in p53-mutated cells (HT29, SW620, and WiDr). This synergistic effect was significantly correlated with Top-I up-regulation by 5-aza, and coupled to p16 demethylation and Sp1 up-regulation. p16 demethylation was also associated with enhanced cell cycle arrest after irinotecan treatment. In contrast, 5-aza down-regulated Top-I expression in the p53 wild-type LS174T cells in a p53-dependent manner, thereby reducing SN38 cytotoxicity. In conclusion, 5-aza modulates Top-I expression by several mechanisms involving Sp1, p16, and p53. If confirmed in other models, these results suggest that p16 and p53 status affects the 5-aza–irinotecan interaction. [Mol Cancer Ther 2009;8(7):1964–73]
Distinct Roles for Histone Methyltransferases G9a and GLP in Cancer Germ-Line Antigen Gene Regulation in Human Cancer Cells and Murine Embryonic Stem Cells
Authors: Link Petra A. , Gangisetty Omkaram , James Smitha R. , Woloszynska-Read Anna , Tachibana Makoto , Shinkai Yoichi , Karpf Adam R. 
Published: June 2009

Abstract
The H3K9me2 histone methyltransferases G9a and GLP repress Mage-a class cancer germ-line (CG) antigen gene expression in murine embryonic stem (ES) cells, but the role of these enzymes in CG antigen gene regulation in human cancer cells is unknown. Here we show that whereas independent or dual knockdown of G9a and GLP in human cancer cells leads to reduced global and CG antigen promoter–associated H3K9me2 levels, it does not activate CG antigen gene expression. Moreover, CG antigen gene repression is maintained following pharmacologic targeting of G9a or treatment of G9a knockdown cells with the histone deacetylase inhibitor trichostatin A. However, G9a knockdown cells display increased sensitivity to CG antigen gene activation mediated by the DNA methyltransferase inhibitor decitabine. To account for these findings, we examined DNA methylation at CG antigen gene promoters in both cell types. We found robust DNA hypomethylation in G9a/GLP targeted murine ES cells but a lack of DNA methylation changes in G9a/GLP targeted human cancer cells; intriguingly, this distinction also extended to markers of global DNA methylation. These data reveal that G9a/GLP is required for DNA methylation of CG antigen genes and genomic DNA in murine ES cells, but not human cancer cells, and implicate DNA methylation status as the key epigenetic mechanism involved in CG antigen gene repression. (Mol Cancer Res 2009;7(6):851–62)
Inhibition of G1 to S Phase Progression by a Novel Zinc Finger Protein P58TFL at P-bodies
Authors: Minagawa Kentaro , Katayama Yoshio , Nishikawa Shinichiro , Yamamoto Katsuya , Sada Akiko , Okamura Atsuo , Shimoyama Manabu , Matsui Toshimitsu 
Published: June 2009

Abstract
We recently reported the translocation of the immunoglobulin (Ig) light chain κ locus gene with a possible tumor suppressor gene, TFL, in transformed follicular lymphoma. However, the functional significance in cell transformation remains to be elucidated. Here, we first identified two gene products, P58TFL and P36TFL, derived by alternative splicing. The expression was prominent in normal human lymphocytes but defective in some leukemia/lymphoma cell lines. Overexpression of either protein in a mouse pro-B cell line, Ba/F3, and a human leukemia cell line, Jurkat, inhibited G1 to S phase progression through suppression of retinoblastoma protein (Rb) phosphorylation. The dominant gene product, P58TFL, colocalized with mRNA-processing body markers, eukaryotic translation initiation factor 2C and DCP1 decapping-enzyme homolog A, but not with a stress granule maker, T-cell intracellular antigen 1, in the cytoplasm. Taken together with the unique CCCH-type zinc finger motif, the present study suggests that P58TFL could play an important role in the regulation of cell growth through posttranscriptional modification of cell cycle regulators, at least partially, upstream of Rb. (Mol Cancer Res 2009;7(6):880–9)
Pediatric Ependymoma: Biological Perspectives
Authors: Kilday John-Paul , Rahman Ruman , Dyer Sara , Ridley Lee , Lowe James , Coyle Beth , Grundy Richard 
Published: June 2009

Abstract
Pediatric ependymomas are enigmatic tumors that continue to present a clinical management challenge despite advances in neurosurgery, neuroimaging techniques, and radiation therapy. Difficulty in predicting tumor behavior from clinical and histological factors has shifted the focus to the molecular and cellular biology of ependymoma in order to identify new correlates of disease outcome and novel therapeutic targets. This article reviews our current understanding of pediatric ependymoma biology and includes a meta-analysis of all comparative genomic hybridization (CGH) studies done on primary ependymomas to date, examining more than 300 tumors. From this meta-analysis and a review of the literature, we show that ependymomas in children exhibit a different genomic profile to those in adults and reinforce the evidence that ependymomas from different locations within the central nervous system (CNS) are distinguishable at a genomic level. Potential biological markers of prognosis in pediatric ependymoma are assessed and the ependymoma cancer stem cell hypothesis is highlighted with respect to tumor resistance and recurrence. We also discuss the shifting paradigm for treatment modalities in ependymoma that target molecular alterations in tumor-initiating cell populations. (Mol Cancer Res 2009;7(6):765–86)
Local Mixing Events in the Upper Troposphere and Lower Stratosphere. Part II: Seasonal and Interannual Variability
Authors: Shuckburgh Emily , d’Ovidio Francesco , Legras Bernard 
Published: June 2009

Abstract
The Lyapunov diffusivity is used to investigate local isentropic mixing events in the upper troposphere–lower stratosphere (UTLS) region. The diagnostic highlights the seasonal cycle of the longitudinally varying mixing properties, in particular those associated with the monsoon circulations and the westerly ducts in the subtropics. The results are broadly consistent with studies of Rossby wave–breaking frequencies. The mixing structure is shown to be modulated by modes of atmospheric variability. El Niño–Southern Oscillation (ENSO) is found to strongly influence the mixing structure throughout the tropics and subtropics. The subtropical jet is associated with longitudinal bands of mixing minima (isentropic mixing barriers) separated by synoptic-scale regions of strong mixing activity. The greatest ENSO modulation in December–February is confined to the Pacific sector, where the barriers associated with the subtropical jets extend farther into the eastern Pacific, and in the western Pacific a barrier is found at the equator during the positive phase. During June–August, the influence is seen to extend beyond the Pacific region, with the barrier at the subtropical jet in the Southern Hemisphere increasing in strength at all longitudes and with an increase in strength (and isolation of) monsoon-related mixing over Asia and North America. The local influence of the North Atlantic Oscillation in wintertime is investigated. During the positive phase, a double-barrier structure is associated with the subtropical jet, the northern branch crosses the Atlantic toward Scandinavia, and the southern branch tends toward North Africa. The Antarctic Oscillation is shown to influence whether the subvortex region is isolated from midlatitudes.
Identifying Signatures of Natural Climate Variability in Time Series of Global-Mean Surface Temperature: Methodology and Insights
Authors: Thompson David W. J. , Wallace John M. , Jones Phil D. , Kennedy John J. 
Published: June 2009

Abstract
Global-mean surface temperature is affected by both natural variability and anthropogenic forcing. This study is concerned with identifying and removing from global-mean temperatures the signatures of natural climate variability over the period January 1900–March 2009. A series of simple, physically based methodologies are developed and applied to isolate the climate impacts of three known sources of natural variability: the El Niño–Southern Oscillation (ENSO), variations in the advection of marine air masses over the high-latitude continents during winter, and aerosols injected into the stratosphere by explosive volcanic eruptions. After the effects of ENSO and high-latitude temperature advection are removed from the global-mean temperature record, the signatures of volcanic eruptions and changes in instrumentation become more clearly apparent. After the volcanic eruptions are subsequently filtered from the record, the residual time series reveals a nearly monotonic global warming pattern since ∼1950. The results also reveal coupling between the land and ocean areas on the interannual time scale that transcends the effects of ENSO and volcanic eruptions. Globally averaged land and ocean temperatures are most strongly correlated when ocean leads land by ∼2–3 months. These coupled fluctuations exhibit a complicated spatial signature with largest-amplitude sea surface temperature perturbations over the Atlantic Ocean.
Application of Airborne Passive Microwave Observations for Monitoring Inland Flooding Caused by Tropical Cyclones
Authors: Buckley Courtney D. , Hood Robbie E. , LaFontaine Frank J. 
Published: June 2009

Abstract
Inland flooding from tropical cyclones is a significant factor in storm-related deaths in the United States and other countries, with the majority of tropical cyclone fatalities recorded in the United States resulting from freshwater flooding. Information collected during National Aeronautics and Space Administration (NASA) tropical cyclone field experiments suggests that surface water and flooding can be detected and therefore monitored at a greater spatial resolution by using passive microwave airborne radiometers than by using satellite sensors. The 10.7-GHz frequency of the NASA Advanced Microwave Precipitation Radiometer (AMPR) has demonstrated high-resolution detection of anomalous surface water and flooding in numerous situations.
In this study, an analysis of three cases is conducted utilizing satellite and airborne radiometer data. Data from the 1998 Third Convection and Moisture Experiment (CAMEX-3) are utilized to detect surface water during the landfalling Hurricane Georges in both the Dominican Republic and Louisiana. Another case studied was the landfalling Tropical Storm Gert in eastern Mexico during the Tropical Cloud Systems and Processes (TCSP) experiment in 2005. AMPR data are compared to topographic data and vegetation indices to evaluate the significance of the surface water signature visible in the 10.7-GHz information. The results illustrate the AMPR’s utility in monitoring surface water that current satellite-based passive microwave radiometers are unable to monitor because of their coarser resolutions. This suggests the benefit of a radiometer with observing frequencies less than 11 GHz deployed on a manned aircraft or unmanned aircraft system to provide early detection in real time of expanding surface water or flooding conditions.
Methodology for Water Monitoring in the Upper Troposphere with Raman Lidar at the Haute-Provence Observatory
Authors: Hoareau Christophe , Keckhut Philippe , Sarkissian Alain , Baray Jean-Luc , Durry Georges 
Published: June 2009

Abstract
A Raman water vapor lidar has been developed at the Haute-Provence Observatory to study the distribution of water in the upper troposphere and its long-term evolution. Some investigations have been proposed and described to ensure a pertinent monitoring of water vapor in the upper troposphere. A new method to take into account the geophysical variability for time integration processes has been developed based on the stationarity of water vapor. Successive measurements, considered as independent, have been used to retrieve H2O profiles that were recorded during the same nighttimes over a few hours. Various calibration methods, including zenith clear-sky observation, standard meteorological radiosondes, and total water vapor column, have been investigated. A method to evaluate these calibration techniques has been proposed based on the variance weakening. For the lidar at the Haute-Provence Observatory, the calibration based on the total water vapor column appears to be the optimum method. Radiosondes also give comparable results, but do not allow lidar to be independent. The clear-sky zenith observation is an original technique, and seems to accurately identify discontinuities. However, it appears to be less reliable, based on the variance investigation, than the two others. It is also sensitive to aerosol loading, which is also expected to vary with time.
Correcting Calibrated Infrared Sky Imagery for the Effect of an Infrared Window
Authors: Nugent Paul W. , Shaw Joseph A. , Pust Nathan J. , Piazzolla Sabino 
Published: June 2009

AbstractA method is demonstrated for deriving a correction for the effects of an infrared window when used to weatherproof a radiometrically calibrated thermal infrared imager. The technique relies on initial calibration of two identical imagers without windows and subsequently operating the imagers side by side: one with a window and one without. An equation is presented that expresses the scene radiance in terms of through-window radiance and the transmittance, reflectance, and emissivity of the window. The window’s optical properties are determined as a function of angle over the imager’s field of view through a matrix inversion using images observed simultaneously with and without a window. The technique is applied to calibrated sky images from infrared cloud imager systems. Application of this window correction algorithm to data obtained months before or after the algorithm was derived leads to an improvement from 0.46 to 0.91 for the correlation coefficient between data obtained simultaneously from imagers with and without a window. Once the window correction has been determined, the windowed imager can operate independently and provide accurate measurements of sky radiance.