bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I and Pharmacokinetic Study of Lapatinib in Combination with Letrozole in Patients with Advanced Cancer
Authors: Chu Quincy S.C. , Cianfrocca Mary E. , Goldstein Lori J. , Gale Meg , Murray Nicholas , Loftiss Jill , Arya Nikita , Koch Kevin M. , Pandite Lini , Fleming Ronald A. , Paul Elaine , Rowinsky Eric K. 
Published: July 2008

AbstractPurpose: The main objectives of this phase I and pharmacokinetic, open-label study were to determine the optimally tolerated regimen (OTR), safety, pharmacokinetics, and clinical activity of lapatinib in combination with letrozole in patients with advanced solid malignancies.Experimental Design: Patients with advanced breast cancer with immunohistochemically detectable estrogen or progesterone receptors or other cancers were eligible. Doses of lapatinib were escalated in cohorts of three subjects from 1,250 to a maximum of 1,500 mg/d based on dose-limiting toxicities in the first treatment cycle. The letrozole dose was fixed at 2.5 mg/d. Additional patients were enrolled at the OTR dose level to further evaluate safety and for pharmacokinetic analyses.Results: Thirty-nine patients were enrolled in the study: 12 in the dose-escalation group, 7 in the OTR safety group, and 20 in the pharmacokinetic group. The OTR dose level was identified as 1,500 mg/d lapatinib and 2.5 mg/d letrozole. The most common (&gt;25% of patients) drug-related adverse events were diarrhea (77%), rash (62%), nausea (46%), and fatigue (26%). No significant differences were observed in the pharmacokinetic variables (Cmax and AUC) of lapatinib and letrozole when coadministered compared with single-agent administration. One patient with endometrial cancer had a confirmed partial response.Conclusions: Clinically relevant doses of lapatinib in combination with letrozole were well tolerated and did not result in a pharmacokinetic interaction, and clinical antitumor activity was observed.
Class III β-Tubulin Isotype Predicts Response in Advanced Breast Cancer Patients Randomly Treated Either with Single-Agent Doxorubicin or Docetaxel
Authors: Galmarini Carlos M. , Treilleux Isabelle , Cardoso Fatima , Bernard-Marty Chantal , Durbecq Virginie , Gancberg David , Bissery Marie-Christine , Paesmans Marianne , Larsimont Denis , Piccart Martine J. , Di Leo Angelo , Dumontet Charles 
Published: July 2008

AbstractPurpose: To evaluate the role of microtubule-associated variables as potential predictors of response and clinical outcome in patients with advanced breast cancer receiving single-agent docetaxel or doxorubicin chemotherapy.Experimental Design: The analysis was done on 173 tumor samples from patients with locally advanced or metastatic breast cancer who have participated in the TAX-303 phase III trial in which patients were randomly assigned to receive docetaxel or doxorubicin. Expression of total α- and β-tubulin, classes II to IV β-tubulin isotypes, and τ protein was evaluated by immunohistochemistry on formalin-fixed, paraffin-embedded tumors from the primary breast cancer.Results: We observed that patients with “high” expression of class III β-tubulin isotype had a higher probability of response to docetaxel than to doxorubicin treatment (odds ratio, 1.9; 95% confidence interval, 1.01-3.7; P = 0.05). No difference was observed in terms of time to progression or in terms of overall survival.Conclusions: This study suggests that the superiority of docetaxel over doxorubicin seems to be confined to the subgroup of patients with “high” expression of class III β-tubulin isotype.
Dual Tyrosine Kinase Inhibitor for Focal Adhesion Kinase and Insulin-like Growth Factor-I Receptor Exhibits Anticancer Effect in Esophageal Adenocarcinoma In vitro and In vivo
Authors: Watanabe Nobuyuki , Takaoka Munenori , Sakurama Kazufumi , Tomono Yasuko , Hatakeyama Shinji , Ohmori Osamu , Motoki Takayuki , Shirakawa Yasuhiro , Yamatsuji Tomoki , Haisa Minoru , Matsuoka Junji , Beer David G. , Nagatsuka Hitoshi , Tanaka Noriaki , Naomoto Yoshio 
Published: July 2008

Abstract
Purpose: Focal adhesion kinase (FAK) regulates integrin and growth factor–mediated signaling pathways to enhance cell migration, proliferation, and survival, and its up-regulation correlates malignant grade and poor outcome in several types of cancer. In this study, we aimed to raise a potential therapeutic strategy using a FAK inhibitor for Barrett's esophageal adenocarcinoma.
Experimental Design: The expression status of FAK in clinical Barrett's esophageal adenocarcinoma tissues was determined by immunohistochemistry. Cultured esophageal adenocarcinoma cells were treated with TAE226, a specific FAK inhibitor with an additional effect of inhibiting insulin-like growth factor-I receptor (IGF-IR), to assess its anticancer effect in vitro. Western blot was carried out to explore a participating signaling pathway for TAE226-induced cell death. Furthermore, TAE226 was orally administered to s.c. xenograft animals to investigate its anticancer effect in vivo.
Results: Strong expression of FAK was found in 94.0% of Barrett's esophageal adenocarcinoma compared with 17.9% of Barrett's epithelia, suggesting that FAK might play a critical role in the progression of Barrett's esophageal adenocarcinoma. When esophageal adenocarcinoma cells were treated with TAE226, cell proliferation and migration were greatly inhibited with an apparent structural change of actin fiber and a loss of cell adhesion. The activities of FAK, IGF-IR, and AKT were suppressed by TAE226 and subsequent dephosphorylation of BAD at Ser136 occurred, resulting in caspase-mediated apoptosis. In vivo tumor volume was significantly reduced by oral administration of TAE226.
Conclusions: These results suggest that TAE226, a dual tyrosine kinase inhibitor for FAK and IGF-IR, could become a new remedy for Barrett's esophageal adenocarcinoma.
Analysis of Overall Survival in Patients with Nonmetastatic Castration-Resistant Prostate Cancer Treated with Vaccine, Nilutamide, and Combination Therapy
Authors: Madan Ravi A. , Gulley James L. , Schlom Jeffrey , Steinberg Seth M. , Liewehr David J. , Dahut William L. , Arlen Philip M. 
Published: July 2008

Abstract
Purpose: We reported previously the first randomized study of any kind in patients with nonmetastatic, castrate-resistant prostate cancer. The study employed vaccine, the hormone nilutamide, and the combined therapy (crossover for each arm) with an endpoint of time to progression. We now report survival analyses at 6.5 years from the initiation of therapy with a median potential follow-up of 4.4 years.
Experimental Design: Forty-two patients were randomized to receive either a poxvirus-based prostate-specific antigen (PSA) vaccine or nilutamide. Patients in either arm who developed increasing PSA without radiographic evidence of metastasis could cross over to receive the combined therapies.
Results: Median survival among all patients was 4.4 years from date of enrollment. Median survival exhibited a trend toward improvement for patients initially randomized to the vaccine arm (median, 5.1 versus 3.4 years; P = 0.13). Starting from the on-study date, the retrospectively determined subset of 12 patients who initially received vaccine and then later received nilutamide suggested improved survival compared with the 8 patients who began with nilutamide and subsequently were treated with vaccine (median, 6.2 versus 3.7 years; P = 0.045). A subgroup analysis of patients randomized to the vaccine arm versus the nilutamide arm showed substantial improvements in survival if at baseline patients had a Gleason score &lt;7 (P = 0.033) and PSA &lt;20 ng/dL (P = 0.013) or who had prior radiation therapy (P = 0.018).
Conclusions: These data indicate that patients with nonmetastatic castration-resistant prostate cancer (D0.5) who receive vaccine before second-line hormone therapy may potentially result in improved survival compared with patients who received hormone therapy and then vaccine. These data also suggest that patients with more indolent disease may derive greater clinical benefit from vaccine alone or vaccine before second-line hormone therapy compared with hormone therapy alone or hormone therapy followed by vaccine. These findings have potential implications for both the design and endpoint analysis of larger vaccine combination therapy trials.
Ixabepilone in Combination with Capecitabine and as Monotherapy for Treatment of Advanced Breast Cancer Refractory to Previous Chemotherapies
Authors: Lechleider Robert J. , Kaminskas Edvardas , Jiang Xiaoping , Aziz Robeena , Bullock Julie , Kasliwal Ravindra , Harapanhalli Ravi , Pope Sarah , Sridhara Rajeshwari , Leighton John , Booth Brian , Dagher Ramzi , Justice Robert , Pazdur Richard 
Published: July 2008

Abstract
Purpose: To describe the considerations leading to marketing approval of ixabepilone in combination with capecitabine and as monotherapy for the treatment of advanced breast cancer that is refractory to other chemotherapies.
Experimental Design: Data from one randomized multicenter trial comparing combination therapy with ixabepilone and capecitabine to capecitabine alone were analyzed for support of the combination therapy indication. For monotherapy, a single-arm trial of ixabepilone was analyzed. Supporting data came from an additional single-arm combination therapy study and two single-arm monotherapy studies.
Results: In patients with metastatic or locally advanced breast cancer who had disease progression on or following an anthracycline and a taxane, ixabepilone plus capecitabine showed an improvement in progression-free survival compared with capecitabine alone {median progression-free survival, 5.7 [95% confidence interval (95% CI), 4.8-6.7] versus 4.1 (95% CI, 3.1-4.3) months, stratified log-rank P &lt; 0.0001; hazard ratio, 0.69 (95% CI, 0.58-0.83)}. As monotherapy for patients who had disease progression on or following an anthracycline, a taxane, and capecitabine, ixabepilone as monotherapy showed a 12% objective response rate by independent blinded review and 18% by investigator assessment. The major toxicities from ixabepilone therapy were peripheral neuropathy and myelosuppression, particularly neutropenia.
Conclusions: On October 16, 2007, the Food and Drug Administration approved ixabepilone for injection in combination with capecitabine or as monotherapy for the treatment of patients with advanced breast cancer who have experienced disease progression on previous chemotherapies.
Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia
Authors: Quintás-Cardama Alfonso , Cortes Jorge 
Published: July 2008

Abstract
Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of resistance continues to challenge the treatment of this disease. Mutations within the kinase domain of BCR-ABL1 constitute the most frequent mechanism of resistance in patients with chronic myelogenous leukemia treated with imatinib or the second generation tyrosine kinase inhibitors nilotinib and dasatinib. Of particular concern is the substitution of the threonine residue at the highly conserved gatekeeper residue 315 with a bulkier hydrophobic isoleucine amino acid. This mutation causes steric hindrance precluding the access ATP-competitive inhibitors to the ATP-binding pocket. To expedite the identification of strategies to override the resistance imposed by the T315I mutation, several strategies have been pursued, including the exploitation of BCR-ABL1 kinase sites distant from the ATP-binding pocket to cripple the kinase activity of the enzyme and inhibiting signaling pathways downstream from BCR-ABL1. Recent insights gained regarding the structural biology of T315I have led to the development of a variety of compounds against this mutant. We herein summarize the most clinically promising anti-T315I therapies.
RLIP76 and Cancer
Authors: Awasthi Sanjay , Singhal Sharad S. , Awasthi Yogesh C. , Martin Bryan , Woo Jung-Hee , Cunningham C. Casey , Frankel Arthur E. 
Published: July 2008

AbstractRLIP76 is a multifunctional membrane protein that transports glutathione conjugates of electrophilic compounds and other xenobiotics including chemotherapy agents out of cells. The protein is overexpressed in lung carcinomas, ovarian carcinomas, and melanomas. The protein also binds Ral and participates in mitotic spindle function, clathrin-dependent endocytosis, and triggers GTPase-activating protein activity. It is found throughout the cell, in membrane, cytosol, and the nucleus, and is known to shift between these compartments in response to stress. Loss of RLIP76 by antibody or antisense therapy is associated with increased sensitivity to radiation and chemotherapy. Conversely, liposomally delivered RLIP may treat poisoning and wounds.
Children and Participation in South Africa: An Overview
Authors: Moses Susan 
Published: July 2008

AbstractThis paper examines the current policy and practice around children's participation in South Africa. By situating the analysis from the perspective of the socio-economic and normative context within South Africa the paper critiques current typologies of children's participation for focusing too narrowly on processes internal to participatory processes. The paper argues that theorisations of children's participation need to take account of the range of activities which are labelled as children's participation and interrogate issues around who gets to participate and why, what the purposes of the participation are and under what conditions it is possible. This requires examining participatory processes and the children involved in them in relation to adult actors within and beyond the process as well as in relation to broader socio-political and economic environments.
The Impact of Nudging in the Meteorological Model for Retrospective Air Quality Simulations. Part I: Evaluation against National Observation Networks
Authors: Otte Tanya L. 
Published: July 2008

Abstract
It is common practice to use Newtonian relaxation, or nudging, throughout meteorological model simulations to create “dynamic analyses” that provide the characterization of the meteorological conditions for retrospective air quality model simulations. Given the impact that meteorological conditions have on air quality simulations, it has been assumed that the resultant air quality simulations would be more skillful by using dynamic analyses rather than meteorological forecasts to characterize the meteorological conditions, and that the statistical trends in the meteorological model fields are also reflected in the air quality model. This article, which is the first of two parts, demonstrates the impact of nudging in the meteorological model on retrospective air quality model simulations. Here, meteorological simulations are generated by the fifth-generation Pennsylvania State University–National Center for Atmospheric Research Mesoscale Model (MM5) using both the traditional dynamic analysis approach and using forecasts for a summertime period. The resultant fields are then used to characterize the meteorological conditions for emissions processing and air quality simulations using the Community Multiscale Air Quality (CMAQ) Modeling System. As expected, on average, the near-surface meteorological fields show a significant degradation over time in the forecasts (when nudging is not used), while the dynamic analyses maintain nearly constant statistical scores in time. The use of nudged MM5 fields in CMAQ generally results in better skill scores for daily maximum 1-h ozone mixing ratio simulations. On average, the skill of the daily maximum 1-h ozone simulation deteriorates significantly over time when nonnudged MM5 fields are used in CMAQ. The daily maximum 1-h ozone mixing ratio also degrades over time in the CMAQ simulation that uses MM5 dynamic analyses, although to a much lesser degree, despite no aggregate loss of skill over time in the dynamic analyses themselves. These results affirm the advantage of using nudging in MM5 to create the meteorological characterization for CMAQ for retrospective simulations, and it is shown that MM5-based dynamic analyses are robust at the surface throughout 5.5-day simulations.
The Impact of Nudging in the Meteorological Model for Retrospective Air Quality Simulations. Part II: Evaluating Collocated Meteorological and Air Quality Observations
Authors: Otte Tanya L. 
Published: July 2008

Abstract
For air quality modeling, it is important that the meteorological fields that are derived from meteorological models reflect the best characterization of the atmosphere. It is well known that the accuracy and overall representation of the modeled meteorological fields can be improved for retrospective simulations by creating dynamic analyses in which Newtonian relaxation, or “nudging,” is used throughout the simulation period. This article, the second of two parts, provides additional insight into the value of using nudging-based data assimilation for dynamic analysis in the meteorological fields for air quality modeling. Meteorological simulations are generated by the fifth-generation Pennsylvania State University–National Center for Atmospheric Research Mesoscale Model (MM5) using both the traditional dynamic analysis approach and forecasts for a summertime period. The resultant meteorological fields are then used for emissions processing and air quality simulations using the Community Multiscale Air Quality Modeling System (CMAQ). The predictions of surface and near-surface meteorological fields and ozone are compared with a small network of collocated meteorological and air quality observations. Comparisons of 2-m temperature, 10-m wind speed, and surface shortwave radiation show a significant degradation over time when nudging is not used, whereas the dynamic analyses maintain consistent statistical scores over time for those fields. Using nudging in MM5 to generate dynamic analyses, on average, leads to a CMAQ simulation of hourly ozone with smaller error. Domainwide error patterns in specific meteorological fields do not directly or systematically translate into error patterns in ozone prediction at these sites, regardless of whether nudging is used in MM5, but large broad-scale errors in shortwave radiation prediction by MM5 directly affect ozone prediction by CMAQ at specific sites.
Near-Real-Time Applications of CloudSat Data
Authors: Mitrescu Cristian , Miller Steven , Hawkins Jeffrey , L’Ecuyer Tristan , Turk Joseph , Partain Philip , Stephens Graeme 
Published: July 2008

Abstract
Within 2 months of its launch in April 2006 as part of the Earth Observing System A-Train satellite constellation, the National Aeronautics and Space Administration Earth System Science Pathfinder (ESSP) CloudSat mission began making significant contributions toward broadening the understanding of detailed cloud vertical structures around the earth. Realizing the potential benefit of CloudSat to both the research objectives and operational requirements of the U.S. Navy, the Naval Research Laboratory coordinated early on with the CloudSat Data Processing Center to receive and process first-look 94-GHz Cloud Profiling Radar datasets in near–real time (4–8 h latency), thereby making the observations more relevant to the operational community. Applications leveraging these unique data, described herein, include 1) analysis/validation of cloud structure and properties derived from conventional passive radiometers, 2) tropical cyclone vertical structure analysis, 3) support of research field programs, 4) validation of numerical weather prediction model cloud fields, and 5) quantitative precipitation estimation in light rainfall regimes.
Comparisons of Transport and Dispersion Model Predictions of the Joint Urban 2003 Field Experiment
Authors: Warner Steve , Platt Nathan , Urban Jeffry T. , Heagy James F. 
Published: July 2008

Abstract
For a hazardous material release in a city or densely populated area, effective mitigation requires an understanding of the transport and dispersion of these hazards in the complex urban environment. Improved characterization and understanding of urban transport and dispersion will allow for more robust modeling. The Defense Threat Reduction Agency has developed a Hazard Prediction Assessment Capability (HPAC) that includes features to address hazardous releases within an urban environment. During the summer of 2003, a series of tracer gas releases were carried out in Oklahoma City, Oklahoma, and extensive meteorological and tracer concentration measurements were collected in a field experiment known as Joint Urban 2003 (JU03). This analysis uses the observations of JU03 to evaluate “Urban HPAC.” Twenty sets of simulations, or “predictions,” using four Urban HPAC modes and five meteorological input options, were created and compared using a variety of metrics. Strong consistency was found between the conclusions of this study and those of two previously reported Urban HPAC evaluations. For example, improved predictions were associated with the inclusion of a simple empirically based urban dispersion model within HPAC, whereas improvements associated with the inclusion of a more computationally intensive urban wind module were not found. In this study, two new results are reported. First, there was a substantial difference in the performance of Urban HPAC as a function of release time—day or night—that was not discovered earlier because the previously examined urban field experiments focused on nighttime releases only. Daytime releases tended to be underpredicted and nighttime releases tended to be overpredicted. Second, and with respect to the under- and overpredictions described above, the inclusion of the new “Micro” Stationary Wind Fit and Turbulence (SWIFT) “SPRAY” (MSS) Urban HPAC mode typically led to less underprediction during the day and less overprediction at night than the other Urban HPAC modes. In addition, predictions that included MSS typically resulted in the least scatter between observations and predictions. These improvements warrant further investigation to determine whether this conclusion can be extended to other urban environments.
Use of Numerical Forecasts for Improving TMI Rain Retrievals over the Mountainous Area in Korea
Authors: Kwon Eun-Han , Sohn Byung-Ju , Chang Dong-Eon , Ahn Myoung-Hwan , Yang Song 
Published: July 2008

Abstract
Topographical influences on the Tropical Rainfall Measuring Mission (TRMM) Microwave Imager (TMI) rain retrievals over the terrain area of the Korean peninsula were examined using a training dataset constructed from numerical mesoscale model simulations in conjunction with radiative transfer calculations. By relating numerical model outputs to rain retrievals from simulated brightness temperatures, a positive relationship between topographically forced vertical motion and rain retrievals in the upstream region over the mountainous area was found. Based on the relationship obtained, three topographical correction methods were developed by incorporating slope-forced vertical motion and its associated upward vapor flux, and vapor flux convergence in the surface boundary layer into a scattering-based TMI rain retrieval algorithm.
The developed correction methods were then applied for the rain retrievals from simulated TMI brightness temperatures with model outputs and measured TMI brightness temperatures. Results showed that orographic influences on the rain formation can be included in the TMI rainfall algorithms, which tend to underestimate rainfall over the complex terrain area. It was shown that topographical corrections surely improve the rain retrieval when a strong rain event is present over the upslope region. Among various elements, moisture convergence in the boundary layer appears to be an important factor needed in the topographical correction. Overall topography-corrected estimates of rainfall showed a better agreement with ground measurements than those without correction, suggesting that satellite rain retrieval over the terrain area can be improved when accurate numerical forecast outputs are incorporated into the rain retrieval algorithm.