bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of ΔNp73 and TAp73α Independently Associated with Radiosensitivities and Prognoses in Cervical Squamous Cell Carcinoma
Authors: Liu Stephanie Si , Chan Kelvin Yuen-Kwong , Cheung Annie Nga-Yin , Liao Xiao-Yun , Leung Tsin-Wah , Ngan Hextan Yuen-Sheung 
Published: July 2006

Abstract
Purpose: The p73 gene produces different protein isoforms using alternative promoters and splicing, which have different biological characteristics. This study was to investigate the expression patterns of two distinct p73 isoforms (ΔNp73 and TAp73α) in cervical squamous cell carcinomas (SCC) and the relationship between their expressions and prognostic significance in cervical SCC patients.
Experimental Design: We investigated the protein expressions of ΔNp73 and TAp73α in 117 cervical SCC and 113 normal cervical tissues using immunohistochemistry. The expression levels were analyzed with clinical variables and patients' survival.
Results: ΔNp73and TAp73α were significantly overexpressed in cervical SCC compared with those in normal cervical epithelium (P &lt; 0.001). However, their expressions were inversely correlated (P &lt; 0.001, R = −0.368) and associated with differential tumor radiosensitivity. Overexpression of ΔNp73 was significantly found in SCC resistant to irradiation (P &lt; 0.001), whereas increase of TAp73α expression was observed in the majority of SCC sensitive to irradiation (P &lt; 0.001). Multivariate and survival analyses indicated that the expressions of ΔNp73 and TAp73α were independently associated with prognosis: ΔNp73 was associated with recurrence of the disease [P = 0.001; odds ratio (OR), 4.857] and an adverse outcome (P = 0.012; OR, 4.676), whereas TAp73α predicted a better survival of cervical SCC patients (P = 0.018; OR, 0.065).
Conclusions: The p73 gene might be an important determinant of cellular response to irradiation. The expressions of the two main isoforms (ΔNp73 and TAp73α) might be potential markers for predicting the prognosis and sensitivity to radiotherapy in patients with cervical SCC.
Orotate Phosphoribosyltransferase Gene Polymorphism Predicts Toxicity in Patients Treated with Bolus 5-Fluorouracil Regimen
Authors: Ichikawa Wataru , Takahashi Takehiro , Suto Kenichi , Sasaki Yasutsuna , Hirayama Renzo 
Published: July 2006

Abstract
Purpose: We investigated whether the determination of orotate phosphoribosyltransferase (OPRT) and thymidylate synthase (TYMS) polymorphisms could predict the toxicity of 5-fluorouracil (5-FU) in colorectal cancer patients.
Experimental Design: The determination of OPRT and TYMS genotypes were done in genomic DNA extracted from blood by PCR amplification in 69 patients treated with bolus 5-FU as adjuvant chemotherapy. Associations between these polymorphisms and toxicity were evaluated retrospectively.
Results: The Ala allele in OPRT Gly213Ala polymorphism and the two tandem repeats (2R) in TYMS promoter polymorphism were associated with grade 3 to 4 neutropenia and diarrhea. The multivariate logistic regression models revealed that only TYMS promoter polymorphism had an independent value to predict grade 3 to 4 neutropenia [odds ratio, 19.2 for patients with the 2R allele compared with patients with homozygous with the three repeat (3R) alleles], whereas both OPRT and TYMS promoter polymorphisms were independent predictive factors for grade 3 to 4 diarrhea (odds ratio, 13.3 for patients with the Ala allele compared with patients in the Gly/Gly genotype and 11.1 for patients with the 2R allele compared with patients in the 3R/3R genotype). A significant difference was observed in the time to onset of severe toxicity, defined as grade 4 neutropenia and/or grade 3 to 4 gastrointestinal toxicities according to OPRT and TYMS promoter polymorphisms.
Conclusion: OPRT Gly213Ala polymorphism seems to be a useful marker for predicting toxicity to bolus 5-FU chemotherapy. Prospective translational treatment trials including larger number of patients are needed to confirm our results.
Immune Escape Associated with Functional Defects in Antigen-Processing Machinery in Head and Neck Cancer
Authors: Ferris Robert L. , Whiteside Theresa L. , Ferrone Soldano 
Published: July 2006

Abstract
Recent revival of interest in the role of immune surveillance in the pathogenesis and control of malignant diseases has focused attention on escape mechanisms used by tumor cells to evade immune recognition. Defects in the host's tumor antigen–specific immune responses and abnormalities in tumor cell expression of HLA class I molecules and tumor antigen are known to contribute to tumor progression. However, the mechanism(s) responsible for the lack of tumor cell recognition by functional HLA class I antigen–restricted, tumor antigen–specific CTLs despite expression of the restricting HLA class I allele and targeted tumor antigen by tumor cells remain(s) unexplained. In squamous cell carcinomas of the head and neck (SCCHN), this type of tumor escape is a rule rather than the exception. Here, we discuss evidence pointing to functional defects in the antigen-processing machinery as one mechanism underlying resistance of SCCHN cells to recognition and lysis by HLA class I antigen–restricted, tumor antigen–specific CTL. In addition, based on the restoration by IFN-γ of SCCHN cell sensitivity to recognition by these CTL, we suggest strategies that may improve the clinical course of the disease by enhancing susceptibility of malignant cells to immune recognition.
Accurate Prediction of BRCA1 and BRCA2 Heterozygous Genotype Using Expression Profiling after Induced DNA Damage
Authors: Kote-Jarai Zsofia , Matthews Lucy , Osorio Ana , Shanley Susan , Giddings Ian , Moreews Francois , Locke Imogen , Evans D. Gareth , Eccles Diana ,   The Carrier Clinic Collaborators, Williams Richard D. , Girolami Mark , Campbell Colin , Eeles Ros 
Published: July 2006

Abstract
Purpose: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells.
Experimental Design: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used.
Results: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90%, and the Gaussian process classifier achieved 100% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes.
Conclusions: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations.
Phase I Trial of Doxorubicin-Containing Low Temperature Sensitive Liposomes in Spontaneous Canine Tumors
Authors: Hauck Marlene L. , LaRue Susan M. , Petros William P. , Poulson Jean M. , Yu Daohai , Spasojevic Ivan , Pruitt Amy F. , Klein Allison , Case Beth , Thrall Donald E. , Needham David , Dewhirst Mark W. 
Published: July 2006

AbstractPurpose: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors.Experimental Design: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle.Results: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received ≥2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 ± 6.17 ng/mg tissue.Conclusion: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.
Clinical Significance of Aminopeptidase N in Non–Small Cell Lung Cancer
Authors: Tokuhara Takahiro , Hattori Noboru , Ishida Hisao , Hirai Tatsuya , Higashiyama Masahiko , Kodama Ken , Miyake Masayuki 
Published: July 2006

Abstract
Purpose: The aim of our study is to investigate the mechanism of metastasis, to detect novel metastasis-associated molecules, and to evaluate the molecules from the point of view of clinical application. A monoclonal antibody MH8-11, which we established, recognizes a glycoprotein that is identical to aminopeptidase N (APN/CD13). APN/CD13 degrades the extracellular matrix, while it is also involved in cell motility and improves angiogenesis.
Experimental Design: We investigated the expression of APN/CD13 in 194 cases of non–small cell lung cancer (NSCLC) by immunohistochemical analyses and reverse transcription-PCR assay to determine the significance of this prognostic factor; 95 tumors were stage I, 36 were stage II, 39 were stage IIIA, and 24 were stage IIIB. Moreover, we investigated that the relationship between the expression of APN/CD13 and angiogenesis and prognosis for patients with NSCLC.
Results: We found a correlation between the expression of APN/CD13 and angiogenesis (r = 0.659; P &lt; 0.0001). In the 194 patients with NSCLC, we found 68 patients to be APN/CD13+ and 126 patients to be APN/CD13−. The 5-year survival rate in patients with APN/CD13+ tumors was significantly lower than in those whose tumors had negative APN/CD13 (48.3% versus 67.1%; P = 0.0001).
Conclusion: Our data suggest the expression of APN/CD13 for patients with NSCLC to be associated with a poor prognosis and angiogenesis. This is the first study to show the relationship between the expression of APN/CD13 and the prognosis of patients with NSCLC. The inhibition of APN/CD13 may be an effective new molecular target therapy for patients with NSCLC.
Calcitonin Gene-Related Peptide and Substance P Regulate the Intestinal Radiation Response
Authors: Wang Junru , Qiu Xiaohua , Kulkarni Ashwini , Hauer-Jensen Martin 
Published: July 2006

AbstractPurpose: Intestinal toxicity is important in the therapeutic use of radiation as well as in nontherapeutic radiation exposure scenarios. Enteric sensory nerves are critical for mucosal homeostasis and for an appropriate response to injury. This study assessed the role of the two major neuropeptides released by sensory nerves, calcitonin gene-related peptide (CGRP) and substance P, in the intestinal radiation response.Experimental Design: Male rats received full-length CGRP, CGRP antagonist (CGRP8-37), a modified substance P peptide (GR73632), a small-molecule substance P receptor antagonist (neurokinin-1 receptor antagonist, SR140333), or vehicle for 2 weeks after localized X irradiation of a 4-cm loop of small bowel. Structural, cellular, and molecular aspects of the intestinal radiation response were assessed.Results: Intestinal CGRP and substance P transcript levels increased after irradiation. Multivariate analysis showed that CGRP and SR140333 ameliorated and CGRP8-37 and GR73632 exacerbated intestinal radiation injury. Univariate analysis revealed increased radiation injury score, bowel wall thickening, and collagen III deposition after treatment with CGRP8-37, whereas SR140333 ameliorated radiation injury score, loss of mucosal surface area, collagen III deposition, and mucosal inflammation.Conclusions: The two major neuropeptides released by sensory neurons, CGRP and substance P, are overexpressed after irradiation and have opposing effects during development of intestinal radiation injury. Systematic studies to assess CGRP agonists and/or neurokinin-1 receptor blockers as protectors against intestinal toxicity during radiation therapy and after nontherapeutic radiation exposure are warranted.
Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable variable to improve drug delivery
Authors: Martinive Philippe , De Wever Julie , Bouzin Caroline , Baudelet Christine , Sonveaux Pierre , Grégoire Vincent , Gallez Bernard , Feron Olivier 
Published: July 2006

AbstractMaturation of tumor vasculature involves the recruitment of pericytes that protect the endothelial tubes from a variety of stresses, including antiangiogenic drugs. Mural cells also provide mature tumor blood vessels with the ability to either relax or contract in response to substances present in the tumor microenvironment. The observed cyclic alterations in tumor blood flow and the associated deficit in chemotherapeutic drug delivery could in part arise from this vasomodulatory influence. To test this hypothesis, we focused on endothelin-1 (ET-1), which, besides its autocrine effects on tumor cell growth, is a powerful vasoconstrictor. We first document that an ETA receptor antagonist induced relaxation of microdissected tumor arterioles and selectively and quantitatively increased tumor blood flow in experimental tumor models. We then combined dye staining of functional vessels, fluorescent microsphere-based mapping, and magnetic resonance imaging to identify heterogeneities in tumor blood flow and to examine the reversibility of such phenomena. Data from all these techniques concurred to show that administration of an ETA receptor antagonist could reduce the extent of underperfused tumor areas, proving the key role of vessel tone variations in tumor blood flow heterogeneity. We also provide evidence that ETA antagonist administration could, despite an increase in tumor interstitial fluid pressure, improve access of cyclophosphamide to the tumor compartment and significantly influence tumor growth. In conclusion, tumor endogenous ET-1 production participates largely in the temporal and spatial variations in tumor blood flow. ETA antagonist administration may wipe out such heterogeneities, thus representing an adjuvant strategy that could improve the delivery of conventional chemotherapy to tumors. [Mol Cancer Ther 2006;5(6):1620–7]
Potent cytotoxicity of an auristatin-containing antibody-drug conjugate targeting melanoma cells expressing melanotransferrin/p97
Authors: Smith Leia M. , Nesterova Albina , Alley Stephen C. , Torgov Michael Y. , Carter Paul J. 
Published: July 2006

AbstractIdentifying factors that determine the sensitivity or resistance of cancer cells to cytotoxicity by antibody-drug conjugates is essential in the development of such conjugates for therapy. Here the monoclonal antibody L49 is used to target melanotransferrin, a glycosylphosphatidylinositol-anchored glycoprotein first identified as p97, a cell-surface marker in melanomas. L49 was conjugated via a proteolytically cleavable valine-citrulline linker to the antimitotic drug, monomethylauristatin F (vcMMAF). Effective drug release from L49-vcMMAF likely requires cellular proteases most commonly located in endosomes and lysosomes. Melanoma cell lines with the highest surface p97 expression (80,000–280,000 sites per cell) were sensitive to L49-vcMMAF whereas most other cancer cell lines with lower p97 expression were resistant, as were normal cells with low copy numbers (≤20,000 sites per cell). Cell line sensitivity to L49-vcMMAF was found by immunofluorescence microscopy to correlate with intracellular fate of the conjugate. Specifically, L49-vcMMAF colocalized with the lysosomal marker CD107a within sensitive cell lines such as SK-MEL-5 and A2058. In contrast, in resistant cells expressing lower p97 levels (H3677; 72,000 sites per cell), L49-vcMMAF colocalized with caveolin-1, a protein prominent in caveolae, but not with CD107a. Thus, for antibody-drug conjugates targeting p97, antigen level and trafficking to the lysosomes are important factors for achieving robust in vitro cytotoxicity against cancer cells. Immunohistochemical analysis with L49 revealed that 62% of metastatic melanoma tumors had strong staining for p97. Overexpression of p97 in melanoma as compared with normal tissue, in conjunction with the greater sensitivity of tumor cells to L49-vcMMAF, supports further evaluation of antibody-drug conjugates for targeting p97-overexpressing tumors. [Mol Cancer Ther 2006;5(6):1474–82]
B cell translocation gene 1 contributes to antisense Bcl-2-mediated apoptosis in breast cancer cells
Authors: Nahta Rita , Yuan Linda X.H. , Fiterman Derek J. , Zhang Li , Symmans W. Fraser , Ueno Naoto T. , Esteva Francisco J. 
Published: July 2006

Abstract
The antiapoptotic protein Bcl-2 is overexpressed in a majority of breast cancers, and is associated with a diminished apoptotic response and resistance to various antitumor agents. Bcl-2 inhibition is currently being explored as a possible strategy for sensitizing breast cancer cells to standard chemotherapeutic agents. Antisense Bcl-2 oligonucleotides represent one method for blocking the antiapoptotic effects of Bcl-2. In this study, we show that antisense Bcl-2 efficiently blocks Bcl-2 expression, resulting in the apoptosis of breast cancer cells. Antisense Bcl-2-mediated cytotoxicity was associated with the induction of the B cell translocation gene 1 (BTG1). Importantly, knockdown of BTG1 reduced antisense Bcl-2-mediated cytotoxicity in breast cancer cells. Furthermore, BTG1 expression seems to be negatively regulated by Bcl-2, and exogenous expression of BTG1 induced apoptosis. These results suggest that BTG1 is a Bcl-2-regulated mediator of apoptosis in breast cancer cells, and that its induction contributes to antisense Bcl-2-mediated cytotoxic effects. [Mol Cancer Ther 2006;5(6):1593–601]
Natural Variability in a Stable, 1000-Yr Global Coupled Climate–Carbon Cycle Simulation
Authors: Doney Scott C. , Lindsay Keith , Fung Inez , John Jasmin 
Published: July 2006

Abstract
A new 3D global coupled carbon–climate model is presented in the framework of the Community Climate System Model (CSM-1.4). The biogeochemical module includes explicit land water–carbon coupling, dynamic carbon allocation to leaf, root, and wood, prognostic leaf phenology, multiple soil and detrital carbon pools, oceanic iron limitation, a full ocean iron cycle, and 3D atmospheric CO2 transport. A sequential spinup strategy is utilized to minimize the coupling shock and drifts in land and ocean carbon inventories. A stable, 1000-yr control simulation [global annual mean surface temperature ±0.10 K and atmospheric CO2 ± 1.2 ppm (1σ)] is presented with no flux adjustment in either physics or biogeochemistry. The control simulation compares reasonably well against observations for key annual mean and seasonal carbon cycle metrics; regional biases in coupled model physics, however, propagate clearly into biogeochemical error patterns. Simulated interannual-to-centennial variability in atmospheric CO2 is dominated by terrestrial carbon flux variability, ±0.69 Pg C yr−1 (1σ global net annual mean), which in turn reflects primarily regional changes in net primary production modulated by moisture stress. Power spectra of global CO2 fluxes are white on time scales beyond a few years, and thus most of the variance is concentrated at high frequencies (time scale &lt;4 yr). Model variability in air–sea CO2 fluxes, ±0.10 Pg C yr−1 (1σ global annual mean), is generated by variability in sea surface temperature, wind speed, export production, and mixing/upwelling. At low frequencies (time scale &gt;20 yr), global net ocean CO2 flux is strongly anticorrelated (0.7–0.95) with the net CO2 flux from land; the ocean tends to damp (20%–25%) slow variations in atmospheric CO2 generated by the terrestrial biosphere. The intrinsic, unforced natural variability in land and ocean carbon storage is the “noise” that complicates the detection and mechanistic attribution of contemporary anthropogenic carbon sinks.
Cirrus Clouds and the Large-Scale Atmospheric State: Relationships Revealed by Six Years of Ground-Based Data
Authors: Mace Gerald G. , Benson Sally , Vernon Erik 
Published: July 2006

AbstractThe properties of cirrus clouds observed at the Atmospheric Radiation Measurement (ARM) Climate Research Facility (ACRF) in Oklahoma are documented from a nearly continuous 6-yr record of 35-GHz cloud radar data. Cirrus frequency over the ACRF is 23% and 28% of the time in the warm (May–September) and cold seasons (November–March), respectively, with maxima and minima during the period studied of 30% and 16% in the warm season and 34% and 24% in the cold seasons. Cirrus, as defined here, reveal a seasonal oscillation in their macroscale properties that can be traced to the seasonal deepening of the troposphere in the Southern Plains region. While the average bulk microphysical properties do not change significantly from season to season, the variability of certain parameters demonstrates seasonal change. It is shown that the properties of cirrus clouds vary perceptively with the large-scale vertical motion. Using NCEP–NCAR reanalysis data to define the large-scale meteorological state when cirrus are observed at the ACRF, the authors find that cirrus tend to exist within a maximum in upper-tropospheric humidity and downstream of the peak upper-tropospheric vertical motion. Cirrus that exist in large-scale ascent upstream of the synoptic-scale middle-tropospheric ridge axis are shown to have higher water contents than cirrus that exist in large-scale subsidence downstream of the ridge axis, although the overall nature of the statistical distributions of water contents do not change greatly, suggesting that it may be difficult to parameterize the properties of cirrus based solely on large-scale vertical motion. The layer-mean particle size, on the other hand, shows no such sensitivity to the large-scale vertical motion.