bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Low Glutamine/Glucose on Hypoxia-Induced Elevation of Hypoxia-Inducible Factor-1α in Human Pancreatic Cancer MiaPaCa-2 and Human Prostatic Cancer DU-145 Cells
Authors: Kwon Seok Joon , Lee Yong J. 
Published: September 2005

Abstract
Purpose and Experimental Design: Tumor microenvironment is characterized by regions of fluctuating and chronic hypoxia, low extracellular pH, and nutrient depletion. Although it is well known that hypoxia stimulates the accumulation of hypoxia-inducible factor-1α (HIF-1α), the role of low extracellular pH and nutrient depletion on hypoxia up-regulation of HIF-1α is not well known. In this study, human pancreatic cancer MiaPaCa-2 and human prostatic cancer DU-145 cells were exposed to hypoxia in the presence or absence of glucose, glutamine, and/or pyruvate.
Results: We observed that low glucose and low glutamine, but not low pyruvate, effectively suppressed the elevation of HIF-1α level during hypoxia (0.1-1% oxygen). Deprivation of glutamine or glucose inhibited the accumulation of HIF-1α in the presence of MG-132, a protease inhibitor, regardless of oxygen tensions. Data from reverse transcription-PCR analysis revealed that the levels of HIF-1α mRNA were not significantly changed at different concentrations of glutamine or glucose under hypoxia. The amount of HIF-1α suppression was proportional to protein synthesis inhibition.
Conclusions: Our data suggest that glutamine or glucose deprivation inhibits the accumulation of HIF-1α under hypoxic conditions by disrupting translational processes rather than transcriptional or proteasomal degradation processes.
Cyclooxygenase-2 Expression in Human Colorectal Cancer Is Unrelated to Overall Patient Survival
Authors: Fux Richard , Schwab Matthias , Thon Klaus-Peter , Gleiter Christoph H. , Fritz Peter 
Published: September 2005

Abstract
Purpose: Cyclooxygenase-2 (COX-2) expression in human colorectal cancer and adenoma tissue seems to be higher than in normal mucosa. However, data about the relation between COX-2 expression and patient survival are inconclusive as yet. Therefore, we studied COX-2 expression in surgery tissue and survival time in a cohort of 747 colorectal cancer patients.
Experimental Design: Surgical specimens of primary colorectal cancer from 747 individuals were immunostained for COX-2 and evaluated under a transmission light microscope. COX-2 expression was scored according to intensity and extent of staining, resulting in the COX-2 immunoreactivity score (IRS-COX2). All possible cutoff points for IRS-COX2 were analyzed for a relation between COX-2 expression and patient survival.
Results: Both univariable and multivariable analysis have shown that the COX-2 expression in human tumor epithelial cells was unrelated to overall patient survival and to disease-free survival, irrespectively of the cutoff point for IRS-COX2. The survival rates for 1, 3, 5, and 10 years were 81.0%, 66.8%, 60.2%, and 49.8% (median: 117.3 months; 95% confidence interval, 102.3-132.0), respectively. In the multivariable analysis, only node and metastasis were significantly related to overall patient survival. Similar results were obtained when stage IV and rectal cancer patients were excluded from the analysis.
Conclusions: COX-2 expression in tumor epithelial cells does not seem to be related to survival of colorectal cancer patients. Besides COX-2, there are several targets, such as the peroxisome proliferator–activated receptors, that are involved in carcinogenesis and may be modulated by nonsteroidal anti-inflammatory drugs. Further studies are needed to determine their prognostic relevance.
Association between Polymorphisms in the DNA Repair Genes, XRCC1, APE1, and XPD and Acute Side Effects of Radiotherapy in Breast Cancer Patients
Authors: Chang-Claude Jenny , Popanda Odilia , Tan Xiang-Lin , Kropp Silke , Helmbold Irmgard , von Fournier Dietrich , Haase Wulf , Sautter-Bihl Marie Luise , Wenz Frederik , Schmezer Peter , Ambrosone Christine B. 
Published: September 2005

Abstract
Purpose: Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility. We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), APE1 (Asp148Glu), and XPD (Lys751Gln and Asp312Asn), with the risk of acute skin reactions following radiotherapy.
Design: We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose.
Results: Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of the APE1 148Glu and the XRCC1 399Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1 148Glu and XRCC1 399Gln alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; Pinteraction = 0.009).
Conclusion: The XRCC1 399Gln or APE1 148Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight.
Expression of Functional B7-H2 and B7.2 Costimulatory Molecules and Their Prognostic Implications inDe novoAcute Myeloid Leukemia
Authors: Tamura Hideto , Dan Kazuo , Tamada Koji , Nakamura Kyoko , Shioi Yumiko , Hyodo Hideya , Wang Sheng-Dian , Dong Haidong , Chen Lieping , Ogata Kiyoyuki 
Published: September 2005

AbstractPurpose: The B7 family molecules have been shown to regulate immune responses in both positive and negative fashions. Their roles in the progression of human cancers, however, are not well established. The aim of this study was to examine whether leukemic cells of acute myeloid leukemia express functional B7 family molecules and, if so, whether such expression has any clinical significance.Experimental Design: The expression of four B7 family molecules, B7.1, B7.2, B7-H1, and B7-H2, on leukemic cells from acute myeloid leukemia patients was analyzed by flow cytometry. The function of the expressed molecules was examined by the allogeneic mixed lymphocyte-leukemic cell reaction, and their relationship to the clinical data and survival was analyzed.Results: Although B7.1 and B7-H1 expressions were rare, the cells from a substantial number of acute myeloid leukemia cases expressed B7.2 and B7-H2 molecules [mean percentages of B7.2- and B7-H2-positive cells were 28.9% (n = 58) and 15.3% (n = 59), respectively]. Patients in whom &gt;25% of leukemic cells expressed B7-H2 had significantly shorter survival, and this B7-H2 positivity had the strongest prognostic value when B7-H2 and other prognostic factors were analyzed together by multivariate analysis (P = 0.0108). Furthermore, B7.2 expression was associated with hyperleukocytosis (P = 0.026). Consistent with this finding, acute myeloid leukemia cells expressing B7.2 and B7-H2 induced allogeneic CD4+ T cells to proliferate and secrete interleukin-4 and interleukin-10 in vitro, effects that were partially blocked by antibodies against B7.2 and B7-H2.Conclusions: Our results indicate the expression of functional B7.2 and B7-H2 molecules, and these molecules may facilitate progression of acute myeloid leukemia.
Radiolabeled Small-Molecule Ligands for Prostate-Specific Membrane Antigen:In vivoImaging in Experimental Models of Prostate Cancer
Authors: Foss Catherine A. , Mease Ronnie C. , Fan Hong , Wang Yuchuan , Ravert Hayden T. , Dannals Robert F. , Olszewski Rafal T. , Heston Warren D. , Kozikowski Alan P. , Pomper Martin G. 
Published: September 2005

AbstractPurpose: Prostate-specific membrane antigen (PSMA) is a cell surface protein that is overexpressed in prostate cancer, including hormone-refractory and metastatic disease. Our goal in this study was to develop a series of PSMA-based imaging agents for clinical use.Experimental Design: We have synthesized and evaluated the in vivo biodistribution of two radiolabeled urea derivatives that have high affinity for PSMA in severe combined immunodeficient mice harboring MCF-7 (breast, PSMA-negative), PC-3 (prostate, PSMA-negative), and LNCaP (prostate, PSMA-positive) xenografts. Radiopharmaceutical binding selectivity and tumor uptake were also evaluated in vivo using dedicated small animal positron emission tomography, single photon emission computed tomography, and gamma scintigraphic imaging devices. N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-[11C]methyl-l-cysteine ([11C]DCMC Ki, 3.1 nmol/L) and N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-[125I]iodo-l-tyrosine ([125C]DCIT Ki, 1.5 nmol/L) were synthesized using [11C]CH3I and with [125I]NaI/Iodogen, respectively.Results: At 30 minutes postinjection, [11C]DCMC and [125I]DCIT showed tumor/muscle ratios of 10.8 and 4.7, respectively, with clear delineation of LNCaP-derived tumors on imaging. MCF-7- and PC-3-derived tumors showed significantly less uptake of [11C]DCMC or [125I]DCIT.Conclusion: These results show the feasibility of imaging PSMA-positive prostate cancer using low molecular weight agents.
Cytotoxic Chemotherapy in Advanced Non-Small Cell Lung Cancer
Authors: Socinski Mark A. 
Published: September 2005

Abstract
A 1995 meta-analysis of nine trials involving 1190 patients by the Non-Small Cell Lung Cancer Collaborative Group reported that in advanced metastatic disease, platinum-based chemotherapy provides a survival benefit compared with best supportive care. Since then, several randomized trials using either platinum-based combination regimens or selected new single agents have confirmed this observation of a modest survival advantage, as well as improved quality of life. New agents such as paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan have shown significant single-agent activity in advanced non-small cell lung cancer. Two recent meta-analyses have suggested that regimens including these newer agents offer modest improvement in outcomes compared with older regimens. Several randomized trials have evaluated these modern platinum-based doublets and suggested that no one combination is superior when using survival as the primary measure of outcome. Future research may improve outcomes through identifying prognostic markers of treatment response to both standard cytotoxic and newer “targeted” therapies.
Update on the Role of Interleukin 2 and Other Cytokines in the Treatment of Patients with Stage IV Renal Carcinoma
Authors: Atkins Michael B. , Regan Meredith , McDermott David 
Published: September 2005

Abstract
Immunoreactive cytokines have been the mainstay of treatment of renal cancer for the past 15 years. Most research has focused on interferon alpha (IFN-α) and interleukin 2 (IL-2). IFN-α has been shown in Phase III studies to produce a modest survival advantage over inactive or non-IFN-containing regimens. Its general tolerability, multiple proposed mechanisms of action, and familiarity have prompted IFN-α to be studied in combination with a variety of agents with potential activity against renal cell carcinoma. These various studies may justify an increased role for IFN-α in the treatment of renal cancer in the foreseeable future. High-dose bolus IL-2 remains the only treatment for stage IV renal cancer approved by the United States Food and Drug Administration. Food and Drug Administration approval was granted in 1992 based on the ability of this agent to produce durable complete responses in a small number of patients. Unfortunately, the toxicity, expense, and restricted accessibility of high-dose IL-2 make it a poor standard. Regimens involving lower doses of IL-2 either alone or in combination with IFN-α have generally produced fewer tumor regressions of less overall quality. Recent efforts have focused on trying to identify factors predictive of response to IL-2 therapy so that this treatment could be limited to those most likely to benefit.
Intracellular Patterns of Her-2/neu, ras, and Ploidy Abnormalities in Primary Human Breast Cancers Predict Postoperative Clinical Disease-Free Survival
Authors: Shackney Stanley E. , Smith Charles A. , Pollice Agnese , Brown Kathryn , Day Roger , Julian Thomas , Silverman Jan F. 
Published: September 2005

Abstract
Purpose: In an earlier study (S. E. Shackney et al., Cancer J. Sci. Am., 2: 106, 1996), the presence of aneuploidy, Her-2/neu overexpression, and ras overexpression in the same cells (triple-positive cells) was of prognostic significance (P &lt; 0.015) in 91 patients with localized breast cancer (median follow up, 32 months). Here, we present results involving a larger group of patients with longer follow-up.
Experimental Design: Fixed cell suspensions prepared from primary tumors of 189 patients with early breast cancer were studied prospectively by multiparameter flow cytometry. Correlated intracellular fluorescence-based measurements of cell DNA content and Her-2/neu and ras protein were obtained on each of &gt;2000 cells in each tumor. Intracellular combinations of abnormalities in these measurements were correlated with subsequent patient disease-free survival (DFS). Median time on study was 54 months (range, 7–128 months).
Results: DFS of patients with ≥5% triple-positive tumor cells was shorter than those who did not meet this criterion (P = 0.004). The difference remained statistically significant after accounting for nodal status, tumor size, and each of the component abnormalities (P = 0.006). Node-negative patients whose tumors had fewer than 2 abnormalities/cell had an especially favorable clinical course, with a 5-year DFS of 96% (lower confidence bound, 86%).
Conclusions: Patterns of accumulated intracellular molecular abnormalities in cells of primary human breast cancers are predictive for subsequent DFS independently of the abnormalities themselves taken individually.
Identification of Serum Amyloid A Protein As a Potentially Useful Biomarker to Monitor Relapse of Nasopharyngeal Cancer by Serum Proteomic Profiling
Authors: Cho William C. S. , Yip Timothy T. C. , Yip Christine , Yip Victor , Thulasiraman Vanitha , Ngan Roger K. C. , Yip Tai-Tung , Lau Wai-Hon , Au Joseph S. K. , Law Stephen C. K. , Cheng Wai-Wai , Ma Victor W. S. , Lim Cadmon K. P. 
Published: September 2005

Abstract
Purpose: Nasopharyngeal cancer (NPC) is a common cancer in Hong Kong, and relapse can occur frequently. Using protein chip profiling analysis, we aimed to identify serum biomarkers that were useful in the diagnosis of relapse in NPC.
Experimental Design: Profiling analysis was performed on 704 sera collected from 42 NPC patients, 39 lung cancer patients, 30 patients with the benign metabolic disorder thyrotoxicosis (TX), and 35 normal individuals (NM). Protein profile in each NPC patient during clinical follow up was correlated with the relapse status.
Results: Profiling analysis identified two biomarkers with molecular masses of 11.6 and 11.8 kDa, which were significantly elevated in 22 of 31 (71%) and 21 of 31 (68%) NPC patients, respectively, at the time of relapse (RP) as compared with 11 patients in complete remission (CR; RP versus CR, P = 0.009), 30 TX (RP versus TX, P &lt; 0.001), or 35 NM (RP versus NM, P &lt; 0.001). The markers were also elevated in 16 of 39 (41%) lung cancer patients at initial diagnosis. By tryptic digestion, followed by tandem mass spectrometry fragmentation, the markers were identified as two isoforms of serum amyloid A (SAA) protein. Monitoring the patients longitudinally for SAA level both by protein chip and immunoassay showed a dramatic SAA increase, which correlated with relapse and a drastic fall correlated with response to salvage chemotherapy. Serum SAA findings were compared with those of serum Epstein-Barr virus DNA in three relapsed patients showing a similar correlation with relapse and chemo-response.
Conclusions: SAA could be a useful biomarker to monitor relapse of NPC.
Synchronous Coexpression of Epidermal Growth Factor Receptor and Cyclooxygenase-2 in Carcinomas of the Uterine Cervix
Authors: Kim Gwi Eon , Kim Yong Bae , Cho Nam Hoon , Chung Hyun-Cheol , Pyo Hong Ryull , Lee Jong Doo , Park Tchan Kyu , Koom Woong Sub , Chun Mison , Suh Chang Ok 
Published: September 2005

Abstract
Purpose: To evaluate the potential of the new prognostic information gained by analyzing the coexpression of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) in cervical cancer patients.
Experimental Design: Sixty-eight patients with International Federation of Gynecology and Obstetrics stage IIB squamous cell carcinoma of the uterine cervix, who underwent concurrent chemoradiotherapy between 1993 and 1996, were divided into the following four groups according to their immunoreactivities for EGFR and COX-2 in paraffin-embedded sections: (a) the EGFR-negative/COX-2-negative group (n = 11); (b) the EGFR-negative/COX-2-positive group (n = 8); (c) the EGFR-positive/COX-2-negative group (n = 27); and (d) the EGFR-positive/COX-2-positive group (n = 22). The clinical features, patterns of treatment failure, and survival data in the four groups were compared.
Results: Positive immunoreactivity for EGFR and COX-2 was observed in 49 of 68 (72%) and 19 of 68 (28%), respectively. However, no strong correlation was found between the levels of EGFR and COX-2 immunopositivity (R2 = 0.05, P = 0.07). Patients in the EGFR-positive/COX-2-positive group had a higher likelihood of locoregional recurrence than those in the other three groups (P = 0.02). Of the patients in the four groups, patients positive for both oncoproteins were found to have the worst prognosis with an overall 5-year disease-free survival rate of 55% compared with 91% for the EGFR-negative/COX-2-negative patients, 88% for the EGFR-negative/COX-2-positive patients, and 69% for the EGFR-positive/COX-2-negative patients (P = 0.05, log-rank test). In addition, the synchronous coexpression of the EGFR and COX-2 oncoproteins was found to be an independent prognostic factor by univariate and multivariate analyses (relative risk = 4.0, P = 0.03).
Conclusions: Given these observations, we conclude that the coexpression of EGFR and COX-2 immunoreactivity may be used as a potent molecular risk factor for predicting the poor survival of patients with the International Federation of Gynecology and Obstetrics stage IIB squamous cell carcinoma of the uterine cervix.
Interleukin-1 and Interleukin-6 Gene Polymorphisms and the Risk of Breast Cancer in Caucasian Women
Authors: Hefler Lukas A. , Grimm Christoph , Lantzsch Tilmann , Lampe Dieter , Leodolter Sepp , Koelbl Heinz , Heinze Georg , Reinthaller Alexander , Tong-Cacsire Dan , Tempfer Clemens , Zeillinger Robert 
Published: September 2005

AbstractPurpose: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown.Experimental Design: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [−889 C/T polymorphism of the IL1α gene (IL1A), −511 C/T polymorphism of the IL1β promoter (IL1B promoter), a polymorphism of IL1β exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the −174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing.Results: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables.Conclusions: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the −174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.
CCR7 and CXCR4 as Novel Biomarkers Predicting Axillary Lymph Node Metastasis in T1 Breast Cancer
Authors: Cabioglu Neslihan , Yazici M. Sertac , Arun Banu , Broglio Kristine R. , Hortobagyi Gabriel N. , Price Janet E. , Sahin Aysegul 
Published: September 2005

Abstract
Purpose: The chemokine receptors CCR7 and CXCR4 have been shown to play an important role in cancer metastasis. We therefore studied the differential expression of CCR7 and CXCR4, along with that of the biomarker HER2-neu, to evaluate whether these biomarkers could predict axillary lymph node metastasis in breast cancer.
Experimental Design: Biomarker expression levels were evaluated using paraffin-embedded tissue sections of lymph node–negative (n = 99) and lymph node–positive (n = 98) T1 breast cancer by immunohistochemical staining.
Results: Lymph node–positive tumors showed higher rates of high cytoplasmic CCR7 staining (21.5% versus 8.5%, P = 0.013) and HER2-neu overexpression (21.5% versus 9.3%, P = 0.019) than did lymph node–negative tumors. Similarly, high cytoplasmic CXCR4 expression occurred more commonly in lymph node–positive tumors (11.2% versus 5.1%, P = 0.113). In contrast, predominantly nuclear CXCR4 staining was more likely to be found in lymph node–negative tumors (54.5% versus 37.8%, P = 0.018). Furthermore, cytoplasmic CXCR4 coexpressed with HER2-neu was the only factor associated with involvement of four or more lymph nodes (16.7% versus 1.2%, P = 0.04) among lymph node–positive tumors. When all three biomarkers (CCR7, CXCR4, HER2-neu) were utilized together, 50.0% of lymph node–positive tumors highly expressed one of these biomarkers compared with 18.8% of the lymph node–negative tumors (P &lt; 0.0001).
Conclusions: Our results suggest that the chemokine receptor CCR7 is a novel biomarker that can predict lymph node metastases in breast cancer. Utilization of additional markers, such as CXCR4 and HER2-neu, further improves the prediction of the presence and extent of lymph node involvement.