bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disruption of Cooperation Between Ras and MycN in Human Neuroblastoma Cells Promotes Growth Arrest
Authors: Yaari Shira , Jacob-Hirsch Jasmine , Amariglio Ninette , Haklai Ronit , Rechavi Gideon , Kloog Yoel 
Published: September 2005

Abstract
Purpose: Our aim was to examine whether active Ras and MycN cooperation contributes to the malignant phenotype of human neuroblastoma with amplified MycN gene, an aggressive incurable tumor.
Experimental Design: Human neuroblastoma LAN-1 cells, in which the MycN gene is amplified, were used to examine the impact of the Ras inhibitor farnesylthiosalicylic acid on cell growth, on the levels Ras and MycN proteins, and on profiles of gene expression.
Results: We show that LAN-1 cells express relatively large amounts of MycN and active Ras-GTP. Inhibition of active Ras by farnesylthiosalicylic acid led to attenuation of the Raf-MEK-ERK and phosphoinositide 3-kinase-Akt-glycogen synthase-3 (GSK-3) pathways, to reduction in cyclin D1, phospho-retinoblastoma, and E2F, and to increase in the cyclin-dependent kinase inhibitor p27 and in retinoblastoma-binding protein-1, an inhibitor of E2F transcriptional activity. Ras inhibition by farnesylthiosalicylic acid or by a dominant-negative Ras also led to complete disappearance of MycN protein from the nuclei of LAN-1 cells. This was a result of blocking of Akt inactivation of GSK-3, leading to GSK-3-dependent phosphorylation with consequent proteosomal degradation of MycN. Loss of active Ras and of MycN in LAN-1 cells was manifested in profiles of gene expression that could be expected from the loss of MycN transcriptional activity and of Ras signaling. These changes explain the farnesylthiosalicylic acid–induced inhibition of LAN-1 cell growth.
Conclusions: Active Ras is needed to block MycN degradation, promoting cooperative Ras- and MycN-dependent cell cycle progression in LAN-1 cells. Ras inhibitors are therefore likely candidates for the treatment of advanced neuroblastoma characterized by high expression of MycN.
9-cis-Retinoic Acid Treatment Increases Serum Concentrations of α-Tocopherol in Former Smokers
Authors: Han Ji-Youn , Liu Diane D. , Lee J. Jack , Kurie Jonathan , Lotan Reuben , Hong Waun K. , Lee Ho-Young 
Published: September 2005

Abstract
Purpose: Low serum concentrations of antioxidants may be associated with an increased risk of cancer. Based on the accumulated evidence, we hypothesized that retinoids would elevate serum α-tocopherol. This study was designed to determine whether 9-cis-retinoic acid (9-cis-RA), the most common chemopreventive agent, could alter serum α-tocopherol in former smokers. Because hyperlipidemia is a known side effect of retinoids, we also evaluated the association between serum α-tocopherol and lipids in the same population.
Experimental Design: Subjects who had stopped smoking at least 12 months before the study were randomly assigned to receive oral 9-cis-RA or placebo daily for 3 months. Clinical information and blood samples were obtained monthly; serum α-tocopherol concentrations were measured by high-performance liquid chromatography and lipid levels by enzymatic assays before treatment and every month during the treatment.
Results: Of the 149 subjects in the study, 113 completed 3 months of treatment and provided samples for evaluation of serum α-tocopherol. Serum α-tocopherol levels in the 9-cis-RA group (n = 52) were higher after treatment (r = 0.445, P &lt; 0.01) than before. The incidences of grade ≥2 hypertriglyceridemia and hypercholesterolemia were higher in the 9-cis-RA group than in the placebo group (P = 0.0005 and P = 0.01, respectively), but there were no serious complications related to hyperlipidemia.
Conclusions: Treatment of former smokers with 9-cis-RA significantly increased their serum α-tocopherol levels, and this could be a benefit. In addition, serum α-tocopherol could serve as a biomarker for 9-cis-RA treatment.
Predictors of the Response to Gefitinib in Refractory Non–Small Cell Lung Cancer
Authors: Kim Kyu-Sik , Jeong Ju-Yeon , Kim Young-Chul , Na Kook-Joo , Kim Yun-Hyeon , Ahn Sung-Ja , Baek Sun-Mi , Park Chang-Soo , Park Chang-Min , Kim Yu-Il , Lim Sung-Chul , Park Kyung-Ok 
Published: September 2005

Abstract
Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has a response rate of 10% to 20% in refractory non–small cell lung carcinoma. Although female gender, adenocarcinoma, and never having smoked are possible markers of a favorable response, mutations of the EGFR gene have also been reported to be highly significant predictors of response. Seventy patients with relapsed non–small cell lung carcinoma were enrolled in the Expanded Access Program. After the drug became available commercially, 28 more patients were treated with gefitinib. Response evaluations were feasible in 80 patients. Twenty-seven tumor specimens (8 responders and 19 nonresponders) were available for the sequence analysis of the EGFR gene. The response rate was 25% (20/80) and the disease control rate (remission + stable disease) was 47.5% (38/80). The response rate was significantly higher for adenocarcinoma (41.0%) versus non-adenocarcinoma (9.8%, P = 0.001), in those who never smoked (58.8%) versus smokers (15.9%, P &lt; 0.001), and in females (42.1%) versus males (19.7%, P = 0.049). A deletion or mutation of the EGFR gene was found in six of eight responders. Remission was noted in all patients with a mutation, whereas the response rate was 9.5% (2/21) in patients without a mutation (P &lt; 0.001). The predictors of response showed significant correlations with survival and time to progression. In a multivariate logistic analysis, the independent predictors of response were smoking history and adenocarcinoma. Given that 9.5% of smokers and 6.7% of those with non-adenocarcinoma showed a mutation of the EGFR gene, the genetic profile may replace those variables as an independent predictor of a response.
p12CDK2-AP1 Gene Therapy Strategy Inhibits Tumor Growth in an In vivo Mouse Model of Head and Neck Cancer
Authors: Figueiredo Marxa L. , Kim Yong , St. John Maie A.R. , Wong David T.W. 
Published: September 2005

Abstract
Purpose: To test the potential of p12CDK2-AP1 (p12), a cell cycle regulator and cyclin-dependent kinase-2-associating protein commonly down-regulated in head and neck squamous cell carcinoma (∼70%), as a gene therapy in inhibiting head and neck squamous cell carcinoma growth in vivo.
Experimental Design: We addressed the effect of p12 expression on tumor growth by using a well-established squamous cell carcinoma VII/SF floor of mouth xenograft mouse model. The effect of therapy on tumor growth was determined for: (a) no treatment, (b) PBS, (c) vehicle (1,2-dioleoyloxy-3-trimethylammonium propane:cholesterol liposomes / 5% dextrose), (d) empty vector controls, and (e) p12-encoding vector experimental groups.
Results: p12 gene therapy significantly induced antitumor effects as compared with controls, including (a) size and weight of p12-treated tumors decreased by 51% to 72% compared with all controls (P &lt; 0.02), (b) tumor growth rate post-therapy was inhibited by 55% to 64% compared with empty vector controls (P &lt; 0.0001), and (c) p12 expression was higher in p12-treated than controls (P &lt; 0.002) by two-tailed t test analyses. Mechanistically, p12 treatment affected cell turnover kinetics as assessed by apoptotic and cell proliferation indices. p12 therapy significantly increased terminal nucleotidyl transferase–mediated nick end labeling (P &lt; 0.05) and morphology-based apoptotic indices (P &lt; 0.05) as well as significantly decreased Ki-67 cell proliferation indices (P &lt; 0.001) compared with controls, resulting in a net cell turnover reduction in p12-treated tumors.
Conclusions: We show that this novel therapeutic modality can significantly induce antitumor responses in vivo. These results support a role for p12 as a novel tumor growth suppressor gene therapy and suggest that optimization and/or combination with current therapies may hold considerable promise in preparation for clinical trials.
Serum Cystatin C is a Better Marker of Topotecan Clearance than Serum Creatinine
Authors: Hoppe Antje , Séronie-Vivien Sophie , Thomas Fabienne , Delord Jean-Pierre , Malard Laurence , Canal Pierre , Chatelut Etienne 
Published: September 2005

Abstract
Purpose: To evaluate plasma cystatin level as a covariate to predict topotecan pharmacokinetics. Cystatin C, a member of the cystatin superfamily of cysteine proteinase inhibitors, has been recently proposed as an alternative endogenous marker of glomerular filtration. Renal function is known as a key factor of topotecan clearance.
Experimental Design: Data were obtained from 59 patients who underwent drug monitoring for individual dosing of topotecan. Topotecan plasma concentrations versus time were analyzed using a nonlinear mixed effect model according to a two-compartment pharmacokinetic model and a first-order conditional estimation method. A proportional error model was used for residual and interpatient variabilities. Data-splitting was done randomly to create a model-building data set (44 patients) and a model validation data set (15 patients).
Results: Using the building data set, four covariates significantly decreased the objective function value and interindividual variability on topotecan clearance (CL) when tested individually: ideal body weight (IBW), serum creatinine, age, and cystatin C level. The best model was: CL (L/hour) = 20.2 [cystatin C (mg/L) / 1.06]−0.60 [IBW (kg) / 57]0.95. Prospective evaluation using the validation data set confirmed that the model based on cystatin C had a better predictive value than the models based on serum creatinine or body surface area.
Conclusion: Cystatin C is a marker of drug elimination which is superior to serum creatinine for topotecan. It deserves to be further explored as a promising covariate for drug dosing as well as selection criteria for clinical studies of drugs eliminated mainly or partially by the kidney.
Histone Deacetylase Inhibitors Radiosensitize Human Melanoma Cells by Suppressing DNA Repair Activity
Authors: Munshi Anupama , Kurland John F. , Nishikawa Takashi , Tanaka Toshimitsu , Hobbs Marvette L. , Tucker Susan L. , Ismail Sheikh , Stevens Craig , Meyn Raymond E. 
Published: September 2005

Abstract
Purpose: Histone deacetylase (HDAC) inhibitors have emerged recently as promising anticancer agents. They arrest cells in the cell cycle and induce differentiation and cell death. The antitumor activity of HDAC inhibitors has been linked to their ability to induce gene expression through acetylation of histone and nonhistone proteins. However, it has recently been suggested that HDAC inhibitors may also enhance the activity of other cancer therapeutics, including radiotherapy. The purpose of this study was to evaluate the ability of HDAC inhibitors to radiosensitize human melanoma cells in vitro.
Experimental Design: A panel of HDAC inhibitors that included sodium butyrate (NaB), phenylbutyrate, tributyrin, and trichostatin A were tested for their ability to radiosensitize two human melanoma cell lines (A375 and MeWo) using clonogenic cell survival assays. Apoptosis and DNA repair were measured by standard assays.
Results: NaB induced hyperacetylation of histone H4 in the two melanoma cell lines and the normal human fibroblasts. NaB radiosensitized both the A375 and MeWo melanoma cell lines, substantially reducing the surviving fraction at 2 Gy (SF2), whereas it had no effect on the normal human fibroblasts. The other HDAC inhibitors, phenylbutyrate, tributyrin, and trichostatin A had significant radiosensitizing effects on both melanoma cell lines tested. NaB modestly enhanced radiation-induced apoptosis that did not correlate with survival but did correlate with functional impairment of DNA repair as determined based on the host cell reactivation assay. Moreover, NaB significantly reduced the expression of the repair-related genes Ku70 and Ku86 and DNA-dependent protein kinase catalytic subunit in melanoma cells at the protein and mRNA levels. Normal human fibroblasts showed no change in DNA repair capacity or levels of DNA repair proteins following NaB treatment. We also examined γ-H2AX phosphorylation as a marker of radiation response to NaB and observed that compared with controls, γ-H2AX foci persisted long after ionizing exposure in the NaB-treated cells.
Conclusions: HDAC inhibitors radiosensitize human tumor cells by affecting their ability to repair the DNA damage induced by ionizing radiation and that γ-H2AX phosphorylation can be used as a predictive marker of radioresponse.
A Molecular Signature in Superficial Bladder Carcinoma Predicts Clinical Outcome
Authors: Dyrskjøt Lars , Zieger Karsten , Kruhøffer Mogens , Thykjaer Thomas , Jensen Jens L. , Primdahl Hanne , Aziz Natasha , Marcussen Niels , Møller Klaus , Ørntoft Torben F. 
Published: September 2005

Abstract
Purpose: Cancer of the urinary bladder is a common malignant disease in the western countries. The majority of patients presents with superficial tumors with a high recurrence frequency, a minor fraction of these patients experience disease progression to a muscle invasive stage. No clinical useful molecular markers exist to identify patients showing later disease progression. The purpose of this study was to identify markers of disease progression using full-genome expression analysis.
Experimental Design: We did a full-genome expression analysis (59,619 genes and expressed sequence tags) of superficial bladder tumors from 29 bladder cancer patients (13 without later disease progression and 16 with later disease progression) using high-density oligonucleotide microarrays. We used supervised learning for identification of the optimal genes for predicting disease progression. The identified genes were validated on an independent test set (74 superficial tumor samples) using in house-fabricated 60-mer oligonucleotide microarrays.
Results: We identified a 45-gene signature of disease progression. By monitoring this progression signature in an independent test set, we found a significant correlation between our classifications and the clinical outcome (P &lt; 0.03). The genes identified as differentially expressed were involved in regulating apoptosis, cell differentiation, and cell cycle and hence may represent potential therapeutic targets.
Conclusions: Our results indicate that it may be possible to identify patients with a high risk of disease progression at an early stage using a molecular signature present already in the superficial tumors. In this way, better treatment and follow-up regimens could be assigned to patients suffering from superficial bladder cancer.
An Innovative Microarray Strategy Identities Informative Molecular Markers for the Detection of Micrometastatic Breast Cancer
Authors: Mikhitarian Kaidi , Gillanders William E. , Almeida Jonas S. , Hebert Martin Renee , Varela Juan C. , Metcalf John S. , Cole David J. , Mitas Michael 
Published: September 2005

Abstract
There is increasing evidence that molecular detection of micrometastatic breast cancer in the axillary lymph nodes (ALN) of breast cancer patients can improve staging. Molecular analyses of samples obtained from the Minimally Invasive Molecular Staging of Breast Cancer Trial (n = 489 patients) indicate that whereas the majority of molecular markers are informative for the detection of metastatic breast cancer (significant disease burden), only a few are sensitive for the detection of micrometastatic disease (limited disease burden). Frequency distribution and linear regression analyses reveal that relative levels of gene expression are highly correlated with apparent sensitivity for the detection of micrometastic breast cancer (P &lt; 0.05). These data provides statistical validation of the concept that the most informative markers for detection of micrometastatic disease are those that are most highly expressed in metastatic disease. To test this hypothesis, we developed an innovative microarray strategy. RNA from a metastatic breast cancer ALN was diluted into RNA from a normal lymph node and analyzed using Affymetrix microarrays. Expression analysis indicated that only two genes [mammaglobin (mam) and trefoil factor 1 (TFF1)] were significantly overexpressed at a dilution of 1:50. Real-time reverse transcription-PCR analysis of pathology-negative ALN (n = 72) confirm that of all the markers tested, mam and TFF1 have the highest apparent sensitivity for detection of micrometastatic breast cancer. We conclude that a dilutional microarray approach is a simple and reliable method for the identification of informative molecular markers for the detection of micrometastatic cancer.
High Mutagen Sensitivity in Peripheral Blood Lymphocytes Predicts Poor Overall and Disease-Specific Survival in Patients with Stage III Non–Small Cell Lung Cancer Treated with Radiotherapy and Chemotherapy
Authors: Chang Joe Y. , Komaki Ritsuko , Sasaki Ryohei , Liao Zhongxing , Stevens Craig W. , Lu Charles , Fossella Frank V. , Allen Pamela K. , Cox James D. , Spitz Margaret R. , Wu Xifeng 
Published: September 2005

Abstract
Purpose: To investigate whether the bleomycin sensitivity assay, an in vitro peripheral blood lymphocyte assay, can predict outcome in patients with inoperable stage III non–small-cell lung cancer (NSCLC) treated with definitive radiotherapy and chemotherapy.
Experimental Design: We identified 102 patients with inoperable stage III NSCLC cell lung cancer treated with definitive radiotherapy and chemotherapy. The patients' pretreatment peripheral blood lymphocyte cultures were treated with the radiomimetic mutagen bleomycin. An index of bleomycin sensitivity was determined by counting the number of chromatid breaks in 50 metaphases. The correlation between bleomycin sensitivity (expressed as mean breaks per cell) and clinical outcome was analyzed.
Results: High bleomycin sensitivity (defined as a mean of &gt;1.02 chromatid breaks/cell, representing the third quartile of bleomycin sensitivity) predicted poor disease-specific survival and overall survival. The 6-year disease-specific survival was 27% in patients with high bleomycin sensitivity compared with 46% in patients without such sensitivity (P = 0.0094). The association remained statistically significant when adjusted for smoking status, age, and radiation dose. The 6-year overall survival was 19% for patients with high bleomycin sensitivity and 29% for those without (P = 0.0193). There was a trend toward worse local regional control and worse disease-free survival among patients with high bleomycin sensitivity. There was no difference between the two groups in distant metastasis-free survival or radiation treatment-related complications.
Conclusions: High bleomycin sensitivity correlated with poor overall survival and disease-specific survival in these patients with stage III NSCLC treated with radiotherapy and chemotherapy. Bleomycin sensitivity may function as a biomarker for poor clinical outcome for this group of patients.
Characterization of a New Antibody Raised against the NH2 Terminus of P-Glycoprotein
Authors: Rao Prema S. , Govindarajan Rajgopal , Mallya Kavita B. , West William , Rao U. Subrahmanyeswara 
Published: September 2005

Abstract
Purpose: Cancers exposed to chemotherapy develop multidrug resistance, a major cause for chemotherapy failure. One mechanism of multidrug resistance development is due to overexpression of P-glycoprotein (Pgp) in these cancer cells. Thus, a prechemotherapy evaluation of Pgp in cancer cells aids in the design of alternative regimens that can circumvent such failure. As few Pgp-specific antibodies are available in detecting low levels of Pgp, there is a need for preparing an antibody that allows the detection of Pgp by various immunologic methods.
Experimental Design: We selected the amino acid stretch 11 to 34 in the cytoplasmically located NH2 terminus of Pgp as antigen, which was chemically synthesized and used to raise an antibody in a rabbit, termed NH211 antibody. We compared the properties of NH211 antibody with that of the well-characterized Pgp-specific antibody, C219, by Western blotting, immunoprecipitation, immunocytochemistry, and immunohistochemistry.
Results: Immunoblotting analysis suggested that NH211 antibody efficiently interacts with both recombinant and constitutively expressed Pgp in cancerous and noncancerous human cells. Immunoprecipitation reactions indicated that the NH211 antibody selectively immunoprecipitates Pgp. Immunocytochemical analyses indicated that the NH211 antibody detects Pgp in drug-resistant breast cancer cells as well as in human prostate and breast adenocarcinoma tissue sections.
Conclusion: As the NH211 antibody detects Pgp present in cells and tissues, we conclude that the amino acid sequence to which this antibody was raised is highly antigenic and the antibody is useful in the detection of Pgp by a variety of immunologic methods.
CD44 Expression Is Associated with Increased Survival in Node-Negative Invasive Breast Carcinoma
Authors: Diaz Leslie K. , Zhou Xiao , Wright Edward T. , Cristofanilli Massimo , Smith Terry , Yang Ying , Sneige Nour , Sahin Aysegul , Gilcrease Michael Z. 
Published: September 2005

Abstract
Purpose: CD44 is a multifunctional cell surface receptor with many known splice variants, some of which have been reported to play a role in tumor progression. The purpose of this study was to evaluate the prognostic significance of CD44 isoforms in early-stage, lymph node–negative invasive breast carcinoma.
Experimental Design: Immunohistochemical staining for CD44 isoforms was done on archival paraffin tissue sections of invasive breast carcinoma from a cohort of lymph node–negative patients who received no adjuvant tamoxifen or chemotherapy and who had a mean clinical follow-up period of 15 years. Immunohistochemical staining was done with antibodies to CD44s, the standard isoform of CD44, and to isoforms containing variant exon 6 (CD44v6); levels of staining were correlated with clinical outcome data.
Results: There was a trend towards increased disease-free survival for patients whose tumors had high anti-CD44s positivity (P = 0.05), and a significant association was observed between anti-CD44s positivity and disease-related survival (P = 0.04). Expression of CD44v6 isoforms did not correlate with clinical outcome.
Conclusion: CD44 expression, as assessed by immunohistochemical staining with anti-CD44s, may be a favorable prognostic factor in patients with node-negative invasive breast carcinoma.