bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteopontin as an Adjunct to CA125 in Detecting Recurrent Ovarian Cancer
Authors: Schorge John O. , Drake Richard D. , Lee Hang , Skates Steven J. , Rajanbabu Ramababu , Miller David S. , Kim Jae-Hoon , Cramer Daniel W. , Berkowitz Ross S. , Mok Samuel C. 
Published: September 2005

Abstract
Purpose: CA125 is currently the only tumor marker to have a validated role in the postoperative monitoring of ovarian cancer. Osteopontin (OPN) is a putative plasma biomarker that was recently identified using high-throughput cDNA microarray technology. The purpose of this study was to test the hypothesis that OPN is a clinically useful adjunct to CA125 in detecting recurrent ovarian cancer.
Experimental Design: Thirty-eight ovarian cancer patients had a single pretreatment blood sample and 200 postoperative specimens were prospectively collected during chemotherapy and follow-up. OPN measurements were performed using an enzyme-linked immunoassay, and CA125 levels were concurrently obtained. Wilcoxon’s signed rank-sum test was used to perform paired comparisons between pretreatment and postoperative OPN and CA125 measurements. Longitudinal mixed effects polynomial models were used to determine whether OPN and CA125 levels correlated with the development of recurrent ovarian cancer.
Results: The median pretreatment OPN level was 178 ng/ml (range, 12–3468) and the median CA125 measurement was 812 units/ml (range, 12–81,500). There was a trend for OPN levels to decline after treatment was initiated (P = 0.07), but decreasing CA125 measurements were more consistently observed (P = 0.0009). The quadratic functional trends of OPN and CA125 were each highly significant (P &lt; 0.0001). Although inferior to CA125 in predicting clinical response to therapy, OPN rose earlier in 90% (95% confidence interval, 56–100%) of the patients developing recurrent disease (median lead time, 3 months).
Conclusions: OPN may be a clinically useful adjunct to CA125 in detecting recurrent ovarian cancer.
Expression of Thyrotropin-Releasing Hormone by Human Melanoma and Nevi
Authors: Ellerhorst Julie A. , Naderi Aresu A. , Johnson Marilyn K. , Pelletier Pauline , Prieto Victor G. , Diwan A. Hafeez , Johnson Marcella M. , Gunn Debra C. , Yekell Sandra , Grimm Elizabeth A. 
Published: September 2005

Abstract
Purpose: Thyrotropin-releasing hormone (TRH) is a tripeptide hormone produced by the hypothalamus in response to hypothyroidism. RNA transcripts for the TRH prohormone have recently been described in melanoma cell lines. To expand these findings, we have examined cultured melanoma cells and melanocytes, human melanoma tumors, and nevi for the expression of TRH.
Experimental Design: Five melanoma cell lines were analyzed by reverse transcription-PCR/Southern blotting for preproTRH message. The same melanoma lines and two melanocyte lines were examined by immunocytochemistry for TRH protein expression and for growth response to exogenous TRH. Immunohistochemistry was used to test for TRH protein in sections of 19 melanomas, 33 dysplastic nevi, and 27 benign nevi.
Results: TRH message and protein were detected in all melanoma cell lines examined. Melanocytes were also found to express TRH protein. Four of the five melanoma cell lines but neither melanocyte line responded with a increase in proliferation to low concentrations of exogenous TRH. TRH immunoreactivity was observed in 12 of 19 melanomas (63%), 23 of 33 (69.7%) dysplastic nevi, and 14 of 27 (51.9%) benign nevi. Expression in dysplastic nevi was significantly greater than in benign nevi. Upon separate analysis of nevi from melanoma patients, the difference between dysplastic and benign nevi was even more significant. However, in healthy individuals, no difference between dysplastic and benign nevi was observed. Furthermore, dysplastic nevi from melanoma patients had a significantly higher percentage of TRH-positive cells when compared with healthy individuals.
Conclusions: TRH is commonly expressed by melanomas and dysplastic nevi and may function as a melanoma autocrine growth factor. The presence of TRH in dysplastic nevi may be predictive for the development of melanoma. Our findings have significant clinical and biological implications for future research into the early stages of melanoma initiation and progression.
Clinical Trial Substantiates the Predictive Value of
O-6-Methylguanine-DNA Methyltransferase
Promoter Methylation in Glioblastoma Patients Treated with Temozolomide
Authors: Hegi Monika E. , Diserens Annie-Claire , Godard Sophie , Dietrich Pierre-Yves , Regli Luca , Ostermann Sandrine , Otten Philippe , Van Melle Guy , de Tribolet Nicolas , Stupp Roger 
Published: September 2005

Abstract
Purpose: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy.
Experimental Design: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR.
Results: Inactivation of the MGMT gene by promoter methylation was associated with longer survival (P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation (P = 0.002; Fisher’s exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor (P = 0.017; Cox regression).
Conclusions: This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine, a noncytotoxic substrate of this enzyme.
In vitro
and
In vivo
Activity of the Nuclear Factor-κB Inhibitor Sulfasalazine in Human Glioblastomas
Authors: Robe Pierre A. , Bentires-Alj Mohamed , Bonif Marianne , Rogister Bernard , Deprez Manuel , Haddada Heddi , Khac Minh-Tuan Nguyen , Jolois Olivier , Erkmen Kadir , Merville Marie-Paule , Black Peter M. , Bours Vincent 
Published: September 2005

Abstract
Glioblastomas, the most common primary brain cancers, respond poorly to current treatment modalities and carry a dismal prognosis. In this study, we demonstrated that the transcription factor nuclear factor (NF)-κB is constitutively activated in glioblastoma surgical samples, primary cultures, and cell lines and promotes their growth and survival. Sulfasalazine, an anti-inflammatory drug that specifically inhibits the activation of NF-κB, blocked the cell cycle and induced apoptosis in several glioblastoma cell lines and primary cultures, as did gene therapy with a vector encoding a super-repressor of NF-κB. In vivo, sulfasalazine also significantly inhibited the growth of experimental human glioblastomas in nude mice brains. Given the documented safety of sulfasalazine in humans, these results may lead the way to a new class of glioma treatment.
Amplification of the BRCA2 Pathway Gene
EMSY
in Sporadic Breast Cancer Is Related to Negative Outcome
Authors: Rodriguez Carmen , Hughes-Davies Luke , Vallès Hélène , Orsetti Béatrice , Cuny Marguerite , Ursule Lisa , Kouzarides Tony , Theillet Charles 
Published: September 2005

Abstract
DNA amplification at band q13 of chromosome 11 is common in breast cancer, and CCND1 and EMS1 remain the strongest candidate genes. However, amplification patterns are consistent with the existence of four cores of amplification, suggesting the involvement of additional genes. Here we present evidence strongly suggesting the involvement of the recently characterized EMSY gene in the formation of the telomeric amplicon. EMSY maps at 11q13.5, 100 kb centromeric to the GARP gene, which has been mapped within the core of the distal amplicon. The EMSY protein was shown to interact with BRCA2 and has a role in chromatin remodeling. This makes EMSY a strong candidate oncogene for the 11q13.5 amplicon. DNA amplification was studied in a total of 940 primary breast tumors and 39 breast cancer cell lines. Amplification profiles were consistent with the EMSY-GARP locus being amplified independently of CCND1 and/or EMS1. EMSY RNA expression levels were studied along with those of five other genes located at 11q13.5 by real-time quantitative PCR in the 39 cell lines and a subset of 65 tumors. EMSY overexpression correlated strongly with DNA amplification in both primary tumors and cell lines. In a subset of 296 patients, EMSY amplification was found by both uni- and multivariate analyses to correlate with shortened disease-free survival. These data indicate that EMSY is a strong candidate oncogene for the 11q13.5 amplicon.
Antisense Protein Kinase A RIα Inhibits 7,12-Dimethylbenz(
a
)anthracene-Induction of Mammary Cancer
Authors: Nesterova Maria V. , Cho-Chung Yoon S. 
Published: September 2005

Abstract
Purpose: There are two types of cyclic AMP (cAMP)-dependent protein kinase (PKA), type I (PKA-I) and type II (PKA-II), which share a common catalytic (C) subunit but contain distinct regulatory (R) subunits, RI versus RII, respectively. Evidence suggests that increased expression of PKA-I and its regulatory subunit (RIα) correlates with tumorigenesis and tumor growth. We investigated the effect of sequence-specific inhibition of RIα gene expression at the initial phase of 7,12-dimethylbenz(αa)anthracene (DMBA)-induced mammary carcinogenesis.
Experimental Design: Antisense RIα oligodeoxynucleotide (ODN) targeted against PKA RIα was administered (0.1 mg/day/rat, i.p.) 1 day before DMBA intubation and during the first 9 days post-DMBA intubation to determine the anticarcinogenic effects.
Results: Antisense RIα, in a sequence-specific manner, inhibited the tumor production. At 90 days after DMBA intubation, untreated controls and RIα-antisense-treated rats exhibited an average mean number of tumors per rat of 4.2 and 1.8, respectively, and 90% of control and 45% of antisense-treated animals had tumors. The antisense also delayed the first tumor appearance. An increase in RIα and PKA-I levels in the mammary gland and liver preceded DMBA-induced tumor production, and antisense down-regulation of RIα restored normal levels of PKA-I and PKA-II in these tissues. Antisense RIα in the liver induced the phase II enzymes, glutathione S-transferase and quinone oxidoreductase, c-fos protein, and activator protein 1 (AP-1)- and cAMP response element (CRE)-directed transcription. In the mammary glands, antisense RIα promoted DNA repair processes. In contrast, the CRE transcription-factor decoy could not mimic these effects of antisense RIα.
Conclusions: The results demonstrate that RIα antisense produces dual anticarcinogenic effects: (a) increasing DMBA detoxification in the liver by increasing phase II enzyme activities, increasing CRE-binding-protein phosphorylation and enhancing CRE- and Ap-1-directed transcription; and (b) activating DNA repair processes in the mammary gland by down-regulating PKA-I.
Epidermal Growth Factor Receptor, c-MET, β-Catenin, and p53 Expression as Prognostic Indicators in Stage II Colon Cancer
Authors: Resnick Murray B. , Routhier Justin , Konkin Tamako , Sabo Edmond , Pricolo Victor E. 
Published: September 2005

Abstract
Purpose: Through the use of molecular markers, it may be possible to identify aggressive tumor phenotypes and tailor therapies to treat them. This approach would be particularly useful for stage II colon cancer. The purpose of this study was to define the prognostic value of epidermal growth factor receptor (EGFR), c-MET, β-catenin, and p53 protein expression in TNM stage II colon cancer using tissue microarray technology.
Experimental Design: In this study, we retrospectively analyzed, resected, and otherwise untreated paraffin-embedded specimens from 134 consecutive patients with Tumor-Node-Metastasis stage II colonic carcinomas for EGFR, c-MET, β-catenin, and p53 protein expression by immunohistochemistry.
Results: Thirty-five percent, 77, and 65% of tumors exhibited strong (+2 and +3 immunopositivity) expression of EGFR, c-MET, and β-catenin, respectively. Fifty-four percent exhibited nuclear staining for p53 in &gt;10% of the tumor cells. Univariate analysis revealed that increased nuclear p53 expression (P = 0.001), strong membranous EGFR expression (P = 0.04), and lymphovascular invasion (P = 0.01) were significantly related to disease recurrence and that p53 (P = 0.02) and EGFR (P = 0.05) expression were associated with decreased survival. Increased nuclear p53 expression also correlated with the presence of distal metastasis (P = 0.027). No significant association was seen between c-MET expression and prognosis, whereas a strong trend was detected between loss of β-catenin (P = 0.065) expression and poor outcome. Multivariate analysis indicated that p53 (P = 0.04), EGFR (P = 0.05), and lymphovascular invasion (P = 0.03) were independent predictors of recurrence and that p53 (P = 0.02) and EGFR (P = 0.01) expression were both associated with poor survival.
Conclusions: This retrospective tumor microarray study, restricted to Tumor-Node-Metastasis stage II colon cancer patients who did not undergo adjuvant therapy, supports the use of EGFR and p53 as biological markers, which may assist in predicting disease recurrence and survival.
In vitro
Toxicity of A-431 Carcinoma Cells with Antibodies to Epidermal Growth Factor Receptor and Epithelial Glycoprotein-1 Conjugated to Radionuclides Emitting Low-Energy Electrons
Authors: Michel Rosana B. , Castillo Mary Ellen , Andrews Philip M. , Mattes M. Jules 
Published: September 2005

Abstract
Purpose: The ability of antibodies (Abs) conjugated to radionuclides emitting low-energy electrons to specifically kill nonadherent lymphoma target cells in vitro was demonstrated previously. This study extends this work to adherent carcinoma cells. The fact that these cells are spread out on plastic can potentially make it more difficult to deliver radiation to the nucleus from decays in the cytoplasm or on the cell surface.
Experimental Design: The Abs tested were anti-epidermal growth factor receptor and anti-epithelial glycoprotein-1, conjugated to indium-111 or iodine-125, which emit low-energy Auger and conversion electrons. Conjugates of the β-particle emitter, iodine-131, also were tested, for comparison. Abs were incubated with the cells for 2 days, and then the treated cells were assayed for colony-forming units. The radiation dose delivered to the nucleus was calculated from the cumulative decays per cell.
Results: With conjugates of 111In, very potent killing was obtained with both of the Abs, with 100% kill (approximately 4–5 logs) even at subsaturating Ab concentrations. Lower levels of kill were obtained with 125I or 131I conjugates. Conjugates with 131I, a β-particle emitter, produced greater nonspecific toxicity. The greater potency of 111In could be attributed to the higher specific activity that was obtained routinely with this radiolabel, up to 70 mCi/mg. Uptake of radioactivity peaked at approximately 200 cpm per cell. Dosimetry calculations, using subcellular S values, demonstrated that the toxicity observed was consistent with the amount of radiation delivered to the nucleus.
Conclusions: These results are similar to previous results obtained with B lymphoma cells and indicate that this approach is applicable to a wide range of tumor types. Radionuclides emitting low-energy electrons are effective at killing target cells with relatively little nonspecific toxicity, if sufficient activity is delivered to the cell. Most Abs to high-density cell surface antigens would probably be effective.
Overexpressed eIF4E Is Functionally Active in Surgical Margins of Head and Neck Cancer Patients via Activation of the Akt/Mammalian Target of Rapamycin Pathway
Authors: Nathan Cherie-Ann O. , Amirghahari Nazanin , Abreo Fleurette , Rong Xiaohua , Caldito Gloria , Jones M. Lamar , Zhou Huijuan , Smith Melanie , Kimberly Donnellan , Glass Jonathan 
Published: September 2005

Abstract
Purpose: Overexpression of eIF4E in surgical margins of head and neck cancer patients is an independent risk factor for recurrence. We hypothesize that overexpressed eIF4E is functionally active in tumor margins through activation of the Akt/mammalian target of rapamycin (mTOR) pathway
Experimental Design: Western blots and/or immunohistochemistry were performed to determine whether phosphorylation of mTOR and activation of its downstream molecules eIF4E-binding protein-1 (4E-BP1) and p70 S6 kinase and the upstream modulator of mTOR, Akt, were expressed in margins overexpressing eIF4E.
Results: There was a significant association between phospho-4E-BP1 and eIF4E expression of a margin or a significant difference in phospho-4E-BP1 expression between the eIF4E-positive and -negative margins (P &lt; 0.01). A significant association between eIF4E and phospho-p70 S6 kinase as well as eIF4E and phospho-mTOR was also noted (P &lt; 0.05). Western blot analysis indicated a highly significant difference in the phosphorylation status of 4E-BP1 between tumors and resection margins. A total of 89% of the 4E-BP1-expressing margins expressed more of the phosphorylated (β, γ, and δ) isoforms, whereas 81% of the 4E-BP1-expressing tumors expressed more of the unphosphorylated α isoform. A similar difference in Akt activation was noted between eIF4E-positive margins and tumors (P &lt; 0.05).
Conclusions: Overexpression of eIF4E is functionally active in tumor margins through activation of the Akt/mTOR signaling pathway. The greater degree of expression of downstream targets and upstream regulators of mTOR in margins compared with the tumors indicates preferential activation of the Akt/mTOR signaling pathway in margins overexpressing eIF4E. Rapamycin analogs can potentially be used as adjuvant therapy for patients with eIF4E-positive margins.
Nuclear Localization of KLF4 Is Associated with an Aggressive Phenotype in Early-Stage Breast Cancer
Authors: Pandya Ashka Y. , Talley Lynya I. , Frost Andra R. , Fitzgerald Thomas J. , Trivedi Vivek , Chakravarthy Mithun , Chhieng David C. , Grizzle William E. , Engler Jeffrey A. , Krontiras Helen , Bland Kirby I. , LoBuglio Albert F. , Lobo-Ruppert Susan M. , Ruppert J. Michael 
Published: September 2005

Abstract
Purpose: The Krüppel-like transcription factor KLF4/GKLF induces both malignant transformation and a slow-growth phenotype in vitro. Although KLF4 expression is increased in most cases of breast cancer, it was unknown whether these cases represent a distinct subtype with a different clinical outcome.
Experimental Design: We examined expression of KLF4 by immunostaining 146 cases of human primary infiltrating ductal carcinoma of the breast. Staining patterns were correlated with clinical outcome and with established prognostic factors.
Results: Subcellular localization exhibited case-to-case variation. Tumors with high nuclear staining and low cytoplasmic staining were termed type 1. For patients with early-stage disease (i.e., stage I or IIA), type 1 staining was associated with eventual death because of breast cancer (hazard ratio, 2.8; 95% confidence interval, 1.23–6.58; P = 0.011). The association was stronger in patients with early-stage cancer and small primary tumors (i.e., ≤2.0 cm in diameter; hazard ratio, 4.3; 95% confidence interval, 1.75–10.62; P &lt; 0.001). For patients with early-stage disease, multivariate analysis indicated that type 1 staining was independently associated with outcome (adjusted hazard ratio 2.6; 95% confidence interval, 1.10–6.05; P = 0.029). Type 1 staining was also associated with high histological grade (P = 0.032), increased expression of Ki67 (P = 0.016), and reduced expression of BCL2 (P = 0.032). In vitro, KLF4 was localized within the nucleus of transformed RK3E epithelial cells, consistent with a nuclear function of this transcription factor during induction of malignant transformation.
Conclusions: The results suggest that localization of KLF4 in the nucleus of breast cancer cells is a prognostic factor and identify KLF4 as a marker of an aggressive phenotype in early-stage infiltrating ductal carcinoma.
Decreased Expression of 14-3-3σ Is Associated with Advanced Disease in Human Epithelial Ovarian Cancer
Authors: Akahira Jun-ichi , Sugihashi Youko , Suzuki Takashi , Ito Kiyoshi , Niikura Hitoshi , Moriya Takuya , Nitta Makoto , Okamura Hitoshi , Inoue Satoshi , Sasano Hironobu , Okamura Kunihiro , Yaegashi Nobuo 
Published: September 2005

Abstract
Purpose: In this study, we examined the promoter methylation status and expression of 14-3-3σ and evaluated its clinical significance in epithelial ovarian cancer.
Experimental Design: Twelve ovarian cancer cell lines; 2 ovarian surface epithelial cell lines; and 8 normal, 8 benign, 12 borderline, and 102 ovarian cancer tissues were examined. Methylation-specific PCR, quantitative reverse transcription-PCR, and immunohistochemistry were used to evaluate methylation status and expression of 14-3-3σ gene and protein.
Results: Among the 12 ovarian cancer cell lines, the presence of a methylated band was detected in seven cell lines. Median values of relative 14-3-3σ gene expression in cancers with methylation (3.27) were significantly lower than those without methylation (16.4; P &lt; 0.001). Treatment of 5-aza-2′-deoxycitidine resulted in the demethylation of the promoter CpG islands and reexpression. All of the normal, benign, and borderline tissues were positive for 14-3-3σ protein, and in ovarian cancer tissues, 73.5% (75 of 102) were positive for 14-3-3σ protein and was almost consistent with methylation status. Negative immunoreactivity of 14-3-3σ was significantly correlated with high age and serous histology, high-grade, advanced-stage residual tumor of &gt;2 cm, high serum CA125, high Ki-67 labeling index, and positive p53 immunoreactivity. 14-3-3σ immunoreactivity was significantly associated with overall survival (P = 0.0058).
Conclusions: Our findings suggest that 14-3-3σ is inactivated mainly by aberrant DNA methylation and that it may play an important role in the pathogenesis of epithelial ovarian cancer.