bluuebunny/crossref_metadata_2025_split huggingface dataset:
Demethylation of the
Synuclein
γ Gene CpG Island in Primary Gastric Cancers and Gastric Cancer Cell Lines
Authors: Yanagawa Naoki , Tamura Gen , Honda Teiichiro , Endoh Makoto , Nishizuka Satoshi , Motoyama Teiichi 
Published: September 2005

Abstract
Purpose: Whereas synuclein γ (SNCG) gene expression is usually highly tissue-specific and restricted to the nervous system, SNCG is expressed in advanced-stage breast and ovarian cancers. When overexpressed, SNCG stimulates cancer cell proliferation and metastasis. It is thought that the molecular mechanism of CpG island demethylation may underlie aberrant SNCG expression. To determine whether aberrant SNCG expression and demethylation play a role in gastric carcinogenesis, we examined the expression and methylation status of SNCG in primary gastric cancers, gastric cancer cell lines, and non-neoplastic gastric mucosal tissues.
Experimental Design: Ten gastric cancer cell lines, 105 primary gastric cancers, and 10 non-neoplastic gastric mucosal tissues were examined. SNCG expression and methylation status were examined by reverse transcription-PCR and bisulfite-single-strand conformational polymorphism followed by direct sequencing, respectively. The relationship between SNCG methylation status and various clinicopathological factors of the primary gastric cancers was then analyzed.
Results: SNCG mRNA expression was observed in 5 of 10 cell lines. Analysis of cell lines positive for SNCG expression revealed that most of the SNCG CpGs were demethylated. SNCG mRNA was not expressed in the 10 non-neoplastic gastric mucosal tissues, although several CpGs were demethylated. Of the 105 primary gastric cancers, 40 (38.1%) showed apparent SNCG demethylation, similar to the result obtained using cell lines. SNCG demethylation was more frequent in primary gastric cancers positive for lymph node metastasis (51%; 26 of 51) than in cancers without lymph node involvement (26%; 14 of 54; P &lt; 0.05), and also more common in stage II-IV (48%; 27 of 56) than in stage I (27%; 13 of 49) cancers (P &lt; 0.05).
Conclusions: Aberrant SNCG gene expression can occur via CpG island demethylation, and tends to occur during the more progressive stages of gastric carcinogenesis.
Down-Regulated Expression of Cytokeratin 18 Promotes Progression of Human Breast Cancer
Authors: Woelfle Ute , Sauter Guido , Santjer Sonja , Brakenhoff Ruud , Pantel Klaus 
Published: September 2005

Abstract
Purpose: Cytokeratins (CKs) have been recognized for &gt;20 years as structural marker proteins specific for epithelial cells. Recent expression profiling analyses indicate, however, that CK down-regulation may occur in breast cancer.
Experimental Design: Here we evaluated the expression pattern of CK18 by immunohistochemical analysis of primary breast carcinomas (n = 1458) spotted on a high-density tissue microarray. The findings were correlated to histopathological risk factors and clinical outcome.
Results: Down-regulation of CK18 (as compared to normal breast tissue) was observed in 25.4% of the tumors with a lower rate in lobular carcinomas (17.0%) than in ductal carcinomas (25.4%) or other histological entities (32.5%). CK down-regulation was significantly correlated to advanced tumor stage and high grade but not to axillary lymph node status. Kaplan-Meier survival analysis revealed CK18 as a prognostic indicator of overall survival (P = 0.015) and cancer-specific survival (P = 0.005).
Conclusions: Down-regulation of the luminal CK18 is not rare and a clinically relevant event in breast cancer. This finding has important implications for the use of CK18 as epithelial tumor marker. The correlations with clinical follow-up suggest that CK18 might suppress tumor pro-gression.
Biologically Different Subgroups of Invasive Ductal Carcinoma of the Pancreas
Authors: Takahashi Hidenori , Oda Tatsuya , Hasebe Takahiro , Aoyagi Yasuyuki , Kinoshita Taira , Konishi Masaru , Nakagohri Toshio , Inoue Kazuto , Takahashi Shinichiro , Kawahira Hiroshi , Monden Morito , Ochiai Atsushi 
Published: September 2005

Abstract
Purpose: Among invasive ductal carcinomas of the pancreas (IDCP), there is a morphologically characteristic subgroup accompanied by abundant intraductal carcinoma components (ICCs). With the aim of determining whether ICC-rich IDCP are biologically different from ICC-poor IDCP, the expression status of Dpc4 protein was analyzed.
Experimental Design: A total of 43 IDCP was subdivided into two groups: (a) ICC-rich IDCP (ICCs area occupies ≥10% of the entire tumorous area); and (b) ICC-poor IDCP (with &lt;10% of ICCs area). A total of 10 invasive carcinomas derived from intraductal papillary-mucinous neoplasms (ICs from IPMNs) were also analyzed. Each invasive and intraductal carcinoma area was then evaluated for Dpc4 protein status by immunohistochemistry.
Results: In a total of 43 IDCP, there were 23 ICC-rich IDCP and 20 ICC-poor IDCP. Dpc4-positive immunostaining was observed in the invasive carcinoma component of ICC-rich IDCP, ICC-poor IDCP, and ICs from IPMN in 18 of 23 (78%), 4 of 20 (20%), and 7 of 10 (70%) cases, respectively. In the intraductal component, positive staining for Dpc4 was found in 20 of 23 (87%), 3 of 7 (41%), and 8 of 10 (80%) cases, respectively. Dpc4 expression was found in both the invasive and ICC components of ICC-rich IDCP, similar to that found in IC derived from IPMN, whereas the expression of Dpc4 was largely diminished in ICC-poor IDCP.
Conclusions: Morphologically distinct subgroups of invasive ductal carcinomas of the pancreas, namely ICC-rich IDCP and ICC-poor IDCP, are also biologically distinguishable as revealed by the differential expression of Dpc4.
Ribonucleotide Reductase Messenger RNA Expression and Survival in Gemcitabine/Cisplatin-Treated Advanced Non-Small Cell Lung Cancer Patients
Authors: Rosell Rafael , Danenberg Kathleen D. , Alberola Vincente , Bepler Gerold , Sanchez Jose Javier , Camps Carlos , Provencio Mariano , Isla Dolores , Taron Miquel , Diz Pilar , Artal Angel ,   on behalf of the Spanish Lung Cancer Group
Published: September 2005

Abstract
Purpose: No chemotherapy regimen, including the widely used combination of gemcitabine/cisplatin, confers significantly improved survival over any other in metastatic non-small cell lung cancer (NSCLC); however, the selection of patients according to key genetic characteristics can help to tailor chemotherapy. Ribonucleotide reductase subunit M1 (RRM1) is involved in DNA synthesis and repair and in gemcitabine metabolism, and the excision repair cross-complementing group 1 (ERCC1) gene has been related to cisplatin activity.
Experimental Design: Patients were part of a large randomized trial carried out from September 1998 to July 2000, comparing gemcitabine/cisplatin versus gemcitabine/cisplatin/vinorelbine versus gemcitabine/vinorelbine followed by vinorelbine/ifosfamide. We analyzed RRM1 and ERCC1 mRNA expression in paraffin-embedded samples obtained from bronchoscopy by real-time quantitative reverse transcription-PCR. Results were correlated with survival using the Kaplan-Meier method.
Results: A total of 100 patients were assessed. There was a strong correlation between RRM1 and ERCC1 mRNA expression levels (Spearman r = 0.410; P &lt; 0.001). In the gemcitabine/cisplatin arm, patients with low RRM1 mRNA expression levels had significantly longer median survival than those with high levels [13.7 versus 3.6 months; 95% confidence interval (CI), 9.6–17.8 months; P = 0.009]. Median survival was also significantly longer among patients with low mRNA expression levels of both RRM1 and ERCC1 (not reached), than among those with high levels of both genes (6.8 months; 95% CI, 2.6–11.1 months; P = 0.016).
Conclusions: RRM1 mRNA expression is a crucial predictive marker of survival in gemcitabine/cisplatin-treated patients. Genetic testing of RRM1 mRNA expression levels can and should be used to personalize chemotherapy.
Phase I Trial of Temozolomide and Protracted Irinotecan in Pediatric Patients with Refractory Solid Tumors
Authors: Wagner Lars M. , Crews Kristine R. , Iacono Lisa C. , Houghton Peter J. , Fuller Christine E. , McCarville M. Beth , Goldsby Robert E. , Albritton Karen , Stewart Clinton F. , Santana Victor M. 
Published: September 2005

Abstract
Purpose: The purpose is to estimate the maximum-tolerated dose (MTD) of temozolomide and irinotecan given on a protracted schedule in 28-day courses to pediatric patients with refractory solid tumors.
Experimental Design: Twelve heavily pretreated patients received 56 courses of oral temozolomide at 100 mg/m2/day for 5 days combined with i.v. irinotecan given daily for 5 days for 2 consecutive weeks at either 10 mg/m2/day (n = 6) or 15 mg/m2/day (n = 6). We assessed toxicity, the pharmacokinetics of temozolomide and irinotecan, and the DNA repair phenotype in tumor samples.
Results: Two patients experienced dose-limiting toxicity (DLT) at the higher dose level; one had grade 4 diarrhea, whereas the other had bacteremia with grade 2 neutropenia. In contrast, no patient receiving temozolomide and 10 mg/m2/day irinotecan experienced DLT. Myelosuppression was minimal and noncumulative. No pharmacokinetic interaction was observed. Drug metabolite exposures at the MTD were similar to exposures previously associated with single-agent antitumor activity. One complete response, two partial responses, and one minor response were observed in Ewing’s sarcoma and neuroblastoma patients previously treated with stem cell transplant. Responding patients had low or absent O6-methylguanine-DNA methyltransferase expression in tumor tissue.
Conclusions: The MTD using this schedule was temozolomide (100 mg/m2/day) and irinotecan (10 mg/m2/day), with DLT being diarrhea and infection. Drug clearance was similar to single-agent values, and clinically relevant SN-38 lactone and MTIC exposures were achieved at the MTD. As predicted by xenograft models, this combination and schedule appears to be tolerable and active in pediatric solid tumors. Evaluation of a 21-day schedule is planned.
Elevated Expression of Valosin-Containing Protein (p97) Is Associated with Poor Prognosis of Prostate Cancer
Authors: Tsujimoto Yuichi , Tomita Yasuhiko , Hoshida Yoshihiko , Kono Takuro , Oka Toshitsugu , Yamamoto Shinji , Nonomura Norio , Okuyama Akihiko , Aozasa Katsuyuki 
Published: September 2005

Abstract
Purpose: Valosin-containing protein (VCP) has been shown to be associated with metastasis and prognosis in human cancers. In the present study, the correlation of VCP with recurrence and prognosis in patients with prostate cancer (PCA) receiving conservative therapy was examined.
Experimental Design: VCP expression was analyzed immunohistochemically in 136 patients ranging from 46 to 92 years (median, 72 years), who received conservative therapy, including androgen deprivation, radiotherapy, or watchful waiting. Staining intensity of tumor cells was categorized as weaker (level 1) or equal to or stronger (level 2) than that in endothelial cells. The correlation of VCP expression between the mRNA and protein levels was examined in 10 patients.
Results: Thirty-two cases (23.5%) showed level 1 and 100 (76.5%) level 2 VCP expression. Quantitative reverse transcription-PCR analysis revealed greater VCPmRNA expression in level 2 (n = 5) than level 1 cases (n = 5; P &lt; 0.05). A significant difference was observed between VCP level 1 and 2 patients in the positive rate for the digital rectal examination (P &lt; 0.01), serum prostate-specific antigen level (P &lt; 0.0001), cancer volume (P &lt; 0.0001), Gleason score (P &lt; 0.0001), stage (P &lt; 0.0001), and progression-free and overall survival (P &lt; 0.0001 for both). Multivariate analysis revealed VCP expression level, serum prostate-specific antigen level, and Gleason score to be independent prognosticators for progression-free and overall survival. Progression of PCA was found in 9.4% of level 1 but in 64% of level 2 patients.
Conclusions: PCA with level 1 VCP expression could be treated conservatively.
Noninvasive Measurements of Capecitabine Metabolism in Bladder Tumors Overexpressing Thymidine Phosphorylase by Fluorine-19 Magnetic Resonance Spectroscopy
Authors: Chung Yuen-Li , Troy Helen , Judson Ian R. , Leek Russell , Leach Martin O. , Stubbs Marion , Harris Adrian L. , Griffiths John R. 
Published: September 2005

Abstract
Purpose: Previous studies have shown that tumor response to capecitabine strongly correlates with tumor thymidine phosphorylase (TP). The aims of our study were to (a) investigate the pharmacological role of TP by measuring the pharmacokinetics (PK) of capecitabine in a human bladder tumor model that was characterized by the overexpression of TP and (b) develop the use of PK measurements for capecitabine by fluorine-19 magnetic resonance spectroscopy as a noninvasive surrogate marker for determining TP levels in tumors and for predicting tumor response to capecitabine in patients.
Experimental Design: TP overexpressing (2T10) and control tumors were grown s.c. in nude mice. Mice were given a dose of capecitabine or 5′-deoxy-5-fluorouridine (5′DFUR). 19F tumor spectra were acquired for determination of rate constants of capecitabine breakdown and buildup and subsequent breakdown of intermediates, 5′-deoxy-5-fluorocytidine (5′DFCR) and 5′DFUR. The rate constant of 5′DFUR breakdown was also evaluated.
Results: The rate constant of breakdown of intermediates was significantly faster in 2T10 tumors than controls (P &lt; 0.003). No significant differences in the rate of capecitabine breakdown or intermediate buildup were observed. The rate constant of 5′DFUR breakdown in the 2T10 tumors was doubled compared with controls (P &lt; 0.001).
Conclusions: This study confirmed the expected pathway of capecitabine metabolism and showed that the level of TP was related to the rate of 5′DFUR conversion. Using in vivo fluorine-19 magnetic resonance spectroscopy to mea-sure the PK of capecitabine and its intermediate metabolites in tumors may provide a noninvasive surrogate method for determining TP levels in tumors and for predicting tumor response to capecitabine in patients.
Evaluating Antiangiogenesis Agents in the Clinic
Authors: Sparano Joseph A. , Gray Robert , Giantonio Bruce , O’Dwyer Peter , Comis Robert L. 
Published: September 2005

Abstract
Recent evidence indicates that treatment with a humanized monoclonal antibody (bevacizumab) directed at vascular endothelial growth factor improves response and survival in metastatic colorectal cancer when added to standard chemotherapy, validating angiogenesis as a therapeutic target. Investigators from the Eastern Cooperative Oncology Group (ECOG) have initiated a number of Phase III studies that will help further define the role of antiangiogenic agents for the treatment of breast, colon, lung, renal, and head and neck cancer, as well as melanoma and myeloma. The agents being evaluated target various biological functions involved in angiogenesis, including vascular endothelial growth factor (bevacizumab), endothelial cell proliferation (thalidomide, IFN-α), and matrix metalloproteinases (marimastat). These clinical trials include correlative laboratory studies aimed at elucidating how these agents may exert their clinical effects. The portfolio of Eastern Cooperative Oncology Group studies will serve to further define the role of this therapeutic strategy for patients with advanced cancer.
Predictive Significance of the Alterations of p16INK4A, p14ARF, p53, and Proliferating Cell Nuclear Antigen Expression in the Progression of Cervical Cancer
Authors: Wang Jian-Liu , Zheng Bi-Ying , Li Xi-Dan , Ångström Tord , Lindström Mikael S. , Wallin Keng-Ling 
Published: September 2005

AbstractPurpose: The purpose of this research was to evaluate the clinical significance of p16INK4A, p14ARF, p53, and proliferating cell nuclear antigen (PCNA) expression in tumor progression of cervical cancer.Design: Seventeen patients (40 samples) with consecutive cervical lesions from normal squamous epithelium, inflammation of the cervix to cervical intraepithelial neoplasm (CIN) and invasive cervical squamous cell cancer (SCC), or from CIN to SCC were collected for this study. Expression of p16INK4A, p14ARF, p53, and PCNA were detected by immunohistochemistry on paraffin-embedded sections. Human papillomavirus DNA was detected simultaneously with PCR and typed according to its DNA sequence.Results: p16INK4A overexpression was significantly higher in CIN (75%) and in SCC (75%) than in normal or inflammation of the cervix (12.5%; P &lt; 0.01, P &lt; 0.05, respectively). The positive rate of p14ARF expression was higher in SCC (83%) than in normal/inflammation of the cervix (25%; P &lt; 0.05). PCNA expression was negative in normal or inflammation of the cervix, but an increased in expression was seen in 63.2% in CIN and 100% in SCC (P &lt; 0.01, P &lt; 0.05). When the time interval for disease progression from initial biopsy to CIN 3 or invasive cancer was compared with states of p16INK4A expression, cases stained positive for p16INK4A progressed within 64.2 months as compared with 122.3 months among those stained negatively (P &lt; 0.01). Cases with increased p14ARF expression also had a short time interval for disease progression of 78.8 months as compared with 108.3 months in cases that were p14ARF negative. Cases with stable or decreased p53 expression had the shortest time interval for progression of 32.3 months in contrast to cases with no p53 expression (113.9 months). However, cases with increasing p53 expression progressed within 60.8 months.Conclusions: Our results suggested that altered states of p16INK4A, p14ARF, p53, and PCNA may be valuable markers to predict the progression of cervical neoplasia.
Specific Chemopreventive Agents Trigger Proteasomal Degradation of G1 Cyclins: Implications for Combination Therapy
Authors: Dragnev Konstantin H. , Pitha-Rowe Ian , Ma Yan , Petty W. Jeffrey , Sekula David , Murphy Bryan , Rendi Mara , Suh Nanjoo , Desai Neil B. , Sporn Michael B. , Freemantle Sarah J. , Dmitrovsky Ethan 
Published: September 2005

Abstract
Purpose: There is a need to identify cancer chemoprevention mechanisms. We reported previously that all-trans-retinoic acid (RA) prevented carcinogenic transformation of BEAS-2B immortalized human bronchial epithelial cells by causing G1 arrest, permitting repair of genomic DNA damage. G1 arrest was triggered by cyclin D1 proteolysis via ubiquitin-dependent degradation. This study investigated which chemopreventive agents activated this degradation program and whether cyclin E was also degraded.
Experimental Design: This study examined whether: (a) cyclin E protein was affected by RA treatment; (b) cyclin degradation occurred in derived BEAS-2B-R1 cells that were partially resistant to RA; and (c) other candidate chemopreventive agents caused cyclin degradation.
Results: RA treatment triggered degradation of cyclin E protein, and ALLN, a proteasomal inhibitor, inhibited this degradation. Induction of the retinoic acid receptor β, growth suppression, and cyclin degradation were each inhibited in BEAS-2B-R1 cells. Transfection experiments in BEAS-2B cells indicated that RA treatment repressed expression of wild-type cyclin D1 and cyclin E, but ALLN inhibited this degradation. Mutation of threonine 286 stabilized transfected cyclin D1, and mutations of threonines 62 and 380 stabilized transfected cyclin E, despite RA treatment. Specific chemopreventive agents triggered cyclin degradation. Nonclassical retinoids (fenretinide and retinoid X receptor agonists) and a synthetic triterpenoid (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) each suppressed BEAS-2B growth and activated this degradation program. However, a vitamin D3 analog (RO-24–5531), a cyclooxygenase inhibitor (indomethacin), and a peroxisome proliferator-activated receptor γ agonist (rosiglitazone) each suppressed BEAS-2B growth, but did not cause cyclin degradation. BEAS-2B-R1 cells remained responsive to nonclassical retinoids and to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid.
Conclusions: Specific chemopreventive agents activate cyclin proteolysis. Yet, broad resistance did not occur after acquired resistance to a single agent. This provides a therapeutic rationale for combination chemoprevention with agents activating non-cross-resistant pathways.
Phase I and Pharmacologic Study of Intermittently Administered 9-Nitrocamptothecin in Patients with Advanced Solid Tumors
Authors: Zamboni William C. , Jung Laura L. , Egorin Merrill J. , Potter Douglas M. , Friedland David M. , Belani Chandra P. , Agarwala Sanjiv S. , Wong Michael M. W. , Fakih Marwan , Trump Donald L. , Jin Ruzhi , Strychor Sandra , Vozniak Michael , Troetschel Monica , Ramanathan Ramesh K. 
Published: September 2005

AbstractPurpose: 9-Nitrocamptothecin (9NC) is an oral camptothecin analogue currently administered at 1.5 mg/m2/day × 5 days/week in Phase III studies for pancreatic carcinoma. In an effort to increase the dose administered per day and determine whether the daily dose or number of days of treatment influence toxicity, we performed a Phase I study of 9NC using intermittent schedules of administration.Experimental Design: On schedule A, 9NC was administered orally daily × 5 days for 2 weeks every 4 weeks (one cycle). On schedule B, 9NC was administered orally daily × 14 days every 4 weeks (one cycle). Dose levels were determined by adaptive dose finding. Serial blood samples were obtained on day 1 of each schedule for pharmacokinetic studies of 9NC and its 9-aminocamptothecin (9AC) metabolite, and lactone forms were measured by high-performance liquid chromatography.Results: The recommended Phase II doses for schedules A and B were 2.43 and 1.70 mg/m2/day, respectively, each providing the same dose intensity (i.e., 24 mg/m2/cycle). The primary toxicities on schedules A and B were neutropenia, thrombocytopenia, and diarrhea. On schedule A, two patients with gastric cancer and two patients with pancreatic cancer had stable disease for more than six cycles. On schedule B, one patient with pancreatic cancer had stable disease for more than six cycles, and a patient with pancreatic cancer had a partial response. There was significant interpatient variability in the disposition of 9NC and 9AC. Most of the drug remained in the 9NC form with a ratio of 9NC to 9AC of ∼4 to 1.Conclusions: These studies suggest that 9NC administered on an intermittent schedule is tolerable and may be an active regimen in patients with gastric or pancreatic cancers. Dosing 9NC on a mg/m2 basis does not reduce pharmacokinetic variability.