bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiation and Transforming Growth Factor-β Cooperate in Transcriptional Activation of the Profibrotic Plasminogen Activator Inhibitor-1 Gene
Authors: Hageman Jurre , Eggen Bart J. , Rozema Tom , Damman Kevin , Kampinga Harm H. , Coppes Robert P. 
Published: September 2005

Abstract
Radiation-induced fibrosis is an important side effect in the treatment of cancer. Profibrotic proteins, such as plasminogen activator inhibitor-1 (PAI-1), transforming growth factor-β (TGF-β), and tissue type inhibitor of metalloproteinases-1 (Timp-1), are thought to play major roles in the development of fibrosis via the modulation of extracellular matrix integrity. We did a detailed analysis of transcriptional activation of these profibrotic genes by radiation and TGF-β. Irradiation of HepG2 cells led to a high increase in PAI-1 mRNA levels and a mild increase in Timp-1 mRNA levels. In contrast, TGF-β1 and Smad7 were not increased. Radiation and TGF-β showed strong cooperative effects in transcription of the PAI-1 gene. The TGF-β1 gene showed a mild cooperative activation, whereas Timp-1 and Smad7 were not cooperatively activated by radiation and TGF-β. Analysis using the proximal 800 bp of the human PAI-1 promoter revealed a dose-dependent increase of PAI-1 levels between 2 and 32 Gy γ-rays that was independent of latent TGF-β activation. Subsequent site-directed mutagenesis of the PAI-1 promoter revealed that mutation of a p53-binding element abolished radiation-induced PAI-1 transcription. In line with this, PAI-1 was not activated in p53-null Hep3B cells, indicating that p53 underlies the radiation-induced PAI-1 activation and the cooperativity with the TGF-β/Smad pathway. Together, these data show that radiation and TGF-β activate PAI-1 via partially nonoverlapping signaling cascades that in concert synergize on PAI-1 transcription. This may play a role in patient-to-patient variations in susceptibility toward fibrosis after radiotherapy.
Preclinical Evaluation of the Breast Cancer Cell-Binding Peptide, p160
Authors: Askoxylakis Vasileios , Zitzmann Sabine , Mier Walter , Graham Keith , Krämer Susanne , von Wegner Frederic , Fink Rainer H.A. , Schwab Manfred , Eisenhut Michael , Haberkorn Uwe 
Published: September 2005

Abstract
Purpose: Selective delivery of drugs into the target tissue is expected to result in high drug concentrations in the tissue of interest and therefore enhanced drug efficacy. To develop a peptide-based radiopharmaceutical, we investigated the properties of a peptide with affinity for human breast cancer, which has been selected through phage display.
Experimental Design: The bioactivity of the p160 peptide (VPWMEPAYQRFL) was evaluated in vitro and in vivo. The specific binding to human breast cancer MDA-MB-435 cells was confirmed in competition experiments. Internalization of the peptide was investigated with confocal microscopy. Furthermore, the biodistribution of 131I-labeled p160 was studied in tumor-bearing mice. In vivo stability was evaluated at different periods after tracer administration using high-performance liquid chromatography analysis.
Results: The binding of 125I-labeled p160 was inhibited up to 95% by the unlabeled peptide with an IC50 value of 0.6 μmol/L. In addition, 40% of the total bound activity was found to be internalized into the human breast cancer cells. Although a rapid degradation was seen, biodistribution studies in nude mice showed a higher uptake in tumor than in most of the organs. Perfusion of the animals caused a reduction of the radioligand accumulation in the healthy tissues, whereas the tumor uptake remained constant. A comparison of [131I]p160 with a 131I-labeled Arg-Gly-Asp peptide revealed a higher tumor-to-organ ratio for [131I]p160.
Conclusions: p160 has properties that make it an attractive carrier for tumor imaging and the intracellular delivery of isotopes or chemotherapeutic drugs.
Gene Expression Profiles of Serous, Endometrioid, and Clear Cell Subtypes of Ovarian and Endometrial Cancer
Authors: Zorn Kristin K. , Bonome Tomas , Gangi Lisa , Chandramouli Gadisetti V.R. , Awtrey Christopher S. , Gardner Ginger J. , Barrett J. Carl , Boyd Jeff , Birrer Michael J. 
Published: September 2005

Abstract
Purpose: The presence of similar histologic subtypes of epithelial ovarian and endometrial cancers has long been noted, although the relevance of this finding to pathogenesis and clinical management is unclear. Despite similar clinical characteristics, histologic subtypes of cancers of the ovary and endometrium are treated according to organ of origin. This study compares the gene expression profiles of analogous histologic subtypes of cancers of the ovary and endometrium using the same genomic platform to determine the similarities and differences between these tumors.
Experimental Design: Gene expression profiles of 75 cancers (endometrioid, serous, and clear cell) of the ovary and endometrium, five renal clear cell cancers, and seven normal epithelial brushings were determined using a 11,000-element cDNA array. All images were analyzed using BRB ArrayTools. Validation was done using real-time PCR on select genes and immunohistochemical staining.
Results: Comparison across endometrial and ovarian cancers and serous and endometrioid tumors showed expression patterns reflecting their organ of origin. Clear cell tumors, however, showed remarkably similar expression patterns regardless of their origin, even when compared with renal clear cell samples. A set of 43 genes was common to comparisons of each of the three histologic subtypes of ovarian cancer with normal ovarian surface epithelium.
Conclusions: The comparison of the gene expression profiles of endometrioid and serous subtypes of ovarian and endometrial cancer are largely unique to the combination of a particular subtype in a specific organ. In contrast, clear cell cancers show a remarkable similarity in gene expression profiles across organs (including kidney) and could not be statistically distinguished.
Immunologic Evaluation of Personalized Peptide Vaccination for Patients with Advanced Malignant Glioma
Authors: Yajima Naoki , Yamanaka Ryuya , Mine Takashi , Tsuchiya Naoto , Homma Jumpei , Sano Masakazu , Kuramoto Terukazu , Obata Yayoi , Komatsu Nobukazu , Arima Yoshimi , Yamada Akira , Shigemori Minoru , Itoh Kyogo , Tanaka Ryuichi 
Published: September 2005

AbstractPurpose: The primary goal of this phase I study was to assess the safety and immunologic responses of personalized peptide vaccination for patients with advanced malignant glioma.Experimental Design: Twenty-five patients with advanced malignant glioma (8 grade 3 and 17 grade 4 gliomas) were evaluated in a phase I clinical study of a personalized peptide vaccination. For personalized peptide vaccination, prevaccination peripheral blood mononuclear cells and plasma were provided to examine cellular and humoral responses to 25 or 23 peptides in HLA-A24+ or HLA-A2+ patients, respectively; then, only the reactive peptides (maximum of four) were used for in vivo administration.Results: The protocols were well tolerated with local redness and swelling at the injection site in most cases. Twenty-one patients received more than six vaccinations and were evaluated for both immunologic and clinical responses. Increases in cellular or humoral responses specific to at least one of the vaccinated peptides were observed in the postvaccination (sixth) samples from 14 or 11 of 21 patients, respectively. More importantly, significant levels of peptide-specific IgG were detected in the postvaccination tumor cavity or spinal fluid of all of the tested patients who showed favorable clinical responses. Clinical responses were 5 partial responses, 8 cases of stable disease, and 8 cases of progressive disease. The median overall survival for patients with recurrent glioblastoma multiforme in this study (n = 17) was 622 days.Conclusions: Personalized peptide vaccinations were recommended for the further clinical study to malignant glioma patients.
Activation of Signal Transducer and Activator of Transcription-5 in Prostate Cancer Predicts Early Recurrence
Authors: Li Hongzhen , Zhang Ying , Glass Andrew , Zellweger Tobias , Gehan Edmund , Bubendorf Lukas , Gelmann Edward P. , Nevalainen Marja T. 
Published: September 2005

Abstract
Purpose: We have shown previously that the signal transducer and activator of transcription-5 (Stat5) is a critical survival factor in human prostate cancer cells. In addition, we recently showed that Stat5 is activated at a high level, particularly in high-grade human prostate cancers. Here, we investigated whether activation of Stat5 in prostate cancer was linked to clinical outcome with disease recurrence as end point.
Experimental Design: Immunohistochemistry was used to detect active, nuclear Stat5 in 357 paraffin-embedded prostate cancer specimens on a tissue microarray with clinical follow-up data. Stat5 activation status in prostate cancer specimens was analyzed by univariate and multivariate survival analysis to determine whether activation of Stat5 predicts earlier prostate cancer recurrence. Separate sets of statistical analysis were done for all patients regardless of Gleason grade and for patients with prostate cancer of intermediate Gleason grades (3 and 4).
Results and Conclusions: Stat5 activation in prostate cancer was associated with early disease recurrence (P = 0.0399). Importantly, active Stat5 also predicted shorter progression-free survival in intermediate Gleason grade prostate cancers (P = 0.0409). Stat5 activation remained an independent prognostic marker after adjusting for Gleason grade, pT stage, perineural invasion, or seminal vesicle infiltration in all patients (P = 0.0565) and in Gleason grade 3 or 4 patients (P = 0.0582). The results of this work also confirmed our previous finding of association of Stat5 activation with a high histologic grade of prostate cancer (R = 0.11, P = 0.033). In summary, our study shows that active Stat5 distinguished prostate cancer patients whose disease is likely to progress earlier; therefore, active Stat5 may be a useful marker for selection of more individualized treatment. The results of this study need to be validated in a large prospective cohort.
Promoter Hypermethylation Is the Predominant Mechanism in hMLH1 and hMSH2 Deregulation and Is a Poor Prognostic Factor in Nonsmoking Lung Cancer
Authors: Hsu Han-Shui , Wen Chiao-Kai , Tang Yen-An , Lin Ruo-Kai , Li Wing-Yin , Hsu Wen-Hu , Wang Yi-Ching 
Published: September 2005

Abstract
Purpose and Experimental Design: The etiologic association and prognostic significance of mismatch repair gene/protein alterations have never been examined in nonsmoking lung cancer. Therefore, we investigated protein expression and promoter hypermethylation of hMLH1 and hMSH2 genes in the tumor specimens from 105 nonsmoking female non–small cell lung cancer (NSCLC) patients. Immunohistochemistry and restriction enzyme–based multiplex PCR were used to examine the protein expression and promoter hypermethylation, respectively. The occurrence of gene/protein alteration for each gene was compared with the patients' clinicopathologic variables as well as the overall survival and cancer-specific survival rates.
Results: Protein expression alteration and promoter hypermethylation were observed in 66% to 67% and 30% to 34% of tumor specimens for hMLH1 and hMSH2 genes, respectively. Loss of hMLH1 and hMSH2 protein expression was significantly associated with their promoter hypermethylation (P &lt; 0.0001 and P = 0.049). The overall survival and cancer-specific survival rates were significantly lower in patients with promoter hypermethylation of hMSH2 gene than in those without hypermethylation (P = 0.038 and P = 0.004). The poor prognosis was still especially significant in adenocarcinoma (P = 0.035 and P = 0.061) and early-stage NSCLC patients (P = 0.067 and P = 0.041).
Conclusion: Our data suggest that hMLH1 is the major altered mismatch repair gene involved in nonsmoking NSCLC tumorigenesis and that promoter methylation is the predominant mechanism in hMLH1 and hMSH2 deregulation. In addition, promoter methylation of the hMSH2 gene may be a potential prognostic factor in nonsmoking female lung cancer.
Roxithromycin Inhibits Constitutive Activation of Nuclear Factor κB by Diminishing Oxidative Stress in a Rat Model of Hepatocellular Carcinoma
Authors: Ueno Shinichi , Aoki Dai , Kubo Fumitake , Hiwatashi Kiyokazu , Matsushita Kenji , Oyama Tohru , Maruyama Ikuro , Aikou Takashi 
Published: September 2005

AbstractPurpose: Recently, 14-member macrolide antibiotics such as clarithromycin and roxithromycin have been shown to have anticancer and antiangiogenic effects. We investigated the suppressive effect of roxithromycin on accelerated hepatocellular carcinoma growth in a rat hepatocarcinogenetic model and compared results with effects from TNP-470.Experimental Design: Tumor was induced by oral diethylnitrosamine administration for 17 weeks. Normal saline, TNP-470 (50 mg/kg), or roxithromycin (40 or 100 mg/kg) was administered i.p. thrice per week from week 10 to 17.Results: Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Tumor growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of nuclear factor κB, and increased lipid peroxidation level. All these effects were absent in animals that received roxithromycin or TNP-470. The inhibitory effect of roxithromycin was dose dependent and no clear differences were noted between groups given roxithromycin 100 mg/kg and TNP-470 50 mg/kg.Conclusions: Our results indicate that roxithromycin inhibits oxidative stress, nitric oxide production, and nuclear factor κB activation induced by experimental hepatocarcinogenesis. The data provide additional evidence for the potential use of roxithromycin in treatment of hepatocellular carcinoma prevention.
Possible Involvement of RUNX3 Silencing in the Peritoneal Metastases of Gastric Cancers
Authors: Sakakura Chouhei , Hasegawa Kazunori , Miyagawa Koji , Nakashima Susumu , Yoshikawa Tetsuji , Kin Shuichi , Nakase Yuenn , Yazumi Shujiro , Yamagishi Hisakazu , Okanoue Takeshi , Chiba Tsutomu , Hagiwara Akeo 
Published: September 2005

Abstract
Purpose: Our previous results suggested that a lack of RUNX3 function contributed to human gastric carcinogenesis, but the role of RUNX3 in progression and metastasis remains unclear. We examined RUNX3 expression in clinical samples of peritoneal metastases in gastric cancers. Changes in metastatic potential were assessed in animal experiments using stable RUNX3 transfectants of gastric cancer cells. Finally, global expression changes were analyzed using a cDNA microarray.
Experimental Design and Results: Significant down-regulation of RUNX3 through methylation on the promoter region was observed in primary tumors (75%) as well as in all clinical peritoneal metastases of gastric cancers (100%) compared with normal gastric mucosa. Stable transfection of RUNX3 inhibited cell proliferation slightly, and modest transforming growth factor-β (TGF-β)–induced antiproliferative and apoptotic effects were observed. Interestingly, it strongly inhibited peritoneal metastases of gastric cancers in animal model (P &lt; 0.01). Furthermore, we did globally analyzed expression profiles of ∼21,000 genes in parent cells and stable transfectant of RUNX3 using a cDNA microarray. Microarray analysis identified ∼28 candidate genes under the possible downstream control of RUNX3, some of these genes were considered to be possibly involved in peritoneal metastases, which were related to signal transduction (vav3, TOLL-like receptor, MAPKK, MET, S1 00A1 1, and cathepsin E), apoptosis (caspase 9), immune responses (CD55 and TLR1O), and cell adhesion (sialyltransferase 1 and galectin 4). Some of the genes are involved in the TGF-β signaling pathway.
Conclusion: These results indicate that silencing of RUNX3 affects expression of important genes involved in aspects of metastasis including cell adhesion, proliferation, apoptosis, and promoting the peritoneal metastasis of gastric cancer. Identification of such genes could suggest new therapeutic modalities and therapeutic targets.
Phase I and Pharmacologic Study of Infusional Topotecan and Carboplatin in Relapsed and Refractory Acute Leukemia
Authors: Kaufmann Scott H. , Karp Judith E. , Letendre Louis , Kottke Timothy J. , Safgren Stephanie , Greer Jackie , Gojo Ivana , Atherton Pamela , Svingen Phyllis A. , Loegering David A. , Litzow Mark R. , Sloan Jeff A. , Reid Joel M. , Ames Matthew M. , Adjei Alex A. , Erlichman Charles 
Published: September 2005

Abstract
Purpose: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias.
Experimental Design: Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response.
Results: Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting &gt;50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions, 1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1 and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1 correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test).
Conclusions: The maximum tolerated dose was 1.6 mg/m2/d topotecan plus 150 mg/m2/d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression.
Sequential Platinum-Based Chemotherapy-Thoracic Radiotherapy in Early Stage Non–Small Cell Lung Cancer
Authors: Thatcher Nick , Faivre-Finn Corinne , Blackhall Fiona , Anderson Heather , Lorigan Paul 
Published: September 2005

Abstract
Combined chemoradiotherapy (CTRT) is intended to reduce the risk of local regional recurrence and distant relapse in patients with early stage non–small cell lung cancer (NSCLC). Sequential CTRT allows full doses of each modality while avoiding the additive toxicity that occurs with concurrent therapy. This review will encompass studies in the three main settings where sequential CTRT has been applied in early stage NSCLC: as adjuvant therapy after resection, as neoadjuvant chemotherapy and surgery followed by radiotherapy, and in unresectable stage III disease.
Future of Early Detection of Lung Cancer: The Role of Mouse Models
Authors: Shaw Alice T. , Kirsch David G. , Jacks Tyler 
Published: September 2005

Abstract
Early detection represents one of the most promising approaches to improving lung cancer survival. To date, no screening strategies have been shown to decrease mortality from the disease. Furthermore, no reliable circulating biomarkers of lung cancer have been identified that allow early diagnosis. With the advent of gene targeting technology, new genetically engineered mouse models of lung cancer closely recapitulate the pathobiology of human disease. These mouse models have enabled novel approaches to early detection, including the identification of cancer-associated serum markers using proteomic technologies and the development of new molecular imaging tools. The application of innovative technologies to accurate mouse models promises to accelerate the discovery of new molecular targets and imaging biomarkers for the early detection of lung cancer.
Adjuvant Chemotherapy for Non–Small Cell Lung Cancer: Contribution of the International Adjuvant Lung Trial
Authors: Dunant Ariane , Pignon Jean-Pierre ,   Thierry Le Chevalier on behalf of the International Adjuvant Lung Cancer Trial Collaborative Group
Published: September 2005

Abstract
The recently reported International Adjuvant Lung Cancer Trial (IALT) was designed to assess the potential benefit of three to four cycles of adjuvant cisplatin-based chemotherapy after complete resection of non–small cell lung cancer (NSCLC). Each center predetermined the cisplatin dose (total 300-400 mg/m2), the combined drug (etoposide or a Vinca alkaloid), and the radiotherapy policy. From 1995 to 2000, 1,867 patients were randomized in 148 centers from 33 countries. On September 1, 2002, median follow-up was 56 months and &gt;98% of patients had an updated follow-up. Overall survival was significantly different between the two arms: 5-year survival rate was 44.5% in the chemotherapy arm versus 40.4% in the control arm [relative risk = 0.86 (0.76-0.98), P &lt; 0.03]. Disease-free survival, incidence of local recurrence, and incidence of distant metastases (but not brain metastases) were likewise significantly different, with an advantage for the chemotherapy arm. We concluded that adjuvant cisplatin-based chemotherapy in resected NSCLC should become part of the standard management of operable NSCLC. Two other recently reported randomized prospective studies also showed a significant benefit for postoperative platin-based doublets in stage IB and II NSCLC and confirmed the role of adjuvant chemotherapy as part of the treatment of these patients. The Lung Adjuvant Cisplatin Evaluation program, a pooled analysis of all recent platin-based adjuvant trials, and the IALT-Bio study, which will investigate over 30 markers in the IALT patients' specimens, should allow us to better define the populations more likely to benefit from postoperative chemotherapy.
The ALPI Trial: The Italian/European Experience with Adjuvant Chemotherapy in Resectable Non–Small Lung Cancer
Authors: Scagliotti Giorgio V. ,   on behalf of the Adjuvant Lung Cancer Project Italy/European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group
Published: September 2005

Abstract
Postoperative treatments for lung cancer have been evaluated for more than two decades, but in the majority of the studies no significant and clinically meaningful effect on survival has been shown. In 1995, a meta-analysis of eight cisplatin-based adjuvant chemotherapy trials in 1,394 patients with non–small cell lung cancer showed a 13% reduction in the risk of death (P = 0.08). The nonstatistically significant benefit reported in the meta-analysis prompted the planning of several randomized studies of platinum-based chemotherapy. Three studies addressed the issue of adjuvant chemotherapy in all the resected stages of non–small cell lung cancer (I-IIIA): the Italian/European study Adjuvant Lung Cancer Project Italy, the International Adjuvant Lung Cancer study, and the British Big Lung Trial. In contrast to the International Adjuvant Lung Cancer, the Adjuvant Lung Cancer Project Italy and the underpowered British Big Lung Trial failed to prospectively confirm a significant role of adjuvant chemotherapy in completely resected non–small cell lung cancer. In this article, we will discuss the findings of the Adjuvant Lung Cancer Project Italy study in the context of the International Adjuvant Lung Cancer and British Big Lung Trial.