bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro Drug Response and Molecular Markers Associated with Drug Resistance in Malignant Gliomas
Authors: Fruehauf John P. , Brem Henry , Brem Steven , Sloan Andrew , Barger Geoffrey , Huang Weidong , Parker Ricardo
Published: August 2006

Purpose: Drug resistance in malignant gliomas contributes to poor clinical outcomes. We determined the in vitro drug response profiles for 478 biopsy specimens from patients with the following malignant glial histologies: astrocytoma (n = 71), anaplastic astrocytoma (n = 39), glioblastoma multiforme (n = 259), oligodendroglioma (n = 40), and glioma (n = 69).

Experimental Design: Samples were tested for drug resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, dacarbazine, paclitaxel, vincristine, and irinotecan. Biomarkers associated with drug resistance were detected by immunohistochemistry, including multidrug resistance gene-1, glutathione S-transferase π (GSTP1), O6-methylguanine-DNA methyltransferase (MGMT), and mutant p53.

Results: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Conclusions: Assessment of in vitro drug response and profiles of relevant tumor-associated biomarkers may assist the clinician in stratifying patient treatment regimens.
Prognosis and Gene Expression Profiling of 20q13-Amplified Breast Cancers
Authors: Ginestier Christophe , Cervera Nathalie , Finetti Pascal , Esteyries Séverine , Esterni Benjamin , Adélaïde José , Xerri Luc , Viens Patrice , Jacquemier Jocelyne , Charafe-Jauffret Emmanuelle , Chaffanet Max , Birnbaum Daniel , Bertucci François
Published: August 2006

Purpose: Amplification of chromosomal region 20q13 occurs in breast cancer but remains poorly characterized.

Experimental Design: To establish the frequency of 20q13 amplification and select the amplified cases to be studied, we used fluorescence in situ hybridization of bacterial artificial chromosome probes for three 20q13 loci (MYBL2, STK6, ZNF217) on sections of tissue microarrays containing 466 primary carcinoma samples. We used Affymetryx whole-genome DNA microarrays to establish the gene expression profiles of 20q13-amplified tumors and quantitative reverse transcription-PCR to validate the results.

Results: We found 36 (8%) 20q13-amplified samples. They were distributed in two types: type 1 tumors showed ZNF217 amplification only, whereas type 2 tumors showed amplification at two or three loci. Examination of the histoclinical features of the amplified tumors showed two strikingly opposite data. First, type 1 tumors were more frequently lymph node–negative tumors but were paradoxically associated with a poor prognosis. Second, type 2 tumors were more frequently lymph node–positive tumors but were paradoxically associated with a good prognosis. Type 1 and type 2 showed different gene expression profiles. No 20q13 gene could be associated with type 1 amplification, whereas several 20q13 genes were overexpressed in type 2 tumors.

Conclusions: Our results suggest that amplified tumors of types 1 and 2 are two distinct entities resulting from two different mechanisms and associated to different prognosis.
Increased Bioavailability of Intravenous Versus Oral CI-1033, a Pan erbB Tyrosine Kinase Inhibitor: Results of a Phase I Pharmacokinetic Study
Authors: Simon George R. , Garrett Christopher R. , Olson Stephen C. , Langevin Michael , Eiseman Irene A. , Mahany John J. , Williams Charles C. , Lush Richard , Daud Adil , Munster Pamela , Chiappori Alberto , Fishman Mayer , Bepler Gerold , Lenehan Peter F. , Sullivan Daniel M.
Published: August 2006

Purpose: In phase I studies with oral CI-1033, dose-limiting toxicities were primarily gastrointestinal, supporting the exploration of i.v. dosing to achieve optimal drug exposures by increasing bioavailability.

Experimental Design: Fifty-three patients with advanced nonhematologic malignancies received i.v. CI-1033 via 30-minute infusions (10-500 mg) on a thrice-weekly schedule. Pharmacokinetic samples were collected on days 1 and 8 and evaluated using noncompartmental analysis.

Results: Dose levels evaluated were 10, 20, 30, 45, 67.5, 100, 150, 225, 337.5, and 500 mg. The maximum administered dose was 500 mg, whereas the maximum tolerated dose was 225 mg. The most common treatment-related grade 1 to 2 adverse events were rashes (38% of patients), nausea (17%), vomiting (17%), stomatitis (14%), and diarrhea (13%). Most common grade 3 adverse events were hypersensitivity reactions (7.5%), rashes (3.8%), and diarrhea (3.8%). No grade 4 toxicities were observed. Ten of the 53 (19%) patients had disease stabilization at their first efficacy evaluation visit (including two with minor responses). A 5- to 10-fold increase in i.v. Cmax was noted with a 3-fold increase in AUC compared with oral CI-1033 at equivalent doses. Treatment-related gastrointestinal adverse events were notably less frequent with this i.v. regimen.

Conclusions: CI-1033 was safely given i.v. up to 225 mg/dose on a thrice-weekly schedule, with evidence of antitumor activity. At equivalent doses, the bioavailability of i.v. CI-1033 is thrice that of the oral formulation. Treatment with i.v. CI-1033 is feasible and may be warranted when increased drug exposures are desired.
Cutaneous Melanoma Subtypes Show Different BRAF and NRAS Mutation Frequencies
Authors: Saldanha Gerald , Potter Linda , DaForno Philip , Pringle J. Howard
Published: August 2006

Purpose: BRAF mutations are present in two thirds of cutaneous melanomas and many of the rest have NRAS mutations. However, cutaneous melanoma is a heterogeneous disease with many clinicopathologic subtypes. Of these, the majority fits into four categories: superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma (ALM). Thus far, there is very limited data combining BRAF and NRAS mutation analysis to explore differences between cutaneous melanoma subtypes. The aim of this study was to address this issue.

Experimental Design: The frequency of BRAF and NRAS hotspot mutations, in exons 15 and 2, respectively, was assessed in 59 cutaneous melanomas comprising superficial spreading, nodular, lentigo maligna, and ALM using single-strand conformational polymorphism and RFLP-PCR analysis.

Results: Only 2 of 21 (9.5%) ALM showed BRAF exon 15 mutation compared with 9 of 14 (64.3%) superficial spreading malignant melanomas, 4 of 11 (36.4%) nodular melanomas, and 7 of 13 (53.4%) lentigo maligna melanomas (P < 0.01). However, our key finding is that the combined analysis of BRAF exon 15 and NRAS exon 2 showed that there were no significant differences in the overall mutation frequency between subtypes. In particular, 9 of 19 (47.4%) ALM without BRAF exon 15 mutation had an NRAS exon 2 mutation.

Conclusions: We show that the overall BRAF/NRAS frequency in mutation hotspots is not significantly different among cutaneous melanoma subtypes. These data show that mitogen-activated protein kinase pathway activation may be important in all major subtypes of cutaneous melanoma, although the mechanism by which this is achieved varies.
Hypoxia-Inducible Factor-1α Expression Predicts a Poor Response to Primary Chemoendocrine Therapy and Disease-Free Survival in Primary Human Breast Cancer
Authors: Generali Daniele , Berruti Alfredo , Brizzi Maria P. , Campo Leticia , Bonardi Simone , Wigfield Simon , Bersiga Alessandra , Allevi Giovanni , Milani Manuela , Aguggini Sergio , Gandolfi Valeria , Dogliotti Luigi , Bottini Alberto , Harris Adrian L. , Fox Stephen B.
Published: August 2006

Purpose: To investigate the relationship of hypoxia-inducible factor-1α (HIF-1α) tumor expression in predicting the response to epirubicin and disease-free survival (DFS) in patients with breast cancer enrolled in a single institution trial of primary anthracycline and tamoxifen therapy.

Experimental Design: The expression of HIF-1α was assessed by immunohistochemistry in 187 patients with T2-4 N0-1 breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin + tamoxifen as primary systemic treatment. All patients postoperatively received four cycles of the four weekly i.v. CMF regimen (cyclophosphamide, methotrexate, and 5-fluorouracil). Patients with estrogen receptor (ER)-positive primary tumors also underwent 5 years of treatment with adjuvant tamoxifen. Carbonic anhydrase IX (CAIX) was also scored as a marker of HIF activity.

Results: Overall response to therapy progressively decreased with increasing tumor HIF-1α (P < 0.05), and HIF-1α was an independent predictor of response (P < 0.048). HIF-1α expression was also associated with a significantly shorter DFS (P < 0.02) in all patients and in ER-positive but not in ER-negative patients. Furthermore, CAIX positivity conferred a significantly shorter DFS (P = 0.02) compared with CAIX-negative tumors in patients with HIF-1α-negative tumors.

Conclusions: HIF-1α expression in patients with breast cancer is a marker of poor therapy response and outcome, especially in ER-positive patients. The combination of two hypoxia markers has greater utility than assessing just one, and patients with hypoxia markers in their tumors may be suitable for administration of drugs that reduce HIF-1α expression and increase oxygen delivery to the tumor bed before starting neoadjuvant therapies.
Hypoxia-Inducible Factor-1 Inhibition in Combination with Temozolomide Treatment Exhibits Robust Antitumor Efficacy In vivo
Authors: Li Leiming , Lin Xiaoyu , Shoemaker Alex R. , Albert Daniel H. , Fesik Stephen W. , Shen Yu
Published: August 2006

Purpose: Inhibiting hypoxia-inducible factor-1 (HIF-1) represents a unique mechanism for cancer therapy. It is conceived that HIF-1 inhibitors may synergize with many classes of cancer therapeutic agents, such as angiogenesis inhibitors and cytotoxic drugs, to achieve a more robust tumor response. However, these hypotheses have not been rigorously tested in tumor models in vivo. The present study was carried out to evaluate the antitumor efficacy of combining HIF-1 inhibition with angiogenesis inhibitors or cytotoxic agents.

Experimental Design: Using a D54MG-derived tumor model that allows knockdown of HIF-1α on doxycycline treatment, we examined the tumor responses to chemotherapeutic agents, including the angiogenesis inhibitor ABT-869 and cytotoxic agents 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide, in the presence or absence of an intact HIF-1 pathway.

Results: Surprisingly, inhibiting HIF-1 in tumors treated with the angiogenesis inhibitor ABT-869 did not produce much added benefit compared with ABT-869 treatment alone, suggesting that the combination of an angiogenesis inhibitor with a HIF-1 inhibitor may not be a robust therapeutic regimen. In contrast, the cytotoxic drug temozolomide, when used in combination with HIF-1α knockdown, exhibited a superadditive and likely synergistic therapeutic effect compared with the monotherapy of either treatment alone in the D54MG glioma model.

Conclusions: Our results show that the DNA alkylating agent temozolomide exhibits robust antitumor efficacy when used in combination with HIF-1 inhibition in D54MG-derived tumors, suggesting that the combination of temozolomide with HIF-1 inhibitors might be an effective regimen for cancer therapy. In addition, our results also show that the RNA interference–based inducible knockdown model can be a valuable platform for further evaluation of the combination treatment of other cancer therapeutics with HIF-1 inhibition.
The Chemokine CCL5 as a Potential Prognostic Factor Predicting Disease Progression in Stage II Breast Cancer Patients
Authors: Yaal-Hahoshen Neora , Shina Sima , Leider-Trejo Leonor , Barnea Itay , Shabtai Esther L. , Azenshtein Elina , Greenberg Iulia , Keydar Iafa , Ben-Baruch Adit
Published: August 2006

Purpose: The aim of this study was to determine the prognostic value of the chemokine CCL5, considered as a promalignancy factor in breast cancer, in predicting breast cancer progression and to evaluate its ability to strengthen the prognostic significance of other biomarkers.

Experimental Design: The expression of CCL5, alone and in conjunction with estrogen receptor (ER)-α, ER-β, progesterone receptor (PR), and HER-2/neu (ErbB2), was determined in breast tumor cells by immunohistochemistry. The study included 142 breast cancer patients, including individuals in whom disease has progressed.

Results: Using Cox proportional hazard models, univariate analysis suggested that, in stage I breast cancer patients, CCL5 was not a significant predictor of disease progression. In contrast, in stage II patients, the expression of CCL5 (CCL5+), the absence of ER-α (ER-α−), and the lack of PR expression (PR−) increased significantly the risk for disease progression (P = 0.0045, 0.0041, and 0.0107, respectively). The prognostic strength of CCL5, as well as of ER-α−, improved by combining them together (CCL5+/ER-α−: P = 0.0001), being highly evident in the stage IIA subgroup [CCL5+/ER-α− (P = 0.0003); ER-α− (P = 0.0315)]. In the stage II group as a whole, the combinations of CCL5−/ER-α+ and CCL5−/PR+ were highly correlated with an improved prognosis. Multivariate analysis indicated that, in stage II patients, ER-α and CCL5 were independent predictors of disease progression.

Conclusions: CCL5 could be considered as a biomarker for disease progression in stage II breast cancer patients, with the CCL5+/ER-α− combination providing improved prediction of disease progression, primarily in the stage IIA subgroup.
An In vivo Platform for Translational Drug Development in Pancreatic Cancer
Authors: Rubio-Viqueira Belen , Jimeno Antonio , Cusatis George , Zhang Xianfeng , Iacobuzio-Donahue Christine , Karikari Collins , Shi Chanjusn , Danenberg Kathleen , Danenberg Peter V. , Kuramochi Hidekazu , Tanaka Koji , Singh Sharat , Salimi-Moosavi Hossein , Bouraoud Nadia , Amador Maria L. , Altiok Soner , Kulesza Piotr , Yeo Charles , Messersmith Wells , Eshleman James , Hruban Ralph H. , Maitra Anirban , Hidalgo Manuel
Published: August 2006

Effective development of targeted anticancer agents includes the definition of the optimal biological dose and biomarkers of drug activity. Currently available preclinical models are not optimal to this end. We aimed at generating a model for translational drug development using pancreatic cancer as a prototype. Resected pancreatic cancers from 14 patients were xenografted and expanded in successive groups of nude mice to develop cohorts of tumor-bearing mice suitable for drug therapy in simulated early clinical trials. The xenografted tumors maintain their fundamental genotypic features despite serial passages and recapitulate the genetic heterogeneity of pancreatic cancer. The in vivo platform is useful for integrating drug screening with biomarker discovery. Passages of tumors in successive cohorts of mice do not change their susceptibility to anticancer agents and represent a perpetual live bank, facilitating the application of new technologies that will result in the creation of an integrated stable database of tumor-drug response data and biomarkers.
Induction of Interleukin-6 by Hepatitis C Virus Core Protein in Hepatitis C–Associated Mixed Cryoglobulinemia and B-Cell Non–Hodgkin's Lymphoma
Authors: Feldmann Georg , Nischalke Hans Dieter , Nattermann Jacob , Banas Brigitte , Berg Thomas , Teschendorf Christian , Schmiegel Wolff , Dührsen Ulrich , Halangk Juliane , Iwan Agathe , Sauerbruch Tilman , Caselmann Wolfgang H. , Spengler Ulrich
Published: August 2006

Purpose: Chronic hepatitis C carries the risk to develop mixed cryoglobulinemia (MC) and B-cell non–Hodgkin's lymphoma (B-NHL), possibly because viral antigens stimulate the host's inflammatory response via extracellular pattern recognition receptors (PRR). To clarify this issue, we studied whether recognition of hepatitis C virus (HCV) proteins by PRR is involved in the pathogenesis of HCV-associated MC or B-NHL.

Experimental Design: Peripheral blood mononuclear cells of patients with HCV-associated B-NHL (n = 12), MC (n = 14), uncomplicated hepatitis C (n = 12), and healthy volunteers (n = 12) were incubated with the recombinant HCV proteins E2, core, and NS3 to study induction of cytokine production, stimulation of B-cell proliferation, and immunoglobulin secretion. In addition, serum levels of interleukin-6 (IL-6) were measured by ELISA.

Results: HCV core was the only studied protein, which induced production of IL-6 and IL-8 in CD14+ cells. IL-6 induction was mediated via Toll-like receptor 2 (TLR2) and lead to increased B-cell proliferation in vitro. TLR2 expression on monocytes and IL-6 serum concentrations were increased in all groups of HCV-infected patients compared with healthy controls and were highest in MC (P < 0.05).

Conclusions: Increased secretion of IL-6 via stimulation of TLR2 by HCV core protein may play a role in the pathogenesis of hepatitis C–associated MC and B-NHL.
Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia
Authors: Kirschner-Schwabe Renate , Lottaz Claudio , Tödling Jörn , Rhein Peter , Karawajew Leonid , Eckert Cornelia , von Stackelberg Arend , Ungethüm Ute , Kostka Dennis , Kulozik Andreas E. , Ludwig Wolf-Dieter , Henze Günter , Spang Rainer , Hagemeier Christian , Seeger Karl
Published: August 2006

Purpose: In childhood acute lymphoblastic leukemia (ALL), ∼25% of patients suffer from relapse. In recurrent disease, despite intensified therapy, overall cure rates of 40% remain unsatisfactory and survival rates are particularly poor in certain subgroups. The probability of long-term survival after relapse is predicted from well-established prognostic factors (i.e., time and site of relapse, immunophenotype, and minimal residual disease). However, the underlying biological determinants of these prognostic factors remain poorly understood.

Experimental Design: Aiming at identifying molecular pathways associated with these clinically well-defined prognostic factors, we did gene expression profiling on 60 prospectively collected samples of first relapse patients enrolled on the relapse trial ALL-REZ BFM 2002 of the Berlin-Frankfurt-Münster study group.

Results: We show here that patients with very early relapse of ALL are characterized by a distinctive gene expression pattern. We identified a set of 83 genes differentially expressed in very early relapsed ALL compared with late relapsed disease. The vast majority of genes were up-regulated and many were late cell cycle genes with a function in mitosis. In addition, samples from patients with very early relapse showed a significant increase in the percentage of S and G2-M phase cells and this correlated well with the expression level of cell cycle genes.

Conclusions: Very early relapse of ALL is characterized by an increased proliferative capacity of leukemic blasts and up-regulated mitotic genes. The latter suggests that novel drugs, targeting late cell cycle proteins, might be beneficial for these patients that typically face a dismal prognosis.
Predicting Cancer Drug Response by Proteomic Profiling
Authors: Ma Yan , Ding Zhenyu , Qian Yong , Shi Xianglin , Castranova Vince , Harner E. James , Guo Lan
Published: August 2006

Purpose: Accurate prediction of an individual patient's drug response is an important prerequisite of personalized medicine. Recent pharmacogenomics research in chemosensitivity prediction has studied the gene-drug correlation based on transcriptional profiling. However, proteomic profiling will more directly solve the current functional and pharmacologic problems. We sought to determine whether proteomic signatures of untreated cells were sufficient for the prediction of drug response.

Experimental Design: In this study, a machine learning model system was developed to classify cell line chemosensitivity exclusively based on proteomic profiling. Using reverse-phase protein lysate microarrays, protein expression levels were measured by 52 antibodies in a panel of 60 human cancer cell (NCI-60) lines. The model system combined several well-known algorithms, including random forests, Relief, and the nearest neighbor methods, to construct the protein expression–based chemosensitivity classifiers. The classifiers were designed to be independent of the tissue origin of the cells.

Results: A total of 118 classifiers of the complete range of drug responses (sensitive, intermediate, and resistant) were generated for the evaluated anticancer drugs, one for each agent. The accuracy of chemosensitivity prediction of all the evaluated 118 agents was significantly higher (P < 0.02) than that of random prediction. Furthermore, our study found that the proteomic determinants for chemosensitivity of 5-fluorouracil were also potential diagnostic markers of colon cancer.

Conclusions: The results showed that it was feasible to accurately predict chemosensitivity by proteomic approaches. This study provides a basis for the prediction of drug response based on protein markers in the untreated tumors.
A Phase I Study of Intravenous LBH589, a Novel Cinnamic Hydroxamic Acid Analogue Histone Deacetylase Inhibitor, in Patients with Refractory Hematologic Malignancies
Authors: Giles Francis , Fischer Thomas , Cortes Jorge , Garcia-Manero Guillermo , Beck Joachim , Ravandi Farhad , Masson Eric , Rae Patricia , Laird Glen , Sharma Sunil , Kantarjian Hagop , Dugan Margaret , Albitar Maher , Bhalla Kapil
Published: August 2006

Purpose: LBH589 is a novel histone deacetylase inhibitor that inhibits proliferation and induces apoptosis in tumor cell lines. In this phase I study, LBH589 was administered i.v. as a 30-minute infusion on days 1 to 7 of a 21-day cycle.

Experimental Design: Fifteen patients (median age, 63 years; range, 42-87 years) with acute myeloid leukemia (13 patients), acute lymphocytic leukemia (1 patient), or myelodysplastic syndrome (1 patient) were treated with LBH589 at the following dose levels (mg/m2): 4.8 (3 patients), 7.2 (3 patients), 9.0 (1 patient), 11.5 (3 patient), and 14.0 (5 patients). The levels of histone acetylation were measured using quantitative flow cytometry and plasma LBH589 concentrations were assayed.

Results: Four dose-limiting toxicities (grade 3 QTcF prolongation) were observed, four at 14.0 mg/m2 and one at 11.5 mg/m2. QTcF prolongation was asymptomatic and reversed on LBH589 discontinuation. Other potentially LBH589-related toxicities included nausea (40%), diarrhea (33%), vomiting (33%), hypokalemia (27%), loss of appetite (13%), and thrombocytopenia (13%). In 8 of 11 patients with peripheral blasts, transient reductions occurred with a rebound following the 7-day treatment period. H3 acetylation increase was significant in B-cells (CD19+; P = 0.02) and blasts (CD34+; P = 0.04). The increase in H2B acetylation was highest in CD19+ and CD34+ cells [3.8-fold (P = 0.01) and 4.4-fold (P = 0.03), respectively]. The median acetylation of histones H2B and H3 in CD34+ and CD19+ cells significantly increased on therapy as did apoptosis in CD14+ cells. Area under the curve increased proportionally with dose with a terminal half-life of ∼11 hours.

Conclusion: Intravenous administration of LBH589 was well tolerated at doses <11.5 mg/m2 with consistent transient antileukemic and biological effects.
Minicircle-IFNγ Induces Antiproliferative and Antitumoral Effects in Human Nasopharyngeal Carcinoma
Authors: Wu Jiangxue , Xiao Xia , Zhao Peng , Xue Gang , Zhu Yinghui , Zhu Xiaofeng , Zheng Limin , Zeng Yixin , Huang Wenlin
Published: August 2006

Purpose: The aims of this work were to investigate the antitumor effect of IFNγ gene transfer on human nasopharyngeal carcinoma (NPC) and to assess the potential of minicircle vector for antitumor gene therapy.

Experimental Design: We developed a recombinant minicircle vector carrying the human IFNγ gene and evaluated the effects of minicircle-mediated IFNγ gene transfer on NPC cell lines in vitro and on xenografts in vivo.

Results: Relative to p2ΦC31-IFNγ, minicircle-mediated IFNγ gene transfer in vitro resulted in 19- to 102-fold greater IFNγ expression levels in transfected cells (293, NIH 3T3, CNE-1, CNE-2, and C666-1) and inhibited the growth of CNE-1, CNE-2, and C666-1 cells more efficiently, reducing relative growth rates to 7.1 ± 1.6%, 2.7 ± 1.0%, and 6.1 ± 1.6%, respectively. Flow cytometry and caspase-3 activity assays suggested that the antiproliferative effects of IFNγ gene transfer on NPC cell lines could be attributed to G0-G1 arrest and apoptosis. Minicircle-mediated intratumoral IFNγ expression in vivo was 11 to 14 times higher than p2ΦC31-IFNγ in CNE-2- and C666-1-xenografted mice and lasted for 21 days. Compared with p2ΦC31-IFNγ treatment, minicircle-IFNγ treatment significantly increased survival and achieved inhibition rates of 77.5% and 83%, respectively.

Conclusions: Our data indicate that IFNγ gene transfer exerts antiproliferative effects on NPC cells in vitro and leads to a profound antitumor effect in vivo. Minicircle-IFNγ is more efficient than corresponding conventional plasmids due to its capability of mediating long-lasting high levels of IFNγ gene expression. Therefore, minicircle-mediated IFNγ gene transfer is a promising novel approach in the treatment of NPC.
Temozolomide-Mediated Radiation Enhancement in Glioblastoma: A Report on Underlying Mechanisms
Authors: Chakravarti Arnab , Erkkinen Michael G. , Nestler Ulf , Stupp Roger , Mehta Minesh , Aldape Ken , Gilbert Mark R. , Black Peter McL. , Loeffler Jay S.
Published: August 2006

Purpose: In this study, we investigated the mechanisms by which temozolomide enhances radiation response in glioblastoma cells.

Experimental Design: Using a panel of four primary human glioblastoma cell lines with heterogeneous O6-methylguanine-DNA methyltransferase (MGMT) protein expression, normal human astrocytes, and U87 xenografts, we investigated (a) the relationship of MGMT status with efficacy of temozolomide-based chemoradiation using a panel of in vitro and in vivo assays; (b) underlying mechanisms by which temozolomide enhances radiation effect in glioblastoma cells; and (c) strategies to overcome resistance to radiation + temozolomide.

Results: Temozolomide enhances radiation response most effectively in glioblastomas without detectable MGMT expression. On concurrent radiation + temozolomide administration in MGMT-negative glioblastomas, there seems to be decreased double-strand DNA (dsDNA) repair capacity and enhanced dsDNA damage compared either with radiation alone or with sequentially administered temozolomide. Our data suggest that O6-benzylguanine can enhance the antitumor effects of concurrent radiation + temozolomide in MGMT-positive cells by enhancing apoptosis and the degree of dsDNA damage. O6-Benzylguanine was most effective when administered concurrently with radiation + temozolomide and had less of an effect when administered with temozolomide in the absence of radiation or when administered sequentially with radiation. Our in vivo data using U87 xenografts confirmed our in vitro findings.

Conclusions: The present study shows that temozolomide enhances radiation response most effectively in MGMT-negative glioblastomas by increasing the degree of radiation-induced double-strand DNA damage. In MGMT-positive glioblastomas, depletion of MGMT by the addition of O6-benzylguanine significantly enhances the antitumor effect of concurrent radiation + temozolomide. These are among the first data showing mechanisms of synergy between radiation and temozolomide and the effect of MGMT.
Statistical Analysis of DNA Microarray Data in Cancer Research
Authors: Fan Jianqing , Ren Yi
Published: August 2006

Microarray techniques have been widely used to monitor gene expression in many areas of biomedical research. They have been widely used for tumor diagnosis and classification, prediction of prognoses and treatment, and understanding of molecular mechanisms, biochemical pathways, and gene networks. Statistical methods are vital for these scientific endeavors. This article reviews recent developments of statistical methods for analyzing data from microarray experiments. Emphasis has been given to normalization of expression from multiple arrays, selecting significantly differentially expressed genes, tumor classifications, and gene expression pathways and networks.
A Clue for Telangiectasis in Systemic Sclerosis: Elevated Serum Soluble Endoglin Levels in Patients with the Limited Cutaneous Form of the Disease
Authors: Fujimoto M. , Hasegawa M. , Hamaguchi Y. , Komura K. , Matsushita T. , Yanaba K. , Kodera M. , Takehara K. , Sato S.
Published: August 2006

Background: The transforming growth factor-β (TGF-β) system plays a critical role both in systemic sclerosis (SSc) and hereditary hemorrhagic telangiectasia (HHT). Endoglin, known as a gene responsible for HHT, is a TGF-β receptor preferentially expressed on endothelial cells. The role of endoglin in SSc is potentially intriguing since limited cutaneous SSc (lcSSc) and HHT share several symptoms, including telangiectasia. Objective: To determine serum levels of soluble endoglin (sEndoglin) and clinical associations in patients with SSc. Methods: Serum sEndoglin levels were examined by ELISA in 70 patients with SSc, 20 patients with systemic lupus erythematosus and 20 healthy individuals. Results: Serum sEndoglin levels were significantly elevated in patients with lcSSc compared with diffuse cutaneous SSc and systemic lupus erythematosus patients as well as normal controls. Patients with elevated sEndoglin levels had telangiectasia more frequently than those with normal sEndoglin levels. Furthermore, pulmonary artery pressure was positively correlated with sEndoglin levels in patients with lcSSc. Conclusion: Abnormal expression/function of endoglin may be linked to lcSSc-specific manifestations.
Eosinophilic Fasciitis 30 Years after – What Do We Really Know?
Authors: Antic Milos , Lautenschlager Stephan , Itin Peter H.
Published: August 2006

Background: Eosinophilic fasciitis (EF) is a rare fibrosing disorder associated with peripheral eosinophilia and scleroderma-like induration of the distal extremities which affects substantially quality of life. Although the disease has been described 30 years ago, the etiology and pathomechanisms are still obscure, and consensus for therapy is lacking. Numerous case reports of patients with EF exist but series are scarce. Patients and Methods: Eleven patients with EF from the Department of Dermatology, Kantonsspital Aarau, the University Hospital Basel and the Outpatient Clinic of Dermatology, Triemli Hospital Zurich, Switzerland, were retrospectively studied. Results: In 4 patients the initial diagnosis was not recognized by the referring nondermatologists. The median age was 55 years, excluding the youngest patient ever diagnosed with EF (age = 1 year). All patients showed an induration of the skin, which led to painful contractures in the joints in 3 cases. All but 2 patients demonstrated edema. A slight predominance of the upper extremities was observed. Sclerodactyly was noticed in 1 patient. Three patients reported an initial trauma at the affected site. Two patients were tested positive for borreliosis. One patient subsequently developed aplastic anemia and Hashimoto thyroiditis. Visceral or extracutaneous involvement was absent. Eight patients had a full or partial recovery under corticosteroids whereas in 2, improvement could be achieved only with cyclosporine, azathioprine or cyclophosphamide. Conclusions: The diagnosis of EF can be established by clinical, laboratory and histological findings. In general, corticosteroids are highly efficacious in EF and only a minority of patients need other immunosuppressive or cytostatic drugs.
Work Limitations and Productivity Loss Are Associated with Health-Related Quality of Life but Not with Clinical Severity in Patients with Psoriasis
Authors: Schmitt Jochen M. , Ford Daniel E.
Published: August 2006

Background: According to current guidelines the cost of productivity loss should be considered in pharmacoeconomic analyses. The cost of health-related productivity loss in psoriasis patients is unknown. Objective: To estimate the cost of productivity loss in psoriasis and its association with health-related quality of life and clinical disease severity. Methods: Cross-sectional study, recruitment of adult participants through Internet advertisements. 201 (72.3%) out of 278 eligible participants completed the study. Health-related work productivity loss, quality of life and clinical severity of psoriasis were assessed by standardized instruments. Results: Indirect costs of productivity loss clearly exceed the total direct cost. In contrast to objective clinical disease severity, health-related quality of life (measured by the Dermatology Life Quality Index) is an independent predictor of work productivity. Conclusions: There is good reason to believe that intervention can reduce health-related productivity loss by improving patients’ quality of life. Savings from increased work productivity might offset comparatively high acquisition costs of biological agents.
Estrogen-Receptor-Alpha-Positive Extramammary Paget’s Disease Treated with Hormonal Therapy
Authors: Iijima M. , Uhara H. , Ide Y. , Sakai S. , Onuma H. , Muto M. , Hayashi K. , Mitsura F. , Kobayashi S. , Yoshizawa A. , Saida T.
Published: August 2006

The patient was an 80-year-old man with scrotal and penile extramammary Paget’s disease and prostate cancer. Both diseases were in advanced stages. Tumor cells of extramammary Paget’s disease strongly expressed estrogen receptor α. The patient was concurrently treated with two kinds of hormonal therapy: the anti-estrogen tamoxifen (20 mg/day orally) for extramammary Paget’s disease and the anti-androgen bicalutamide (80 mg/day orally) for prostate cancer. The toxicity of the therapy was mild. All of the metastatic lesions remained stable for 2 months after initiation of dual hormonal therapy. During a follow-up period of 22 months, performance status was well maintained for 17 months. Hormonal therapy may be an alternative for selected cases of advanced extramammary Paget’s disease.
Tempting Liver Fibrosis? Long-Term Psoriatic Methotrexate Therapy and Heterozygous α1-Antitrypsin Deficiency
Authors: Mathew Joseph , Igbokwe Uchechi O. , Morley Nick , Burt Alastair D.
Published: August 2006

Background: Dermatologists, or pathologists, occasionally need to decide whether or not to continue methotrexate therapy in a patient with an identifiable risk factor for liver fibrosis, in this instance heterozygous α1-antitrypsin deficiency. Case Presentation: We relate our experience with an elderly male patient, diagnosed as having α1-antitrypsin deficiency on a liver biopsy, genotypically confirmed as PiMZ. He had been receiving methotrexate for psoriasis for 17 years with a cumulative dose of 7,200 mg. He was monitored by biochemical profiling and interval (10) liver biopsies. Non-specific changes were seen on liver histology although grade 1 liver fibrosis was seen in his last 2 biopsies. Conclusion: We suggest that methotrexate therapy is relatively safe in patients with heterozygous α1-antitrypsin deficiency, with no other risk factor. We however advise that the risk of fibrosis should be monitored and that the patient receives appropriate counselling.
Acquired Melanocytic Naevus in Childhood Vulval Pemphigoid
Authors: Lebeau S. , Braun R.P. , Masouyé I. , Perrinaud A. , Harms M. , Borradori L.
Published: August 2006

Background: Eruptive epidermolysis bullosa (EB) naevi comprise a subset of melanocytic naevi with atypical features that characteristically occur in areas of former blistering in patients suffering from hereditary EB. Observation: The case is reported of a girl who presented with pruritus, blistering and erosions of the vulval region. Clinical and immunopathological features were consistent with the diagnosis of childhood vulval pemphigoid. In the course of the disease, she developed an atypical melanocytic naevus on the left labium at a site of former blistering. Although its clinical and dermoscopic features resembled malignant melanoma, the lesion completely regressed clinically during the 24-month follow-up. Conclusion: This is the first report describing the development of a melanocytic naevus at sites of blistering in an auto-immune subepidermal blistering disease in childhood. Our observation extends the spectrum of disorders, in addition to the group of congenital EB, in which ‘eruptive’ atypical melanocytic naevi may occur. Knowledge of this complication is important for appropriate management and follow-up and to avoid radical surgery.
Spores, Sporodochia and Fomites in Onychomycosis
Authors: Piérard Gérald E.
Published: August 2006

Onychomycosis is a frequent infection. Contagion rarely depends on direct contamination, but rather on environmental propagule dispersion including the intervention of fomites. The potential release of fungal cells in the environment from the affected nails has not been thoroughly studied. Observations made by histomycology suggest that arthroconidia and chlamydoconidia issued from invading fungi can be involved. In addition, the sporodochium, which is an exophytic fungal ball, may be attached underneath the distal free edge of some onychomycoses. It might represent an important source of fungal propagules in patients with poor nail trimming.
Associations between Major Depression, Bipolar Disorders, Dysthymia and Cardiovascular Diseases in the General Adult Population
Authors: Baune Bernhard T. , Adrian Ina , Arolt Volker , Berger Klaus
Published: August 2006

Background: Cardiovascular diseases (CVD) and affective disorders are both very prevalent in the general population. However, it is unclear on a population level if the prevalence of different subtypes of affective disorders like unipolar major depression or dysthymia is different in individuals with specific CVDs. Methods: In 4,181 participants of the general population, lifetime prevalences for affective disorders were assessed through the Composite International Diagnostic Interview and cardiovascular diseases by self-report and subsequent physician-verified diagnosis. Multivariable logistic regression was used in the analysis. Results: Prevalences of unipolar depression, bipolar disorder and dysthymia were significantly higher in participants with coronary heart disease or stroke compared to those without these CVDs. Dysthymia had a stronger (OR = 2.03; 95% CI = 1.21–3.39) association with coronary heart disease than unipolar depression (OR = 1.58; 95% CI = 1.09–2.30) or any depression (OR = 1.92; 95% CI = 1.37–2.70). In contrast, unipolar depression (OR = 2.27; 95% CI = 1.29–3.99) showed a significant OR for the relation with stroke compared to dysthymia that reached no statistical significance. The commonly used category ‘any depression’ revealed higher odds (OR = 2.50; 95% CI = 1.46–4.28) for the relationship with stroke than unipolar depression or dysthymia, but lower odds than bipolar I disorder (OR = 5.71, 95% CI = 1.23–26.66). Conclusions: Classification into diagnostic subgroups of affective disorders is important for an improved clinical and pathophysiological understanding of their relationship with CVDs. Dysthymia, in particular, plays an important role regarding the relation of affective disorders and CVDs. Future research on biological models may elucidate the pathophysiological link between subtypes of affective disorders and CVDs.
Beta-Amlyoid 1–42 and Tau-Protein in Cerebrospinal Fluid of Patients with Parkinson’s Disease Dementia
Authors: Mollenhauer Brit , Trenkwalder Claudia , von Ahsen Nicolas , Bibl Mirko , Steinacker Petra , Brechlin Peter , Schindehuette Jan , Poser Sigrid , Wiltfang Jens , Otto Markus
Published: August 2006

Measurement of τ-protein and β-amyloid1–42 (Aβ42) in cerebrospinal fluid (CSF) has gained increasing acceptance in the differential diagnosis of Alzheimer’s disease. We investigated CSF τ-protein and Aβ42 concentrations in 73 patients with advanced idiopathic Parkinson’s disease with dementia (PDD) and 23 patients with idiopathic Parkinson’s disease without dementia (PD) and in a comparison group of 41 non-demented neurological patients (CG) using commercially available enzyme-linked-immunoabsorbant-assay (ELISA). τ-Protein levels were statistically significantly higher and Aβ42 lower in the PDD patients compared to PD patients and the CG. This observation was most marked (p < 0.05) in a subgroup of patients with PDD carrying the apolipoprotein genotype Ε3/Ε3. The distribution of the apolipoprotein genotypes in PDD and PD patients was similar to that of the CG. Although a significant difference in τ-protein values was observed between PDD and CG, no diagnostic cut-off value was established. These findings suggest that such protein CSF changes may help to support the clinical diagnosis of cognitive decline in PD and that there may be apolipoprotein-E-isoform-specific differences in CSF protein regulation in advanced PDD.
Prospective Memory Complaints Can Be Predicted by Prospective Memory Performance in Older Adults
Authors: Zeintl Melanie , Kliegel Matthias , Rast Philippe , Zimprich Daniel
Published: August 2006

Background/Aims: The aim of this study was to explore if prospective memory complaints reflect actual prospective memory performance in older adults. Methods: Three hundred and sixty-four older adults aged 65–80 years were investigated with regard to prospective memory complaints, prospective memory test performance, self-reported depressive symptoms, and self-reported memory capacity. Results: Separate analyses revealed that about half of the participants showed a significant relation between subjective and objective prospective memory. Conclusion: Older adults appear to be heterogeneous with regard to the association between objective and subjective prospective memory. For older adults with relatively few depressive symptoms and memory concerns, prospective memory complaints may serve as a valid criterion in the assessment of prospective memory ability.
Comparison of Properties and Structures of Compact and Conventional Spun Yarns
Authors: Basal Guldemet , Oxenham William
Published: August 2006

The properties and structural parameters of compact and conventional ring yarns produced at five different twist levels were compared. A modified version of the tracer fiber technique ( J. Textile Inst., 43, T60-T66, 1952) combined with the Image Analysis Application Version 3.0 (B.A.R.N. Engineering) was utilized to explore yarn structure. Results obtained from these analyses showed that the high tenacity values of compact yarns can be attributed to the higher rate and amplitude of fiber migration in these yarns compared to those in conventional ring yarns. Another important finding was the superiority of compact yarns in terms of tensile properties is less noticeable at higher twist levels and in 50/50 polyester/cotton blend.
Political Participation and Civic Engagement in Kathmandu: An Empirical Analysis with Structural Equations
Authors: Wagle Udaya R.
Published: August 2006

Researchers generally accept the thesis that strong relationships exist between civic engagement and political participation. However, the specific nature and magnitude of the relationships are yet to be ascertained empirically. Operationalizing political participation in terms of electoral and other forms of participation, this article uncovers a large degree of political and civic inequality across different demographic and socioeconomic groups in Kathmandu. Findings suggest that civic engagement encourages participation in other political activities, which in turn contributes to electoral participation. The identification of the specific characteristics of political and civic participants provides important policy implications for maximizing electoral participation.
Political Narratives and Political Reality
Authors: Shenhav Shaul R.
Published: August 2006

This article develops directions of thought for evaluating how faithfully political narratives represent “political reality,” and suggests several strategies for performing this evaluation. Based on a discussion of these strategies it claims that the concept of political narrative can be used by scholars with an entire range of perspectives or “basic views,” and not only by those who adhere to a radical relativism. Studying the role of these basic views in the political domain can also facilitate our understanding of the possible coexistence between different political narratives.
Halieutical commons in the Mediterranean: holistic and engendered governance forms for eco-social development pathways
Authors: Collet Serge
Published: August 2006

By setting the uniqueness of inshore coastal fishing communities in the Mediterranean as a social halieutical morphology inscribed in the very long span of time, this article underlines why, without any romanticism, these communities have to be scaled up, valorized. It demonstrates how and why some of these robust communal appropriation forms have worked with a low discount rate, which embeds wisdom of the sea, or halieusophy, based on the principle of giving for keeping. Backed by these successful experiences, the author analyses the trajectories of community re-invention, the pathways of their empowering through the setting up of a new institution, ecomuseums for the sea, as ethically based local governance institutions capable of fine-tuning and improving the relationship between humans and marine entities. In the last, thought-provoking, part, the author raises the question: why does this strategic pathway have to come back to the very essence of the scope of the valuable, i.e. women? And he answers: because women in inshore coastal fishing communities ensure, more than in other communities, the holding and ordering of the fluctuations and contingency in family life, and, at a more ontological level of reflection, they embody a disposition for a long-term time horizon and a nondestruction principle. The governance perspectives in fisheries in their global and local modalities have to be en-gendered.
War and Violence
Authors: Bourke Joanna
Published: August 2006

The brutalities of the past century have taken place in the milieu of Enlightenment values. At present, even the ideals of human rights have been used to (at the very least) tolerate and (and at its worst) justify barbaric acts, such as torture. This article interrogates the diverse ways British, American, and Australian individuals engaged in extremes of violence during three major conflicts of the 20th century. Like servicemen and servicewomen today, these combatants struggled to find a language capable of making sense of their violent deeds. Constraining their excesses of violence proved a formidable task. In particular, I examine the ways in which sexual violence was normalized. Finally, on returning home after the war, these individuals and civilian society more broadly struggled with the problem of ‘remembering’ wartime violence in the post-war world. The act of ‘framing’ extremes of violence was integral to the process of enabling perpetrators of violence to assimilate his or her acts into a peacetime self.