bluuebunny/crossref_metadata_2025 huggingface dataset:
Aberrant Expression of a Disintegrin and Metalloproteinase 17/Tumor Necrosis Factor-α Converting Enzyme Increases the Malignant Potential in Human Pancreatic Ductal Adenocarcinoma
Authors: Ringel Jörg , Jesnowski Ralf , Moniaux Nicolas , Lüttges Jutta , Ringel Jens , Choudhury Amit , Batra Surinder K. , Klöppel Günter , Löhr Matthias
Published: September 2006

A disintegrin and metalloproteinase (ADAM) molecules are known for their unique potential to combine adhesion, proteolysis, and signaling. To understand the role of ADAM17/tumor necrosis factor-α (TNF-α) converting enzyme (TACE) in pancreatic ductal adenocarcinoma (PDAC), we investigated its expression, function, and in vitro regulation. ADAM17/TACE mRNA was expressed in 3 of 10 normal pancreatic tissues, 6 of 8 samples from patients with chronic pancreatitis, 10 of 10 PDAC tissues, and 9 of 9 pancreatic cancer cell lines, but it was absent in primary duct epithelial cells. Immunohistochemical staining revealed positive cancer cells in 8 of 10 PDACs but no staining of ducts in normal pancreas. ADAM17/TACE was found in 0 of 16 pancreatic intraepithelial neoplasia (PanIN)-1A lesions, 1 of 30 PanIN-1B lesions, 2 of 13 PanIN-2 lesions but, in 13 of 15 PanIN-3 lesions, associated with PDAC. Western blot, flow cytometry, and confocal microscopy analyses showed the aberrant expression of ADAM17/TACE protein in pancreatic cancer cell lines. The proteolytic activity of ADAM17/TACE, assessed by the release of TNF-α, was inhibited by TNF-α protease inhibitor. ADAM17/TACE gene silencing using small interfering RNA technique in vitro reduced invasion behavior dramatically, whereas proliferation was unaffected. Furthermore, ADAM17/TACE mRNA expression was down-regulated in pancreatic cancer cells arrested in G2-M phase as well as in a time-dependent manner after TNF-α and interleukin-6 incubation. In conclusion, our findings provide evidence of aberrant expression of the proteolytically active ADAM17/TACE in advanced precursor lesions (PanIN-3) and PDAC while identifying its critical involvement in the invasion process. (Cancer Res 2006; 66(18): 9045-53)
Role of p53 Up-regulated Modulator of Apoptosis and Phosphorylated Akt in Melanoma Cell Growth, Apoptosis, and Patient Survival
Authors: Karst Alison M. , Dai Derek L. , Cheng Jin Q. , Li Gang
Published: September 2006

Malignant melanoma is an aggressive and chemoresistant form of skin cancer characterized by rapid metastasis and poor patient prognosis. The development of innovative therapies with improved efficacy is critical to treatment of this disease. Here, we show that aberrant expression of two proteins, p53 up-regulated modulator of apoptosis (PUMA) and phosphorylated Akt (p-Akt), is associated with poor patient survival. Using tissue microarray analysis, we found that patients exhibiting both weak PUMA expression and strong p-Akt expression in their melanoma tumor tissue had significantly worse 5-year survival than patients with either weak PUMA or strong p-Akt expression alone (P < 0.001). Strikingly, no patients exhibiting strong PUMA expression and weak p-Akt expression in primary tumor tissue died within 5 years of diagnosis. We propose a two-pronged therapeutic strategy of (a) boosting PUMA expression and (b) inhibiting Akt phosphorylation in melanoma tumor tissue. Here, we report that a recombinant adenovirus containing human PUMA cDNA (ad-PUMA) efficiently inhibits human melanoma cell survival in vitro, rapidly induces apoptosis, and dramatically suppresses human melanoma tumor growth in a severe combined immunodeficient mouse xenograft model. In melanoma cells strongly expressing p-Akt, we show that Akt/protein kinase B signaling inhibitor-2 (API-2; a small-molecule Akt inhibitor) reduces cell survival in a dose- and time-dependent manner and enhances ad-PUMA-mediated growth inhibition of melanoma cells. Finally, we show that, by combining ad-PUMA and API-2 treatments, human melanoma tumor growth can be inhibited by >80% in vivo compared with controls. Our results suggest that a strategy to correct dysregulated PUMA and p-Akt expression in malignant melanoma may be an effective therapeutic option. (Cancer Res 2006; 66(18): 9221-6)
Anticancer Activity of BIM-46174, a New Inhibitor of the Heterotrimeric Gα/Gβγ Protein Complex
Authors: Prévost Grégoire P. , Lonchampt Marie O. , Holbeck Susan , Attoub Samir , Zaharevitz Daniel , Alley Mike , Wright John , Brezak Marie C. , Coulomb Hélène , Savola Ann , Huchet Marion , Chaumeron Sophie , Nguyen Quang-Dé , Forgez Patricia , Bruyneel Erik , Bracke Mark , Ferrandis Eric , Roubert Pierre , Demarquay Danièle , Gespach Christian , Kasprzyk Philip G.
Published: September 2006

A large number of hormones and local agonists activating guanine-binding protein-coupled receptors (GPCR) play a major role in cancer progression. Here, we characterize the new imidazo-pyrazine derivative BIM-46174, which acts as a selective inhibitor of heterotrimeric G-protein complex. BIM-46174 prevents the heterotrimeric G-protein signaling linked to several GPCRs mediating (a) cyclic AMP generation (Gαs), (b) calcium release (Gαq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Gαo/i and Gαq). BIM-46174 inhibits the growth of a large panel of human cancer cell lines, including anticancer drug-resistant cells. Exposure of cancer cells to BIM-46174 leads to caspase-3-dependent apoptosis and poly(ADP-ribose) polymerase cleavage. National Cancer Institute COMPARE analysis for BIM-46174 supports its novel pharmacologic profile compared with 12,000 anticancer agents. The growth rate of human tumor xenografts in athymic mice is significantly reduced after administration of BIM-46174 combined with either cisplatin, farnesyltransferase inhibitor, or topoisomerase inhibitors. Our data validate the feasibility of targeting heterotrimeric G-protein functions downstream the GPCRs to improve anticancer chemotherapy. (Cancer Res 2006; 66(18): 9227-34)
Death Receptor-3, a New E-Selectin Counter-Receptor that Confers Migration and Survival Advantages to Colon Carcinoma Cells by Triggering p38 and ERK MAPK Activation
Authors: Gout Stéphanie , Morin Chantale , Houle François , Huot Jacques
Published: September 2006

E-selectin-mediated adhesion of colon cancer cells to endothelial cells is a key event in metastasis. However, the signaling mechanisms that confer metastatic advantages to cancer cells adhering to E-selectin are ill defined. By using affinity column chromatography and pull-down assays on purified membrane extracts of HT29 and LoVo cells coupled to mass spectrometry analysis, we obtained the first evidence indicating that E-selectin binds to death receptor-3 (DR3) expressed by the cancer cells. Thereafter, we accumulated several results, suggesting that DR3 is an E-selectin receptor on colon cancer cells and that its activation by E-selectin triggers the activation of p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) and confers migration and survival advantages. First, by Western blotting, we found that the E-selectin-binding protein, identified as DR3, is recognized by two anti-DR3 antibodies. Second, the neutralization of DR3 with an antibody and its knockdown by small interfering RNA decrease the adhesion of colon cancer cells to E-selectin and E-selectin-expressing human umbilical vein endothelial cells. Third, inhibiting DR3 and knocking down its expression impair transendothelial migration of HT29 cells and block the activation of p38 and ERK by E-selectin. Fourth, high molecular weight isoforms of DR3 are expressed in samples of primary human colon carcinoma but not in samples from normal colon tissue. Intriguingly, DR3 is a death receptor but its activation by E-selectin does not induce apoptosis in colon cancer cells, except when ERK is inhibited. Our findings identify novel signaling and functional roles of DR3 activated in response to E-selectin and highlight the potential link between DR3 and metastasis. (Cancer Res 2006; 66(18): 9117-24)
HLA Class I Antigen Down-regulation in Primary Laryngeal Squamous Cell Carcinoma Lesions as a Poor Prognostic Marker
Authors: Ogino Takeshi , Shigyo Hiroshi , Ishii Hideyuki , Katayama Akihiro , Miyokawa Naoyuki , Harabuchi Yasuaki , Ferrone Soldano
Published: September 2006

We have investigated the role of antigen-processing machinery (APM) component defects in HLA class I antigen down-regulation in laryngeal squamous cell carcinoma (SCC) lesions and assessed the clinical significance of these defects. To this end, 63 formalin-fixed, paraffin-embedded tumor lesions were examined for APM component and HLA class I antigen expression by immunohistochemistry. Calnexin, calreticulin, and ERp57 were down-regulated in ∼25% of the lesions tested, whereas LMP2, TAP1, tapasin, and HLA class I antigens were down-regulated in at least 70% of the lesions tested. LMP2 and tapasin expression was significantly correlated with HLA class I antigen expression suggesting APM component defects as a mechanism underlying HLA class I antigen down-regulation in laryngeal SCC lesions. The expression of most APM components and HLA class I antigens was correlated with the extent of CD8+ T cell infiltration into tumor lesions. Furthermore, LMP2 and HLA class I antigen down-regulation and low CD8+ T cell infiltration were significantly associated with reduced patients' survival. Multivariate analysis identified HLA class I antigen down-regulation as an independent unfavorable prognostic marker. This association is likely to reflect the reduction in the extent of CD8+ T cell infiltration in laryngeal SCC lesions. (Cancer Res 2006; 66(18): 9281-9)
A Mouse Model for the Molecular Characterization of Brca1-Associated Ovarian Carcinoma
Authors: Xing Deyin , Orsulic Sandra
Published: September 2006

Little is known about the mechanisms that underlie Brca1-associated ovarian tumorigenesis, mainly due to the lack of an appropriate experimental model. We developed genetically defined primary mouse ovarian surface epithelial (OSE) cell lines in which the loss of functional Brca1 and p53 recapitulates the events that are thought to occur in early ovarian cancer development in patients with Brca1 mutations. This system allows for the introduction of additional oncogenes that are thought to cooperate with the loss of Brca1 and p53 to induce tumorigenesis. We showed that Myc is sufficient to induce transformation of ovarian cells that are deficient for both Brca1 and p53 but not sufficient for the transformation of cells that are deficient for either Brca1 or p53. The transformed Brca1-deficient OSE cells display an increased number of centrosomes, acquire complex chromosome aberrations, and lack Rad51 nuclear foci in the presence of DNA-damaging agents, such as mitomycin C and cisplatin. Immunocompetent mice injected with transformed OSE cells develop tumors that resemble human metastatic serous ovarian carcinoma, the most common type of ovarian cancer in women. Consistent with the reported platinum chemosensitivity in patients with Brca1-associated ovarian cancer, the Brca1-deficient OSE cells have increased sensitivity to the DNA-damaging agent cisplatin, whereas sensitivity to the microtubule poison paclitaxel is similar between Brca1 wild-type and Brca1-deficient cells. The Brca1 wild-type and Brca1-deficient mouse ovarian tumors and cell lines provide a new experimental system for the evaluation of therapies that target the Brca1 pathway. (Cancer Res 2006; 66(18): 8949-53)
Asynchronous Growth of Prostate Cancer Is Reflected by Circulating Tumor Cells Delivered from Distinct, Even Small Foci, Harboring Loss of Heterozygosity of the PTEN Gene
Authors: Schmidt Hartmut , DeAngelis Gabriela , Eltze Elke , Gockel Iris , Semjonow Axel , Brandt Burkhard
Published: September 2006

The clinical value of prostate-specific antigen (PSA)–positive circulating tumor cells (CTCs) is still a matter of debate and it is also still unclear if these CTCs actually represent the primary tumor. Therefore, we isolated PSA-positive CTCs from the peripheral blood of patients suffering from multifocal cancers and did genetic profiling of each cancer focus by a multiplex PCR–based microsatellite analysis (D7S522, D8S522, NEFL, D10S541, D13S153, D16S400, D16S402, D16S422, and D17S855). In 17 of 20 prostate cancer cases, the loss of heterozygosity (LOH) pattern of the CTCs was identical with only one focus of the primary tumor. Moreover, in six cases, the LOH pattern suggested that smaller foci, down to 0.2 cm3, might deliver CTCs. Interestingly, the highest number of LOHs was observed at the marker D10S541 (85%), the PTEN gene, which was observed much less frequently in unifocal prostate cancer (48%). Furthermore, the infrequently occurring LOH in the BRCA1 gene (38%) was found in four of the five cases where a biochemical recurrence was seen within 3 years after prostatectomy. Therefore, the data might support the assumption that CTCs in prostate cancer are derived from distinct foci of a primary tumor. The size of the tumor focus is not related to the delivery of cells. Although the number of cases that were investigated in this study was small, it might be suggested that the LOH at distinct markers such as D10S541 and D17S855 represent the genes PTEN and BRCA1, which might be associated with the occurrence of CTCs in the peripheral blood of patients as well as an early biochemical recurrence. (Cancer Res 2006; 66(18): 8959-65)
β2-Microglobulin Is a Signaling and Growth-Promoting Factor for Human Prostate Cancer Bone Metastasis
Authors: Huang Wen-Chin , Wu Daqing , Xie Zhihui , Zhau Haiyen E. , Nomura Takeo , Zayzafoon Majd , Pohl Jan , Hsieh Chia-Ling , Weitzmann M. Neale , Farach-Carson Mary C. , Chung Leland W.K.
Published: September 2006

The protein factor β2-microglobulin (β2M), purified from the conditioned medium of human prostate cancer cell lines, stimulated growth and enhanced osteocalcin (OC) and bone sialoprotein (BSP) gene expression in human prostate cancer cells by activating a cyclic AMP (cAMP)–dependent protein kinase A signaling pathway. When β2M was overexpressed in prostate cancer cells, it induced explosive tumor growth in mouse bone through increased phosphorylated cAMP-responsive element binding protein (CREB) and activated CREB target gene expression, including OC, BSP, cyclin A, cyclin D1, and vascular endothelial growth factor. Interrupting the β2M downstream signaling pathway by injection of the β2M small interfering RNA liposome complex produced an effective regression of previously established prostate tumors in mouse bone through increased apoptosis as shown by immunohistochemistry and activation of caspase-9, caspase-3, and cleavage of poly(ADP-ribose) polymerase. These results suggest that β2M signaling is an attractive new therapeutic target for the treatment of lethal prostate cancer bone metastasis. (Cancer Res 2006; 66(18): 9108-16)
Inhibition of Hsp90 Compromises the DNA Damage Response to Radiation
Authors: Dote Hideaki , Burgan William E. , Camphausen Kevin , Tofilon Philip J.
Published: September 2006

Inhibitors of the molecular chaperone Hsp90 have been shown to enhance tumor cell radiosensitivity. To begin to address the mechanism responsible, we have determined the effect of the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG) on the DNA damage response to radiation. Exposure of MiaPaCa tumor cells to 17DMAG, which results in radiosensitization, inhibited the repair of DNA double-strand breaks according to γH2AX foci dispersal and the neutral comet assay. This repair inhibition was associated with reduced DNA-PK catalytic subunit (DNA-PKcs) phosphorylation after irradiation and a disruption of DNA-PKcs/ErbB1 interaction. These data suggest that the previously established 17DMAG-mediated reduction in ErbB1 activity reduces its interaction with DNA-PKcs and thus accounts for the attenuation of radiation-induced DNA-PK activation. 17DMAG was also found to abrogate the activation of the G2- and S-phase cell cycle checkpoints. Associated with these events was a reduction in radiation-induced ataxia-telangiectasia mutated (ATM) activation and foci formation in 17DMAG-treated cells. Although no interaction between ATM and Hsp90 was detected, Hsp90 was found to interact with the MRE11/Rad50/NBS1 (MRN) complex. 17DMAG exposure reduced the ability of the MRN components to form nuclear foci after irradiation. Moreover, 17DMAG exposure reduced the interaction between NBS1 and ATM, although no degradation of the MRN complex was detected. These results suggest that the diminished radiation-induced activation of ATM in 17DMAG-treated cells was the result of a compromise in the function of the MRN complex. These data indicate that Hsp90 can contribute to the DNA damage response to radiation affecting both DNA repair and cell cycle checkpoint activation. (Cancer Res 2006; 66(18): 9211-20)
The Archaeabacterial Flagellar Filament: A Bacterial Propeller with a Pilus-Like Structure
Authors: Trachtenberg Shlomo , Cohen-Krausz Sara
Published: September 2006

Common prokaryotic motility modes are swimming by means of rotating internal or external flagellar filaments or gliding by means of retracting pili. The archaeabacterial flagellar filament differs significantly from the eubacterial flagellum: (1) Its diameter is 10–14 nm, compared to 18–24 nm for eubacterial flagellar filaments. (2) It has 3.3 subunits/turn of a 1.9 nm pitch left-handed helix compared to 5.5 subunits/turn of a 2.6 nm pitch right-handed helix for plain eubacterial flagellar filaments. (3) The archaeabacterial filament is glycosylated, which is uncommon in eubacterial flagella and is believed to be one of the key elements for stabilizing proteins under extreme conditions. (4) The amino acid composition of archaeabacterial flagellin, although highly conserved within the group, seems unrelated to the highly conserved eubacterial flagellins. On the other hand, the archaeabacterial flagellar filament shares some fundamental properties with type IV pili: (1) The hydrophobic N termini are largely homologous with the oligomerization domain of pilin. (2) The flagellin monomers follow a different mode of transport and assembly. They are synthesized as pre-flagellin and have a cleavable signal peptide, like pre-pilin and unlike eubacterial flagellin. (3) The archaeabacterial flagellin, like pilin, is glycosylated. (4) The filament lacks a central channel, consistent with polymerization occurring at the cell-proximal end. (5) The diameter of type IV pili, 6–9 nm, is closer to that of the archaeabacterial filament, 10–14 nm. A large body of data on the biochemistry and molecular biology of archaeabacterial flagella has accumulated in recent years. However, their structure and symmetry is only beginning to unfold. Here, we review the structure of the archaeabacterial flagellar filament in reference to the structures of type IV pili and eubacterial flagellar filaments, with which it shares structural and functional similarities, correspondingly.
Cytoskeletal Elements in Bacteria Mycoplasma pneumoniae, Thermoanaerobacterium sp., and Escherichia coli as Revealed by Electron Microscopy
Authors: Mayer Frank
Published: September 2006

Recently, electron microscopic studies on the eubacteria Mycoplasma pneumoniae, Thermoanaerobacterium sp., and Escherichia coli have revealed the existence of cytoskeletal elements so far unknown in prokaryotes. The wall-less bacterium M. pneumoniae contains, in close vicinity to the inner face of the cytoplasmic membrane, a helically organized lining composed of protein elements that form a regular network of meshes that encloses the entire cytoplasm. Numerous regularly spaced pin-like structural elements, the stalks with terminal knobs, connect the lining with the cytoplasmic membrane. In this bacterium, a specific rod-like structural element is located in the tip region. Occasionally, it is bent or twisted. It consists of two matching blade-like sub-elements. A number of parallel linkers, extending from the edges of the rod, make contact with the lining. The proximal end of the rod is attached to a wheel-like complex. Fibrils originating from the wheel cross the cytoplasm and make contact with the lining. E. coli contains a similar helically organized lining close to the inner face of the cytoplasmic membrane. Groups of ribosomes (polysomes) were seen to be attached to the helical elements of the lining. A feature that is common to both bacteria and to Thermoanaerobacterium sp. appears to be that the lining and the fibrils crossing the cytoplasm contain a high number of copies of the bacterial elongation factor Tu (EF-Tu). This indicates that this protein may play an important role as a structural element in bacterial cytoskeletons. This notion was supported by experiments in which the cytoskeleton in E. coli was destabilized by induced expression of truncated EF-Tu, with the consequence of cell lysis, and by the finding that in vitro polymerization of monomeric EF-Tu into protofilaments was hindered in a mixture of full-size EF-Tu and truncated EF-Tu consisting of domain 3 only. Current research and developmental efforts are aimed at the design of a new class of antibacterial drugs, acting by destabilization of the EF-Tu-containing bacterial cytoskeleton, and of an innovative mode of inducible lysis of recombinant bacteria by controlled destabilization of the EF-Tu-containing cytoskeleton.
Cytoskeleton of Mollicutes
Authors: Miyata Makoto , Ogaki Hiroshi
Published: September 2006

Mollicutes are a class of bacteria that lack a peptidoglycan layer but have various cell shapes. They perform chromosome segregation and binary fission in a well-organized manner. Especially, species with polarized cell morphology duplicate their membrane protrusion at a position adjacent to the original one and move the new protrusion laterally to the opposite end pole before cell division. The featured various cell shapes of Mollicutes are supported by cytoskeletal structures composed of proteins. Recent progress in the study of cytoskeletons of walled bacteria and genome sequencing has revealed that the cytoskeletons of Mollicutes are not common with those of other bacteria. Mollicutes have special cytoskeletal proteins and structures that are sometimes not shared even by other mollicute species.
The Cytoskeleton of Spiroplasma: A Complex Linear Motor
Authors: Trachtenberg Shlomo
Published: September 2006

Spiroplasma are wall-less, helical bacteria from the class Mollicutes. The Mollicutes (Mycoplasma, Acholeplasma, Spiroplasma) evolved by regressive evolution to generate one of the simplest and minimal free-living and self-replicating forms of life. The spiroplasmas are the more advanced members in the class and are the closest to their clostridial ancestors. Spiroplasmas were discovered and identified as such only in 1972 and the finding of a unique and well-defined internal cytoskeleton, believed to be uncommon in bacteria, followed in 1973. Structural analysis suggests that the core of the spiroplasmal cytoskeleton is a flat, monolayered ribbon comprised of the 59-kDa fib gene product. The ribbon follows the shortest helical line of the polar cell from end to end. The structural building blocks of the cytoskeletal ribbon are fibrils assembling into a structure with ∼10-nm axial and lateral repeats. Differential length changes of the fibrils may generate a wide dynamic spectrum of helical and non-helical geometries allowing for directional motility in low Reynolds number environments. The presence of other cytoskeletal elements (FtsZ, FtsA, EF-TU, MreB) has been demonstrated only recently in Spiroplasma cells. The cellular and molecular structure and dynamics of spiroplasmas and their cytoskeletal elements are reviewed.
Mild Cognitive Impairment: What’s in a Name?
Authors: Dierckx E. , Engelborghs S. , De Raedt R. , De Deyn P.P. , Ponjaert-Kristoffersen I.
Published: September 2006

Background: Nowadays the term mild cognitive impairment (MCI) is used to fill the gap between cognitive changes associated with normal ageing and those associated with dementia. Despite some agreement in general definitions, MCI is still a heterogeneous clinical syndrome for which no DSM-IV criteria have yet been established. Criteria by Petersen et al. are presently the most applied in clinical practice. Moreover, little attention has been paid to the specific relation between MCI and depression. Objective: This review highlights some concerns about the concept of MCI and provides guidelines within the field of neuropsychology to solve them. In a second part, the paper focuses on the specific relationship between depression in the elderly and MCI. Results: We hypothesize that certain test instruments can be used to operationalize the criteria proposed by Petersen et al. Moreover, we suggest that cued recall might be of help to differentiate between progressive and non-progressive MCI. Concerning the specific relation between depression and MCI, we assume that elderly depression with concomitant cognitive problems can be seen as an MCI. Conclusion: The proposed adjustments and additions (neuropsychological instruments and the incorporation of depressive symptoms) in the diagnostic flowchart of Petersen may serve as useful tools for clinicians when making a diagnosis of MCI.
Low-Dose Oxaliplatin Enhances the Antitumor Efficacy of Paclitaxel in Human Gastric Cancer Cell Lines
Authors: Gu Jinyu , Yamamoto Hirofumi , Lu Xueying , Ngan Chew Yee , Tsujino Tadashi , Konishi Ken , Takemasa Ichiro , Ikeda Masataka , Nagata Hiroshi , Hashimoto Shusuke , Matsuzaki Takeshi , Sekimoto Mitsugu , Takagi Akimitsu , Monden Morito
Published: September 2006

Background: The enhanced antitumor effect of paclitaxel when used with oxaliplatin in gastric cancer is reported, however the underlying biological mechanism is unknown. Methods: We tested the cytotoxic activity, apoptosis, and mitotic catastrophe of paclitaxel and oxaliplatin in MKN-28 and MKN-45 gastric cancer cell lines. The modulation of survivin expression was determined by Western blotting. Results: WST-1 assay indicated that paclitaxel plus oxaliplatin showed better cytotoxicity than paclitaxel alone, even when low concentrations of oxaliplatin were used. Flow cytometry analysis revealed significantly greater increases in apoptotic cells after treatment with paclitaxel followed by low-dose oxaliplatin (1 µM) than after any single-reagent regimen in the MKN-45 cell line. In MKN-28, a difference existed only between combination treatment and oxaliplatin treatment. Morphologic examination showed that the cells undergoing mitotic catastrophe were highest in the combination groups in the both cell lines. Downregulation of survivin expression was found by Western blotting with treatment by paclitaxel, oxaliplatin, or their combination. Conclusion: Our findings suggest that the mechanism of enhanced cytotoxicity might be through enhanced mitotic catastrophe and apoptosis, which is possibly due to chemotherapy-induced downregulation of surviving. The combination of paclitaxel and low-dose oxaliplatin should be incorporated into the design of a clinical trial.
Physical activity and diet relative to socio-economic status and gender in British young people
Authors: Thomas Non-Eleri , Cooper Stephen-Mark , Baker Julien S , Davies Bruce
Published: September 2006

Objective This study considers the physical activity (PA) and dietary habits of British young people according to socio-economic status (SES).

Methods The PA and dietary habits of 98 boys and 101 girls (12.9 0.3 years) from two Welsh secondary schools (school 1 and school 2) were examined. Free school meal eligibility and Census 2001 data were used as indicators of SES. School 1 was designated high SES, while school 2 represented low SES. Participants were classified according to SES. Physical activity was estimated by seven-day recall and questionaire; dietary patterns were assessed using a seven-day food diary and questionnaire.

Results Two-thirds of all participants had not taken part in vigorous activity over the last week. Furthermore, 83.8 per cent of participants did not meet the Health Education Authority's5 recommendation of one hour per day moderate activity. Boys were more active than girls, (P ≤ 0.05), but SES did not influence time spent in activity. Ninety-four percent of participants were taken to school via motorized transport. There were no significant differences in fat intake between the sexes or across SES. In addition, 93 per cent of the participants, irrespective of SES, exceeded the 10 per cent saturated fat cut off point recommended by the World Health Organization12

Conclusion Physical activity and dietary patterns are modifiable through suitable lifestyle changes. The present data support the notion that preventative strategies for combating chronic diseases should begin early in life and across socio-economic statuses.
To what extent are school drop-in clinics meeting pupils' self-identified health concerns?
Authors: Kay C M , Morgan D L , Tripp J H , Davies C , Sykes S
Published: September 2006

Objective This paper explores young peoples' health concerns and their knowledge and views of school nurse drop-in clinics (drop-ins) held in their schools.

Design Cross section survey of adolescents using questionnaires delivered in schools to 10 per cent of the population, and school drop-in monitoring data from the Primary Care Trust (PCT).

Setting 11 secondary schools in a suburban south-east London borough.

Method Data from 590 11-17 year olds were used to determine their health concerns, sources of advice for health concerns, views and peceptions of their school based drop-in clinics, and attendance at these clinics.

Results Young people have a number of health concerns, notably in the area of inter-personal issues, emotional heath and well-being; however, few had sought help with these. Awareness of school based drop-ins was high but knowledge of times and locations was patchy. The droins were viewed positively, especially by users. Issues such as timing of drop-ins, their location and confidentiality were raised by students. Most consultations were dealt with by support or advice from the school nurse. Monitoring data suggested the service may be under-used but those who did attend often returned. Sixty-two per cent of students felt drop-ins were an important service in schools, this rose to 92 per cent among those who had accessed the service.

Conclusion: School based drop-ins offer a valuable service but need planing and promotion to achieve good attendance figures. A school droin may be the first time a young person has accessed any health care setting by themselves and valuable transferable skills may be learnt.
Project MAINSTREAM's first fellowship cohort: Pilot test of a national dissemination model to enhance substance abuse curriculum at health professions schools
Authors: Brown Richard L , Marcus Marianne T , Lal S , Straussner A , Graham Antonette V , Madden Theresa , Schoener Eugene , Henry Rebecca
Published: September 2006

Objective Generalist health professional training on substance abuse prevention is patchy. This study assessed the effects of Project MAINSTREAM, a national interdisciplinary faculty development fellowship program, whose principal objective was to enhance curriculum on basic substance abuse services at health professions training institutions. Five interdisciplinary teams of three health professions' faculty were selected as fellows. This study assessed changes in curriculum, training, fellows' knowledge, and fellows' academic productivity in substance abuse.

Design Pre and post-program surveys and interviews were administered.

Setting Fellows were located in five cities in the USA.

Method The two-year, part-time training program featured training meetings, on-site and distance mentoring, and internet-based instructional materials. Principal learning activities consisted of developing independent projects in curriculum enhancement and prevention services delivery.

Results Fellows implemented 45 distinct curricula, providing 19,000 hours of new instruction to over 5000 trainees. Over 80 per cent of the training occurred as required curricular experiences. Fellows' academic accomplishments included five peer-reviewed publications, seven additional submitted papers, 78 presentations, and 23 awards or appointments. Fellows' knowledge increased significantly.

Conclusions Project MAINSTREAM shows promise as a national model for enhancing health professional training on substance abuse.
The experience of condom use and other sexual risk practices among male brewery employees who recently migrated in Nigeria
Authors: Sunmola Adegbenga M , Adebayo Dada , Olapegba Makinde , Alarape Aderemi
Published: September 2006

Objective To identify factors that predict condom use and sexual practices of brewery employees who had recently been on short- and longterm migration in the course of their jobs in Nigeria.

Design A cross-sectional survey design was adopted to investigate the relationship between sexual practices and condom use of migrant employees, and to determine the predictors of condom use at last intercourse during migration.

Setting The study was conducted in a large multinational brewery in Nigeria with operational locations in various parts of the country.

Method A sample of 936 male employees was selected consecutively in the brewery in 2002. They were independently invited to respond to a questionnaire consisting of items that covered background characteristics, condom use and sexual experiences.

Results The findings showed that 40 per cent of participants reported they were using alcohol occasionally prior to sex and 54 per cent reported that they either received or paid money for sex. Forty-seven per cent of men indicated that they used condoms at their last intercourse during migration, while 62 per cent had had one to three sexual partners during their last migration. The odds of using a condom at last intercourse were significantly lower for married than for single participants (odds ratio, 0.57). Compared with participants without the intention to use a condom in next intercourse during migration, those with the intention were significantly more likely to report condom use (odds ratio, 9.7). The odds of condom use were significantly higher for participants who perceived that a condom prevents HIV transmission than those who either did not have the perception or were not sure (odds ratio, 0.30-1.80).

Conclusion Steps are needed to promote condom use among brewery employees on migration. Intervention programmes aimed to enhance condom use among prospective migrant employees may be more effective if they provide opportunities for the employees to think about the advantages of condoms in sexual encounters under migration conditions.
Pharmacokinetics of Desmopressin Administrated as an Oral Lyophilisate Dosage Form in Children With Primary Nocturnal Enuresis and Healthy Adults
Authors: Østerberg Ole , Savic Radojka M. , Karlsson Mats O. , Simonsson Ulrika S. H. , Nørgaard Jens Peter , Walle Johan Vande , Agersø Henrik
Published: September 2006

The population pharmacokinetics of desmopressin in children with nocturnal enuresis and in healthy adults were compared using a 1‐compartment model with first‐order absorption and first‐order elimination. In addition, the model consisted of a number of transit compartments before absorption to describe a lag‐time. The model gave an adequate description of adult as well as children data and provided a statistically significant better fit to data than a standard lag‐time model. The main difference in the pharmacokinetics between children and adults was the absorption delay. The pharmacokinetic difference was minor and presumably of no clinical relevance.
Exile and Nationalism: The Case of the Risorgimento
Authors: Isabella Maurizio
Published: September 2006

Italian nationalism was essentially the product of exile, as most Risorgimento patriots lived and published their work abroad after successive failed revolutions. Exile was turned by political refugees into one of the foundational myths of the Risorgimento as the narrative of the Italian nation fighting for independence. The article examines the different aspects of the representation of exile in political and literary texts, which justified exile as the only choice available when faced with despotism at home. It surveys the research on exile published after independence, and highlights how the mythical interpretation of exile developed in the Risorgimento-influenced historiography until the post-war period. Finally, it suggests that in order to understand the effects of exile on Italian identity formation, we need to study Italian nationalism as part of trans-national intellectual exchanges.
The Cumulative Effect of Rural and Regional Residence on the Health of Older Adults
Authors: Ziembroski Jessica S. , Breiding Matthew J.
Published: September 2006

Objective: This study considers whether rural status or living in a particular region of the United States has effects on mental and physical health. The analyses examine whether there are independent and interactive effects of rural status and region of residence on health, beyond individual level factors related to poverty. Methods:Ordinary least squares (OLS) regression models are used to examine the relationships between rural and regional residence and health across three time periods. Results: Negative health effects of rural residence were found only in the South region. Positive health effects of rural residence were found only in the Midwest region. There are no observed health risks associated with rural or regional residence across group. Discussion: The results indicate a cumulative risk of rural and Southern residence for older men and women. Living in a rural place in the midwestern United States seems to provide unique sources of health benefits.
Development of a Screening Tool for Identifying Elderly People at Risk of Abuse by Their Caregivers
Authors: Cohen Miri , Halevi-Levin Sarah , Gagin Roni , Friedman Gideon
Published: September 2006

Objective: This study developed and assessed an instrument to identify older people at high risk of abuse based on Reis and Nahmiash's Indicators of Abuse (IOA) screen. Method: A total of 108 people 65 and older, hospitalized in internal medicine departments at two major hospitals in Israel, were screened together with their principal caregivers. The interview was based on the expanded IOA (E-IOA) and a list of evident signs of abuse. Results: Reliability and validity of the E-IOA were tested and confirmed. Indicators proved to be a significant predictor of evident signs of abuse. The E-IOA correctly discerned 92.7% of those at high risk for abuse and 97.9% of those who did not suffer abuse. The main indicators for risk were behavioral problems, emotional problems, and family problems of the caregiver and the elderly person. Fourteen (13%) experienced abuse. Discussion: The proposed assessment tool can be an instrumental guide to identify elderly people who suffer abuse (unidentified) or who are at high risk.
Elderly Veterans' Beliefs Concerning Life-Sustaining Treatment and the Control of Their End-of-Life Health and Health Care
Authors: Rodriguez Keri L. , Young Amanda J.
Published: September 2006

Objective: This study used qualitative methods to explore patients' beliefs about control of their end-of-life health and health care. Method: The authors recruited 30 elderly patients from a large, urban Veterans Administration medical center in the United States and engaged them in semistructured interviews about end-of-life care concepts. Using grounded theory methods, they coded, categorized, and compared responses. Results: The authors discovered that patients' decisions about using life sustaining treatment were interconnected with their beliefs about their degree of control over circumstances and the role of external factors, including a higher power; institutions and individuals; medical interventions; medical conditions; and luck, chance, or fate. Discussion: The results shed light on why patients do or do not take active roles in advance decisions concerning the use of life-sustaining treatment.
Comparison of Data Quality for Reports and Ratings of Ambulatory Care by African American and White Medicare Managed Care Enrollees
Authors: Fongwa Marie N. , Cunningham William , Weech-Maldonado Robert , Gutierrez Peter R. , Hays Ron D.
Published: September 2006

Objective: Compare missing data and reliability of health care evaluations between African Americans and Whites in Medicare managed care health plans. Method: Consumer Assessment of Healthcare Providers and Systems (CAHPS) 3.0 health plan survey data collected from 109,980 Medicare managed care enrollees (101,189 Whites, 8,791 African Americans) in 321 plans. Participants self-administered the survey and four single-item global ratings of care. Results: Missing data rates were significantly higher for African Americans than Whites on all CAHPS items ( p < .0001). Internal consistency reliability estimates for the CAHPS scales did not differ significantly between African Americans and Whites, but plan-level reliability estimates for the scales and global rating items were significantly lower for African Americans than Whites. Discussion: Higher missing data rates and lower plan-level reliability estimates for African American Medicare managed care enrollees suggest caution in making race/ethnicity comparisons. Future efforts are needed to enhance the quality of data collected from older African Americans.
Predictors of Self-Assessed Health, Anxiety, and Depressive Symptoms in Nursing Home Residents at Week 1 Postrelocation
Authors: Keister Kathy J.
Published: September 2006

Objective: The purpose of this study was to determine if person factors, situation factors, and cognitive appraisal predict health outcomes during the first week postrelocation in older adults relocating to a nursing home.Method: Data were collected using face-to-face interviews with a convenience sample of 114 older adults. The study was guided by Lazarus and Folkman’s stress-appraisal-coping framework. Results: Hierarchical regression analyses accounted for 12% of the variance in self assessed health, 48% of the variance in anxiety, and 55% of the variance in depressive symptoms. For all three health outcomes, at least one type of cognitive appraisal provided additional explanation of the dependent variable beyond that of the person and situation factors. Discussion: The findings provide additional empirical evidence for Lazarus and Folkman’s stress-appraisal-coping framework. Findings from this study emphasized the importance of mastery, social support, and cognitive appraisal of the older adult relocating successfully to a nursing home.
The Role of Pain in the Recovery of Instrumental and Social Functioning After Hip Fracture
Authors: Williams Christianna S. , Tinetti Mary E. , Kasl Stanislav V. , Peduzzi Peter N.
Published: September 2006

Objective: It is critical to identify modifiable factors associated with functional recovery from hip fracture. The authors examined the association between pain intensity and two functional endpoints—instrumental activities of daily living and social activity participation—after hip fracture. Method: A total of 270 cognitively intact, community-dwelling persons older than 65 who underwent surgical hip fracture repair in New Haven, Connecticut, were followed for 12 months. Results: Pain intensity was strongly negatively associated with both instrumental and social functioning ( p values < .001). Increases in pain intensity between 6 and 12 months were also associated with concurrent decreases in function ( p values < .001). These relationships were partly explained by depressive symptoms and a marker of physical ability—gait speed. Discussion: Interventions to control pain may enhance functional status after hip fracture; however, pain relief must be maintained to sustain recovery. Attention to the complex relationships among pain, depressive symptoms, and physical impairments should inform intervention development.
The horse has already bolted
Authors: Thomson Mark
Published: September 2006

Another media lawyer argues that "The PCC code is...changing and being updated, but to me one glaring omission is the lack of any obligation to notify an intended target of the gist of any story prior to publication. This should be included as simple matter of fairness and decency but could also avoid costly mistakes for the publications involved. Maybe this should be the new clause 1 of the PCC code." And he concludes: "The major flaw in the regulatory system is that the regulators have no power to stop broadcast or publication. The only remedy is adjudication, by which time the information has already been published and the damage done."
La littérature en archipel ou le retour de l’Insulaire
Authors: Lestringant Frank
Published: September 2006

L’archipel est la figure géographique de la diaspora. On voudrait ici interroger les ‘fictions en archipel’, dont la fragmentation narrative épouse un ordre cartographique ouvert. Ce propos fait suite à celui qui a été exposé dans Le Livre des îles (Lestringant, 2002), tout en l’élargissant vers la littérature du XXe siècle, jusqu’au Petit Prince de Saint-Exupéry, au Voyage en Grande Garabagne d’Henri Michaux et aux Villes invisibles de Calvino. L’archipel comme figure du multiple et de l’inachèvement, devient, par voie de métaphore, l’image d’une littérature éclatée.
Phenomenology in Diaspora
Authors: James Ian
Published: September 2006

This article examines Paul Virilio’s account of modern technology and situates it in relation to the phenomenology of Edmund Husserl, and, in particular, to the account of technology and the life-world given in his major work of the 1930s, The Crisis of European Sciences and Transcendental Phenomenology. Against the accusations levelled by Alan Sokal and Jean Bricmont that Virilio abuses scientific terminology and concepts, this piece argues that Virilio’s theories can only be understood as an instance of a very specific French reception of German phenomenology. In particular it argues that, for Virilio, modern forms of transport and data transmission transform individual and collective experience of space. Virilio highlights a transformation in the structure of geopolitical global space which overturns the traditional opposition of origin and exile, centre and periphery, governing the experience of diaspora and with that the notion of departure or dispersal which it implies.
Paradox in the Pursuit of a Critical Theorization of the Development of Self in Family Relationships
Authors: Hollway Wendy
Published: September 2006

This article starts with my dissatisfaction with the post-structuralist treatment of the production of subjectivity within regulatory discourses and practices due to its neglect of psychological processes. Taking starting points from within the history set out in the previous article, it highlights the paradox for critical psychologists like myself involved in both applying a post-structuralist critique to ‘psy’ discourses and trying to theorize subjectivity in a way that goes beyond the dualism of individual and society, of psychology and sociology. The relational, or intersubjective, approach to self that originates in object relations psychoanalysis as it emerged in the mid-20th-century UK is central to both of these activities; object of the former and resource for the latter. I explore the paradox that this creates for critical psychology, both epistemological and ontological. In aiming to provide a psycho-social account of self in family relationships, I deploy the radical conceptualization of intersubjectivity initiated in British object relations theory as a way of going beyond both the individualized self and the neglect of psychological processes in constructionist theorizing subjectivity.