bluuebunny/crossref_metadata_2025 huggingface dataset:
Promotion of intestinal tumor formation by inulin is associated with an accumulation of cytosolic β‐catenin in Min mice
Authors: Pajari Anne‐Maria , Rajakangas Johanna , Päivärinta Essi , Kosma Veli‐Matti , Rafter Joseph , Mutanen Marja
Published: July 2003

Inulin, polydisperse β (2‐1) fructan, has been suggested to protect against colon carcinogenesis and is currently used in a number of food applications. However, the data regarding the role of inulin in intestinal carcinogenesis remains controversial since the results of our previous study suggested that inulin promotes intestinal tumor formation in Min mice, an animal model for intestinal cancer with a mutation in the Apc tumor suppressor gene (Carcinogenesis 2000;21:1167–73). In our present study, we further examined the effects of inulin on intestinal tumor formation in Min mice by carefully analyzing β‐catenin expression and cellular localization at 3 different time points during the tumorigenic process. Min mice were fed a high‐fat inulin‐enriched (10% w/w) diet or the high‐fat diet without any added fiber from the age of 6 weeks to the ages of 9, 12 or 15 weeks. The results showed that inulin significantly increased the number (by 20%) and especially the size (by 44%) of adenomas in the small intestine. At week 15, the promotion of tumor development was accompanied by an accumulation of cytosolic β‐catenin in the adenoma tissue. In the normal appearing mucosa, levels of membrane β‐catenin and PCNA were reduced in the inulin‐fed mice, possibly indicating impaired enterocyte migration. These data do not support the earlier suggestions on the cancer preventive effects of inulin and emphasize the need for further research and evaluation where health claims for inulin are concerned. © 2003 Wiley‐Liss, Inc.
Prognostic value ofERBBfamily mRNA expression in breast carcinomas
Authors: Bièche Ivan , Onody Peter , Tozlu Sengül , Driouch Keltouma , Vidaud Michel , Lidereau Rosette
Published: July 2003

The ErbB‐driven autocrine growth pathway has been implicated in the development and progression of most common human epithelial malignancies; its blockade is therefore a promising therapeutic strategy, and several candidate drugs are currently undergoing clinical trials. Paradoxically, little is known of the expression pattern of these 4 genes in human tumors, and the clinical significance of the 2 most recently discoveredERBBgenes,ERBB3andERBB4, is unclear. We used a real‐time quantitative RT‐PCR assay to quantifyERBBfamily mRNA copy numbers in a large series of breast tumors from patients with known long‐term outcome.ERBBgene expression varied widely, by more than 2 orders of magnitude forERBB1andERBB3, more than 3 orders forERBB2and more than 4 orders forERBB4. We found a positive correlation betweenERBB3andERBB4mRNA levels, and a negative correlation between the expression of these 2 latter genes and that ofERBB1. Compared to normal breast tissue,ERBB1was underexpressed (82.3% of tumors),ERBB2(16.9%) andERBB3(46.2%) were overexpressed andERBB4was both underexpressed (24.6%) and overexpressed (29.2%). Links were also found betweenERBBstatus on the one hand and Scarff‐Bloom‐Richardson (SBR) histopathological grade and estrogen receptor alpha (ERa) status on the other hand. Relapse‐free survival (RFS) was shorter among patients withERBB3‐overexpressing tumors (p=0.0092) and longer among those withERBB4‐underexpressing tumors (p=0.0085) relative to patients with normal expression of the respective genes; in contrast, RFS was not significantly influenced byERBB1orERBB2mRNA status. OnlyERBB4status retained prognostic significance in Cox multivariate regression analysis (p=0.015). Our results point to the involvement of several ErbB‐specific ligands (amphiregulin and neuregulin 1) and enzymes or adaptor molecules (PI3K, Src, Shc and Grb7) in the ErbB pathway dysregulation associated with breast cancer. These findings reveal a complex expression pattern ofERBBgene family members in breast tumors and suggest that it is this pattern of expression, rather than the expression of individual family members, that should be taken into account when evaluating antitumoral drugs designed to target these receptors. © 2003 Wiley‐Liss, Inc.
Phagocytosis by dendritic cells rather than MHC IIhigh macrophages is associated with skin tumour regression
Authors: Byrne Scott N. , Halliday Gary M.
Published: July 2003

Dendritic cells (DC) are important for the induction of anti‐tumour immunity and are currently being used in clinical trials. Whether DC in tumours behave the same as DC in normal tissues or whether the tumours subvert DC phenotype and function remains unknown. To address this, we have used a unique animal tumour model to compare the DC infiltrating regressing tumours with the DC infiltrating progressing skin tumours. Compared to progressor tumours, the regressor tumours were infiltrated by greater numbers of DC that were also less mature, based on MHC II expression. Apart from this, the phenotype of DC in both tumours was similar. However, compared to various control DC, they could not be classed as either mature or immature. Similar to terminally maturated DC but in contrast to fresh DC, tumour‐derived DC did not express CCR5 or CXCR4, suggesting that they most closely resembled terminally matured DC. Macrophages that expressed high MHC II levels were found infiltrating progressor but not regressor tumours and in vivo were the major phagocytic cell. In contrast, DC were found to be the major phagocytic cell in regressor tumours. The results show that immune destruction and eventual regression of skin tumours occurs if DC rather than MHC IIhigh macrophages are the major phagocytic cell. © 2003 Wiley‐Liss, Inc.
Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889
Authors: Endo Mika , Miwa Masanori , Eda Hiroyuki , Ura Masako , Tanimura Hiromi , Ishikawa Tohru , Miyazaki‐Nose Taeko , Hattori Kazuo , Shimma Nobuo , Yamada‐Okabe Hisafumi , Ishitsuka Hideo
Published: July 2003

Capecitabine is an orally available fluoropyrimidine and is finally converted to 5‐FU selectively in tumor tissues. In our study, we examined whether the antitumor activity of capecitabine is directly affected by a modulation of dihydropyrimidine dehydrogenase (DPD). The modulations were carried out by the overexpression of DPD in tumor cells and by tumor selective DPD inhibition. The DPD‐overexpressing cells were obtained by transfection of human DPD cDNA into HCT116 human colorectal cancer cells. The HCT116 cells bearing DPD cDNA expressed about 13 times higher DPD activities than the parental HCT116 cells, and they became significantly less susceptible to capecitabine than the parental cells when transplanted into nude mice. Administration of RO0094889 that is converted to a DPD inhibitor 5‐vinyluracil selectively in tumor tissues restored the antitumor activity of capecitabine against the tumor of the HCT116 cells carrying DPD cDNA and various tumors expressing DPD. As compared to 5‐ethynyluracil or 5‐vinyluracil, which inhibited DPD not only in tumor tissues but also in other non‐cancerous tissues, the effective dose range of RO0094889 in augmenting the efficacy of capecitabine was much broader. These results indicate that the antitumor activity of capecitabine is directly affected by DPD activities in tumor tissues and therefore, the combination of capecitabine and a tumor selective DPD inhibitor, RO0094889, will be beneficial to patients who have tumors with high levels of DPD. © 2003 Wiley‐Liss, Inc.
Energy restriction and the risk of spontaneous mammary tumors in mice: A meta‐analysis
Authors: Dirx Miranda J.M. , Zeegers Maurice P.A. , Dagnelie Pieter C. , van den Bogaard Ton , van den Brandt Piet A.
Published: July 2003

Our meta‐analysis was aimed at providing a systematic review of the literature regarding the effect of energy restriction on spontaneous mammary tumors in mice and at providing a more precise pooled (summary) estimate of the risk of mammary tumors. A sensitivity analysis was conducted to obtain insight in potential heterogeneity between the animal studies. A literature search was conducted with the following terms to identify relevant articles: animal studies, mammary tumors, fat restricted, dietary carbohydrates, energy restriction and calorie restriction. A criteria list for the assessment of quality items (i.e., study characteristics) in animal experiments was developed that was intended to quantitatively assess potential factors that underlie heterogeneous results of different animal experiments. Incidence figures were used to calculate the risk difference. The pooled risk difference was calculated by random effects meta regression analysis. Fourteen animal experiments were included in this meta‐analysis. Publication bias could not be identified. The pooled risk difference for the 14 studies was −0.55 with a narrow 95% confidence interval (−0.69; −0.41), implying that the energy‐restricted animal groups developed 55% less mammary tumors than the control groups. No heterogeneity could be detected between the studies based on study characteristics that included the age of mice at the start of intervention, duration of intervention, allocation of the mice, use of ad libitum control group, fertility of the mice and the type of energy‐providing nutrient (fat, carbohydrate or protein). This meta‐analysis confirms that energy restriction in itself consistently protects against the development of mammary tumor in mice, irrespective of the type of restricted nutrient or other study characteristics. © 2003 Wiley‐Liss, Inc.
Human pHyde is not a classical tumor suppressor gene in prostate cancer
Authors: Porkka Kati P. , Nupponen Nina N. , Tammela Teuvo L.J. , Vessella Robert L. , Visakorpi Tapio
Published: July 2003

A novel putative tumor suppressor gene, pHyde, was recently cloned from rat prostate. The rat gene has been shown to inhibit prostate cancer cell proliferation both in vitro and in vivo. However, the role of human pHyde in prostate cancer has not been studied before. Here, we analyzed human prostate cancer cell lines (LNCaP, DU145, PC‐3, 22Rv1), xenografts (LuCaP 23.1, 35, 41, 49, 58, 69, 70 and 73) and clinical prostate carcinomas for genetic alterations and expression of pHyde. The expression of pHyde in normal human tissues as well as in prostate cancer was studied by Northern analysis and real‐time quantitative RT‐PCR. It was ubiquitously expressed in all normal tissues analyzed. Although, the expression was significantly (p=0.007) lower in poorly differentiated than in well and moderately differentiated carcinomas, there were no differences in the expression levels between benign prostate hyperplasia, untreated primary and recurrent hormone‐refractory prostate carcinomas (p=0.607). Altogether, missense mutations were detected in 2 out of 68 samples studied (∼3%) by denaturing high‐performance liquid chromatography (DHPLC) and sequencing. One of the samples with the mutation also exhibited a loss of a gene copy by fluorescence in situ hybridization (FISH). This was the only sample that exhibited a genetic alteration in both alleles, suggesting that the human pHyde is not a classical prostate tumor suppressor gene. The reduced expression of the gene found in some tumors warrant further studies. © 2003 Wiley‐Liss, Inc.
Magnetic resonance imaging of the pancreas and pancreatic tumors in a mouse orthotopic model of human cancer
Authors: Grimm Jan , Potthast Andreas , Wunder Andreas , Moore Anna
Published: July 2003

Pancreatic adenocarcinoma has a rising incidence and a very poor survival rate. To develop new treatment strategies, extensive research is performed on animal models of pancreatic cancer. Orthotopic pancreatic tumors models, where the tumor is implanted into the pancreas, resemble the human disease more closely than subcutaneous tumor models, yet are difficult to monitor. In our study we report a magnetic resonance imaging (MRI) approach to visualize the pancreas in mice and to monitor orthotopically implanted pancreatic tumors. An MRI scanner was used to image normal murine pancreas and the pancreas of mice implanted with a human pancreatic adenocarcinoma cell line. Gadolinium (Gd)‐DTPA‐enhanced T1‐ and T2‐weighted standard sequences were used with the objective to identify the pancreas and to monitor the growth of orthotopic tumors during 30 days. The pancreas as well as the implanted tumors could be easily identified using MRI. On T2‐weighted images, the implanted tumors were easily visualized at the implantation side with high signal intensity. After application of a contrast agent, the tumors showed an enhancement. Heterogeneities within the tumor could be delineated, corresponding to histology, and the size of the tumor could be measured precisely. MR serves as a noninvasive high‐resolution image modality to monitor murine pancreas as well as size, growth and even areas of heterogeneity in orthotopic pancreatic tumors. © 2003 Wiley‐Liss, Inc.
Identification of potential biomarkers of lymph node metastasis in oral squamous cell carcinoma by cDNA microarray analysis
Authors: Nagata Masaki , Fujita Hajime , Ida Hiroko , Hoshina Hideyuki , Inoue Tatsuo , Seki Yukie , Ohnishi Makoto , Ohyama Tokio , Shingaki Susumu , Kaji Masataka , Saku Takashi , Takagi Ritsuo
Published: July 2003

We surveyed the expression of 557 cancer‐related genes in 15 cases of well‐differentiated OSCC by cDNA microarray analysis. To identify potential biomarkers for lymph node metastasis, all microarray data were compared by the Mann‐Whitney test and the significance analysis of microarrays between OSCCs with and those without lymph node metastasis. The tissues of OSCCs with lymph node metastasis exhibited increased expression levels of MMP‐1, MMP‐3, uPA, integrin‐α3, paxillin, tenascin C and IL‐6 transcripts. All of these genes were included in common clusters on the Cluster/TreeView analysis, implying that functional gene groups of proteolytic enzymes and integrin‐related molecules are involved in cervical lymph node metastasis. The results of RTQ‐PCR for differentially expressed genes were in accord with those of cDNA microarray analyses, suggesting that the data obtained by microarray gene expression analyses were valid. Consistent with cooperative expression patterns, immunohistochemical analyses demonstrated that products of MMP‐1, MMP‐3 and uPA were colocalized to components of the neoplastic stroma, particularly mononuclear inflammatory cells with well‐developed eosinophilic cytoplasm. Our results suggest that expression levels of molecules involved in tissue remodeling and cell–ECM adhesion, especially MMP‐1 and integrin‐α3, can provide an accurate biomarker system for predicting the risk of cervical lymph node metastasis in OSCC. © 2003 Wiley‐Liss, Inc.
Transfection of the genes for interleukin‐12 into the K1735 melanoma and the EMT6 mammary sarcoma murine cell lines reveals distinct mechanisms of antitumor activity
Authors: Moran James P. , Gerber Scott A. , Martin Celeste A. , Frelinger John G. , Lord Edith M.
Published: July 2003

Interleukin 12 (IL‐12) is a pleiotropic cytokine with multiple effects on the immune system. The antitumor effects of locally produced IL‐12 were examined in 2 tumor model systems. IL‐12 expressing EMT6 mammary sarcomas (EMT6/IL‐12) grew temporarily and then regressed resulting in mice that were immune to a further challenge of EMT6 cells. Interestingly, the IL‐12 expressing K1735 melanomas (K1735/IL‐12) maintained a lag phase of nonmeasurable growth for several weeks, followed by tumor outgrowth that was associated with a loss of IL‐12 production. Tumor‐infiltrating lymphocytes (TILs) isolated from EMT6/IL‐12 tumors effectively lysed EMT6 target cells, whereas K1735/IL‐12 TILs lacked lytic activity. Both IL‐12 expressing tumors, however, grew progressively in nude mice indicating an important role for T cells in each case. Recombinant murine interferon gamma (rmIFN‐γ) inhibited the growth of EMT6 cells, but not K1735 cells in vitro, and strongly induced the expression of the antiangiogenic chemokine interferon‐inducible protein 10 (IP‐10) by both cell lines. Of interest, only the EMT6 cell line was able to secrete the proangiogenic molecule, vascular endothelial growth factor (VEGF), in response to low oxygen conditions. Fluorescent staining of the vascular endothelium at the tumor injection site provided images depicting early stages of angiogenesis prior to K1735/IL‐12 tumor outgrowth. These results indicate that locally produced IL‐12 likely mediates the rejection of EMT6 tumors through tumor cell lysis by host immune cells, whereas its antiangiogenic potential may be counterbalanced by the strong induction of VEGF by hypoxic tumor cells. In contrast, IL‐12 does not induce protective immunity to K1735 tumors. However, an antiangiogenic mechanism may be responsible for controlling tumor growth. © 2003 Wiley‐Liss, Inc.
Plasma MMP‐9 (92 kDa‐MMP) activity is useful in the follow‐up and in the assessment of prognosis in breast cancer patients
Authors: Ranuncolo Stella Maris , Armanasco Eduardo , Cresta Carlos , Bal de Kier Joffe Elisa , Puricelli Lydia
Published: July 2003

Previously we determined that plasma MMP‐9 activity was significantly elevated in breast cancer patients compared to benign mammary pathologies and healthy controls. Now we analyzed its potential usefulness in the follow‐up and in the prognosis of these patients. MMP‐9 activity was measured by gelatin quantitative zymography in the euglobulin plasma fraction of 46 breast cancer patients in a 38‐month follow‐up study. Blood samples were obtained before surgery (S1), 1 month after (S2) and every 3 months. The relapse‐free survival (RFS) and overall survival (OS) analysis was performed along 56 months in 113 patients using the Kaplan‐Meier curves and Cox analysis. In 63% of the S2 analyzed, MMP‐9 decreased after surgery. In 44 patients evaluated during the adjuvant period who developed a complete response, MMP‐9 decreased compared to their S1, whereas 2 patients showed an enhancement in correlation with lack of response. Further analysis indicated that in all patients who never showed evidence of recurrence, plasma MMP‐9 activity remained low, but it increased 1 to 8 months preceding the clinical detection of progression in those patients who relapsed. Kaplan‐Meier curves indicated that high levels of plasma MMP‐9 activity at the moment of breast cancer diagnosis were associated with a worse OS rate. Cox analysis showed it was not associated with tumor stage or patient's age. Our results, which show a good correlation between plasma MMP‐9 activity and the clinical status of each patient, suggest its usefulness as a marker both in the follow‐up and in the prognosis of breast cancer patients. © 2003 Wiley‐Liss, Inc.
Nitric oxide suppresses apoptosis in human colon cancer cells by scavenging mitochondrial superoxide anions
Authors: Wenzel Uwe , Kuntz Sabine , de Sousa Ulrike Jambor , Daniel Hannelore
Published: July 2003

In cells lacking a functional p53 tumor suppressor protein, the endogenous free radical nitric oxide (NO) appears to inhibit apoptosis, and thereby promotes growth of cancer cells. In order to elucidate the underlying mechanisms on a molecular basis, we used HT‐29 human colon carcinoma cells, carrying a p53 loss‐of‐function mutation, and examined the effects of NO on apoptosis when induced either by the flavonoid flavone or by the chemotherapeutic drug camptothecin (CPT), which is able to scavenge NO by superoxide anion production. Caspase‐3 activation as well as nuclear fragmentation, both indicative of apoptosis, were dose dependently inhibited by the NO‐liberating agents sodium nitroprusside (SNP) or S‐nitroso‐N‐acetyl‐D,L‐penicillamine (SNAP) when apoptosis was initiated by flavone with only minor effects on apoptosis when initiated by camptothecin. The transcript levels of 9 apoptosis‐related genes were assessed and NO liberation was shown to completely and specifically prevent the flavone‐induced but not camptothecin‐induced decrease in bcl‐XL mRNA levels. These results were also confirmed at the protein level. The effects of NO on the mitochondrial apoptosis pathway were further evidenced by the scavenging of superoxide anions as produced in mitochondria of cells undergoing apoptosis. Scavenging of mitochondrial superoxide anions by NO prevents the downregulation of bcl‐XL, the depolarization of the mitochondrial membrane potential, the cytochrome c release and finally the activation of caspase‐3. In conclusion, NO effectively inhibits apoptosis by scavenging superoxide anions generated in the mitochondria of p53 mutant cells and thereby prevents the downregulation of the antiapoptotic factor bcl‐XL, which controls the mitochondrial apoptosis pathway. © 2003 Wiley‐Liss, Inc.
Neutrophils influence melanoma adhesion and migration under flow conditions
Authors: Slattery Margaret J. , Dong Cheng
Published: July 2003

We have studied human melanoma cell (C8161) adhesion and migration in response to stimulation by soluble collagen IV (CIV) using a modified Boyden chamber. In this modified chamber, shear flow can be introduced over the cell‐substrate interface, affecting tumor cell chemotactic migration through a microporous filter. A relatively high level of intercellular adhesion molecule‐1 (ICAM‐1) was found on C8161 cells. In contrast, levels of β2‐integrins (e.g., LFA‐1 and Mac‐1), the molecules that would be necessary for C8161 stable adhesion to the endothelium substrate, were found to be very low on these melanoma cells. As a result, C8161 transendothelial migration under a flow condition of 4 dyn/cm2 decreased by 70% as compared to static migration. When human neutrophils (PMNs) were present in the tumor cell suspension, C8161 migration recovered by 85% over C8161 cells alone under the 4 dyn/cm2 flow condition. Blocking ICAM‐1 on C8161 cells or Mac‐1 on PMNs significantly inhibited C8161‐PMN adhesion and subsequent C8161 migration through the endothelium under flow conditions. In addition, increased interleukin‐8 production and Mac‐1 expression by PMNs were detected when they were co‐cultured with C8161 melanoma cells. These results suggest that transmigration of C8161 cells under flow conditions can be influenced by PMNs, mediated by Mac‐1/ICAM‐1 adhesive interactions and enhanced by altered cytokine production. © 2003 Wiley‐Liss, Inc.
Arginine deiminase and other antiangiogenic agents inhibit unfavorable neuroblastoma growth: Potentiation by irradiation
Authors: Gong Hong , Pöttgen Christoph , Stüben Georg , Havers Werner , Stuschke Martin , Schweigerer Lothar
Published: July 2003

In spite of aggressive therapy, children suffering from neuroblastoma have a poor prognosis. Therapeutic failure is most often observed in neuroblastomas with unfavorable features, including amplification/over‐expression of the N‐myc oncogene, rapid growth, effective angiogenesis and/or the tendency to metastasize. Here, we have used cultured human neuroblastoma cells with such features and we have examined whether antiangiogenic agents alone or in combination with tumor irradiation inhibit their angiogenesis and growth in vivo. We report that antiangiogenic agents (arginine deiminase, SU5416 and DC101) inhibit in vivo growth of neuroblastomas with unfavorable properties and that these effects are potentiated by simultaneous irradiation. Combination of either agent with irradiation leads to a reduction in the absolute number of tumor vessels and of perfused tumor vessels. Combination of arginine deiminase or DC101 with irradiation does not increase tumor hypoxia. Our data demonstrate for the first time that arginine deiminase suppresses the growth of unfavorable experimental neuroblastomas and that this effect is potentiated by irradiation. We suggest that antiangiogenesis alone or in combination with established therapeutic regimen may improve the outcome of unfavorable neuroblastomas in a clinical setting. © 2003 Wiley‐Liss, Inc.
Silibinin sensitizes human prostate carcinoma DU145 cells to cisplatin‐ and carboplatin‐induced growth inhibition and apoptotic death
Authors: Dhanalakshmi Sivanandhan , Agarwal Priyanka , Glode L. Michael , Agarwal Rajesh
Published: July 2003

In several recent studies, we have shown that silibinin inhibits the growth of human prostate cancer cells (PCA) both in vitro and in vivo. Here, we investigated the effect of silibinin in combination with cisplatin and carboplatin on human PCA DU145 cell growth and apoptosis. Cisplatin alone at 2 μg/ml dose produced 48% cell growth inhibition, whereas a combination with 50–100 μM silibinin resulted in 63–80% (p<0.05–0.001) growth inhibition. Similarly, compared to 68% growth inhibition at 20 μg/ml carboplatin, addition of 50–100 μM doses of silibinin caused 80–90% inhibition (p<0.005–0.001). In the studies assessing the effect of these combinations on cell cycle progression, a combination of cisplatin or carboplatin with silibinin resulted in a stronger G2‐M arrest, compared to these agents alone showing a moderate G2‐M and G1 arrests in case of cisplatin and silibinin, and a complete S phase arrest with carboplatin, respectively. A stronger G2‐M arrest by these combinations was accompanied by a substantial decrease in the levels of cdc2, cyclin B1 and cdc25C. Silibinin/platinum compound combinations were also effective in inducing apoptosis where cisplatin and carboplatin when combined with silibinin enhanced apoptosis from 8 to 15% and from 20 to 40%, respectively. Apoptosis induction was further confirmed by PARP and caspases 3, 9 and 7 whose cleaved levels were also enhanced by combination treatment. In addition, there was a significant increase in cytochrome c release in the cytosol following treatment of DU145 cells with these combinations. Together, these results show a substantial increase in the efficacy of platinum compounds on human PCA cells, when combined with silibinin, which provide a rationale for further investigations with these combinations. © 2003 Wiley‐Liss, Inc.
Imbalances of chemokines, chemokine receptors and cytokines in Hodgkin lymphoma: Classical Hodgkin lymphoma vs. Hodgkin‐like ATLL
Authors: Ohshima Koichi , Karube Kennosuke , Hamasaki Makoto , Suefuji Hiroaki , Tutiya Takeshi , Yamaguchi Takahiro , Suzumiya Junji , Kikuchi Masahiro
Published: July 2003

Classical Hodgkin lymphoma (HL) is characterized by the presence of Hodgkin and Reed‐Sternberg cells (H&RS) and a prominent lymphocytic infiltration. We previously reported Hodgkin‐like adult T‐cell leukemia/lymphoma (HL‐like ATLL) (new WHO classification). Various CXC and CC chemokines are expressed on H&RS cells and the relationships between chemokines and the chemokine receptor (R) are thought to be important for selectivity of local immunity of Th1 and Th2 T cells. To clarify the role of T‐cell immunity in classical HL and Hodgkin‐like ATLL, we performed gene expression profiling (chemokine, chemokine R and cytokine DNA chips) in 12 cases {classical HL, 8 cases [mixed cellularity (MC) type, 4; nodular sclerosis (NS) type, 4]; Hodgkin‐like ATLL, 4 cases} and immunohistochemical staining in 29 cases (MC, 10; NS, 10; Hodgkin‐like ATLL, 9). EBV‐infected H&RS cells were detected in 9 of 10 cases of HL MC, 5 of 9 of HL‐like ATLL and 2 of 10 HL NS. T‐cell‐directed chemokine thymus‐ and activation‐regulated chemokine (TARC)‐ and/or macrophage‐derived chemokine (MDC)‐positive H&RS cells were detected in all 20 cases of HL MC and HL NS but only in 5 of 9 cases of HL‐like ATLL. Interferon‐γ‐inducible protein‐10 (IP10)‐ and monokine induced by interferon‐γ (MIG)‐positive H&RS cells were detected in all 10 HL MC but only in 5 of 10 cases of HL NS and 2 of 9 cases of HL‐like ATLL. However, 2 of 5 cases of HL‐like ATLL with EBV infection and 2 of 2 HL NS with EBV had IP10/MIG‐positive H&RS cells. The chemokine expressions in H&RS cells seemed to be associated with EBV infection rather than histologic subtypes. In the DNA chip expression analysis, classical HL and HL‐like ATLL had a mixed Th1/Th2‐type profile, and HL MC (EBV‐positive) and HL NS (EBV‐negative) were differentially clustered. However, 2 cases of HL‐like ATLL clustered with HL MS and the other 2 cases of HL‐like ATLL clustered with HL NS. The former HL‐like ATLL had EBV infection in H&RS cells, whereas the latter did not have EBV infection. This finding also suggests that EBV might influence local expression of chemokines rather than HL subtypes. Our results indicate that local immunologic disorder or imbalance appears to influence the formation of H&RS cells and that in HL‐like ATLL, HTLV‐1 infection might not be necessary for H&RS cell formation. © 2003 Wiley‐Liss, Inc.
Association of aspirin and other non‐steroidal anti‐inflammatory drug use with incidence of non‐hodgkin lymphoma
Authors: Cerhan James R. , Anderson Kristin E. , Janney Carol A. , Vachon Celine M. , Witzig Thomas E. , Habermann Thomas M.
Published: July 2003

Non‐steroidal anti‐inflammatory drugs (NSAIDs), including aspirin, seem to have chemopreventive properties against several types of cancer, particularly colon cancer. Persons with rheumatoid arthritis, an autoimmune disease for which NSAIDs are used commonly, have been reported to be at lower risk of colon cancer but at elevated risk of non‐Hodgkin lymphoma (NHL), raising the possibility that NSAIDs may be a risk factor for NHL. We evaluated the association of use of NSAIDs, arthritis history, and risk of NHL in a prospective cohort of 27,290 postmenopausal women from the state of Iowa. The frequency of use of aspirin and of other NSAIDs excluding aspirin (e.g., ibuprofen), as well as a physician diagnosis of rheumatoid arthritis (RA) or osteoarthritis (OA), were self‐reported on a questionnaire mailed in 1992. The incidence of NHL was ascertained through annual linkages to the Iowa SEER Cancer Registry. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. Through 7 years of follow‐up, 131 cases of NHL were identified. Compared to women who did not use either aspirin or other non‐aspirin NSAIDs, women using aspirin exclusively (RR = 1.71; 95% CI = 0.94–3.13), non‐aspirin NSAIDs exclusively (RR = 2.39; 95% CI = 1.18–4.83), or both types of drugs (RR = 1.97; 95% CI = 1.06–3.68) were at increased risk of NHL. A diagnosis of RA (RR = 1.75; 95% CI = 1.09–2.79), but not OA (RR = 1.06; 95% CI = 0.67–1.68), was associated with risk of NHL, but the positive association of use of aspirin and other NSAIDs with NHL was independent of RA history. Multivariate adjustment for other NHL risk factors only attenuated slightly these associations, whereas exclusion of cases occurring during the first 2 years of follow‐up strengthened the associations. These data suggest that use of NSAIDs, either aspirin or other non‐aspirin NSAIDs, are associated positively with risk of NHL, and that this association is independent of RA history. © 2003 Wiley‐Liss, Inc.
Destination environment quality and tourists' spatial behaviour in Nigeria: a case study of third world tropical Africa
Authors: Awaritefe Onome Danniel
Published: July 2003

In order to ascertain important features of tourist behaviour and destination environments that could form the basis for destination quality improvement in Nigeria, 376 tourists were randomly sampled from seven tourism destinations, using a simple rating scheme in a questionnaire survey. Results obtained showed that activities involving leisure/recreation, cultural appreciation and appreciation of nature, history and cultural artifacts were dominant experiences, values and motivation for destination visit. Results also showed variations in quality of environmental features between tourists in various destinations and between foreign and domestic tourists in their spatial behaviour, values and motivations. The study provides unique implications for tourism planning management and marketing, and a context for cross‐cultural comparison with similar western studies. Copyright © 2003 John Wiley &Sons, Ltd.
Singapore's image as a tourist destination
Authors: Hui Tak Kee , Wan Tai Wai David
Published: July 2003

The present study seeks to examine the image of Singapore as a tourist destination. A sample of 131 tourists was collected at the Singapore Changi International Airport's two departure halls. In addition to answering a short Likert‐scale questionnaire, respondents were asked to describe in their own words the unique aspects of the country. Comparisons of response differences in respect of gender, age groups, educational levels as well as countries of origin were also conducted. Significant perceptual differences were detected with respect to the last three categories. Copyright © 2003 John Wiley &Sons, Ltd.
Waterfall attractions in coastal tourist areas: the Yorkshire coast and Queensland's Gold Coast compared
Authors: Hudson Brian J.
Published: July 2003

A comparative study of tourism development on the Yorkshire coast and Queensland's Gold Coast illustrates the importance of waterfalls as attractions, even in beach orientated tourist areas catering mainly for seaside holidaymakers. A relative decline in the importance of the Yorkshire coast waterfall attractions whereas those of the Gold Coast hinterland continue to play a major role is attributed to differences in quantity and quality of these scenic resources, problems of access and the availability of other, and, for many, superior, waterfall attractions within easy reach. Appropriate levels of development at and access to waterfall sites are discussed. Copyright © 2003 John Wiley &Sons, Ltd.
Photodynamic therapy for human oral squamous cell carcinoma and xenografts using a new photosensitizer, PAD‐S31
Authors: Date Masataka , Sakata Isao , Fukuchi Kazuhide , Ohura Kiyoshi , Azuma Yasutaka , Shinohara Mitsuko , Matsuzaki Koichi , Namiki Yoshihisa , Takahashi Hiroshi
Published: July 2003

Background and Objectives

Photodynamic therapy (PDT) is a novel and promising cancer treatment that employs a combination of photosensitizer and visible light. We examined the effect of PDT using a new photosensitizer, PAD‐S31, and the 670‐nm diode laser in human oral squamous cell carcinomas (SCC).

Study Design/Materials and Methods

SAS and HSC‐4 cell lines were used in all the experiments. Cell viability was determined by a modified MTT assay. Two methods were used for the determination of apoptosis in human oral SCC cells: TUNEL assay and detection of fragmented mono‐ and oligo‐nucleosomes by ELISA. Xenografts of human oral SCC cells were generated in KSN S1c nude mice.

Results

In vitro PDT using PAD‐S31 and the 670‐nm diode laser showed cytotoxicity that was a function of laser energy, drug concentration, and time to the SAS and HSC‐4 cell lines. On the other hand, PAD‐S31 without irradiation had no effect on cell viability. The combinated use of PAD‐S31 and the laser irradiation showed excellent anti‐tumor activity against tumor xenografts without severe side effects. PDT‐mediated cell death occurred predominantly by apoptosis in vitro and in vivo.

Conclusions

The present study demonstrates that PAD‐S31 may serve as a potent photosensitizer for PDT. Furthermore, it is expected that this therapy will be clinically useful for the treatment of patients with oral carcinoma. Lasers Surg. Med. 33:57–63, 2003. © 2003 Wiley‐Liss, Inc.
Necrotic and apoptotic cell death of human malignant melanoma cells following photodynamic therapy using an amphiphilic photosensitizer, ATX‐S10(Na)
Authors: Nagata Satoshi , Obana Akira , Gohto Yuko , Nakajima Susumu
Published: July 2003

Background and Objectives

To investigate the phototoxic effect on and cell death modes of human malignant melanoma cells following photodynamic therapy (PDT) using ATX‐S10(Na), an amphiphilic photosensitizer.

Materials and Methods

Cultured human malignant melanoma cells were incubated in a medium containing various concentrations of ATX‐S10(Na) and irradiated with a 670 nm wavelength diode laser. Phototoxicity was analyzed by a 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium inner salt (MTS) assay, and cell death modes were investigated by fluorescence microscopy using a Hoechst 33342‐propidium iodide double‐staining method as well as by static gel electrophoresis. The subcellular localization of ATX‐S10(Na) and mitochondrial destabilization following PDT were observed by fluorescence microscopy.

Results

Higher phototoxicity was obtained with higher dye and/or laser doses. Most of the dead cells appeared apoptotic with dye and irradiation doses that induced less than 70% cytotoxicity. In contrast, most of them appeared necrotic with doses that induced 99% cytotoxicity. Cells receiving PDT showed disturbances of mitochondrial trans‐membrane potential, although the primary site of ATX‐S10(Na) accumulation was in lysosomes.

Conclusions

ATX‐S10(Na) has a phototoxic effect on malignant melanoma cells and, therefore, potential as a photosensitizing agent for PDT designed to kill these cells. Apoptotic pathways may be activated via mitochondrial destabilization following the damage of lysosomes by PDT. Further study, including investigation of therapeutic efficacy in vivo, is warranted. Lasers Surg. Med. 33:64–70, 2003. © 2003 Wiley‐Liss, Inc.
Can patients treat themselves with a small novel light based hair removal system?
Authors: Rohrer Thomas E. , Chatrath Vandana , Yamauchi Paul , Lask Gary
Published: July 2003

Background and Objectives

This study was designed to evaluate the safety and effectiveness of a small, low energy light based system for hair removal, when used by non‐healthcare professionals (“patients”) for self treatment in home‐like environment following instructions and guidance provided by a physician.

Study Design/Materials and Methods

A total of 73 patients between the ages of 19 and 54 years with skin types I through IV were enrolled in the study out of which 67 completed the study. Two treatment sites were chosen from among the arms, axilla, legs, bikini, back, belly, chest or face. The hair on the sites was trimmed and photographed. Each patient performed two self‐treatments, using the hair removal device on their designated body sites, under the Investigator's direction. The first self‐treatment was performed at the Investigator's office by the patient while the second self‐treatment was performed 4 weeks later at a hotel room, simulating the home environment. Follow‐up visits to evaluate the safety and efficacy of the treatments were performed 2 and 12 weeks following the last self‐treatment.

Results

The mean hair reduction was 33.6%, 4 weeks after the first self‐treatment, 44.3%, 2 weeks following the last self‐treatment, and 32.3%, 12 weeks following the last treatment. All the noted side effects were mild and transient. Transient erythema was noted in 47.5% of the patients. Other transient side effects reported include edema (5%), hyperpigmentation (4.75%), crusting (2.35%), hypopigmentation (1.55%), and blistering (1.4%). All noted side effects were resolved by the 12‐week follow‐up visit.

Conclusions

With adequate training and instruction, patients may administer self‐treatments for hair removal with this small light based unit in a safe and effective manner. Lasers Surg. Med. 33:25–29, 2003. © 2003 Wiley‐Liss, Inc.
An unusual case of jaundice in secondary diabetes
Authors: Reynolds RM , Laidlaw SR , Campbell IW , Nawroz I
Published: July 2003

A 66‐year‐old insulin‐requiring diabetic male with diabetes secondary to pancreatic damage from alcohol abuse, with well‐established alcoholic liver disease and cirrhosis, developed obstructive jaundice from gall stones and later from a biliary stricture associated with gram‐negative septicaemia. Death occurred from a haemorrhagic cholecystitis with ruptured gall bladder. At autopsy, a surprise finding was a non‐functioning pancreatic islet cell tumour invading the ampulla of Vater. Cholestasis in this case was due to multiple factors. Copyright © 2002 John Wiley & Sons, Ltd.
Adopting more aggressive strategies for the management of renal disease in type 2 diabetes
Authors: Barnett AH
Published: July 2003

Diabetes and hypertension commonly co‐exist and this combination is associated with major morbidity and mortality from cardiovascular disease and diabetic nephropathy. Diabetic nephropathy is extremely common and increasing – it is associated with development of chronic renal failure and greatly increased cardiovascular morbidity. Elevated blood pressure is the principal factor in progression of diabetic nephropathy and tight blood pressure control is vital in delaying progression.

There is now good evidence for involvement of the renin‐angiotensin system (RAS) in the pathogenesis of diabetic nephropathy and agents that inhibit this system (traditionally ACE inhibitors) may have beneficial effects on disease progression over and above their effects on systemic blood pressure. For this reason, ACE inhibitors are usually recommended first line although multiple antihypertensive therapies from different drug classes are normally required to reach target.

More recently, other agents that block the RAS at the angiotensin II‐receptor site (angiotensin II‐receptor antagonists) have been developed. Three large studies have now been published in type 2 diabetes that demonstrate renal protective effects at both the stage of microalbuminuria (incipient nephropathy) and in patients with more advanced renal disease (overt nephropathy). Given the excellent tolerability profile of these agents and increasing evidence for renal protection, it is reasonable to suggest that angiotensin II‐receptor antagonists can also be considered as suitable first‐line agents in the management of hypertensive type 2 diabetic patients at risk of developing, or with overt, diabetic nephropathy. Copyright © 2003 John Wiley & Sons, Ltd. Copyright © 2002 John Wiley & Sons, Ltd.
Reciprocal learning in teams
Authors: Zeilstra Donald
Published: July 2003

Effective teams—the fundraising professional and the volunteer—develop work practices and access knowledge from one another in a unique way, described as reciprocal learning, that enhances their joint performance.
Relationship building between volunteers and fundraising professionals: Does the adult child of an alcoholic prevail in our profession? A preliminary study
Authors: Hunter Rebecca E.
Published: July 2003

Is the adult child of an alcoholic more adept at building relationships because of his or her experiences in navigating and surviving an alcoholic family, and more prevalent in this profession than in the general U.S. population? If so, for what reasons?
The old college try: Volunteers in fundraising efforts for small liberal arts colleges
Authors: Abzug Jody , Abzug Rikki
Published: July 2003

The preceding chapters examined fundraising volunteers' roles from a large‐scale perspective. This chapter refines the view to a smaller, more localized level by addressing one subset of organizations—the small liberal arts college. College and university fundraising is an area familiar to nearly all professionals in our field, and the use of educational fundraising as an example helps apply previously outlined concepts.
Orchestrating change by empowering volunteer fundraisers: A case study
Authors: Jones Alan , Loguercio Angela , Makar Arthur
Published: July 2003

The Everybody Wins! Foundation (EW!) was at a crossroads in 2000. Through a million‐dollar grant, the U.S. Department of Education was funding a nationwide replication of EW!'s successful literacy and mentoring program. As a result, EW!'s founder separated from the original operation to lead the nationwide expansion of Everybody Wins! USA, and an executive director was hired to spearhead the prototype program, now called Everybody Wins! Metro New York.
Molecular modeling studies on CNG channel from bovine retinal rod: A structural model of the cyclic nucleotide‐binding domain
Authors: Punta Marco , Cavalli Andrea , Torre Vincent , Carloni Paolo
Published: July 2003

A dimeric model of the cyclic nucleotide‐binding domain of the all‐α homomeric cyclic nucleotide‐gated channel from bovine retinal rod is constructed. The model, based on the structure of the fairly homologous catabolite gene activator protein (Weber and Steitz, J Mol Biol 1987;198:311–326), is obtained by use of comparative modeling and molecular dynamics simulations. Our model provides a structural basis for the experimentally measured difference in activity between cAMP and cGMP, as well as the different solvent accessibilities of GLY597 in the complex with cGMP, with cAMP and in the protein in free state. In addition, it provides support for the rearrangement of the domain C helix on ligand binding and releasing proposed by Matulef et al. (Neuron 1999;24:443–452). Proteins 2003;52:332–338. © 2003 Wiley‐Liss, Inc.
Parallel tempering simulations of HP‐36
Authors: Lin Chai‐Yu , Hu Chin‐Kun , Hansmann Ulrich H. E.
Published: July 2003

We report results from all‐atom Monte Carlo simulations of the 36‐residue villin headpiece subdomain HP‐36. Protein‐solvent interactions are approximated by an implicit solvent model. The parallel tempering is used to overcome the problem of slow convergence in low‐temperature protein simulations. Our results show that this technique allows one to sample native‐like structures of small proteins and points out the need for improved energy functions. Proteins 2003;52:436–445. © 2003 Wiley‐Liss, Inc.
Detecting distant homologs using phylogenetic tree‐based HMMs
Authors: Qian Bin , Goldstein Richard A.
Published: July 2003

It is often desired to identify further homologs of a family of biological sequences from the ever‐growing sequence databases. Profile hidden Markov models excel at capturing the common statistical features of a group of biological sequences. With these common features, we can search the biological database and find new homologous sequences. Most general profile hidden Markov model methods, however, treat the evolutionary relationships between the sequences in a homologous group in an ad‐hoc manner. We hereby introduce a method to incorporate phylogenetic information directly into hidden Markov models, and demonstrate that the resulting model performs better than most of the current multiple sequence‐based methods for finding distant homologs. Proteins 2003;52:446–453. © 2003 Wiley‐Liss, Inc.
Fold recognition, homology modeling, docking simulations, kinetics analysis and mutagenesis of ATP/CTP:tRNA nucleotidyltransferase from Methanococcus jannaschii
Authors: Bujnicki Janusz M. , Albert Megan A. , Nelson Donald J. , Thurlow David L.
Published: July 2003

ATP/CTP:tRNA nucleotidyltransferases (NTases) and poly(A) polymerases (PAPs) belong to the same superfamily and their catalytic domains are remotely related. Based on the results of fold‐recognition analysis and comparison of secondary structure patterns, we predicted that these two NTase families share three domains, corresponding to “palm,” “fingers,” and “fingernails” in the PAP crystal structure. A homology model of tRNA NTase from Methanococcus jannaschii was constructed. Energy minimization calculations of enzyme‐nucleotide complexes and computer‐aided docking of nucleotides onto the enzyme's surface were carried out to explore possible ATP and CTP binding sites. Theoretical models were used to guide experimental analysis. Recombinant His‐tagged enzyme was expressed in Escherichia coli, and kinetic properties were characterized. The apparent KM for CTP was determined to be 38 μM, and the apparent KM for ATP was 21 μM. Three mutations of basic amino acids to alanine were created in a highly conserved region predicted to be in the vicinity of the nucleotide binding site. A deletion was also constructed to remove the C‐terminal structural domain defined by the model; it retained about 1% of wild type enzymatic activity using CTP as co‐substrate, confirming that detectable catalytic activity is exhibited by the N‐terminal domain, as defined by the model. Our results suggest a mechanism of differential ATP and CTP binding, which explains how the tRNA NTase, having only one catalytic site, utilizes different nucleotide triphosphates depending on the nature of the tRNA substrate. Proteins 2003;51:349–359. © 2003 Wiley‐Liss, Inc.