bluuebunny/crossref_metadata_2025 huggingface dataset:
Nicotine induces cell proliferation, invasion and epithelial‐mesenchymal transition in a variety of human cancer cell lines
Authors: Dasgupta Piyali , Rizwani Wasia , Pillai Smitha , Kinkade Rebecca , Kovacs Michelle , Rastogi Shipra , Banerjee Sarmistha , Carless Melanie , Kim Esther , Coppola Domenico , Haura Eric , Chellappan Srikumar
Published: October 2008

Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer (NSCLC). Nicotine, an active component of cigarettes, has been found to induce proliferation of lung cancer cell lines. In addition, nicotine can induce angiogenesis and confer resistance to apoptosis. All these events are mediated through the nicotinic acetylcholine receptors (nAChRs) on lung cancer cells. In this study, we demonstrate that nicotine can promote anchorage‐independent growth in NSCLCs. In addition, nicotine also induces morphological changes characteristic of a migratory, invasive phenotype in NSCLCs on collagen gel. These morphological changes were similar to those induced by the promigratory growth factor VEGF. The proinvasive effects of nicotine were mediated by α7‐nAChRs on NSCLCs. RT‐PCR analysis showed that the α7‐nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines. Nicotine was found to promote proliferation and invasion in human breast cancer. The proinvasive effects of nicotine were mediated via a nAChR, Src and calcium‐dependent signaling pathway in breast cancer cells. In a similar fashion, nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells. Most importantly, nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition (EMT), characterized by reduction of epithelial markers like E‐cadherin expression, ZO‐1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells. Therefore, it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers. © 2008 Wiley‐Liss, Inc.
Transcriptional upregulation of HSP70‐2 by HIF‐1 in cancer cells in response to hypoxia
Authors: Huang Wen‐Jie , Xia Li‐Min , Zhu Fan , Huang Bo , Zhou Chun , Zhu Hui‐Fen , Wang Bo , Chen Bin , Lei Ping , Shen Guan‐Xin , De‐AnTian
Published: October 2008

Heat shock protein 70‐2 (HSP70‐2) can be expressed by cancer cells and act as an important regulator of cancer cell growth and survival. Here, we show the molecular mechanisms by which hypoxia regulate HSP70‐2 expression in cancer cells. When cells were subjected to hypoxia (1% O2), the expression of HSP70‐2 had a significant increase in cancer cells. Such increase was due to the direct binding of hypoxia‐inducible factor to hypoxia‐responsive elements (HREs) in the HSP70‐2 promoter. By luciferase assays, we demonstrated that the HRE1 at position −446 was essential for transcriptional activation of HSP70‐2 promoter under hypoxic conditions. We also demonstrated that HIF‐1α binds to the HSP70‐2 promoter and the binding is specific, as revealed by HIF binding/competition and chromatin immunoprecipitation assays. Consequently, the upregulation of HSP70‐2 enhanced the resistance of tumor cells to hypoxia‐induced apoptosis. These findings provide a new insight into how tumor cells overcome hypoxic stress and survive, and also disclose a new regulatory mechanism of HSP70‐2 expression in tumor cells. © 2008 Wiley‐Liss, Inc.
A Joinpoint regression analysis of long‐term trends in cancer mortality in Japan (1958–2004)
Authors: Qiu Dongmei , Katanoda Kota , Marugame Tomomi , Sobue Tomotaka
Published: October 2008

Cancer is one of the major targets of disease control programs in Japan. A Joinpoint regression model was used to analyze the long‐term trends of mortality related to overall cancer and the 15 most common cancers based on published data from the National Vital Statistics of Japan between 1958 and 2004. Since 1996, a decline has been seen in overall cancer for both sexes in Japan. Most of the common sites, including cancers of the stomach, colon, liver, gallbladder and lung and leukemia in both sexes, cancer of esophagus in men and rectal and ovarian cancers in women showed a decreasing trend, and cancers of the rectum, pancreas, prostate and urinary bladder and malignant lymphoma in men and cancers of the esophagus and uterus in women leveled off during the most recent period. However, an increasing trend was confirmed for cancers of the pancreas, breast and urinary bladder and malignant lymphoma in women. An effective cancer control program including prevention, early detection and treatment should be implemented to further reduce the cancer mortality, particularly for cancer sites that show higher mortality rates or increasing trends. © 2008 Wiley‐Liss, Inc.
Somatic mutations of adenomatous polyposis coli gene and nuclear b‐catenin accumulation have prognostic significance in invasive urothelial carcinomas: Evidence for Wnt pathway implication
Authors: Kastritis Efstathios , Murray Samuel , Kyriakou Fani , Horti Maria , Tamvakis Nicolaos , Kavantzas Nicolaos , Patsouris Efstratios S. , Noni Aphrodite , Legaki Sofia , Dimopoulos Meletios A. , Bamias Aristotle
Published: October 2008

Wnt pathway signaling is crucial in many cancers and data indicate crosstalk with other key cancer pathways, however in urothelial carcinogenesis it has not been extensively studied. We searched for mutations in adenomatous polyposis coli (APC), a key regulator of the pathway, and studied b‐catenin expression and interactions with the expression of other markers of apoptosis, angiogenesis, and proliferation in patients with invasive urothelial cancer. The mutation cluster region of APC was directly sequenced in 70 patients with muscle invasive disease who were treated with surgery and adjuvant chemotherapy. COX‐2, p53, Ki67, and b‐catenin were studied immunohistochemically and micro vessel density was quantified by CD105 expression. Single somatic amino‐acid substitutions (missense) were found in 9 (13%) and frameshift deletions in 2 (3%) tumors, all located in regions adjacent to b‐catenin binding sites. Patients having either APC missense mutations or b‐catenin nuclear accumulation had less frequent COX‐2 overexpression (24% vs. 76%, p = 0.043) and more frequent lymph node involvement (75% vs. 38%, p = 0.023). Patients with either APC mutations or b‐catenin accumulation had shorter disease‐free interval (13.4 vs. 28 months, p = 0.07), whereas in multivariate analysis they had shorter disease‐specific survival (60.5 vs. 20.6 months, p = 0.048). Somatic APC missense mutations are not rare in advanced urothelial neoplasms. Either APC mutations and/or aberrant expression of b‐catenin are associated with worse outcome. Further study of the role of the Wnt pathway, potential crosstalk with other pathways and potential candidate therapeutic targets in urothelial cancer is needed. © 2008 Wiley‐Liss, Inc.
Serum pepsinogens and risk of esophageal squamous dysplasia
Authors: Kamangar Farin , Diaw Lena , Wei Wen‐Qiang , Abnet Christian C. , Wang Guo‐Qing , Roth Mark J. , Liu Bing , Lu Ning , Giffen Carol , Qiao You‐Lin , Dawsey Sanford M.
Published: October 2008

Pepsinogens are a class of endopeptidases that are secreted by the gastric epithelium and released into the circulation. Low serum pepsinogen I (PGI) and low serum pepsinogen I/pepsinogen II ratio (PGI/II ratio) are markers of gastric fundic atrophy, and have recently been shown to be associated with increased risk of esophageal squamous cell carcinoma (ESCC). We conducted the current study to test whether these markers are also associated with esophageal squamous dysplasia (ESD), the precursor lesion of ESCC. We measured serum PGI and PGII, using enzyme‐linked immunosorbent assays, in 125 case subjects (patients with moderate or severe ESD) and 250 sex‐matched control subjects (no ESD) selected from an endoscopic screening study in Linxian, China. We used conditional logistic regression models adjusted for age, smoking and place of residence to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Serum PGI showed no statistically significant association with ESD, whether analyzed as a dichotomous, ordinal (quartiles) or continuous variable. Lower serum PGI/II ratio, however, showed a dose‐response association with increased risk of ESD, with an adjusted OR (95% CI) of 2.12 (1.08–4.18), comparing the lowest versus the highest quartile. The association between the lower serum PGI/II ratio and log OR of ESD was nearly linear, and the p‐value for the continuous association was 0.03. Lower serum PGI/II ratio was linearly associated with higher risk of ESD. This result is consistent with recent findings that gastric atrophy may increase the risk of ESCC. Published 2008 Wiley‐Liss, Inc.
EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes
Authors: Barreiros Ana Paula , Sprinzl Martin , Rosset Sylvia , Höhler Thomas , Otto Gerd , Theobald Matthias , Galle Peter R. , Strand Dennis , Strand Susanne
Published: October 2008

The hepatitis B virus (HBV) is a major causative agent of chronic liver disease and subsequent liver cirrhosis worldwide. The reduced sensitivity of virus‐infected liver cells to apoptosis may play a role in the failure to remove virus‐infected cells and eventually promote viral chronicity. The purpose of our study was to investigate whether survival factors induced during compensatory liver regeneration may protect hepatocytes against apoptosis. We evaluated the serum levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) in HBV‐infected patients and found significant increases in HGF and EGF in patients with active virus infection. In primary human hepatocytes we show that HGF and EGF have a protective effect against CD95‐mediated apoptosis and cytotoxic T‐cell killing. Simultaneous treatment with both regeneration factors enhanced the cytoprotective effect. The PI 3‐K/Akt kinase inhibitor, wortmannin, and the STAT3 pathway inhibitor, Tyrphostin AG490, both effectively attenuated the cytoprotective effect of HGF and EGF. Furthermore, we show an EGF/HGF‐dependent upregulation of β1‐integrin chains, increased adhesion to extracellular matrix and an increase in focal adhesions, suggesting outside‐in signaling from the extracellular matrix as an additional cytoprotective mechanism. Our study demonstrates that HGF and EGF can interfere with CD95‐mediated apoptosis and the action of cytotoxic T‐cells through multiple mechanisms in human hepatocytes. Together our results argue that a survival mileau generated by activation of liver regeneration factors may be a risk factor for establishing viral persistence. © 2008 Wiley‐Liss, Inc.
Diagnostic value of FDG‐PET in recurrent colorectal carcinoma: A meta‐analysis
Authors: Zhang Chenpeng , Chen Yumei , Xue Huiping , Zheng Ping , Tong Jinlu , Liu Jianjun , Sun Xiaoguang , Huang Gang
Published: October 2008

Accurate detection of recurrent colorectal carcinoma remains a diagnostic challenge. The purposes of this study were to evaluate the diagnostic value of Positron emission tomography (PET) using fluor‐18‐deoxyglucose (FDG) in recurrent colorectal carcinoma with a meta‐analysis. All the published studies in English relating the diagnostic value of FDG‐PET in the detection of recurrent colorectal carcinoma were collected. Methodological quality of the included studies was evaluated. Pooled sensitivity, specificity and diagnostic odds ratio and SROC (summary receiver operating characteristic curves) were obtained by the statistical software. Twenty‐seven studies were included in the meta‐analysis. The pooled sensitivity and specificity for FDG‐PET detecting distant metastasis or whole body involvement in recurrent colorectal carcinoma were 0.91 (95% CI 0.88–0.92) and 0.83 (95% CI 0.79–0.87), respectively. The pooled sensitivity and specificity for FDG‐PET detecting hepatic metastasis were 0.97 (95% CI 0.95–0.98) and 0.98 (95% CI 0.97–0.99). The pooled sensitivity and specificity for pelvic metastasis or local regional recurrence were 0.94 (95% CI 0.91–0.97) and 0.94 (95% CI 0.92–0.96). FDG‐PET is valuable for the assessment of recurrent colorectal carcinoma. © 2008 Wiley‐Liss, Inc.
Space‐time clustering of childhood cancer around the residence at birth
Authors: McNally Richard J.Q. , Bithell John F. , Vincent Tim J. , Murphy Michael F.G.
Published: October 2008

Previously, we identified space‐time clustering in certain childhood cancers around diagnosis residence. These findings provided support for the involvement of environmental agents in etiological processes occurring close to diagnosis. We have reanalyzed the same British population‐based dataset. The aim of the study was to determine whether there was space‐time clustering around the residence at birth in relation to time of birth and separately from time of diagnosis. A total of 29,553 cases, diagnosed during the period 1969–1993, were examined by a second‐order procedure based on K‐functions. Locations were birth addresses, but separately, both dates of birth and diagnosis were analyzed. There was statistically significant space‐time clustering for Hodgkin lymphoma (HL) and central nervous system (CNS) tumors (p = 0.047 and 0.01, respectively, based on birth date) and for total leukemia at ages 1–4 years only, Non‐Hodgkin lymphoma (NHL) and Wilms tumor (p = 0.01, 0.02 and 0.006, respectively, based on diagnosis date). These results, interpreted together with other epidemiological evidence, suggest an etiological role for environmental factors focused around birth address for certain childhood cancers. For HL and CNS tumors, findings suggest that etiological exposures occurred at similar ages or in utero. For leukemia, NHL and Wilms tumor there is support for exposures occurring at similar times before diagnosis. For leukemia, HL, NHL and CNS tumors, but not Wilms tumor, the findings are consistent with infectious hypotheses. © 2008 Wiley‐Liss, Inc.
Inhibition of migration and invasion of carcinoma cells by urokinase‐derived antagonists of αvβ5 integrin activation
Authors: Vocca Immacolata , Franco Paola , Alfano Daniela , Votta Giuseppina , Carriero Maria Vincenza , Estrada Yeriel , Caputi Mario , Netti Paolo A. , Ossowski Liliana , Stoppelli Maria Patrizia
Published: October 2008

We previously showed that, while binding to urokinase receptor (uPAR) through its growth factor domain (GFD, residues 1–49), urokinase (uPA) can engage αvβ5 integrin through an internal domain (CP, residues 132–158). This novel uPA/αvβ5 interaction promotes cytoskeletal rearrangements and directional cell migration (Franco et al., J Cell Sci 2006;119:3424–34). We now show that treatment of cells with phosphomimic uPA (uPA138E/303E, serine 138 and 303 substituted with glutamic acid) strongly inhibits matrix‐induced cell migration. Unlike uPA, binding of uPA138E/303E to cell surface did not induce F‐actin enriched protruding structures and caused a 5‐fold reduction in cell translocation speed, as determined by video tracking of living cells. Inhibition of migration was found to be independent of uPAR, since uPA variants lacking the GFD domain, but carrying the relevant Ser to Glu substitutions were as effective inhibitor as uPA138E/303E. Through several independent approaches, we established that the phosphomimics specifically bind to αvβ5 integrin through the CP region carrying the S138E mutation. This interaction blocks integrin activation, as determined by a decreased affinity of αvβ5 to vitronectin and a reduced association of the β5 cytoplasmic tail with talin. Finally, stable expression of uPA138E/303E in human squamous carcinoma cells prevented tumor cell invasion in vivo. Thus, when expressed in cancer cells, the inhibitory phosphomimic effect was dominant over the effect of endogenously produced uPA. These results shed light on the regulation of cell migration by uPA phosphorylation and provide a realistic opportunity for a novel antiinvasive/metastatic therapeutic intervention. © 2008 Wiley‐Liss, Inc.
NDRG2 suppresses cell proliferation through down‐regulation of AP‐1 activity in human colon carcinoma cells
Authors: Kim Young Jun , Yoon Sun Young , Kim Jong‐Tae , Choi Seung Cheol , Lim Jong‐Seok , Kim Joo Heon , Song Eun Young , Lee Hee Gu , Choi Inpyoi , Kim Jae Wha
Published: October 2008

Recently, the anti‐tumor activity of N‐myc downstream‐regulated gene 2 (NDRG2) was elucidated, but the molecular mechanism of how NDRG2 works as a tumor suppressor is not well known. To determine the function of NDRG2 as a tumor suppressor, we established stable cell lines expressing NDRG2 protein or its mutant forms, and studied their effects on tumor cell growth. Interestingly, constitutive expression of wild‐type NDRG2 induced the growth retardation of SW620 colon carcinoma cells. Introduction of NDRG2 into SW620 cells induced the decrease of c‐Jun phosphorylation at Ser63, followed by the attenuation of activator protein‐1 (AP‐1) function as a transcriptional activator. Subsequently, the down‐regulation of cyclin D1, which is known as a major target for AP‐1 transcription activator, resulted in cell cycle arrest at G1/S phase. Additionally, treatment of NDRG2‐siRNA on NDRG2‐expressing cells has induced the recovery of c‐Jun phosphorylation and cyclin D1 expression. Cell proliferation of those cells was also increased compared with untreated cells. NDRG2 mutants of which the phosphorylation sites at C‐terminal region were removed by deletion or site‐directed mutagenesis have shown no effect on cyclin D1 expression and could not induce cell growth retardation. In conclusion, NDRG2 modulates intracellular signals to control cell cycle through the regulation of cyclin D1 expression via phosphorylation pathway. © 2008 Wiley‐Liss, Inc.
Modification of HER2 pre‐mRNA alternative splicing and its effects on breast cancer cells
Authors: Wan Jing , Sazani Peter , Kole Ryszard
Published: October 2008

The oncogene HER2 is overexpressed in a variety of human tumors, providing a target for anti‐cancer molecular therapies. Here, we employed a 2′‐O‐methoxyethyl (MOE) splice switching oligonucleotide, SSO111, to induce skipping of exon 15 in HER2 pre‐mRNA, leading to significant downregulation of full‐length HER2 mRNA, and simultaneous upregulation of Δ15HER2 mRNA. SSO111 treatment of SK‐BR‐3 cells, which highly overexpress HER2, led to inhibition of cell proliferation and induction of apoptosis. The novel Δ15HER2 mRNA encodes a soluble, secreted form of the receptor. Treating SK‐BR‐3 cells with exogenous Δ15HER2 protein reduced membrane‐bound HER2 and decreased HER3 transphosphorylation. Δ15HER2 protein thus has similar activity to an autoinhibitory, natural splice variant of HER2, Herstatin, and to the breast cancer drug Herceptin. Both SSO111 and Δ15HER2 may be potential candidates for the development of novel HER2‐targeted cancer therapeutics. © 2008 Wiley‐Liss, Inc.
Hypertension is an independent predictor of survival disparity between African‐American and white breast cancer patients
Authors: Braithwaite Dejana , Tammemagi C. Martin , Moore Dan H. , Ozanne Elissa M. , Hiatt Robert A. , Belkora Jeff , West Dee W. , Satariano William A. , Liebman Michael , Esserman Laura
Published: October 2008

The objective of this study was to determine whether comorbidity, or pre‐existing conditions, can account for some of the disparity in survival between African‐American and white breast cancer patients. A historical cohort study was conducted of 416 African‐American and 838 white women diagnosed with breast cancer between 1973 and 1986, and followed through 1999 in the Kaiser Permanente Northern California Medical Care Program. Information on comorbidity, tumor characteristics and breast cancer treatment was obtained from medical records, and Surveillance, Epidemiology and End Results, Northern California Cancer Center Registry. Associations between comorbidity and survival were analyzed with multiple Cox proportional hazards regression. Over a mean follow‐up of 9 years, African Americans had higher overall crude mortality than whites: 165 (39.7%) versus 279 (33.3%), respectively. When age, race, tumor characteristics and breast cancer treatment were controlled, the presence of hypertension was associated with all cause survival [hazard ratio (HR) = 1.33, 95% confidence intervals (CI) 1.07–1.67] and it accounted for 30% of racial disparity in this outcome. Hypertension‐augmented Charlson Comorbidity Index was a significant predictor of survival from all causes (HR = 1.32, 95%CI 1.18–1.49), competing causes (HR = 1.52, 95%CI 1.32–1.76) and breast cancer specific causes (HR = 1.18, 95%CI 1.03–1.35). In conclusion, hypertension has prognostic significance in relation to survival disparity between African‐American and white breast cancer patients. If our findings are replicated in contemporary cohorts, it may be necessary to include hypertension in the Charlson Comorbidity Index and other comorbidity measures. © 2008 Wiley‐Liss, Inc.
How different are luminal A and basal breast cancers?
Authors: Bertucci François , Finetti Pascal , Cervera Nathalie , Charafe‐Jauffret Emmanuelle , Buttarelli Max , Jacquemier Jocelyne , Chaffanet Max , Maraninchi Dominique , Viens Patrice , Birnbaum Daniel
Published: October 2008

Heterogeneity of breast cancer makes its evolution difficult to predict, and its treatment far from being optimal. At least 5 main molecular subtypes exist. Two major subtypes are luminal A and basal subtypes, which have opposite features, notably survival. To characterize these 2 subtypes better, with the hope of better understanding their different biology and clinical outcome, we have profiled a series of 138 tumours (80 luminal A and 58 basal) using Affymetrix whole‐genome DNA microarrays. We have identified 5,621 probe sets as differentially expressed between the 2 subtypes in our series. These differences were validated in 6 independent public series (more than 600 tumours) profiled using different DNA microarrays platforms. Analysis of functions and pathways related to these probe sets, and the extent of the observed differences, confirmed that the 2 subtypes represent very distinct entities. Genes associated with proliferation, cell cycle, cell motility, angiogenesis, and NFkB signalling were overexpressed in basal tumours. Genes involved in fatty acid metabolism, TGFB signalling, and oestrogen receptor (ER) signalling were overexpressed in luminal A samples. Half of the genes overexpressed in luminal tumours contained ER‐binding sites. The number of differentially expressed genes was as high as the set of genes discriminating 2 cancers of different anatomical origin (breast and colon) or discriminating acute myeloid and lymphoid leukaemia. We provide a comprehensive list of genes/pathways that define potential diagnostic, prognostic and therapeutic targets for these 2 subtypes, which should be treated differently given the profound differences observed at the molecular level. © 2008 Wiley‐Liss, Inc.
N6‐isopentenyladenosine inhibits cell proliferation and induces apoptosis in a human colon cancer cell line DLD1
Authors: Laezza Chiara , Caruso Maria Gabriella , Gentile Teresa , Notarnicola Maria , Malfitano Anna Maria , Di Matola Tiziana , Messa Caterina , Gazzerro Patrizia , Bifulco Maurizio
Published: October 2008

N6‐isopentenyladenosine (i6A) is a modified nucleoside with a pentaatomic isopentenyl derived from mevalonate that induces inhibition of tumor cell proliferation and apoptosis in several tumor cell lines. In this study, we reported that N6‐isopentenyladenosine inhibited the proliferation and promotes apoptosis in DLD1 human colon cancer cells. It suppressed the proliferation of cells through inhibition of DNA synthesis, causing a cell cycle arrest that correlated with a decrease in the levels of cyclin E, cyclin A and cyclin D1 and with a concomitant increase in the levels of cyclin‐dependent kinase inhibitor p21waf and p27kip1. Moreover, it induced apoptosis through an increase in the number of annexin V‐positive cells, a downregulation of antiapoptotic products and caspase‐3 activation. The apoptotic effects of N6‐isopentenyladenosine were accompanied by sustained phosphorylation and activation of c‐jun N‐terminal kinase (JNK) that induced phosphorylation of c‐jun. Overall, our data show that JNK, could play an important role in i6A‐mediated apoptosis in DLD1 human colon cancer cells © 2008 Wiley‐Liss, Inc.
Global expression profiling of sex cord stromal tumors from Men1 heterozygous mice identifies altered TGF‐β signaling, decreased Gata6 and increased Csf1r expression
Authors: Mould Arne W. , Duncan Russell , Serewko‐Auret Magdalena , Loffler Kelly A. , Biondi Christine , Gartside Michael , Kay Graham F. , Hayward Nicholas K.
Published: October 2008

Heterozygous disruption of the Men1 gene predisposes mice to the development of multiple endocrine tumors, accurately mimicking the human MEN1 cancer predisposition syndrome. Additionally, Men1+/– mice frequently develop sex cord adenomas. The mechanism underlying the susceptibility of these mice to sex cord tumor development has not been fully determined, but data suggest it may involve transcriptional regulation of key growth promoting/repressing genes. To identify potential menin‐regulated genes that may be important for tumor suppression in sex cord cells, we compared the global gene expression profiles of testis and ovary adenomas with other endocrine tumors of the pancreas and pituitary from Men1 heterozygous mice and with control tissues. Gonadal tumors clustered separately from pancreas and pituitary tumors with only a few genes (e.g., Cdkn2c) commonly dysregulated in all tumor types. Testis and ovary tumors displayed a higher level of transcriptional similarity to each other than they did to their respective control tissues. Among genes that had decreased expression in tumors was significant over‐representation of genes associated with the TGF‐β, hedgehog and Wnt signaling, indicating that loss of menin function affects these pathways at the level of transcription. Aberrant protein expression in Leydig and granulosa cells of 2 transcriptionally dysregulated gene products, Gata6 and Csf1r were confirmed by immunohistochemistry. We propose that sex cord tumor susceptibility in Men1+/– mice involves deregulated cell proliferation due to dysregulation of multiple cell growth regulating genes including: reduced Cdkn2c transcription, loss of TGF‐β pathway tumor suppressor function (e.g., Gata6) and transcriptional activation of Csf1r. © 2008 Wiley‐Liss, Inc.
Chromosomes 6 and 18 induce neoplastic suppression in epithelial ovarian cancer cells
Authors: Dafou Dimitra , Ramus Susan J. , Choi Ken , Grun Barbara , Trott Deborah A. , Newbold Robert F. , Jacobs Ian J. , Jones Christopher , Gayther Simon A.
Published: October 2008

Metaphase comparative genomic hybridisation (CGH) studies indicate that chromosomes 4, 5, 6, 13, 14, 15 and 18 are frequently deleted in primary ovarian cancers (OCs). Therefore we used microcell‐mediated chromosome transfer (MMCT) to establish the functional effects of transferring normal copies of these chromosomes into 2 epithelial OC cell lines (TOV112D and TOV21G). The in vitro neoplastic phenotype (measured as anchorage dependent and independent growth and invasion) was compared between recipient OC cell lines and multiple MMCT hybrids. Chromosomes 6 and 18 showed strong evidence of functional, neoplastic suppression for multiple hybrids in both cell lines. We also found evidence in 1 cancer cell line suggesting that chromosomes 4, 13 and 14 may also cause functional suppression. Array CGH and microsatellite analyses were used to characterise the extent of genomic transfer in chromosome 6 and 18 hybrids. A 36 MB deletion on chromosome 6 in 2 hybrids from 1 cell line mapped the candidate region proximal to 6q15 and distal to 6q22.2; and an ∼10 MB candidate region spanning the centromere on chromosome 18 was identified in 2 hybrids from the other cell line. These data support reported functional effects of chromosome 6 in OC cell lines; but to our knowledge, this is the first time that functional suppression for chromosome 18 has been reported. This suggests that these chromosomes may harbour tumour suppressor‐“like” genes. The future identification of these genes may have a significant impact on the understanding and treatment of the disease and the identification of novel therapeutic targets. © 2008 Wiley‐Liss, Inc.
Physical activity, sedentary behavior, and endometrial cancer risk in the NIH‐AARP Diet and Health Study
Authors: Gierach Gretchen L. , Chang Shih‐Chen , Brinton Louise A. , Lacey James V. , Hollenbeck Albert R. , Schatzkin Arthur , Leitzmann Michael F.
Published: October 2008

Consistent with a strong hormonal etiology, endometrial cancer is thought to be influenced by both obesity and physical activity. Although obesity has been consistently related to risk, associations with physical activity have been inconclusive. We examined relationships of activity patterns with endometrial cancer incidence in the NIH‐AARP Diet and Health Study cohort, which included 109,621 women, ages 50–71, without cancer history, who in 1995–1996 completed a mailed baseline questionnaire capturing daily routine and vigorous (defined as any period of ≥20 min of activity at work or home causing increases in breathing, heart rate, or sweating) physical activity. A second questionnaire, completed by 70,351 women, in 1996–1997 collected additional physical activity information. State cancer registry linkage identified 1,052 primary incident endometrial cancers from baseline through December 31, 2003. In multivariate proportional hazards models, vigorous activity was inversely associated with endometrial cancer in a dose‐response manner (p for trend = 0.02) (relative risk (RR) for ≥5 times/week vs. never/rarely = 0.77, 95% confidence interval (CI): 0.63–0.95); this association was more pronounced among overweight and obese women (body mass index ≥25; RR = 0.61, 95% CI: 0.47–0.79) than among lean women (body mass index <25; RR = 0.76, 95% CI: 0.52–1.10; p for interaction = 0.12). Although we observed no associations with light/moderate, daily routine or occupational physical activities, risk did increase with number of hours of daily sitting (p for trend = 0.02). Associations with vigorous activities, which may interact with body mass index, suggest directions for future research to clarify underlying biologic mechanisms, including those relating to hormonal alterations. © 2008 Wiley‐Liss, Inc.
Characteristic gene expression in stromal cells of gastric cancers among atomic‐bomb survivors
Authors: Oue Naohide , Sentani Kazuhiro , Sakamoto Naoya , Motoshita Junichi , Nishisaka Takashi , Fukuhara Toshiyuki , Matsuura Hiroo , Sasaki Hiroki , Nakachi Kei , Yasui Wataru
Published: October 2008

To elucidate the mechanism of radiation‐induced cancers, molecular analysis of cancers in atomic‐bomb survivors is important. In our study, we developed a custom oligonucleotide array of 208 genes. We analyzed gene expression profiles of gastric cancers (GCs) from atomic‐bomb survivors and identified 9 genes with significantly lower expression in GCs from exposed patients than in GCs from nonexposed patients. Among these 9 genes, expression of versican and osteonectin was investigated in greater detail using immunohistochemistry in 116 GCs from 64 exposed and 52 nonexposed patients who developed GC after the bombing. In the Stage I/II GCs, the clinicopathologic, phenotypic and proliferative characteristics of GCs from exposed and nonexposed patients did not differ significantly; however, versican and osteonectin were expressed at much lower levels in the area of tumor‐associated stroma of exposed patients than in nonexposed patients (p = 0.026 and p = 0.024, respectively). These results suggest that the characteristics of tumor‐associated stromal cells differ between GCs from exposed and nonexposed patients. © 2008 Wiley‐Liss, Inc.
Interest rate transmission in the UK: a comparative analysis across financial firms and products
Authors: Fuertes Ana‐Maria , Heffernan Shelagh A.
Published: October 2008

This paper differentiates itself from the existing literature by testing for heterogeneities in the interest rate transmission mechanism using a large sample of 662 monthly retail rate histories (1993–2004) on seven key deposit and loan products. Error correction models are estimated to analyse the long‐run pass‐through, the long‐run mark‐up and the short‐run speed of adjustment. The prediction that the official and retail rates move together in the long run is supported by the data. The evidence suggests weak between‐product heterogeneity but notable differences were found between financial firms in the way they adjust their rates, which could hinder the achievement of monetary policy objectives. Consumer responses to official rate changes could therefore be more phased and intricate than hitherto believed. Heterogeneity in adjustment is found to be linked to menu costs and key financial ratios under managerial control. Copyright © 2008 John Wiley & Sons, Ltd.
International value versus growth: evidence from stochastic dominance analysis
Authors: Abhyankar Abhay , Ho Keng‐Yu , Zhao Huainan
Published: October 2008

We investigate the value versus growth investment strategies from the perspective of stochastic dominance analysis. Using G7 country data on value and growth stocks, we find that value stocks stochastically dominate growth stocks only for the US, Canada, and Japan, while there are no significant stochastic dominance relationships between value and growth portfolios for the UK, France, Germany, and Italy. Our results imply that the value premium may be country and sample specific. Copyright © 2008 John Wiley & Sons, Ltd.
The euro as a reserve currency: a challenge to the pre‐eminence of the US dollar?
Authors: Galati Gabriele , Wooldridge Philip
Published: October 2008

Well‐developed financial markets are a necessary condition for a currency to play a role as a reserve currency. The introduction of the euro greatly improved the functioning of euro financial markets. This paper investigates whether euro financial markets have developed sufficiently to facilitate the emergence of the euro as a reserve currency on par with the US dollar. We find that the liquidity and breadth of euro financial markets are fast approaching those of dollar markets, and as a result the euro is eroding some of the advantages that have historically supported the pre‐eminence of the US dollar as a reserve currency. This strengthens the incentive for monetary authorities to reconsider the currency composition of their reserves. Nevertheless, the introduction of the euro has not yet resulted in a significant change in the currency composition of official reserve holdings. The US dollar has maintained its place as the dominant reserve currency, supported perhaps by the edge that dollar financial markets still have over euro markets in terms of size, credit quality, and liquidity, as well as inertia in the use of international currencies. Copyright © 2008 John Wiley & Sons, Ltd.
Announcement effects on exchange rates
Authors: Bask Mikael
Published: October 2008

An asset pricing model for exchange rate determination is presented, where technical analysis in currency trade is incorporated in the form of a moving average technique. As a result, the model has jmax+1 rational expectations equilibria (REE), where jmax is large, since jmax past exchange rates affect the current rate due to technical analysis. There is, however, a unique REE that is economically relevant, and focusing on this REE, it is shown that the exchange rate is much more sensitive to a change in money supply than when technical analysis is absent in currency trade. This result is important since it sheds light on the so‐called exchange rate disconnect puzzle in international finance. Copyright © 2008 John Wiley & Sons, Ltd.
Substrate rigidity regulates Ca2+ oscillation via RhoA pathway in stem cells
Authors: Kim Tae‐Jin , Seong Jihye , Ouyang Mingxing , Sun Jie , Lu Shaoying , Hong Jun Pyu , Wang Ning , Wang Yingxiao
Published: October 2008

Substrate rigidity plays crucial roles in regulating cellular functions, such as cell spreading, traction forces, and stem cell differentiation. However, it is not clear how substrate rigidity influences early cell signaling events such as calcium in living cells. Using highly sensitive Ca2+ biosensors based on fluorescence resonance energy transfer (FRET), we investigated the molecular mechanism by which substrate rigidity affects calcium signaling in human mesenchymal stem cells (HMSCs). Spontaneous Ca2+ oscillations were observed inside the cytoplasm and the endoplasmic reticulum (ER) using the FRET biosensors targeted at subcellular locations in cells plated on rigid dishes. Lowering the substrate stiffness to 1 kPa significantly inhibited both the magnitudes and frequencies of the cytoplasmic Ca2+ oscillation in comparison to stiffer or rigid substrate. This Ca2+ oscillation was shown to be dependent on ROCK, a downstream effector molecule of RhoA, but independent of actin filaments, microtubules, myosin light chain kinase, or myosin activity. Lysophosphatidic acid, which activates RhoA, also inhibited the frequency of the Ca2+ oscillation. Consistently, either a constitutive active mutant of RhoA (RhoA‐V14) or a dominant negative mutant of RhoA (RhoA‐N19) inhibited the Ca2+ oscillation. Further experiments revealed that HMSCs cultured on gels with low elastic moduli displayed low RhoA activities. Therefore, our results demonstrate that RhoA and its downstream molecule ROCK may mediate the substrate rigidity‐regulated Ca2+ oscillation, which determines the physiological functions of HMSCs. J. Cell. Physiol. 218: 285–293, 2009. © 2008 Wiley‐Liss, Inc.
Model cell culture system for defining the molecular and biochemical events mediating terminal differentiation of human melanoma cells
Authors: Staudt Michelle R. , DePass Anthony L. , Sarkar Devanand , Fisher Paul B.
Published: October 2008

Cancer cells are commonly less differentiated than their normal progenitors; a phenotype that correlates with loss of specialized functions and an increased capability to self‐renew. Melanoma is an ideal model to analyze cancer progression and differentiation since a well‐characterized process of step‐wise tumor progression has been defined. Our lab previously described a combinatorial in vitro treatment protocol to induce terminal differentiation of human melanoma cells using a low dose of the PKC activator Mezerein (Mez) combined with interferon‐β (IFN‐β), which also activates IFN‐stimulated gene expression in addition to the re‐differentiation program. In principle, using an alternate way to induce terminal differentiation not including IFN‐β would be more compatible with gene expression profiling. A higher concentration of Mez alone induced terminal differentiation of HO‐1 human melanoma cells as measured by morphological, growth and biochemical assays. Pre‐treatment with the PKC inhibitor GF109203x blocked changes associated with differentiation and inhibited the ability of Mez to force irreversible/terminal differentiation. By combining this efficient method of inducing terminal differentiation with microarray analyses we now identify potential regulators of this process and demonstrate utility of this novel in vitro model in which to study the molecular determinants and mechanisms of human melanoma differentiation. J. Cell. Physiol. 218: 304–314, 2009. © 2008 Wiley‐Liss, Inc.
Kinetic resolution of 1‐phenylethanol integrated with separation of substrates and products by a supported ionic liquid membrane
Authors: Hernández‐Fernández F. J. , de los Ríos A. P. , Tomás‐Alonso F. , Gómez D. , Víllora G.
Published: October 2008

BACKGROUND: In the present study, the kinetic resolution of rac‐1‐phenylethanol by transesterification with several vinyl esters catalysed by a commercial immobilized Candida antarctica lipase B (Novozym 435) was carried out in n‐hexane at different water contents. The subtrates and products involved in the kinetic resolution were separated using a membrane bioreactor containing a supported liquid membrane based on the ionic liquid 1‐butyl‐3‐methylimidazolium tetrafluoroborate [bmim+][BF4−].

RESULTS: Variables affecting the kinetic resolution performance of the enzyme were studied. First, the influence of water content of the medium on the synthetic activity, selectivity and enantioselectivity of the enzyme was analysed in order to establish the optimal amount of water. The use of vinyl esters of different alkyl chain length (vinyl propionate, vinyl butyrate and vinyl laurate) as acyl donors to kinetic resolution was studied. Finally, the integrated reaction/separation process for the resolution of rac‐1‐phenylethanol was carried out in the optimal conditions found.

CONCLUSION: These investigations demonstrate that the coupling of lipase enantioselectivity with the selective separation of supported liquid membranes based on ionic liquids provides a promising basis for practical production of enantiomerically pure or enriched compounds. Copyright © 2008 Society of Chemical Industry
Development of the powder reaction moulding process
Authors: Zhao Lei , Collins Maurice N. , Birkinshaw Colin
Published: October 2008

BACKGROUND: The powder reaction moulding process uses a reactive monomer as carrier and binder for the moulding of metal or ceramic powders. De‐binding is achieved using thermal depolymerisation which is followed by sintering to give the finished component. Binder can be recovered for re‐use.

RESULTS: Moulding compounds, with various powder volume fractions, have been prepared using stainless steel, silicon nitride and alumina with n‐butyl cyanoacrylate as binder, and the stability of the compounds established. Rheological properties of the compounds have been measured using both pressure flow and drag flow methods. Compounds are strongly pseudoplastic. Comparison of experimental results with theoretical models, describing suspension flow behaviour shows that experimental maximum volume fractions are close to the theoretical volume fraction of 0.42 for silicon nitride, 0.68 for alumina and 0.7 for stainless steel. Differential scanning calorimetry and thermogravimetry have been used to simulate de‐binding and show a rapid loss of binder through depolymerisation. Post‐sintering porosity of the ceramic materials is high but this is thought to arise from the low pressure moulding techniques used. Porosity of the stainless steel mouldings is much lower.

CONCLUSIONS: The results validate the powder reaction moulding idea and demonstrate applicability to three widely different powder materials. Copyright © 2008 Society of Chemical Industry
Time Warner Cable Kansas City looks beyond the usual suspects for ways to retain and engage customer‐facing employees
Authors: Vega Wendy
Published: October 2008

When too many new hires are leaving after just a few months on the job, despite effective recruitment and on‐boarding programs, it is time to look for answers in new places. This company set out to strengthen the relationship between frontline supervisors and their new—mostly Generation Y—customer care specialists, and found it's never too early to start building engagement. Keys to early development of a strong supervisor‐employee bond include beginning relationship building during the hiring interview; supervisor participation in new‐hire training; learning the individual's personal drivers of engagement; 30‐/60‐/90‐day assessments with coaching and mentoring; and exposing the new hire to positive high‐performing peers (while buffering them from negative influencers). © 2008 Wiley Periodicals, Inc.
How socially responsible engagement can change your business model: The radical experience of Armor Lux
Authors: Vial Virginie
Published: October 2008

Despite a growing consensus on corporate social responsibility (CSR) issues relevant to companies, there is no one‐size‐fits‐all way to structure and organize CSR. The lack of clarity and transparency in the structure leads stakeholders, rightly or wrongly, to accuse companies of “greenwashing strategies.'' The author analyzes the case of a small French textile company that has radically turned its business model toward CSR in order to survive. It provides a good example of real social engagement and how it transforms the business model. It also raises the question of whether sustainable development issues, scarcity of resources, and deindustrialization of developed countries will move other manufacturers to consider services and intangible assets as part of their business model. © 2008 Wiley Periodicals, Inc.
Designing merger agreements to ease merger integration
Authors: Schmidt Sascha L. , Urlichs Robert , Richter Ansgar
Published: October 2008

Many mergers fail as a result of difficulties in the integration phase. Such problems can arise when the corporate strategy concept of the merged firm does not build in a meaningful way on the actual corporate strategies of the predecessor organizations. Primarily addressed to practitioners, this article introduces the framework of a “merger scan” that enables executives negotiating a deal to analyze whether alternative versions of the new corporate strategy strike an optimal balance between the desire for continuity and the need for strategic renewal. Applying this framework helps executives allocate sufficient time and attention to those integration aspects that involve breaking with the directions of the predecessor firms and thus require change. © 2008 Wiley Periodicals, Inc.
Japan—new business opportunities in an established market
Authors: Haghirian Parissa , Sinkovics Rudolf R. , Bamiatzi Vicky
Published: October 2008

The recession during the last decade hit Japan's image as an economic powerhouse hard. It added a layer of skepticism to the already existing difficulties in coping with tariff and nontariff entry barriers as well as cultural and business differences. However, even against the background of strong economic transformations in countries such as India and especially China and a strong enthusiasm for dealing with these upcoming economies, it should not be forgotten that Japan is still the world's second‐largest economy in terms of gross domestic product. Japan offers an array of business opportunities for foreign investors. As employment and other traditions are under pressure from a young generation more in tune with Western culture and ideas, the Japanese triad market allows for a promising future. This article aims to inform managers who wish to extend their market reach of the tremendous opportunities in the Japanese market. We unveil cultural particulars and challenges for foreign businesses that allow for a refreshed look into the economic miracle of the second half of the twentieth century. © 2008 Wiley Periodicals, Inc.
Mass spectrometry in the characterization of human genetic N‐glycosylation defects
Authors: Barone Rita , Sturiale Luisa , Garozzo Domenico
Published: October 2008

Human genetic diseases that affect N‐glycosylation result from the defective synthesis of the N‐linked sugar moiety (glycan) of glycoproteins. The role of glycans for proper protein folding and biological functions is illustrated in the variety and severity of clinical manifestations shared by congenital disorders of glycosylation (CDG). This family of inherited metabolic disorders includes defects in the assembly of the oligosaccharide precursor that lead to an under‐occupancy of N‐glycosylation sites (CDG‐I), and defects of glycan remodeling (CDG‐II). Mass spectrometry constitutes a key tool for characterization of CDG‐I defects by mass resolution of native protein glycoforms that differ for glycosylation‐site occupancy. Glycan MS analyses in CDG‐II is mandatory to detect whenever possible a repertoire of structures to pinpoint candidate enzymes and genes responsible for the abnormal N‐glycan synthesis. In this manuscript, we review the MS applications in the area of CDG and related disorders with a special emphasis on those techniques that have been already applied or might become functional for diagnosis, characterization, and treatment monitoring in some specific conditions. © 2008 Wiley Periodicals, Inc., Mass Spec Rev 28:517–542, 2009