bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptional profiling of epidermal differentiation
Authors: Radoja Nada , Gazel Alix , Banno Tomohiro , Yano Shoichiro , Blumenberg Miroslav
Published: July 2006

In epidermal differentiation basal keratinocytes detach from the basement membrane, stop proliferating, and express a new set of structural proteins and enzymes, which results in an impermeable protein/lipid barrier that protects us. To define the transcriptional changes essential for this process, we purified large quantities of basal and suprabasal cells from human epidermis, using the expression of β4 integrin as the discriminating factor. The expected expression differences in cytoskeletal, cell cycle, and adhesion genes confirmed the effective separation of the cell populations. Using DNA microarray chips, we comprehensively identify the differences in genes expressed in basal and differentiating layers of the epidermis, including the ECM components produced by the basal cells, the proteases in both the basal and suprabasal cells, and the lipid and steroid metabolism enzymes in suprabasal cells responsible for the permeability barrier. We identified the signaling pathways specific for the two populations and found two previously unknown paracrine and one juxtacrine signaling pathway operating between the basal and suprabasal cells. Furthermore, using specific expression signatures, we identified a new set of late differentiation markers and mapped their chromosomal loci, as well as a new set of melanocyte-specific markers. The data represent a quantum jump in understanding the mechanisms of epidermal differentiation.
Insulin-Like Growth Factor-I Receptor Expression Regulates Neuroblastoma Metastasis to Bone
Authors: van Golen Cynthia M. , Schwab Tracy S. , Kim Bhumsoo , Soules Mary E. , Su Oh Sang , Fung Kevin , van Golen Kenneth L. , Feldman Eva L.
Published: July 2006

Neuroblastoma is a pediatric tumor that preferentially metastasizes to bone. Patients with bone metastases have a mortality rate >93%, indicating a need for novel treatment targets. Our laboratory has shown that type I insulin-like growth factor receptor (IGF-IR) expression and activation regulate neuroblastoma cell proliferation, motility, invasion, and survival, and that expression of the IGF-IR correlates with neuroblastoma tumorigenicity. Bone expresses large amounts of IGF ligands, and the IGF system is required for normal bone physiology. The current study addresses the role of the IGF system in neuroblastoma metastasis to bone. Upon reaching the bone marrow through the circulation, neuroblastoma cells must dock at the bone marrow endothelium, extravasate into the bone microenvironment, and destroy bone tissue to allow for tumor growth. This report examines the effects of high IGF-IR expression on neuroblastoma cell interaction with bone. The current data show that neuroblastoma cells with high IGF-IR expression, either endogenously or through transfection, adhere to human bone marrow endothelial cells and subsequently migrate toward both IGF-I and human bone stromal cells. High IGF-IR–expressing neuroblastoma cells adhere tightly to bone stromal cells, flatten, and extend processes. When neuroblastoma cells are injected directly into the tibiae of mice, those cells with increased IGF-IR form both osteolytic lesions within the tibiae and secondary tumors within other sites. These results support the hypothesis that IGF-IR expression in neuroblastoma cells increases tumor cell interaction with the bone microenvironment, resulting in greater formation of metastases.(Cancer Res 2006; 66(13): 6570-8)
DDX3, a DEAD Box RNA Helicase with Tumor Growth–Suppressive Property and Transcriptional Regulation Activity of the p21waf1/cip1 Promoter, Is a Candidate Tumor Suppressor
Authors: Chao Chi-Hong , Chen Chun-Ming , Cheng Pei-Lin , Shih Jing-Wen , Tsou Ann-Ping , Wu Lee Yan-Hwa
Published: July 2006

DDX3 is a DEAD box RNA helicase with diverse biological functions. Using colony formation assay, our results revealed that DDX3 inhibited the colony formation ability of various tumor cells, and this inhibition might be due to a reduced growth rate caused by DDX3. Additionally, we identified p21waf1/cip1, a cyclin-dependent kinase inhibitor, as a target gene of DDX3, and the up-regulation of p21waf1/cip1 expression accounted for the colony-suppressing activity of DDX3. Moreover, DDX3 exerted its transactivation function on p21waf1/cip1 promoter through an ATPase-dependent but helicase-independent mechanism, and the four Sp1 sites located within the −123 to −63 region, relative to the transcription start site of p21waf1/cip1 promoter, were essential for the response to DDX3. Furthermore, DDX3 interacted and cooperated with Sp1 to up-regulate the promoter activity of p21waf1/cip1. To determine the relevance of DDX3 in clinical cancers, the expression profile of DDX3 in various tumors was also examined. A declined expression of DDX3 mRNA and protein was found in ∼58% to 73% of hepatoma specimens, which led to the reduction of p21waf1/cip1 expression in a manner independent of p53 status. Additionally, an alteration of subcellular localization from nuclei to cytoplasm was also observed in >70% of cutaneous squamous cell carcinoma samples. Because DDX3 exhibits tumor suppressor functions, such as a growth-suppressive property and transcriptional activation of the p21waf1/cip1 promoter, and is inactivated through down-regulation of gene expression or alteration of subcellular localization in tumor cells, all these features together suggest that DDX3 might be a candidate tumor suppressor. (Cancer Res 2006; 66(13): 6579-88)
Activation of Mammalian Target of Rapamycin Signaling Pathway Contributes to Tumor Cell Survival in Anaplastic Lymphoma Kinase–Positive Anaplastic Large Cell Lymphoma
Authors: Vega Francisco , Medeiros L. Jeffrey , Leventaki Vasiliki , Atwell Coralyn , Cho-Vega Jeong Hee , Tian Ling , Claret Francois-Xavier , Rassidakis George Z.
Published: July 2006

Anaplastic lymphoma kinase (ALK)–positive anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in aberrant expression of chimeric nucleophosmin-ALK. Previously, nucleophosmin-ALK has been shown to activate phosphatidylinositol 3-kinase (PI3K) and its downstream effector, the serine/threonine kinase AKT. In this study, we hypothesized that the mammalian target of rapamycin (mTOR) pathway, which functions downstream of AKT, mediates the oncogenic effects of activated PI3K/AKT in ALK+ ALCL. Here, we provide evidence that mTOR signaling phosphoproteins, including mTOR, eukaryotic initiation factor 4E–binding protein-1, p70S6K, and ribosomal protein S6, are highly phosphorylated in ALK+ ALCL cell lines and tumors. We also show that AKT activation contributes to mTOR phosphorylation, at least in part, as forced expression of constitutively active AKT by myristoylated AKT adenovirus results in increased phosphorylation of mTOR and its downstream effectors. Conversely, inhibition of AKT expression or activity results in decreased mTOR phosphorylation. In addition, pharmacologic inhibition of PI3K/AKT down-regulates the activation of the mTOR signaling pathway. We also show that inhibition of mTOR with rapamycin, as well as silencing mTOR gene product expression using mTOR-specific small interfering RNA, decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis in ALK+ ALCL cells. Cell cycle arrest was associated with modulation of G1-S-phase regulators, including the cyclin-dependent kinase inhibitors p21waf1 and p27kip1. Apoptosis following inhibition of mTOR expression or function was associated with down-regulation of antiapoptotic proteins, including c-FLIP, MCL-1, and BCL-2. These findings suggest that the mTOR pathway contributes to nucleophosmin-ALK/PI3K/AKT-mediated tumorigenesis and that inhibition of mTOR represents a potential therapeutic strategy in ALK+ ALCL. (Cancer Res 2006; 66(13): 6589-97)
MYC Can Induce DNA Breaks In vivo and In vitro Independent of Reactive Oxygen Species
Authors: Ray Suma , Atkuri Kondala R. , Deb-Basu Debabrita , Adler Adam S. , Chang Howard Y. , Herzenberg Leonore A. , Felsher Dean W.
Published: July 2006

MYC overexpression is thought to initiate tumorigenesis by inducing cellular proliferation and growth and to be restrained from causing tumorigenesis by inducing cell cycle arrest, cellular senescence, and/or apoptosis. Here we show that MYC can induce DNA breaks both in vitro and in vivo independent of increased production of reactive oxygen species (ROS). We provide an insight into the specific circumstances under which MYC generates ROS in vitro and propose a possible mechanism. We found that MYC induces DNA double-strand breaks (DSBs) independent of ROS production in murine lymphocytes in vivo as well as in normal human foreskin fibroblasts (NHFs) in vitro in normal (10%) serum, as measured by γH2AX staining. However, NHFs cultured in vitro in low serum (0.05%) and/or ambient oxygen saturation resulted in ROS-associated oxidative damage and DNA single-strand breaks (SSBs), as measured by Ape-1 staining. In NHFs cultured in low versus normal serum, MYC induced increased expression of CYP2C9, a gene product well known to be associated with ROS production. Specific inhibition of CYP2C9 by small interfering RNA was shown to partially inhibit MYC-induced ROS production. Hence, MYC overexpression can induce ROS and SSBs under some conditions, but generally induces widespread DSBs in vivo and in vitro independent of ROS production. (Cancer Res 2006; 66(13): 6598-605)
Hair Cycle–Dependent Basal Cell Carcinoma Tumorigenesis in Ptc1neo67/+ Mice Exposed to Radiation
Authors: Mancuso Mariateresa , Leonardi Simona , Tanori Mirella , Pasquali Emanuela , Pierdomenico Maria , Rebessi Simonetta , Di Majo Vincenzo , Covelli Vincenzo , Pazzaglia Simonetta , Saran Anna
Published: July 2006

We examined the effects of hair cycle phase on basal cell carcinoma (BCC) tumorigenesis induced by radiation in mice lacking one Patched allele (Ptc1neo67/+). Our results show that Ptc1neo67/+ mouse skin irradiated in early anagen is highly susceptible to tumor induction, as a 3.2-fold incidence of visible BCC-like tumors was observed in anagen-irradiated compared with telogen-irradiated mice. Microscopic nodular BCC-like tumors were also enhanced by irradiation during active hair-follicle growth phases. Interestingly, histologic examination of the tumors revealed a qualitative difference in BCC tumorigenesis depending on hair growth phase at the time of exposure. In fact, in addition to typical BCC-like tumors, we observed development of a distinct basal cell tumor subtype characterized by anti–cytokeratin 14 and anti–smooth muscle actin reactivity. These tumors showed relatively short latency and rapid growth and were strictly dependent on age at irradiation, as they occurred only in mice irradiated in early anagen phase. Examination of anatomic and immunohistochemical relationships revealed a close relation of these tumors with the follicular outer root sheath of anagen skin. In contrast, there are strong indications for the derivation of typical, smooth muscle actin–negative BCC-like tumors from cell progenitors of interfollicular epidermis. These results underscore the role of follicular bulge stem cells and their progeny with high self-renewal capacity in the formation of basal cell tumors and contribute to clarify the relationship between target cell and tumor phenotype in BCC tumorigenesis induced by radiation. (Cancer Res 2006; 66(13): 6606-14)
Genetic Background Controls Tumor Development in Pten-Deficient Mice
Authors: Freeman Dan , Lesche Ralf , Kertesz Nathalie , Wang Shungyou , Li Gang , Gao Jing , Groszer Matthias , Martinez-Diaz Hilda , Rozengurt Nora , Thomas George , Liu Xin , Wu Hong
Published: July 2006

PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. Germ line mutations of PTEN have been detected in three rare autosomal-dominant disorders. However, identical mutations in the PTEN gene may lead to different symptoms that have traditionally been described as different disorders, such as Cowden disease, Lhermitte-Duclos disease, and Bannayan-Zonana syndromes. This lack of genotype-phenotype correlation prompted us to directly test the possible effects of genetic background or modifier genes on PTEN-controlled tumorigenesis using genetically engineered mouse models. In this study, we generated two animal models in which either exon 5 (PtenΔ5) or promoter to exon 3 (Pten−) of the murine Pten gene were deleted and compared phenotypes associated with individual mutations on two genetic backgrounds. We found that the onset and spectrum of tumor formation depend significantly on the genetic background but less on the type of mutation generated. Our results suggest that PTEN plays a critical role in cancer development, and genetic background may influence the onset, the spectrum, and the progression of tumorigenesis caused by Pten mutation. (Cancer Res 2006; 66(13): 6492-6)
TP53 and KRAS2 Mutations in Plasma DNA of Healthy Subjects and Subsequent Cancer Occurrence: A Prospective Study
Authors: Gormally Emmanuelle , Vineis Paolo , Matullo Giuseppe , Veglia Fabrizio , Caboux Elodie , Le Roux Emilie , Peluso Marco , Garte Seymour , Guarrera Simonetta , Munnia Armelle , Airoldi Luisa , Autrup Herman , Malaveille Christian , Dunning Alison , Overvad Kim , Tjønneland Anne , Lund Eiliv , Clavel-Chapelon Françoise , Boeing Heiner , Trichopoulou Antonia , Palli Domenico , Krogh Vittorio , Tumino Rosario , Panico Salvatore , Bueno-de-Mesquita H. Bas , Peeters Petra H. , Pera Guillem , Martinez Carmen , Dorronsoro Miren , Barricarte Aurelio , Navarro Carmen , Quirós José Ramón , Hallmans Göran , Day Nicholas E. , Key Timothy J. , Saracci Rodolfo , Kaaks Rudolf , Riboli Elio , Hainaut Pierre
Published: July 2006

In cancer patients, plasma often contains mutant DNA released by cancer cells. We have assessed the significance of plasma DNA mutations for subsequent cancer development in healthy subjects in a large longitudinal prospective study. The European Prospective Investigation into Cancer and Nutrition study was analyzed with a nested case-control design. Cases were nonsmokers or ex-smokers for >10 years and newly diagnosed with lung, bladder, or upper aerodigestive tract cancers or leukemia accrued after a median follow-up of 6.3 years. Controls were matched 2:1 for follow-up, age, sex, area of recruitment, and smoking status. KRAS2 mutations were detected by mutant-enriched PCR and sequencing (n = 1,098). TP53 mutations were detected by denaturing high-performance liquid chromatography, temporal temperature gradient electrophoresis, and sequencing (n = 550). KRAS2 or TP53 mutations were detected in 13 of 1,098 (1.2%) and 20 of 550 (3.6%) subjects, respectively, 16 of whom developed cancer on average after 18.3 months of follow-up. Among 137 subjects who developed bladder cancer, 5 had KRAS2 mutations [odds ratio (OR), 4.25; 95% confidence interval (95% CI), 1.27-14.15] and 7 had TP53 mutations (OR, 1.81; 95% CI, 0.66-4.97). There was a nonsignificant trend for association between TP53 mutations and bulky adducts in lymphocyte DNA (OR, 2.78; 95% CI, 0.64-12.17). This is the first report of TP53 or KRAS2 mutations in the plasma of healthy subjects in a prospective study, suggesting that KRAS2 mutation is detectable ahead of bladder cancer diagnosis. TP53 mutation may be associated with environmental exposures. These observations have implications for monitoring early steps of carcinogenesis. (Cancer Res 2006; 66(13): 6871-6)
Coexpression of NRASQ61R and BRAFV600E in Human Melanoma Cells Activates Senescence and Increases Susceptibility to Cell-Mediated Cytotoxicity
Authors: Petti Carlotta , Molla Alessandra , Vegetti Claudia , Ferrone Soldano , Anichini Andrea , Sensi Marialuisa
Published: July 2006

Activating mutations in BRAF and NRAS oncogenes in human melanomas are mutually exclusive. This finding has suggested an epistatic relationship but is consistent even with synthetic lethality. To evaluate the latter possibility, a mutated NRASQ61R oncogene was expressed, under a constitutive or a doxycycline-regulated promoter, in a metastatic melanoma clone (clone 21) harboring an activated BRAFV600E oncogene. After the first 10 to 12 in vitro passages, the constitutive NRASQ61R transfectant displayed progressive accumulation in G0-G1 phase of the cell cycle and stained for the senescence-associated β-galactosidase activity (SA-β-Gal). Inducible expression of NRASQ61R, by the Tet-Off system, in clone 21 cells (21NRAS61ON) led to overactivation of the RAS/RAF/mitogen-activated protein kinase signaling pathway and, after the 10th in vitro passage, led to promotion of senescence. This was documented by reduced proliferation, flattened cell morphology, reduced growth in Matrigel, positive staining for SA-β-Gal, and expression of AMP-activated protein kinase and of the cell cycle inhibitor p21waf1/Cip1. These effects were detected neither in 21 cells with silenced NRASQ61R (21NRAS61OFF) nor in cells transfected with an inducible wild-type NRAS gene (21NRASWTON). In addition, when compared with parental 21 cells, or with 21NRAS61OFF, 21NRAS61ON and constitutive NRASQ61R transfectants cells showed increased susceptibility to cytotoxicity by both HLA class I antigen–restricted and nonspecific T cells and up-regulation of several MHC class I antigen processing machinery components. These results suggest a relationship of synthetic lethality between NRAS and BRAF oncogenes, leading to selection against “double-mutant” cells. (Cancer Res 2006; 66(13): 6503-11)
GM2 Expression in Renal Cell Carcinoma: Potential Role in Tumor-Induced T-Cell Dysfunction
Authors: Biswas Kaushik , Richmond Amy , Rayman Patricia , Biswas Soumika , Thornton Mark , Sa Gaurisankar , Das Tanya , Zhang Renliang , Chahlavi Ali , Tannenbaum Charles S. , Novick Andrew , Bukowski Ronald , Finke James H.
Published: July 2006

Multiple mechanisms have been proposed to account for immune escape by tumors. Although gangliosides have long been known to suppress T-cell immunity, few studies have examined the effect of human tumor-derived gangliosides on immune responses. Here, we show that gangliosides isolated from renal cell carcinoma (RCC) cell lines and clear cell tumor tissue can induce apoptosis in peripheral blood T cells. The RCC tissue-derived gangliosides also suppressed IFN-γ and, in many cases, interleukin-4 production by CD4+ T cells at concentrations (1 ng/mL-100 pg/mL) well below those that induce any detectable T-cell death (4-20 μg/mL). Additional findings show that GM2 expressed by RCC plays a significant role in promoting T-cell dysfunction. This is supported by the demonstration that all RCC cell lines examined (n = 5) expressed GM2 as did the majority of tumors (15 of 18) derived from patients with clear cell RCC. Furthermore, an antibody specific for GM2 (DMF10.167.4) partially blocked (50-60%) T-cell apoptosis induced by coculturing lymphocytes with RCC cell lines or with RCC tissue-derived gangliosides. DMF10.167.4 also partially blocked the suppression of IFN-γ production induced by RCC tissue-derived gangliosides, suggesting that GM2 plays a role in down-regulating cytokine production by CD4+ T cells. (Cancer Res 2006; 66(13): 6816-25)
Direct Transcriptional Up-regulation of Cyclooxygenase-2 by Hypoxia-Inducible Factor (HIF)-1 Promotes Colorectal Tumor Cell Survival and Enhances HIF-1 Transcriptional Activity during Hypoxia
Authors: Kaidi Abderrahmane , Qualtrough David , Williams Ann C. , Paraskeva Christos
Published: July 2006

Cyclooxygenase (COX)-2, the inducible key enzyme for prostanoid biosynthesis, is overexpressed in most colorectal carcinomas and a subset of colorectal adenomas. Genetic, biochemical, and clinical evidence indicates an important role for COX-2 in colorectal tumorigenesis. Although COX-2 can be induced by aberrant growth factor signaling and oncogene activation during colorectal tumorigenesis, the role of microenvironmental factors such as hypoxia in COX-2 regulation remains to be elucidated. For the first time, we report that under hypoxic conditions COX-2 protein levels increase in colorectal adenoma and carcinoma cells. Rigorous analyses reveal that COX-2 up-regulation is transcriptional and is associated with hypoxia-inducible factor (HIF)-1α induction. Oligonucleotide pull-down and chromatin immunoprecipitation assays reveal that HIF-1α binds a hypoxia-responsive element on the COX-2 promoter. COX-2 up-regulation during hypoxia is accompanied by increased levels of prostaglandin E2 (PGE2), which promote tumor cell survival under hypoxic conditions. In addition, elevated levels of PGE2 in hypoxic colorectal tumor cells enhance vascular endothelial growth factor expression and HIF-1 transcriptional activity by activating the mitogen-activated protein kinase pathway, showing a potential positive feedback loop that contributes to COX-2 up-regulation during hypoxia. This study identifies COX-2 as a direct target for HIF-1 in colorectal tumor cells. In addition, COX-2 up-regulation represents a pivotal cellular adaptive response to hypoxia with implication for colorectal tumor cell survival and angiogenesis. We propose that using modified COX-2-selective inhibitors, which are only activated under hypoxic conditions, could potentially be a novel more selective strategy for colorectal cancer prevention and treatment. (Cancer Res 2006; 66(13): 6683-91)
NUP98-HOXA9 Induces Long-term Proliferation and Blocks Differentiation of Primary Human CD34+ Hematopoietic Cells
Authors: Takeda Akiko , Goolsby Charles , Yaseen Nabeel R.
Published: July 2006

NUP98-HOXA9, the chimeric protein resulting from the t(7;11)(p15;p15) chromosomal translocation, is a prototype of several NUP98 fusions that occur in myelodysplastic syndromes and acute myeloid leukemia. We examined its effect on differentiation, proliferation, and gene expression in primary human CD34+ hematopoietic cells. Colony-forming cell (CFC) assays in semisolid medium combined with morphologic examination and flow cytometric immunophenotyping revealed that NUP98-HOXA9 increased the numbers of erythroid precursors and impaired both myeloid and erythroid differentiation. In continuous liquid culture, cells transduced with NUP98-HOXA9 exhibited a biphasic growth curve with initial growth inhibition followed by enhanced long-term proliferation, suggesting an increase in the numbers of primitive self-renewing cells. This was confirmed by a dramatic increase in the numbers of long-term culture-initiating cells, the most primitive hematopoietic cells detectable in vitro. To understand the molecular mechanisms underlying the effects of NUP98-HOXA9 on hematopoietic cell proliferation and differentiation, oligonucleotide microarray analysis was done at several time points over 16 days, starting at 6 hours posttransduction. The early growth suppression was preceded by up-regulation of IFNβ1 and accompanied by marked up-regulation of IFN-induced genes, peaking at 3 days posttransduction. In contrast, oncogenes such as homeobox transcription factors, FLT3, KIT, and WT1 peaked at 8 days or beyond, coinciding with increased proliferation. In addition, several putative tumor suppressors and genes associated with hematopoietic differentiation were repressed at later time points. These findings provide a comprehensive picture of the changes in proliferation, differentiation, and global gene expression that underlie the leukemic transformation of human hematopoietic cells by NUP98-HOXA9. (Cancer Res 2006; 66(13): 6628-37)
Proteomic Analysis Reveals Field-Wide Changes in Protein Expression in the Morphologically Normal Mucosa of Patients with Colorectal Neoplasia
Authors: Polley Abigael C.J. , Mulholland Francis , Pin Carmen , Williams Elizabeth A. , Bradburn D. Mike , Mills Sarah J. , Mathers John C. , Johnson Ian T.
Published: July 2006

Models for the pathogenesis of colorectal cancer tend to focus on the localized lesion, with less attention paid to changes in normal-appearing mucosa. Here we used two-dimensional gel electrophoresis and mass spectrometry to define patterns of protein expression in morphologically normal colonic mucosa from 13 healthy subjects, 9 patients with adenomatous polyps, and 9 with cancer. Tumor samples were also compared with the normal mucosa. Systematic gel comparisons identified a total of 839 spots that differed significantly between one or more groups (P < 0.05). Principle component analysis indicated that the first three components accounted for ∼37% of the total variation and provided clear evidence that flat mucosa from healthy subjects differed significantly from that of patients with polyps or cancer. Sixty-one proteins differed significantly between mucosa from healthy subjects and all other tissue types, and 206 differed significantly between healthy mucosa and polyp mucosa. Several of the proteins showing significant underexpression in tumor tissue were cytokeratins and other cytoskeletal components. In contrast, cytokeratins, including several isoforms of cytokeratin 8, were overexpressed in apparently normal mucosa from polyp and cancer patients compared with mucosa from healthy subjects. These findings indicate that protein expression in the apparently normal colonic mucosal field is modified in individuals with neoplastic lesions at sites distant from the lesion. Recognition and further characterization of this field effect at the molecular level may provide protein biomarkers of susceptibility to colorectal cancer and facilitate development of hypotheses for the role of diet and other environmental factors in its causation. (Cancer Res 2006; 66(13): 6553-62)
The Crucial Role of Cyclooxygenase-2 in Osteopontin-Induced Protein Kinase C α/c-Src/IκB Kinase α/β–Dependent Prostate Tumor Progression and Angiogenesis
Authors: Jain Shalini , Chakraborty Goutam , Kundu Gopal C.
Published: July 2006

The regulation of tumor progression towards its malignancy needs the interplay among several cytokines, growth factors, and enzymes, which are controlled in the tumor microenvironment. Here, we report that osteopontin, a small integrin-binding ligand N-linked glycoprotein family of calcified extracellular matrix–associated protein, regulates prostate tumor growth by regulating the expression of cyclooxygenase-2 (COX-2). We have shown that osteopontin stimulates the activation of protein kinase C α/nuclear factor–inducing kinase/nuclear factor-κB–dependent signaling cascades that induces COX-2 expression, which in turn regulates the prostaglandin E2 production, matrix metalloproteinase-2 activation, and tumor progression and angiogenesis. We have revealed that suppression of osteopontin-induced COX-2 expression by the nonsteroidal anti-inflammatory drug celecoxib or blocking the EP2 receptor by its blocking antibody resulted in significant inhibition of cell motility and tumor growth and angiogenesis. The data also showed that osteopontin-induced mice PC-3 xenograft exhibits higher tumor load, increased tumor cell infiltration, nuclear polymorphism, and neovascularization. Interestingly, use of celecoxib or anti-EP2 blocking antibody drastically suppressed osteopontin-induced tumor growth that further indicated that suppression of COX-2 or its metabolites could significantly inhibit osteopontin-induced tumor growth. Human clinical prostate cancer specimen analysis also supports our in vitro and animal model studies. Our findings suggest that blockage of osteopontin and/or COX-2 is a promising therapeutic approach for the inhibition of prostate tumor progression and angiogenesis. (Cancer Res 2006; 66(13): 6638-48)
Non–Small-Cell Lung Cancer and Ba/F3 Transformed Cells Harboring the ERBB2 G776insV_G/C Mutation Are Sensitive to the Dual-Specific Epidermal Growth Factor Receptor and ERBB2 Inhibitor HKI-272
Authors: Shimamura Takeshi , Ji Hongbin , Minami Yuko , Thomas Roman K. , Lowell April M. , Shah Kinjal , Greulich Heidi , Glatt Karen A. , Meyerson Matthew , Shapiro Geoffrey I. , Wong Kwok-Kin
Published: July 2006

Mutation-specific cancer therapy has shown promising clinical efficacy. In non–small-cell lung cancer (NSCLC), the presence of mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase correlates with clinical response to small-molecule tyrosine kinase inhibitors. Here, we show that cells harboring the G776insV_G/C mutation in the related ERBB2 tyrosine kinase (also known as HER2 or Neu), present in a small percentage of NSCLCs, are sensitive to HKI-272, an irreversible dual-specific kinase inhibitor targeting both EGFR and ERBB2. In the ERBB2-mutant NCI-H1781 cell line, HKI-272 treatment inhibited proliferation by induction of G1 arrest and apoptotic cell death. Furthermore, HKI-272 abrogated autophosphorylation of both ERBB2 and EGFR. Finally, Ba/F3 murine pro-B cells, engineered to express mutant ERBB2, became independent of interleukin-3 and sensitive to HKI-272. Thus, the subset of NSCLC patients with tumors carrying the ERBB2 G776insV_G/C mutation may benefit from treatment with HKI-272. (Cancer Res 2006; 66(13): 6487-91)
Risk of Microsatellite-Unstable Colorectal Cancer Is Associated Jointly with Smoking and Nonsteroidal Anti-inflammatory Drug Use
Authors: Chia Victoria M. , Newcomb Polly A. , Bigler Jeannette , Morimoto Libby M. , Thibodeau Stephen N. , Potter John D.
Published: July 2006

Smoking has been consistently associated with an increased risk of colorectal adenomas and hyperplastic polyps as well as colorectal cancer. Conversely, nonsteroidal anti-inflammatory drugs (NSAID) have been associated with reduced colorectal cancer risk. We conducted a population-based case-control study to evaluate the joint association between smoking and regular NSAID use with colorectal cancer risk; we also examined these associations stratified by tumor microsatellite instability (MSI). We analyzed 1,792 incident colorectal cancer cases and 1,501 population controls in the Seattle, Washington area from 1998-2002. MSI, defined as MSI high (MSI-H) or MSI-low/microsatellite stable (MSI-L/MSS), was assessed in tumors of 1,202 cases. Compared with nonsmokers, colorectal cancer risk was modestly increased among individuals who had ever smoked. Current NSAID use was associated with a 30% lower risk compared with nonusers. There was a statistically significant interaction between smoking duration and use of NSAIDs (Pinteraction = 0.05): relative to current NSAID users who never smoked, individuals who had both smoked for >40 years and had never used NSAIDs were at the highest risk for colorectal cancer (adjusted odds ratio, 2.8; 95% confidence intervals, 1.8-4.1). Compared with nonsmokers, there was a stronger association within MSI-H tumors with current smoking than there was within MSI-L/MSS tumors. Smokers of long duration were at elevated risk of MSI-H tumors even with NSAID use. The risk of MSI-L/MSS tumors was not elevated among long-duration smokers with long exposure to NSAIDs but was elevated among long-duration smokers who had never used NSAIDs. There seems to be a synergistic inverse association (implying protection) against colorectal cancer overall as a result of NSAID use and nonsmoking, but risk of MSI-H colorectal cancer remains elevated among smokers even when they have a history of NSAID use. (Cancer Res 2006; 66(13): 6877-83)
Satellite Measurement of Stratospheric Winds and Ozone Using Doppler Michelson Interferometry. Part I: Instrument Model and Measurement Simulation
Authors: Rahnama Peyman , Rochon Yves J. , McDade Ian C. , Shepherd Gordon G. , Gault William A. , Scott Alan
Published: July 2006

This paper presents an instrument model and observation simulations for the measurement of stratospheric winds and ozone concentration using a satellite instrument employing imaging and the Doppler Michelson interferometery technique. The measurement technique and instrument concept are described. The instrument model and simulations are based on initial design characteristics of the Canadian Stratospheric Wind Interferometer for Transport Studies (SWIFT) satellite instrument. SWIFT employs an imaging array and a field-widened Michelson interferometer. It will measure stratospheric winds and ozone densities using the wind-induced phase shifts of interferograms from atmospheric limb radiance spectra in the vicinity of the vibration–rotation ozone line at 1133.4335 cm−1. The measurement simulation and analysis tools have been developed to assess the SWIFT instrument performance and to evaluate the impact of instrument and measurement characteristics on expected wind and ozone errors. Sample results of the measurement simulation and the related line-of-sight wind error noise levels are presented.
The Closure of the Ocean Mixed Layer Temperature Budget Using Level-Coordinate Model Fields
Authors: Kim Seung-Bum , Fukumori Ichiro , Lee Tong
Published: July 2006

Entrainment is an important element of the mixed layer mass, heat, and temperature budgets. Conventional procedures to estimate entrainment heat advection often do not permit the closure of heat and temperature budgets because of inaccuracies in its formulation. In this study a rigorous approach to evaluate the effect of entrainment using the output of a general circulation model (GCM) that does not have an explicit prognostic mixed layer model is described. The integral elements of the evaluation are 1) the rigorous estimates of the temperature difference between mixed layer water and entrained water at each horizontal grid point, 2) the formulation of the temperature difference such that the budget closes over a volume greater than one horizontal grid point, and 3) the apparent warming of the mixed layer during the mixed layer shoaling to account for the weak vertical temperature gradient within the mixed layer.

This evaluation of entrainment heat advection is compared with the estimates by other commonly used ad hoc formulations by applying them in three regions: the north-central Pacific, the Kuroshio Extension, and the Niño-3 areas in the tropical Pacific. In all three areas the imbalance in the mixed layer temperature budget by the ad hoc estimates is significant, reaching a maximum of about 4 K yr−1.
Identification of the Melting Layer through Dual-Polarization Radar Measurements at Vertical Incidence
Authors: Baldini Luca , Gorgucci Eugenio
Published: July 2006

Features of the melting layer of precipitation such as height and thickness are important in many meteorological applications. Doppler radar observations with a vertically pointing antenna have often been used in order to derive these features and to investigate the physical processes governing formation of the precipitation. This paper presents a technique to detect the characteristics of the melting layer based on the standard deviation of polarimetric radar measurements taken at vertical incidence. Using two case studies with stratiform and convective precipitation, the proposed technique is compared with conventional techniques based on reflectivity and mean Doppler velocity profiles. Data presented in this paper were obtained by the coherent dual-polarization C-band radar, Polar 55C, in Rome, Italy, during the summer and the fall of 2004.
Rhetoric and Public Reasoning
Authors: Yack Bernard
Published: July 2006

This essay asks why Aristotle, certainly no friend to unlimited democracy, seems so much more comfortable with unconstrained rhetoric in political deliberation than current defenders of deliberative democracy. It answers this question by reconstructing and defending a distinctly Aristotelian understanding of political deliberation, one that can be pieced together out of a series of separate arguments made in the Rhetoric, the Politics, and the Nicomachean Ethics.
Sex Trafficking Into The United States: A Literature Review
Authors: Schauer Edward J. , Wheaton Elizabeth M.
Published: July 2006

This study is an investigation of the literature relating to the trafficking of women and children into the United States for sexual exploitation. The intent is to discover the extent and complexity of the problem, the cost in both human and economic terms, and research directions toward the development of probable political, legal, economic, and social solutions. A subject rife with research possibilities and probable solutions, trafficking is poorly defined, differentially and intermittently quantified, and handicapped by obsolete legal codes and a sexist prostitution enforcement paradigm. Recommended are state statute creation, police training and paradigm change, and increased/broadened victims’ services.
The Implications of an Ethnographer’s Sexuality
Authors: La Pastina Antonio C.
Published: July 2006

This article discusses the implications of an ethnographer’s sexuality with regard to his fieldwork. Adopting a self-reflexive stance, the author discusses how his queer identity and the fear of repercussions against his intellectual and physical body affected his fieldwork. As a native Brazilian, he was still an outsider in the rural community in which he did his fieldwork. But more than his outsider status, his memories of growing up in the closet in Brazil informed some of his research choices and shaped his reactions to the experience of returning to the closet to conduct research in a community where machista attitudes, notions of queerness, and his own internalized homophobia positioned his queer self as an outsider.
The Effect of Service Evaluations on Behavioral Intentions and Quality of Life
Authors: Dagger Tracey S. , Sweeney Jillian C.
Published: July 2006

Understanding the contribution of marketing to economic and social outcomes is fundamental to broadening the focus of marketing. The authors develop a comprehensive model that integrates the impact of service quality and service satisfaction on both economic and societal outcomes. The model is validated using two random samples involving intensive health services. The results indicate that service quality and service satisfaction significantly enhance quality of life and behavioral intentions, highlighting that customer service has social as well as economic outcomes. This is an important finding given the movement toward recognizing social and environmental outcomes, such as emphasized through triple bottom-line reporting. The findings have important implications for managing service processes, for improving the quality of life of customers, and for enhancing customers' behavioral intentions toward the organization.
Quality of Electronic Services
Authors: Fassnacht Martin , Koese Ibrahim
Published: July 2006

For providers of electronic services, quality is a major driving force on the route to long-term success. Comprehensive measurement of quality, in turn, is the key to effective quality management. Marketing academia has just started to attend to quality measurement in the context of electronic services. A review of existing literature on the subject reveals that important research gaps exist, both conceptually and methodologically. Building on extant research and findings from a qualitative study, the authors develop a broadly applicable, hierarchical quality model for electronic services, which includes three dimensions and nine sub-dimensions. The proposed model is rigorously tested by means of a large aggregated sample drawn from the customer bases of three different electronic services. The authors find support for the conceptualization and discuss important findings of the study as well as implications for managerial practice and research.
The Impact of Sponsor Fit on Brand Equity
Authors: Becker-Olsen Karen L. , Hill Ronald Paul
Published: July 2006

As the nonprofit sector becomes increasingly competitive, it is critical for nonprofit service organizations to become more brand centered and to differentiate themselves in the marketplace. The two studies show that high-fit sponsorship programs between nonprofit service firms and businesses positively influence brand identity via broad associations and brand meaning, brand response, and brand relationships through specific associations. Conversely, low-fit sponsorship programs are likely to hinder nonprofit brand management strategies by negatively affecting brand identity, brand meaning, brand response, and brand relationships. Finally, the results reveal that nonprofit service organizations can use supportive communications to counter the risks of strategic alliances with low-fit businesses.
Marketing Practices and Performance of Small Service Firms
Authors: Coviello Nicole , Winklhofer Heidi , Hamilton Karla
Published: July 2006

Marketing practices have been examined in many studies, yet the literature is dominated by a focus on larger firms offering a service that is often contractual or potentially continuous in nature. To contrast with this, the authors identify the practices of smaller firms likely to provide a noncontractual service and then test the link between marketing practices and firm performance. Results from 242 firms in the tourism accommodation sector indicate that success requires an emphasis on both transaction marketing and interaction-based relationship marketing to acquire customers and achieve sales growth. More contemporary practices such as database marketing, e-marketing, and network marketing are in evidence, but they are not found to influence performance. Furthermore, it is success with customer acquisition rather than customer retention that leads to profitability for these firms. The implications of these and other results are discussed and begin to provide a more balanced perspective to the literature.
Worldviews of Adult Learning in the Workplace: A Core Concept in Human Resource Development
Authors: Johansen Barry-Craig P. , McLean Gary N.
Published: July 2006

The problem and the solution. The workplace, classrooms, and the world in general are becoming increasingly diverse. Globalization, communications technology, immigration, an increased focus on religion and spirituality, and the ease of both domestic and international travel offer an opportunity to work, learn, and interact with people whose backgrounds differ from our own. To be effective, HRD practitioners must recognize how cultural background, assumptions, and view of the world influence an understanding of adult learning. The dangers of not developing such an understanding include inconsistent and/or atheoretical practice, misunderstandings, miscommunication, and the dangers of cultural imperialism.
A Hindu Worldview of Adult Learning in the Workplace
Authors: Ashok H. S. , Thimmappa M. S.
Published: July 2006

The problem and the solution. The Hindu religion has abundant literature applicable to human resource development (HRD). Using a holistic approach, Hindu texts address the process of developing people at both the micro and macro levels. Theoretical constructs related to adult learning in the workplace and organization development from the ancient Hindu scriptures are examined.
An Experiment with Data Collection Modes and Incentives in the Dutch Family and Fertility Survey for Young Moroccans and Turks
Authors: van den Brakel Jan A. , Vis-Visschers Rachel , Schmeets J. J. G.
Published: July 2006

In this article, the authors discuss the results of an experiment embedded in the Dutch Family and Fertility Survey for Young Moroccans and Turks. The effects of two factors on response rates and data quality are investigated. The first factor is a promised incentive versus no incentive. In the second factor, the part of the questionnaire with presumed sensitive questions is administered via computer-assisted self-interviewing (CASI), instead of completely administering the questionnaire via computer-assisted personal interviewing (CAPI). No significant main effect of the promised incentive on the response rates could be found. There are, however, interactions between the incentive, gender, and ethnicity, which show that different subpopulations react differently to the promised incentive. Furthermore, there is no evidence that the data collected by means of CASI results in more valid answers. Still, when the data are collected by means of CASI, a substantial increase in the rate of “don't know” responses is observed.
Predicting the Persistence and Performance of Newly Recruited Telephone Interviewers
Authors: Link Michael W.
Published: July 2006

The impact of personal characteristics and work environment on telephone interviewer job persistence, efficiency, and effectiveness is examined. Data included interviewer demographics, experience, skills, and attitudes, as well as time-clock and production statistics from 383 newly recruited telephone interviewers working on two large-scale national surveys. Findings indicate that interviewer success results from a complex mix of individual and workplace characteristics. Workplace factors such as location of facility, shift worked, and study assignment appear more relevant to predicting persistence in the job, while individual attributes, including telephone skills, previous experience, and having a confident yet realistic attitude toward survey research are more closely related to job performance. These findings have implications for both the recruitment of and the training of successful telephone interviewers.
Collecting Data among Ethnic Minorities in an International Perspective
Authors: Feskens Remco , Hox Joop , Lensvelt-Mulders Gerty , Schmeets Hans
Published: July 2006

This article examines strategies to reduce nonresponse rates among ethnic minorities. The authors review nonresponse rates and data collection strategies among ethnic minorities with respect to response rates and response bias in six European countries. The national statistical institutes of these six countries use different definitions of ethnic minorities. This is why the definitions of ethnic minorities and their impact on the number of members of ethnic minorities in the six countries are compared. Nonresponse rates are usually higher among ethnic minorities than among the native population. Dissecting the nonresponse phenomenon shows that contact rates among ethnic minorities are lower, nonresponse due to an inability to produce the required information is higher, and cooperation rates are higher among ethnic minorities than among the native population. Increasing the response rates among ethnic minorities should focus on enhancing the contact rate and reducing the number of nonrespondents who are unable to produce the required information.
An Exploratory Study about Inaccuracy and Invalidity in Adolescent Self-Report Surveys
Authors: Fan Xitao , Miller Brent C. , Park Kyung-Eun , Winward Bryan W. , Christensen Mathew , Grotevant Harold D. , Tai Robert H.
Published: July 2006

Using Add Health data, the authors provide evidence that some adolescents gave inaccurate and/or invalid responses on a self-administered questionnaire. Further analyses show that these adolescents were much more likely to report extreme levels on psychosocial and behavioral outcome variables. A distinction was made between inaccurate responders (e.g., inaccurate/false responses due to carelessness or confusion) and jokesters (e.g., intentional false responses). The findings show that the jokesters showed considerably more pronounced distorting effects on some psychosocial and behavioral outcome variables than the inaccurate responders did. The authors suggest that although this jokester effect may not seriously bias the results in studies that focus on large groups, for research focusing on some special subgroups (e.g., adoption groups, immigrant groups, disability groups), this effect could pose a serious challenge for the validity of research findings.