bluuebunny/crossref_metadata_2025 huggingface dataset:
TIMELINESAs we may recall
Authors: Buckland Michael
Published: November 2009

Editor's Note: Occasionally in studying HCI history, I have stumbled upon large topics that I was unaware existed. Perhaps the most surprising has been the development of advanced information technologies, which preceded computers. In some ways, the constraints imposed by those technologies forced deeper thinking about information itself. In this column, Berkeley Professor Emeritus Michael Buckland describes the work of four dedicated creative pioneers.---Jonathan Grudin
Guest editorial on cultural issues in global e-commerce diffusion, adoption and use
Authors: Dwivedi Yogesh K. , Singh Nitish , Williams Michael D.
Published: November 2009

It gives us great pleasure to welcome you to this special issue of DATA BASE for Advances in Information Systems, the focus of which is on "Cultural Issues in Global E-commerce Diffusion, Adoption and Use."

Electronic (e)-commerce is expanding at a rapid rate, with the online population approaching almost one and a half billion, and global online revenues being measured in trillions of dollars. This global expansion of e-commerce represents growth opportunities for businesses worldwide. However, one of the obstacles for companies attempting to extend their e-business internationally is to understand global consumers and overcome cultural barriers and language differences on the web (Singh and Pereira, 20051; Violino, 20012). Many companies are realizing that building an e-commerce website to suit an international audience is a more complex endeavor than they expected (Sheldon and Strader, 20023). As companies set up their global e-businesses, it is important for them to understand, what global trends are facilitating the rise of the web, what cultural factors influence consumer use of international websites, what motivates global consumers to make purchases at international websites, and what cultural barriers exist to diffusion and adoption of e-commerce.

This Special Issue of DATA BASE aims to advance the knowledge on the role of national culture in global e-commerce expansion. More specifically, it aims to address issues related to the impact of national culture on macro-level issues related to diffusion and adoption of ecommerce, and micro-level issues related to web site localization, international web site usage, and global online consumer behavior. The Special Issue has solicited theoretical, conceptual, and empirical studies that are inter-disciplinary in nature, as global e-commerce research is not just emerging as an important area of study in the information systems domain, but also in marketing, international business, linguistics and other disciplines.
Culture and acceptance of global web sites
Authors: Li Xin , Hess Traci J. , McNab Anna L. , Yu Yanjun
Published: November 2009

E-businesses have experienced the challenges of developing global web sites that serve consumers with different national cultures. Researchers have studied the influence that national cultural values have on technology-related beliefs and behaviors, and have noted the need for further research on cultural issues. This study investigates the influence of national cultural values on acceptance of a personal web portal by users in China and the United States. Subjects from these two countries evaluated country-specific versions of a personal web portal designed to support the gathering of news, blogs, and other shared information and to provide communication features. The five national cultural dimensions of power distance, individualism/collectivism, masculinity/femininity, uncertainty avoidance, and time orientation were measured at the individual level to enable assessment of the influence from each cultural dimension on technology beliefs and adoption intentions. A research model integrating both moderating and direct effects of cultural values was proposed. Individualism and time orientation were found to influence perceived ease of use and perceived usefulness directly. No moderating cultural effects were significant. The results stress the importance of including the cultural value of time orientation in studies of technology acceptance and measuring cultural values at the individual level. Our findings suggest that e-businesses should continue to focus on the cultural congruency of global web sites and consider how personalization features may assist in pursuit of this congruency.
Does culture affect the adoption of advanced mobile services?
Authors: Constantiou Ioanna D. , Papazafeiropoulou Anastasia , Vendelø Morten Thanning
Published: November 2009

Mobile TV has been rapidly adopted in the Asian markets such as South Korea and Japan, whereas in Europe the diffusion has been slow and the services less popular. The present study explores the relationship between young adults' perceptions of value elements and their adoption intentions of mobile TV. Building on the theory of reason-based choice from the behavioural economics field, the study investigates how culture affects; 1) the perceived costs and the perceived benefits relationships with the adoption intentions, and 2) the preferences for particular mobile TV services. The data collection is based on a survey conducted in two different cultural contexts in Europe; Denmark and the UK. The results of the study show that culture moderates the relationship between perceived benefits and adoption intentions, whereas the relationship between perceived costs and adoption intentions is not affected by culture. Culture also affects the preferences for several entertainment services offered by mobile TV.
Skeletal muscle NAMPT is induced by exercise in humans
Authors: Costford Sheila R. , Bajpeyi Sudip , Pasarica Magdalena , Albarado Diana C. , Thomas Shantele C. , Xie Hui , Church Timothy S. , Jubrias Sharon A. , Conley Kevin E. , Smith Steven R.
Published: November 2009

In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is responsible for the first and rate-limiting step in the conversion of nicotinamide to nicotinamide adenine dinucleotide (NAD+). NAD+is an obligate cosubstrate for mammalian sirtuin-1 (SIRT1), a deacetylase that activates peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which in turn can activate mitochondrial biogenesis. Given that mitochondrial biogenesis is activated by exercise, we hypothesized that exercise would increase NAMPT expression, as a potential mechanism leading to increased mitochondrial content in muscle. A cross-sectional analysis of human subjects showed that athletes had about a twofold higher skeletal muscle NAMPT protein expression compared with sedentary obese, nonobese, and type 2 diabetic subjects ( P < 0.05). NAMPT protein correlated with mitochondrial content as estimated by complex III protein content ( R2= 0.28, P < 0.01), MRS-measured maximal ATP synthesis ( R2= 0.37, P = 0.002), and V̇o2max( R2= 0.63, P < 0.0001). In an exercise intervention study, NAMPT protein increased by 127% in sedentary nonobese subjects after 3 wk of exercise training ( P < 0.01). Treatment of primary human myotubes with forskolin, a cAMP signaling pathway activator, resulted in an ∼2.5-fold increase in NAMPT protein expression, whereas treatment with ionomycin had no effect. Activation of AMPK via AICAR resulted in an ∼3.4-fold increase in NAMPT mRNA ( P < 0.05) as well as modest increases in NAMPT protein ( P < 0.05) and mitochondrial content ( P < 0.05). These results demonstrate that exercise increases skeletal muscle NAMPT expression and that NAMPT correlates with mitochondrial content. Further studies are necessary to elucidate the pathways regulating NAMPT as well as its downstream effects.
Some Coupled Fixed Point Theorems in Cone Metric Spaces
Authors: Sabetghadam F. , Masiha H. P. , Sanatpour A. H.
Published: November 2009

We prove some coupled fixed point theorems for mappings satisfying different contractive conditions on complete cone metric spaces.
Nitric Oxide Production by the Human Intestinal Microbiota by Dissimilatory Nitrate Reduction to Ammonium
Authors: Vermeiren Joan , Van de Wiele Tom , Verstraete Willy , Boeckx Pascal , Boon Nico
Published: November 2009

The free radical nitric oxide (NO) is an important signaling molecule in the gastrointestinal tract. Besides eukaryotic cells, gut microorganisms are also capable of producing NO. However, the exact mechanism of NO production by the gut microorganisms is unknown. Microbial NO production was examined under in vitro conditions simulating the gastrointestinal ecosystem using L‐arginine or nitrate as substrates. L‐arginine did not influence the microbial NO production. However, NO concentrations in the order of 90 ng NO‐N per L feed medium were produced by the fecal microbiota from nitrate.  15N tracer experiments showed that nitrate was mainly reduced to ammonium by the dissimilatory nitrate reduction to ammonium (DNRA) pathway. To our knowledge, this is the first study showing that gastrointestinal microbiota can generate substantial amounts of NO by DNRA and not by the generally accepted denitrification or L‐arginine pathway. Further work is needed to elucidate the exact role between NO produced by the gastrointestinal microbiota and host cells.
Review: Biofunctionalized Quantum Dots in Biology and Medicine
Authors: Mazumder Sonal , Dey Rajib , Mitra M. K. , Mukherjee S. , Das G. C.
Published: November 2009

Quantum dot (QD) nanocrystals which have important optical properties, in particular, the wavelength of their fluorescence, depend strongly on their size. Colloidal QDs once dispersed in a solvent are quite interesting fluorescence probes for all types of labelling studies because of their reduced tendency to photo bleach. In this review, we will give an overview on how QDs have been used so far in cell biology. In particular, we will discuss the biologically relevant properties of QDs and focus on four topics: labeling of cellular structures and receptors with QDs, incorporation of QDs by living cells, tracking the path and the fate of individual cells using QD labels, and QDs as contrast agents. QDs are seen to be much better in terms of efficacy over radioisotopes in tracing medicine in vivo. They are rapidly being applied to existing and emerging technologies but here this review deals with a comprehensive compilation of the biological relevance of quantum dots. It covers important information from 1999 till 2008 with few from 1982 to 1997.
Mathematical Transform of Traveling‐Wave Equations and Phase Aspects of Quantum Interaction
Authors: Bakhoum Ezzat G. , Toma Cristian
Published: November 2009

The traveling wave equation is an essential tool in the study of vibrations and oscillating systems. This paper introduces an important extension to the Fourier/Laplace transform that is needed for the analysis of signals that are represented by traveling wave equations. Another objective of the paper is to present a mathematical technique for the simulation of the behavior of large systems of optical oscillators.
Epigenetic Repression of microRNA-129-2 Leads to Overexpression of SOX4 Oncogene in Endometrial Cancer
Authors: Huang Yi-Wen , Liu Joseph C. , Deatherage Daniel E. , Luo Jingqin , Mutch David G. , Goodfellow Paul J. , Miller David S. , Huang Tim H-M.
Published: November 2009

Genetic amplification, mutation, and translocation are known to play a causal role in the upregulation of an oncogene in cancer cells. Here, we report an emerging role of microRNA, the epigenetic deregulation of which may also lead to this oncogenic activation. SOX4, an oncogene belonging to the SRY-related high mobility group box family, was found to be overexpressed (P < 0.005) in endometrial tumors (n = 74) compared with uninvolved controls (n = 20). This gene is computationally predicted to be the target of a microRNA, miR-129-2. When compared with the matched endometria, the expression of miR-129-2 was lost in 27 of 31 primary endometrial tumors that also showed a concomitant gain of SOX4 expression (P < 0.001). This inverse relationship is associated with hypermethylation of the miR-129-2 CpG island, which was observed in endometrial cancer cell lines (n = 6) and 68% of 117 endometrioid endometrial tumors analyzed. Reactivation of miR-129-2 in cancer cells by pharmacologic induction of histone acetylation and DNA demethylation resulted in decreased SOX4 expression. In addition, restoration of miR-129-2 by cell transfection led to decreased SOX4 expression and reduced proliferation of cancer cells. Further analysis found a significant correlation of hypermethylated miR-129-2 with microsatellite instability and MLH1 methylation status (P < 0.001) and poor overall survival (P < 0.039) in patients. Therefore, these results imply that the aberrant expression of SOX4 is, in part, caused by epigenetic repression of miR-129-2 in endometrial cancer. Unlike the notion that promoter hypomethylation may upregulate an oncogene, we present a new paradigm in which hypermethylation-mediated silencing of a microRNA derepresses its oncogenic target in cancer cells. [Cancer Res 2009;69(23):9038–46]
Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma
Authors: Goto Yasuhiro , Shinjo Keiko , Kondo Yutaka , Shen Lanlan , Toyota Minoru , Suzuki Hiromu , Gao Wentao , An Byonggu , Fujii Makiko , Murakami Hideki , Osada Hirotaka , Taniguchi Tetsuo , Usami Noriyasu , Kondo Masashi , Hasegawa Yoshinori , Shimokata Kaoru , Matsuo Keitaro , Hida Toyoaki , Fujimoto Nobukazu , Kishimoto Takumi , Issa Jean-Pierre J. , Sekido Yoshitaka
Published: November 2009

Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease. Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets. [Cancer Res 2009;69(23):9073–82]
Toll-like Receptors 3 and 7 Agonists Enhance Tumor Cell Lysis by Human γδ T Cells
Authors: Shojaei Hamed , Oberg Hans-Heinrich , Juricke Matthias , Marischen Lothar , Kunz Monika , Mundhenke Christoph , Gieseler Frank , Kabelitz Dieter , Wesch Daniela
Published: November 2009

Toll-like receptor (TLR) agonists are considered adjuvants in clinical trials of cancer immunotherapy. Here, we investigated the modulation of γδ T cell–mediated tumor cell lysis by TLR ligands. γδ T-cell cytotoxicity and granzyme A/B production were enhanced after pretreatment of tumor cells with TLR3 [poly(I:C)] or TLR7 ligand (imiquimod). We examined TLR3- and TLR7-expressing pancreatic adenocarcinomas, squamous cell carcinomas of head and neck and lung carcinomas. Poly(I:C) treatment of pancreatic adenocarcinomas followed by coculture with γδ T cells resulted in an upregulation of CD54 on the tumor cells. The interaction of CD54 and the corresponding ligand CD11a/CD18 expressed on γδ T cells is responsible for triggering effector function in γδ T cells. Moreover, treatment with imiquimod downregulated MHC class I molecules on tumor cells possibly resulting in a reduced binding affinity for inhibitory receptor NKG2A expressed on γδ T cells. These results indicate that TLR3 or TLR7 ligand stimulation of tumor cells enhances the cytotoxic activity of expanded γδ T cells of cancer patients in vitro. [Cancer Res 2009;69(22):8710–7]
Mammary Tumor Development in Dogs Is Associated with BRCA1 and BRCA2
Authors: Rivera Patricio , Melin Malin , Biagi Tara , Fall Tove , Häggström Jens , Lindblad-Toh Kerstin , von Euler Henrik
Published: November 2009

Breast cancer is a major contributor to overall morbidity and mortality in women. Several genes predisposing to breast cancer have been identified, but the majority of risk factors remain unknown. Even less is known about the inherited risk factors underlying canine mammary tumors (CMT). Clear breed predispositions exist, with 36% of English springer spaniels (ESS) in Sweden being affected. Here, we evaluate 10 human breast cancer genes (BRCA1, BRCA2, CHEK2, ERBB2, FGFR2, LSP1, MAP3K1, RCAS1, TOX3, and TP53) for association with CMTs. Sixty-three single-nucleotide polymorphisms (SNPs; four to nine SNPs per gene) were genotyped by iPLEX in female ESS dogs, 212 CMT cases and 143 controls. Two genes, BRCA1 and BRCA2, were significantly associated with CMT (Bonferroni corrected P = 0.005 and P = 0.0001, respectively). Borderline association was seen for FGFR2. Benign and malignant cases were also analyzed separately. Those findings supported the association to BRCA1 and BRCA2 but with a stronger association to BRCA1 in malignant cases. Both BRCA1 and BRCA2 showed odds ratios of ∼4. In conclusion, this study indicates that BRCA1 and BRCA2 contribute to the risk of CMT in ESS, suggesting that dogs may serve as a good model for human breast cancer. [Cancer Res 2009;69(22):8770–4]
Ubiquitination and Downregulation of BRCA1 by Ubiquitin-Conjugating Enzyme E2T Overexpression in Human Breast Cancer Cells
Authors: Ueki Tomomi , Park Jae-Hyun , Nishidate Toshihiko , Kijima Kyoko , Hirata Koichi , Nakamura Yusuke , Katagiri Toyomasa
Published: November 2009

Breast cancer is generated through a multistep genetic and epigenetic process including activations of oncogenes and inactivations of tumor suppressor genes. Here, we report a critical role of ubiquitin-conjugating enzyme E2T (UBE2T), an E2 ubiquitin-conjugating enzyme, in mammary carcinogenesis. Immunocytochemical staining and in vitro binding assay revealed that UBE2T interacted and colocalized with the BRCA1/BRCA1-associated RING domain protein (BARD1) complex. Knocking down of UBE2T expression with small interfering RNA drastically suppressed the growth of breast cancer cells. Interestingly, in vivo ubiquitination assay indicated BRCA1 to be polyubiquitinated by incubation with wild-type UBE2T protein, but not with C86A-UBE2T protein, an E2 activity–dead mutant, in which the 86th residue of cysteine was replaced with alanine. Furthermore, knocking down of UBE2T protein induced upregulation of BRCA1 protein in breast cancer cells, whereas its overexpression caused the decrease of the BRCA1 protein. Our data imply a critical role of UBE2T in development and/or progression of breast cancer through the interaction with and the regulation of the BRCA1/BARD1 complex. [Cancer Res 2009;69(22):8752–60]
Cell Fusion as a Hidden Force in Tumor Progression
Authors: Lu Xin , Kang Yibin
Published: November 2009

Cell fusion plays an essential role in fertilization, formation of placenta, bone and muscle tissues, immune response, tissue repair, and regeneration. Increasing recognition of cell fusion in somatic cell dynamics has revitalized the century-old hypothesis that cell fusion may contribute to the initiation and progression of cancer. In this review, we discuss findings from experimental and clinical studies that suggest a potentially multifaceted involvement of cell fusion in different stages of tumor progression, including aneuploidy and tumor initiation, origin of cancer stem cells, multidrug resistance, and the acquisition and diversification of metastatic abilities. [Cancer Res 2009;69(22):8536–9]
Lipid Rafts and Caveolin-1 Are Required for Invadopodia Formation and Extracellular Matrix Degradation by Human Breast Cancer Cells
Authors: Yamaguchi Hideki , Takeo Yukiko , Yoshida Shuhei , Kouchi Zen , Nakamura Yoshikazu , Fukami Kiyoko
Published: November 2009

Invadopodia are ventral membrane protrusions through which invasive cancer cells degrade the extracellular matrix. They are thought to function in the migration of cancer cells through tissue barriers, which is necessary for cancer invasion and metastasis. Although many protein components of invadopodia have been identified, the organization and the role of membrane lipids in invadopodia are not well understood. In this study, the role of lipid rafts, which are cholesterol-enriched membrane microdomains, in the assembly and function of invadopodia in human breast cancer cells was investigated. Lipid rafts are enriched, internalized, and dynamically trafficked at invadopodia sites. Perturbation of lipid raft formation due to depleting or sequestering membrane cholesterol blocked the invadopodia-mediated degradation of the gelatin matrix. Caveolin-1 (Cav-1), a resident protein of lipid rafts and caveolae, accumulates at invadopodia and colocalizes with the internalized lipid raft membranes. Membrane type 1 matrix metalloproteinase (MT1-MMP), a matrix proteinase associated with invadopodia, is localized at lipid raft-enriched membrane fractions and cotrafficked and colocalized with Cav-1 at invadopodia. The small interfering RNA–mediated silencing of Cav-1 inhibited the invadopodia-mediated and MT1-MMP–dependent degradation of the gelatin matrix. Furthermore, Cav-1 and MT1-MMP are coexpressed in invasive human breast cancer cell lines that have an ability to form invadopodia. These results indicate that invadopodia are the sites where enrichment and trafficking of lipid rafts occur and that Cav-1 is an essential regulator of MT1-MMP function and invadopodia-mediated breast cancer cell invasion. [Cancer Res 2009;69(22):8594–602]
Functional Significance of Wnt Inhibitory Factor-1 Gene in Kidney Cancer
Authors: Kawakami Kazumori , Hirata Hiroshi , Yamamura Soichiro , Kikuno Nobuyuki , Saini Sharanjot , Majid Shahana , Tanaka Yuichiro , Kawamoto Ken , Enokida Hideki , Nakagawa Masayuki , Dahiya Rajvir
Published: November 2009

Wnt inhibitory factor-1 (WIF-1) has been identified as one of the secreted antagonists that bind Wnt protein. WIF-1 has been described as a tumor suppressor in various types of cancer. However, the molecular function of WIF-1 gene has never been examined in human renal cell carcinoma (RCC). Therefore, we hypothesized that WIF-1 functions as a tumor suppressor gene and overexpression of this gene may induce apoptosis and inhibit tumor growth in RCC cells. Immunohistochemistry and real-time reverse transcription-PCR revealed that WIF-1 was significantly downregulated in RCC samples and RCC cell lines, respectively. Bisulfite sequencing of the WIF-1 promoter region in RCC cell lines showed it to be densely methylated, whereas there was no methylation of WIF-1 promoter in normal kidney. Significant inhibition of cell growth and colony formation in WIF-1–transfected cells compared with controls were observed. WIF-1 transfection significantly induced apoptosis and suppressed in vivo tumor growth. Also, Wnt signaling activity and β-catenin expression were reduced by WIF-1 transfection. In conclusion, this is the first report documenting that the WIF-1 is downregulated by promoter methylation and functions as a tumor suppressor gene by inducing apoptosis in RCC cells. [Cancer Res 2009;69(22):8603–10]
Antiphosphatidylserine Antibody Combined with Irradiation Damages Tumor Blood Vessels and Induces Tumor Immunity in a Rat Model of Glioblastoma
Authors: He Jin , Yin Yi , Luster Troy A. , Watkins Linda , Thorpe Philip E.
Published: November 2009

Purpose: The vascular targeting antibody bavituximab is being combined with chemotherapy in clinical trials in cancer patients. Bavituximab targets the membrane phospholipid, phosphatidylserine, complexed with 2-glycoprotein I. Phosphatidylserine is normally intracellular but becomes exposed on the luminal surface of vascular endothelium in tumors. Phosphatidylserine exposure on tumor vessels is increased by chemotherapy and irradiation. Here, we determined whether treatment with the murine equivalent of bavituximab, 2aG4, combined with irradiation can suppress tumor growth in a rat model of glioblastoma.

Experimental Design: F98 glioma cells were injected into the brains of syngeneic rats where they grow initially as a solid tumor and then infiltrate throughout the brain. Rats with established tumors were treated with 10 Gy whole brain irradiation and 2aG4.

Results: Combination treatment doubled the median survival time of the rats, and 13 of animals were rendered disease free. Neither treatment given individually was as effective. We identified two mechanisms. First, irradiation induced phosphatidylserine exposure on tumor blood vessels and enhanced antibody-mediated destruction of tumor vasculature by monocytes/macrophages. Second, the antibody treatment induced immunity to F98 tumor cells, which are normally weakly immunogenic. Surviving rats were immune to rechallenge with F98 tumor cells. In vitro, 2aG4 enhanced the ability of dendritic cells (DCs) to generate F98-specific cytotoxic T cells. Phosphatidylserine exposure, which is induced on tumor cells by irradiation, likely suppresses tumor antigen presentation, and 2aG4 blocks this tolerogenic effect.

Conclusion: Bavituximab combined with radiotherapy holds promise as a vascular targeting and immune enhancement strategy for the treatment of human glioblastoma. (Clin Cancer Res 2009;15(22):687180)
Homozygous Deletion of MTAP Gene as a Poor Prognosticator in Gastrointestinal Stromal Tumors
Authors: Huang Hsuan-Ying , Li Shau-Hsuan , Yu Shih-Chen , Chou Fong-Fu , Tzeng Ching-Cherng , Hu Tsung-Hui , Uen Yih-Huei , Tian Yu-Fang , Wang Yu-Hui , Fang Fu-Min , Huang Wen-Wei , Wei Yu-Ching , Wu Jing-Mei , Li Chien-Feng
Published: November 2009

Purpose: Chromosome 9 is frequently deleted in high-risk gastrointestinal stromal tumors (GISTs), whereas its specific tumor suppressor genes (TSGs) are less understood. We did an integrative study of MTAP gene at 9p21 to analyze its implication in GISTs.

Experimental Design: To search TSGs on chromosome 9, we used ultrahigh-resolution array comparative genomic hybridization to profile DNA copy number alterations of 22 GISTs, with special attention to MTAP gene. MTAP immunoexpression was assessable for 306 independent GISTs on tissue microarrays, with 146 cases analyzed for MTAP homozygous deletion, 181 for mutations of KIT and PDGFRA receptor tyrosine kinase genes, and 7 for MTAP hypermethylation.

Results: Array comparative genomic hybridization identified 11 candidate TSGs on 9p and six on 9q. MTAP and/or CDKN2A/CDKN2B at 9p21.3 were deleted in one intermediate-risk (11) and seven high-risk (70) GISTs with two cases homozygously codeleted at both loci. MTAP homozygous deletion, present in 25 of 146 cases, was highly associated with larger size and higher mitotic rate, Ki-67 index, and risk level (all P < 0.01) but not with receptor tyrosine kinase genotypes. Whereas MTAP homozygous deletion correlated with MTAP protein loss (P < 0.001), 7 of 30 GISTs without MTAP expression did not show homozygous deletion, including three MTAP-hypermethylated cases. MTAP homozygous deletion was univariately predictive of decreased disease-free survival (P < 0.0001) and remained multivariately independent (P = 0.0369, hazard ratio = 2.166), together with high-risk category (P < 0.0001), Ki-67 index >5 (P = 0.0106), and nongastric location (P = 0.0416).

Conclusions: MTAP homozygous deletion, the predominant mechanism to deplete protein expression, is present in 17 of GISTs. It correlates with important prognosticators and independently predicts worse outcomes, highlighting the role in disease progression. (Clin Cancer Res 2009;15(22):696372)
Phase II Study of Androgen Synthesis Inhibition with Ketoconazole, Hydrocortisone, and Dutasteride in Asymptomatic Castration-Resistant Prostate Cancer
Authors: Taplin Mary-Ellen , Regan Meredith M. , Ko Yoo-Joung , Bubley Glenn J. , Duggan Stephen E. , Werner Lillian , Beer Tomasz M. , Ryan Christopher W. , Mathew Paul , Tu Shi-Ming , Denmeade Samuel R. , Oh William K. , Sartor Oliver , Mantzoros Christos S. , Rittmaster Roger , Kantoff Philip W. , Balk Steven P.
Published: November 2009

Purpose: Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC).

Experimental Design: Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.5 mg/d).

Results: Prostate-specific antigen response rate (50 decline) was 56 (32 of 57; 95 confidence interval, 42.4-69.3); the median duration of response was 20 months. In patients with measurable disease, 6 of 20 (30) responded by the Response Evaluation Criteria in Solid Tumors. Median duration of treatment was 8 months; 9 patients remained on therapy with treatment durations censored at 18 to 32 months. Median time to progression was 14.5 months. Grade 3 toxicities occurred in 32 with only one reported grade 4 (thrombosis) toxicity. Dehydroepiandrosterone sulfate declined by 89, androstenedione by 56, and testosterone by 66, and dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone. Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders versus nonresponders, and hormone levels were not significantly increased from nadir levels at relapse.

Conclusion: The response proportion to ketoconazole, hydrocortisone, and dutasteride was at least comparable with previous studies of ketoconazole alone, whereas time to progression was substantially longer. Combination therapies targeting multiple steps in androgen synthesis warrant further investigation. (Clin Cancer Res 2009;15(22):7099105)
A Multimarker Prognostic Assay for Primary Cutaneous Melanoma
Authors: Kashani-Sabet Mohammed , Venna Suraj , Nosrati Mehdi , Rangel Javier , Sucker Antje , Egberts Friederike , Baehner Frederick L. , Simko Jeff , Leong Stanley P.L. , Haqq Chris , Hauschild Axel , Schadendorf Dirk , Miller James R. , Sagebiel Richard W.
Published: November 2009

Purpose: To determine the prognostic significance of a multimarker assay incorporating expression levels of three molecular markers in primary cutaneous melanoma.

Experimental Design: We assessed expression levels of NCOA3, SPP1, and RGS1 using immunohistochemical analysis in a tissue microarray cohort of 395 patients. For each marker, we identified optimal cut-points for expression intensity to predict disease-specific survival (DSS) and, as a secondary endpoint, sentinel lymph node (SLN) status. The cumulative overexpression of all three markers was embodied in a multimarker index, and its prognostic effect on DSS and SLN status was assessed using Cox regression, Kaplan-Meier analysis, and logistic regression. The prognostic effect of this multimarker assay on DSS was assessed in an independent cohort of 141 patients, in which marker expression levels were scored using immunohistochemical analysis of stained tissue sections.

Results: Increasing multimarker index scores were significantly predictive of reduced DSS and increased SLN metastasis in the 395-patient cohort. Multivariate logistic regression analysis revealed multimarker expression scores as an independent predictor of SLN status (P = 0.001). Multivariate Cox regression analysis showed the independent effect of the multimarker index on DSS (P < 0.001). The multimarker index was the most significant factor predicting DSS when compared with other clinical and histologic factors, including SLN status (P = 0.002). Multimarker expression scores were also the most significantly predictive of DSS in the independent cohort (P = 0.01).

Conclusions: These results describe a multimarker assay with independent prognostic effect on the prediction of survival associated with melanoma in two distinct cohorts. (Clin Cancer Res 2009;15(22):698792)
Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents
Authors: Boone Julien J.M. , Bhosle Jaishree , Tilby Mike J. , Hartley John A. , Hochhauser Daniel
Published: November 2009

HER2 (ErbB2) is overexpressed in up to 30% of human breast cancers. Preclinical and clinical studies suggest synergy between some chemotherapeutic agents and the humanized anti-HER2 antibody trastuzumab (Herceptin). This study investigated the effects of etoposide and cisplatin on the repair of DNA damage in breast cancer cell lines. We examined the potential significance of HER2 nuclear expression in DNA repair. MCF-7, SK-BR-3, and MDA-MB-453 cells were treated with cisplatin and etoposide. Repair of DNA interstrand crosslinks (ICL) and strand breaks, following incubation with cisplatin and etoposide, respectively, were quantitated by the single-cell gel electrophoresis (comet) assay. Intrastrand crosslinks produced by cisplatin were assessed by ELISA. The effects of trastuzumab were measured in combination with these drugs. Similar experiments were done using HER2-negative MDA-MB-468 cells transfected with HER2 and a construct lacking the nuclear localization sequence. Incubation of breast cancer cell lines with trastuzumab delayed the repair of ICL produced by cisplatin. There were no effects on the repair of intrastrand crosslinks produced by cisplatin, or repair of DNA strand breaks following etoposide treatment. Transfection of HER2 into MDA-MB-468 cells inhibited the repair of cisplatin-induced ICL, whereas transfection of a HER2 construct lacking the nuclear localization sequence did not affect DNA repair. These results indicate that HER2 expression modulates the repair of specific DNA lesions produced by chemotherapy. The effect on ICL repair requires nuclear expression of HER2. Understanding the mechanisms of interaction between DNA-interacting agents and HER2 inhibitors will inform the design of clinical trials and optimize the therapeutic effects of these combinations. [Mol Cancer Ther 2009;8(11):3015–23]
Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents
Authors: Hirai Hiroshi , Iwasawa Yoshikazu , Okada Megumu , Arai Tsuyoshi , Nishibata Toshihide , Kobayashi Makiko , Kimura Toshifumi , Kaneko Naoki , Ohtani Junko , Yamanaka Kazunori , Itadani Hiraku , Takahashi-Suzuki Ikuko , Fukasawa Kazuhiro , Oki Hiroko , Nambu Tadahiro , Jiang Jian , Sakai Takumi , Arakawa Hiroharu , Sakamoto Toshihiro , Sagara Takeshi , Yoshizumi Takashi , Mizuarai Shinji , Kotani Hidehito
Published: November 2009

Wee1 is a tyrosine kinase that phosphorylates and inactivates CDC2 and is involved in G2 checkpoint signaling. Because p53 is a key regulator in the G1 checkpoint, p53-deficient tumors rely only on the G2 checkpoint after DNA damage. Hence, such tumors are selectively sensitized to DNA-damaging agents by Wee1 inhibition. Here, we report the discovery of a potent and selective small-molecule inhibitor of Wee1 kinase, MK-1775. This compound inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. MK-1775 abrogates G2 DNA damage checkpoint, leading to apoptosis in combination with DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin selectively in p53-deficient cells. In vivo, MK-1775 potentiates tumor growth inhibition by these agents, and cotreatment does not significantly increase toxicity. The enhancement of antitumor effect by MK-1775 was well correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles. Our data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies. [Mol Cancer Ther 2009;8(11):2992–3000]
Mcl-1 is an important determinant of the apoptotic response to the BH3-mimetic molecule HA14-1 in cisplatin-resistant ovarian carcinoma cells
Authors: Simonin Karin , Brotin Emilie , Dufort Sandrine , Dutoit Soizic , Goux Didier , N'Diaye Monique , Denoyelle Christophe , Gauduchon Pascal , Poulain Laurent
Published: November 2009

Chemoresistance of ovarian carcinoma has been associated previously to the absence of Bcl-xL expression downregulation in response to cisplatin. Among BH3-mimetic molecules constituting promising anticancer agents able to inhibit the activity of antiapoptotic Bcl-2 family proteins, we evaluated the effect of one of them, HA14-1, on various ovarian carcinoma cell lines. In response to HA14-1, the cisplatin-resistant IGROV1-R10 cell line underwent massive cell death, whereas other cell lines presented a partial response (IGROV1, SKOV3, and A2780) or did not respond to this molecule (OAW42 and OAW42-R). However, the expression of HA14-1 targets (Bcl-2 and Bcl-xL) did not correlate to these different responses. In contrast, cell death was associated with the disappearance of Mcl-1 after exposure to HA14-1. We showed that, in the HA14-1 nonresponsive cell lines (SKOV3 and OAW42), small interfering RNA–mediated Mcl-1 downregulation allowed HA14-1–induced massive apoptosis in the absence of chemotherapy. Furthermore, cisplatin-induced Mcl-1 downregulation was also able to sensitize highly chemoresistant SKOV3 cells to HA14-1. Taken together, these results show that Bcl-xL and Mcl-1 are able to cooperate to protect ovarian carcinoma cells against oncogenic stress or chemotherapy-induced apoptosis and suggest that the development of multitargeted strategies directed against these two antiapoptotic proteins may constitute a major challenge for the therapeutic care of chemoresistant ovarian carcinomas. BH3-mimetic compounds represent promising tools for this purpose either on their own (direct or indirect pan-inhibitors) or in combination with new drugs aiming to inactivate Mcl-1. [Mol Cancer Ther 2009;8(11):3162–70]
MUC1 oncoprotein is a druggable target in human prostate cancer cells
Authors: Joshi Maya Datt , Ahmad Rehan , Yin Li , Raina Deepak , Rajabi Hasan , Bubley Glenn , Kharbanda Surender , Kufe Donald
Published: November 2009

Human prostate cancers are dependent on the androgen receptor for their progression. The MUC1 heterodimeric oncoprotein is aberrantly overexpressed in prostate cancers; however, it is not known if MUC1 is of functional importance to these tumors. To assess dependence on MUC1, we synthesized an inhibitor, designated GO-201, which interacts directly with the MUC1-C subunit at its oligomerization domain. Treatment of MUC1-positive DU145 and PC3 prostate cancer cells with GO-201, and not an altered version, resulted in inhibition of proliferation. GO-201 also induced necrotic cell death that was associated with increases in reactive oxygen species, loss of mitochondrial transmembrane potential, and depletion of ATP. By contrast, GO-201 had no effect against MUC1-negative LNCaP, CWR22Rv1, and MDA-PCa-2b prostate cancer cells. Significantly, GO-201 treatment of DU145 and PC3 xenografts growing in nude mice resulted in complete tumor regression and prolonged lack of recurrence. These findings indicate that certain prostate cancer cells are dependent on MUC1-C for growth and survival and that directly targeting MUC1-C results in their death in vitro and in tumor models. [Mol Cancer Ther 2009;8(11):3056–65]
The Impact of Dialysis Modality on Serum Heat Shock Proteins in Children and Young Adults with Chronic Kidney Disease
Authors: Musiał Kinga , Szczepańska Maria , Szprynger Krystyna , Zwolińska Danuta
Published: November 2009

Background/Aims: The acceleration of atherosclerosis by dialysis is not completely understood. The elevated levels of heat shock proteins (HSP) and antibodies against them were described in adults with atherosclerotic lesions, but there are no investigations on them in dialyzed patients. The aim of the studywas to evaluate the serum HSP, their connections with dialysis modality and their possible role as markers of atherosclerosis. Methods: Hsp60, Hsp90-α, anti-Hsp60 and anti-Hsp70 concentrations were assessed by ELISA in 19 children on automated peritoneal dialysis (APD) and 17 patients on hemodialysis (HD). hsCRP, sE-selectin, IL-4, IL-12 and the lipid profile were also estimated. Results: Hsp60 values were lower, whereas Hsp90-α was higher in the dialyzed children than in the controls, without any difference between the dialysis modalities. The anti-Hsp60 concentrations were increased in all patients and higher in HD patients than in APD patients. The anti-Hsp70 levels in the APD children were decreased versus controls. Anti-Hsp60 correlated with HDL-cholesterol in APD children, and with total cholesterol and LDL-cholesterol in HD patients. Anti-Hsp70 correlated with sE-selectin in HD subjects. Conclusions: The levels of antibodies against HSP seem to distinguish between the dialysis modalities and the correlations with the lipid profile and sE-selectin, suggesting their potential role as markers of atherosclerosis.
Autosomal Dominant Polycystic Kidney Disease: New Treatment Options and How to Test Their Efficacy
Authors: Wüthrich Rudolf P. , Serra Andreas L. , Kistler Andreas D.
Published: November 2009

Autosomal dominant polycystic kidney disease (ADPKD) represents a slowly progressing cystic kidney disorder which evolves into end-stage renal disease in the majority of patients. Currently, there are no established treatments to retard the progression of the disease, but several promising therapeutic options are being tested in ongoing clinical trials. An inherent dilemma for the investigation of therapies in ADPKD is the dissociation of the early onset and constant rate of cyst growth from the delayed but accelerated loss of renal function. In order to prevent the latter, one needs to act on the former, i.e. current belief by experts in the field is that (1) retardation of cyst growth will ultimately improve the loss of glomerular filtration rate, and (2) cyst volume is an ideal surrogate parameter for outcome in early ADPKD. The present review will discuss the utility and the techniques for kidney and cyst volume measurements to assess disease progression in ADPKD, and summarizes ongoing clinical trials testing novel therapeutic options.
“Prettier Than They Used to Be”: Femininity, Fashion, and the Recasting of Radcliffe's Reputation, 1900–1950
Authors: Clemente Deirdre
Published: November 2009

Brains and beauty? From the pants suit of Wellesley grad Hillary Clinton to the toned arms of Princetonian Michelle Obama, the American public is preoccupied with the physical appearance of highly educated women. This article explores how administrators, publicists, and students at Radcliffe College mounted a half-century-long campaign to convince America that smart girls can be sexy.
A Commentary: A Communication about a Communication
Authors: Hartman Lars
Published: November 2009

To analyze some possible foci of a commentator's work a model of interpretation is applied: through Text (the commentary) a Sender/the Interpreter (the commentator) interprets a Text (the biblical text) to Recipients (the readers of the commentary) as the Message of Sender (the biblical author) with a certain Purpose to a Recipient (the addressee in the early church) who is in a given Situation (in the early church).
Effects of Inclined Magnetic Field on a Fluid with Non‐linear Variable Viscosity in a Uniform Tube with Peristalsis
Authors: Abd Elnaby A.H. , El Shamy I.I.
Published: November 2009

In order to determined the characteristics of peristaltic transport of the Newtonian fluid with variable viscosity through a cylindrical tube having walls that are transversely displaced by an in finite, harmonic traveling wave of large wavelength and negligibly small Reynolds number was analyzed in the presence of magnetic field directed with an angle π A perturbation method of solution is thought. The viscosity parameter a <<1 is chosen as a perturbation parameter. It serves as a model for the study of flow of chyme through small intestines. The governing equations are developed up to first‐order in the viscosity parameter (a). In case of the first‐order system, simpling a complicated group of products of Bessel functions by approximating polynomial. The results show that, the increasing of magnetic field increases the pressure rise. Also, the pressure rise at normal magnetic field (ω=π/2) is greater than the pressure rise at inclined magnetic field (O<ω>π/2). In addition, the pressure rise increases as the viscosity parameter decreases at certain values of flow rate. Comparisons with other studies are given.
Velocity and Temperature Structure Functions in the Upper Troposphere and Lower Stratosphere from High-Resolution Aircraft Measurements
Authors: Wroblewski Donald E. , Coté Owen R. , Hacker Jorg M. , Dobosy Ronald J.
Published: November 2009

High-resolution measurements obtained from NOAA “best” atmospheric turbulence (BAT) probes mounted on an EGRETT high-altitude research aircraft were used to characterize turbulence in the upper troposphere and lower stratosphere at scales from 2 m to 20 km, focusing on three-dimensional behavior in the sub-kilometer-scale range. Data were analyzed for 129 separate level flight segments representing 41 h of flight time and 12 600 km of wind-relative flight distances. The majority of flights occurred near the tropopause layer of the winter subtropical jet stream in the Southern Hemisphere. Second-order structure functions for velocity and temperature were analyzed for the separate level-flight segments, individually and in various ensembles. A 3D scaling range was observed at scales less than about 100 m, with power-law exponents for the structure functions of the velocity component in the flight direction varying mostly between 0.4 and 0.75 for the separate flight segments, but close to ⅔ for the ensemble-averaged curves for all levels and for various subensembles. Structure functions in the 3D scaling range were decoupled from those at scales greater than 10 km, with the large-scale structure functions showing less variation than those at smaller scales. Weakly anisotropic behavior was observed in the 3D range, with structure parameters for the lateral and vertical velocities on the same order as those in the flight direction but deviating from the expected isotropic value. Anisotropy was correlated with turbulence intensity, with greater anisotropy associated with weaker turbulence.