bluuebunny/crossref_metadata_2025 huggingface dataset:
Publisher FrameWork (PFW)
Authors: Klein Judith , Sotirovski Drasko
Published: October 2006

One of the lasting challenges in building distributed fault tolerant systems is keeping application code size and complexity down. This can be done by capturing the nuances of distributed computing environment and redundant fault tolerant elements into a common infrastructure layer, thus factoring the code that would otherwise need to be written again and again by each distributed fault tolerant software component. When the application code has many complexities, and Air Traffic Control (ATC) is certainly one such example, achieving this goal becomes paramount.Under a project called En Route Automation Modernization (ERAM), the Federal Aviation Administration (FAA) is developing a replacement for its aging en route assets. At the same time, a foundation is being created for the anticipated future enhancements, driven by the projected increase in air traffic. At the core of the ERAM design is a distributed object oriented (OO) framework called Publisher FrameWork (PFW), which is ERAM's answer to the aforementioned OO challenge. This paper describes the PFW properties, the experiences with it accumulated through the first build of the ERAM program, and its applicability to fault tolerant computing.
Zooming versus multiple window interfaces
Authors: Plumlee Matthew D. , Ware Colin
Published: October 2006

In order to investigate large information spaces effectively, it is often necessary to employ navigation mechanisms that allow users to view information at different scales. Some tasks require frequent movements and scale changes to search for details and compare them. We present a model that makes predictions about user performance on such comparison tasks with different interface options. A critical factor embodied in this model is the limited capacity of visual working memory, allowing for the cost of visits via fixating eye movements to be compared to the cost of visits that require user interaction with the mouse. This model is tested with an experiment that compares a zooming user interface with a multi-window interface for a multiscale pattern matching task. The results closely matched predictions in task performance times; however error rates were much higher with zooming than with multiple windows. We hypothesized that subjects made more visits in the multi-window condition, and ran a second experiment using an eye tracker to record the pattern of fixations. This revealed that subjects made far more visits back and forth between pattern locations when able to use eye movements than they made with the zooming interface. The results suggest that only a single graphical object was held in visual working memory for comparisons mediated by eye movements, reducing errors by reducing the load on visual working memory. Finally we propose a design heuristic: extra windows are needed when visual comparisons must be made involving patterns of a greater complexity than can be held in visual working memory.
Investigating interaction in CAVE virtual environments
Authors: Sutcliffe Alistair , Gault Brian , Fernando Terence , Tan Kevin
Published: October 2006

An experimental comparison of interaction in the real world and a CAVE virtual environment was carried out, varying interaction with and without virtual hands and comparing two manipulation tasks. The double-handed task was possible in the real world but nearly impossible in the VE, leading to changed behavior. The single-handed task showed more errors in the VE but few behavioral differences. Users encountered more errors in the CAVE condition without the virtual hand than with it, and few errors in the real world. Visual feedback caused many usability problems in both tasks. The implications for VE usability and virtual prototyping are discussed.
A large scale, corpus-based approach for automatically disambiguating biomedical abbreviations
Authors: Yu Hong , Kim Won , Hatzivassiloglou Vasileios , Wilbur John
Published: October 2006

Abbreviations and acronyms are widely used in the biomedical literature and many of them represent important biomedical concepts. Because many abbreviations are ambiguous (e.g.,
CAT
denotes both
chloramphenicol acetyl transferase
and
computed axial tomography
, depending on the context), recognizing the full form associated with each abbreviation is in most cases equivalent to identifying the meaning of the abbreviation. This, in turn, allows us to perform more accurate natural language processing, information extraction, and retrieval. In this study, we have developed supervised approaches to identifying the full forms of ambiguous abbreviations within the context they appear. We first automatically assigned multiple possible full forms for each abbreviation; we then treated the in-context full-form prediction for each specific abbreviation occurrence as a case of word-sense disambiguation. We generated automatically a dictionary of all possible full forms for each abbreviation. We applied supervised machine-learning algorithms for disambiguation. Because some of the links between abbreviations and their corresponding full forms are explicitly given in the text and can be recovered automatically, we can use these explicit links to automatically provide training data for disambiguating the abbreviations that are not linked to a full form within a text. We evaluated our methods on over 150 thousand abstracts and obtain for coverage and precision results of 82% and 92%, respectively, when performed as tenfold cross-validation, and 79% and 80%, respectively, when evaluated against an external set of abstracts in which the abbreviations are not defined.
Expressiveness and complexity of XML Schema
Authors: Martens Wim , Neven Frank , Schwentick Thomas , Bex Geert Jan
Published: October 2006

The common abstraction of XML Schema by unranked regular tree languages is not entirely accurate. To shed some light on the actual expressive power of XML Schema, intuitive semantical characterizations of the Element Declarations Consistent (EDC) rule are provided. In particular, it is obtained that schemas satisfying EDC can only reason about regular properties of ancestors of nodes. Hence, with respect to expressive power, XML Schema is closer to DTDs than to tree automata. These theoretical results are complemented with an investigation of the XML Schema Definitions (XSDs) occurring in practice, revealing that the extra expressiveness of XSDs over DTDs is only used to a very limited extent. As this might be due to the complexity of the XML Schema specification and the difficulty of understanding the effect of constraints on typing and validation of schemas, a simpler formalism equivalent to XSDs is proposed. It is based on contextual patterns rather than on recursive types and it might serve as a light-weight front end for XML Schema. Next, the effect of EDC on the way XML documents can be typed is discussed. It is argued that a cleaner, more robust, larger but equally feasible class is obtained by replacing EDC with the notion of 1-pass preorder typing (1PPT): schemas that allow one to determine the type of an element of a streaming document when its opening tag is met. This notion can be defined in terms of grammars with restrained competition regular expressions and there is again an equivalent syntactical formalism based on contextual patterns. Finally, algorithms for recognition, simplification, and inclusion of schemas for the various classes are given.
Triggers over nested views of relational data
Authors: Shao Feng , Novak Antal , Shanmugasundaram Jayavel
Published: October 2006

Current systems that publish relational data as nested (XML) views are
passive
in the sense that they can only respond to user-initiated queries over the nested views. In this article, we propose an
active
system whereby users can place triggers on (unmaterialized) nested views of relational data. In this architecture, we present scalable and efficient techniques for processing triggers over nested views by leveraging existing support for SQL triggers over flat relations in commercial relational databases. We have implemented our proposed techniques in the context of the Quark XML middleware system. Our performance results indicate that our proposed techniques are a feasible approach to supporting triggers over nested views of relational data.
Sketching shiny surfaces
Authors: Weidenbacher Ulrich , Bayerl Pierre , Neumann Heiko , Fleming Roland
Published: October 2006

Many materials including water, plastic, and metal have specular surface characteristics. Specular reflections have commonly been considered a nuisance for the recovery of object shape. However, the way that reflections are distorted across the surface depends crucially on 3D curvature, suggesting that they could, in fact, be a useful source of information. Indeed, observers can have a vivid impression of, 3D shape when an object is perfectly mirrored (i.e., the image contains nothing but specular reflections). This leads to the question what are the underlying mechanisms of our visual system to extract this 3D shape information from a perfectly mirrored object. In this paper we propose a biologically motivated recurrent model for the extraction of visual features relevant for the perception of 3D shape information from images of mirrored objects. We qualitatively and quantitatively analyze the results of computational model simulations and show that bidirectional recurrent information processing leads to better results than pure feedforward processing. Furthermore, we utilize the model output to create a rough nonphotorealistic sketch representation of a mirrored object, which emphasizes image features that are mandatory for 3D shape perception (e.g., occluding contour and regions of high curvature). Moreover, this sketch illustrates that the model generates a representation of object features independent of the surrounding scene reflected in the mirrored object.
E-Cadherin Regulates Human Nanos1, which Interacts with p120ctn and Induces Tumor Cell Migration and Invasion
Authors: Strumane Kristin , Bonnomet Arnaud , Stove Christophe , Vandenbroucke Roosmarijn , Nawrocki-Raby Beatrice , Bruyneel Erik , Mareel Marc , Birembaut Philippe , Berx Geert , van Roy Frans
Published: October 2006

Down-regulation of the epithelial cell-cell adhesion molecule E-cadherin is frequently associated with tumor formation and progression. Besides its role in physical cell-cell adhesion, E-cadherin is also thought to be involved in intracellular signaling in normal epithelial cells. In these cells, the Armadillo catenin p120ctn binds to the cytoplasmic domain of E-cadherin and stabilizes the adhesion complexes. On loss of E-cadherin, cytoplasmic p120ctn might accumulate and contribute to tumor malignancy. We used suppression subtractive hybridization to search for genes regulated by E-cadherin expression. We isolated human Nanos1 as a transcript of which levels decrease on E-cadherin reexpression in a human breast cancer cell line. The hNanos1 protein bears a COOH-terminal (CCHC)2 zinc finger domain and belongs to an evolutionarily conserved protein family sharing functions in germ cell development in both vertebrates and invertebrates. We found an inverse correlation between E-cadherin and hNanos1 expression in various cell lines and under diverse conditions. Conditional expression of hNanos1 in human colorectal DLD1 cancer cells functionally abolished cell-cell adhesion. It induced cytoplasmic translocation of p120ctn, as well as strong migratory and invasive properties. We also found that the NH2-terminal domain of hNanos1, which is conserved only among mammals, interacts with p120ctn. hNanos1 counteracted the stimulatory effect of p120ctn on cell protrusion formation. Together, these findings describe a new function for hNanos1 as a downstream effector of E-cadherin loss contributing to tumor progression. Targeting hNanos1 might be a promising strategy in the treatment of E-cadherin–negative tumors in particular. (Cancer Res 2006; 12(20): 10007-15)
Connexins Act as Tumor Suppressors in Three-dimensional Mammary Cell Organoids by Regulating Differentiation and Angiogenesis
Authors: McLachlan Elizabeth , Shao Qing , Wang Hong-ling , Langlois Stephanie , Laird Dale W.
Published: October 2006

Connexins are tumor suppressors, and human breast connexin 26 (Cx26) and connexin 43 (Cx43) gap junctions are often down-regulated in breast cancer. We previously showed that Cx26 and Cx43 overexpressed in MDA-MB-231 breast cancer cells inhibited tumor growth in vivo but not in two-dimensional cultures. In the current study, we show that overexpression of Cx26 or Cx43 has tumor-suppressive properties in a three-dimensional environment such that they reduced anchorage-independent cell growth and induced partial redifferentiation of three-dimensional organoids of MDA-MB-231 cells. Importantly, the majority of exogenous connexins did not localize to the cell-cell interface or rescue gap junctional intercellular communication (GJIC) as assessed by dye transfer, providing evidence of a GJIC-independent mechanism of mammary tumor suppression. To further elucidate the mechanisms involved in connexin-induced three-dimensional redifferentiation of tumor cells, we examined whether connexin expression has a role in epithelial to mesenchymal transition (EMT). Cx26 and Cx43 reduced cell migration, increased cytokeratin 18 expression, and decreased vimentin levels, indicating a shift from a mesenchymal towards an epithelial phenotype. In addition, we examined the role of connexins in angiogenesis by probing an angiogenesis antibody array with conditioned media from three-dimensional MDA-MB-231 cultures. This revealed that connexin overexpression regulated various angiogenesis-linked proteins. Furthermore, secreted factors from connexin overexpressing cells inhibited endothelial cell tubulogenesis and migration, and xenografts of Cx43 overexpressing MDA-MB-231 cells showed reduced tumor angiogenesis. In summary, Cx26 and Cx43 inhibit the malignant properties of MDA-MB-231 cells via GJIC-independent mechanisms, including regulation of EMT and angiogenesis. (Cancer Res 2006; 66(20): 9886-94)
Cleavage of Misfolded Nuclear Receptor Corepressor Confers Resistance to Unfolded Protein Response–Induced Apoptosis
Authors: Ng Angela Ping Ping , Howe Fong Jek , Sijin Nin Dawn , Hirpara Jayshree L. , Asou Norio , Chen Chien-Shing , Pervaiz Shazib , Khan Matiullah
Published: October 2006

We have recently reported that accumulation of misfolded nuclear hormone receptor corepressor (N-CoR) as insoluble protein aggregates in acute promyelocytic leukemia (APL) cells induces endoplasmic reticulum (ER) stress and activates unfolded protein response (UPR). Although accumulation of misfolded proteins is known to trigger UPR-induced cytotoxic cell death in several neurodegenerative disorders, APL cells are notably resistant to UPR-induced apoptosis. The molecular basis for the paradoxical response of APL cells to UPR is not known. Here, we report that a glycoprotease, selectively expressed in APL cells, regulates the response of APL cells to UPR-induced apoptosis through processing of misfolded N-CoR protein. Results show that misfolded N-CoR is cleaved selectively in APL cells, and cellular extracts of APL cells and human primary APL cells contain activity that cleaves N-CoR protein. Purification and spectrometric analysis of N-CoR cleaving activity from an APL cell line reveals that it is a glycoprotein endopeptidase known as OSGEP. Furthermore, the cleavage of N-CoR in APL cells could be blocked by the broad-spectrum protease inhibitor AEBSF and by RNA interference–mediated down-regulation of OSGEP expression. AEBSF selectively inhibits growth and promotes apoptosis of APL cells possibly through a mechanism involving AEBSF-induced accumulation of insoluble N-CoR protein and by triggering ER stress. Taken together, these findings suggest that selective induction of protease activity in APL cells may represent a novel cytoprotective component of UPR, which could be exploited by tumor cells to survive the toxic insult of misfolded protein(s). (Cancer Res 2006; 66(20): 9903-12)
ADAM28 Is Overexpressed in Human Breast Carcinomas: Implications for Carcinoma Cell Proliferation through Cleavage of Insulin-like Growth Factor Binding Protein-3
Authors: Mitsui Yoko , Mochizuki Satsuki , Kodama Takahide , Shimoda Masayuki , Ohtsuka Takashi , Shiomi Takayuki , Chijiiwa Miyuki , Ikeda Tadashi , Kitajima Masaki , Okada Yasunori
Published: October 2006

A disintegrin and metalloproteinases (ADAMs) are involved in various biological events including cell adhesion, cell fusion, membrane protein shedding, and proteolysis. In the present study, our reverse transcription-PCR analysis showed that among the 12 different ADAM species with a putative metalloproteinase motif, prototype membrane-anchored ADAM28m and secreted-type ADAM28s are selectively expressed in human breast carcinoma tissues. By real-time quantitative PCR, their expression levels were significantly higher in carcinomas than in nonneoplastic breast tissues. In situ hybridization, immunohistochemistry, and immunoblotting analyses indicated that ADAM28 is predominantly expressed in an active form by carcinoma cells within carcinoma tissues. A direct correlation was observed between mRNA expression levels and proliferative activity of the carcinoma cells. Treatment of ADAM28-expressing breast carcinoma cells (MDA-MB231) with insulin-like growth factor-I (IGF-I) increased cell proliferation, cleavage of IGF binding protein (IGFBP)-3, as well as IGF-I cell signaling; these processes were all significantly inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. Down-regulation of ADAM28 expression in MDA-MB231 cells with small interfering RNA significantly reduced cell proliferation, IGFBP-3 cleavage, and growth of xenografts in mice. In addition, cleavage of IGFBP-3 in breast carcinoma tissues was correlated with ADAM28 expression levels and inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. These results show that ADAM28 is overexpressed in an activated form in human breast carcinoma cells and suggest that ADAM28 is involved in cell proliferation through enhanced bioavailability of IGF-I released from the IGF-I/IGFBP-3 complex by selective IGFBP-3 cleavage in human breast carcinomas. (Cancer Res 2006; 66(20): 9913-20)
Low-Dose Etoposide Enhances Telomerase-Dependent Adenovirus-Mediated Cytosine Deaminase Gene Therapy through Augmentation of Adenoviral Infection and Transgene Expression in a Syngeneic Bladder Tumor Model
Authors: Shieh Gia-Shing , Shiau Ai-Li , Yo Yi-Te , Lin Pey-Ru , Chang Chao-Ching , Tzai Tzong-Shin , Wu Chao-Liang
Published: October 2006

The human telomerase reverse transcriptase (hTERT) promoter can selectively drive transgene expression in many telomerase-positive human cancer cells. Here we evaluated combination therapy of adenoviral vector Ad-hTERT-CD encoding E. coli cytosine deaminase (CD) driven by the hTERT promoter and low-dose etoposide (0.1 μg/mL) for treating bladder cancer. Ad-hTERT-CD conferred sensitivity to 5-fluorocytosine (5-FC) in bladder cancer cells, which could be enhanced by etoposide treatment, but not in normal cells. Such effect was correlated with up-regulation of hypoxia-inducible factor (HIF)-1α expression. By contrast, etoposide activated p53 and down-regulated hTERT promoter activity in normal cells. Etoposide also increased adenoviral infection via enhancement of coxsackie-adenovirus receptor expression on bladder cancer and normal cells. Combination index analysis revealed that combined therapy of Ad-hTERT-CD (109 plaque-forming units)/5-FC (200 mg/kg) with etoposide (2 mg/kg) synergistically suppressed tumor growth and prolonged survival in mice bearing syngeneic MBT-2 bladder tumors. This combination therapy regimen induced complete tumor regression and generated antitumor immunity in 75% of tumor-bearing mice. Furthermore, increased infiltrating CD4+ and CD8+ T cells and necrosis within tumors were found in mice receiving combination therapy of Ad-hTERT-CD and etoposide compared with those treated with either treatment alone. Thus, the potential high therapeutic index of the combination therapy may be an appealing therapeutic intervention for bladder cancer. Furthermore, because a majority of human tumors exhibit high telomerase activity, adenovirus-mediated CD gene therapy driven by the hTERT promoter in combination with low-dose etoposide may be applicable to a broad spectrum of cancers. (Cancer Res 2006; 66(20): 9957-66)
Localization of a Prostate Cancer Predisposition Gene to an 880-kb Region on Chromosome 22q12.3 in Utah High-Risk Pedigrees
Authors: Camp Nicola J. , Farnham James M. , Cannon-Albright Lisa A.
Published: October 2006

Chromosome 22q has become recently a region of interest for prostate cancer. We identified previously a logarithm of odds (LOD) of 2.42 at chromosome 22q12.3. Additionally, this region has been noted by eight other studies, with linkage evidence ranging from LOD of 1.50 to 3.57. Here, we do fine mapping and localization of the region using a pedigree-specific recombinant mapping approach in 14 informative, high-risk Utah pedigrees. These 14 pedigrees were chosen because they were either “linked” or “haplotype-sharing” pedigrees or both. “Linked” pedigrees were those with significant pedigree-specific linkage evidence (LOD, >0.588; P < 0.05) to the 22q12.3 region, regardless of the number of prostate cancer cases sharing the segregating haplotype. “Haplotype-sharing” pedigrees were those with at least five prostate cancer cases sharing a segregating haplotype in the 22q12.3 region, regardless of the linkage evidence. In each pedigree, the most likely haplotype configuration (in addition to the multipoint LOD graph for linked pedigrees) was used to infer the position of recombinant events and delimit the segregating chromosomal segment in each pedigree. These pedigree-specific chromosomal segments were then overlaid to form a consensus recombinant map across all 14 pedigrees. Using this method, we identified a 881,538-bp interval at 22q12.3, between D22S1265 and D22S277, which is the most likely region that contains the 22q prostate cancer predisposition gene. The unique Utah extended high-risk pedigree resource allows this powerful localization approach in pedigrees with evidence for segregating predisposition to prostate cancer. We are mutation screening candidate genes in this region to identify specific genetic variants segregating in these pedigrees. (Cancer Res 2006; 66(20): 10205-12)
Cyclin D1 Induction of Cellular Migration Requires p27KIP1
Authors: Li Zhiping , Jiao Xuanmao , Wang Chenguang , Ju Xiaoming , Lu Yinan , Yuan Liangping , Lisanti Michael P. , Katiyar Sanjay , Pestell Richard G.
Published: October 2006

The cyclin D1 gene is amplified and overexpressed in human breast cancer, functioning as a collaborative oncogene. As the regulatory subunit of a holoenzyme phosphorylating Rb, cyclin D1 promotes cell cycle progression and a noncatalytic function has been described to sequester the cyclin-dependent kinase inhibitor protein p27. Cyclin D1 overexpression correlates with tumor metastasis and cyclin D1–deficient fibroblasts are defective in migration. The genetic mechanism by which cyclin D1 promotes migration and movement is poorly understood. Herein, cyclin D1 promoted cellular migration and cytokinesis of mammary epithelial cells. Cyclin D1 enhanced cellular migratory velocity. The induction of migration by cyclin D1 was abolished by mutation of K112 or deletion of NH2-terminal residues 46 to 90. These mutations of cyclin D1 abrogated physical interaction with p27KIP1. Cyclin D1−/− cells were p27KIP1 deficient and the defect in migration was rescued by p27KIP1 reintroduction. Conversely, the cyclin D1 rescue of cyclin D1−/− cellular migration was reversed by p27KIP1 small interfering RNA. Cyclin D1 regulated p27KIP1 abundance at the posttranslational level, inhibiting the Skp2 promoter, Skp2 abundance, and induced p27KIP1 phosphorylation at Ser10. Together, these studies show cyclin D1 promotes mammary epithelial cell migration. p27KIP1 is required for cyclin D1–mediated cellular migration. (Cancer Res 2006; 66(20): 9986-94)
Selenium Regulates Cyclooxygenase-2 and Extracellular Signal-Regulated Kinase Signaling Pathways by Activating AMP-Activated Protein Kinase in Colon Cancer Cells
Authors: Hwang Jin-Taek , Kim Young Min , Surh Young-Joon , Baik Haing Woon , Lee Seong-Kyu , Ha Joohun , Park Ock Jin
Published: October 2006

Epidemiologic and experimental evidences indicate that selenium, an essential trace element, can reduce the risk of a variety of cancers. Protection against certain types of cancers, particularly colorectal cancers, is closely associated with pathways involving cyclooxygenase-2 (COX-2). We found that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, mediates critical anticancer effects of selenium via a COX-2/prostaglandin E2 signaling pathway. Selenium activated AMPK in tumor xenografts as well as in colon cancer cell lines, and this activation seemed to be essential to the decrease in COX-2 expressions. Transduction with dominant-negative AMPK into colon cancer cells or application of cox-2−/−-negative cells supported the evidence that AMPK is an upstream signal of COX-2 and inhibits cell proliferation. In HT-29 colon cancer cells, carcinogenic agent 12-O-tetradecanoylphorbol-13-acetate (TPA) activated extracellular signal-regulated kinase (ERK) that led to COX-2 expression and selenium blocked the TPA-induced ERK and COX-2 activation via AMPK. We also showed the role of a reactive oxygen species as an AMPK activation signal in selenium-treated cells. We propose that AMPK is a novel and critical regulatory component in selenium-induced cancer cell death, further implying AMPK as a prime target of tumorigenesis. (Cancer Res 2006; 66(20): 10057-63)
Down-regulation of Androgen Receptor by 3,3′-Diindolylmethane Contributes to Inhibition of Cell Proliferation and Induction of Apoptosis in Both Hormone-Sensitive LNCaP and Insensitive C4-2B Prostate Cancer Cells
Authors: Bhuiyan Mohammad M.R. , Li Yiwei , Banerjee Sanjeev , Ahmed Fakhara , Wang Zhiwei , Ali Shadan , Sarkar Fazlul H.
Published: October 2006

Despite the initial efficacy of androgen deprivation therapy, most patients with advanced prostate cancer eventually progress to hormone-refractory prostate cancer, for which there is no curative therapy. Previous studies from our laboratory and others have shown the antiproliferative and proapoptotic effects of 3,3′-diindolylmethane (DIM) in prostate cancer cells. However, the molecular mechanism of action of DIM has not been investigated in androgen receptor (AR)–positive hormone-responsive and -nonresponsive prostate cancer cells. Therefore, we investigated the effects of B-DIM, a formulated DIM with greater bioavailability, on AR, Akt, and nuclear factor κB (NF-κB) signaling in hormone-sensitive LNCaP (AR+) and hormone-insensitive C4-2B (AR+) prostate cancer cells. We found that B-DIM significantly inhibited cell proliferation and induced apoptosis in both cell lines. By Akt gene transfection, reverse transcription-PCR, Western blot analysis, and electrophoretic mobility shift assay, we found a potential crosstalk between Akt, NF-κB, and AR. Importantly, B-DIM significantly inhibited Akt activation, NF-κB DNA binding activity, AR phosphorylation, and the expressions of AR and prostate-specific antigen, suggesting that B-DIM could interrupt the crosstalk. Confocal studies revealed that B-DIM inhibited AR nuclear translocation, leading to the down-regulation of AR target genes. Moreover, B-DIM significantly inhibited C4-2B cell growth in a severe combined immunodeficiency–human model of experimental prostate cancer bone metastasis. These results suggest that B-DIM-induced cell proliferation inhibition and apoptosis induction are partly mediated through the down-regulation of AR, Akt, and NF-κB signaling. These observations provide a rationale for devising novel therapeutic approaches for the treatment of hormone-sensitive, but more importantly, hormone-refractory prostate cancer by using B-DIM alone or in combination with other therapeutics. (Cancer Res 2006; 66(20): 10064-72)
A Novel Mechanism for p53 to Regulate Its Target Gene ECK in Signaling Apoptosis
Authors: Jin Y. Jenny , Wang Jianli , Qiao Changhong , Hei Tom K. , Brandt-Rauf Paul W. , Yin Yuxin
Published: October 2006

Transcription factor p53 regulates its target genes through binding to DNA consensus sequence and activating the promoters of its downstream genes. The conventional p53 consensus binding sequence was defined as two copies of the 10-bp motif 5′-PuPuPuC(A/T)(T/A)GPyPyPy-3′ with a spacer of 0 to 13 bp, which exists in the regulatory regions of some p53 target genes. However, there is no such p53 consensus sequence in the promoters of a number of p53-responsive genes, suggesting that there might be other mechanisms whereby p53 transactivates the promoters of its target genes. We report here that p53 uses a novel binding mechanism to regulate the transcription of epithelial cell kinase (ECK), a receptor protein-tyrosine kinase implicated in signal transduction. We show that p53 binds to a 10-bp perfect palindromic decanucleotide (GTGACGTCAC) in the ECK promoter, activates the ECK promoter, and increases the transcription of ECK. This palindrome is required for p53-mediated transactivation of the ECK promoter. ECK is highly responsive to oxidative damage that leads to cell death. Ectopic expression of ECK causes spontaneous apoptosis in breast cancer cells. We found that ectopic expression of a mutant ECK fails to induce apoptosis in cancer cells. Our findings show that p53 is a transcriptional regulator of ECK in mediating apoptosis. The discovery of the novel p53-binding motif in the promoter may lead to the identification of a new class of p53 target genes. (Mol Cancer Res 2006;4(10):769–78)
Detection of Parent-of-Origin Effects in Nuclear Families Using Haplotype Analysis
Authors: Becker Tim , Baur Max P. , Knapp Michael
Published: October 2006

Despite the potential pitfalls of stratification, population-based association studies nowadays are being conducted more often than family-based association studies. However, the mechanism of genomic imprinting has lately been implicated in the etiology of genetic complex diseases and can be detected using statistics only in family-based designs. Powerful tests for association and imprinting have been proposed previously for case-parent trios and single markers. Since the power of association studies can be improved if multiple affected children and haplotypes are considered, we extended the parental asymmetry test (PAT) for imprinting to a test that is suited for both general nuclear families and haplotypes, called HAP-PAT. Significance of the HAP-PAT is determined via a Monte-Carlo simulation procedure. In addition to the HAP-PAT, we modified a haplotype-based association test, proposed by us before, in such a way that either only paternal or maternal transmissions contribute to the test statistic. The approaches were implemented in FAMHAP and we evaluated their performance under a variety of disease models. We were able to demonstrate the usefulness of our haplotype-based approaches to detect parent-of-origin effects. Furthermore, we showed that also in the presence of imprinting it is more reasonable to consider all affected children of a nuclear family, than to randomly select one affected child from each family and to conduct a trio study using the selected individuals.
Analytical Correction for Multiple Testing in Admixture Mapping
Authors: Sha Qiuying , Zhang Xihuan , Zhu Xiaofeng , Zhang Shuanglin
Published: October 2006

Admixture mapping, using unrelated individuals from the admixture populations that result from recent mating between members of each parental population, is an efficient approach to localize disease-causing variants that differ in frequency between two or more historically separated populations. Recently, several methods have been proposed to test linkage between a susceptibility gene and a disease locus by using admixture-generated linkage disequilibrium (LD) for each of the genotyped markers. In a genome scan, admixture mapping usually tests 2,000 to 3,000 markers across the genome. Currently, either a very conservative Sidak (or Bonferroni) correction or a very time consuming simulation-based method is used to correct for the multiple tests and evaluate the overall p value. In this report, we propose a computationally efficient analytical approach for correction of the multiple tests and for calculating the overall p value for an admixture genome scan. Except for the Sidak (or Bonferroni) correction, our proposed method is the first analytical approach for correction of the multiple tests and for calculating the overall p value for a genome scan. Our simulation studies show that the proposed method gives correct overall type I error rates for genome scans in all cases, and is much more computationally efficient than simulation-based methods.
Locus-Specific Heritability Estimation via the Bootstrap in Linkage Scans for Quantitative Trait Loci
Authors: Wu Long Yang , Sun Lei , Bull Shelley B.
Published: October 2006

Background/Aims: In genome-wide linkage analysis ofquantitative trait loci (QTL), locus-specific heritability estimates are biased when the original data are used to both localize linkage and estimate effects, due to maximization of the LOD score over the genome. Positive bias is increased by adoption of stringent significance levels to control genome-wide type I error. We propose multi-locus bootstrap resampling estimators for bias reduction in the situation in which linkage peaks at more than one QTL are of interest. Methods: Bootstrap estimates were based on repeated sample splitting in the original dataset. We conducted simulation studies in nuclear families with 0 to 5 QTLs and applied the methods in a genome-wide analysis of a blood pressure phenotype in extended pedigrees from the Framingham Heart Study (FHS). Results: Compared to naïve estimates in the original simulation samples, bootstrap estimates had reduced bias and smaller mean squared error. In the FHS pedigrees, the bootstrap yielded heritability estimates as much as 70% smaller than in the original sample. Conclusions: Because effect estimates obtained in an initial study are typically inflated relative to those expected in an independent replication study, successful replication will be more likely when sample size requirements are based on bias-reduced estimates.
Salvage Chemotherapy with Gemcitabine and Oxaliplatin in Heavily Pretreated Patients with Metastatic Breast Cancer: A Multicenter Phase II Study
Authors: Kakolyris S. , Kalbakis K. , Potamianou A. , Malamos N. , Vamvakas L. , Christophillakis C. , Tselepatiotis E. , Giassas S. , Mavroudis D. , Amarantidis K. , Georgoulias V.
Published: October 2006

Purpose: It was the aim of this study to evaluate the activity and tolerance of gemcitabine and oxaliplatin in pretreated metastatic breast cancer patients. Methods: Thirty-one patients who had disease relapse or progression after completion of an anthracycline- and/or taxane-based front-line regimen were treated with gemcitabine 1,500 mg/m2 on days 1 and 8 as a 30-min intravenous infusion and oxaliplatin 130 mg/m2 on day 8 as a 4-hour intravenous infusion, in cycles of 21 days. Results: Complete response occurred in 1 patient (3%) and partial response in 4 patients (13%) (overall response rate 16%; 95% confidence interval 3.2–29.1). Nine patients (29%) had stable disease and 17 (55%) progressive disease. Three partial responses (13%) were achieved among 23 patients receiving the regimen as third-line treatment. The median duration of response was 6 months (range 3–44.8), the median time to tumor progression 4.6 months (range 0.8–43.8), and the median survival 14.4 months (range 2.1–44.8). Grade 3 and 4 neutropenia occurred in 14 patients (45%), grade 3 and 4 thrombocytopenia in 6 patients (20%), and grade 2 and 3 asthenia in 4 patients (13%). There was no episode of febrile neutropenia. Conclusion: The gemcitabine-oxaliplatin combination is a relatively active and well-tolerated salvage regimen in patients with heavily pretreated metastatic breast cancer.
Duration of Tamoxifen Effect on Lipidemic Profile of Postmenopausal Breast Cancer Patients following Deprivation of Treatment
Authors: Markopoulos C. , Chrissochou M. , Antonopoulou Z. , Xepapadakis G. , Papadiamantis J. , Tzoracoleftherakis E. , Gogas H.
Published: October 2006

Objective: It was the aim of this study to investigate the effect of tamoxifen withdrawal on markers of lipid metabolism in postmenopausal women with breast cancer who completed tamoxifen therapy and received no further treatment. Methods: Lipidemic profile changes were studied in 190 postmenopausal patients with operable breast cancer, following cessation of 5–7 years of tamoxifen treatment. Assessments of total cholesterol, high-density lipoprotein, low-density lipoprotein and total serum triglycerides were performed at baseline, 6 months and 12 months. Results: By 6 months, both total cholesterol and low-density lipoprotein levels were significantly increased, and total triglyceride levels were significantly reduced compared with baseline values and maintained to 12 months. There was no significant alteration observed for high-density lipoprotein levels over the study period. Conclusion: The beneficial effect of tamoxifen on the lipidemic profile of postmenopausal breast cancer patients seems to be lost in less than 12 months time following cessation of 5–7 years of tamoxifen treatment. A ‘rebound effect’ on the lipidemic parameters should be expected and those patients should be monitored carefully.
Revised Criteria for Mild Cognitive Impairment: Validation within a Longitudinal Population Study
Authors: Artero Sylvaine , Petersen Ronald , Touchon Jacques , Ritchie Karen
Published: October 2006

Background: Mild cognitive impairment (MCI) refers to the transitional zone between normal ageing and dementia. Current criteria perform poorly within the general population setting. Revisions have been proposed based on results obtained from clinical and epidemiological studies. Objective: To evaluate revised diagnostic criteria for mild cognitive impairment (MCI-R) incorporating changes in activity level and non-mnesic cognitive functioning. Method: MCI-R subjects were recruited from a representative network of general practitioners in the south of France. A computerized neuropsychometric examination was given. At 2 years of follow-up, a diagnosis of dementia was made by a neurologist using DSM-IIIR criteria and without knowledge of the results of the cognitive testing. Rates of conversion to incident dementia were assessed by receiver operating characteristics analysis. Results: The MCI-R prevalence was found to be 16.6% using revised criteria. A significantly better prediction of transition to dementia (AUC = 0.80, sensitivity: 95%, specificity: 66%) was obtained with MCI-R than with the previous MCI criteria (AUC = 0.48, sensitivity: 5%, specificity: 91%). The predictive power was found to increase when MCI subtypes were combined. Conclusion: Incorporating the possibility of change in activity level and alteration of non-mnesic cognitive functions have been found to ameliorate the original algorithm and better define subjects converting to dementia. This definition may be applicable to both clinical and population research.
Mutational Analysis of AKT1, AKT2 and AKT3 Genes in Common Human Carcinomas
Authors: Soung Young Hwa , Lee Jong Woo , Nam Suk Woo , Lee Jung Young , Yoo Nam Jin , Lee Sug Hyung
Published: October 2006

Objective: Mounting evidence indicates that alterations in AKT proteins play an important role in the pathogenesis of cancer. The objective of this study was to see whether common human carcinomas harbor AKT mutations that might contribute to the development of cancer. Methods: We performed mutational analysis of the kinase domains of AKT1–AKT3 by a single-strand conformation polymorphism assay in 294 carcinoma tissues from the stomach, lung, colon and breast. Results: Overall, we detected three somatic mutations in AKT2, but no mutations in AKT1 or AKT3 in the 294 cancer tissues. The AKT2 mutations were detected in 1 of 51 gastric carcinomas (2.0%) and 2 of 79 lung carcinomas (2.5%). AKT2 mutations consisted of one missense mutation and 2 splice site mutations in the intron. We simultaneously analyzed somatic mutations in EGFR, ERBB2, K-RAS, PIK3CA and BRAF genes in the 3 samples with the AKT2 mutations, and found a lung adenocarcinoma with the AKT2 missense mutation harbored an EGFR mutation. Conclusion: This study demonstrated that somatic mutations in the kinase domain of AKT2 occur in a small fraction of common human cancers, and suggested that alterations in the AKT2-mediated signaling pathway by AKT2 mutation could contribute to the development of some cases of human cancers.
Driving Abilities in Frontotemporal Dementia Patients
Authors: de Simone V. , Kaplan L. , Patronas N. , Wassermann E.M. , Grafman J.
Published: October 2006

Objective: To evaluate driving competency and the relationship between neuropsychiatric symptoms and driving behavior in frontotemporal dementia (FTD) patients. Methods: Fifteen patients with a diagnosis of FTD and 15 healthy controls were administered a driving simulation task. Measures of driving performance and neuropsychiatric symptoms were assessed. Results: The FTD patients received more speeding tickets, ran more stop signs and were involved in more off-road crashes and collisions than the controls. The patients’ overall average speed was significantly higher. Driving performance was correlated with agitated behavior. Conclusions: Behavioral changes characteristic of FTD patients have an impact on their driving skills leading to inappropriate driving behavior.
Matrix Metalloproteinases and Atherogenesis in Dependence of Age
Authors: Kunz Jochen
Published: October 2006

Background: Changes in the proteoglycan metabolism of the intima of arteries belong to the initial lesions of atherosclerosis (AS). The accumulation of proteoglycans, alterations of pericellular glycoproteins and modulations of collagen turnover also play a fundamental role in the progression of AS. They influence lipid retention, cell behavior and calcinosis. The decisive role played by the matrix metalloproteinases (MMPs) and their inhibiting factors (tissue inhibitors of metalloproteinases [TIMPs]) in these processes is not yet fully understood and therefore the subject of this overview. The causes of the abrupt change of a long-term existing stabile AS to a vulnerable plaque as well as the participation of age-related vascular wall remodeling in the progression of AS also remain open questions. Discussion: Apart from the well-known risk factors for AS, less well-known influences like the disturbances of gene expression in vascular smooth muscle cells affect an MMP/TIMP imbalance. The various consequences of this imbalance range from intima cell proliferation as an early change in AS as well as accelerated progression to the destabilization of fibrous plaques by increased collagenolysis as well as the formation of aneurysms. Infectious or toxic influences may trigger these mechanisms; an involvement of age-related vessel wall changes should also be considered. The prognostic significance of circulating MMP concentrations for the existence of instabile plaques are of great interest, as is the plaque stabilizing effect of statins by suppression of MMPs. Conclusions: MMPs navigate the behavior of vascular wall cells in different AS stages, in adaptive remodeling, in normal aging and in non-atherosclerotic vessel disease. The clinical relevance of a disturbance in the MMP/TIMP balance is demonstrated firstly by the initiation of AS due to migration and proliferation of intima cells and secondly in the collagenolysis, necrotic transformation and apoptosis of existing fibrous lesions resulting in instabile rupture proned plaques. Investigations into the genetic typing of MMPs and the results of experimental gene deficiency models have significantly contributed to the clarification of these facts.
Mapping Global Values
Authors: Inglehart Ronald
Published: October 2006

Modernization goes through two main phases, each of which brings distinctive changes in people's worldviews. The Industrial Revolution was linked with a shift from traditional to secular-rational values, bringing bureaucratization, centralization, standardization and the secularization of authority. In the post-industrial phase of modernization, a shift from survival values to self-expression values, brings increasing emancipation from both religious and secular-rational authority. Rising mass emphasis on self-expression values makes democracy increasingly likely to emerge.Although the desire for freedom is a universal human aspiration, it does not take top priority when people grow up with the feeling that survival is uncertain. But when survival seems secure, increasing emphasis on self-expression values makes the emergence of democracy increasingly likely where it does not yet exist, and makes democracy increasingly effective where it already exists.
Democratization in the Human Development Perspective
Authors: Welzel Christian
Published: October 2006

This article describes a model that considers the emergence and florescence of democracies as something embedded in a more encompassing evolutionary process. Democratization in this light is the institutional component of a broader process of human development that promotes people empowerment on various fronts. In this process increasing individual resources give rise to emancipative values that in turn release democratizing social pressures.
Visit to the Tomb of Al-Husayn B. 'Alī in Shiite Poetry: First to Fifth Centuries AH (8th-11th Centuries CE)
Authors: Sindawi Khalid
Published: October 2006

The present study concerns visiting the tomb of Husayn b. 'Alī (d. 680 CE) in Karbalī', as reflected in Shiite poetry written between the first and fifth centuries AH. The article opens with a description of the visit, the ceremonies it involves, the virtues and purposes attributed to it, as well as the motivation behind the poetry associated with it. The study then describes the characteristics of this "visit poetry," its language and its artistic structure.
The Work of the International Law Commission on Shared Natural Resources: The Pursuit of Competence and Relevance
Authors: Rainne Juha
Published: October 2006

A growing demand for rules that regulate the use of shared or transboundary natural resources is evident. The exploitation of water, oil or other transboundary natural resources in one state may often have consequences that delimit the possibilities of the neighbouring state to exploit the same resources. As natural resources in the boundary areas are expected to be a major source of controversy in the 21st century, it is reasonable to call for the development of norms that would set the minimum requirements for international co-operation and the maximum limits of state sovereignty in the utilisation of transboundary natural resources. The present article addresses the matter by analysing the work of the International Law Commission on the topic of shared natural resources. The Commission faces a difficult challenge as it undertakes to universally regulate a subject matter that is highly technical and politically sensitive and encompasses diverse regional situations. It is argued that the relevance of the work of the International Law Commission in this field and the competence of its legal experts can be questioned, as the Commission balances between too general and too technical an approach to the topic.