bluuebunny/crossref_metadata_2025 huggingface dataset:
INFORMATION EXCHANGE AND SUPPLY CHAIN PERFORMANCE
Authors: RAMAYAH T. , OMAR ROAIMAH
Published: February 2010

The purpose of this study is to examine the effects of operational and strategic information exchange on supply chain performance and the moderating role of information quality in relation to both operational and strategic information exchange. The study was conducted using manufacturing companies located in the Northern region of Malaysia. Hierarchical multiple regressions were applied to test the hypotheses developed for the study. It was found that operational and strategic information exchange is significantly related to supply chain performance. The impact of strategic information exchange is greater as opposed to operational information exchange. Information quality does not moderate the relationship between both operational and strategic information exchange and supply chain performance. Nonetheless, this study provides evidence that both strategic information exchange and operational information exchange are required to enhance supply chain performance. As such supply chain partners should effectively exchange strategic information as the impact is greater on performance.
THE RESEARCH TREND OF INFORMATION TECHNOLOGY AND DECISION MAKING IN 2009
Authors: SHI YONG
Published: February 2010

The research topics of the 39 papers published in the International Journal of Information Technology and Decision Making (IT&DM) in 2009 can be classified into three major directions: decision support, multiple criteria decision making, and data mining and risk analysis. The Editor-in-Chief, on behalf of the editorial board and advisory board, highlights the key ideas of these contributions. The seven papers in first issue of 2010 IT&DM are also introduced.
TIME-SCALE APPROACH FOR CHIRP DETECTION II
Authors: MORVIDONE MARCELA
Published: February 2010

A new approach for joint detection and estimation of signals embedded in stationary random noise is considered and compared to previously studied methods, for the subclass of amplitude and frequency modulated signals. The method is a "reassigned" version of the Hough-wavelet transform and it is compared to the matched filter approach and the Hough-wavelet transform itself. Extensions to previous results obtained with these two methods are also presented. As target application, the problem of gravitational waves at interferometric detectors is considered. Our main conclusion is that there is no gain in introducing the reassignment operation.
Calcium Dynamics Encode the Magnitude of a Graded Memory Underlying Sensorimotor Adaptation
Authors: Dembrow Nikolai C. , Pettit Diana L. , Zakon Harold H.
Published: February 2010

The role of Ca2+ in the induction of neural correlates of memory has frequently been described in binary terms despite the fact that many forms of memory are graded in their strength and/or persistence. We find that Ca2+ dynamics encode the magnitude of sensorimotor adaptation of the electromotor output in a weakly electric fish. The neural correlate of this memory is a synaptically induced Ca2+-dependent enhancement of intrinsic excitability of neurons responsible for setting the electromotor output. Changes in Ca2+ during induction accurately predict the magnitude of this graded memory over a wide range of stimuli. Thus despite operating over a range from seconds to tens of minutes, the encoding of graded memory can be mediated by a relatively simple cellular mechanism.
Postnatal Maturation of Primary Auditory Cortex in the Mustached Bat, Pteronotus parnellii
Authors: Vater M. , Foeller E. , Mora E. C. , Coro F. , Russell I. J. , Kössl M.
Published: February 2010

The primary auditory cortex (AI) of adult Pteronotus parnellii features a foveal representation of the second harmonic constant frequency (CF2) echolocation call component. In the corresponding Doppler-shifted constant frequency (DSCF) area, the 61 kHz range is over-represented for extraction of frequency-shift information in CF2 echoes. To assess to which degree AI postnatal maturation depends on active echolocation or/and reflects ongoing cochlear maturation, cortical neurons were recorded in juveniles up to postnatal day P29, before the bats are capable of active foraging. At P1-2, neurons in posterior AI are tuned sensitively to low frequencies (22–45 dB SPL, 28–35 kHz). Within the prospective DSCF area, neurons had insensitive responses (>60 dB SPL) to frequencies <40 kHz and lacked sensitive tuning curve tips. Up to P10, when bats do not yet actively echolocate, tonotopy is further developed and DSCF neurons respond to frequencies of 51–57 kHz with maximum tuning sharpness ( Q10dB) of 57. Between P11 and 20, the frequency representation in AI includes higher frequencies anterior and dorsal to the DSCF area. More multipeaked neurons (33%) are found than at older age. In the oldest group, DSCF neurons are tuned to frequencies close to 61 kHz with Q10dB values ≤212, and threshold sensitivity, tuning sharpness and cortical latencies are adult-like. The data show that basic aspects of cortical tonotopy are established before the bats actively echolocate. Maturation of tonotopy, increase of tuning sharpness, and upward shift in the characteristic frequency of DSCF neurons appear to strongly reflect cochlear maturation.
Identifying genetic loci and spleen gene coexpression networks underlying immunophenotypes in BXD recombinant inbred mice
Authors: Lynch Rachel M. , Naswa Sudhir , Rogers Gary L. , Kania Stephen A. , Das Suchita , Chesler Elissa J. , Saxton Arnold M. , Langston Michael A. , Voy Brynn H.
Published: February 2010

The immune system plays a pivotal role in the susceptibility to and progression of a variety of diseases. Due to a strong genetic basis, heritable differences in immune function may contribute to differential disease susceptibility between individuals. Genetic reference populations, such as the BXD (C57BL/6J × DBA/2J) panel of recombinant inbred (RI) mouse strains, provide unique models through which to integrate baseline phenotypes in healthy individuals with heritable risk for disease because of the ability to combine data collected from these populations across both multiple studies and time. We performed basic immunophenotyping (e.g., percentage of circulating B and T lymphocytes and CD4+and CD8+T cell subpopulations) in peripheral blood of healthy mice from 41 BXD RI strains to define the immunophenotypic variation in this strain panel and to characterize the genetic architecture that underlies these traits. Significant QTL models that explained the majority (50–77%) of phenotypic variance were derived for each trait and for the T:B cell and CD4+:CD8+ratios. Combining QTL mapping with spleen gene expression data uncovered two quantitative trait transcripts, Ptprk and Acp1, as candidates for heritable differences in the relative abundance of helper and cytotoxic T cells. These data will be valuable in extracting genetic correlates of the immune system in the BXD panel. In addition, they will be a useful resource for prospective, phenotype-driven model selection to test hypotheses about differential disease or environmental susceptibility between individuals with baseline differences in the composition of the immune system.
Constructing Multi‐Branches Complete Chaotic Maps That Preserve Specified Invariant Density
Authors: Huang Weihong
Published: February 2010

A general formulation for multi‐branches complete chaotic maps that preserve a specified invariant density is provided and an implication relationship among this class of maps is revealed. Such relationship
helps to derive a whole family of complete chaotic maps that preserve not only the same invariant measure
but also the same degree of chaos in terms of Lyapunov component.
Global Dynamics Behaviors of Viral Infection Model for Pest Management
Authors: Wei Chunjin , Chen Lansun
Published: February 2010

According to biological strategy for pest control, a mathematical model with periodic releasing virus particles for insect viruses attacking pests is considered. By using Floquet′s theorem, small‐amplitude perturbation skills and
comparison theorem, we prove that all solutions of the system are uniformly ultimately bounded and there exists a globally asymptotically stable pest‐eradication periodic solution when the amount of virus particles released is larger than some critical value. When the amount of virus particles released is less than some critical value, the system is shown to be permanent, which implies that the trivial pest‐eradication solution loses its stability. Further, the mathematical results are also confirmed by means of
numerical simulation.
On Some Properties of Hyperconvex Spaces
Authors: Borkowski Marcin , Bugajewski Dariusz , Phulara Dev
Published: February 2010

We are going to answer some open questions in the theory of hyperconvex metric spaces. We prove that in complete "Equation missing"-trees hyperconvex hulls are uniquely determined. Next we show that hyperconvexity of subsets of normed spaces implies their convexity if and only if the space under consideration is strictly convex. Moreover, we prove a Krein-Milman type theorem for "Equation missing"-trees. Finally, we discuss a general construction of certain complete metric spaces. We analyse its particular cases to investigate hyperconvexity via measures of noncompactness.
Evolvable Block-Based Neural Network Design for Applications in Dynamic Environments
Authors: Merchant Saumil G. , Peterson Gregory D.
Published: February 2010

Dedicated hardware implementations of artificial neural networks promise to provide faster, lower-power operation when compared to software implementations executing on microprocessors, but rarely do these implementations have the flexibility to adapt and train online under dynamic conditions. A typical design process for artificial neural networks involves offline training using software simulations and synthesis and hardware implementation of the obtained network offline. This paper presents a design of block-based neural networks (BbNNs) on FPGAs capable of dynamic adaptation and online training. Specifically the network structure and the internal parameters, the two pieces of the multiparametric evolution of the BbNNs, can be adapted intrinsically, in-field under the control of the training algorithm. This ability enables deployment of the platform in dynamic environments, thereby significantly expanding the range of target applications, deployment lifetimes, and system reliability. The potential and functionality of the platform are demonstrated using several case studies.
Evolution and Diversity of the Human Hepatitis D Virus Genome
Authors: Huang Chi-Ruei , Lo Szecheng J.
Published: February 2010

Human hepatitis delta virus (HDV) is the smallest RNA virus in genome. HDV genome is divided into a viroid-like sequence and a protein-coding sequence which could have originated from different resources and the HDV genome was eventually constituted through RNA recombination. The genome subsequently diversified through accumulation of mutations selected by interactions between the mutated RNA and proteins with host factors to successfully form the infectious virions. Therefore, we propose that the conservation of HDV nucleotide sequence is highly related with its functionality. Genome analysis of known HDV isolates shows that the C-terminal coding sequences of large delta antigen (LDAg) are the highest diversity than other regions of protein-coding sequences but they still retain biological functionality to interact with the heavy chain of clathrin can be selected and maintained. Since viruses interact with many host factors, including escaping the host immune response, how to design a program to predict RNA genome evolution is a great challenging work.
(L, M)‐Fuzzy σ‐Algebras
Authors: Shi Fu-Gui
Published: February 2010

The notion of (L, M)‐fuzzy σ‐algebras is introduced in the lattice value fuzzy set theory. It is a generalization of Klement′s fuzzy σ‐algebras. In our definition of (L, M)‐fuzzy σ‐algebras, each L‐fuzzy subset can be regarded as an L‐measurable set to some degree.
New Hybrid Iterative Schemes for an Infinite Family of Nonexpansive Mappings in Hilbert Spaces
Authors: Guo Baohua , Wang Shenghua
Published: February 2010

We propose some new iterative schemes for finding common fixed point of an infinite family of nonexpansive mappings in a Hilbert space and prove the strong convergence of the proposed schemes. Our results extend and improve ones of Nakajo and Takahashi (2003).
The Lipid Moiety of Haemozoin (Malaria Pigment) andP. falciparumParasitised Red Blood Cells Bind Synthetic and Native Endothelin-1
Authors: Basilico Nicoletta , Parapini Silvia , Sisto Francesca , Omodeo-Salè Fausta , Coghi Paolo , Ravagnani Fernando , Olliaro Piero , Taramelli Donatella
Published: February 2010

Endothelin1 (ET-1) is a 21-amino acid peptide produced by the vascular endothelium under hypoxia, that acts locally as regulator of vascular tone and inflammation. The role of ET-1 inPlasmodium falciparummalaria is unknown, although tissue hypoxia is frequent as a result of the cytoadherence of parasitized red blood cell (pRBC) to the microvasculature. Here, we show that both synthetic and endothelial-derived ET-1 are removed by parasitized RBC (D10 and W2 strains, chloroquine sensitive, and resistant, resp.) and native haemozoin (HZ, malaria pigment), but not by normal RBC, delipidized HZ, or synthetic beta-haematin (BH). The effect is dose dependent, selective for ET-1, but not for its precursor, big ET-1, and not due to the proteolysis of ET-1. The results indicate that ET-1 binds to the lipids moiety of HZ and membranes of infected RBCs. These findings may help understanding the consequences of parasite sequestration in severe malaria.
Extreme Thermal Sensitivity and Pain-Induced Sensitization in a Fibromyalgia Patient
Authors: Wong Fong , Rodrigues Anthony , Schmidt Siegfried , Vierck Charles J. , Mauderli Andre P.
Published: February 2010

During the course of a psychophysical study of fibromyalgia syndrome (FMS), one of the subjects with a long history of headache and facial pain displayed an extraordinarily severe thermal allodynia. Her stimulus-response function for ratings of cutaneous heat pain revealed a sensitivity clearly beyond that of normal controls and most FMS subjects. Specially designed psychophysical methods showed that heat sensitivity sometimes increased dramatically within a series of stimuli. Prior exposure to moderate heat pain served as a trigger for allodynic ratings of series of normally neutral thermal stimulation. These observations document a case of breakthrough pain sensitivity with implications for mechanisms of FMS pain.
Regulation of the MicroRNA Processor DGCR8 by the Tumor Suppressor ING1
Authors: Gómez-Cabello Daniel , Callejas Sergio , Benguría Alberto , Moreno Alberto , Alonso Javier , Palmero Ignacio
Published: February 2010

The ING family of tumor suppressor proteins controls several cellular functions relevant to antitumor protection, such as cell cycle control, apoptosis, senescence, or migration. ING proteins are functionally linked to the p53 pathway, and they participate in transcriptional control via the recognition of histone marks and recruitment of protein complexes with chromatin-modifying activity to specific promoters. Here, we have investigated the global effect of ING1 in gene regulation through genome-wide analysis of expression profiles in primary embryonic fibroblasts deficient for the Ing1 locus. We find that Ing1 has a predominant role as transcriptional repressor in this setting, affecting the expression of genes involved in a variety of cellular functions. Within the subset of genes showing differential expression, we have identified DGCR8, a protein involved in the early steps of microRNA biogenesis. We show that ING1 binds to the DGCR8 promoter and controls its transcription through chromatin regulation. We also find that ING1 and DGCR8 can cooperate in restraining proliferation. In summary, this study reveals a novel connection between ING1 and a regulator of microRNA biogenesis and identifies new links between tumor suppressor proteins and the microRNA machinery. Cancer Res; 70(5); 1866–74
Atm-Deficient Mice Exhibit Increased Sensitivity to Dextran Sulfate Sodium–Induced Colitis Characterized by Elevated DNA Damage and Persistent Immune Activation
Authors: Westbrook Aya M. , Schiestl Robert H.
Published: February 2010

The role of ataxia telangiectasia mutated (ATM), a DNA double-strand break recognition and response protein, in inflammation and inflammatory diseases is unclear. We have previously shown that high levels of systemic DNA damage are induced by intestinal inflammation in wild-type mice. To determine the effect of Atm deficiency in inflammation, we induced experimental colitis in Atm−/−, Atm+/−, and wild-type mice via dextran sulfate sodium (DSS) administration. Atm−/− mice had higher disease activity indices and rates of mortality compared with heterozygous and wild-type mice. Systemic DNA damage and immune response were characterized in peripheral blood throughout and after three cycles of treatment. Atm−/− mice showed increased sensitivity to levels of DNA strand breaks in peripheral leukocytes, as well as micronucleus formation in erythroblasts, compared with heterozygous and wild-type mice, especially during remission periods and after the end of treatment. Markers of reactive oxygen and nitrogen species–mediated damage, including 8-oxoguanine and nitrotyrosine, were present both in the distal colon and in peripheral leukocytes, with Atm−/− mice manifesting more 8-oxoguanine formation than wild-type mice. Atm−/− mice showed greater upregulation of inflammatory cytokines and significantly higher percentages of activated CD69+ and CD44+ T cells in the peripheral blood throughout treatment. ATM, therefore, may be a critical immunoregulatory factor dampening the deleterious effects of chronic DSS-induced inflammation, necessary for systemic genomic stability and homeostasis of the gut epithelial barrier. Cancer Res; 70(5); 1875–84
Signal Transduction Networks in Cancer: Quantitative Parameters Influence Network Topology
Authors: Klinke David J.
Published: February 2010

Networks of fixed topology are used to summarize the collective understanding of the flow of signaling information within a cell (i.e., canonical signaling networks). Moreover, these canonical signaling networks are used to interpret how observed oncogenic changes in protein activity or expression alter information flow in cancer cells. However, creating a novel branch within a signaling network (i.e., a noncanonical edge) provides a mechanism for a cell to acquire the hallmark characteristics of cancer. The objective of this study was to assess the existence of a noncanonical edge within a receptor tyrosine kinase (RTK) signaling network based upon variation in protein expression alone, using a mathematical model of the early signaling events associated with epidermal growth factor receptor 1 (ErbB1) signaling network as an illustrative example. The abundance of canonical protein–RTK complexes (e.g., growth factor receptor bound protein 2–ErbB1 and Src homology 2 domain containing transforming protein 1–ErbB1) were used to establish a threshold that was correlated with ligand-dependent changes in cell proliferation. Given the available data, the uncertainty associated with this threshold was estimated using an empirical Bayesian approach. Using the variability in protein expression observed among a collection of breast cancer cell lines, this model was used to assess whether a noncanonical edge (e.g., Irs1-ErbB1) exceeds the threshold and to identify cell lines where this noncanonical edge is likely to be observed. Taken together, the simulations suggest that the topology of signal transduction networks within cells is influenced by quantitative parameters, such as protein expression and binding affinity. Moreover, forming this noncanonical pathway was not due solely to overexpression of the cell surface receptor but was influenced by overexpression of all members of the multiprotein complex. Multivariate alterations in expression of signaling proteins in cancer cells may activate noncanonical pathways and may rewire the signaling network within a cell. Cancer Res; 70(5); 1773–82
FGFR1 Amplification Drives Endocrine Therapy Resistance and Is a Therapeutic Target in Breast Cancer
Authors: Turner Nicholas , Pearson Alex , Sharpe Rachel , Lambros Maryou , Geyer Felipe , Lopez-Garcia Maria A. , Natrajan Rachael , Marchio Caterina , Iorns Elizabeth , Mackay Alan , Gillett Cheryl , Grigoriadis Anita , Tutt Andrew , Reis-Filho Jorge S. , Ashworth Alan
Published: February 2010

Amplification of fibroblast growth factor receptor 1 (FGFR1) occurs in ∼10% of breast cancers and is associated with poor prognosis. However, it is uncertain whether overexpression of FGFR1 is causally linked to the poor prognosis of amplified cancers. Here, we show that FGFR1 overexpression is robustly associated with FGFR1 amplification in two independent series of breast cancers. Breast cancer cell lines with FGFR1 overexpression and amplification show enhanced ligand-dependent signaling, with increased activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase–AKT signaling pathways in response to FGF2, but also show basal ligand-independent signaling, and are dependent on FGFR signaling for anchorage-independent growth. FGFR1-amplified cell lines show resistance to 4-hydroxytamoxifen, which is reversed by small interfering RNA silencing of FGFR1, suggesting that FGFR1 overexpression also promotes endocrine therapy resistance. FGFR1 signaling suppresses progesterone receptor (PR) expression in vitro, and likewise, amplified cancers are frequently PR negative, identifying a potential biomarker for FGFR1 activity. Furthermore, we show that amplified cancers have a high proliferative rate assessed by Ki67 staining and that FGFR1 amplification is found in 16% to 27% of luminal B–type breast cancers. Our data suggest that amplification and overexpression of FGFR1 may be a major contributor to poor prognosis in luminal-type breast cancers, driving anchorage-independent proliferation and endocrine therapy resistance. Cancer Res; 70(5); 2085–94
Activation of Phosphatidylcholine Cycle Enzymes in Human Epithelial Ovarian Cancer Cells
Authors: Iorio Egidio , Ricci Alessandro , Bagnoli Marina , Pisanu Maria Elena , Castellano Giancarlo , Di Vito Massimo , Venturini Elisa , Glunde Kristine , Bhujwalla Zaver M. , Mezzanzanica Delia , Canevari Silvana , Podo Franca
Published: February 2010

Altered phosphatidylcholine (PC) metabolism in epithelial ovarian cancer (EOC) could provide choline-based imaging approaches as powerful tools to improve diagnosis and identify new therapeutic targets. The increase in the major choline-containing metabolite phosphocholine (PCho) in EOC compared with normal and nontumoral immortalized counterparts (EONT) may derive from (a) enhanced choline transport and choline kinase (ChoK)–mediated phosphorylation, (b) increased PC-specific phospholipase C (PC-plc) activity, and (c) increased intracellular choline production by PC deacylation plus glycerophosphocholine-phosphodiesterase (GPC-pd) or by phospholipase D (pld)–mediated PC catabolism followed by choline phosphorylation. Biochemical, protein, and mRNA expression analyses showed that the most relevant changes in EOC cells were (a) 12-fold to 25-fold ChoK activation, consistent with higher protein content and increased ChoKα (but not ChoKβ) mRNA expression levels; and (b) 5-fold to 17-fold PC-plc activation, consistent with higher, previously reported, protein expression. PC-plc inhibition by tricyclodecan-9-yl-potassium xanthate (D609) in OVCAR3 and SKOV3 cancer cells induced a 30% to 40% reduction of PCho content and blocked cell proliferation. More limited and variable sources of PCho could derive, in some EOC cells, from 2-fold to 4-fold activation of pld or GPC-pd. Phospholipase A2 activity and isoform expression levels were lower or unchanged in EOC compared with EONT cells. Increased ChoKα mRNA, as well as ChoK and PC-plc protein expression, were also detected in surgical specimens isolated from patients with EOC. Overall, we showed that the elevated PCho pool detected in EOC cells primarily resulted from upregulation/activation of ChoK and PC-plc involved in PC byosinthesis and degradation, respectively. Cancer Res; 70(5); 2126–35
Molecular Profiling Uncovers a p53-Associated Role for MicroRNA-31 in Inhibiting the Proliferation of Serous Ovarian Carcinomas and Other Cancers
Authors: Creighton Chad J. , Fountain Michael D. , Yu Zhifeng , Nagaraja Ankur K. , Zhu Huifeng , Khan Mahjabeen , Olokpa Emuejevoke , Zariff Azam , Gunaratne Preethi H. , Matzuk Martin M. , Anderson Matthew L.
Published: February 2010

MicroRNAs (miRNA) regulate complex patterns of gene expression, and the relevance of altered miRNA expression to ovarian cancer remains to be elucidated. By comprehensively profiling expression of miRNAs and mRNAs in serous ovarian tumors and cell lines and normal ovarian surface epithelium, we identified hundreds of potential miRNA-mRNA targeting associations underlying cancer. Functional overexpression of miR-31, the most underexpressed miRNA in serous ovarian cancer, repressed predicted miR-31 gene targets including the cell cycle regulator E2F2. MIR31 and CDKN2A, which encode p14ARF and p16INK4A, are located at 9p21.3, a genomic region commonly deleted in ovarian and other cancers. p14ARF promotes p53 activity, and E2F2 overexpression in p53 wild-type cells normally leads via p14ARF to an induction of p53-dependent apoptosis. In a number of serous cancer cell lines with a dysfunctional p53 pathway (i.e., OVCAR8, OVCA433, and SKOV3), miR-31 overexpression inhibited proliferation and induced apoptosis; however, in other lines (i.e., HEY and OVSAYO) with functional p53, miR-31 had no effect. Additionally, the osteosarcoma cell line U2OS and the prostate cancer cell line PC3 (p14ARF-deficient and p53-deficient, respectively) were also sensitive to miR-31. Furthermore, miR-31 overexpression induced a global gene expression pattern in OVCAR8 associated with better prognosis in tumors from patients with advanced stage serous ovarian cancer, potentially affecting many genes underlying disease progression. Our findings reveal that loss of miR-31 is associated with defects in the p53 pathway and functions in serous ovarian cancer and other cancers, suggesting that patients with cancers deficient in p53 activity might benefit from therapeutic delivery of miR-31. Cancer Res; 70(5); 1906–15
Cyclooxygenase-2 Inhibition Does Not Improve the Reduction in Ductal Carcinoma In situ Proliferation with Aromatase Inhibitor Therapy: Results of the ERISAC Randomized Placebo-Controlled Trial
Authors: Bundred Nigel J. , Cramer Angela , Morris Julie , Renshaw Lorna , Cheung Kwok-Leung , Flint Pamela , Johnson Rachael , Young Oliver , Landberg Göran , Grassby Sue , Turner Lorraine , Baildam Andrew , Barr Lester , Dixon J. Michael
Published: February 2010

Purpose: Tamoxifen reduces risk of recurrence after breast conservation surgery for ductal carcinoma in situ (DCIS), but no data exists on the effectiveness of aromatase inhibitors for DCIS. Cyclooxygenase-2 (COX-2) is overexpressed in DCIS, representing another potential therapeutic target. The aim of the study was to determine the effect of aromatase and/or COX-2 inhibition on epithelial proliferation and apoptosis in a presurgical study of estrogen receptor (ER)–positive DCIS.

Methods: Postmenopausal women with ER-positive DCIS diagnosed by core biopsy were randomized to a 2 × 2 design of either 14 days of exemestane or placebo and celecoxib, or placebo immediately before surgery. Paired baseline and end point biopsies were analyzed for proliferation (Ki67), apoptosis, human epidermal growth factor receptor 2 (HER2), COX-2, and progesterone receptor (PR) expression by immunohistochemistry. The primary end point was a decrease in Ki67 between diagnosis and surgical excision.

Results: Ninety women were randomized: all were ER positive, 49 (54%) had grade III tumors, and 29 (32%) were HER2 positive (3+). Exemestane reduced proliferation compared with placebo with a median reduction of 9% (95% confidence interval, 6-14; P < 0.001). Progesterone receptor was reduced by exemestane (mean decrease, 19%; 95% confidence interval, 9-28; P = 0.011). The effect of exemestane on proliferation was seen regardless of grade, HER2, or PR expression. Celecoxib had no effect on proliferation or apoptosis alone, or in combination with exemestane.

Conclusions: Exemestane reduces proliferation in ER-positive DCIS. Aromatase inhibition is a potential alternative to tamoxifen in patients who have undergone breast conservation for ER-positive DCIS. Clin Cancer Res; 16(5); 1605–12
Neuroblastoma Progression Correlates with Downregulation of the Lymphangiogenesis Inhibitor sVEGFR-2
Authors: Becker Jürgen , Pavlakovic Helena , Ludewig Fabian , Wilting Fabiola , Weich Herbert A. , Albuquerque Romulo , Ambati Jayakrishna , Wilting Jörg
Published: February 2010

Purpose: Tumor progression correlates with the induction of a dense supply of blood vessels and the formation of peritumoral lymphatics. Hemangiogenesis and lymphangiogenesis are potently regulated by members of the vascular endothelial growth factor (VEGF) family. Previous studies have indicated the upregulation of VEGF-A and -C in progressed neuroblastoma, however, quantification was performed using semiquantitative methods, or patients who had received radiotherapy or chemotherapy were studied.

Experimental Design: We have analyzed primary neuroblastoma from 49 patients using real-time reverse transcription-PCR and quantified VEGF-A, -C, and -D and VEGF receptors (VEGFR)-1, 2, 3, as well as the soluble form of VEGFR2 (sVEGFR-2), which has recently been characterized as an endogenous inhibitor of lymphangiogenesis. None of the patients had received radiotherapy or chemotherapy before tumor resection.

Results: We did not observe upregulation of VEGF-A, -C, and -D in metastatic neuroblastoma, but found significant downregulation of the lymphangiogenesis inhibitor sVEGFR-2 in metastatic stages III, IV, and IVs. In stage IV neuroblastoma, there were tendencies for the upregulation of VEGF-A and -D and the downregulation of the hemangiogenesis/lymphangiogenesis inhibitors VEGFR-1 and sVEGFR-2 in MYCN-amplified tumors. Similarly, MYCN transfection of the neuroblastoma cell line SH-EP induced the upregulation of VEGF-A and -D and the switching-off of sVEGFR-2.

Conclusion: We provide evidence for the downregulation of the lymphangiogenesis inhibitor sVEGFR-2 in metastatic neuroblastoma stages, which may promote lymphogenic metastases. Downregulation of hemangiogenesis and lymphangiogenesis inhibitors VEGFR-1 and sVEGFR-2, and upregulation of angiogenic activators VEGF-A and VEGF-D in MYCN-amplified stage IV neuroblastoma supports the crucial effect of this oncogene on neuroblastoma progression. Clin Cancer Res; 16(5); 1431–41
New Strategies in Kidney Cancer: Therapeutic Advances through Understanding the Molecular Basis of Response and Resistance
Authors: Rini Brian I.
Published: February 2010

The emergence of viable therapeutic strategies in metastatic renal cell carcinoma has invigorated translational and clinical research in this disease. Building upon the clinical activity observed with inhibition of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, novel strategies are being investigated to extend existing clinical benefits. Preclinical study has identified potential molecular mechanisms of response and resistance, providing a rational basis for biomarker development as well as sequential and combination therapy strategies. Several treatment strategies have emerged that are in the early phases of clinical testing. Further clinical and translational research is needed to validate initial hypotheses and translate observations into novel treatment strategies. Clin Cancer Res; 16(5); 1348–54
An Adenoviral Vaccine Encoding Full-Length Inactivated Human Her2 Exhibits Potent Immunogenicty and Enhanced Therapeutic Efficacy without Oncogenicity
Authors: Hartman Zachary C. , Wei Junping , Osada Takuya , Glass Oliver , Lei Gangjun , Yang Xiao-Yi , Peplinski Sharon , Kim Dong-Wan , Xia Wenle , Spector Neil , Marks Jeffrey , Barry William , Hobeika Amy , Devi Gayathri , Amalfitano Andrea , Morse Michael A. , Lyerly H. Kim , Clay Timothy M.
Published: February 2010

Purpose: Overexpression of the breast cancer oncogene HER2 correlates with poor survival. Current HER2-directed therapies confer limited clinical benefits and most patients experience progressive disease. Because refractory tumors remain strongly HER2+, vaccine approaches targeting HER2 have therapeutic potential, but wild type (wt) HER2 cannot safely be delivered in imunogenic viral vectors because it is a potent oncogene. We designed and tested several HER2 vaccines devoid of oncogenic activity to develop a safe vaccine for clinical use.

Experimental Design: We created recombinant adenoviral vectors expressing the extracellular domain of HER2 (Ad-HER2-ECD), ECD plus the transmembrane domain (Ad-HER2-ECD-TM), and full-length HER2 inactivated for kinase function (Ad-HER2-ki), and determined their immunogenicity and antitumor effect in wild type (WT) and HER2-tolerant mice. To assess their safety, we compared their effect on the cellular transcriptome, cell proliferation, anchorage-dependent growth, and transformation potential in vivo.

Results: Ad-HER2-ki was the most immunogenic vector in WT animals, retained immunogenicity in HER2-transgenic tolerant animals, and showed strong therapeutic efficacy in treatment models. Despite being highly expressed, HER2-ki protein was not phosphorylated and did not produce an oncogenic gene signature in primary human cells. Moreover, in contrast to HER2-wt, cells overexpressing HER2-ki were less proliferative, displayed less anchorage-independent growth, and were not transformed in vivo.

Conclusions: Vaccination with mutationally inactivated, nononcogenic Ad-HER2-ki results in robust polyclonal immune responses to HER2 in tolerant models, which translates into strong and effective antitumor responses in vivo. Ad-HER2-ki is thus a safe and promising vaccine for evaluation in clinical trials. Clin Cancer Res; 16(5); 1466–77
Cytotoxic Effects Induced by Docetaxel, Gefitinib, and Cyclopamine on Side Population and Nonside Population Cell Fractions from Human Invasive Prostate Cancer Cells
Authors: Mimeault Murielle , Johansson Sonny L. , Henichart Jean-Pierre , Depreux Patrick , Batra Surinder K.
Published: February 2010

The present study has been undertaken to establish the therapeutic benefit of cotargeting epidermal growth factor receptor (EGFR) and sonic hedgehog pathways by using gefitinib and cyclopamine, respectively, for improving the efficacy of the current chemotherapeutic drug docetaxel to counteract the prostate cancer progression from locally invasive to metastatic and recurrent disease stages. The data from immuofluorescence analyses revealed that EGFR/Tyr1173-pEGFR, sonic hedgehog ligand, smoothened coreceptor, and GLI-1 were colocalized with the CD133+ stem cell–like marker in a small subpopulation of prostate cancer cells. These signaling molecules were also present in the bulk tumor mass of CD133− prostate cancer cells with a luminal phenotype detected in patient's adenocarcinoma tissues. Importantly, the results revealed that the CD133+/CD44high/AR−/low side population (SP) cell fraction endowed with a high self-renewal potential isolated from tumorigenic and invasive WPE1-NB26 cells by the Hoechst dye technique was insensitive to the current chemotherapeutic drug, docetaxel. In contrast, the docetaxel treatment induced significant antiproliferative and apoptotic effects on the CD133−/CD44low/AR+ non-SP cell fraction isolated from the WPE1-NB26 cell line. Of therapeutic interest, the results have also indicated that combined docetaxel, gefitinib, and cyclopamine induced greater antiproliferative and apoptotic effects on SP and non-SP cell fractions isolated from WPE1-NB26 cells than individual drugs or two-drug combinations. Altogether, these observations suggest that EGFR and sonic hedgehog cascades may represent the potential therapeutic targets of great clinical interest to eradicate the total prostate cancer cell mass and improve the current docetaxel-based therapies against locally advanced and invasive prostate cancers, and thereby prevent metastases and disease relapse. Mol Cancer Ther; 9(3); 617–30
Gene Expression Patterns in the Human Breast after Pregnancy
Authors: Asztalos Szilard , Gann Peter H. , Hayes Meghan K. , Nonn Larisa , Beam Craig A. , Dai Yang , Wiley Elizabeth L. , Tonetti Debra A.
Published: February 2010

Epidemiologic studies have established that pregnancy has a bidirectional, time-dependent effect on breast cancer risk; a period of elevated risk is followed by a long-term period of protection. The purpose of the present study was to determine whether pregnancy and involution are associated with gene expression changes in the normal breast, and whether such changes are transient or persistent. We examined the expression of a customized gene set in normal breast tissue from nulliparous, recently pregnant (0-2 years since pregnancy), and distantly pregnant (5-10 years since pregnancy) age-matched premenopausal women. This gene set included breast cancer biomarkers and genes related to immune/inflammation, extracellular matrix remodeling, angiogenesis, and hormone signaling. Laser capture microdissection and RNA extraction were done from formalin-fixed paraffin-embedded reduction mammoplasty and benign biopsy specimens and analyzed using real-time PCR arrays containing 59 pathway-specific and 5 housekeeping genes. We report 14 of 64 (22%) of the selected gene set to be differentially regulated (at P < 0.05 level) in nulliparous versus parous breast tissues. Based on gene set analysis, inflammation-associated genes were significantly upregulated as a group in both parous groups compared with nulliparous women (P = 0.03). Moreover, parous subjects had significantly reduced expression of estrogen receptor α (ERα, ESR1), progesterone receptor (PGR), and ERBB2 (Her2/neu) and 2-fold higher estrogen receptor-β (ESR2) expression compared with nulliparous subjects. These initial data, among the first on gene expression in samples of normal human breast, provide intriguing clues about the mechanisms behind the time-dependent effects of pregnancy on breast cancer risk. Cancer Prev Res; 3(3); 301–11
Selenomethionine and α-Tocopherol Do Not Inhibit Prostate Carcinogenesis in the Testosterone plus Estradiol–Treated NBL Rat Model
Authors: Özten Nur , Horton Lori , Lasano Salamia , Bosland Maarten C.
Published: February 2010

Previous studies with selenium and/or vitamin E in prostate carcinogenesis animal models have been negative, but these models may not involve oxidative stress mechanisms. In this study, we examined the potential of selenomethionine and α-tocopherol to modulate prostate cancer development in the testosterone plus estradiol–treated NBL rat, a model that does involve sex hormone–induced oxidative stress mechanisms and prostatic inflammation. One week following the implantation with hormone-filled Silastic implants, rats were fed diets containing l-selenomethionine (1.5 or 3.0 mg/kg), DL-α-tocopherol acetate (2,000 or 4,000 mg/kg), or a natural ingredient control diet (NIH-07). The development of prostate carcinomas was not affected by dietary treatment with either agent. Food intake, body weight, and mortality were also not affected. The high dose of selenomethionine reduced the severity of epithelial dysplasia in the lateral prostate that was not associated with inflammation, and α-tocopherol reduced in a dose-related fashion the incidence of marked inflammation and marked epithelial dysplasia in the lateral prostate, regardless of whether these lesions were associated with inflammation. α-Tocopherol significantly increased the incidence of adenocarcinomas of the mammary glands at both dietary concentrations. Collectively, our findings suggest that selenomethionine and α-tocopherol supplementation does not prevent prostate cancer in rats fed diets with nutritionally adequate levels of selenium and vitamin E. Importantly, the results of the current animal studies and those reported previously were fully predictive of the outcome of the Selenium and Vitamin E Cancer Prevention Trial. Cancer Prev Res; 3(3); 371–80
Upper Airway Gene Expression in Smokers: The Mouth as a “Window to the Soul” of Lung Carcinogenesis?
Authors: Spira Avrum
Published: February 2010

This perspective on Boyle et al. (beginning on page 266 in this issue of the journal) explores transcriptomic profiling of upper airway epithelium as a biomarker of host response to tobacco smoke exposure. Boyle et al. have shown a striking relationship between smoking-related gene expression changes in the mouth and bronchus. This relationship suggests that buccal gene expression may serve as a relatively noninvasive surrogate marker of the physiologic response of the lung to tobacco smoke that could be used in large-scale screening and chemoprevention studies for lung cancer. Cancer Prev Res; 3(3); 255–8
Changing Prison Into a Therapeutic Milieu: Evidence From the Israeli National Rehabilitation Center for Prisoners
Authors: Gideon Lior , Shoham Efrat , Weisburd David L.
Published: February 2010

This study examines how a change in prison milieu affected both inmate and staff experiences of treatment within a regular correctional facility. Specifically, the study seeks to demonstrate how a change in prison milieu brought change on inmates and staff behavior and perception. Data were gathered using semistructured interviews with inmates and prison staff, and narratives were later analyzed. Results suggest that the therapeutic milieu inside the Sharon prison was significantly different from other prison-based therapeutic modalities and that this difference may be responsible for improved treatment retention and compliance as well as lowering recidivism rates. Potential explanations for these findings are discussed, and their implications for prison-based treatment and rehabilitation programs are explored.
Population Pharmacokinetic/Pharmacodynamic Model for C.E.R.A. in Both ESA‐Naïve and ESA‐Treated Chronic Kidney Disease Patients With Renal Anemia
Authors: Chanu Pascal , Gieschke Ronald , Charoin Jean‐Eric , Pannier Anne , Reigner Bruno
Published: February 2010

This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for C.E.R.A., a continuous erythropoietin receptor activator. C.E.R.A. is administered via intravenous (IV) and subcutaneous (SC) routes once every 2 weeks (Q2W) or once every 4 weeks (Q4W), respectively, to correct or maintain hemoglobin levels in chronic kidney disease (CKD) patients. Population models were specified to describe C.E.R.A. (PK) and hemoglobin (PD) concentrations over time, using data from 3 phase III, open‐label, randomized, parallel‐group, multicenter studies that examined IV or SC C.E.R.A. administration Q2W and Q4W in erythropoiesis‐stimulating agent (ESA)–naive and ESA‐treated patients. C.E.R.A. PK was described by a 1‐compartment model: drug clearance = 0.75 L/d, volume of distribution = 4.72 L, and half‐life = 105 hours in accordance with previous reported values. The PD model, a life span sequential PK/PD model, adequately described hemoglobin data. Dosing schedule, administration route, and study type did not affect drug‐related PD parameters or system‐specific parameters (eg, red blood cell life span). This model adequately described C.E.R.A.'s PK and PD properties according to C.E.R.A. posology, thus permitting simulations exploring alternative drug administration scenarios. It supports use of C.E.R.A. IV and SC; Q2W for anemia correction in ESA‐Naïve CKD patients and monthly administration in the hemoglobin maintenance phase.
Cognitive Performance Associated With Self-care Activities in Mexican Adults With Type 2 Diabetes
Authors: Compeán-Ortiz Lidia G. , Gallegos Esther C. , Gonzalez-Gonzalez José G. , Gomez-Meza Marco V. , Therrien Barbara , Salazar Bertha C.
Published: February 2010

Purpose

The purpose of this study was to determine the effect of memory-learning on self-care activities in adults with type 2 diabetes moderated by previous education/ understanding in diabetes and to explore the explicative capacity of age, gender, schooling, diabetes duration, and glycemic control in memory-learning.

Methods

A descriptive correlational study was conducted in a randomized sample of 105 Mexican adult patients with type 2 diabetes at a community-based outpatient clinic. Evaluation measures included the Wechsler Memory Scale for memory-learning; 2 questionnaires for self-care activities and previous education/understanding in diabetes, respectively; and glycosylated hemoglobin for glycemic control. Multiple linear regression analysis was used to examine the effect of memory-learning on self-care activities and the moderator capacity of previous education/understanding on diabetes. Multivariate analysis was used to identify the capacity of age, schooling, diabetes duration, and glycemic control in memory-learning types.

Results

A significant positive effect of memory-learning on self-care activities was found. Education/understanding in diabetes moderated the relationship between immediate and delayed memory-learning and self-care in glucose monitoring and diet. Gender, schooling, and the gender-glycemic control interaction explained memory-learning performance.

Conclusions

Immediate and delayed verbal and visual memory-learning were important for the patient to carry out self-care activities, and this relationship can be moderated by previous education/understanding in diabetes. These findings suggest potential benefits in emphasizing cognitive strategies to promote relearning of self-care behaviors in persons who live with diabetes.
Evaluation of Experimental Parameters in the Microbond Test with Regard to Lyocell Fibers
Authors: Adusumalli Ramesh-Babu , Weber Hedda K. , Roeder Thomas , Sixta Herbert , Gindl Wolfgang
Published: February 2010

Microbond technique is used to measure the interfacial shear strength (IFSS) of cellulose fiber-reinforced composites. Critical aspect ratios are provided for a variety of cellulose fiber-polymer matrix systems to avoid the fiber breakage during microbond test. The influence of fiber cross-section and droplet curing condition on the force-displacement curve and the corresponding change of IFSS are discussed for lyocell-polypropylene system. Finally, a relationship between the contact angle of a polymer drop on a fiber and IFSS is established for composite systems involving thermoset and thermoplastic matrices.
Experimental Study on Damage-induced Helium Leakage in Flexible Composites
Authors: Yao X.F. , Lei Y.M. , Xiong C. , Wang X.Q. , Wang Y.Q.
Published: February 2010

Damage-induced helium leakages in flexible composites are experimentally studied in this article. First, both surface and inner damage were produced in the flexible composites. Helium leakage with different damage patterns were studied based on the measurement of differential pressure. Second, the influence of damage pattern on helium leakage parameters in flexible composites was investigated. Finally, the damage-induced helium leakage mechanism in flexible composites was given. The results show that the inner damage is the main leakage source in flexible composites.