bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1α
Authors: Li Shan Hua , Shin Dong Hoon , Chun Yang-Sook , Lee Myung Kyu , Kim Myung-Suk , Park Jong-Wan
Published: December 2008

Hypoxia-inducible factor (HIF)-1 plays a key role in tumor promotion by inducing ∼60 genes required for tumor adaptation to hypoxia; thus, it is viewed as a target for cancer therapy. For this reason, YC-1, which down-regulates HIF-1α and HIF-2α at the post-translational level, is being developed as a novel anticancer drug. We here found that YC-1 acts in a novel manner to inhibit HIF-1. In the Gal4 reporter system, which is not degraded by YC-1, YC-1 was found to significantly inactivate the COOH-terminal transactivation domain (CAD) of HIF-1α, whereas it failed to inactivate CAD(N803A) mutant. In coimmunoprecipitation assays, YC-1 stimulated factor inhibiting HIF (FIH) binding to CAD even in hypoxia, whereas it failed to increase the cellular levels of hydroxylated Asn803 of CAD. It was also found that YC-1 prevented p300 recruitment by CAD in mammalian two-hybrid and coimmunoprecipitation assays. The involvement of FIH in YC-1-induced CAD inactivation was confirmed in EPO-enhancer and Gal4 reporter systems using FIH small interfering RNA and dimethyloxalylglycine FIH inhibitor. Indeed, FIH inhibition rescued HIF target gene expressions repressed by YC-1. In cancer cell lines other than Hep3B, YC-1 inhibits HIF-1α via the FIH-dependent CAD inactivation as well as via the protein down-regulation. Given these results, we suggest that the functional inactivation of HIF-α contributes to the YC-1-induced deregulation of hypoxia-induced genes. [Mol Cancer Ther 2008;7(12):3729–38]
In vivocharacterization of a polymeric nanoparticle platform with potential oral drug delivery capabilities
Authors: Bisht Savita , Feldmann Georg , Koorstra Jan-Bart M. , Mullendore Michael , Alvarez Hector , Karikari Collins , Rudek Michelle A. , Lee Carlton K. , Maitra Amarnath , Maitra Anirban
Published: December 2008

Nanotechnology has enabled significant advances in the areas of cancer diagnosis and therapy. The field of drug delivery is a sterling example, with nanoparticles being increasingly used for generating therapeutic formulations of poorly water-soluble, yet potent anticancer drugs. Whereas a number of nanoparticle-drug combinations are at various stages of preclinical or clinical assessment, the overwhelming majorities of such systems are injectable formulations and are incapable of being partaken orally. The development of an oral nano-delivery system would have distinct advantages for cancer chemotherapy. We report the synthesis and physicochemical characterization of orally bioavailable polymeric nanoparticles composed of N-isopropylacrylamide, methylmethacrylate, and acrylic acid in the molar ratios of 60:20:20 (designated NMA622). Amphiphilic NMA622 nanoparticles show a size distribution of <100 nm (mean diameter of 80 ± 34 nm) with low polydispersity and can readily encapsulate a number of poorly water-soluble drugs such as rapamycin within the hydrophobic core. No apparent systemic toxicities are observed in mice receiving as much as 500 mg/kg of the orally administered void NMA622 for 4 weeks. Using NMA622-encapsulated rapamycin (“nanorapamycin”) as a prototype for oral nano-drug delivery, we show favorable in vivo pharmacokinetics and therapeutic efficacy in a xenograft model of human pancreatic cancer. Oral nanorapamycin leads to robust inhibition of the mammalian target of rapamycin pathway in pancreatic cancer xenografts, which is accompanied by significant growth inhibition (P < 0.01) compared with control tumors. These data indicate that NMA622 nanoparticles provide a suitable platform for oral delivery of water-insoluble drugs like rapamycin for cancer therapy. [Mol Cancer Ther 2008;7(12):3878–88]
Critical role of indoleamine 2,3-dioxygenase in tumor resistance to repeated treatments with targeted IFNγ
Authors: Gasparri Anna Maria , Jachetti Elena , Colombo Barbara , Sacchi Angelina , Curnis Flavio , Rizzardi Gian-Paolo , Traversari Catia , Bellone Matteo , Corti Angelo
Published: December 2008

Targeted delivery of IFNγ to tumors has been achieved by fusing this cytokine with GCNGRC, a tumor neovasculature homing peptide. Although the therapeutic efficacy of this protein (called IFNγ-NGR) in animal models is greater than that of IFNγ, frequent administrations of IFNγ-NGR may result in lower efficacy and tumor resistance. We investigated the role of indoleamine 2,3-dioxygenase (IDO), an IFNγ-inducible enzyme that may down-regulate T cells by affecting local tryptophan catabolism in tumor resistance to repeated treatments with IFNγ-NGR. The study was carried out in immunocompetent mice and in nu/nu mice bearing RMA lymphoma, B16F melanoma, or WEHI-164 fibrosarcoma and in vitro using cultured tumor cells. IDO activity was increased in lymphoma homogenates after multiple treatments with IFNγ-NGR but not after a single treatment. Coadministration of 1-methyl-tryptophan, an inhibitor of IDO, increased tumor responses to multiple treatments in the lymphoma, melanoma, and fibrosarcoma models. No synergism between IFNγ-NGR and 1-methyl-tryptophan was observed in vitro in tumor cell proliferation assays or in nu/nu tumor-bearing mice, suggesting that the antitumor effect was host mediated. We conclude that IDO is critically involved in tumor resistance to repeated treatments with IFNγ-NGR, likely causing excessive stimulation of tryptophan catabolism and inhibiting antitumor immune mechanisms. Coadministration of IFNγ-NGR with IDO inhibitors could represent a new strategy for increasing its antitumor activity. [Mol Cancer Ther 2008;7(12):3859–66]
Nitric oxide initiates progression of human melanoma via a feedback loop mediated by apurinic/apyrimidinic endonuclease-1/redox factor-1, which is inhibited by resveratrol
Authors: Yang Zhen , Yang Sun , Misner Bobbye J. , Chiu Rita , Liu Feng , Meyskens Frank L.
Published: December 2008

It is well recognized that nitric oxide (NO) is involved in tumor progression, including melanoma. Measurement of proliferative and metastatic capacity by MTS and Matrigel invasion assays, respectively, was done and showed that NO-treated melanoma cells exhibited a higher capacity compared with control, especially metastatic Lu1205 cells. Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) is a multifunctional protein and its role in tumor biology has attracted considerable attention. To determine whether APE/Ref-1 plays a role in mediating NO stimulation of melanoma progression, we investigated the effect of DETA/NO on levels of APE/Ref-1 and related downstream targets [activator protein-1 (AP-1)/JunD, matrix metalloproteinase-1 (MMP-1), Bcl-2, and inducible nitric oxide synthase (iNOS)] by Western blot and reverse transcription-PCR analysis. Following DETA/NO treatment, APE/Ref-1 and other downstream molecules were induced. Knockdown of APE/Ref-1 or AP-1/JunD by specific small interfering RNA markedly reversed the induction by NO stress of target proteins. These results present evidence for the existence of a functional feedback loop contributing to progression and metastasis of melanoma cells. Resveratrol has been shown to be an APE/Ref-1 inhibitor and significant decreases in AP-1/JunD, MMP-1, Bcl-2, and iNOS protein levels occurred after exposure to resveratrol. This phenolic antioxidant may be an appropriate choice for combining with other compounds that develop resistance by up-regulation of these molecules. [Mol Cancer Ther 2008;7(12):3751–60]
MicroRNAs and cancer: past, present, and potential future
Authors: Nelson Kristen M. , Weiss Glen J.
Published: December 2008

MicroRNAs (miRNAs) are a class of small RNAs that have revealed a new level of gene regulation in the cell. After being processed by Drosha and Dicer RNase III endonucleases, mature miRNAs can inhibit the translation of mRNA by directing a RNA-induced silencing complex (RISC) to the target mRNA. miRNAs are making an impact in our understanding of cancer biology. Acting as either tumor suppressors or oncogenes, miRNAs regulate several genes known to play important roles in cancer. With the discovery of miRNAs comes the need for new techniques to study their activity. Bioinformatic tools can be used to predict mRNA targets of miRNA, but validation of miRNA regulation of predicted targets is imperative. miRNAs are differentially expressed in normal and tumor cells as well as between tumor subtypes. These differences may be useful as prognostic and predictive markers in cancer patients. The study of miRNAs holds much promise for improving diagnosis and treatment of cancer. [Mol Cancer Ther 2008;7(12):3655–60]
Monoclonal antibody 14C5 targets integrin αvβ5
Authors: Burvenich Ingrid , Schoonooghe Steve , Vervoort Liesbet , Dumolyn Caroline , Coene Elisabeth , Vanwalleghem Lieve , Van Huysse Jacques , Praet Marleen , Cuvelier Claude , Mertens Nico , De Vos Filip , Slegers Guido
Published: December 2008

This study identifies and characterizes the antigen recognized by monoclonal antibody (mAb) 14C5. We compared the expression of antigen 14C5 with the expression of eight integrin subunits (α1, α2, α3, αv, β1, β2, β3, and β4) and three integrin heterodimers (αvβ3, αvβ5, and α5β1) by flow cytometry. Antigen 14C5 showed a similar expression to αvβ5 in eight different epithelial cancer cell lines (A549, A2058, C32, Capan-2, Colo16, HT-1080, HT-29, and SKBR-3). Specific binding of P1F6, an anti-αvβ5 specific antibody, was blocked by mAb 14C5. After transient expression of αvβ5 in 14C5-negative Colo16 cells, mAb 14C5 was able to bind a subpopulation of αvβ5-positive cells. We evaluated the tissue distribution of the 14C5 antigen in colon (n = 20) and lung (n = 16) cancer tissues. The colon carcinoma cells stained positive for 14C5 in 50% of tumors analyzed, whereas bronchoalveolar lung carcinoma and typical carcinoid were not positive for the antigen. More common types of non–small cell lung cancer, i.e., squamous (n = 5) and adenocarcinoma (n = 3), stained positive in 2 of 5 squamous carcinomas and in 1 of 3 investigated adenocarcinoma. Colon (95%) and lung (50%) carcinoma tissues showed extensive expression of antigen 14C5 in the stroma surrounding the tumor cells and on the membrane of the adjacent fibroblasts. We show for the first time that mAb 14C5 binds the vascular integrin αvβ5, suggesting that mAb 14C5 can be used as a screening agent to select colon and lung cancer patients that are eligible for anti-αvβ5–based therapies. [Mol Cancer Ther 2008;7(12):3771–9]
Carbonic anhydrase IX has chaperone-like functions and is an immunoadjuvant
Authors: Wang Yanping , Wang Xiang-Yang , Subjeck John R. , Kim Hyung L.
Published: December 2008

Carbonic anhydrase IX (CA9) is a hypoxia-regulated, transmembrane protein associated with neoplastic growth in a large spectrum of human tumors. CA9 is expressed in nearly all clear-cell renal tumors; levels of CA9 expression predict prognosis and response to interleukin-2 therapy. These observations may be explained by a novel chaperone-like function of CA9, which allows it to serve as an immunoadjuvant and stimulate an adaptive immune response against tumor antigens. Classic heat shock proteins (HSP) such as HSP110 and HSP70 are up-regulated in response to cellular stress and function to protect intracellular proteins from aggregation. Similarly, CA9 formed complexes with client proteins and inhibited heat-induced aggregation and enabled refolding of denatured client protein. HSP released from injured cells activate an immune response. CA9 bound dendritic cells in a receptor-specific manner. Bound CA9 was internalized by dendritic cells and processed primarily through the proteosomal pathway. In a murine melanoma model, a complex of CA9 and gp100 generated a gp100-specific antitumor response. A soluble form of CA9 shed from tumor cells had the same chaperone-like functions, providing renal tumors and hypoxic cells with a mechanism for stimulating an immune response against extracellular antigens. Interleukin-2 treatment of patient renal tumors in short-term culture increased CA9 shedding, suggesting a strategy for augmenting the immunogenicity of renal tumors. CA9 has chaperone-like functions and CA9 shed from tumors may play a direct role in stimulating an adaptive immune response. [Mol Cancer Ther 2008;7(12):3867–77]
Anti-Gout Agent Allopurinol Exerts Cytotoxicity to Human Hormone-Refractory Prostate Cancer Cells in Combination with Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand
Authors: Yasuda Takashi , Yoshida Tatsushi , Goda Ahmed E. , Horinaka Mano , Yano Kimihiro , Shiraishi Takumi , Wakada Miki , Mizutani Yoichi , Miki Tsuneharu , Sakai Toshiyuki
Published: December 2008

Allopurinol has been used for the treatment of gout and conditions associated with hyperuricemia for several decades. We explored the potential of allopurinol on cancer treatment. Allopurinol did not expose cytotoxicity as a single treatment in human hormone refractory prostate cancer cell lines, PC-3 and DU145. However, allopurinol drastically induced apoptosis of PC-3 and DU145 in combination with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), which is a promising candidate for anticancer agent but its efficacy is limited by the existence of resistant cancer cells. We examined the underlying mechanism by which allopurinol overcomes the resistance of prostate cancer cells to TRAIL. Allopurinol up-regulated the expression of a proapoptotic TRAIL receptor, death receptor 5 (DR5). Allopurinol increased DR5 protein, mRNA, and promoter activity. Using DR5 small interfering RNA (siRNA), we showed that allopurinol-mediated DR5 up-regulation contributed to the enhancement of TRAIL effect by allopurinol. Furthermore, we examined the mechanism of allopurinol-mediated DR5 up-regulation. DR5 promoter activity induced by allopurinol was diminished by a mutation of a CAAT/enhancer binding protein homologous protein (CHOP)-binding site. In addition, allopurinol also increased CHOP expression, suggesting that allopurinol induced DR5 expression via CHOP. Allopurinol possesses the activity of a xanthine oxidase (XO) inhibitor. We used XO siRNA instead of allopurinol. XO siRNA also up-regulated DR5 and CHOP expression and sensitized the prostate cancer cells to TRAIL-induced apoptosis. Here, we show the novel potential of allopurinol in cancer treatment and indicate that the combination of allopurinol with TRAIL is effective strategy to expand the TRAIL-mediated cancer therapy. (Mol Cancer Res 2008;6(12):1852–60)
Hedgehog-Induced Survival of B-Cell Chronic Lymphocytic Leukemia Cells in a Stromal Cell Microenvironment: A Potential New Therapeutic Target
Authors: Hegde Ganapati V. , Peterson Katie J. , Emanuel Katy , Mittal Amit K. , Joshi Avadhut D. , Dickinson John D. , Kollessery Gayathri J. , Bociek Robert G. , Bierman Philip , Vose Julie M. , Weisenburger Dennis D. , Joshi Shantaram S.
Published: December 2008

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by an accumulation of neoplastic B cells due to their resistance to apoptosis and increased survival. Among various factors, the tumor microenvironment is known to play a role in the regulation of cell proliferation and survival of many cancers. However, it remains unclear how the tumor microenvironment contributes to the increased survival of B-CLL cells. Therefore, we studied the influence of bone marrow stromal cell–induced hedgehog (Hh) signaling on the survival of B-CLL cells. Our results show that a Hh signaling inhibitor, cyclopamine, inhibits bone marrow stromal cell–induced survival of B-CLL cells, suggesting a role for Hh signaling in the survival of B-CLL cells. Furthermore, gene expression profiling of primary B-CLL cells (n = 48) indicates that the expression of Hh signaling molecules, such as GLI1, GLI2, SUFU, and BCL2, is significantly increased and correlates with disease progression of B-CLL patients with clinical outcome. In addition, SUFU and GLI1 transcripts, as determined by real-time PCR, are significantly overexpressed and correlate with adverse indicators of clinical outcome in B-CLL patients, such as cytogenetics or CD38 expression. Furthermore, selective down-regulation of GLI1 by antisense oligodeoxynucleotides (GLI1-ASO) results in decreased BCL2 expression and cell survival, suggesting that GLI1 may regulate BCL2 and, thereby, modulate cell survival in B-CLL. In addition, there was significantly increased apoptosis of B-CLL cells when cultured in the presence of GLI1-ASO and fludarabine. Together, these results reveal that Hh signaling is important in the pathogenesis of B-CLL and, hence, may be a potential therapeutic target. (Mol Cancer Res 2008;6(12):1928–36)
Neural Stem Cell Tropism to Glioma: Critical Role of Tumor Hypoxia
Authors: Zhao Donghong , Najbauer Joseph , Garcia Elizabeth , Metz Marianne Z. , Gutova Margarita , Glackin Carlotta A. , Kim Seung U. , Aboody Karen S.
Published: December 2008

Hypoxia is a critical aspect of the microenvironment in glioma and generally signifies unfavorable clinical outcome. Effective targeting of hypoxic areas in gliomas remains a significant therapeutic challenge. New therapeutic platforms using neural stem cells (NSC) for tumor-targeted drug delivery show promise in treatment of cancers that are refractory to traditional therapies. However, the molecular mechanisms of NSC targeting to hypoxic tumor areas are not well understood. Therefore, we investigated the role of hypoxia in directed migration of NSCs to glioma and identified the specific signaling molecules involved. Our data showed that hypoxia caused increased migration of human HB1.F3 NSCs to U251 human glioma-conditioned medium in vitro. In HB1.F3 NSCs, hypoxia led to up-regulation of CXCR4, urokinase-type plasminogen activator receptor (uPAR), vascular endothelial growth factor receptor 2 (VEGFR2), and c-Met receptors. Function-inhibiting antibodies to these receptors inhibited the migration of HB1.F3 cells to glioma-conditioned medium. Small interfering RNA knockdown of hypoxia-inducible factor-1α in glioma cells blocked the hypoxia-induced migration of NSCs, which was due to decreased expression of stromal cell–derived factor-1 (SDF-1), uPA, and VEGF in glioma cells. Our in vivo data provided direct evidence that NSCs preferentially distributed to hypoxic areas inside intracranial glioma xenografts, as detected by pimonidazole hypoxia probe, as well as to the tumor edge, and that both areas displayed high SDF-1 expression. These observations indicate that hypoxia is a key factor in determining NSC tropism to glioma and that SDF-1/CXCR4, uPA/uPAR, VEGF/VEGFR2, and hepatocyte growth factor/c-Met signaling pathways mediate increased NSC-to-glioma tropism under hypoxia. These results have significant implications for development of stem cell–mediated tumor-selective gene therapies. (Mol Cancer Res 2008;6(12):1819–29)
Mutations in theSOD2Promoter Reveal a Molecular Basis for an Activating Protein 2-Dependent Dysregulation of Manganese Superoxide Dismutase Expression in Cancer Cells
Authors: Xu Yong , Fang Fang , Dhar Sanjit K. , Bosch Antonio , St. Clair William H. , Kasarskis Edward J. , St. Clair Daret K.
Published: December 2008

A primary antioxidant enzyme in mitochondria, manganese superoxide dismutase (MnSOD), plays a critical role in the survival of aerobic life. It is well documented that, compared with normal cell counterparts, MnSOD level is decreased in neoplastic transformed cells but is increased in aggressive cancers. However, the underlying mechanism for the observed dysregulation of MnSOD in cancer is unknown. We have identified previously a unique set of mutations located in the promoter region of the SOD2 gene in several types of cancer cells. We found that a C-to-T transition at -102 and an insertion of A at -93 down-regulate MnSOD transcription by interrupting the formation of a single-stranded loop that is essential for a high level of promoter activity. Here, we show that the additional downstream mutation, C-to-G transversion at -38, creates a binding site for the transcription factors specificity protein 1 (Sp1) and activating protein 2 (AP-2). The promoter function is regulated by the relative levels of Sp1 and AP-2. In cytokine-induced expression of the SOD2 gene, Sp1 cooperates with a transcriptional complex containing nuclear factor-κB and nucleophosmin. The presence of AP-2 attenuates this induction. Our results suggest that the high level of MnSOD observed in aggressive cancer cells may be due, in part, to the absence of AP-2 transcriptional repression. (Mol Cancer Res 2008;6(12):1881–93)
Effect of Hypoxic-Ischemic Injury on Serine Palmitoyltransferase Activity in the Developing Rat Brain
Authors: Daigo Masaki , Arai Yasuhiro , Oshida Kyoichi , Kitamura Yohei , Hayashi Masaharu , Shimizu Toshiaki , Yamashiro Yuichiro
Published: December 2008

Background: Sphingolipid metabolism is strongly associated with central nervous system myelination. Ceramide is the most active of the sphingolipid metabolites. On the basis of ceramide biosynthesis indicated by serine palmitoyltransferase activity and cerebroside generated by ceramide, the evaluation of serine palmitoyltransferase activity in developing brains or hypoxic-ischemic damaged brains is worthwhile. Methods: Using a scintillation counter, we assessed serine palmitoyltransferase activity, a rate-limiting enzyme of sphingolipid metabolism, in the brains of developing rats and compared the activity with hypoxic-ischemic brains, using the method of Rice on postnatal day 7 (P7). Results: In the control groups, serine palmitoyltransferase activity was detected in the microsomal fraction of whole brain homogenates from P4, which was earlier than the initial expression of myelin-specific proteins such as myelin basic protein and proteolipid protein on immunochemistry. Serine palmitoyltransferase activity increased along with development on P8, P10, P14 and P21. However, hypoxic-ischemic brains showed lower serine palmitoyltransferase activity than control brains on P8, P10, P14 and P21. Conclusions: These results suggest that increase in serine palmitoyltransferase activity before myelin-specific protein expression may be an initial step in myelinogenesis and a decline in serine palmitoyltransferase activity in hypoxic-ischemic brains may be one of the major causes of delayed myelination.
Expression of Angiogenesis-Related Genes Regulates Different Steps in the Process of Tumor Growth and Metastasis in Human Urothelial Cell Carcinoma of the Urinary Bladder
Authors: Chikazawa M. , Inoue K. , Fukata S. , Karashima T. , Shuin T.
Published: December 2008

Objective: This study was designed to determine the relative activity of angiogenesis-related genes in the regulation of tumorigenicity and subsequent metastases of urothelial cell carcinomas (UC) of the urinary bladder. Methods: We selected the clones with the highest and lowest expression level of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF)/vascular permeability factor or interleukin-8 (IL-8) in the highly tumorigenic and metastatic human UC cell line 253J B-V. Tumorigenicity and production of spontaneous lymph node metastases were evaluated 1, 2, 4, 8 and 12 weeks after orthotopic implantation of each specific expression clone into the urinary bladder of athymic nude mice. Moreover, the transitional changes in the expression of angiogenesis-related genes and neovascularization were determined in tumors and metastases. Results: At the early stage of tumor growth following orthotopic implantation, tumorigenicity and metastases were significantly increased in the clones with the highest expression of bFGF and IL-8, while they were significantly inhibited in the clones with the lowest expression of bFGF and IL-8 compared to parental 253J B-V. In the tumors, specific expression of angiogenesis-related genes and intratumor neovascularity of each clone were gradually regulated to the same level as parental 253J B-V. In metastasized tumors of the highest and lowest IL-8-expressing clones, IL-8 expression was consistently high and low, respectively. Conclusions: These findings indicate that at the early stage of tumor growth, bFGF and IL-8 expression play important roles in the regulation of angiogenesis, tumorigenicity and subsequent metastases of human bladder cancer.
Immunohistochemical Analysis of Cell Cycle-Related Molecules in Gastric Carcinoma: Prognostic Significance, Correlation with Clinicopathological Parameters, Proliferation and Apoptosis
Authors: Lee Kyung-Hee , Lee Hee Eun , Cho Sung Jin , Cho Yu Jin , Lee Hye Seung , Kim Ji Hun , Nam Seon Young , Chang Mee Soo , Kim Woo Ho , Lee Byung Lan
Published: December 2008

Objective: We aimed to investigate the biological significance of cell cycle regulators in gastric carcinoma. Methods: Immunohistochemistry and TUNEL staining were performed on tissue array slides containing 293 gastric carcinoma specimens. The relationship between the protein expression of each of the cell cycle regulators and prognosis, clinicopathological features, proliferation, or apoptosis was evaluated. Results: The nuclear immunoreactivity for cyclin D1, cyclin E, p21, and p27 was observed in 22, 14, 31 and 27% of cases, respectively. The expression of cyclin D1, p21, or p27 positively correlated with early pTNM stages, tumor cell proliferation (represented by Ki-67 labeling) and good prognosis, whereas it inversely correlated with the lymph node metastasis (p < 0.05). On the other hand, p27 expression inversely correlated with the apoptosis index represented by TUNEL staining (p < 0.001). In addition, the expression of cyclin D1 positively correlated with that of p21 or p27 (p < 0.05). Conclusions: Our results showed that the expression of cyclin D1, p21 and p27, alone or in combination, are early events in gastric tumorigenesis and may serve as a candidate molecular marker for the early gastric carcinoma.
Functional Neuroanatomy of Contextual Acquisition of Concrete and Abstract Words
Authors: Mestres-Missé Anna , Münte Thomas F. , Rodriguez-Fornells Antoni
Published: December 2008

The meaning of a novel word can be acquired by extracting it from linguistic context. Here we simulated word learning of new words associated to concrete and abstract concepts in a variant of the human simulation paradigm that provided linguistic context information in order to characterize the brain systems involved. Native speakers of Spanish read pairs of sentences in order to derive the meaning of a new word that appeared in the terminal position of the sentences. fMRI revealed that learning the meaning associated to concrete and abstract new words was qualitatively different and recruited similar brain regions as the processing of real concrete and abstract words. In particular, learning of new concrete words selectively boosted the activation of the ventral anterior fusiform gyrus, a region driven by imageability, which has previously been implicated in the processing of concrete words.
Lesion Evidence That Two Distinct Regions within Prefrontal Cortex are Critical for n-Back Performance in Humans
Authors: Tsuchida Ami , Fellows Lesley K.
Published: December 2008

Although prefrontal cortex is clearly important in executive function, the specific processes carried out by particular regions within human prefrontal cortex remain a matter of debate. A rapidly growing corpus of functional imaging work now implicates various areas within prefrontal cortex in a wide range of “executive” tasks. Loss-of-function studies can help constrain the interpretation of such evidence by testing to what extent particular brain areas are necessary for a given cognitive process. Here we apply a component process analysis to understand prefrontal contributions to the n-back task, a widely used test of working memory, in a cohort of patients with focal prefrontal damage. We investigated letter 2-back task performance in 27 patients with focal damage to various regions within prefrontal cortex, compared to 29 demographically matched control subjects. Both “behavior-defined” approaches, using qualitative lesion analyses and voxel-based lesion–symptom mapping methods, and more conventional “lesion-defined” groupwise comparisons were undertaken to determine the relationships between specific sites of damage within prefrontal cortex and particular aspects of n-back task performance. We confirmed a critical role for left lateral prefrontal cortex in letter 2-back performance. We also identified a critical role for medial prefrontal cortex in this task: Damage to dorsal anterior cingulate cortex and adjacent dorsal fronto-medial cortex led to a pattern of impairment marked by high false alarm rates, distinct from the impairment associated with lateral prefrontal damage. These findings provide converging support for regionally specific models of human prefrontal function.
Sources of Top–Down Control in Visual Search
Authors: Weidner Ralph , Krummenacher Joseph , Reimann Brit , Müller Hermann J. , Fink Gereon R.
Published: December 2008

Endogenous control of visual search can influence search guidance at the level of a supradimensional topographic saliency map [Wolfe, J. M. Guided Search 2.0: A revised model of visual search. Psychonomic Bulletin & Review, 1, 202–238, 1994], and modulate nonspatial mechanisms coding saliency in dimension-specific input modules [Müller, H. J., Reimann, B., & Krummenacher, J. Visual search for singleton feature targets across dimensions: Stimulus- and expectancy-driven effects in dimensional weighting. Journal of Experimental Psychology: Human Perception and Performance, 29, 1021–1035, 2003]. The current experiment used fMRI to dissociate these mechanisms in a singleton feature search task in which the likely target dimension (color or orientation) was semantically precued and target saliency in each dimension was varied parametrically. BOLD signal increases associated with increased demands for top–down guidance were observed within the fronto-parietal attention network and in the right anterior middle frontal gyrus. Decreasing requirements for top–down control led to BOLD signal increases in medial anterior prefrontal cortex, consistent with a gating mechanism in favor of stimulus-related processing [Burgess, P. W., Dumontheil, I., & Gilbert, S. J. The gateway hypothesis of rostral prefrontal cortex (area 10) function. Trends in Cognitive Sciences, 11, 290–298, 2007]. Another network of brain areas consisting of left lateral fronto-polar cortex, the left supramarginal gyrus, and the cerebellum, as well as a bilateral network consisting of the posterior orbital gyrus, the inferior frontal gyrus, and the pre-SMA were associated with top–down dimensional (re-) orienting. These data argue in favor of distinct endogenous control systems for visuospatial and dimension-based attentional processing. Finally, cue validity modulated saliency processing in the left temporo-parietal junction (TPJ), pointing to a crucial role of the left TPJ in integrating an endogenous dimension-based attention set with bottom–up saliency signals.
Co-localization of Stroop and Syntactic Ambiguity Resolution in Broca's Area: Implications for the Neural Basis of Sentence Processing
Authors: January David , Trueswell John C. , Thompson-Schill Sharon L.
Published: December 2008

For over a century, a link between left prefrontal cortex and language processing has been accepted, yet the precise characterization of this link remains elusive. Recent advances in both the study of sentence processing and the neuroscientific study of frontal lobe function suggest an intriguing possibility: The demands to resolve competition between incompatible characterizations of a linguistic stimulus may recruit top–down cognitive control processes mediated by prefrontal cortex. We use functional magnetic resonance imaging to test the hypothesis that individuals use shared prefrontal neural circuitry during two very different tasks—color identification under Stroop conflict and sentence comprehension under conditions of syntactic ambiguity—both of which putatively rely on cognitive control processes. We report the first demonstration of within-subject overlap in neural responses to syntactic and nonsyntactic conflict. These findings serve to clarify the role of Broca's area in, and the neural and psychological organization of, the language processing system.
On the Influence of Random Wind Stress Errors on the Four-Dimensional, Midlatitude Ocean Inverse Problem
Authors: Wakamatsu Tsuyoshi , Foreman Michael G. G. , Cummins Patrick F. , Cherniawsky Josef Y.
Published: December 2008

The effects of the parameterized wind stress error covariance function on the a priori error covariance of an ocean general circulation model (OGCM) are examined. These effects are diagnosed by computing the projection of the a priori model state error covariance matrix to sea surface height (SSH). The sensitivities of the a priori error covariance to the wind stress curl error are inferred from the a priori SSH error covariance and are shown to differ between the subpolar and subtropical gyres because of different contributions from barotropic and baroclinic ocean dynamics. The spatial structure of the SSH error covariance due to the wind stress error indicates that the a priori model state error is determined indirectly by the wind stress curl error. The impact of this sensitivity on the solution of a four-dimensional inverse problem is inferred.
Parent Perspectives of Diabetes Management in Schools
Authors: Jacquez Farrah , Stout Stacey , Alvarez-Salvat Rose , Fernandez Michelle , Villa Manuela , Sanchez Janine , Eidson Margaret , Nemery Robin , Delamater Alan
Published: December 2008

Purpose The purpose of this study is to investigate parent reports of the diabetes care support their children receive in school, their concerns about diabetes management in school, and their knowledge of federal laws that protect children with diabetes. In addition, the study explores ethnic and socioeconomic status differences in diabetes management in school.

Methods An ethnically heterogeneous sample of 309 parents of children with diabetes was recruited from a community-based and a university-based diabetes outpatient clinic. Parents completed a survey assessing supports their child's school provides for diabetes care, worries about diabetes care in school, and awareness of federal laws that pertain to children with diabetes.

Results Many children did not have a written care plan or a nurse at school, but significantly more white children had these supports than Hispanic or black children. Most children were not allowed to check blood glucose levels or administer insulin in class. Most parents were worried about hyperglycemia and hypoglycemia in school, and most were not at all or only a little confident in the school's ability to care for diabetes. Most parents were not aware of federal laws, but high-income and white parents were more likely to be aware.

Conclusions According to parents in the current study, children receive inadequate diabetes management support in schools. Minority children are less likely to receive supports than white children. Parents are worried about diabetes management in school, but most do not have the knowledge of federal laws necessary to protect their children.
Affecting Behavior Change in Individuals With Diabetes Findings From the Study to Help Improve Early Evaluation and Management of Risk Factors Leading to Diabetes (SHIELD)
Authors: Bazata Debbra D. , Robinson Jennifer G. , Fox Kathleen M. , Grandy Susan , SHIELD Study Group
Published: December 2008

Purpose This study evaluated whether health knowledge, attitudes, and behaviors of individuals with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus and those at high or low risk of T2DM were reflected in healthy behaviors and whether these attributes differed for T2DM respondents who did or did not see a health educator.

Methods SHIELD, a U.S. population-based study, included respondents (‡18 years of age) with T1DM (n = 366), T2DM (n = 3897), high risk (HR, n = 5449) defined as ‡3 of the following: abdominal obesity, high body mass index, dyslipidemia, hypertension, cardiovascular disease, and low risk (LR, n = 5725) defined as £2 factors.

Results T2DM respondents were more likely to receive health care professional recommendations to change their lifestyle habits (56%-62%) during their average 11 visits annually than the other groups (P < .0001). More T2DM and HR respondents tried losing weight, but fewer exercised regularly than T1DM and LR (P < .0001). T2DM respondents who saw a dietitian or health educator reported better current health and expectations for better future health, tried to make healthy food choices, and followed a prescribed eating plan than those who did not see these providers (P < .01). However, £30% of these T2DM respondents exercised regularly, or maintained desired weight.

Conclusions SHIELD findings show that respondents know and understand that improving their diet or exercise will affect their health, but the majority of respondents have not translated it into a behavior. Interaction with health educators and patient-empowering support may improve the transition to behavior change.
REFUGEE, MINORITY, CITIZEN, THREAT
Authors: Rolfe Ella
Published: December 2008

Ideas of ‘the refugee’ in India, long integrated with concepts of the nation through the partition experience, have significantly contributed to India's lack of formal refugee legislation. The present article argues that the resultant vague conceptual basis—or ‘script’—for refugee treatment has allowed India to deal relatively successfully with refugee situations of great variation and huge scale in the past when refugees were largely integrated into an existing narrative of ‘minorities’, a vital component of India's national identity and political landscape. However, recent pressures from within and from the international community to standardise refugee treatment and introduce a formal refugee law have combined with political events of recent years to disadvantage some refugee groups. This article seeks to understand the changes in refugee treatment in India today and focuses on Tibetans, who appear to suffer increasingly from association with a changing narrative that links refugees, penetration by outsiders, and threats to national security, arising partly as a result of the activities of refugee Tamils from Sri Lanka, and non–refugee incomers from Pakistan.
SOCIO–CULTURAL SECURITY, EMOTIONS AND EXCHANGE MARRIAGES IN AN AGRARIAN COMMUNITY
Authors: Zaman Muhammad
Published: December 2008

Examining patterns of mate selection and the core issue of agency, this brief article reports on fieldwork in a remote community in Pakistan, where the family continues to have supervening influence over individual choices in mate selection through exchange marriages. It explores the role of the family as a security provider and demonstrates the limited scope for individual agency. The behaviour of the family in mate selection, where strong security concerns are observed, indicates a culture–centered approach to tackle the issue in a clan context, where members try to maximise various aspects of security in the exchange of mate relations. Intensive fieldwork indicates significant feelings of insecurity among individuals over spouse selection and adoption of family–centered choices. Often the families of this agrarian community give priority to exchange marriages of their offspring, leaving limited options for the evasion of family control, since social security concerns normally prevail. The article also considers briefly the wider implications of such research.
Moral Hazard, Transaction Costs and the Reform of Public Service Employment Relations
Authors: Bordogna Lorenzo
Published: December 2008

This article analyses the reform of public service employment relations inspired by the New Public Management (NPM) approach, which has challenged both the traditional `sovereign employer' and `model employer' approaches to public service employment regulation. It envisages a double process of convergence: between public and private sector employment relations within each country, and in public service employment relations between different countries. However, the outcomes are mixed, and unexpected or perverse effects have often followed the reform attempts. These stem from a neglect of the distinctiveness of the public sector employer as a political institution and an excessive attention to moral hazard and agency costs. What is needed is a richer variety of mechanisms, more sophisticated and less unilateral than those borrowed from agency theory
European Sectoral Social Dialogue: An Analytical Framework
Authors: Léonard Evelyne
Published: December 2008

The European sectoral social dialogue involves complex relationships between the players directly or indirectly involved, and between the European level and the member organizations in national industrial relations systems. This article proposes a synthetic analytical framework to highlight these relationships, showing that the sectoral social dialogue constitutes a very specific `system of action'.
ChangAn Automotive Co.—Making Supply Chains Work
Authors: Goh Mark K.H. , Garg Miti
Published: December 2008

The car has evolved from being a horseless carriage to becoming a sophisticated engineering marvel. Accordingly, the challenges of modern day automotive supply chain management have become increasingly complex. This article describes the situation faced in a Chinese automotive supply chain by ChangAn Auto Co. Ltd (ChangAn)—China's fourth largest automotive manufacturer. The article elaborates upon the supply chain visibility and speed-to-market issues for ChangAn in the context of China's fast growth market realities and institutional environment.
`Mexican' labor in the Hollywood imaginary
Authors: Brayton Sean
Published: December 2008

This paper explores the manifold ways in which `Mexican' labor functions as a representational resource in three contemporary Hollywood texts: the films Friends with Money (2006) and Transamerica (2005), as well as the television sitcom Arrested Development (2003—2006). While the narratives partake in the racialization of labor in the US, they also visualize types of work and workers that often pass unacknowledged in white bourgeois culture. They rely on similar images of Hispanics as domestic, agricultural, service, and construction workers to a variety of diegetic ends, not all of which align with conservative xenophobic agendas. Although Hispanics are often depicted as self-identical foreigners irrespective of national origin and citizenship status racialized images of labor may be used to politically question mythologies of white bourgeois normativity.
The Oxford Conference on the Synoptic Problem
Authors: Batovici Dan
Published: December 2008

The past two centuries have witnessed a wide spectrum of solutions for the Synoptic Problem. Even though quite far from a consensus, the problem tends to incorporate new domains from ongoing connected research: the relevance of the Gospel of Thomas, the Synoptic authors' use of the Old Testament or recent studies on communication media in antiquity. This article surveys a number of issues presented in the papers of the Oxford Conference on the Synoptic Problem, held in May 2008, ranging from challenging past and present solutions of the Synoptic Problem from different perspectives to new directions of research on this topic.
The Tyranny of Bureaucracy
Authors: Fitzgerald Tanya
Published: December 2008

Fiscal efficiency and organizational effectiveness were the primary objectives that underpinned the reform of educational administration in New Zealand in the late 1980s. The consequent re-organization of schools and schooling located responsibility and accountability for school performance, teachers' work and student outcomes firmly at the door of local schools. The response from schools, as this article reports, was to devise bureaucratic solutions to deal with a complex mix of new tasks that were created; this included marketing, financial management, human resources management and strategic planning. One of the unintended consequences was schools increasingly became hierarchical and this invariably placed some teachers in roles of authority over others. Although terms such as `senior manager', `middle manager' or `middle leader' have been variously used to describe these roles, an empirical project conducted in three New Zealand secondary schools reveals that management tasks and activities dominate teachers' work and that there is, consequently, little or no time for leadership. In the words of one participant `the tyranny of bureaucracy leaves little time for leadership'.
The relationship between challenging behaviour and mental ill-health in people with intellectual disabilities
Authors: Allen David
Published: December 2008

Challenging behaviours and problems of mental ill-health are common amongst people with intellectual disabilities. The article examines conceptual similarities and differences between these conditions, examines the data on comorbidity, and explores possible hypothetical relationships between behavioural and psychiatric disorder in this population. While there is little evidence at present to suggest that many of the challenging behaviours seen in people with intellectual disabilities are underpinned by problems of mental ill-health, only qualified conclusions are possible because of limitations in the quality and scope of existing research. A conceptual model for looking at the risk variables that may contribute to both conditions is suggested, and requirements for future research and current multi-disciplinary practice are outlined.
Intellectual disability in homeless adults
Authors: Oakes Peter M. , Davies Ros C.
Published: December 2008

There has been considerable recent interest in the health and associated socio-economic inequalities faced by adults with learning disabilities. A serious and so far under-reported aspect of this is homelessness. This study sought to determine the prevalence of intellectual disability in a homeless population. Fifty people registered at a general practice in north-east England for socially excluded groups, and staying in temporary accommodation for the homeless during 2006—7, were assessed for learning disability. Full-scale and verbal IQ scores for the group were significantly lower than would be expected in the general population, but there was no significant difference in performance IQ. Homeless people are significantly more likely to have an intellectual disability than the general population. The implications for practice and policy development are far reaching. Further work is required to confirm these findings and to explore the experience of homeless people with intellectual disability.