bluuebunny/crossref_metadata_2025 huggingface dataset:
Vessel Fractions in Tumor Xenografts Depicted by Flow- or Contrast-Sensitive Three-Dimensional High-Frequency Doppler Ultrasound Respond Differently to Antiangiogenic Treatment
Authors: Palmowski Moritz , Huppert Jochen , Hauff Peter , Reinhardt Michael , Schreiner Karin , Socher Michaela A. , Hallscheidt Peter , Kauffmann Guenter W. , Semmler Wolfhard , Kiessling Fabian
Published: August 2008

High-frequency volumetric Power Doppler ultrasound (HF-VPDU) captures flow-dependent signals in blood vessels and can be used to assess antiangiogenic therapy effects in rodent tumors. However, the sensitivity is limited to vessels larger than capillaries. Contrast-enhanced HF-VPDU reveals all perfused vessels by assessing stimulated acoustic emissions from disintegrating microbubbles. Thus, we investigated whether flow-sensitive and contrast-enhanced HF-VPDU can depict different vessel fractions and assess their early response to antiangiogenic therapy. Mice with A431 tumors were scanned before and after administration of polybutylcyanoacrylate microbubbles by HF-VPDU. Animals received either antiangiogenic treatment (SU11248) or a control substance and were imaged repeatedly over 9 days. At each time point, tumors were removed for immunohistochemical analysis. During growth of untreated tumors, vascularization decreased correspondingly on flow-sensitive and contrast-enhanced scans. Treated tumors showed a significantly (P < 0.05) stronger decline in vascularization than controls, which was more pronounced in contrast-enhanced scans. Surprisingly, whereas vascularization remained low in contrast-enhanced scans, flow-sensitive ultrasound indicated a reincrease after day 6 with a higher vascularization than the controls at day 9. Histologic evaluation indicated that immature vessels degraded markedly on therapy, whereas large mature vessels on the tumor periphery were more therapy resistant and drew closer due to tumor shrinkage. In conclusion, contrast-enhanced HF-VPDU and flow-sensitive HF-VPDU are both capable of assessing the effects of antiangiogenic therapy. Because contrast-sensitive ultrasound is more sensitive for small immature vessels and flow-sensitive ultrasound mostly captures large vessels at the tumor periphery, the combination of both methods can provide evidence of vascular maturity in tumors. [Cancer Res 2008;68(17):7042–9]
Podoplanin Is a Novel Fos Target Gene in Skin Carcinogenesis
Authors: Durchdewald Moritz , Guinea-Viniegra Juan , Haag Daniel , Riehl Astrid , Lichter Peter , Hahn Meinhard , Wagner Erwin F. , Angel Peter , Hess Jochen
Published: August 2008

Expression and function of the oncogenic transcription factor activator protein (AP-1; mainly composed of Jun and Fos proteins) is required for neoplastic transformation of keratinocytes in vitro and tumor promotion as well as malignant progression in vivo. Here, we describe the identification of 372 differentially expressed genes comparing skin tumor samples of K5-SOS-F transgenic mice (Fosf/f SOS+) with samples derived from animals with a specific deletion of c-Fos in keratinocytes (FosΔep SOS+). Fos-dependent transcription of selected genes was confirmed by quantitative real-time PCR analysis using tumor samples and mouse back skin treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). One of the most differentially expressed genes encodes the small mucin–like glycoprotein Podoplanin (Pdpn), whose expression correlates with malignant progression in mouse tumor model systems and human cancer. We found Pdpn and Fos expression in chemically induced mouse skin tumors, and detailed analysis of the Pdpn gene promoter revealed impaired activity in Fos-deficient mouse embryonic fibroblasts, which could be restored by ectopic Fos expression. Direct Fos protein binding to the Pdpn promoter was shown by chromatin immunoprecipitation and a TPA-induced complex at a TPA-responsive element–like motif in the proximal promoter was identified by electrophoretic mobility shift assays. In summary, we could define a Fos-dependent genetic program in a well-established model of skin tumors. Systematic analysis of these novel target genes will guide us in elucidating the molecular mechanisms of AP-1–regulated pathways that are critically implicated in neoplastic transformation and/or malignant progression. [Cancer Res 2008;68(17):6877–83]
Combined Lysophosphatidic Acid/Platelet-Derived Growth Factor Signaling Triggers Glioma Cell Migration in a Tenascin-C Microenvironment
Authors: Lange Katrin , Kammerer Martial , Saupe Falk , Hegi Monika E. , Grotegut Stefan , Fluri Erika , Orend Gertraud
Published: August 2008

The antiadhesive extracellular matrix molecule tenascin-C abrogates cell spreading on fibronectin through competitive inhibition of syndecan-4, thereby preventing focal adhesion kinase (FAK) activation and triggering enhanced proteolytic degradation of both RhoA and tropomyosin 1 (TM1). Here, we show that simultaneous signaling by lysophosphatidic acid (LPA) and platelet-derived growth factor (PDGF) initiates glioma cell spreading and migration through syndecan-4–independent activation of paxillin and FAK and by stabilizing expression of RhoA, TM1, TM2, and TM3. By using gene silencing methods, we show that paxillin, TM1, TM2, and TM3 are essential for LPA/PDGF-induced cell spreading on a fibronectin/tenascin-C (FN/TN) substratum. LPA/PDGF-induced cell spreading and migration on FN/TN depends on phosphatidylinositol 3-kinase, RhoKinase, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 but is independent of phospholipase C and Jun kinase. RNA microarray data reveal expression of tenascin-C, PDGFs, LPA, and the respective receptors in several types of cancer, suggesting that the TN/LPA/PDGF axis exists in malignant tumors. These findings may in turn be relevant for diagnostic or therapeutic applications targeting cancer. [Cancer Res 2008;68(17):6942–52]
BRCA1-Associated Protein-1 Is a Tumor Suppressor that Requires Deubiquitinating Activity and Nuclear Localization
Authors: Ventii Karen H. , Devi Narra S. , Friedrich Kenneth L. , Chernova Tatiana A. , Tighiouart Mourad , Van Meir Erwin G. , Wilkinson Keith D.
Published: August 2008

BRCA1-associated protein-1 (BAP1), a deubiquitinating enzyme of unknown cellular function, is mutated in breast and lung cancers. In this study, we have shown for the first time that BAP1 has tumor suppressor activity in vivo by showing that BAP1 can suppress tumorigenicity of lung cancer cells in athymic nude mice. We show that BAP1 fulfills another criterion of a genuine tumor suppressor because cancer-associated BAP1 mutants are deficient in deubiquitinating activity. We show for the first time that one of the two predicted nuclear targeting motifs is required for nuclear localization of BAP1 and that a truncation mutant found in a lung cancer cell line results in BAP1 that fails to localize to the nucleus. Furthermore, we show that deubiquitinating activity and nuclear localization are both required for BAP1-mediated tumor suppression in nude mice. We show that BAP1 exerts its tumor suppressor functions by affecting the cell cycle, speeding the progression through the G1-S checkpoint, and inducing cell death via a process that has characteristics of both apoptosis and necrosis. Surprisingly, BAP1-mediated growth suppression is independent of wild-type BRCA1. Because deubiquitinating enzymes are components of the ubiquitin proteasome system, this pathway has emerged as an important target for anticancer drugs. The identification of the deubiquitinating enzyme BAP1 as a tumor suppressor may lead to further understanding of how the ubiquitin proteasome system contributes to cancer and aid in the identification of new targets for cancer therapy. [Cancer Res 2008;68(17):6953–62]
Protease-Activated Receptor (PAR) 2, but not PAR1, Signaling Promotes the Development of Mammary Adenocarcinoma in Polyoma Middle T Mice
Authors: Versteeg Henri H. , Schaffner Florence , Kerver Marjolein , Ellies Lesley G. , Andrade-Gordon Patricia , Mueller Barbara M. , Ruf Wolfram
Published: August 2008

The G protein–coupled protease-activated receptors (PAR) are key signaling components for proteases in vascular biology and tumor progression. To address the contributions of PAR1 and PAR2 to breast cancer development, we established cohorts of mouse mammary tumor virus–polyoma middle T (PyMT) PAR1−/− and PAR2−/− mice, considering that the PyMT model recapitulates aspects of human disease. Appearance of palpable tumors, tumor expansion, and metastasis was indistinguishable between wild-type and PAR1−/− mice. PAR1−/− breast cancer cells were no longer responsive to thrombin in vitro, excluding compensatory up-regulation of alternative thrombin receptors and indicating that thrombin-PAR1 signaling is dispensable in breast tumor microenvironments. In contrast, palpable tumors and multifocal disease developed slower in PAR2−/− mice, and as a consequence of delayed tumor onset, metastasis was reduced. Analysis of early tumors showed persistence of adenomas with delayed appearance of vascularized adenocarcinomas in PAR2−/− mice. Furthermore, CXCL1 production by early PAR2−/− tumors was reduced. These results are consistent with previous xenograft data that implicated breast cancer PAR2 signaling in the induction of proangiogenic growth factors and chemokines. This study establishes that protease signaling contributes to mammary tumor development and that PAR2, rather than the thrombin receptor PAR1, plays a crucial role in the angiogenic switch. [Cancer Res 2008;68(17):7219–27]
Pontin and Reptin, Two Related ATPases with Multiple Roles in Cancer
Authors: Huber Otmar , Ménard Ludovic , Haurie Valérie , Nicou Alexandra , Taras Danièle , Rosenbaum Jean
Published: August 2008

Studies in model organisms or cultured human cells suggest potential implications in carcinogenesis for the AAA+ ATPases Pontin and Reptin. Both proteins are associated with several chromatin-remodeling complexes and have many functions including transcriptional regulation, DNA damage repair, and telomerase activity. They also interact with major oncogenic actors such as β-catenin and c-myc and regulate their oncogenic function. We only now begin to get insight into the role of Pontin and Reptin in human cancers. [Cancer Res 2008;68(17):6873–6]
Inflammatory Cytokines Induce Phosphorylation and Ubiquitination of Prostate Suppressor Protein NKX3.1
Authors: Markowski Mark C. , Bowen Cai , Gelmann Edward P.
Published: August 2008

Inflammation of the prostate is a risk factor for the development of prostate cancer. In the aging prostate, regions of inflammatory atrophy are foci for prostate epithelial cell transformation. Expression of the suppressor protein NKX3.1 is reduced in regions of inflammatory atrophy and in preinvasive prostate cancer. Inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin-1β accelerate NKX3.1 protein loss by inducing rapid ubiquitination and proteasomal degradation. The effect of TNF-α is mediated via the COOH-terminal domain of NKX3.1 where phosphorylation of serine 196 is critical for cytokine-induced degradation. Mutation of serine 196 to alanine abrogates phosphorylation at that site and the effect of TNF-α on NKX3.1 ubiquitination and protein loss. This is in contrast to control of steady-state NKX3.1 turnover, which is mediated by serine 185. Mutation of serine 185 to alanine increases NKX3.1 protein stability by inhibiting ubiquitination and doubling the protein half-life. A third COOH-terminal serine at position 195 has a modulating effect on both steady-state protein turnover and on ubiquitination induced by TNF-α. Thus, cellular levels of the NKX3.1 tumor suppressor are affected by inflammatory cytokines that target COOH-terminal serine residues to activate ubiquitination and protein degradation. Our data suggest that strategies to inhibit inflammation or to inhibit effector kinases may be useful approaches to prostate cancer prevention. [Cancer Res 2008;68(17):6896–901]
CXCL13 Is Highly Produced by Sézary Cells and Enhances Their Migratory Ability via a Synergistic Mechanism Involving CCL19 and CCL21 Chemokines
Authors: Picchio Maria Cristina , Scala Enrico , Pomponi Debora , Caprini Elisabetta , Frontani Marina , Angelucci Irene , Mangoni Antonella , Lazzeri Cristina , Perez Marie , Remotti Daniele , Bonoldi Emanuela , Benucci Roberto , Baliva Giannandrea , Lombardo Giuseppe Alfonso , Napolitano Monica , Russo Giandomenico , Narducci Maria Grazia
Published: August 2008

Chemokine and chemokine receptors expressed by normal and neoplastic lymphocytes play a key role in cell recruitment into skin and lymph nodes. The aim of this study was to get further insights into the role of chemokines in pathogenesis and progression of cutaneous T-cell lymphoma (CTCL) with particular regard to Sézary Syndrome (SS), a CTCL variant with blood involvement. Here, we show that functional CXCL13 homeostatic chemokine is strongly up-regulated in SS cells, well-detectable in skin lesions and lymph nodes, and measurable at high concentration in plasma of SS patients, at different levels during disease progression. Furthermore, we show that the addition of CXCL13 to CCL19 or to CCL21, the selective CCR7 agonists responsible for lymph node homing, strongly enhances the migration of CCR7+ SS cells. We also show that neutralization of the CCR7 receptor strongly impairs CCL19/21-induced chemotaxis of SS cells both in the absence or presence of CXCL13. Additional experiments performed to investigate the survival, adhesion, and metalloproteases secretion indicate that CXCL13 combined with CCL19 and CCL21 mainly affects the chemotaxis of SS cells. Our findings suggest that this newly described CXCL13 expression in SS represents a new pathogenetic mechanism of diagnostic significance. [Cancer Res 2008;68(17):7137–46]
Thrombospondin 1 Promotes Tumor Macrophage Recruitment and Enhances Tumor Cell Cytotoxicity of Differentiated U937 Cells
Authors: Martin-Manso Gema , Galli Susana , Ridnour Lisa A. , Tsokos Maria , Wink David A. , Roberts David D.
Published: August 2008

Inhibition of tumor growth by thrombospondin (TSP) 1 is generally attributed to its antiangiogenic activity, but effects on tumor immunity should also be considered. We show that overexpression of TSP1 in melanoma cells increases macrophage recruitment into xenograft tumors grown in nude or beige/nude mice. In vitro, TSP1 acutely induces expression of plasminogen activator inhibitor-1 (PAI-1) by monocytic cells, suggesting that TSP1-induced macrophage recruitment is at least partially mediated by PAI-1. Tumor-associated macrophages (TAM) can either promote or limit tumor progression. The percentage of M1-polarized macrophages expressing inducible nitric oxide synthase is increased in TSP1-expressing tumors. Furthermore, soluble TSP1 stimulates killing of breast carcinoma and melanoma cells by IFN-γ–differentiated U937 cells in vitro via release of reactive oxygen species. TSP1 causes a significant increase in phorbol ester–mediated superoxide generation from differentiated monocytes by interaction with α6β1 integrin through its NH2-terminal region. The NH2-terminal domain of TSP2 also stimulates monocyte superoxide production. Extracellular calcium is required for the TSP1-induced macrophage respiratory burst. Thus, TSP1 may play an important role in antitumor immunity by enhancing recruitment and activation of M1 TAMs, which provides an additional selective pressure for loss of TSP1 and TSP2 expression during tumor progression. [Cancer Res 2008;68(17):7090–10]
LRRC3B, Encoding a Leucine-Rich Repeat-Containing Protein, Is a Putative Tumor Suppressor Gene in Gastric Cancer
Authors: Kim Mirang , Kim Jeong-Hwan , Jang Hay-Ran , Kim Hwan-Mook , Lee Chang-Woo , Noh Seung-Moo , Song Kyu-Sang , Cho June-Sik , Jeong Hyun-Yong , Hahn Yoonsoo , Yeom Young-Il , Yoo Hyang-Sook , Kim Yong Sung
Published: August 2008

Leucine-rich repeat-containing 3B (LRRC3B) is an evolutionarily highly conserved leucine-rich repeat-containing protein, but its biological significance is unknown. Using restriction landmark genomic scanning and pyrosequencing, we found that the promoter region of LRRC3B was aberrantly methylated in gastric cancer. Gastric cancer cell lines displayed epigenetic silencing of LRRC3B, but treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine and/or the histone deacetylase inhibitor trichostatin A increased LRRC3B expression in gastric cancer cell lines. Real-time reverse transcription-PCR analysis of 96 paired primary gastric tumors and normal adjacent tissues showed that LRRC3B expression was reduced in 88.5% of gastric tumors compared with normal adjacent tissues. Pyrosequencing analysis of the promoter region revealed that LRRC3B was significantly hypermethylated in gastric tumors. Stable transfection of LRRC3B in SNU-601 cells, a gastric cancer cell line, inhibited anchorage-dependent and anchorage-independent colony formation, and LRRC3B expression suppressed tumorigenesis in nude mice. Microarray analysis of LRRC3B-expressing xenograft tumors showed induction of immune response–related genes and IFN signaling genes. H&E-stained sections of LRRC3B-expressing xenograft tumors showed lymphocyte infiltration in the region. We suggest that LRRC3B is a putative tumor suppressor gene that is silenced in gastric cancers by epigenetic mechanisms and that LRRC3B silencing in cancer may play an important role in tumor escape from immune surveillance. [Cancer Res 2008;68(17):7147–55]
Synergistic Inhibition with a Dual Epidermal Growth Factor Receptor/HER-2/neu Tyrosine Kinase Inhibitor and a Disintegrin and Metalloprotease Inhibitor
Authors: Witters Lois , Scherle Peggy , Friedman Steven , Fridman Jordan , Caulder Eian , Newton Robert , Lipton Allan
Published: August 2008

The ErbB family of receptors is overexpressed in numerous human tumors. Overexpression correlates with poor prognosis and resistance to therapy. Use of ErbB-specific antibodies to the receptors (Herceptin or Erbitux) or ErbB-specific small-molecule inhibitors of the receptor tyrosine kinase activity (Iressa or Tarceva) has shown clinical efficacy in several solid tumors. An alternative method of affecting ErbB-initiated tumor growth and survival is to block sheddase activity. Sheddase activity is responsible for cleavage of multiple ErbB ligands and receptors, a necessary step in availability of the soluble, active form of the ligand and a constitutively activated ligand-independent receptor. This sheddase activity is attributed to the ADAM (a disintegrin and metalloprotease) family of proteins. ADAM 10 is the main sheddase of epidermal growth factor (EGF) and HER-2/neu cleavage, whereas ADAM17 is required for cleavage of additional EGF receptor (EGFR) ligands (transforming growth factor-α, amphiregulin, heregulin, heparin binding EGF-like ligand). This study has shown that addition of INCB3619, a potent inhibitor of ADAM10 and ADAM17, reduces in vitro HER-2/neu and amphiregulin shedding, confirming that it interferes with both HER-2/neu and EGFR ligand cleavage. Combining INCB3619 with a lapatinib-like dual inhibitor of EGFR and HER-2/neu kinases resulted in synergistic growth inhibition in MCF-7 and HER-2/neu–transfected MCF-7 human breast cancer cells. Combining the INCB7839 second-generation sheddase inhibitor with lapatinib prevented the growth of HER-2/neu–positive BT474-SC1 human breast cancer xenografts in vivo. These results suggest that there may be an additional clinical benefit of combining agents that target the ErbB pathways at multiple points. [Cancer Res 2008;68(17):7083–9]
EBV Latent Membrane Protein 1 Effects on Plakoglobin, Cell Growth, and Migration
Authors: Shair Kathy H.Y. , Schnegg Caroline I. , Raab-Traub Nancy
Published: August 2008

Latent membrane protein 1 (LMP1), the major oncoprotein of EBV, is likely responsible for many of the altered cellular growth properties in EBV-associated cancers, including nasopharyngeal carcinoma (NPC). In this study, the effects of LMP1 on cell growth and migration were studied in the context of the EBV-positive C666-1 NPC cell line. In the soft agar transformation and Transwell metastasis assays, LMP1 enhanced cell growth and migration through activation of phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-κB (NF-κB) signaling. Inhibitors of PI3K, Akt, and NF-κB signaling dramatically reduced these enhanced properties. An IκBα super-repressor also blocked these effects. However, constitutive activation of Akt alone did not alter cell growth, suggesting that both PI3K/Akt and NF-κB activation are required by LMP1. These enhanced effects required the full-length LMP1 encompassing both the PI3K/Akt-activating COOH-terminal activation region (CTAR) 1 and the nonredundant NF-κB–activating regions CTAR1 and CTAR2. LMP2A, a latent protein that is also frequently expressed in NPC, similarly activates the PI3K/Akt pathway; however, its overexpression in C666-1 cells did not affect cell growth or migration. LMP1 also decreased expression of the junctional protein plakoglobin, which was shown to be partially responsible for enhanced migration induced by LMP1. This study reveals that in epithelial cells the transforming properties of LMP1 require activation of both PI3K/Akt and NF-κB and shows that the loss of plakoglobin expression by LMP1 is a significant factor in the enhanced migration. [Cancer Res 2008;68(17):6997–7005]
Tumor-Associated Galectin-3 Modulates the Function of Tumor-Reactive T Cells
Authors: Peng Weiyi , Wang Helen Y. , Miyahara Yoshihiro , Peng Guangyong , Wang Rong-Fu
Published: August 2008

T cells play an important role in cancer immunosurveillance and tumor destruction. However, tumor cells alter immune responses by modulating immune cells through antigen stimulation and immunoregulatory cytokines. A better understanding of the interplay between tumor cells and T cells might provide new strategies to enhance antitumor immunity. Through an antigen-screening approach using colorectal tumor–reactive T cells, we identified an HLA-DR11–restricted T-cell epitope encoded by KIAA0040 as well as MHC-unrestricted human galectin-3 (Gal-3) expressed by tumor cells. Although the biological function of KIAA0040 remains to be determined, we found that Gal-3 functioned as an immune regulator for direct T-cell activation and function. T-cell activation induced by Gal-3 resulted in T-cell apoptosis. We showed that a high level of expression of Gal-3 promoted tumor growth in vitro and in vivo. Using a mouse tumor model, we showed that delivery of high doses of Gal-3 inhibited tumor-reactive T cells and promoted tumor growth in mice receiving tumor-reactive CD8+ T cells. These findings suggest that Gal-3 may function as an immune regulator to inhibit T-cell immune responses and promote tumor growth, thus providing a new mechanism for tumor immune tolerance. [Cancer Res 2008;68(17):7228–36]
Characterization of the Recurrent 8p11-12 Amplicon Identifies PPAPDC1B, a Phosphatase Protein, as a New Therapeutic Target in Breast Cancer
Authors: Bernard-Pierrot Isabelle , Gruel Nadège , Stransky Nicolas , Vincent-Salomon Anne , Reyal Fabien , Raynal Virginie , Vallot Céline , Pierron Gaëlle , Radvanyi François , Delattre Olivier
Published: August 2008

The 8p11-12 chromosome region is one of the regions most frequently amplified in breast carcinoma (10–15% of cases). Several genes within this region have been identified as candidate oncogenes, as they are both amplified and overexpressed. However, very few studies have explored the role of these genes in cell transformation, with the aim of identifying valuable therapeutic targets. An analysis of comparative genomic hybridization array and expression profiling data for a series of 152 ductal breast carcinomas and 21 cell lines identified five genes (LSM1, BAG4, DDHD2, PPAPDC1B, and WHSC1L1) within the amplified region as consistently overexpressed due to an increased gene copy number. The use of small interfering RNA to knock down the expression of each of these genes showed the major role played by two genes, PPAPDC1B and WHSC1L1, in regulating the survival and transformation of two different cell lines harboring the 8p amplicon. The role of these two genes in cell survival and cell transformation was also confirmed by long-term knockdown expression studies using short hairpin RNAs. The potential of PPAPDC1B, which encodes a transmembrane phosphatase, as a therapeutic target was further shown by the strong inhibition of growth of breast tumor xenografts displaying 8p11-12 amplification induced by the silencing of PPAPDC1B. The oncogenic properties of PPAPDC1B were further shown by its ability to transform NIH-3T3 fibroblasts, inducing their anchorage-independent growth. Finally, microarray experiments on PPAPDC1B knockdown indicated that this gene interfered with multiple cell signaling pathways, including the Janus-activated kinase-signal transducer and activator of transcription, mitogen-activated protein kinase, and protein kinase C pathways. PPAPDC1B may also potentiate the estrogen receptor pathway by down-regulating DUSP22. [Cancer Res 2008;68(17):7165–75]
Identification of Secreted Proteins that Mediate Cell-Cell Interactions in an In vitro Model of the Lung Cancer Microenvironment
Authors: Zhong Li , Roybal Jonathon , Chaerkady Raghothama , Zhang Wan , Choi Kuicheon , Alvarez Cristina A. , Tran Hai , Creighton Chad J. , Yan Shaoyu , Strieter Robert M. , Pandey Akhilesh , Kurie Jonathan M.
Published: August 2008

Non–small cell lung cancer (NSCLC) cells with somatic mutations in K-ras recruit to the tumor a variety of cell types (hereafter collectively termed “stromal cells”) that can promote or inhibit tumorigenesis by mechanisms that have not been fully elucidated. Here, we postulated that stromal cells in the tumor microenvironment alter the tumor cell secretome, including those proteins required for tumor growth and dissemination, and we developed an in vitro model to test this hypothesis. Coculturing a murine K-ras mutant lung adenocarcinoma cell line (LKR-13) with a murine lung stromal cell (macrophage, endothelial cell, or fibroblast) enhanced stromal cell migration, induced endothelial tube formation, increased LKR-13 cell proliferation, and regulated the secretion of proteins involved in angiogenesis, inflammation, cell proliferation, and epithelial-to-mesenchymal transition. Among these proteins, CXCL1 has been reported to promote NSCLC development, whereas interleukin-18 (IL-18) has an undefined role. Genetic and pharmacologic strategies to inhibit CXCL1 and IL-18 revealed that stromal cell migration, LKR-13 cell proliferation, and LKR-13 cell tumorigenicity required one or both of these proteins. We conclude that stromal cells enhanced LKR-13 cell tumorigenicity partly through their effects on the secretome of LKR-13 cells. Strategies to inhibit tumor/stromal cell interactions may be useful as therapeutic approaches in NSCLC patients. [Cancer Res 2008;68(17):7237–45]
Chemokines as Mediators of Neovascularization
Authors: Keeley Ellen C. , Mehrad Borna , Strieter Robert M.
Published: August 2008

Chemokines are a superfamily of homologous heparin-binding proteins, first described for their role in recruiting leukocytes to sites of inflammation. Chemokines have since been recognized as key factors mediating both physiological and pathological neovascularization in such diverse clinical settings as malignancy, wound repair, chronic fibroproliferative disorders, myocardial ischemia, and atherosclerosis. Members of the CXC chemokine family, structurally defined as containing the ELR amino acid motif, are potent inducers of angiogenesis, whereas another subset of the CXC chemokines inhibits angiogenesis. In addition, CCL2, a CC chemokine ligand, has been implicated in arteriogenesis. In this article, we review the current literature on the role of chemokines as mediators of neovascularization.
Caffeine Enhances Endothelial Repair by an AMPK-Dependent Mechanism
Authors: Spyridopoulos Ioakim , Fichtlscherer Stephan , Popp Rüdiger , Toennes Stefan W. , Fisslthaler Beate , Trepels Thomas , Zernecke Alma , Liehn Elisa A. , Weber Christian , Zeiher Andreas M. , Dimmeler Stefanie , Haendeler Judith
Published: August 2008

Objective—

Migratory capacity of endothelial progenitor cells (EPCs) and mature endothelial cells (ECs) is a key prerequisite for endothelial repair after denuding injury or endothelial damage.

Methods and Results—

We demonstrate that caffeine in physiologically relevant concentrations (50 to 100 μmol/L) induces migration of human EPCs as well as mature ECs. In patients with coronary artery disease (CAD), caffeinated coffee increased caffeine serum concentration from 2 μmol/L to 23 μmol/L, coinciding with a significant increase in migratory activity of patient-derived EPCs. Decaffeinated coffee neither affected caffeine serum levels nor migratory capacity of EPCs. Treatment with caffeine for 7 to 10 days in a mouse-model improved endothelial repair after denudation of the carotid artery. The enhancement of reendothelialization by caffeine was significantly reduced in AMPK knockout mice compared to wild-type animals. Transplantation of wild-type and AMPK
−/−
bone marrow into wild-type mice revealed no difference in caffeine challenged reendothelialization. ECs which were depleted of mitochondrial DNA did not migrate when challenged with caffeine, suggesting a potential role for mitochondria in caffeine-dependent migration.

Conclusion—

These results provide evidence that caffeine enhances endothelial cell migration and reendothelialization in part through an AMPK-dependent mechanism, suggesting a beneficial role for caffeine in endothelial repair.
Associations Between Single Nucleotide Polymorphisms on Chromosome 9p21 and Risk of Coronary Heart Disease in Chinese Han Population
Authors: Zhou Li , Zhang Xiaomin , He Mei'an , Cheng Longxian , Chen Ying , Hu Frank B. , Wu Tangchun
Published: August 2008

Objectives—

We aimed to determine whether the single nucleotide polymorphisms (SNPs) on chromosome 9p21 were associated with coronary heart disease (CHD) in a Chinese Han population.

Methods and Results—

We determined the genotypes of rs2383206 and rs2383207 on chromosome 9p21 in 1360 CHD patients and 1360 age- and sex-frequency–matched controls from an unrelated Chinese Han population.
GG
genotypes in rs2383207 occurred more frequently in CHD patients compared to controls, and the odds ratio (OR) was 1.52 (95% CI 1.13 to 2.04), after adjusting for conventional risk factors. In stratified analysis, the risk associated with the
GG
genotype of the two SNPs was stronger in subjects who were males, less than 60 years old, overweight, and smokers. The SNP rs2383207 had significant interactions with gender and smoking (
P
=0.018 and 0.037, respectively). The risk allele
G
of rs2383207 plus family history of CHD had a cumulative association with CHD (
P
for trend, 1.0×10
−6
); the OR for CHD was 4.59 (95% CI 2.52 to 8.37) for those with all the risk factors as compared with subjects without any of the factors.

Conclusions—

The SNP rs2383207 on chromosome 9p21 is significantly associated with CHD in Chinese. This SNP combined with family history has a cumulative association with CHD.
Antagonism of Sphingosine 1-Phosphate Receptor-2 Enhances Migration of Neural Progenitor Cells Toward an Area of Brain Infarction
Authors: Kimura Atsushi , Ohmori Tsukasa , Kashiwakura Yuji , Ohkawa Ryunosuke , Madoiwa Seiji , Mimuro Jun , Shimazaki Kuniko , Hoshino Yuichi , Yatomi Yutaka , Sakata Yoichi
Published: August 2008

Background and Purpose—

We have previously shown that the sphingosine 1-phosphate (S1P)/S1P receptor-1 (S1P
1
R) axis contributes to the migration of transplanted neural progenitor cells (NPCs) toward areas of spinal cord injury. In the current study, we examined a strategy to increase endogenous NPC migration toward the injured central nervous system to modify S1PR.

Methods—

S1P concentration in the ischemic brain was measured in a mouse thrombosis model of the middle cerebral artery. NPC migration in vitro was assessed by a Boyden chamber assay. Endogenous NPC migration toward the insult was evaluated after ventricular administration of the S1P
2
R antagonist JTE-013.

Results—

The concentration of S1P in the brain was increased after ischemia and was maximal 14 days after the insult. The increase in S1P in the infarcted brain was primarily caused by accumulation of microglia at the insult. Mouse NPCs mainly expressed S1P
1
R and S1P
2
R as S1PRs, and S1P significantly induced the migration of NPCs in vitro through activation of S1P
1
R. However, an S1P
1
R agonist failed to have any synergistic effect on S1P-mediated NPC migration, whereas pharmacologic or genetic inhibition of S1P
2
R by JTE-013 or short hairpin RNA expression enhanced S1P-mediated NPC migration but did not affect proliferation and differentiation. Interestingly, administration of JTE-013 into a brain ventricle significantly enhanced endogenous NPC migration toward the area of ischemia.

Conclusions—

Our findings suggest that S1P is a chemoattractant for NPCs released from an infarcted area and regulation of S1P
2
R function further enhances the migration of NPCs toward a brain infarction.
Psychotic-Like Ideations Among a Group of Young Normal Subjects in Iran
Authors: Sharifi Vandad , Sajjadifar Ali , Amini Homayoun
Published: August 2008

Background: Recent studies show that self-reported psychotic-like experiences in general population samples are quite common and on a continuum with psychotic symptoms in clinical samples. However, most evidence comes from western settings and there is a dearth of research in developing countries. Examination of these experiences across different cultures adds to their validity.

Aims: To assess psychotic-like ideations and its association with poor mental health in a group of young normal individuals in Iran.

Methods: A total of 150 medical students with no history of a psychiatric disorder completed the Peters et al. Delusions Inventory (PDI-40) and the General Health Questionnaire (GHQ-28). Psychotic-like ideations were rated on the basis of their presence, as well as their levels of distress, preoccupation and conviction (PDI sub-scores).

Results: On average, 9.4 psychotic-like ideations were reported by the subjects (range 0—28). More frequent psychotic-like ideations and higher distress and preoccupation associated with these ideations were correlated with poor mental health as assessed by the GHQ.

Conclusion: Frequency of psychotic-like ideation and its dimensions, as well as its association with poor mental health, were comparable to the studies on healthy subjects conducted in Europe.
Psychiatriform Disorders: Psychiatric Analogues of Somatoform Disorders
Authors: Mullen Richard , Menkes David B.
Published: August 2008

Background: Somatoform disorders can be understood to mimic supposedly more `legitimate' physical disorders. To the extent that mental disorders are now also often considered legitimate, might clinicians expect to encounter the psychiatric equivalent of somatoform disorders, `psychiatriform disorders'?

Method: The relevant literature on somatoform disorders is reviewed in light of the tendency for mental and physical symptoms to co-occur.

Discussion: Illness attribution and behaviour may explain some of the recent rise in the prevalence of mental disorder. Hypotheses regarding the cause and nature of somatoform disorders are applied to their proposed psychiatric equivalent. Despite lack of current recognition, there is a strong theoretical basis for the existence of psychiatriform disorders. Psychiatriform disorders can be expected to have similar causes, comorbidity, and response to treatment, as somatoform disorders. A variety of cultural forces may be contributing to a rise in prevalence.

Conclusion: As with somatoform disorders, psychiatriform disorders present problems in their distinction from conscious fabrication and from the `legitimate' disorders they mimic. Given their likely prevalence and associated impairments, psychiatriform disorders warrant further examination, despite the methodological difficulties this presents.
Pharmacy Students' Attitudes Toward and Professional Interactions With People With Mental Disorders
Authors: Volmer Daisy , Mäesalu Martin , Bell J. Simon
Published: August 2008

Background: Health professionals frequently exhibit negative attitudes toward people with mental disorders. It is not known whether stigmatising attitudes among pharmacy students predict less positive attitudes toward consumer participation in decision-making about medications.

Aims: (1) To assess the attitudes of pharmacy students toward people with schizophrenia, and (2) to determine whether stigma predicts less positive attitudes toward concordant medication counselling.

Method: All pharmacy students enrolled in a five-year degree program were invited to participate. Students completed the seven-item Social Distance Scale, six items related to stereotypical attributes of people with schizophrenia and the 14-item Leeds Attitudes Toward Concordance Scale.

Results: Completed survey instruments were received from 157 students (94% response rate). Previous employment in a pharmacy and personal experience of a mental disorder were associated with low social distance. Later year of study, believing that people with schizophrenia are difficult to talk to, and believing people with schizophrenia have themselves to blame were predictive of high social distance. Low social distance and later year of study were associated with positive attitudes toward providing concordant medication counselling.

Conclusion: Mental health stigma was common and predictive of less positive attitudes toward consumer participation in decision-making about medications.
Prevalence of Mental Disorder and Associated Factors in Civilian Guatemalans With Disabilities Caused By the Internal Armed Conflict
Authors: Herrera Rivera Walter , De Jesus Mari Jair , Baxter Andreoli Sergio , Ines Quintana Maria , Pacheco De Toledo Ferraz Marcos
Published: August 2008

Background: The 34-year-long, Guatemalan war left at least 1,841 persons disabled in the country. The aim of this study was to describe the prevalence of mental disorders in individuals who acquired their disability as a result of the war, and to identify probable risk factors.

Method: A cross-sectional study was conducted of a group of 99 civilians with a disability in Guatemala. Participants were selected from four civilian organizations serving disabled persons in the municipality of Nebaj, Quiche. The diagnostic instrument was the computerized version of the Composite International Diagnostic Instrument 2.1 (CIDI 2.1). Data were collected from 2002 to 2004.

Results: Of the 99 disabled persons who completed the interview, 44 had some type of lifetime psychiatric disorder. Post-traumatic stress disorder (PTSD) was the most prevalent, with 34.34% (34 cases), followed by dysthymia, with 10.10% (10 cases), and depression, with 6.06% (6 cases).

Conclusion: The traumatic events experienced during the conflict caused long-term psychological sequelae in people who were disabled as a result of the war. Increased exposure to traumatic events, being married, physical disability, illiteracy and advanced age were identified as probable risk factors for mental disorders .
Attitudes of Ward Attendants Towards Mental Illness: Comparisons and Predictors
Authors: Vibha Pandey , Saddichha Sahoo , Kumar Ranjeet
Published: August 2008

Background: In India few studies exist that explore attitudes of mental health professionals, especially psychiatric ward attendants, towards psychiatric illnesses. This study aimed to explore attitudes of psychiatric ward attendants since they work closely with psychiatric patients in the hospital ward, and which may differ given their cultural and social background.

Methods: Five hundred psychiatric ward attendants were targeted and a 100 sample size chosen based on systematic random sampling. A control group from guardians attending the outpatient department of Central Institute of Psychiatry was selected using the same methods. Attitudes of both groups were assessed using Community Attitudes towards Mental Illness (CAMI) after written informed consent.

Results: There were no significant differences noted in Authoritarianism and Benevolence domains of CAMI. However, there were significant differences in the domains of Social Restrictiveness and Community Mental Health Ideology with psychiatric ward attendants scoring higher than the general attendants. Among the socio-demographic variables, there was significant correlation between age, duration of contact and educational background and various domains of CAMI.

Conclusions: Psychiatric ward attendants had more positive attitudes than general attendants towards psychiatric illnesses. Socio-demographic variables like older age, higher education and longer duration of contact with the psychiatrically ill predicted more favourable attitudes.
Marital Intentions and the Stability of First Cohabitations
Authors: Guzzo Karen Benjamin
Published: August 2008

Using Cycle 6 of the National Survey of Family Growth (NSFG), this article documents the extent to which cohabitors begin their union with intentions to marry (indicated by either being engaged or having definite plans to marry) and how this is related to subsequent cohabitation transitions, building on earlier literature examining expectations. Almost half of all first cohabitations begin with intentions to marry, and having marital intentions increases the likelihood of marriage and decreases the odds of dissolution. Blacks and Hispanics are more likely to report having marital intentions but less likely to transition to marriage. Prior family experiences also influence having marital intentions and the outcome of the cohabiting union, with significant differences by gender. Results suggest that although many individuals believe their cohabitation is part of the marriage process, gender and race/ethnicity play an important role in whether plans to marry will be realized.
The pragmatics of forgiveness: judgments of apologies in the Israeli political arena
Authors: Kampf Zohar
Published: August 2008

Although the theme of forgiveness has been studied extensively in various fields of humanities and social science, it has thus far been neglected by discourse scholars. Drawing on data from the Israeli political discourse between 1997 and 2004, this article analyzes the ways in which apologies are interpreted and judged by political actors as members of a distinctive interpretive community. The findings show that although realized infelicitously, most of the apologies made by Israeli political figures were accepted by the offended parties or their representatives. One explanation for this finding is that the traditional felicity conditions are replaced in the political arena by the `embarrassment condition', that is, the extent to which the gesture is perceived by the forgiver as threatening the apologizer's political image. Other reasons to forgive are less dependent on the judgment of the linguistic performance than on the various interests on the part of the forgiver. In cases in which the interest of the offended party is to detract from the symbolic power of his/her rival, even a full and humble apology may be refused. Inversely, even an incomplete form may be accepted if the offended is motivated to forgive. These findings are in line with Mills' argument regarding the total dependency of the apology on the way in which it is judged by its recipient.
Modern racism in the media: constructions of `the possibility of change' in accounts of two Australian `riots'
Authors: Simmons Katie , Lecouteur Amanda
Published: August 2008

Recent discursive research suggests that contemporary racism is typically accomplished in terms of subtle, flexibly managed and locally contingent discussion of the `problems' associated with minority groups. This study contributes to this work by focusing on the ways in which a particular formulation: `the possibility of change' was repeatedly implicated in descriptions of two `riots' that received widespread media attention in Australia: one involving Indigenous, and the other involving non-Indigenous, community members. Data were drawn from a corpus of newspaper articles, television and radio interviews, and parliamentary debates. Analysis demonstrated how, in respect to the event involving Indigenous Australians, `change' was repeatedly represented as an outcome that was not achievable. By contrast, descriptions of problems within the non-Indigenous community regularly represented `change' as an achievable outcome. We discuss how discourses around `the possibility of change' can thus be seen as another identifiable practice in terms of which `modern' forms of racism are regularly accomplished in media discourse.
The Extensive Sexual Violation and Sexual Abuse Histories of Incarcerated Women
Authors: McDaniels-Wilson Cathy , Belknap Joanne
Published: August 2008

A growing body of research reports on the lifetime prevalence of sexual victimization experiences among incarcerated women. However, none of this research provides a detailed account of the many types and levels of sexual violations and sexual abuses, the age of occurrence, and the victim–offender relationship. This study used the Sexual Abuse Checklist (designed by the first author) and a modified version of the Sexual Experiences Survey (SES) to obtain a detailed account of 391 incarcerated women's self-reported sexual violation and abuse histories. Seventy percent of the women reported at least one violation consistent with what qualifies as “rape” in most states in the United States today, and half of the women reported child sexual abuse victimization. The most prevalent victim–offender relationships were male strangers, male lovers or boyfriends, male dates, husbands, uncles, brothers, male cousins, and stepfathers.
Addressing Women's Fear of Victimization in Transportation Settings
Authors: Loukaitou-Sideris Anastasia , Fink Camille
Published: August 2008

Past research has shown that transit passengers' fears and concerns about safety influence their travel decisions. While the relationship between women's fear of crime and public space has been the focus of considerable research, transit environments—which are especially threatening to female passengers—have received much less attention. This study examines the issue of women's safety on transit through a survey of U.S. transit operators. The findings show that most respondents believe women have distinct safety and security needs, but most do not think agencies should put specific programs into place to address these needs. In addition, only a handful of agencies currently have programs that target the safety and security needs of women. This survey suggests that there is a significant mismatch between the safety and security needs and desires of female passengers and the types and locations of strategies that transit agencies use.