bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular Endothelial Cadherin Promotes Breast Cancer Progression via Transforming Growth Factor β Signaling
Authors: Labelle Myriam , Schnittler Hans J. , Aust Daniela E. , Friedrich Katrin , Baretton Gustavo , Vestweber Dietmar , Breier Georg
Published: March 2008

Epithelial-to-mesenchymal transition (EMT) is an important event during carcinoma progression and leads to increased tumor cell malignancy. Here, we show that vascular endothelial (VE)-cadherin is induced during EMT in mammary tumor cells and is aberrantly expressed in invasive human breast carcinomas. VE-cadherin enhanced the capacity of fibroblastoid tumor cells to proliferate, form cord-like invasive structures, and adhere to endothelial cells, characteristics that are key contributors to their increased malignancy and metastatic potential. Consistently, VE-cadherin expression in malignant fibroblastoid tumor cells promoted the growth of experimental mammary carcinomas in vivo. Analysis of the signaling mechanisms involved revealed that VE-cadherin expression influences the levels of Smad2 phosphorylation and expression of target genes of transforming growth factor-β (TGF-β), a major mediator of advanced tumor progression and malignant tumor cell proliferation. VE-cadherin might thus promote tumor progression not only by contributing to tumor angiogenesis but also by enhancing tumor cell proliferation via the TGF-β signaling pathway. This article provides evidence for a novel function of VE-cadherin in tumor progression and reveals a previously unknown molecular link between VE-cadherin expression and TGF-β signaling. Our findings may have important implications for the clinical application of anti–VE-cadherin strategies. [Cancer Res 2008;68(5):1388–97]
DNA Damage–Dependent Translocation of B23 and p19ARF Is Regulated by the Jun N-Terminal Kinase Pathway
Authors: Yogev Orli , Saadon Keren , Anzi Shira , Inoue Kazushi , Shaulian Eitan
Published: March 2008

The dynamic behavior of the nucleolus plays a role in the detection of and response to DNA damage of cells. Two nucleolar proteins, p14ARF/p19ARF and B23, were shown to translocate out of the nucleolus after exposure of cells to DNA-damaging agents. This translocation affects multiple cellular functions, such as DNA repair, proliferation, and survival. In this study, we identify a pathway and scrutinize the mechanisms leading to the translocation of these proteins after exposure of cells to DNA-damaging agents. We show that redistribution of B23 and p19ARF after the exposure to genotoxic stress occurs preferentially when the c-Jun-NH2-kinase (JNK) pathway is activated and is inhibited when the JNK pathway is impaired. The stress-induced translocation of alternative reading frame (ARF) is JNK dependent and mediated by two activator proteins, c-Jun and JunB. Thr91 and Thr93 of c-Jun are required for the translocation, but the transcriptional activity of c-Jun is dispensable. Instead, c-Jun interacts with B23 in a dose-dependent manner. c-Jun itself is excluded from the nucleolus in a JNK-dependent manner. Hence, we suggest that c-Jun translocates B23 and ARF from the nucleolus after JNK activation by means of protein interactions. In senescent cells, JNK activity and c-Jun levels are reduced concomitantly with ARF nucleolar accumulation, and UV radiation does not cause the translocation of ARF. [Cancer Res 2008;68(5):1398–406]
Clonal Selection in Malignant Transformation of Human Fibroblasts Transduced with Defined Cellular Oncogenes
Authors: Mahale Alka M. , Khan Zahid A.T. , Igarashi Makoto , Nanjangud Gouri J. , Qiao Rui Fang , Yao Shen , Lee Sam W. , Aaronson Stuart A.
Published: March 2008

Recent evidence has implied that disruption of a limited number of defined cellular pathways is necessary and sufficient for neoplastic conversion of a variety of normal human cell types in tissue culture. We show instead that malignancy in such models results from an iterative process of clonal selection in vitro and/or in vivo. Normal human fibroblasts underwent malignant transformation after transduction with telomerase, cyclin-dependent kinase 4, dominant-negative p53, and activated Ras or MEK. Furthermore, culture conditions favoring overgrowth resulted in clonal selection, which with added Ras or MEK oncogenes led to the emergence of tumorigenic clones. Such tumors showed variable degrees of malignancy with some even exhibiting metastasis. SV40 small t antigen (ST) has been reported to be necessary and sufficient to convert human fibroblasts with these pathway aberrations to a polyclonal tumor. However, we observed that clonal tumors emerged even with ST addition. Genomic instability was markedly increased by p53 and Rb pathway abrogation. Under the same conditions, fibroblasts with these alterations failed to induce tumors, implying that genomic instability may be necessary but not sufficient for malignant transformation. These findings indicate that the minimum number of events required for malignant transformation of human fibroblasts is greater than has been enumerated by such oncogene addition strategies and support a stochastic cancer progression model initiated by four defined cellular alterations. [Cancer Res 2008;68(5):1417–26]
Survival Advantage of EBV-Associated Gastric Carcinoma: Survivin Up-regulation by Viral Latent Membrane Protein 2A
Authors: Hino Rumi , Uozaki Hiroshi , Inoue Yoko , Shintani Yukako , Ushiku Tetsuo , Sakatani Takashi , Takada Kenzo , Fukayama Masashi
Published: March 2008

EBV-associated gastric carcinoma is a distinct subset of gastric carcinoma infected with EBV, which shows latency I type expression of EBV latent genes (EBNA1, EBER, BARF0, and LMP2A). To clarify the role of EBV in this type of gastric carcinoma, the cell biological characteristics (growth, apoptosis, and migration) were evaluated in gastric carcinoma cell lines (MKN-1, TMK1, MKN-74 and MKN-7) with and without infection of recombinant EBV harboring the neomycin resistance gene. The infection reiterated the latency I type infection, and the only difference observed in EBV-infected gastric carcinoma cell lines was the resistance to serum deprivation–induced apoptosis. Comparative analyses of transcripts of apoptosis-associated genes in MKN-1 and EBV–MKN-1 and subsequent quantitative reverse transcription-PCR analysis showed up-regulation of the cellular survivin gene in EBV-infected gastric carcinoma cell lines. Small interfering RNA–mediated knockdown of survivin increased apoptosis in EBV–MKN-1 to the level of the original MKN-1 cells. Transfection of EBV-latent genes into MKN-1 showed that LMP2A, but not EBNA1, EBER, or BARF0, up-regulated survivin gene expression. LMP2A-mediated survivin up-regulation in gastric carcinoma cells was inhibited with a nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082. In parallel with these findings in vitro, survivin expression was frequent in carcinoma tissues of gastric carcinoma by immunohistochemistry, and significantly more in EBV-associated gastric carcinoma (12 of 13) than in EBV-negative gastric carcinoma in the advanced stage (P = 0.0307). Thus, EBV uses its latent protein, LMP2A, to activate the NF-κB–survivin pathway to rescue EBV-infected epithelial cells from serum deprivation, and up-regulation of survivin may play a role in the progression of this specific type of gastric carcinoma infected with EBV. [Cancer Res 2008;68(5):1427–35]
Altered TAB1:IκB Kinase Interaction Promotes Transforming Growth Factor β–Mediated Nuclear Factor-κB Activation during Breast Cancer Progression
Authors: Neil Jason R. , Schiemann William P.
Published: March 2008

The conversion of transforming growth factor β (TGF-β) from a tumor suppressor to a tumor promoter occurs frequently during mammary tumorigenesis, yet the molecular mechanisms underlying this phenomenon remain undefined. We show herein that TGF-β repressed nuclear factor-κB (NF-κB) activity in normal NMuMG cells, but activated this transcription factor in their malignant counterparts, 4T1 cells, by inducing assembly of TGF-β–activated kinase 1 (TAK1)–binding protein 1 (TAB1):IκB kinase β (IKKβ) complexes, which led to the stimulation of a TAK1:IKKβ:p65 pathway. TAB1:IKKβ complexes could only be detected in NMuMG cells following their induction of epithelial-mesenchymal transition (EMT), which, on TGF-β treatment, activated NF-κB. Expression of a truncated TAB1 mutant [i.e., TAB1(411)] reduced basal and TGF-β–mediated NF-κB activation in NMuMG cells driven to undergo EMT by TGF-β and in 4T1 cells stimulated by TGF-β. TAB1(411) expression also inhibited TGF-β–stimulated tumor necrosis factor-α and cyclooxygenase-2 expression in 4T1 cells. Additionally, the ability of human MCF10A-CA1a breast cancer cells to undergo invasion in response to TGF-β absolutely required the activities of TAK1 and NF-κB. Moreover, small interfering RNA–mediated TAK1 deficiency restored the cytostatic activity of TGF-β in MCF10A-CA1a cells. Finally, expression of truncated TAB1(411) dramatically reduced the growth of 4T1 breast cancers in syngeneic BALB/c, as well as in nude mice, suggesting a potentially important role of NF-κB in regulating innate immunity by TGF-β. Collectively, our findings have defined a novel TAB1:TAK1:IKKβ:NF-κB signaling axis that forms aberrantly in breast cancer cells and, consequently, enables oncogenic signaling by TGF-β. [Cancer Res 2008;68(5):1462–70]
A Novel Recurrent Chromosomal Inversion Implicates the Homeobox GeneDlx5in T-Cell Lymphomas from Lck-Akt2 Transgenic Mice
Authors: Tan Yinfei , Timakhov Roman A. , Rao Mamta , Altomare Deborah A. , Xu Jinfei , Liu Zemin , Gao Qingshen , Jhanwar Suresh C. , Di Cristofano Antonio , Wiest David L. , Knepper Janice E. , Testa Joseph R.
Published: March 2008

The oncogene v-akt was isolated from a retrovirus that induced murine thymic lymphomas. Transgenic mice expressing a constitutively activated form of the cellular homologue Akt2 specifically in immature T cells develop spontaneous thymic lymphomas. We hypothesized that tumors from these mice might exhibit oncogenic chromosomal rearrangements that cooperate with activated Akt2 in lymphomagenesis. Cytogenetic analysis revealed a recurrent clonal inversion of chromosome 6, inv(6), in thymic lymphomas from multiple transgenic founder lines, including one line in which 15 of 15 primary tumors exhibited this same rearrangement. Combined fluorescence in situ hybridization, PCR, and DNA sequence analyses showed that the distal inv(6) breakpoint resides at the T-cell receptor β chain locus, Tcrb. The proximal breakpoint maps to a region near a locus comprising the linked homeobox/transcription factor genes Dlx5 and Dlx6. Expression analysis of genes translocated to the vicinity of the Tcrb enhancer revealed that Dlx5 and Dlx6 are overexpressed in tumors exhibiting the inv(6). Experimental overexpression of Dlx5 in mammalian cells resulted in enhanced cell proliferation and increased colony formation, and clonogenic assays revealed cooperativity when both Dlx5 and activated Akt2 were coexpressed. In addition, DLX5, but not DLX6, was found to be abundantly expressed in three of seven human T-cell lymphomas tested. These findings suggest that the Dlx5 can act as an oncogene by cooperating with Akt2 to promote lymphomagenesis. [Cancer Res 2008;68(5):1296–302]
EBV MicroRNAs in Primary Lymphomas and Targeting of CXCL-11 by ebv-mir-BHRF1-3
Authors: Xia Tianli , O'Hara Andrea , Araujo Iguaracyra , Barreto Jose , Carvalho Eny , Sapucaia Jose Bahia , Ramos Juan Carlos , Luz Estela , Pedroso Celia , Manrique Michele , Toomey Ngoc L. , Brites Carlos , Dittmer Dirk P. , Harrington William J.
Published: March 2008

EBV-encoded microRNAs (miRNAs) have been identified and their functions are being studied. The expression pattern of these miRNAs in clinical samples of EBV-associated non–Hodgkin's lymphomas is unknown. We analyzed five primary “endemic” pediatric Burkitt's lymphomas (BL), two acquired immunodeficiency syndrome (AIDS)-related type I latency BL lines, a type III latency line, three EBV+ primary effusion lymphomas (PEL), and three AIDS-related diffuse large B-cell lymphomas (DLBCL) for expression of EBV-encoded miRNAs. A markedly elevated expression of miRNA BHRF1-3 in type III relative to its parental type I BL line was found. Primary unmanipulated type I BLs and EBV+ PELs expressed high levels of BART2 miRNA, whereas DLBCLs expressed both BART2 and BHRF1-3 species. BHRF1-3 miRNA expression inversely correlated with levels of a putative cellular target, the IFN-inducible T-cell attracting chemokine CXCL-11/I-TAC, and suppression of this factor was reversed by transfection of an antisense oligo to the EBV miRNA BHRF1-3. EBV-encoded miRNAs are expressed in primary lymphomas classically linked to the virus and are associated with the viral latency status. Targeted suppression of CXCL-11/I-TAC by a viral-encoded miRNA may serve as an immunomodulatory mechanism in these tumors. [Cancer Res 2008;68(5):1436–42]
Equilibrium between Host and Cancer Caused by Effector T Cells Killing Tumor Stroma
Authors: Zhang Bin , Zhang Yi , Bowerman Natalie A. , Schietinger Andrea , Fu Yang-Xin , Kranz David M. , Rowley Donald A. , Schreiber Hans
Published: March 2008

The growth of solid tumors depends on tumor stroma. A single adoptive transfer of CD8+ CTLs that recognize tumor antigen–loaded stromal cells, but not the cancer cells because of MHC restriction, caused long-term inhibition of tumor growth. T cells persisted and continuously destroyed CD11b+ myeloid-derived, F4/80+ or Gr1+ stromal cells during homeostasis between host and cancer. Using high-affinity T-cell receptor tetramers, we found that both subpopulations of stromal cells captured tumor antigen from surrounding cancer cells. Epitopes on the captured antigen made these cells targets for antigen-specific T cells. These myeloid stromal cells are immunosuppressive, proangiogenic, and phagocytic. Elimination of these myeloid cells allowed T cells to remain active, prevented neovascularization, and prevented tumor resorption so that tumor size remained stationary. These findings show the effectiveness of adoptive CTL therapy directed against tumor stroma and open a new avenue for cancer treatments. [Cancer Res 2008;68(5):1563–71]
Targeted Delivery of Small Interfering RNA: Approaching Effective Cancer Therapies
Authors: Pirollo Kathleen F. , Chang Esther H.
Published: March 2008

Three of the primary requirements for the development of effective dual-targeting therapeutic modalities for the treatment of cancer are the tumor-targeted delivery of the therapeutic molecules of interest to the tumor site(s) in the body (both primary and metastatic), passage of the molecular therapeutic through the cell membrane, and targeting specifically a growth or apoptotic pathway. However, lack of efficient targeted delivery, low transfection efficiency, instability to nucleases, poor tissue penetration, and nonspecific immune stimulation have hindered the translation of small interfering RNA (siRNA) into clinical applications. The development of a systemically administered, tumor-specific immunoliposome nanocomplex with high transfection efficiency could overcome these limitations and thus realize the potential of siRNAs to become effective anticancer clinical modalities. [Cancer Res 2008;68(5):1247–50]
Mouse Models for Xeroderma Pigmentosum Group A and Group C Show Divergent Cancer Phenotypes
Authors: Melis Joost P.M. , Wijnhoven Susan W.P. , Beems Rudolf B. , Roodbergen Marianne , van den Berg Jolanda , Moon Hojin , Friedberg Errol , van der Horst Gijsbertus T.J. , Hoeijmakers Jan H.J. , Vijg Jan , van Steeg Harry
Published: March 2008

The accumulation of DNA damage is a slow but hazardous phenomenon that may lead to cell death, accelerated aging, and cancer. One of the most versatile defense mechanisms against the accumulation of DNA damage is nucleotide excision repair, in which, among others, the Xeroderma pigmentosum group C (XPC) and group A (XPA) proteins are involved. To elucidate differences in the functions of these two proteins, comprehensive survival studies with Xpa−/−, Xpc−/− and wild-type control female mice in a pure C57BL/6J background were done. The median survival of Xpc−/− mice showed a significant decrease, whereas the median survival of Xpa−/− mice did not. Strikingly, Xpa−/− and Xpc−/− mice also showed a phenotypical difference in terms of tumor spectrum. Xpc−/− mice displayed a significant increase in lung tumors and a trend toward increased liver tumors compared with Xpa-deficient or wild-type mice. Xpa−/− mice showed a significant elevation in liver tumors. Additionally, Xpc-deficient mice exhibited a strong increase in mutant frequency in lung compared with Xpa−/− mice, whereas in both models mutant frequency is increased in liver. Our in vitro data displayed an elevated sensitivity to oxygen in Xpc−/− in mouse embryonic fibroblasts (MEF) when compared with Xpa−/− and wild-type fibroblasts. We believe that XPC plays a role in the removal of oxidative DNA damage and that, therefore, Xpc−/− mice display a significant increase in lung tumors and a significant elevation in mutant frequency in lung, and Xpc-deficient MEFs show greater sensitivity to oxygen when compared with Xpa−/− and wild-type mice. [Cancer Res 2008;68(5):1347–53]
Oncogene-Mediated Inhibition of Glycogen Synthase Kinase 3β Impairs Degradation of Prolactin Receptor
Authors: Plotnikov Alexander , Li Ying , Tran Thai H. , Tang Weigang , Palazzo Juan P. , Rui Hallgeir , Fuchs Serge Y.
Published: March 2008

Prolactin receptors (PRLr) expressed in a majority of breast cancer are activated by prolactin and growth hormone. The PRLr is commonly stabilized in human breast cancer due to decreased phosphorylation of residue Ser349, which, when phosphorylated, recruits the βTrcp E3 ubiquitin ligase and facilitates PRLr degradation. Here, we show that constitutive oncogenic signaling downstream of ErbB2 and Ras stabilizes PRLr via inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β) on Ser9. Importantly, inactivation of GSK3β correlates with elevated levels of PRLr protein in clinical human breast cancer specimens. Additional studies using pharmacologic, biochemical, and genetic approaches reveal that GSK3β is a bona fide PRLr kinase that phosphorylates PRLr on Ser349 and is required for the recognition of PRLr by βTrcp, as well as for PRLr ubiquitination and degradation. [Cancer Res 2008;68(5):1354–61]
Insulin-like Growth Factor-I Receptor Signaling Pathway Induces Resistance to the Apoptotic Activities of SCH66336 (Lonafarnib) through Akt/Mammalian Target of Rapamycin–Mediated Increases in Survivin Expression
Authors: Oh Seung Hyun , Jin Quanri , Kim Edward S. , Khuri Fadlo R. , Lee Ho-Young
Published: March 2008

Although preclinical studies have suggested that farnesyltransferase inhibitors (FTI) have promising antitumor activity, clinical trials have shown that FTI activity in patients is actually limited. The mechanism that induces resistance to FTI treatment is still not fully understood. The FTI SCH66336 has been shown to induce apoptotic and antiangiogenic activities in a subset of head and neck squamous cell carcinoma (HNSCC) and non–small cell lung cancer (NSCLC) cell lines. We therefore investigated the mechanisms mediating resistance to the therapeutic activities of SCH66336 in HNSCC and NSCLC. Our various analyses showed that insulin-like growth factor-I receptor (IGF-IR) activation interferes with the antitumor activity of SCH66336 in HNSCC and NSCLC cells. Treatment with SCH66336 activated the IGF-IR/phosphatidylinositol 3-kinase/Akt pathway, leading to increased mammalian target of rapamycin (mTOR)-mediated protein synthesis of survivin in a subset of HNSCC and NSCLC cell lines that were insensitive to the apoptotic activities of the drug. Inhibition of IGF-IR, Akt, or mTOR or the knockdown of survivin expression abolished resistance to SCH66336 and induced apoptosis in the cells. Overexpression of survivin by the use of adenoviral vector protected SCH66336-sensitive HNSCC cells from the apoptotic activities of the drug. Our results suggest that expression of phosphorylated IGF-IR, phosphorylated Akt, phosphorylated mTOR, and survivin serves as biological markers of SCH66336 responsiveness in HNSCC and NSCLC cells and that SCH66336 induces survivin expression through an IGF-IR/Akt/mTOR–dependent pathway. Thus, combining inhibitors of IGF-IR, phosphatidylinositol 3-kinase/Akt, mTOR, or survivin with SCH66336 may be an effective anticancer therapeutic strategy for patients with HNSCC or NSCLC.
Vascular Imaging of Solid Tumors in Rats with a Radioactive Arsenic-Labeled Antibody that Binds Exposed Phosphatidylserine
Authors: Jennewein Marc , Lewis Matthew A. , Zhao Dawen , Tsyganov Edward , Slavine Nikolai , He Jin , Watkins Linda , Kodibagkar Vikram D. , O'Kelly Sean , Kulkarni Padmakar , Antich Peter P. , Hermanne Alex , Rösch Frank , Mason Ralph P. , Thorpe Philip E.
Published: March 2008

Purpose: We recently reported that anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of vascular endothelial cells in tumors, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we tested the hypothesis that a chimeric monoclonal antibody that binds phosphatidylserine could be labeled with radioactive arsenic isotopes and used for molecular imaging of solid tumors in rats.

Experimental Design: Bavituximab was labeled with 74As (β+, T1/2 17.8 days) or 77As (β−, T1/2 1.6 days) using a novel procedure. The radionuclides of arsenic were selected because their long half-lives are consistent with the long biological half lives of antibodies in vivo and because their chemistry permits stable attachment to antibodies. The radiolabeled antibodies were tested for the ability to image subcutaneous Dunning prostate R3227-AT1 tumors in rats.

Results: Clear images of the tumors were obtained using planar γ-scintigraphy and positron emission tomography. Biodistribution studies confirmed the specific localization of bavituximab to the tumors. The tumor-to-liver ratio 72 h after injection was 22 for bavituximab compared with 1.5 for an isotype-matched control chimeric antibody of irrelevant specificity. Immunohistochemical studies showed that the bavituximab was labeling the tumor vascular endothelium.

Conclusions: These results show that radioarsenic-labeled bavituximab has potential as a new tool for imaging the vasculature of solid tumors.
WDR19 Expression is Increased in Prostate Cancer Compared with Normal Cells, but Low-Intensity Expression in Cancers is Associated with Shorter Time to Biochemical Failures and Local Recurrence
Authors: Lin Biaoyang , Utleg Angelita G. , Gravdal Karsten , White James T. , Halvorsen Ole J. , Lu Wei , True Lawrence D. , Vessella Robert , Lange Paul H. , Nelson Peter S. , Hood Leroy , Kalland Karl-Henning , Akslen Lars A.
Published: March 2008

Purpose: Prostate cancer is the third leading cause of cancer death in the United States, following lung and colorectal cancer. We previously identified WDR19 as a prostate-specific, androgen-regulated gene. Here, we evaluate its utility as a prostate cancer tissue marker for diagnosis and prognostic evaluation.

Experimental Design: Real-time quantitative PCR was done on a panel of prostate tissue isolated by laser capture microdissection. After generating antibodies against WDR19, tissue microarrays (TMA) were employed to compare WDR19 expression between normal, benign prostatic hyperplasia, and prostate cancer tissue.

Results: Using microarrays and real-time quantitative PCR, we showed that WDR19 mRNA expression was increased in cancer. We further showed that WDR19 protein is localized to cytoplasmic subcellular granules and is expressed exclusively in prostate epithelia. Large-scale immunohistochemical staining using TMAs reveals a significant percentage of increase in intensely staining tissue cores in cancer tissue when compared with normal or benign prostatic hyperplastic tissue. Based on the analysis of a separate TMA for which clinical follow-up information was available, low-intensity WDR19 staining was significantly associated with decreased time to biochemical failure (P = 0.006) and with decreased time to locoregional recurrence (P = 0.050).

Conclusions: WDR19 should be added to the list of prostate cancer tissue markers. The continued expansion of a multiple-marker panel will conceivably increase the sensitivity and specificity of prostate cancer diagnosis and prognosis.
Prognostic Significance of Macrophage Infiltration in Leiomyosarcomas
Authors: Lee Cheng-Han , Espinosa Inigo , Vrijaldenhoven Suzan , Subramanian Subbaya , Montgomery Kelli D. , Zhu Shirley , Marinelli Robert J. , Peterse Johannes L. , Poulin Neal , Nielsen Torsten O. , West Rob B. , Gilks C. Blake , van de Rijn Matt
Published: March 2008

Purpose: Macrophages are migratory cells that are frequently recruited to the site of tumors. Their presence is associated with poor clinical outcome in a variety of epithelial malignancies. The aim of this study is to examine the prognostic significance of tumor-associated macrophages in sarcomas.

Experimental Design: Global gene expression profiling data of a series of soft tissue tumors were analyzed for macrophage-associated gene expression. Immunohistochemistry on tissue microarrays containing leiomyosarcoma cases with known clinical outcome was used to verify the presence of macrophages and to examine the relationship between tumor-associated macrophages and clinical outcome.

Results: Gene expression profiling revealed high-level expression of several macrophage-associated genes such as CD163 and CD68 in a subset of leiomyosarcomas, indicating the presence of variable numbers of tumor-infiltrating macrophages. This was confirmed by CD68 and CD163 immunostaining of a tissue microarray containing 149 primary leiomyosarcomas. Kaplan-Meier survival analysis showed that high density of tumor-infiltrating macrophages as identified by CD163 or CD68 staining is associated with a significantly worse disease-specific survival in nongynecologic leiomyosarcomas, whereas leiomyosarcomas arising from the gynecologic tract showed no significant association between macrophage infiltration and survival. The presence of tumor necrosis did not correlate significantly with outcome.

Conclusions: An increased density of CD163- or CD68-positive tumor-infiltrating macrophages is associated with poor outcome in nongynecologic leiomyosarcomas. This may help the clinical management of patients with leiomyosarcomas.
hsa-miR-210 Is Induced by Hypoxia and Is an Independent Prognostic Factor in Breast Cancer
Authors: Camps Carme , Buffa Francesca M. , Colella Stefano , Moore John , Sotiriou Christos , Sheldon Helen , Harris Adrian L. , Gleadle Jonathan M. , Ragoussis Jiannis
Published: March 2008

Purpose: MicroRNA (miRNA) expression alterations have been described in cancer. Many cancers are characterized by areas of hypoxia, enhanced hypoxia-inducible factor (HIF) levels, and increased expression of hypoxically regulated genes, all of which correlate with patient outcome. We examined hypoxia-induced miRNA expression changes to identify markers of survival in breast cancer.

Experimental Design: We used microarrays to analyze miRNA expression changes induced by hypoxia in MCF7 breast cancer cell lines and validated results by quantitative-PCR (Q-PCR). Small interfering RNA against HIF-1α and HIF-2α, and RCC4 cells transfected with the von Hippel-Lindau (VHL) protein were used to investigate HIF dependency of miRNA expression. miRNA Q-PCR assays were done on 219 early breast cancer samples with long-term follow-up. Correlation of expression with clinical variables was done using Pearson and Spearman's rank tests, univariate, and Cox multivariate analysis.

Results: hsa-miR-210 induction was the most significant change under hypoxia by microarray analysis (3.4-fold, P < 0.001). hsa-miR-210 expression changes were validated by Q-PCR and detected in other cancer cell lines. Using small interfering RNAs and RCC4 cells transfected with VHL, we showed that the regulation by hypoxia of hsa-miR-210 was mediated by the HIF-1α/VHL transcriptional system but not HIF-2α. hsa-miR-210 expression levels in breast cancer samples correlated directly with a hypoxia score based on the expression of 99 genes. hsa-miR-210 expression levels showed an inverse correlation with disease-free and overall survival, significant in both univariate and multivariate analyses.

Conclusions: We show that hsa-miR-210 overexpression is induced by hypoxia in a HIF-1α– and VHL-dependent fashion and its expression levels in breast cancer samples are an independent prognostic factor.
Tumor-Infiltrating Lymphocytes and Perforation in Colon Cancer Predict Positive Response to 5-Fluorouracil Chemotherapy
Authors: Morris Melinda , Platell Cameron , Iacopetta Barry
Published: March 2008

Purpose: The major pathologic markers of prognosis in colorectal cancer include vascular invasion by tumor cells, invasion of adjacent lymph nodes, and perforation of the serosal wall. Recent work suggests that a high density of tumor-infiltrating lymphocytes (TIL) is associated with good outcome independently of these established prognostic markers. The aim of the present study was to investigate the prognostic significance of TILs and other routinely reported pathologic features in colon cancer, particularly in relation to the use of adjuvant chemotherapy.

Experimental Design: Pathologic markers, disease-specific survival, and the use of adjuvant chemotherapy were recorded in a retrospective, population-based series of 1,156 stage III colon cancer patients with a median follow-up time of 52 months.

Results: In patients treated by surgery alone (n = 851), markers with significant prognostic value included poor histologic grade, T4 stage, N2 nodal status, vascular invasion, and perforation, but not the presence of TILs. In patients treated with 5-fluorouracil–based chemotherapy (n = 305), TILs were associated with significantly improved survival [hazard ratio (HR), 0.52; 95% confidence interval, 0.30-0.91; P = 0.02] and perforation with a trend for improved survival (HR, 0.67; 95% confidence interval, 0.27-1.05; P = 0.16). Patients with TILs or perforation seemed to gain more survival benefit from chemotherapy (HR, 0.22 and 0.21, respectively) than patients without these features (HR, 0.84 and 0.82, respectively).

Conclusion: The apparent survival advantage from 5-fluorouracil associated with TILs and perforation requires confirmation in prospective studies. Because the presence of TILs reflects an adaptive immune response and perforation is associated with inflammatory response, these results suggest that there may be interactions between the immune system and chemotherapy leading to improved survival of colon cancer patients.
Tumor Escape from Endogenous, Extracellular Matrix–Associated Angiogenesis Inhibitors by Up-Regulation of Multiple Proangiogenic Factors
Authors: Fernando Namali T. , Koch Moritz , Rothrock Courtney , Gollogly Lila K. , D'Amore Patricia A. , Ryeom Sandra , Yoon Sam S.
Published: March 2008

Purpose: Thrombospondin-1 (Tsp1), endostatin, and tumstatin are extracellular matrix–associated proteins that inhibit angiogenesis. We examined the mechanisms by which tumor cells may bypass the antiangiogenic effects of these endogenous regulators.

Experimental Design: CT26 colon and RenCa renal carcinoma cells were stably transfected with Tsp1, endostatin, or tumstatin cDNA. Subcutaneous and metastatic tumor growth in syngeneic mice was analyzed. Expression of proangiogenic factors in resulting tumors was measured by quantitative real-time PCR. The combination of Tsp1 and vascular endothelial growth factor (VEGF) receptor-2 inhibition was also examined.

Results: There was significant suppression of angiogenesis in flank tumors and liver metastases formed from cells overexpressing Tsp1, endostatin, or tumstatin. However, all tumors ultimately escaped angiogenesis inhibition. The combination of all three angiogenesis inhibitors had no additive effect beyond overexpression of a single inhibitor. Using quantitative real-time PCR, we found that VEGF and platelet-derived growth factor (PDGF)-A levels were routinely up-regulated at least 5-fold in all CT26 tumors overexpressing any antiangiogenic protein, and there were variable increases in angiopoietin 2 (Ang2), basic fibroblast growth factor, and PDGF-B. In contrast, RenCa tumors, which have high baseline levels of VEGF and PDGF-B, relied on basic fibroblast growth factor, Ang1, and PDGF-A up-regulation to counteract Tsp1 overexpression. Growth of CT26 cells with Tsp1 overexpression was suppressed when anti–VEGFR-2 treatment was added.

Conclusions: Cancer cells with overexpression of three different endogenous angiogenesis inhibitor eventually escape angiogenesis inhibition by up-regulation of various proangiogenic factors. Tsp1, endostatin, and tumstatin may be functionally redundant in this system. These endogenous angiogenesis inhibitors are likely best used in combination with the blockade of proangiogenic pathways or with traditional chemotherapy or radiation therapy.
IFN-α-2b–Induced Signal Transduction and Gene Regulation in Patient Peripheral Blood Mononuclear Cells Is Not Enhanced by a Dose Increase from 5 to 10 Megaunits/m2
Authors: Zimmerer Jason M. , Lehman Amy M. , Ruppert Amy S. , Noble Carl W. , Olencki Thomas , Walker Michael J. , Kendra Kari , Carson William E.
Published: March 2008

Purpose: The precise molecular targets of IFN-α therapy of melanoma are unknown but likely involve signal transducer and activator of transcription (STAT) 1 signal transduction within host immune effector cells. We hypothesized that intermediate and high doses of IFN-α would be equally effective in activating patient immune cells.

Experimental Design: Eleven metastatic melanoma patients who were enrolled in a clinical trial of bevacizumab in combination with escalating doses of IFN-α-2b (5 megaunits/m2 and then 10 megaunits/m2) were included in the study. Peripheral blood mononuclear cells (PBMC) were procured from patient blood just before therapy and again 1 h after each dose of IFN-α-2b and analyzed for the presence of phosphorylated STAT1, phosphorylated STAT2, and the induction of IFN-stimulated gene (ISG) transcripts.

Results: Phosphorylated STAT1 was significantly greater at the 5 megaunits/m2 dose compared with the 10 megaunits/m2 dose of IFN-α-2b (P = 0.02). In contrast, no significant difference in phosphorylated STAT2 was observed at a dose of 5 megaunits/m2 compared with 10 megaunits/m2 (P = 0.20). There were also no significant differences in the induction of ISGs within PBMCs between the two doses (P > 0.4 for all ISGs). Suppressor of cytokine signaling 1 and 3 (two inhibitors of IFN-α signaling) transcripts were significantly higher among patient PBMCs following the 10 megaunits/m2 dose of IFN-α (P < 0.001).

Conclusion: These results suggest that lower doses of IFN-α-2b are as effective as higher doses with respect to the induction of Janus-activated kinase-STAT signal transduction and the transcription of ISGs within immune effector cells.
Impact of Angiogenesis Inhibition by Sunitinib on Tumor Distribution of Temozolomide
Authors: Zhou Qingyu , Guo Ping , Gallo James M.
Published: March 2008

Purpose: As combination chemotherapy of antiangiogenic agents with conventional chemotherapeutic drugs continues to evolve, an understanding of the pharmacokinetic and pharmacodynamic variables associated with optimal treatment is needed. Thus, the effect of the multitargeted tyrosine kinase inhibitor sunitinib on tumor distribution of temozolomide was investigated to evaluate conditions for optimal combination chemotherapy.

Experimental Design: In mice bearing SF188V+ human glioma xenografts, measurements of temozolomide pharmacokinetic properties and sunitinib pharmacodynamic activities were evaluated, the latter including determinants for vascular normalization, including CD31, collagen IV, and α-SMA.

Results: Sunitinib given in a daily dose of either 10 or 40 mg/kg orally over 14 days increased temozolomide tumor distribution, as indicated by the tumor-to-plasma AUC ratio compared with control; however, only the 10 mg/kg group reached statistical significance (P < 0.05). From the pharmacodynamic analysis, a “vascular normalization index” incorporating the microvessel density (MVD) and protein expression of α-SMA and collagen IV was proposed as an indication of the number of tumor vessels with relatively good quality, which was found to be significantly correlated with the unbound temozolomide AUC in tumor interstitial fluid (P = 0.05). Furthermore, both sunitinib-treated groups maintained the molecular balance between angiopoietins Ang-1 and Ang-2, suggesting a critical role of angiopoietins in vascular normalization.

Conclusions: Several important factors relevant to the antiangiogenic agent–induced tumor vascular normalization have been identified and incorporated into a vascular normalization index that may serve to correlate the angiogenic phenotype to the distribution of cytotoxic drugs in solid tumors.
Phase I and Pharmacokinetic Study of Bortezomib in Combination with Idarubicin and Cytarabine in Patients with Acute Myelogenous Leukemia
Authors: Attar Eyal C. , DeAngelo Daniel J. , Supko Jeffrey G. , D'Amato Ferdinando , Zahrieh David , Sirulnik Andres , Wadleigh Martha , Ballen Karen K. , McAfee Steve , Miller Kenneth B. , Levine James , Galinsky Ilene , Trehu Elizabeth G. , Schenkein David , Neuberg Donna , Stone Richard M. , Amrein Philip C.
Published: March 2008

Purpose: Proteasome inhibition results in cytotoxicity to the leukemia stem cell in vitro. We conducted this phase I study to determine if the proteasome inhibitor bortezomib could be safely added to induction chemotherapy in patients with acute myelogenous leukemia (AML).

Experimental Design: Bortezomib was given on days 1, 4, 8, and 11 at doses of 0.7, 1.0, 1.3, or 1.5 mg/m2 with idarubicin 12 mg/m2 on days 1 to 3 and cytarabine 100 mg/m2/day on days 1 to 7.

Results: A total of 31 patients were enrolled. The median age was 62 years, and 16 patients were male. Nine patients had relapsed AML (ages, 18-59 years, n = 4 and ≥60 years, n = 5). There were 22 patients of ≥60 years with previously untreated AML (eight with prior myelodysplasia/myeloproliferative disorder or cytotoxic therapy). All doses of bortezomib, up to and including 1.5 mg/m2, were tolerable. Nonhematologic grade 3 or greater toxicities included 12 hypoxia (38%; 11 were grade 3), 4 hyperbilirubinemia (13%), and 6 elevated aspartate aminotransferase (19%). Overall, 19 patients (61%) achieved complete remission (CR) and three had CR with incomplete platelet recovery. Pharmacokinetic studies revealed that the total body clearance of bortezomib decreased significantly (P < 0.01, N = 26) between the first (mean ± SD, 41.9 ± 17.1 L/h/m2) and third (18.4 ± 7.0 L/h/m2) doses. Increased bone marrow expression of CD74 was associated with CR.

Conclusions: The combination of bortezomib, idarubicin, and cytarabine showed a good safety profile. The recommended dose of bortezomib for phase II studies with idarubicin and cytarabine is 1.5 mg/m2.
Sympathetic Innervation of Human Mesenteric Artery and Vein
Authors: Birch David J. , Turmaine Mark , Boulos Paul B. , Burnstock Geoffrey
Published: March 2008

Background: Innervation of blood vessels shows inter-species variability. There are few studies on the innervation of human vessels; thus, healthy mesenteric vessels were studied to identify the expression of immunomarkers and the morphology of sympathetic innervation as the basis for a study of mesenteric vessels in inflammatory bowel disease. Methods and Results: Electron microscopy studies examined the relationships of nerves to smooth muscle cells. In veins, nerves were distributed throughout the medial smooth muscle coat, often in close apposition (50 nm) to smooth muscle cells. In arteries, nerves were located at the adventitial-medial border, few closer than 2,000 nm to smooth muscle cells, often with interposing connective tissue and Schwann cell processes. There was a significantly greater nerve density in veins than in arteries (227 vs. 41 mm2; p = 0.03). Immunohistochemical studies revealed the presence of sympathetic and sensory-motor nerves in arteries and veins. Conclusions: It is suggested that in humans with an upright stance, the mesenteric venous system plays a particularly important role in controlling mesenteric capacitance, which is reflected by their dense innervation. It is speculated that transmitters released from perivascular nerves supplying the human mesenteric arteries may play a long-term (trophic) role in addition to short-term signalling roles.
Inhaled Corticosteroids as Additional Treatment in Alpha-1-Antitrypsin-Deficiency-Related COPD
Authors: Corda Luciano , Bertella Enrica , La Piana Giuseppe Emanuele , Boni Enrico , Redolfi Stefania , Tantucci Claudio
Published: March 2008

Background: No consistent data are available regarding the effect of inhaled corticosteroids (ICS) in α1-antitrypsin-deficiency (AATD)-related COPD. Recent data report inflammatory effects of the polymers of α1-antitrypsin on the peripheral lung. Objectives: The aim of this study was to assess the effectiveness of an extra-fine ICS, hydrofluoroalkane-134a beclometasone dipropionate (HFA-BDP) with a mass median aerodynamic diameter of 1.1 µm, on lung function and exercise tolerance in COPD patients with AATD when added to long-acting bronchodilators (LABAs). Methods: After a 1-week washout, 8 steroid-naïve COPD patients with AATD (ZZ genotype), within a double-blind randomized cross-over study, were assigned to one of the following 16-week treatments: (1) HFA-BDP 400 µg b.i.d., salmeterol 50 µg b.i.d. and oxitropium bromide 200 µg t.i.d. or (2) placebo, salmeterol 50 µg b.i.d. and oxitropium bromide 200 µg t.i.d; after a 2-week washout period they received the other treatment. In weeks 1, 17, 19 and 35, patients took a spirometry assessment (breathing air and heliox) and a shuttle walking test (SWT) with dyspnea assessed by the modified Borg scale. Results: Significant differences in improvement were found in FEV1, FVC, IC, distance covered and dyspnea perceived during SWT between the 2 treatments and baseline values (p < 0.05; Friedman’s test). However, further analysis showed that only the LABAs + ICS condition showed significant increases in the FEV1, FVC, IC, ΔMEF50% and distance covered during SWT along with a reduction in maximum isostep exertional dyspnea (p < 0.05; Wilcoxon test). A greater distance was walked at the end of the SWT with LABA + ICS than LABAs alone (301 ± 105 vs. 270 ± 112 m; p < 0.05). Conclusions: In AATD-related COPD patients (ZZ genotype) the addition of extra-fine ICS to LABAs decreases airway narrowing, mostly in the small airways, further reducing dynamic hyperinflation with a marked improvement in exercise tolerance and dyspnea, suggesting that a peripheral inflammatory process contributes to airflow obstruction in these patients.
Faith-based programs and outcomes for street-living youth in Los Angeles, Mumbai and Nairobi
Authors: Ferguson Kristin M. , Dortzbach Karl , Dyrness Grace R. , Dabir Neela , Spruijt-Metz Donna
Published: March 2008

English

This study explores programs and outcomes for homeless street youth in faith-based organizations in Los Angeles, Mumbai and Nairobi. Findings reveal differences in conceptions of street youth and services provided. Similarities are manifested in client outcomes. Recommendations are offered to improve social welfare policies and service provision for street youth.

French

Cette étude examine les programmes innovants pour les jeunes de la rue émanant des organisations basées sur la foi et la vie communautaire à Los Angeles, Bombay et Nairobi. Les résultats révèlent des différences de conceptions sur les jeunes de la rue et en matière de services proposés. Des similarités sont observées dans les résultats relatifs aux usagers. Des recommandations politiques sont proposées dans le but d'améliorer la formulation des politiques sociale à l'égard des jeunes des rues.

Spanish

Este estudio examina programas innovadores creados por organizaciones comunitarias y religiosas destinados a los jóvenes que viven en las calles de Los Ángeles, Bombay y Nairobi. Los descubrimientos de este estudio revelan diferencias en las concepciones que se tienen acerca de los jóvenes que viven en las calles y los servicios proporcionados. Las semejanzas se manifiestan en las respuestas de los clientes. Recomendaciones de políticas a utilizar son ofrecidas para mejorar la formulación de políticas sociales para los jóvenes que viven en la calle.
Constructing spiritually modified interventions
Authors: Hodge David R.
Published: March 2008

English

Although cognitive therapy is widely used, little attention has been given to the value assumptions embedded in the self-statements that are at the heart of the change process. Constructing statements that have been repackaged with values drawn from clients' spiritual belief systems may increase their effectiveness with a variety of populations.

French

Bien que la thérapie cognitive soit largement utilisée, trop peu d'attention a été portée aux jugements de valeur inclus dans les auto-évaluations au cœur du processus de changement. La construction d'évaluations ayant été "reconfigurées" à partir des valeurs issues des systèmes de croyance spirituelle des usagers peut accroître leur effectivité pour populations.

Spanish

A pesar de que la terapia cognitiva es ampliamente utilizada, se le ha prestado poca atención a las suposiciones de valor que estÁn arraigadas a las declaraciones propias que estÁn en el corazón del proceso de cambio. Construir declaraciones que han sido"reempacadas" con valores extraídos de los sistemas de creencia espiritual de los clientes pudiera aumentar su efectividad con una variedad de poblaciones.
The delivery of social services in northern Thailand
Authors: Nye Catherine
Published: March 2008

English

This article describes parallel professional secular and traditional religious social service delivery systems in northern Thailand within global trends towards secular provision. It locates these systems in their cultural, historical context and raises questions about the future directions of these parallel service delivery models.

French

Cet article met en parallèle les systèmes des services sociaux professionnel laïc et religieux traditionnel dans le nord de la Thaïlande dans le cadre des tendances globales de développement des services laïcs. Il situe ces systèmes dans leur contexte culturel et historique et fait émerger des questions sur les orientations futures de ces modèles parallèles de mise à disposition de services.

Spanish

Este ensayo describe los sistemas paralelos de provisión de servicios sociales en el norte de Tailandia, profesionales seculares por un lado y tradicionales religiosos por el otro, dentro de las tendencias globales hacia la provisión secular. Estos sistemas son ubicados en sus contextos histórico y cultural y promueven preguntas acerca de las direcciones futuras de estos modelos paralelos de provisión de servicios.