bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and In Vitro Expansion of Functional Antigen-Specific CD25
+
FoxP3
+
Regulatory T Cells in Hepatitis C Virus Infection
Authors: Ebinuma Hirotoshi , Nakamoto Nobuhiro , Li Yun , Price David A. , Gostick Emma , Levine Bruce L. , Tobias J. , Kwok William W. , Chang Kyong-Mi 
Published: March 2008

ABSTRACT

CD4
+
CD25
+
regulatory T cells (CD25
+
Tregs) play a key role in immune regulation. Since hepatitis C virus (HCV) persists with increased circulating CD4
+
CD25
+
T cells and virus-specific effector T-cell dysfunction, we asked if CD4
+
CD25
+
T cells in HCV-infected individuals are similar to natural Tregs in uninfected individuals and if they include HCV-specific Tregs using the specific Treg marker FoxP3 at the single-cell level. We report that HCV-infected patients display increased circulating FoxP3
+
Tregs that are phenotypically and functionally indistinguishable from FoxP3
+
Tregs in uninfected subjects. Furthermore, HCV-specific FoxP3
+
Tregs were detected in HCV-seropositive persons with antigen-specific expansion, major histocompatibility complex class II/peptide tetramer binding affinity, and preferential suppression of HCV-specific CD8 T cells. Transforming growth factor β contributed to antigen-specific Treg expansion in vitro, suggesting that it may contribute to antigen-specific Treg expansion in vivo. Interestingly, FoxP3 expression was also detected in influenza virus-specific CD4 T cells. In conclusion, functionally active and virus-specific FoxP3
+
Tregs are induced in HCV infection, thus providing targeted immune regulation in vivo. Detection of FoxP3 expression in non-HCV-specific CD4 T cells suggests that immune regulation through antigen-specific Treg induction extends beyond HCV.
Human Herpesvirus 8 Infects and Replicates in Primary Cultures of Activated B Lymphocytes through DC-SIGN
Authors: Rappocciolo Giovanna , Hensler Heather R. , Jais Mariel , Reinhart Todd A. , Pegu Amarendra , Jenkins Frank J. , Rinaldo Charles R. 
Published: March 2008

ABSTRACTHuman herpesvirus 8 (HHV-8) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and some forms of multicentric Castleman's disease. Although latent HHV-8 DNA can be detected in B cells from persons with these cancers, there is little information on the replication of HHV-8 in B cells. Indeed, B cells are relatively resistant to HHV-8 infection in vitro. We have recently shown that DC-SIGN, a C-type lectin first identified on dendritic cells (DC), is an entry receptor for HHV-8 on DC and macrophages. We have also demonstrated previously that B lymphocytes from peripheral blood and tonsils express DC-SIGN and that this expression increases after B-cell activation. Here we show that activated blood and tonsillar B cells can be productively infected with HHV-8, as measured by an increase in viral DNA, the expression of viral lytic and latency proteins, and the production of infectious virus. The infection of B cells with HHV-8 was blocked by the pretreatment of the cells with antibody specific for DC-SIGN or with mannan but not antibody specific for xCT, a cystine/glutamate exchange transporter that has been implicated in HHV-8 fusion to cells. The infection of B cells with HHV-8 resulted in increased expression of DC-SIGN and a decrease in the expression of CD20 and major histocompatibility complex class I. HHV-8 could also infect and replicate in B-cell lines transduced to express full-length DC-SIGN but not in B-cell lines transduced to express DC-SIGN lacking the transmembrane domain, demonstrating that the entry of HHV-8 into B cells is related to DC-SIGN-mediated endocytosis. The role of endocytosis in viral entry into activated B cells was confirmed by blocking HHV-8 infection with endocytic pathway inhibitors. Thus, the expression of DC-SIGN is essential for productive HHV-8 infection of and replication in B cells.
CD81 and Claudin 1 Coreceptor Association: Role in Hepatitis C Virus Entry
Authors: Harris Helen J. , Farquhar Michelle J. , Mee Christopher J. , Davis Christopher , Reynolds Gary M. , Jennings Adam , Hu Ke , Yuan Fei , Deng HongKui , Hubscher Stefan G. , Han Jang H. , Balfe Peter , McKeating Jane A. 
Published: March 2008

ABSTRACTHepatitis C virus (HCV) is an enveloped positive-stranded RNA hepatotropic virus. HCV pseudoparticles infect liver-derived cells, supporting a model in which liver-specific molecules define HCV internalization. Three host cell molecules have been reported to be important entry factors or receptors for HCV internalization: scavenger receptor BI, the tetraspanin CD81, and the tight junction protein claudin-1 (CLDN1). None of the receptors are uniquely expressed within the liver, leading us to hypothesize that their organization within hepatocytes may explain receptor activity. Since CD81 and CLDN1 act as coreceptors during late stages in the entry process, we investigated their association in a variety of cell lines and human liver tissue. Imaging techniques that take advantage of fluorescence resonance energy transfer (FRET) to study protein-protein interactions have been developed.Aequorea coerulescensgreen fluorescent protein- andDiscosomasp. red-monomer fluorescent protein-tagged forms of CD81 and CLDN1 colocalized, and FRET occurred between the tagged coreceptors at comparable frequencies in permissive and nonpermissive cells, consistent with the formation of coreceptor complexes. FRET occurred between antibodies specific for CD81 and CLDN1 bound to human liver tissue, suggesting the presence of coreceptor complexes in liver tissue. HCV infection and treatment of Huh-7.5 cells with recombinant HCV E1-E2 glycoproteins and anti-CD81 monoclonal antibody modulated homotypic (CD81-CD81) and heterotypic (CD81-CLDN1) coreceptor protein association(s) at specific cellular locations, suggesting distinct roles in the viral entry process.
The Protein Phosphatase Activity of PTEN Regulates Src Family Kinases and Controls Glioma Migration
Authors: Dey Nandini , Crosswell Hal E. , De Pradip , Parsons Ramon , Peng Qiong , Su Jing Dong , Durden Donald L. 
Published: March 2008

Abstract
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is mutated or lost in 60% to 70% of advanced gliomas and is associated with malignant phenotypic changes such as migration, which contribute to the morbidity and mortality of this disease. Most of the tumor suppressor function of PTEN has been attributed to its ability to dephosphorylate the second messenger, phosphatidylinositol 3,4,5-triphosphate, resulting in the biological control of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Despite recent work suggesting that the protein phosphatase activity of PTEN controls glioma cell migration, the mechanisms by which this occurs are unclear. Herein, we show using glioma cell lines (U87MG and U373MG) stably transfected with wild-type PTEN or catalytically altered mutants of PTEN that PTEN controls integrin-directed migration in a lipid phosphatase, PI3K/AKT–independent manner. Confirming this observation, we show that the stable overexpression of COOH-terminal Src kinase, the physiologic negative regulator of SRC family kinases (SFK), or treatment with the SFK inhibitor PP1 abrogates glioma migration. The results provide direct evidence that the downstream effect of the protein phosphatase activity of PTEN is to suppress SFK and FYN, and to regulate RAC-GTPase activity after αv integrin stimulation. Furthermore, studying vitronectin-directed migration using (a) Fyn small interfering RNA and (b) astrocytes from Fyn heterozygous (+/−) mice, Pten heterozygous (+/−) mice, Pten and Fyn double heterozygous (+/−) mice, or Fyn knockout (−/−) mice confirmed a role of FYN in αv integrin–mediated haptotaxis in glial cells. Our combined results provide direct biochemical and genetic evidence that PTEN's protein phosphatase activity controls FYN kinase function in glioma cells and regulates migration in a PI3K/AKT–independent manner. [Cancer Res 2008;68(6):1862–71]
Dietary Genistein Inhibits Metastasis of Human Prostate Cancer in Mice
Authors: Lakshman Minalini , Xu Li , Ananthanarayanan Vijayalakshmi , Cooper Joshua , Takimoto Chris H. , Helenowski Irene , Pelling Jill C. , Bergan Raymond C. 
Published: March 2008

Abstract
Dietary genistein has been linked to lower prostate cancer (PCa) mortality. Metastasis is the ultimate cause of death from PCa. Cell detachment and invasion represent early steps in the metastatic cascade. We had shown that genistein inhibits PCa cell detachment and cell invasion in vitro. Genistein-mediated inhibition of activation of focal adhesion kinase (FAK) and of the p38 mitogen-activated protein kinase (MAPK)–heat shock protein 27 (HSP27) pathway has been shown by us to regulate PCa cell detachment and invasion effects, respectively. To evaluate the antimetastatic potential of genistein, we developed an animal model suited to evaluating antimetastatic drug efficacy. Orthotopically implanted human PC3-M PCa cells formed lung micrometastasis by 4 weeks in &gt;80% of inbred athymic mice. Feeding mice dietary genistein before implantation led to blood concentrations similar to those measured in genistein-consuming men. Genistein decreased metastases by 96%, induced nuclear morphometric changes in PC3-M cells indicative of increased adhesion (i.e., decreased detachment) but did not alter tumor growth. Genistein increased tumor levels of FAK, p38 MAPK, and HSP27 “promotility” proteins. However, the ratio of phosphorylated to total protein trended downward, indicating a failure to increase relative amounts of activated protein. This study describes a murine model of human PCa metastasis well suited for testing antimetastatic drugs. It shows for the first time that dietary concentrations of genistein can inhibit PCa cell metastasis. Increases in promotility proteins support the notion of cellular compensatory responses to antimotility effects induced by therapy. Studies of antimetastatic efficacy in man are warranted and are under way. [Cancer Res 2008;68(6):2024–32]
NOTCH3 Signaling Pathway Plays Crucial Roles in the Proliferation of ErbB2-Negative Human Breast Cancer Cells
Authors: Yamaguchi Noritaka , Oyama Tetsunari , Ito Emi , Satoh Hitoshi , Azuma Sakura , Hayashi Mitsuhiro , Shimizu Ken , Honma Reiko , Yanagisawa Yuka , Nishikawa Akira , Kawamura Mika , Imai Jun-ichi , Ohwada Susumu , Tatsuta Kuniaki , Inoue Jun-ichiro , Semba Kentaro , Watanabe Shinya 
Published: March 2008

Abstract
ErbB2-negative breast tumors represent a significant therapeutic hurdle because of a lack of effective molecular targets. Although NOTCH proteins are known to be involved in mammary tumorigenesis, the functional significance of these proteins in ErbB2-negative breast tumors is not clear. In the present study, we examined the expression of activated NOTCH receptors in human breast cancer cell lines, including ErbB2-negative and ErbB2-positive cell lines. Activated NOTCH1 and NOTCH3 proteins generated by γ-secretase were detected in most of the cell lines tested, and both proteins activated CSL-mediated transcription. Down-regulation of NOTCH1 by RNA interference had little or no suppressive effect on the proliferation of either ErbB2-positive or ErbB2-negative cell lines. In contrast, down-regulation of NOTCH3 significantly suppressed proliferation and promoted apoptosis of the ErbB2-negative tumor cell lines. Down-regulation of NOTCH3 did not have a significant effect on the ErbB2-positive tumor cell lines. Down-regulation of CSL also suppressed the proliferation of ErbB2-negative breast tumor cell lines, indicating that the NOTCH-CSL signaling axis is involved in cell proliferation. Finally, NOTCH3 gene amplification was detected in a breast tumor cell line and one breast cancer tissue specimen even though the frequency of NOTCH3 gene amplification was low (&lt;1%). Taken together, these findings indicate that NOTCH3-mediated signaling rather than NOTCH1-mediated signaling plays an important role in the proliferation of ErbB2-negative breast tumor cells and that targeted suppression of this signaling pathway may be a promising strategy for the treatment of ErbB2-negative breast cancers. [Cancer Res 2008;68(6):1881–8]
PTEN Has Tumor-Promoting Properties in the Setting of Gain-of-Function p53 Mutations
Authors: Li Yunqing , Guessous Fadila , Kwon Sherwin , Kumar Manish , Ibidapo Opeyemi , Fuller Lauren , Johnson Elizabeth , Lal Bachchu , Hussaini Isa , Bao Yongde , Laterra John , Schiff David , Abounader Roger 
Published: March 2008

Abstract
We show, for the first time, that the tumor suppressor PTEN can have tumor-promoting properties. We show that PTEN acquires these unexpected properties by enhancing gain-of-function mutant p53 (mut-p53) protein levels. We find that PTEN restoration to cells harboring mut-p53 leads to induction of G1-S cell cycle progression and cell proliferation and to inhibition of cell death. Conversely, PTEN inhibition in cells expressing wild-type PTEN and mut-p53 leads to inhibition of cell proliferation and inhibition of in vivo tumor growth. We show the dependency of the tumor-promoting effects of PTEN on mut-p53 by showing that knockdown of mut-p53 expression inhibits or reverses the tumor-promoting effects of PTEN. Mechanistically, we show that PTEN expression enhances mut-p53 protein levels via inhibition of mut-p53 degradation by Mdm2 and possibly also via direct protein binding. These findings describe a novel function of PTEN and have important implications for experimental and therapeutic strategies that aim at manipulating PTEN or p53 in human tumors. They suggest that the mutational status of PTEN and p53 should be considered to achieve favorable therapeutic outcomes. The findings also provide an explanation for the low frequency of simultaneous mutations of PTEN and p53 in human cancer. [Cancer Res 2008;68(6):1723–31]
Lipid Bodies Are Reservoirs of Cyclooxygenase-2 and Sites of Prostaglandin-E2 Synthesis in Colon Cancer Cells
Authors: Accioly Maria T. , Pacheco Patricia , Maya-Monteiro Clarissa M. , Carrossini Nina , Robbs Bruno K. , Oliveira Silvia S. , Kaufmann Cristiane , Morgado-Diaz José A. , Bozza Patricia T. , Viola João P.B. 
Published: March 2008

AbstractLipid bodies (lipid droplets) are emerging as dynamic organelles involved in lipid metabolism and inflammation. Increased lipid body numbers have been described in tumor cells; however, its functional significance in cancer has never been addressed. Here, we showed increased number of lipid bodies in tumor tissues from patients with adenocarcinoma of colon submitted to surgical resection when compared with an adjacent normal tissue. Accordingly, increased numbers of lipid bodies were observed in human colon adenocarcinoma cell lines and in a H-rasV12–transformed intestinal epithelial cell line (IEC-6 H-rasV12) compared with nontransformed IEC-6 cells. The functions of lipid bodies in eicosanoid synthesis in cancer cells were investigated. CACO-2 cells have increased expression of cyclooxygenase-2 (COX-2) when compared with IEC-6 cells. We showed by immunolocalization that, in addition to perinuclear stain, COX-2 and prostaglandin E (PGE) synthase present punctate cytoplasmic localizations that were concordant with adipose differentiation–related protein–labeled lipid bodies. The colocalization of COX-2 at lipid bodies was confirmed by immunoblot of subcellular fractionated cells. Direct localization of PGE2 at its synthesis locale showed that lipid bodies are sources of eicosanoids in the transformed colon cancer cells. Treatment with either aspirin or the fatty acid synthase inhibitor C75 significantly reduced the number of lipid bodies and PGE2 production in CACO-2 and in IEC-6 H-rasV12 cells with effects in cell proliferation. Together, our results showed that lipid bodies in colon cancer cells are dynamic and functional active organelles centrally involved in PGE2 synthesis and may potentially have implications in the pathogenesis of adenocarcinoma of colon. [Cancer Res 2008;68(6):1732–40]
Human Tumor Antigens Tn and Sialyl Tn Arise from Mutations inCosmc
Authors: Ju Tongzhong , Lanneau Grainger S. , Gautam Tripti , Wang Yingchun , Xia Baoyun , Stowell Sean R. , Willard Margaret T. , Wang Wenyi , Xia Jonathan Y. , Zuna Rosemary E. , Laszik Zoltan , Benbrook Doris M. , Hanigan Marie H. , Cummings Richard D. 
Published: March 2008

AbstractNeoplastic lesions typically express specific carbohydrate antigens on glycolipids, mucins, and other glycoproteins. Such antigens are often under epigenetic control and are subject to reversion and loss upon therapeutic selective pressure. We report here that two of the most common tumor-associated carbohydrate antigens, Tn and sialyl Tn (STn), result from somatic mutations in the gene Cosmc that encodes a molecular chaperone required for formation of the active T-synthase. Diverse neoplastic lesions, including colon cancer and melanoma-derived cells lines, expressed both Tn and STn antigen due to loss-of-function mutations in Cosmc. In addition, two human cervical cancer specimens that showed expression of the Tn/STn antigens were also found to have mutations in Cosmc and loss of heterozygosity for the cross-linked Cosmc locus. This is the first example of somatic mutations in multiple types of cancers that cause global alterations in cell surface carbohydrate antigen expression. [Cancer Res 2008;68(6):1636–46]
EphA2 Is an Essential Mediator of UV Radiation–Induced Apoptosis
Authors: Zhang Guoqi , Njauw Ching-Ni , Park Jong Min , Naruse Chie , Asano Masahide , Tsao Hensin 
Published: March 2008

AbstractOne of the physiologic consequences of excessive UV radiation (UVR) exposure is apoptosis. This critical response serves to eliminate genetically injured cells and arises, in part, from activation of DNA damage and p53 signaling. Other contributory pathways, however, likely exist but have not been fully characterized. In a recent global screen of UVR response genes in melanocytes, we identified the receptor tyrosine kinase EPHA2. Using a combination of genetic and pharmacologic approaches, we set out to investigate the upstream regulation of EphA2 by UVR and the functional consequences of this effect. We found that the UVR-associated increase in EphA2 occurs in melanocytes, keratinocytes, and fibroblasts from both human and murine sources. More specifically, UVR effectively up-regulated EphA2 individually in p53-null, p63-null, and p73-null murine embryonic fibroblasts (MEF), suggesting that the p53 family of transcription factors is not essential for the observed effect. However, inhibition of mitogen-activated protein kinase (MAPK) signaling by U0126 and PD98059 significantly reduced the UVR response whereas overexpression of oncogenic NRAS led to an increase in EphA2. These results confirm that UVR induces EphA2 by a p53-independent, but MAPK-dependent, mechanism. In response to UV irradiation, Epha2−/− MEFs were highly resistant to UVR-mediated cytotoxicity and apoptosis whereas introduction of EphA2 into both wild-type and p53-null MEFs led to activation of an apoptotic program that can be blocked by caspase-8 inhibition. These functional findings suggest that EphA2 is in fact an essential p53-independent, caspase-8–dependent proapoptotic factor induced by UVR. [Cancer Res 2008;68(6):1691–6]
Histamine Suppresses Fibulin-5 and Insulin-like Growth Factor-II Receptor Expression in Melanoma
Authors: Pos Zoltan , Wiener Zoltan , Pocza Peter , Racz Melinda , Toth Sara , Darvas Zsuzsanna , Molnar Viktor , Hegyesi Hargita , Falus Andras 
Published: March 2008

AbstractWe previously showed that transgenic enhancement of histamine production in B16-F10 melanomas strongly supports tumor growth in C57BL/6 mice. In the present study, gene expression profiles of transgenic mouse melanomas, secreting different amounts of histamine, were compared by whole genome microarrays. Array results were validated by real-time PCR, and genes showing histamine-affected behavior were further analyzed by immunohistochemistry. Regulation of histamine-coupled genes was investigated by checking the presence and functional integrity of all four known histamine receptors in experimental melanomas and by administering histamine H1 receptor (H1R) and H2 receptor (H2R) antagonists to tumor-bearing mice. Finally, an attempt was made to integrate histamine-affected genes in known gene regulatory circuits by in silico pathway analysis. Our results show that histamine enhances melanoma growth via H1R rather than through H2R. We show that H1R activation suppresses RNA-level expression of the tumor suppressor insulin-like growth factor II receptor (IGF-IIR) and the antiangiogenic matrix protein fibulin-5 (FBLN5), decreases their intracellular protein levels, and also reduces their availability in the plasma membrane and extracellular matrix, respectively. Pathway analysis suggests that because plasma membrane-bound IGF-IIR is required to activate matrix-bound, latent transforming growth factor-β1, a factor suggested to sustain FBLN5 expression, the data can be integrated in a known antineoplastic regulatory pathway that is suppressed by H1R. On the other hand, we show that engagement of H2R also reduces intracellular protein pools of IGF-IIR and FBLN5, but being a downstream acting posttranslational effect with minimal consequences on exported IGF-IIR and FBLN5 protein levels, H2R is rather irrelevant compared with H1R in melanoma. [Cancer Res 2008;68(6):1997–2005]
Capture of Tumor Cell Membranes by Trogocytosis Facilitates Detection and Isolation of Tumor-Specific Functional CTLs
Authors: Machlenkin Arthur , Uzana Ronny , Frankenburg Shoshana , Eisenberg Galit , Eisenbach Lea , Pitcovski Jacob , Gorodetsky Raphael , Nissan Aviram , Peretz Tamar , Lotem Michal 
Published: March 2008

AbstractThe success of adoptive cell transfer in the treatment of metastatic cancer in humans is dependent on the selection of highly active tumor-specific cytotoxic T cells. We report here that CTLs capture membrane fragments from their targets while exerting cytotoxic activity and thus gain a detectable functional signature by which they can be identified. Fluorochrome labeling or biotinylation was used to tag tumor cells. CD8+ T cells were coincubated with the tagged targets, sorted, and functionally evaluated. Our results show that membrane capture by CD8+ lymphocytes is T-cell receptor dependent, epitope specific, and preferentially associated with highly cytotoxic clonal subsets. CTLs that captured membranes from unmodified melanoma exhibited enhanced cytotoxic activity against tumor cell lines and autologous melanoma. In a human melanoma in vivo model, adoptive transfer of membrane-capturing, peptide-specific T cells, but not noncapturing or bulk CD8+ T cells, inhibits tumor progression. Membrane capture is therefore a signature of antigen-specific CTLs endowed with high functional avidity and may have direct relevance in the clinical application of adoptive immunotherapy. [Cancer Res 2008;68(6):2006–13]