bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trafficking of tumor peptide‐specific cytotoxic T lymphocytes into the tumor microcirculation
Authors: Ali Selman , Ahmad Murrium , Lynam June , Rees Robert C. , Brown Nicola 
Published: March 2004

AbstractThe major histocompatibility complex class I‐restricted CD8+ cytotoxic T‐lymphocyte (CTL) effector arm of the adaptive immune response can specifically recognize and destroy tumor cells expressing peptide antigens. Although adoptive T‐cell therapy has been successfully used for the treatment of viral and malignant diseases, little is known of the trafficking and fate of adoptively transferred antigen‐specific T cells. In the present study, splenocytes derived from mice that rejected their tumors (CT26 or CT26‐clone 25 tumors) in response to direct intratumor injection of disabled infectious single‐cycle herpes simplex virus (DISC‐HSV) encoding murine GM‐CSF were restimulated with peptide in vitro. CTLs specific for the AH‐1 and β‐gal peptides expressed by CT26 and CT26‐clone 25 tumor cells, respectively, were generated and used for adoptive cellular therapy and trafficking studies. Intravenous administration of AH‐1‐specific CTLs 3 days following i.v. injection of CT26 cells resulted in significant tumor growth inhibition, whereas administration of control CTLs generated against a bacterial β‐gal peptide did not inhibit the growth of tumors. Trafficking of AH‐1‐specific lymphocytes and their interaction with the CT26 tumor microcirculation was analyzed using real‐time in vivo microscopy (IVM). AH‐1‐specific but not β‐gal‐specific CTLs adhered and localized in the CT26 tumor microvasculature, but neither population adhered to the endothelium of the normal microcirculation. This study provides direct visual evidence suggesting that AH‐1‐specific CTLs that mediate a therapeutic response traffic to and localize within the tumor microenvironment. © 2004 Wiley‐Liss, Inc.
Association of metabolic gene polymorphisms with tobacco consumption in healthy controls
Authors: Smits Kim M. , Benhamou Simone , Garte Seymour , Weijenberg Matty P. , Alamanos Yannis , Ambrosone Christine , Autrup Herman , Autrup Judith L. , Baranova Helena , Bathum Lisa , Boffetta Paolo , Bouchardy C. , Brockmoller Jurgen , Butkiewicz Dorota , Cascorbi Ingolf , Clapper Margie L. , Coutelle Christiane , Daly Ann K. , Muzi Giacomo , Dolzan Vita , Duzhak Tatyana G. , Farker Katrin , Golka Klaus , Haugen Aage , Hein David W. , Hildesheim Allan , Hirvonen Ari , Hsieh Ling L. , Ingelman‐Sundberg Magnus , Kalina Ivan , Kang Daehee , Katoh Takahiko , Kihara Masahiro , Ono‐Kihara Masako , Kim Heon , Kiyohara Chikako , Kremers Pierre , Lazarus Philip , Le Marchand Loic , Lechner Maria C. , London Stephanie , Manni Johannes J. , Maugard Christine M. , Morgan Gareth J. , Morita Shunji , Nazar‐Stewart Valle , Kristensen Vessela Nedelcheva , Oda Yoshio , Parl Fritz F. , Peters Wilbert H.M. , Rannug Agneta , Rebbeck Timothy , Pinto Luis F. Ribeiro , Risch Angela , Romkes Marjorie , Šalagovic Jan , Schoket Bernadette , Seidegard Janeric , Shields Peter G. , Sim Edith , Sinnett Daniel , Strange Richard C. , Stucker Isabelle , Sugimura Haruhiko , To‐Figueras Jordi , Vineis Paolo , Yu Mimi C. , Zheng Wei , Pedotti Paola , Taioli Emanuela 
Published: March 2004

AbstractPolymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case‐control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20,938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected. © 2004 Wiley‐Liss, Inc.
Imatinib mesylate effectively combines with chaperone‐rich cell lysate‐loaded dendritic cells to treat bcr‐abl+ murine leukemia
Authors: Zeng Yi , Graner Michael W. , Feng Hanping , Li Gang , Katsanis Emmanuel 
Published: March 2004

AbstractImatinib mesylate has become an effective agent for the treatment of chronic myeloid leukemia (CML). However, the development of drug resistance has led to examination of combination therapies. In this study, we investigated the effects of combining imatinib with immunotherapy against a murine bcr‐abl+ leukemia, 12B1. We have previously shown that multiple chaperone proteins may be enriched into a vaccine form from tumor cell lysates by a free‐solution isoelectric focusing method. We refer to these vaccines as chaperone‐rich cell lysates (CRCLs) and have found that they are potent immunologic agents against a variety of murine tumors, including 12B1. We now demonstrate that the combination of imatinib with dendritic cells loaded with 12B1‐derived CRCL yields high activation of anti‐12B1‐specific T cells and potent antitumor activity, resulting in tumor‐free survival in up to 63% of mice with bcr‐abl+ 12B1 tumors. Our data suggest that immunotherapy can be effectively combined with imatinib for the treatment of CML. © 2004 Wiley‐Liss, Inc.
Histone deacetylase inhibitors FK228, N‐(2‐aminophenyl)‐4‐[N‐(pyridin‐3‐yl‐methoxycarbonyl)amino‐ methyl]benzamide and m‐carboxycinnamic acid bis‐hydroxamide augment radiation‐induced cell death in gastrointestinal adenocarcinoma cells
Authors: Zhang Yubin , Adachi Masaaki , Zhao Xudong , Kawamura Rina , Imai Kohzoh 
Published: March 2004

AbstractHDAC inhibitors induce histone hyperacetylation by a relative increase of histone acetyltransferase activity. Histone hyperacetylation may affect chromatin structure and susceptibility to DNA‐damaging stress, such as IR. We here investigate whether these inhibitors can radiosensitize human gastric MKN45 and colorectal DLD1 adenocarcinoma cells. In both cells, FK228 pretreatment at minimally toxic concentrations clearly augmented IR‐induced cell death, DNA fragmentation and caspase‐3/‐8 activation. In contrast, 5‐FU did not clearly augment IR‐induced cell death and caspase‐3 activation. FK228 increased expression of proapoptotic BH3‐only Bim proteins, and gene transfer–mediated overexpression of Bimα radiosensitized DLD1 cells. These data suggest that the FK228‐mediated increase of Bim expression may at least partially contribute to its augmentation of radiation‐induced apoptosis. However, FK228 did not distinctly affect IR‐induced phosphorylation of H2AX, which is an initial event followed by DNA damage. FK228 strongly augmented IR‐induced growth suppression of MKN45 tumor xenografts. In addition, other HDAC inhibitors, MS275 and CBHA, similarly augmented IR‐induced cell death in both cell types. Our results suggest that these HDAC inhibitors may enhance the efficacy of radiation therapy in gastrointestinal cancer cells. © 2004 Wiley‐Liss, Inc.
Sarcoendoplasmic reticulum Ca2+ ATPase type 2 downregulated in human oral squamous cell carcinoma
Authors: Endo Yosuke , Uzawa Katsuhiro , Mochida Yoshiyuki , Shiiba Masashi , Bukawa Hiroki , Yokoe Hidetaka , Tanzawa Hideki 
Published: March 2004

AbstractMice with a heterozygous deletion of the Atp2a2 gene (Atp2a2+/−) encoding SERCA2 spontaneously develop SCCs of the skin and upper digestive tract, including the oral cavity. To elucidate the contribution of ATP2A2 to human oral carcinogenesis, we analyzed genetic and epigenetic changes as well as mRNA and protein expression in primary OSCCs and OPLs. With the exception of one OSCC‐derived cell line showing a 12 bp deletion of ATP2A2, we found no mutations in the coding sequence of the gene in primary OSCCs (n = 52), OPLs (n = 32) and cell lines (n = 8). In immunohistochemistry, however, high frequencies of ATP2A2 downregulation were evident not only in primary OSCCs (42%, 42/100) but also in OPLs (31%, 10/32). Real‐time quantitative RT‐PCR data were consistent with the protein expression status. Aberrant DNA methylation within ATP2A2 also was detected in 9 of 30 ATP2A2‐downregulated OSCCs. Moreover, restoration or elevated expression of the ATP2A2 protein was induced in most of the cell lines showing ATP2A2 methylation after treatment with 5‐aza‐2′‐dC, a DNA demethylating agent. These results suggest that inactivation of the ATP2A2 gene is a frequent and early event during oral carcinogenesis and that loss of expression may be regulated partly by an epigenetic mechanism. © 2004 Wiley‐Liss, Inc.
Identification of an HLA‐A*0201 cytotoxic T lymphocyte epitope specific to the endothelial antigen Tie‐2
Authors: Ramage Judith M. , Metheringham Rachael , Conn Andrew , Spendlove Ian , Moss Robert S. , Patton Daniel T. , Murray J. Clifford , Rees Robert C. , Durrant Lindy G. 
Published: March 2004

AbstractTie‐2 stabilises pericyte–endothelial interactions during angiogenesis and is highly expressed on endothelium during several diseases, including arthritis, age‐related macular degeneration and cancer. A vaccine that targets endothelium overexpressing Tie‐2 may result in vessel damage and stimulate an inflammatory cascade resulting in disease regression. We have identified a region unique to Tie‐2 (amino acids 1–196) that is homologous in humans and mice. Using computer algorithms, several HLA‐A*0201 epitopes that are identical in mice and humans were predicted within this region; however, binding assays showed that the majority of these epitopes were of low affinity. Modification of the anchor residues of 4 epitopes enhanced HLA binding. These epitopes were incorporated by site‐directed mutagenesis into a Tie‐2 DNA construct. Immunisation of HLA*0201 transgenic mice with one of the modified Tie‐2 constructs stimulated CTLs that recognised both wild‐type and modified peptide‐pulsed target cells. In contrast, no CTLs were generated in mice immunised with wild‐type Tie‐2 construct, demonstrating that the modified epitope was necessary in the generation of CTLs. Moreover, CTLs from mice immunised with the modified construct killed HLA‐A*0201 endothelial cells overexpressing Tie‐2. Our study demonstrates that it is possible to break tolerance to the endothelial antigen Tie‐2, suggesting that it may be feasible to design a vaccine to activate CTLs to kill endothelial cells overexpressing Tie‐2. © 2004 Wiley‐Liss, Inc.
Molecular alterations associated with cyclin d1 overexpression in endometrial cancer
Authors: Moreno‐Bueno Gema , Rodríguez‐Perales Sandra , Sánchez‐Estévez Carolina , Marcos Raquel , Hardisson David , Cigudosa Juan C. , Palacios José 
Published: March 2004

AbstractCyclin D1 is frequently overexpressed in human neoplasias by gene rearrangement and amplification. In addition, Ras, PTEN and β‐catenin appear to modulate cyclin D1 levels. Since the causes of cyclin D1 overexpression are poorly understood in EC, we investigated whether or not this alteration is due to cyclin D1 gene amplification or to RAS, PTEN and β‐catenin mutation. We analyzed cyclin D1 expression in 18 AEHs, 65 EECs and 27 NEECs by immunohistochemistry as well as CCND1 gene amplification by FISH. In EECs, mutations in K‐RAS, PTEN, β‐catenin and CCND1 were studied by PCR‐SSCP and sequencing and MSI was evaluated by analyzing BAT‐25 and BAT‐26 microsatellites. Contingency tests were used to evaluate the relationships between variables. Cyclin D1 overexpression was not observed in AEHs but was present in 13.8% of EECs and 11.2% of NEECs (p = 0.031). CCND1 amplification was more frequent in NEECs (26.3%) than in EECs (2.1%) (p = 0.002). In EECs, cyclin D1 overexpression was not associated with mutations in K‐RAS, PTEN or β‐catenin. However, in EECs with β‐catenin mutations, cyclin D1 was expressed mainly by cells expressing β‐catenin in the cytoplasm and nucleus but not in those with membranous expression. Finally, cyclin D1 overexpression was associated with MSI (p = 0.047). The molecular alterations associated with cyclin D1 overexpression differ in the 2 clinicopathologic types of EC. Cyclin D1 overexpression is associated with gene amplification in NEECs and with nucleocytoplasmic expression of β‐catenin and MSI in EECs. © 2004 Wiley‐Liss, Inc.
Bovine lactoferrin inhibits tumor‐induced angiogenesis
Authors: Shimamura Mariko , Yamamoto Yukio , Ashino Hiromi , Oikawa Tsutomu , Hazato Tadahiko , Tsuda Hiroyuki , Iigo Masaaki 
Published: March 2004

AbstractRecent studies have demonstrated that bovine lactoferrin (bLF) suppresses tumor growth and metastasis in the mouse and rat and moreover may inhibit angiogenesis. To determine whether angiogenesis inhibition might contribute to antitumor activity, we examined the influence of bLF on tumor‐induced angiogenesis and endothelial cell functions as well as angiogenesis‐related cytokine production. Bovine LF exhibited dose‐dependent inhibition of angiogenesis on 4–6‐day‐old chick embryo chorioallantoic membranes (CAMs) that lack a mature immune response. This inhibition was reversed when bLF was simultaneously treated with basic fibroblast growth factor (bFGF). It also inhibited in vitro formation of tube‐like structures of mouse endothelial KOP2.16 cells. Moreover, it potently suppressed bFGF‐ or VEGF‐induced proliferation of mouse endothelial KOP2.16 cells, but not of mouse fibroblast A31 cells and Lewis lung carcinoma (3LL) cells. In mice, both orally and intraperitoneally administered bLF significantly and dose‐dependently suppressed 3LL cell‐induced angiogenesis in a dorsal air sac assay. As orally administered bLF was reported to exhibit antitumor activity through production of interferon (IFN)‐γ and interleukin (IL)‐18 in intestinal mucosa (Kuhara T et al., Nutr Cancer 2000;38:192–9), production of these cytokines in mouse serum and peritoneal macrophages by bLF was examined. IFN‐γ was not detected in serum by bLF administration. However, bLF markedly elevated IL‐18 concentration in serum by oral administration, but not by intraperitoneal administration. It also induced IL‐18 in peritoneal macrophages in vitro. These results suggest that bLF participates as a regulator of angiogenesis, possibly explained by blocking endothelial function and inducing IL‐18 production. Antitumor activity of bLF may thus be partly mediated by angiogenesis inhibition. © 2004 Wiley‐Liss, Inc.
Epstein‐Barr virus seroreactivity among unaffected individuals within high‐risk nasopharyngeal carcinoma families in Taiwan
Authors: Pickard Amy , Chen Chien‐Jen , Diehl Scott R. , Liu Mei‐Ying , Cheng Yu‐Juen , Hsu Wan‐Lun , Sun Brenda , Hsu Mow‐Ming , Chen I‐How , Chen Jen‐Yang , Yang Czau‐Siung , Mittl Beth L. , Chou Sheng‐Ping , Ruggles Deborah D. , Goldstein Alisa M. , Hildesheim Allan 
Published: March 2004

AbstractMost adults have been infected with EBV. Many studies have indicated that antibodies against specific EBV antigens, particularly IgA antibodies, can be predictive or prognostic of EBV‐associated malignancies, such as NPC. We hypothesized that healthy individuals from families with a history of multiple members affected with NPC (who therefore might be genetically susceptible to NPC themselves) might have an EBV antibody profile that is distinct from that seen in healthy individuals from the community at large. To explore this possibility and examine determinants of anti‐EBV antibody levels in healthy, high‐risk individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which included 1,229 healthy members of families in which 2 or more individuals were affected with NPC and 320 controls from the community at large. Blood collected from participants was tested for IgA antibodies against EBV VCA and EBNA‐1 and for neutralizing antibodies against EBV DNase using standard assays. We observed evidence of familial aggregation of EBV seroreactivity among individuals from high‐risk, multiplex NPC families. Anti‐VCA IgA and anti‐EBNA‐1 IgA antibody seroprevalence in unaffected family members of NPC cases was 5–6 times higher than in members of the community (p < 0.01). This elevated seroprevalence among unaffected individuals from high‐risk families was observed regardless of the relationship of the unaffected individual to the closest affected relative (siblings, parents, children or spouses). No sociodemographic or environmental factors examined were found to strongly and consistently correlate with elevated seroprevalence, but patterns emerged of increasing seroprevalence among older individuals and among females. Unaffected individuals from high‐risk NPC families have elevated anti‐EBV IgA antibody titers. The etiologic and clinical implications of this finding remain to be established. © 2004 Wiley‐Liss, Inc.
Detection of occult tumour cells in lymph nodes of colorectal cancer patients using real‐time quantitative RT‐PCR for CEA and CK20 mRNAS
Authors: Öberg Åke N.V. , Lindmark Gudrun E. , Israelsson Anne C.E. , Hammarström Sten G. , Hammarström Marie‐Louise K.C. 
Published: March 2004

AbstractThe purpose of our study was to develop specific, sensitive, objective assays for early detection of disseminated tumour cells in patients with colorectal cancer (CRC). Carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) were chosen as markers because they are selectively expressed in epithelial cells with maintained expression in CRC. Real‐time quantitative RT‐PCR assays with RNA copy standards were constructed. Regional lymph nodes were collected from patients with CRC (n = 51) and benign intestinal disease (n = 10). Results were compared to routine histopathology and anti‐CEA immunohistochemistry. Lymph node levels of CEA and CK20 mRNA correlated strongly (p < 0.0001, r = 0.8). Lymph nodes from non‐CRC patients had <0.01 CEA and <0.001 CK20 mRNA copies/18S rRNA unit. Lymph nodes from 3/6 Dukes' A, 17/26 Dukes' B, 10/10 Dukes' C and 7/9 Dukes' D patients had CEA mRNA levels above cut‐off. Corresponding figures for CK20 mRNA were 3/6, 10/26, 9/10 and 5/9, respectively. CEA mRNA levels varied from 0.001 to 100 copies/18S rRNA unit in Dukes' A and B, and 50% of the Dukes' B patients had CEA mRNA levels within the range of Dukes' C patients. Three Dukes' B patients have died from CRC or developed distant metastases. All 3 had high CEA and CK20 mRNA levels. Determination of mRNA was superior to immunohistochemistry in showing CEA expression in lymph nodes. The present qRT‐PCR assay for CEA mRNA seems to be a superior tool to identify individuals with disseminated tumour cells. Future extended studies will establish the clinically most relevant cut‐off level. © 2004 Wiley‐Liss, Inc.
Loss of cyclin E requirement in cell growth of an oral squamous cell carcinoma cell line implies deregulation of its downstream pathway
Authors: Yamada Shumpei , Sumrejkanchanakij Piyamas , Amagasa Teruo , Ikeda Masa‐Aki 
Published: March 2004

AbstractCyclin E and Cdk2 have been shown to play an important role in G1/S transition of the cell cycle. Two E‐type cyclins (E1 and E2) have been identified to date and share functionally similarities. Upregulation of these cyclins has been observed frequently in human cancers. We examined the expression profile of cyclin E1 and E2 in cell lines derived from human oral squamous cell carcinoma (SCC), and found that the expression of cyclin E1 protein was hardly detected in HSC‐2 cells. Although cyclin E2 was abundantly expressed, histone H1 kinase activities of both E‐type cyclins were virtually undetectable in this cell line. Inhibition of cyclin E1, but not that of E2, by using vectors expressing antisense‐oriented their cDNAs induced drastic growth suppression on HOC313 cells that express both E‐type cyclins. Inhibition of neither cyclin E1 nor E2 suppressed the growth of HSC‐2 cells, and compensatory elevation of cyclin E1 was not evident in cyclin E2‐inhibited HSC‐2 cells. In contrast, HSC‐2 cells expressed cyclin D1 and hyperphosphorylated forms of Rb family proteins, and were arrested in G1 by overexpression of p16INK4, a specific inhibitor against D‐type cyclin activity. These results indicate that HSC‐2 cells lost proper growth control specifically mediated by cyclin E and suggest that deregulation of its downstream pathway may contribute to tumorigenesis of oral SCC. © 2004 Wiley‐Liss, Inc.
Interferon receptor expression regulates the antiproliferative effects of interferons on cancer cells and solid tumors
Authors: Wagner T. Charis , Velichko Sharlene , Chesney Steven K. , Biroc Sandra , Harde Dean , Vogel David , Croze Ed 
Published: March 2004

AbstractIn addition to antiviral effects, Type I interferons (IFN) have potent antiproliferative and immunomodulatory activities. Because of these properties IFNs have been evaluated as therapeutics for the treatment of a number of human diseases, including cancer. Currently, IFNs have been shown to be efficacious for the treatment of only a select number of cancers. The reason for this is unclear. Recent evidence has demonstrated that some cancer cell types seem to be defective in their ability to respond to IFN. It has been suggested that defects in IFN signaling is one mechanism by which cancer cells escape responsiveness to Type I IFNs and growth control in general. We report that transfection and enhanced expression of the Type I IFN receptor chain (IFNAR2c) in 3 different human cancer cell lines markedly increases the sensitivity of these cells to the antiproliferative effects of IFNs. In cancer cells transfected with IFNAR2c, dose response curves demonstrate a significant decrease in the concentrations of IFN required to achieve maximum cell death. Furthermore, in these transfected cells, we observe a significant increase in the number of cells undergoing apoptosis, as measured by DNA fragmentation and Caspase 3 activation. In addition, using an in vivo xenograft tumor model we show an increase in the effectiveness of systemically delivered Betaseron™ in decreasing tumor burden in animals in which solid tumors were generated from IFNAR2c transfected cells. These data show that specific regulation of IFN receptor expression can play a major role in determining the clinical outcome of IFN‐based cancer therapeutics by regulating the relative sensitivity of cancer cells to IFN‐dependent growth control. © 2004 Wiley‐Liss, Inc.