bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carcinogenic polycyclic aromatic hydrocarbon‐DNA adducts and mechanism of action
Authors: Baird William M. , Hooven Louisa A. , Mahadevan Brinda 
Published: February 2005

AbstractPolycyclic aromatic hydrocarbons (PAHs) are a class of widespread environmental carcinogens. Most of our knowledge of their mechanisms of metabolic activation to DNA‐binding “ultimate carcinogenic” metabolites has come from analysis of the DNA interaction products formed by these highly reactive intermediates. Studies of their role in forming DNA‐binding intermediates identical to those formed in vivo from the PAH itself have also allowed identification of the particular cytochrome P450 enzymes involved in activating various structural classes of carcinogenic PAHs. It has been established that PAHs, after metabolic activation in vivo, are capable of inducing mutations in oncogenes and, by inducing multiple mutations, may result in tumors. PAHs also cause changes in cellular gap‐junction communication similar to those caused by the tumor promoter 12‐O‐tetradecanoylphorbol‐13‐acetate. Thus, PAHs may also act through a promotional mechanism in addition to serving as tumor initiators. Previous studies on these mechanisms are described and summarized. Environ. Mol. Mutagen., 2005. © 2005 Wiley‐Liss, Inc.
Generation of loss of heterozygosity and its dependency on p53 status in human lymphoblastoid cells
Authors: Honma Masamitsu 
Published: February 2005

AbstractLoss of heterozygosity (LOH) is a critical event in the development of human cancers. LOH is thought to result from either a large deletion or recombination between homologous alleles during repair of DNA double‐strand breaks (DSBs). These types of genetic alterations produce mutations in the TK gene mutation assay, which detects a wide mutational spectrum, ranging from point mutations to LOH‐type mutations. TK6, a human lymphoblastoid cell line, is heterozygous for the thymidine kinase (TK) gene and has a wild‐type p53 gene. The related cell lines, TK6‐E6 and WTK‐1, which are p53‐deficient and p53‐mutant (Ile237), respectively, are also heterozygous for the TK gene and LOH‐type mutation can be detected in these cells. Therefore, comparative studies of TK mutation frequency and spectrum with these cell lines are useful for elucidating the role of p53 in generating LOH and maintaining genomic stability in human cells. We demonstrate here that LOH and its associated genomic instability strongly depend on the p53 status in these cells. TK6‐E6 and WTK‐1 are defective in the G1/S checkpoint and in apoptosis. Unrepaired DSBs that escape from the checkpoint can potentially initiate genomic instability after DNA replication, resulting in LOH and a variety of chromosome changes. Moreover, genomic instability is enhanced in WTK‐1 cells. It is likely that the mutant p53 protein in WTK‐1 cells increases LOH in a dominant‐negative manner due to its abnormal recombination capacity. We discuss the mutator phenotype and genomic instability associated with p53 inactivation with the goal of elucidating the mechanisms of mutation and DNA repair in untargeted mutagenesis. Environ. Mol. Mutagen., 2005. © 2005 Wiley‐Liss, Inc.
Use of biomarkers to elucidate genetic susceptibility to cancer
Authors: Au William W. , Salama Salama A. 
Published: February 2005

AbstractGenetic variations have generally been accepted to be the major mechanism for the differences observed in susceptibility to cancer. However, extensive investigations on genotype‐disease associations have not produced consistent results. The inconsistency may be caused by many factors, such as improper study design, insufficient sample size, complexity of the traits under investigation, heterogeneity of the study subjects, incorrect assumptions about the underlying genetic architecture, misclassification of the disease, improper selection of potential alleles, and overinterpretation of the data. Besides these “traditional” factors, a recent problem is that the function of many variant genotypes is unknown, especially with regard to polymorphic DNA repair genes. Therefore, in addition to the genotype‐disease relationship, it may be prudent to step back and investigate the fundamental role of genetic variation in the development of cancer. The latter studies may focus on understanding the genotype‐exposure interactions and evaluating genotype‐health risk associations. This review will emphasize the use of relevant biomarkers and polymorphic DNA repair genes for investigations. These data will be useful for a better understanding of the complexity of disease causation and development, developing new models for human disease, and identifying pathways for prevention of cancer. Environ. Mol. Mutagen., 2005. © 2005 Wiley‐Liss, Inc.
Human population studies with cytogenetic biomarkers: Review of the literature and future prospectives
Authors: Bonassi Stefano , Ugolini Donatella , Kirsch‐Volders Micheline , Strömberg Ulf , Vermeulen Roel , Tucker James D. 
Published: February 2005

AbstractCytogenetic biomarkers are by far the most frequently used endpoints in human population studies. Their sensitivity for measuring exposure to genotoxic agents and their role as early predictors of cancer risk have contributed to this success. In this article, we present an overview of the last 25 years of population studies with cytogenetic biomarkers, describing the evolution of this research and addressing the most promising innovations for the future. The evaluation has been restricted to the most popular assays, i.e., chromosomal aberrations (CAs) and micronucleus (MN), which are considered to be causally related to early stages of chronic diseases, especially cancer, and may therefore play a major role in prevention. An extensive literature search covering the period 1 January 1980 to 31 December 2003 was performed using the Medline/PubMed database. A total of 833 population studies using CAs and 434 using matched MN inclusion criteria were included in the analysis. We report the distribution of selected papers by year of publication, country, language, agents investigated, and methods employed. The state of the art and future prospects regarding cytogenetic techniques and epidemiologic and statistical methods are discussed. The role of susceptibility and its potential impact on genotoxic damage are discussed with special attention to the effect of major genetic polymorphisms on the baseline frequency of CAs and micronuclei. Environ. Mol. Mutagen., 2005. © 2005 Wiley‐Liss, Inc.
Serial in vivo loss and in vitro gain of Fas expression and function in human cancerous pancreatic duct cells
Authors: Radfar Soroosh , Davrinche Christian , Hollande Etienne 
Published: February 2005

AbstractRecent studies have shown the involvement of the Fas system (Fas receptor and its ligand FasL) in cancerous processes. The absence or downregulation of Fas, reported in the majority of human tumors, conflicts with its presence in cancerous cells from the same tumors but maintained in vitro. Recently, the eventual role of environmental factors in the loss of Fas expression, or in the in vivo selection of a Fas‐negative cell population has been suggested. We determined the Fas expression and function in the Capan‐1 human cancerous pancreatic duct cells over 2 successive passages in vivo separated by a period of 10–20 passages in vitro. We showed that Capan‐1 cells express Fas and are sensitive to Fas‐mediated apoptosis when maintained in vitro. When these cells were xenografted into nude mice the expression of Fas was lost in the majority of the tumors. Culture of tumor‐derived cells exhibited that they became Fas‐positive and sensitive to Fas‐mediated apoptosis after a short period in vitro. The loss/gain of Fas was reproduced after re‐explantation and re‐culture of these Fas‐expressing cells. Furthermore, RT‐PCR evidenced a strong inhibition of Fas, FLICE and FADD mRNAs expression in the xenografts. Our observations indicate that the expression of Fas and its function could depend to factors in the tumoral environment. The in vivo loss of Fas may thus play an important role in the tumor formation and in the evasion of tumor cells from immune surveillance. © 2005 Wiley‐Liss, Inc.
Simultaneous targeting of IL2 and IL12 to Hodgkin's lymphoma cells enhances activation of resting NK cells and tumor cell lysis
Authors: Hombach Andreas , Heuser Claudia , Abken Hinrich 
Published: February 2005

AbstractHodgkin's disease (HD) is characterized by the accumulation of functionally anergic T cells in the vicinity of the malignant Hodgkin/Reed‐Sternberg (H/RS) cells. To revert cellular anergy against H/RS cells, we generated an anti‐CD30‐antibody‐interleukin‐(IL)‐2 and an anti‐CD30‐antibody‐IL12 fusion protein that target IL2 and IL12, respectively, specifically to CD30+ H/RS cells. Both antibody‐cytokine fusion proteins act cooperatively in the activation of resting NK cells, the induction of IFN‐gγ secretion and enhanced target cell lysis. The cooperative activity of the targeted cytokines suggests that the application of both antibody‐cytokine fusion proteins may be particularly suitable for the specific immunotherapy of Hodgkin's lymphoma. © 2005 Wiley‐Liss, Inc.
Tissue inhibitor of metalloproteinase‐3 (TIMP‐3) gene is methylated in the development of esophageal adenocarcinoma: Loss of expression correlates with poor prognosis
Authors: Darnton S. Jane , Hardie Laura J. , Muc Ronald S. , Wild Christopher P. , Casson Alan G. 
Published: February 2005

AbstractAmongst involvement in diverse physiological and pathological processes, TIMP‐3 may have an important role in tumour development, growth and metastasis by interaction with metalloproteases in the extracellular matrix. We studied the role and prognostic effect of TIMP‐3 in esophageal adenocarcinoma (EADC). TIMP‐3 gene methylation and TIMP‐3 mRNA expression were analysed in 5 esophageal cell lines and 24 resected EADCs. TIMP‐3 protein expression was examined in the 5 cell lines and 79 resected EADCs with known clinicopathological features. TIMP‐3 methylation signal was only detected in the OE33 EADC cell line. In tissues, 0% of case‐matched normal, 72% of BE and 90% of EADC were positive for methylation. TIMP‐3 mRNA was detected in all the cell lines and normal, metaplastic and tumour tissues. TIMP‐3 protein was localised to the cytoplasm in cell lines and tissues. Demethylating treatment of OE33 increased protein expression. At the invading edge of tumours, protein staining was equal to, or reduced, compared to normal tissues. Reduction of protein expression was associated with disease stage (p = 0.046) and poor patient survival (OR 2.1, 95% CI 1.2–3.5, p = 0.007). Mean survival time was halved in patients with reduced tumour TIMP‐3 expression, from 49 to 24 months. These studies have demonstrated association between methylation of the TIMP‐3 gene and BE and EADC. Reduced expression of TIMP‐3 protein in EADC is associated with increased tumour invasiveness and reduced patient survival. © 2005 Wiley‐Liss, Inc.
Characterization of a rat model with site‐specific bone metastasis induced by MDA‐MB‐231 breast cancer cells and its application to the effects of an antibody against bone sialoprotein
Authors: Bäuerle Tobias , Adwan Hassan , Kiessling Fabian , Hilbig Heidegard , Armbruster Franz P. , Berger Martin R. 
Published: February 2005

AbstractMetastasis into the skeleton is a serious complication of certain neoplastic diseases such as breast, prostate and lung cancer, but the reasons for this osteotropism are poorly understood. Our aim was to establish a physiologically relevant animal model that is characterized by osteolytic lesions confined to the hind leg of nude rats. For this purpose, we injected 1×105 MDA‐MB‐231 human breast cancer cells transfected with GFP into the superficial epigastric artery, which is an anastomosing vessel between the femoral and iliac arteries. As assessed with the aid of X‐rays, computed tomography and immunohistochemisty, osteolytic lesions occurred exclusively in the femur, tibia and fibula of the animals. The tumor take rate was 93% in a series of 96 rats and the increase in lesion size was observed up to 110 days after tumor cell inoculation. When applying this animal model to the effects of an antibody against bone sialoprotein (BSP), a significantly reduced osteolytic lesion size was observed after preincubation of cells (2 hr, 600 μg/ml anti‐BSP) prior to intra‐arterial tumor cell injection resulting in 19 T/C% at day 60 after tumor implantation (p < 0.05). In addition, the osteolytic lesion size was also significantly reduced after s.c. treatment of the animals with the antibody (20 mg/kg anti‐BSPx3 within 5 days after tumor implantation), resulting in 30 T/C% at day 60 after tumor cell implantation (p < 0.05). In conclusion, the novel rat model for site‐specific osteolytic lesions provides in vivo evidence that preincubation of MDA‐MB‐231GFP cells and treatment of rats after tumor implantation with an antibody against BSP significantly reduces the size of lytic lesions in bone. © 2005 Wiley‐Liss, Inc.
Effect of α‐naphthyl isothiocyanate on 2‐amino‐3‐methylimidazo[4,5‐b]pyridine (PhIP)‐induced mammary carcinogenesis in rats
Authors: Sugie Shigeyuki , Ohnishi Masami , Ushida Jun , Yamamoto Tomohiro , Hara Akira , Koide Akihiro , Mori Yukio , Kohno Hiroyuki , Suzuki Rikako , Tanaka Takuji , Wakabayashi Keiji , Mori Hideki 
Published: February 2005

AbstractThe modifying effects of α‐naphthyl isothiocyanate (ANIT) on 2‐amino‐3‐methylimidazo[4,5‐b]pyridine (PhIP)‐induced mammary carcinogenesis were investigated in female Sprague‐Dawley (SD) rats, and the hepatic activities of the phase II detoxifying enzymes glutathione S‐transferase (GST) and quinone reductase (QR) were also assayed. Ninety‐eight rats were divided into 4 groups. Starting at 6 weeks of age, rats were fed the high‐fat diet without ANIT (Groups 1 and 4) or the experimental diet (high‐fat diet mixed with 400 ppm ANIT, Groups 2 and 3). At 7 weeks of age, Groups 1 and 2 were given PhIP in corn oil (85 mg/kg body weight, 8 times for 11 days) by intragastric intubation. One week after the last PhIP injection, 5 rats in each group were sacrificed to assay GST and QR activities, and the experimental diets for Groups 2 and 3 were switched to the high‐fat diet without ANIT until termination of the experiment. Group 4 served as the vehicle control. All rats were sacrificed at 24 weeks after the start of the experiment. At termination of the experiment, mammary tumours were detected in Groups 1 (PhIP alone) and 2 (PhIP + ANIT) and were shown histologically to be adenocarcinomas; their incidences (multiplicities) were 56.3% (1.66 ± 2.31/rat) in Group 1 and 6.7% (0.07 ± 0.25/rat) in Group 2 (p < 0.001). Mean sizes of the tumours were 10.6 ± 5.3 mm in Group 1 and 6.5 mm in Group 2. No mammary tumours were observed in rats of Groups 3 and 4. In addition, ANIT treatment significantly increased the activities of GST and QR in the livers of rats in Groups 2 and 3 as compared to Groups 1 and 4. These results imply that the isothiocyanate compound ANIT shows potent inhibitory effects on mammary carcinogenesis induced by PhIP in female SD rats when administered during the initiation stage. © 2005 Wiley‐Liss, Inc.
Fas‐associated factor‐1 mediates chemotherapeutic‐induced apoptosis via death effector filament formation
Authors: Park Min‐Young , Ryu Seung‐Wook , Kim Kwang Dong , Lim Jong‐Seok , Lee Zee‐Won , Kim Eunhee 
Published: February 2005

AbstractFas‐associated factor‐1 (FAF1) is a newly introduced member of the Fas death‐inducing signaling complex and potentiates Fas‐mediated apoptosis. Clinical study has revealed that FAF1 is significantly reduced in gastric carcinomas. The present study demonstrates that FAF1 mediates chemotherapeutic‐induced apoptosis via participation in the formation of death effector filament (DEF), a cytoskeleton‐like structure found in receptor‐independent apoptosis. Overexpression of FAF1 enhanced DEF assembly and cell death induced by chemotherapeutics such as staurosporine (STS), cisplatin (CDDP) and etoposide (VP16). FAF1 sensitized cells to STS, CDDP and VP16 in dose‐ and time‐dependent manner. Introduction of antisense FAF1 construct inhibited DEF assembly and chemotherapeutic‐induced apoptosis. Analysis using FAF1 truncates showed that the FAF1 domain interacting with DEDs of FADD and caspase‐8 was sufficient to enhance DEF assembly. Confocal microscopy revealed that FAF1 was present in DEFs together with FADD and caspase‐8. Collectively, our data provide a molecular mechanism for the chemosensitization by FAF1 (i.e., mediating DEF assembly). © 2005 Wiley‐Liss, Inc.
Tumor HLA‐DR expression linked to early intrahepatic recurrence of hepatocellular carcinoma
Authors: Matoba Katsuhiro , Iizuka Norio , Gondo Toshikazu , Ishihara Tokuhiro , Yamada‐Okabe Hisafumi , Tamesa Takao , Takemoto Norikazu , Hashimoto Kiichiro , Sakamoto Kazuhiko , Miyamoto Takanobu , Uchimura Shunji , Hamamoto Yoshihiko , Oka Masaaki 
Published: February 2005

AbstractThe outcome of patients with hepatocellular carcinoma (HCC) remains poor because of the high frequency of intrahepatic recurrence (IHR), particularly early IHR within 1 year of hepatectomy. To search for genes involved in early IHR, we performed DNA microarray analysis in a training set of 33 HCCs and selected 46 genes linked to early IHR from approximately 6,000 genes by means of a supervised learning method. Gene selection was validated by a false discovery rate of 0.37%. The 46 genes included many immune response‐related genes, which were all downregulated in HCCs with early IHR. Four of these genes (HLA‐DRA, HLA‐DRB1, HLA‐DG and HLA‐DQA), encoding MHC class II antigens, were coordinately downregulated in HCCs with early IHR compared to levels in HCCs with nonrecurrence. A cluster analysis reproduced expression patterns of the 4 MHC class II genes in 27 blinded HCC samples. To localize the major site of production of HLA‐DR protein in the tumor, we used 50 frozen specimens from 50 HCCs. Immunofluorescence staining showed that HLA‐DR protein levels in tumor cells, but not in stromal cells, were associated with the transcription levels of HLA‐DRA determined by both DNA microarray analysis and real‐time quantitative reverse transcription‐PCR. Univariate analysis showed that tumor HLA‐DR protein expression, pTNM stage and venous invasion were associated with early IHR. Multivariate analysis showed that tumor HLA‐DR protein expression was one of the independent risk factors for early IHR, suggesting HLA‐DR protein potential as a biomarker and a molecular target for therapeutic intervention. © 2005 Wiley‐Liss, Inc.
HPV16 semiquantitative viral load and serologic biomarkers in oral and oropharyngeal squamous cell carcinomas
Authors: Kreimer Aimée R. , Clifford Gary M. , Snijders Peter J.F. , Castellsagué Xavier , Meijer Chris J.L.M. , Pawlita Michael , Viscidi Raphael , Herrero Rolando , Franceschi Silvia 
Published: February 2005

AbstractA considerable subset of oropharyngeal squamous cell carcinomas (SCCs) are positive for human papillomavirus (HPV); however, delineating etiologically‐associated HPV infections from SCCs with concurrent HPV infection unrelated to tumorigenesis is challenging. Viral load assessment in biopsy specimens may help facilitate such differentiation. HPV16 viral load and serologic markers were assessed among oral and oropharyngeal cases from a multinational study conducted by the International Agency for Research on Cancer (IARC). HPV16 viral load, measured semiquantitatively by PCR‐enzyme immunoassay, was dichotomized as high or low based on the median optical density value. Serologic antibodies to HPV16 virus‐like particles (VLPs) and to HPV16 E6 and E7 proteins were measured by ELISA. Compared to HPV DNA‐negative cases (n = 852), HPV16 DNA‐positive cases with high viral load (n = 26) were significantly more likely to originate in the oropharynx (odds ratio [OR], 12.0; 95% confidence interval [CI], 5.2–27.5) and, after adjustment for tumor site (AdjOR), have antibodies against HPV16 VLPs (AdjOR, 14.6; 95% CI, 6.0–35.6), E6 (AdjOR, 57.6; 95% CI, 21.4–155.3) and E7 (AdjOR, 25.6; 95% CI, 9.3–70.8). HPV16 DNA‐positive cases with low viral load (n = 27) were more commonly oropharyngeal (OR, 2.7; 95% CI, 1.1–6.2) and seropositive for HPV16 VLPs (AdjOR, 2.7; 95% CI, 1.1–6.9), E6 (AdjOR, 3.0; 95% CI, 0.7–14.0) and E7 (AdjOR, 3.5; 95% CI, 0.7–16.3), compared to HPV DNA‐negative cases; the associations, however, were neither as strong nor as significant as the associations for high viral load. As there appears to be a strong association between HPV16 serologic markers and viral load, in the absence of data on serologic markers, HPV16 viral load may be used to help delineate the subset of HPV16 DNA‐positive oral and oropharyngeal cancers that may be the consequence of HPV infection. © 2005 Wiley‐Liss, Inc.
Cyclooxygenase‐2 inhibitor celecoxib augments chemotherapeutic drug‐induced apoptosis by enhancing activation of caspase‐3 and ‐9 in prostate cancer cells
Authors: Dandekar Devendra S. , Lopez Monica , Carey Robert I. , Lokeshwar Bal L. 
Published: February 2005

AbstractMany tumors constitutively express high levels of the inducible form of proinflammatory enzyme, cyclooxygenase‐2 (COX‐2). Increased COX‐2 expression is associated with tumor cell resistance to many cytotoxic chemotherapy drugs. Furthermore, increased resistance to cytotoxic antitumor drugs is also known to be dependent on associated stromal cells in many tumors. We investigated whether prostate tumor‐associated stromal cells, marrow‐derived osteoblasts, affect cytotoxicity of 2 antitumor drugs, COL‐3 and docetaxel (TXTR), and whether it is dependent on COX‐2 activity. We further examined whether inhibiting the activity of COX‐2 negate the stroma‐induced decrease in drug sensitivity in tumor cells. COX‐2‐specific inhibitor celecoxib (CXB) was used to inhibit COX‐2 activity and associated alteration in cell death signaling was investigated. Coculturing PC‐3ML cells with osteoblasts decreased the cytotoxicity of the tested antitumor drugs and was associated with increased COX‐2 activity in PC‐3ML cells. A significant decrease in drug‐induced PGE2 increase and an increase in cytotoxicity were observed when cells were treated with COL‐3 or TXTR combined with CXB. Cytotoxicity of single or combination treatment increased apoptosis, which was associated with caspase‐3 and ‐9 activation, PARP cleavage, increased BAD protein, but decreased protein levels of XIAP and BCL‐xL. Oral administration of CXB (40 mg/kg) to mice with PC‐3ML tumors for 42 days increased tumor latency, decreased tumor growth and enhanced tumor control with COL‐3 or TXTR. Overall, a synergistic enhancement of antitumor activity in combination treatment was observed in vitro and an additive effect in vivo. These observations suggest a potential clinical use of combined dosing of COX‐2 inhibitors and cytotoxic drugs at lower, nontoxic dose than currently used to treat advanced prostate cancer. © 2005 Wiley‐Liss, Inc.