bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoxia‐inducible factor‐1α in non small cell lung cancer: Relation to growth factor, protease and apoptosis pathways
Authors: Swinson Daniel E.B. , Jones J. Louise , Cox Giles , Richardson Donna , Harris Adrian L. , O'Byrne Kenneth J. 
Published: March 2004

AbstractHypoxia‐inducible factor (HIF)‐1α is the regulatory subunit of HIF‐1 that is stabilized under hypoxic conditions. Under different circumstances, HIF‐1α may promote both tumorigenesis and apoptosis. There is conflicting data on the importance of HIF‐1α as a prognostic factor. This study evaluated HIF‐1α expression in 172 consecutive patients with stage I–IIIA non small cell lung cancer (NSCLC) using standard immunohistochemical techniques. The extent of HIF‐1α nuclear immunostaining was determined using light microscopy and the results were analyzed using the median (5%) as a low cut‐point and 60% as a high positive cut‐point. Using the low cut‐point, positive associations were found with epidermal growth factor receptor (EGFR; p = 0.01), matrix metalloproteinase (MMP)‐9 (p = 0.003), membranous (p < 0.001) and perinuclear (p = 0.004) carbonic anhydrase (CA) IX, p53 (p = 0.008), T‐stage (p = 0.042), tumor necrosis (TN; p < 0.001) and squamous histology (p < 0.001). No significant association was found with Bcl‐2 or either N‐ or overall TMN stage or prognosis. When the high positive cut‐point was used, HIF‐1α was associated with a poor prognosis (p = 0.034). In conclusion, the associations with EGFR, MMP‐9, p53 and CA IX suggest that these factors may either regulate or be regulated by HIF‐1α. The association with TN and squamous‐type histology, which is relatively more necrotic than other NSCLC types, reflects the role of hypoxia in the regulation of HIF‐1α. The prognostic data may reflect a change in the behavior of HIF‐1α in increasingly hypoxic environments. © 2004 Wiley‐Liss, Inc.
Potential efficacy of p16 gene therapy for EBV‐positive nasopharyngeal carcinoma
Authors: Li Anna Aihua , Ng Emily , Shi Wei , Lee Andrew , Chia Marie , Liu Ta‐Jen , Huang Dolly , O'Sullivan Brian , Gullane Pat , Liu Fei‐Fei 
Published: April 2004

AbstractThe p16 cell cycle inhibitory gene is a potentially critical molecular abnormality in nasopharyngeal carcinoma (NPC). Its expression is silenced through either deletion or promoter methylation in the vast majority of NPC. This in turn is associated with absent or reduced protein expression, which has been previously demonstrated by our group to correlate with inferior clinical outcome. Therefore, we were interested in evaluating the potential of adenoviral mediated p16 gene therapy (adv.p16) in an EBV‐positive NPC model (C666‐1). We confirm that under basal conditions, p16 protein is undetectable in C666‐1 cells, which, in turn, is associated with retention of retinoblastoma protein (pRb) expression. P16 expression was observed as early as 4 hr after infection of C666‐1 cells with adv.p16 (10 pfu/cell) with no discernible perturbation in pRb for up to 24 hr. At 48 hr post‐infection, p16 expression continued to increase, but at this point, pRb expression started to decline significantly. Cell viability decreased in a dose‐dependent manner, down to 20% using 50 pfu/cell of adv.p16. The addition of radiation therapy (RT) administered 24 hr post‐infection achieved only a slightly additive cytotoxicity. Adv.p16 therapy resulted in multiple mechanisms of cytotoxicity, including cell cycle arrest at the G0/G1 phase, induction of senescence, along with apoptosis. Ex vivo infection of C666‐1 cells with adv.p16 (25 pfu/cell) with subsequent implantation into scid mice completely prevented tumor formation, followed for up to 51 days. Our study demonstrates the potential efficacy of adv.p16 gene therapy for NPC, mediated through multimodal mechanisms of cytotoxicity. Future evaluations will examine strategies to increase in vivo tumor transduction with a view towards future clinical applications. © 2004 Wiley‐Liss, Inc.
Frequent epigenetic inactivation of RIZ1 by promoter hypermethylation in human gastric carcinoma
Authors: Oshimo Yasuhiro , Oue Naohide , Mitani Yoshitsugu , Nakayama Hirofumi , Kitadai Yasuhiko , Yoshida Kazuhiro , Chayama Kazuaki , Yasui Wataru 
Published: March 2004

AbstractThe retinoblastoma protein‐interacting zinc finger gene, RIZ1 (GenBank accession number U17838), is involved in chromatin‐mediated gene expression and is also a target for frameshift mutation in microsatellite‐unstable cancers. Methylation of the RIZ1 promoter CpG island has been shown to be a common mechanism in inactivating the RIZ1 gene in human liver and breast cancers. We investigated levels of RIZ1 mRNA in 45 gastric carcinoma tissues by quantitative RT‐PCR and in gastric carcinoma cell lines by RT‐PCR. In addition, we examined CpG island methylator phenotype (CIMP) status, p53 mutation status, and the correlation between promoter methylation status and RIZ1 mRNA expression. CIMP status was investigated by examining the methylation status of MINT1, MINT2, MINT12, MINT25 and MINT31. p53 mutation status was examined by PCR‐single strand conformation polymorphism and promoter methylation status was examined by methylation‐specific PCR. Promoter hypermethylation of the RIZ1 gene was found in 31 (69%) of 45 gastric carcinoma tissues and in 3 (21%) of 14 corresponding non‐neoplastic mucosae, the incidence being significantly different (p = 0.002). None of the 12 normal gastric tissues from young non‐cancer individuals showed hypermethylation. Promoter hypermethylation was associated with reduced RIZ1 expression in gastric carcinoma tissues (p = 0.029). Promoter hypermethylation of the RIZ1 gene was significantly associated with CIMP (p = 0.002). Mutation status of the p53 gene was not associated with methylation status or RIZ1 expression in gastric carcinoma. In gastric carcinoma cell lines MKN‐28 and KATO‐III, the RIZ1 promoter was hypermethylated and RIZ1 transcription was inactive. Treatment of these cells with demethylating agent 5‐aza‐2′‐deoxycytidine restored RIZ1 transcription. Our results suggest that transcriptional inactivation of the RIZ1 gene by promoter hypermethylation may participate in stomach carcinogenesis. © 2004 Wiley‐Liss, Inc.
Cancer mortality in Europe, 1995–1999, and an overview of trends since 1960
Authors: Levi Fabio , Lucchini Franca , Negri Eva , Boyle Peter , La Vecchia Carlo 
Published: March 2004

AbstractMortality data, abstracted from the World Health Organization database, are presented in tabular form for 26 cancer sites or groups of sites, plus total cancer mortality, in 36 European countries during the period 1995–1999. Trends in mortality are also given in graphic form for 23 major countries plus the European Union as a whole over the period 1960–1999. In the European Union, total cancer mortality declined by 7% for both sexes over the last 5 years considered. The fall since the late 1980s was 10% in both sexes, corresponding to the avoidance of over 90,000 deaths per year, as compared to the rates of the late 1980s. For the first time, over the last few years, some leveling of mortality was reported also in the Russian Federation, the Czech Republic, Poland, Hungary and other Eastern European countries, although cancer rates in those areas remain exceedingly high. The overall favorable pattern of cancer mortality over recent years is largely driven by the decline of tobacco‐related cancer mortality in men. However, important components of the trends are also the persistence of substantial falls in gastric cancer, mainly in Russia and Eastern Europe, the recent decline in intestinal cancer in both sexes and of breast cancer in women, together with the long‐term falls in uterine (cervical) cancer, leukemias, Hodgkin's disease and other neoplasms amenable to advancements in diagnosis and treatment. Female lung cancer mortality has been declining in the Russian Federation, but is still rising in other areas of the continent. Thus, urgent intervention is needed to bring under control the tobacco‐related lung cancer epidemic in European women before it reaches the high level observed in North America. Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020‐7136/suppmat/index.html © 2004 Wiley‐Liss, Inc.
Carboplatin selectively induces the VEGF stress response in endothelial cells: Potentiation of antitumor activity by combination treatment with antibody to VEGF
Authors: Wild Robert , Dings Ruud P.M. , Subramanian Indira , Ramakrishnan S. 
Published: April 2004

AbstractVascular Endothelial Growth Factor (VEGF) functions as a key regulator in tumor angiogenesis. In addition, VEGF is an important survival factor for endothelial cells under chemical or physical stress. In our report, we show that treatment of endothelial cells with the chemotherapeutic agent carboplatin significantly increased the expression of VEGF. Furthermore, neutralization of secreted VEGF with specific polyclonal anti‐VEGF antibodies or monoclonal antibody sensitized endothelial cells to carboplatin treatment and increased apoptosis several‐fold. Interestingly, carboplatin treatment did not alter VEGF expression in tumor cells. Similarly, antibody to VEGF did not change the chemosensitivity of tumor cells to this drug. Most importantly, tumor‐bearing animals treated with carboplatin showed an increase in VEGF immunoreactivity in the tumor vasculature, confirming the in vitro studies. Based on these observations, we determined whether neutralization of VEGF could enhance the anti‐tumor activity of carboplatin in an in vivo ovarian cancer model system. A combination therapy consisting of a suboptimal dose of carboplatin (32.5 mg/kg/inj., q3d×5; i.p.) and polyclonal anti‐VEGF antibody (2 mg/inj., q3d×10; i.p.) significantly enhanced solid tumor growth inhibition over individual monotherapies and included multiple complete responses. These findings suggest that VEGF is a critical endothelial cell specific survival factor that is induced by carboplatin and contributes to the protection of tumor vasculature during chemotherapy treatment. In addition, these results provide evidence for a potential mechanism that underlies enhanced anti‐tumor activity achieved with chemotherapy and anti‐VEGF antibody combination treatment regimens as recently reported in a number of clinical trials. We conclude that a similar type of combination therapy may be applicable to many types of malignancies since VEGF expression was differentially induced in the tumor host environment (i.e., tumor vasculature) and not in the tumor cells themselves; hence, this phenomenon may be independent of the type and origin of the primary cancer. © 2004 Wiley‐Liss, Inc.
Comparative genomic hybridization analysis of hereditary swine cutaneous melanoma revealed loss of the swine 13q36‐49 chromosomal region in the nodular melanoma subtype
Authors: Apiou Françoise , Vincent‐Naulleau Silvia , Spatz Alain , Vielh Philippe , Geffrotin Claudine , Frelat Geffrotin , Dutrillaux Bernard , Le Chalony Catherine 
Published: March 2004

AbstractGenetic alterations implicated in malignant melanoma are still poorly understood. Malignant melanomas present highly variable histologic and cytologic patterns. The aim of the present study is to define genomic imbalances associated with the development of 2 histologic types of swine hereditary cutaneous melanoma. We have investigated 11 swine tumors by comparative genomic hybridization (CGH), 4 superficial spreading melanomas (SSMs) and 7 nodular melanomas (NMs). Following laser capture microdissection and degenerate oligonucleotide primed‐polymerase chain reaction, we were able to isolate and then amplify DNA from the 2 histologic subtypes. Consensus regions of chromosome gains were identified on both histologic subtypes, on swine chromosomes 3p13‐p17 (75% of the SSMs and 71% of the NMs), 12q (100% of the SSMs and 57% of the NMs) and 14q11‐q21 (75% of the SSMs and 42% of NMs). Chromosomal loss was restricted to NM lesions and the swine 13q36‐49 region was lost in 100% of the NMs. Interphase fluorescence in situ hybridization with a probe mapping to the 13q41‐q42 region indicates loss of the corresponding region on NM lesions. Taking into account this CGH analysis and the comparative genomic data between swine and human genomes, we suggest that a role for the human chromosomes 3p11‐qter and chromosome 21 losses should be investigated in human nodular melanoma progression. © 2004 Wiley‐Liss, Inc.
Dietary phytoestrogen intake and premenopausal breast cancer risk in a German case‐control study
Authors: Linseisen Jakob , Piller Regina , Hermann Silke , Chang‐Claude Jenny 
Published: March 2004

AbstractA diet high in isoflavonoids (soy) is associated with lower breast cancer risk in Asian populations. Due to the low soy intake, dietary lignans may be the more important phytoestrogen class in Western populations. We used a population‐based case‐control study of breast cancer by age 50 in southern Germany to evaluate the association between dietary intake of different phytoestrogens and premenopausal breast cancer risk. Dietary information was collected from 278 premenopausal cases and 666 age‐matched controls, using a validated FFQ. Using multivariate logistic regression, the highest vs. lowest intake quartiles of daidzein and genistein yielded significantly reduced ORs (95% CI) for breast cancer risk of 0.62 (0.40–0.95) and 0.47 (0.29–0.74), respectively. The protective effects of daidzein and genistein were found only for hormone receptor‐positive tumors. High intake of other isoflavonoids, e.g., formononetin and biochanin A, as well as the sum of isoflavonoids were not associated with a decrease in risk. Breast cancer risk significantly decreased with a high intake of the plant lignan matairesinol (OR = 0.58, 95% CI 0.37–0.94) but not secoisolariciresinol or the sum of plant lignans. However, both estimated mammalian lignans, enterodiol and enterolactone, were inversely associated with breast cancer risk, with ORs (95% CI) of 0.61 (0.39–0.98) and 0.57 (0.35–0.92), respectively. No effect was found for total phytoestrogen intake. Our results suggest an important role of dietary intake of daidzein and genistein, despite low levels, as well as of matairesinol and mammalian lignans to reduce premenopausal breast cancer risk in this study population. © 2004 Wiley‐Liss, Inc.
Impact of GSTT1, GSTM1, GSTP1 and NAT2 genotypes on KRAS2 and TP53 gene mutations in colorectal cancer
Authors: Ferraz Jean‐Marc , Zinzindohoué Franck , Lecomte Thierry , Cugnenc Paul‐Henri , Loriot Marie‐Anne , Beaune Philippe , Stücker Isabelle , Berger Anne , Laurent‐Puig Pierre 
Published: March 2004

AbstractWhich carcinogens are of influence in the development of human colorectal cancers remains a question; one answer could be the finding that specific polymorphisms in xenobiotic metabolizing enzymes are related to particular mutations in cancer genes. KRAS2 and TP53 gene mutations as well as genotypes for GSTM1, GSTP1, GSTT1 and NAT2 were determined in an exploratory series of 165 stable colorectal cancers. Mutations in KRAS2 and TP53 were found in 34% and 57.5% of cases, respectively. The KRAS2 mutation frequency was significantly lower in patients with a GSTT1 null genotype than in those with a GSTT1 non‐null genotype (18% vs. 38%, p = 0.03). The overall risk of KRAS2 mutation for patients with distal colorectal cancer and GSTT1 null genotype was 0.3 (95% CI 0.1–0.9) compared to patients with distal colorectal cancer and non‐null GSTT1 genotype. The overall risk of KRAS2 mutation was similarly reduced (OR = 0.4, 95% CI 0.2–0.9) for patients with distal colorectal cancer and GSTP1 mutated genotypes compared to patients with distal colorectal cancer and wild‐type genotype. Patients with GSTP1 wild‐type genotype appeared to be at significantly lower risk for TP53 mutation compared to patients with mutated genotypes (p = 0.023). Our results suggest that GSTT1 and GSTP1 could play a role in the occurrence of KRAS2 and TP53 mutations in colorectal cancer and generate a hypothesis on the dietary factors that could be incriminated. © 2004 Wiley‐Liss, Inc.
Natural killer cell depletion confounds the antitumor mechanism of endogenous IL‐12 overexpression
Authors: Miller George , Bleier Joshua I. , Antonescu Cristina , Pillarisetty Venu G. , Shah Alaap B. , Lahrs Svenja , DeMatteo Ronald P. 
Published: April 2004

AbstractIL‐12 gene transfer to hepatocytes using a recombinant adenovirus vector (AdIL‐12) has been shown to protect against primary and metastatic liver tumors in mice. However, the mechanism of protection has been elusive and studies using depleting monoclonal antibodies or transgenic mice have purported it to be independent of T and NK cells. We postulated that depletion of NK cells may distort the experimental model and misrepresent the antitumor mechanism by altering the magnitude and duration of transgene expression. We show in mice treated with AdIL‐12 that NK depletion increased serum IL‐12 levels by more than 250‐fold and prolonged transgene expression by nearly 2 weeks compared to nondepleted mice. To determine the contribution of NK cells to tumor protection after AdIL‐12 treatment, we analyzed NK cells from treated animals. Isolated NK cells were markedly activated in terms of their lytic activity and IFN‐γ secretion. Adoptive transfer of NK cells from mice that had been treated with AdIL‐12 to naive mice was sufficient to confer protection against colorectal hepatic metastases. This protection was mediated in part by NK‐cell production of IFN‐γ. Our findings indicate that NK‐cell depletion distorts the model of systemic AdIL‐12 administration by markedly altering transgene expression, which then may potentiate other antitumor mechanisms, and that endogenous IL‐12 overexpression activates NK cells, rendering them sufficient to protect against liver metastases. These data have critical implications for investigating the immunologic mechanisms of experimental models that utilize gene transfer. © 2004 Wiley‐Liss, Inc.
Null association between pregnancy termination and breast cancer in a registry‐based study of parous women
Authors: Lash Timothy L. , Fink Aliza K. 
Published: April 2004

AbstractStudies suggesting a positive association between pregnancy termination and breast cancer risk have often been of retrospective case‐control design, so subject to selection and recall biases. We undertook a registry‐based analysis with minimal selection bias and prospective record‐based ascertainment of terminations. The source population comprised Massachusetts women with a record of giving birth between 1987 and 1999 in the Massachusetts Vital Statistics Registry. Primary breast cancer cases were 25–55 years old at diagnosis between 1988 and 2000 and had a record of the diagnosis in the Massachusetts Cancer Registry. We matched 3 controls to each case on maternal age, year of giving birth and birth facility. Information on terminations (induced and spontaneous) before the birth of record, the matched factors and potential confounders were collected from the birth certificate. After adjustment for the matched factors, age, parity and maternal and paternal education, the odds ratio associating any termination history with breast cancer risk equaled 0.91 (95% CI = 0.79–1.05). The marginally protective adjusted odds ratio largely derived from a protective effect among women with parity equaled to 1 (OR for any termination = 0.68; 95% CI = 0.45–1.03), suggesting a protective effect of terminated pregnancy among women with one live birth. © 2004 Wiley‐Liss, Inc.
Non‐Hodgkin's lymphoma and hepatitis C virus: A case‐control study from northern and southern Italy
Authors: Talamini Renato , Montella Maurizio , Crovatto Marina , Dal Maso Luigino , Crispo Anna , Negri Eva , Spina Michele , Pinto Antonio , Carbone Antonino , Franceschi Silvia 
Published: April 2004

AbstractHCV has been associated with NHL, but the evidence from case series and case‐control studies is not totally consistent. Between 1999 and 2002, we conducted a hospital case‐control study on the association between HCV, HBV and NHL in 2 areas of Italy where HCV infection is relatively frequent. Cases (n = 225, median age 59 years) were consecutive patients with a new diagnosis of NHL admitted to local specialized and general hospitals. Controls (n = 504, median age 63 years) were patients with a wide spectrum of acute conditions admitted to the same hospitals as cases. HCV prevalence was 19.6% among NHL cases and 8.9% among controls (adjusted OR = 2.6, 95% CI 1.6–4.3). The ORs for HCV were similar for low‐grade and intermediate‐/high‐grade B‐cell NHL (3.2 and 2.4, respectively) as well as for nodal and extranodal NHL (2.7 and 2.6, respectively). Positivity for HBsAg was found in 3.8% of cases and 0.9% of controls (OR = 4.1, 95% CI 1.2–14.4). An elevated OR was also found for history of hepatitis C (OR = 4.7, 95% CI 2.3–9.5). History of blood transfusion before 1990 was associated with HCV positivity among controls but not with NHL risk. In conclusion, HCV infection was associated with an increase in NHL risk, and the fraction of NHL cases attributable to HCV was 12.4% (range 6.3–18.5%). © 2004 Wiley‐Liss, Inc.
Interferon‐γ differentially regulates susceptibility of lung cancer cells to telomerase‐specific cytotoxic T lymphocytes
Authors: Tajima Kouhei , Ito Yoshinori , Demachi Ayako , Nishida Keiko , Akatsuka Yoshiki , Tsujimura Kunio , Hida Toyoaki , Morishima Yasuo , Kuwano Hiroyuki , Mitsudomi Tetsuya , Takahashi Toshitada , Kuzushima Kiyotaka 
Published: April 2004

AbstractThere is accumulating evidence that peptides derived from the catalytic subunit of human telomerase reverse transcriptase (hTERT) are specifically recognized by CD8+ cytotoxic T lymphocytes. We investigated the cytotoxicity of a human leukocyte antigen (HLA)‐A*2402‐restricted hTERT‐derived peptide 461–469 (hTERT461)‐specific CD8+ T‐cell clone, designated as K3‐1, established from a healthy donor by repetitive peptide stimulation. This clone exhibited cytotoxicity against 4 out of 6 HLA‐A24‐positive lung cancer cell lines with positive telomerase activity but not 4 HLA‐A24‐negative examples. When the target cells were pretreated with 100 U/ml of interferon (IFN)‐γ for 48 hr, the susceptibility to K3‐1 increased with PC9 cells but unexpectedly decreased with LU99 cells. However, in both cell lines, the expression of molecules associated with epitope presentation such as HLA‐A24, transporters associated with antigen processing, low molecular weight polypeptide 7 and proteasome activator 28 was similarly increased after IFN‐γ treatment. Results of CTL assays using acid‐extracted peptides indicated that the epitope increased on PC9 cells but not on LU99 cells after IFN‐γ treatment. Semi‐quantitative reverse transcriptase polymerase chain reaction disclosed that the expression of hTERT was attenuated in LU99 but not in PC9 cells, accounting for the decreased cytotoxicity mediated by K3‐1. The attenuation of the hTERT expression and K3‐1‐mediated cell lysis after IFN‐γ treatment was also observed in primary adenocarcinoma cells obtained from pulmonary fluid of a lung cancer patient. Our data underline the utility of peptide hTERT461 in immunotherapy for lung cancer, as with other malignancies reported earlier, and suggest that modulation of hTERT expression by IFN‐γ needs to be taken into account in therapeutic approach. © 2004 Wiley‐Liss, Inc.