bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased chromosome instability but not cancer predisposition in haploinsufficient Bub3 mice
Authors: Kalitsis Paul , Fowler Kerry J. , Griffiths Belinda , Earle Elizabeth , Chow C. W. , Jamsen Kris , Choo K. H. Andy 
Published: May 2005

AbstractMitotic spindle checkpoint proteins have been shown to play a crucial role in the accurate segregation of chromosomes during cell division. Bub3 is a member of a group of mitotic checkpoint proteins that are essential for this process. To investigate the role of Bub3 in chromosome segregation and cancer development, we analyzed haploinsufficient cells in mice. Heterozygous Bub3 embryonic fibroblasts displayed increased aneuploidy and premature sister‐chromatid separation. In addition, when challenged with the microtubule disruptor nocodazole, the cells showed a slight increase in chromatid breakage and a decrease in the mitotic index. No substantial differences were observed between wild‐type and Bub3 heterozygous mice in the frequency or the rate at which tumors appeared. Crossing Bub3+/− mice onto a heterozygous tumor‐suppressor background of Trp53 or Rb1 similarly revealed no substantial differences in either the number or the rate at which tumors appeared. These results suggest that haploinsufficiency of Bub3 causes a slight increase in chromosome instability but is not clearly associated with a noticeable rise in the probability of tumor formation in the animal, possibly because of a partially functional mitotic checkpoint, or cells exhibiting chromosome instability could have activated the apoptosis pathway and thus escaped tumor induction and detection. © 2005 Wiley‐Liss, Inc.
Statistical modeling and projections of lung cancer mortality in 4 industrialized countries
Authors: Shibuya Kenji , Inoue Mie , Lopez Alan D. 
Published: May 2005

AbstractThe purpose of this work was to model lung cancer mortality as a function of past exposure to tobacco and to forecast age‐sex‐specific lung cancer mortality rates. A 3‐factor age‐period‐cohort (APC) model, in which the period variable is replaced by the product of average tar content and adult tobacco consumption per capita, was estimated for the US, UK, Canada and Australia by the maximum likelihood method. Age‐ and sex‐specific tobacco consumption was estimated from historical data on smoking prevalence and total tobacco consumption. Lung cancer mortality was derived from vital registration records. Future tobacco consumption, tar content and the cohort parameter were projected by autoregressive moving average (ARIMA) estimation. The optimal exposure variable was found to be the product of average tar content and adult cigarette consumption per capita, lagged for 25–30 years for both males and females in all 4 countries. The coefficient of the product of average tar content and tobacco consumption per capita differs by age and sex. In all models, there was a statistically significant difference in the coefficient of the period variable by sex. In all countries, male age‐standardized lung cancer mortality rates peaked in the 1980s and declined thereafter. Female mortality rates are projected to peak in the first decade of this century. The multiplicative models of age, tobacco exposure and cohort fit the observed data between 1950 and 1999 reasonably well, and time‐series models yield plausible past trends of relevant variables. Despite a significant reduction in tobacco consumption and average tar content of cigarettes sold over the past few decades, the effect on lung cancer mortality is affected by the time lag between exposure and established disease. As a result, the burden of lung cancer among females is only just reaching, or soon will reach, its peak but has been declining for 1 to 2 decades in men. Future sex differences in lung cancer mortality are likely to be greater in North America than Australia and the UK due to differences in exposure patterns between the sexes. © 2005 Wiley‐Liss, Inc.
Physical activity and the risk of ovarian cancer: A case‐control study in Canada
Authors: Pan Sai Yi , Ugnat Anne‐Marie , Mao Yang ,   The Canadian Cancer Registries Epidemiology Research Group
Published: May 2005

AbstractWe evaluated the impact of recreational and occupational physical activity on ovarian cancer risk using data from a population‐based case‐control study of 442 cases with histologically confirmed incident ovarian cancer and 2,135 controls aged 20–76 years, conducted in 1994–1997 in Canada. Frequency and intensity of physical activity were collected through self‐administered questionnaires. Compared to women in the lowest tertiles of moderate, vigorous and total recreational activity, those in the highest tertiles had multivariable‐adjusted odds ratios (and 95% confidence intervals) of 0.67 (0.50–0.88), 0.93 (0.70–1.24) and 0.73 (0.58–0.98), respectively. There were statistically significant trends of decreasing risk with increasing levels of moderate and total recreational activity, with similar patterns for premenopausal and postmenopausal women. A significant reduction in risk associated with higher level of moderate recreational activity was observed for serous, endometrioid and other but not mucinous types of tumors. The analyses in one province with the largest number of cases and controls indicated that occupational activity was associated with reduced ovarian cancer risk by lifetime activity and by various life periods (early 20s, early 30s, early 50s and 2 years before interview). Our study suggests that occupational and regular moderate recreational physical activity reduce ovarian cancer risk. © 2005 Wiley‐Liss, Inc.
Immunotherapy of malignant ascites with trifunctional antibodies
Authors: Heiss Markus M. , Ströhlein Michael A. , Jäger Michael , Kimmig Rainer , Burges Alexander , Schoberth Alexandra , Jauch Karl‐Walter , Schildberg Friedrich‐Wilhelm , Lindhofer Horst 
Published: May 2005

AbstractA new class of intact bispecific antibodies shows unmet effector qualities by activation of not only T cells but also simultaneous activation of Fcγ receptor type I/III+ cells (macrophages, NK‐cells and DC). These trifunctional antibodies (trAb) lead to efficient specific killing of targeted tumor cells without any pre‐ or co‐stimulation. This concept was investigated in vivo in patients with malignant ascites in a clinical situation that allowed monitoring of tumor cell elimination and correlation with clinical effects. In a prospective study, 8 patients with malignant ascites due to peritoneal carcinomatosis were treated with intraperitoneal application of trAb, which bound either the EpCAM‐ or Her2/neu‐antigen on tumor cells. Treatment consisted of 4–6 applications within 9–23 days with a total amount of 145–940 μg. Seven of eight patients required no further paracentesis during follow‐up or until death with a mean paracentesis‐free interval of 38 weeks (median = 21.5, range = 4–136). Tumor cell monitoring showed a complete elimination of tumor cells in ascites already at total doses as low as 40–140 μg. Clinical response with disappearance of ascites accumulation was seen in all patients, which was correlated with elimination of tumor cells (p = 0.0014). Severe adverse events were not observed. Clinically relevant side effects were fever, moderate abdominal pain and skin reactions. Intraperitoneal immunotherapy with trAb showed convincing efficacy in patients with malignant ascites. This treatment offers new therapeutic options for patients with peritoneal carcinomatosis. © 2005 Wiley‐Liss, Inc.
Association of the BCRP C421A polymorphism with nonpapillary renal cell carcinoma
Authors: Korenaga Yoshihito , Naito Katsusuke , Okayama Naoko , Hirata Hiroshi , Suehiro Yutaka , Hamanaka Yuichiro , Matsuyama Hideyasu , Hinoda Yuji 
Published: May 2005

AbstractBreast cancer resistance protein (BCRP), the second member of the ATP‐binding cassette membrane transporter family, has a single nucleotide polymorphism, C421A (resulting in Q141K), that is of functional importance. Our aim was to explore the relationship between this polymorphism of the BCRP gene and the risk of renal cell carcinoma (RCC) development. For a case‐control study, DNA samples from 200 nonpapillary RCC patients and 200 healthy control subjects were analyzed using the TaqMan technique. The genotypic frequencies of the BCRP C421A polymorphism were compared between RCC patients and control subjects. The frequency of the C/C genotype was significantly higher in RCC patients than in control subjects (age‐ and gender‐adjusted OR = 1.96, 95% CI 1.32–2.93). No associations were observed between the BCRP C421A polymorphism and clinicopathologic or epidemiologic factors, including age, gender, tumor grade, stage, cigarette smoking, family history of cancer and body mass index. Carriers with the C/C genotype of the BCRP C421A polymorphism are at risk of developing nonpapillary RCC. These data suggest that BCRP is a candidate RCC susceptibility gene. © 2005 Wiley‐Liss, Inc.
Efficient induction of T‐cell responses to carcinoembryonic antigen by a heterologous prime‐boost regimen using DNA and adenovirus vectors carrying a codon usage optimized cDNA
Authors: Mennuni Carmela , Calvaruso Francesco , Facciabene Andrea , Aurisicchio Luigi , Storto Mariangela , Scarselli Elisa , Ciliberto Gennaro , La Monica Nicola 
Published: May 2005

AbstractThe immunogenic properties of plasmid DNA and recombinant adenovirus (Ad) encoding the carcinoembryonic antigen (CEA) were examined in mice by measuring both the amplitude and type of immune response, and the immunogenicity of codon usage optimized cDNA encoding CEA (CEAopt) was assessed both in C57Bl/6 and CEA transgenic mice. Vectors were injected into quadriceps muscle either alone or in combination, and plasmid DNA was electroporated to enhance gene expression efficiency and immunogenicity. Injection of plasmid pVIJ/CEA followed by Ad‐CEA boost elicited the highest amplitude of both CD4+ and CD8+ T‐cell response to the target antigen, measured by both IFNγ‐ELIspot assay and intracellular staining. Vectors carrying cDNA of CEAopt expressed a greater amount of the CEA protein than their wild‐type counterparts, and this enhanced expression was associated with greater immunogenicity. Both CD4+ and CD8+ T‐cell epitopes were mapped in the C‐terminal portion of the protein. In CEA transgenic mice, only immunization based on repeated injections of pVIJ/CEAopt followed by Ad‐CEAopt was able to elicit a CEA‐specific CD8+ T‐cell response, whereas the wild‐type vectors did not break tolerance to this target antigen. MC38‐CEA tumor cells injected s.c. in CEA transgenic mice vaccinated with CEAopt vectors exhibited delayed growth kinetics. These studies demonstrate that this type of genetic vaccine is highly immunogenic and can break tolerance to CEA tumor antigen in CEA transgenic mice. © 2005 Wiley‐Liss, Inc.
SCCA antigen combined with alpha‐fetoprotein as serologic markers of HCC
Authors: Giannelli Gianluigi , Marinosci Felice , Trerotoli Paolo , Volpe Anna , Quaranta Michele , Dentico Pietro , Antonaci Salvatore 
Published: May 2005

AbstractHepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Because of its increased incidence in the last decade and the estimated further increase in the next 2 decades, HCC is arousing great interest. In Europe and North America, it commonly develops on cirrhotic livers, and surveillance programs have therefore been suggested to identify early HCC, at a stage when it remains suitable for surgical therapy and has a better clinical outcome. The only serologic marker used in clinical practice is α‐fetoprotein (α‐FP), but its sensitivity is poor. In our study, 120 patients with HCC and 90 patients with liver cirrhosis were investigated. We report for the first time to our knowledge that as a marker of HCC, the squamous cell carcinoma (SCCA) antigen has high sensitivity (84.2%) but low specificity (48.9%). However, the combination of α‐FP and SCCA yielded a correct serologic diagnosis in 90.83% of the HCC patients. A small percentage of patients remain undetected, likely because of the low specificity of SCCA. In conclusion, the combined use of α‐FP and SCCA antigen represents a more powerful tool for the serologic detection of HCC. © 2005 Wiley‐Liss, Inc.
Modulation of hepatic cytochromes P450 and phase II enzymes by dietary doses of sulforaphane in rats: Implications for its chemopreventive activity
Authors: Yoxall Victoria , Kentish Peter , Coldham Nick , Kuhnert Nikolai , Sauer Maurice J. , Ioannides Costas 
Published: May 2005

AbstractThe principal objectives of our study were to ascertain whether sulforaphane, at dietary levels of intake, modulates rat hepatic cytochrome P450 and phase II enzyme systems and to evaluate the impact of such changes in the chemopreventive activity of this isothiocyanate. Animals were exposed to sulforaphane in their drinking water for 10 days, equivalent to daily doses of 3 and 12 mg/kg. Depentylation of pentoxyresorufin decreased and was paralleled by a decline in CYP2B apoprotein levels. At the higher dose, erythromycin N‐demethylase activity declined and was accompanied by a similar decrease in CYP3A2 apoprotein levels. However, sulforaphane treatment upregulated CYP1A2 levels, determined immunologically, but the dealkylations of methoxy‐ and ethoxyresorufin were not similarly increased. Hepatic S9 preparations from sulforaphane‐treated rats were less effective than control preparations in converting IQ (2‐amino‐3‐methylimidazo‐[4,5‐f]quinoline) to mutagenic intermediates in the Ames test. To clarify the underlying mechanism, in vitro studies were undertaken. In β‐naphthoflavone‐treated rats, the inhibition by sulforaphane of the O‐dealkylations of methoxy‐ and ethoxyresorufin was enhanced if the isothiocyanate was preincubated in the presence of NADPH. It may be inferred that sulforaphane induces hepatic CYP1A2 but the enzyme is not catalytically competent because of bound sulforaphane metabolite(s). Finally, sulforaphane stimulated, in a dose‐dependent fashion, quinone reductase but failed to influence glutathione S‐transferase, epoxide hydrolase and glucuronosyl transferase activities. It is concluded that, even at dietary doses, sulforaphane can modulate the xenobiotic‐metabolising enzyme systems, shifting the balance of carcinogen metabolism toward deactivation, and this may be an important mechanism of its chemopreventive activity. © 2005 Wiley‐Liss, Inc.
TP53 alterations and patterns of carcinogen exposure in a U.S. population‐based study of bladder cancer
Authors: Kelsey Karl T. , Hirao Tomoko , Hirao Shuya , Devi‐Ashok Tara , Nelson Heather H. , Andrew Angeline , Colt Joanne , Baris Dalsu , Morris J. Steven , Schned Alan , Karagas Margaret 
Published: May 2005

AbstractThe molecular pathology of bladder cancer has been the subject of considerable interest, and current efforts are targeted toward elucidating the interrelationships between individual somatic gene loss and both etiologic and prognostic factors. Mutation of theTP53gene has been associated with more invasive bladder cancer, and evidence suggests thatTP53mutation, independent of stage, may be predictive of outcome in this disease. However, there is no consensus in the literature that bladder carcinogen exposure is associated with inactivation of theTP53gene. Work to date has been primarily hospital based and, as such, subject to possible bias associated with selection of more advanced cases for study. We examined exposure relationships with bothTP53gene mutation and TP53 protein alterations in a population‐based study of 330 bladder cancer cases in New Hampshire. Tobacco smoking was not associated with TP53 alterations. We found a higher prevalence ofTP53inactivation (i.e.,mutation and nuclear accumulation) among hair dye users (odd ratio [OR] = 4.1; 95% confidence interval [CI] 1.2–14.7), and the majority of these mutations were transversions. Men who had “at risk” occupations were more likely to have mutatedTP53tumors (OR = 2.9; 95% CI 1.1–7.6). There also was a relative absence ofTP53mutation (OR = 0.4; 95% CI 0.0–2.9) and TP53 protein alterations (OR = 0.6; 95% CI 0.3–1.4) in bladder cancers from individuals with higher arsenic exposure. Our data suggest that there is exposure‐specific heterogeneity in inactivation of the TP53 pathway in bladder cancers and that integration of the spectrum of pathway alterations in population‐based approaches (capturing the full range of exposures to bladder carcinogens) may provide important insights into bladder tumorigenesis. © 2005 Wiley‐Liss, Inc.
Combination therapy with tumor‐lysate pulsed dendritic cells and antiangiogenic drug TNP‐470 for mouse pancreatic cancer
Authors: Miyazaki Junichi , Tsuzuki Yoshikazu , Matsuzaki Koji , Hokari Ryota , Okada Yoshikiyo , Kawaguchi Atsushi , Nagao Shigeaki , Itoh Kazuro , Miura Soichiro 
Published: May 2005

AbstractMost cases of pancreatic cancer are inoperable when diagnosed. Since immunotherapy and antiangiogenic therapy have been reported to be promising for pancreatic cancer, we examined whether the combination of immunotherapy with dendritic cells (DCs) and the antiangiogenic drug TNP‐470 induces tumor regression. Syngeneic mouse pancreatic adenocarcinoma cells were orthotopically inoculated into C57/BL6 mice. DCs with or without tumor lysate (TL) were administered i.p. at 4 and 5 weeks. TNP‐470 was injected s.c. into tumor‐bearing mice every other day from 4 weeks to 6 weeks. We compared anticancer effects in 6 groups: NT (no treatment), DC/TL− (DCs without TL), DC/TL+ (DCs pulsed with TL), TNP (TNP‐470 alone), DC/TL–TNP (DC/TL− plus TNP‐470) and DC/TL+TNP (DC/TL+ plus TNP‐470). We measured tumor volume, mean vascular density (MVD) and vessel diameter by FITC‐dextran using an intravital microscope; degrees of proliferation and apoptosis of cancer cells by PCNA and TUNEL; infiltrating lymphocytes and expression levels of VEGF and MMP‐9 by immunohistochemistry and immunoblotting. Tumor volume and MVD were significantly suppressed in the treatment groups with prolonged survival rate, especially in the DC/TL+TNP group. There were no significant differences in apoptosis among the 6 groups except DC/TL+. The number of infiltrating CD4+ cells in the DC/TL+ group was higher than that in the NT group. VEGF expression was significantly suppressed in the treatment groups containing TNP‐470, and MMP‐9 was also suppressed in the groups containing DC/TL+. Our data suggested that TL‐pulsed DCs combined with TNP‐470 induced regression of mouse pancreatic cancer, possibly through induction of immune responses and suppression of angiogenesis. © 2005 Wiley‐Liss, Inc.
HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri
Authors: Beskow Anna H. , Moberg Martin , Gyllensten Ulf B. 
Published: May 2005

AbstractHuman papillomavirus (HPV) infection is the most important risk factor for development of cervical carcinoma. Carriers of certain HLA class II alleles, e.g., DRB1*1501 and DQB1*0602, are more prone to HPV 16 infection and cervical carcinoma, whereas other alleles, e.g., DRB1*1301 and DQB1*0603, render carriers less susceptible to the disease. In our study comprising 484 cases and 601 controls, we examine the effect of HLA class II alleles on viral load of the oncogenic types HPV 18/45 and HPV 31 and risk of developing cervical carcinoma in situ. We find that carriers of the commonly reported protective DRB1*1301 and DQB1*0603 alleles have lower HPV 18/45 load compared to noncarriers and a lower risk of developing HPV 18/45‐positive cervical carcinoma. This provides further evidence that the HLA class II‐mediated immune response to HPV is important for controlling viral load and outcome of an infection. © 2005 Wiley‐Liss, Inc.
Thymoquinone induces apoptosis through activation of caspase‐8 and mitochondrial events in p53‐null myeloblastic leukemia HL‐60 cells
Authors: El‐Mahdy Mohamed A. , Zhu Qianzheng , Wang Qi‐En , Wani Gulzar , Wani Altaf A. 
Published: May 2005

AbstractThymoquinone (TQ), the major biologically active component isolated from a traditional medicinal herb, Nigella sativa Linn, is a potential chemopreventive and chemotherapeutic compound. Despite the promising antineoplastic activities of TQ, the molecular mechanism of its pharmacologic effects is poorly understood. Here, we report that TQ exhibits antiproliferative effect, induces apoptosis, disrupts mitochondrial membrane potential and triggers the activation of caspases 8, 9 and 3 in myeloblastic leukemia HL‐60 cells. The apoptosis induced by TQ was inhibited by a general caspase inhibitor, z‐VAD‐FMK; a caspase‐3‐specific inhibitor, z‐DEVD‐FMK; as well as a caspase‐8‐specific inhibitor, z‐IETD‐FMK. Moreover, the caspase‐8 inhibitor blocked the TQ‐induced activation of caspase‐3, PARP cleavage and the release of cytochrome c from mitochondria into the cytoplasm. In addition, TQ treatment of HL‐60 cells caused a marked increase in Bax/Bcl2 ratios due to upregulation of Bax and downregulation of Bcl2 proteins. These results indicate that TQ‐induced apoptosis is associated with the activation of caspases 8, 9 and 3, with caspase‐8 acting as an upstream activator. Activated caspase‐8 initiates the release of cytochrome c during TQ‐induced apoptosis. Overall, these results offer a potential mechanism for TQ‐induced apoptosis in p53‐null HL‐60 cancer cells. © 2005 Wiley‐Liss, Inc.
Significance of HDMX‐S (or MDM4) mRNA splice variant overexpression and HDMX gene amplification on primary soft tissue sarcoma prognosis
Authors: Bartel Frank , Schulz Jördis , Böhnke Anja , Blümke Karen , Kappler Matthias , Bache Matthias , Schmidt Hannelore , Würl Peter , Taubert Helge , Hauptmann Steffen 
Published: May 2005

AbstractThe product of the HDMX (or MDM4) gene is structurally related to the MDM2 oncoprotein and is also capable of interacting with the tumor suppressor protein p53. The aim of our study was to determine the amplification status of the HDMX gene and the expression of the HDMX mRNA (particularly that of the HDMX‐S splice variant) in soft‐tissue sarcomas (STS). Patients with STS were evaluated for the status of HDMX gene amplification (n = 66) and HDMX‐S mRNA expression (n = 57) within their tumors. DNA, total RNA and protein were isolated from frozen tumor tissue. We determined that the HDMX‐S splice variant transcript was predominant in a subset (14%) of tumor samples and that its expression was correlated with decreased patient survival (15 vs. 53 months, p < 0.0001, log‐rank test) and with a 17‐fold increased risk of a tumor‐related death (p < 0.0001, multivariate Cox's regression model). The tumors from these patients also expressed elevated levels of HDMX‐S protein. The HDMX gene was amplified in 17% of STSs, and the gene amplification was associated with poor prognosis (RR = 6.5, p < 0.0001). There was no correlation between the HDMX gene amplification and overexpression of the HDMX‐S splice variant. In summary, our data indicate that both the overexpression of the HDMX‐S transcript as well as HDMX gene amplification are important prognostic markers for STS. © 2005 Wiley‐Liss, Inc.