Defects in death-inducing signalling complex formation prevent JNK activation and Fas-mediated apoptosis in DU 145 prostate carcinoma cells

Androgen-independent prostate carcinomas are resistant to chemotherapy and cell lines derived from androgen-independent prostate carcinomas such as DU 145 cells are highly resistant to Fas-mediated apoptosis. The incubation of DU 145 cells with anti-Fas IgM agonistic antibody of Fas receptor fails to activate JNK, a stress kinase involved in regulating apoptosis. We have previously shown that JNK activation is sufficient and necessary to promote Fas-mediated apoptosis in DU 145 cells. We investigate the mechanisms by which JNK activation and apoptosis are abrogated. HSP27 is overexpressed in DU 145 cells and has previously been reported to sequester DAXX and prevent JNK activation in cells treated with anti-Fas IgM. However, we find no evidence that HSP27 interacts with DAXX in DU 145 cells. Instead, we find that FADD does not interact with caspase-8 and this results in defective death-inducing signalling complex formation following Fas receptor activation

Determinants of participation in a web-based health risk assessment and consequences for health promotion programs

Background: The health risk assessment (HRA) is a type of health promotion program frequently offered at the workplace. Insight into the underlying determinants of participation is needed to evaluate and implement these interventions. Objective: To analyze whether individual characteristics including demographics, health behavior, self-rated health, and work-related factors are associated with participation and nonparticipation in a Web-based HRA. Methods: Determinants of participation and nonparticipation were investigated in a cross-sectional study among individuals employed at five Dutch organizations. Multivariate logistic regression was performed to identify determinants of participation and nonparticipation in the HRA after controlling for organization and all other variables. Results: Of the 8431 employees who were invited, 31.9% (2686/8431) enrolled in the HRA. The online questionnaire was completed by 27.2% (1564/5745) of the nonparticipants. Determinants of participation were some periods of stress at home or work in the preceding year (OR 1.62, 95% CI 1.08-2.42), a decreasing number of weekdays on which at least 30 minutes were spent on moderate to vigorous physical activity (ORdayPA0.84, 95% CI 0.79-0.90), and increasing alcohol consumption. Determinants of nonparticipation were less-than-positive self-rated health (poor/very poor vs very good, OR 0.25, 95% CI 0.08-0.81) and tobacco use (at least weekly vs none, OR 0.65, 95% CI 0.46-0.90). Conclusions: This study showed that with regard to isolated health behaviors (insufficient physical activity, excess alcohol consumption, and stress), those who could benefit most from the HRA were more likely to participate. However, tobacco users and those who rate

cDNA sequencing improves the detection of P53 missense mutations in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Recently published data showed discrepancies beteween <it>P53 </it>cDNA and DNA sequencing in glioblastomas. We hypothesised that similar discrepancies may be observed in other human cancers.</p> <p>Methods</p> <p>To this end, we analyzed 23 colorectal cancers for <it>P53 </it>mutations and gene expression using both DNA and cDNA sequencing, real-time PCR and immunohistochemistry.</p> <p>Results</p> <p>We found <it>P53 </it>gene mutations in 16 cases (15 missense and 1 nonsense). Two of the 15 cases with missense mutations showed alterations based only on cDNA, and not DNA sequencing. Moreover, in 6 of the 15 cases with a cDNA mutation those mutations were difficult to detect in the DNA sequencing, so the results of DNA analysis alone could be misinterpreted if the cDNA sequencing results had not also been available. In all those 15 cases, we observed a higher ratio of the mutated to the wild type template by cDNA analysis, but not by the DNA analysis. Interestingly, a similar overexpression of <it>P53 </it>mRNA was present in samples with and without <it>P53 </it>mutations.</p> <p>Conclusion</p> <p>In terms of colorectal cancer, those discrepancies might be explained under three conditions: 1, overexpression of mutated <it>P53 </it>mRNA in cancer cells as compared with normal cells; 2, a higher content of cells without <it>P53 </it>mutation (normal cells and cells showing <it>K-RAS </it>and/or <it>APC </it>but not <it>P53 </it>mutation) in samples presenting <it>P53 </it>mutation; 3, heterozygous or hemizygous mutations of <it>P53 </it>gene. Additionally, for heterozygous mutations unknown mechanism(s) causing selective overproduction of mutated allele should also be considered. Our data offer new clues for studying discrepancy in <it>P53 </it>cDNA and DNA sequencing analysis.</p

Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra®, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome

<p>Abstract</p> <p>Background</p> <p>Ezatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m²) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m²IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle.</p> <p>Results</p> <p>54 patients with histologically confirmed MDS were enrolled. The most common adverse events were grade 1 or 2, respectively, chills (11%, 9%), back pain (15%, 2%), flushing (19%, 0%), nausea (15%, 0%), bone pain (6%, 6%), fatigue (0%, 13%), extremity pain (7%, 4%), dyspnea (9%, 4%), and diarrhea (7%, 4%) related to acute infusional hypersensitivity reactions. The concentration of the primary active metabolites increased proportionate to ezatiostat dosage. Trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. Hematologic Improvement-Erythroid (HI-E) was observed in 9 of 38 patients (24%), HI-Neutrophil in 11 of 26 patients (42%) and HI-Platelet in 12 of 24 patients (50%). These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements. Improvement in bone marrow maturation and cellularity was also observed.</p> <p>Conclusion</p> <p>Phase 2 studies of ezatiostat hydrochloride liposomes for injection in MDS are supported by the tolerability and HI responses observed. An oral formulation of ezatiostat hydrochloride tablets is also in phase 2 clinical development.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov: NCT00035867</p

The 2003 Australian Breast Health Survey: survey design and preliminary results

<p>Abstract</p> <p>Background</p> <p>The Breast Health Surveys, conducted by the National Breast Cancer Centre (NBCC) in 1996 and 2003, are designed to gain insight into the knowledge, attitudes and behaviours of a nationally representative sample of Australian women on issues relevant to breast cancer. In this article, we focus on major aspects of the design and present results on respondents' knowledge about mammographic screening.</p> <p>Methods</p> <p>The 2003 BHS surveyed English-speaking Australian women aged 30–69 without a history of breast cancer using computer-assisted telephone interviewing. Questions covered the following themes: knowledge and perceptions about incidence, mortality and risk; knowledge and behaviour regarding early detection, symptoms and diagnosis; mammographic screening; treatment; and accessibility and availability of information and services. Respondents were selected using a complex sample design involving stratification. Sample weights against Australian population benchmarks were used in all statistical analyses. Means and proportions for the entire population and by age group and area of residence were calculated. Statistical tests were conducted using a level of significance of 0.01.</p> <p>Results</p> <p>Of the 3,144 respondents who consented to being interviewed, 138 (4.4%) had a previous diagnosis of breast cancer and were excluded leaving 3,006 completed interviews eligible for analysis. A majority of respondents (61.1%) reported ever having had a mammogram and 29.1% identified mammography as being the best way of finding breast cancer. A majority of women (85.9%) had heard of the BreastScreen Australia (BSA) program, the national mammographic screening program providing free biennial screening mammograms, with 94.5% believing that BSA attendance was available regardless of the presence or absence of symptoms. There have been substantial gains in women's knowledge about mammographic screening over the seven years between the two surveys.</p> <p>Conclusion</p> <p>The NBCC Breast Health Surveys provide a valuable picture of the knowledge of Australian women about a range of issues. The present analysis shows significant gains in knowledge and behaviours relating to mammographic screening, while identifying additional areas for targeted improvement, as in the need to better communicate with women about screening and diagnostic services. Further analysis of additional core topic areas (eg., incidence, mortality, risk and treatment) will provide equally noteworthy insight.</p

Efficacy of c-Met inhibitor for advanced prostate cancer

<p>Abstract</p> <p>Background</p> <p>Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer.</p> <p>Methods</p> <p>We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression.</p> <p>Results</p> <p>We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration.</p> <p>Conclusions</p> <p>The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer.</p

B Vitamins, Methionine and Alcohol Intake and Risk of Colon Cancer in Relation to BRAF Mutation and CpG Island Methylator Phenotype (CIMP)

One-carbon metabolism appears to play an important role in DNA methylation reaction. Evidence suggests that a low intake of B vitamins or high alcohol consumption increases colorectal cancer risk. How one-carbon nutrients affect the CpG island methylator phenotype (CIMP) or BRAF mutation status in colon cancer remains uncertain.Utilizing incident colon cancers in a large prospective cohort of women (the Nurses' Health Study), we determined BRAF status (N = 386) and CIMP status (N = 375) by 8 CIMP-specific markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT-1, MINT-31, p14, and WRN). We examined the relationship between intake of one-carbon nutrients and alcohol and colon cancer risk, by BRAF mutation or CIMP status.Higher folate intake was associated with a trend towards low risk of CIMP-low/0 tumors [total folate intake ≥400 µg/day vs. <200 µg/day; the multivariate relative risk = 0.73; 95% CI = 0.53-1.02], whereas total folate intake had no influence on CIMP-high tumor risks (P(heterogeneity) = 0.73). Neither vitamin B(6), methionine or alcohol intake appeared to differentially influence risks for CIMP-high and CIMP-low/0 tumors. Using the 16-marker CIMP panel did not substantially alter our results. B vitamins, methionine or alcohol intake did not affect colon cancer risk differentially by BRAF status.This molecular pathological epidemiology study suggests that low level intake of folate may be associated with an increased risk of CIMP-low/0 colon tumors, but not that of CIMP-high tumors. However, the difference between CIMP-high and CIMP-low/0 cancer risks was not statistically significant, and additional studies are necessary to confirm these observations

Association between an 8q24 locus and the risk of colorectal cancer in Japanese

<p>Abstract</p> <p>Background</p> <p>A genome-wide association study (GWAS), which assessed multiple ethnicities, reported an association between single nucleotide polymorphisms in the 8q24 region and colorectal cancer risk. Although the association with the identified loci was strong, information on its impact in combination with lifestyle factors is limited.</p> <p>Methods</p> <p>We conducted a case-control study in 481 patients with colorectal cancer (CRC) and 962 sex-age matched non-cancer controls. Data on lifestyle factors, including diet, were obtained by self-administered questionnaire. Two 8q24 loci, rs6983267 and rs10090154, were assessed by the TaqMan method. Associations were then assessed by multivariate logistic regression models that considered potential confounders.</p> <p>Results</p> <p>We found an increased risk of CRC with rs6983267 but not with rs10090154. An allelic OR was 1.22 (1.04-1.44, p for trend = 0.014), which remained significant after adjustment for confounders (OR = 1.25). No statistically significant interaction with potential confounding factors was observed.</p> <p>Conclusion</p> <p>The polymorphism rs6983267 showed a significant association with CRC in a Japanese population. Further investigation of the biological mechanism of this association is warranted.</p