Activated androgen receptor binds to androgen-responsive elements (AREs) in genome to regulate target gene transcription and, consequently, mediates physiological or tumorigenic processes of the ...prostate. Our aim was to determine whether genetic variants in AREs are associated with clinical outcomes after androgen-deprivation therapy (ADT) in prostate cancer patients.
We systematically investigated 55 common single-nucleotide polymorphisms (SNPs) in the genome-wide insilico-predicted AREs in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT was assessed by Kaplan–Meier analysis and Cox regression model.
In univariate analysis, two, five, and four SNPs were associated with disease progression, PCSM, and ACM, respectively. After adjusting for known prognostic factors, ARRDC3 rs2939244, FLT1 rs9508016, and SKAP1 rs6504145 remained as significant predictors for PCSM and FBXO32 rs7830622 and FLT1 rs9508016 remained as significant predictors for ACM in multivariate analysis. Moreover, strong combined genotype effects on PCSM and ACM were also observed (Ptrend < 0.001).
Our results suggest that SNPs in AREs influence prostate cancer survival and may further advance our understanding of the disease progression.
. Huang C‐N, Huang S‐P, Pao J‐B, Hour T‐C, Chang T‐Y, Lan Y‐H, Lu T‐L, Lee H‐Z, Juang S‐H, Wu P‐P, Huang C‐Y, Hsieh C‐J, Bao B‐Y (Kaohsiung Medical University Hospital, Kaohsiung; Kaohsiung Medical ...University, Kaohsiung; Taipei City Hospital, Taipei; Kaohsiung Medical University, Kaohsiung; China Medical University, Taichung; National Taiwan University Hospital; Oriental Institute of Technology; National Taiwan University, Taipei; China Medical University Hospital, Taichung, Taiwan). Genetic polymorphisms in oestrogen receptor‐binding sites affect clinical outcomes in patients with prostate cancer receiving androgen‐deprivation therapy. J Intern Med 2012; 271: 499–509.
Background. Accumulating evidence indicates that oestrogens have significant direct effects on normal prostate development and carcinogenesis. The majority of the biological activities of oestrogens are mediated through the oestrogen receptor (ER), which functions as a hormone‐inducible transcription factor to regulate target gene expression by binding to oestrogen response elements (EREs) in the regulatory regions of target genes. Sequence variants in EREs might affect the ER–ERE interaction and subsequent physiological activities. Therefore, we tested whether common single‐nucleotide polymorphisms (SNPs) inside EREs are related to the clinical outcomes of androgen‐deprivation therapy (ADT) in men with prostate cancer.
Methods. We systematically evaluated 49 ERE SNPs predicted using a genome‐wide database in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer‐specific mortality (PCSM) and all‐cause mortality (ACM) after ADT was assessed using Kaplan–Meier analysis and a Cox regression model.
Results. Based on multiple hypothesis testing, BNC2 rs16934641 was found to be associated with disease progression; in addition, TACC2 rs3763763 was associated with PCSM, and ALPK1 rs2051778 and TACC2 rs3763763 were associated with ACM. These SNPs remained significant in multivariate analyses that included known clinicopathological predictors. Moreover, a combined genotype effect on ACM was observed when ALPK1 rs2051778 and TACC2 rs3763763 were analysed in combination. Patients with a greater number of unfavourable genotypes had a shorter time to ACM during ADT (P for trend <0.001).
Conclusion. The incorporation of ERE SNPs into models with known predictors might improve outcome prediction in patients with prostate cancer receiving ADT.
Friction stir welds in Al 5456 were analyzed to determine their microstructure, mechanical properties, and corrosion behavior as a function of position across the transverse cross-section of the ...weld. The microstructural evolution that occurred in each weld-affected region was correlated to the properties of those regions to determine the microstructural basis for the observed tensile, fatigue, and corrosion properties. In particular, the effects of weld-induced deformation recovery (both in terms of reduced dislocation density and its implications on solute content and precipitation), grain growth, and precipitate evolutions will be discussed.
ObjectiveTo examine the association between serum concentrations of total cholesterol, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol, triglycerides, apolipoprotein ...A-I (apoA), apolipoprotein B and the incidence of colorectal cancer (CRC).DesignNested case–control study.SettingThe study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), a cohort of more than 520 000 participants from 10 western European countries.Participants1238 cases of incident CRC, which developed after enrolment into the cohort, were matched with 1238 controls for age, sex, centre, follow-up time, time of blood collection and fasting status.Main outcome measuresSerum concentrations were quantitatively determined by colorimetric and turbidimetric methods. Dietary and lifestyle data were obtained from questionnaires. Conditional logistic regression models were used to estimate incidence rate ratios (RRs) and 95% CIs which were adjusted for height, weight, smoking habits, physical activity, education, consumption of fruit, vegetables, meat, fish, alcohol, fibre and energy.ResultsAfter adjustments, the concentrations of HDL and apoA were inversely associated with the risk of colon cancer (RR for 1 SD increase of 16.6 mg/dl in HDL and 32.0 mg/dl in apoA of 0.78 (95% CI 0.68 to 0.89) and 0.82 (95% CI 0.72 to 0.94), respectively). No association was observed with the risk of rectal cancer. Additional adjustment for biomarkers of systemic inflammation, insulin resistance and oxidative stress or exclusion of the first 2 years of follow-up did not influence the association between HDL and risk of colon cancer.ConclusionsThese findings show that high concentrations of serum HDL are associated with a decreased risk of colon cancer. The mechanism behind this association needs further elucidation.
The Syk cytoplasmic protein-tyrosine kinase has two amino-terminal SH2 domains and a carboxy-terminal catalytic domain. Syk, and its close relative ZAP-70, are apparently pivotal in coupling antigen- ...and Fc-receptors to downstream signalling events. Syk associates with activated Fc receptors, the T cell receptor complex and the B-cell antigen-receptor complex (BCR) in immature and mature B lymphocytes. On receptor activation, the tandem SH2 domains of Syk bind dual phosphotyrosine sites in the conserved ITAM motifs of receptor signalling chains, such as the immunoglobulin alpha and beta-chains of the BCR, leading to Syk activation. Here we have investigated Syk function in vivo by generating a mouse strain with a targeted mutation in the syk gene. Homozygous syk mutants suffered severe haemorrhaging as embryos and died perinatally, indicating that Syk has a critical role in maintaining vascular integrity or in wound healing during embryogenesis. Analysis of syk-/- lymphoid cells showed that the syk mutation impaired the differentiation of B-lineage cells, apparently by disrupting signalling from the pre-BCR complex and thereby preventing the clonal expansion, and further maturation, of pre-B cells.
Dietary energy density (ED) reductions are associated with energy intake (EI) reductions. Little is known about influences on body weight (BW).
We examined the effects of behavioral interventions on ...ED values and explored how 6-mo ED changes relate to BW.
Prehypertensive and hypertensive persons were randomly assigned to 1 of 3 groups: the established group received an 18-session intervention implementing well-established hypertension recommendations (eg, weight loss, sodium reduction, and physical activity), the established+Dietary Approaches to Stop Hypertension (DASH) group received an 18-session intervention also implementing the DASH diet, and the advice group received 1 session on these topics. Two 24-h dietary recalls were collected (n=658).
Each group had significant declines in EI, ED, and BW. The established and established+DASH groups had the greatest EI and BW reductions. The established+DASH group had the greatest ED reduction and the greatest increase in the weight of food consumed. When groups were combined and analyzed by ED change tertiles, participants in the highest tertile (ie, largest ED reduction) lost more weight (5.9 kg) than did those in the middle (4.0 kg) or lowest (2.4 kg) tertile. Participants in the highest and middle tertiles increased the weight of food they consumed (300 and 80 g/d, respectively) but decreased their EI (500 and 250 kcal/d). Conversely, those in the lowest tertile decreased the weight of food consumed (100 g/d), with little change in EI. The highest and middle tertiles had favorable changes in fruit, vegetable, vitamin, and mineral intakes.
Both large and modest ED reductions were associated with weight loss and improved diet quality.
Cold water extract of P. citrinopileatus (CWEPC) was fractioned into 4 fractions, PC‐I (<1 kDa), PC‐II (1‐3.5 kDa), PC‐III (3.5‐10 kDa), and PC‐IV (>10 kDa), by ultrafiltration. The antioxidant ...activities, the inhibition of pancreatic α‐amylase, intestinal α‐glucosidase, and hypertension‐linked angiotensin converting enzyme (ACE), as well as the contents of polysaccharides, protein, and phenolic compounds of 4 fractions were determined. The results showed that lower MW fractions exerted a higher antioxidant activity, which was correlated to phenolic contents. The high molecular fraction (PC‐IV) exhibited significantly higher inhibitory activity on α‐amylase, α‐glucosidase, and ACE compared to CWEPC and the other 3 lower MW fractions (<10 kDa), which was more related to protein contents. The inhibition capability of CWEPC and PC‐IV on α‐amylase activity was 1/13.4 to 1/2.7 relative to that of acarbose, respectively. Kinetic data revealed that PC‐IV fraction followed a noncompetitive inhibition pattern on α‐glucosidase activity. The study demonstrated that various MW fractions and types of components contribute to different biological functions of P. citrinopileatus and it is protein constituents but not peptides responsible for the hypoglycemic potential of CWEPC.
Results from previous studies investigating the association between fluid intake and urothelial cell carcinomas (UCC) are inconsistent. We evaluated this association among 233,236 subjects in the ...European Prospective Investigation into Cancer and Nutrition (EPIC), who had adequate baseline information on water and total fluid intake. During a mean follow‐up of 9.3 years, 513 first primary UCC occurred. At recruitment, habitual fluid intake was assessed by a food frequency questionnaire. Multivariable hazard ratios were estimated using Cox regression stratified by age, sex and center and adjusted for energy intake, smoking status, duration of smoking and lifetime intensity of smoking. When using the lowest tertile of intake as reference, total fluid intake was not associated with risk of all UCC (HR 1.12; 95%CI 0.86–1.45, p‐trend = 0.42) or with risk of prognostically high‐risk UCC (HR 1.28; 95%CI 0.85–1.93, p‐trend = 0.27) or prognostically low‐risk UCC (HR 0.93; 95%CI 0.65–1.33, p‐trend = 0.74). No associations were observed between risk of UCC and intake of water, coffee, tea and herbal tea and milk and other dairy beverages. For prognostically low‐risk UCC suggestions of an inverse association with alcoholic beverages and of a positive association with soft drinks were seen. Increased risks were found for all UCC and prognostically low‐risk UCC with higher intake of fruit and vegetable juices. In conclusion, total usual fluid intake is not associated with UCC risk in EPIC. The relationships observed for some fluids may be due to chance, but further investigation of the role of all types of fluid is warranted.
We show that a functional component of the
C. elegans mitotic machinery regulates X chromosome gene expression. This protein, MIX-1, is a member of the dosage compensation complex that associates ...specifically with hermaphrodite X chromosomes to reduce their gene expression during interphase. MIX-1 also associates with all mitotic chromosomes to ensure their proper segregation. Both dosage compensation and mitosis are severely disrupted by
mix-1 mutations. MIX-1 belongs to the SMC protein family required for mitotic chromosome condensation and segregation in yeast and frogs. Thus, an essential, conserved component of mitotic chromosomes has been recruited to the dosage compensation process. Rather than dosage compensation and mitosis being achieved by two separate sets of related genes, these two processes share an identical component, indicating a common mechanism for establishing higher order chromosome structure and proper X chromosome gene expression.
Electronic waste (E-waste), including all obsolete electronic products, has become the fastest growing component in the solid waste stream. Personal computers (PCs)—the most significant component in ...E-waste stream—were studied for their potential leaching toxicity of contaminants. All the components in a PC that are composed of, or contain printed wire boards (PWBs) including the motherboard, various expansion cards, disk drives, and power supply unit were tested by the toxicity characteristic leaching procedure (TCLP). The total contents of eight heavy metals including arsenic, barium, cadmium, chromium, lead, mercury, selenium, and silver in the PWBs and their TCLP leaching from the PWBs were examined. Among these eight heavy metals lead was found to be the predominant element that causes the toxicity characteristic of the PC components. The lead concentrations in the TCLP extracts of the vast majority of the PWBs ranged from 150 to
500
mg∕L
, which are 30–100 times the regulatory level of
5
mg∕L
for classifying a waste as hazardous. The motherboard in a PC contributed 50–80% of the total lead that could leach out from all the PWBs in the PC under the TCLP test conditions. The contents of barium and silver were found to be high in some components, but they were not leachable under the TCLP test conditions. The contents of other five elements in all the PC components were hardly detectable. They would not have the potential to cause toxicity characteristic leaching concern.
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