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Mo K Razak Z Rao P Yu Z Adachi H Katsuno M Sobue G Lieberman AP Westwood JT Monks DA 《PloS one》2010,5(9):e12922
Background
Emerging evidence implicates altered gene expression within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disease. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q), a polyQ AR transgenic model (AR97Q), and a transgenic mouse that overexpresses wild type AR solely in skeletal muscle (HSA-AR). HSA-AR mice were included because they substantially reproduce the KD/SBMA phenotype despite the absence of polyQ AR.Methodology/Principal Findings
We performed microarray analysis of lower hindlimb muscles taken from these three models relative to wild type controls using high density oligonucleotide arrays. All microarray comparisons were made with at least 3 animals in each condition, and only those genes having at least 2-fold difference and whose coefficient of variance was less than 100% were considered to be differentially expressed. When considered globally, there was a similar overlap in gene changes between the 3 models: 19% between HSA-AR and AR97Q, 21% between AR97Q and AR113Q, and 17% between HSA-AR and AR113Q, with 8% shared by all models. Several patterns of gene expression relevant to the disease process were observed. Notably, patterns of gene expression typical of loss of AR function were observed in all three models, as were alterations in genes involved in cell adhesion, energy balance, muscle atrophy and myogenesis. We additionally measured changes similar to those observed in skeletal muscle of a mouse model of Huntington''s Disease, and to those common to muscle atrophy from diverse causes.Conclusions/Significance
By comparing patterns of gene expression in three independent models of KD/SBMA, we have been able to identify candidate genes that might mediate the core myogenic features of KD/SBMA. 相似文献3.
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Background
Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism.Methods
Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney.Results
Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation.Conclusion
AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality. 相似文献6.
Background
The association between meat consumption and prostate cancer remains unclear, perhaps reflecting heterogeneity in the types of tumors studied and the method of meat preparation—which can impact the production of carcinogens.Methods
We address both issues in this case-control study focused on aggressive prostate cancer (470 cases and 512 controls), where men reported not only their meat intake but also their meat preparation and doneness level on a semi-quantitative food-frequency questionnaire. Associations between overall and grilled meat consumption, doneness level, ensuing carcinogens and aggressive prostate cancer were assessed using multivariate logistic regression.Results
Higher consumption of any ground beef or processed meats were positively associated with aggressive prostate cancer, with ground beef showing the strongest association (OR = 2.30, 95% CI:1.39–3.81; P-trend = 0.002). This association primarily reflected intake of grilled or barbequed meat, with more well-done meat conferring a higher risk of aggressive prostate cancer. Comparing high and low consumptions of well/very well cooked ground beef to no consumption gave OR''s of 2.04 (95% CI:1.41–2.96) and 1.51 (95% CI:1.06–2.14), respectively. In contrast, consumption of rare/medium cooked ground beef was not associated with aggressive prostate cancer. Looking at meat mutagens produced by cooking at high temperatures, we detected an increased risk with 2-amino-3,8-Dimethylimidazo-[4,5-f]Quinolaxine (MelQx) and 2-amino-3,4,8-trimethylimidazo(4,5-f)qunioxaline (DiMelQx), when comparing the highest to lowest quartiles of intake: OR = 1.69 (95% CI:1.08–2.64;P-trend = 0.02) and OR = 1.53 (95% CI:1.00–2.35; P-trend = 0.005), respectively.Discussion
Higher intake of well-done grilled or barbequed red meat and ensuing carcinogens could increase the risk of aggressive prostate cancer. 相似文献7.
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Watanabe Y Castoro RJ Kim HS North B Oikawa R Hiraishi T Ahmed SS Chung W Cho MY Toyota M Itoh F Estecio MR Shen L Jelinek J Issa JP 《PloS one》2011,6(8):e23320
Background
MLL3 is a histone 3- lysine 4 methyltransferase with tumor-suppressor properties that belongs to a family of chromatin regulator genes potentially altered in neoplasia. Mutations in MLL3 were found in a whole genome analysis of colorectal cancer but have not been confirmed by a separate study.Methods and Results
We analyzed mutations of coding region and promoter methylation in MLL3 using 126 cases of colorectal cancer. We found two isoforms of MLL3 and DNA sequencing revealed frameshift and other mutations affecting both isoforms of MLL3 in colorectal cancer cells and 19 of 134 (14%) primary colorectal samples analyzed. Moreover, frameshift mutations were more common in cases with microsatellite instability (31%) both in CRC cell lines and primary tumors. The largest isoform of MLL3 is transcribed from a CpG island-associated promoter that has highly homology with a pseudo-gene on chromosome 22 (psiTPTE22). Using an assay which measured both loci simultaneously we found prominent age related methylation in normal colon (from 21% in individuals less than 25 years old to 56% in individuals older than 70, R = 0.88, p<0.001) and frequent hypermethylation (83%) in both CRC cell lines and primary tumors. We next studied the two loci separately and found that age and cancer related methylation was solely a property of the pseudogene CpG island and that the MLL3 loci was unmethylated.Conclusions
We found that frameshift mutations of MLL3 in both CRC cells and primary tumor that were more common in cases with microsatellite instability. Moreover, we have shown CpG island-associated promoter of MLL3 gene has no DNA methylation in CRC cells but also primary tumor and normal colon, and this region has a highly homologous of pseudo gene (psiTPTE22) that was age relate DNA methylation. 相似文献9.
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Qin T Castoro R El Ahdab S Jelinek J Wang X Si J Shu J He R Zhang N Chung W Kantarjian HM Issa JP 《PloS one》2011,6(8):e23372
Purpose
The DNA methylation inhibitor 5-aza-2′-deoxycytidine (DAC) is approved for the treatment of myelodysplastic syndromes (MDS), but resistance to DAC develops during treatment and mechanisms of resistance remain unknown. Therefore, we investigated mechanisms of primary and secondary resistance to DAC in MDS.Patients and Methods
We performed Quantitative Real-Time PCR to examine expression of genes related to DAC metabolism prior to therapy in 32 responders and non-responders with MDS as well as 14 patients who achieved a complete remission and subsequently relapsed while on therapy (secondary resistance). We then performed quantitative methylation analyses by bisulfite pyrosequencing of 10 genes as well as Methylated CpG Island Amplification Microarray (MCAM) analysis of global methylation in secondary resistance.Results
Most genes showed no differences by response, but the CDA/DCK ratio was 3 fold higher in non-responders than responders (P<.05), suggesting that this could be a mechanism of primary resistance. There were no significant differences at relapse in DAC metabolism genes, and no DCK mutations were detected. Global methylation measured by the LINE1 assay was lower at relapse than at diagnosis (P<.05). On average, the methylation of 10 genes was lower at relapse (16.1%) compared to diagnosis (18.1%) (P<.05).MCAM analysis showed decreased methylation of an average of 4.5% (range 0.6%–9.7%) of the genes at relapse. By contrast, new cytogenetic changes were found in 20% of patients.Conclusion
Pharmacological mechanisms are involved in primary resistance to DAC, whereas hypomethylation does not prevent a relapse for patients with DAC treatment. 相似文献12.
Background
The aim of this study was to evaluate a possible association between malignancy and anxiety disorders (AD) in Taiwan.Methods
We employed data from the National Health Insurance system of Taiwan. The AD cohort contained 24,066 patients with each patient randomly frequency matched according to age and sex with 4 individuals from the general population without AD. Cox''s proportional hazard regression analysis was conducted to estimate the influence of AD on the risk of cancer.Results
Among patients with AD, the overall risk of developing cancer was only 1% higher than among subjects without AD, and the difference was not significant (hazard ratio [HR] = 1.01, 95% confidence interval [95% CI] = 0.95–1.07). With regard to individual types of cancer, the risk of developing prostate cancer among male patients with AD was significantly higher (HR = 1.32, 95% CI = 1.02–1.71). On the other hand, the risk of cervical cancer among female patients with AD was marginally significantly lower than among female subjects without AD (HR = 0.72, 95% CI = 0.51–1.03).Limitations
One major limitation is the lack of information regarding the life style or behavior of patients in the NHI database, such as smoking and alcohol consumption.Conclusions
Despite the failure to identify a relationship between AD and the overall risk of cancer, we found that Taiwanese patients with AD had a higher risk of developing prostate cancer and a lower risk of developing cervical cancer. 相似文献13.
Major JM Klonoff-Cohen HS Pierce JP Slymen DJ Saltzstein SL Macera CA Mercola D Kattan MW 《PloS one》2011,6(2):e17382
Purpose
Nomograms are tools used in clinical practice to predict cancer outcomes and to help make decisions regarding management of disease. Since its conception, utility of the prostate cancer nomogram has more than tripled. Limited information is available on the relation between the nomograms'' predicted probabilities and obesity. The purpose of this study was to examine whether the predictions from a validated postoperative prostate cancer nomogram were associated with obesity.Methods
We carried out a cross-sectional analysis of 1220 patients who underwent radical prostatectomy (RP) in southern California from 2000 to 2008. Progression-free probabilities (PFPs) were ascertained from the 10-year Kattan postoperative nomogram. Multivariable logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs).Results
In the present study, aggressive prostate cancer (Gleason ≥7), but not advanced stage, was associated with obesity (p = 0.01). After adjusting for age, black race, family history of prostate cancer and current smoking, an inverse association was observed for 10-year progression-free predictions (OR = 0.50; 95% CI = 0.28–0.90) and positive associations were observed for preoperative PSA levels (OR = 1.23; 95% CI = 1.01–1.50) and Gleason >7 (OR = 1.45; 95% CI = 1.11–1.90).Conclusion
Obese RP patients were more likely to have lower PFP values than non-obese patients, suggesting a higher risk of experiencing prostate cancer progression. Identifying men with potentially higher risks due to obesity may improve disease prognosis and treatment decision-making. 相似文献14.
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Chariyalertsak S Kosachunhanan N Saokhieo P Songsupa R Wongthanee A Chariyalertsak C Visarutratana S Beyrer C 《PloS one》2011,6(9):e24295
Background
HIV prevalence among men who have sex with men (MSM) and transgender (TG) persons is high and increasing in Chiang Mai, northern Thailand.Objectives
To describe demographic, socioeconomic, sexual behavior and interest in future HIV prevention trials among gay and bisexual MSM and TG presenting for HIV testing (VCT) and pre-screening for the iPrEx pre-exposure chemoprophylaxis trail.Methods
In 2008–09, MSM/TG participants attending VCT were interviewed and tested for HIV and STI. Univariate and multivariate regression analyses were done to assess associations with HIV infection.Results
A total of 551 MSM clients (56.1% gay, 25.4% TG, and 18.5% bisexual (BS)) were enrolled. The mean age was 23.9 years. HIV prevalence among MSM overall was 12.9% (71/551); 16.5% among gay men, 9.3% among TG, and 6.9% among BS. Consistent use of condom was low, 33.3% in insertive anal sex and 31.9% in receptive anal sex. Interest in participation was high, 86.3% for PrEP, 69.7% for HIV vaccine trials, but 29.9% for circumcision. HIV was independently associated with being gay identified, aOR 2.8, p = 0.037 and with being aged 25–29, aOR 2.7, p = 0.027. Among repeat testers, HIV incidence was 8.2/100 PY, 95% CI, 3.7/100PY to 18.3/100PY.Conclusion
HIV risks and rates varied by self-reported sexual orientation and gender identity. HIV was associated with sexual practices, age, and being gay-identified. These are populations are in need of novel prevention strategies and willing to participate in prevention research. 相似文献16.
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Nankabirwa J Cundill B Clarke S Kabatereine N Rosenthal PJ Dorsey G Brooker S Staedke SG 《PloS one》2010,5(10):e13438