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(2007)Journal ArticleBiallelic promoter methylation and transcriptional silencing of the MLH1 gene occurs in the majority of sporadic colorectal cancers exhibiting microsatellite instability due to defective DNA mismatch repair. Long-range epigenetic silencing of contiguous genes has been found on chromosome 2q14 in colorectal cancer. We hypothesized that epigenetic silencing of MLH1 could occur on a regional scale affecting additional genes within 3p22, rather than as a focal event. We studied the levels of CpG island methylation and expression of multiple contiguous genes across a 4 Mb segment of 3p22 including MLH1 in microsatellite-unstable and -stable cancers, and their paired normal colonic mucosa. We found concordant CpG island hypermethylation, H3-K9 dimethylation and transcriptional silencing of MLH1 and multiple flanking genes spanning up to 2.4 Mb in microsatellite-unstable colorectal cancers. This region was interspersed with unmethylated genes, which were also transcriptionally repressed. Expression of both methylated and unmethylated genes was reactivated by methyltransferase and histone deacetylase inhibitors in a microsatellite-unstable colorectal carcinoma cell line. Two genes at the telomeric end of the region were also hypermethylated in microsatellite-stable cancers, adenomas, and at low levels in normal colonic mucosa from older individuals. Thus, the cluster of genes flanking MLH1 that was specifically methylated in the microsatellite-unstable group of cancers extended across 1.1 Mb. Our results show that coordinate epigenetic silencing extends across a large chromosomal region encompassing MLH1 in microsatellite-unstable colorectal cancers. Simultaneous epigenetic silencing of this cluster of 3p22 genes may contribute to the development or progression of this type of cancer.
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(2013)Journal ArticleActivated pancreatic stellate cells (PSCs) are responsible for the fibrotic matrix of chronic pancreatitis and pancreatic cancer. In vitro protocols examining PSC biology have usually involved PSCs cultured on plastic, a non-physiological surface. However, PSCs cultured on physiological matrices e.g. MatrigelTM (normal basement membrane) and collagen (fibrotic pancreas), may have distinctly different behaviours compared to cells cultured on plastic. Therefore, we aimed to i) compare PSC gene expression after culture on plastic, MatrigelTM and collagen I; ii) validate the gene array data for transgelin, the most highly dysregulated gene in PSCs grown on activating versus non-activating matrices, at mRNA and protein levels; iii) examine the role of transgelin in PSC function; and iv) assess transgelin expression in human chronic pancreatitis sections. Culture of PSCs on different matrices significantly affected their gene expression pattern. 146, 619 and 432 genes respectively were differentially expressed (p < 0.001) in PSCs cultured on collagen I vs MatrigelTM, MatrigelTM vs plastic and collagen I vs plastic. The highest fold change (12.5 fold upregulation) in gene expression in cells on collagen I vs MatrigelTM, was observed for transgelin (an actin stress fibre associated protein). Transgelin was significantly increased in activated PSCs versus quiescent PSCs. Silencing transgelin expression decreased PSC proliferation and also reduced platelet derived growth factor (PDGF)-induced PSC migration. Notably, transgelin was highly expressed in chronic pancreatitis in stromal areas and peri-acinar spaces but was absent in acinar cells. These findings suggest that transgelin is a potentially useful target protein to modulate PSC function so as to ameliorate pancreatic fibrosis.
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(2011)Journal ArticleObjective Three decades into the HIV epidemic and with the advancement of HIV treatments, condom and non-condom-based anal intercourse among gay men in resource-rich countries needs to be re-assessed. Methods The proportions of men engaging in a range of anal intercourse practices were estimated from the ongoing cross-sectional Gay Community Periodic Surveys in six states in Australia from 2007 to 2009. Comparisons were made between HIV-negative men, HIV-positive men with an undetectable viral load and those with a detectable viral load. Results Condoms play a key role in gay men's anal intercourse practices: 33.8% of HIV-negative men, 25.1% of HIV-positive men with an undetectable viral load and 22.5% of those with a detectable viral load reported consistent condom use with all male partners in the 6 months before the survey. Among HIV-negative men, the second largest group were men who had unprotected anal intercourse (UAI) only in the context of HIV-negative seroconcordant regular relationships. Among HIV-positive men, the second largest group was men who had UAI in casual encounters preceded by HIV status disclosure to some, but not all, casual partners. Conclusions A minority, yet sizeable proportion, of men consistently engaged in a number of UAI practices in specific contexts, suggesting they have adopted deliberate HIV risk-reduction strategies. While it is important that HIV behavioural prevention continues to reinforce condom use, it needs to address both the challenges and opportunities of the substantial uptake of non-condom-based risk-reduction strategies.
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(2007)Journal ArticleThe metabolic response to two different forms of high intensity intermittent cycle exercise was investigated in young females. Subjects (8 trained and 8 untrained) performed two bouts of high intensity intermittent exercise: short sprint (SS) (8 s sprint, 12 s recovery) and long sprint (LS) (24 s sprint, 36 s recovery) for 20 min on two separate occasions. Both workload and oxygen uptake were greater in the trained subjects but were not significantly different for SS and LS. Plasma glycerol concentrations increased during exercise but peaked earlier for the trained women. Lactate concentrations rose over the 20 min and were higher for the trained women. Catecholamine concentration was also higher postexercise when compared to pre-exercise for both groups. Both SS and LS produced similar metabolic response although both lactate and catecholamines were higher after the 24 s sprint. In conclusion, these results show that high intensity intermittent exercise resulted in significant elevations in catecholamines that appear to be related to increased venous glycerol concentrations. Trained compared to the untrained women tended to show increased plasma glycerol concentrations, earlier during high intensity exercise. Keywords: intermittent exercise, fat oxidation, RER, catecholamines
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(2008)Journal ArticleAbstract OBJECTIVE: to determine the effects of a 15-week high intensity intermittent exercise (HIIE) program on subcutaneous and trunk fat and insulin resistance of young women. DESIGN AND PROCEDURES: subjects were randomly assigned to one of three groups: HIIE (n = 15), steady state exercise (SSE; n=15), or control (CONT; n=15). HIIE and SSE groups underwent a 15-week exercise intervention. SUBJECTS: forty-five women with a mean BMI of 23.2 + 2.0 kg/m2 and age of 20.2 + 2.0 years. RESULTS: both exercise groups demonstrated a significant improvement, P < 0.05, in cardiovascular fitness. However, only the HIIE group had a significant reduction in total body mass (TBM), fat mass (FM), trunk fat, and fasting plasma insulin levels. There was significant fat loss, P < 0.05, in legs compared to arms in the HIIE group only. Lean compared to overweight women lost less fat after HIIE. Decreases in leptin concentrations were negatively correlated with increases in (r = -.57, P < 0.05) and positively correlated with decreases in TBM (r = .47; P < 0.0001). There was no significant change in adiponectin levels after training. CONCLUSIONS: HIIE three times per week for 15 weeks compared to the same frequency of SSE exercise was associated with significant reductions in total body fat, subcutaneous leg and trunk fat, and insulin resistance in young women. Keywords: intermittent sprinting, body fat, insulin
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(2000)Journal ArticleThe route of estrogen replacement therapy has a major impact on the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis. Estrogen administration by the oral, but not the transdermal, route reduces IGF-I and increases GH levels in postmenopausal women. This perturbation of the GH-IGF-I axis occurs with different forms of estrogen treatment, indicating that the dissociation of the somatotropic axis and concomitant increase in GH-binding protein levels are intrinsic effects of the oral route of estrogen administration. In clinical studies, oral estrogen reduced postprandial lipid oxidation, compared with transdermal estrogen. Oral estrogen was also associated with a reduction in lean body mass and an increase in fat mass, compared with transdermal estrogen. In contrast, the route of estrogen therapy had no impact on carbohydrate metabolism or the estrogen-induced increase in bone mineral density. The findings of route-dependent changes in body composition add a new dimension to health considerations concerning estrogen therapy in postmenopausal women and may have significant implications for estrogen replacement therapy in young hypogonadal females.
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(2013)Journal ArticleBackground: ATP13A2 (PARK9) loss of function mutations are a genetic cause of an early-onset form of Parkinson’s disease (PD), with in vitro studies showing that ATP13A2 deficits lead to lysosomal and mitochondrial dysfunction and α-synuclein accumulation, while elevated ATP13A2 expression reduces α-synuclein toxicity. The three human brain tissue studies assessing changes in ATP13A2 expression in PD produced divergent results; mRNA is increased while protein levels were observed to be either increased or decreased. This apparent conflict in protein levels might have arisen from examining Lewy body disease cases with coexisting Alzheimer-type pathologies. To assess whether ATP13A2 levels in Lewy body disease are modified by Alzheimer-type β-amyloid deposition, we evaluated cases of pure PD and pure dementia with Lewy bodies (DLB) for changes in ATP13A2, α-synuclein and β-amyloid protein levels in cortical regions with and without Lewy bodies. Results: In all Lewy body disease cases, we identified decreased ATP13A2 protein levels that correlated with increases in both α-synuclein and β-amyloid. Partial colocalization was observed between ATP13A2 and α-synuclein in Lewy bodies, whereas ATP13A2 did not colocalize with pathological β-amyloid deposition. Conclusions: Our data show that patients with Lewy body diseases have an overall deficit in ATP13A2 protein levels, with the remaining protein being more insoluble and partially redistributing towards Lewy bodies. This supports the concept that increasing ATP13A2 levels may offer potential therapeutic benefits to patients with Lewy body diseases.
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(1995)Journal ArticleShort term GH administration increases lipid breakdown and oxidation (lipidox) and reduces glucose uptake and carbohydrate oxidation (CHOox). It is not clear whether similar shifts in substrate oxidation occur in acromegaly, and our aim was to investigate this. Using indirect calorimetry, we compared energy expenditure, CHOox, and lipidox in 20 acromegalic patients and 20 normal subjects pair-matched for sex, age, height, and weight. Investigations were performed in the basal state (12-h fast) and during a 75-g oral glucose tolerance test (OGTT). Acromegalic patients had significantly higher fasting glucose levels and greater glucose and insulin responses during an OGTT than normal subjects. Fasting nonesterified free fatty acid and insulin-like growth factor (IGF)-binding protein-1 levels were similar in the two groups, and both were acutely suppressed by oral glucose to the same degree. Basal energy expenditure was significantly greater in the acromegalic patients (1682 +/- 49 vs. 1540 +/- 45 Cal/24 h; P < 0.05), who showed a trend toward higher basal CHOox. Oral glucose resulted in a significantly higher rise in energy expenditure in the normal compared to the acromegalic subjects. During the OGTT, CHOox significantly increased in both groups, but rose to a higher level in the acromegalic patients (177 +/- 10 vs. 138 +/- 9 mg/min; P = 0.004). Oral glucose significantly reduced lipidox in both groups, but lipidox was reduced to a significantly lower level in the acromegalic patients (32 +/- 4 vs. 46 +/- 3 mg/min; P = 0.004). In acromegaly, basal CHOox (r = 0.56; P = 0.01) and postglucose CHOox (r = 0.79; P = 0.0001) were both positively correlated to IGF-I, but not to insulin and/or glucose. In normal subjects, postglucose CHOox was positively correlated to IGF- I. In summary, hyperinsulinemia in acromegaly was associated with higher glucose levels and a blunted thermogenic response to glucose, and displayed no relationship to the pattern of substrate oxidation. CHOox was increased, and lipidox was reduced in acromegaly, and the extent of IGF-I elevation was related to CHOox in the basal and postglucose states. We conclude that 1) the chronic effects of GH excess on substrate oxidation differ from the short term effects of GH administration; 2) impaired insulin action in acromegaly extends to effects on energy expenditure; and 3) IGF-I may be an important regulator of substrate oxidation in acromegaly.