Telomerase activity : detection and clinical implications in human cancer

Telomerase is an extremely important enzyme required for the immortalisation of tumour cells. Because the gene is activated in the vast majority of tumour tissues and remains unused in most somatic cells, it represents a marker with huge diagnostic, prognostic and treatment implications in cancer. This article summarises the basic structure and functions of telomerase and considers its clinical implications in colorectal and other cancers.

Quantitative analysis of survivin in colorectal adenocarcinoma : increased expression and correlation with telomerase activity

The aims of the present study are to quantitatively analyze survivin expression, its clinicopathologic roles, and correlation with telomerase activity in a large cohort of patients with colorectal adenocarcinoma. Real-time polymerase chain reaction was used to quantitate expression level of survivin messenger RNA and human telomerase reverse transcriptase messenger RNA (telomerase activity) in 51 patients with colorectal adenocarcinomas. The findings were correlated with the clinicopathologic features of patients, which were prospectively collected into a computerized database. Survivin messenger RNA was expressed in all tumor samples. The level of expression in tumor tissues was increased in comparison with matched nontumor mucosa in the same patient (P = .01). The level of expression of survivin was significantly correlated with the level of human telomerase reverse transcriptase expression (P = .008) and size of the colorectal adenocarcinomas (P = .004). Survival of the patients with colorectal adenocarcinoma was associated with the TNM stages (P = .001) and not with the level of expression of survivin. Thus, survivin activity was altered in colorectal adenocarcinoma. The high prevalence of survivin expression and correlation with telomerase activity are important factors for consideration in gene targeting therapy for colorectal adenocarcinoma.

The benefits and challenges of conducting an overview of systematic reviews in public health: a focus on physical activity

Introduction The ultimate aim of Cochrane systematic reviews is to inform policy and practice decisions for better health outcomes. However, due to the increasing numbers of scientific publications, wading through the available evidence of both individual studies and systematic reviews can be challenging and overwhelming even for avid authors and readers. This paper briefly describes the first overview (a systematic review of reviews) of the Cochrane Public Health Group (CPHG) in development and proposes a way forward for the methodologies under consideration.

Physical activity, walking and quality of life in women with depressive symptoms

Background Physical activity (PA) has a positive association with health-related quality of life (HRQL) in the general population. The association between PA and HRQL in those with poor mental health is less clear. Purpose To examine the concurrent and prospective dose-response relationships between total physical activity (TPA) and walking only with HRQL in women aged 50-55 with depressive symptoms in 2001. Methods Participants were 1904 women born in 1946-1951 who completed mailed surveys for the Australian Longitudinal Study on Women's Health in 2001, 2004, 2007 and 2010 and who, in 2001, reported depressive symptoms. At each time point, they reported their weekly minutes of walking, moderate PA, and vigorous PA. A summary TPA score was created that accounted for differences in energy expenditure among the three PA types. Mixed models were used to examine associations between TPA and HRQL (SF-36 component and subscale scores) and between walking and HRQL, for women who reported walking as their only PA. Analyses were conducted in 2013-2014. Results Concurrently, higher levels of TPA and walking were associated with better HRQL (p<0.05). The strongest associations were found for physical functioning, vitality, and social functioning subscales. In prospective models, associations were attenuated, yet compared with women doing no TPA or walking, women doing “sufficient” TPA or walking had significantly better HRQL over time for most SF-36 scales. Conclusions This study extends previous work by demonstrating trends between both TPA and walking and HRQL in women reporting depressive symptoms.

Influence of visible work activity on drivers’ speed choice at roadworks

Vehicle traffic through roadwork sites creates a hazardous work environment, with speed limit noncompliance a major contributor to the high risk and high severity of roadwork crashes. This paper examines responses to an online survey to better understand the factors underlying drivers’ work zone speed choices. Drivers’ stated speed choice was compared between two photographs of the same work zone section – one with workers and machinery present and another with no visible activity. Drivers also provided comments on any aspect of roadwork safety they thought was important. A paired t-test of stated speed choice revealed that significantly lower mean speeds were nominated when workers and machinery were clearly present and active (41.7 vs 53.5 km/h, p<0.01). Participants expressed concern about roadwork signage and reduced speed limits being left in place when there was no apparent work activity. Driver perceptions, and thus compliance, may be improved through technological and operational changes.

Comparative analysis of FimB and FimE recombinase activity

FimB and FimE are site-specific recombinases, part of the λ integrase family, and invert a 314 bp DNA switch that controls the expression of type 1 fimbriae in Escherichia coli. FimB and FimE differ in their activity towards the fim switch, with FimB catalysing inversion in both directions in comparison to the higher-frequency but unidirectional on-to-off recombination catalysed by FimE. Previous work has demonstrated that FimB, but not FimE, recombination is completely inhibited in vitro and in vivo by a regulator, PapB, expressed from a distinct fimbrial locus. The aim of this work was to investigate differences between FimB and FimE activity by exploiting the differential inhibition demonstrated by PapB. The research focused on genetic changes to the fim switch that alter recombinase binding and its structural context. FimB and FimE still recombined a switch in which the majority of fimS DNA was replaced with a larger region of non-fim DNA. This demonstrated a minimal requirement for FimB and FimE recombination of the Fim binding sites and associated inverted repeats. With the original leucine-responsive regulatory protein (Lrp) and integration host factor (IHF)-dependent structure removed, PapB was now able to inhibit both recombinases. The relative affinities of FimB and FimE were determined for the four ‘half sites’. This analysis, along with the effect of extensive swaps and duplications of the half sites on recombination frequency, demonstrated that FimB recruitment and therefore subsequent activity was dependent on a single half site and its context, whereas FimE recombination was less stringent, being able to interact initially with two half sites with equally high affinity. While increasing FimB recombination frequencies failed to overcome PapB repression, mutations made in recombinase binding sites resulted in inhibition of FimE recombination by PapB. Overall, the data support a model in which the recombinases differ in loading order and co-operative interactions. PapB exploits this difference and FimE becomes susceptible when its normal loading is restricted or changed.

Species differences in the glutathione transferase GSTT1-1 activity towards the model substrates methyl chloride and dichloromethane in liver and kidney

Glutathione transferase (GST) GSTT1-1 is involved in the biotransformation of several chemicals widely used in industry, such as butadiene and dichloro methane DCM. The polymorphic hGSTT1-1 may well play a role in the development of kidney tumours after high and long-term occupational exposure against trichloroethylene. Although several studies have investigated the association of this polymorphism with malignant diseases little is known about its enzyme activity in potential extrahepatic target tissues. The known theta-specific substrates methyl chloride (MC) dichloromethane and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) were used to assay GSTT1-1 activity in liver and kidney of rats, mice, hamsters and humans differentiating the three phenotypes (non-conjugators, low conjugators, high conjugators) seen in humans. In addition GSTT1-1 activity towards MC and DCM was determined in human erythrocytes. No GSTT1-1 activity was found in any tissue of non-conjugators (NC). In all organs high conjugators (HC) showed twofold higher activity towards MC and DCM than low conjugators (LC). The activity in human samples towards EPNP was too close to the detection limit to differentiate between the three conjugator phenotypes. GSTT1-1 activity towards MC was two to seven-times higher in liver cytosol than in kidney cytosol. The relation for MC between species was identical in both organs: mouse > HC > rat > LC > hamster > NC. In rats, mice and hamsters GSTT1-1 activity in liver cytosol towards DCM was also two to seven-times higher than in the kidney cytosol. In humans this activity was twice as high in kidney cytosol than in liver cytosol. The relation between species was mouse > rat > HC > LC > hamster > NC for liver, but mouse > HC > LC/rat > hamster/NC for kidney cytosol. The importance to heed the specific environment at potential target sites in risk assessment is emphasized by these results.

Comparison of GST theta activity in liver and kidney of four species

Glutathione transferases (GSTs) catalyzing the conjugation of glutathione with electrophilic substrates are important enzymes in the metabolism of xenobiotics. Several isozymes exhibit polymorphisms in humans. The two deletion polymorphisms of hGSTM1 and hGSTT1 result in total loss of enzyme activity in homozygous null genotype (GSTM1*0 and GSTT1*0 respectively) individuals (Seidegård et al. 1988; Pemble et al. 1994). Individuals that are heterozygous for hGSTT1 show distinctly lower enzyme activities than individuals carrying two functional alleles of hGSTT1 (Wiebel et al. 1996). A similar effect is conceivable for the hGSTM1 polymorphism but has not been verified so far.

Workplace physical activity interventions : a systematic review

Objective. To assess the effectiveness of workplace interventions in improving physical activity. Data Source. EBSCO research database (and all subdatabases). Study Inclusion and Exclusion Criteria. Articles were published from 2000 to 2010 in English, had appropriate designs, and measured employees' physical activity, energy consumption, and/or body mass index (BMI) as primary outcomes. Articles that did not meet the inclusion criteria were excluded. Data Extraction. Data extracted included study design, study population, duration, intervention activities, outcomes, and results. Data Synthesis. Data were synthesized into one table. Results of each relevant outcome including p values were combined. Results. Twelve (60%) of 20 selected interventions reported an improvement in physical activity level, steps, or BMI, and there was one slowed step reduction in the intervention group. Among these, 10 were less than 6 months in duration; 9 used pedometers; 6 applied Internet-based approaches; and 5 included activities targeting social and environmental levels. Seven of 8 interventions with pre-posttest and quasi-experimental controlled design showed improvement on at least one outcome. However, 7 of 12 randomized controlled trials (RCTs) did not prove effective in any outcome. Conclusion. Interventions that had less rigorous research designs, used pedometers, applied Internet-based approaches, and included activities at social and environmental levels were more likely to report being effective than those without these characteristics.

Food insecurity and physical activity among U.S. populations

Objectives: Examine the association between food insecurity (FI) and physical activity (PA) in the U.S. population. Methods: Accelerometry (PAM) and self-report PA (PAQ) data from NHANES 2003-2006 were used. Those aged less than six years or were older than 65 years, pregnant, with physical limitations, or with family income above 350% of the poverty line were excluded. FI was measured by the USDA Household Food Security Survey Module. Crude and adjusted odd ratios were calculated from logistic regression to identify the association between FI and adherence to the PA recommendation. Crude and adjusted coefficients were calculated from linear regression to identify the association between FI and both sedentary and activity minutes. Results: In children, FI was not associated with adherence to PA recommendation measured via PAM or PAQ (p>0.05) but was significantly associated with sedentary minutes (adjusted coefficient=10.74, one-sided p<0.05). Food-insecure children did less moderate-to-vigorous PA than did food-secure children (adjusted coefficient = -5.31, p = 0.032). In adults, FI was significantly associated with PA (adjusted OR=0.722 for PAM and OR=0.839 for PAQ, one-sided p<0.05) but not associated with sedentary minutes (p>0.05) Conclusions: FI children were more sedentary and FI adults were less likely to adhere to the PA recommendation than those without FI.