Alterations in beta-catenin expression and localization in prostate cancer

BACKGROUND: Wnt signaling is thought to be important in prostate cancer, in part because proteins such as beta-catenin can also affect androgen receptor signaling. beta-Catenin forms a cell adhesion complex with E-cadherin raising the possibility that loss of expression or a change in beta-catenin distribution in the cell could also alter downstream signaling, decreased inter-cellular adhesion and the promotion of metastasis. A number of studies have reported the altered expression and/or localization of beta-catenin as a biomarker in prostate cancer. METHODS: Tissue microarrays comprised of BPH and low, moderate and high-grade prostate cancer (n=77) were assessed for beta-catenin expression and distribution using immunohistochemistry. Staining was also performed on a tissue microarray containing tissue from patients before and after hormone manipulation. The effects of fixation and different antibodies was assessed on fixed LNCaP cell pellets and small prostate tissue microarrays. RESULTS: We have observed increased beta-catenin expression in only high Gleason score (>7) prostate cancer. A nuclear re-distribution of beta-catenin has previously been reported. We noted nuclear beta-catenin in benign prostatic hyperplasia and a gradual loss in nuclear distribution with increasing Gleason grade. We found no evidence for an alteration in beta-catenin expression or re-distribution with hormone ablation. Altered fixation, antibodies and antibody concentration did affect the intensity and specificity of staining. CONCLUSIONS: A loss of nuclear beta-catenin is the most consistent feature in prostate cancer rather than absolute levels of expression. We also suggest that variation in immunohistochemical protocols may explain variations in the reported literature.     

Targeting protein translation in human non small cell lung cancer via combined MEK and mammalian target of rapamycin suppression

Lung cancer is a genetically heterogeneous disease characterized by the acquisition of somatic mutations in numerous protein kinases, including components of the rat sarcoma viral oncogene homolog (RAS) and AKT signaling cascades. These pathways intersect at various points, rendering this network highly redundant and suggesting that combined mitogen-activated protein/extracellular signal-regulated kinase (MEK) and mammalian target of rapamycin (mTOR) inhibition may be a promising drug combination that can overcome its intrinsic plasticity. The MEK inhibitors, CI-1040 or PD0325901, in combination with the mTOR inhibitor, rapamycin, or its analogue AP23573, exhibited dose-dependent synergism in human lung cancer cell lines that was associated with suppression of proliferation rather than enhancement of cell death. Concurrent suppression of MEK and mTOR inhibited ribosomal biogenesis by 40% within 24 h and was associated with a decreased polysome/monosome ratio that is indicative of reduced protein translation efficiency. Furthermore, the combination of PD0325901 and rapamycin was significantly superior to either drug alone or PD0325901 at the maximum tolerated dose in nude mice bearing human lung tumor xenografts or heterotransplants. Except for a PTEN mutant, all tumor models had sustained tumor regressions and minimal toxicity. These data (a) provide evidence that both pathways converge on factors that regulate translation initiation and (b) support therapeutic strategies in lung cancer that simultaneously suppress the RAS and AKT signaling network.     

Hepatitis C disease transmission and treatment uptake: impact on the cost-effectiveness of new direct-acting antiviral therapies

Background

Hepatitis C virus (HCV) treatment can reduce the incidence of future infections through removing opportunities for onward transmission. This benefit is not captured in conventional cost-effectiveness evaluations of treatment and is particularly relevant in patient groups with a high risk of transmission, such as those people who inject drugs (PWID), where the treatment rates have been historically low. This study aimed to quantify how reduced HCV transmission changes the cost-effectiveness of new direct-acting antiviral (DAA) regimens as a function of treatment uptake rates.

Methods

An established model of HCV disease transmission and progression was used to quantify the impact of treatment uptake (10–100%), within the PWID population, on the cost-effectiveness of a DAA regimen versus pre-DAA standard of care, conducted using daclatasvir plus sofosbuvir in the UK setting as an illustrative example.

Results

The consequences of reduced disease transmission due to treatment were associated with additional net monetary benefit of £24,304–£90,559 per patient treated at £20,000/QALY, when 10–100% of eligible patients receive treatment with 100% efficacy. Dependent on patient genotype, the cost-effectiveness of HCV treatment using daclatasvir plus sofosbuvir improved by 36–79% versus conventional analysis, at 10–100% treatment uptake in the PWID population.

Conclusions

The estimated cost-effectiveness of HCV treatment was shown to improve as more patients are treated, suggesting that the value of DAA regimens to the NHS could be enhanced by improved treatment uptake rates among PWID. However, the challenge for the future will lie in achieving increased rates of treatment uptake, particularly in the PWID population.

     

A 6-year study of cognition and spatial function in the demented and non-demented elderly: the Sydney Older Persons Study

BACKGROUND: Spatial function has been suggested to be disproportionately worse in people with dementia with Lewy bodies (DLB) than other dementia groups, and poor performance on the Mini-Mental State Examination pentagon copying (PC) task has been proposed as adequate for assessing this. We aimed to establish the prevalence of poor PC in the non-demented elderly; determine the validity of the use of PC as a spatial function test, and determine if poor PC is more common in DLB than non-DLB dementias. METHODS: In a population-based sample of 299 participants, 126 were rated as being cognitively normal (clinical rating scale [CDR] = 0), 95 mildly cognitively impaired (CDR = 0.5), and 78 met criteria for dementia, 19 of whom met criteria for probable DLB (pDLB) and 25 with none of the core features of DLB (non-DLB). The accuracy of PC performance was determined across CDR groups, and the relationship of PC to performance on a broad range of cognitive tests was evaluated. The dementia groups were compared cross-sectionally to determine differences in PC and other cognitive test performance, as well as 3 and 6 years earlier to determine cognitive differences at initial stages of cognitive decline. RESULTS: Poor PC was common in the non-demented elderly (39% CDR = 0; 43% CDR = 0.5). In this non-demented group, PC was selectively related to tests of spatial function. Poor PC was not significantly different in the pDLB and non-DLB groups at any assessment time, however it became more prevalent as dementia severity increased. Memory function and verbal fluency were more impaired in the pDLB group in the early stages of the disorder. COMMENT: PC appears to be a good measure of spatial function in the elderly. However, in contrast to other findings of poor spatial skills in DLB when dementia is in the mild to moderate stages, poor PC performance has not been shown to be a good early marker of DLB and its clinical correlates are yet to be determined.     

Prolonged unloading in growing rats reduces cortical osteocyte lacunar density and volume in the distal tibia

Bone dynamically adapts its structure to the environmental demands placed upon it. Load-related stimuli play an important role in this adaptation. It has been postulated that osteocytes sense changes in these stimuli and initiate adaptive responses, across a number of scales, through a process known as mechanotransduction. While much research has focused on gross and tissue-level adaptation, relatively little is known regarding the relation between cellular-level features (e.g. osteocyte lacunar density, volume and shape) and loading. The increasing availability of high resolution 3D imaging modalities, including synchrotron-based techniques, has made studying 3D cellular-level features feasible on a scale not previously possible. The primary objective of this study was to test the hypothesis that unloading (sciatic neurectomy) during growth results in altered osteocyte lacunar density in the tibial diaphysis of the rat. Secondarily, we explored a potential effect of unloading on mean lacunar volume. Lacunar density was significantly (p < 0.05) lower in immobilized bones (49,642 ± 11,955 lacunae per mm³; n = 6) than in control bones (63,138 ± 1956 lacunae per mm³; n = 6). Mean lacunar volume for immobilized bones (209 ± 72 μm³; n = 6) was significantly smaller (p < 0.05) than that for the control bones (284 ± 28 μm³; n = 6). Our results demonstrate that extreme differences in loading conditions, such as those created by paralysis, do indeed result in changes in osteocyte lacunar density and volume. Further investigation is warranted to examine relations between these measures and more subtle variation in loading as well as pathological states, which have been linked to alterations in mechanotransduction.     

The effects of the Two-Week Rule on NHS colorectal cancer diagnostic services: A systematic literature review

Background  

The Two-Week Rule (TWR) was introduced to ensure that all patients with a suspected colorectal cancer (CRC) saw a hospital specialist within 14 days of an urgent GP referral. Guidelines were available to GPs to facilitate the appropriate TWR referral of patients exhibiting high-risk CRC symptoms.     

Association between sitting and occupational LBP

Low back pain (LBP) has been identified as one of the most costly disorders among the worldwide working population. Sitting has been associated with risk of developing LBP. The purpose of this literature review is to assemble and describe evidence of research on the association between sitting and the presence of LBP. The systematic literature review was restricted to those occupations that require sitting for more than half of working time and where workers have physical co-exposure factors such as whole body vibration (WBV) and/or awkward postures. Twenty-five studies were carefully selected and critically reviewed, and a model was developed to describe the relationships between these factors. Sitting alone was not associated with the risk of developing LBP. However, when the co-exposure factors of WBV and awkward postures were added to the analysis, the risk of LBP increased fourfold. The occupational group that showed the strongest association with LBP was Helicopter Pilots (OR=9.0, 90% CI 4.9–16.4). For all studied occupations, the odds ratio (OR) increased when WBV and/or awkward postures were analyzed as co-exposure factors. WBV while sitting was also independently associated with non-specific LBP and sciatica. Vibration dose, as well as vibration magnitude and duration of exposure, were associated with LBP in all occupations. Exposure duration was associated with LBP to a greater extent than vibration magnitude. However, for the presence of sciatica, this difference was not found. Awkward posture was also independently associated with the presence of LBP and/or sciatica. The risk effect of prolonged sitting increased significantly when the factors of WBV and awkward postures were combined. Sitting by itself does not increase the risk of LBP. However, sitting for more than half a workday, in combination with WBV and/or awkward postures, does increase the likelihood of having LBP and/or sciatica, and it is the combination of those risk factors, which leads to the greatest increase in LBP.