The Yin and Yang of vitamin D receptor (VDR) signaling in neoplastic progression: Operational networks and tissue-specific growth control

Substantive evidence implicates vitamin D receptor (VDR) or its natural ligand 1a,25-(OH)2 D3 in modulation of tumor growth. However, both human and animal studies indicate tissue-specificity of effect. Epidemiological studies show both inverse and direct relationships between serum 25(OH)D levels and common solid cancers. VDR ablation affects carcinogen-induced tumorigenesis in a tissue-specific manner in model systems. Better understanding of the tissue-specificity of vitamin D-dependent molecular networks may provide insight into selective growth control by the seco-steroid, 1a,25-(OH)2 D3. This commentary considers complex factors that may influence the cell- or tissue-specificity of 1a,25-(OH)2 D3/VDR growth effects, including local synthesis, metabolism and transport of vitamin D and its metabolites, vitamin D receptor (VDR) expression and ligand-interactions, 1a,25-(OH)2 D3 genomic and non-genomic actions, Ca2+ flux, kinase activation, VDR interactions with activating and inhibitory vitamin D responsive elements (VDREs) within target gene promoters, VDR coregulator recruitment and differential effects on key downstream growth regulatory genes. We highlight some differences of VDR growth control relevant to colonic, esophageal, prostate, pancreatic and other cancers and assess the potential for development of selective prevention or treatment strategies.

Micro-environmental change as a trigger for granite decay in offshore Irish lighthouses: implications for the long-term preservation of operational historic buildings.

Following automation of lighthouses around the coastline of Ireland, reports of accelerated deterioration of interior granite stonework have increased significantly with an associated deterioration in the historic structure and rise in related maintenance costs. Decay of granite stone- work primarily occurs through granular disintegration with the effective grusification of granite surfaces. A decay gradient exists within the towers whereby the condition of granite in the lower levels is much worse than elsewhere. The lower tower levels are also regions with highest rela- tive humidity values and greatest salt concentrations. Data indicate that post-automation decay may have been trig- gered by a change in micro-environmental conditions within the towers associated with increased episodes of condensation on stone surfaces. This in turn appears to have facilitated deposition and accumulation of hygro- scopic salts (e.g. NaCl) giving rise to widespread evidence of deliquescence in the lower tower levels. Evidence indicates that the main factors contributing to accelerated deterioration of interior granite stonework are changes in micro-environmental conditions, salt weathering, chemical weathering through the corrosive effect of strongly alkaline conditions on alumino-silicate minerals within the granite and finally, the mica-rich characteristics of the granite itself which increases its structural and chemical susceptibility to subaerial weathering processes by creating points of weakness within the granite. This case study demonstrates how seemingly minor changes in micro-environmental conditions can unintentionally trigger the rapid and extensive deterioration of a previously stable rock type and threaten the long-term future of nationally iconic opera- tional historic structures.

Microsatellite standardization and evaluation of genotyping error in a large multi-partner research programme for conservation of Atlantic salmon (Salmo salar L.).

Microsatellite genotyping is a common DNA characterization technique in population, ecological and evolutionary genetics research. Since different alleles are sized relative to internal size-standards, different laboratories must calibrate and standardize allelic designations when exchanging data. This interchange of microsatellite data can often prove problematic. Here, 16 microsatellite loci were calibrated and standardized for the Atlantic salmon, Salmo salar, across 12 laboratories. Although inconsistencies were observed, particularly due to differences between migration of DNA fragments and actual allelic size ('size shifts'), inter-laboratory calibration was successful. Standardization also allowed an assessment of the degree and partitioning of genotyping error. Notably, the global allelic error rate was reduced from 0.05 ± 0.01 prior to calibration to 0.01 ± 0.002 post-calibration. Most errors were found to occur during analysis (i.e. when size-calling alleles; the mean proportion of all errors that were analytical errors across loci was 0.58 after calibration). No evidence was found of an association between the degree of error and allelic size range of a locus, number of alleles, nor repeat type, nor was there evidence that genotyping errors were more prevalent when a laboratory analyzed samples outside of the usual geographic area they encounter. The microsatellite calibration between laboratories presented here will be especially important for genetic assignment of marine-caught Atlantic salmon, enabling analysis of marine mortality, a major factor in the observed declines of this highly valued species.

An international standardization programme towards the application of gene expression profiling in routine leukaemia diagnostics: the Microarray Innovations in LEukemia study prephase

Gene expression profiling has the potential to enhance current methods for the diagnosis of haematological malignancies. Here, we present data on 204 analyses from an international standardization programme that was conducted in 11 laboratories as a prephase to the Microarray Innovations in LEukemia (MILE) study. Each laboratory prepared two cell line samples, together with three replicate leukaemia patient lysates in two distinct stages: (i) a 5-d course of protocol training, and (ii) independent proficiency testing. Unsupervised, supervised, and r(2) correlation analyses demonstrated that microarray analysis can be performed with remarkably high intra-laboratory reproducibility and with comparable quality and reliability.

Impact of gate-source/drain channel architecture on the performance of an operational transconductance amplifier (OTA)

In this work, we report on the significance of gate-source/drain extension region (also known as underlap design) optimization in double gate (DG) FETs to improve the performance of an operational transconductance amplifier (OTA). It is demonstrated that high values of intrinsic voltage gain (A(VO_OTA)) > 55 dB and unity gain frequency (f(T_OTA)) similar to 57 GHz in a folded cascode OTA can be achieved with gate-underlap channel design in 60 nm DG MOSFETs. These values correspond to 15 dB improvement in A(VO_OTA) and three fold enhancement in f(T_OTA) over a conventional non-underlap design. OTA performance based on underlap single gate SOI MOSFETs realized in ultra-thin body (UTB) and ultra-thin body BOX (UTBB) technologies is also evaluated. A(VO_OTA) values exhibited by a DG MOSFET-based OTA are 1.3-1.6 times higher as compared to a conventional UTB/UTBB single gate OTA. f(T_OTA) values for DG OTA are 10 GHz higher for UTB OTAs whereas a twofold improvement is observed with respect to UTBB OTAs. The simultaneous improvement in A(VO_OTA) and f(T_OTA) highlights the usefulness of underlap channel architecture in improving gain-bandwidth trade-off in analog circuit design. Underlap channel OTAs demonstrate high degree of tolerance to misalignment/oversize between front and back gates without compromising the performance, thus relaxing crucial process/technology-dependent parameters to achieve 'idealized' DG MOSFETs. Results show that underlap OTAs designed with a spacer-to-straggle (s/sigma) ratio of 3.2 and operated below a bias current (IBIAS) of 80 mu A demonstrate optimum performance. The present work provides new opportunities for realizing future ultra-wide band OTA design with underlap DG MOSFETs.

Standardization of diagnostic biomarker concentrations in urine; the hematuria caveat

Sensitive and specific urinary biomarkers can improve patient outcomes in many diseases through informing early diagnosis. Unfortunately, to date, the accuracy and translation of diagnostic urinary biomarkers into clinical practice has been disappointing. We believe this may be due to inappropriate standardization of diagnostic urinary biomarkers. Our objective was therefore to characterize the effects of standardizing urinary levels of IL-6, IL-8, and VEGF using the commonly applied standards namely urinary creatinine, osmolarity and protein. First, we report results based on the biomarker levels measured in 120 hematuric patients, 80 with pathologically confirmed bladder cancer, 27 with confounding pathologies and 13 in whom no underlying cause for their hematuria was identified, designated “no diagnosis”. Protein levels were related to final diagnostic categories (p = 0.022, ANOVA). Osmolarity (mean = 529 mOsm; median = 528 mOsm) was normally distributed, while creatinine (mean = 10163 µmol/l, median = 9350 µmol/l) and protein (0.3297, 0.1155 mg/ml) distributions were not. When we compared AUROCs for IL-6, IL-8 and VEGF levels, we found that protein standardized levels consistently resulted in the lowest AUROCs. The latter suggests that protein standardization attenuates the “true” differences in biomarker levels across controls and bladder cancer samples. Second, in 72 hematuric patients; 48 bladder cancer and 24 controls, in whom urine samples had been collected on recruitment and at follow-up (median = 11 (1 to 20 months)), we demonstrate that protein levels were approximately 24% lower at follow-up (Bland Altman plots). There was an association between differences in individual biomarkers and differences in protein levels over time, particularly in control patients.