The Flavonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention

Flavonoids have emerged as promising compounds capable of preventing colorectal cancer (CRC) due to their anti-oxidant and anti-inflammatory properties. It is hypothesized that the metabolites of flavonoids are primarily responsible for the observed anti-cancer effects owing to the unstable nature of the parent compounds and their degradation by colonic microflora. In this study, we investigated the ability of one metabolite, 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) to inhibit Cyclin Dependent Kinase (CDK) activity and cancer cell proliferation. Using in vitro kinase assays, we demonstrated that 2,4,6-THBA dose-dependently inhibited CDKs 1, 2 and 4 and in silico studies identified key amino acids involved in these interactions. Interestingly, no significant CDK inhibition was observed with the structurally related compounds 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) and phloroglucinol, suggesting that orientation of the functional groups and specific amino acid interactions may play a role in inhibition. We showed that cellular uptake of 2,4,6-THBA required the expression of functional SLC5A8, a monocarboxylic acid transporter. Consistent with this, in cells expressing functional SLC5A8, 2,4,6-THBA induced CDK inhibitory proteins p21Cip1 and p27Kip1 and inhibited cell proliferation. These findings, for the first time, suggest that the flavonoid metabolite 2,4,6-THBA may mediate its effects through a CDK- and SLC5A8-dependent pathway contributing to the prevention of CRC

Activin induces tactile allodynia and increases calcitonin gene-related peptide after peripheral inflammation

Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide important in inflammatory pain that conveys pain information centrally and dilates blood vessels peripherally. Previous studies indicate that activin A increases CGRP-immunoreactive (IR) sensory neurons in vitro, and following wound, activin A protein increases in the skin and more neurons have detectable CGRP expression in the innervating dorsal root ganglion (DRG). These data suggest some adult sensory neurons respond to activin A or other target-derived factors with increased neuropeptide expression. This study was undertaken to test whether activin contributes to inflammatory pain and increased CGRP and to learn which neurons retained plasticity. After adjuvant-induced inflammation, activin mRNA, but not NGF or glial cell line-derived neurotrophic factor, increased in the skin. To examine which DRG neurons increased CGRP immunoreactivity, retrograde tracer-labeled cutaneous neurons were characterized after inflammation. The proportion and size of tracer-labeled DRG neurons with detectable CGRP increased after inflammation. One-third of CGRP-IR neurons that appear after inflammation also had isolectin B4 binding, suggesting that some mechanoreceptors became CGRP-IR. In contrast, the increased proportion of CGRP-IR neurons did not appear to come from RT97-IR neurons. To learn whether central projections were altered after inflammation, CGRP immunoreactivity in the protein kinase Cγ-IR lamina IIi was quantified and found to increase. Injection of activin A protein alone caused robust tactile allodynia and increased CGRP in the DRG. Together, these data support the hypothesis that inflammation and skin changes involving activin A cause some sensory neurons to increase CGRP expression and pain responses. Copyright © 2005 Society for Neuroscience

An Experimental Survey of Metal Artefact Reduction in Computed Tomography

We present a survey of techniques for the reduction of streaking artefacts caused by metallic objects in X-ray Computed Tomography (CT) images. A comprehensive review of the existing state-of- the-art Metal Artefact Reduction (MAR) techniques, drawn almost exclusively from the medical CT literature, is supported by an experimental comparison grounded in an evaluation based on a standard scienti c comparison protocol for MAR methods using a software generated medical phan- tom image. This experimental comparison is further extended by considering novel applications of CT imagery consisting of isolated metal objects with no surrounding tissue, as is encountered in typical engineering and security screening CT applications. We nd that the performance of twelve state-of-the-art MAR techniques to be fairly consistent across the two domains and demonstrate the feasibility of a reference-free quantitative performance measure. The literature review and experi- mentation demonstrate several trends. In particular, the major limitations of state-of-the-art MAR techniques are a dependence on prior knowledge, a sensitivity to input parameters and a shortage of comprehensive performance analyses. This study thus extends previous works by: comparing several state-of-the-art MAR techniques; considering both medical and non-medical applications and performing a comprehensive quantitative analysis, taking into account image quality as well as computational requirements

A Distance Weighted Method for Metal Artefact Reduction in CT

This paper presents an extension to a recent intensity-limiting sinogram completion-based Metal Artefact Reduction (MAR) algorithm for Computed Tomography (CT) images containing multiple metal objects. A novel weighting scheme is introduced, whereby the intensities of the MAR-corrected pixels are modified based on their spatial locations relative to the metal objects. Pixels falling within the straight-line regions connecting multiple metal objects are subjected to less intensive intensity-limiting, thereby compensating for the characteristic dark bands occurring in these regions. Extensive experimentation is performed on a state-of-the-art numerical simulation, a clinical CT data set and a baggage security CT data set. Comprehensive performance analysis, using reference and reference-free error metrics, Bland-Altman plots and visual comparisons, demonstrate an improvement in the restoration of the underestimated intensities occurring in the regions connecting multiple metal objects. Index Terms — metal artefact reduction, CT, baggage CT 1

Bias Reduction for Low-Statistics PET: Maximum Likelihood Reconstruction With a Modified Poisson Distribution

Positron emission tomography data are typically reconstructed with maximum likelihood expectation maximization (MLEM). However, MLEM suffers from positive bias due to the non-negativity constraint. This is particularly problematic for tracer kinetic modeling. Two reconstruction methods with bias reduction properties that do not use strict Poisson optimization are presented and compared to each other, to filtered backprojection (FBP), and to MLEM. The first method is an extension of NEGML, where the Poisson distribution is replaced by a Gaussian distribution for low count data points. The transition point between the Gaussian and the Poisson regime is a parameter of the model. The second method is a simplification of ABML. ABML has a lower and upper bound for the reconstructed image whereas AML has the upper bound set to infinity. AML uses a negative lower bound to obtain bias reduction properties. Different choices of the lower bound are studied. The parameter of both algorithms determines the effectiveness of the bias reduction and should be chosen large enough to ensure bias-free images. This means that both algorithms become more similar to least squares algorithms, which turned out to be necessary to obtain bias-free reconstructions. This comes at the cost of increased variance. Nevertheless, NEGML and AML have lower variance than FBP. Furthermore, randoms handling has a large influence on the bias. Reconstruction with smoothed randoms results in lower bias compared to reconstruction with unsmoothed randoms or randoms precorrected data. However, NEGML and AML yield both bias-free images for large values of their parameter

Iterative correction of beam hardening artifacts in CT

Purpose. To reduce beam hardening artifacts in CT in case of an unknown X-ray spectrum and unknown material properties. Methods. We assume that the object can be segmented into a few materials with different attenuation coefficients, and parameterize the spectrum using a small number of energy bins. The corresponding unknown spectrum parameters and material attenuation values are estimated by minimizing the difference between the measured sinogram data and a simulated polychromatic sinogram. Three iterative algorithms are derived from this approach: two reconstruction algorithms IGR and IFR, and one sinogram precorrection method ISP. Results. The methods are applied on real X-ray data of a high and a low-contrast phantom. All three methods successfully reduce the cupping artifacts caused by the beam polychromaticity in such a way that the reconstruction of each homogeneous region is to good accuracy homogeneous, even in case the segmentation of the preliminary reconstruction image is poor. In addition, the results show that the three methods tolerate relatively large variations in uniformity within the segments. Conclusions. We show that even without prior knowledge about materials or spectrum, effective beam hardening correction can be obtained.status: publishe