Plasma PCSK9 levels are significantly modified by statins and fibrates in humans

<p>Abstract</p> <p>Background</p> <p>Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men.</p> <p>Results</p> <p>Herein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6× vs 1.5×, respectively at 10 μM), while fenofibrate did not induce changes in either.</p> <p>Conclusion</p> <p>These results suggest that <it>in vivo </it>(1) statins directly increase PCSK9 expression while (2) fibrates affect PCSK9 expression indirectly through its modulation of cholesterol levels and (3) that these therapies could be improved by combination with a PCSK9 inhibitor, constituting a novel hypercholesterolemic therapy, since PCSK9 was significantly upregulated by both treatments.</p

Time-resolved diffuse optical tomography for non-invasive flap viability assessment: Pre-clinical tests on rats

We present a new setup for time-resolved diffuse optical tomography based on multiple source-detector acquisitions analysed by means of the Mellin-Laplace transform. The proposed setup has been used to perform pre-clinical measurements on rats in order to show its suitability for non-invasive assessment of flap viability

Detecting wildlife in unmanned aerial systems imagery using convolutional neural networks trained with an automated feedback loop

Using automated processes to detect wildlife in uncontrolled outdoor imagery in the field of wildlife ecology is a challenging task. This is especially true in imagery provided by an Unmanned Aerial System (UAS), where the relative size of wildlife is small and visually similar to its background. This work presents an automated feedback loop which can be used to train convolutional neural networks with extremely unbalanced class sizes, which alleviates some of these challenges. This work utilizes UAS imagery collected by the Wildlife@Home project, which has employed citizen scientists and trained experts to go through collected UAS imagery and classify it. Classified data is used as inputs to convolutional neural networks (CNNs) which seek to automatically mark which areas of the imagery contain wildlife. The output of the CNN is then passed to a blob counter which returns a population estimate for the image. The feedback loop was developed to help train the CNNs to better differentiate between the wildlife and the visually similar background and deal with the disparate amount of wildlife training images versus background training images. Utilizing the feedback loop dramatically reduced population count error rates from previously published work, from +150% to −3.93% on citizen scientist data and +88% to +5.24% on expert data

Continuous non-perturbative regularization of QED

We regularize in a continuous manner the path integral of QED by construction of a non-local version of its action by means of a regularized form of Dirac's $\delta$ functions. Since the action and the measure are both invariant under the gauge group, this regularization scheme is intrinsically non-perturbative. Despite the fact that the non-local action converges formally to the local one as the cutoff goes to infinity, the regularized theory keeps trace of the non-locality through the appearance of a quadratic divergence in the transverse part of the polarization operator. This term which is uniquely defined by the choice of the cutoff functions can be removed by a redefinition of the regularized action. We notice that as for chiral fermions on the lattice, there is an obstruction to construct a continuous and non ambiguous regularization in four dimensions. With the help of the regularized equations of motion, we calculate the one particle irreducible functions which are known to be divergent by naive power counting at the one loop order.Comment: 23 pages, LaTeX, 5 Encapsulated Postscript figures. Improved and revised version, to appear in Phys. Rev.

Mutations in BHD and TP53 genes, but not in HNF1β gene, in a large series of sporadic chromophobe renal cell carcinoma

BHD, TP53, and HNF1β on chromosome 17 were studied in 92 cases of renal cell carcinoma (46 chromophobe, 19 clear cell, 18 oncocytoma, and nine papillary). Six, thirteen, and zero cases had, respectively BHD, TP53, and HNF1β mutations, (84% mutations involved chromophobe), suggesting a role for BHD and TP53 in chromophobe subtype

Epigenetically controlled tumor antigens derived from splice junctions between exons and transposable elements

Oncogenesis often implicates epigenetic alterations, including derepression of transposable elements (TEs) and defects in alternative splicing. Here, we explore the possibility that noncanonical splice junctions between exons and TEs represent a source of tumor-specific antigens. We show that mouse normal tissues and tumor cell lines express wide but distinct ranges of mRNA junctions between exons and TEs, some of which are tumor specific. Immunopeptidome analyses in tumor cell lines identified peptides derived from exon-TE splicing junctions associated to MHC-I molecules. Exon-TE junction-derived peptides were immunogenic in tumor-bearing mice. Both prophylactic and therapeutic vaccinations with junction-derived peptides delayed tumor growth in vivo. Inactivation of the TE-silencing histone 3-lysine 9 methyltransferase Setdb1 caused overexpression of new immunogenic junctions in tumor cells. Our results identify exon-TE splicing junctions as epigenetically controlled, immunogenic, and protective tumor antigens in mice, opening possibilities for tumor targeting and vaccination in patients with cancer