Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization

Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies

Gene Expression Patterns in Peripheral Blood Correlate with the Extent of Coronary Artery Disease

Systemic and local inflammation plays a prominent role in the pathogenesis of atherosclerotic coronary artery disease, but the relationship of whole blood gene expression changes with coronary disease remains unclear. We have investigated whether gene expression patterns in peripheral blood correlate with the severity of coronary disease and whether these patterns correlate with the extent of atherosclerosis in the vascular wall

Bile acids in drug induced liver injury: Key players and surrogate markers

Bile acid research has gained great momentum since the role of bile acids as key signaling molecules in the enterohepatic circulation was discovered. Their physiological function in regulating their own homeostasis, as well as energy and lipid metabolism make them interesting targets for the pharmaceutical industry in the context of diseases such as bile acid induced diarrhea, bile acid induced cholestasis or nonalcoholic steatohepatitis. Changes in bile acid homeostasis are also linked to various types of drug-induced liver injury (DILI). However, the key question whether bile acids are surrogate markers for monitoring DILI or key pathogenic players in the onset and progression of DILI is under intense investigation. The purpose of this review is to summarize the different facets of bile acids in the context of normal physiology, hereditary defects of bile acid transport and DILI

VIP.

<p>Variable Importance in the Projection (VIP) for the separate PLS analyses of the three different cohorts compared to the PLS analysis including all subjects. Displayed are the 24 probesets with the highest VIP. The curve shows a steep decrease for the first 8 genes (listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007037#pone-0007037-t002" target="_blank">table 2</a>); the contribution of further genes is comparable as suggested by almost linear curves.</p

Partial least squares plot per cohort.

<p>Results of the partial least squares regression analysis with 160 genes applied separately to each of the three cohorts (A) “Matched Men” (B) “Unmatched Men” and (C) ‘“Unmatched Women”. Models were each time constructed in two cohorts and then tested in the third cohort. Individual patients are ordered by their CAD-Index. Labels represent the individual CAD-Index. Controls (full line) have all CAD-Index 0, and the CAD-Index of cases (dotted line) increases from 23 up to 100. While the controls remain quite stable in the range of -2 standard deviations, the t1-scores increase with increasing CAD-Index (t1 indicates the t1 score vector result from the PLS analysis).</p

Bile acid sequestration by cholestyramine mitigates FGFR4 inhibition-induced ALT elevation

The FGF19-FGFR4-βKlotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma (HCC), establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for HCC, currently in Phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1, elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one (C4), increased BA pool size, decreased serum cholesterol and diarrhea in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in the absence of any observable adverse histopathological findings in the liver, or in any other organs. We hypothesized that the increase in ALT could be secondary to increased BAs and conducted an investigative study in dogs with FGF401 and co-administration of the BA sequestrant cholestyramine (CHO). CHO prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. Correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid (TLCA) and taurodeoxycholic acid (TDCA), the major secondary BAs in dog plasma, indicating a mechanistic link between ALT elevation and changes in BA pool hydrophobicity. Thus, CHO may offer the potential to mitigate elevations in serum aminotransferases in human subjects that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels

Partial least squares plot of nominal CAD index versus predicted CAD index.

<p>Result of the partial least squares analysis including all controls and all cases; n = 222 and 160 genes. Cases are represented as triangles and controls as circles. The CAD-index as predicted by the gene expression is plotted versus the nominal CAD-index as obtained from coronary angiography. Regression line of the predicted CAD index versus nominal CAD-Index is displayed by the full line including 95% confidence interval of the regression (dotted lines) and the 95% prediction interval (striped lines). Goodness of fit is indicated by r² = 0.776 (p<0.001).</p

List of 160-gene model predictive of the extent of coronary artery disease.

<p>The 8 most predictive genes according to the VIP analysis are listed in bold; °° indicated the 19 genes and °or°° the 90 genes that were found to be differentially expressed in a multiway ANOVA.</p