Donor genetic variants as risk factors for thrombosis after liver transplantation: A genome-wide association study

Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10⁻⁰⁵) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696-C, p = 2.62 × 10⁻⁰⁵) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia-related variants, are associated with increased risk of thrombosis after liver transplantation.     

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of bile acids leads to their accumulation in the liver, which is thought to underlie pruritus and liver‐damaging inflammation. One approach to reducing pathologic bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting bile acids to an external stoma). These procedures can normalize serum bile acids, reduce pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs bile acids from the intestine. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of paediatric cholestatic liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic liver diseases including ALGS and PFIC.     

Effect of genetic variation in the human S-adenosylhomocysteine hydrolase gene on total homocysteine concentrations and risk of recurrent venous thrombosis

Hyperhomocysteinemia is an independent and graded risk factor for arterial vascular disease and venous thrombosis. It is still debated via which mechanism homocysteine (Hcy) causes vascular disease. S-adenosylhomocysteine hydrolase (AHCY) catalyses the reversible hydrolysis of S-adenosylhomocysteine (AdoHcy) to Hcy. As an increase in AdoHcy, a strong inhibitor of many methyltransferases, is observed in hyperhomocysteinemic individuals, AdoHcy may play a role in the development of cardiovascular diseases by inhibiting transmethylation reactions. We sequenced the entire coding region and parts of the untranslated regions (UTRs) of the AHCY gene of 20 patients with recurrent venous thrombosis in order to identify genetic variation within this gene. We identified three sequence variants in the AHCY gene: a C > T transition in the 5' UTR (-34 bp C > T), a missense mutation in exon 2, which mandates an amino-acid conversion at codon 38 (112 C > T; Arg38Trp) and a silent mutation in exon 4 (390 C > T; Asp130Asp). We studied the effect of the first two variants on total plasma Hcy and venous thrombosis risk in a case-control study on recurrent venous thrombosis. The two polymorphisms under study seem to have no evident effect on tHcy. The adjusted relative risk of venous thrombosis associated with the 112CT genotype compared with 112CC individuals was 1.27 (95% CI 0.55-2.94), whereas the -34CT genotype confers a risk of 1.25 (95% CI 0.44-3.52) compared with the wild-type genotype at this locus. However, the wide confidence intervals do not allow firm conclusions to be drawn.     

Automated analysis of contrast enhancement in breast MRI lesions using mean shift clustering for ROI selection

PURPOSE: To evaluate a new method for automated determination of a region of interest (ROI) for the analysis of contrast enhancement in breast MRI. MATERIALS AND METHODS: Mean shift multidimensional clustering (MS-MDC) was employed to divide 92 lesions into several spatially contiguous clusters each, based on multiple enhancement parameters. The ROIs were defined as the clusters with the highest probability of malignancy. The performance of enhancement analysis within these ROIs was estimated using the area under the receiver operator characteristic curve (AUC), and compared against a radiologist's final assessment and a classifier using histogram analysis (HA). For HA, the first, second, and third quartiles were evaluated. RESULTS: MS-MDC resulted in AUC = 0.88 with a 95% confidence interval (CI) of 0.81-0.95. The AUC for the radiologist's assessment was 0.93 (95%CI = 0.87-0.97). Best HA performance was found using the first quartile, with AUC = 0.79 (95%CI = 0.69-0.88). There was no significant difference between MS-MDC and the radiologist (P = 0.40). The improvement of MS-MDC over HA was significant (P = 0.018). CONCLUSION: Mean shift clustering followed by automated selection of the most suspicious cluster resulted in accurate ROIs in breast MRI lesions.     

Evaluation of a robotic technique for transrectal MRI-guided prostate biopsies

Objectives  

To evaluate the accuracy and speed of a novel robotic technique as an aid to perform magnetic resonance image (MRI)-guided prostate biopsies on patients with cancer suspicious regions.     

Expression and characterization of the extracellular Ca(2+)-sensing receptor in melanotrope cells of Xenopus laevis

The extracellular Ca(2+)-sensing receptor (CaR) is expressed in many different organs in various species, ranging from mammals to fish. In some of these organs, this G protein-coupled receptor is involved in the control of systemic Ca(2+) homeostasis, whereas in other organs its role is unclear (e.g. in the pituitary gland). We have characterized the CaR in the neuroendocrine melanotrope cell of the intermediate pituitary lobe of the South African clawed toad Xenopus laevis. First, the presence of CaR mRNA was demonstrated by RT-PCR and in situ hybridization. Then it was shown that activation of the CaR by an elevated extracellular Ca(2+) concentration and different CaR-activators, including L-phenylalanine and spermine, stimulates both Ca(2+) oscillations and secretion from the melanotrope. Furthermore, it was revealed that activation of the receptor stimulates Ca(2+) oscillations through opening of voltage-operated Ca(2+) channels in the plasma membrane of the melanotropes. Finally, it was shown that the CaR activator L-phenylalanine could induce the biosynthesis of proopiomelanocortin in the intermediate lobe. Thus, in this study it is demonstrated that the CaR is present and functional in a defined cell type of the pituitary gland, the amphibian melanotrope cell.     

Computer aided analysis of breast MRI enhancement kinetics using mean shift c lustering and multifeature iterative region of interest selection

Purpose:

To evaluate automatic characterization of a breast MR lesion by its spatially coherent region of interest (ROI).

Materials and Methods:

The method delineated 247 enhancing lesions using Otsu thresholding after manually placing a sphere. Mean Shift Clustering subdivided each volume, based on features including pharmacokinetic parameters. An iteratively trained classifier to predict the most suspicious ROI (IsR) was used, to predict the malignancy likelihood of each lesion. Performance was evaluated using receiver operator characteristic (ROC) analysis, and compared with a previous prototype. IsR was compared with noniterative training. The effect of adding BI‐RADS? morphology (from a radiologist) to the classifier was investigated.

Results:

The area under the ROC curve (AUC) was 0.83 (95% confidence interval [CI] of 0.77–0.88), and was 0.75 (95%CI = 0.68–0.81; P = 0.029) without pharmacokinetic features. IsR performed better than conventional selection, based on one feature (AUC 0.75, 95%CI = 0.68–0.81; P = 0.035). With morphology, the AUC was 0.84 (95%CI = 0.78–0.88) versus 0.82 without (P = 0.40).

Conclusion:

Breast lesions can be characterized by their most suspicious, contiguous ROI using multi‐feature clustering and iterative training. Characterization was improved by including pharmacokinetic modeling, while in our experiments, including morphology did not improve characterization. J. Magn. Reson. Imaging 2012;36:1104–1112. © 2012 Wiley Periodicals, Inc.