Repeatability and reproducibility of multiparametric magnetic resonance imaging of the liver

As the burden of liver disease reaches epidemic levels, there is a high unmet medical need to develop robust, accurate and reproducible non-invasive methods to quantify liver tissue characteristics for use in clinical development and ultimately in clinical practice. This prospective cross-sectional study systematically examines the repeatability and reproducibility of iron-corrected T1 (cT1), T2*, and hepatic proton density fat fraction (PDFF) quantification with multiparametric MRI across different field strengths, scanner manufacturers and models. 61 adult participants with mixed liver disease aetiology and those without any history of liver disease underwent multiparametric MRI on combinations of 5 scanner models from two manufacturers (Siemens and Philips) at different field strengths (1.5T and 3T). We report high repeatability and reproducibility across different field strengths, manufacturers, and scanner models in standardized cT1 (repeatability CoV: 1.7%, bias -7.5ms, 95% LoA of -53.6 ms to 38.5 ms; reproducibility CoV 3.3%, bias 6.5 ms, 95% LoA of -76.3 to 89.2 ms) and T2* (repeatability CoV: 5.5%, bias -0.18 ms, 95% LoA -5.41 to 5.05 ms; reproducibility CoV 6.6%, bias -1.7 ms, 95% LoA -6.61 to 3.15 ms) in human measurements. PDFF repeatability (0.8%) and reproducibility (0.75%) coefficients showed high precision of this metric. Similar precision was observed in phantom measurements. Inspection of the ICC model indicated that most of the variance in cT1 could be accounted for by study participants (ICC = 0.91), with minimal contribution from technical differences. We demonstrate that multiparametric MRI is a non-invasive, repeatable and reproducible method for quantifying liver tissue characteristics across manufacturers (Philips and Siemens) and field strengths (1.5T and 3T)

Selective inhibition of intestinal guanosine 3,5-cyclic monophosphate signaling by small-molecule protein kinase inhibitors

The guanosine 3,5-cyclic monophosphate (cGMP)-dependent protein kinase II (cGKII) serine/threonine kinase relays signaling through guanylyl cyclase C (GCC) to control intestinal fluid homeostasis. Here, we report the discovery of small-molecule inhibitors of cGKII. These inhibitors were imidazole-aminopyrimidines, which blocked recombinant human cGKII at submicromolar concentrations but exhibited comparatively little activity toward the phylogenetically related protein kinases cGKI and cAMP-dependent protein kinase (PKA). Whereas aminopyrimidyl motifs are common in protein kinase inhibitors, molecular modeling of these imidazole-aminopyrimidines in the ATP-binding pocket of cGKII indicated an unconventional binding mode that directs their amine substituent into a narrow pocket delineated by hydrophobic residues of the hinge and the C-helix. Crucially, this set of residues included the Leu-530 gatekeeper, which is not conserved in cGKI and PKA. In intestinal organoids, these compounds blocked cGKII-dependent phosphorylation of the vasodilator-stimulated phosphoprotein (VASP). In mouse small intestinal tissue, cGKII inhibition significantly attenuated the anion secretory response provoked by the GCC-activating bacterial heat-stable toxin (STa), a frequent cause of infectious secretory diarrhea. In contrast, both PKA-dependent VASP phosphorylation and intestinal anion secretion were unaffected by treatment with these compounds, whereas experiments with T84 cells indicated that they weakly inhibit the activity of cAMP-hydrolyzing phosphodiesterases. As these protein kinase inhibitors are the first to display selective inhibition of cGKII, they may expedite research on cGMP signaling and may aid future development of therapeutics for managing diarrheal disease and other pathogenic syndromes that involve cGKII

Transcriptome analysis of the distal small intestine of Cftr null mice

Cystic fibrosis (CF) is caused by mutations in the gene encoding the CFTR anion channel. Loss of CFTR function in pancreatic, biliary and intestinal epithelia, severely affects gastrointestinal function. Transcriptome analysis indicated the activation of an innate and adaptive immune response in the distal small intestine of Cftr null mice. Inflammation was associated with differential regulation of numerous genes involved in the transport and metabolism of nutrients and, particularly, lipids, that are targeted by ligand-dependent nuclear receptors and/or HNF4α. Among the most strongly down-regulated genes are the FXR targets Fgf15 and Nr0b2, the PPARα target Pdk4, and the PXR target Ces2a, whereas expression of the CF modifier gene Slc6a14 was strongly increased. Most changes in gene expression were reversed by bacterial containment. Our data suggest that the gut microbiota has a pervasive effect on gene expression in CF mice, affecting enterocyte maturation, lipid metabolism, and nutrient absorption in CF

Impaired Intestinal Farnesoid X Receptor Signaling in Cystic Fibrosis Mice

Background & Aims: The bile acid (BA)-activated farnesoid X receptor (FXR) controls hepatic BA synthesis and cell proliferation via the intestinal hormone fibroblast growth factor 19. Because cystic fibrosis (CF) is associated with intestinal dysbiosis, anomalous BA handling, and biliary cirrhosis, we investigated FXR signaling in CF. Methods: Intestinal and hepatic expression of FXR target genes and inflammation markers was assessed in Cftr null mice and controls. Localization of the apical sodium-dependent BA transporter was assessed, and BAs in gastrointestinal tissues were analyzed. The CF microbiota was characterized and FXR signaling was investigated in intestinal tissue and organoids. Results: Ileal murine fibroblast growth factor 19 ortholog (Fgf15) expression was strongly reduced in CF mice, compared with controls. Luminal BA levels and localization of apical sodium-dependent BA transporter was not affected, and BAs induced Fgf15 up to normal levels in CF ileum, ex vivo, and CF organoids. CF mice showed a dysbiosis that was associated with a marked up-regulation of genes involved in host–microbe interactions, including those involved in mucin glycosylation, antimicrobial defense, and Toll-like receptor signaling. Antibiotic treatment reversed the up-regulation of inflammatory markers and restored intestinal FXR signaling in CF mice. Conversely, FXR-dependent gene induction in ileal tissue and organoids was repressed by bacterial lipopolysaccharide and proinflammatory cytokines, respectively. Loss of intestinal FXR activity was associated with a markedly blunted hepatic trophic response to oral BA supplementation, and with impaired repression of Cyp7a1, the gene encoding the rate-limiting enzyme in BA synthesis. Conclusions: In CF mice, the gut microbiota represses intestinal FXR activity, and, consequently, FXR-dependent hepatic cell proliferation and feedback control of BA synthesis

Phospholipid oxidation and carotenoid supplementation in Alzheimer’s disease patients

Alzheimer's disease (AD) is a progressive, neurodegenerative disease, characterised by decline of memory, cognitive function and changes in behaviour. Generic markers of lipid peroxidation are increased in AD, therefore reactive oxygen species have been suggested to be involved in the aetiology of cognitive decline. Carotenoids are depleted in AD serum, therefore we have compared serum lipid oxidation between AD and age-matched control subjects before and after carotenoid supplementation. The novel oxidised phospholipid biomarker 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) was analysed using electrospray ionization tandem mass spectrometry (MS) with multiple reaction monitoring (MRM), 8-isoprostane (IsoP) was measured by ELISA and ferric reducing antioxidant potential (FRAP) was measured by a colorimetric assay. AD patients (n=21) and healthy age-matched control subjects (n=16) were supplemented with either Macushield™ (10 mg meso-zeaxanthin, 10 mg lutein, 2 mg zeaxanthin) or placebo (sunflower oil) for six months. The MRM-MS method determined serum POVPC sensitively (from 10 µl serum) and reproducibly (CV=7.9%). At baseline, AD subjects had higher serum POVPC compared to age-matched controls, (p=0.017) and cognitive function was correlated inversely with POVPC (r=−0.37; p=0.04). After six months of carotenoid intervention, serum POVPC was not different in AD patients compared to healthy controls. However, POVPC was significantly higher in control subjects after six months of carotenoid intervention compared to their baseline (p=0.03). Serum IsoP concentration was unrelated to disease or supplementation. Serum FRAP was significantly lower in AD than healthy controls but was unchanged by carotenoid intervention (p=0.003). In conclusion, serum POVPC is higher in AD patients compared to control subjects, is not reduced by carotenoid supplementation and correlates with cognitive function

Annexin A1 expression in a pooled breast cancer series: Association with tumor subtypes and prognosis

Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods: Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results: The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P adj = 1.35; 95 % CI = 1.05-1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91-1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17-2.45). Conclusions: ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases

Gas adsorption properties of ZSM-5 zeolites heated to extreme temperatures

Zeolites are broadly useful catalysts and molecular sieve adsorbents for purification. In this work the thermal degradations of bare and platinum-loaded ZSM-5 was studied with the goal of understanding the behavior of nanoporous solids at extreme temperatures comparable to those present in nuclear fuels. Zeolites were heated in air and nitrogen at temperatures up to 1500 °C, and then characterized for thermal stability via X-ray diffraction (XRD) and for gas adsorption by the Brunauer-Emmett-Teller (BET) method. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) were also employed. These results indicate zeolites are stable when heat-treated up to 800 °C and degrade slowly at higher temperatures. However, significant surface area degradation begins at 1025–1150 °C with an activation energy of 400 kJ/mole. At 1500 °C, gas adsorption measurements and SEM images show complete collapse of the porous structure. Critically for nuclear fuel applications, however, the zeolites still adsorb helium in significant quantities

Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

A search for the decay B+→K+ννˉB^+ \to K^+ \nu \bar{\nu}

We search for the rare flavor-changing neutral-current decay $B^+ \to K^+ \nu \bar{\nu}$ in a data sample of 82 fb$^{-1}$ collected with the {\sl BABAR} detector at the PEP-II B-factory. Signal events are selected by examining the properties of the system recoiling against either a reconstructed hadronic or semileptonic charged-B decay. Using these two independent samples we obtain a combined limit of ${\mathcal B}(B^+ \to K^+ \nu \bar{\nu})<5.2 \times 10^{-5}$ at the 90% confidence level. In addition, by selecting for pions rather than kaons, we obtain a limit of ${\mathcal B}(B^+ \to \pi^+ \nu \bar{\nu})<1.0 \times 10^{-4}$ using only the hadronic B reconstruction method.Comment: 7 pages, 8 postscript figures, submitted to Phys. Rev. Let