The diterpenoid alkaloid noroxoaconitine is a Mapkap kinase 5 (MK5/PRAK) inhibitor

The mitogen-activated protein kinase-activated protein kinase MK5 is ubiquitously expressed in vertebrates and is implicated in cell proliferation, cytoskeletal remodeling, and anxiety behavior. This makes MK5 an attractive drug target. We tested several diterpenoid alkaloids for their ability to suppress MK5 kinase activity. We identified noroxoaconitine as an ATP competitor that inhibited the catalytic activity of MK5 in vitro (IC50 = 37.5 μM; Ki = 0.675 μM) and prevented PKA-induced nuclear export of MK5, a process that depends on kinase active MK5. MK5 is closely related to MK2 and MK3, and noroxoaconitine inhibited MK3- and MK5- but not MK2-mediated phosphorylation of the common substrate Hsp27. Molecular docking of noroxoaconitine into the ATP binding sites indicated that noroxoaconitine binds more strongly to MK5 than to MK3. Noroxoaconitine and derivatives may help in elucidating the precise biological functions of MK5 and may prove to have therapeutic values

Gadoxetate disodium-enhanced MRI: Assessment of arterial phase artifacts and hepatobiliary uptake in a large series.

To report the quality of gadoxetate disodium MRI in a large series by assessing the prevalence of: 1) arterial phase (AP) artifacts and its predictive factors, 2) decreased hepatic contrast uptake during the hepatobiliary phase (HBP). This retrospective single center study included 851 patients (M/F:537/314, mean age: 63y) with gadoxetate disodium MRI. The MRI protocol included unenhanced, dual arterial [early and late arterial phases (AP)], portal venous, transitional and hepatobiliary phases. Three radiologists graded dynamic images using a 5-scale score (1: no motion, 5: severe, nondiagnostic) for assessment of transient severe motion (TSM, defined as a score ≥4 during at least one AP with a score ≤3 during other phases). HBP uptake was assessed using a 3-scale score (based on portal vein/hepatic signal). The association between demographic, clinical and acquisition parameters with TSM was tested in uni- and multivariate logistic regression. TSM was observed in 103/851 patients (12.1 %): 83 (9.8 %) in one AP and 20 (2.3 %) in both APs. A score of 5 (nondiagnostic) was assigned in 7 patients in one AP (0.8 %) and none in both. Presence of TSM was significantly associated with age (p = 0.002) and liver disease (p = 0.033) in univariate but not in multivariate analysis (p > 0.05). No association was found between acquisition parameters and TSM occurrence. Limited or severely limited HBP contrast uptake was observed in 87 patients (10.2 %), and TSM was never associated with severely limited HBP contrast uptake. TSM was present in approximately 12 % of gadoxetate disodium MRIs, rarely on both APs (2.3 %), and was poorly predicted. TSM was never associated with severely limited HBP contrast uptake

FDG-PET/MRI for the preoperative diagnosis and staging of peritoneal carcinomatosis: a prospective multireader pilot study.

To assess the diagnostic performance of FDG-PET/MRI for the preoperative diagnosis and staging of peritoneal carcinomatosis (PC) using surgical Sugarbaker's PC index (PCI) as the reference in a multireader pilot study. Fourteen adult patients (M/F: 3/11, mean age: 57 ± 12 year) with PC were prospectively included in this single-center study. Patients underwent FDG-PET/MRI prior to surgery (mean delay: 14 d, range: 1-63 d). Images were reviewed independently by 2 abdominal radiologists and 2 nuclear medicine physicians. The radiologists assessed contrast-enhanced abdominal MR images, while the nuclear medicine physicians assessed PET images fused with T2-weighted images. The abdomen was divided in 13 regions, scored from 0 to 3. A hybrid FDG-PET/MRI radiological PCI was created by combining the study data. Radiological PCI was compared to the surgical PCI on a per-patient and per-region basis. Inter-reader agreement was evaluated. Mean surgical PCI was 10 ± 8 (range: 0-24). Inter-reader agreement was almost perfect for all sets for radiologic PCI (Kappa: 0.81-0.98). PCI scores for all reading sets significantly correlated with the surgical PCI score (r range: 0.57-0.74, p range: < 0.001-0.003). Pooled per-patient sensitivity, specificity, and accuracy were 75%/50%/71.4% for MRI, 66.7%/50%/64.3% for FDG-PET, and 91.7%/50%/85.7% for FDG-PET/MRI, without significant difference (p value range 0.13-1). FDG-PET/MRI achieved 100% sensitivity and 100% specificity for a cutoff PCI of 20. Per-region sensitivity and accuracy were lower: 37%/61.8% for MRI, 17.8%/64.3% for FDG-PET, and 52.7%/60.4% for FDG-PET/MRI, with significantly higher sensitivity for FDG-PET/MRI. Per-region specificity was higher for FDG-PET (95%) compared to MRI (78.4%) and FDG-PET/MRI (66.5%). FDG-PET/MRI achieved an excellent diagnostic accuracy per-patient and weaker performance per-region for detection of PC. The added value of PET/MRI compared to MRI and FDG-PET remains to be determined

EHPred: an SVM-based method for epoxide hydrolases recognition and classification

A two-layer method based on support vector machines (SVMs) has been developed to distinguish epoxide hydrolases (EHs) from other enzymes and to classify its subfamilies using its primary protein sequences. SVM classifiers were built using three different feature vectors extracted from the primary sequence of EHs: the amino acid composition (AAC), the dipeptide composition (DPC), and the pseudo-amino acid composition (PAAC). Validated by 5-fold cross tests, the first layer SVM classifier can differentiate EHs and non-EHs with an accuracy of 94.2% and has a Matthew’s correlation coefficient (MCC) of 0.84. Using 2-fold cross validation, PAAC-based second layer SVM can further classify EH subfamilies with an overall accuracy of 90.7% and MCC of 0.87 as compared to AAC (80.0%) and DPC (84.9%). A program called EHPred has also been developed to assist readers to recognize EHs and to classify their subfamilies using primary protein sequences with greater accuracy