P38 Mitogen-Activated Protein Kinase Inhibitor, FR167653, Inhibits Parathyroid Hormone Related Protein-Induced Osteoclastogenesis and Bone Resorption

p38 mitogen-activated protein kinase (MAPK) acts downstream in the signaling pathway that includes receptor activator of NF-κB (RANK), a powerful inducer of osteoclast formation and activation. We investigated the role of p38 MAPK in parathyroid hormone related protein (PTHrP)-induced osteoclastogenesis in vitro and PTHrP-induced bone resorption in vivo. The ability of FR167653 to inhibit osteoclast formation was evaluated by counting the number of tartrate-resistant acid phosphatase positive multinucleated cells (TRAP-positive MNCs) in in vitro osteoclastgenesis assays. Its mechanisms were evaluated by detecting the expression level of c-Fos and nuclear factor of activated T cells c1 (NFATc1) in bone marrow macrophages(BMMs) stimulated with sRANKL and M-CSF, and by detecting the expression level of osteoprotegerin (OPG) and RANKL in bone marrow stromal cells stimulated with PTHrP in the presence of FR167653. The function of FR167653 on bone resorption was assessed by measuring the bone resorption area radiographically and by counting osteoclast number per unit bone tissue area in calvaria in a mouse model of bone resorption by injecting PTHrP subcutaneously onto calvaria. Whole blood ionized calcium levels were also recorded. FR167653 inhibited PTHrP-induced osteoclast formation and PTHrP-induced c-Fos and NFATc1 expression in bone marrow macrophages, but not the expression levels of RANKL and OPG in primary bone marrow stromal cells treated by PTHrP. Furthermore, bone resorption area and osteoclast number in vivo were significantly decreased by the treatment of FR167653. Systemic hypercalcemia was also partially inhibited. Inhibition of p38 MAPK by FR167653 blocks PTHrP-induced osteoclastogenesis in vitro and PTHrP-induced bone resorption in vivo, suggesting that the p38 MAPK signaling pathway plays a fundamental role in PTHrP-induced osteoclastic bone resorption

Diffusion-tensor-based method for robust and practical estimation of axial and radial diffusional kurtosis.

OBJECTIVES: A new method that can estimate diffusional kurtosis image (DKI), estimated DKI (eDKI), parallel and perpendicular to neuronal fibres from greatly limited image data was designed to enable quick and practical assessment of DKI in clinics. The purpose of this study was to discuss the potential of this method for clinical use.\nMETHODS: Fourteen healthy volunteers were examined with a 3-Tesla MRI. The diffusion-weighting parameters included five different b-values (0, 500, 1,500, 2,000 and 2,500 s/mm2) with 64 different encoding directions for each of the b-values. K values were calculated by both conventional DKI (convDKI) and eDKI from these complete data, and also from the data that the encoding directions were abstracted to 32, 21, 15, 12 and 6. Error-pixel ratio and the root mean square error (RMSE) compared with the standard were compared between the methods (Wilcoxon signed-rank test: P < 0.05 was considered significant).\nRESULTS: Error-pixel ratio was smaller in eDKI than in convDKI and the difference was significant. In addition, RMSE was significantly smaller in eDKI than in convDKI, or otherwise the differences were not significant when they were obtained from the same data set.\nCONCLUSION: eDKI might be useful for assessing DKI in clinical settings

Development of Total Orbital Real-Time Attitude Control Simulator for Small Satellites

This paper presents the overview of the mathematical simulator TORA-Sim (Total Orbital Real-time Attitude control Simulator) developed by Kyushu University and Mitsubishi Precision Co.,Ltd. used for the satellite attitude control and the simulation results for the typical small satellite application. The results have demonstrated the validity of this simulator in use for the study of the attitude control law. This simulator was used for the development of onboard software for the attitude control of the Kyushu University’s small satellite “QSAT-EOS” launched last autumn

Distribution and clinical impact of molecular subtypes with dark zone signature of DLBCL in a Japanese real-world study

The distribution and clinical impact of cell-of-origin (COO) subtypes of diffuse large B-cell lymphoma (DLBCL) outside Western countries remain unknown. Recent literature also suggests that there is an additional COO subtype associated with the germinal center dark zone (DZ) that warrants wider validation to generalize clinical relevance. Here, we assembled a cohort of Japanese patients with untreated DLBCL and determined the refined COO subtypes, which include the DZ signature (DZsig), using the NanoString DLBCL90 assay. To compare the distribution and clinical characteristics of the molecular subtypes, we used a data set from the cohort of British Columbia Cancer (BCC) (n = 804). Through the 1050 patient samples on which DLBCL90 assay was successfully performed in our cohort, 35%, 45%, and 6% of patients were identified to have germinal center B-cell–like (GCB) DLBCL, activated B-cell–like (ABC) DLBCL, and DZsig-positive (DZsigpos) DLBCL, respectively, with the highest prevalence of ABC-DLBCL, differing significantly from the BCC result (P < .001). GCB-DLBCL, ABC-DLBCL, and DZsigpos-DLBCL were associated with 2-year overall survival rates of 88%, 75%, and 66%, respectively (P < .0001), with patients with DZsigpos-DLBCL having the poorest prognosis. In contrast, GCB-DLBCL without DZsig showed excellent outcomes after rituximab-containing immunochemotherapy. DZsigpos-DLBCL was associated with the significant enrichment of tumors with CD10 expression, concurrent MYC/BCL2 expression, and depletion of microenvironmental components (all, P < .05). These results provide evidence of the distinct distribution of clinically relevant molecular subtypes in Japanese DLBCL and that refined COO, as measured by the DLBCL90 assay, is a robust prognostic biomarker that is consistent across geographical areas