Recombinant human FGF-2 for the treatment of early-stage osteonecrosis of the femoral head: TRION, a single-arm, multicenter, Phase II trial

Aim: This study aimed to evaluate the 2-year outcomes from a clinical trial of recombinant human FGF-2 (rhFGF-2) for osteonecrosis of the femoral head (ONFH). Patients & methods: Sixty-four patients with nontraumatic, precollapse and large ONFHs were percutaneously administered with 800 μg rhFGF-2 contained in gelatin hydrogel. Setting the end point of radiological collapse, we analyzed the joint preservation period of the historical control. Changes in two validated clinical scores, bone regeneration and safety were evaluated. Results: Radiological joint preservation time was significantly higher in the rhFGF-2 group than in the control group. The ONFHs tended to improve to smaller ONFHs. The postoperative clinical scores significantly improved. Thirteen serious adverse events showed recovery. Conclusion: rhFGF-2 treatment increases joint preservation time with clinical efficacy, radiological bone regeneration and safety

OISTER optical and near-infrared monitoring observations of peculiar radio-loud active galactic nucleus SDSS J110006.07+442144.3

We present monitoring campaign observations at optical and near-infrared (NIR) wavelengths for a radio-loud active galactic nucleus (AGN) at z = 0.840, SDSS J110006.07+442144.3 (hereafter, J1100+4421), which was identified during a flare phase in late 2014 February. The campaigns consist of three intensive observing runs from the discovery to 2015 March, mostly within the scheme of the OISTER collaboration. Optical-NIR light curves and simultaneous spectral energy distributions (SEDs) are obtained. Our measurements show the strongest brightening in 2015 March. We found that the optical-NIR SEDs of J1100+4421 show an almost steady shape despite the large and rapid intranight variability. This constant SED shape is confirmed to extend to ∼5 μm in the observed frame using the archival WISE data. Given the lack of absorption lines and the steep power-law spectrum of α ν ∼ -1.4, where fνναν, synchrotron radiation by a relativistic jet with no or small contributions from the host galaxy and the accretion disk seems most plausible as an optical-NIR emission mechanism. The steep optical-NIR spectral shape and the large amplitude of variability are consistent with this object being a low ν peak jet-dominated AGN. In addition, sub-arcsecond resolution optical imaging data taken with Subaru Hyper Suprime-Cam does not show a clear extended component and the spatial scales are significantly smaller than the large extensions detected at radio wavelengths. The optical spectrum of a possible faint companion galaxy does not show any emission lines at the same redshift, and hence a merging hypothesis for this AGN-related activity is not supported by our observations. © The Author 2017. Published by Oxford University Press on behalf of the Astronomical Society of Japan. All rights reserved

Reduced dynamic loads due to hip dislocation induce acetabular cartilage degeneration by IL-6 and MMP3 via the STAT3/periostin/NF-κB axis

Abstract Developmental dysplasia of the hip (DDH) is characterized by anatomical abnormalities of the hip joint, ranging from mild acetabular dysplasia to hip subluxation and eventually dislocation. The mechanism underlying the cartilage degeneration of the hip joints exposed to reduced dynamic loads due to hip dislocation remains unknown. We established a rodent hip dislocation (disarticulation; DA) model of DDH (DA-DDH rats and mice) by swaddling. Expression levels of periostin (Postn) and catabolic factors, such as interleukin-6 (IL-6) and matrix metalloproteinase 3 (Mmp3), increased and those of chondrogenic markers decreased in the acetabular cartilage of the DA-DDH models. Postn induced IL-6 and Mmp3 expression in chondrocytes through integrin αVβ3, focal adhesion kinase, Src, and nuclear factor-κB (NF-κB) signaling. The microgravity environment created by a random positioning machine induced Postn expression in chondrocytes through signal transducer and activator of transcription 3 (STAT3) signaling. IL-6 stimulated Postn expression via STAT3 signaling. Furthermore, cartilage degeneration was suppressed in the acetabulum of Postn −/− DA-DDH mice compared with that in the acetabulum of wild type DA-DDH mice. In summary, reduced dynamic loads due to hip dislocation induced acetabular cartilage degeneration via IL-6 and MMP3 through STAT3/periostin/NF-κB signaling in the rodent DA-DDH models

Loss of Hep Par 1 immunoreactivity in the livers of patients with carbamoyl phosphate synthetase 1 deficiency

The hepatocyte paraffin 1 (Hep Par 1) antibody is widely used as a hepatocyte marker, recognizing carbamoyl phosphate synthetase 1 (CPS1), an essential component of the urea cycle. Various missense, nonsense, and frameshift mutations occur in the CPS1 gene. In neonatal patients with homozygous CPS1 deficiency (CPS1D), urea cycle defects with resulting severe hyperammonemia can be fatal, though liver transplantation provides a complete cure for CPS1D. We performed Hep Par 1 immunostaining in the explanted livers of 10 liver transplant patients with CPS1D. Seven were negative for Hep Par 1 in the hepatocytes and the other three showed normal diffuse granular cytoplasmic staining. As expected, all three Hep Par 1-positive patients had at least one missense mutation, and all four patients who had only nonsense or frameshift mutations were Hep Par 1-negative. The other three patients were unexpectedly negative for Hep Par 1, even though each had one missense mutation. These results suggest that CPS1D can be related to the loss of Hep Par 1 reactivity due to the loss of protein production, a one amino acid substitution resulting in an abortive protein product, or both. Hep Par 1 immunohistochemistry can be used as a simple method to confirm CPS1D

SAR Exploration Guided by LE and Fsp³: Discovery of a Selective and Orally Efficacious RORγ Inhibitor

A novel series of RORγ inhibitors was identified starting with the HTS hit <b>1</b>. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp³ carbon atoms (Fsp³), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor <b>3z</b>