Non-small-cell lung cancer (NSCLC) is the third most common cancer that spreads to the bone, resulting in osteolytic lesions caused by hyperactivation of osteoclasts. Activating mutations in ...epidermal growth factor receptor-tyrosine kinase (EGF-TK) are frequently associated with NSCLC, and afatinib is a first-line therapeutic drug, irreversibly targeting EGF-TK. However, the effects of afatinib on osteoclast differentiation and activation as well as the underlying mechanism remain unclear. In this study, afatinib significantly suppressed receptor activator of nuclear factor κB (RANK) ligand (RANKL)-induced osteoclast formation in bone marrow macrophages (BMMs). Consistently, afatinib inhibited the expression of osteoclast marker genes, whereas, it upregulated the expression of negative modulator genes. The bone resorbing activity of osteoclasts was also abrogated by afatinib. In addition, afatinib significantly inhibited RANKL-mediated Akt/protein kinase B and c-Jun N-terminal kinase phosphorylation. These results suggest that afatinib substantially suppresses osteoclasto-genesis by downregulating RANK signaling pathways, and thus may reduce osteolysis after bone metastasis. BMB Reports 2017; 50(3): 150-155
Incorporating bioactive molecules into synthetic ceramic scaffolds is challenging. In this study, to enhance bone regeneration, a magnesium phosphate (MgP) ceramic scaffold was incorporated with a ...novel indene compound, KR-34893. KR-34893 induced the deposition of minerals and expression of osteoblast marker genes in primary human bone marrow mesenchymal stem cells (BMSCs) and a mouse osteoblastic MC3T3-E1 cell line. Analysis of the mode of action showed that KR-34893 induced the phosphorylation of MAPK/extracellular signal-regulated kinase and extracellular signal-regulated kinase, and subsequently the expression of bone morphogenetic protein 7, accompanied by SMAD1/5/8 phosphorylation. Accordingly, KR-34893 was incorporated into an MgP scaffold prepared by 3D printing at room temperature, followed by cement reaction. KR-34893-incorporated MgP (KR-MgP) induced the expression of osteoblast differentiation marker genes in vitro. In a rat calvaria defect model, KR-MgP scaffolds enhanced bone regeneration and increased bone volume compared with MgP scaffolds, as assessed by micro-computed tomography and histological analyses. In conclusion, we developed a method for producing osteoinductive MgP scaffolds incorporating a bioactive organic compound, without high temperature sintering. The KR-MgP scaffolds enhanced osteoblast activation in vitro and bone regeneration in vivo.
As a part of the research and development activities for long-life core sodium-cooled fast reactors, the cladding performance of the ultra-long cycle fast reactor (UCFR) is evaluated with two design ...power levels (1000MWe and 100MWe) and cladding peak temperatures (873K and 923K). The key design concept of the UCFR is that it is non-refueling during its 30–60years of operation. This concept may require a maximum peak cladding temperature of 923K and a cladding radiation damage of over 200dpa (displacements per atom). Therefore, for the design of the UCFR, deformation due to thermal creep, irradiation creep, and swelling must be taken into consideration through quantitative evaluations. As candidate cladding materials for use in UCFRs, ferritic–martensitic (FM) steels, oxide dispersion strengthened (ODS) steels, and SiC-based composite materials are studied using deformation behavior modeling for a feasibility evaluation. The results of this study indicate that SiC is a potential UCFR cladding material, with the exception of irradiation creep due to high neutron fluence stemming from its long operating time of about 30–60years.
The purpose of this study is to investigate the interaction between austenitic stainless steel, AISI 316L, and gallium liquid metal at a high temperature, for the potential application to advanced ...fast reactor coolants. Test specimens of AISI 316L were exposed to static gallium at 500°C for up to 700h in two different cover-gas conditions, including air and vacuum. Similar experimental tests were conducted in gallium alloy liquid metal environments, including Ga–14Sn–6Zn and Ga–8Sn–6Zn, in order to study the effect of addition of alloying elements. The results have shown that the weight change and metal loss of specimens were generally reduced in Ga–14Sn–6Zn and Ga–8Sn–6Zn compared to those in pure gallium at a high temperature.
Wear particle-induced osteolysis is a serious complication that occurs in individuals with titanium (Ti)-based implants following long-term usage due to loosening of the implants. The control of ...excessive osteoclast differentiation and inflammation is essential for protecting against wear particle-induced osteolysis. The present study evaluated the effect of britanin, a pseudoguaianolide sesquiterpene isolated from Inula japonica, on osteoclastogenesis in vitro and Ti particle-induced osteolysis in vivo. The effect of britanin was examined in the osteoclastogenesis of mouse bone marrow-derived macrophages (BMMs) using TRAP staining, RT-PCR, western blotting and immunocytochemistry. The protective effect of britanin was examined in a mouse calvarial osteolysis model and evaluated using micro-CT and histomorphometry. Britanin inhibited osteoclast differentiation and F-actin ring formation in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor kB ligand in BMMs. The expression of osteoclast-specific marker genes, including tartrate-resistant acid phosphatase, cathepsin K, dendritic cell-specific transmembrane protein, matrix metallopeptidase 9 and nuclear factor of activated T-cells cytoplasmic 1, in the BMMs was significantly reduced by britanin. In addition, britanin reduced the expression of B lymphocyte-induced maturation protein-1, which is a transcriptional repressor of negative osteoclastogenesis regulators, including interferon regulatory factor-8 and B-cell lymphoma 6. Conversely, britanin increased the expression levels of anti-oxidative stress genes, namely nuclear factor erythroid-2-related factor 2, NAD(P)H quinone oxidoreductase 1 and heme oxygenase 1 in the BMMs. Furthermore, the administration of britanin significantly reduced osteolysis in a Ti particle-induced calvarial osteolysis mouse model. Based on these findings, it is suggested that britanin may be a potential therapeutic agent for wear particle-induced osteolysis and osteoclast-associated disease.
FDXR encodes the mitochondrial ferredoxin reductase, which is associated with auditory neuropathy spectrum disorder (ANSD) and optic atrophy. Only two studies have described FDXRrelated hearing loss. ...The auditory rehabilitation outcomes of this disease entity have not been investigated, and the pathophysiologic mechanism is not well elucidated. Here we report a hearingimpaired subject with co-segregation of the FDXR variant and post-synaptic type ANSD, who underwent cochlear implantation (CI) with favorable outcomes. We suggest a possible pathophysiologic mechanism of adult-onset ANSD via mitochondrial dysfunction.ObjectivesFDXR encodes the mitochondrial ferredoxin reductase, which is associated with auditory neuropathy spectrum disorder (ANSD) and optic atrophy. Only two studies have described FDXRrelated hearing loss. The auditory rehabilitation outcomes of this disease entity have not been investigated, and the pathophysiologic mechanism is not well elucidated. Here we report a hearingimpaired subject with co-segregation of the FDXR variant and post-synaptic type ANSD, who underwent cochlear implantation (CI) with favorable outcomes. We suggest a possible pathophysiologic mechanism of adult-onset ANSD via mitochondrial dysfunction.A 35-year-old woman was ascertained to have ANSD. Exome sequencing identified the genetic cause of hearing loss, and functional study measuring mitochondrial activity was performed to provide molecular evidence of pathophysiology. Expression of FDXR in the mouse cochlea was evaluated by immunohistochemistry. Intraoperatively, electrically-evoked compound action potential (ECAP) responses were measured, and mapping parameters were adjusted accordingly. Audiological outcomes were monitored for over 1 year.MethodsA 35-year-old woman was ascertained to have ANSD. Exome sequencing identified the genetic cause of hearing loss, and functional study measuring mitochondrial activity was performed to provide molecular evidence of pathophysiology. Expression of FDXR in the mouse cochlea was evaluated by immunohistochemistry. Intraoperatively, electrically-evoked compound action potential (ECAP) responses were measured, and mapping parameters were adjusted accordingly. Audiological outcomes were monitored for over 1 year.In lymphoblastoid cell lines (LCLs) carrying a novel FDXR variant, decreased ATP and MtMP levels and increased ROS levels were observed compared to control LCLs. These dysfunctions were restored by administering mitochondria isolated from umbilical cord mesenchymal stem cells, confirming the pathogenic potential of this variant via mitochondrial dysfunction. Partial ECAP responses during CI and FDXR expression in the mouse cochlea indicate that FDXR-related ANSD is postsynaptic. By increasing the pulse width during mapping, the patient's CI outcomes showed significant improvement over 1-year post-CI.ResultsIn lymphoblastoid cell lines (LCLs) carrying a novel FDXR variant, decreased ATP and MtMP levels and increased ROS levels were observed compared to control LCLs. These dysfunctions were restored by administering mitochondria isolated from umbilical cord mesenchymal stem cells, confirming the pathogenic potential of this variant via mitochondrial dysfunction. Partial ECAP responses during CI and FDXR expression in the mouse cochlea indicate that FDXR-related ANSD is postsynaptic. By increasing the pulse width during mapping, the patient's CI outcomes showed significant improvement over 1-year post-CI.Post-synaptic ANSD due to a novel FDXR variant linked to mitochondrial dysfunction was identified first in a Korean, and 1-year post CI outcomes were reported for the first time in the literature. Excellent audiologic results were obtained, and our results reiterate the correlation between genotype and CI outcomes in ANSD.ConclusionPost-synaptic ANSD due to a novel FDXR variant linked to mitochondrial dysfunction was identified first in a Korean, and 1-year post CI outcomes were reported for the first time in the literature. Excellent audiologic results were obtained, and our results reiterate the correlation between genotype and CI outcomes in ANSD.
The tectorial membrane (TM) is an apical extracellular matrix (ECM) that hovers over the cochlear sensory epithelium and plays an essential role in auditory transduction. The TM forms facing the ...luminal endolymph-filled space and exhibits complex ultrastructure. Contrary to the current extracellular assembly model, which posits that secreted collagen fibrils and ECM components self-arrange in the extracellular space, we show that surface tethering of α-tectorin (TECTA) via a glycosylphosphatidylinositol anchor is essential to prevent diffusion of secreted TM components. In the absence of surface-tethered TECTA, collagen fibrils aggregate randomly and fail to recruit TM glycoproteins. Conversely, conversion of TECTA into a transmembrane form results in a layer of collagens on the epithelial surface that fails to form a multilayered structure. We propose a three-dimensional printing model for TM morphogenesis: A new layer of ECM is printed on the cell surface concomitant with the release of a preestablished layer to generate the multilayered TM.
PDF
