The reactive elements (Ti, Al and Zr) have been widely used for the improvement of the strength or the oxide resistance of ODS steels. In the present work, we studied the effect of the reactive ...elements on the precipitation of oxide particles, especially focusing upon the appropriate amount of the oxide composing elements, by addition of the large amounts of Y
2
O
3
and reactive elements. The mechanically alloyed powders are annealed in a wide temperature range from 773 to 1423 K and then analysed by various analysis methods (small-angle X-ray scattering and X-ray diffraction by synchrotron radiation X-ray, scanning transmission electron microscope combined with energy dispersion X-ray spectroscopy, high-resolution transmission microscopy and 3D-atom probe). Ti, Al and Zr enhanced the growth of oxide particles, opposite to the many studies of Ti- and Zr-added ODS steels, as a result of the addition of Y
2
O
3
and these elements ten times larger than those for usual use. The nucleation and growth of oxide particles are discussed by simulating the critical radius of nucleation and the growth based on the LSW theory. Y
4
Zr
3
O
12
is stable and easy to precipitate even at lower annealing temperature. All reactive elements enhance the growth of oxide particles because of their big molar volume as compared to that of Y
2
O
3
.
The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth ...factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1R
CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.
Abstract Clinically, bisphosphonate-related osteonecrosis (BRON) only occurs in the jaw (BRONJ). We aimed to determine differences between the jaw and other bones, as well as the relationship between ...periodontal pathogens and BRON. Twelve male Wistar rats were divided into two groups: group Z ( n = 6) were subcutaneously injected with zoledronic acid weekly for 4 weeks; group C ( n = 6) were injected with saline. One week after the final injection, rats in both groups were divided into three subgroups: Aa subgroup was injected with freeze-dried Aggregatibacter actinomycetemcomitans into bone marrow of the mandibles and femurs, while CFA and saline subgroups were injected with complete Freund's adjuvant (CFA) or saline using the same protocol. Four weeks after those injections, the rats were euthanized. Areas of osteonecrosis were measured histologically. Statistically, rats in group Z showed significantly wider osteonecrosis areas in both mandibles and femurs with each type of local injection than rats in group C. In group Z, mandibles and femurs stimulated with A. actinomycetemcomitans or CFA had significantly wider osteonecrosis areas than those stimulated with saline. We have developed a rat model with BRONJ-like lesions. Our results showed BRON to develop not only in the jaw but also in other types of bone following an inflammatory stimulus.
Tongue muscle damage impairs speaking and eating, thereby degrading overall health and quality of life. Skeletal muscles of the body are diverse in embryonic origin, anatomic location, and gene ...expression profiles. Responses to disease, atrophy, aging, or drugs vary among different muscles. Currently, most muscle studies are focused on limb muscles and the tongue is neglected. The regenerative ability of tongue muscle remains unknown, and thus there is need for tongue muscle research models. Here, we present a comprehensive characterization of the spatiotemporal dynamics in a mouse model of tongue muscle regeneration and establish a method for the isolation of primary tongue-derived satellite cells. We compare and contrast our observations with the tibialis anterior (TA) limb muscle. Acute injury was induced by intramuscular injection of cardiotoxin, a cytolytic agent, and examined at multiple timepoints. Initially, necrotic myofibers with fragmented sarcoplasm became infiltrated with inflammatory cells. Concomitantly, satellite cells expanded rapidly. Seven days postinjury, regenerated myofibers with centralized nuclei appeared. Full regeneration, as well as an absence of fibrosis, was evident 21 d postinjury. Primary tongue-derived satellite cells were isolated by enzymatic separation of tongue epithelium from mesenchyme followed by magnetic-activated cell sorting. We observed that tongue displays an efficient regenerative response similar to TA but with slightly faster kinetics. In vitro, tongue-derived satellite cells differentiated robustly into mature myotubes with spontaneous contractile behavior and myogenic marker expression. Comparison of gene expression signatures between tongue and TA-derived satellite cells revealed differences in the expression of positional-identity genes, including the HOX family. In conclusion, we have established a model for tongue regeneration useful for investigations of orofacial muscle biology. Furthermore, we showed that tongue is a viable source of satellite cells with unique properties and inherited positional memory.
Nonsteroidal anti-inflammatory drugs (NSAIDs) induce cytokines, including tumor necrosis factor-α and interleukins (ILs), in the small intestine via a Toll-like receptor 4 (TLR4)-dependent pathway, ...leading to intestinal ulceration. Activation of the inflammasome promotes pro-caspase-1 cleavage, leading to pro-IL-1β maturation. We examined the role of NLRP3 inflammasome in NSAID-induced enteropathy. Small intestinal damage developed 3 h after indomethacin administration, accompanied by increases in IL-1β and NLRP3 mRNA expression and mature caspase-1 and IL-1β levels. In vivo blocking of IL-1β using neutralizing antibodies attenuated indomethacin-induced damage, whereas exogenous IL-1β aggravated it. NLRP3(-/-) and caspase-1(-/-) mice exhibited resistance to the damage with reduction of mature IL-1β production. This resistance was abolished by exogenous IL-1β. TLR4 deficiency prevented intestinal damage and inhibited upregulation of NLRP3 and IL-1β mRNAs and maturation of pro-caspase-1 and pro-IL-1β, whereas TLR4 activation by its agonists exerted opposite effects. Apyrase, an adenosine triphosphate (ATP) scavenger, or Brilliant Blue G, a purinergic P2X7 receptor antagonist, inhibited the damage as well as caspase-1 activation and IL-1β processing, despite there being sufficient amounts of pro-IL-1β and NLRP3. These results suggest that NLRP3 inflammasome-derived IL-1β plays a crucial role in NSAID-induced enteropathy and that both TLR4- and P2X7-dependent pathways are required for NLRP3 inflammasome activation.
Retinoblastoma (RB) protein inactivation during tumor progression is often associated with acquisition of immature phenotypes and resistance to therapy. Determination of an RB inactivation signature ...in a context of gaining undifferentiated phenotype in a p53-null sarcoma system revealed a critical role for interleukin (IL)-6. Using a Gene Set Enrichment Analysis (GSEA), we discovered that poorly differentiated breast cancers are enriched for this RB inactivation signature. Accelerated IL-6 secretion following RB inactivation in an RB-intact luminal-type breast cancer cell line MCF-7 promoted a positive feed forward loop between IL-6 and STAT3 driving tumor growth and endocrine therapy resistance. In addition, some of RB-intact basal-like type breast cancer cell lines exhibited a similar phenotype following RB depletion. The mechanism whereby RB inactivation increases IL-6 production in MCF-7 cells appeared to involve fatty acid oxidation (FAO)-dependent mitochondrial metabolism and c-Jun NH(2)-terminal kinase (JNK). In addition, IL-6, via STAT3-mediated feedback to mitochondria, autonomously adjusts mitochondrial superoxide to levels suitable to maintain stem cell-like activity. The gene expression profile of luminal-type breast cancer patients with low RB expression revealed high enrichment of genes involved in mitochondrial respiration and downstream targets of IL-6. These findings unveiled an unexpected strategy whereby RB suppresses malignant features of cancer cells through metabolic reprogramming and cell-autonomous inflammation.
Oral Diseases (2011) 17, 462–468
Oral squamous cell carcinomas (SCCs) are malignant tumours that frequently invade the mandibular bone and bone invasion is a common clinical problem. Recent studies ...have revealed that bone resorption by osteoclasts is an important step in the process of bone invasion by oral SCCs. However, the cellular and molecular mechanisms of bone invasion by oral SCCs remain unclear. Oral SCCs invade the mandibular bone through an erosive, mixed or infiltrative pattern that correlates with clinical behaviours. The expressions of interleukin (IL)‐6, IL‐11, tumour necrosis factor (TNF) α and parathyroid hormone‐related protein (PTHrP) were higher in the infiltrative pattern than in the erosive pattern. These cytokines lead to receptor activator of NF‐κB ligand (RANKL) expression or osteoprotegerin (OPG) suppression not only in oral SCC cells but also in cancer stromal cells to induce osteoclastogenesis. Taken together, oral SCCs provide a suitable microenvironment for osteoclastogenesis to regulate the balance of RANKL and OPG. In this review, we introduce recent advances in the knowledge of the cellular and molecular mechanisms, by which oral SCC invades mandibular bone based on the recent findings of our lab and others.
Methyl levulinate is a promising building block which can be derived from cellulosic biomass. In this paper, a combination of aluminum compounds and organic sulfonic acids was found to be an ...efficient catalyst system for direct methyl levulinate synthesis from both microcrystalline cellulose and wood powder. Electrospray ionization mass analysis revealed the formation of aluminum sulfonate complexes in the reaction solution. The reaction properties of this catalyst system suggested that cooperative catalysis of aluminum sulfonates and organic sulfonic acids in methanol was responsible for the efficient formation of methyl levulinate.
In this study, we analyzed long-term trends in calcium (Ca) concentrations for 70 Norwegian lakes spanning a broad geographical range and for a wide range of ambient drivers. A striking decline in Ca ...concentrations was observed during the past 30 yr. The trend was most pronounced in southern, previously acidified localities, while there were weaker and less consistent patterns for central and northern regions. For previously acidified areas, this observed decline in Ca is likely related to base cation depletion or reduced Ca mobilization as a consequence of reduced H₂SO₄-deposition. However, lower chloride concentrations, increased runoff and forest density (represented by Normalized Difference Vegetation Index, NDVI) also exerted strong negative impacts on Ca-concentrations. For lakes with a significant negative trend (n = 34), the average decline was −11.05% per decade, corresponding to −0.023 mg Ca L−1 yr−1. This trend may pull levels of Ca in these already Ca-deficient poor lakes toward, or below, critically low levels for a range of organisms. A somewhat paradoxical effect of the successful battle against anthropogenic acidification is thus that it may impose an increased Ca-deficiency of freshwater ecosystems.
Streptococcal toxic shock syndrome (STSS) is a severe invasive infection characterized by the sudden onset of shock, multi-organ failure, and high mortality. In Japan, appropriate notification ...measures based on the Infectious Disease Control law are mandatory for cases of STSS caused by β-haemolytic streptococcus. STSS is mainly caused by group A streptococcus (GAS). Although an average of 60–70 cases of GAS-induced STSS are reported annually, 143 cases were recorded in 2011. To determine the reason behind this marked increase, we characterized the emm genotype of 249 GAS isolates from STSS patients in Japan from 2010 to 2012 and performed antimicrobial susceptibility testing. The predominant genotype was found to be emm1, followed by emm89, emm12, emm28, emm3, and emm90. These six genotypes constituted more than 90% of the STSS isolates. The number of emm1, emm89, emm12, and emm28 isolates increased concomitantly with the increase in the total number of STSS cases. In particular, the number of mefA-positive emm1 isolates has escalated since 2011. Thus, the increase in the incidence of STSS can be attributed to an increase in the number of cases associated with specific genotypes.
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