Mutated KIT Tyrosine Kinase as a Novel Molecular Target in Acute Myeloid Leukemia

KIT is a type-III receptor tyrosine kinase that contributes to cell signaling in various cells. Since KIT is activated by overexpression or mutation and plays an important role in the development of some cancers, such as gastrointestinal stromal tumors and mast cell disease, molecular therapies targeting KIT mutations are being developed. In acute myeloid leukemia (AML), genome profiling via next-generation sequencing has shown that several genes that are mutated in patients with AML impact patients’ prognosis. Moreover, it was suggested that precision-medicine-based treatment using genomic data will improve treatment outcomes for AML patients. This paper presents (1) previous studies regarding the role of KIT mutations in AML, (2) the data in AML with KIT mutations from the HM-SCREEN-Japan-01 study, a genome profiling study for patients newly diagnosed with AML who are unsuitable for the standard first-line treatment (unfit) or have relapsed/refractory AML, and (3) new therapies targeting KIT mutations, such as tyrosine kinase inhibitors and heat shock protein 90 inhibitors. In this era when genome profiling via next-generation sequencing is becoming more common, KIT mutations are attractive novel molecular targets in AML.     

Structure and formation of ant transportation networks

Many biological systems use extensive networks for the transport of resources and information. Ants are no exception. How do biological systems achieve efficient transportation networks in the absence of centralized control and without global knowledge of the environment? Here, we address this question by studying the formation and properties of inter-nest transportation networks in the Argentine ant (Linepithema humile). We find that the formation of inter-nest networks depends on the number of ants involved in the construction process. When the number of ants is sufficient and networks do form, they tend to have short total length but a low level of robustness. These networks are topologically similar to either minimum spanning trees or Steiner networks. The process of network formation involves an initial construction of multiple links followed by a pruning process that reduces the number of trails. Our study thus illuminates the conditions under and the process by which minimal biological transport networks can be constructed.     

Processing effects on in-flight particle state and functional coating properties of plasma-sprayed manganese zinc ferrite

Magnetic properties of manganese zinc ferrite (MZF) coatings deposited by atmospheric dc plasma spraying largely depend on zinc and oxygen loss during particle flight. The temperature and velocity of in-flight MZF particles were widely varied by changing plasma spray conditions to examine these chemistry changes and resultant magnetic properties. Zn loss increases with increased particle temperature or decreased particle velocity. Meanwhile, wüstite (FeO) formation, related to the oxygen loss, is more complicated, partly because oxygen, which is lost during flight in the high-temperature zone of the plasma jet, can be recovered at longer spray distances. As a result, the saturation magnetization of MZF coatings decreases and the coercivity increases with increased particle temperature or decreased particle velocity.     

Characteristics of the Arc Voltage of a High‐Current Air Arc in a Sealed Chamber

The effect of the arc voltage on various factors of design and control was investigated for high currents in order to develop design guidelines for circuit breakers. In this study, the dependence on such factors, namely, the current, arc length, electrode surface area, and internal pressure of the arc voltage, was evaluated quantitatively. As a result of the evaluations, it was estimated that the arc voltage near the electrode surface rises linearly with the arc current and the power ?0.8 of the surface area, and that the voltage in the arc column rises as the 0.3 power of the pressure increase. We confirmed the validity of the estimated voltage characteristics by comparison with the generated voltage in an actual arc‐extinction chamber. The characteristics of the estimated voltage can provide effective guidelines for the design of arc extinguishing chambers. © 2013 Wiley Periodicals, Inc. Electr Eng Jpn, 186(1): 34–42, 2014; Published online in Wiley Online Library ( wileyonlinelibrary.com ). DOI 10.1002/eej.22487     

Therapeutic Targets and Emerging Treatments in Advanced Chondrosarcoma

Simple SummaryChondrosarcomas develop chemoresistance to standard anticancer drugs, making it difficult to control unresectable or metastatic chondrosarcomas. To improve the clinical outcomes of chondrosarcoma, new treatment approaches, such as molecule-targeting agents and immunotherapy, are needed. Recent research has revealed promising biomarkers and therapeutic targets for chondrosarcoma. In addition, several molecule-targeting agents have shown favorable antitumor activities in several clinical studies in patients with advanced sarcomas, including chondrosarcoma. This review summarizes recent basic studies on biomarkers and therapeutic targets and recent clinical studies on treating chondrosarcomas.AbstractDue to resistance to standard anticancer agents, it is difficult to control the disease progression in patients with metastatic or unresectable chondrosarcoma. Novel therapeutic approaches, such as molecule-targeting drugs and immunotherapy, are required to improve clinical outcomes in patients with advanced chondrosarcoma. Recent studies have suggested several promising biomarkers and therapeutic targets for chondrosarcoma, including IDH1/2 and COL2A1. Several molecule-targeting agents and immunotherapies have shown favorable antitumor activity in clinical studies in patients with advanced chondrosarcomas. This review summarizes recent basic studies on biomarkers and molecular targets and recent clinical studies on the treatment of chondrosarcomas.     

Detail analysis of fusion neutronics benchmark experiment for iron

In order to specify the best nuclear data on iron, the fusion neutronics benchmark experiment on iron at Japan Atomic Energy Agency (JAEA)/Fusion Neutronics Source (FNS) was analyzed in detail with MCNP-4C and the latest nuclear data libraries, JENDL-3.3, FENDL-2.1, JEFF-3.1 and ENDF/B-VII.0. As a result, totally the calculation result with ENDF/B-VII.0 agreed with the measurement best, except that it underestimated the measured neutron flux above 10 MeV with the depth. It was noted that the calculation result with JENDL-3.3 overestimated the measured neutrons below a few keV. Through the DORT calculations based on the iron data in ENDF/B-VII.0, it was found out that the first inelastic scattering cross-section data of ⁵⁷Fe in JENDL-3.3 caused the overestimation.     

Application of Homology Modeling by Enhanced Profile–Profile Alignment and Flexible-Fitting Simulation to Cryo-EM Based Structure Determination

Application of cryo-electron microscopy (cryo-EM) is crucially important for ascertaining the atomic structure of large biomolecules such as ribosomes and protein complexes in membranes. Advances in cryo-EM technology and software have made it possible to obtain data with near-atomic resolution, but the method is still often capable of producing only a density map with up to medium resolution, either partially or entirely. Therefore, bridging the gap separating the density map and the atomic model is necessary. Herein, we propose a methodology for constructing atomic structure models based on cryo-EM maps with low-to-medium resolution. The method is a combination of sensitive and accurate homology modeling using our profile–profile alignment method with a flexible-fitting method using molecular dynamics simulation. As described herein, this study used benchmark applications to evaluate the model constructions of human two-pore channel 2 (one target protein in CASP13 with its structure determined using cryo-EM data) and the overall structure of Enterococcus hirae V-ATPase complex.     

Cytoskeletal Protein 4.1G Is Essential for the Primary Ciliogenesis and Osteoblast Differentiation in Bone Formation

The primary cilium is a hair-like immotile organelle with specific membrane receptors, including the receptor of Hedgehog signaling, smoothened. The cilium organized in preosteoblasts promotes differentiation of the cells into osteoblasts (osteoblast differentiation) by mediating Hedgehog signaling to achieve bone formation. Notably, 4.1G is a plasma membrane-associated cytoskeletal protein that plays essential roles in various tissues, including the peripheral nervous system, testis, and retina. However, its function in the bone remains unexplored. In this study, we identified 4.1G expression in the bone. We found that, in the 4.1G-knockout mice, calcium deposits and primary cilium formation were suppressed in the trabecular bone, which is preosteoblast-rich region of the newborn tibia, indicating that 4.1G is a prerequisite for osteoblast differentiation by organizing the primary cilia in preosteoblasts. Next, we found that the primary cilium was elongated in the differentiating mouse preosteoblast cell line MC3T3-E1, whereas the knockdown of 4.1G suppressed its elongation. Moreover, 4.1G-knockdown suppressed the induction of the cilia-mediated Hedgehog signaling and subsequent osteoblast differentiation. These results demonstrate a new regulatory mechanism of 4.1G in bone formation that promotes the primary ciliogenesis in the differentiating preosteoblasts and induction of cilia-mediated osteoblast differentiation, resulting in bone formation at the newborn stage.