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.     

Focused Design of Novel Cyclic Peptides Endowed with GABARAP-Inhibiting Activity

(1) Background: Disfunctions in autophagy machinery have been identified in various conditions, including neurodegenerative diseases, cancer, and inflammation. Among mammalian autophagy proteins, the Atg8 family member GABARAP has been shown to be greatly involved in the autophagy process of prostate cancer cells, supporting the idea that GABARAP inhibitors could be valuable tools to fight the progression of tumors. (2) Methods: In this paper, starting from the X-ray crystal structure of GABARAP in a complex with an AnkirinB-LIR domain, we identify two new peptides by applying in silico drug design techniques. The two ligands are synthesized, biophysically assayed, and biologically evaluated to ascertain their potential anticancer profile. (3) Results: Two cyclic peptides (WC8 and WC10) displayed promising biological activity, high conformational stability (due to the presence of disulfide bridges), and K_d values in the low micromolar range. The anticancer assays, performed on PC-3 cells, proved that both peptides exhibit antiproliferative effects comparable to those of peptide K1, a known GABARAP inhibitor. (4) Conclusions: WC8 and WC10 can be considered new GABARAP inhibitors to be employed as pharmacological tools or even templates for the rational design of new small molecules.     

Development of Sensor and Control Systems of a Wearable Robot to Walk on a Step

The goal of our study is to develop a system for walking on a step using a wearable robot. Our system consists of (1) sensing of a step from the movement of the walker, (2) detection of the foot placement state related to the step, and (3) generation of gait patterns of climbing and stepping down for the step. In the generation of gait patterns for the step, toe trajectories are generated according to the height of the step to avoid collision of the swinging leg with the step. The hip trajectory is generated by an optimization technique that minimizes the sum of the joint angular jerk of the robot subject to constraints on the hip position and the velocity at toe liftoff. Each joint angle trajectory is calculated from the generated trajectories by means of inverse kinematic equations. We investigated the feasibility of the proposed sensor and control systems for two steps with different heights.     

Homogeneous Strain Introduction Using Reciprocation Technique in High-Pressure Sliding

Metallurgical and Materials Transactions A - This study examines strain distribution occurring in the high-pressure sliding (HPS) processing for rods of pure Al and an AZ61 alloy. The strain...     

Efficacy and Mechanisms of Communication Disruption of the Red Clover Casebearer Moth (Coleophora deauratella) with Complete and Partial Pheromone Formulations

The red clover casebearer, Coleophora deauratella Leinig and Zeller (Lepidoptera: Coleophoridae), is a major pest of red clover (Trifolium pratense L.) grown for seed in Canada and parts of Europe. Insecticides are ineffective against C. deauratella, and other control methods, such as pheromone-mediated mating disruption, need to be explored. The efficacy and mechanisms of communication disruption were evaluated in small-plot trials (0.25 ha) with reservoir-type rope dispensers loaded with either the complete pheromone blend [10:1 ratio of (Z)-7-dodecenyl acetate: (Z)-5-dodecenyl acetate] or the major component alone [(Z)-7-dodecenyl acetate]. Both formulations reduced catches of male C. deauratella in pheromone traps (>99.6 %). In pheromone-treated plots, more males were caught on yellow sticky cards near dispensers that released the complete pheromone blend, than on cards near dispensers releasing the major component. In the laboratory, after pre-exposure to either the complete blend or the major component for 1 h, male C. deauratella antennae became adapted, as measured by electroantennograms conducted 5 min. after treatment. Adaptation due to pre-exposure to either formulation resulted in a shift in the pheromone response threshold; antennae from pre-exposed moths responded more strongly to high pheromone dosages (5–50 μg) than did antennae from untreated control moths. Antennae from moths held in clean air for 24 h after pre-exposure recovered and responded similarly to pheromone as antennae from control moths. These results suggest that both formulations have the potential to disrupt pheromone communication in C. Deauratella, but that the disruption mechanisms of the two formulations likely differ.     

Wave venation in downward gas-liquid two-phase flow (part I,time-spatial behavior chart of interface and analysis of main wave-vein)

Time-series information on both the cross-sectional mean liquid holdup along a tube axis and the gas-liquid phase distribution along a tube diameter was obtained by means of supermultiple cross-sectional mean liquid holdup probes (S-CHOP) and semi-supermultiple point-electrode probes (SS-PEP) for vertical downward gas-liquid two-phase flow. Typical time-spatial behavior charts of interface and gas-liquid interfacial profiles are presented. Close inspection of these results reveals that a huge wave and a disturbance wave appear in downward two-phase flow as well as upward flow. It was clarified that the huge wave flow region covers a wide range of superficial gas velocities. Wave velocity, wave width and maximum liquid holdup of individual waves were examined by wave-vein analysis. Histograms of these flow parameters were also studied. It was found that there exist distinct differences in wave width between the huge wave and the disturbance wave. © 1997 Scripta Technica, Inc. Heat Trans Jpn Res, 25(8): 499–510, 1996