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.     

Fracture and acoustic emission characteristics of glass fiber reinforced plastics panels for hot water

This study deals with the fracture process and acoustic emission (AE) characteristics of a randomly oriented E-glass fiber mat reinforcement with a crosslinked polyester. These panels were evaluated after they were immersed in hot water. The fiber volume content of the panel was 19%. Glass fiber reinforced plastics (GFRP) panels wer immersed in water at 81°C. Bending and AE monitoring tests were Performed and after bending, the cross-section of the specimen was observed by an optical microscope and SEM. The influence of degradation, due to water immersion, on the changes of fracture process of GFRP is discussed. The dominant fracture mode of the virgin specimen was matrix cracks, whereas that of the immersed specimen was debondings at the fiber bundle/matrix and fiber/matrix interfaces. This change was caused by reduction of the bonding strength at the interface. The scale of fracture can be estimated by both AE amplitude and AE energy and this estimation method was used to estimate the fracture mode changes of GFRP panels immersed in hot water.     

Melatonin-Induced Postconditioning Suppresses NMDA Receptor through Opening of the Mitochondrial Permeability Transition Pore via Melatonin Receptor in Mouse Neurons

Mitochondrial membrane potential regulation through the mitochondrial permeability transition pore (mPTP) is reportedly involved in the ischemic postconditioning (PostC) phenomenon. Melatonin is an endogenous hormone that regulates circadian rhythms. Its neuroprotective effects via mitochondrial melatonin receptors (MTs) have recently attracted attention. However, details of the neuroprotective mechanisms associated with PostC have not been clarified. Using hippocampal CA1 pyramidal cells from C57BL mice, we studied the involvement of MTs and the mPTP in melatonin-induced PostC mechanisms similar to those of ischemic PostC. We measured changes in spontaneous excitatory postsynaptic currents (sEPSCs), intracellular calcium concentration, mitochondrial membrane potential, and N-methyl-D-aspartate receptor (NMDAR) currents after ischemic challenge, using the whole-cell patch-clamp technique. Melatonin significantly suppressed increases in sEPSCs and intracellular calcium concentrations. The NMDAR currents were significantly suppressed by melatonin and the MT agonist, ramelteon. However, this suppressive effect was abolished by the mPTP inhibitor, cyclosporine A, and the MT antagonist, luzindole. Furthermore, both melatonin and ramelteon potentiated depolarization of mitochondrial membrane potentials, and luzindole suppressed depolarization of mitochondrial membrane potentials. This study suggests that melatonin-induced PostC via MTs suppressed the NMDAR that was induced by partial depolarization of mitochondrial membrane potential by opening the mPTP, reducing excessive release of glutamate and inducing neuroprotection against ischemia-reperfusion injury.     

Mouse Gastric Epithelial Cells Resist CagA Delivery by the Helicobacter pylori Type IV Secretion System

The initial step in bacterial infection is adherence of the bacterium to the target cell surface. Helicobacter pylori exploits the interaction of bacterial adhesin protein HopQ with human epithelial CEACAMs (CEACAM1, 5, and 6) to stably adhere to gastric epithelial cells, which is necessary for delivery of the H. pylori CagA oncoprotein into the epithelial cells via a type IV secretion system. In contrast to human CEACAMs, however, HopQ does not interact with Ceacam1 (mouse CEACAM1) in vitro or in CHO cells ectopically expressing Ceacam1. Since the mouse genome lacks Ceacam5 and Ceacam6, no significant HopQ–Ceacam interaction may occur in mouse gastric epithelial cells. Here, we found that the mouse stomach has a much lower expression level of Ceacam1 than the expression level of CEACAM1 in the human stomach. Consistently, mouse gastric epithelial cells resist CagA delivery by cagA-positive H. pylori, and the delivery is restored by ectopic expression of human CEACAM1 or CEACAM5 in mouse gastric epithelial cells. Thus, despite the fact that mice are routinely used for H. pylori infection studies, a low expression level of Ceacam1 in the mouse stomach together with the loss or greatly reduced interaction of HopQ with Ceacams make the mouse an inappropriate model for studying the role of H. pylori-delivered CagA in gastric pathogenesis, including the development of gastric cancer.     

Design and control of a microrobotic system using magneticlevitation

Presents a prototype microrobot based on magnetic principles. Miniature items are to be transported and assembled in hazardous environments. A microrobot can be remotely operated with 3 DOF in an enclosed environment by transferring magnetic energy and optical signals from outside. The magnetic drive unit consists of 8 electromagnets (4 pairs), 2 permanent magnets, a return yoke and a pole piece. The microrobot is manipulated under the pole piece by regulating magnetic field. It consists of a magnetic head, a body (electronic circuit and batteries), and copper alloy ribbon ringers. A shape memory alloy actuator activates the fingers by illuminating/extinguishing several LED. PID controls were applied. To cope with uncertainties and variations in payload masses, an adaptive control law was also employed for positioning along the z axis to enable the controller parameters to be adjusted in real-time. Effectiveness of the control was verified by the results of several experiments. The microrobot has a net mass of 8.1 g and it can elevate and manipulate objects with masses up to 1.5 g within a volume of 29×29×26 mm³ with a precision of 0.05 mm     

Relationship between local structure and stability in hen egg white lysozyme mutant with alanine substituted for glycine

We prepared five mutant lysozymes in which glycines whose dihedralangles are located in the region of the left-handed helix, Gly49,Gly67, Gly71, Gly102 and Gly117, were mutated to an alanineresidue. From analyses of their thermal stabilities using differentialscanning calorimetry, most of them were more destabilized thanthe native lysozyme, except for the G102A mutant, which hasa stability similar to that of the native lysozyme at pH 2.7.As for the destabilized mutant lysozymes, their X-ray crystallographicanalyses showed that their global structures did not changebut that the local structures changed slightly. By examiningthe dihedral angles at the mutation sites based on X-ray crystallographicresults, it was found that the dihedral angles at these mutationsites tended to adopt favorable values in a Ramachandran plotand that the extent and direction of their shifts from the originalvalue had similar tendencies. Therefore, the change in dihedralangles may be the cause of the slight local structural changesaround the mutation site. On the other hand, regarding the mutationof G102A, the global structure was almost identical with thatof the native structure but the local structure was drasticallychanged. Therefore, it was suggested that the drastic localconformational change might be effective in releasing the unfavorableinteraction of the native state at the mutation site.     

Change of orientation by thermal contraction of polyacrylonitrile fiber

Polyacrylonitrile polymer powder was dissolved in 70% nitric acid and spun into isotropic filament through a glass nozzle of 0.5 mm. diameter in a coagulating bath of 30% nitric acid. Stretching was carried out in two stages: the first stretching was done in water at 20°C. followed by drying, and the second stretching was done in a boiling saturated solution of ammonium sulfate. The total stretching ratio was 23. These filaments were shrunk freely in water at 70–180°C. The change in orientation factors was traced by x-ray, infrared dichroism, visible dichroism, and sonic modulus methods. The relation between the reciprocal absolute temperature of thermal contraction and the logarithm of fiber length is a straight line which has two inflection points at 93 and 175°C. The orientation factors by x-ray and infrared dichroism remain unchanged up to 175°C. On the contrary, the orientation factors by visible dichroism and sonic modulus drop suddenly at about 90°C. This indicates the occurrence of relaxation of the amorphous chain at the glass transition temperature and shows the polymer is not perfect single-phase material. Orientation of crystalline and amorphous phases is stable from 100 to 170°C. in spite of considerable thermal contraction. The stability of orientation can be explained by the growth of a folded structure in the polymer.     

Poly(4-diphenylaminostyrene) with a well-defined polymer chain structure: Controllable optical and electrical properties

The effect of polymer chain structure on the optical and electrical properties are reported for poly(4-diphenylaminostyrene) (PDAS), which was prepared by the living anionic polymerization of 4-diphenylaminostyrene (DAS) with the benzyllithium (BzLi)/N,N,N′,N′-tetramethylethylenediamine (TMEDA) system. The optical properties of PDAS are strongly affected by the stereoregularity of the PDAS polymer chain; intramolecular excimer-forming fluorescence was observed from PDAS with a syndiotactic-rich configuration. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels of PDAS were approximately −5.4 and −2.0 eV, respectively, regardless of the polymer chain structure. The hole and electron drift mobilities for PDAS were in the order of 10⁻⁴ to 10⁻⁵ (cm²/V s) and 10⁻⁵ (cm²/V s), respectively, with negative slopes. The distance of each triphenylamino (TPA) group in the polymer chain was a major factor influencing the drift mobility of PDAS. The current-voltage (I-V) characteristics of PDAS were controllable according to the polymer chain structure of PDAS.     

Reaction of Syringylglycerol-β-Syringyl Ether Type of Lignin Model Compounds in Alkaline Medium

Reactions of three kind of syringylglycerol- β-syringyl ether type model compounds under alkaline medium were investigated. Sinapyl alcohol and β-hydroxypropiosyringone were formed as phenyl propanoid moieties from syringylglycerol- β-(methyl-syringyl) ether 1 by the β-aryl ether cleavage under soda treatment, while only sinapyl alcohol was formed from syringylglycerol- β-syringyl ether 2. The formation of both two degradation products are quite interesting because there is no nucleophilic additives in soda liquor. A possible reaction mechanisms for the β-aryl cleavage of syringylglycerol-β-syringyl ether type is homolytical cleavage via quinone methide.