可観測な車両モデルを利用した応答計測型軌道変位推定とその検証

学位の種別: 課程博士審査委員会委員 : （主査）東京大学特任講師 蘇 迪, 東京大学准教授 市村 強, 東京大学准教授 長山 智則, 東京大学准教授 山口 敦, 東京大学准教授 中野 公彦University of Tokyo(東京大学

Percutaneous trigger thumb release: a safe push-pull technique

Background: Stenosing tenosynovitis of the thumb is an inflammation of flexor tendon sheath of A1 pulley. Percutaneous release has recently gained popularity. Successful percutaneous release depends upon proper prediction of the location of the A1 pulley and circumventing injury to the neurovascular bundles. The aim of this study was to determine the safety of percutaneous release of trigger thumb.Methods: Twenty eight patients were included in the study between 2015 and 2018. All the patients were percutaneously released using push-pull technique. Steroid injection was given following the release. Quinnell grading, patient questionnaire and visual analogue scale score was used to assess the patients at 2 weeks, 6 weeks and 6 months and 1 year.Results: Satisfactory results were found in 93% of patients. Two patients complained of pain and swelling till third week. No digital nerve injury occurred in any patients.Conclusions: Percutaneous trigger thumb release using this push-pull technique is a simple and a safe technique with very minimal complications.

Benzenesulfonamide Analogs : Synthesis, Anti-GBM Activity and Pharmacoprofiling

The tropomyosin receptor kinase A (TrkA) family of receptor tyrosine kinases (RTKs) emerge as a potential target for glioblastoma (GBM) treatment. Benzenesulfonamide analogs were identified as kinase inhibitors possessing promising anticancer properties. In the present work, four known and two novel benzenesulfonamide derivatives were synthesized, and their inhibitory activities in TrkA overexpressing cells, U87 and MEF cells were investigated. The cytotoxic effect of benzenesulfonamide derivatives and cisplatin was determined using trypan blue exclusion assays. The mode of interaction of benzenesulfonamides with TrkA was predicted by docking and structural analysis. ADMET profiling was also performed for all compounds to calculate the drug likeness property. Appropriate QSAR models were developed for studying structure–activity relationships. Compound 4-[2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfon-amide (AL106) and 4-[2-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (AL107) showed acceptable binding energies with the active sites for human nerve growth factor receptor, TrkA. Here, AL106 was identified as a potential anti-GBM compound, with an IC50 value of 58.6 µM with a less toxic effect in non-cancerous cells than the known chemotherapeutic agent, cisplatin. In silico analysis indicated that AL106 formed prominent stabilizing hydrophobic interactions with Tyr359, Ser371, Ile374 and charged interactions with Gln369 of TrkA. Furthermore, in silico analysis of all benzenesulfonamide derivatives revealed that AL106 has good pharmacokinetics properties, drug likeness and toxicity profiles, suggesting the compound may be suitable for clinical trial. Thus, benzenesulfonamide analog, AL106 could potentially induce GBM cell death through its interaction with TrkA and might be an attractive strategy for developing a drug targeted therapy to treat glioblastoma.Peer reviewe

Methanodibenzo[b,f][1,5]dioxocins as Novel Glutaminase Inhibitor with Anti-Glioblastoma Potential

Glutamine metabolism is an important hallmark of several cancers with demonstrated antitumor activity in glioblastoma cancer cells (GBM). GBM cells regulate glutamine and use it as a major energy source for their proliferation through the glutaminolysis process. Enzymes, such as glutaminase in glutaminolysis, can be targeted by small-molecule inhibitors, thus exhibiting promising anticancer properties. The resistance to glutaminolysis demands the development of new therapeutic molecules to overcome drug resistance. Herein, we have reported a novel library of constrained methanodibenzo[b,f][1,5]dioxocin derivatives as glutaminase (GLS) inhibitors and their anti-GBM potential. The library consisting of seven molecules was obtained through self-condensation of 2′-hydroxyacetophenones, out of which three molecules, namely compounds 3, 5, and 6, were identified with higher binding energy values ranging between −10.2 and −9.8 kcal/mol with GLS (PDB ID; 4O7D). Pharmacological validation of these compounds also showed a higher growth inhibition effect in GBM cells than the standard drug temozolomide (TMZ). The most promising compound, 6, obeyed Lipinski’s rule of five and was identified to interact with key residues Arg307, Asp326, Lys328, Lys399, and Glu403 of GLS. This compound exhibited the best cytotoxic effect with IC50 values of 63 µM and 83 µM in LN229 and SNB19 cells, respectively. The potential activation of GLS by the best-constrained dibenzo[b,f][1,5]dioxocin in the tested series increased apoptosis via reactive oxygen species production in both GBM cells, and exhibited anti-migratory and anti-proliferative properties over time in both cell lines. Our results highlight the activation mechanism of a dibenzo[b,f][1,5]dioxocin from the structural basis and demonstrate that inhibition of glutaminolysis may facilitate the pharmacological intervention for GBM treatment.publishedVersionPeer reviewe

Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis

KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with KrasG12D to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy

Analysis of Preload Effect in the Axisymmetric Damped Steel Wire Using Ultrasonic Guided Wave Monitoring

Guided ultrasonic wave propagation characteristics in the axisymmetric prestressed viscoelastic waveguide, using the semi-analytical finite element (SAFE) method, are studied broadly for acoustic emission monitoring. For the numerical investigation, a single high strength steel wire is considered. The SAFE method for an axisymmetric cross-section in cylindrical-coordinates is utilized to analyze the two main influencing factors of steel wire in a practical scenario, namely, material damping and initial tension. For pre-stress effect, the calculation shows that the initial tensile stress can increase and decrease the energy velocity and attenuation factor of most modal waves above the cut-off frequency, which is linear

Non-Destructive Testing Mechanism for Pre-Stressed Steel Wire Using Acoustic Emission Monitoring

In this paper, the guided ultrasonic wave propagation characteristics in the axisymmetric pre-stressed viscoelastic waveguide for acoustic emission (AE) monitoring, using the semi-analytical finite element (SAFE) method, is studied broadly. For the numerical investigation, a single high-strength steel wire is considered. A comprehensive and in-depth study on the AE signal’s propagation characteristics is carried out based on the SAFE method. Both undamped and damped waveguides are considered for attaining SAFE solutions and presented in a detailed manner. The SAFE method for an axisymmetric cross-section in cylindrical coordinates analyzes the two main influencing factors of steel wire in a practical scenario: Material damping and initial tension. For the effect of initial stress, the calculation shows that the initial tensile stress can increase and decrease the energy velocity and attenuation factor of most modal waves above the cut-off frequency, and the effect is linear. Some longitudinal wave modes in the high-frequency region show their potential for AE monitoring as these modes have a low attenuation factor and small external surface vibration. By considering various states of initial stress in a damped waveguide, the effect of pre-stress on the dispersion characteristics is understood in a better manner. A non-destructive testing (NDT) mechanism for pre-stressed steel wire using AE monitoring is proposed for the health monitoring of structures

Structural Damage Detection through EMI and Wave Propagation Techniques Using Embedded PZT Smart Sensing Units

Lead Zirconate Titanate (PZT) sensors have become popular in structural health monitoring (SHM) using the electromechanical impedance (EMI) technique for damage identification. The vibrations generated during the casting process in concrete structures substantially impact the conductance signature’s (real part of admittance) magnitude and sensitivity. The concept of smart sensing units (SSU) is presented, composed of a PZT patch, an adhesive layer, and a steel plate. It is embedded in the concrete structure to study the impact of damage since it has high sensitivity to detect any structural changes, resulting in a high electrical conductance signature. The conductance signatures are obtained from the EMI technique at the damage state in the 10–500 kHz high-frequency range. The wave propagation technique proposes implementing the novel embedded SSUs to detect damage in the host structure. The numerical simulation is carried out with COMSOL multiphysics, and the received voltage signal is compared between the damaged and undamaged concrete beam with the applied actuation signal. A five-cycle sine burst modulated by a Hanning window is employed as the transient excitation signal. For numerical investigation, six cases are explored to better understand how the wave travels when a structural discontinuity is accounted for. The changes in the received signal during actuator–receiver mode in the damage state of the host structure are quantified using time of flight (TOF). Furthermore, the numerical studies are carried out by combining the EMI-WP technique, which implies synchronous activation of EMI-based measurements and wave stimulation. The fundamental idea is to implement EMI-WP to improve the effectiveness of SSU patches in detecting both near-field and far-field damage in structures. One SSU is used as an EMI admittance sensor for local damage identification. Meanwhile, the same EMI admittance sensor is used to acquire elastic waves generated by another SSU to monitor damages outside the EMI admittance sensor’s sensing area. Finally, the experimental validation is carried out to verify the proposed methodology. The results show that combining both techniques is an effective SHM method for detecting damage in concrete structures