SMNは、骨格筋分化においてMYOD-miRNA 経路を制御することにより、ミトコンドリアの機能的成熟を促進する

京都大学新制・論文博士博士(医学)乙第13564号論医博第2291号新制||医||1068(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 齊藤, 博英, 教授 滝田, 順子, 教授 萩原, 正敏学位規則第4条第2項該当Doctor of Medical ScienceKyoto UniversityDFA

Au Electrodeposition at the Liquid-Liquid Interface: mechanistic aspects

The deposition mechanism of metallic gold was investigated based on charge transfer voltammetry at the water/1,2-dichloroethane (W/DCE) interface, and the corresponding redox voltammetry of the metal precursor in W and the reductant, triphenylamine (TPA), in DCE. The metal precursor was present as Au(III) (AuCl_4^[−]), or Au(I) (AuCl_2^[−]) in W or DCE. Electron transfer could be observed voltammetrically at the interface between W containing both Au precursors and DCE containing TPA. Au particles, formed by constant potential electrolysis at the W/DCE interface, were examined by transmission electron microscopy. It was shown that deposit size could be controlled via the applied potential and time, with specific conditions to form particles of less than 10 nm identified

Utility of gastric biopsy in diagnosing IgG4‐related gastrointestinal disease

The utility of gastric biopsy for diagnosing immunoglobulin (Ig)G4‐related gastrointestinal disease (IgG4‐GID) remains unclear. Bottom‐heavy plasmacytosis (BHP) is a distinct feature of IgG4‐GID. To clarify the feasibility of using gastric biopsies to diagnose BHP in IgG4‐GID, we analyzed the histological features and immunostaining of gastric biopsy specimens from 31 known IgG4‐related disease (IgG4‐RD) patients and we assessed the presence of BHP in 1696 consecutive routine gastric biopsies. Cases with both >10 IgG4‐positive plasma cells per high‐power field and an IgG4/IgG‐positive ratio >40% were defined as IgG4‐high. Ten of the 31 IgG4‐RD patients were concluded to have IgG4‐GID, in which IgG4‐positive plasma cells were notably detected at the deeper part of the mucosa. Six cases displayed BHP whereas the remaining four cases showed transmural infiltration with concomitant Helicobacter pylori‐associated gastritis. In addition to BHP, we identified two unique histologic features for IgG4‐GID: plasmacytic aggregation in the muscularis mucosae and permeative plasmacytic infiltration between fundic glands in the non‐atrophic mucosa. Six of the routine cases (0.35%) displayed BHP, including a case with IgG4‐RD. IgG4‐GID can be suspected by the presence of gastric biopsy specimens with characteristic histological features. Such cases are recommended to undergo further examinations to determine whether IgG4‐RD is present

Revaluation of equilibrium quotient between titanium ions and metallic titanium in NaCl–KCl equimolar molten salt

In this study, the effect of oxide ion on the equilibrium between titanium ions and metallic titanium was investigated in NaCl–KCl equimolar molten salt. The soluble species containing Ti^[3+] and O^[2−] was not confirmed in the molten salt by absorption spectroscopy. The result of XRD for the solidified sample containing Ti^[3+] and O^[2−] implies that O2− reacts with Ti^[3+] and Cl^− to form TiOCl(s). The concentration quotient of the equilibrium between titanium ions (Ti^[2+], Ti^[3+]) and metallic Ti, Kc, was revaluated at 740℃ as follows:3Ti^[2+]⇄2Ti^[3+]+Ti, Kc=8.0×10^[−2] mol L−1=1.2×10^[−1] mol kg^[−1]. In addition, the solubility product of TiOCl(s) in NaCl–KCl equimolar molten salt, Ksp, at 700℃ was determined using the results of absorption spectra, Ksp=1.2×10^[−2] mol^2 L−2=5.1×10^[−3] mol^2 kg^[−2]

Novel anti‐tumor mechanism of galanin receptor type 2 in head and neck squamous cell carcinoma cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102710/1/cas12315.pd

AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells

A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells

Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC