化合物スクリーニングにより、膀胱癌のシスプラチン感受性を増強するリポジショナブルドラッグとしてジスルフィラムを同定した

京都大学新制・課程博士博士(医学)甲第23565号医博第4779号新制||医||1054(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 武藤 学, 教授 万代 昌紀, 教授 上杉 志成学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

The Direct/Indirect Association of ADHD/ODD Symptoms with Self-esteem, Self-perception, and Depression in Early Adolescents

The present study aimed to reveal the influences of attention-deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) symptoms on self-esteem and self-perception during early adolescence and to clarify the spillover effect of self-esteem on depressive symptoms. ADHD symptoms in 564 early adolescents were evaluated via teacher-rating scales. Self-esteem and depressive symptoms were assessed via self-reported scales. We analyzed the relationships among these symptoms using structural equation modeling. Severe inattentive symptoms decreased self-esteem and hyperactive–impulsive symptoms affected self-perception for non-academic domains. Although these ADHD symptoms did not directly affect depressive symptoms, low self-esteem led to severe depression. ODD symptoms had a direct impact on depression without the mediating effects of self-esteem. These results indicated that inattentive symptoms had a negative impact on self-esteem and an indirect negative effect on depressive symptoms in adolescents, even if ADHD symptoms were subthreshold. Severe ODD symptoms can be directly associated with depressive symptoms during early adolescence

Wide frequency tuning of continuous terahertz wave generated by difference frequency mixing under exciton-excitation conditions in a GaAs/AlAs multiple quantum well

Continuous terahertz wave sources with narrow bandwidth and wide frequency tunability enable high-resolution terahertz spectroscopy and high-speed information communication. In this study, using the optical nonlinearity of excitons as the source of second-order nonlinear polarization, we realize a continuous terahertz electromagnetic wave demonstrating wide frequency tunability from 0.1 to 18 THz without a decrease in intensity due to phonon scattering. Because of excitation of two exciton states in a Ga As / Al As multiple quantum well using two continuous-wave lasers, terahertz waves are emitted as a result of difference-frequency mixing, where the intensity shows a square dependence on the excitation intensity. Using the inhomogeneous width of exciton lines, we achieve wide frequency tunability without phonon effects

Metformin Prevents and Reverses Inflammation in a Non-Diabetic Mouse Model of Nonalcoholic Steatohepatitis

13301乙第2044号博士（医学）金沢大学博士論文本文Full 以下に掲載：Plos ONE 7(9) pp.e43056-e43056 2012. Plos ONE. 共著者：Yuki Kita, Toshinari Takamura, Hirofumi Misu, Tsuguhito Ota, Seiichiro Kurita, Yumie Takeshita, Masafumi Uno, Naoto Matsuzawa-Nagata, Ken-ichiro Kato, Hitoshi Ando, Akio Fujimura, Koji Hayashi, Toru Kimura, Shuichi Kanek

Cellular senescence and wound healing in aged and diabetic skin

Cellular senescence is a biological mechanism that prevents abnormal cell proliferation during tissue repair, and it is often accompanied by the secretion of various factors, such as cytokines and chemokines, known as the senescence-associated secretory phenotype (SASP). SASP-mediated cell-to-cell communication promotes tissue repair, regeneration, and development. However, senescent cells can accumulate abnormally at injury sites, leading to excessive inflammation, tissue dysfunction, and intractable wounds. The effects of cellular senescence on skin wound healing can be both beneficial and detrimental, depending on the condition. Here, we reviewed the functional differences in cellular senescence that emerge during wound healing, chronic inflammation, and skin aging. We also review the latest mechanisms of wound healing in the epidermis, dermis, and subcutaneous fat, with a focus on cellular senescence, chronic inflammation, and tissue regeneration. Finally, we discuss the potential clinical applications of promoting and inhibiting cellular senescence to maximize benefits and minimize detrimental effects

Fat-free mass and calf circumference as body composition indices to determine non-exercise activity thermogenesis in patients with diabetes

Aims/Introduction: To investigate the clinical and anthropometrical parameters that are associated with non-exercise activity thermogenesis that is composed of basal energy expenditure (BEE) and diet-induced thermogenesis (DIT) in patients with diabetes. Materials and Methods: Body composition was assessed using bioelectrical impedance, and BEE and DIT were measured using indirect calorimetry in 40 Japanese patients with diabetes. Results: BEE correlated positively with bodyweight, body mass index, fat mass, and fat-free mass, and correlated negatively with age in both men and women. In multivariate logistic regression analysis, BEE correlated positively with both fat mass and fat-free mass independently of sex and age. In addition, DIT correlated positively with bodyweight, body mass index, fat mass and fat-free mass, and correlated negatively with age in women, but not men. Fat-free mass contributed to DIT at least partly, and an aging-related decrease in DIT was observed. The best anthropometric parameter that reflected fat mass and fat-free mass was hip circumference (HC) and calf circumference (CC), respectively, in both men and women. Indeed, both HC (men β = 0.600, P < 0.001; women β = 0.752, P < 0.001) and CC (men β = 0.810, P = 0.012; women β = 0.821, P = 0.002) were correlated with BEE independently of age and sex. In addition, CC (β = 0.653, P = 0.009), but not HC was correlated with DIT significantly only in females, independently of age. Conclusions: HC reflects fat mass and was positively associated with BEE, but not with DIT. In contrast, CC reflects fat-free mass, and was positively associated with BEE in both men and women, and with DIT in women. © 2015 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd

Sitagliptin versus mitiglinide switched from mealtime dosing of a rapid-acting insulin analog in patients with type 2 diabetes: a randomized, parallel-group study

Purpose We determined the feasibility of substituting sitagliptin or mitiglinide for bolus insulin injection therapy in patients with type 2 diabetes. Methods 60 patients with type 2 diabetes were enrolled and randomized to switch from mealtime dosing of a rapid-acting insulin analog to either sitagliptin or mitiglinide for 16 weeks. Results Body weight, body mass index, and waist circumference decreased significantly in both groups at the end of the study. Mitiglinide significantly increased fasting plasma glucose (FPG) levels at the end of the study from 146.5±36.3 to 168.0±38.8 mg/dL, whereas sitagliptin did not affect FPG. Glycated hemoglobin (HbA1c) and 1,5-anhydroglucitol increased significantly in both groups. The C peptide immunoreactivity (CPR) responses after arginine were diminished in both groups. γ-GTP and triglycerides increased, and high-density lipoprotein cholesterol and adiponectin decreased, in the sitagliptin group, but not in the mitiglinide group. Mean Diabetes Treatment Satisfaction Questionnaire scores improved significantly in both groups. Patients whose mean total daily doses of rapid-acting insulin analog were 16.6 and 17.8 units were switched to sitagliptin and mitiglinide, respectively, without a change in the HbA1c level. Total insulin doses/body weight predicted changes in HbA1c only in the sitagliptin group, but not in the mitiglinide group. Use of >0.27 IU/kg of a rapid-acting insulin analog predicted an increase in HbA1c after switching to sitagliptin. The CPR index (CPI) was also a predictor for a change in HbA1c in the sitagliptin group, but not in the mitiglinide group; patients with a CPI<1.4 developed a worse HbA1c after switching to sitagliptin. Conclusions Sitagliptin may predominantly act on FPG, whereas mitiglinide may act on postprandial plasma glucose to achieve glycemic control after switching from a bolus insulin regimen. Additional therapy to sitagliptin or mitiglinide is clearly required to obtain equivalent glycemic control in patients using a higher dose of insulin

Selective cytotoxicity of dihydroorotate dehydrogenase inhibitors to human cancer cells under hypoxia and nutrient-deprived conditions

Human dihydroorotate dehydrogenase (HsDHODH) is a key enzyme of pyrimidine de novo biosynthesis pathway. It is located on the mitochondrial inner membrane and contributes to the respiratory chain by shuttling electrons to the ubiquinone pool. We have discovered ascofuranone (1), a natural compound produced by Acremonium sclerotigenum, and its derivatives are a potent class of HsDHODH inhibitors. We conducted a structure–activity relationship study and have identified functional groups of 1 that are essential for the inhibition of HsDHODH enzymatic activity. Furthermore, the binding mode of 1 and its derivatives to HsDHODH was demonstrated by co-crystallographic analysis and we show that these inhibitors bind at the ubiquinone binding site. In addition, the cytotoxicities of 1 and its potent derivatives 7, 8, and 9were studied using human cultured cancer cells. Interestingly, they showed selective and strong cytotoxicity to cancer cells cultured under microenvironment (hypoxia and nutrient-deprived) conditions. The selectivity ratio of 8 under this microenvironment show the most potent inhibition which was over 1000-fold higher compared to that under normal culture condition. Our studies suggest that under microenvironment conditions, cancer cells heavily depend on the pyrimidine de novo biosynthesis pathway. We also provide the first evidence that 1 and its derivatives are potential lead candidates for drug development which target the HsDHODH of cancer cells living under a tumor microenvironment

The Endocannabinoid 2-Arachidonoylglycerol Produced by Diacylglycerol Lipase α Mediates Retrograde Suppression of Synaptic Transmission

SummaryEndocannabinoids are released from postsynaptic neurons and cause retrograde suppression of synaptic transmission. Anandamide and 2-arachidonoylglycerol (2-AG) are regarded as two major endocannabinoids. To determine to what extent 2-AG contributes to retrograde signaling, we generated and analyzed mutant mice lacking either of the two 2-AG synthesizing enzymes diacylglycerol lipase α (DGLα) and β (DGLβ). We found that endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus, and striatum of DGLα knockout mice, whereas the retrograde suppression was intact in DGLβ knockout brains. The basal 2-AG content was markedly reduced and stimulus-induced elevation of 2-AG was absent in DGLα knockout brains, whereas the 2-AG content was normal in DGLβ knockout brains. Morphology of the brain and expression of molecules required for 2-AG production other than DGLs were normal in the two knockout mice. We conclude that 2-AG produced by DGLα, but not by DGLβ, mediates retrograde suppression at central synapses

Helical tomotherapy for asymptomatic chemotherapy-refractory or -unfit multiple (3 or more) metastases

Background: Despite chemotherapy innovations, prognosis of patients with chemotherapy-refractory or -unfit multiple metastases (CRMM/CUMM) remains poor. In this prospective study, the efficacy and toxicity of helical tomotherapy for CRMM/CUMM were evaluated. Materials and methods: Between 2014 and 2020, asymptomatic patients with CRMM/CUMM with ≥ 3 lesions and no prior radiotherapy of the targets were enrolled. Patients who had intolerable toxicities to chemotherapy and those who refused chemotherapy were included in the CRMM and CUMM groups, respectively. Prostate cancer patients and patients with metastases mainly localized in the liver, lung, or brain were excluded. By helical tomotherapy, up to 10 lesions per patient were irradiated in order of volume. The standard dose was 50–60 Gy in 25–30 fractions. Results: Forty-five patients (median age, 63 years; 35 CRMM/10 CUMM) were enrolled. Primary tumors included lung, gynecological, and gastrointestinal cancers. The most frequently treated targets were lymph node metastases, followed by peritoneal/pleural disseminations and bone tumors. The 1-year survival rate was 51% (median, 12.5 months). In the 35 patients with CRMM, the median survival time was 12.5 months, and the median pre-radiation chemotherapy period was 8.8 months (p &gt; 0.05). The 6-month target control rate was 78%. Acute adverse events (grade ≥ 2) occurred in 33 patients: hematologic toxicities in 23, dermatitis in 6, and others in 8. Late grade ≥ 2 toxicities occurred in 6 patients: pneumonitis in 4 and gastric hemorrhage in 2. Conclusion: Tomotherapy for CRMM/CUMM resulted in median survival times &gt; 1 year. This treatment should be investigated further in larger prospective studies