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71.
Kamisuki S Shirakawa T Kugimiya A Abu-Elheiga L Choo HY Yamada K Shimogawa H Wakil SJ Uesugi M 《Journal of medicinal chemistry》2011,54(13):4923-4927
Fatostatin, a recently discovered small molecule that inhibits activation of sterol regulatory element-binding protein (SREBP), blocks biosynthesis and accumulation of fat in obese mice. We synthesized and evaluated a series of fatostatin derivatives. Our structure-activity relationships led to the identification of N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide (24, FGH10019) as the most potent druglike molecule among the analogues tested. Compound 24 has high aqueous solubility and membrane permeability and may serve as a seed molecule for further development. 相似文献
72.
Tsuruta T Kozaki K Uesugi A Furuta M Hirasawa A Imoto I Susumu N Aoki D Inazawa J 《Cancer research》2011,71(20):6450-6462
The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer. 相似文献
73.
74.
Akihide Oi Katsumi Morishita Takumi Awogi Atsushi Ozaki Masanao Umezato Shinji Fujita Eiji Hosoki Hajime Morimoto Nobuya Ishiharada Hironobu Ishiyama Tohru Uesugi Masaya Miyatake Tadashi Senba Toshiyuki Shiragiku Naoto Nakagiri Norio Ito 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2011,25(1):91-99
Purpose
In the present study, the nonclinical safety profile of tolvaptan was evaluated.Methods
A series of safety pharmacology and toxicology studies were performed in vitro and in mice, rats, dogs, rabbits and guinea pigs.Results
In safety pharmacological studies, tolvaptan had no adverse effects on the central nervous, somatic nervous, autonomic nervous, smooth muscle, respiratory and cardiovascular, or digestive systems. In general toxicity studies, a single dose of tolvaptan up to 2,000 mg/kg was not lethal in rats and dogs. Tolvaptan did not cause any target organ toxicity in rats after treatment for 26 weeks or in dogs after treatment for 52 weeks at oral doses of up to 1,000 mg/kg/day. The toxicities observed in the present studies were generally attributable to the exaggerated pharmacological action of tolvaptan. In reproductive and developmental toxicity studies in rats, fertility was not affected. Suppressed viability or growth observed in the prenatal and postnatal progeny occurred at the maternally toxic dose of 1,000 mg/kg/day. In rabbits, tolvaptan showed teratogenicity at 1,000 mg/kg/day, a dose that was maternally toxic causing abortion. Tolvaptan was not genotoxic or carcinogenic, and did not induce phototoxicity, antigenicity or immunotoxicity.Conclusion
Nonclinical toxicity that precludes the safe administration of tolvaptan to humans was not observed. However, appropriate cautions should be taken in women of childbearing potential.75.
Mitomo S Koeda K Fujiwara H Chiba T Takahashi M Uesugi N Sugai T Wakabayashi G 《Gan to kagaku ryoho. Cancer & chemotherapy》2012,39(1):115-118
We describe a 46-year-old man who presented with the chief complaint of lower back pain. The patient was diagnosed with advanced gastric cancer accompanied by multiple bone metastases, with compression fractures in the thoracolumbar vertebrae as well as distant lymph node metastases. He was administered eight courses of S-1/CDDP combination chemotherapy. Treatment results were as follows: primary lesion, non-CR/non-PD; lymph node metastases, CR; and bone metastases, non-CR/non-PD. As only the primary lesion showed a tendency toward progression after completion of eight courses, distal gastrectomy with D1 dissection was performed. Histopathological test results were ypT1b(SM1)and ypN1(2/22). The histological grade following treatment was grade 2 for both the primary lesion and the lymph nodes Following subsequent treatment with S-1 monotherapy and zoledronic acid, the disease did not progress, and at one year and four months since diagnosis and six months since surgery, CR and non-CR/non-PD have been maintained for the lymph node metastases and bone metastases, respectively. 相似文献
76.
Masaaki Higashino Ryo Kawata Koutetsu Lee Shuji Nishikawa Shimpei Ichihara Yasuo Uesugi 《Auris, nasus, larynx》2014
Objective
We examined the completion rate, safety, and adverse events in patients with T2N0 glottic carcinoma who received chemoradiotherapy with S-1 (tegafur–gimeracil–oteracil potassium).Methods
In T2N0 glottic carcinoma patients, we retrospectively compared the local control rate and outpatient therapy completion rate between 20 patients who received radiotherapy plus S-1 (S-1 group) and 20 who received radiotherapy alone (RT group).Results
Local recurrence was not detected in any of the 20 subjects from the S-1 group, whereas local recurrence was found in 4 of the 20 subjects (20%) from the RT group (p < 0.05). Outpatient treatment was completed by 15 of the 20 subjects from the S-1 group and 17 of the 20 subjects from the RT group (p = 0.43).Conclusion
We investigated chemoradiotherapy with S-1 in patients who had T2N0 glottic carcinoma and found a higher local control rate when compared with radiotherapy alone as well as comparable safety for outpatient delivery. 相似文献77.
T Yoshida Y Ozawa T Kimura Y Sato G Kuznetsov S Xu M Uesugi S Agoulnik N Taylor Y Funahashi J Matsui 《British journal of cancer》2014,110(6):1497-1505
Background:
Eribulin mesilate (eribulin), a non-taxane microtubule dynamics inhibitor, has shown trends towards greater overall survival (OS) compared with progression-free survival in late-stage metastatic breast cancer patients in the clinic. This finding suggests that eribulin may have additional, previously unrecognised antitumour mechanisms beyond its established antimitotic activity. To investigate this possibility, eribulin''s effects on the balance between epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) in human breast cancer cells were investigated.Methods:
Triple negative breast cancer (TNBC) cells, which are oestrogen receptor (ER−)/progesterone receptor (PR−)/human epithelial growth receptor 2 (HER2−) and have a mesenchymal phenotype, were treated with eribulin for 7 days, followed by measurement of EMT-related gene and protein expression changes in the surviving cells by quantitative real-time PCR (qPCR) and immunoblot, respectively. In addition, proliferation, migration, and invasion assays were also conducted in eribulin-treated cells. To investigate the effects of eribulin on TGF-β/Smad signalling, the phosphorylation status of Smad proteins was analysed. In vivo, the EMT/MET status of TNBC xenografts in mice treated with eribulin was examined by qPCR, immunoblot, and immunohistochemical analysis. Finally, an experimental lung metastasis model was utilised to gauge the metastatic activity of eribulin-treated TNBC in the in vivo setting.Results:
Treatment of TNBC cells with eribulin in vitro led to morphological changes consistent with transition from a mesenchymal to an epithelial phenotype. Expression analyses of EMT markers showed that eribulin treatment led to decreased expression of several mesenchymal marker genes, together with increased expression of several epithelial markers. In the TGF-β induced EMT model, eribulin treatment reversed EMT, coincident with inhibition of Smad2 and Smad3 phosphorylation. Consistent with these changes, TNBC cells treated with eribulin for 7 days showed decreased capacity for in vitro migration and invasiveness. In in vivo xenograft models, eribulin treatment reversed EMT and induced MET as assessed by qPCR, immunoblot, and immunohistochemical analyses of epithelial and mesenchymal marker proteins. Finally, surviving TNBC cells pretreated in vitro with eribulin for 7 days led to decreased numbers of lung metastasis when assessed in an in vivo experimental metastasis model.Conclusions:
Eribulin exerted significant effects on EMT/MET-related pathway components in human breast cancer cells in vitro and in vivo, consistent with a phenotypic switch from mesenchymal to epithelial states, and corresponding to observed decreases in migration and invasiveness in vitro as well as experimental metastasis in vivo. These preclinical findings may provide a plausible scientific basis for clinical observations of prolonged OS by suppression of further spread of metastasis in breast cancer patients treated with eribulin. 相似文献78.
I Nakagawa H Hamada F Uesugi A Sakai C Katsuya Y Matsubara 《Masui. The Japanese journal of anesthesiology》2001,50(11):1189-1195
Electrically elicited blink reflexes were investigated in 60 patients with peripheral facial nerve palsy. The purpose of this study was to evaluate the utility of analysis of R 2 wave in blink reflex as a prognostic indicator for the patients with facial palsy. The patients treated by stellate ganglion block were classified into three groups: Group I scored more than 90 points (full score is 100 points) within 2 weeks, Group II scored more than 90 points over 2 weeks, and Group III scored less than 90 points. The examinations were performed at the first visit, and 2, 4, 6 weeks after the onset of facial palsy. Latencies of ipsilateral and contralateral R 2 wave were measured by electrical stimulation on both side. There were significant differences of R 2 latency between ipsilateral and contralateral side in each of the three groups at the first visit. In Group II, contralateral R 2 latency obtained by stimulation of the paralytic side was prolonged significantly. In Group III, the ipsilateral R 2 wave was not observed. The results of this study indicate that measurement of the R 2 latency of blink reflex is useful in judging the severity of the peripheral facial nerve palsy. The R 2 latencies obtained by stimulation of ipsilateral and contralateral side should be used as one of the parameters for evaluation of the prognosis of patients with peripheral facial nerve palsy. 相似文献
79.
Yu-Fei Jiao Shin-ichi Nakamura Tsukasa Oikawa Tamotsu Sugai Noriyuki Uesugi 《Virchows Archiv : an international journal of pathology》2001,438(5):505-508
We report here the first case of sebaceous gland metaplasia arising within an intraductal papilloma of the breast of a 70-year-old female. Several lobules and nests composed of clear cells closely resembling sebaceous glands of the skin were discovered within an intraductal papilloma of the breast. Squamous metaplasia was also noted in certain areas of the tumor. Immunohistochemically, the cells of the lobules and nests stained positively for monoclonal antibodies anti-cytokeratin 14 and epithelial membrane antigen. This study confirms a novel type of metaplasia of the breast. 相似文献
80.
Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. 总被引:33,自引:0,他引:33
Chronic alcohol administration increases gut-derived endotoxin in the portal blood, which activates Kupffer cells and causes liver injury. Mice (C3H/HeJ) with mutations in toll-like receptor 4 (TLR4) are hyporesponsive to endotoxin. To test the hypothesis that TLR4 is involved in early alcohol-induced liver injury, the long-term intragastric ethanol feeding protocol developed by Tsukamoto and French for rats was adapted to mice. Animals with nonfunctional TLR4 and wild-type mice (C3H/HeOuJ) were compared. Two-month-old female mice were fed a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin as control continuously for 4 weeks. There was no difference in mean urine alcohol concentrations between the groups. Dietary alcohol significantly increased liver-to-body weight ratios and serum alanine transaminase (ALT) levels in wild-type mice (109 +/- 18 U/L) over high-fat controls (40 +/- 3 U/L), effects that were blunted significantly in mice with a mutation of TLR4 (55 +/- 9 U/L). While no significant pathologic changes were observed in high-fat controls, dietary ethanol caused steatosis, mild inflammation, and focal necrosis in wild-type animals (pathology score = 5.2 +/- 1.2). These pathologic changes were significantly lower in TLR4-deficient mice fed ethanol (score = 2.0 +/- 1.3). Endotoxin levels in the portal vein were increased significantly after 4 weeks in both groups fed ethanol. Moreover, ethanol increased tumor necrosis factor alpha (TNF-alpha) mRNA expression in wild-type, but not in TLR4-deficient, mice. These data are consistent with the hypothesis that Kupffer cell activation by endotoxin via TLR4 is involved in early alcohol-induced liver injury. 相似文献