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1.  Dual pharmacological inhibition of glutathione and thioredoxin systems synergizes to kill colorectal carcinoma stem cells 
Cancer Medicine  2016;5(9):2544-2557.
NRF2 stabilizes redox potential through genes for glutathione and thioredoxin antioxidant systems. Whether blockade of glutathione and thioredoxin is useful in eliminating cancer stem cells remain unknown. We used xenografts derived from colorectal carcinoma patients to investigate the pharmacological inhibition of glutathione and thioredoxin systems. Higher expression of five glutathione S‐transferase isoforms (GSTA1, A2, M4, O2, and P1) was observed in xenograft‐derived spheroids than in fibroblasts. Piperlongumine (2.5–10 μmol/L) and auranofin (0.25–4 μmol/L) were used to inhibit glutathione S‐transferase π and thioredoxin reductase, respectively. Piperlongumine or auranofin alone up‐regulated the expression of NRF2 target genes, but not TP53 targets. While piperlongumine showed modest cancer‐specific cell killing (IC 50 difference between cancer spheroids and fibroblasts: P = 0.052), auranofin appeared more toxic to fibroblasts (IC 50 difference between cancer spheroids and fibroblasts: P = 0.002). The synergism of dual inhibition was evaluated by determining the Combination Index, based on the number of surviving cells with combination treatments. Molar ratios indicated synergism in cancer spheroids, but not in fibroblasts: (auranofin:piperlongumine) = 2:5, 1:5, 1:10, and 1:20. Cancer‐specific cell killing was achieved at the following drug concentrations (auranofin:piperlongumine): 0.25:2.5 μmol/L, 0.5:2.5 μmol/L, or 0.25:5 μmol/L. The dual inhibition successfully decreased CD44v9 surface presentation and delayed tumor emergence in nude mouse. However, a small subpopulation persistently survived and accumulated phosphorylated histone H2A. Such “persisters” still retained lesser but significant tumorigenicity. Thus, dual inhibition of glutathione S‐transferase π and thioredoxin reductase could be a feasible option for decreasing the tumor mass and CD44v9‐positive fraction by disrupting redox regulation.
PMCID: PMC5055185  PMID: 27485632
colorectal carcinoma; glutathione; NRF2; pentose phosphate pathway; thioredoxin
2.  Colonic Angiodysplasia with a Huge Submucosal Hematoma in the Sigmoid Colon 
Case Reports in Surgery  2016;2016:3457367.
Colonic angiodysplasia (AD) with bleeding as a comorbidity in the aging population is being increasingly reported. However, to our knowledge, there is no report on colonic AD accompanied by a huge hematoma. Herein, we report a case of colonic AD with a huge submucosal hematoma. A 75-year-old man with sudden melena was referred to our hospital. Helical computed tomographic angiography (CTA) revealed bleeding from the sigmoid colon. Additionally, colonoscopy showed a huge submucosal hematoma with bleeding in the sigmoid colon. As endoscopic hemostasis was difficult, sigmoidectomy was performed. The pathological diagnosis was colonic AD. The present case indicates that colonic AD should be considered in the differential diagnosis for melena. In addition, the case shows that helical CTA, which is a noninvasive imaging modality, is useful for the diagnosis of colonic AD and is as effective as colonoscopy and angiography for diagnosis.
PMCID: PMC4906173  PMID: 27340585
3.  Lenalidomide and low‐dose dexamethasone in Japanese patients with newly diagnosed multiple myeloma: A phase II study 
Cancer Science  2016;107(5):653-658.
In the FIRST trial (MM‐020), lenalidomide plus low‐dose dexamethasone (Rd) reduced the risk of disease progression or death compared with combination melphalan–prednisone–thalidomide. As the FIRST trial did not include any Japanese patients, the efficacy and safety of continuous treatment with Rd was evaluated in 26 Japanese patients with newly diagnosed multiple myeloma (NDMM) in a single‐arm, multicenter, open‐label phase II trial (MM‐025). Patients received lenalidomide on days 1–21 of each 28‐day cycle, with a starting dose of 25 mg/day (dose adjusted for renal impairment), and 40 mg/day dexamethasone (dose adjusted for age) on days 1, 8, 15 and 22 of each 28‐day cycle until disease progression or discontinuation for any reason. In the efficacy evaluable population, overall response rate was 87.5%, including 29.2% of patients who achieved a complete response/very good partial response. Median durations of response, progression‐free survival and overall survival have not been reached. The most common grade 3–4 adverse events were neutropenia (23%) and anemia (19%). The efficacy and safety of Rd were consistent with data from larger studies, including the FIRST trial, thereby supporting the use of Rd continuous in Japanese patients with NDMM who are ineligible for stem cell transplantation.
PMCID: PMC4970832  PMID: 26914369
Dexamethasone; Japan; Japanese; lenalidomide; multiple myeloma
4.  Disseminated Mycobacterium marinum Infection With a Destructive Nasal Lesion Mimicking Extranodal NK/T Cell Lymphoma 
Medicine  2016;95(11):e3131.
Mycobacterium marinum is a ubiquitous waterborne organism that mainly causes skin infection in immunocompetent patients, and its disseminated infection is rare. Extranodal NK/T cell lymphoma, nasal type (ENKL) usually localizes at the nasal and/or paranasal area, but occasionally disseminates into the skin/soft tissue and gastrointestinal tract. Compromised immunity is a risk factor for developing nontuberculous mycobacterial (NTM) infection and malignant lymphoma, and the 2 diseases may share similar clinical presentation; however, only a few reports have described NTM infection mimicking malignant lymphoma.
A 43-year-old Japanese man presented to our hospital complaining of multiple progressive skin nodules and purulent nasal discharge for 3 weeks. He was diagnosed with Crohn disease with refractory enteropathic arthritis and has been treated with anti-tumor necrosis factor alpha agents for 25 years. Fiberoptic nasal examination revealed septal perforation with hemorrhagic mucus and purulent rhinorrhea. Histological examination of the nasal septum revealed the infiltration of atypical medium-to-large-sized cells with erosion. The cells were positive for cytoplasmic CD3, granzyme B, and Epstein–Barr virus-encoded small RNA. Histological examination of the skin nodules and auricle also showed infiltration of atypical lymphocytes. The patient was tentatively diagnosed with ENKL, and chemotherapy was considered. However, the skin lesions decreased in size after discontinuation of immunosuppressive agents and minocycline administration. Two weeks later, nasal septum and lavage fluid and left leg skin cultures were positive for M marinum, and minocycline was discontinued. The skin and the nasal lesions improved after 2 months.
To the best of our knowledge, this is the first case of disseminated M marinum infection with a destructive nasal lesion mimicking ENKL. The differentiation between M marinum infection and ENKL is clinically important because misdirected treatment leads to a poor prognosis. NTM infections including M marinum should be considered in differential diagnosis of ENKL. Bacterial cultures, pathological analysis, and close monitoring are required for the differentiation of ENKL and disseminated M marinum infection; both are serious diseases and early diagnostic distinction between them and immediate appropriate treatment will improve the patient's prognosis.
PMCID: PMC4839948  PMID: 26986167
5.  Evidence that Altered Cis Element Spacing Affects PpsR Mediated Redox Control of Photosynthesis Gene Expression in Rubrivivax gelatinosus 
PLoS ONE  2015;10(6):e0128446.
PpsR is a major regulator of photosynthesis gene expression among all characterized purple photosynthetic bacteria. This transcription regulator has been extensively characterized in Rhodobacter (Rba.) capsulatus and Rba. sphaeroides which are members of the α-proteobacteria lineage. In this study, we have investigated the biochemical properties and mutational effects of a ppsR deletion strain in the β-proteobacterium Rubrivivax (Rvi.) gelatinosus in order to reveal phylogenetically conserved mechanisms and species-specific characteristics. A deletion of the ppsR gene resulted in de-repression of photosystem synthesis showing that PpsR functions as a repressor of photosynthesis genes in this species. We also constructed a Rvi. gelatinosus PpsR mutant in which a conserved cysteine at position 436 was changed to an alanine to examine whether or not this residue is important for sensing redox, as reported in Rhodobacter species. Surprisingly, the Cys436 Ala mutant retained the ability to repress photosynthesis gene expression under aerobic conditions, suggesting that PpsR from Rvi. gelatinosus has different redox-responding characteristics. Furthermore, biochemical analyses demonstrated that Rvi. gelatinosus PpsR only shows redox-dependent binding to promoters with 9-bp spacing, but not 8-bp spacing, between two PpsR-recognition sequences. These results indicate that redox-dependent binding of PpsR requires appropriate cis configuration of PpsR target sequences in Rvi. gelatinosus. These results also indicate that PpsR homologs from different species regulate photosynthesis genes with altered biochemical properties.
PMCID: PMC4452267  PMID: 26030916
6.  Outcome of Hepatectomy for Hepatocellular Carcinoma in Elderly Patients With Portal Hypertension 
International Surgery  2014;99(2):153-160.
The outcome of liver resection (LR) for elderly hepatocellular carcinoma (HCC) patients with portal hypertension (PHT) who may be excluded as liver transplantation candidates has not been fully evaluated. One hundred ninety-five patients who underwent initial curative LR for HCC with PHT were divided into 2 groups: age <70 years (n = 131) and age ≥70 years (n = 64). Clinicopathologic data and postoperative complications were compared. Preoperative characteristics and postoperative complications were similar in both groups. However, in-hospital mortality was significantly more frequent in elderly than in younger patients (11% versus 1%, P = 0.002). No significant intergroup differences were observed in the 5-year disease-free survival rate or recurrence rate (19.7% versus 17.2%; P = 0.338, 63% versus 56%; P = 0.339). Although LR for elderly HCC patients with PHT can be performed with curative intent and gives results comparable with those in younger patients, it is associated with higher in-hospital mortality.
PMCID: PMC3968842  PMID: 24670026
Liver resection; Recurrence; Portal hypertension; Liver transplantation; Liver failure
7.  Supplementation of parenteral nutrition with fish oil attenuates acute lung injury in a rat model 
Fish oil rich in n-3 polyunsaturated fatty acids has diverse immunomodulatory properties and attenuates acute lung injury when administered in enternal nutrition. However, enteral nutrition is not always feasible. Therefore, we investigated the ability of parenteral nutrition supplemented with fish oil to ameliorate acute lung injury. Rats were infused with parenteral nutrition solutions (without lipids, with soybean oil, or with soybean oil and fish oil) for three days. Lipopolysaccharide (15 mg/kg) was then administered intratracheally to induce acute lung injury, characterized by impaired lung function, polymorphonuclear leukocyte recruitment, parenchymal tissue damage, and upregulation of mRNAs for inflammatory mediators. Administration of parenteral nutrition supplemented with fish oil prior to lung insult improved gas exchange and inhibited neutrophil recruitment and upregulation of mRNAs for inflammatory mediators. Parenteral nutrition supplemented with fish oil also prolonged survival. To investigate the underlying mechanisms, leukotriene B4 and leukotriene B5 secretion was measured in neutrophils from the peritoneal cavity. The neutrophils from rats treated with fish oil-rich parenteral nutrition released significantly more leukotriene B5, an anti-inflammatory eicosanoid, than neutrophils isolated from rats given standard parenteral nutrition. Parenteral nutrition with fish oil significantly reduced lipopolysaccharide-induced lung injury in rats in part by promoting the synthesis of anti-inflammatory eicosanoids.
PMCID: PMC3947972  PMID: 24688221
omega-3 fatty acids; nutritional support; acute lung injury; rat model; fish oil
8.  Frequent alteration of the protein synthesis of enzymes for glucose metabolism in hepatocellular carcinomas 
Journal of Gastroenterology  2013;49(9):1324-1332.
Cancer cells show enhanced glycolysis and inhibition of oxidative phosphorylation, even in the presence of sufficient oxygen (aerobic glycolysis). Glycolysis is much less efficient for energy production than oxidative phosphorylation, and the reason why cancer cells selectively use glycolysis remains unclear.
Biospecimens were collected from 45 hepatocellular carcinoma patients. Protein samples were prepared through subcellular localization or whole-cell lysis. Protein synthesis was measured by SDS-PAGE and immunoblotting. mRNA transcription was measured using quantitative RT-PCR. Statistical correlation among immunoblotting data and clinicolaboratory factors were analyzed using SPSS.
Enzymes for oxidative phosphorylation (SDHA and SDHB) were frequently decreased (56 and 48 % of patients, respectively) in hepatocellular carcinomas. The lowered amount of the SDH protein complex was rarely accompanied by stabilization of HIF1α and subsequent activation of the hypoxia response. On the other hand, protein synthesis of G6PD and TKT, enzymes critical for pentose phosphate pathway (PPP), was increased (in 45 and 55 % of patients, respectively), while that of ALDOA, an enzyme for mainstream glycolysis, was eliminated (in 55 % of patients). Alteration of protein synthesis was correlated with gene expression for G6PD and TKT, but not for TKTL1, ALDOA, SDHA or SDHB. Augmented transcription and synthesis of PPP enzymes were accompanied by nuclear accumulation of NRF2.
Hepatocellular carcinomas divert glucose metabolism to the anabolic shunt by activating transcription factor NRF2.
Electronic supplementary material
The online version of this article (doi:10.1007/s00535-013-0895-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4156784  PMID: 24203292
Aerobic glycolysis; Succinate dehydrogenase; HIF-1α; Pentose phosphate pathway; NRF2
9.  Neutrophil-to-Lymphocyte Ratio Has a Close Association With Gangrenous Appendicitis in Patients Undergoing Appendectomy 
International Surgery  2012;97(4):299-304.
The purpose of this study was to clarify the clinical features most closely associated with gangrenous appendicitis. From among 314 patients who had undergone open appendectomy in our collected database, 222 for whom sufficient data were evaluable were enrolled. The results of univariate analysis revealed that age (≤40/>40 years), sex (female/male), fever (≤37°/>37°C), the serum levels of C-reactive protein and albumin, the Glasgow prognostic score (0, 1/2), and the neutrophil-to-lymphocyte ratio (NLR) (≤8/>8) were associated with gangrenous appendicitis. Among these 7 clinical features, multivariate analysis disclosed that age (≤40/>40 years) (odds ratio, 3.435; 95% confidence interval 1.744–6.766; P < 0.001) and NLR (≤8/>8) (odds ratio, 3.016; 95% confidence interval 1.535–5.926; P  =  0.001) were associated with gangrenous appendicitis. The sensitivity and specificity of these two clinical features were 65% and 27%, and 73% and 39%, respectively. NLR (>8) shows a significant association with gangrenous appendicitis in patients undergoing appendectomy.
PMCID: PMC3727267  PMID: 23294069
Acute appendicitis; Catarrhal appendicitis; Gangrenous appendicitis; Phlegmonous appendicitis; Neutrophil-to-lymphocyte ratio
10.  Complete Genome Sequence of Phototrophic Betaproteobacterium Rubrivivax gelatinosus IL144 
Journal of Bacteriology  2012;194(13):3541-3542.
Rubrivivax gelatinosus is a facultative photoheterotrophic betaproteobacterium living in freshwater ponds, sewage ditches, activated sludge, and food processing wastewater. There have not been many studies on photosynthetic betaproteobacteria. Here we announce the complete genome sequence of the best-studied phototrophic betaproteobacterium, R. gelatinosus IL-144 (NBRC 100245).
PMCID: PMC3434721  PMID: 22689232
11.  Clinical Characteristics of Newly Diagnosed Primary, Pigmentary, and Pseudoexfoliative Open-Angle Glaucoma in the Collaborative Initial Glaucoma Treatment Study 
The British journal of ophthalmology  2012;96(9):1180-1184.
Three types of open-angle glaucoma (OAG) – primary, pigmentary, and pseudoexfoliative – are frequently encountered. The aim of this study was to compare demographic, ocular, and systemic medical information collected on people with these three OAG types at diagnosis, and determine if the OAG type affected prognosis.
Information on 607 participants of the Collaborative Initial Glaucoma Treatment Study was accessed. Descriptive statistics characterized their demographic, ocular, and medical status at diagnosis. Comparisons were made using analysis of variance (ANOVA), and chi-square or Fisher exact tests. Multinomial, mixed, and logistic regression analyses were also performed.
Relative to people with primary OAG, those with pigmentary OAG were younger, more likely to be white, less likely to have a family history of glaucoma, and were more myopic. Those with pseudoexfoliative OAG were older, more likely to be white, more likely to be female, less likely to have bilateral disease, and presented with higher IOP and better VA. The type of glaucoma was not associated with intraocular pressure or visual field progression during follow-up.
Characteristics of newly-diagnosed enrollees differed by the type of OAG. While some of these differences relate to the pathogenesis of OAG type, other differences are noteworthy for further evaluation within population-based samples of subjects with newly-diagnosed OAG.
PMCID: PMC3480313  PMID: 22773091
Glaucoma; Epidemiology
12.  Effect of an omega-3 lipid emulsion in reducing oxidative stress in a rat model of intestinal ischemia−reperfusion injury 
Pediatric Surgery International  2012;28(9):913-918.
The usefulness of omega-3 lipid emulsions has been extensively studied. The objectives of the present study were to examine the effect of an omega-3 lipid emulsion in reducing oxidative stress in a rat model of intestinal ischemia−reperfusion injury and the underlying mechanism.
A total of 66 rats were divided into three dietary groups (lipid-free, soybean oil, and fish oil groups). Each animal was administered total parenteral nutrition for 3 days, followed by induction of intestinal ischemia for 100 min. Animals subjected to sham surgery served as the controls. Intestinal tissue and blood were harvested 6 and 12 h after the surgery, then, assessment of the histological damage score, plasma-related parameters, and statistical evaluation were performed.
The histological damage score in the intestinal tissues was significantly lower in the fish oil group than in the soybean oil group (P = 0.0121). The late-phase urinary level of 8-hydroxy-2-deoxyguanosine was also significantly lower in the fish oil group as compared with that in the other groups (P = 0.0267). Furthermore, the plasma level of high-mobility group box 1 protein was also significantly lower in the fish oil group as compared with that in the lipid-free group (P = 0.0398).
It appeared that intravenous administration of an omega-3 lipid emulsion prior to ischemia−reperfusion injury reduced the oxidative stress and severity of tissue damage. Modification of membrane fatty acids may serve as the mechanism underlying this reduction of tissue damage.
PMCID: PMC3433667  PMID: 22907722
Ischemia–reperfusion injury; Omega-3; Oxidative stress; HMGB1
13.  Surgical Ligation of Extrahepatic Shunt under Guidance of Doppler Ultrasound, Portography, and Portal Pressure Monitoring 
Case Reports in Surgery  2012;2012:346759.
A 54-year-old man with chronic hepatitis C was admitted to our hospital because of a disturbance of consciousness and hyperammonemia. Abdominal angiography revealed a portosystemic shunt between the superior mesenteric vein and inferior vena cava. Endoscopic examination showed no varix. As interventional treatment was unsuccessful, surgical ligation of the shunt was performed. After surgery, portography revealed a huge shunt. Before ligation, the portal pressure, portal flow speed, and volume at the umbilical portion were 24 H2O. 5.6 cm/s and 203 ml/min, respectively. Finally the shunt was ligated. The portal flow speed and volume increased for 14 days following surgery and then stabilized. No varices were observed postoperatively. Doppler ultrasound, portography, and portal pressure monitoring can be used to reveal haemodynamic changes in the portal system and justify surgical ligation of portosystemic shunt.
PMCID: PMC3424649  PMID: 22928143

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