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1.  The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells 
Blood Cancer Journal  2011;1(5):e17-.
In Ph-positive (Ph+) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph+ acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγnull (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G0 cells in the CD34+CD38− population compared with the CD34+CD38+ and CD34− populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34+CD38− population than in the other populations. Although slow-cycling G0 cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34+CD38− population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34+ cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph+ leukemia due to quiescence.
PMCID: PMC3255258  PMID: 22829152
everolimus; mTOR inhibitor; Ph+ ALL; imatinib resistance
2.  Interleukin 1Β proinflammatory genotypes protect against gastro‐oesophageal reflux disease through induction of corpus atrophy 
Gut  2006;55(2):158-164.
Background and aims
The relationship between Helicobacter pylori infection and gastro‐oesophageal reflux disease (GORD) is controversial but it is accepted that GORD is associated with increased exposure to gastric acidity. The proinflammatory interleukin (IL)‐1B polymorphisms increase the risk of hypochlorhydria and gastric atrophy. We examined the association between proinflammatory cytokine gene polymorphisms, presence of gastric atrophy, and risk of GORD in H pylori positive and negative subjects in Japan.
We studied 320 consecutive dyspeptic patients without peptic ulcers or cancers. GORD symptoms were scored using the Carlsson‐Dent questionnaire and erosive oesophagitis was assessed endoscopically. H pylori infection was diagnosed by urea breath test, histological examination, and serology. Gastric atrophy was assessed histologically, and polymorphisms in the IL‐1B, IL‐10, and tumour necrosis factor α (TNF‐A) genes were genotyped.
Two hundred and eight patients were H pylori positive and 112 were negative. One hundred and eight (34%) were found to have erosive oesophagitis by endoscopic criteria (grade A: 78; grade B: 23; grade C: 6; grade D: 1). Erosive oesophagitis and GORD symptoms were significantly more common in H pylori negative compared with H pylori positive subjects (p<0.05). H pylori positive subjects were more likely to have corpus gastric atrophy than H pylori negative subjects (p<0.001). Among H pylori positive patients, those without erosive oesophagitis or GORD symptoms were significantly more likely to have corpus atrophy than subjects with erosive oesophagitis or GORD symptoms (p<0.05). Among H pylori positive patients, subjects homozygous for the proinflammatory allele IL‐1B−511T had a significantly lower risk of erosive oesophagitis (odds ratio (OR) 0.06 (95% confidence interval (CI) 0.006–0.51); p = 0.01) and GORD symptoms (OR 0.10 (95% CI 0.01–0.85); p = 0.04) compared with those homozygous for the −511C allele, while none of the two other proinflammatory cytokine gene polymorphisms had significant correlations with erosive oesophagitis or GORD symptoms.
A proinflammatory IL‐1B genotype is associated with increased risk of atrophy and decreased risk of GORD in H pylori infected subjects in Japan. These data indicate that in some genetically predisposed subjects, H pylori infection may protect against GORD through induction of gastric atrophy.
PMCID: PMC1856489  PMID: 16120761
gastro‐oesophageal reflux disease;  Helicobacter pylori ; gastric atrophy; genetic polymorphisms; interleukin 1β
3.  Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas 
Gut  2005;54(8):1162-1168.
Background and aims: Hepatitis B virus (HBV) DNA integration into or close to cellular genes is frequently detected in HBV positive hepatocellular carcinomas (HCC). We have previously shown that viral integration can lead to aberrant target gene transcription. In this study, we attempted to investigate common pathways to hepatocarcinogenesis.
Methods: By using a modified Alu-polymerase chain reaction approach, we analysed 50 HCCs along with 10 previously published cases.
Results: Sixty eight cellular flanking sequences (seven repetitive or unidentified sequences, 42 cellular genes, and 19 sequences potentially coding for unknown proteins) were obtained. Fifteen cancer related genes and 25 cellular genes were identified. HBV integration recurrently targeted the human telomerase reverse transcriptase gene (three cases) and genes belonging to distinct pathways: calcium signalling related genes, 60s ribosomal protein encoding genes, and platelet derived growth factor and mixed lineage leukaemia encoding genes. Two tumour suppressor genes and five genes involved in the control of apoptosis were also found at the integration site. The viral insertion site was distributed over all chromosomes except 13, X, and Y.
Conclusions: In 61/68 (89.7%) cases, HBV DNA was integrated into cellular genes potentially providing cell growth advantage. Identification of recurrent viral integration sites into genes of the same family allows recognition of common cell signalling pathways activated in hepatocarcinogenesis.
PMCID: PMC1774867  PMID: 16009689
hepatocellular carcinoma; hepatitis B virus; DNA integration; human telomerase reverse transcriptase
4.  Use of perfluorocarbon liquid during vitrectomy for severe proliferative diabetic retinopathy 
Aim: To evaluate the value of using perfluorocarbon liquid (PFCL) during vitrectomy in eyes with proliferative diabetic retinopathy (PDR).
Methods: The surgical records of eyes with PDR (291 eyes of 228 patients) that underwent vitrectomy in the vitreoretinal service of Osaka Medical College (April 1999 to October 2001) were reviewed. From these, 18 eyes of 15 patients had PFCL used during vitrectomy, and the preoperative and postoperative findings of these eyes were analysed.
Results: All of the 18 eyes had advanced PDR with tractional and/or rhegmatogenous retinal detachment. PFCL enabled easier flattening of the retinal folds and effective endophotocoagulation. In two cases, PFCL was used to flatten a bullous retinal detachment that developed when a tight vitreoretinal adhesion was loosened. In two other cases with combined traction/rhegmatogenous retinal detachment, PFCL was used to tamponade the detached retina which then allowed successful membrane dissection. Anatomical success was obtained in 16 of the 18 cases (mean follow up time 13.3 months) with visual acuity of 20/200 or better in nine eyes (50%).
Conclusions: PFCL is considered to be a useful adjunct during vitrectomy for the treatment of severe PDR.
PMCID: PMC1771679  PMID: 12714393
perfluorocarbon liquid; proliferative diabetic retinopathy
5.  Effects of sarin on the nervous system in rescue team staff members and police officers 3 years after the Tokyo subway sarin attack. 
Environmental Health Perspectives  2001;109(11):1169-1173.
Although the clinical manifestations of acute sarin poisoning have been reported in detail, no comprehensive study of the chronic physical and psychiatric effects of acute sarin poisoning has been carried out. To clarify the chronic effects of sarin on the nervous system, a cross-sectional epidemiologic study was conducted 3 years after the Tokyo subway sarin attack. Subjects consisted of the rescue team staff members and police officers who had worked at the disaster site. Subjects consisted of 56 male exposed subjects and 52 referent subjects matched for age and occupation. A neurobehavioral test, stabilometry, and measurement of vibration perception thresholds were performed, as well as psychometric tests to assess traumatic stress symptoms. The exposed group performed less well in the backward digit span test than the referent group in a dose-effect manner. This result was the same after controlling for possible confounding factors and was independent of traumatic stress symptoms. In other tests of memory function, except for the Benton visual retention test (mean correct answers), effects related to exposure were also suggested, although they were not statistically significant. In contrast, the dose-effect relationships observed in the neurobehavioral tests (psychomotor function) were unclear. None of the stabilometry and vibration perception threshold parameters had any relation to exposure. Our findings suggest the chronic decline of memory function 2 years and 10 months to 3 years and 9 months after exposure to sarin in the Tokyo subway attack, and further study is needed.
PMCID: PMC1240479  PMID: 11713003
7.  Chemoprevention of DMBA-induced mammary carcinogenesis in rats by low-dose EPA and DHA. 
British Journal of Cancer  1997;75(3):348-353.
We investigated the effects of low-dose eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the incidence and growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in rats fed a high-fat (HF) diet. We also examined the effects of these treatments on the fatty acid composition of tumour and serum. Tumour incidence was significantly decreased by the administration of low-dose EPA and DHA, whereas their inhibitory effects on tumour growth did not reach significance. Serum arachidonic acid (AA) level was decreased by the administration of low-dose EPA and tended to be decreased by the administration of low-dose DHA, whereas tumour AA levels were not changed. The administration of low-dose EPA and DHA may be useful for inhibiting the incidence of breast cancer.
PMCID: PMC2063366  PMID: 9020478
8.  Cellular autoimmunity to retinal specific antigens in patients with Behçet's disease. 
The notion that autoimmune mechanisms play a role in the pathogenesis of certain uveitic conditions in humans is supported by the observation that lymphocytes from such patients respond in culture against retinal specific antigens which are uveitogenic in animals. A large proportion of uveitis patients with Behçet's disease are reported to respond well to S antigen, to interphotoreceptor retinoid binding protein (IRBP) and to several of their uveitogenic peptides, in particular, the S antigen derived peptide M. Patients with Behçet's disease without ocular involvement were reported not to differ in their responses to S antigen from the responses in the control group, yet 35% of them responded to IRBP and approximately two thirds of them responded to the peptides (peptide M, peptide N, R-4, or R-14). The responses were inhibited by monoclonal antibodies to CD4 and to class II MHC HLA-DR molecules. The presence of lymphocyte responses to retinal antigens in patients with Behçet's disease without uveitis might indicate a preclinical stage of ocular involvement. Thus, these data support the idea that autoimmunity to retinal specific antigens may play a role in the ocular inflammation in Behçet's disease.
PMCID: PMC513957  PMID: 8218058
9.  Stereospecific reduction of virginiamycin M1 as the virginiamycin resistance pathway in Streptomyces virginiae. 
In a cell extract of Streptomyces virginiae, virginiamycin M1 was inactivated in the presence of NADPH, while virginiamycin S remained intact. The inactivated product of virginiamycin M1 was isolated, and structure analysis revealed that the inactivation involves reduction of a C-16 carbonyl group leading to the formation of 16-dihydrovirginiamycin M1. Acetonide and benzylidene acetal derivatives were synthesized from the two hydroxyl groups on C-14 and C-16, and the C-16 stereochemistry was determined by 13C nuclear magnetic resonance spectroscopy. Two methyl groups of the acetonide derivative gave 13C signals of 20.1 and 30.1 ppm, indicating that the relative stereochemistry of the C-14 and C-16 hydroxy groups is syn. Furthermore, irradiation of the benzylidene methine proton gave clear nuclear Overhauser effect enhancement of the C-14 or C-16 methine protons, indicating that H-14 and H-16 were in an axial configuration. From the (14S) absolute configuration of natural virginiamycin M1 and the syn relative configuration for the C-14 and C-16 hydroxyl groups of the inactivated product, the C-16 absolute configuration of the inactivated product was thus identified as R.
PMCID: PMC163164  PMID: 8851577
11.  Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. XI. Pseudogenetic restrictions of hybridoma suppressor factors 
Suppressor factor derived from three different murine T cell hybridomas were characterized . They specifically inhibited 4-hydroxy-3-nitrophenyl acetyl cutaneous sensitivity responses. The factors bind antigen and bear I-J and idiotypic determinants, but lack conventional immunoglobulin constant-region determinants. The factors function during the induction phase of the immune response, by inducing a second population of suppressor cells (Ts(e)). Suppressor factor can inhibit both cellular and plaque-forming cell responses in appropriate strains of mice. These hybridoma suppressor factors directly suppress strains of mice that are Igh-V homologous with the strain producing the factor. Thus, there is an apparent Igh-V restriction in the activity of these factors. However, this is a pseudogenetic restriction because these factors generate second order suppressor cells (Ts(e)) in Igh-incompatible mice, but in order to express the suppressive activity, the cells must be adoptively transferred into recipients that are Igh compatible with the strain producing the suppressor factor. Finally, it was shown that the factor-induced Ts(e) population is under an apparent dual genetic restriction. Thus, Igh and H-2 homology is required in order for the Ts(e) population to express its suppressive activity.
PMCID: PMC2186408  PMID: 6167654

Results 1-12 (12)