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- Watanabe, A., et al.
(author)
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Association of aberrant ASNS imprinting with asparaginase sensitivity and chromosomal abnormality in childhood BCP-ALL
- 2020
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 136:20, s. 2319-2333
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Journal article (peer-reviewed)abstract
- Karyotype is an important prognostic factor in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but the underlying pharmacogenomics remain unknown. Asparaginase is an integral component in current chemotherapy for childhood BCP-ALL. Asparaginase therapy depletes serum asparagine. Normal hematopoietic cells can produce asparagine by asparagine synthetase (ASNS) activity, but ALL cells are unable to synthesize adequate amounts of asparagine. The ASNS gene has a typical CpG island in its promoter. Thus, methylation of the ASNS CpG island could be one of the epigenetic mechanisms for ASNS gene silencing in BCP-ALL. To gain deep insights into the pharmacogenomics of asparaginase therapy, we investigated the association of ASNS methylation status with asparaginase sensitivity. The ASNS CpG island is largely unmethylated in normal hematopoietic cells, but it is allele-specifically methylated in BCP-ALL cells. The ASNS gene is located at 7q21, an evolutionally conserved imprinted gene cluster. ASNS methylation in childhood BCP-ALL is associated with an aberrant methylation of the imprinted gene cluster at 7q21. Aberrant methylation of mouse Asns and a syntenic imprinted gene cluster is also confirmed in leukemic spleen samples from ETV6-RUNX1 knockin mice. In 3 childhood BCP-ALL cohorts, ASNS is highly methylated in BCP-ALL patients with favorable karyotypes but is mostly unmethylated in BCP-ALL patients with poor prognostic karyotypes. Higher ASNS methylation is associated with higher L-asparaginase sensitivity in BCP-ALL through lower ASNS gene and protein expression levels. These observations demonstrate that silencing of the ASNS gene as a result of aberrant imprinting is a pharmacogenetic mechanism for the leukemia-specific activity of asparaginase therapy in BCP-ALL.
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| 4. |
- Takeda, H, et al.
(author)
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Effects of beta(3)-adrenoceptor stimulation on prostaglandin E-2-induced bladder hyperactivity and on the cardiovascular system in conscious rats
- 2002
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In: Neurourology and Urodynamics. - : Wiley. - 0733-2467 .- 1520-6777. ; 21:6, s. 558-565
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Journal article (peer-reviewed)abstract
- Aims. To investigate the effects of selective beta(2)- and selective beta(3)-adrenoceptor (AR) agonists on prostaglandin (PG) E-2-induced bladder hyperactivity in conscious free-moving rats. Methods. Female Sprague-Dawley rats were anesthetized for implantation of bladder, intravenous, and intra-arterial catheters. The effects of a beta(3)-AR agonist (CL316,243) on cystometric and cardiovascular parameters were assessed in conscious rats. Intravesical instillation of PGE(2) (20-60 muM, 6 mL/hr) in conscious rats produced a concentration-dependent increase in voiding frequency. Results. In this model i.v. CL316,243 (beta(3)-AR agonist) reduced basal bladder pressure, increased micturition volume, and prolonged micturition interval in a dose-dependent manner, without affecting threshold pressure or micturition pressure. On the other hand, i.v. procaterol (beta(2)-AR agonist) did not counteract the bladder hyperactivity. Atropine (muscarinic antagonist) reduced micturition pressure and micturition volume, and shortened micturition interval. CL316,243 slightly decreased mean blood pressure and increased heart rate only when given at high doses (10 and 100 mug/kg, iv.). In contrast, procaterol caused a significant decrease in mean blood pressure and a significant increase in heart rate. Atropine significantly increased heart rate. Conclusions. The present results clearly demonstrated that the beta(3)-AR agonist prolonged the micturition interval without producing significant cardiovascular side effects. The human detrusor, like the rat detrusor, relaxes on beta(3)-AR stimulation. Provided that these results are valid in humans, selective beta(3)-AR agonists might be clinically useful for controlling a certain type of bladder overactivity.
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| 5. |
- Kaidoh, K, et al.
(author)
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Effects of selective beta 2 and beta 3-adrenoceptor agonists on detrusor hyperreflexia in conscious cerebral infarcted rats
- 2002
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In: Journal of Urology. - 1527-3792. ; 168:3, s. 1247-1252
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Journal article (peer-reviewed)abstract
- Purpose: We evaluated the effects of beta-adrenoceptor agonists on detrusor hyperreflexia in cerebral infarcted rats. Materials and Methods: To produce cerebral infarction in Sprague-Dawley rats the left middle cerebral artery was occluded by introducing a monofilament nylon thread into the artery. In sham operated rats the same artery was exposed but not occluded. After these operations cystometric and cardiovascular experiments were performed with no anesthesia or restraint. Results: After the operation bladder capacity was significantly decreased and voiding pressure was significantly increased in cerebral infarcted but not in sham operated animals. The difference in cerebral infarcted and sham operated rats was significant for each parameter (p < 0.01). Post-void residual urine volume was not affected in either group. In the cerebral infarction group intravenous administration of CL316243 ([R,R]-5-2-[[2-(3-chlorophenyl-2-hydroxyethyl]-amino] propyl]-1,3-benzodioxole-2,2-dicarboxylate) (Kissei Central Laboratories, Hotaka, Japan) a selective beta3-adrenoceptor agonist, significantly increased bladder capacity at 10 and 100 mug./kg. without affecting voiding pressure or post-void residual urine volume. Procaterol, a selective beta2-adrenoceptor agonist, significantly increased bladder capacity and post-void residual urine volume at 10 mug./kg. intravenously without affecting voiding pressure. In separate experiments procaterol (1 to 100 mug./kg. intravenously) decreased mean blood pressure and increased heart rate in a dose dependent manner. In contrast, the effects of CL316243 (0.1 to 100 mug./kg. intravenously) on mean blood pressure and heart rate were minimal. Conclusions: These results indicate that in cerebral infarcted rats detrusor hyperreflexia can be suppressed by the selective beta3-adrenoceptor agonist CL316243 without increasing post-void residual volume and without significant cardiovascular side effects. If the current results hold true in humans, selective beta3-adrenoceptor agonists may prove useful for treating detrusor hyperreflexia associated with cerebral infarction.
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| 6. |
- Naruse, M., et al.
(author)
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Percolation of optical excitation mediated by near-field interactions
- 2017
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In: Physica A: Statistical Mechanics and its Applications. - : Elsevier. - 0378-4371. ; 471, s. 162-168
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Journal article (peer-reviewed)abstract
- Optical excitation transfer in nanostructured matter has been intensively studied in various material systems for versatile applications. Herein, we theoretically and numerically discuss the percolation of optical excitations in randomly organized nanostructures caused by optical near-field interactions governed by Yukawa potential in a two-dimensional stochastic model. The model results demonstrate the appearance of two phases of percolation of optical excitation as a function of the localization degree of near-field interaction. Moreover, it indicates sublinear scaling with percolation distances when the light localization is strong. Furthermore, such a character is maximized at a particular size of environments. The results provide fundamental insights into optical excitation transfer and will facilitate the design and analysis of nanoscale signal-transfer characteristics.
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