Theory of stimulated Raman adiabatic passage in a degenerated reaction system: Application to control of molecular handedness

科研費報告書収録論文(課題番号:13640497・基盤研究(C)(2) ・H13～H14/研究代表者:藤村, 勇一/光化学異性化反応の量子制御

Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis

NASH 患者では IRP 活性化による DMT 1 の発現促進を介した腸管からの鉄吸収亢進が肝内鉄蓄積の一因である．また鉄吸収試験は NASH 患者において除鉄療法の有用性を推測するために有用である可能性が示唆された

Membrane transport of camptothecin: facilitation by human P-glycoprotein (ABCB1) and multidrug resistance protein 2 (ABCC2)

BACKGROUND: The purpose of the present study was to continue the investigation of the membrane transport mechanisms of 20-(S)-camptothecin (CPT) in order to understand the possible role of membrane transporters on its oral bioavailability and disposition. METHODS: The intestinal transport kinetics of CPT were characterized using Caco-2 cells, MDCKII wild-type cells and MDCKII cells transfected with human P-glycoprotein (PGP) (ABCB1) or human multidrug resistance protein 2 (MRP2) (ABCC2). The effects of drug concentration, inhibitors and temperature on CPT directional permeability were determined. RESULTS: The absorptive (apical to basolateral) and secretory (basolateral to apical) permeabilities of CPT were found to be saturable. Reduced secretory CPT permeabilities with decreasing temperatures suggests the involvement of an active, transporter-mediated secretory pathway. In the presence of etoposide, the CPT secretory permeability decreased 25.6%. However, inhibition was greater in the presence of PGP and of the breast cancer resistant protein inhibitor, GF120918 (52.5%). The involvement of additional secretory transporters was suggested since the basolateral to apical permeability of CPT was not further reduced in the presence of increasing concentrations of GF120918. To investigate the involvement of specific apically-located secretory membrane transporters, CPT transport studies were conducted using MDCKII/PGP cells and MDCKII/MRP2 cells. CPT carrier-mediated permeability was approximately twofold greater in MDCKII/PGP cells and MDCKII/MRP2 cells than in MDCKII/wild-type cells, while the apparent K(m )values were comparable in all three cell lines. The efflux ratio of CPT in MDCKII/PGP in the presence of 0.2 μM GF120918 was not completely reversed (3.36 to 1.49). However, the decrease in the efflux ratio of CPT in MDCKII/MRP2 cells (2.31 to 1.03) suggests that CPT efflux was completely inhibited by MK571, a potent inhibitor of the Multidrug Resistance Protein transporter family. CONCLUSIONS: The current results provide evidence that PGP and MRP2 mediate the secretory transport of CPT in vitro. However, the involvement of other transporters cannot be ruled out based on these studies. Since these transporters are expressed in the intestine, liver and kidney variations in their expression levels and/or regulation may be responsible for the erratic oral absorption and biliary excretion of CPT observed in human subjects

Coordinated and Cohesive Movement of Two Small Conspecific Fish Induced by Eliciting a Simultaneous Optomotor Response

BACKGROUND: In animal groups such as herds, schools, and flocks, a certain distance is maintained between adjacent individuals, allowing them to move as a cohesive unit. Proximate causations of the cohesive and coordinated movement under dynamic conditions, however, have been poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We established a novel and simple behavioral assay using pairs of small fish (medaka and dwarf pufferfish) by eliciting a simultaneous optomotor response (OMR). We demonstrated that two homospecific fish began to move cohesively and maintained a distance of 2 to 4 cm between them when an OMR was elicited simultaneously in the fish. The coordinated and cohesive movement was not exhibited under a static condition. During the cohesive movement, the relative position of the two fish was not stable. Furthermore, adult medaka exhibited the cohesive movement but larvae did not, despite the fact that an OMR could be elicited in larvae, indicating that this ability to coordinate movement develops during maturation. The cohesive movement was detected in homospecific pairs irrespective of body-color, sex, or albino mutation, but was not detected between heterospecific pairs, suggesting that coordinated movement is based on a conspecific interaction. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that coordinated behavior between a pair of animals was elicited by a simultaneous OMR in two small fish. This is the first report to demonstrate induction of a schooling-like movement in a pair of fish by an OMR and to investigate the effect of age, sex, body color, and species on coordination between animals under a dynamic condition

Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines

Recent data suggest that expression of the membrane P170-glycoprotein (P-gp) may confer resistance to the topoisomerase- I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 μM completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function. © 1999 Cancer Research Campaig

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

BACKGROUND: Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial. METHODS: Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan-Meier and Cox regression. RESULTS: Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44-3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis. CONCLUSIONS: The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity

Xist regulation and function eXplored

X chromosome inactivation (XCI) is a process in mammals that ensures equal transcript levels between males and females by genetic inactivation of one of the two X chromosomes in females. Central to XCI is the long non-coding RNA Xist, which is highly and specifically expressed from the inactive X chromosome. Xist covers the X chromosome in cis and triggers genetic silencing, but its working mechanism remains elusive. Here, we review current knowledge about Xist regulation, structure, function and conservation and speculate on possible mechanisms by which its action is restricted in cis. We also discuss dosage compensation mechanisms other than XCI and how knowledge from invertebrate species may help to provide a better understanding of the mechanisms of mammalian XCI