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S-(4-Nitrobenzyl)-6-thioinosine (NBMPR) is Not a Selective Inhibitor of Equilibrative Nucleoside Transporters but Also Blocks Efflux Activity of Breast Cancer Resistance Protein.

S-(4-硝基苄基)-6-硫代肌苷 (NBMPR) 不是平衡核苷转运蛋白的选择性抑制剂,也阻断乳腺癌耐药蛋白的外排活性。

  • 影响因子:3.89
  • DOI:10.1007/s11095-020-2782-5
  • 作者列表:"Karbanova S","Sorf A","Jiraskova L","Lalinska A","Ptackova Z","Staud F","Cerveny L
  • 发表时间:2020-02-21
Abstract

PURPOSE:S-(4-Nitrobenzyl)-6-thioinosine (NBMPR) is routinely used at concentrations of 0.10 μM and 0.10 mM to specifically inhibit transport of nucleosides mediated by equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2), respectively. We recently showed that NBMPR (0.10 mM) might also inhibit placental active efflux of [3H]zidovudine and [3H]tenofovir disoproxil fumarate. Here we test the hypothesis that NBMPR abolishes the activity of P-glycoprotein (ABCB1) and/or breast cancer resistance protein (ABCG2). METHODS:We performed accumulation assays with Hoechst 33342 (a model dual substrate of ABCB1 and ABCG2) and bi-directional transport studies with the ABCG2 substrate [3H]glyburide in transduced MDCKII cells, accumulation studies in choriocarcinoma-derived BeWo cells, and in situ dual perfusions of rat term placenta with glyburide. RESULTS:NBMPR inhibited Hoechst 33342 accumulation in MDCKII-ABCG2 cells (IC50 = 53 μM) but not in MDCKII-ABCB1 and MDCKII-parental cells. NBMPR (0.10 mM) also inhibited bi-directional [3H]glyburide transport across monolayers of MDCKII-ABCG2 cells and blocked ABCG2-mediated [3H]glyburide efflux by rat term placenta in situ. CONCLUSION:NBMPR at a concentration of 0.10 mM abolishes ABCG2 activity. Researchers using NBMPR to evaluate the effect of ENTs on pharmacokinetics must therefore interpret their results carefully if studying compounds that are substrates of both ENTs and ABCG2.

摘要

目的: 常规使用浓度为 0.10 μ m 和 0.10 mM 的 S-(4-硝基苄基)-6-硫代肌苷 (NBMPR) 特异性抑制平衡核苷转运蛋白 1 (ENT1) 介导的核苷转运和 2 (ENT2),分别。我们最近发现 NBMPR (0.10 mM) 也可能抑制 [3 H] 齐多夫定和 [3 H] 替诺福韦酯的胎盘主动外排。这里我们检验了 NBMPR 废除 P-糖蛋白 (ABCB1) 和/或乳腺癌耐药蛋白 (ABCG2) 活性的假设。 方法: 我们用 Hoechst 33342 (ABCB1 和 ABCG2 的模型双底物) 进行积累试验,用 ABCG2 底物 [3 H] 格列本脲在转导的 MDCKII 细胞中进行双向转运研究。绒毛膜癌来源的 BeWo 细胞中的蓄积研究,以及大鼠足月胎盘与格列本脲的原位双重输注。 结果: NBMPR 抑制 Hoechst 33342 在 MDCKII-ABCG2 细胞中的蓄积 (IC50 = 53 μ m),而在 MDCKII-ABCB1 和 MDCKII 亲本细胞中没有抑制作用。NBMPR (0.10 mM) 也抑制双向 [3 H] 格列本脲跨单层 MDCKII-ABCG2 细胞的转运,并阻断大鼠足月胎盘原位 ABCG2-mediated [3 H] 格列本脲外排。 结论: 0.10 mM 浓度的 NBMPR 可消除 ABCG2 活性。因此,使用 NBMPR 评估 ent 对药代动力学的影响的研究人员必须仔细解释他们的结果,如果研究是 ent 和 abcg2 的底物的化合物。

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影响因子:1.69
发表时间:2020-01-01
DOI:10.1016/j.jmig.2019.03.015
作者列表:["Oxley SG","Mallick R","Odejinmi F"]

METHODS:STUDY OBJECTIVE:To evaluate the differences in perioperative outcomes and immediate complication rates between laparoscopic myomectomy for submucous myomas and laparoscopic myomectomy for myomas in other locations. DESIGN:Retrospective cohort study. SETTING:University-affiliated hospital in London. PATIENTS:A total of 350 patients with symptomatic uterine myomas underwent laparoscopic myomectomy. Thirty-three of these were performed for submucous myomas (group 1), and 317 were for myomas in other uterine locations (group 2). INTERVENTIONS:Analysis of prospectively collected data on patient demographics, myoma characteristics, perioperative outcomes, and immediate complications. MEASUREMENTS AND MAIN RESULTS:Patient demographics, including age, body mass index, and parity, were similar in the 2 groups. No significant differences in myoma characteristics were seen between groups 1 and 2, including the mean dimension of largest myoma (7.1 vs 7.8 cm, respectively; p = .35), mean number of myomas removed (3.8 vs 4.1; p = .665), and mean mass of myomas removed (142.0 g vs 227.3 g; p = .186). There were also no significant between-group differences in any perioperative outcomes, including mean blood loss (226.8 mL vs 266.4 mL; p = .373), duration of surgery (103 minutes vs 113 minutes; p = .264), and duration of hospital stay (1.4 days vs 1.7 days; p = .057). No complications arose from laparoscopic resection of submucous myomas. CONCLUSION:Laparoscopic myomectomy for submucous myomas has similar perioperative outcomes and immediate complications as laparoscopic myomectomy for other myomas and can be considered for large or type 2 submucous myomas.

翻译标题与摘要 下载文献
影响因子:2.21
发表时间:2020-01-01
DOI:10.1111/aogs.13713
作者列表:["de Milliano I","Huirne JAF","Thurkow AL","Radder C","Bongers MY","van Vliet H","van de Lande J","van de Ven PM","Hehenkamp WJK"]

METHODS:INTRODUCTION:Laparoscopic myomectomy can be difficult when fibroids are large and numerous. This may result in extensive intraoperative bleeding and the need for a conversion to a laparotomy. Medical pretreatment prior to surgery might reduce these risks by decreasing fibroid size and vascularization of the fibroid. We compared pretreatment with ulipristal acetate (UPA) vs gonadotropin-releasing hormone agonists (GnRHa) prior to laparoscopic myomectomy on several intra- and postoperative outcomes. MATERIAL AND METHODS:We performed a non-inferiority double-blind randomized controlled trial in nine hospitals in the Netherlands. Women were randomized between daily oral UPA for 12 weeks and single placebo injection or single intramuscular injection with leuprolide acetate and daily placebo tablets for 12 weeks. The primary outcome was intraoperative blood loss. Secondary outcomes were reduction of fibroid volume, suturing time, total surgery time and surgical ease. RESULTS:Thirty women received UPA and 25 women leuprolide acetate. Non-inferiority of UPA regarding intraoperative blood loss was not demonstrated. When pretreated with UPA, median intraoperative blood loss was statistically significantly higher (525 mL [348-1025] vs 280 mL[100-500]; P = 0.011) and suturing time of the first fibroid was statistically significantly longer (40 minutes [28-48] vs 22 minutes [14-33]; P = 0.003) compared with GnRHa. Pretreatment with UPA showed smaller reduction in fibroid volume preoperatively compared with GnRHa (-7.2% [-35.5 to 54.1] vs -38.4% [-71.5 to -19.3]; P = 0.001). Laparoscopic myomectomies in women pretreated with UPA were subjectively judged more difficult than in women pretreated with GnRHa. CONCLUSIONS:Non-inferiority of UPA in terms of intraoperative blood loss could not be established, possibly due to the preliminary termination of the study. Pretreatment with GnRHa was more favorable than UPA in terms of fibroid volume reduction, intraoperative blood loss, hemoglobin drop directly postoperatively, suturing time of the first fibroid and several subjective surgical ease parameters.

影响因子:2.67
发表时间:2020-02-01
来源期刊:Histopathology
DOI:10.1111/his.14007
作者列表:["Liu C","Dillon J","Beavis AL","Liu Y","Lombardo K","Fader AN","Hung CF","Wu TC","Vang R","Garcia JE","Xing D"]

METHODS:AIMS:Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the Fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aimed to investigate the incidence and mutational profiles of FH-negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance. METHODS AND RESULTS:We evaluated 153 cases of uterine leiomyomas from women aged up to 30 years for loss of FH expression by tissue microarray (TMA)-based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulphite sequencing. Loss of FH protein expression was detected in seven (4.6%) of 153 tested uterine leiomyomas from young patients. All FH-negative leiomyomas displayed staghorn vasculature and fibrillary/neurophil-like cytoplasm. We found that six (86%) of seven FH-negative tumours detected by immunohistochemistry harboured FH mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in FH gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours. CONCLUSION:Our study showed a relatively high rate of FH germline mutation in FH-negative uterine leiomyomas from patients aged up to 30 years. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype.

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