Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients

Purpose The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods We studied 282 patients with hormone receptor–positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen

胸部外科手術後のPeak cough flow とMaximum phonation time の関係

研究論文Original Articles　手術後の肺活量（VC）が咳嗽力（PCF）に影響を及ぼすことは明らかだが，最大発声持続時間（MPT）で評価される声門閉鎖機能低下がPCF に及ぼす影響は明らかとなっていない．本研究では呼吸器外科手術後の患者28 例においてMPT とPCF の関係を明らかにすることを目的とし，手術後1 日目〜5 日目にPCF，MPT，VC を測定した．手術後5 日目までPCF およびMPT は，手術前と比較し有意に低下した（p <0.05）． またPCF とMPT の回復率には手術後1 日目のみに相関関係を認めた（r= 0.53，p <0.05）．PCF とVC の回復率は手術後1 日目〜5 日目まで相関を認めた（r = 0.41-0.27，p <0.05）．手術後の声門閉鎖機能低下が咳嗽力に及ぼす影響は，人工呼吸器離脱後１日目までで，その後はVC の影響を強く受けると考えられた．　The vital capacity（ VC） after thoracic surgery affects peak cough flow（ PCF）.　However, the influence of glottic closure deterioration evaluated by maximum phonation time （MPT） on PCF is not clear. We clarified the relationship between coughing and vocal cord function in 28 patients after thoracic surgery. We measured the PCF, MPT, and VC on postoperative days 1 to 5. On postoperative day 1, the mean PCF decreased to 58.0% and the mean MPT decreased to 62.5%. The mean PCFs and MPTs on postoperative days 1 to 5 were significantly lower than the preoperative PCF and MPT, respectively （p < 0.05）. There was a positive correlation between the rates of change in the PCF and MPT only on postoperative day 1 （r = 0.53, p < 0.05）. There was also a positive correlation between the rates of change in the PCF and VC on postoperative days 1 to 5 （r = 0.41–0.27, p < 0.05）. Cough intensity was affected by the vocal cord function on postoperative day 1. However, after postoperative day 2, the cough intensity was not influenced by the vocal cord function. Declining glottal closure function（ vocal cord function） immediately after surgery affects the cough intensity and vocal function. The influence of reduction in glottic closure function after surgery on coughing decline was observed up to 1 day after the withdrawal of ventilatory support. After the secondpostoperative day, the PCF was strongly influenced by the VC

Effects of membrane properties on CO2 recovery performance in a gas absorption membrane contactor

AbstractGlobal warming is a serious global environmental problem. CCS (Carbon dioxide Capture and Storage) is considered to be an emergency measure to mitigate the increase in atmospheric CO2. Chemical absorption is the major separation technique employed in CCS. Recently, the focus has been on chemical absorption using a membrane contactor with microporous hollow fibres because of the large contact area between the gas and liquid as well as the absence of problems such as flooding and channelling.In this study, we changed the properties of the polyethylene microporous hollow fibre membranes by two treatments: (i) drawing in the axial direction and (ii) soaking in concentrated nitric acid solution. The effects of these treatments on CO2 recovery performance were investigated by a CO2 recovery experiment using the untreated and treated membranes and a MEA aqueous solution.The CO2 recovery rate for the membrane treated by drawing was higher than that for the untreated membrane. Additionally, the CO2 recovery rate increased with an increase in the drawing ratio. The nitric acid treatment also increased the CO2 recovery rate compared with the untreated membrane.Changes in membrane dimensions, porosity and pore size distribution were expected to be major reasons for the increase in CO2 recovery rate for the membrane treated by drawing. On the other hand, nitric acid treatment did not induce any changes in membrane dimensions or pore size distribution but only reduced the surface roughness. As a result, the decrease in surface roughness was a major reason for the increase in CO2 recovery rate for the membrane treated with nitric acid

17 beta-HSD Type 12-Like Is Responsible for MaturationInducing Hormone Synthesis During Oocyte Maturation in Masu Salmon

The maturation-inducing hormone 17(alpha), 20(beta)-dihydroxy-4-pregnen-3-one (DHP) was first identified in the amago salmon. Although carbonyl reductase-like 20 beta-hydroxysteroid dehydrogenase (CR/20b-HSD) was reported to convert 17 alpha-hydroxyprogesterone (17OHP) to DHP in rainbow trout, we previously found that CR/20 beta-HSD messenger RNA (mRNA) was not upregulated in stimulated granulosa cells from masu salmon, which suggested that DHP is synthesized by a different enzyme. Accordingly, the current study aimed to identify the specific 20 beta-hydroxysteroid dehydrogenase (20 beta-HSD) responsible for DHP production by granulosa cells during final oocyte maturation in masu salmon. RNA sequencing was performed on granulosa layers that were isolated from ovarian follicles at 1 month before ovulation and incubated with or without forskolin, which was used to mimic luteinizing hormone, and similar to 12 million reads were obtained, which yielded 71,062 contigs of > 100 bp. tBlastx analysis identified 1 contig (#f103496)as similar to 17 beta-hydroxysteroid dehydrogenase type 12 (hsd17 beta 12); however, because the full-length #f103496 sequence was different from hsd17 beta 12, it was termed hsd17 beta 12-like (hsd17 beta 12l). We found that mammalian cells transfected with full-length hsd171 beta 2l exhibited considerable 20b-HSD activity, as indicated by efficient conversion of exogenous 17OHP to DHP. In addition, we found that hsd17 beta 12l mRNA levels were consistently low in follicles during vitellogenic growth; however, the levels increased significantly during final oocytematuration. The levels of hsd17 beta 12lmRNA were also considerably increased in granulosa layers in which 20 beta-HSD activity was induced by salmon pituitary extract. Therefore, we suggest that hsd17 beta 12l, not CR/20 beta-HSD, is the 20 beta-HSD responsible for DHP production by granulosa cells in masu salmon during final oocytematuration

Predictive impact of absolute lymphocyte counts for progression-free survival in human epidermal growth factor receptor 2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel

Abstracts Background Although peripheral blood-based parameters (PBBPs) are reported as prognostic indicators in patients with breast cancers, their utility has not been studied in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Tumor-infiltrating lymphocytes (TILs) might be a predictive factor in patients with HER2-positive ABC treated with pertuzumab and trastuzumab (PT) plus docetaxel. We aimed to evaluate whether PBBPs could have predictive value in HER2-positive ABC treated with pertuzumab and trastuzumab (PT) combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX). Methods Data from 51 patients included in two single-arm, phase II trials were included in this retrospective-prospective study; the ERI + PT (N = 30) and Nab-PTX + PT (N = 21) combinations were registered under clinical trials number UMIN000012375 and UMIN000006838, respectively. We assessed PBBPs using prospectively collected data and investigated the association with progression-free survival (PFS); we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values for ALC, NLR, and PLR were set at 1000 or 1500 cells/μL, 2, and 250, respectively. Results PFS was significantly improved in patients with ALC ≥1500/μL compared to those with ALC 1000–, <1500/μL or ALC < 1000/μL (P = 0.0106). High baseline ALC was significantly associated with improved PFS (≥1500/μL; hazard ratio [HR]: 0.3715; 95% confidence interval [CI]: 0.1735–0.7955; P = 0.0108). In contrast, improved PFS was not significantly associated with NLR or PLR. Improved PFS in patients with ALC ≥1500/μL was observed irrespective of visceral metastasis or chemotherapy regimen. Conclusions Our results showed that baseline ALC was a predictive factor for PFS in HER2-positive ABC treated with PT irrespective of combined chemotherapy regimen. Anti-tumor effects might be mediated not only by the tumor microenvironment, but also by systemic peripheral circulating lymphocytes. Baseline systemic parameters such as peripheral lymphocyte count might be beneficial in addition to disease extent for predicting the efficacy of PT treatment. Trial registration UMIN000012375, registration date: 21NOV2013, and UMIN000006838, registration date: 6DEC2011