长链脂肪酸对脂周素2表达的影响

目的研究长链脂肪酸对肝细胞脂周素2表达的影响,并揭示其调控的相关分子机制。方法应用实时定量PCR测定不同长度脂肪酸对脂周素2mRNA表达的影响。应用实时定量PCR和West-ernblot分别测定长链脂肪酸油酸对脂周素2mRNA和蛋白表达的影响。应用荧光素酶活性分析方法检测油酸对脂周素2启动子活性的影响。结果长链脂肪酸油酸、软脂酸、亚油酸、亚麻酸和花生四烯酸明显增加了脂周素2的表达,而短链脂肪酸己酸没有作用。油酸以剂量和浓度依赖方式上调脂周素2mRNA和蛋白的表达,乙酰辅酶A合成酶抑制剂triacsinC没有抑制油酸诱导的脂周素2表达。小鼠脂周素2启动子含有Ets/AP-1结合位点和PPARs反应元件(PPRE)。油酸以剂量依赖的方式显著增强了脂周素2的-2090bp启动子活性。Ets位点突变没有影响脂周素2的启动子活性,但AP-1位点突变,及PPRE突变显著抑制了油酸诱导的启动子活性。结论在肝细胞中,长链脂肪酸油酸诱导脂周素2的表达,需要启动子区域的AP-1和PPARs反应元件,为防治脂肪肝新药研发提供了新的靶点。     

Plasma C-reactive protein and risk of colorectal cancer in a nested case-control study: Japan Public Health Center-based prospective study.

C-reactive protein is a biomarker indicating inflammation in the body. We measured plasma C-reactive protein to assess whether this biomarker could predict subsequent colorectal cancer incidence. A nested case-control study was conducted within a Japan Public Health Center-based prospective study. During a 11.5-year follow-up, 375 newly diagnosed colorectal cancers were identified in a cohort of 38,373 adults who had returned the baseline questionnaire and provided blood samples. Two controls were selected from the cohort for each case matched by age, sex, study area, date of blood drawn, and fasting time at blood donation. The odds ratio of colorectal cancer for plasma C-reactive protein was estimated using a conditional logistic regression model adjusted for pack-years of smoking, body mass index, alcohol consumption, physical exercise, and family history of colorectal cancer. The highest quartile group of plasma C-reactive protein was significantly associated with colorectal cancer compared with the lowest group (odds ratio, 1.6; 95% confidence interval, 1.1-2.5; P(trend) = 0.053). The association became clearer after excluding cases of rectal cancer (P(trend) = 0.041) and limiting colorectal cancer to the intramucosal type (P(trend) = 0.017). This association was unchanged after deletion of the first 2-year cases. In conclusion, plasma levels of C-reactive protein were associated with a subsequent risk of colon cancer. Inflammation may be involved at the early stage of colon tumor growth.     

An assessment of femoral rotational alignment of mini-incision total knee arthroplasty: A comparison based on the transepicondylar line from the kneeling view and the intraoperative posterior condylar line

Background

Rotational alignment of the distal femur is important in total knee arthroplasty. The purpose of this study is to use a roentgenographic technique to evaluate the accuracy of mini-incision total knee arthroplasty (MIS TKA) performed based on the transepicondylar line from the kneeling view.

Coffee and green tea consumption and subsequent risk of acute myeloid leukemia and myelodysplastic syndromes in Japan

Although coffee and green tea are suggested to reduce the risk of some types of cancers, only a few epidemiological studies have investigated their effect on the risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Here, we investigated the association of coffee and green tea consumption and the risk of AML and MDS in a large‐scale population‐based cohort study in Japan. A total of 95,807 Japanese subjects (45,937 men and 49,870 women; age 40–69 years at baseline) were followed to the end of 2012, for an average of 18 years. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between coffee and green tea consumption at baseline and the risk of AML and MDS were assessed using a Cox proportional hazards model with adjustment for potential confounders. During 1,751.956 person‐years, we identified 85 AML cases and 70 MDS cases. Our findings showed no significant association between coffee consumption and the risk of AML, or between green tea consumption and the risk of AML or MDS. In contrast, we observed a decreasing dose‐response relationship between coffee consumption and the risk of MDS among men (almost none: reference, 1–4 times/week: HR = 0.83, 95% CI: 0.43–1.62; ≥1cups/day: HR = 0.47, 0.22–0.99, p for trend = 0.049). Stratified analysis by smoking status suggested that the observed relative risk for AML and MDS of coffee drinkers relative to non‐coffee drinkers might be due to residual confounding by smoking. These findings deserve further investigation in future studies.     

Metabolome analysis for pancreatic cancer risk in nested case‐control study: Japan Public Health Center‐based prospective Study

Discovery of a high‐risk group for pancreatic cancer is important for prevention of pancreatic cancer. The present study was conducted as a nested case‐control study including 170 pancreatic cancer cases and 340 matched controls of our population‐based cohort study involving 30 239 subjects who answered a baseline questionnaire and supplied blood samples. Twelve targeted metabolites were quantitatively analyzed by gas chromatography/tandem mass spectrometry. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were calculated using conditional logistic regression models. Statistically significant P‐value was defined as P < .05. Increasing 1,5‐anhydro‐d ‐glucitol (1,5‐AG) levels were associated with a decreasing trend in pancreatic cancer risk (OR of quartile 4 [Q4], 0.50; 95% CI, 0.27‐0.93; P = .02). Increasing methionine levels were also associated with an increasing trend of pancreatic cancer risk (OR of Q4, 1.79; 95% CI, 0.94‐3.40: P = .03). Additional adjustment for potential confounders attenuated the observed associations of 1,5‐AG and methionine (P for trend = .06 and .07, respectively). Comparing subjects diagnosed in the first 0‐6 years, higher levels of 1,5‐AG, asparagine, tyrosine and uric acid showed a decreasing trend for pancreatic cancer risk (P for trend = .04, .04, .04 and .02, respectively), even after adjustment for potential confounders. We found that the 12 target metabolites were not associated with pancreatic cancer risk. However, metabolic changes in the subjects diagnosed in the first 0‐6 years showed a similar tendency to our previous reports. These results might suggest that these metabolites are useful for early detection but not for prediction of pancreatic cancer.     

Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study

Background

Eribulin is a nontaxane microtubule inhibitor with activity in patients with metastatic breast cancer (MBC). We conducted a phase I dose-finding study of eribulin and capecitabine in patients with MBC pretreated with anthracycline and taxane.

Methods

Women with MBC aged ≤70 years were enrolled. A 3 + 3 dose escalation design was used: level 0 dosing, eribulin (1.4 mg/m² intravenously on days 1 and 8) plus capecitabine [825 mg/m² orally twice daily (BID)]; 2-weeks-on, 1-week-off in a 21-day cycle. If there were no dose-limiting toxicities (DLTs), level 1 capecitabine dose was 1000 mg/m² BID. The primary objective was to determine maximum tolerated dose, DLTs, and recommended dose (RD). Secondary objectives included pharmacokinetics, safety, and best overall response rate.

Results

Nine women with MBC were enrolled; six at level 0, three at level 1. One patient had grade 4 DLTs at level 0 (serum creatinine 7.65 mg/dL and uric acid 13.4 mg/dL), considered associated with study drugs. Level 1 dosing was taken as the RD. Neutropenia was the most common ≥grade 3 toxicity. Pharmacokinetic parameters of eribulin were not influenced by co-administration of capecitabine. Of three patients in level 1, one achieved partial response and one had prolonged stable disease.

Conclusion

Eribulin with capecitabine in the level 1 dosing schedule was associated with manageable toxicities and promising clinical activity. This combination is recommended for phase II investigation.

     

Validity and reliability of a self-administered food frequency questionnaire for the JPHC study: The assessment of amino acid intake

Background

The Japanese database of food amino acid composition was revised in 2010 after a 24-year interval. To examine the impact of the 2010 revision compared with that of the 1986 revision, we evaluated the validity and reliability of amino acid intakes assessed using a food frequency questionnaire (FFQ).

Frequent BCOR aberrations in extranodal NK/T‐Cell lymphoma,nasal type

Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK‐STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, targeted capture sequencing of 602 cancer‐related genes from 25 frozen ENKTL samples was performed, 11 of which were matched to normal samples. Several recurrent somatic mutations involving BCOR (32%), TP53 (16%), DDX3X (12%), FAT4 (8%), NRAS (8%), MLL3 (12%), and MIR17HG (8%) were identified. The pattern of BCOR aberrations (1 nonsense and 5 frame‐shift mutations, a mutation leading to a splicing error, and gene loss) suggested that loss of function of BCOR was the functionally important outcome of such changes. The literature was reviewed and the public data on BCOR aberrations was reanalyzed and it was found that the aberrations were frequently found in myeloid neoplasms, but, interestingly, were highly specific to ENKTL among lymphoid malignancies. Given the high frequency and pattern of aberration, BCOR is likely to play an important role in ENKTL pathogenesis as a tumor suppressor gene. © 2016 Wiley Periodicals, Inc.