Plasma Exosomal miRNA-139-3p is a Novel Biomarker of Colorectal Cancer.

Objectives: This study investigated plasma exosomal miRNA-139-3p as a blood-based biomarker for the early diagnosis and metastasis monitoring of colorectal cancer (CRC). Patients and Methods: Exosome-rich fractions were isolated from the plasma of 80 CRC patients, and 23 controls using a kit method. We then used real-time polymerase chain reaction (RT-qPCR) to detect miR-139-3p levels in all subjects to evaluate expression levels and the predictive value of plasma exosomal miR-139-3p in CRC. We also collected clinicopathological data to explore correlations between abnormal miR-139-3p expression and clinicopathological parameters. Results: When compared with healthy controls, exosomal miR-139-3p expression levels in CRC patients were significantly down-regulated. Furthermore, these expression levels were lower in metastatic colorectal cancer (mCRC) and submucosal patients. Receiver operating characteristic (ROC) curve analysis showed that exosomal miR-139-3p levels were differentiated between CRC patients and healthy controls, as well as between non-metastatic and metastatic patients. Conclusion: Our findings show that decreased exosomal miR-139-3p expression levels in CRC patient plasma may act as a novel biomarker for the early diagnosis and metastasis monitoring in CRC.

Urinary circulating DNA profiling in non-small cell lung cancer patients following treatment shows prognostic potential.

BACKGROUND: Disease relapse in non-small cell lung cancer (NSCLC) requires close monitoring for early detection. The aim of the current study examines the use of urinary circulating DNA for patients after first line therapies. METHODS: EGFR positive NSCLC patients in stages I-III were profiled using digital droplet PCR (ddPCR). Urinary circulating DNA was collected prior to treatment and all monitored patients had detectable EGFR mutations. Post treatment urinary DNA measurements were taken at multiple time intervals. Results were matched to disease-free survival. RESULTS: Among the 213 patients recruited, 130 had matched EGFR profiles to corresponding tumor tissues. Concentrations of mutant DNA varied with different patients and mean concentration was 220±237 copies/mL. Measurements taken post-treatment showed a significant number of patients with undetectable EGFR mutations in their urine samples. Other patients registered a significant decline in urinary DNA concentrations. For measurements taken post treatment (6-month), we observed a significant increase of positively identified EGFR mutations in urine samples. In the patient group with higher urinary DNA concentration, 91% of the cohort experienced recurrence. CONCLUSIONS: Our results indicated that urinary DNA measurements can potentially be useful for disease monitoring of minimal residual disease (MRD) in NSCLC. This can complement current serial radiographic imaging to provide early detection for lung cancer relapse.

ABCB1 hypomethylation is associated with decreased antiplatelet effects of clopidogrel in Chinese ischemic stroke patients.

Current predictive models including the CYP2C19 polymorphism and clinical factors still explain only about 12% of variability of clopidogrel responsiveness. Up until recently, the precise mechanism of clopidogrel resistance remains unclear. P-glycoprotein (P-gp) encoded by ABCB1, a transmembrane calcium-dependent efflux pump for clopidogrel, implicated a role in clopidogrel resistance. In this present study, we investigated the methylation status of ABCB1 gene promoter in relation to ABCB1 mRNA expressions and the antiplatelet effects of clopidogrel. This study was a prospective cohort analysis of eligible stroke patients (n = 183, aged 18-75 years) who received clopidogrel (75 mg/day) for at least 5 days before discharge. A final subcohort of 87 patients with CYP2C19*1/*1 genotype were enrolled in the study population. Patients were grouped in quartiles of maximum platelet aggregation (MPA values (Q1, Q2, Q3 and Q4, MPA(Q1) < 14.1%, MPA(Q4) > 35.4%). The methylation status of the ABCB1 promoter was 1.8 times in the Q1 MPA group (10.1 ± 2.4%) than in the Q4 MPA group (5.5 ± 2.1%) (P < 0.001). ABCB1 methylation correlated inversely with MPA (R = - 0.764, P < 0.001) and mRNA expression (R = - 0.839, P < 0.001). Results of a multivariate linear regression model demonstrated that ABCB1 methylation was independently associated with MPA (ß(coef ficient) = - 4.71, P < 0.001). ABCB1 expression was 0.62 times in the Q1 MPA group (5.3 ± 1.4 per thousand) than in the Q4 MPA (8.5 ± 2.5%o), and the expression of ABCB1 correlated positively with ADP-induced MPA (R = 0.791, P < 0.001). ABCB1 promoter methylation status in whole blood appears to be inversely associated with ABCB1 mRNA expressions and MPA. In conclusions, hypomethylation of ABCB1 promoter is associated with a decreased response to clopidogrel in ischemic stroke patients via increased ABCB1 mRNA expression.

Pharmacokinetics and tolerability of single and multiple doses of ticagrelor in healthy Chinese subjects: an open-label, sequential, two-cohort, single-centre study.

BACKGROUND AND OBJECTIVES: Ticagrelor (Brilinta™) is an antithrombotic agent that reversibly binds to P2Y(12) receptors and inhibits adenosine diphosphate-induced platelet aggregation. Ticagrelor has undergone evaluation in the phase III PLATO trial, which enrolled 18 624 patients with acute coronary syndromes (ACS) from 43 countries, and 6% of patients were Asian. Subsequently, ticagrelor has now been approved in more than 40 countries for the prevention of atherothrombotic events in adult patients with ACS. Gene polymorphisms in drug-metabolizing enzymes may vary with ethnicity, and can alter drug exposure, potentially impacting drug efficacy and/or tolerability. The objectives of this study were to assess the pharmacokinetic parameters of ticagrelor and its active metabolite AR-C124910XX, and the safety and tolerability of ticagrelor in healthy Chinese subjects, following single and multiple oral doses of ticagrelor. METHODS: This trial was an open-label, sequential, two-cohort, single-centre study investigating 90 mg and 180 mg doses of ticagrelor in healthy Chinese subjects. On day 1, 12 subjects received a single oral dose of ticagrelor 90 mg. Following a 2-day washout period, ticagrelor was administered twice daily (90 mg twice daily) on days 4-9 and as a single dose on day 10. After completion of this phase, additional subjects (n = 14) were recruited into the ticagrelor 180 mg group, and received ticagrelor 180 mg under the same dosing schedule. On days 1 and 10 of both dosing schedules, blood samples for pharmacokinetic analyses were collected for 72 hours. RESULTS: Following single and multiple doses at both dose levels, ticagrelor was rapidly absorbed (median time [t(max)] to reach maximum plasma concentration [C(max)] 2 hours) with a mean elimination half-life (t(1/2;)) of 10.9-14.9 hours. AR-C124910XX was rapidly formed (median t(max) 2.0-3.0 hours; mean t(1/2;) 9.1-11.9 hours). Steady-state concentrations of ticagrelor and AR-C124910XX were rapidly established with both dosing regimens. Both parent and metabolite exhibited linear and predictable pharmacokinetics with single and multiple dosing as mean minimum plasma concentration (C(min)), C(max) and area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) were approximately 2-fold higher with ticagrelor 180 mg (e.g. multiple-dosing, geometric mean [% coefficient of variation]: C(max) 1973 [27] and AUC(∞) 18 035 [46]) versus 90 mg (e.g. multiple dosing: C(max) 915 [32] and AUC(∞) 7168 [35]) dosing regimens. Overall, ticagrelor was generally well tolerated in healthy Chinese subjects. Two subjects discontinued in the ticagrelor 90 mg group due to elevated serum levels of ALT and AST. Mild ticagrelor-associated adverse events were seen: bleeding events (90 mg: epistaxis n = 1; 180 mg: gingival bleeding n = 1) and dyspnoea (180 mg: n = 3). CONCLUSION: In healthy Chinese subjects, ticagrelor and AR-C124910XX pharmacokinetics were linear and predictable. Although ticagrelor and AR-C124910XX exposure at steady state were found to be slightly higher in Chinese subjects, these results were broadly similar to previous data in Caucasian subjects. Overall, ticagrelor was well tolerated in healthy Chinese subjects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00721448.