ALBERT

Description: Li4Ti5O12 (LTO) is recognized as being one of the most promising anode materials for high power Li ion batteries; however, its insulating nature is a major drawback. In recent years, a simple thermal treatment carried out in a reducing atmosphere has been shown to generate oxygen vacancies (VO) for increasing the electronic conductivity of this material. Such structural defects, however, lead to re-oxidization over time, causing serious deterioration in anode performance. Herein, we report a unique approach to increasing the electronic conductivity with simultaneous improvement in structural stability. Doping of LTO with Mo in a reducing atmosphere resulted in extra charges at Ti sites caused by charge compensation by the homogeneously distributed Mo6+ ions, being delocalized over the entire lattice, with fewer oxygen vacancies (VO) generated. Using this simple method, a marked increase in electronic conductivity was achieved, in addition to an extremely high rate capability, with no performance deterioration over time. Scientific Reports 4 doi: 10.1038/srep04350

Description: Abstract 3322 Objectives The aim of this study was to assess the degree of platelet inhibition by adjunctive cilostazol in patients with acute myocardial infarction (AMI) according to CYP2C19 genotype. Background Although adjunctive cilostazol intensifies platelet inhibition in AMI patients, it is not established whether this regimen can overcome the loss-of-function effect of CYP2C19 variants. Methods We randomly assigned 126 AMI patients with available CYP2C19 genotyping to receive adjunctive cilostazol (triple group; n = 64) or high maintenance-dose (MD) clopidogrel of 150-mg/day (high-MD group; n = 62). Using conventional aggregometry and VerifyNow, platelet reactivity was measured at pre-discharge and 30-day follow-up. Primary endpoint was change in maximal platelet aggregation (Aggmax). High post-treatment platelet reactivity (HPPR) was defined as 5 μmol/l ADP-induced Aggmax 〉 50%. Results In non-carriers, the two groups did not differ with respect to changes in platelet measures, and could achieve fewer rates of HPPR at 30-day follow-up (〈 5%). In carriers, changes in 5 and 20 μmol/l ADP-induced Aggmax were significantly higher in the triple (n = 39) versus high-MD group (n = 38) (21.8 ± 13.9% vs. 9.0 ± 13.3%, p 〈 0.001, and 24.2 ± 17.2% vs. 7.7 ± 15.5%, p 〈 0.001, respectively). Likewise, changes in late platelet aggregation and P2Y12 reaction unit were consistently greater in the triple vs. high-MD group. Fewer patients in the triple group met the criteria of HPPR at 30-day follow-up compared with the high-MD group (2.6% vs. 21.1%, p = 0.014). Conclusions Among AMI patients with CYP2C19 variants, adjunctive cilostazol enhances platelet inhibition and reduces the rate of HPPR, as compared with high-MD clopidogrel. (Adjunctive Cilostazol Versus High-MD ClopidogrEL in Patients With Acute Myocardial Infarction According to CYP2C19 genotype [ACCEL-AMI-CYP2C19]; NCT00915733). Disclosures: No relevant conflicts of interest to declare.

Description: Adipose-derived mesenchymal stem cells (AD-MSCs) have been studied as desirable cell sources for regenerative medicine and therapeutic application. However, it has still remained a challenge to obtain enough adequate and healthy cells in large quantities. To overcome this limitation, various biomaterials have been used to promote expansion of MSCs in vitro. Recently, hexanoyl glycol chitosan (HGC) was introduced as a new biomaterial for various biomedical applications, in particular 3D cell culture, because of its biodegradability, biocompatibility, and other promising biofunctional properties. In this study, the effect of HGC on the proliferation of AD-MSCs was examined in vitro, and its synergistic effect with basic fibroblast growth factor (bFGF), which has been widely used to promote proliferation of cells, was evaluated. We found that the presence of HGC increased the proliferative capacity of AD-MSCs during long-term culture, even at low concentrations of bFGF. Furthermore, it suppressed the expression of senescence-related genes and improved the mitochondrial functionality. Taken all together, these findings suggest that the HGC demonstrate a potential for sustained growth of AD-MSCs in vitro.

Description: Abstract 2315 Background: Multiple lines of evidence have demonstrated a relationship between high on-treatment platelet reactivity (HPR) measured by multiple platelet assays and adverse clinical ischemic events. Although the Working Group on High On-Treatment Platelet Reactivity recently provided a consensus opinion on the definition of HPR, correlations between HPR cut-offs have not been validated yet. Therefore, we performed this study to provide a comprehensive analysis on the agreement and correlation of HPR cut-offs based on the consensual definition among the different platelet function measurements. Methods: We analyzed data from coronary intervention-treated patients on dual antiplatelet therapy (n = 962). Platelet measures were concurrently 5 and 20 μM ADP-stimulated light transmittance aggregometry (LTA), the VerifyNow P2Y12 analyzer, and flow cytometric analysis of vasodilator-stimulated phosphoprotein (VASP)-platelet reactivity index (PRI). As the Working Group noted, HPR cut-offs were defined as 5 and 20 μM ADP-induced maximal platelet aggregation (PRmax) 〉 46% and 59%, the VerifyNow P2Y12 assay 〉 240 P2Y12 reaction unit (PRU), and the VASP-PRI 〉 50%, respectively. Agreement between the consensual cut-off points of different tests was determined by kappa statistics, and 95% confidence intervals (CI) were also calculated. Receiver-operating characteristics (ROC) curve analysis was performed to identify the matched points for consensual definition-based cut-offs for HPR. Results: The consensual cut-off as 5μmol/l ADP-induced PRmax 〉46% showed a substantial agreement with 20 μmol/l ADP-induced PRmax, however, this cut-off showed a moderate agreement with the VerifyNow P2Y12 assay 〉 240 PRU and the VASP-PRI 〉 50%, respectively (Table 1). Fair correlations were observed between ADP-induced PRmax, the VerifyNow P2Y12 assay, and VASP-PRI according to the ROC curve analyses (Table 2). The cut-offs for 5μmol/l ADP-induced PRmax 〉46% based HPR matched well with the VerifyNow P2Y12 assay 〉 284 PRU (AUC 0.791, 95% CI 0.763–0.819, sensitivity 62.0%, and specificity 80.7%, p 〈 0.001), and the VASP-PRI 〉 60.3% (AUC 0.788, 95% CI 0.759–0.816, sensitivity 78.2%, and specificity 70.2%, p 〈 0.001) by the ROC curve analysis, respectively. The consensus-defined cut-offs of VerifyNow P2Y12 assay and VASP index overestimated HPR risk based on LTA cut-offs. Conclusion: Although the VerifyNow P2Y12 and VASP assay correlated significantly with LTA, there are moderate agreements and fair correlations among the consensual cut-offs of HPR. These data suggest the platelet function measurements need to be improved to become clinically used diagnostic tests and the need for a new cut-offs to balance safety and efficacy of P2Y12 receptor antagonists. Further, it still may be too early to define the gold standard method for assessing platelet reactivity and generally acceptable cut-off values. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Cytochrome P450 (CYP) 2C19 is an enzyme showing genetic polymorphism that may cause marked interindividual and interethnic variation in the metabolism and disposition of its substrates. CYP2C19*2 and CYP2C19*3 are the most common of CYP2C19 polymorphisms, and show phenotypic poor metabolism. Recent data have shown that the CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet response to clopidogrel in healthy controls and Caucasian patients with acute coronary syndrome. However, It is unknown whether CYP2C19 *3, which is frequently noted in Asian, is also associated with platelet response to clopidogrel. Therefore, this study was conducted to analyze the effect of CYP2C19 *2 and *3 polymorphisms on high post-treatment platelet reactivity (HPPR) on clopidogrel in Korean patients with acute coronary syndrome, as a representative of Asian populations. Methods: The study included 136 consecutive patients undergoing percutanous coronary intervention (PCI). Adenosine diphosphate (ADP)-induced platelet aggregation by light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay (Ultegra rapid platelet function assay; Accumetrics Inc., USA) were assessed after a loading dose and after the maintenance dose of clopidogrel before discharge. CYP2C19 genotype was analyzed by Snapshot method. Results: The genotypic distributions of CYP2C19*1/*1, *1/*2, *1/*3, *2/*2, and *2/*3 were 57 (41.9%), 47 (34.6%), 12 (8.8%), 14 (10.3%), 6 (4.4%), and 6(4.4%), respectively. The frequencies of CYP2C19 mutant alleles in Korean were higher than Caucasians. The CYP2C19*2 and CYP2C19*3 polymorphisms were significantly associated with persistent higher platelet aggregation by LTA, and lower inhibition of platelet reactivity by VerifyNow P2Y12 assay after clopidogrel than CYP2C19*1 genotype. The CYP2C19*2 and *3 alleles were more frequent in clopidogrel hyporesponsiveness, defined by persistent HPPR (5 uM ADP-induced platelet aggregation 〉50%; p = 0.01). Conclusions: This study suggests that the CYPC19*2 and *3 alleles influence clopidogrel hyporesponsiveness after clopidogrel in Asian patients with acute coronary syndromes undergoing PCI. These findings can have a significant impact on the future design of pharmacognetic antiaggregant strategies for acute coronary syndrome on antiplatelet treatment.

Description: Abstract 1093 Background Flow cytometric analysis of platelet reactivity index of vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) is a suitable test to evaluate the “high post-treatment platelet reactivity (HPPR)”. A reliable cut-off of VASP-P index is needed to identify the HPPR. However, an ideal cut-off identifying HPPR using the VASP-P index remains undetermined. We aimed to show the comparison between light transmittance aggregometry (LTA) and flow cytometric analysis of VASP-P index and assess the cut-offs of identifying HPPR using VASP-P index. Methods We enrolled consecutively patients undergoing percutaneous coronary intervention (PCI) in real clinical practice (n = 516). They all received clopidogrel and aspirin, performed LTA (5 and 20 μmol/l ADP-induced, and 1.6 nmol/l arachidonic acid (AA)-induced PR) and flow cytometric analysis of VASP-P index simultaneously and compared the different platelet measures. Based on previously suggested cut-offs, 5 μmol/l ADP-induced maximal platelet reactivity (PRmax) 〉 42.9%, 5 μmol/l ADP-induced PRmax 〉 50%, 20 μmol/l ADP-induced PRmax 〉 62%, 20 μmol/l ADP-induced PRmax 〉 64.5%, and 1.6 mmol/l AA-induced PRmax 〉 20%, the cut-offs of identifying HPPR using flow cytometric analysis of VASP-P were determined by receiver-operating characteristics (ROC) curve analysis. Results Excellent correlations were observed between LTA with ADP-induced PRmax and flow cytometric analysis of VASP-P according to the ROC curve analyses. The ROC curve analyses demonstrated that 5 μmol/l ADP-induced PRmax 〉 42.9% could distinguish between patients with and without VASP-P index 〉 54.9% (area under curve [AUC] 0.926, 95% confidence interval (CI) 0.903–0.949, sensitivity 82.8%, and specificity 88.5%, p 〈 0.001) and 5 μmol/l ADP-induced PRmax 〉 50% could distinguish between patients with and without VASP-P index 〉 57.4% (AUC 0.937, 95% CI 0.914–0.961, sensitivity 91.5%, and specificity 85.2%, p 〈 0.001). ROC curve analysis demonstrated 20 μmol/l ADP-induced PRmax 〉 62% could distinguish between patients with and without VASP-P index 〉 55.2% (AUC 0.948, 95% CI 0.927–0.969, sensitivity 95.7%, and specificity 87.3%, p 〈 0.001) and 20 μmol/l ADP-induced PRmax 〉 64.5% could distinguish between patients with and without VASP-P index 〉 55.9% (AUC 0.925, 95% CI 0.900–0.951, sensitivity 88.3%, and specificity 83.0%, p 〈 0.001), respectively. However, fair correlation was observed between AA-induced PRmax and VASP-P index and 1.6 nmol/l AA-induced PRmax 〉 20% could distinguish between patients with and without VASP-P index 〉 52.4% (AUC 0.761, 95% CI 0.719–0.802, sensitivity 68.5%, and specificity 72.7%, p 〈 0.001). We defined the ideal threshold of VASP-P index 〉 56%. The VASP-P index 〉 56% showed a substantial agreement with 5 μmol/l and 20 μmol/l ADP-induced PRmax (Table 1). However, VASP-P index 〉 56% showed a moderate agreement with 1.6 nmol/l AA)-induced PRmax 〉 20% (Table 1). Conclusion There are significant correlations between the suggested cut-offs of HPPR. Because VASP-P index 〉 56 is well matched with 5 μmol/l ADP-induced PRmax 〉 42.9%, 5 μmol/l ADP-induced PRmax 〉 50%, 20 μmol/l ADP-induced PRmax 〉 62%, and 20 μmol/l ADP-induced PRmax 〉 64.5%., it might suggest that VASP-P index 〉 56 has a practical implication for stratification of high-risk ischemic events. Disclosures: No relevant conflicts of interest to declare.

Description: The changes in telomere length and mitochondrial DNA copy number (mtDNAcn) are considered to be aging markers. However, many studies have provided contradictory or only fragmentary information about changes of these markers in animal models, due to inaccurate analysis methods and a lack of objective aging standards. To establish chronological aging standards for these two markers, we analyzed telomere length and mtDNAcn in 12 tissues—leukocytes, prefrontal cortex, hippocampus, pituitary gland, adrenal gland, retina, aorta, liver, kidney, spleen, skeletal muscle, and skin—from a commonly used rodent model, C57BL/6 male mice aged 2–24 months. It was found that at least one of the markers changed age-dependently in all tissues. In the leukocytes, hippocampus, retina, and skeletal muscle, both markers changed age-dependently. As a practical application, the aging marker changes were analyzed after chronic immobilization stress (CIS) to see whether CIS accelerated aging or not. The degree of tissue-aging was calculated using each standard curve and found that CIS accelerated aging in a tissue-specific manner. Therefore, it is expected that researchers can use our standard curves to objectively estimate tissue-specific aging accelerating effects of experimental conditions for least 12 tissues in C57BL/6 male mice.