Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature.

Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML.Experimental Design: We compared outcomes in 259 adults with AML (n = 217) and MDS (n = 42) randomized to receive either AZA monotherapy (75 mg/m2 × 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients.Results: Co-administration of VOR did not increase the overall response rate (P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P = 0.0001), IDH1 (P = 0.004), and TP53 (P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment.Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430-40. ©2017 AACR.

Association of the CETP Taq1B and LIPG Thr111Ile Polymorphisms with Glycated Hemoglobin and Blood Lipids in Newly Diagnosed Hyperlipidemic Patients.

OBJECTIVE: To examine the association of 2 common polymorphisms in high-density lipoprotein (HDL)-related genes, namely, cholesterol ester transfer protein CETP Taq1B (rs708272) and endothelial lipase LIPG Thr111Ile (rs2000813), with glycated hemoglobin (A1C), blood lipid levels and the risk for type 2 diabetes in a group of hyperlipidemic patients from northern Greece. METHODS: We categorized 175 patients with hyperlipidemia into 2 subgroups according to the presence or absence of type 2 diabetes, defined as a recent diagnosis, A1C >6.5% and/or fasting glucose >126 mg/dL. Genotypes for the 2 polymorphisms studied were determined by polymerase chain reaction-restriction fragment length polymorphism. Both polymorphisms were analyzed by multivariate and univariate analyses of baseline A1C levels and plasma lipids. The genotype and allele frequencies of the 2 subgroups were compared. RESULTS: The CETP Taq1B polymorphism was associated with HDL-cholesterol (HDL-C) and A1C levels, but this association was affected by type 2 diabetes; the association with A1C levels was significant only in type 2 diabetes (p=0.005), whereas the association with HDL-C occurred only in the subgroup without type 2 diabetes (p<0.001). LIPG Thr111Ile did not affect plasma HDL-C or A1C levels independently but appeared to modulate their association with CETP Taq1B, and LIPG 111IleIle homozygotes tended to be present at a higher frequency in the hyperlipidemic patients with type 2 diabetes compared to the hyperlipidemic patients without type 2 diabetes (p=0.056). CONCLUSIONS: In hyperlipidemic patients, apart from its known association with HDL-C, CETP Taq1B is also associated with A1C levels, and both associations are modified by type 2 diabetes and LIPG Thr111Ile.

Common ABCB1 polymorphisms in Greek patients with chronic hepatitis C infection: A comparison with hyperlipidemic patients and the general population.

BACKGROUND: Hepatitis C virus infectivity and replication efficiency appears to be dependent on the lipid content and organization of the plasma membrane of the host cell, as well as of the intracellular membranous web. As there is increasing awareness of a role played by the efflux pump ABCB1 (p-glycoprotein, P-gp) in lipid homeostasis, its function could be a determinant of chronic HCV infection. The aim of the present study was to examine and compare the distribution of common ABCB1 genotypes in patients with chronic HCV infection (n=168), hyperlipidemic patients (n=168) and a control group (n=173), all from Greece. METHODS: Participants were genotyped for the ABCB12677G>T/A and 3435C>T polymorphisms with previously reported PCR-RFLP methods. Genotype and allele frequency distributions were compared between the three groups with the χ(2) test of independence. RESULTS: The ABCB1 2677GG (ancestral) genotypes were significantly over-represented in patients with chronic hepatitis C compared to controls (39.3% vs. 26.6%, p=0.015 according to the dominant model). A similar result was obtained when hyperlipidemic patients were compared to controls (45.2% vs. 26.6%, p<0.001 according to the dominant model). Comparison of ABCB1 3435C>T genotype and allele distributions provided similar but not as significant differences. Genotype and allele distributions for both ABCB12677G>T/A and 3435C>T were very similar between HCV patients and hyperlipidemic patients. CONCLUSION: Our findings imply an influence of ABCB1 polymorphisms on HCV infectivity, possibly through an effect on lipid homeostasis.

Association of the CYP2B6 c.516G>T polymorphism with high blood propofol concentrations in women from northern Greece.

Cytochrome P450 2B6 (CYP2B6) is responsible for the initial biotransformation of profol, an extensively metabolized intravenous anesthetic. In this study we examined the effect of the apparently functional CYP2B6 c.516G>T polymorphism on the distribution of propofol concentrations, quantified by GC/MS analysis following a single bolus dose, in the blood of 44 Greek women undergoing oocyte retrieval. Univariate analysis using age, height, weight and smoking status as covariates, as well as the Mann-Whitney non-parametric test, revealed a strong trend of association of the T allele with high propofol concentrations determined in whole blood, shortly after a single bolus dose. Propofol concentrations which were higher than one standard deviation of the mean were almost invariably associated with carriage of the T allele.

DNA barcoding analysis of fish species diversity in four north Greek lakes.

MATERIALS AND METHODS: The present study is the first to apply DNA barcoding on identifying 37 freshwater fish species from the rich Balkan ichthyofauna. RESULTS: The results are highly successful since in most cases barcodes cluster according to species, in agreement with morphological taxonomic studies. This is also evident based on mean conspecific and congeneric Kimura two-parameter distance values. The 5.6-fold difference between these values is lower than previous barcoding studies, possibly due to the restricted samplings and the recent taxonomy reevaluation for several species. A number of species were identified, where future work is needed: For the species Scardinius erythrophthalmus, Perca fluviatilis, and Rutilus rutilus, the divergence values found among conspecific populations could warrant their placement into different species; for Barbus and Rhodeus populations, the reported interspecific distances found were lower than expected; and for Cobitis species, the application of barcoding seems problematic, due to their complicated reproduction. CONCLUSION: The extension of this work to other Greek or even Balkan freshwater systems should clarify the situation.