Enzymatic Changes in Red Blood Cells of Diamond-Blackfan Anemia.

Diamond-Blackfan anemia is a congenital bone marrow failure syndrome characterized by red blood cell (RBC) aplasia with varied malformations in infants. Elevated activity of adenosine deaminase (ADA) has been considered as a useful biomarker of Diamond-Blackfan anemia, and ADA assay has been shown to be more sensitive than genetic diagnosis. Approximately, 80% of the examined patients showed elevated ADA activity, whereas genetic tests of ribosome subunit genes identified mutations in approximately 60% of the patients. We previously reported that reduced glutathione (GSH) levels in RBCs may serve as a biomarker of Diamond-Blackfan anemia. In this study, to confirm the universality of our data, we extended the analysis to seven RBC enzymes and GSH of 14 patients with Diamond-Blackfan anemia and performed a cross-analysis study using enzyme activity assay and recently reported proteome data. Statistical analysis revealed that both data exhibited high similarity, upregulation in the hexokinase and pentose-phosphate pathway, and downregulation in glycolytic enzymes such as phosphofructokinase and pyruvate kinase, in the RBCs obtained from the subjects with Diamond-Blackfan anemia. The only discrepancy between enzyme activity and proteome data was observed in glucose-6-phosphate dehydrogenase (G6PD), as increased G6PD activity showed no relation with the significant elevation in protein levels. These results suggest that our enzymatic activity data of Diamond-Blackfan anemia are universal and that the enzymatic activation of G6PD via a hitherto-unveiled mechanism is another metabolic feature of RBCs of Diamond-Blackfan anemia.

Association between SLCO1B1 rs4149056 and tegafur-uracil-induced hepatic dysfunction in breast cancer.

Aim: The aim of this study was to identify pharmacogenomic biomarkers to predict tegafur-uracil (UFT)-induced liver dysfunction. Patients & methods: A total of 68 patients, who were administered UFT, were evaluated using a two-step pharmacogenomics analysis. Results: The first screening revealed the association between five SNPs and UFT-induced hepatic dysfunction. In the second step, SLCO1B1 (rs4149056) was found to be the only SNP associated with UFT treatment-related elevation of aspartate aminotransferase (odds ratio: C/C vs T/T = 7.8, C/T vs T/T = 5.7; p = 0.037) and alanine transaminase (odds ratio: C/C vs T/T = 12.2, C/T vs T/T = 4.1; p = 0.034) levels. Conclusion: The SLCO1B1 polymorphisms are possible predictors of UFT treatment-related hepatic dysfunction.

Genetic Counseling for Couples Seeking Noninvasive Prenatal Testing in Japan: Experiences of Pregnant Women and their Partners.

The recent advent of noninvasive prenatal testing (NIPT) has had a significant impact in the field of prenatal testing. Although reports on pregnant women who used NIPT have accumulated, little is known about the experiences of their male partners. In this study, we assessed the experiences of couples who were expecting a child and undergoing NIPT, with a focus on both the pregnant women and their partners. Questionnaires were administered to 282 participants focusing on their specific experiences at three time points: after pre-test counseling (first visit), when undergoing NIPT (second visit), and when results were received (third visit). Responses were analyzed to assess the differences between pregnant women and their partners. We found that more partners selected "family" as their first information source about NIPT and "my partner" as the first person to request NIPT than did pregnant women (35.6 vs. 5.9 %; p < 0.001 and 19.3 vs.1.5 %; p < 0.001). However, pregnant women more often consulted others including family and friends until undergoing NIPT than their partners (89.1 vs. 54.6 %; p < 0.001). Our findings suggest that it is important to encourage male partners to be actively involved in the NIPT decision-making process. Differences between pregnant women and their partners should be seriously considered when providing genetic counseling.

Erythrocyte glutathione is a novel biomarker of Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia with mutations in ribosomal protein (RP) genes. Elevated activity of erythrocyte adenosine deaminase (eADA) has been utilized as a biomarker of DBA. We examined erythrocyte reduced glutathione (GSH) as well as eADA in 22 patients in 18 DBA families, in whom RP gene mutations had been identified. Simultaneous evaluation of both eADA and GSH demonstrated that all examined DBA patients showed elevated values of either eADA or GSH, whereas presence of both eADA and GSH elevation was able to distinguish DBA patients from 34 normal controls and 14 unaffected members of the DBA families. Furthermore, a support vector machines analysis using both eADA and GSH levels yielded a formula to differentiate DBA from both normal controls and non-DBA family members. To confirm the usefulness of the formula, we analyzed additional 7 patients diagnosed by the clinical criteria. Although eADA showed within normal values in 3 patients, all of these patients were diagnosed as 'DBA' by use of the formula. Because extensive analysis of the RP genes failed to detect no causative mutation in approximately 40% of clinically diagnosed DBA patients, GSH may be useful an additional biomarker for diagnosis of DBA.

An SNP in CYP39A1 is associated with severe neutropenia induced by docetaxel.

PURPOSE: Docetaxel is one of the most widely used chemotherapy drugs for gynecological cancers. A dose-limiting factor of docetaxel is severe neutropenia, and previous reports showed that grade 4 neutropenia was observed in approximately 70% of Japanese patients treated with docetaxel. In order to elucidate a valid biomarker for docetaxel-induced neutropenia, we analyzed 42 Japanese patients with gynecological cancers such as ovarian cancer and endometrial cancer of the uterus. METHODS: As a first step, AUC of docetaxel was examined in 10 patients and 1,936 SNPs of 225 genes were genotyped using DMET Plus™ genotyping systems. RESULTS: The first screening revealed that 28 SNPs were associated with the AUC (P < 0.05), and we analyzed the associations between the 28 SNPs and neutrophil counts in the other 32 patients, with the result that CYP39A1 (rs7761731) was found to be the only SNP significantly associated (P = 0.049 OR = 9.0) with the incidence of grade 4 neutropenia among 28 SNPs. CONCLUSIONS: This SNP in CYP39A1 may be a useful biomarker for predicting the risk of docetaxel-induced neutropenia.