Atsushi Iwabuchi

Serum dipeptidyl peptidase 4 activity in children with type 1 diabetes mellitus.

Abstract Background: It is poorly understood whether dipeptidyl peptidase 4 (DPP4) activity is altered and how DPP4 contributes to glycemic control in patients with type 1 diabetes mellitus (T1DM). Aim: The aim of this study was to measure serum DPP4 activity and to assess its relationships to metabolic variables in T1DM children. Methods: Serum DPP4 activity was determined using a fluorometric assay in 43 T1DM and 26 control children. Results: Serum DPP4 activity was significantly higher in T1DM children than in controls (3.57±0.99 vs. 2.67±0.77 U/mL, p<0.001). In the T1DM children, DPP4 activity was not correlated with HbA1c, blood glucose, or diabetes duration. A significant negative correlation was found between DPP4 activity and serum adiponectin levels in the T1DM group (r=–0.35, p<0.05). Conclusions: Serum DPP4 activity was increased in the T1DM children, whereas it was not associated with glycemic control. Given the negative correlation between serum DPP4 and adiponectin levels, further investigations are warranted to elucidate the role of DPP4 on insulin sensitivity in T1DM children.

Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age

The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.

Influence of SLCO1B1 polymorphism on maintenance therapy for childhood leukemia

Management of the adverse effects of chemotherapy is essential to improve outcome of children with leukemia. Some genetic polymorphisms can predict treatment‐related toxicity, and be used individually in dose modification of 6‐mercaptopurine (6‐MP) and methotrexate (MTX) in maintenance therapy for childhood acute lymphoblastic leukemia (ALL). We investigated associations between clinical course and candidate gene polymorphisms less evaluated in Japanese patients.

Identification of amino acids in antigen-binding site of class II HLA proteins independently associated with hepatitis B vaccine response

BACKGROUND & AIMS Genetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine. METHODS We performed a case-control study to assess whether HLA-DRB1, -DQB1, and -DPB1 4-digit alleles were associated with the response to primary HBV vaccination in 574 healthy Japanese students. To identify causative variants, we next assessed independently associated amino acid variants in these loci using conditional logistic regression analysis. Furthermore, to clarify the functional effects of these variants on HLA proteins, we performed computational structural studies. RESULTS HLA-DRB1∗01:01, HLA-DRB1∗08:03, HLA-DQB1∗05:01, and HLA-DPB1∗04:02 were significantly associated with sufficient response, whereas HLA-DPB1∗05:01 was associated with poor response. We then identified amino acids independently associated with sufficient response, namely, leucine at position 26 of HLA-DRβ1 and glycine-glycine-proline-methionine at positions 84-87 of HLA-DPβ1. These amino acids were located in antigen-binding pocket 4 of HLA-DR and pocket 1 of HLA-DP, respectively, which are important structures for selective binding of antigenic peptides. In addition, the detected variations in HLA-DP protein were responsible for the differences in the electrostatic potentials of the pocket, which can explain in part the sufficient/poor vaccine responses. CONCLUSION HLA-DRβ1 position 26 and HLA-DPβ1 positions 84-87 are independently associated with anti-HBs production against HBV vaccine. Our results suggest that HBsAg presentation through these HLA pocket structures plays an important role in the inter-individual variability of HBV vaccination.

Polymorphisms of MTHFR Associated with Higher Relapse/Death Ratio and Delayed Weekly MTX Administration in Pediatric Lymphoid Malignancies

Backgrounds. Outcome of childhood malignancy has been improved mostly due to the advances in diagnostic techniques and treatment strategies. While methotrexate (MTX) related polymorphisms have been under investigation in childhood malignancies, many controversial results have been offered. Objectives. To evaluate associations of polymorphisms related MTX metabolisms and clinical course in childhood lymphoid malignancies. Method. Eighty-two acute lymphoblastic leukemia and 21 non-Hodgkins lymphoma children were enrolled in this study. Four single nucleotide polymorphisms in 2 genes (MTHFR (rs1801133/c.677C>T/p.Ala222Val and rs1801131/c.1298A>C/p.Glu429Ala) and SLCO1B1 (rs4149056/c.521T>C/p.V174A and rs11045879/c.1865+4846T>C)) were genotyped by Taqman PCR method or direct sequencing. Clinical courses were reviewed retrospectively. Results. No patient who had the AC/CC genotype of rs1801131 (MTHFR) had relapsed or died, in which distribution was statistically different among the AA genotype of rs1801131 (P = 0.004). Polymorphisms of SLCO1B1 (rs11045879 and rs4149056) were not correlated with MTX concentrations, adverse events, or disease outcome. Conclusions. Polymorphisms of MTHFR (rs1801131) could be the plausive candidate for prognostic predictor in childhood lymphoid malignancies.

Association of adiponectin polymorphism with cord blood adiponectin concentrations and intrauterine growth.

To assess whether adiponectin gene (ADIPOQ) polymorphism is associated with intrauterine fetal growth and cord blood adiponectin, we investigated eight single-nucleotide polymorphisms (SNPs; rs182052, rs710445, rs16861205, rs12495941, rs1501299, rs3774261, rs2082940 and rs266729) in ADIPOQ and birth weight and cord blood adiponectin in 526 healthy neonates. We found that the neonates carrying the G allele of rs266729 had a significantly greater birth weight s.d. score than those homozygous for the C allele (CC: −0.06±0.75 versus CG: 0.20±0.64 versus GG: 0.07±0.78; P=1.65 × 10−3, adjusted P=9.90 × 10−3). However, this difference was not significant after adjustment for cord blood adiponectin (P=0.04, adjusted P=0.26). The rs266729 SNP was strongly associated with cord blood adiponectin; neonates with rs266729 GG had the highest adiponectin (CC: 34.1±20.2 versus CG: 44.3±26.1 versus GG: 54.1±36.7 μg ml–1, P=2.80 × 10−9, adjusted P=1.68 × 10−8). This association remained after adjustment for birth weight s.d. score (P=6.63 × 10−8, adjusted P=3.98 × 10−7). Our results suggest that the influence of the rs266729 SNP in ADIPOQ on birth weight may be dependent on circulating adiponectin.

Cord blood insulin-like growth factor (IGF)-1, IGF-binding proteins and adiponectin, and birth size in offspring of women with mild gestational diabetes

OBJECTIVE To clarify the impact of a mild form of gestational diabetes mellitus (GDM) on neonatal birth size, and on insulin-related hormones and adiponectin (AdipoQ) in cord blood. METHODS Two hundred and sixteen Japanese pregnant women diagnosed as having normal glucose tolerance according to the JSOG criteria were enrolled. Of the 216 women, 38 women were reclassified into a mild GDM (mGDM) group according to the IADPSG criteria. Of the remaining 178 women, 135 women with normal 50-g glucose challenge test were reclassified into a normal glucose tolerance (NGT) group. Cord blood insulin-like growth factor (IGF)-1, IGF-binding proteins (IGFBPs) and AdipoQ were measured in the offspring of the two groups. RESULTS Birth weight and its SD scores were larger in the mGDM group than in the NGT group. The incidence of large-for-gestational age (LGA) newborns was higher in the mGDM than in the NGT group. No differences in cord blood free IGF-1, IGFBP-1, IGFBP-2 or AdipoQ levels were observed between the mGDM and NGT groups. CONCLUSIONS Our study suggests that mild GDM reclassified according to the IADPSG criteria influences neonatal birth size, but neither the IGF-IGFBP axis nor AdipoQ can account for the changes of birth size in offspring of women with mild GDM.

Co-morbidity and quality of life in childhood cancer survivors treated with proton beam therapy

The rate of childhood cancer survival has recently reached >80%. Various adverse events among childhood cancer survivors (CCS) have been reported. Proton beams are able to avoid unnecessary irradiation to normal/vital organs. We conducted a quality of life (QOL) study for CCS who were treated with proton beam therapy (PBT).

Japanese boy with maturity-onset diabetes of the young type 3 who developed diabetes at 19 months old

Maturity‐onset diabetes of the young type 3 (MODY3) is caused by hepatocyte nuclear factor 1α gene mutation and is clinically characterized by young onset and insufficient insulin secretion. We report a 19‐month‐old Japanese boy with a family history of young‐onset diabetes who was initially diagnosed with type 1 diabetes. Mutational analysis of the hepatocyte nuclear factor 1α gene revealed a novel heterozygous frameshift mutation (c.593delA p.Lys198fs) resulting in a truncated protein in the patient and his father. The patient was diagnosed as having MODY3 and was successfully treated with insulin glargine. We could not determine the genetic or environmental factors to explain the difference in the age of disease onset within the same family. This is the youngest case of a MODY3 child presenting with overt diabetes. Our experience suggests that clinicians should always consider the possible diagnosis of MODY3 in a diabetic child with a family history of young‐onset diabetes and should perform molecular investigations.

Interinstitutional patient transfers between rapid chemotherapy cycles were feasible to utilize proton beam therapy for pediatric Ewing sarcoma family of tumors

Aim To assess the feasibility of transferring to the University of Tsukuba Hospital for proton beam therapy (PBT) during intensive chemotherapy in children with Ewing sarcoma family of tumors (ESFT) who had been diagnosed and started their first-line treatment at prefectural or regional centers for pediatric oncology. Background The treatment of ESFT relies on a multidisciplinary approach using intensive neoadjuvant and adjuvant chemotherapies with surgery and radiotherapy. Multi-agent chemotherapy comprising vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC-IE) is widely used for ESFT, and the interval between each course is very important for maintaining the intensity and effect of chemotherapy. Materials and methods Clinical information of patients who received PBT and VDC-IE between April 2009 and May 2016 was collected retrospectively. The intervals between each course of VDC-IE and adverse events were assessed. Results Fifteen patients were evaluated. No delays in the intervals of chemotherapy due to transfer were observed. There were no adverse events caused during/just after transfer and no increases in adverse events. The estimated 4-year overall and event-free survival rates were 94.6% and 84.8%, respectively. Discussion Although the results of efficacy are preliminary, survival rates were comparable with past studies. More experience and follow-up are required to further assess the efficacy of PBT for patients with ESFT. Conclusion Multidisciplinary therapy for children with ESFT involving transfer to our hospital for PBT during VDC-IE was feasible without treatment delay or an increase in adverse events.