Molecular analysis of holocarboxylase synthetase deficiency: a missense mutation and a single base deletion are predominant in Japanese patients

AbstractHolocarboxylase synthetase (HCS) deficiency is an inherited disease of biotin metabolism characterized by a unique pattern of organic aciduria, metabolic acidosis, and skin lesions. By analysis of five patients in four unrelated families, two mutations were identified: a transition from T to C which causes an amino-acid substitution of proline for leucine at position 237 (L237P) and a single deletion of guanine (delG 1067) followed by premature termination. One patient was homozygous for the L237P mutation, three patients in two families were compound heterozygotes of the missense and deletion alleles, and the other patient was heterozygous for the L237P mutation. Inheritance was successfully demonstrated in all of the patients' families by a modified PCR followed by restriction enzyme digestion. The two mutations accounted for seven of eight mutant alleles, while neither mutation was detected in 108 normal healthy Japanese children (216 alleles). Transient expression in cultured fibroblasts from a patient showed that the L237P mutation was responsible for decreased HCS activity. These results suggest that the L237P and delG1067 mutations are frequent disease-causing mutations in Japanese patients with HCS deficiency. This PCR-based technique may therefore be useful for detecting mutations among Japanese patients

Promoting Effects of Sucrose-rich Diet on N-Nitrosobis (2-oxopropyl) amine-induced Pancreatic Carcinogenesis in Hamsters

It has been reported that there is an association between pancreatic cancer and obesity, impaired glucose metabolism and diabetes based on excess dietary fat and sugar intakes. A number of studies have suggested that a high-fat diet increases development of carcinomas in various organs and possible risk factors for pancreatic cancer. However, how an excess sugar intake promotes pancreatic carcinogenesis is still unknown. In the present study, we investigated the influence of an excess sugar intake on pancreatic carcinogenesis by administration of a sucrose-rich diet in which starch was replaced by sucrose in order to contain the same calories and other nutrients. Two similar experiments were performed. Six-week-old male Syrian golden hamsters were given N-nitrosobis (2-oxopropyl) amine (BOP) at a dose of 50 and 20 mg/kg body weight as a carcinogen in Week 0 and 1, respectively. In Week 2, the animals were divided into control and experimental groups. In experiment 1, 15 animals received a control diet or sucrose-rich diet in which 100% of the starch was replaced by sucrose, respectively. Since five animals fed on the sucrose-rich diet died by Week 12, the diet was changed to a sucrose-rich diet in which 50% of the starch was replaced by sucrose. In experiment 2, 15 animals received a control diet or sucrose-rich diet in which 50 or 20% of the starch was replaced by sucrose, respectively. All animals were sacrificed 25 weeks after the start of the experiment, and histological examination of the pancreas was performed. No significant difference was seen in the body weight at the end of the experiment. There were no significant differences in the glycosylated hemoglobin (HbA1c) and serum triglyceride, total cholesterol and HDL-cholesterol levels between the control and sucrose-rich diet groups in experiments 1 and 2. The incidence and number of carcinomas increased in hamsters fed the sucrose-rich diet compared with the control diet in experiments 1 and 2. These results suggest that an excess sucrose intake may promote the development of pancreatic cancer in hamsters

Pilot study to estimate the safety and effectiveness of hydroxyurea and methotrexate recurrent langerhans cell histiocytosis (LCH-HU-pilot)

This study was a non-blinded, multicenter, single-arm study. Recurrent (relapsed) LCH is defined as the appearance of new lesions or the enlargement of preexisting lesions due to LCH. In this study, all patients received hydroxyurea, and if the treatment response was unsatisfactory, methotrexate was added. The duration of treatment was 48 weeks. The primary endpoint was the rate of non-active disease achievement, which was 24 weeks after initiating hydroxyurea administration. No active disease is defined as the resolution of all the signs and symptoms related to LCH

Safety of Silk-elastin Sponges in Patients with Chronic Skin Ulcers: A Phase I/II, Single-center, Open-label, Single-arm Clinical Trial

Background: Although traditional wound dressings such as collagen scaffolds promote granulation tissue formation, the efficacy of these dressings in chronic wounds is limited because of high susceptibility to bacterial growth. Biomaterials that can be applied to chronic wounds should have an anti-bacterial function. We previously reported that administering a silk-elastin solution that forms moisturizing hydrogels to wound surfaces of diabetic mice reduced bacterial growth and promoted granulation tissue formation compared with control or carboxymethyl cellulose hydrogels. We hypothesized that silk-elastin promotes wound healing in human chronic wounds by suppressing bacterial growth. Methods: An open-label, clinical case series was conducted with a prospective, single-arm design at Kyoto University Hospital in Kyoto, Japan. In this study, 6 patients with chronic skin ulcers of any origin (2 < ulcer area (cm2) < 25) on their lower extremities were included; patients with critical ischemia were excluded. Silk-elastin sponges were applied and covered with a polyurethane film without changing the dressing for 14 days. Inflammation triggered treatment discontinuation due to fear of infection. The primary study endpoint was adverse events, including inflammation and infection. Results: Poor hydrogel formation, possibly due to continuous exudation, was observed. No serious adverse events were noted. Two patients discontinued treatment on day 6 and day 7, respectively, due to inflammation, but they were not infected. The other 4 patients completed the 14-day silk-elastin sponge treatment without infection. Conclusion: Silk-elastin sponge is safe for chronic skin ulcers, and its ability to promote wound healing should be determined by confirmatory clinical trials

Identifying the target genes of SUPPRESSOR OF GAMMA RESPONSE 1, a master transcription factor controlling DNA damage response in Arabidopsis

In mammalian cells, the transcription factor p53 plays a crucial role in transmitting DNA damage signals to maintain genome integrity. However, in plants, orthologous genes for p53 and checkpoint proteins are absent. Instead, the plant-specific transcription factor SUPPRESSOR OF GAMMA RADIATION 1 (SOG1) controls most of the genes induced by gamma irradiation and promotes DNA repair, cell cycle arrest, and stem cell death. Thus far, the genes directly controlled by SOG1 remain largely unknown, limiting the understanding of DNA damage signaling in plants. Here, we conducted a microarray analysis and chromatin immunoprecipitation (ChIP)-sequencing, and identified 146 Arabidopsis genes as direct targets of SOG1. By using the ChIP-sequencing data, we extracted the palindromic motif [CTT(N)7AAG] as a consensus SOG1-binding sequence, which mediates target gene induction in response to DNA damage. Furthermore, DNA damage-triggered phosphorylation of SOG1 is required for efficient binding to SOG1-binding sequence. Comparison between SOG1 and p53 target genes showed that both transcription factors control genes responsible for cell cycle regulation, such as CDK inhibitors, and DNA repair proteins, whereas SOG1 preferentially targets genes involved in homologous recombination. We also found that defense-related genes were enriched in the SOG1 target genes. Consistent with this, SOG1 is required for resistance against the hemi-biotrophic fungus Colletotrichum higginsianum, suggesting that SOG1 has a unique function in controlling immune response. This article is protected by copyright. All rights reserved

Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method

Selected genetic and clinical parameters of gastric cancer patients. (XLS 33 kb

ツマ ノ ショトク ガ フサイ ショトク ノ カクサ ニ アタエル エイキョウ ニ カンスル ブンセキ ツマ ノ シュウギョウ シュウギョウ リレキ ト ショトク カクサ

The recent upsurge of the employment rate of Japanese women seems to cause a widening of earnings disparities among married-couple households. Based on panel data derived from the Japanese Panel Survey of Consumers (the Institute for Research on Household Economics), we explore women’s employment and decisions on their career path at their first birth (continue to work / leave / change jobs), and examine the impacts on the family earnings inequality among them. Our findings confirm the following three points. First, wives in their 20s and 30s are likely to work if their husbands’ earnings are low (Douglas-Arisawa’s Law). Second, wives’ earnings contribute to increase family earnings inequality until 2003 but to equalize it after 2008. Third, among couples of working mothers, although wives’ earnings have an effect to equalize family earning inequality regardless of wives’ career decisions, the effect is larger among the couples of wives who choose to continue to work after the first birth, compared to the couples in which wives chose to leave or change jobs after the first birth.野村茂治教授退職記念論文集In Honor of Prof. Shigeharu NOMUR