The glycosylphosphatidylinositol-linked aspartyl protease Yps1 is transcriptionally regulated by the calcineurin-Crz1 and Slt2 MAPK pathways in Candida glabrata.

In the pathogenic fungus Candida glabrata, the YPS1 gene, which encodes a glycosylphosphatidylinositol-linked aspartyl protease, is required for cell wall integrity and virulence. Although the expression of YPS1 has been studied in Saccharomyces cerevisiae, the transcriptional regulation of this gene in C. glabrata is not well understood. Here, we report that C. glabrata Yps1 is required for cell growth at elevated temperatures, and that the heat-induced expression of YPS1 is regulated predominantly by the calcineurin-Crz1 pathway and partially by the Slt2 MAPK pathway. Although a total of 11 YPS genes are present in the C. glabrata genome, the loss of transcriptional induction in a calcineurin mutant was observed only for YPS1. The results of a YPS1 promoter-lacZ reporter assay using a series of constructs with mutated promoter elements indicated that the transcription factor Crz1 binds to multiple sites in the promoter region of YPS1. To date, as none of the putative Crz1 targets in C. glabrata have been characterized using a Δcrz1 mutant, monitoring the expression of YPS1 represents an effective method for measuring the activity of the calcineurin-Crz1 signaling pathway in this fungus

Strong Evidence of a Combination Polymorphism of the Tyrosine Kinase 2 Gene and the Signal Transducer and Activator of Transcription 3 Gene as a DNA-Based Biomarker for Susceptibility to Crohn’s Disease in the Japanese Population

OBJECTIVE: An association between susceptibility to inflammatory bowel disease (IBD) and polymorphisms of both the tyrosine kinase 2 gene (TYK2) and the signal transducer and activator of transcription 3 gene (STAT3) was examined in a Japanese population in order to identify the genetic determinants of IBD. METHODS: The study subjects comprised 112 patients with ulcerative colitis, 83 patients with Crohn's disease (CD), and 200 healthy control subjects. Seven tag single-nucleotide polymorphisms (SNPs) in TYK2 and STAT3 were detected by PCR-restriction fragment length polymorphism. RESULTS: The frequencies of a C allele and its homozygous C/C genotype at rs2293152 SNP in STAT3 in CD patients were significantly higher than those in control subjects (P = 0.007 and P = 0.001, respectively). Furthermore, out of four haplotypes composed of the two tag SNPs (rs280519 and rs2304256) in TYK2, the frequencies of a Hap 1 haplotype and its homozygous Hap 1/Hap1 diplotype were significantly higher in CD patients in comparison to those in control subjects (P = 0.023 and P = 0.024, respectively). In addition, the presence of both the C/C genotype at rs2293152 SNP in STAT3 and the Hap 1/Hap 1 diplotype of TYK2 independently contributes to the pathogenesis of CD and significantly increases the odds ratio to 7.486 for CD (P = 0.0008). CONCLUSION: TYK2 and STAT3 are genetic determinants of CD in the Japanese population. This combination polymorphism may be useful as a new genetic biomarker for the identification of high-risk individuals susceptible to CD

Outcomes of patients who developed subsequent solid cancer after hematopoietic cell transplantation

To characterize the outcomes of patients who developed a particular subsequent solid cancer after hematopoietic cell transplantation (HCT), age at cancer diagnosis, survival, and causes of death were compared with the respective primary cancer in the general population, using data from the national HCT registry and population-based cancer registries in Japan. Among 31 867 patients who underwent a first HCT between 1990 and 2013 and had progression-free survival at 1 year, 713 patients developed subsequent solid cancer. The median age at subsequent solid cancer diagnosis was 55 years, which was significantly younger than the 67 years for primary cancer patients in the general population (P < .001). The overall survival probability was 60% at 3 years after diagnosis of subsequent solid cancer and differed according to cancer type. Development of most solid cancers was associated with an increased risk of subsequent mortality after HCT. Subsequent solid cancers accounted for 76% of causes of death. Overall survival probabilities adjusted for age, sex, and year of diagnosis were lower in the HCT population than in the general population for colon, bone/soft tissue, and central nervous system cancers and did not differ statistically for other cancers. In conclusion, most subsequent solid cancers occurred at younger ages than primary cancers, emphasizing the need for cancer screening at younger ages. Subsequent solid cancers showed similar or worse survival compared with primary cancers. Biological and genetic differences between primary and subsequent solid cancers remain to be determined

Genetic variants in antioxidant pathway: Risk factors for hepatotoxicity in tuberculosis patients

Tuberculosis (TB) treatment can cause serious sequelae including adverse effects such as anti-TB drug-induced hepatotoxicity (ATDH). We performed a candidate gene-based association study between single nucleotide polymorphisms (SNPs) in 10 genes in the antioxidant pathway and ATDH susceptibility. The subjects comprised 100 Japanese patients with pulmonary TB who received a treatment regimen including isoniazid and rifampicin. Out of them, 18 patients had ATDH. Thirty-four tag SNPs in 10 genes were analyzed by PCR-restriction fragment length polymorphism or PCR-direct DNA sequencing. The frequencies of alleles and genotypes between patients with and without ATDH were compared in three different genetic models. Statistical analyses revealed that a C/C genotype at rs11080344 in NOS2A, a C/C genotype at rs2070401 in BACH1, and a G/A or A/A genotype at rs4720833 in MAFK independently conferred ATDH susceptibility. Remarkably, the association of the latter two tag SNPs with ATDH susceptibility was highly statistically significant (P = 0.0006) with an odds ratio of 9.730. This study is the first report to demonstrate that NOS2A, BACH1, and MAFK appear to be genetic determinants of ATDH in Japanese patients with TB. Furthermore, a combination of BACH1 and MAFK polymorphisms may be useful as new biomarkers to identify high-risk Japanese TB patients for ATDH

ヨード ゾウエイ ザイ ニヨル アナフィラキシー ショック ノ 3レイ : ブンケンテキ コウサツ

造影CT検査は悪性腫瘍の質的診断や病期診断,解離性動脈瘤の診断に欠かせない.しかし,ヨード造影剤で重篤な副作用が生じる危険性がある.気管支喘息など危険因子はいわれているものの,実際,副作用発現は予測不能である.今回,我々は,ここ8ヶ月の間にヨード造影剤による重篤なアナフィラキシーショックを生じた3例を経験したので文献的考察を加えて報告する.Recently, iodinated contrast media are necessary for CT examinations and they occupy an important position in the radiological diagnosis. Nonionic contrast media significantly reduce the prevalence of all degree of adverse reaction to contrast media rather than ionic contrast media. So, generally, iodinated contrast media are safe and widely used, but adverse reaction after intravenous iodinated contrast media are not uncommon. Severe and potentially life-threatening reaction occur by using the iodinated contrast media practically. Patients at risk must be identified before the contrast media study, and all possible measures must be taken to deal effectively with spontaneous anaphylactic reactions. We report three cases of anaphylactic reactions by iodinated contrast media on CT

The evidence of polymorphisms of the liver X receptor gene as a DNA-based biomarker for susceptibility to coronary artery disease in a Japanese population

Coronary artery disease (CAD) is a multifactorial and polygenic disorder, which arises due to atherosclerosis of the coronary arteries. Both numerous genetic factors and environmental risk factors may contribute to the pathogenesis of atherosclerosis. Thus, in order to identify the genetic determinants of CAD, an association of genetic polymorphisms of the liver X receptoralpha (NR1H3) and -beta (NR1H2) genes with susceptibility to CAD was examined in a Japanese population. Eight tag single nucleotide polymorphisms (SNPs) in NR1H3 and NR1H2 were analyzed by PCR-restriction fragment length polymorphism or PCR-direct DNA sequencing method in 143 Japanese patients with CAD and 164 healthy control subjects with normal coronary arteries. Subsequently, haplotypes composed of the two tag SNPs in NR1H2 were constructed. Significant differences in the clinical risk factors, dyscholesteremia and diabetes mellitus, were observed between CAD patients and controls (P = 0.040 and P = 0.005, respectively). The frequencies of a C allele in the multiplicative model and its homozygous C/C genotype in the recessive model at rs2279238 in NR1H3 were significantly higher in CAD patients as compared to those in controls (P = 0.039 and P = 0.016, respectively). Furthermore, the frequency of a Hap 4/any diplotype of NR1H2 was significantly higher in CAD patients in comparison to controls (P = <0.0001, OR = 17.16). Multivariate logistic regression analysis revealed that these polymorphisms, dyscholesteremia, and diabetes mellitus independently contributed to susceptibility to CAD. In conclusion, NR1H3 and NR1H2 appears to be the genetic determinants of CAD. Furthermore, the genetic polymorphisms of NR1H3 and NR1H2 may be useful as new DNA-based diagnostic biomarkers for identifying high-risk individuals susceptible to CAD

Role of the Slt2 mitogen-activated protein kinase pathway in cell wall integrity and virulence in Candida glabrata.

Abstract The Slt2 mitogen-activated protein kinase pathway plays a major role in maintaining fungal cell wall integrity. In this study, we investigated the effects of SLT2 deletion and overexpression on drug susceptibility and virulence in the opportunistic fungal pathogen Candida glabrata. While the Deltaslt2 strain showed decreased tolerance to elevated temperature and cell wall-damaging agents, the SLT2-overexpressing strain exhibited increased tolerance to these stresses. A mutant lacking Rlm1, a transcription factor downstream of Slt2, displayed a cell wall-associated phenotype intermediate to that of the Deltaslt2 strain. When RLM1 was overexpressed, micafungin tolerance was increased in the wild-type strain and partial restoration of the drug tolerance was observed in the Deltaslt2 background. It was also demonstrated that echinocandin-class antifungals were more effective against C. glabrata under acidic conditions or when used concurrently with the chitin synthesis inhibitor nikkomycin Z. Finally, in a mouse model of disseminated candidiasis, the deletion and overexpression of C. glabrata SLT2 resulted in mild decreases and increases, respectively, in the CFUs from murine organs compared with the wild-type strain. These fundamental data will help in further understanding the mechanisms of cell wall stress response in C. glabrata and developing more effective treatments using echinocandin antifungals in clinical settings