Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA

Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region

IntroductionRecent studies identified STAT4 (signal transducers and activators of transcription-4) as a susceptibility gene for systemic lupus erythematosus (SLE). STAT1 is encoded adjacently to STAT4 on 2q32.2-q32.3, upregulated in peripheral blood mononuclear cells from SLE patients, and functionally relevant to SLE. This study was conducted to test whether STAT4 is associated with SLE in a Japanese population also, to identify the risk haplotype, and to examine the potential genetic contribution of STAT1. To accomplish these aims, we carried out a comprehensive association analysis of 52 tag single nucleotide polymorphisms (SNPs) encompassing the STAT1-STAT4 region.MethodsIn the first screening, 52 tag SNPs were selected based on HapMap Phase II JPT (Japanese in Tokyo, Japan) data, and case-control association analysis was carried out on 105 Japanese female patients with SLE and 102 female controls. For associated SNPs, additional cases and controls were genotyped and association was analyzed using 308 SLE patients and 306 controls. Estimation of haplotype frequencies and an association study using the permutation test were performed with Haploview version 4.0 software. Population attributable risk percentage was estimated to compare the epidemiological significance of the risk genotype among populations.ResultsIn the first screening, rs7574865, rs11889341, and rs10168266 in STAT4 were most significantly associated (P < 0.01). Significant association was not observed for STAT1. Subsequent association studies of the three SNPs using 308 SLE patients and 306 controls confirmed a strong association of the rs7574865T allele (SLE patients: 46.3%, controls: 33.5%, P = 4.9 × 10-6, odds ratio 1.71) as well as TTT haplotype (rs10168266/rs11889341/rs7574865) (P = 1.5 × 10-6). The association was stronger in subgroups of SLE with nephritis and anti-double-stranded DNA antibodies. Population attributable risk percentage was estimated to be higher in the Japanese population (40.2%) than in Americans of European descent (19.5%).ConclusionsThe same STAT4 risk allele is associated with SLE in Caucasian and Japanese populations. Evidence for a role of STAT1 in genetic susceptibility to SLE was not detected. The contribution of STAT4 for the genetic background of SLE may be greater in the Japanese population than in Americans of European descent

Single nucleotide polymorphism-based genome-wide linkage analysis in Japanese atopic dermatitis families

<p>Abstract</p> <p>Background</p> <p>Atopic dermatitis develops as a result of complex interactions between several genetic and environmental factors. To date, 4 genome-wide linkage studies of atopic dermatitis have been performed in Caucasian populations, however, similar studies have not been done in Asian populations. The aim of this study was to identify chromosome regions linked to atopic dermatitis in a Japanese population.</p> <p>Methods</p> <p>We used a high-density, single nucleotide polymorphism genotyping assay, the Illumina BeadArray Linkage Mapping Panel (version 4) comprising 5,861 single nucleotide polymorphisms, to perform a genome-wide linkage analysis of 77 Japanese families with 111 affected sib-pairs with atopic dermatitis.</p> <p>Results</p> <p>We found suggestive evidence for linkage with 15q21 (LOD = 2.01, NPL = 2.87, <it>P </it>= .0012) and weak linkage to 1q24 (LOD = 1.26, NPL = 2.44, <it>P </it>= .008).</p> <p>Conclusion</p> <p>We report the first genome-wide linkage study of atopic dermatitis in an Asian population, and novel loci on chromosomes 15q21 and 1q24 linked to atopic dermatitis. Identification of novel causative genes for atopic dermatitis will advance our understanding of the pathogenesis of atopic dermatitis.</p

Impact of a Rice-Centered Diet on the Quality of Sleep in Association with Reduced Oxidative Stress: A Randomized, Open, Parallel-Group Clinical Trial

Previously, we found that a Japanese diet was associated with psychological status, and a combination of rice and miso was related to mental and physical health. We hypothesized that the intake of a rice-based diet affected mental and physical health and aimed to investigate the consequences of a dietary intervention with rice. We conducted a randomized, open-label, parallel-group clinical trial that included 60 participants, who were randomly assigned to receive either rice-based meals or meals with other cereals for three daily meals over 2 months. The participants were surveyed for psychological status and biochemical changes. Sleep quality index scores showed significant improvement after the rice-based intervention. Additionally, blood oxidative stress levels were reduced in the rice-diet group compared with the no-rice-diet group. Although the molecular mechanisms should be investigated in detail, our findings suggest that controlling oxidative stress through the intake of a rice-centered diet may be key to improving sleep quality

Data table

The table includes: ID, Sex, Age, Height, Weight, BMI, Regular physical activity, Smoking, Habitual Drinking, SF8, BIS-11(Barrat impulsiveness scale), PHQ-9, PSQI-J, Rice intake frequency, Bread intake frequency, Noodle intake frequency, adjusted values of BDH

Changes in subunit composition of NMDA receptors in animal models of schizophrenia by repeated administration of methamphetamine

The dopamine and glutamate hypotheses reflect only some of the pathophysiological changes associated withschizophrenia. We have proposed a new“comprehensive progressive pathophysiology model”based on the“dopamine to glutamate hypothesis.”Repeated administration of methamphetamine (METH) at a dose of2.5 mg/kg in rats has been used to assess dynamic changes in the pathophysiology of schizophrenia. Previous useof this model suggestedN-methyl-D-aspartate receptor (NMDA-R) dysfunction, but the mechanism could only beinferred from limited, indirect observations. In the present study, we used this model to investigate changes inthe expression of NMDA-R subunits. Repeated administration of METH significantly decreased the gene ex-pression levels of glutamate ionotropic receptor NMDA type subunit (Grin) subtypesGrin1andGrin2cin theprefrontal cortex (PFC),Grin1andGrin2ain the hippocampus (HPC), andGrin1,Grin2b, andGrin2din thestriatum (ST).We observed a significant difference inGrin1expression between the PFC and ST. Furthermore,repeated administration of METH significantly decreased the protein expression of GluN1 in both cytosolic andsynaptosomal fractions isolated from the PFC, and significantly decreased the protein expression of GluN1 in thecytosolic fraction, but not the synaptosomal fraction from the ST. These regional differences may be due tovariations in the synthesis of GluN1 or intracellular trafficking events in each area of the brain. Considering thatknockdown ofGrin1in mice affects vulnerability to develop schizophrenia, these results suggest that this modelreflects some of the pathophysiological changes of schizophrenia, combining both the dopamine and glutamatehypotheses

Impact of a Rice-Centered Diet on the Quality of Sleep in Association with Reduced Oxidative Stress : A Randomized, Open, Parallel-Group Clinical Trial

Previously, we found that a Japanese diet was associated with psychological status, and a combination of rice and miso was related to mental and physical health. We hypothesized that the intake of a rice-based diet affected mental and physical health and aimed to investigate the consequences of a dietary intervention with rice. We conducted a randomized, open-label, parallel-group clinical trial that included 60 participants, who were randomly assigned to receive either rice-based meals or meals with other cereals for three daily meals over 2 months. The participants were surveyed for psychological status and biochemical changes. Sleep quality index scores showed significant improvement after the rice-based intervention. Additionally, blood oxidative stress levels were reduced in the rice-diet group compared with the no-rice-diet group. Although the molecular mechanisms should be investigated in detail, our findings suggest that controlling oxidative stress through the intake of a rice-centered diet may be key to improving sleep quality

The relationship between a low grain intake dietary pattern and impulsive behaviors in middle-aged Japanese people

Several studies indicate that dietary habits are associated with mental health. We are interested in identifying not a specific single nutrient/food group but the population preferring specific food combinations that can be related to mental health. Very few studies have examined relationships between dietary patterns and multifaceted mental states using cluster analysis. The purpose of this study was to investigate population-level dietary patterns associated with mental state using cluster analysis. We focused on depressive state, sleep quality, subjective well-being, and impulsive behaviors using rating scales. Two hundred and seventy-nine Japanese middle-aged people participated in the present study. Dietary pattern was estimated using a brief self-administered diet-history questionnaire (the BDHQ). We conducted K-means cluster analysis using thirteen BDHQ food groups: milk, meat, fish, egg, pulses, potatoes, green and yellow vegetables, other vegetables, mushrooms, seaweed, sweets, fruits, and grain. We identified three clusters characterized as "vegetable and fruit dominant," "grain dominant," and "low grain tendency" subgroups. The vegetable and fruit dominant group showed increases in several aspects of subjective wellbeing demonstrated by the SF-8. Differences in mean subject characteristics across clusters were tested using ANOVA. The low frequency intake of grain group showed higher impulsive behavior, demonstrated by BIS-11 deliberation and sum scores. The present study demonstrated that traditional Japanese dietary patterns, such as eating rice, can help with beneficial changes in mental health