RAC1B function is essential for breast cancer stem cell maintenance and chemoresistance of breast tumor cells.

Breast cancer stem cells (BCSC) are presumed to be responsible for treatment resistance, tumor recurrence and metastasis of breast tumors. However, development of BCSC-targeting therapies has been held back by their heterogeneity and the lack of BCSC-selective molecular targets. Here, we demonstrate that RAC1B, the only known alternatively spliced variant of the small GTPase RAC1, is expressed in a subset of BCSCs in vivo and its function is required for the maintenance of BCSCs and their chemoresistance to doxorubicin. In human breast cancer cell line MCF7, RAC1B is required for BCSC plasticity and chemoresistance to doxorubicin in vitro and for tumor-initiating abilities in vivo. Unlike Rac1, Rac1b function is dispensable for normal mammary gland development and mammary epithelial stem cell (MaSC) activity. In contrast, loss of Rac1b function in a mouse model of breast cancer hampers the BCSC activity and increases their chemosensitivity to doxorubicin treatment. Collectively, our data suggest that RAC1B is a clinically relevant molecular target for the development of BCSC-targeting therapies that may improve the effectiveness of doxorubicin-mediated chemotherapy.

Chronotypical characteristics and related miR-142-3p levels of children with attention deficit and hyperactivity disorder.

To compare children with Attention Deficit and Hyperactivity Disorder (ADHD) and a healthy control group in terms of chronotype characteristics and miRNA-142-3p/miRNA-378 levels. 50 children with ADHD and 44 healthy children were included in the study. Childhood Chronotype Questionnaire was used to identify the chronotype preferences of children. Serum miR-142-3p and miR- 378 levels were determined. Preference for nighttime was higher in children with ADHD. Additionally, a night preference was found to be associated with attention deficit in both groups. While a significant correlation was found between the psychopathology rate in mothers and the presence of ADHD, there was no such correlation in fathers. In the comparison between children with ADHD and the control group, no significant difference was found between miRNA levels. Both the miR-142-3p and miR-378 values of the children with ADHD that have immediate relatives with a psychiatric disorder were lower, compared to control group. We found that shift to night preference in the circadian rhythm was higher and this preference was associated with attention deficit in the children with ADHD. In addition, the presence of psychopathology in the family and the mother's psychopathology affected the miR-142-3p and miR378 levels.

Identification of the variations in the CPT1B and CHKB genes along with the HLA-DQB1*06:02 allele in Turkish narcolepsy patients and healthy persons.

BACKGROUND: The HLA-DQB1*06:02 allele across all ethnic groups and the rs5770917 variation between CPT1B and CHKB genes in Japanese and Koreans are common genetic susceptibility factors for narcolepsy. This comprehensive genetic study sought to assess variations in CHKB and CPT1B susceptibility genes and HLA-DQB1*06:02 allele status in Turkish patients with narcolepsy and healthy persons. METHODS: CHKB/CPT1B genes were sequenced in patients with narcolepsy (n=37) and healthy persons (n=100) to detect variations. The HLA-DQB1*06:02 allele status was determined by sequence specific polymerase chain reaction. RESULTS: The HLA-DQB1*06:02 allele was significantly more frequent in narcoleptic patients than in healthy persons (p=2×10(-7)) and in patients with narcolepsy and cataplexy than in those without (p=0.018). The mean of the multiple sleep latency test, sleep-onset rapid eye movement periods, and frequency of sleep paralysis significantly differed in the HLA-DQB1*06:02-positive patients. rs5770917, rs5770911, rs2269381, and rs2269382 were detected together as a haplotype in three patients and 11 healthy persons. In addition to this haplotype, the indel variation (rs144647670) was detected in the 5' upstream region of the human CHKB gene in the patients and healthy persons carrying four variants together. CONCLUSION: This study identified a novel haplotype consisting of the indel variation, which had not been detected in previous studies in Japanese and Korean populations, and observed four single-nucleotide polymorphisms in CHKB/CPT1B. The study confirmed the association of the HLA-DQB1*06:02 allele with narcolepsy and cataplexy susceptibility. The findings suggest that the presence of HLA-DQB1*06:02 may be a predictor of cataplexy in narcoleptic patients and could therefore be used as an additional diagnostic marker alongside hypocretin.