The FK506 binding protein 5 (FKBP5) is a co-chaperone that regulates the activity of the glucocorticoid receptor (GR) and has been reported to mediate stress resilience. This study aimed to determine the effects of Fkbp5 deletion on acute stress-induced recognition memory impairment and hippocampal GR signaling. Wild-type and Fkbp5-knockout mice were subjected to acute uncontrollable stress induced by restraint and electrical tail shock. First, we assessed the cognitive status of mice using a novel object recognition task. Next, we measured plasma corticosterone, GR levels, and the levels of GR phosphorylation at serine 211 in the hippocampus. Wild-type mice exhibited stress-induced memory impairments, whereas Fkbp5-knockout mice did not. Plasma corticosterone and GR levels did not differ between the non-stressed wild-type and Fkbp5-knockout mice, but the levels of phosphorylated GR were lower in Fkbp5-knockout mice than in wild-type mice. Wild-type and Fkbp5-knockout mice showed increased nuclear GR levels following stress, indicating GR translocation. However, cytosolic phosphorylated GR levels were lower in the hippocampi of Fkbp5-knockout mice following stress than in those of wild-type mice. These results suggest that FKBP5 deficiency increases resilience to acute stress by altering GR signaling.

Complications arising from breast augmentation procedures are broadly categorized as either surgery-related or prosthesis-related. Many reports have described complications associated with breast augmentation. However, to date, periareolar post-inflammatory hyperpigmentation (PIH) after breast augmentation has not been reported. Herein, we report a case of PIH after augmentation mammoplasty using a silicone implant through the periareolar approach. A 35-year-old woman, who underwent bilateral breast augmentation using a periareolar approach, presented with bilateral periareolar tissue changes, with dark brown, irregular macules appearing 6 weeks postoperatively. Based on clinical symptoms and histological examination, the lesion was diagnosed as PIH. Topical hydroquinone and retinoic acid were applied for 8 weeks after the pigmentation appeared. After 6 months of observation, the pigmentation faded. To summarize, we report a case of pigmentation around the bilateral nipples after periareolar breast augmentation along with a literature review.

Purpose: Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to treat desmoid tumor. However, the molecular mechanism of why imatinib works remains unclear. Here, we describe potential roles of NOTCH2 and HES1 in clinical response to imatinib at genome and transcriptome levels. Materials and Methods: We identified somatic mutations in coding and noncoding regions via whole-genome sequencing. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale whole-genome sequencing and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. Results: Among 20 patients, four (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥ 1 year. With gene-wise functional analyses, we detected a significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on Pan-Cancer Analysis of Whole Genomes data analyses, NOTCH2 mutations affect expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate between responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders. Conclusion Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, and an important therapeutic consideration for desmoid tumor.

Background/Aims: Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays a key role in Th2-mediated inflammation, both directly by promoting the proliferation of naïve CD4 Th2 cells, and indirectly by activating dendritic cells (DCs). TSLP-activated DCs induce the expansion of chemoattractant receptor homologous molecule expressed on Th2 (CRTH2)+ CD4+ Th2 memory cells, which undergo a Th2 response and express prostaglandin D2 (PGD2) synthase. CRTH2, a PGD2 receptor, is a selective Th2-cell surface marker. We investigated the effects of an anti-TSLP antibody (Ab) and a CRTH2 antagonist, as well as their mechanisms of action, in a mouse model of acute asthma. Methods: BALB/c mice were sensitized and challenged with ovalbumin. We then evaluated the effects of the administration of an anti-TSLP Ab either alone or together with a CRTH2 antagonist on cell counts, Th2 cytokine levels in bronchoalveolar fluid, and the levels of epithelium-derived cytokines such as TSLP, interleukin (IL) 33, and IL-25 in lung homogenates, as well as airway hyper-responsiveness (AHR). Results: Anti-TSLP Ab and the CRTH2 antagonist significantly attenuated eosinophilic airway inflammation, AHR, and the expression of Th2 cytokines. The expression of GATA-3 and the levels of IL-33 and IL-25 in lung tissues were affected by the combined anti-TSLP and CRTH2 antagonist treatment. Conclusions These results suggest that the dual blockade of TSLP and CRTH2 may serve as an effective treatment target for eosinophilic asthma.

Human breast cancer cell line, MDA-MB-231, is highly invasive and aggressive, compared to less invasive cell line, MCF-7. To explore the genes that might influence the malignancy of MDA-MB-231, DNA microarray analysis was performed. The results showed that G0/G1 switch 2 (G0S2) was one of the most highly expressed genes among the genes upregulated in MDA-MB-231. Although G0S2 acts as a direct inhibitor of adipose triglyceride lipase, action of G0S2 in cancer progression is not yet understood. To investigate whether G0S2 affects invasiveness of MDA-MB-231 cells, G0S2 expression was inhibited using siRNA, which led to decreased cell proliferation, migration, and invasion of MDA-MB-231 cells. Consequently, G0S2 inhibition inactivated integrin-regulated FAK-Src signaling, which promoted Hippo signaling and inactivated ERK1/2 signaling. In addition, G0S2 downregulation decreased β-catenin expression, while E-cadherin expression was increased. It was demonstrated for the first time that G0S2 mediates the Hippo pathway and induces epithelial to mesenchymal transition (EMT). Taken together, our results suggest that G0S2 is a major factor contributing to cell survival and metastasis of MDA-MB-231 cells.
Breast Neoplasms ; Breast ; Cadherins ; Cell Line ; Cell Proliferation ; Cell Survival ; Down-Regulation ; Humans ; Lipase ; Neoplasm Metastasis ; Oligonucleotide Array Sequence Analysis ; RNA, Small Interfering ; Signal Transduction

OBJECTIVES: Sleep disturbance is a very rapidly growing disease with aging. The purpose of this study was to investigate the prevalence of sleep disturbances and its predictive factors in a three-year cohort study of people aged 60 years and over in Korea. METHODS: In 2012 and 2014, we obtained data from a survey of the Korean Social Life, Health, and Aging Project. We asked participants if they had been diagnosed with stroke, myocardial infarction, angina pectoris, arthritis, pulmonary tuberculosis, asthma, cataract, glaucoma, hepatitis B, urinary incontinence, prostate hypertrophy, cancer, osteoporosis, hypertension, diabetes, hyperlipidemia, or metabolic syndrome. Cognitive function was assessed using the Mini-Mental State Examination for dementia screening in 2012, and depression was assessed using the Center for Epidemiologic Studies Depression Scale in 2012 and 2014. In 2015, a structured clinical interview for Axis I psychiatric disorders was administered to 235 people, and sleep disturbance was assessed using the Pittsburgh Sleep Quality Index. The perceived stress scale and the State-trait Anger Expression Inventory were also administered. Logistic regression analysis was used to predict sleep disturbance by gender, age, education, depression score, number of coexisting diseases in 2012 and 2014, current anger score, and perceived stress score. RESULTS: Twenty-seven percent of the participants had sleep disturbances. Logistic regression analysis showed that the number of medical diseases three years ago, the depression score one year ago, and the current perceived stress significantly predicted sleep disturbances. CONCLUSION: Comorbid medical disease three years previous and depressive symptoms evaluated one year previous were predictive of current sleep disturbances. Further studies are needed to determine whether treatment of medical disease and depressive symptoms can improve sleep disturbances.
Aged* ; Aging ; Anger ; Angina Pectoris ; Arthritis ; Asthma ; Cataract ; Cognition ; Cohort Studies ; Comorbidity ; Dementia ; Depression ; Education ; Epidemiologic Studies ; Follow-Up Studies* ; Glaucoma ; Hepatitis B ; Humans ; Hyperlipidemias ; Hypertension ; Hypertrophy ; Korea ; Logistic Models ; Mass Screening ; Myocardial Infarction ; Osteoporosis ; Prevalence ; Prostate ; Sleep Initiation and Maintenance Disorders ; Stroke ; Tuberculosis, Pulmonary ; Urinary Incontinence

OBJECTIVES: Firefighters and rescue workers are likely to be exposed to a variety of traumatic events; as such, they are vulnerable to the risk of post-traumatic stress disorder (PTSD). The psychometric properties of the Korean version of the PTSD Checklist (PCL), a widely used self-report screening tool for PTSD, were assessed in South Korean firefighters and rescue workers. METHODS: Data were collected via self-report questionnaires and semi-structured clinical interviews administered to 221 firefighters. Internal consistency, item-total correlation, one-week test-retest reliability, convergent validity, and divergent validity were examined. Content validity of the PCL was evaluated using factor analysis and receiver operating characteristic (ROC) analyses were used to estimate the optimal cutoff point and area under the curve. RESULTS: The PCL demonstrated excellent internal consistency (alpha = 0.97), item-total correlation (r = 0.72-0.88), test-retest reliability (r = 0.95), and convergent and divergent validity. The total score of PCL was positively correlated with the number of traumatic events experienced (p < 0.001). Factor analysis revealed two theoretically congruent factors: re-experience/avoidance and numbing/hyperarousal. The optimal cutoff was 45 and the area under the ROC curve was 0.97. CONCLUSIONS: The Korean version of the PCL may be a useful PTSD screening instrument for firefighters and rescue workers, further maximizing opportunities for accurate PTSD diagnosis and treatment.
Checklist* ; Diagnosis ; Firefighters* ; Humans ; Mass Screening ; Psychometrics ; Reproducibility of Results* ; Rescue Work* ; ROC Curve ; Stress Disorders, Post-Traumatic*

DNA microarray and next-generation sequencing provide data that can be used for the genetic analysis of multiple quantitative traits such as gene expression levels, transcription factor binding profiles, and epigenetic signatures. In particular, chromatin opening is tightly coupled with gene transcription. To understand how these two processes are genetically regulated and associated with each other, we examined the changes of chromatin accessibility and gene expression in response to genetic variation by means of quantitative trait loci mapping. Regulatory patterns commonly observed in yeast and human across different technical platforms and experimental designs suggest a higher genetic complexity of transcription regulation in contrast to a more robust genetic architecture of chromatin regulation.
Chromatin* ; Epigenesis, Genetic ; Epigenomics ; Gene Expression ; Genetic Variation ; Humans ; Oligonucleotide Array Sequence Analysis ; Quantitative Trait Loci ; Regulatory Sequences, Nucleic Acid ; Research Design ; Transcription Factors ; Yeasts

Genome-wide association studies have proven the highly polygenic architecture of complex diseases or traits; therefore, single-locus-based methods are usually unable to detect all involved loci, especially when individual loci exert small effects. Moreover, the majority of associated single-nucleotide polymorphisms resides in non-coding regions, making it difficult to understand their phenotypic contribution. In this work, we studied epistatic interactions associated with three common diseases using Korea Association Resource (KARE) data: type 2 diabetes mellitus (DM), hypertension (HT), and coronary artery disease (CAD). We showed that epistatic single-nucleotide polymorphisms (SNPs) were enriched in enhancers, as well as in DNase I footprints (the Encyclopedia of DNA Elements [ENCODE] Project Consortium 2012), which suggested that the disruption of the regulatory regions where transcription factors bind may be involved in the disease mechanism. Accordingly, to identify the genes affected by the SNPs, we employed whole-genome multiple-cell-type enhancer data which discovered using DNase I profiles and Cap Analysis Gene Expression (CAGE). Assigned genes were significantly enriched in known disease associated gene sets, which were explored based on the literature, suggesting that this approach is useful for detecting relevant affected genes. In our knowledge-based epistatic network, the three diseases share many associated genes and are also closely related with each other through many epistatic interactions. These findings elucidate the genetic basis of the close relationship between DM, HT, and CAD.
Coronary Artery Disease ; Deoxyribonuclease I ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; DNA ; Gene Expression ; Genome-Wide Association Study ; Hypertension ; Korea ; Polymorphism, Single Nucleotide ; Regulatory Sequences, Nucleic Acid ; Transcription Factors

BACKGROUND/OBJECTIVES: Rubus Coreanus Miquel (RCM), used as a traditional Korean medicine, reduces chronic inflammatory diseases such as cancer and rheumatoid arthritis. However, its mechanism has not been elucidated. In this study, we examine the anti-inflammatory effects of RCM and their possible mechanisms using RAW 264.7 cells. MATERIALS/METHODS: Unripe RCM ethanol extract (UE), unripe RCM water extract (UH), ripe RCM ethanol extract (RE), and ripe RCM water extract (RH) were prepared. Inflammatory response was induced with LPS treatment, and expression of pro-inflammatory mediators (iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6) and NO and PGE2 productions were assessed. To determine the anti-inflammatory mechanism of RCM, we measured NF-kappaB and MAPK activities. RESULTS: UE and UH treatment significantly reduced NF-kappaB activation and JNK and p38 phosphorylation and reduced transcriptional activities decreased iNOS, COX-2, and pro-inflammatory cytokines expressions, and NO and PGE2 productions. RE and RH treatments reduced IL-1beta and IL-6 expressions through suppressions of JNK and p38 phosphorylation. CONCLUSIONS: In this study, we showed that RCM had anti-inflammatory effects by suppression of pro-inflammatory mediator expressions. Especially, unripe RCM showed strong anti-inflammatory effects through suppression of NF-kappaB and MAPK activation. These findings suggest that unripe RCM might be used as a potential functional material to reduce chronic inflammatory responses.
Arthritis, Rheumatoid ; Cytokines ; Dinoprostone ; Ethanol ; Inflammation ; Interleukin-6 ; NF-kappa B* ; Phosphorylation ; Phosphotransferases* ; Tumor Necrosis Factor-alpha ; Water