The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast and ovarian cancer syndromes in women. The tumor suppressor, BRCA1 is known as a major player in the DNA damage response. These are evident from its loss, which causes malignant transformation in breast and ovary, and renders cells to become sensitive to a wide variety of DNA damaging agents. Here, we have implications on functional coupling of the pleiotropic roles of BRCA1, including DNA damage signal networking, DNA repair, transcription, and checkpoint of cell cycle, to tumor suppression by examining the molecular mechanisms and functions of BRCA1. The breast cancer susceptibility 1 (BRCA1) gene was identified and mapped to chromosome 17q21 by analyzing families at high risk from breast and ovarian cancer, and was first cloned in 1994 (1). The BRCA1 gene encodes a large nuclear protein that is ubiquitously expressed in a number of tissues. BRCA1 shares little structural resemblance to the majority of other known proteins (Fig. 1). Its ortholog is only found in mammals but not in yeast, fly, worm, or zebra fish, indicating that BRCA1 may come later in evolution and it may have more specialized and tissue-specific functions in mammalian cells. Although a number of studies delineating and deciphering the real biological roles of BRCA1 have accumulated, understanding these BRCA1 unique features still remains to be challengingly elucidated.
Breast ; Breast Neoplasms ; Cell Cycle ; Clone Cells ; Diptera ; DNA Damage* ; DNA Repair ; DNA* ; Female ; Genes, BRCA1 ; Humans ; Mammals ; Nuclear Proteins ; Ovarian Neoplasms ; Ovary ; Yeasts ; Zebrafish

Tuberous sclerosis(TS), a type of neurocutaneous syndrome, is inherited in an autosomal dominant manner. Approximately 60% of children with TS have rhabdomyomas of the heart, and 40% of fetuses in whom rhabdomyomas are detected by a prenatal ultrasonography eventually end up with TS. Therefore, when multiple cardiac rhabdomyomas are detected by a fetal ultrasonography, TS should be suspected and further examination should be considered after birth. Infantile spasms is a common type of seizure among young children with TS. We describe a patient with TS who showed cardiac tumors on a fetal ultrasound. Also, hypomelanotic macules, retinal tumors, brain cortical tubers, nodules in subependymal regions, and infantile spasms was detected after birth.
Brain ; Child ; Fetus ; Heart ; Heart Neoplasms ; Humans ; Infant ; Infant, Newborn ; Neurocutaneous Syndromes ; Parturition ; Retinal Neoplasms ; Rhabdomyoma ; Seizures ; Spasms, Infantile ; Tuberous Sclerosis ; Ultrasonography, Prenatal

PURPOSE: Post-lumbar puncture headache is common complaint. A study of post-diagnostic lumbar puncture headache in children is rare. Various factors that might influence the occurrence of post- diagnostic lumbar puncture headache in children exist. The purpose of this prospective study was to assess the frequency and risk factors for post-diagnostic lumbar puncture headache in children. METHODS: From March 2005 to February 2006, 44 patients with suspected meningitis were enrolled. Patients were received diagnostic lumbar puncture at the Chosun University Hospital, Gwangju, Korea. We evaluated age, sex, previous headache history, number of puncture attempts, volume of cerebrospinal fluid (CSF), pressure of CSF, cell count in CSF, final diagnosis, and the frequency and duration of headaches. RESULTS: Of the 44 patients (mean age 7.36+/-2.04, range 4-13 years), 16 patients (36.4%, male 13/33, 39.4%, female 3/11, 27.2%) had headache. The frequency of headaches was significantly higher in patients with previous headache history compare to those without previous headache history (P= 0.037). The mean of cell count of CSF was significantly higher in patients with post-lumbar puncture headache (P=0.012). The other factors did not influence the post-diagnostic lumbar puncture headache. CONCLUSION: Post-diagnostic lumbar puncture headache in children was more common than other studies. The factors that influence post-diagnostic lumbar puncture headache in children are previous headache history and cell count in CSF.
Cell Count ; Cerebrospinal Fluid ; Child* ; Diagnosis ; Female ; Gwangju ; Headache* ; Humans ; Korea ; Male ; Meningitis ; Post-Dural Puncture Headache ; Prospective Studies ; Punctures ; Risk Factors ; Spinal Puncture*

PURPOSE: To report on the current practices in breast magnetic resonance imaging (MRI) in Korea. MATERIALS AND METHODS: We invited the 68 members of the Korean Society of Breast Imaging who were working in hospitals with available breast MRI to participate in a survey on how they performed and interpreted breast MRI. We asked one member from each hospital to respond to the survey. A total of 22 surveys from 22 hospitals were analyzed. RESULTS: Out of 22 hospitals, 13 (59.1%) performed at least 300 breast MRI examinations per year, and 5 out of 22 (22.7%) performed > 1200 per year. Out of 31 machines, 14 (45.2%) machines were 1.5-T scanners and 17 (54.8%) were 3.0-T scanners. All hospitals did contrast-enhanced breast MRI. Full-time breast radiologists supervised the performance and interpreted breast MRI in 19 of 22 (86.4%) of hospitals. All hospitals used BI-RADS for MRI interpretation. For computer-aided detection (CAD), 13 (59.1%) hospitals sometimes or always use it and 9 (40.9%) hospitals did not use CAD. Two (9.1%) and twelve (54.5%) hospitals never and rarely interpreted breast MRI without correlating the mammography or ultrasound, respectively. The majority of respondents rarely (13/21, 61.9%) or never (5/21, 23.8%) interpreted breast MRI performed at an outside facility. Of the hospitals performing contrast-enhanced examinations, 15 of 22 (68.2%) did not perform MRI-guided interventional procedures. CONCLUSION: Breast MRI is extensively performed in Korea. The indication and practical patterns are diverse. The information from this survey would provide the basis for the development of Korean breast MRI practice guidelines.
Breast Neoplasms ; Breast* ; Diagnosis ; Korea ; Magnetic Resonance Imaging* ; Mammography ; Surveys and Questionnaires ; Ultrasonography

Chromatin structure has a crucial role in a diversity of physiological processes, including development, differentiation and stress responses, via regulation of transcription, DNA replication and DNA damage repair. Histone deacetylase (HDAC) inhibitors regulate chromatin structure and activate the DNA damage checkpoint pathway involving Ataxia-telangiectasia mutated (ATM). Herein, we investigated the impact of histone acetylation/deacetylation modification on the ATM-mediated transcriptional modulation to provide a better understanding of the transcriptional function of ATM. The prototype HDAC inhibitor trichostain A (TSA) reprograms expression of the myeloid cell leukemia-1 (MCL1) and Gadd45alpha genes via the ATM-mediated signal pathway. Transcription of MCL1 and Gadd45alpha is enhanced following TSA treatment in ATM+ cells, but not in isogenic ATM- or kinase-dead ATM expressing cells, in the ATM-activated E2F1 or BRCA1-dependent manner, respectively. These findings suggest that ATM and its kinase activity are essential for the TSA-induced regulation of gene expression. In summary, ATM controls the transcriptional upregulation of MCL1 and Gadd45alpha through the activation of the ATM-mediated signal pathway in response to HDAC inhibition. These findings are important in helping to design combinatory treatment schedules for anticancer radio- or chemo-therapy with HDAC inhibitors.
Cell Cycle Proteins/genetics/*metabolism ; DNA Damage/*genetics ; DNA-Binding Proteins/*metabolism ; E2F1 Transcription Factor/metabolism ; Gene Expression Regulation/drug effects ; Histone Deacetylase Inhibitors/*pharmacology ; Histone Deacetylases/*metabolism ; Humans ; Hydroxamic Acids/pharmacology ; Nuclear Proteins/genetics/metabolism ; Promoter Regions, Genetic/genetics ; Protein Binding/drug effects ; Protein-Serine-Threonine Kinases/*metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; *Transcription, Genetic/drug effects ; Tumor Suppressor Proteins/*metabolism

Colon tumors develop more frequently in male than in female. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays differential roles in the stage of tumorigenesis. The purpose of this study was to investigate the role of Nrf2 on colitis-associated tumorigenesis using Nrf2 knockout (KO) female mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO female mice were sacrificed at week 2 and 16 after AOM injection. Severity of colitis, tumor incidence, and levels of inflammatory mediators were evaluated in AOM/DSS-treated WT and Nrf2 KO mice. Furthermore, qRT-PCR, Western blot abnalysis, and ELISA were performed in colon tissues. At week 2, AOM/DSS-induced colon tissue damages were significantly greater in Nrf2 KO than in WT mice. At week 16, tumor numbers (> 2 mm size) were significantly lower in both the proximal and distal colon in Nrf2 KO compared to WT. The overall incidences of adenoma/cancer of the proximal colon and submucosal invasive cancer of the distal colon were reduced by Nrf2 KO. The mRNA and protein expression levels of NF-κB-related mediators (i.e., iNOS and COX-2) and Nrf2-related antioxidants (i.e., heme oxygenase-1 and glutamate-cysteine ligase catalytic subunit) were significantly lower in the Nrf2 KO than in WT mice. Interestingly, the protein level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) was higher in AOM/DSS-treated Nrf2 KO than in WT mice. Our results support the oncogenic effect of Nrf2 in the later stage of carcinogenesis and upregulation of tumor suppressor 15-PGDH might contribute to the repression of colitis-associated tumorigenesis in Nrf2 KO female mice.

Colon tumors develop more frequently in male than in female. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays differential roles in the stage of tumorigenesis. The purpose of this study was to investigate the role of Nrf2 on colitis-associated tumorigenesis using Nrf2 knockout (KO) female mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO female mice were sacrificed at week 2 and 16 after AOM injection. Severity of colitis, tumor incidence, and levels of inflammatory mediators were evaluated in AOM/DSS-treated WT and Nrf2 KO mice. Furthermore, qRT-PCR, Western blot abnalysis, and ELISA were performed in colon tissues. At week 2, AOM/DSS-induced colon tissue damages were significantly greater in Nrf2 KO than in WT mice. At week 16, tumor numbers (> 2 mm size) were significantly lower in both the proximal and distal colon in Nrf2 KO compared to WT. The overall incidences of adenoma/cancer of the proximal colon and submucosal invasive cancer of the distal colon were reduced by Nrf2 KO. The mRNA and protein expression levels of NF-κB-related mediators (i.e., iNOS and COX-2) and Nrf2-related antioxidants (i.e., heme oxygenase-1 and glutamate-cysteine ligase catalytic subunit) were significantly lower in the Nrf2 KO than in WT mice. Interestingly, the protein level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) was higher in AOM/DSS-treated Nrf2 KO than in WT mice. Our results support the oncogenic effect of Nrf2 in the later stage of carcinogenesis and upregulation of tumor suppressor 15-PGDH might contribute to the repression of colitis-associated tumorigenesis in Nrf2 KO female mice.

Background: Copeptin is secreted in equimolar amounts as arginine vasopressin, main hormone regulating body fluid homeostasis. A recent study reported a copeptin-based classification of osmoregulatory defects in syndromes of inappropriate antidiuresis that may aid in prediction of therapeutic success. We investigated usefulness of copeptin for differentiating etiologies of hyponatremia and predicting efficacy and safety of hypertonic saline treatment in hyponatremic patients. Methods: We performed a multicenter, prospective cohort study of 100 inpatients with symptomatic hyponatremia (corrected serum sodium [sNa] ≤ 125 mmol/L) treated with hypertonic saline. Copeptin levels were measured at baseline and 24 hours after treatment initiation, and patients were classified as being below or above median of copeptin at baseline or at 24 hours, respectively. Correlations between target, under correction, and overcorrection rates of sNa within 24 hours/24–48 hours and copeptin levels at baseline/24 hours were analyzed. Results: Mean sNa and median copeptin levels were 117.9 and 16.9 pmol/L, respectively. Ratio of copeptin-to-urine sodium allowed for an improved differentiation among some (insufficient effective circulatory volume), but not all hyponatremia etiologic subgroups. Patients with below-median copeptin levels at baseline achieved a higher target correction rate in 6/24 hours (odds ratio [OR], 2.97; p = 0.02/OR, 6.21; p = 0.006). Patients with below-median copeptin levels 24 hours after treatment showed a higher overcorrection rate in next 24 hours (OR, 18.00, p = 0.02). Conclusion There is a limited diagnostic utility of copeptin for differential diagnosis of hyponatremia. However, copeptin might be useful for predicting responses to hypertonic saline treatment in hyponatremic patients.

Background/Aims: The gut microbiome has emerged as a key player that mechanistically links various risk factors to colorectal cancer (CRC) etiology. However, the role of the gut microbiome in CRC pathogenesis remains unclear. This study aimed to characterize the gut microbiota in healthy controls (HCs) and patients with colorectal adenoma (AD) and CRC in subgroups based on sex and age. Methods: Study participants who visited the hospital for surveillance of CRC or gastrointestinal symptoms were prospectively enrolled, and the gut microbiome was analyzed based on fecal samples. Results: In terms of HC-AD-CRC sequence, commensal bacteria, including lactate-producing (Streptococcus salivarius) and butyrate-producing (Faecalibacterium prausnitzii, Anaerostipes hadrus, and Eubacterium hallii) bacteria, were more abundant in the HC group than in the AD and CRC groups. In the sex comparison, the female HC group had more lactate-producing bacteria (Bifidobacterium adolescentis, Bifidobacterium catenulatum, and Lactobacillus ruminis) than the male HC group. In age comparison, younger subjects had more butyrate-producing bacteria (Agathobaculum butyriciproducens and Blautia faecis) than the older subjects in the HC group.Interestingly, lactate-producing bacteria (B. catenulatum) were more abundant in females than males among younger HC group subjects. However, these sex- and age-dependent differences were not observed in the AD and CRC groups. Conclusions The gut microbiome, specifically lactate- and butyrate-producing bacteria, which were found to be abundant in the HC group, may play a role in preventing the progression of CRC. In particular, lactate-producing bacteria, which were found to be less abundant in healthy male controls may contribute to the higher incidence of CRC in males.

Dysbiosis in gut microbiota is known to contribute to development of irritable bowel syndrome. We tried to investigate the effect of Bifidobacterium longum on repeated water avoidance stress (WAS) in a Wistar rat model. The three groups (no-stress, WAS, and WAS with B. longum) of rats were allocated to sham or WAS for 1 hour daily for 10 days, and B. longum was administered through gavage for 10 days. Fecal pellet numbers were counted at the end of each 1-hour session of WAS. After 10 days of repeated WAS, the rats were eutanized, and the feces were collected. WAS increased fecal pellet output (FPO) significantly in both sexes (P < 0.001), while the female B. longum group showed significantly decreased FPO (P = 0.005). However, there was no consistent change of myeloperoxidase activity and mRNA expression of interleukin-1ββ and TNF-αα. Mast cell infiltration at colonic submucosa increased in the female WAS group (P = 0.016). In terms of fecal microbiota, the repeated WAS groups in both sexes showed different beta-diversity compared to control and WAS with B. longum groups. WAS-induced mast cell infiltration was reduced by the administration of B. longum in female rats. Moreover, administration of B. longum relieved WAS-caused dysbiosis, especially in female rats. In conclusion, B. longum was beneficial for WAS-induced stress in rats, especially in females.