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

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.

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.

This study aimed to establish an organoid culture model using small intestine tissues from male and female C57BL/6 mice and to compare it with rat organoid cultures derived from frozen tissues. Crypts were isolated from the small intestines of eight-week-old male and female mice and cultured in 3D extracellular matrix with Wnt, R-spondin, and Noggin. In addition, small intestine tissues from sixteen-week-old F344 rats were preserved in a storage solution immediately post-sacrifice and stored at –80°C before being transferred to a nitrogen tank. Upon thawing, crypts from frozen rat tissues failed to develop into organoids due to structural damage, suggesting the need for fresh tissues or optimized preservation methods. In contrast, mouse-derived organoids showed viability for 7 days, with distinct morphological changes and clear differentiation by Day 7. Quantitative real-time PCR analysis revealed that Lgr5, a stem cell marker, showed significantly higher expression in organoids than in tissues, confirming the successful establishment of the organoid culture. Among epithelial markers, the antimicrobial enzyme Lyz1 was more highly expressed in organoids, while Muc2, a key goblet cell marker, was more highly expressed in male tissues. The enterocyte marker Alp exhibited higher expression in male organoids compared to females, with no sex differences in tissues. These findings highlight sex-specific differences in gene expression related to small intestine differentiation and demonstrate the challenges in organoid culture from frozen rat tissues. The results suggest the importance of immediate tissue processing or improved preservation methods for successful organoid cultures.

This study aimed to establish an organoid culture model using small intestine tissues from male and female C57BL/6 mice and to compare it with rat organoid cultures derived from frozen tissues. Crypts were isolated from the small intestines of eight-week-old male and female mice and cultured in 3D extracellular matrix with Wnt, R-spondin, and Noggin. In addition, small intestine tissues from sixteen-week-old F344 rats were preserved in a storage solution immediately post-sacrifice and stored at –80°C before being transferred to a nitrogen tank. Upon thawing, crypts from frozen rat tissues failed to develop into organoids due to structural damage, suggesting the need for fresh tissues or optimized preservation methods. In contrast, mouse-derived organoids showed viability for 7 days, with distinct morphological changes and clear differentiation by Day 7. Quantitative real-time PCR analysis revealed that Lgr5, a stem cell marker, showed significantly higher expression in organoids than in tissues, confirming the successful establishment of the organoid culture. Among epithelial markers, the antimicrobial enzyme Lyz1 was more highly expressed in organoids, while Muc2, a key goblet cell marker, was more highly expressed in male tissues. The enterocyte marker Alp exhibited higher expression in male organoids compared to females, with no sex differences in tissues. These findings highlight sex-specific differences in gene expression related to small intestine differentiation and demonstrate the challenges in organoid culture from frozen rat tissues. The results suggest the importance of immediate tissue processing or improved preservation methods for successful organoid cultures.