PURPOSE: Recurrence and chemoresistance (CR) are the leading causes of death in patients with high-grade serous carcinoma (HGSC) of the ovary. The aim of this study was to identify genetic changes associated with CR mechanisms using a patient-derived xenograft (PDX) mouse model and genetic sequencing. MATERIALS AND METHODS: To generate a CR HGSC PDX tumor, mice bearing subcutaneously implanted HGSC PDX tumors were treated with paclitaxel and carboplatin. We compared gene expression and mutations between chemosensitive (CS) and CR PDX tumors with whole exome and RNA sequencing and selected candidate genes. Correlations between candidate gene expression and clinicopathological variables were explored using the Cancer Genome Atlas (TCGA) database and the Human Protein Atlas (THPA). RESULTS: Three CR and four CS HGSC PDX tumor models were successfully established. RNA sequencing analysis of the PDX tumors revealed that 146 genes were significantly up-regulated and 54 genes down-regulated in the CR group compared with the CS group. Whole exome sequencing analysis showed 39 mutation sites were identified which only occurred in CR group. Differential expression of SAP25,HLA-DPA1, AKT3, and PIK3R5 genes and mutation of TMEM205 and POLR2A may have important functions in the progression of ovarian cancer chemoresistance. According to TCGA data analysis, patients with high HLA-DPA1 expression were more resistant to initial chemotherapy (p=0.030; odds ratio, 1.845). CONCLUSION: We successfully established CR ovarian cancer PDX mouse models. PDX-based genetic profiling study could be used to select some candidate genes that could be targeted to overcome chemoresistance of ovarian cancer.
Animals ; Carboplatin ; Cause of Death ; Drug Therapy ; Exome ; Female ; Gene Expression ; Genome ; Heterografts ; Humans ; Mice ; Odds Ratio ; Ovarian Neoplasms ; Ovary ; Paclitaxel ; Recurrence ; Sequence Analysis, RNA ; Statistics as Topic

O-linked N-acetylglucosamine (O-GlcNAc) represents a key regulatory post-translational modification (PTM) that is reversible and often reciprocal with phosphorylation of serine and threonine at the same or nearby residues. Although recent technical advances in O-GlcNAc site-mapping methods combined with mass spectrometry (MS) techniques have facilitated study of the fundamental roles of O-GlcNAcylation in cellular processes, an efficient technique for examining the dynamic, reciprocal relationships between O-GlcNAcylation and phosphorylation is needed to provide greater insights into the regulatory functions of O-GlcNAcylation. Here, we describe a strategy for selectively identifying both O-GlcNAc- and phospho-modified sites. This strategy involves metal affinity separation of O-GlcNAcylated and phosphorylated peptides, beta-elimination of O-GlcNAcyl or phosphoryl functional groups from the separated peptides followed by dithiothreitol (DTT) conjugation (BEMAD), affinity purification of DTT-conjugated peptides using thiol affinity chromatography, and identification of formerly O-GlcNAcylated or phosphorylated peptides by MS. The combined metal affinity separation and BEMAD approach allows selective enrichment of O-GlcNAcylated peptides over phosphorylated counterparts. Using this approach with mouse brain synaptosomes, we identified the serine residue at 605 of the synapsin-1 peptide, 603QASQAGPGPR612, and the serine residue at 692 of the tau peptide, 688SPVVSGDTSPR698, which were found to be potential reciprocal O-GlcNAcylation and phosphorylation sites. These results demonstrate that our strategy enables mapping of the reciprocal site occupancy of O-GlcNAcylation and phosphorylation of proteins, which permits the assessment of cross-talk between these two PTMs and their regulatory roles.
Acetylglucosamine/*metabolism ; Amino Acid Sequence ; Animals ; Brain/*metabolism ; Chromatography, Affinity ; Glycosylation ; Mice ; Molecular Sequence Data ; Peptides/isolation & purification ; Phosphorylation ; Synapsins/chemistry/*metabolism ; Synaptosomes/*metabolism ; Tandem Mass Spectrometry ; tau Proteins/chemistry/*metabolism

Adequate intake of nutrients by pregnant women diagnosed with gestational diabetes mellitus (GDM) or type 2 diabetes (T2DM) is very important for appropriate weight gain and maintenance of normoglycemia without ketonuria. The aim of this study was to investigate the nutritional intake of pregnant women with GDM or T2DM who had not been provided with nutritional education regarding blood glucose management. Between June 2008 and May 2010, 125 pregnant women who had been diagnosed with GDM or T2DM and had not received any nutrition education regarding glycemic control and proper diet during pregnancy were interviewed to collect data regarding background characteristics, health-related behaviors, and course of pregnancy and instructed to record their dietary intake using a 24-hour recall method for one day. Using the collected data, the index of nutritional quality, nutrient adequacy ratio, and mean adequacy ratio values of the subjects were calculated. Analysis of the values indicated that the majority of the subjects did not meet recommended intake levels for most micronutrients and consumed an undesirable ratio of macronutrients, specifically a higher percentage of total carbohydrates than the current recommendation level. The GDM and T2DM groups obtained 56.6% and 63.6%, respectively (p = 0.012), of their calories by carbohydrate intake, which exceeded the recommended levels (125.8% in GDM groups, 141.3% in T2DM groups).
Blood Glucose ; Carbohydrates ; Diabetes Mellitus, Type 2* ; Diabetes, Gestational* ; Diet ; Education ; Female ; Humans ; Ketosis ; Micronutrients ; Nutritive Value ; Pregnancy ; Pregnant Women* ; Weight Gain

PURPOSE: Histone deacetylase inhibitors (HDACIs) induce accumulation of acetylated histones in nucleosomes, which lead to reactivate gene expression and inhibit the growth and survival of tumor cells. This study evaluated the efficacy of HDACIs in breast cancer cells in comparison with other established drug regimens. METHODS: Drug responses of tumor samples from mastectomy specimens of 78 breast cancer patients were evaluated using the histoculture drug response assay (HDRA). Tumor inhibition rates (IRs) of established drug regimens such as doxorubicin, cyclophosphamide, doxorubicin with cyclophosphamide (AC), paclitaxel, docetaxel and doxorubicin with docetaxel (AT), as well as those of three HDACIs (SAHA, PXD101, and a novel compound CG-2) were evaluate. RESULTS: The percentages of chemosensitive tumors (chemoresponsiveness) were 26.9-60.3% with established regimens and 61.5-73.1% with HDACIs when the cutoff value for inhibition rate was set at 30%. Breast cancer cells appeared to be more chemoresponsive to HDACIs than to established drug regimens. Chemoresponsiveness to AT was the highest among the established drug regimens. A combination regimen offered higher activity than did a single drug (doxorubicin vs AT; p<0.001). HER2/Neu-overexpressing breast cancers were chemosensitive to SAHA and AT (p=0.031 and 0.04, respectively). CONCLUSION: Our findings show that breast cancer cells were sensitive to HDACIs, with therapeutic efficacies comparable to those of established drug regimens. Specific biological markers such as HER2/Neu could be assessed for effectiveness as HDACIs chemosensitivity markers in further clinical trials.
Biomarkers ; Breast ; Breast Neoplasms ; Cyclophosphamide ; Doxorubicin ; Gene Expression ; Histone Deacetylase Inhibitors ; Histone Deacetylases ; Histones ; Humans ; Hydroxamic Acids ; Mastectomy ; Nucleosomes ; Paclitaxel ; Sulfonamides ; Taxoids

OBJECTIVE: The purpose of this study is to survey the clinical practice pattern of postterm pregnancy in Korea. METHODS: A questionnaire was mailed to 1114 physicians who are registered in Korean Society of Obstetrics and Gynecology (KSOG) and work in primary and secondary hospital as well as tertiary care center. The questions included information about the practice pattern implicating definition of postterm pregnancy, the time and the method of routine fetal surveillance and induction of labor as well as demographic information such as age, sex, location, professional part and the number of delivery. We got 23.2% (258/1114) of surveys returned and analyzed the data. RESULTS: Seventy-four percent (73.6%) of the respondents define 42 weeks gestation or greater to be postterm. However, 84.5% consider induction of labor at 41 weeks of gestation. Sixty-eight percent (68.3%) of the respondents start postterm pregnancy fetal testing at 40 weeks and 59.3% of them perform testing every week. For fetal surveillance testing, 85.7% of the respondents use NST and 39.5% of them use modified BPP. As for induction of labor, 65% of practitioners use oxytocin and 45% of them use prostaglandins (misoprostol and dinoprostone) when inducing both nulliparous and multiparous women with unfavorable cervix. CONCLUSION: Most of the respondents (84.5%) routinely induce low-risk singleton pregnancy at 41 weeks gestation, whereas the majority of them (73.6%) define postterm pregnancy beyond 42 weeks gestation.
Cervix Uteri ; Surveys and Questionnaires ; Female ; Gynecology ; Humans ; Korea* ; Obstetrics ; Oxytocin ; Physician's Practice Patterns* ; Postal Service ; Pregnancy* ; Prostaglandins ; Surveys and Questionnaire ; Tertiary Care Centers

OBJECTIVE:The purpose of this study was to investigate the role of sonographic findings and tumor markers in predicting malignancy of adnexal masses in pregnancy. METHODS:From January 1995 to September 2005, 190 cases of adnexal masses were operated during pregnancy. We reviewed their sonographic findings and medical records retrospectively. Sonographic features and tumor markers were correlated with malignant pathology. Pregnancy and neonatal outcomes were also studied after treatment of adnexal mass during pregnancy. RESULTS:From 190 cases, there were 10 cases (5.3%) of malignant tumor or tumors of borderline malignancy. In the 180 cases of benign adnexal mass, the most common type was mature cystic teratoma (36.7%). Preoperative sonographic findings were available in 110 cases. The median size was 6.3 cm for benign masses and 7.7 cm for malignant masses (p=0.05). Mixed echogenecity, septa and mural nodule were more frequently found in malignant masses (p=0.003, 0.029, 0.013, respectively). Tumor markers were available in 47 cases. In the 1st trimester, the level of serum CA-125 of the patients with benign masses were not different from those with malignant masses. However, in the 2nd and 3rd trimester, the difference was statistically significant (p=0.031). Forty- six patients underwent antepartum surgery and the overall pregnancy outcome was similar between the laparoscopic group and the laparotomy group. CONCLUSION:Mixed echogenecity, septa and mural nodule showed significant correlation with malignant adnexal mass in pregnancy.
Female ; Humans ; Laparotomy ; Medical Records ; Pathology* ; Pregnancy Outcome ; Pregnancy* ; Retrospective Studies ; Teratoma ; Biomarkers, Tumor ; Ultrasonography*

OBJECTIVE: To investigate the maternal and neonatal outcomes in pregnancies complicated with idiopathic thrombocypenic purpura (ITP) and to identify antenatal factors to predict the neonatal thrombocytopenia. METHODS: We analyzed retrospectively maternal and neonatal outcomes of the32 pregnant women with ITP who were delivered over a 12-year period. RESULTS: The prevalence incidence of ITP in pregnancy was 0.87 per 1,000 live births in this study population. The diagnosis of ITP was made more before pregnancy than with afterduring during pregnancy (63% vs 37%). Maternal platelet transfusion was done in 62.5 % of pregnancies with ITP. Sixty nine percent of pregnancies with ITP received medical therapies; steroid only in 8 cases (25%), steroid + IVIG (intravenous immunoglobulin) in 6 cases (18.7%), IVIG only in 2 cases (6.2%), and steroid + IVIG + anti-Rh (anti-D) in 1 case (3.1%). Overall response rate (Plt > 50 x 10(9)/L) to medical treatment was 77%. Neonatal thrombocytopenia (Plt < 50 x 10(9)/Ll) was observed seen in 4 cases (14.2%) immunoglobulin. There was no correlation between the maternal and the neonatal platelet count. Moreover medical treatment during pregnancy did not make any difference in neonatal platelet count. There was one case of neonatal ICH (germinal matrix hemorrhage). CONCLUSION: Although neonatal thrombocytopenia occurred in 140% of pregnancies with ITP, no antenatal factor could predict neonatal thrombocytopenia.
Diagnosis ; Female ; Humans ; Immunoglobulins ; Immunoglobulins, Intravenous ; Incidence ; Live Birth ; Platelet Count ; Platelet Transfusion ; Pregnancy* ; Pregnant Women ; Prevalence ; Purpura ; Purpura, Thrombocytopenic, Idiopathic* ; Retrospective Studies ; Thrombocytopenia, Neonatal Alloimmune

PURPOSE: We wanted to evaluate the detectability of gallstones on magnetic resonance cholangiopancreatography (MRCP) and to compare the accuracy between the single-shot turbo spin-echo (SSTSE) sequence and the three-dimensional turbo spin-echo (3DTSE) sequence with the sensitivity encoding (SENSE) technique. MATERIALS AND METHODS: A total of 141 patients who had undergone MRCP for a year period since August, 2003 were involved in the study. The source axial-SSTSE, coronal-SSTSE, source coronal-3D TSE and maximum intensity projection (MIP)-3DTSE images were obtained. Based on the operative findings and the findings of the ultrasound and CT examinations, the results of the reading by two investigators for the presence of gallstones were compared and analyzed. RESULTS: Among 141 patients, 135 patients were included in the study. 69 cases (51%) were found to have gallstones. In terms of detection of gallstones, the accuracy was 85%. The reading by one investigator greatly accorded with that of the other investigator (κ=0.94). As a result of comparing the four kinds of images obtained with the different techniques, it was found that gallstones were seen best on the source axial-SSTSE and source coronal-3DTSE images; the coronal-SSTSE image was the next best image and the MIP-3DTSE image followed (p<0.01). CONCLUSION: The detectability of gallstones on MRCP was relatively excellent and the source axial-SSTSE and source coronal-3DTSE imagings should be included for the detection of gallstones.
Cholangiopancreatography, Magnetic Resonance ; Gallbladder ; Gallstones* ; Humans ; Research Personnel ; Ultrasonography

Pyoderma gangrenosum (PG) is a vasculitic process, often associated with systemic diseases, including Takayasu's arteritis (TA), rheumatoid arthritis, and inflammatory bowel disease. Most cases of PG associated with TA have been observed in Japan. However, this association is not commonly observed in North American and European patients. PG is often refractory to therapy, requiring high dosages of glucocorticoids. Here, we describe a case of recalcitrant PG that was associated with TA and successfully treated with methotrexate.
Arthritis, Rheumatoid ; Glucocorticoids ; Humans ; Inflammatory Bowel Diseases ; Japan ; Methotrexate* ; Pyoderma Gangrenosum* ; Pyoderma* ; Takayasu Arteritis*

OBJECTIVE: To evaluate the association of level of CA-125 and severity of dysmenorrhea with lesion depth in adenomyosis. METHODS: Sixty-eight women who had undergone hysterectomy and were found to have pure adenomyosis on histopathologic examination were reviewed retrospectively. Specimens were stratified according to the degree of adenomyosis penetration into 4 groups: group A consisted of specimens with adenomyosis penetration into myometrium of up to 25%; group B, 26-50%; group C, 51-75%, and group D, >75%. All women were submitted to serum determination of CA-125. Severity of dysmenorrhea was assessed by means of a modification of 10-point verbal rating scale. RESULTS: Each group was not correlated with severity of dysmenorrhea (p=0.7394 Fisher's exact test). The means of serum CA-125 levels was increased corresponding to depth of adenomyosis (p=0.0441 ANOVA test). CONCLUSION: In this study, serum CA-125 level is associated with the depth lesion and severity of dysmenorrhea is not. Therefore, the level of serum CA-125 might be useful indicator in management of adenomyosis before surgery.
Adenomyosis* ; Animals ; Dysmenorrhea* ; Female ; Humans ; Hysterectomy ; Mice ; Myometrium ; Retrospective Studies