Carnitine sensitizes TRAIL-resistant cancer cells to TRAIL-induced apoptotic cell death through the up-regulation of Bax.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family with apoptosis-inducing activity. Given that TRAIL selectively induces cell death in various tumors but has little or no toxicity to normal cells, TRAIL agonists have been considered as promising anti-cancer therapeutic agents. However, the resistance of many primary tumors and cancer cells to TRAIL poses a challenge. In our present study, we found that carnitine, a metabolite that transfers long-chain fatty acids into mitochondria for beta-oxidation and modulates protein kinase C activity, sensitizes TRAIL-resistant cancer cells to TRAIL. Combination of carnitine and TRAIL was found to synergistically induce apoptotic cell death through caspase activation, which was blocked by a pan caspase inhibitor, but not by an inhibitor of autophagy or an inhibitor of necrosis. The combination of carnitine and TRAIL reversed the resistance to TRAIL in lung cancer cells, colon carcinoma cells, and breast carcinoma cells. We further demonstrate that carnitine, either alone or in combination with TRAIL, enhances the expression of the pro-apoptotic Bcl-2 family protein, Bcl-2-associated X protein (Bax). The down-regulation of Bax expression by small interfering RNA reduced caspase activation when cells were treated with TRAIL, and experiments with cells from Bax knockout mice confirmed this result. Taken together, our current results suggest that carnitine can reverse the resistance of cancer cells to TRAIL by up-regulating Bax expression. Thus, a combined delivery of carnitine and TRAIL may represent a new therapeutic strategy to treat TRAIL-resistant cancer cells.

Oral misoprostol and uterine rupture in the first trimester of pregnancy: a case report.

We are reporting the case of a woman with 8 weeks of amenorrhea who orally received a single dose of misoprostol 400 microg at midnight for ripening of cervix before uterine evacuation of an intrauterine gestational sac containing a single fetus (6.3 weeks of gestation) without cardiac activity. The patient had severe abdominal pain an hour later. Her blood pressure was 70/40 mmHg and her abdomen was slightly distended with direct and rebound tenderness. A transvaginal ultrasonography showed a 3-cm depth of a free fluid collection in the rectouterine pouch. Her hemoglobin and hematocrit levels were of 6.5 g/dL and 18.4%, respectively. A rupture of 1.5 cm at the left uterine horn with a protruding gestational sac was identified by laparoscopy. The gestational sac was removed and hemoperitoneal collection were successfully drained. The site of uterine rupture was primarily sutured and postoperative course was satisfactory. In summary, misoprostol administered in the first trimester of pregnancy may produce uterine rupture.

Detection of genetic alterations in Korean ovarian carcinomas by degenerate oligonucleotide primed polymerase chain reaction-comparative genomic hybridization.

Chromosomal aberrations in 22 Koreans with ovarian carcinomas were investigated by degenerate oligonucleotide primed-polymerase chain reaction comparative genomic hybridization. The common sites of copy number increases were 20q (90%), 17q23 approximately qter (86%), 8q22 approximately qter (68%), 3q25 approximately qter (59%), 6p21 (59%), 11q13 (54%), 16p (40%), 2q31 approximately qter (36%), 7q (36%), 14q31 (36%), 15q24 approximately qter (36%), and 1q32 approximately qter (31%). DNA amplification was identified in 18 carcinomas (82%). The frequent sites of amplification were 20q13.2 approximately qter, 8q24.1, 17q23 approximately qter, 3q25 approximately qter, and 6p21. The most frequent sites of copy number decreases were 4q21 approximately q31 (54%), 5q13 approximately q21 (50%), and 13q14 approximately q21 (45%). The recurrent gains and losses of chromosomal regions identified in this study provide candidate regions that may contain oncogenes or tumor suppressor genes, respectively.

Down-Regulation of Survivin by Nemadipine-A Sensitizes Cancer Cells to TRAIL-Induced Apoptosis.

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines. TRAIL selectively induces apoptotic cell death in various tumors and cancer cells, but it has little or no toxicity in normal cells. Agonism of TRAIL receptors has been considered to be a valuable cancer-therapeutic strategy. However, more than 85% of primary tumors are resistant to TRAIL, emphasizing the importance of investigating how to overcome TRAIL resistance. In this report, we have found that nemadipine-A, a cell-permeable L-type calcium channel inhibitor, sensitizes TRAIL-resistant cancer cells to this ligand. Combination treatments using TRAIL with nemadipine-A synergistically induced both the caspase cascade and apoptotic cell death, which were blocked by a pan caspase inhibitor (zVAD) but not by autophagy or a necrosis inhibitor. We further found that nemadipine-A, either alone or in combination with TRAIL, notably reduced the expression of survivin, an inhibitor of the apoptosis protein (IAP) family of proteins. Depletion of survivin by small RNA interference (siRNA) resulted in increased cell death and caspase activation by TRAIL treatment. These results suggest that nemadipine-A potentiates TRAIL-induced apoptosis by down-regulation of survivin expression in TRAIL resistant cells. Thus, combination of TRAIL with nemadipine-A may serve a new therapeutic scheme for the treatment of TRAIL resistant cancer cells, suggesting that a detailed study of this combination would be useful.

Factors associated with a positive intake of folic acid in the periconceptional period among Korean women.

OBJECTIVE: We aimed to investigate the factors associated with a positive intake of folic acid (FA) during the periconceptional period among Korean women. DESIGN: In a cross-sectional study of demographic, obstetric and socio-economic data, history of periconceptional intake of FA and awareness of the benefits of FA supplementation in pregnancy were obtained and analysed using the chi2 test, followed by multiple logistic regression analysis. SETTING: The Maternity School, Cheil General Hospital and Women's Healthcare Center, Seoul, South Korea, between October 2005 and March 2006. SUBJECTS: In total 1313 pregnant women participating in a two-day training course available every month. RESULTS: After excluding subjects with incomplete or inconsistent data, there were 1277 women included in the analysis. Participants were aged 29.4 (sd 2.9) years and had a mean gestational age of 27.9 (sd 7.1) weeks. Only 131 (10.3 %) women took FA during the periconceptional period. According to multiple logistic regression analyses, the adjusted OR for FA supplementation was 1.79 (95 % CI 1.10, 2.91) in women who had previous spontaneous abortions, 4.10 (95 % CI 2.43, 6.78) in women who planned their pregnancy and 6.63 (95 % CI 2.08, 21.12) in those who were aware of the protective effects of FA. CONCLUSIONS: Periconceptional intake of FA was more likely among Korean women with a history of previous spontaneous abortion, who planned their pregnancy or who were aware of the protective effects of FA during pregnancy. However, the proportion of women who took FA in the periconceptional period was low.

Increased sFlt-1 to PlGF ratio in women who subsequently develop preeclampsia.

The purpose of this study was to determine whether the levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placenta growth factor (PlGF) are altered during the second trimester in the plasma of women who subsequently develop preeclampsia. We performed a case-control study to compare the levels of sFlt-1 and PlGF in the preeclamptic (n=46) and normal pregnant women (n=100). The maternal plasma levels of sFlt-1 and PlGF were measured by enzyme-linked immunosorbent assay. The sFlt-1 levels were significantly higher in the preeclamptic women than in normal controls (p<0.001), while the PlGF levels were significantly lower (p<0.001). In normal controls, sFlt-1 levels were positively correlated (r=0.27, p=0.008), whereas, in the preeclamptic women, those were negatively correlated with the PlGF levels (r=-0.423, p=0.005). Furthermore, the log[sFlt-1/PlGF] ratio was significantly higher in the preeclamptic women than in normal controls (p<0.001). The receiver operating characteristic curve revealed a specificity of 78% with a diagnostic sensitivity of 80.4%; the optimal cut-off value of the log[sFlt-1/PlGF] ratio was 1.4 (95% CI 0.756-0.910, p<0.001). Preeclampsia showed a strong association with increased levels of sFlt-1 and decreased levels of PlGF in the second trimester maternal plasma. Accordingly, the sFlt-1/PlGF ratio may provide early prediction of subsequent development of preeclampsia.

Perinatal outcome in twin pregnancies complicated by gestational diabetes mellitus: a comparative study.

The purpose of this study is to compare perinatal outcomes of twin pregnancies complicated by gestational diabetes (GDM) with those unaffected by GDM. A total of 1,154 twin pregnancies who delivered at Cheil General Hospital, between January 1998 and December 2002 were recruited to participate in a retrospective analysis. Out of these twin pregnancies, 37 women were had GDM. Four pregnancies exposed to GDM were excluded due to the loss of medical records; therefore 33 twin pregnancies exposed to GDM were enrolled. We matched the GDM pregnancies with pregnancies unaffected by GDM in a 1:2 ratio; therefore there were 33 GDM/66 without GDM who delivered during the study period. Our findings show that there were no significant differences including birth weight, Apgar score, respiratory distress syndrome, meconium aspiration pneumonia, transient tachypnea of new born, hyperbilirubinemia, hypoglycemia, hypocalcemia and congenital anomalies. Therefore, well controlled GDM may not increase perinatal complications in twin pregnancies. Careful pregnancy management and fetal surveillance in twin pregnancies is important to decrease perinatal complications and maintain a sound pregnancy and healthy offspring.

Threshold of nuchal translucency for the detection of chromosomal aberration: comparison of different cut-offs.

This study evaluated the sensitivities and false positive rates of the screening test using ultrasonographic measurement of thickness of nuchal translucency (NT) with different cut-offs for chromosomal aberration in a Korean population. We included 2,570 singleton pregnancies undergoing ultrasound between 11 weeks and 14 weeks of gestation in this study. We analyzed the sensitivities of NT alone for screening chromosomal aberration using three cut-offs -2.5 mm, 3.0 mm, and 95th percentile for each crown rump length (CRL). There were 31 chromosomal aberrations (1.2%) including 12 cases of trisomy 21. The numbers of chromosomal aberrations that were detected by NT with different cut-offs of 2.5 mm, 3.0 mm and the 95th percentile CRL were 22, 18 and 23, respectively. At a threshold of 2.5 mm, the sensitivity and the false positive rate for total chromosomal aberrations were 67.7% and 6.3%, respectively. At 3.0 mm, those were 54.8% and 3.5%, respectively. At the 95th percentile CRL, those were 70.9% and 5.8%, respectively. The use of CRL-dependent cut-offs for nuchal translucency improves the detection of chromosomal aberrations when compared to fixed cut-offs in a Korean population.

Risk factors for preterm birth in Korea: a multicenter prospective study.

Preterm birth is a major determinant of neonatal morbidity and mortality and remains one of the most serious problems in obstetrics. The aim of this study was to investigate the risk factors for preterm birth in Korean pregnant women. A total of 2,645 women were evaluated between 20 and 42 weeks' gestation at 5 centers using a prospective study design. The patient population is limited to singleton gestations. Demographic factors, socioeconomic statuses, previous and current medical histories, complications of current gestation, and drug and alcohol abuse were evaluated, and univariate and multivariate logistic regression analyses performed. Among nulliparous women, the factors that showed a significant association with preterm delivery were as follows; vaginal bleeding during pregnancy (OR 2.6, CI 1.7-4.2), and below USD 1,000 average income (OR 5.1, CI 1.9-13.5). The factors that showed a significant association with preterm delivery among multiparous women were as follows; a history of spontaneous abortion (OR 2.4, CI 1.1-5.2), and a history of preterm delivery (OR 3.5, CI 1.02-11.8). In conclusion, vaginal bleeding during pregnancy, below USD 1,000 of average income, prior spontaneous abortion, and prior preterm delivery, were positively associated with preterm birth.

Differentiation of endothelial cells from human umbilical cord blood AC133-CD14+ cells.

Endothelial progenitor cells (EPCs) participate in neovascularization and are consistent with postnatal vasculogenesis. In vitro, they differentiate into endothelial cells (ECs). Prior reports have suggested that circulating human AC133(+) cells have the capacity to differentiate into ECs as progenitor cells. However, recent studies have demonstrated that circulating CD34(-)CD14(+) cells also have EPC-like properties in vitro and in vivo. We tested whether AC133(-)CD14(+) cells from human umbilical cord blood (HUCB) have the potential to differentiate into ECs. The AC133(-)CD14(+) cells were isolated from HUCB by magnetic bead selection and cultured on fibronectin-coated six-well trays in M199 medium supplemented with fetal bovine serum (FBS), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and insulin growth factor (IGF-1). The AC133(-)CD14(+) cells adhered slightly within 1 day of culture and subsequently underwent a distinct process of morphological transformation to spindle-shaped cells that sprouted from the edge of the cell clusters. After 14 days, the cells formed cord- and tubular-like structures. The AC133(-)CD14(+) cells showed a strong increase in the endothelial marker P1H12 over time, whereas CD14 decreased, and CD45 did not change, respectively. In addition, the cells expressed endothelial markers von Willebrand's factor (vWF), platelet/endothelial cell adhesion molecule-1 (PECAM-1), vascular endothelial growth factor receptor-1 (VEGFR-1)/Flt-1, VEGFR-2/Flk-1, eNOS, and VE-cadherin, but did not express Tie-2 after 7 days of culture. The present data indicate that AC133(-)CD14(+) cells from HUCB are able to develop endothelial phenotype with expression of endothelial-specific surface markers and even form cord- and tubular-like structures in vitro as progenitor cells.

The distribution of fetal nuchal translucency thickness in normal Korean fetuses.

The aim of present study was to establish normative data for the distribution of nuchal translucency (NT) thickness in normal Korean fetuses. The data were collected from pregnant women with singleton pregnancies in whom fetal ultrasound was performed and the fetal NT thickness was measured between 11 and 14 weeks of gestation. Among them, a total of 2,577 fetuses with a known normal outcome were included in this study. The distribution of multiple of median (MoM) values of the NT thickness with crown-rump length (CRL) in 10-mm intervals and the 95th percentile of MoM were calculated with the linear regression method. The present study showed that NT measurements increase with increasing CRL and a false positive rate increases with increasing gestational age. Therefore, a fixed cut-off point through the first trimester was not appropriate and each NT measurement should be examined according to the gestational age. The present study offers normative data of the fetal NT thickness in a Korean population, which can be used as reference for screening chromosomal aberrations or other congenital abnormalities in the first trimester.