Clinical significance of soft markers in second trimester ultrasonography for pregnant Korean women: a multicenter study and literature review

OBJECTIVE: To evaluate the clinical significance of soft markers for aneuploidy screening in Korean women. METHODS: We retrospectively reviewed the medical records of 5,428 singleton pregnant women who underwent sonography during the second trimester at seven institutions in South Korea. We evaluated the prevalence of the following soft markers: intracardiac echogenic focus, choroid plexus cysts, pyelectasis, echogenic bowel, and mild ventriculomegaly. We developed best-fitted regression equations for the fetal femur and humerus length using our data and defined a short femur and humerus as both long bones below the fifth centile. The results of genetic testing and postnatal outcomes were investigated in patients who had been diagnosed with aforementioned soft markers. RESULTS: The median maternal age of our study population was 33 years, and the median gestational age at the time of ultrasonographic examination was 21 weeks. We detected soft markers in 10.0% (n=540) of fetuses: 9.3% (n=504) were isolated cases and 0.7% (n=36) of cases had two or more markers. We identified only two aneuploides (trisomy 18, 46,XX,t[8;10][q22.1;p13]), of which one was clinically significant. We presented the neonatal outcomes of the fetuses with the respective soft markers. Preterm delivery, low birth weight, and small-for-gestational-age (SGA) were significantly more common in women with a shortened fetal femur (P<0.001, all). However, the presence of a shortened fetal humerus was not associated with those outcomes excluding SGA. CONCLUSION: Soft markers in second-trimester ultrasonography have limited use in screening for fetal aneuploidy in Korean women. However, these markers can be used as a screening tool for adverse outcomes other than chromosomal abnormality

Possible Novel Therapy for Malignant Gliomas with Secretable Trimeric TRAIL

Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and many novel therapeutic approaches, average survival for the patients with malignant gliomas is only about 1 year. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown potent and cancer-selective killing activity and drawn considerable attention as a promising therapy for cancers, but concerns over delivery and toxicity have limited progress. We have developed a secretable trimeric TRAIL (stTRAIL) and here evaluated the therapeutic potential of this stTRAIL-based gene therapy in brain tumors. An adenovirus (Ad-stTRAIL) delivering stTRAIL was injected into intra-cranial human glioma tumors established in nude mice and tumor growth monitored using the magnetic resonance imaging (MRI). Ad-stTRAIL gene therapy showed potent tumor suppressor activity with no toxic side effects at therapeutically effective doses. When compared with 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a conventional therapy for malignant gliomas, Ad-stTRAIL suppressed tumor growth more potently. The combination of Ad-stTRAIL and BCNU significantly increased survival compared to the control mice or mice receiving Ad-stTRAIL alone. Our data indicate that Ad-stTRAIL, either alone or combined with BCNU, has promise as a novel therapy for malignant gliomas

Transition between Two Regimes Describing Internal Fluctuation of DNA in a Nanochannel

We measure the thermal fluctuation of the internal segments of a piece of DNA confined in a nanochannel about 50100 nm wide. This local thermodynamic property is key to accurate measurement of distances in genomic analysis. For DNA in 100 nm channels, we observe a critical length scale 10 m for the mean extension of internal segments, below which the de Gennes' theory describes the fluctuations with no fitting parameters, and above which the fluctuation data falls into Odijk's deflection theory regime. By analyzing the probability distributions of the extensions of the internal segments, we infer that folded structures of length 150250 nm, separated by 10 m exist in the confined DNA during the transition between the two regimes. For 50 nm channels we find that the fluctuation is significantly reduced since the Odijk regime appears earlier. This is critical for genomic analysis. We further propose a more detailed theory based on small fluctuations and incorporating the effects of confinement to explicitly calculate the statistical properties of the internal fluctuations. Our theory is applicable to polymers with heterogeneous mechanical properties confined in non-uniform channels. We show that existing theories for the end-to-end extension/fluctuation of polymers can be used to study the internal fluctuations only when the contour length of the polymer is many times larger than its persistence length. Finally, our results suggest that introducing nicks in the DNA will not change its fluctuation behavior when the nick density is below 1 nick per kbp DNA

Ultrasonographic assessment of abnormal fetal growth related to uteroplacental-fetal biometrics and Doppler (U-AID) indices: Protocol for multicenter retrospective cohort study trial

Fetal growth restriction (FGR) is one of the leading causes of perinatal morbidity and mortality. Many studies have reported an association between FGR and fetal Doppler indices focusing on umbilical artery (UA), middle cerebral artery (MCA), and ductus venosus (DV). The uteroplacental-fetal circulation which affects the fetal growth consists of not only UA, MCA, and DV, but also umbilical vein (UV), placenta and uterus itself. Nevertheless, there is a paucity of large-scale cohort studies that have assessed the association between UV, uterine wall, and placental thickness with perinatal outcomes in FGR, in conjunction with all components of the uteroplacental-fetal circulation. Therefore, this multicenter study will evaluate the association among UV absolute flow, placental thickness, and uterine wall thickness and adverse perinatal outcome in FGR fetuses. This multicenter retrospective cohort study will include singleton pregnant women who undergo at least one routine fetal ultrasound scan during routine antepartum care. Pregnant women with fetuses having structural or chromosomal abnormalities will be excluded. The U-AID indices (UtA, UA, MCA, and UV flow, placental and uterine wall thickness, and estimated fetal body weight) will be measured during each trimester of pregnancy. The study population will be divided into two groups: (1) FGR group (pregnant women with FGR fetuses) and (2) control group (those with normal growth fetus). We will assess the association between U-AID indices and adverse perinatal outcomes in the FGR group and the difference in U-AID indices between the two groups

Addition of Cervical Elastography May Increase Preterm Delivery Prediction Performance in Pregnant Women with Short Cervix: a Prospective Study

BACKGROUND: We investigated whether there is a difference in elastographic parameters between pregnancies with and without spontaneous preterm delivery (sPTD) in women with a short cervix (</= 25 mm), and examined the ability of elastographic parameters to predict sPTD in those women. METHODS: E-Cervix(TM) (WS80A: Samsung Medison, Seoul, Korea) elastography was used to examine the cervical strain. Elastographic parameters were compared between pregnancies with and without sPTD. Diagnostic performance of elastographic parameters to predict sPTD </= 37 weeks, both alone and in combination with other parameters, was compared with that of cervical length (CL) using area under receiver operating characteristic curve (AUC) analysis. RESULTS: A total of 130 women were included. Median gestational age (GA) at examination was 24.4 weeks (interquartile range, 21.4-28.9), and the prevalence of sPTD was 20.0% (26/130). Both the elastographic parameters and CL did not show statistical difference between those with and without sPTD. However, when only patients with CL >/= 1.5 cm (n = 110) were included in the analysis, there was a significant difference between two groups in elasticity contrast index (ECI) within 0.5/1.0/1.5 cm from the cervical canal (P /= 1.5 cm, the combination of parameters (CL + pre-pregnancy body mass index + GA at exam + ECI within 0.5/1.0/1.5 cm) showed a significantly higher AUC than CL alone (P < 0.05). CONCLUSION: An addition of cervical elastography may improve the ability to predict sPTD in women with a short CL between 1.5 and 2.5 cm

Effect of Cervical Cerclage on the Risk of Recurrent Preterm Birth after a Twin Spontaneous Preterm Birth

BACKGROUND: This study aimed to evaluate the effect of cervical cerclage on the recurrence risk for preterm birth in singleton pregnant women after a twin spontaneous preterm birth (sPTB). METHODS: This multicenter retrospective cohort study included women who had a singleton pregnancy from January 2009 to December 2018 at 10 referral hospitals and a twin sPTB before the current pregnancy. We compared the cervical lengths during pregnancy and pregnancy outcomes, according to the placement of prophylactic or emergency cerclage. We evaluated the independent risk factors for sPTB (&lt; 37 weeks of gestation) in a subsequent singleton pregnancy. RESULTS: For the index singleton pregnancy, preterm birth occurred in seven (11.1%) of 63 women. There was no significant difference in the cervical lengths during pregnancy in women with and without cerclage. In a multivariate logistic regression analysis, the placement of emergency cerclage was an independent risk factor for subsequent singleton preterm birth (odds ratio [OR], 93.188; 95% confidence interval [CI], 1.633-5,316.628; P = 0.027); however, the placement of prophylactic cerclage (OR, 19.264; 95% CI, 0.915-405.786; P = 0.057) was not a factor. None of the women who received prophylactic cerclage delivered before 35 weeks' gestation in the index singleton pregnancy. CONCLUSION: Cerclage did not lower the risk of preterm birth in a subsequent singleton pregnancy after a twin sPTB. However, emergency cerclage was an independent risk factor for preterm birth and there was no preterm birth before 35 weeks' gestation in the prophylactic cerclage group. Therefore, close monitoring of the cervical length and prophylactic cerclage might be considered in women who have experienced a twin sPTB at extreme gestation

A comprehensive characterization of the caspase gene family in insects from the order Lepidoptera

<p>Abstract</p> <p>Background</p> <p>The cell suicide pathway of apoptosis is a necessary event in the life of multicellular organisms. It is involved in many biological processes ranging from development to the immune response. Evolutionarily conserved proteases, called caspases, play a central role in regulating apoptosis. Reception of death stimuli triggers the activation of initiator caspases, which in turn activate the effector caspases. In Lepidoptera, apoptosis is crucial in processes such as metamorphosis or defending against baculovirus infection. The discovery of p35, a baculovirus protein inhibiting caspase activity, has led to the characterization of the first lepidopteran caspase, Sf-Caspase-1. Studies on Sf-Caspase-1 mode of activation suggested that apoptosis in Lepidoptera requires a cascade of caspase activation, as demonstrated in many other species.</p> <p>Results</p> <p>In order to get insights into this gene family in Lepidoptera, we performed an extensive survey of lepidopteran-derived EST datasets. We identified 66 sequences distributed among 27 species encoding putative caspases. Phylogenetic analyses showed that Lepidoptera possess at least 5 caspases, for which we propose a unified nomenclature. According to homology to their <it>Drosophila </it>counterparts and their primary structure, we determined that Lep-Caspase-1, -2 and -3 are putative effector caspases, whereas Lep-Caspase-5 and -6 are putative initiators. The likely function of Lep-Caspase-4 remains unclear. Lep-Caspase-2 is absent from the silkworm genome and appears to be noctuid-specific, and to have arisen from a tandem duplication of the Caspase-1 gene. In the tobacco hawkmoth, 3 distinct transcripts encoding putative Caspase-4 were identified, suggesting at least 2 duplication events in this species.</p> <p>Conclusions</p> <p>The basic repertoire of five major types of caspases shared among Lepidoptera seems to be smaller than for most other groups studied to date, but gene duplication still plays a role in lineage-specific increases in diversity, just as in Diptera and mammals.</p

TNFα Cooperates with IFN-γ to Repress Bcl-xL Expression to Sensitize Metastatic Colon Carcinoma Cells to TRAIL-mediated Apoptosis

BACKGROUND: TNF-related apoptosis-inducing ligand (TRAIL) is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: The efficacy and underlying molecular mechanism of cooperation between TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis were examined. The functional significance of TNFα- and IFN-γ-producing T lymphocyte immunotherapy in combination with TRAIL therapy in suppression of colon carcinoma metastasis was determined in an experimental metastasis mouse model. We observed that TNFα or IFN-γ alone exhibits minimal sensitization effects, but effectively sensitized metastatic colon carcinoma cells to TRAIL-induced apoptosis when used in combination. TNFα and IFN-γ cooperate to repress Bcl-xL expression, whereas TNFα represses Survivin expression in the metastatic colon carcinoma cells. Silencing Bcl-xL expression significantly increased the metastatic colon carcinoma cell sensitivity to TRAIL-induced apoptosis. Conversely, overexpression of Bcl-xL significantly decreased the tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, TNFα and IFN-γ also synergistically enhanced TRAIL-induced caspase-8 activation. TNFα and IFN-γ was up-regulated in activated primary and tumor-specific T cells. TRAIL was expressed in tumor-infiltrating immune cells in vivo, and in tumor-specific cytotoxic T lymphocytes (CTL) ex vivo. Consequently, TRAIL therapy in combination with TNFα/IFN-γ-producing CTL adoptive transfer immunotherapy effectively suppressed colon carcinoma metastasis in vivo. CONCLUSIONS/SIGNIFICANCE: TNFα and IFN-γ cooperate to overcome TRAIL resistance at least partially through enhancing caspase 8 activation and repressing Bcl-xL expression. Combined CTL immunotherapy and TRAIL therapy hold great promise for further development for the treatment of metastatic colorectal cancer

A physical map of Brassica oleracea shows complexity of chromosomal changes following recursive paleopolyploidizations

<p>Abstract</p> <p>Background</p> <p>Evolution of the Brassica species has been recursively affected by polyploidy events, and comparison to their relative, <it>Arabidopsis thaliana</it>, provides means to explore their genomic complexity.</p> <p>Results</p> <p>A genome-wide physical map of a rapid-cycling strain of <it>B. oleracea </it>was constructed by integrating high-information-content fingerprinting (HICF) of Bacterial Artificial Chromosome (BAC) clones with hybridization to sequence-tagged probes. Using 2907 contigs of two or more BACs, we performed several lines of comparative genomic analysis. Interspecific DNA synteny is much better preserved in euchromatin than heterochromatin, showing the qualitative difference in evolution of these respective genomic domains. About 67% of contigs can be aligned to the Arabidopsis genome, with 96.5% corresponding to euchromatic regions, and 3.5% (shown to contain repetitive sequences) to pericentromeric regions. Overgo probe hybridization data showed that contigs aligned to Arabidopsis euchromatin contain ~80% of low-copy-number genes, while genes with high copy number are much more frequently associated with pericentromeric regions. We identified 39 interchromosomal breakpoints during the diversification of <it>B. oleracea </it>and <it>Arabidopsis thaliana</it>, a relatively high level of genomic change since their divergence. Comparison of the <it>B. oleracea </it>physical map with Arabidopsis and other available eudicot genomes showed appreciable 'shadowing' produced by more ancient polyploidies, resulting in a web of relatedness among contigs which increased genomic complexity.</p> <p>Conclusions</p> <p>A high-resolution genetically-anchored physical map sheds light on Brassica genome organization and advances positional cloning of specific genes, and may help to validate genome sequence assembly and alignment to chromosomes.</p> <p>All the physical mapping data is freely shared at a WebFPC site (<url>http://lulu.pgml.uga.edu/fpc/WebAGCoL/brassica/WebFPC/</url>; Temporarily password-protected: account: pgml; password: 123qwe123.</p