Co-regulated expression of HAND2 and DEIN by a bidirectional promoter with asymmetrical activity in neuroblastoma

<p>Abstract</p> <p>Background</p> <p><it>HAND2</it>, a key regulator for the development of the sympathetic nervous system, is located on chromosome 4q33 in a head-to-head orientation with <it>DEIN</it>, a recently identified novel gene with stage specific expression in primary neuroblastoma (NB). Both genes are expressed in primary NB as well as most NB cell lines and are separated by a genomic sequence of 228 bp. The similar expression profile of both genes suggests a common transcriptional regulation mediated by a bidirectional promoter.</p> <p>Results</p> <p>Northern Blot analysis of <it>DEIN </it>and <it>HAND2 </it>in 20 primary NBs indicated concurrent expression levels of the two genes, which was confirmed by microarray analysis of 236 primary NBs (Pearson's correlation coefficient r = 0.65). While <it>DEIN </it>expression in the latter cohort was associated with stage 4S (p = 0.02), <it>HAND2 </it>expression was not associated with tumor stage. In contrast, both <it>HAND2 </it>and <it>DEIN </it>transcript levels were highly associated with age at diagnosis <12 months (p = 0.001). The intergenic region shows substantial homology in different species (89%, 72% and 53% identity between human and mouse, chicken and zebrafish, respectively) and contains many highly conserved putative transcription factor binding sites. Using luciferase reporter gene constructs, asymmetrical bidirectional promoter activity was found in four NB cell lines: In <it>DEIN </it>orientation, an average 3.4 fold increase in activity was observed as compared to the promoterless vector, whereas an average 15.4 fold activation was detected in <it>HAND2 </it>orientation. The presence of two highly conserved putative regulatory elements, one of which was shown to enhance <it>HAND2 </it>expression in branchial arches previously, displayed weak repressor activity for both genes.</p> <p>Conclusion</p> <p><it>HAND2 </it>and <it>DEIN </it>represent a gene pair that is tightly linked by a bidirectional promoter in an evolutionary highly conserved manner. Expression of both genes in NB is co-regulated by asymmetrical activity of this promoter and modulated by the activity of two cis-regulatory elements acting as weak repressors. The concurrent quantitative and tissue specific expression of <it>HAND2 </it>and <it>DEIN </it>suggests a functional link between both genes.</p

Maximum predictive power of the microarray-based models for clinical outcomes is limited by correlation between endpoint and gene expression profile

<p>Abstract</p> <p>Background</p> <p>Microarray data have been used for gene signature selection to predict clinical outcomes. Many studies have attempted to identify factors that affect models' performance with only little success. Fine-tuning of model parameters and optimizing each step of the modeling process often results in over-fitting problems without improving performance.</p> <p>Results</p> <p>We propose a quantitative measurement, termed consistency degree, to detect the correlation between disease endpoint and gene expression profile. Different endpoints were shown to have different consistency degrees to gene expression profiles. The validity of this measurement to estimate the consistency was tested with significance at a p-value less than 2.2e-16 for all of the studied endpoints. According to the consistency degree score, overall survival milestone outcome of multiple myeloma was proposed to extend from 730 days to 1561 days, which is more consistent with gene expression profile.</p> <p>Conclusion</p> <p>For various clinical endpoints, the maximum predictive powers of different microarray-based models are limited by the correlation between endpoint and gene expression profile of disease samples as indicated by the consistency degree score. In addition, previous defined clinical outcomes can also be reassessed and refined more coherent according to related disease gene expression profile. Our findings point to an entirely new direction for assessing the microarray-based predictive models and provide important information to gene signature based clinical applications.</p

Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas

Differences in MYCN/c-MYC target gene expression are associated with distinct neuroblastoma subtypes and clinical outcome

Comparison of Two Respiratory Support Strategies for Stabilization of Very Preterm Infants at Birth: A Matched-Pairs Analysis

Objective: Respiratory support for stabilizing very preterm infants at birth varies between centers. We retrospectively compared two strategies that involved either increasing continuous positive airway pressures (CPAP), or increasing oxygen supplementation.Methods: Matched-pairs of infants (&lt;28 weeks of gestation) were born either at the Leiden University Medical Center [low-pressure: CPAP 5–8 cmH2O and/or positive pressure ventilation (PPV) and fraction of inspired oxygen (FiO2) 0.3–1.0; n = 27], or at the University Hospital of Cologne (high-pressure: CPAP 12–35 cmH2O, no PPV and FiO2 0.3–0.4; n = 27). Respiratory support was initiated non-invasively via facemask at both units. Infants (n = 54) were matched between centers for gestational age and birth weight, to compare physiological and short-term clinical outcomes.Results: In the low-pressure group, 20/27 (74%) infants received 1–2 sustained inflations (20, 25 cm H2O) and 22/27 (81%) received PPV (1:19–3:01 min) using pressures of 25–27 cm H2O. Within 3 min of birth [median (IQR)], mean airway pressures [12 (6–15) vs. 19 (16–23) cmH2O, p &lt; 0.001] and FiO2 [0.30 (0.28–0.31) vs. 0.22 (0.21–0.30), p &lt; 0.001] were different in low- vs. high-pressure groups, respectively. SpO2 and heart rates were similar. After 3 min, higher FiO2 levels [0.62 (0.35–0.98) vs. 0.28 (0.22–0.38), p = 0.005] produced higher SpO2 levels [77 (50–92) vs. 53 (42–69)%, p &lt; 0.001] in the low-pressure group, but SpO2/FiO2 and heart rates were similar. While intubation rates during admission were significantly different (70 vs. 30%, p = 0.013), pneumothorax rates (4 vs. 19%, p = 0.125) and the occurrence of spontaneous intestinal perforations (0 vs. 15%, p = 0.125) were similar between groups.Conclusion: Infants (&lt;28 weeks) can be supported non-invasively at birth with either higher or lower pressures and while higher-pressure support may require less oxygen, it does not eliminate the need for oxygen supplementation. Future studies need to examine the effect of high pressures and pressure titration in the delivery room

Cross-study analysis of gene expression data for intermediate neuroblastoma identifies two biological subtypes

Abstract Background Neuroblastoma patients show heterogeneous clinical courses ranging from life-threatening progression to spontaneous regression. Recently, gene expression profiles of neuroblastoma tumours were associated with clinically different phenotypes. However, such data is still rare for important patient subgroups, such as patients with MYCN non-amplified advanced stage disease. Prediction of the individual course of disease and optimal therapy selection in this cohort is challenging. Additional research effort is needed to describe the patterns of gene expression in this cohort and to identify reliable prognostic markers for this subset of patients. Methods We combined gene expression data from two studies in a meta-analysis in order to investigate differences in gene expression of advanced stage (3 or 4) tumours without MYCN amplification that show contrasting outcomes (alive or dead) at five years after initial diagnosis. In addition, a predictive model for outcome was generated. Gene expression profiles from 66 patients were included from two studies using different microarray platforms. Results In the combined data set, 72 genes were identified as differentially expressed by meta-analysis at a false discovery rate (FDR) of 8.33%. Meta-analysis detected 34 differentially expressed genes that were not found as significant in either single study. Outcome prediction based on data of both studies resulted in a predictive accuracy of 77%. Moreover, the genes that were differentially expressed in subgroups of advanced stage patients without MYCN amplification accurately separated MYCN amplified tumours from low stage tumours without MYCN amplification. Conclusion Our findings support the hypothesis that neuroblastoma consists of two biologically distinct subgroups that differ by characteristic gene expression patterns, which are associated with divergent clinical outcome.</p

Crystallization and preliminary X-ray diffraction data of an LNA 7-mer duplex derived from a ricin aptamer

An all-LNA duplex was designed from the stem region of an RNA aptamer which has been generated against ricin. The LNA duplex was crystallized and preliminary X-ray diffraction analysis revealed diffraction to a resolution of up to 2.8 Å

Cross-study analysis of gene expression data for intermediate neuroblastoma identifies two biological subtypes-0

<p><b>Copyright information:</b></p><p>Taken from "Cross-study analysis of gene expression data for intermediate neuroblastoma identifies two biological subtypes"</p><p>http://www.biomedcentral.com/1471-2407/7/89</p><p>BMC Cancer 2007;7():89-89.</p><p>Published online 25 May 2007</p><p>PMCID:PMC1904223.</p><p></p>lowing clinical variables: Status: black – unfavourable outcome, grey – favourable outcome; Age (at diagnosis): black – older than one year, grey – younger than one year; Stage: black – INSS stage 4, grey – INSS stage 3