Oncogenic potential of yin yang 1 mediated through control of imprinted genes

The transcription factor Yin Yang (YY) 1 is one of the most evolutionarily well-conserved DNA binding proteins that is ubiquitously expressed among different tissue types. YY1 functions as a critical regulator for a diverse set of genes, making its role in the cancerous environment elusive. Recent studies have demonstrated that clusters of YY1 binding sites are overrepresented in imprinted gene loci. These clustered binding sites may function as a molecular rheostat with respect to YY1 protein levels. YY1 levels were documented to be altered in various tumor tissues in conjunction with the transcriptional levels of the imprinted genes it regulates. This review highlights the unexplored mechanism through which fluctuations in YY1 protein levels alter the transcriptional status of imprinted genes containing clustered YY1 binding sites, which potentially could affect cancer development and/or progression. © 2011 by Begell House, Inc

Series LLCs: What Happens When One Series Fails? Key Considerations and Issues

Entity choice law is constantly evolving and innovating. The series LLC form is one such example. Although the form provides governance and operational flexibility and efficiencies, the law governing the form is still developing. As such, uncertainties linger, particularly in the context of a financially distressed or insolvent series. This article explores many of the issues that arise when a master LLC or one of its series experiences financial distress and contemplates a bankruptcy filing. It also identifies strategies for parties to potentially mitigate certain of these issues in the planning stage. The article concludes by suggesting parties using the series LLC form consider its overall impact on the business plan and objectives, including potential negative consequences on the rights and remedies of owners and certain creditors and on the cost of capital

BRAINSTORM: A multi-institutional phase 1/2 study of RRx-001 in combination with whole brain radiation therapy for patients with brain metastases

PURPOSE: To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response. METHODS AND MATERIALS: Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m RESULTS: Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01). CONCLUSIONS: The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response

Nurses’ perceptions of the sustainability of a standardised assessment for preventing complications in a ICU: a qualitative study

Background: Quality improvement projects have been widely adopted to prevent complications in the ICU. Objective: This paper describes nurses' perceptions of implementation strategies and the potential sustainability of a practice change intervention to prevent complications in a Malaysian ICU. Design: A participatory action research using five focus group discussions were undertaken with 19 nurses in a single ICU in regional Malaysia. Focus group transcripts were analysed using thematic analysis. Results: The main themes derived from the interviews were: [1] Empowering staff to embrace evidence-based practices; [2] Staff knowledge, attitudes, and beliefs that impact on behaviour; and [3] management support and leadership are influential in staff behaviours (acceptance & perseverance of change process). Discussion: Resistance to change was recognized as a barrier to adopting evidence based recommendations. There is a need to improve nurses' knowledge, attitude and awareness of the importance of assessment for VAP, CRBSI and PIs in the ICU

DNA-binding motif and target genes of the imprinted transcription factor PEG3

The Peg3 gene is expressed only from the paternally inherited allele located on proximal mouse chromosome 7. The PEG3 protein encoded by this imprinted gene is predicted to bind DNA based on its multiple zinc finger motifs and nuclear localization. In the current study, we demonstrated PEG3\u27s DNA-binding ability by characterizing its binding motif and target genes. We successfully identified target regions bound by PEG3 from mouse brain extracts using chromatin immunoprecipitation analysis. PEG3 was demonstrated to bind these candidate regions through the consensus DNA-binding motif AGTnnCnnnTGGCT. In vitro promoter assays established that PEG3 controls the expression of a given gene through this motif. Consistent with these observations, the transcriptional levels of a subset of the target genes are also affected in a mutant mouse model with reduced levels of PEG3 protein. Overall, these results confirm PEG3 as a DNA-binding protein controlling specific target genes that are involved in distinct cellular functions. © 2012

Meal fatty acids have differential effects on postprandial blood pressure and biomarkers of endothelial function but not vascular reactivity in postmenopausal women in the Randomized Controlled Dietary Intervention and VAScular function (DIVAS)-2 Study

Background: Elevated postprandial triacylglycerol concentrations, impaired vascular function and hypertension are important independent cardiovascular disease (CVD) risk factors in women. However, the effects of meal fat composition on postprandial lipemia and vascular function in postmenopausal women are unknown. Objective: This study investigated the impact of sequential meals rich in saturated (SFAs), monounsaturated (MUFAs) or n-6 polyunsaturated fatty acids (PUFAs) on postprandial flow-mediated dilatation (FMD, primary outcome measure), vascular function and associated CVD risk biomarkers (secondary outcomes) in postmenopausal women. Methods: A double-blind, randomized, cross-over, postprandial study was conducted with 32 postmenopausal women (58 ± 1 years, BMI 25.9 ± 0.7 kg/m2). After fasting overnight, participants consumed high-fat meals at breakfast (0 min; 50 g fat, containing 33-36 g SFAs, MUFAs or n-6 PUFAs) and lunch (330 min; 30 g fat, containing 19-20 g SFAs, MUFAs or n-6 PUFAs), on separate occasions. Blood samples were collected before breakfast and regularly after the meals for 480 min, with specific time points selected for measuring vascular function and blood pressure. Results: Postprandial FMD, laser Doppler imaging and digital volume pulse responses were not different after consuming the test fats. The incremental AUC (IAUC) for diastolic blood pressure was lower (-0.5-fold) after the MUFA than SFA-rich meals (P=0.009), with a similar trend for systolic blood pressure (-0.4-fold; P=0.012). This corresponded with a lower IAUC (-6.4-fold) for the plasma nitrite response after the SFA than MUFA-rich meals (P=0.010). The soluble intercellular adhesion molecule-1 (sICAM-1) time course profile, AUC and IAUC were lower after the n-6 PUFA than SFA and MUFA-rich meals (P≤0.001). Lipids, glucose and markers of insulin sensitivity did not differ between the test fats. Conclusions: Our study revealed a differential impact of meal fat composition on blood pressure, plasma nitrite and sICAM-1, but no effect on postprandial FMD or lipemia in postmenopausal women

Imprinting control region (ICR) of the Peg3 domain

The imprinting and transcription of the 500 kb genomic region surrounding the mouse Peg3 is predicted to be regulated by the Peg3-differentially methylated region (DMR). In the current study, this prediction was tested using a mutant mouse line lacking this potential imprinting control region (ICR). At the organismal level, paternal and maternal transmission of this knockout (KO) allele caused either reduced or increased growth rates in the mouse, respectively. In terms of the imprinting control, the paternal transmission of the KO allele resulted in bi-allelic expression of the normally maternally expressed Zim2, whereas the maternal transmission switched the transcriptionally dominant allele for Zfp264 (paternal to maternal). However, the allele-specific DNA methylation patterns of the DMRs of Peg3, Zim2 and Zim3 were not affected in the mice that inherited the KO allele either paternally or maternally. In terms of the transcriptional control, the paternal transmission caused a dramatic down-regulation in Peg3 expression, but overall up-regulation in the other nearby imprinted genes. Taken together, deletion of the Peg3-DMR caused global changes in the imprinting and transcription of the Peg3 domain, confirming that the Peg3-DMR is an ICR for this imprinted domain. © The Author 2012. Published by Oxford University Press. All rights reserved