SUV420-mediated heterochromatin changes in pediatric brain cancers

Silencing mechanisms play a role in genomic stability by maintaining condensed, non-active regions of the genome. SUV420 enzymes contain a SET domain conferring methyltransferase activity toward histones. The Histone H4 lysine 20 trimethylation (H4K20me3) mark maintained by SUV420H2 is associated with heterochromatin formation and gene silencing, whereas the dimethylated mark (H4K20me2) is associated with DNA repair. In studies of epigenetic factors in large patient cohorts with ependymoma, it was found that SUV420H2 expression was lost or diminished in patients with reciprocal increases in prognostic markers such as hTERT. To better understand the normal function of Suv4-20H1/H2 enzyme in neural progenitors, and pathological changes in cancers, a variety of differentiation paradigms were used. The NT2D1 neurally restricted cell line, and BGO1V and H9 human embryonic stem cells (ESCs), and differentiated progeny, were used alongside tumors to better understand enzyme targets and functional outcomes (e.g.,lineage, differentiation, regional chromatin modifications). Lineage stages were verified with stage-specific markers by immunofluorescence and qPCR. Suv4-20 H1 and H2 were present in ESCs and neural progenitors and decreased thereafter. RNAi knockdown of SUV420 enzymes led to decreased H4K20 methylation in cancer cells. DNA methylation microarrays and ChIP-PCR suggest 1) that SUV420 is not regulated by DNA methylation in ependymomas; 2) that active chromatin marks such as H3K4 dimethylation are enriched near the transcriptional start site in the SUV420H2 gene, and 3) that hTERT is hyper-methylated at specific CpG islands and histones in a tumor sub-group-specific manner. This data supports the hypothesis that Suv4-20H2 is highly active in progenitor cells and functionally lost in some brain cancers. These studies begin to elucidate coincident mechanisms of gene silencing active in neural progenitors that may be altered in a subset of pediatric brain cancers

Characteristics of multi-institutional health sciences education research: a systematic review

Objectives: Multi-institutional research increases the generalizability of research findings. However, little is known about characteristics of collaborations across institutions in health sciences education research. Using a systematic review process, the authors describe characteristics of published, peer-reviewed multi-institutional health sciences education research to inform educators who are considering such projects. Methods: Two medical librarians searched MEDLINE, the Education Resources Information Center (ERIC), EMBASE, and CINAHL databases for English-language studies published between 2004 and 2013 using keyword terms related to multi-institutional systems and health sciences education. Teams of two authors reviewed each study and resolved coding discrepancies through consensus. Collected data points included funding, research network involvement, author characteristics, learner characteristics, and research methods. Data were analyzed using descriptive statistics. Results: One hundred eighteen of 310 articles met inclusion criteria. Sixty-three (53%) studies received external and/or internal financial support (87% listed external funding, 37% listed internal funding). Forty-five funded studies involved graduate medical education programs. Twenty (17%) studies involved a research or education network. Eighty-five (89%) publications listed an author with a master’s degree or doctoral degree. Ninety-two (78%) studies were descriptive, whereas 26 studies (22%) were experimental. The reported study outcomes were changes in student attitude (38%; n=44), knowledge (26%; n=31), or skill assessment (23%; n=27), as well as patient outcomes (9%; n=11). Conclusions: Multi-institutional descriptive studies reporting knowledge or attitude outcomes are highly published. Our findings indicate that funding resources are not essential to successfully undertake multi-institutional projects. Funded studies were more likely to originate from graduate medical or nursing programs

Novel chromatin regulatory activity of ESCO2 in cancer and neural development

ESCO2 has a well characterized role in the stabilization of the cohesin ring through its acetyltransferase activity. Quantitative PCR studies comparing RNA from tissue collected from ependymoma biopsies and tissue from non-tumor brain, show an increased level of ESCO2 transcription in ependymoma. High levels of ESCO2 protein expression in ependymoma tissue samples were confirmed via immunostaining and confocal microscopy. ESCO2 expression ordinarily peaks during mitosis in order to stabilize the cohesin ring, and is reported to increase the rate of replication. However, some ESCO2 expressing cells are not mitotic in these tumors. Because of the detrimental effects of deletion of ESCO2 on neural development and its high expression in ependymoma, a type of tumor that exhibits many characteristics of primitive neural cells, the current study sought to investigate the broader role of ESCO2 in primitive neural cells. Studies carried out in Zebrafish were performed to explore the possibility of an additional role for ESCO2 as a regulator of neural development. QPCR on Zebrafish embryos at developmental timepoints indicated that ESCO2 expression was highest 48 hours post-fertilization, and then declined thereafter. Confocal microscopy on transgenic NeuroD-EGFP embryos at 24-96 hpf confirmed that the proportion of ESCO2 positive brain cells decreases by 96 hpf, that non-mitotic ESCO2 expressing cells decline, and that 48 hpf appear to display a unique pattern of ESCO2 staining associated with the 4th ventricle. Using FACS and subsequent chromatin immunoprecipitation studies, Esco2- bound chromatin was isolated from NT2 neural progenitor cells and NeuroD-EGFP+ transgenic zebrafish, and utilized to identify novel sites of Esco2 regulation. The data obtained suggests an additional layer of neural regulatory activity that may be unrelated to the reported SMC3 acetyltransferase activity of ESCO2, and that could play a role in neural pathologies such as cancer. Esco2 may be a novel therapeutic target for ependymoma

Lymph node ratio is an important and independent prognostic factor for patients with stage III melanoma

INTRODUCTION: The incidence of melanoma is dramatically increasing worldwide. We hypothesized that the ratio of metastatic to examined lymph node ratio (LNR) would be the most important prognostic factor for stage III patients. METHODS: We retrospectively reviewed our institutional database of melanoma patients and identified 168 patients who underwent lymph node dissection (LND) for stage III disease between 1993 and 2007. Patients were divided into three groups based on LNR (≤10%, n = 93; 10-≤25%, n = 45; and \u3e25%, n = 30). Univariate and multivariate analysis was performed using Cox proportional hazards model. RESULTS: The median survival time of the entire group of patients was 34 months. The median number of positive nodes was 2 (range = 1, 55), and the median number of examined nodes was 22 (range = 5-123). Tumor characteristics of the primary melanoma (such as thickness, ulceration, and primary site) were not significant predictors of survival in this analysis. By univariate analysis, LNR was an important prognostic factor. Patients with LNR 10-25% and \u3e25% had decreased survival compared to those patients with LNR ≤10% (HR = hazard ratio = 2.0 and 3.1, respectively; P ≤ 0.005). The number of positive lymph nodes also impacted on survival (P = 0.001). In multivariate analysis, LNR of 10-25% and \u3e25% predicted survival (HR = 2.5 and 4.0, respectively). CONCLUSION: LNR is an important prognostic factor in patients undergoing LND for stage III melanoma. It can be used to stratify patients being considered for adjuvant therapy trials and should be evaluated using a larger prospective database

Need for Aeromedical Evacuation High-Level Containment Transport Guidelines

Circumstances exist that call for the aeromedical evacuation high-level containment transport (AE-HLCT) of patients with highly hazardous communicable diseases. A small number of organizations maintain AE-HLCT capabilities, and little is publicly available regarding the practices. The time is ripe for the development of standards and consensus guidelines involving AE-HLCT

Issues of the Ends of Life: The Segelberg Series

The Segelberg Series explores the intersection of religious faith and public policy. This book contains the lectures focused on The Ends of Life. Dalhousie University’s School of Public Administration managed the series through a lecture committee under the able leadership of the former Dean of Dalhousie’s Law School, Professor Innis Christie, QC

Time course of changes in torque and neuromuscular parameters during a sustained isometric forearm flexion task to fatigue anchored to a constant rating of perceived exertion

Objective: This study examined the time course of changes in torque and electromyographic (EMG) and mechanomyographic (MMG) responses during a sustained isometric task anchored to a constant perception of exertion (RPE). Methods: Twelve college-aged men performed an isometric forearm flexion task to failure anchored to RPE=7 (OMNI-RES scale). The amplitude (AMP) and frequency (MPF) of the EMG and MMG signals from the biceps brachii were recorded. Repeated measures ANOVAs were used to examine differences for the normalized (%MVIC) torque and neuromuscular parameters. Results: The time to task failure (TTF) was 678.0±468.1s. Torque decreased significantly (p\u3c0.001, ηp 2=0.774) across time and all subjects reduced torque to zero. Post-hoc comparisons indicated that the torque values from 20–100% TTF were less than the value at 10% TTF. There were no significant (p\u3e0.05) changes from 10–100% TTF for the EMG and MMG parameters. Conclusion: We hypothesize that RPE was maintained by various mechanisms throughout the task: group III/IV afferent neurons, adequate blood flow, and a combination of reduced contractile efficiency, collective afferent feedback (group III/IV afferents) from muscles involved with forearm flexion, and motivation that resulted in an initial decrease, plateau, and final decline in torque to zero, respectively

Does Intraoperative Radiation Therapy Improve Local Tumor Control in Patients Undergoing Pancreaticoduodenectomy for Pancreatic Adenocarcinoma? A Propensity Score Analysis

Background: Locoregional recurrence (LRR) is an important factor after pancreaticoduodenectomy (PD) for pancreatic cancer. IORT administered to the resection bed may improve local tumor control. Methods: We performed a retrospective analysis of patients who underwent PD at Thomas Jefferson University Hospital (TJUH) between 1995 and 2005 to identify patients who underwent resection with and without intraoperative radiation therapy (IORT). Data collected included age, gender, complications, margin status, stage, survival, and recurrence. Unadjusted analyses of the IORT and non-IORT groups were performed using Fisher’s chi-square method for discrete variables and Wilcoxon Rank Sum test for continuous variables. To account for biases in patient selection for IORT, a propensity score was calculated for each patient and adjusted statistical analyses were performed for survival and recurrence outcomes. Results: Between January 1995 and November 2005, 122 patients underwent PD for perimpullary tumors, including 99 pancreatic cancers. Of this group, 37 patients were treated with IORT, and there was adequate follow-up information for a group of 46 patients who underwent PD without IORT. The IORT group contained a higher percentage of Stage IIB or higher tumors (65%) than in the non-IORT group (39.1%), though differences in stage did not reach significance (p = 0.16). There was a non-significant decrease in the rate of LRR in patients who had IORT (39% non-IORT vs. 23% IORT, p = 0.19). The median survival time of patients who received IORT was 19.2 months, which was not significantly different than patients managed without IORT, 21.0 months (p=0.78). In the propensity analyses, IORT did not significantly influence survival or recurrence after PD. Conclusions: IORT can be safely added to management approaches for resectable pancreatic cancer, with acceptable morbidity and mortality. IORT did not improve loco-regional control and did not alter survival for patients with resected pancreatic cancer. IORT is an optional component of adjuvant chemoradiation for pancreatic cancer. In the future, IORT may be combined with novel therapeutic agents in the setting of a clinical trial in order to attempt to improve outcomes for patients with pancreatic cancer. Annals of Surgical Oncology, Volume 16, Edition 8, August, 2009, pages 2116-22, “Does intraoperative radiation therapy improve local tumor control in patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma? A propensity score analysis”. Authors: Showalter TN, Rao AS, Anné PR, Rosato FE, Rosato EL, Andrel J, Hyslop T, Xu X, Berger AC

The Effects of Anchor Schemes on Performance Fatigability, Neuromuscular Responses and the Perceived Sensations That Contributed to Task Termination

The present study examined the effect of anchor schemes on the time to task failure (TTF), performance fatigability, neuromuscular responses, and the perceived sensations that contributed to task termination following the sustained, isometric forearm flexion tasks. Eight women completed sustained, isometric forearm flexion tasks anchored to RPE = 8 (RPEFT) and the torque (TRQFT) that corresponded to RPE = 8. The subjects performed pre-test and post-test maximal isometric contractions to quantify performance fatigability and changes in electromyographic amplitude (EMG AMP) and neuromuscular efficiency (NME). In addition, the subjects completed a post-test questionnaire (PTQ) to quantify the contributions of perceived sensations to task termination. Repeated measure ANOVAs were used to assess the mean differences for TTF, performance fatigability, and neuromuscular responses. Wilcoxon Signed Rank Tests were used to assess the differences between anchor schemes for the average values from the PTQ item scores. For TTF, the RPEFT was longer than the TRQFT (174.9 ± 85.6 vs. 65.6 ± 68.0 s; p = 0.006). Collapsed across the anchor scheme, there were decreases in torque (23.7 ± 5.5 Nm vs. 19.6 ± 4.9 Nm; p \u3c 0.001) and NME (1.00 ± 0.00 vs. 0.76 ± 0.15; p = 0.003). There were no significant (p \u3e 0.577) changes for EMG AMP. For the PTQ, there were no differences (p \u3e 0.05) between anchor schemes. There were, however, inter-individual differences in the response scores. The current findings indicated that performance fatigability was likely due to peripheral fatigue (based on NME), not central fatigue (based on EMG AMP). Furthermore, the use of a PTQ may serve as a simple tool to assess the contributions of perceived sensations to task termination