Object
Although most meningiomas are benign, about 20% are atypical (Grade II or III) and have increased mortality and morbidity. Identifying tumors with greater malignant potential can have ...significant clinical value. This validated genome-wide methylation study comparing Grade I with Grade II and III meningiomas aims to discover genes that are aberrantly methylated in atypical meningiomas.
Methods
Patients with newly diagnosed meningioma were identified as part of the Ohio Brain Tumor Study. The Infinium HumanMethylation27 BeadChip (Illumina, Inc.) was used to interrogate 27,578 CpG sites in 14,000 genes per sample for a discovery set of 33 samples (3 atypical). To verify the results, the Infinium HumanMethylation450 BeadChip (Illumina, Inc.) was used to interrogate 450,000 cytosines at CpG loci throughout the genome for a verification set containing 7 replicates (3 atypical), as well as 12 independent samples (6 atypical). A nonparametric Wilcoxon exact test was used to test for difference in methylation between benign and atypical meningiomas in both sets. Heat maps were generated for each set. Methylation results were validated for the 2 probes with the largest difference in methylation intensity by performing Western blot analysis on a set of 20 (10 atypical) samples, including 11 replicates.
Results
The discovery array identified 95 probes with differential methylation between benign and atypical meningiomas, creating 2 distinguishable groups corresponding to tumor grade when visually examined on a heat map. The validation array evaluated 87 different probes and showed that 9 probes were differentially methylated. On heat map examination the results of this array also suggested the existence of 2 major groups that corresponded to histological grade. IGF2BP1 and PDCD1, 2 proteins that can increase the malignant potential of tumors, were the 2 probes with the largest difference in intensity, and for both of these the atypical meningiomas had a decreased median production of protein, though this was not statistically significant (p = 0.970 for IGF2BP1 and p = 1 for PDCD1).
Conclusions
A genome-wide methylation analysis of benign and atypical meningiomas identified 9 genes that were reliably differentially methylated, with the strongest difference in IGF2BP1 and PDCD1. The mechanism why increased methylation of these sites is associated with an aggressive phenotype is not evident. Future research may investigate this mechanism, as well as the utility of IGF2BP1 as a marker for pathogenicity in otherwise benign-appearing meningiomas.
Gain-of-function NOTCH1 mutations are oncogenic drivers in a high fraction of T-cell lymphoblastic leukemia/lymphoma (T-LL). These mutations variously cause increased production or stabilization of ...the free intracellular domain of NOTCH1, which regulates gene expression by forming a transcription complex with the DNA-binding factor RBPJ and coactivators of the MAML family. Using expression profiling and ChIP-seq, we have shown that NOTCH1/RBPJ complexes activate most target genes by binding to super-enhancers, large regulatory elements that switch on transcription through long-range interactions with gene promoters. MYC is a critical target of Notch in normal and malignant pre-T cells, but how Notch regulates MYC is unknown. To understand which regulatory element(s) regulate MYC expression, we used chromatin conformation capture (3C) assays to test the interaction between putative enhancer(s) and the MYC promoter in T-LL cell lines, and reporter gene assays to confirm enhancer function of candidate sites. We identified a distal site located >1 Mb 3’ of human and murine MYC termed the Notch-dependent MYC enhancer (NDME) that binds Notch transcription complexes and physically interacts with the MYC proximal promoter. An ~1 kb DNA fragment containing this site activates a luciferase reporter gene in a Notch-dependent fashion in T-LL cells but not in heterologous cell types. The Notch binding site lies within a large enhancer region (>600 kb in breadth) containing multiple discrete H3K27ac peaks. Remarkably, acute changes in Notch activation produce rapid changes in H3K27 acetylation across the entire enhancer region and the MYC promoter that correlate with NOTCH1/RBPJ complex binding and MYC expression. T-LL cells selected for resistance to gamma-secretase inhibitors (GSIs) exhibit epigenetic silencing of the NDME and loss of NDME looping interactions with the MYC promoter, yet maintain MYC expression. 3C analysis of GSI resistant cells shows preferential interaction between the MYC promoter and a more 3’ enhancer element recently described as a BRD4-dependent regulator of MYC expression in acute myeloid leukemia cells. In line with this observation, BRD4 antagonists are potent inhibitors of MYC expression in GSI resistant T-LL cells but not GSI-sensitive cells. We also studied a case of Notch-mutated early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL). ChIP-Seq analysis of the leukemic blasts revealed an “AML-like” MYC enhancer chromatin state, and as predicted from our analysis of cell lines, the blasts rapidly down-regulated MYC in response to BRD4 inhibitor but not in response to GSI. These findings suggest that specific MYC chromatin states predict responsiveness to Notch and BRD4 inhibitors, and provide a rationale for use of Notch and BRD4 inhibitor combinations in Notch-mutated leukemias.
No relevant conflicts of interest to declare.
Abstract
Aim
Ecological niche models are increasingly being used to aid in predicting the effects of future climate change on species distributions. Complex models that show high predictive ...performance on current distribution data may do a poor job of predicting new data due to overfitting. In addition, model performance is often evaluated using techniques that are sensitive to spatial sampling bias. Here, we explore the effects of model complexity and spatial sampling bias on niche models for 90 vertebrate taxa of conservation concern.
Location
California,
USA
.
Methods
We used Akaike information criterion (
AIC
c) to select variables and tune
M
axent's built‐in regularization parameter (β) to constrain model complexity. In addition, we incorporated several estimates of spatial sampling bias based on interpolations of target group data. Ensemble forecasts were developed for future conditions from two emission scenarios and three climate change models for the year 2050.
Results
Reducing the number of predictors and tuning β resulted in a reduction in the number of parameters in models built with sample sizes greater than approximately 10 occurrence points. Reducing the number of predictors had a substantially higher impact on the relative prioritization of different grid cells than did increasing regularization. There was little difference in prioritization of habitat when comparing models built using different spatial sampling bias estimates. Over half of the taxa were predicted to experience >80% reductions in environmental suitability in currently occupied cells, and this pattern was consistent across taxonomic groups.
Main Conclusions
Our results demonstrate that reducing the number of correlated predictor variables tends to decrease the breadth of models, while tuning regularization using
AIC
c tends to increase it. These two strategies may provide a reasonable bracketing strategy for assessing climate change impacts.
Background: Antimicrobial overuse contributes to antimicrobial resistance. In the ambulatory setting, where more than 90% of antibiotics are dispensed, there are no Canadian benchmarks for ...appropriate use. This study aims to define the expected appropriate outpatient antibiotic prescribing rates for three age groups (<2, 2–18, >18 years) using a modified Delphi method. Methods: We developed an online questionnaire to solicit from a multidisciplinary panel (community–academic family physicians, adult–paediatric infectious disease physicians, and antimicrobial stewardship pharmacists) what percentage of 23 common clinical conditions would appropriately be treated with systemic antibiotics followed with in-person meetings to achieve 100% consensus. Results: The panelists reached consensus for one condition online and 22 conditions face-to-face, which took an average of 2.6 rounds of discussion per condition (range, min–max 1–5). The consensus for appropriate systemic antibiotic prescribing rates were, for pneumonia, pyelonephritis, non-purulent skin and soft tissue infections (SSTI), other bacterial infections, and reproductive tract infections, 100%; urinary tract infections, 95%–100%; prostatitis, 95%; epididymo-orchitis, 85%–88%; chronic obstructive pulmonary disease, 50%; purulent SSTI, 35%–50%; otitis media, 30%–40%; pharyngitis, 18%–40%; acute sinusitis, 18%–20%; chronic sinusitis, 14%; bronchitis, 5%–8%; gastroenteritis, 4%–5%; dental infections, 4%; eye infections, 1%; otitis externa, 0%–1%; and asthma, common cold, influenza, and other non-bacterial infections (0%). (Note that some differed by age group.) Conclusions: This study resulted in expert consensus for defined levels of appropriate antibiotic prescribing across a broad set of outpatient conditions. These results can be applied to community antimicrobial stewardship initiatives to investigate the level of inappropriate use and set targets to optimize antibiotic use.
The administration of bone marrow-derived stem cells may provide a new treatment option for patients with heart failure. Transcatheter cell injection may require multi-imaging modalities to optimize ...delivery. This study sought to evaluate whether endomyocardial injection of mesenchymal precursor cells (MPCs) could be guided by real-time 3D echocardiography (RT3DE) in treating chronic, postinfarction (MI) left ventricular (LV) dysfunction in sheep. Four weeks after induction of an anterior wall myocardial infarction in 39 sheep, allogeneic MPCs in doses of either 25 × 106 (n = 10), 75 × 106 (n = 9), or 225 × 106 (n = 10) cells or nonconditioned control media (n = 10) were administered intramyocardially into infarct and border zone areas using a catheter designed for combined fluoroscopic and RT3DE-guided injections. LV function was assessed before and after injection. Infarct dimension and vascular density were evaluated histologically. RT3DE-guided injection procedures were safe. Compared to controls, the highest dose MPC treatment led to increments in ejection fraction (3±3% in 225M MPCs vs. −5±4% in the control group, p < 0.01) and wall thickening in both infarct (4±4% in 225M MPCs vs. −3±6% in the control group, p = 0.02) and border zones (4±6% in 225M MPCs vs. −8±9% in the control group, p = 0.01). Histology analysis demonstrated significantly higher arteriole density in the infarct and border zones in the highest dose MPC-treated animals compared to the lower dose or control groups. Endomyocardial implantation of MPCs under RT3DE guidance was safe and without observed logistical obstacles. Significant increases in LV performance (ejection fraction and wall thickening) and neovascularization resulted from this technique, and so this technique has important implications for treating patients with postischemic LV dysfunction.
This study compared the extracellular matrix (ECM) and cellular responses after stenting to balloon angioplasty (BA) and to determine the late effects of matrix metalloproteinase (MMP) inhibition on ...arterial repair after stenting.
Although stenting is the predominant form of coronary intervention, there is limited understanding of the early and late arterial response.
In a double-injury rabbit model, adjacent iliac arteries in 87 animals received BA (3.0 mm diameter) or stenting (3.0 mm NIR). Rabbits were treated for 1 week postprocedure with either GM6001 (100 mg/kg per day), an MMP inhibitor or placebo and sacrificed at 1 week or at 10 weeks’ postprocedure. Arteries were analyzed for morphometry, collagen content, gelatinase activity, cell proliferation and DNA content.
Stented arteries had significant increases in collagen content (2-fold) at 10 weeks compared to BA-treated arteries. At one week, overall gelatinase activity was increased >2-fold in stented arteries, with both 72 kD and 92 kD gelatinase activity. Stented arteries also had increases in both intimal DNA content (1.5-fold) and absolute cell proliferation (4-fold). Compared to placebo, GM6001 significantly inhibited intimal hyperplasia and intimal collagen content, and it increased lumen area in stented arteries without effects on proliferation rates.
Stenting causes a more vigorous ECM and MMP response than BA, which involves all layers of the vessel wall. Inhibition by MMP blocks in-stent intimal hyperplasia and offers a novel approach to prevent in-stent restenosis.
Abstract Objectives The Monitor Practice Program demonstrated that regular monitoring and noninvasive management of dental caries is effective in reducing the incremental DMFT (decayed, missing, and ...filled teeth) in patients, within the construct of a 3-year randomized clinical trial. This analysis evaluates the long-term cost-effectiveness of the preventive approach underpinning the Caries Management System, used in the general practice setting and modeled to the Australian population. Methods An individual patient-simulation Markov model was developed to compare the long-term costs and outcomes of the Caries Management System versus standard dental care in a hypothetical sample representative of the Australian population. Eight Markov submodels were developed, representing eight molar teeth (excluding wisdom teeth), each consisting of 11 health states simulating the incidence and progression of dental caries, and future interventions such as fillings and crowns. Transition probabilities and costs assigned to health states were based on claims data from the second largest private health insurer in Australia. The economic evaluation was performed from the Australian private dental practitioner perspective. The incremental cost per DMFT avoided was calculated at three time points: 2 years, 3 years, and lifetime. Univariate sensitivity analysis was conducted to test the robustness of the results. Results The incremental cost per DMFT avoided at 2 years, 3 years, and lifetime was estimated to be $1287.07, $1148.91, and $1795.06, respectively. Conclusion The analysis suggests that the Caries Management System is most cost-effective in patients with a high risk of dental caries.
The mu‐opioid system has a key role in hedonic and motivational processes critical to substance addiction. However, existing mu‐opioid antagonists have had limited success as anti‐addiction ...treatments. GSK1521498 is a selective and potent mu‐opioid antagonist being developed for the treatment of overeating and substance addictions. In this study, 28 healthy participants were administered single doses of GSK1521498 20 mg, ethanol 0.5 g/kg body weight, or both in combination, in a double blind placebo controlled four‐way crossover design. The primary objective was to determine the risk of significant adverse pharmacodynamic and pharmacokinetic (PK) interactions. The effects of GSK1521498 on hedonic and consummatory responses to alcohol and the attentional processing of alcohol‐related stimuli, and their modulation by the OPRM1 A118G polymorphism were also explored. GSK1521498 20 mg was well tolerated alone and in combination with ethanol. There were mild transient effects of GSK1521498 on alertness and mood that were greater when it was combined with ethanol. These effects were not of clinical significance. There were no effects of GSK1521498 on reaction time, hedonic or consummatory responses. These findings provide encouraging safety and PK data to support continued development of GSK1521498 for the treatment of alcohol addiction.
Data Monitoring Committees (DMCs) play a crucial role in the conducting of clinical trials to ensure the safety of study participants and to maintain a trial's scientific integrity. Generally ...accepted standards exist for DMC composition and operational conduct. However, some relevant issues are not specifically addressed in current guidance documents, resulting in uncertainties regarding optimal approaches for communication between the DMC, steering committee, and sponsors, release of information, and liability protection for DMC members. The Heart Failure Association (HFA) of the European Society of Cardiology (ESC), in collaboration with the Clinical Trials Unit of the European Heart Agency (EHA) of the ESC convened a meeting of international experts in DMCs for cardiovascular and cardiometabolic clinical trials to identify specific issues and develop steps to resolve challenges faced by DMCs.The main recommendations from the meeting relate to methodological consistency, independence, managing conflicts of interest, liability protection, and training of future DMC members. This paper summarizes the key outcomes from this expert meeting, and describes the core set of activities that might be further developed and ultimately implemented by the ESC, HFA, and other interested ESC constituent bodies. The HFA will continue to work with stakeholders in cardiovascular and cardiometabolic clinical research to promote these goals.
Regional atrophy of the corpus callosum in dementia Hallam, Bradley J; Brown, Warren S; Ross, Chris ...
Journal of the International Neuropsychological Society,
05/2008, Letnik:
14, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The regional distribution of degeneration of the corpus callosum (CC) in dementia is not yet clear. This study compared regional CC size in participants (n = 179) from the Cache County Memory and ...Aging Study. Participants represented a range of cognitive function: Alzheimer's disease (AD), vascular dementia (VaD), mild ambiguous (MA-cognitive problems, but not severe enough for diagnosis of dementia), and healthy older adults. CC outlines obtained from midsagittal magnetic resonance images were divided into 99 equally spaced widths. Factor analysis of these callosal widths identified 10 callosal regions. Multivariate analysis of variance revealed significant group differences for anterior and posterior callosal regions. Post-hoc pairwise comparisons of CC regions in patient groups as compared to the control group (controlling for age) revealed trends toward smaller anterior and posterior regions, but not all were statistically significant. As compared to controls, significantly smaller anterior and posterior CC regions were found in the AD group; significantly smaller anterior CC regions in the VaD group; but no significant CC regional differences in the MA group. Findings suggest that dementia-related CC atrophy occurs primarily in the anterior and posterior portions.
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