Epigenetics in T-cell acute lymphoblastic leukemia

Normal T-cell development is a strictly regulated process in which hematopoietic progenitor cells migrate from the bone marrow to the thymus and differentiate from early T-cell progenitors toward mature and functional T cells. During this maturation process, cooperation between a variety of oncogenes and tumor suppressors can drive immature thymocytes into uncontrolled clonal expansion and cause T-cell acute lymphoblastic leukemia (T-ALL). Despite improved insights in T-ALL disease biology and comprehensive characterization of its genetic landscape, clinical care remained largely similar over the past decades and still consists of high-dose multi-agent chemotherapy potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable side effects, clinical outcome is still extremely poor in a significant subset of T-ALL patients as a result of therapy resistance or hematological relapses. Recent genetic studies have identified recurrent somatic alterations in genes involved in DNA methylation and post-translational histone modifications in T-ALL, suggesting that epigenetic homeostasis is critically required in restraining tumor development in the T-cell lineage. In this review, we provide an overview of the epigenetic regulators that could be implicated in T-ALL disease biology and speculate how the epigenetic landscape of T-ALL could trigger the development of epigenetic-based therapies to further improve the treatment of human T-ALL.     

Clinical investigation of bacterial species and endotoxin in endodontic infection and evaluation of root canal content activity against macrophages by cytokine production

Introduction

This study investigated the presence of different Gram-negative bacterial species and the levels of endotoxins found in primary endodontic infection (PEI), determining their stimulation ability against macrophages through the levels of interleukin (IL)-1, IL-6, IL-10, and tumor necrosis factor alpha (TNF-α), and evaluated their relationship with clinical and radiographic findings.

Material and methods

Samples were taken from 21 root canals with primary endodontic infection with apical periodontitis (PEIAP). Molecular techniques were used for bacterial detection. Limulus amebocyte lysate assay was used to measure endotoxins. Pro-inflammatory cytokines were measured by ELISA assay.

Results

All samples were positive for bacterial DNA (21/21). Prevotella nigrescens (57.2 %) was the most frequent species. Higher levels of endotoxins were found in teeth with pain on palpation and exudation (all p?<?0.05). Positive correlations were found between endotoxins and the levels of TNF-α and IL-1β, whereas a negative correlation was found between endotoxin and the amount of IL-10 (p?<?0.05). Endotoxin levels were found to be a risk factor for exudation and increased the number of Gram-negative bacterial species for the presence of a larger area of bone destruction (all p?<?0.05).

Conclusion

A wide variety of Gram-negative bacterial species are involved in primary endodontic infection, with participation of different Treponema species. Thus, the levels of endotoxins and the number of Gram-negative bacteria species present in root canals were considered risk factors for the severity of endodontic infection.

Clinical relevance

The present study revealed that Gram-negative bacterial species and endotoxins play an important role in the development of signs/symptoms and the severity of bone destruction, this knowledge is essential for the establishment of an effective therapy.

     

A percutaneous coronary intervention-thrombolytic predictive instrument to assist choosing between immediate thrombolytic therapy versus delayed primary percutaneous coronary intervention for acute myocardial infarction

Based on the thrombolytic predictive instrument (TPI), we sought to create electrocardiographically based, real-time decision support to immediate identification of patients with ST-segment elevation myocardial infarction (STEMI) likely to benefit from primary percutaneous coronary intervention (PCI) compared with thrombolysis. Using data from the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) Trial, we tested a mathematical model predicting mortality in patients with STEMI if treated with PCI and if treated with thrombolytic therapy. We adapted the model for incorporation into computerized electrocardiograms as a PCI-TPI. For patients with STEMI in the C-PORT Trial, the model yielded unbiased mortality predictions: for those receiving thrombolysis, it predicted 6.3% mortality and actual mortality was 6.0% (95% confidence interval 3.0 to 10.6); for those receiving PCI, it predicted 4.5% mortality and actual mortality was 3.9% (95% confidence interval 1.4 to 8.2). Excellent discrimination was reflected by its receiver operating characteristic curve area of 0.86. According to the model, and validated by actual trial outcomes, 1/3 of subjects accounted for all the mortality benefit from PCI. In conclusion, for STEMI, the PCI-TPI accurately predicts mortality for treatment with PCI and with thrombolytic therapy. Incorporated into electrocardiogram, it may assist targeting PCI to those who benefit most and identifying patients before hospitalization for whom a receiving hospital should prepare for PCI.     

A geospatial analysis of emergency transport and inter-hospital transfer in ST-segment elevation myocardial infarction

Primary percutaneous coronary intervention (PCI) yields better outcomes than thrombolytic therapy in the treatment of patients with ST-segment elevation myocardial infarctions (STEMIs). Emergency medical service systems are potentially important partners in efforts to expand the use of PCI. This study was conducted to explore the probable impact on patient mortality and hospital volumes of competing strategies for the emergency transport of patients with STEMIs. Emergency transport was simulated for 2,000 patients with STEMIs from the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) trial in a geospatial model of Dallas County, Texas. Patient mortality estimates were obtained from a recently developed predictive model comparing PCI and thrombolytic therapy. A strategy of transporting patients to the closest hospital and treating with PCI if available and thrombolytic therapy if not yielded a 5.2% 30-day mortality rate (95% confidence interval [CI] 4.2% to 6.3%). A strategy of universal PCI, in which patients were transported only to PCI-capable hospitals, yielded 4.4% (95% CI 3.6% to 5.4%) mortality and an increase in patient volume at 2 full-time PCI hospitals of >1,000%. A strategy of targeted PCI, in which high-benefit patients were transported or transferred to PCI-capable hospitals, yielded 4.5% (95% CI 3.8% to 5.5%) mortality if transfers were decided in the emergency department and 4.2% (95% CI 3.4% to 5.1%) if transport was decided in the emergency vehicle. Targeted PCI strategies increased patient volumes at full-time PCI hospitals by about 700%. In conclusion, the selection of high-benefit patients for transport or transfer to PCI-capable hospitals can reduce mortality while minimizing major shifts in hospital patient volumes.     

Periodontal conditions of teeth presenting pathologic migration

The aim of the present study was to evaluate the periodontal conditions of anterior teeth that presented pathologic migration in patients with chronic periodontitis and to compare periodontal destruction in migrated versus non-migrated teeth. The sample included 32 patients of both sexes (mean age: 46.0 +/- 11.6 years) diagnosed with generalized chronic periodontitis and selected on the basis of the presence of pathologic migration in one or more anterior teeth. This migration was classified according to the following categories: facial flaring, diastema, proximal tilting, rotation or extrusion. The periodontal parameters recorded were clinical attachment loss (CAL) and percentage of radiographic bone loss (BL). Mean CAL of 5.50 +/- 2.20 mm and mean BL of 41.90 +/- 15.40% were found in 115 teeth assessed. The most frequent type of migration was facial flaring (34.80%), followed by diastema (27.00%). Extrusion was hardly observed in the sample (4.30%). However, greater severity of BL and CAL were observed in teeth with this type of migration (59.44% and 8.42 mm, respectively), and in teeth with facial flaring (45.17% of BL and 6.07 mm of CAL). Kruskal-Wallis test indicated that BL presented by teeth with extrusion or facial flaring was greater than that observed in rotated or tilted teeth (p < 0.05), while there was no difference between groups regarding CAL (p = 0.11). It was observed that anterior teeth with pathologic migration presented greater CAL and BL (5.1 mm and 40%) than non-migrated teeth (4.1 and 31%). The study indicated that the most prevalent kind of pathologic migration is facial flaring, which was associated to higher level of bone loss.     

Human Mesenchymal Stem/Stromal Cells Cultured as Spheroids are Self-activated to Produce Prostaglandin E2 that Directs Stimulated Macrophages into an Anti-inflammatory Phenotype

Culturing cells in three dimension (3D) provides an insight into their characteristics in vivo. We previously reported that human mesenchymal stem/stromal cells (hMSCs) cultured as 3D spheroids acquire enhanced anti-inflammatory properties. Here, we explored the effects of hMSC spheroids on macrophages that are critical cells in the regulation of inflammation. Conditioned medium (CM) from hMSC spheroids inhibited lipopolysaccharide-stimulated macrophages from secreting proinflammatory cytokines TNFα, CXCL2, IL6, IL12p40, and IL23. CM also increased the secretion of anti-inflammatory cytokines IL10 and IL1ra by the stimulated macrophages, and augmented expression of CD206, a marker of alternatively activated M2 macrophages. The principal anti-inflammatory activity in CM had a small molecular weight, and microarray data suggested that it was prostaglandin E2 (PGE2). This was confirmed by the observations that PGE2 levels were markedly elevated in hMSC spheroid-CM, and that the anti-inflammatory activity was abolished by an inhibitor of cyclooxygenase-2 (COX-2), a silencing RNA for COX-2, and an antibody to PGE2. The anti-inflammatory effects of the PGE2 on stimulated macrophages were mediated by the EP4 receptor. Spheroids formed by human adult dermal fibroblasts produced low levels of PGE2 and displayed negligible anti-inflammatory effects on stimulated macrophages, suggesting the features as unique to hMSCs. Moreover, production of PGE2 by hMSC spheroids was dependent on the activity of caspases and NFκB activation in the hMSCs. The results indicated that hMSCs in 3D-spheroid cultures are self-activated, in part by intracellular stress responses, to produce PGE2 that can change stimulated macrophages from a primarily proinflammatory M1 phenotype to a more anti-inflammatory M2 phenotype. STEM Cells2012;30:2283-2296.     

The utility of EEG band power analysis in the study of infancy and early childhood

Research employing electroencephalographic (EEG) techniques with infants and young children has flourished in recent years due to increased interest in understanding the neural processes involved in early social and cognitive development. This review focuses on the functional characteristics of the alpha, theta, and gamma frequency bands in the developing EEG. Examples of how analyses of EEG band power have been applied to specific lines of developmental research are also discussed. These examples include recent work on the infant mu rhythm and action processing, frontal alpha asymmetry and approach-withdrawal tendencies, and EEG power measures in the study of early psychosocial adversity.