Genome-wide promoter methylation analysis in neuroblastoma identifies prognostic methylation biomarkers

ChIP-seq is a powerful method for obtaining genome-wide maps of protein-DNA interactions and epigenetic modifications. CHANCE (CHip-seq ANalytics and Confidence Estimation) is a standalone package for ChIP-seq quality control and protocol optimization. Our user-friendly graphical software quickly estimates the strength and quality of immunoprecipitations, identifies biases, compares the user's data with ENCODE's large collection of published datasets, performs multi-sample normalization, checks against quantitative PCR-validated control regions, and produces informative graphical reports. CHANCE is available at https://github.com/songlab/chance.     

A simple method to vary soil heterogeneity in three dimensions in experimental mesocosms

Soil heterogeneity affects terrestrial plant communities both directly and indirectly. In nature, the exploration of the role of heterogeneity is made difficult because any co-varying factors (nutrients, soil depth, etc.) render it problematic to clearly link cause and effect. Attributing changes specifically to heterogeneity is facilitated if heterogeneity is varied in a controlled manner and other possible confounding factors are kept constant. The experiments conducted in such a way have up till now only considered heterogeneity in two dimensions, horizontally or vertically. In this methodological study, we present a novel technique that enables researchers to vary both qualitative and configurational heterogeneity in three dimensions by building up the soil cell by cell in experimental mesocosms. We illustrate the technique with an experiment where we test the effect of cell size (i.e. configurational heterogeneity) on the performance of grassland species that vary in nutrient preference (high N and low N species). Cell size did not affect aboveground biomass but modified species richness, both at the mesocosm and the patch scale, with most species being found when cells were small yet distinct (cell size 12 cm). High N species had significantly greater aboveground biomass and species richness than low N species, both on nutrient rich and nutrient poor cells. Remarkably, those differences disappeared when plants grew on the mesocosms with cell size close to zero. By allowing greater complexity in the design of experimental mesocosms, the 3-D approach can improve understanding of the interplay between soil heterogeneity and plant and ecosystem functioning.     

The value of the ECG for decision-making at first medical contact in the patient with acute chest pain

Background/Objectives. Rapid risk stratification of the patient with acute chest pain is essential to select the best management. We investigated the value of the ECG at first medical contact to determine size of the ischaemic myocardial area and thereby severity of risk. Methods. In 386 patients with acute chest pain, ECG findings were correlated with the coronary angiogram. Using ST-segment deviation patterns the location of the coronary culprit lesion was predicted and thereby size of the area at risk. Four groups of patients were present. Those with a narrow QRS and a total 12-lead ST-segment deviation score of ≥5 mm (group 1) or ≤4 mm (group 2); a QRS width of ≥120 ms (group 3), and patients with previous coronary bypass grafting (CABG) or percutaneous coronary intervention (PCI) (group 4). Results. Correct coronary culprit lesion localisation was possible in 84% of the 185 patients in group 1, 40% of the total cohort. Accurate prediction was not possible in most patients in groups 2, 3 and 4, in spite of extensive coronary artery disease in group 3 and 4. Conclusions. Using the 12-lead ECG the size of the myocardial area at risk can be accurately predicted when the total ST-segment deviation score is ≥5 mm, allowing identification of those in need of a PCI. In most patients with bundle branch block, previous CABG or PCI, the ECG can not localise the culprit lesion. This approach simplifies and accelerates decision-making at first medical contact. (Neth Heart J 2010;18:301-6.)     

Arrhythmogenic right ventricular dysplasia/cardiomyopathy: new avenues for diagnosis and treatment

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a heart muscle disorder of unknown course that is characterised pathologically by fatty or fibrofatty replacement of the right ventricular myocardium and electrical instability. Clinical manifestations include structural and functional malformations of the right ventricle, electrocardiographic abnormalities, and presentation of ventricular tachycardias with left bundle branch pattern or sudden death. The disease is often familial with an autosomal inheritance. In addition to right ventricular dilatation, right ventricular aneurysms are typical deformities of ARVD/C and they are distributed in the so-called ''triangle of dysplasia'', i.e. the right ventricular outflow tract, apex and infundibulum. Ventricular aneurysms at these sites can be considered highly suggestive for ARVD/C. Another typical hallmark of ARVD/C is fatty or fibrofatty infiltration of the right ventricular free wall with potential extension to the left ventricle. These functional and morphological characteristics are relevant to clinical imaging investigations such as contrast angiography, echocardiography, radionuclide angiography, ultrafast-computed tomography and magnetic resonance (MR) imaging. Among these techniques, MR imaging allows the most comprehensive assessment of the heart, in particular because it provides functional and flow-dynamic information in addition to anatomic images. Furthermore, MR imaging offers the specific advantage of visualising adipose infiltration as a bright signal of the right ventricular myocardium.Non-pharmacological treatment by radio-frequency ablation and implantable defibrillators will play an increasing role in the treatment of patients with ARVD/C, especially in case of drug ineffectivity. Despite new diagnostic and therapeutic approaches in ARVD/C, there remain many unanswered issues since the current guidelines present criteria that are highly specific but lack sensitivity. Therefore, optimal assessment of diagnostic criteria would require a prospective evaluation from a large population obtained by an international registry.     

Proceedings: The effects of hypothalamic and reflexogenic hypertension on renal and femoral circulation.

In anaesthetized dogs, electrical stimulation of the median posterior hypothalamus provoked hypertension accompanied by a decrease of renal blood flow and an increase of femoral blood flow. Similar hypothalamic reactions occurred after bilateral cervical vagotomy or after atropine, 2 mg/kg i.v. During reflexogenic hypertension induced by bilateral carotid occlusion in bivagotomized dogs, the renal and femoral blood flows were not significantly modified. The decrease of the renal blood flow and the increase of the femoral blood flow, during hypothalamic stimulation were greatly reduced or reversed after R 28935 equals erythro-1-(1--e12-(1,4-benzodioxan-2-yl)-2-OH-Et]-4-piperidyl)-2-benzimidaxolinone, 80 mug/kg i.v., but not after clonidine, 5 mug/kg i.v.     

Therapeutic Efficacy Assessment of CK6, a Monoclonal KIT Antibody,in a Panel of Gastrointestinal Stromal Tumor Xenograft Models

We evaluated the efficacy of CK6, a KIT monoclonal antibody, in a panel of human gastrointestinal stromal tumor (GIST) xenograft models. Nude mice were bilaterally transplanted with human GIST xenografts (four patient derived and two cell line derived), treated for 3 weeks, and grouped as follows: control (untreated); CK6 (40 mg/kg, 3 × weekly); imatinib (50 mg/kg, twice daily); sunitinib (40 mg/kg, once daily); imatinib + CK6; sunitinib + CK6 (same doses and schedules as in the single-agent treatments). Tumor volume assessment, Western blot analysis, and histopathology were used for evaluation of efficacy. Statistical analysis was performed using Mann-Whitney U (MWU) and Wilcoxon matched-pairs tests. CK6 as a single agent only reduced tumor growth rate in the UZLX-GIST3 model (P = .053, MWU compared to control), while in none of the other GIST models an effect on tumor growth rate was observed. CK6 did not result in significant anti-proliferative or pro-apoptotic effects in any of the GIST models, and moreover, CK6 did not induce a remarkable inhibition of KIT activation. Furthermore, no synergistic effect of combining CK6 with tyrosine kinase inhibitors (TKIs) was observed. Conversely, in certain GIST xenografts, anti-tumor effects seemed to be inferior under combination treatment compared to single-agent TKI treatment. In the GIST xenografts tested, the anti-tumor efficacy of CK6 was limited. No synergy was observed on combination of CK6 with TKIs in these GIST models. Our findings highlight the importance of using relevant in vivo human tumor xenograft models in the preclinical assessment of drug combination strategies.