Oncogenic role of miR‐155 in anaplastic large cell lymphoma lacking the t(2;5) translocation

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non‐Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin‐anaplastic lymphoma tyrosine kinase (NPM–ALK) fusion protein (ALCL ALK⁺). However, little is known about the molecular features and tumour drivers in ALK‐negative ALCL (ALCL ALK^?), which is characterized by a worse prognosis. We found that ALCL ALK^?, in contrast to ALCL ALK⁺, lymphomas display high miR‐155 expression. Consistent with this, we observed an inverse correlation between miR‐155 promoter methylation and miR‐155 expression in ALCL. However, no direct effect of the ALK kinase on miR‐155 levels was observed. Ago2 immunoprecipitation revealed miR‐155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over‐expressed miR‐155 in ALCL ALK⁺ cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK^?, we showed that anti‐miR‐155 mimics are able to reduce tumour growth. This goes hand‐in‐hand with increased levels of cleaved caspase‐3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR‐155 induces IL‐22 expression and suppresses the C/EBPβ target IL‐8. These data suggest that miR‐155 can act as a tumour driver in ALCL ALK^? and blocking miR‐155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Transcranial direct current stimulation of the posterior parietal cortex modulates arithmetic learning

The successful acquisition of arithmetic skills is an essential step in the development of mathematical competencies and has been associated with neural activity in the left posterior parietal cortex (PPC). It is unclear, however, whether this brain region plays a causal role in arithmetic skill acquisition and whether arithmetic learning can be modulated by means of non‐invasive brain stimulation of this key region. In the present study we addressed these questions by applying transcranial direct current stimulation (tDCS) over the left PPC during a short‐term training that simulates the typical path of arithmetic skill acquisition (specifically the transition from effortful procedural to memory‐based problem‐solving strategies). Sixty participants received either anodal, cathodal or sham tDCS while practising complex multiplication and subtraction problems. The stability of the stimulation‐induced learning effects was assessed in a follow‐up test 24 h after the training. Learning progress was modulated by tDCS. Cathodal tDCS (compared with sham) decreased learning rates during training and resulted in poorer performance which lasted over 24 h after stimulation. Anodal tDCS showed an operation‐specific improvement for subtraction learning. Our findings extend previous studies by demonstrating that the left PPC is causally involved in arithmetic learning (and not only in arithmetic performance) and that even a short‐term tDCS application can modulate the success of arithmetic knowledge acquisition. Moreover, our finding of operation‐specific anodal stimulation effects suggests that the enhancing effects of tDCS on learning can selectively affect just one of several cognitive processes mediated by the stimulated area.     

A genome-wide visual screen reveals a role for sphingolipids and ergosterol in cell surface delivery in yeast

Recently synthesized proteins are sorted at the trans-Golgi network into specialized routes for exocytosis. Surprisingly little is known about the underlying molecular machinery. Here, we present a visual screen to search for proteins involved in cargo sorting and vesicle formation. We expressed a GFP-tagged plasma membrane protein in the yeast deletion library and identified mutants with altered marker localization. This screen revealed a requirement of several enzymes regulating the synthesis of sphingolipids and ergosterol in the correct and efficient delivery of the marker protein to the cell surface. Additionally, we identified mutants regulating the actin cytoskeleton (Rvs161p and Vrp1p), known membrane traffic regulators (Kes1p and Chs5p), and several unknown genes. This visual screening method can now be used for different cargo proteins to search in a genome-wide fashion for machinery involved in post-Golgi sorting.     

The diagnostic value of oral glucose tolerance test and combined B-cell stimulation in chronic pancreatitis

The secretory capacity of the B-cells in 40 patients with chronic or chronic relapsing pancreatitis was examined by means of the oral glucose tolerance test (100 g of glucose, orally) and combined stimulation (100 g of glucose, orally, 1 mg of glucagon, and 0.5 g of tolbutamide intravenously. Under both the test conditions, the immunologically measurable insulin was significantly reduced compared to that of controls. The maximal insulin differences and the insulinogenic index (35-minute value) of the combined stimulation method were most satisfactory for the diagnosis of the secretory B-cell insufficiency. In addition to these parameters, the constancy of insulin levels in the period between 35 and 60 minutes indicated a dysfunction of the endocrine pancreas.Presented in part at the Seventh Congress of the German Diabetic Society, Bad Nauheim, 4–6 May 1972.     

Identifying inadequate response among patients with ankylosing spondylitis and psoriatic arthritis prescribed advanced therapy in a real-world,commercially insured adult population in the USA

Clinical Rheumatology - This study aimed to assess treatment patterns and frequency of inadequate response associated with advanced therapy initiation among patients with ankylosing spondylitis...