Expression of 19 microRNAs in glioblastoma and comparison with other brain neoplasia of grades I–III

Several biomarkers have been proposed as useful parameters to better specify the prognosis or to delineate new target therapy strategies for glioblastoma patients. MicroRNAs could represent putative target molecules, considering their role in tumorigenesis, cancer progression and their specific tissue expression. Although several studies have tried to identify microRNA signature for glioblastoma, a microRNA profile is still far from being well‐defined.In this work the expression of 19 microRNAs (miR‐7, miR‐9, miR‐9∗, miR‐10a, miR‐10b, miR‐17, miR‐20a, miR‐21, miR‐26a, miR‐27a, miR‐31, miR‐34a, miR‐101, miR‐137, miR‐182, miR‐221, miR‐222, miR‐330, miR‐519d) was evaluated in sixty formalin‐fixed and paraffin‐embedded glioblastoma samples using a locked nucleic acid real‐time PCR. Moreover, a comparison of miRNA expressions was performed between primary brain neoplasias of different grades (grades IV–I).The analysis of 14 validated miRNA expression in the 60 glioblastomas, using three different non‐neoplastic references as controls, revealed a putative miRNA signature: mir‐10b and miR‐21 were up‐regulated, while miR‐7, miR‐31, miR‐101, miR‐137, miR‐222 and miR‐330 were down‐regulated in glioblastomas. Comparing miRNA expression between glioblastoma group and gliomas of grades I–III, 3 miRNAs (miR‐10b, mir‐34a and miR‐101) showed different regulation statuses between high‐grade and low‐grade tumors. miR‐10b was up‐regulated in high grade and significantly down‐regulated in low‐grade gliomas, suggesting that could be a candidate for a GBM target therapy.This study provides further data for the identification of a miRNA profile for glioblastoma and suggests that different‐grade neoplasia could be characterized by different expression of specific miRNAs.     

Role of serotonergic system in the pathogenesis of fibrosis in canine idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies are muscle diseases characterized by inflammation, necrosis, and fibrosis. The neurotransmitter serotonin (5-HT) has been shown to promote fibrosis in many tissues and organs by activating TGFβ-1 signaling. In this study, we evaluated the potential role of 5-HT in the pathogenesis of fibrosis in canine idiopathic inflammatory myopathies. Muscle biopsies from dogs affected by masticatory muscle myositis or polymyositis and from healthy dogs were processed for immunohistochemistry and Western blotting. The immunohistochemical analysis showed a strong expression of 5-HT in muscle tissues of affected dogs, whereas the amine was absent in the muscles of healthy dogs. Biochemical analysis showed increased expression levels of the selective 5-HT2A receptor in the muscle specimens of the most severely affected dogs versus controls. Further, increased phosphorylation levels of the TGFβ-1 signaling mediators SMAD2/3 and ERK1/2 were detected in tissue samples from affected dogs as compared to tissues from healthy dogs. Although further studies are needed, our findings highlight for the first time a potential role of 5-HT in the development of fibrosis in canine idiopathic inflammatory myopathies, thus supporting other evidence that 5-HT pro-fibrotic activity occurs via activation of TGFβ-1 signaling pathway.     

The correlation between cardiac and skeletal muscle pathology in animal models of idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIMs) represent a heterogeneous group of disorders in which skeletal muscle is inappropriately targeted by the immune system. IIMs are characterized by inflammation of muscle and varying degrees of muscle dysfunction. Extra-muscular manifestations may involve heart, skin, joints, lungs, and gastrointestinal tract. Cardiovascular involvement is a feared event because is one of the leading causes of mortality in IIM patients. As the myocardium shares many features with the skeletal muscle, it is supposed that it can be affected by the same inflammatory processes, which take place during the different forms of IIMs. However, the full extent of this link and the mechanisms behind it are still not fully understood. Animal models have greatly improved our understanding of IIM pathomechanisms and have proven to be a useful tool for discovering therapeutic drug targets. Here we report the evidence of heart muscle involvement in different animal models of spontaneous IIMs, assuming a common autoimmune mechanism and presenting them as study models for human pathology.Key words: neuromuscular disorders, myocarditis, myositis, idiopathic inflammatory myopathy, animal models     

Continuous oral capecitabine at fixed dose in patients older than 75 years with metastatic colorectal and gastric cancer: a study of the Multidisciplinary Oncology Group on Gastrointestinal Tumors

The aim of this study was to investigate the safety profile of continuous oral capecitabine at fixed dose in patients older than 75 years, having metastatic colorectal and gastric cancer. Capecitabine was administered at a fixed dose of 2000 mg daily without interruptions. Thirty-four patients were considered evaluable for toxicity and efficacy. The median age was 81 years (range 76-85). The median duration of treatment was 113 days (range 24-238 days). No grade 4 toxicity was observed. One patient had grade 3 nausea and vomiting, and one had grade 3 diarrhea. Partial responses were observed in six patients with colorectal cancer, and in one patient with gastric cancer. This study suggests that continuous oral capecitabine at a fixed daily dose of 2000 mg is well tolerated, and that it allows for the simplification and ease of dosing in elderly patients with metastatic colorectal and gastric cancer.     

Functional involvement of cerebral cortex in duchenne muscular dystrophy

Transcranial stimulation was performed in 4 patients with Duchenne muscular dystrophy and 4 control subjects. The patients' central motor conduction time was normal. The threshold for evoking electromyographic responses using electrical anodal stimulation was the same in both groups, but the threshold for stimulation with a circular magnetic coil at the vertex was higher in the patients. This is compatible with reduced cortical excitability that may be related to the deficiency of brain synaptic dystrophin. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:662–664, 1998.     

Cerebrospinal fluid pentraxin 3 early after subarachnoid hemorrhage is associated with vasospasm

Purpose

To investigate plasma and cerebrospinal fluid (CSF) concentrations of pentraxin 3 (PTX3), a prototypic long pentraxin protein induced by proinflammatory signals, in subarachnoid hemorrhage (SAH), and its relation with SAH-associated vasospasm.

Methods

Serial plasma and CSF samples were collected from 38 consecutive SAH patients admitted to the Neurosurgical Intensive Care. PTX3 concentrations were analyzed in relation to clinical status and clinical vasospasm (defined as neuro-worsening and angiographic confirmation of vessel narrowing). Since neutrophils are an important source of preformed PTX3, myeloperoxidase (MPO) in CSF was measured to assess the correlation with CSF PTX3 and establish whether blood contamination was the determinant of PTX3 increase.

Results

PTX3 was elevated in all SAH patients both in plasma and CSF. Acute peak (first 48?h after SAH) CSF PTX3 was significantly higher in patients who later developed vasospasm [median 13.6 (range 2.3?C51.9)?ng/ml] compared to those who did not [3.2 (0.1?C50.5)?ng/ml, p?=?0.03]. The temporal pattern of CSF PTX3 in patients with vasospasm was triphasic with a peak during the first 48?h after SAH, a subsequent decrease in the following 48?C96?h and a secondary significant increase with the occurrence of vasospasm. A loose correlation between CSF PTX3 and MPO was observed (r ²?=?0.13), indicating that following SAH there is a brain production of PTX3.

Conclusions

Acute increased concentrations of PTX3 in CSF but not in plasma are related to the occurrence of vasospasm, indicating that measurement of CSF PTX3 associated with the clinical evaluation can improve early diagnosis of this complication.     

Syrian hamster infected with Leishmania infantum: A new experimental model for inflammatory myopathies

Idiopathic inflammatory myopathies (IIMs) are inflammatory disorders of unknown origin. On the basis of clinical, histopathological, and immunological features, they can be differentiated into three major and distinct subsets: dermatomyositis; polymyositis; and inclusion‐body myositis. Although a few animal models for IIM are currently available, they lack several characteristic aspects of IIMs. The aim of our study was to examine skeletal muscle involvement in an experimental animal model of visceral leishmaniasis, a disseminated infection caused by the protozoan parasite Leishmania infantum, and to compare features of associated inflammation with those of human IIM. Syrian hamsters infected intraperitoneally with amastigotes of L. infantum were killed at 3 or 4 months post‐infection, and the skeletal muscles were studied. Focal inflammation was predominantly observed in the endomysium and, to a lesser extent, in perivascular areas. Degenerating muscle fibers were also found, as well as myonecrosis. Immunofluorescence with confocal laser scanning microscopy was used to characterize the phenotype of inflammatory infiltrates and the distribution of MHC class I and II in muscle biopsies. The infiltrating inflammatory cells consisted mainly of T cells, and CD8⁺ T cells were found in non‐necrotic muscle fibers that expressed MHC class I on the sarcolemma. In addition to T cells, several macrophages were present. The model we are proposing closely resembles polymyositis and may be useful in studying certain aspects of this disease such as the role of T cells in muscle inflammation and myocytotoxicity, while also providing novel therapeutic targets. Muscle Nerve, 2009