Oligodeoxynucleotide IMT504: Effects on Central Nervous System Repair Following Demyelination.

Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) disease characterized by demyelination resulting from oligodendrocyte loss and inflammation. Cuprizone (CPZ) administration experimentally replicates MS pattern-III lesions, generating an inflammatory response through microgliosis and astrogliosis. Potentially remyelinating agents include oligodeoxynucleotides (ODN) with a specific immunomodulatory sequence consisting of the active motif PyNTTTTGT. In this work, the remyelinating effects of ODN IMT504 were evaluated through immunohistochemistry and qPCR analyses in a rat CPZ-induced demyelination model. Subcutaneous IMT504 administration exacerbated the pro-inflammatory response to demyelination and accelerated the transition to an anti-inflammatory state. IMT504 reduced microgliosis in general and the number of phagocytic microglia in particular and expanded the population of oligodendroglial progenitor cells (OPCs), later reflected in an increase in mature oligodendrocytes. The intracranial injection of IMT504 and intravenous inoculation of IMT504-treated B lymphocytes rendered comparable results. Altogether, these findings unveil potentially beneficial properties of IMT504 in the regulation of neuroinflammation and oligodendrogenesis, which may aid the development of therapies for demyelinating diseases such as MS.

Type 1 IGF Receptor Localization in Paediatric Gliomas: Significant Association with WHO Grading and Clinical Outcome.

Nuclear localization of insulin-like growth factor receptor type 1 (IGF-1R) has been described as adverse prognostic factor in some cancers. We studied the expression and localization of IGF-1R in paediatric patients with gliomas, as well as its association with World Health Organization (WHO) grading and survival. We conducted a single cohort, prospective study of paediatric patients with gliomas. Samples were taken at the time of the initial surgery; IGF-1R expression and localization were characterized by immunohistochemistry (IHC), subcellular fractionation and western blotting. Tumours (47/53) showed positive staining for IGF-1R by IHC. IGF-1R nuclear labelling was observed in 10/47 cases. IGF-1R staining was mostly non-nuclear in low-grade tumours, while IGF-1R nuclear labelling was predominant in high-grade gliomas (p = 0.0001). Survival was significantly longer in patients with gliomas having non-nuclear IGF-1R localization than in patients with nuclear IGF-1R tumours (p = 0.016). In gliomas, IGF-1R nuclear localization was significantly associated with both high-grade tumours and increased risk of death. Based on a prospective design, we provide evidence of a potential usefulness of intracellular localization of IGF-1R as prognostic factor in paediatric patients with gliomas.

Prognostic significance of TRAIL-R3 and CCR-2 expression in tumor epithelial cells of patients with early breast cancer.

BACKGROUND: Tumor epithelial cells (TEpCs) and spindle-shaped stromal cells, not associated with the vasculature, of patients with early breast cancer express osteoprotegerin (OPG), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), receptor activator of nuclear factor kappa B ligand, stromal cell derived factor-1, interleukin-6, macrophage colony stimulating factor, chemokine (C-C motif) ligand-2 (CCL-2) and their receptors at significantly higher levels compared with non-neoplastic breast tissues. We evaluated the clinicopathological significance of these ligands and receptors in TEpC and spindle-shaped stromal cells, not associated with the vasculature, to determine their impact on prognosis of patients with early-stage breast cancer. METHODS: We conducted immunohistochemical analyses of protein expression in primary tumors of patients with early breast cancer and analyzed their association with standard prognostic parameters and clinical outcomes, including local relapse, metastatic recurrence, disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). RESULTS: Elevated levels of TRAIL-R3 and chemokine (C-C motif) receptor 2 (CCR-2) in TEpCs and OPG and CCL-2 in stromal cells were significantly associated with a higher risk of metastasis (p = 0.032, p = 0.003, p = 0.038, and p = 0.049; respectively). Moreover, high expression of TRAIL-R3 and CCR-2 in TEpCs was associated with shorter DFS, MFS, and OS. High TRAIL-R3 expression in TEpCs was an independent prognostic factor for DFS and OS, and high CCR-2 expression in these cells was an independent prognostic factor for MFS. CONCLUSIONS: High levels of TRAIL-R3 and CCR-2 expression in TEpCs identified patients with early breast cancer with poor outcomes.

Influence of obesity and insulin resistance on left atrial size in children.

BACKGROUND: Left atrial (LA) enlargement has been linked to obesity and insulin resistance in adults. OBJECTIVE: The purpose of this study was to determine the association in children between LA area and: (i) different components of the metabolic syndrome including obesity (OB), measures of body mass index (BMI) and waist circumference (WC), homeostasis model assessment-insulin resistance (HOMA-IR, proinsulin), and blood pressure (BP); and (ii) left ventricular mass (LVM) and diastolic function, measured using echo Doppler. METHODS AND RESULTS: Eighty-four (44 females) subjects, [40 OB (BMI>95%), 28 overweight (BMI>85%)], 16 non-OB (BMI<85%)] aged 9+/-2.24 yrs were matched for sex and age. BMI, WC, BP, Tanner stage, and Mode M, 2-dimensional and Doppler transmitral echocardiography were assessed. A standard oral glucose tolerance test (OGTT) was done, measuring glucose, insulin, and proinsulin concentrations. Hypertension was only present in OB subjects (25%). Significant univariate association (p<0.001) was found between LA area and height (r=0.52), age (r=0.45), Tanner stage (r=0.45), BMI (r=0.66), WC (r=0.70), systolic BP (r=0.52), diastolic BP (r=0.53), proinsulin (r=0.36), and HOMA-IR (r=0.36). In the multivariate regression analysis, independent variables were entered in a stepwise fashion: initially, gender (p=0.006) and Tanner stage (p=0.011) were still significant independent correlates of LA area after adjusting for age, gender, and Tanner stage. Subsequently, incorporation of WC showed that WC (p=0.018) was a significant independent correlate of LA area. A larger model constructed to test the significance of adjustment factors, including WC, BP, LVM, and HOMA-IR showed that WC (p<0.001) was the only significant independent variable. CONCLUSION: LA enlargement is present in childhood and is related to abdominal OB and insulin resistance, suggesting that children with central OB are at increased risk for cardiovascular disease.