The neural mechanisms that support the late postnatal development of spatial navigation are currently unknown. We investigated this in rats and found that an increase in the duration of AMPAR-mediated synaptic responses in the hippocampus was related to the emergence of spatial navigation. More specifically, spontaneous alternation rate, a behavioral indicator of hippocampal integrity, increased at the end of the third postnatal week in association with increases in AMPAR response duration at SC-CA1 synapses and synaptically driven postsynaptic discharge of CA1 pyramidal neurons. Pharmacological prolongation of glutamatergic synaptic transmission in juveniles increased the spontaneous alternation rate and CA1 postsynaptic discharge and reduced the threshold for the induction of activitydependent synaptic plasticity at SC-CA1 synapses. A decrease in GluA1 and increases in GluA3 subunit and transmembrane AMPAR regulatory protein (TARP) expression at the end of the third postnatal week provide a molecular explanation for the increase in AMPAR response duration and reduced efficacy of AMPAR modulators with increasing age. A shift in the composition of AMPARs and increased association with AMPAR protein complex accessory proteins at the end of the third postnatal week likely "turns on" the hippocampus by increasing AMPAR response duration and postsynaptic excitability and reducing the threshold for activitydependent synaptic potentiation.

Hepatitis C virus (HCV) genome encodes for one long polyprotein that is processed by cellular and viral proteases to generate 10 polypeptides. The viral structural proteins include the core protein, and the envelope glycoproteins E1 and E2, present at the surface of HCV particles. Non-structural (NS) proteins consist of NS1, NS2, NS3, NS4A, NS4B, NS5a, and NS5b and have a variable function in HCV RNA replication and particle assembly. Recent findings evidenced the capacity of HCV virus to modulate host cell factors to create a favorable environment for replication. Indeed, increasing evidence has indicated that the presence of HCV is significantly associated with aberrant miRNA expression in host cells, and HCV structural and non-structural proteins may be responsible for these alterations. In this review, we summarize the recent findings on the role of HCV structural and non-structural proteins in the modulation of host cell miRNAs, with a focus on the molecular mechanisms responsible for the cell re-programming involved in viral replication, immune system escape, as well as the oncogenic process. In this regard, structural and non-structural proteins have been shown to modulate the expression of several onco-miRNAs or tumor suppressor miRNAs.

Background: Hepatic resection, radiofrequency ablation (RF), and liver transplantation (LT) represent the only available curative treatments for early stage hepatocellular carcinoma (HCC). Various studies showed that the 5-year overall survival (OS) rate reaches ∼70% after resection and ∼60% after RF. Objective: To improve the success rate of curative therapies and consequently the OS, an improvement in patients’ selection and management should be pursued. In this regard, microRNAs (miRNAs) can be helpful prognostic biomarkers. Materials and Methods: In this retrospective study, a miRNA array profiling was performed on 34 HCC blood samples which is collected before therapy (T0), 1 month (T1), and 6 months (T2) after curative treatments (resection and RF) to identify noninvasive biomarker candidates for therapy response and OS. MiRNAs were validated in 80 blood HCC samples using quantitative real-time PCR (qRT-PCR). Patients were divided into complete responder (CR) and partial responder and progressive disease (PRPD). Results: Among the selected miRNAs, miR-3201 is significantly associated with treatment response in the validation phase, showing a 23% reduction ( P = .026) in CR compared to PRPD. MiR-3201 was able to distinguish CR from PRPD (area under the curve [AUC] = 0.69, 71% sensitivity, 70% specificity, P = .0036). Furthermore, lower levels of miR-3201 were associated with longer OS (hazard ratio [HR] = 2.61, P = .0006). Conclusions: Blood miR-3201 could be used as a prognostic biomarker for curative therapy response and OS in HCC.

Purpose: Recent evidence suggests that expression of CXCR4 is associated with the growth and progression of neuroblastoma. The purpose of this study was to determine the value of CXCR4 as in independent predictive biomarker and evaluate its potential as a therapeutic target in neuroblastoma. Experimental Design: mRNA Expression profiling was performed on 101 diagnostic neuroblastoma primary tumor samples using Affymetrix oligonucleotide arrays. CXCR4 expression was stratified by risk and stage, and statistically significant differences in mRNA levels were determined. Protein expression profiling was performed by conducting immunohistochemical analysis of CXCR4 expression in 92 neuroblastoma tumors on a tissue microarray constructed at Children's Hospital of Philadelphia (CHOP); expression levels were stratified by stage and compared to determine significant correlations. To examine the role of CXCR4 in neuroblastoma progression, the selective CXCR4 inhibitor AMD3100 was used to observe the effect of CXCR4 inhibition on the growth of neuroblastoma cells in culture and in mice. Results: CXCR4 expression was significantly higher in stage 1 vs. ganglioneuroma tumors, as assessed at the protein level (P<0.0001), and in stage 4 tumors vs. stage 1 tumors, at both the mRNA and protein levels (P<0.01). Additionally, a comparison of CXCR4 transcriptional expression in patient tumors stratified by risk revealed greater CXCR4 expression in high-risk groups compared to low and intermediate groups (P<0.002); interestingly, CXCR4 protein expression was not associated with overall survival or progression-free survival (PFS). Treatment of neuroblastoma cells with AMD3100 inhibited growth of these cells in culture and in mouse xenografts. Conclusion: We conclude that increased levels of CXCR4 expression are associated with advanced tumor stage and a high risk population in neuroblastoma patients, demonstrating the clinical value of CXCR4 as an independent biomarker for risk classification and patient stratification; additionally, CXCR4 should be considered a novel and viable candidate for targeted therapeutic intervention in neuroblastoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5566. doi:1538-7445.AM2012-5566