Optogenetic reactivation of memory ensembles in the retrosplenial cortex induces systems consolidation.

The neural circuits underlying memory change over prolonged periods after learning, in a process known as systems consolidation. Postlearning spontaneous reactivation of memory-related neural ensembles is thought to mediate this process, although a causal link has not been established. Here we test this hypothesis in mice by using optogenetics to selectively reactivate neural ensembles representing a contextual fear memory (sometimes referred to as engram neurons). High-frequency stimulation of these ensembles in the retrosplenial cortex 1 day after learning produced a recent memory with features normally observed in consolidated remote memories, including higher engagement of neocortical areas during retrieval, contextual generalization, and decreased hippocampal dependence. Moreover, this effect was only present if memory ensembles were reactivated during sleep or light anesthesia. These results provide direct support for postlearning memory ensemble reactivation as a mechanism of systems consolidation, and show that this process can be accelerated by ensemble reactivation in an unconscious state.

Early on-treatment change in liver stiffness predicts development of liver-related events in chronic hepatitis B patients receiving antiviral therapy.

BACKGROUNDS/AIMS: Monitoring fibrosis is mandatory for detailed prognostification in patients with chronic liver disease. We developed optimized cut-offs for liver stiffness (LS) values, based on the histological subclassification of cirrhosis, and investigated whether early on-treatment changes in LS values can predict long-term prognosis in patients with hepatitis B virus (HBV)-related advanced liver fibrosis receiving antiviral therapy. METHODS: Between 2005 and 2008, 103 patients with F3 or F4 fibrosis on liver biopsy were enrolled prospectively. Cirrhosis was subclassified into three groups (F4A, F4B and F4C) according to Laennec system. The primary end-point was occurrence of liver-related event (LRE), including decompensation, hepatocellular carcinoma and liver-related death. RESULTS: Suggested LS cut-offs for predicting F4B-FC (vs. F3-F4A) and F4C (vs. F3-F4B) were 11.6 and 18.2 kPa respectively. As proportions of patients with LRE occurrence increased according to histological subclassifications stage F3-4A vs. F4B-4C (7.4% vs. 17.1%) and stage F3-4B vs. F4C (13.8% vs. 18.8%), they also increased according to LS cut-off value of 11.6 kPa (5.9% vs. 23.1%) and 18.2 kPa (9.8% vs. 33.3%) respectively (all P < 0.05). Similarly, according to stratified LS values (<11.6, 11.6-18.2 and ≥18.2 kPa), overall incidence of LREs and each constituent event increased significantly (all P < 0.05). In addition, the observed changes in LS values between baseline and 6 months of follow-up showed significant correlations with LRE development. CONCLUSIONS: Stratified LS values based on Laennec system and dynamic changes in LS values on follow-up may be helpful in assessing risk of LREs in subjects with HBV-related advanced liver fibrosis receiving antiviral therapy.

Comparison of CpG island hypermethylation and repetitive DNA hypomethylation in premalignant stages of gastric cancer, stratified for Helicobacter pylori infection.

CpG island hypermethylation and genomic DNA hypomethylation are found not only in gastric cancers but also in associated premalignant lesions. Helicobacter pylori infection induces aberrant CpG island hypermethylation in gastric mucosae. However, little is known about the relationship between H. pylori infection and aberrant methylation in premalignant lesions. The present study characterized methylation changes in a subset of genes and repetitive DNA elements (ALU, LINE-1, SAT2) and examined their relationship with H. pylori infection in premalignant lesions of gastric cancers. We performed MethyLight analysis of 25 genes and SAT2 and COBRA analysis of ALU and LINE-1 in 212 gastric tissue samples. H. pylori infection was closely associated with enhanced hypermethylation of CpG island loci in chronic gastritis samples, but this association was not found among intestinal metaplasias, gastric adenomas and gastric cancers. The number of methylated genes was greater in intestinal metaplasia and gastric adenoma samples than in chronic gastritis samples, regardless of H. pylori infection. Methylation of repetitive DNA elements in gastric lesions generally decreased with progression of the gastric lesion along the multistep carcinogenesis. No difference was noted in the number of methylated genes in chronic gastritis or intestinal metaplasia between gastric cancer patients and non-cancer subjects. In conclusion, we found that there was no enhanced CpG island hypermethylation in gastric cancer and premalignant lesions in association with H. pylori infection and our findings suggest that CpG island hypermethylation and repetitive DNA hypomethylation are enhanced with progression of the gastric lesion through the multistep carcinogenesis, regardless of the status of H. pylori infection.

Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation.

CpG island methylator phenotype (CIMP) is a recently described subset of colorectal cancers (CRC) with widespread methylation of multiple promoter CpG islands. But the prognostic implication of CIMP in CRC has not been clarified. Thus, the aim of the present study was to differentiate the unique characteristics of CIMP from those of microsatellite instability (MSI)-high CRC, especially with regard to prognosis. CIMP, MSI, and mutations of KRAS codons 12 and 13 and of BRAF codon 600 were evaluated in 134 sporadic CRC. Patient survival and other clinicopathological variables were correlated with CIMP or genetic changes. High CIMP, high MSI, and mutations in KRAS or BRAF were detected in 31.3%, 14.2%, 33.6%, and 4.5% of overall CRC, respectively. High CIMP was closely associated with MSI and BRAF mutation but not with KRAS mutation. CIMP-high, microsatellite-stable (MSS) CRC were significantly associated with proximal location and nodal metastasis and had close but non-significant associations with liver metastasis. A worse clinical outcome was found for CIMP-high, MSS CRC with KRAS/BRAF mutation but not for those lacking KRAS/BRAF mutation. The findings support the contention that CIMP-high CRC have distinct clinicopathological and epidemiological features and suggest that the alleged poor clinical outcome of CIMP-high CRC patients is closely associated with the presence of KRAS/BRAF mutation.

Comparative mutagenicity of apicidin and apicidin derivatives (SD-0203 and SD-2007), histone deacetylase inhibitors.

The fungal metabolite apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)] is known to inhibit histone deacetylase (HDAC). In this study, the genotoxicity of apicidin and its derivatives were tested using three tests: a bacterial reverse mutation assay (Ames test), an in vitro chromosome aberration (CA) test, and an in vivo micronucleus (MN) test. Apicidin was negative in the Ames test in the presence and absence of the microsomal metabolizing enzyme system. Apicidin induced a significant increase in the total chromosome aberrations in Chinese hamster ovary (CHO) cells. In the MN test, apicidin induced mutagenic activity at the highest dose (1000 microM/kg). The apicidin derivatives SD-0203 and SD-2007 did not induce mutagenic activity in the Ames test and no significant mutagenic potency was observed in the CA test. However, these compounds significantly and dose-dependently increased the number of micronucleated polychromatic erythrocytes (MNPCEs) as well as the PCE/(PCE + NCE) ratio in the MN test. These results suggest that apicidin and its derivatives preferentially induce CA and MN but are not effective in the Ames test.