Contactin-6-deficient male mice exhibit the abnormal function of the accessory olfactory system and impaired reproductive behavior.

INTRODUCTION: Contactin-6 (CNTN6), also known as NB-3, is a neural recognition molecule and a member of the contactin subgroup of the immunoglobulin superfamily. Gene encoding CNTN6 is expressed in many regions of the neural system, including the accessory olfactory bulb (AOB) in mice. We aim to determine the effect of CNTN6 deficiency on the function of the accessory olfactory system (AOS). METHODS: We examined the effect of CNTN6 deficiency on the reproductive behavior of male mice through behavioral experiments such as urine sniffing and mate preference tests. Staining and electron microscopy were used to observe the gross structure and the circuitry activity of the AOS. RESULTS: Cntn6 is highly expressed in the vomeronasal organ (VNO) and the AOB, and sparsely expressed in the medial amygdala (MeA) and the medial preoptic area (MPOA), which receive direct and/or indirect projections from the AOB. Behavioral tests to examine reproductive function in mice, which is mostly controlled by the AOS, revealed that Cntn6-/- adult male mice showed less interest and reduced mating attempts toward estrous female mice in comparison with their Cntn6+/+ littermates. Although Cntn6-/- adult male mice displayed no obvious changes in the gross structure of the VNO or AOB, we observed the increased activation of granule cells in the AOB and the lower activation of neurons in the MeA and the MPOA as compared with Cntn6+/+ adult male mice. Moreover, there were an increased number of synapses between mitral cells and granule cells in the AOB of Cntn6-/- adult male mice as compared with wild-type controls. CONCLUSION: These results indicate that CNTN6 deficiency affects the reproductive behavior of male mice, suggesting that CNTN6 participated in normal function of the AOS and its ablation was involved in synapse formation between mitral and granule cells in the AOB, rather than affecting the gross structure of the AOS.

A comparison of transcriptome analysis methods with reference genome.

BACKGROUND: The application of RNA-seq technology has become more extensive and the number of analysis procedures available has increased over the past years. Selecting an appropriate workflow has become an important issue for researchers in the field. METHODS: In our study, six popular analytical procedures/pipeline were compared using four RNA-seq datasets from mouse, human, rat, and macaque, respectively. The gene expression value, fold change of gene expression, and statistical significance were evaluated to compare the similarities and differences among the six procedures. qRT-PCR was performed to validate the differentially expressed genes (DEGs) from all six procedures. RESULTS: Cufflinks-Cuffdiff demands the highest computing resources and Kallisto-Sleuth demands the least. Gene expression values, fold change, p and q values of differential expression (DE) analysis are highly correlated among procedures using HTseq for quantification. For genes with medium expression abundance, the expression values determined using the different procedures were similar. Major differences in expression values come from genes with particularly high or low expression levels. HISAT2-StringTie-Ballgown is more sensitive to genes with low expression levels, while Kallisto-Sleuth may only be useful to evaluate genes with medium to high abundance. When the same thresholds for fold change and p value are chosen in DE analysis, StringTie-Ballgown produce the least number of DEGs, while HTseq-DESeq2, -edgeR or -limma generally produces more DEGs. The performance of Cufflinks-Cuffdiff and Kallisto-Sleuth varies in different datasets. For DEGs with medium expression levels, the biological verification rates were similar among all procedures. CONCLUSION: Results are highly correlated among RNA-seq analysis procedures using HTseq for quantification. Difference in gene expression values mainly come from genes with particularly high or low expression levels. Moreover, biological validation rates of DEGs from all six procedures were similar for genes with medium expression levels. Investigators can choose analytical procedures according to their available computer resources, or whether genes of high or low expression levels are of interest. If computer resources are abundant, one can utilize multiple procedures to obtain the intersection of results to get the most reliable DEGs, or to obtain a combination of results to get a more comprehensive DE profile for transcriptomes.

Transcriptional regulation of intermolecular Ca2+ signaling in hibernating ground squirrel cardiomyocytes: The myocardin-junctophilin axis.

The contraction of heart cells is controlled by the intermolecular signaling between L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs), and the nanodistance between them depends on the interaction between junctophilin-2 (JPH2) in the sarcoplasmic reticulum (SR) and caveolin-3 (CAV3) in the transversal tubule (TT). In heart failure, decreased expression of JPH2 compromises LCC-RyR communication leading to deficient blood-pumping power. In the present study, we found that JPH2 and CAV3 transcription was concurrently regulated by serum response factor (SRF) and myocardin. In cardiomyocytes from torpid ground squirrels, compared with those from euthermic counterparts, myocardin expression was up-regulated, which boosted both JPH2 and CAV3 expression. Transmission electron microscopic imaging showed that the physical coupling between TTs and SRs was tightened during hibernation and after myocardin overexpression. Confocal Ca2+ imaging under the whole-cell patch clamp condition revealed that these changes enhanced the efficiency of LCC-RyR intermolecular signaling and fully compensated the adaptive down-regulation of LCCs, maintaining the power of heart contraction while avoiding the risk of calcium overload during hibernation. Our finding not only revealed an essential molecular mechanism underlying the survival of hibernating mammals, but also demonstrated a "reverse model of heart failure" at the molecular level, suggesting a strategy for treating heart diseases.

Ginsenoside compound K exerts antitumour effects in renal cell carcinoma via regulation of ROS and lncRNA THOR.

Renal cell carcinoma (RCC) is a common type of kidney cancer that lacks effective therapeutic options. Ginsenoside compound K (CK), an active metabolite of ginsenosides, has been reported to induce apoptosis in various types of cancer cells. However, the effects of CK in RCC remain to be elucidated. Thus, the aim of the present study was to investigate the antitumor effects of CK on RCC cells. The effects of CK on the proliferation, migration, invasion, cell cycle and apoptosis of RCC cell lines (Caki­1 and 768­O) were investigated using MTT, wound healing, Transwell and flow cytometry assays, respectively. Changes in the expression levels of long non­coding RNAs (lncRNAs) and proteins were measured via reverse transcription­quantitative PCR and western blotting, respectively. Transfections with testis associated oncogenic (THOR) small interfering RNA and pcDNA were performed to knock down and overexpress lncRNA THOR, respectively. It was found that CK could effectively inhibit the proliferation, migration and invasion of RCC cells. CK also induced cell cycle arrest and caspase­dependent apoptosis in RCC cells. Furthermore, the generation of reactive oxygen species and inhibition of the lncRNA THOR played important roles in the antitumour effects of CK in RCC cells. The present data revealed that CK was a potent antitumour agent against RCC.

Lower mutant-allele tumor heterogeneity is a biomarker in FGFR3-mutant bladder cancer for better prognosis.

BACKGROUND: Bladder cancer displays a broad mutational spectrum and intratumor heterogeneity (ITH), which results in difference in molecular phenotypes and resistance to therapies. However, there are currently no clinically available measures to predict patient prognosis using ITH. We aimed to establish a clinically relevant biomarker by using ITH for informing predictive of outcomes. METHODS: We used the Bioconductor R package Maftools to efficiently and comprehensively analyze somatic variants of muscle-invasive bladder cancer (MIBC) from The Cancer Genome Atlas (TCGA). We then used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters as well as mutational subtypes. RESULTS: We observed a broad range of somatic mutations in MIBC from TCGA. MATH value was higher for the high-grade group than for the low-grade group (p < 0.05). There was a strong correlation between higher MATH value and presence of TP53 mutations (p = 0.008), as well as between lower MATH value and presence of FGFR3 mutations (p = 0.006). Patients with FGFR3 mutation and low MATH value exhibit longer overall survival time than that of all BLCA patients (p = 0.044), which was replicated in another bladder cancer database composed of 109 BLCA patients. CONCLUSION: Measures of tumor heterogeneity may be useful biomarkers for identifying patients with bladder cancer. Low MATH value was an independent risk factor that predicted better prognosis for patients with FGFR3 mutation compared to all BLCA patients.

Nanobar Array Assay Revealed Complementary Roles of BIN1 Splice Isoforms in Cardiac T-Tubule Morphogenesis.

Bridging integrator-1 (BIN1) is a family of banana-shaped molecules implicated in cell membrane tubulation. To understand the curvature sensitivity and functional roles of BIN1 splicing isoforms, we engineered vertical nanobars on a cell culture substrate to create high and low curvatures. When expressed individually, BIN1 isoforms with phosphoinositide-binding motifs (pBIN1) appeared preferentially at high-curvature nanobar ends, agreeing well with their membrane tubulation in cardiomyocytes. In contrast, the ubiquitous BIN1 isoform without phosphoinositide-binding motif (uBIN1) exhibited no affinity to membranes around nanobars but accumulated along Z-lines in cardiomyocytes. Importantly, in pBIN1-uBIN1 coexpression, pBIN1 recruited uBIN1 to high-curvature membranes at nanobar ends, and uBIN1 attached the otherwise messy pBIN1 tubules to Z-lines. The complementary cooperation of BIN1 isoforms (comboBIN1) represents a novel mechanism of T-tubule formation along Z-lines in cardiomyocytes. Dysregulation of BIN1 splicing, e.g., during myocardial infarction, underlied T-tubule disorganization, and correction of uBIN1/pBIN1 stoichiometry rescued T-tubule morphology in heart disease.

Identification of a nine-gene panel as a prognostic indicator for recurrence with muscle-invasive bladder cancer.

BACKGROUND AND OBJECTIVES: Bladder cancer is one of the most common and highly recurrent cancers worldwide. Recurrence-associated genes may potentially predict cancer recurrence. We aimed to construct a recurrence-associated gene panel to improve the prognostic prediction of bladder cancer. METHODS: Based on DNA sequencing and clinical data from the TCGA-BLCA project, we identified 10 potential driver genes significantly associated with recurrence of bladder cancer. We performed multivariable logistic regression analysis to construct an optimized recurrence prediction model with nine recurrence-associated genes (EME1, AKAP9, ZNF91, PARD3, STAG2, ZFP36L2, METTL3, POLR3B, and MUC7) and clinical information as the independent variables. RESULTS: The area under the receiver operating characteristic (ROC) curve was 0.80 in this model, much higher than that of the baseline model (AUC = 0.73) and the same trend was also validated in its subset. Decision curve analysis also revealed that there is a significant net benefit gained by adding nine genes mutation to the baseline model. Furthermore, Kaplan-Meier survival analysis showed that eight out of the nine genes (excluding MUC7) had good effects on the overall prognosis of patients. CONCLUSIONS: This nine-gene panel will most likely be a useful tool for prognostic evaluation and will facilitate the personalized management of patients with bladder cancer.

Adjuvant transarterial chemoembolization to improve the prognosis of hepatocellular carcinoma following curative resection.

The present study aimed to investigate the prognostic factors for recurrence of hepatocellular carcinoma (HCC) following curative resection, and evaluate the efficacy of postoperative adjuvant transarterial chemoembolization (TACE) in improving prognosis. A total of 166 patients who underwent curative resection followed by adjuvant TACE, and 190 patients who underwent curative resection alone were studied retrospectively. Univariate and multivariate analyses were performed to investigate the risk factors of recurrence. Separated based on risk factors, subgroup studies were conducted and the association between TACE and recurrence rates was examined. Postoperative overall survival rates were determined using the Kaplan-Meier method and differences between the two therapeutic strategies were identified through log-rank analysis. Computerized tomography (CT)/magnetic resonance imaging (MRI) images were used to evaluate the function of postoperative adjuvant TACE for enhancing the efficacy of CT/MRI in detecting recurrence. The results of the univariate and multivariate analyses revealed that tumor capsule invasion, vascular invasion, and multiple nodules were risk factors of early recurrence. For patients with these risk factors, recurrence rates were markedly decreased at 6 and 12 months, but not at 18 and 24 months, if TACE was added to curative resection. The hepatitis B virus (HBV) was a risk factor for late recurrence. Postoperative TACE was not effective in reducing the recurrence rate in patients with HBV. Survival increased following curative resection with TACE compared with curative resection alone. Furthermore, adjuvant TACE enhanced the efficacy of CT/MRI in detecting recurrence. Postoperative adjuvant TACE may improve the prognosis of HCC following curative resection.

Cntn6 deficiency impairs allocentric navigation in mice.

INTRODUCTION: CNTN6 is an immunoglobulin domain-containing cell adhesion molecule that belongs to the contactin family. It is involved in the development of the nervous system. We aim to determine the effect of Cntn6 deficiency on the allocentric navigation in mice. METHODS: We recorded the travel distance and escape time of wild-type and Cntn6 mutant male and female mice in the Morris water maze task according to the protocol. RESULTS: There was hardly any Cntn6 expression in the hippocampus of postnatal day 0 (P0) mice, while obvious Cntn6 expression was present in the hippocampal CA1 region of the P7 mice. During the acquisition period of Morris water maze task (Day 1 to 4), Cntn6-/- male mice failed to shorten the escape time to reach platform on the third day, while the travel distance to platform was not significantly different. There was no significant difference in both escape time and travel distance to the platform among all female subjects. In the probe trial test (Day 5), spatial memory of the female mutant mice was mildly affected, while Cntn6-/- male mice were normal. In the spatial relearning test (Day 7 to 10), Cntn6-/- male mice showed no difference in escape time to the platform compared to the wild-type male mice, while Cntn6 deficient female mice required shorter escape time to travel to the platform on day 7, day 8, and day 10. CONCLUSIONS: Cntn6 is expressed in the developing hippocampus in mice. Cntn6 deficiency affects spatial learning and memory, indicating that Cntn6 plays a role in the development of hippocampus and affects allocentric navigation of the animals.

Abnormalities in Prefrontal Cortical Gene Expression Profiles Relevant to Schizophrenia in MK-801-Exposed C57BL/6 Mice.

MK-801, a non-competitive NMDA receptor (NMDAR) antagonist, disturbs NMDAR function in rodents and induces psychological and behavioral changes similar to schizophrenia (SCZ). However, the effects of MK-801 treatment on gene expression are largely unknown. Here we performed RNA-sequencing on the prefrontal cortex of MK-801-exposed male mice in order to analyze gene expression and co-expression patterns related to SCZ and to identify mechanisms that underlie the molecular etiology of this disorder. Transcriptome analysis revealed that the differentially expressed genes were more often associated with biological processes that included postsynaptic transmission, immune system process, response to external stimulus and hemostasis. In order to extract comprehensive biological information, we used an approach for biclustering, called FABIA, to simultaneously cluster transcriptomic data across genes and conditions. When combined with analyses using DAVID and STRING databases, we found that co-expression patterns were altered in synapse-related genes and genes central to the mitochondrial network. Abnormal co-expression of genes mediating synaptic vesicle cycling could disturb release, uptake and reuptake of glutamate, and the perturbation in co-expression patterns for mitochondrial respiratory chain complexes was extensive. Our study supports the hypothesis that research using MK-801-exposed male mice as an animal model of SCZ offers important insights into the pathogenesis of SCZ.

Abnormalities in behaviour, histology and prefrontal cortical gene expression profiles relevant to schizophrenia in embryonic day 17 MAM-Exposed C57BL/6 mice.

Gestational and perinatal disruption of neural development increases the risk of developing schizophrenia (SCZ) later in life. Embryonic day 17 (E17) methylazoxymethanol (MAM) treatment leads to histological, physiological and behavioural abnormalities in post-puberty rats that model the neuropathological and cognitive deficits reported in SCZ patients. However, the validity of E17 MAM-exposed mice to model SCZ has not been explored. Here we treated E17 C57BL/6 mouse dams with various dosages of MAM. We found that this mouse strain was more vulnerable to MAM treatment than rats and there were gender differences in behavioural abnormalities, histological changes and prefrontal cortical gene expression profiles in MAM (7.5 mg/kg)-exposed mice. Both male and female MAM-exposed mice had deficits in prepulse inhibition. Female MAM-exposed mice exhibited mildly increased spontaneous locomotion activity and social recognition deficits, while male mice were normal. Consistently, only female MAM-exposed mice exhibited reduced brain weight, decreased size of prefrontal cortex (PFC) and enlarged lateral ventricles. Transcriptome analysis of the PFC revealed that there were more differentially expressed genes in female MAM-exposed mice than those in male mice. Moreover, expression of Pvalb, Arc and genes in their association networks were downregulated in the PFC of female MAM-exposed mice. These results indicate that E17 MAM-exposure in C57BL/6 mice leads to behavioural changes that model certain deficits reported in SCZ patients. MAM-exposed female mice may be used to study gene expression changes, inhibitory neural circuit dysfunction and glutamatergic synaptic plasticity deficits with a possible relation to those in the brains of SCZ patients.

High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer.

Colorectal cancer (CRC) is one of the most common types of malignancy with high morbidity and mortality rates worldwide. This biologically heterogeneous disease results in diverse therapeutic responses, thus, novel prognostic biomarkers are required to improve CRC treatment. Estrogen-related receptor α (ERRα) is a nuclear orphan receptor, which is associated with estrogen receptor α. The present study aimed to investigate the expression of ERRα in patients with CRC, and explore the association between ERRα expression and clinicopathological factors, local recurrence and prognosis. In the present study, ERRα expression was detected in 15 fresh CRC tissues using quantitative real-time polymerase chain reaction (RT-qPCR) and in 128 paraffin-embedded CRC tissues using immunohistochemistry. The associations between ERRα expression and prognosis of CRC patients were evaluated by univariate, and multivariate (Cox proportional hazards model) analysis. RT-qPCR demonstrated that the mRNA expression of ERRα in CRC tissues was significantly higher compared with that in matched normal tissues. Immunohistochemistry revealed that ERRα high expression was detected in the nuclei of cancer cells from 39.1% (50/128) of CRC tissues. ERRα expression based on immunohistochemical staining was significantly associated with tumor differentiation, tumor invasion, lymph node status and Dukes stage (all P<0.05). Furthermore, patients with high ERRα expression were significantly associated with an increased risk of recurrence and poor prognosis, compared with patients with low ERRα expression. ERRα expression was identified as an independent prognostic factor for patients with CRC. In conclusion, ERRα serves important roles in the progression of CRC and is a potential prognostic factor for patients with CRC.

Association between variations in the disrupted in schizophrenia 1 gene and schizophrenia: A meta-analysis.

Schizophrenia is a severe psychiatric disorder. Genetic and functional studies have strongly implicated the disrupted in schizophrenia 1 gene (DISC1) as a candidate susceptibility gene for schizophrenia. Moreover, recent association studies have indicated that several DISC1 single nucleotide polymorphisms (SNPs) are associated with schizophrenia. However, the association is hardly replicate in different ethnic group. Here, we performed a meta-analysis of the association between DISC1 SNPs and schizophrenia in which the samples were divided into subgroups according to ethnicity. Both rs3738401 and rs821616 showed not significantly association with schizophrenia in the Caucasian, Asian, Japanese or Han Chinese populations.

High expression of RBM8A predicts poor patient prognosis and promotes tumor progression in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a huge threat for human health worldwide. As a complicated tumor, the molecular basis for HCC development especially metastasis requires exploration. Although RNA binding motif (RBM) proteins are closely related to various cancers, the clinical importance and underlying mechanisms of RBM8A in HCC remain elusive. In this study, we found that RBM8A was highly expressed in HCC tumor tissues compared to normal liver tissues. Overexpression of RBM8A was associated with HbsAg and Edmondson pathological grading. Moreover, Kaplan-Meier survival analysis showed that high expression of RBM8A was related to the poor overall survival and progression-free survival of patients with HCC. Gain- and loss-of-function experiments further demonstrated that RBM8A promoted tumor cell migration and invasion in HCC via activation of epithelial-mesenchymal transition signaling pathway. It is also noteworthy that RBM8A is required for tumor cell proliferation and anti-apoptosis in HCC. Altogether, our results revealed a close relationship between RBM8A and HCC prognosis as well as a critical tumor-promoting function of RBM8A in HCC progression, suggesting that RBM8A might be a potential bio-marker and drug target in HCC therapy.

The clinical significance and biological function of large tumour suppressor 2 in hepatocellular carcinoma.

OBJECTIVES: Present evidence has suggested that large tumour suppressor 2 (LATS2) is abnormally expressed in most human cancer. However, the clinical and prognostic value in hepatocellular carcinoma (HCC) is still unknown. MATERIALS AND METHODS: Large tumour suppressor 2 mRNA and protein expression levels in HCC tissues and cell lines were detected by qRT-PCR, immunohistochemistry or Western blot. The correlation between LATS2 expression and clinicopathological factors was analysed through immunohistochemistry. The function of LATS2 on HCC cell growth and mobility was explored through MTT, colony formation, Transwell migration and invasion assays. The molecular mechanism of LATS2 was screened and confirmed by qRT-PCR and Western blot. RESULTS AND CONCLUSION: In this study, LATS2 mRNA and protein expressions were decreased in HCC tissues and cell lines compared with normal hepatic tissues and hepatic cell line. Low LATS2 expression was oppositely corrected with tumour stage, vascular invasion and metastasis. The univariate and multivariate analyses suggested that low LATS2 expression was an independent poor prognostic factor for HCC patients. The in vitro experiments showed that LATS2 regulated HCC cells migration and invasion, but had no effect on HCC cells proliferation. Meanwhile, LATS2 modulated metastasis-associated genes expression including E-cadherin, vimentin, snail, slug, MMP2 and MMP9. In conclusion, LATS2 is a prognostic biomarker and a tumour metastasis suppressor in HCC.

Role of FK506-binding protein in Ca2+ spark regulation.

The elementary Ca2+ release events, Ca2+ sparks, has been found for a quarter of century. However, the molecular regulation of the spark generator, the ryanodine receptor (RyR) on the sarcoplasmic reticulum, remains obscure. Although each subunit of the RyR homotetramer has a site for FK506-binding protein (FKBP), the role of FKBPs in modifying RyR Ca2+ sparks has been debated for long. One of the reasons behind the controversy is that most previous studies detect spontaneous sparks, where the mixture with out-of-focus events and local wavelets prevents an accurate characterization of Ca2+ sparks. In the present study, we detected Ca2+ sparks triggered by single L-type Ca2+ channels (LCCs) under loose-seal patch clamp conditions in FK506-treated or FKBP12.6 knockout cardiomyocytes. We found that FKBP dissociation both by FK506 and by rapamycin decreased the Ca2+ spark amplitude in ventricular cardiomyocytes. This change was neither due to decreased releasable Ca2+ in the sarcoplasmic reticulum, nor explained by changed RyR sensitivity. Actually FK506 increased the LCC-RyR coupling probability and curtailed the latency for an LCC to trigger a RyR Ca2+ spark. FKBP12.6 knockout had similar effects as FK506/rapamycin treatment, indicating that the decreased spark amplitude was attributable to the dissociation of FKBP12.6 rather than FKBP12. We also explained how decreased amplitude of spontaneous sparks after FKBP dissociation sometimes appears to be increased or unchanged due to inappropriate data processing. Our results provided firm evidence that without the inter-RyR coordination by functional FKBP12.6, the RyR recruitment during a Ca2+ spark would be compromised despite the sensitization of individual RyRs.

Independent Tumor Origin in Two Cases of Synchronous Bilateral Clear Cell Renal Cell Carcinoma.

Bilateral renal cell carcinomas (RCCs) pose a challenge for clinical treatment and management. Most bilateral RCCs are sporadic, and do not show a hereditary pattern indicative of VHL syndrome or other inherited cancers. The origin and evolution of these sporadic bilateral RCCs remains elusive. We obtained normal and tumor samples from two male patients suffering from early stage synchronous bilateral clear cell RCC (ccRCC), and analyzed genomic DNA using whole exome sequencing and bisulfite pyrosequencing. We detected distinct 3p loss of heterozygosity (LOH) in both tumors in each patient. Two tumors within the same patient harbored distinct driver mutations and different CpG hypermethylation sites in the VHL promoter. Moreover, tumors exhibit independent evolutionary trajectories. Therefore, distinct 3p LOH, combined with contingent driver gene mutations and independent VHL hypermethylation, led to independent tumor origin and parallel evolution of bilateral ccRCC in these two patients. Our results indicate that tumors in these two cases were not due to common germline oncogenic mutations. They were results of multiple de novo mutations in each kidney, rather than primary ccRCC with contralateral renal metastasis. Therefore, histopathologic and genetic profiling from single tumor specimen may underestimate the mutational burden and somatic heterogeneity of bilateral ccRCCs.

Interaction between DISC1 and CHL1 in regulation of neurite outgrowth.

Disrupted-in-schizophrenia 1 (DISC1), a gene susceptible for major mental illnesses, including schizophrenia, plays multiple roles in neural development, including neuronal proliferation, maturation, migration and neurite outgrowth. DISC1 regulates neurite length via interaction with several intracellular proteins, such as NDEL1, FEZ1 and dysbindin. However, the signal transduction mechanism upstream of DISC1 in regulating neurite outgrowth remains to be elucidated. Here we show that DISC1 interacts with the intracellular domain of close homolog of L1 (CHL1), a member of the L1 family of neural cell adhesion molecules. DISC1 and CHL1 proteins co-localize in growth cones of cortical neurons. Moreover, in neurite outgrowth assay, CHL1 rescues the inhibitory effect of DISC1 on the initial phase of neurite outgrowth. Considering the fact that CHL1 also plays crucial roles in neural development, and its coding gene is associated with schizophrenia, our findings indicate that DISC1 and CHL1 may engage in physical and functional interaction in neural development, supporting the notion that DISC1 regulates neurite outgrowth with a receptor belonging to the neural cell adhesion molecules, and disruption of such interaction may contribute to increased risk for schizophrenia.

Comprehensive treatments for hepatocellular carcinoma with tumor thrombus in major portal vein.

AIM: To evaluate the efficacy of transcatheter arterial chemoembolisation (TACE) compared with surgical intervention and sorafenib for treatment of hepatocellular carcinoma (HCC) in patients with tumor thrombus extending to the main portal vein. METHODS: From 2009 to 2013, a total of 418 HCC patients with tumor thrombus extending to the main portal vein were enrolled in this study and divided into four groups. These groups underwent different treatments as follows: TACE (n = 307), surgical intervention (n = 54), sorafenib (n = 15) and palliative treatment (n = 42). Overall survival rates were determined by Kaplan-Meier method, and differences between the groups were identified through log-rank analysis. Cox's proportional hazard model was used to identify the risk factors for survival. RESULTS: The mean survival periods for patients in the TACE, surgical intervention, sorafenib and palliative treatment groups were 10.39, 4.13, 5.54 and 2.82 mo, respectively. For the TACE group, the 3-, 6-, 12- and 24-mo survival rates were 94.1%, 85.9%, 51.5% and 0.0%, respectively. The corresponding rates were 60.3%, 22.2%, 0.0% and 0.0% for the surgical intervention group and 50.9%, 29.5%, 0.0% and 0.0% for the sorafenib group. Evidently, the results in the TACE group were significantly higher than those in the other groups (P < 0.0001). Furthermore, no significant difference among survival rates was observed between TACE with/without sorafenib (10.22 mo vs 10.52 mo, P = 0.615). No significant difference in survival rates was also found among the surgical intervention, sorafenib and palliative treatment groups (P > 0.05). These values significantly increased after TACE with/without sorafenib compared with other treatments (P < 0.05). CONCLUSION: For HCC patients with tumor thrombus extending to the main portal vein, TACE can yield a higher survival rate than surgical intervention or sorafenib treatment.

Hepatic resection versus transarterial chemoembolization for patients with Barcelona Clinic Liver Cancer intermediate stage Child-Pugh A hepatocellular carcinoma.

The present study aimed to compare the overall and recurrence-free survival rates following hepatic resection (HR) and transcatheter arterial chemoembolization (TACE) in patients with Barcelona Clinic Liver Cancer (BCLC) classified intermediate-stage Child-Pugh A hepatocellular carcinoma (HCC). A total of 443 patients were examined, among whom 274 underwent HR, whereas 169 received TACE. The overall survival, recurrence-free survival between groups and subgroups, and risk factors with respect to mortality and recurrence, were analyzed. The 1-, 3- and 5-year overall and recurrence-free survival rates were 70, 46 and 37% and 73, 52, and 37%, respectively after HR, compared with 38, 15, and 12% and 44, 25 and 16%, respectively after TACE. Overall and recurrence-free survival rates were significantly increased following HR compared with TACE. Subgroup analysis in the multi-nodule group showed that the 1-, 3- and 5-year overall survival rates were 68, 38 and 30% after HR, compared with 36, 10 and 0% following TACE. In the solitary tumor group, 1-, 3- and 5-year overall survival rates were 71, 50 and 38% after HR, and 41, 22 and 15% after TACE. The overall survival rate after HR was significantly increased compared with that after TACE in the solitary tumor and multi-nodule groups. The risk factors for mortality include solitary tumor diameter >10 cm, multi-nodules, serum albumin level ≥35 g/l, prothrombin time >13 sec, alphafetoprotein levels >400 ng/ml, and patients with hepatitis B virus. Solitary tumor diameter >10 cm, multi-nodules, and hepatitis B virus (P<0.001) were found to be associated with higher recurrence of HCC. Overall and recurrence-free survival rates were improved after HR compared with those after TACE in BCLC stage B, Child-Pugh A, HCC patients.