Intraoperative neurophysiologic monitoring alteration during en bloc laminectomy surgery for thoracic ossification of ligamentum flavum.

Background: There is real risk during en bloc resection for the treatment of thoracic ossification of ligamentum flavum (TOLF). Intraoperative neurophysiologic monitoring (IONM) has been applied to monitor neurologic functional integration of the spinal cord during surgery. However, the IONM outcome and its relationship with clinical results still needs to be investigated. The purpose of this study is to evaluate the effectiveness and usefulness of IONM in en bloc laminectomy for TOLF. Methods: Data from a total of 68 patients with TOLF who received en bloc resection was collected for this retrospective study. IONM of somatosensory-evoked potentials (SSEPs) and motor-evoked potentials (MEPs) were analyzed in different patterns of signal alerts, i.e. alert in either MEPs or SSEPs, alert in both MEPs and SSEPs, permanent alert, or recovery during surgery. Postoperative motor and sensory neurological function was evaluated in each patient immediately after surgery and at 12-month follow-up after surgery. The relationship of IONM outcomes and postoperative neurologic function were observed. Results: Fifty of 68 patients did not present significant changes over alert criteria of IONM, neither SSEPs nor MEPs. Those 50 patients without IONM alerts did not show post-operative neurologic deterioration. Four patients presented alert of IONM in a single modality, while 2 patients showed only SSEP alert and 2 patients showed only MEP alert. Fourteen patients showed alerts in both SSEP and MEP, while 8 patients showed one or both signals return to normal during surgery and other 6 showed permanent abnormal electrophysiologic signals to the end of surgery. In the follow-up neurologic test, 3 patients presented transient neurologic complications from among 8 patients with both SSEP and MEP alerts and recovery during surgery. Six patients without recovery of IONM showed permanent neurologic complications after surgery. Conclusions: Results of this study prove the effectiveness and usefulness of IONM in in en bloc laminectomy surgery for TOLF. The patterns of IONM changes correlated with postoperative neurologic functions. Special attention must be paid to the rapid loss of IONM without recovery during spinal decompression.

Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism.

Mutations in many synaptic genes are associated with autism spectrum disorders (ASD), suggesting that synaptic dysfunction is a key driver of ASD pathogenesis. Among these mutations, the R451C substitution in the NLGN3 gene that encodes the postsynaptic adhesion molecule Neuroligin-3 is noteworthy because it was the first specific mutation linked to ASDs. In mice, the corresponding Nlgn3 R451C-knockin mutation recapitulates social interaction deficits of ASD patients and produces synaptic abnormalities, but the impact of the NLGN3 R451C mutation on human neurons has not been investigated. Here, we generated human knockin neurons with the NLGN3 R451C and NLGN3 null mutations. Strikingly, analyses of NLGN3 R451C-mutant neurons revealed that the R451C mutation decreased NLGN3 protein levels but enhanced the strength of excitatory synapses without affecting inhibitory synapses; meanwhile NLGN3 knockout neurons showed reduction in excitatory synaptic strengths. Moreover, overexpression of NLGN3 R451C recapitulated the synaptic enhancement in human neurons. Notably, the augmentation of excitatory transmission was confirmed in vivo with human neurons transplanted into mouse forebrain. Using single-cell RNA-seq experiments with co-cultured excitatory and inhibitory NLGN3 R451C-mutant neurons, we identified differentially expressed genes in relatively mature human neurons corresponding to synaptic gene expression networks. Moreover, gene ontology and enrichment analyses revealed convergent gene networks associated with ASDs and other mental disorders. Our findings suggest that the NLGN3 R451C mutation induces a gain-of-function enhancement in excitatory synaptic transmission that may contribute to the pathophysiology of ASD.

Changes of immune-related factors in the blood of schizophrenia and bipolar disorder patients receiving monotherapy.

Schizophrenia (SCZ) and bipolar disorder (BPD) are associated with abnormal expression of immune-related factors (IRFs), which have been proposed as biomarkers of either disease diagnosis (trait markers) or treatment (state markers). However, the state markers have been found to be less reproducible than the trait markers in previous studies. In the current study, we focused on the changes of IRFs in blood of SCZ and BPD patients receiving monotherapy. SCZ (N = 49) and BPD (N = 49) Chinese patients were recruited at acute episode and followed for 9 to 51 days until remission. Blood samples were collected at two state-points, acute state before treatment and remission state after treatment. A total of 41 IRFs in plasma were quantified by the Luminex assay. After adjusting covariates, we found four cytokines or cytokine receptors were significantly increased at remission when compared to acute episode in all the patients, including CD30, BAFF, CCL20, and CXCL10 (Bonferroni corrected p < 0.05). CD30 and BAFF were consistently increased in both SCZ and BPD while the increase of CCL20 was only observed in BPD but not SCZ when analyzing the two disorders separately. CXCL10 change was not significant in either SCZ or BPD alone. The changes of these four factors were correlated with each other, but not with clinical features. CD30 concentration in the BPD acute state was correlated with sleep quality (Spearman's rs = 0.365, Bonferroni corrected p < 0.05). Overall, we found that four factors (CD30, BAFF, CCL20, and CXCL10) might be associated with treatment of psychosis.

Spatiotemporal specificity of correlated DNA methylation and gene expression pairs across different human tissues and stages of brain development.

DNA methylation (DNAm) that occurs on promoter regions is primarily considered to repress gene expression. Previous studies indicated that DNAm could also show positive correlations with gene expression. Both DNAm and gene expression profiles are known to be tissue- and development-specific. This study aims to investigate how DNAm and gene expression are coordinated across different human tissues and developmental stages, as well as the biological significance of such correlations. By analyzing 2,239 samples with both DNAm and gene expression data in the same human subjects obtained from six published datasets, we evaluated the correlations between gene and CpG pairs (GCPs) at cis-regions and compared significantly correlated GCPs (cGCPs) across different tissues and brains at different age groups. A total of 37,363 cGCPs was identified in the six datasets; approximately 38% of the cGCPs were positively correlated. The majority (>90%) of cGCPs was tissue- or development-specific. We also observed that the correlation direction can be opposite in different tissues and ages. Further analysis highlights the importance of cGCPs for their cellular functions and potential roles in complex traits and human diseases. For instance, the early developmental brain possessed a highly unique set of cGCPs that were associated with neurogenesis and psychiatric disorders. By assessing the epigenetic factors involved in cGCPs, we discovered novel regulatory mechanisms of positive cGCPs distinct from negative cGCPs, which were related to multiple factors, such as H3K27me3, CTCF, and JARD2. The catalogue of cGCPs compiled can be used to guide functional interpretation of genetic and epigenetic studies.

Agonal Factors Distort Gene-Expression Patterns in Human Postmortem Brains.

Agonal factors, the conditions that occur just prior to death, can impact the molecular quality of postmortem brains, influencing gene expression results. Our study used gene expression data of 262 samples from ROSMAP with the detailed terminal state recorded for each donor, such as fever, infection, and unconsciousness. Fever and infection were the primary contributors to brain gene expression changes, brain cell-type-specific gene expression, and cell proportion changes. Furthermore, we also found that previous studies of gene expression in postmortem brains were confounded by agonal factors. Therefore, correction for agonal factors is important in the step of data preprocessing. Our analyses revealed fever and infection contributing to gene expression changes in postmortem brains and emphasized the necessity of study designs that document and account for agonal factors.

MAPK4 deletion enhances radiation effects and triggers synergistic lethality with simultaneous PARP1 inhibition in cervical cancer.

BACKGROUND: Cervical cancer is one of the most common cancers among females worldwide and advanced patients have extremely poor prognosis. However, adverse reactions and accumulating resistance to radiation therapy require further investigation. METHODS: The expression levels of mitogen-activated protein kinase 4 (MAPK4) mRNA were analyzed by real-time PCR and its association with overall survival was analyzed using Kaplan-Mier method. Colony formation, immunofluorescence and western blotting were used to examine the effects of MAPK4 knockout or over-expression on cervical cancer cells after radiation treatment. Drug-sensitivity of cervical cancer cells to PARP1 inhibitors, olaparib or veliparib, was analyzed by CCK-8 cell viability assays, and the 50% inhibitory concentration (IC50) was quantified using GraphPad Prism. The functional effects of MAPK4 knockout on the sensitivity of cervical cancer to radiation treatment and PARP1 inhibitors were further examined using xenograft tumor mouse models in vivo. RESULTS: Cervical cancer patients with high MAPK4 mRNA expression have lower survival rate. After radiation treatment, the colony number of MAPK4 knockout cells was markedly reduced, and the markers for DNA double-chain breakage were significantly up-regulated. In addition, MAPK4 knockout reduced protein kinase B (AKT) phosphorylation, whereas its over-expression resulted in opposite effects. In MAPK4 KO cells with irradiation treatment, inhibition of AKT phosphorylation promoted DNA double-chain breakage. Constitutive activation of AKT (CA-AKT) increased the levels of phosphorylated-AKT (p-AKT), and DNA repair-related proteins, phosphorylated-DNA-dependent protein kinase (p-DNA-PK) and RAD51 recombinase (RAD51). Furthermore, MAPK4 knockout was found to affect the sensitivity of cervical cancer cells to poly ADP-ribose polymerase 1 (PARP1) inhibitors by activating the phosphorylation of AKT. Moreover, in vivo results demonstrated that MAPK4 knockout enhanced the sensitivity of cervical cancer to radiation and PARP1 inhibitors in mouse xenograft models. CONCLUSIONS: Collectively, our data suggest that combined application of MAPK4 knockout and PARP1 inhibition can be used as therapeutic strategy in radiation treatment for advanced cervical carcinoma.

A meta-analysis of the relationship between environmental tobacco smoke and lung cancer risk of nonsmoker in China.

BACKGROUND: To investigate the association between exposure to environmental tobacco smoke (EVT) and the incidence of lung cancer (LC) in nonsmoking adults. METHOD: PubMed, Cochrane, Embase, Wanfang, CNKI, and VIP database were searched by the index words to identify the qualified case-control studies, and relevant literature sources were also searched. The latest research was done in June 2017. Odds radio (OR) along with 95% confidence interval (95% CI) were used to analyze the main outcomes. RESULT: Twenty RCTs were involved in the meta-analysis with 13,004 adults in the case group and 11,199 adults in the control group. The results indicated that compared with the nonexposure population, the risk of LC incidence was significantly higher in EVT exposure (OR: 1.64, 95% CI: 1.34-2.01), EVT male exposure (OR: 1.62, 95% CI: 1.16-2.28), EVT female exposure (OR: 1.57, 95% CI: 1.43-1.72), EVT exposure at workplace (OR: 1.78, 95% CI: 1.29-2.44), EVT exposure at home (OR: 1.53, 95% CI: 1.01-2.33), and EVT female exposure at home (OR: 1.55, 95% CI: 1.34-1.79). However, there is still no significant difference among the risk of LC incidence in EVT male exposure at workplace (OR: 1.51, 95% CI: 0.74-3.06), EVT female exposure at workplace (OR: 1.23, 95% CI: 0.99-1.53), and EVT male exposure at home (OR: 1.24, 95% CI: 0.68-2.26). CONCLUSION: EVT exposure is prospectively associated with a significantly increased risk of LC incidence. More high quality studies are required to address the association between EVT exposure and LC incidence.

miRNA targeted signaling pathway in the early stage of denervated fast and slow muscle atrophy.

Denervation often results in skeletal muscle atrophy. Different mechanisms seem to be involved in the determination between denervated slow and fast skeletal muscle atrophy. At the epigenetic level, miRNAs are thought to be highly involved in the pathophysiological progress of denervated muscles. We used miRNA microarrays to determine miRNA expression profiles from a typical slow muscle (soleus muscle) and a typical fast muscle (tibialis anterior muscle) at an early denervation stage in a rat model. Results showed that miR-206, miR-195, miR-23a, and miR-30e might be key factors in the transformation process from slow to fast muscle in denervated slow muscles. Additionally, certain miRNA molecules (miR-214, miR-221, miR-222, miR-152, miR-320, and Let-7e) could be key regulatory factors in the denervated atrophy process involved in fast muscle. Analysis of signaling pathway networks revealed the miRNA molecules that were responsible for regulating certain signaling pathways, which were the final targets (e.g., p38 MAPK pathway; Pax3/Pax7 regulates Utrophin and follistatin by HDAC4; IGF1/PI3K/Akt/mTOR pathway regulates atrogin-1 and MuRF1 expression via FoxO phosphorylation). Our results provide a better understanding of the mechanisms of denervated skeletal muscle pathophysiology.

Increased osteopontin protein expression may be correlated with poor prognosis in non-small-cell lung cancer: A meta analysis.

AIM: The present meta-nalysis investigates the prognostic value of osteopontin. (OPN) expression in patients with non-small-cell lung cancer. (NSCLC). MATERIALS AND METHODS: The Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013) were searched, without language restrictions, to retrieve studies related to OPN and NSCLC. We compiled carefully selected data and a meta-analysis was conducted using STATA software (Version 12.0, Stata Corporation, and College Station, Texas USA). Hazard ratios (HR) with corresponding 95% confidence interval (95%CI) were calculated. RESULTS: Ten clinical cohort studies were selected for statistical analysis, representing a total of 1,133 NSCLC patients. The main findings of our meta-analysis are that patients who were OPN-positive had significantly shorter overall survival than OPN-negative patients. (HR = 1.47, 95%CI = 1.15. ~ 1.79,P< 0.001). Ethnicity.stratified analysis revealed a significant correlation between expression levels of OPN and poor prognosis of NSCLC patients among both Caucasians and Asians. (Asians: HR = 1.53, 95%CI = 0.95. ~ 2.11, P < 0.001; Caucasians: HR = 1.56, 95%CI = 1.08. ~ 2.03, P < 0.001; respectively). CONCLUSIONS: The present meta-analysis is consistent with the hypothesis that increased expression of OPN protein may be significantly associated with poor prognosis in patients with NSCLC.

rs833061 and rs699947 on promoter gene of vascular endothelial growth factor (VEGF) and associated lung cancer susceptibility and survival: a meta-analysis.

BACKGROUND: As 2 important SNPs located in the promoter region of VEGF gene, the roles of rs833061 (-460C>T) and rs699947 (-2578C>A) in lung cancer susceptibility and survival remain inconclusive and controversial. MATERIAL/METHODS: For better understanding of these 2 SNPs in lung cancer risk and survival, a meta-analysis was performed to pool findings of previous studies and to generate large-scale evidence. RESULTS: Based on the 10 eligible studies included, this study observed that the -460C>T polymorphism generally had no significant effect on lung cancer risk. However, subgroup analysis found that -460TT homozygote variant might confer significantly increased cancer risk for Asians (TT vs. CC: OR=1.69, 95% CI 1.08-2.63, p=0.02), but not in Caucasians. Similar results were observed in -2578C>A in Asians (AA vs. CC: OR=3.00, 95% CI 1.51-5.95, p=0.002; AA vs. AC: OR=3.15, 95% CI 1.00-9.91, p=0.05; AA vs. (AC+CC): OR=2.92, 95% CI 1.51-5.65, p=0.001). In lung cancer survival, 4 trials included had conflicting results. One found -460C>T polymorphism had no effect on survival, 1 observed risk increasing, while the remaining 2 observed risk decreasing. This inconsistency was closely related to the different therapeutic practices applied in different studies, the effects of which were significantly affected by VEGF expression. CONCLUSIONS: -460TT and -2578AA homozygote might lead to significantly increased cancer risk for Asians, but the effects on survival remain to be explored. These 2 SNPs might be potential indicators of lung cancer risk for Asians and should be considered when planning chemotherapy and radiotherapy for lung cancer patients.