Advanced prostate cancer (PRAD) patients have poor prognosis and rising morbidity despite the ongoing iteration of molecular therapeutic agents. As newly discovered proteins with several functions, Moonlighting proteins have showed an important role in tumor progression but has not been extensively investigated in PRAD. Our study aimed to identify moonlighting-related prognostic biomarkers and prospective PRAD therapy targets. 103 moonlighting genes were gathered from previous literatures. A PRAD classification and multivariate Cox prognostic signature were constructed using dataset from The Cancer Genome Atlas (TCGA). Subsequently, we tested our signature’s potential to predict biochemical failure-free survival (BFFS) using GSE21032, a prostate cancer dataset from Gene Expression Omnibus (GEO). The performance of this signature was demonstrated by Kaplan-Meier (KM), receiver operator characteristic (ROC), areas under ROC curve (AUC), and calibration curves. Additionally, immune infiltration investigation was conducted to determine the impact of these genes on immune system. This signature’s influence on drug susceptibility was examined using CellMiner’s drug database. Both training and validation cohorts demonstrated well predictive capacity of this 9-gene signature for PRAD. The 3-year AUCs for TCGA-PRAD and GSE21032 were 0.802 and 0.60 respectively. It can effectively classify patients into various biochemical recurrence risk groups. These genes were also assessed to be connected with tumor mutation burden (TMB), immune infiltration and therapy. This work created and validated a moonlighting gene signature, revealing fresh perspectives on moonlighting proteins in predicting prognosis and improving treatment of PRAD.

Background: Lacosamide (LCM), a novel AED (antiepileptic drug), was used as an adjunctive treatment in patients with partial-onset seizures or without secondary generalization. However, no meta-analysis was performed to evaluate the efficacy of LCM as an adjunctive treatment in post-marketing clinical studies.Aims: To assess the safety and efficacy of LCM as an adjunctive treatment in adults with refractory epilepsy, a systematic review and meta-analysis of randomized controlled trials (RCTs) and real-world studies were performed.Methods: All studies were identified from electronic databases. Both RCTs and observational prospective studies were included. Primary outcomes included responder rate, adverse effects (AEs) and withdraw rate. The pooled rates (PR) with their corresponding 95% confidence intervals (CI) were calculated. Publication bias was assessed with Begg's or Egger's tests.Results: Total 16 studies (3,191 patients) including 5 RCTs and 11 real-word studies were enrolled. The pooled 50% responder rate and seizure-free rate were 48% (95% CI: 0.42, 0.54) and 9% (95% CI: 0.06, 0.11) in all studies, respectively. Subgroup analysis showed that the pooled 50% responder rate were 53% (95% CI: 0.44, 0.62) from observational studies and 38% (95% CI: 0.35, 0.42) from RCTs, respectively; the pooled seizure-free rate were 13% (95% CI: 0.09, 0.18) from observational studies and 4% (95% CI: 0.06, 0.11) from RCTs, respectively. Similar incidence of AEs were reported in real-world studies (0.57, 95% CI: 0.43, 0.72) and RCTs (0.59, 95% CI: 0.42–0.76). Finally, a total of 13% (95%CI: 0.09, 0.16) and 13% (95% CI: 0.08, 0.16) of all patients prescribed with LCM was withdrawn in RCTs and real-world studies, respectively, due to the occurrence of AEs. Furthermore, similar to the 50% responder rate, seizure-free rate, incidence of AEs and withdraw rate were reported at 6-month or at least 12-month of LCM adjunction. Publication bias was not detected in these studies.Conclusions: Our results revealed that LCM adjunctive therapy even with long-term treatment was efficacious and well tolerated in adults with refractory epilepsy.

2,5-hexanedione (2,5-HD) is the main active metabolite of n-hexane and induces apoptosis in nerve tissue, however, the mechanism of which remains unclear. In the present study, neuropathic animal models were successfully constructed in rats by injecting 100, 200 and 400 mg/kg 2,5-HD intraperitoneally for 5 weeks. Rats exposed to 2,5-HD exhibited progressive gait abnormalities and slower motor neural response in a dose-dependent manner. TUNEL analysis and immunofluorescence dual labeling revealed that the spinal cord of the 2,5-HD treated rats underwent significantly more apoptosis in the cells of spinal cord than that of the control group. The neuron apoptosis index in spinal cord was 4.1%, 6.7%, 9.8% respectively in rats exposed to 100, 200 and 400 mg/kg 2,5-HD, compared with 1.1% in the control group (p < 0.05). Biochemical analysis showed that 2,5-HD exposure downregulated NGF expression in the spinal cord of the intoxicated rats; inhibited the phosphorylation of Akt and Bad, two key players in PI3K/Akt pathway downstream of NGF; increased the dimerization of Bad with Bcl-xL in the mitochondrial fraction, followed by the release of cytochrome c and activation of caspase-3 in the spinal cord of rats. In vitro study showed that the NGF expression decreased significantly in VSC4.1 cells dosed with 5.0, 10.0 mM 2,5-HD in comparison with the control group. It was also found that NGF supplement repressed the induced apoptosis, and increased p-Akt and p-Bad level in 2,5-HD treated VSC4.1 cells, which could be antagonized by PI3K kinase (the upstream member of Akt) inhibitor LY294002. Taken together, our experimental results indicate that 2,5-HD may induce apoptosis in the spinal cord of rats via downregulating NGF expression and subsequently repressing PI3K/Akt signaling pathway.

We previously reported that arsenic (As) impaired learning and memory by down-regulating calmodulin-dependent protein kinase IV (CaMK IV) in mouse cerebellum. It has been documented that the thyroid hormone receptor (TR)/retinoid X receptor (RXR) heterodimer and thyroid hormone (TH) may be involved in the regulation of CaMK IV. To investigate whether As affects the TR/RXR heterodimer and TH, we determined As concentration in serum and cerebellum, 3,5,3’-triiodothyronine (T3) and thyroxin (T4) levels in serum, and expression of CaMK IV, TR and RXR in cerebellum of mice exposed to As. Cognition function was examined by the step-down passive avoidance task and Morris water maze (MWM) tests. Morphology of the cerebellum was observed by Hematoxylin-Eosin staining under light microscope. Our results showed that the concentrations of As in the serum and cerebellum of mice both increased with increasing As-exposure level. A significant positive correlation was found between the two processes. Adeficit in learning and memory was found in the exposed mice. Abnormal morphologic changes of Purkinje cells were observed in cerebellum of the exposed mice. Moreover, the cerebellar expressions of CaMK IV protein and the TRβ gene, and TRβ1 protein were significantly lower in As-exposed mice than those in controls. Subchronic exposure to As appears to increase its level in serum and cerebella of mice, impairing learning and memory and down-regulating expression of TRβ1 as well as down-stream CaMK IV. It is also suggested that the increased As may be responsible for down-regulation of TRβ1 and CaMK IV in cerebellum and that the down-regulated TRβ1 may be involved in As-induced impairment of learning and memory via inhibiting CaMK IV and its down-stream pathway.

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease. The accumulation of amyloid-beta (Aβ) plaques is a distinctive pathological feature of AD patients. The aims of this study were to evaluate the therapeutic effect of chicoric acid (CA) on AD models and to explore its underlying mechanisms. APPswe/Ind SH-SY5Y cells and 5xFAD mice were treated with CA. Soluble Aβ1–42 and Aβ plaque levels were analyzed by ELISA and immunohistochemistry, respectively. Transcriptome sequencing was used to compare the changes in hippocampal gene expression profiles among the 5xFAD mouse groups. The specific gene expression levels were quantified by qRT-PCR and Western blot analysis. It was found that CA treatment reduced the Aβ1–42 levels in the APPswe/Ind cells and 5xFAD mice. It also reduced the Aβ plaque levels as well as the APP and BACE1 levels. Transcriptome analysis showed that CA affected the synaptic-plasticity-related genes in the 5xFAD mice. The levels of L1CAM, PSD-95 and synaptophysin were increased in the APPswe/Ind SH-SY5Y cells and 5xFAD mice treated with CA, which could be inhibited by administering siRNA-L1CAM to the CA-treated APPswe/Ind SH-SY5Y cells. In summary, CA reduced Aβ levels and increased the expression levels of synaptic-function-related markers via L1CAM in AD models.

Gallbladder carcinoma (GBC) is a vicious and invasive disease. The major challenge in the clinical treatment of GBC is the lack of a suitable prognosis method. Chemokine receptors such as CXCR3, CXCR4 and CXCR7 play vital roles in the process of tumour progression and metastasis. Their expression levels and distribution are proven to be indicative of the progression of GBC, but are hard to be decoded by conventional pathological methods, and therefore, not commonly used in the prognosis of GBC. In this study, we developed a computer‐aided image analysis method, which we used to quantitatively measure the expression levels of CXCR3, CXCR4 and CXCR7 in the nuclei and cytoplasm of glandular and interstitial cells from a cohort of 55 GBC patients. We found that CXCR3, CXCR4 and CXCR7 expressions are associated with the clinicopathological variables of GBC. Cytoplasmic CXCR3, nuclear CXCR7 and cytoplasmic CXCR7 were significant predictive factors of histology invasion, whereas cytoplasmic CXCR4 and nuclear CXCR4 were significantly correlated with T and N stage and were associated with the overall survival and disease‐free survival. These results suggest that the quantification and localisation of CXCR3, CXCR4 and CXCR7 expressions in different cell types should be considered using computer‐aided assessment to improve the accuracy of prognosis in GBC.