Micro-infusion of 5-HT1a receptor antagonists into the ventral subiculum ameliorate MK-801 induced schizophrenia-like behavior in rats.

Recent studies have shown that the 5-HT1a receptor (5-HT1aR) in the central 5-HT (Serotonergic) system is involved in the pathophysiology of schizophrenia through its various receptors, and the dysfunction of the ventral hippocampus may be a key causative factor in schizophrenia. To date, whether the 5-HT1a receptor is involved in ventral hippocampal dysfunction and its internal mechanism remain unclear. In this study, schizophrenia-like animal model was induced by intraperitoneal injection of aspartate receptor antagonist MK-801 in male Sprague Dawley rats, and the role of 5-HT1aR in this animal model was investigated by bilaterally micro-infusing the 5-HT1aR antagonist WAY100635 into the ventral subiculum (vSub) of the hippocampus of rats. Behavioral experiments such as open field test (OFT) and prepulse inhibition (PPI) were performed. The results showed that MK-801 induced hyperactivity and impaired prepulse inhibition in rats, whereas, micro-infusion of 5-HT1aR antagonist WAY100635 into the vSub ameliorated these phenomena. Immunofluorescence analysis revealed that WAY100635 significantly increased the c-Fos expression in vSub. Western blot and immunohistochemical analysis showed that MK-801 induced up-regulation of 5-HT1aR and phospho-extracellular regulated protein kinase (p-ERK) pathway, while micro-infusion of the WAY100635 down-regulated 5-HT1aR and p-ERK in the vSub. Therefore, the results of the present study suggested that in vSub, the 5-HT1aR antagonist WAY100635 may attenuate MK-801-induced schizophrenia-like activity by modulating excitatory neurons and downregulating p-ERK.

Anti-PD-1 and anti-PD-L1 drugs treatment-related adverse events for patients with cancer: Protocol for an overview of systematic reviews with meta-analyses.

BACKGROUND: Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) drugs treatment-related adverse events (AEs) are not uniform based on current study for patients with cancer. The study aimed to provide a complete toxicity profile and toxicity spectrum for anti-PD-1 and anti-PD-L1 drugs. METHODS: All systematic reviews (SRs) with meta-analyses (MAs) relate to the anti-PD-1 and anti-PD-L1 drugs and SRs will be searched in the database of PubMed, Embase, Cochrane Library, and Web of Science from inception to February 2019. Eligible publications must have reported site, organ, or system level data on treatment-related AEs. The following will extract from each SRs: first author, year of publication, country of origin, number of origin study, number of patients enrolled, participant characteristics, duration of cancer diagnosis, cancer types, detailed description of treatment, and occurrence of AEs. Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) and A Measurements Tool to Assess Systematic Reviews 2 (AMSTAR-2) will be used to assess the reporting and methodological quality of SRs/MAs. The characteristics of the included SRs/MAs and their quality will descriptively summarized using systematically structured tables. A network meta-analysis (NMAs) approach versus a narrative synthesis will be used to examine data synthesis considered. Odds ratios and 95% credibility intervals will be used as summary statistics. Evidence mapping (EM) method will to present the evidence landscape related to anti-PD-1 and anti-PD-L1 drugs treatment-related AEs for patients with cancer. DISCUSSION: The results of the overview will be submitted to a peer-reviewed journal for publication. ETHICS AND DISSEMINATION: Because this study is not a clinical study, and we will search and evaluate only existing sources of literature. So, ethical approval is not required.

Efficacy of melanoma patients treated with PD-1 inhibitors: Protocol for an overview, and a network meta-analysis of randomized controlled trials.

BACKGROUND: Melanoma is a malignant tumor of melanocytes that produces pigments and can occur in the whole body. It is characterized by strong invasiveness, high metastasis rate and poor prognosis, and brings heavy burden to patients and society. In order to find the most effective and safe treatment measures, in this study, a network meta-analysis (NMA) for randomized controlled trials (RCTs) of advanced melanoma treated with PD-1 inhibitors will be conducted based on the existing systematic reviews (SRs) of PD-1 inhibitor in the treatment of advanced melanoma. METHODS: PubMed, EMBASE, Web of Science and the Cochrane Library were searched on December 18, 2018 to obtain systematic reviews of PD-1 inhibitor in the treatment of advanced melanoma. Assessing the Methodological Quality of Systematic Reviews (AMSTAR2) will be used to assess the methodological quality of systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach will be applied to evaluate the evidence quality of outcome measures, and the Cochrane's risk of bias tool will be utilized to appraise risks of bias of each embedded RCTs. And the outcomes are overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Hazard ratio (HR) or odds ratio (OR) with their 95% confidence interval (CI) were used to synthesize dichotomous outcomes, while the mean difference (MD) for the continuous variables. R3.5.1 will be used to create a network evidence map for direct and indirect comparative analysis. RESULTS: This study will provide a comprehensive summary of the current evidences related to the efficacy and safety of PD-1 inhibitor in advanced melanoma. CONCLUSION: Our findings will be useful to assist clinicians make reasonable decisions to the treatment of advanced melanoma. ETHICS AND COMMUNICATION: It is unnecessary for this NMA to acquire an ethical approval, because it is based on published researches. PROSPERO REGISTRATION NUMBER: CRD42019120017.

Biomarkers for detecting prostate cancer: Protocol for an umbrella review with integrated network meta-analysis.

BACKGROUND: Prostate cancer (PCa) is common, with it being the 2nd most prevalent cancer in men worldwide and the 6th leading cause of death in men. Screening for any type of cancer aims to increase the chances of successful treatment through early detection of the disease. There were some systematic reviews (SRs) evaluated the diagnostic value of biomarkers for the diagnosis of PCa and no studies have been conducted to analyze the quality of these SRs. We are not clear which kind of marker is the best choice. Thus, this study aims to assess the methodologic quality of the SRs and reanalyze the published data based on SRs for the biomarkers to find the optimal biomarker for the early diagnosis of PCa. METHODS: We performed a systematic literature search of PubMed, Embase, Web of Science, and Cochrane Library and to identify relevant SRs from inception to April 2019. Diagnostic accuracy studies included any type of single biomarker or combined biomarkers aimed at evaluating the diagnostic value is considered eligible for this overview. The Assessment of Multiple Systematic Reviews-2 (AMSTAR-2) instrument will be used to evaluate the risk of bias of the included SRs. Standard pairwise meta-analysis and adjusted indirect comparison will be used to compare the diagnostic value of different biomarkers. RESULTS: The results of this study will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study will reanalyze the published data based on SRs. We hope that the results will help find a biomarker with the superior diagnostic performance for the diagnosis of PCa. PROSPERO REGISTRATION NUMBER: CRD42019125880.

Hormonal biomarkers for the noninvasive diagnosis of endometriosis: A protocol for a network meta-analysis of diagnostic test accuracy.

BACKGROUND: Endometriosis is a major cause of disability and compromised the quality of life in women and teenage girls. The gold standard for diagnosis of endometriosis is laparoscopy with histology of excised endometriosis lesions. However, women can suffer for 8 to 12 years before obtaining a correct diagnosis. Several biomarkers showed good diagnostic value for endometriosis, but no studies directly or indirectly compare the diagnostic value of different biomarkers. We perform this network meta-analysis (NMA) to assess the diagnostic accuracy of hormonal biomarkers, and to find a most effective hormonal biomarker for the diagnosis of endometriosis. METHODS: A systematic search will be performed using PubMed, EMBASE, Cochrane Library and Chinese Biomedicine Literature to identify relevant studies from inception to August 2018. We will include random controlled trials, cross-sectional studies, case-control studies, and cohort studies that evaluated the diagnostic accuracy of hormonal markers for endometriosis. The Quality Assessment of Diagnostic Accuracy Studies 2 quality assessment tool will be used to assess the risk of bias in each study. Standard pairwise meta-analysis and NMA will be performed using STATA V.12.0, MetaDiSc 1.40 and R 3.4.1 software to compare the diagnostic efficacy of different hormonal biomarkers. RESULTS: The results of this study will be published in a peer-reviewed journal. CONCLUSION: This study will summarize the direct and indirect evidence to determine the diagnostic accuracy of the hormonal biomarkers for endometriosis and attempt to find a most effective biomarker for the diagnosis of endometriosis. ETHICS AND DISSEMINATION: Ethics approval and patient consent are not required as this study is a meta-analysis based on published studies. PROSPERO REGISTRATION NUMBER: CRD42018105126.

Nucleolar localization of Small G protein RhoA is associated with active RNA synthesis in human carcinoma HEp-2 cells.

Previous studies have demonstrated that the nuclear localization of ras homolog family member A (RhoA), with prominent concentration in the nucleolus, is a common feature in human cancer tissues and cancer cell lines. Although a previous study has demonstrated that the nuclear translocation of RhoA occurs via active transport, a process that occurs through importin α in a nuclear factor-κB-dependent manner, the mechanism, biological function and pathological meaning of the nucleolar residency of RhoA remain to be elucidated. As the cell nucleolus is the site of ribosome biosynthesis, the aim of the present study was to investigate the association between RNA synthesis and the nucleolar localization of RhoA, as well as the molecular mechanisms underlying the residency of RhoA in the nucleolus of HEp-2 (human larynx epithelial carcinoma) cells. Indirect immunofluorescence microscopy was used to evaluate the subcellular distribution of nuclear RhoA, and immunoblotting analysis was used to determine the total cellular protein level of RhoA. Consistent with the results of previous studies, untreated HEp-2 cells exhibited bright nucleolar staining, indicating an increased concentration of RhoA in the nucleoli. Treatment with actinomycin D for the inhibition of RNA synthesis caused a redistribution of RhoA from the nucleoli to the nucleoplasm with a speckled staining pattern. Immunoblotting revealed that neither the total cellular amount of RhoA nor the integrity of RhoA was affected by treatment with actinomycin D. In cells that were treated at a decreased concentration (0.05 mg/l) of actinomycin D, the redistribution of RhoA was reversible following the removal of the drug from the culture medium. However, this reversal was not observed at an increased drug concentration (1 mg/l). Overall, to the best of our knowledge, the results of the present study provide the first in situ evidence that the inhibition of RNA synthesis induces a redistribution of nucleolar RhoA to the nucleoplasm, and additionally suggest that the nucleolar residency of RhoA in HEp-2 cells may be associated with active RNA synthesis.

Breviscapine, a traditional Chinese medicine, alleviates myocardial ischaemia reperfusion injury in diabetic rats.

OBJECTIVE: The aim of this study was to explore the effects of breviscapine on the expressions of intercellular adhesion molecule-I (ICAM-I), ATPase activities and oxidative stress in ischaemia-reperfused (I/R) myocardium of diabetic rats. METHODS: Sprague Dawley rats were randomly divided into two groups (a diabetic group and a non-diabetic group), and each group divided into two subgroups including a control group and a breviscapine group. Reperfusion surgery was carried out in all rats.The contents of malonaldehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-P(x)) in serum and myocardial tissues were measured. The activities of Na(+)-K(+)-ATPase, Mg(2+)-ATPase, Ca(2+)-ATPase in myocardial mitochondria were measured. The ICAM-I protein expressions in myocardium were determined with the immunohistochemical method. RESULTS: The activities of Na(+)-K(+)-ATPase, Mg(2+)-ATPase, Ca(2+)-ATPase were significantly increased in diabetic rats in the breviscapine group compared with the control group. Compared with the non-diabetic control group, the contents of MDA in serum and myocardium were significantly increased in the diabetic control group. Breviscapine led to a reduction of the contents of MDA in the diabetic and non-diabetic group. Compared with the non-diabetic control group, the activities of SOD and GSH-P(x) in the myocardium were significantly decreased in the diabetic control group.The activities of SOD and GSH-P(x) in serum and myocardium were increased in the diabetic and non-diabetic group after breviscapine treatment. Compared with the non-diabetic control group, the ICAM- I protein expressions were increased significantly in the diabetic control group. Breviscapine decreased the ICAM-I protein expression in the diabetic and the non-diabetic group. CONCLUSION: Breviscapine may have protective effects on myocardial ischaemia reperfusion injury of diabetic rats by scavenging oxygen free radicals, decreasing the expressions of ICAM-I protein in myocardium and increasing the activities of Na(+)-K(+)-ATPase, Mg(2+)-ATPase, Ca(2+)-ATPase in myocardial mitochondria.