Xiaoyao Pills, a Chinese patent medicine, treats mild and moderate depression: A randomized clinical trial combined with DNA methylation analysis.

BACKGROUND: Xiaoyao pills (XYP) is a commercial Chinese patent medicine used in the treatment of depression. However, the mechanisms underlying its therapeutic effects, as well as the patients who can benefit from XYP, have not been evaluated so far. OBJECTIVES: To this end, we conducted a double-blinded, random, and placebo-controlled clinical trial of orally administered XYP in patients with depression. METHODS: The 17-item Hamilton Depression Rating Scale (HAMD-17) scores were recorded at baseline, and every 2 weeks after the start of treatment. To further elucidate the epigenetic mechanism of XYP, we performed mRNA sequencing and genome-wide DNA methylation sequencing using peripheral blood leukocytes of patients and healthy. RESULTS: XYP effectively alleviated the symptoms in patients with mild or moderate depressive disorders, particularly that of psychomotor retardation. XYP restored aberrant gene expression and DNA methylation patterns associated with depression, and the normalization of DNA methylation correlated with downregulation of several genes. In addition, altered DNA methylation levels in the XYP-treated samples were attributed to increased expression of the DNA methyltransferase DNMT1. CONCLUSIONS: Our study provides new insights into the epigenetic mechanism underlying depression and the therapeutic effects of XYP, along with an experimental basis for using XYP in the treatment of depression. TRIAL REGISTRATION INFORMATION: The name of the registry and number: U.S. CLINICAL TRIALS REGISTRY: The link to the registration: ClinicalTrials.gov ISRCTN12746343 (https://www.isrctn.com/ISRCTN12746343). The name of the trial register is "Efficacy and safety of the Xiaoyao pill for improving the clinical symptoms of stagnation of liver qi (chi) and spleen deficiency". The clinical trial registration number is ISRCTN12746343.

Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3.

BACKGROUND: Remodeling eubiosis of the gut microenvironment may contribute to preventing the occurrence and development of depression. Mounting experimental evidence has shown that complement C3 signaling is associated with the pathogenesis of depression, and disruption of the gut microbiota may be an underlying cause of complement system activation. However, the mechanism by which complement C3 participates in gut-brain crosstalk in the pathogenesis of depression remains unknown. RESULTS: In the present study, we found that chronic unpredictable mild stress (CUMS)-induced mice exhibited obvious depression-like behavior as well as cognitive impairment, which was associated with significant gut dysbiosis, especially enrichment of Proteobacteria and elevation of microbiota-derived lipopolysaccharides (LPS). In addition, peripheral and central complement C3 activation and central C3/CR3-mediated aberrant synaptic pruning in microglia have also been observed. Transplantation of gut microbiota from CUMS-induced depression model mice into specific pathogen-free and germ-free mice induced depression-like behavior and concomitant cognitive impairment in the recipient mice, accompanied by increased activation of the complement C3/CR3 pathway in the prefrontal cortex and abnormalities in microglia-mediated synaptic pruning. Conversely, antidepressants and fecal microbiota transplantation from antidepressant-treated donors improved depression-like behaviors and restored gut microbiome disturbances in depressed mice. Concurrently, inhibition of the complement C3/CR3 pathway, amelioration of abnormal microglia-mediated synaptic pruning, and increased expression of the synapsin and postsynaptic density protein 95 were observed. Collectively, our results revealed that gut dysbiosis induces the development of depression-like behaviors through abnormal synapse pruning in microglia-mediated by complement C3, and the inhibition of abnormal synaptic pruning is the key to targeting microbes to treat depression. CONCLUSIONS: Our findings provide novel insights into the involvement of complement C3/CR3 signaling and aberrant synaptic pruning of chemotactic microglia in gut-brain crosstalk in the pathogenesis of depression. Video Abstract.

Roles of microglia in adult hippocampal neurogenesis in depression and their therapeutics.

Adult hippocampal neurogenesis generates functional neurons from neural progenitor cells in the hippocampal dentate gyrus (DG) to complement and repair neurons and neural circuits, thus benefiting the treatment of depression. Increasing evidence has shown that aberrant microglial activity can disrupt the appropriate formation and development of functional properties of neurogenesis, which will play a crucial role in the occurrence and development of depression. However, the mechanisms of the crosstalk between microglia and adult hippocampal neurogenesis in depression are not yet fully understood. Therefore, in this review, we first introduce recent discoveries regarding the roles of microglia and adult hippocampal neurogenesis in the etiology of depression. Then, we systematically discuss the possible mechanisms of how microglia regulate adult hippocampal neurogenesis in depression according to recent studies, which involve toll-like receptors, microglial polarization, fractalkine-C-X3-C motif chemokine receptor 1, hypothalamic-pituitary-adrenal axis, cytokines, brain-derived neurotrophic factor, and the microbiota-gut-brain axis, etc. In addition, we summarize the promising drugs that could improve the adult hippocampal neurogenesis by regulating the microglia. These findings will help us understand the complicated pathological mechanisms of depression and shed light on the development of new treatment strategies for this disease.

Mapping the scientific research on bipolar disorder: A scientometric study of hotspots, bursts, and trends.

Bipolar disorder (BD) is a severe psychiatric illness with an increasing prevalence worldwide. Although the pathological mechanism of and pharmacological interventions for BD have been extensively investigated in preclinical and clinical studies, a scientometric analysis of the developmental trends, interdisciplinary frontiers, and research hotspots in this field has not yet been conducted. Therefore, we performed a comprehensive scientometric review of 55,358 published studies on BD over the past two decades (2002-2021) to identify the most frequently used keywords and explore research hotspots and trajectories. The present findings revealed the main distribution, knowledge structure, topic evolution, and emerging topics of BD research. Analysing the risk factors, pathogenesis, key brain regions, comorbid conditions, and treatment strategies for BD contributed to understanding of the aetiology, progression, and treatment of this disorder. These findings provided substantial support for continued research in this area.

Xiaoyaosan ameliorates depressive-like behavior and susceptibility to glucose intolerance in rat: involvement of LepR-STAT3/PI3K pathway in hypothalamic arcuate nucleus.

BACKGROUND: Accumulating evidence has demonstrated that arcuate nucleus (ARC) of the hypothalamus is likely responsible for the close association between chronic stress, depression, and diabetes. Xiaoyaosan (XYS), a Chinese herbal formula, remarkably improves depressive-like behavior and glucose intolerance, but the mechanism remains unclear. Leptin receptor (LepR) regulates energy expenditure and depression by mediating the action of leptin on the ARC. Therefore, we hypothesized that XYS may regulate depressive-like behavior and glucose intolerance via the leptin and its cascade LepR-STAT3/PI3K pathway in the ARC. METHODS: A rat model of depressive-like behavior and susceptibility to glucose intolerance was induced by exposure to chronic unpredictable mild stress (CUMS) for six weeks. XYS (2.224 g/kg) was orally gavaged for six weeks, and fluoxetine (2.0 mg/kg) was administrated to the positive control group. Depressive-like behaviors were assessed using the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST). Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed to evaluate the effects of XYS on blood glucose. Peripheral leptin and blood lipids were detected using enzyme-linked immunosorbent assay and an automatic biochemical analyzer, respectively. The effects of XYS on the LepR-STAT3/PI3K pathway were detected by quantitative real-time PCR and western blotting. RESULTS: XYS ameliorated CUMS-induced depressive-like behaviors and elevated blood glucose. XYS improved the food intake but have no significant effects on the body weight. Peripheral leptin and its central receptor were also suppressed by XYS, accompanied by the downregulation of JAK2/STAT3 and PI3K/AKT pathway in the ARC. Additionally, XYS increased AGRP and NPY expression but inhibited POMC in the ARC. CONCLUSIONS: XYS improves depressive-like behaviors and susceptibility to glucose intolerance induced by CUMS, which may be achieved by the downregulation of the LepR-STAT3/PI3K signaling pathway in the ARC.

Xiaoyaosan inhibits neuronal apoptosis by regulating the miR-200/NR3C1 signaling in the prefrontal cortex of chronically stressed rats.

BACKGROUND: Depression is a prevalent emotion disorder which is thought to be due to neuronal structural alterations and/or functional impairment within specific brain regions. Several studies have shown that microRNAs are involved in the pathogenesis of depression. As a Chinese herbal formula, Xiaoyaosan (XYS) could have antidepressive effects, although the mechanisms associated with microRNAs are poorly understood. PURPOSE: In this study, we investigated whether inhibition of the miR-200a/b-3p/NR3C1 pathway in the prefrontal cortex is involved in the anti-neuronal apoptosis and anti-stress effects of XYS and then further delineated the underlying mechanism. METHODS: To evaluate the efficacy of XYS in relieving stress behaviors and altering the expression of miRNAs involved in the regulation of these behaviors in vivo, a chronic unpredictable mild stress (CUMS) rodent model and RNA-seq were performed. Primary cortical neurons were used to evaluate the molecular function of miR-200a/b-3p and detect the in vitro neuroprotective function of paeoniflorin, which is one of the main components of XYS. To investigate the function of miR-200a/b-3p in stress behaviors, stereotactic microinjection of AAV2/9-Syn-miR-200a/b-3p was performed to deliver the treatment to the rat mPFC. RESULTS: XYS reduced the anxiety and depression-like behaviors associated with chronic stress and reduced the expression of miR-200a/b-3p and neuronal apoptosis in the prefrontal cortex (PFC). The overexpression of miR-200a/b-3p in primary cortical neurons reduced the expression of the target gene NR3C1, increased the protein expression of cleaved caspase-3 and Bax, and decreased the anti-apoptotic protein Bcl-2. One of the active ingredients of XYS, paeoniflorin, can inhibit miR-200a/b-3p-mediated apoptosis of primary neurons and abnormal expression of apoptosis-related proteins. After overexpressing miR-200a/b-3p in vivo (vmPFC), the rats eventually showed significant anxiety-like behaviors similar to those caused by chronic stress. CONCLUSION: Our findings indicate that XYS can inhibit the CUMS-induced expression of miR-200a/b-3p, regulate miR-200a/b-3p/NR3C1 signaling in the PFC caused by chronic stress, and reduce neuronal apoptosis and stress-related behaviors.

Potential therapeutic effect and methods of traditional Chinese medicine on COVID-19-induced depression: A review.

COVID-19 (coronavirus) has spread all over the world with a high infection rate. Currently, there are no targeted therapeutic drugs for COVID-19 as well as for stress induced by COVID-19. The unpredictable events of COVID-19 can trigger feelings of fear, worry, or unease in people, leading to stress-related disorders such as depression and anxiety. It has been reported that individuals, including COVID-19 patients, medical staff, and ordinary people, are under both physical and psychological pressure, and many of them have developed depression or anxiety during this pandemic. Traditional Chinese medicine (TCM) has been widely used in treating depression with relatively better safety and efficacy and may have an important role in treating stress-related disorders induced by COVID-19. In this review, we collected the common TCM treatment methods including Qigong, Acupuncture, Five Elements Musical Therapy, Five Elements Emotional Therapy, and Chinese herbal medicine from the databases of PubMed and the China National Knowledge Internet to illustrate the effect of TCM on depression. The better knowledge of TCM and implementation of TCM in COVID-19 clinics may help to effectively improve depression induced by COVID-19, may assist people to maintain a healthy physical and mental quality, and may alleviate the current shortage of medical resources.

Xiaoyaosan Improves Antibiotic-Induced Depressive-Like and Anxiety-Like Behavior in Mice Through Modulating the Gut Microbiota and Regulating the NLRP3 Inflammasome in the Colon.

Disturbance of the gut microbiota plays an essential role in mental disorders such as depression and anxiety. Xiaoyaosan, a traditional Chinese medicine formula, has a wide therapeutic spectrum and is used especially in the management of depression and anxiety. In this study, we used an antibiotic-induced microbiome-depleted (AIMD) mouse model to determine the possible relationship between imbalance of the intestinal flora and behavioral abnormalities in rodents. We explored the regulatory effect of Xiaoyaosan on the intestinal flora and attempted to elucidate the potential mechanism of behavioral improvement. We screened NLRP3, ASC, and CASPASE-1 as target genes based on the changes in gut microbiota and explored the effect of Xiaoyaosan on the colonic NLRP3 pathway. After Xiaoyaosan intervention, AIMD mice showed a change in body weight and an improvement in depressive and anxious behaviors. Moreover, the gut flora diversity was significantly improved. Xiaoyaosan increased the abundance of Lachnospiraceae in AIMD mice and decreased that of Bacteroidaceae, the main lipopolysaccharide (LPS)-producing bacteria, resulting in decreased levels of LPS in feces, blood, and colon tissue. Moreover, serum levels of the inflammatory factor, IL-1ß, and the levels of NLRP3, ASC, and CASPASE-1 mRNA and DNA in the colon were significantly reduced. Therefore, Xiaoyaosan may alleviate anxiety and depression by modulating the gut microbiota, correcting excessive LPS release, and inhibiting the immoderate activation of the NLRP3 inflammasome in the colon.

Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential.

Depression is the second most common disease burden worldwide that threatens human health; however, mechanisms underlying the development of depression remain unclear. A family of non-coding RNAs, circular RNAs (circRNAs), has been shown to play a critical role in the development of depression by competitively binding to certain microRNAs (miRNA) and regulating the expression of target genes. Behavioral symptoms of depression may be ameliorated by knockdown or overexpression of depression-associated circRNAs. In this review, we summarized important functions of circRNAs and analyzed the most recent findings regarding the expression and biological function of circRNAs in depression. We discussed novel circRNA-based strategies to illuminate potential therapeutic targets that may aid in the development of new treatments for depression.

Early-Life Stress Alters Synaptic Plasticity and mTOR Signaling: Correlation With Anxiety-Like and Cognition-Related Behavior.

Early-life stress (ELS) predisposes individuals to psychiatric disorders, including anxiety and depression, and cognitive impairments later in life. However, the underlying molecular mechanisms are not completely understood. Developmental deficits in hippocampal synaptic plasticity are among the primary detrimental alterations in brain function induced by ELS. Impaired synaptic plasticity is usually accompanied by decreased synaptic proteins, such as postsynaptic density 95 (PSD95) and synaptophysin, which are important for synaptic function. The mTOR signaling pathway plays a vital role in regulating protein translation, and mTOR activation is functionally associated with synaptic protein synthesis. In the present study, we observed whether ELS impacts synaptic protein synthesis and mTOR signaling, which is involved in synaptic plasticity. Herein, we established a maternal separation (MS) and chronic restraint stress (CRS) model and evaluated anxiety-like behavior and cognitive function (e.g., learning and memory) in adulthood through behavioral examination and analyzed hippocampal expression levels of PSD95 and synaptophysin. To explore whether the mTOR signaling pathway was associated with ELS, we also examined the activity of mTOR and s6. The behavior tests indicated that maternally separated mice showed increased anxiety-like behavior and cognitive impairments. PSD95 and synaptophysin mRNA and protein expression levels were decreased in the hippocampus, and phosphorylated mTOR and phosphorylated s6 were significantly decreased in maternally separated mice vs. those not exposed to MS. Our data demonstrate that MS impairs synaptic plasticity and inhibits mTOR signaling, specifically via s6. Therefore, we speculate that ELS decreased synaptic plasticity via the inhibition of the mTOR pathway in the hippocampus, which may underlie vulnerability to stress and mental disorders in adulthood.

Acetyl-11-keto-ß-boswellic Acid Inhibits Precancerous Breast Lesion MCF-10AT Cells via Regulation of LINC00707/miR-206 that Reduces Estrogen Receptor-α.

PURPOSE: Acetyl-11-keto-ß-boswellic acid (AKBA) has therapeutic effects on a range of diseases, including tumours. lncRNAs, as competing endogenous RNAs (ceRNAs), can interact with miRNAs to regulate the expression of target genes, which can affect the development of tumors. Here, we examined the effects of AKBA on breast precancerous lesions MCF-10AT cells. METHODS: The expression profiles of breast cancer (BC) tissue were collated from The Cancer Genome Atlas (TCGA), and the lncRNA-miRNA-mRNA ceRNA network was constructed. AKBA targets were predicted by network pharmacology. The expression of long intergenic nonprotein-coding RNA 707 (LINC00707), miR-206 and ER-α was determined by qRT-PCR. Cell viability, apoptosis and cycle were assessed by CCK-8 and flow cytometry. Protein levels were measured by Western blotting. RESULTS: A total of 3205 differentially expressed mRNAs, 104 miRNAs, and 605 lncRNAs were identified. The ceRNA network consisting of 9 lncRNAs, 15 miRNAs and 82 mRNAs was constructed. We found that LINC00707 was up-regulated and miR-206 was down-regulated in MCF-10AT cells. Transfected si-LINC00707 could inhibit cell proliferation, induce cell apoptosis and cycle arrest of MCF-10AT cells. In addition, network pharmacology predicted that AKBA may regulate the ESR1 in the treatment of BC. Our research demonstrated that AKBA could induce cell apoptosis and G1-phase arrest and inhibit ER-α expression via LINC00707/miR-206 in MCF-10AT cells. CONCLUSION: AKBA inhibited MCF-10AT cells via regulation of LINC00707/miR-206 that reduces ER-α.

An Integrated Pharmacology-Based Analysis for Antidepressant Mechanism of Chinese Herbal Formula Xiao-Yao-San.

Clinical studies and basic science experiments have widely demonstrated the antidepressant and anxiolytic effects of the herbal formula Xiao-Yao-San (XYS). However, the system mechanism of these effects has not been fully characterized. The present study conducted a comprehensive network pharmacological analysis of XYS and sorted all pharmacologically active components (149) through the TCMSP webserver. Then, all potential molecular targets (449) were predicted, of which there were 99 genes clearly related to depression. To further investigate the mechanism of antidepressant effects of XYS, a compound-depression targets (C-DTs) network was constructed, and Gene Ontology (GO) functional and KEGG pathway enrichment analyses were performed for the 99 targets. Enrichment results revealed that XYS could regulate multiple aspects of depression through these targets, related to metabolism, neuroendocrine function, and neuroimmunity. Prediction and analysis of protein-protein interactions resulted in selection of three hub genes (AKT1, TP53, and VEGFA). In addition, a total of seven ingredients from XYS could act on these hub genes and they were identified through ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS), including paeoniflorin, quercetin, luteolin, acacetin, aloe-emodin, Glyasperin C, kaempferol. Hereafter, we investigated the effects of paeoniflorin and its predicted target, the results suggest that it can reverse the neurotoxicity produced by CORT and could be a neuroprotective effect by promoting the phosphorylation of Akt. Overall, our research revealed the complicated antidepressant mechanism of XYS, and also provided a rational strategy for revealing the complex composition and function of Chinese herbal formula.

Integrating Clinical and Genomic Analyses of Hippocampal-Prefrontal Circuit Disorder in Depression.

Major depressive disorder (MDD) is a prevalent, devastating and recurrent mental disease. Hippocampus (HIP)-prefrontal cortex (PFC) neural circuit abnormalities have been confirmed to exist in MDD; however, the gene-related molecular features of this circuit in the context of depression remain unclear. To clarify this issue, we performed gene set enrichment analysis (GSEA) to comprehensively analyze the genetic characteristics of the two brain regions and used weighted gene correlation network analysis (WGCNA) to determine the main depression-related gene modules in the HIP-PFC network. To clarify the regional differences and consistency for MDD, we also compared the expression patterns and molecular functions of the key modules from the two brain regions. The results showed that candidate modules related to clinical MDD of HIP and PFC, which contained with 363 genes and 225 genes, respectively. Ninety-five differentially expressed genes (DEGs) were identified in the HIP candidate module, and 51 DEGs were identified in the PFC candidate module, with only 11 overlapping DEGs in these two regional modules. Combined with the enrichment results, although there is heterogeneity in the molecular functions in the HIP-PFC network of depression, the regulation of the MAPK cascade, Ras protein signal transduction and Ephrin signaling were significantly enriched in both brain regions, indicating that these biological pathways play important roles in MDD pathogenesis. Additionally, the high coefficient protein-protein interaction (PPI) network was constructed via STRING, and the top-10 coefficient genes were identified as hub genes via the cytoHubba algorithm. In summary, the present study reveals the gene expression characteristics of MDD and identifies common and unique molecular features and patterns in the HIP-PFC network. Our results may provide novel clues from the gene function perspective to explain the pathogenic mechanism of depression and to aid drug development. Further research is needed to confirm these findings and to investigate the genetic regulation mechanisms of different neural networks in depression.

Therapeutic Efficiency of an External Chinese Herbal Formula of Mammary Precancerous Lesions by BATMAN-TCM Online Bioinformatics Analysis Tool and Experimental Validation.

Ruyan Neixiao Cream (RYNXC), a patented Chinese herbal formula, was reported to have the effect of treating mammary precancerous disease. In this study, we predicted the potential targets, pathways, and diseases of the ingredients contained in each herbal of RYNXC and constructed an ingredients-targets-diseases network. Then, we analyzed molecular mechanisms of this Chinese herbal formula by MCF-10AT cells and model rats of breast precancerous lesions. BATMAN-TCM prediction showed that ESR1, PGR, PTGS2, EGFR, and Src were mRNA targets of RYNXC. Our results suggested that RYNXC transdermal fluid downregulated ESR1, PGR, PTGS2, EGFR, and Src expression at gene and protein level in MCF-10AT cells. In the rat breast precancerous lesions model, high and low dose RYNXC could also significantly reduce genes and proteins expression of ESR1, PGR, PTGS2, EGFR, and Src. Taken together these data indicate that RYNXC targets multiple molecules responsible for breast precancerous lesion and is an effective Chinese herbal formula. So RYNXC may be a promising external drug for breast precancerous lesions.

Comparison of different prognostic models for predicting cancer-specific survival in bladder transitional cell carcinoma.

OBJECTIVE: To construct the newly valuable nomogram which can compare the predictive performance with American Joint Committee on Cancer (AJCC) staging system in bladder transitional cell carcinoma (BTCC). METHODS: BTCC patients were screened (2004-2015) from the SEER database. The nomogram incorporating lymph node ratio was constructed to evaluate individualized cancer-specific survival. RESULTS: The C-index of the nomogram for predicting cancer-specific survival was 0.743 (95% CI: 0.720-0.766), which was higher than C-index of the AJCC staging system. CONCLUSION: Lymph node ratio can be a reliable prognostic indicator for BTCC. The proposed nomogram showed more satisfactory predictive accuracy and wider applicability than current AJCC staging system in individualized prediction of BTCC patients.

Weighted gene co­expression network analysis for identifying hub genes in association with prognosis in Wilms tumor.

Wilms tumor (WT) is the most common type of renal malignancy in children. Survival rates are low and high­risk WT generally still carries a poor prognosis. To better elucidate the pathogenesis and tumorigenic pathways of high­risk WT, the present study presents an integrated analysis of RNA expression profiles of high­risk WT to identify predictive molecular biomarkers, for the improvement of therapeutic decision­making. mRNA sequence data from high­risk WT and adjacent normal samples were downloaded from The Cancer Genome Atlas to screen for differentially expressed genes (DEGs) using R software. From 132 Wilms tumor samples and six normal samples, 2,089 downregulated and 941 upregulated DEGs were identified. In order to identify hub DEGs that regulate target genes, weighted gene co­expression network analysis (WGCNA) was used to identify 11 free­scale gene co­expressed clusters. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were annotated using KEGG Orthology Based Annotation System annotation of different module genes. The Search Tool for the Retrieval of Interacting Genes was used to construct a protein­protein interaction network for the identified DEGs, and the hub genes of WGCNA modules were identified using the Cytohubb plugin with Cytoscape software. Survival analysis was subsequently performed to highlight hub genes with a clinical signature. The present results suggest that epidermal growth factor, cyclin dependent kinase 1, endothelin receptor type A, nerve growth factor receptor, opa­interacting protein 5, NDC80 kinetochore complex component and cell division cycle associated 8 are essential to high­risk WT pathogenesis, and they are closely associated with clinical prognosis.

Prognostic nomograms based on log odds of positive lymph nodes for patients with renal cell carcinoma: A retrospective cohort study.

OBJECTIVES: The aim of the current study is to build prognostic nomograms for patients with renal cell carcinoma (RCC) and compare the predictive performance with the American Joint Committee on Cancer (AJCC) staging system. METHODS: A total of 9453 patients were identified (2005-2015) from the Surveillance Epidemiology and End Results (SEER) database. Propensity-score matching (PSM) was conducted to reduce selective bias. The matched cohort was further divided equally into the development and the validation cohort. Nomograms based on log odds of positive lymph nodes (LODDS) were formulated to predict individualized cancer-specific survival (CSS) and overall survival (OS) for RCC. Then, the performance of nomograms was internally and externally validated via the concordance index (C-index) and calibration plots. Decision curve analysis (DCA) was used to compare the clinical practicable between nomograms and AJCC staging system. RESULTS: LODDS was identified as an independent prognostic indicator for CSS and OS using univariate and multivariate Cox regression analyses. Two nomograms incorporating LODDS were formulated. The C-indices of the nomograms for predicting CSS and OS were 0.7561 (95% CI, 0.7356-0.7766) and 0.7140 (95% CI, 0.6936-0.7343) in the development cohort, which was higher than C-index of the AJCC staging system. The results were reproducible in the validation cohort. Moreover, internal and external calibration plots showed that the nomograms-predicted was consistent with the actual observation. Additionally, DCA demonstrated that the nomograms were superior to the AJCC staging system with obtaining more clinical net benefit. CONCLUSIONS: LODDS could be considered as a reliable prognostic factor for patients with RCC. Two nomograms were able to more accurately and applicable than the AJCC staging system for predicting CSS and OS.

Jianpi Bushen, a Traditional Chinese Medicine Therapy, Combined with Chemotherapy for Gastric Cancer Treatment: A Meta-Analysis of Randomized Controlled Trials.

Objective. To investigate the effects of Jianpi Bushen (JPBS), a traditional Chinese medicine that is used to invigorate the spleen and tonify the kidney, combined with chemotherapy for the treatment of gastric cancer. Methods. Literature retrieval was performed in PubMed, EMBASE, Cochrane Library, MEDLINE, CNKI, Wanfang Data Information Site, and VIP from inception to October 2017. Randomized controlled trials to evaluate the effects of JPBS combined with chemotherapy were identified. The primary reported outcomes were KPS (Karnofsky Performance Status), clinical curative efficiency, immune function, blood system, and nonhematologic system. Review Manager 5.3 (RevMan 5.3) was used for data analysis, and the quality of the studies was also appraised. Results. A total of 26 studies were included with 3098 individuals. The results of the meta-analysis indicated that treatment of gastric cancer with the combination of JPBS and chemotherapy resulted in better outcomes compared to chemotherapy alone. Conclusion. Evidence from the meta-analysis suggested that JPBS combined with chemotherapy has a positive effect on gastric cancer treatment. However, additional rigorously designed and large sample randomized controlled trials are required to confirm the efficacy and safety of this treatment.

The efficacy and safety comparison of surgical treatments for stress urinary incontinence: A network meta-analysis.

AIMS: Stress urinary incontinence (SUI) is a common problem worldwide. Mainstream surgical procedures include tension-free vaginal tape (TVT), transobturator tape (TOT), tension-free vaginal tape-obturator (TVT-O), tension-free vaginal tape SECUR (TVT-S), and adjustable single-incision sling (Ajust). The aim of this study was to compare the efficacy and safety of these surgical procedures and assess which surgery is most optimal for SUI by adopting a network meta-analysis (NMA). METHODS: Electronic databases including PubMed, Cochrance Library, and Embase database were researched systematically, until March 21, 2017. The randomized controlled trials (RCTs) that compared the efficacy and safety of TVT, TOT, TVT-O, TVT-S, and Ajust were identified. The studies were included in the analysis when met the predefined inclusion criteria. After demographic and outcome data extraction, a network meta-analysis was conducted with software R 3.3.2 and STATA 14.0. Objective cure rate, subjective cure rate, postoperative complication rate, bladder perforation, tape erosion, urinary retention, and postoperative pain were considered as outcomes, and the outcomes were displayed as odds ratios (ORs) and 95% credible intervals (CrI). The consistency of direct and indirect evidence was assessed by node splitting. The ranks based on probabilities of intervention for the different endpoints were performed. RESULTS: Fourty-five RCTs with 7295 participants were analyzed. The NMA results revealed that, TVT, TOT, and Ajust had a higher objective cure rate than TVT-O and TVT-S (TVT-O: OR = 0.76, 95%CI [0.61, 0.94]; TVT-S: OR = 0.41, 95%CI [0.28, 0.60]). TVT, TOT, and TVT-O had a superior subjective cure rate than TVT-S and Ajust (Ajust: OR = 0.45, 95%CI [0.20, 0.91]; TVT-S: OR = 0.29, 95%CI [0.15, 0.56]). With TVT as the reference, TVT-S had a statistically lower postoperative complication rate (TVT-S: OR = 0.39, 95%CI [0.16, 0.89]). TVT-O, TVT-S, and TOT had a significantly lower bladder perforation rate (TOT: OR = 0.076, 95%CI [0.0060, 0.37]; TVT-O: OR = 4.1e-17, 95%CI [6.1e-48, 0.0032]; TVT-S: OR = 3.8e-17, 95%CI [1.8e-48, 0.0052]). There were no obvious differences between the five treatments for tape erosion. TVT-O exhibited a less postoperative retention (TVT-O: OR = 0.35, 95%CI [0.16, 0.74]). Probabilities of ranking results indicated that TOT was the treatment with best ranking in efficacy and a relatively high safety. CONCLUSIONS: Our study recommend TOT as the optimal regimen for SUI with high efficacy and moderate safety when compared with TVT, TVT-O, TVT-S, and Ajust interventions. However, with the limitation of our study, additional high-quality studies are needed to further evaluate the outcomes.

Integrative analysis of lncRNAs and miRNAs with coding RNAs associated with ceRNA crosstalk network in triple negative breast cancer.

Triple negative breast cancer (TNBC) is a particular subtype of breast malignant tumor with poorer prognosis than other molecular subtypes. Currently, there is increasing focus on long non-coding RNAs (lncRNAs), which can act as competing endogenous RNAs (ceR-NAs) and suppress miRNA functions involved in post-transcriptional regulatory networks in the tumor. Therefore, to investigate specific mechanisms of TNBC carcinogenesis and improve treatment efficiency, we comprehensively integrated expression profiles, including data on mRNAs, lncRNAs and miRNAs obtained from 116 TNBC tissues and 11 normal tissues from The Cancer Genome Atlas. As a result, we selected the threshold with |log2FC|>2.0 and an adjusted p-value >0.05 to obtain the differentially expressed mRNAs, miRNAs and lncRNAs. Hereafter, weighted gene co-expression network analysis was performed to identify the expression characteristics of dysregulated genes. We obtained five co-expression modules and related clinical feature. By means of correlating gene modules with protein-protein interaction network analysis that had identified 22 hub mRNAs which could as hub target genes. Eleven key dysregulated differentially expressed micro RNAs (DEmiRNAs) were identified that were significantly associated with the 22 hub potential target genes. Moreover, we found that 14 key differentially expressed lncRNAs could interact with the key DEmiRNAs. Then, the ceRNA crosstalk network of TNBC was constructed by utilizing key lncRNAs, key miRNAs, and hub mRNAs in Cytoscape software. We analyzed and described the potential characteristics of biological function and pathological roles of the TNBC ceRNA co-regulatory network; also, the survival analysis was performed for each molecule. These findings revealed that ceRNA crosstalk network could play an important role in the development and progression for TNBC. In addition, we also identified that some molecules in the ceRNA network possess clinical correlation and prognosis.