The UAF1-USP1 Deubiquitinase Complex Stabilizes cGAS and Facilitates Antiviral Responses.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects cytoplasmic microbial DNA and self-DNA from genomic instability, initiates innate immunity, and plays fundamental roles in defense against viruses and the development of various diseases. The cellular cGAS level determines the magnitude of the response to DNA. However, the underlying mechanisms of the control of cGAS stability, especially its feedback regulation during viral infection, remain largely unknown. In this study, we show that viral infection induces the expression of the UAF1-USP1 deubiquitinase complex in primary peritoneal macrophages (PMs) of C57BL/6J mice. UAF1-USP interacts with cGAS, selectively cleaves its K48-linked polyubiquitination, and thus stabilizes its protein expression in PMs and HEK293T cells. Concordantly, the UAF1-USP1 deubiquitinase complex enhances cGAS-dependent type I IFN responses in PMs. Uaf1 deficiency and ML323 (a specific inhibitor of UAF1-USP1 deubiquitinase complex) attenuates cGAS-triggered antiviral responses and facilitates viral replication both in vitro and in vivo. Thus, our study uncovers a positive feedback mechanism of cGAS-dependent antiviral responses and suggests the UAF1-USP1 complex as a potential target for the treatment of diseases caused by aberrant cGAS activation.

Epigenetic liquid biopsies for minimal residual disease, what's around the corner?

Liquid biopsy assays for minimal residual disease (MRD) are used to monitor and inform oncological treatment and predict the risk of relapse in cancer patients. To-date, most MRD assay development has focused on targeting somatic mutations. However, epigenetic changes are more frequent and universal than genetic alterations in cancer and circulating tumor DNA (ctDNA) retains much of these changes. Here, we review the epigenetic signals that can be used to detect MRD, including DNA methylation alterations and fragmentation patterns that differentiate ctDNA from noncancerous circulating cell-free DNA (ccfDNA). We then summarize the current state of MRD monitoring; highlight the advantages of epigenetics over genetics-based approaches; and discuss the emerging paradigm of assaying both genetic and epigenetic targets to monitor treatment response, detect disease recurrence, and inform adjuvant therapy.

Oncomicrobial Community Profiling Identifies Clinicomolecular and Prognostic Subtypes of Colorectal Cancer.

BACKGROUND & AIMS: Dysbiosis of gut microbiota is linked to the development of colorectal cancer (CRC). However, microbiota-based stratification of CRC tissue and how this relates to clinicomolecular characteristics and prognosis remains to be clarified. METHODS: Tumor and normal mucosa from 423 patients with stage I to IV CRC were profiled by bacterial 16S rRNA gene sequencing. Tumors were characterized for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), APC, BRAF, KRAS, PIK3CA, FBXW7, SMAD4, and TP53 mutations, subsets for chromosome instability (CIN), mutation signatures, and consensus molecular subtypes (CMS). Microbial clusters were validated in an independent cohort of 293 stage II/III tumors. RESULTS: Tumors reproducibly stratified into 3 oncomicrobial community subtypes (OCSs) with distinguishing features: OCS1 (Fusobacterium/oral pathogens, proteolytic, 21%), right-sided, high-grade, MSI-high, CIMP-positive, CMS1, BRAF V600E, and FBXW7 mutated; OCS2 (Firmicutes/Bacteroidetes, saccharolytic, 44%), and OCS3 (Escherichia/Pseudescherichia/Shigella, fatty acid ß-oxidation, 35%) both left-sided and exhibiting CIN. OCS1 was associated with MSI-related mutation signatures (SBS15, SBS20, ID2, and ID7) and OCS2 and OCS3 with SBS18 related to damage by reactive oxygen species. Among stage II/III patients, OCS1 and OCS3 both had poorer overall survival compared with OCS2 for microsatellite stable tumors (multivariate hazard ratio [HR], 1.85; 95% confidence interval [CI], 1.15-2.99; P = .012; and HR, 1.52; 95% CI 1.01-2.29; P = .044, respectively) and left-sided tumors (multivariate HR, 2.66; 95% CI, 1.45-4.86; P = .002; and HR, 1.76; 95% CI, 1.03-3.02; P = .039, respectively). CONCLUSIONS: OCS classification stratified CRCs into 3 distinct subgroups with different clinicomolecular features and outcomes. Our findings provide a framework for a microbiota-based stratification of CRC to refine prognostication and to inform the development of microbiota-targeted interventions.

TAK1 blockade as a therapy for retinal neovascularization.

Retinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Transforming growth factor-ß-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-ß1 and other proinflammatory cytokines. TAK1 is also a key mediator of proinflammatory signals and plays an important role in maintaining vascular integrity upon proinflammatory cytokine stimulation such as TNFα. However, its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. Here, we investigate the regulatory role of TAK1 in human endothelial cells responding to inflammatory stimuli and in a rat model of oxygen-induced retinopathy (OIR) featured retinal neovascularization. Using TAK1 knockout human endothelial cells that subjected to inflammatory stimuli, transcriptome analysis revealed that TAK1 is required for activation of NFκB signaling and mediates its downstream gene expression related to endothelial activation and angiogenesis. Moreover, pharmacological inhibition of TAK1 by 5Z-7-oxozeaenol attenuated angiogenic activities of endothelial cells. Transcriptome analysis also revealed enrichment of TAK1-mediated NFκB signaling pathway in the retina of OIR rats and retinal neovascular membrane from patients with proliferative diabetic retinopathy. Intravitreal injection of 5Z-7-oxozeaenol significantly reduced hypoxia-induced inflammation and microglial activation, thus attenuating aberrant retinal angiogenesis in OIR rats. Our data suggest that inhibition of TAK1 may have therapeutic potential for the treatment of retinal neovascular pathologies.

Overexpression of Ubiquitin-Conjugating Enzyme E2C Is Associated with Worsened Prognosis in Prostate Cancer.

To evaluate the role of ubiquitin-conjugating enzyme E2C (UBE2C) in prostate cancer (PCa) progression and prognosis, the TCGA and our PCa tissue microarray cohort were included in the study. Weighted gene co-expression network analysis (WGCNA) and non-negative matrix factorization were used to cluster patients and to screen genes that play a vital role in PCa progression (hub gene). Immunohistochemistry staining was used to evaluate the protein level of UBE2C in prostatic tissues. Through WGCNA, we found a gene co-expression module (named the purple module) that is strongly associated with the Gleason score, pathologic T stage, and biochemical recurrent status. Genes in the purple module are enriched in cell cycle and P53 signaling and help us to cluster patients into two groups with distinctive biochemical recurrent survival rates and TP53 mutation statuses. Further analysis showed UBE2C served as a hub gene in the purple module. The expression of UBE2C in PCa was significantly higher than that in paracancerous tissues and was remarkably associated with pathologic grade, Gleason score, and prognosis in PCa patients. To conclude, UBE2C is a PCa-progress-related gene and a biomarker for PCa patients. Therapy targeting UBE2C may serve as a promising treatment of PCa in the future.

m6A Methylation Regulators Are Predictive Biomarkers for Tumour Metastasis in Prostate Cancer.

Prostate cancer (PCa) is one of the most common cancers in men. Usually, most PCas at initial diagnosis are localized and hormone-dependent, and grow slowly. Patients with localized PCas have a nearly 100% 5-year survival rate; however, the 5-year survival rate of metastatic or progressive PCa is still dismal. N6-methyladenosine (m6A) is the most common post-transcriptional mRNA modification and is dynamically regulated by m6A regulators. A few studies have shown that the abnormal expression of m6A regulators is significantly associated with cancer progression and immune cell infiltration, but the roles of these regulators in PCa remain unclear. Here, we examined the expression profiles and methylation levels of 21 m6A regulators across the Cancer Genome Atlas (TCGA), 495 PCas by consensus clustering, and correlated the expression of m6A regulators with PCa progression and immune cell infiltration. Consensus clustering was applied for subtyping Pca samples into clusters based on the expression profiles of m6A regulators. Each subtype's signature genes were obtained by a pairwise differential expression analysis. Featured pathways of m6A subtypes were predicted by Gene Ontology. The m6A score was developed to predict m6A activation. The association of the m6A score with patients' survival, metastasis and immune cell infiltration was also investigated. We identified three distinct clusters in PCa based on the expression profiles of 21 m6A regulators by consensus clustering. The differential expression and pathway analyses on the three clusters uncovered the m6A regulators involved in metabolic processes and immune responses in PCa. Moreover, we developed an m6A score to evaluate the m6A regulator activation for PCa. The m6A score is significantly associated with Gleason scores and metastasis in PCa. The predictive capacity of the m6A score on PCa metastasis was also validated in another independent cohort with an area under the curve of 89.5%. Hence, our study revealed the critical role of m6A regulators in PCa progression and the m6A score is a promising predictive biomarker for PCa metastasis.

An Integrative Multi-Omics Analysis Reveals MicroRNA-143 as a Potential Therapeutic to Attenuate Retinal Angiogenesis.

Retinal neovascularization is a severe complication of proliferative diabetic retinopathy (PDR). MicroRNAs (miRNAs) are master regulators of gene expression that play an important role in retinal neovascularization. In this study, we show that miR-143-3p is significantly downregulated in the retina of a rat model of oxygen-induced retinopathy (OIR) by miRNA-sequencing. Intravitreal injection of synthetic miR-143 mimics significantly ameliorate retinal neovascularization in OIR rats. miR-143 is identified to be highly expressed in the neural retina particularly in the ganglion cell layer and retinal vasculature. In miR-143 treated cells, the functional evaluation showed a decrease in cell migration and delayed endothelial vessel-like tube remodeling. The multiomics analysis suggests that miR-143 negatively impacts endothelial cell activity through regulating cell-matrix adhesion and mediating hypoxia-inducible factor-1 signaling. We predict hub genes regulated by miR-143 that may be involved in mediating endothelial cell function by cytoHubba. We also demonstrate that the retinal neovascular membranes in patients with PDR principally consist of endothelial cells by CIBERSORTx. We then identify 2 hub genes, thrombospondin 1 and plasminogen activator inhibitor, direct targets of miR-143, that significantly altered in the PDR patients. These findings suggest that miR-143 appears to be essential for limiting endothelial cell-matrix adhesion, thus suppressing retinal neovascularization.

Extracellular Vesicles Secreted by Glioma Stem Cells Are Involved in Radiation Resistance and Glioma Progression.

Glioblastoma is the most aggressive brain tumour with short survival, partly due to resistance to conventional therapy. Glioma stem cells (GSC) are likely to be involved in treatment resistance, by releasing extracellular vesicles (EVs) containing specific molecular cargoes. Here, we studied the EVs secreted by glioma stem cells (GSC-EVs) and their effects on radiation resistance and glioma progression. EVs were isolated from 3 GSCs by serial centrifugation. NanoSight measurement, cryo-electron microscopy and live imaging were used to study the EVs size, morphology and uptake, respectively. The non-GSC glioma cell lines LN229 and U118 were utilised as a recipient cell model. Wound healing assays were performed to detect cell migration. Colony formation, cell viability and invadopodium assays were conducted to detect cell survival of irradiated recipient cells and cell invasion post GSC-EV treatment. NanoString miRNA global profiling was used to select for the GSC-EVs' specific miRNAs. All three GSC cell lines secreted different amounts of EVs, and all expressed consistent levels of CD9 but different level of Alix, TSG101 and CD81. EVs were taken up by both LN229 and U118 recipient cells. In the presence of GSC-EVs, these recipient cells survived radiation exposure and initiated colony formation. After GSC-EVs exposure, LN229 and U118 cells exhibited an invasive phenotype, as indicated by an increase in cell migration. We also identified 25 highly expressed miRNAs in the GSC-EVs examined, and 8 of these miRNAs can target PTEN. It is likely that GSC-EVs and their specific miRNAs induced the phenotypic changes in the recipient cells due to the activation of the PTEN/Akt pathway. This study demonstrated that GSC-EVs have the potential to induce radiation resistance and modulate the tumour microenvironment to promote glioma progression. Future therapeutic studies should be designed to interfere with these GSC-EVs and their specific miRNAs.

Transcriptome subtyping of metastatic Castration Resistance Prostate Cancer (mCRPC) for the precision therapeutics: an in silico analysis.

BACKGROUND: Men with metastatic prostate cancer who are treated with androgen deprivation therapy (ADT) typically develop therapeutic resistance eventually and have a dismal outcome. Moreover, the limited survival benefit observed in only a proportion of patients receiving novel therapeutics including immune checkpoint blockade and PARP inhibitors suggests the biological heterogeneity of mCRPCs. METHODS: To understand the heterogeneity of mCRPC, we analyzed the transcriptome of 231 mCRPCs and identified four disparate biological subtypes (Basal, Homologous Recombination Repair (HRR), Neuroendocrine and Luminal). The package "randomForest" was used to construct a Random Forest model. Circular plots were used for visualization of TMPRSS2-ERG fusion in each subtype. RESULTS: The Luminal subtype of mCRPCs has higher Androgen Receptor (AR) expression and copy number alterations as compared with the other subtypes. Genes in HRR pathway are relatively downregulated in most subtypes regardless of the genetic alterations, except for the HRR and NE subtypes, suggesting potential resistance of the HRR and NE mCRPCs to PARP inhibitor treatment. The HRR subtype has relatively more immune cell infiltration and higher expression of immune checkpoints, highlighting that the efficacy of immunotherapy should be evaluated in this particular subtype. TMPRSS2-ERG fusion is the most frequent gene fusion in all mCRPCs, and the Basal subtype has a higher frequency of this fusion than the other subtypes. CONCLUSIONS: Our results reveal that the stratification of mCRPC according to transcriptome is informative of personalized therapeutics in the treatment of mCRPCs. The predictive capacity of the transcriptome subtyping of mCRPC warrants further exploration in the future.

Cancer-associated mesothelial cells promote ovarian cancer chemoresistance through paracrine osteopontin signaling.

Ovarian cancer is the leading cause of gynecological malignancy-related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance. Mesothelial cells are an important cellular component of the ovarian cancer microenvironment that promote metastasis. However, their role in chemoresistance is unclear. Here, we investigated whether cancer-associated mesothelial cells promote ovarian cancer chemoresistance and stemness in vitro and in vivo. We found that osteopontin is a key secreted factor that drives mesothelial-mediated ovarian cancer chemoresistance and stemness. Osteopontin is a secreted glycoprotein that is clinically associated with poor prognosis and chemoresistance in ovarian cancer. Mechanistically, ovarian cancer cells induced osteopontin expression and secretion by mesothelial cells through TGF-ß signaling. Osteopontin facilitated ovarian cancer cell chemoresistance via the activation of the CD44 receptor, PI3K/AKT signaling, and ABC drug efflux transporter activity. Importantly, therapeutic inhibition of osteopontin markedly improved the efficacy of cisplatin in both human and mouse ovarian tumor xenografts. Collectively, our results highlight mesothelial cells as a key driver of ovarian cancer chemoresistance and suggest that therapeutic targeting of osteopontin may be an effective strategy for enhancing platinum sensitivity in ovarian cancer.

MPscore: A Novel Predictive and Prognostic Scoring for Progressive Meningioma.

Meningioma is the most common tumor in central nervous system (CNS). Although most cases of meningioma are benign (WHO grade I) and curable by surgical resection, a few tumors remain diagnostically and therapeutically challenging due to the frequent recurrence and progression. The heterogeneity of meningioma revealed by DNA methylation profiling suggests the demand of subtyping for meningioma. Therefore, we performed a clustering analyses to characterize the progressive features of meningioma and constructed a meningioma progression score to predict the risk of the recurrence. A total of 179 meningioma transcriptome from RNA sequencing was included for progression subtype clustering. Four biologically distinct subtypes (subtype 1, subtype 2, subtype 3 and subtype 4) were identified. Copy number alternation and genomewide DNA methylation of each subtype was also characterized. Immune cell infiltration was examined by the microenvironment cell populations counter. All anaplastic meningiomas (7/7) and most atypical meningiomas (24/32) are enriched in subtype 3 while no WHO II or III meningioma presents in subtype 1, suggesting subtype 3 meningioma is a progressive subtype. Stemness index and immune response are also heterogeneous across four subtypes. Monocytic lineage is the most immune cell type in all meningiomas, except for subtype 1. CD8 positive T cells are predominantly observed in subtype 3. To extend the clinical utility of progressive meningioma subtyping, we constructed the meningioma progression score (MPscore) by the signature genes in subtype 3. The predictive accuracy and prognostic capacity of MPscore has also been validated in three independent cohort. Our study uncovers four biologically distinct subtypes in meningioma and the MPscore is potentially helpful in the recurrence risk prediction and response to treatments stratification in meningioma.

Correction to: Serum microRNA is a biomarker for post-operative monitoring in glioma.

For the reference citation '[57]' in the second paragraph of the Results section of the original article there was no corresponding entry in the References section. It should have referred to the below mentioned article by Ebrahimkhani et al. (2018).

Serum microRNA is a biomarker for post-operative monitoring in glioma.

PURPOSE: A circulating biomarker has potential to provide more accurate information for glioma progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA serum biomarker for longitudinal monitoring of glioma patients. METHODS: A prospectively collected cohort of 91 glioma patients and 17 healthy controls underwent pre and post-operative serum miRNA profiling using Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow up samples and compared to tumor volume based on magnetic resonance imaging. RESULTS: A 9-gene miRNA signature was identified that could distinguish between glioma and healthy controls with 99.8% accuracy. Two miRNAs miR-223 and miR-320e, best demonstrated dynamic changes that correlated closely with tumor volume in LGG and GBM respectively. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions. CONCLUSIONS: We identified a highly accurate 9-miRNA signature associated with glioma serum. Additionally, we observed dynamic changes in specific miRNAs correlating with tumor volume over long-term follow up. These results support a large prospective validation study of serum miRNA biomarkers in glioma.

DNA Methylation Cancer Biomarkers: Translation to the Clinic.

Carcinogenesis is accompanied by widespread DNA methylation changes within the cell. These changes are characterized by a globally hypomethylated genome with focal hypermethylation of numerous 5'-cytosine-phosphate-guanine-3' (CpG) islands, often spanning gene promoters and first exons. Many of these epigenetic changes occur early in tumorigenesis and are highly pervasive across a tumor type. This allows DNA methylation cancer biomarkers to be suitable for early detection and also to have utility across a range of areas relevant to cancer detection and treatment. Such tests are also simple in construction, as only one or a few loci need to be targeted for good test coverage. These properties make cancer-associated DNA methylation changes very attractive for development of cancer biomarker tests with substantive clinical utility. Across the patient journey from initial detection, to treatment and then monitoring, there are several points where DNA methylation assays can inform clinical practice. Assays on surgically removed tumor tissue are useful to determine indicators of treatment resistance, prognostication of outcome, or to molecularly characterize, classify, and determine the tissue of origin of a tumor. Cancer-associated DNA methylation changes can also be detected with accuracy in the cell-free DNA present in blood, stool, urine, and other biosamples. Such tests hold great promise for the development of simple, economical, and highly specific cancer detection tests suitable for population-wide screening, with several successfully translated examples already. The ability of circulating tumor DNA liquid biopsy assays to monitor cancer in situ also allows for the ability to monitor response to therapy, to detect minimal residual disease and as an early biomarker for cancer recurrence. This review will summarize existing DNA methylation cancer biomarkers used in clinical practice across the application domains above, discuss what makes a suitable DNA methylation cancer biomarker, and identify barriers to translation. We discuss technical factors such as the analytical performance and product-market fit, factors that contribute to successful downstream investment, including geography, and how this impacts intellectual property, regulatory hurdles, and the future of the marketplace and healthcare system.

Anticancer effect of icaritin on prostate cancer via regulating miR-381-3p and its target gene UBE2C.

Prostate cancer (PCa) is one of the most common health-related issues in the male individuals of western countries. Icaritin (ICT) is a traditional Chinese herbal medicine that exhibits antitumor efficacy in variety of cancers including PCa. However, the precise function and detailed molecular mechanism of ICT in the regression of PCa remain unclear. Ubiquitin-conjugating enzyme E2C (UBE2C) is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin conjugating enzyme, which acts as an oncogene in PCa progression. The function of ICT in PCa was investigated in transgenic adenocarcinoma mouse prostate (TRAMP) mice using survival analysis, hematoxylin and eosin (HE) staining, TUNEL assay, and immunohistochemistry and in human PCa cell lines using various molecular techniques and functional assays including plasmid construction and transfection. Bioinformatic analyses were performed to identify the interaction between miRNA and UBE2C via the TargetScan algorithm. We demonstrated that ICT inhibited the development and progression of PCa in TRAMP mice by improving the survival rate and tumor differentiation. Furthermore, we found that ICT could significantly inhibit cell proliferation and invasion and induce apoptosis in PCa cells. Consistently, downregulation of UBE2C suppressed the proliferation and invasion of PCa cells. Moreover, a luciferase reporter assay confirmed that UBE2C was a direct target of miR-381-3p. Meanwhile, ICT simultaneously downregulated UBE2C expression and upregulated miR-381-3p levels in human PCa cells. Altogether, our findings provide a strong rationale for the clinical application of ICT as a potential oncotherapeutic agent against PCa via a novel molecular mechanism of regulating the miR-381-3p/UBE2C pathway.

WITHDRAWN: Peripheral nerve blocks for postoperative pain after major knee surgery.

BACKGROUND: Major knee surgery is a common operative procedure to help people with end-stage knee disease or trauma to regain mobility and have improved quality of life. Poorly controlled pain immediately after surgery is still a key issue for this procedure. Peripheral nerve blocks are localized and site-specific analgesic options for major knee surgery. The increasing use of peripheral nerve blocks following major knee surgery requires the synthesis of evidence to evaluate its effectiveness and safety, when compared with systemic, local infiltration, epidural and spinal analgesia. OBJECTIVES: To examine the efficacy and safety of peripheral nerve blocks for postoperative pain control following major knee surgery using methods that permit comparison with systemic, local infiltration, epidural and spinal analgesia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2014), MEDLINE and EMBASE, from their inception to February 2014. We identified ongoing studies by searching trial registries, including the metaRegister of controlled trials (mRCT), clinicaltrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: We included participant-blind, randomized controlled trials of adult participants (15 years or older) undergoing major knee surgery, in which peripheral nerve blocks were compared to systemic, local infiltration, epidural and spinal analgesia for postoperative pain relief. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and extracted data. We recorded information on participants, methods, interventions, outcomes (pain intensity, additional analgesic consumption, adverse events, knee range of motion, length of hospital stay, hospital costs, and participant satisfaction). We used the 5-point Oxford quality and validity scale to assess methodological quality, as well as criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We conducted meta-analysis of two or more studies with sufficient data to investigate the same outcome. We used the I² statistic to explore the heterogeneity. If there was no significant heterogeneity (I² value 0% to 40%), we used a fixed-effect model for meta-analysis, but otherwise we used a random-effects model. For dichotomous data, we present results as a summary risk ratio (RR) and a 95% confidence interval (95% CI). Where possible, we calculated the number needed to treat for an additional beneficial outcome (NNTB) or for an additional harmful outcome (NNTH), together with 95% CIs. For continuous data, we used the mean difference (MD) and 95% CI for similar outcome measures. We describe the findings of individual studies where pooling of data was not possible. MAIN RESULTS: According to the eligibility criteria, we include 23 studies with 1571 participants, with high methodological quality overall. The studies compared peripheral nerve blocks adjunctive to systemic analgesia with systemic analgesia alone (19 studies), peripheral nerve blocks with local infiltration (three studies), and peripheral nerve blocks with epidural analgesia (one study). No study compared peripheral nerve blocks with spinal analgesia.Compared with systemic analgesia alone, peripheral nerve blocks adjunctive to systemic analgesia resulted in a significantly lower pain intensity score at rest, using a 100 mm visual analogue scale, at all time periods within 72 hours postoperatively, including the zero to 23 hours interval (MD -11.85, 95% CI -20.45 to -3.25, seven studies, 390 participants), the 24 to 47 hours interval (MD -12.92, 95% CI -19.82 to -6.02, six studies, 320 participants) and the 48 to 72 hours interval (MD -9.72, 95% CI -16.75 to -2.70, four studies, 210 participants). Subgroup analyses suggested that the high levels of statistical variation in our analyses could be explained by larger effects in people undergoing total knee arthroplasty compared with other types of surgery. Pain intensity was also significantly reduced on movement in the 48 to 72 hours interval postoperatively (MD -6.19, 95% CI -11.76 to -0.62, two studies, 112 participants). There was no significant difference on movement between these two groups in the time period of zero to 23 hours (MD -6.95, 95% CI -15.92 to 2.01, five studies, 304 participants) and 24 to 47 hours (MD -8.87, 95% CI -27.77 to 10.03, three studies, 182 participants). The included studies reported diverse types of adverse events, and we did not conduct a meta-analysis on specific types of adverse event. The numbers of studies and participants were also too few to draw conclusions on the other prespecified outcomes of: additional analgesic consumption; median time to remedication; knee range of motion; median time to ambulation; length of hospital stay; hospital costs; and participant satisfaction. There were insufficient data to compare peripheral nerve blocks and local infiltration or between peripheral nerve blocks and epidural analgesia. AUTHORS' CONCLUSIONS: All of the included studies reported the main outcome of pain intensity but did not cover all the secondary outcomes of interest. The current review provides evidence that the use of peripheral nerve blocks as adjunctive techniques to systemic analgesia reduced pain intensity when compared with systemic analgesia alone after major knee surgery. There were too few data to draw conclusions on other outcomes of interest. More trials are needed to demonstrate a significant difference when compared with local infiltration, epidural analgesia and spinal analgesia.

A comprehensive meta-analysis of circulation miRNAs in glioma as potential diagnostic biomarker.

Glioma is the most common malignant intracranial tumour. Recently, several publications have suggested that miRNAs can be used as potential diagnostic biomarkers of glioma. Here we performed a meta-analysis to identify the diagnostic accuracy of differentially expressed circulating miRNAs in gliomas. Using PubMed, Medline and Cochrane databases, we searched for studies which evaluated a single or panel of miRNAs from circulating blood as potential biomarkers of glioma. Sixteen publications involving 23 studies of miRNAs from serum or plasma met our criteria and were included in this meta-analysis. The pooled diagnostic parameters were calculated by random effect models and overall diagnostic performance of altered miRNAs was illustrated by the summary receiver operator characteristic (SROC) curves. The pooled sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR) from each study were calculated. The pooled PLR, NLR and Diagnostic Odds Ratio were 6.39 (95% CI, 4.61-8.87), 0.15 (95% CI, 0.11-0.21) and 41.91 (95% CI, 23.15-75.88), respectively. The pooled sensitivity, specificity and area under the curve (AUC) were 0.87 (95% CI, 0.82-0.91), 0.86 (95% CI, 0.82-0.90) and 0.93 (95% CI, 0.91-0.95), respectively. This meta-analysis demonstrated that circulating miRNAs are capable of distinguishing glioma from healthy controls. Circulating miRNAs are promising diagnostic biomarkers for glioma and can potentially be used as a non-invasive early detection.

The node-weighted Steiner tree approach to identify elements of cancer-related signaling pathways.

BACKGROUND: Cancer constitutes a momentous health burden in our society. Critical information on cancer may be hidden in its signaling pathways. However, even though a large amount of money has been spent on cancer research, some critical information on cancer-related signaling pathways still remains elusive. Hence, new works towards a complete understanding of cancer-related signaling pathways will greatly benefit the prevention, diagnosis, and treatment of cancer. RESULTS: We propose the node-weighted Steiner tree approach to identify important elements of cancer-related signaling pathways at the level of proteins. This new approach has advantages over previous approaches since it is fast in processing large protein-protein interaction networks. We apply this new approach to identify important elements of two well-known cancer-related signaling pathways: PI3K/Akt and MAPK. First, we generate a node-weighted protein-protein interaction network using protein and signaling pathway data. Second, we modify and use two preprocessing techniques and a state-of-the-art Steiner tree algorithm to identify a subnetwork in the generated network. Third, we propose two new metrics to select important elements from this subnetwork. On a commonly used personal computer, this new approach takes less than 2 s to identify the important elements of PI3K/Akt and MAPK signaling pathways in a large node-weighted protein-protein interaction network with 16,843 vertices and 1,736,922 edges. We further analyze and demonstrate the significance of these identified elements to cancer signal transduction by exploring previously reported experimental evidences. CONCLUSIONS: Our node-weighted Steiner tree approach is shown to be both fast and effective to identify important elements of cancer-related signaling pathways. Furthermore, it may provide new perspectives into the identification of signaling pathways for other human diseases.

Peripheral nerve blocks for postoperative pain after major knee surgery.

BACKGROUND: Major knee surgery is a common operative procedure to help people with end-stage knee disease or trauma to regain mobility and have improved quality of life. Poorly controlled pain immediately after surgery is still a key issue for this procedure. Peripheral nerve blocks are localized and site-specific analgesic options for major knee surgery. The increasing use of peripheral nerve blocks following major knee surgery requires the synthesis of evidence to evaluate its effectiveness and safety, when compared with systemic, local infiltration, epidural and spinal analgesia. OBJECTIVES: To examine the efficacy and safety of peripheral nerve blocks for postoperative pain control following major knee surgery using methods that permit comparison with systemic, local infiltration, epidural and spinal analgesia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2014), MEDLINE and EMBASE, from their inception to February 2014. We identified ongoing studies by searching trial registries, including the metaRegister of controlled trials (mRCT), clinicaltrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: We included participant-blind, randomized controlled trials of adult participants (15 years or older) undergoing major knee surgery, in which peripheral nerve blocks were compared to systemic, local infiltration, epidural and spinal analgesia for postoperative pain relief. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and extracted data. We recorded information on participants, methods, interventions, outcomes (pain intensity, additional analgesic consumption, adverse events, knee range of motion, length of hospital stay, hospital costs, and participant satisfaction). We used the 5-point Oxford quality and validity scale to assess methodological quality, as well as criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We conducted meta-analysis of two or more studies with sufficient data to investigate the same outcome. We used the I² statistic to explore the heterogeneity. If there was no significant heterogeneity (I² value 0% to 40%), we used a fixed-effect model for meta-analysis, but otherwise we used a random-effects model. For dichotomous data, we present results as a summary risk ratio (RR) and a 95% confidence interval (95% CI). Where possible, we calculated the number needed to treat for an additional beneficial outcome (NNTB) or for an additional harmful outcome (NNTH), together with 95% CIs. For continuous data, we used the mean difference (MD) and 95% CI for similar outcome measures. We describe the findings of individual studies where pooling of data was not possible. MAIN RESULTS: According to the eligibility criteria, we include 23 studies with 1571 participants, with high methodological quality overall. The studies compared peripheral nerve blocks adjunctive to systemic analgesia with systemic analgesia alone (19 studies), peripheral nerve blocks with local infiltration (three studies), and peripheral nerve blocks with epidural analgesia (one study). No study compared peripheral nerve blocks with spinal analgesia.Compared with systemic analgesia alone, peripheral nerve blocks adjunctive to systemic analgesia resulted in a significantly lower pain intensity score at rest, using a 100 mm visual analogue scale, at all time periods within 72 hours postoperatively, including the zero to 23 hours interval (MD -11.85, 95% CI -20.45 to -3.25, seven studies, 390 participants), the 24 to 47 hours interval (MD -12.92, 95% CI -19.82 to -6.02, six studies, 320 participants) and the 48 to 72 hours interval (MD -9.72, 95% CI -16.75 to -2.70, four studies, 210 participants). Subgroup analyses suggested that the high levels of statistical variation in our analyses could be explained by larger effects in people undergoing total knee arthroplasty compared with other types of surgery. Pain intensity was also significantly reduced on movement in the 48 to 72 hours interval postoperatively (MD -6.19, 95% CI -11.76 to -0.62, two studies, 112 participants). There was no significant difference on movement between these two groups in the time period of zero to 23 hours (MD -6.95, 95% CI -15.92 to 2.01, five studies, 304 participants) and 24 to 47 hours (MD -8.87, 95% CI -27.77 to 10.03, three studies, 182 participants). The included studies reported diverse types of adverse events, and we did not conduct a meta-analysis on specific types of adverse event. The numbers of studies and participants were also too few to draw conclusions on the other prespecified outcomes of: additional analgesic consumption; median time to remedication; knee range of motion; median time to ambulation; length of hospital stay; hospital costs; and participant satisfaction. There were insufficient data to compare peripheral nerve blocks and local infiltration or between peripheral nerve blocks and epidural analgesia. AUTHORS' CONCLUSIONS: All of the included studies reported the main outcome of pain intensity but did not cover all the secondary outcomes of interest. The current review provides evidence that the use of peripheral nerve blocks as adjunctive techniques to systemic analgesia reduced pain intensity when compared with systemic analgesia alone after major knee surgery. There were too few data to draw conclusions on other outcomes of interest. More trials are needed to demonstrate a significant difference when compared with local infiltration, epidural analgesia and spinal analgesia.

Evaluation of osteopontin as a potential biomarker for central nervous system embryonal tumors.

Osteopontin (OPN) is a protein linked to tumor growth, progression and metastasis of cancers. However, its role in the progression of central nervous system (CNS) embryonal tumors such as atypical teratoid/rhabdoid tumor (AT/RT), medulloblastoma (MB) and primitive neuroepithelial tumors (PNET) remains elusive. In this study, we investigated the value of OPN staining in differential diagnosis of AT/RT from MB and PNET, and assessed the correlation between OPN expression and patients' prognosis. This retrospective study was conducted on tissue sections obtained from children cases with CNS embryonal tumors treated in Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine from 2006 to 2012 by immunohistochemistry (IHC). 49 cases were collected (11 AT/RTs, 25 MBs, and 13 PNETs), with a median follow-up time of 28.9 months. OPN expression in AT/RT was significantly higher than MB and PNET with the positive rates of 100, 32, and 23 %, respectively (P < 0.01). The specificity and sensitivity of OPN staining in diagnosing AT/RT are 97.4 and 90.9 %, respectively, as judged by strong OPN IHC staining level (+++). Patients who had positive OPN staining have increased risks of poorer median overall survival (hazard risk 5.54, 95 % CI 1.87-16.38) and tumor progression (hazard risk 14.47, 95 % CI 4.47-46.85). OPN is a valuable biomarker to aid in the differential diagnosis between AT/RT and MB/PNET. Moreover, OPN is a potential novel prognostic marker for CNS embryonal tumors.