Varicella zoster virus-induced autophagy in human neuronal and hematopoietic cells exerts antiviral activity.

Autophagy is a degradational pathway with pivotal roles in cellular homeostasis and survival, including protection of neurons in the central nervous system (CNS). The significance of autophagy as antiviral defense mechanism is recognized and some viruses hijack and modulate this process to their advantage in certain cell types. Here, we present data demonstrating that the human neurotropic herpesvirus varicella zoster virus (VZV) induces autophagy in human SH-SY5Y neuronal cells, in which the pathway exerts antiviral activity. Productively VZV-infected SH-SY5Y cells showed increased LC3-I-LC3-II conversion as well as co-localization of the viral glycoprotein E and the autophagy receptor p62. The activation of autophagy was dependent on a functional viral genome. Interestingly, inducers of autophagy reduced viral transcription, whereas inhibition of autophagy increased viral transcript expression. Finally, the genotype of patients with severe ocular and brain VZV infection were analyzed to identify potential autophagy-associated inborn errors of immunity. Two patients expressing genetic variants in the autophagy genes ULK1 and MAP1LC3B2, respectively, were identified. Notably, cells of both patients showed reduced autophagy, alongside enhanced viral replication and death of VZV-infected cells. In conclusion, these results demonstrate a neuro-protective role for autophagy in the context of VZV infection and suggest that failure to mount an autophagy response is a potential predisposing factor for development of severe VZV disease.

SAM68 directs STING signaling to apoptosis in macrophages.

DNA is a danger signal sensed by cGAS to engage signaling through STING to activate innate immune functions. The best-studied downstream responses to STING activation include expression of type I interferon and inflammatory genes, but STING also activates other pathways, including apoptosis. Here, we report that STING-dependent induction of apoptosis in macrophages occurs through the intrinsic mitochondrial pathway and is mediated via IRF3 but acts independently of gene transcription. By intersecting four mass spectrometry datasets, we identify SAM68 as crucial for the induction of apoptosis downstream of STING activation. SAM68 is essential for the full activation of apoptosis. Still, it is not required for STING-mediated activation of IFN expression or activation of NF-κB. Mechanistic studies reveal that protein trafficking is required and involves SAM68 recruitment to STING upon activation, with the two proteins associating at the Golgi or a post-Golgi compartment. Collectively, our work identifies SAM68 as a STING-interacting protein enabling induction of apoptosis through this DNA-activated innate immune pathway.

An IKBKE variant conferring functional cGAS/STING pathway deficiency and susceptibility to recurrent HSV-2 meningitis.

The mechanisms underlying susceptibility to recurrent herpes simplex virus type 2 (HSV-2) meningitis remain incompletely understood. In a patient experiencing multiple episodes of HSV-2 meningitis, we identified a monoallelic variant in the IKBKE gene, which encodes the IKKε kinase involved in induction of antiviral IFN genes. Patient cells displayed impaired induction of IFN-ß1 (IFNB1) expression upon infection with HSV-2 or stimulation with double-stranded DNA (dsDNA) and failed to induce phosphorylation of STING, an activation marker of the DNA-sensing cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway. The patient allele encoded a truncated IKKε protein with loss of kinase activity and also capable of exerting dominant-negative activity. In stem cell-derived microglia, HSV-2-induced expression of IFNB1 was dependent on cGAS, TANK binding kinase 1 (TBK1), and IKBKE, but not TLR3, and supernatants from HSV-2-treated microglia exerted IKBKE-dependent type I IFN-mediated antiviral activity upon neurons. Reintroducing wild-type IKBKE into patient cells rescued IFNB1 induction following treatment with HSV-2 or dsDNA and restored antiviral activity. Collectively, we identify IKKε to be important for protection against HSV-2 meningitis and suggest a nonredundant role for the cGAS/STING pathway in human antiviral immunity.

ER stress induces caspase-2-tBID-GSDME-dependent cell death in neurons lytically infected with herpes simplex virus type 2.

Neurotropic viruses, including herpes simplex virus (HSV) types 1 and 2, have the capacity to infect neurons and can cause severe diseases. This is associated with neuronal cell death, which may contribute to morbidity or even mortality if the infection is not controlled. However, the mechanistic details of HSV-induced neuronal cell death remain enigmatic. Here, we report that lytic HSV-2 infection of human neuron-like SH-SY5Y cells and primary human and murine brain cells leads to cell death mediated by gasdermin E (GSDME). HSV-2-induced GSDME-mediated cell death occurs downstream of replication-induced endoplasmic reticulum stress driven by inositol-requiring kinase 1α (IRE1α), leading to activation of caspase-2, cleavage of the pro-apoptotic protein BH3-interacting domain death agonist (BID), and mitochondria-dependent activation of caspase-3. Finally, necrotic neurons released alarmins, which activated inflammatory responses in human iPSC-derived microglia. In conclusion, lytic HSV infection in neurons activates an ER stress-driven pathway to execute GSDME-mediated cell death and promote inflammation.

Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern.

The antimicrobial medication malarone (atovaquone/proguanil) is used as a fixed-dose combination for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travelers. It is an inexpensive, efficacious, and safe drug frequently prescribed around the world. Following anecdotal evidence from 17 patients in the provinces of Quebec and Ontario, Canada, suggesting that malarone/atovaquone may present some benefits in protecting against COVID-19, we sought to examine its antiviral potential in limiting the replication of SARS-CoV-2 in cellular models of infection. In VeroE6 expressing human TMPRSS2 and human lung Calu-3 epithelial cells, we show that the active compound atovaquone at micromolar concentrations potently inhibits the replication of SARS-CoV-2 and other variants of concern including the alpha, beta, and delta variants. Importantly, atovaquone retained its full antiviral activity in a primary human airway epithelium cell culture model. Mechanistically, we demonstrate that the atovaquone antiviral activity against SARS-CoV-2 is partially dependent on the expression of TMPRSS2 and that the drug can disrupt the interaction of the spike protein with the viral receptor, ACE2. Additionally, spike-mediated membrane fusion was also reduced in the presence of atovaquone. In the United States, two clinical trials of atovaquone administered alone or in combination with azithromycin were initiated in 2020. While we await the results of these trials, our findings in cellular infection models demonstrate that atovaquone is a potent antiviral FDA-approved drug against SARS-CoV-2 and other variants of concern in vitro.

Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans.

Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret's meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including ATG4A and LC3B2, led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.

A Preliminary Investigation of PVT1 on the Effect and Mechanisms of Hepatocellular Carcinoma: Evidence from Clinical Data, a Meta-Analysis of 840 Cases, and In Vivo Validation.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) remains a difficult problem that significantly affects the survival of the afflicted patients. Accumulating evidence has demonstrated the functions of long non-coding RNA (lncRNA) in HCC. In the present study, we aimed to explore the potential roles of PVT1 in the tumorigenesis and progression of HCC. METHODS: In this study, quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was applied to detect the differences between PVT1 expression in HCC tissues and cell lines. Then, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were searched to confirm the relationship between PVT1 expression and HCC. Moreover, a meta-analysis comprising TCGA, GEO, and RT-qPCR was applied to estimate the expression of PVT1 in HCC. Then, cell proliferation was evaluated in vitro. A chicken chorioallantoic membrane (CAM) model of HCC was constructed to measure the effect on tumorigenicity in vivo. To further explore the sponge microRNA (miRNA) of PVT1 in HCC, we used TCGA, GEO, a gene microarray, and target prediction algorithms. TCGA and GEO and the gene microarray were used to select the differentially expressed miRNAs, and the different target prediction algorithms were applied to predict the target miRNAs of PVT1. RESULTS: We found that PVT1 was markedly overexpressed in HCC tissue than in normal liver tissues based on both RT-qPCR and data from TCGA, and the overexpression of PVT1 was closely related to the gender and race of the patient as well as to higher HCC tumor grades. Also, a meta-analysis of 840 cases from multiple sources (TCGA, GEO and the results of our in-house RT-qPCR) showed that PVT1 gained moderate value in discriminating HCC patients from normal controls, confirming the results of RT-qPCR. Additionally, the upregulation of PVT1 could promote HCC cell proliferation in vitro and vivo. Based on the competing endogenous RNA (ceRNA) theory, the PVT1/miR-424-5p/INCENP axis was finally selected for further research. The in silico prediction revealed that there were complementary sequences between PVT1 and miR-424-5p as well as between miR-424-5p and INCENP. Furthermore, a negative correlation trend was found between miR-424-5p and PVT1 based on RT-qPCR, whereas a positive correlation trend was found between PVT1 and INCENP based on data from TCGA. Also, INCENP small interfering RNA (siRNA) could significantly inhibit cell proliferation and viability. CONCLUSIONS: We hypothesized that PVT1 could affect the biological function of HCC cells via targeting miR-424-5p and regulating INCENP. Focusing on the new insight of the PVT1/miR-424-5p/INCENP axis, this study provides a novel perspective for HCC therapeutic strategies.

Analysis of microarrays of miR-34a and its identification of prospective target gene signature in hepatocellular carcinoma.

BACKGROUND: Currently, some studies have demonstrated that miR-34a could serve as a suppressor of several cancers including hepatocellular carcinoma (HCC). Previously, we discovered that miR-34a was downregulated in HCC and involved in the tumorigenesis and progression of HCC; however, the mechanism remains unclear. The purpose of this study was to estimate the expression of miR-34a in HCC by applying the microarray profiles and analyzing the predicted targets of miR-34a and their related biological pathways of HCC. METHODS: Gene expression omnibus (GEO) datasets were conducted to identify the difference of miR-34a expression between HCC and corresponding normal tissues and to explore its relationship with HCC clinicopathologic features. The natural language processing (NLP), gene ontology (GO), pathway and network analyses were performed to analyze the genes associated with the carcinogenesis and progression of HCC and the targets of miR-34a predicted in silico. In addition, the integrative analysis was performed to explore the targets of miR-34a which were also relevant to HCC. RESULTS: The analysis of GEO datasets demonstrated that miR-34a was downregulated in HCC tissues, and no heterogeneity was observed (Std. Mean Difference(SMD) = 0.63, 95% confidence intervals(95%CI):[0.38, 0.88], P < 0.00001; Pheterogeneity = 0.08 I2 = 41%). However, no association was found between the expression value of miR-34a and any clinicopathologic characteristics. In the NLP analysis of HCC, we obtained 25 significant HCC-associated signaling pathways. Besides, we explored 1000 miR-34a-related genes and 5 significant signaling pathways in which CCND1 and Bcl-2 served as necessary hub genes. In the integrative analysis, we found 61 hub genes and 5 significant pathways, including cell cycle, cytokine-cytokine receptor interaction, notching pathway, p53 pathway and focal adhesion, which proposed the relevant functions of miR-34a in HCC. CONCLUSION: Our results may lead researchers to understand the molecular mechanism of miR-34a in the diagnosis, prognosis and therapy of HCC. Therefore, the interaction between miR-34a and its targets may promise better prediction and treatment for HCC. And the experiments in vivo and vitro will be conducted by our group to identify the specific mechanism of miR-34a in the progress and deterioration of HCC.

Down-regulation of miR-146a-5p and its potential targets in hepatocellular carcinoma validated by a TCGA- and GEO-based study.

Our previous research has demonstrated that miR-146a-5p is down-regulated in hepatocellular carcinoma (HCC) and might play a tumor-suppressive role. In this study, we sought to validate the decreased expression with a larger cohort and to explore potential molecular mechanisms. GEO and TCGA databases were used to gather miR-146a-5p expression data in HCC, which included 762 HCC and 454 noncancerous liver tissues. A meta-analysis of the GEO-based microarrays, TCGA-based RNA-seq data, and additional qRT-PCR data validated the down-regulation of miR-146a-5p in HCC and no publication bias was observed. Integrated genes were generated by overlapping miR-146a-5p-related genes from predicted and formerly reported HCC-related genes using natural language processing. The overlaps were comprehensively analyzed to discover the potential gene signatures, regulatory pathways, and networks of miR-146a-5p in HCC. A total of 251 miR-146a-5p potential target genes were predicted by bioinformatics platforms and 104 genes were considered as both HCC- and miR-146a-5p-related overlaps. RAC1 was the most connected hub gene for miR-146a-5p and four pathways with high enrichment (VEGF signaling pathway, adherens junction, toll-like receptor signaling pathway, and neurotrophin signaling pathway) were denoted for the overlapped genes. The down-regulation of miR-146a-5p in HCC has been validated with the most complete data possible. The potential gene signatures, regulatory pathways, and networks identified for miR-146a-5p in HCC could prove useful for molecular-targeted diagnostics and therapeutics.

Detecting explosive molecules from nanoliter solution: A new paradigm of SERS sensing on hydrophilic photonic crystal biosilica.

We demonstrate a photonic crystal biosilica surface-enhanced Raman scattering (SERS) substrate based on a diatom frustule with in-situ synthesized silver nanoparticles (Ag NPs) to detect explosive molecules from nanoliter (nL) solution. By integrating high density Ag NPs inside the nanopores of diatom biosilica, which is not achievable by traditional self-assembly techniques, we obtained ultra-high SERS sensitivity due to dual enhancement mechanisms. First, the hybrid plasmonic-photonic crystal biosilica with three dimensional morphologies was obtained by electroless-deposited Ag seeds at nanometer sized diatom frustule surface, which provides high density hot spots as well as strongly coupled optical resonances with the photonic crystal structure of diatom frustules. Second, we discovered that the evaporation-driven microscopic flow combined with the strong hydrophilic surface of diatom frustules is capable of concentrating the analyte molecules, which offers a simple yet effective mechanism to accelerate the mass transport into the SERS substrate. Using the inkjet printing technology, we are able to deliver multiple 100pico-liter (pL) volume droplets with pinpoint accuracy into a single diatom frustule with dimension around 30µm×7µm×5µm, which allows for label-free detection of explosive molecules such as trinitrotoluene (TNT) down to 10-10M in concentration and 2.7×10-15g in mass from 120nL solution. Our research illustrates a new paradigm of SERS sensing to detect trace level of chemical compounds from minimum volume of analyte using nature created photonic crystal biosilica materials.

Lower expressed miR-198 and its potential targets in hepatocellular carcinoma: a clinicopathological and in silico study.

PURPOSE: To investigate the clinicopathological value and potential roles of microRNA-198 (miR-198) in hepatocellular carcinoma (HCC). METHODS: Ninety-five formalin-fixed paraffin-embedded HCC and the para-cancerous liver tissues were gathered. Real-time reverse transcription quantitative polymerase chain reaction was applied to determine the miR-198 expression. The association between the miR-198 expression and clinicopathological features was examined. Meanwhile, potential target messenger RNAs of miR-198 in HCC were obtained from 14 miRNA prediction databases and natural language processing method, in which we pooled the genes related to the tumorigenesis and progression of HCC and classified them by their frequency. The selected target genes were finally analyzed in the Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway. RESULTS: miR-198 expression was significantly lower in HCC than that in adjacent noncancerous liver tissues (1.30±0.72 vs 2.01±0.58, P<0.001). Low miR-198 expression was also correlated to hepatitis C virus infection (r=-0.48, P<0.001), tumor capsular infiltration (r=-0.43, P<0.001), metastasis (r=-0.26, P<0.010), number of tumor nodes (r=-0.25, P=0.013), vaso-invasion (r=-0.24, P=0.017), and clinical tumor node metastasis stage (r=-0.23, P=0.024). Altogether, 1,048 genes were achieved by the concurrent prediction from at least four databases and natural language processing indicated 1,800 genes for HCC. Further, 127 overlapping targets were further proceeded with for pathway analysis. The most enriched Gene Ontology terms in the potential target messenger RNAs of miR-198 were cell motion, cell migration, cell motility, and regulation of cell proliferation in biological process; organelle lumen, membrane-enclosed lumen, and nuclear lumen in cellular component; and enzyme binding, protein domain-specific binding, and protein kinase activity in molecular function. Kyoto Encyclopedia of Genes and Genomes analysis showed that these target genes were obviously involved in focal adhesion and pathways in cancer. CONCLUSION: Lower expression of miR-198 was related to several clinicopathological parameters in HCC patients. miR-198 might play a regulatory role through its target genes in the development of HCC.

An Encapsulation of Gene Signatures for Hepatocellular Carcinoma, MicroRNA-132 Predicted Target Genes and the Corresponding Overlaps.

OBJECTIVES: Previous studies have demonstrated that microRNA-132 plays a vital part in and is actively associated with several cancers, with its tumor-suppressive role in hepatocellular carcinoma confirmed. The current study employed multiple bioinformatics techniques to establish gene signatures for hepatocellular carcinoma, microRNA-132 predicted target genes and the corresponding overlaps. METHODS: Various assays were performed to explore the role and cellular functions of miR-132 in HCC and a successive panel of tasks was completed, including NLP analysis, miR-132 target genes prediction, comprehensive analyses (gene ontology analysis, pathway analysis, network analysis and connectivity analysis), and analytical integration. Later, HCC-related and miR-132-related potential targets, pathways, networks and highlighted hub genes were revealed as well as those of the overlapped section. RESULTS: MiR-132 was effective in both impeding cell growth and boosting apoptosis in HCC cell lines. A total of fifty-nine genes were obtained from the analytical integration, which were considered to be both HCC- and miR-132-related. Moreover, four specific pathways were unveiled in the network analysis of the overlaps, i.e. adherens junction, VEGF signaling pathway, neurotrophin signaling pathway, and MAPK signaling pathway. CONCLUSIONS: The tumor-suppressive role of miR-132 in HCC has been further confirmed by in vitro experiments. Gene signatures in the study identified the potential molecular mechanisms of HCC, miR-132 and their established associations, which might be effective for diagnosis, individualized treatments and prognosis of HCC patients. However, combined detections of miR-132 with other bio-indicators in clinical practice and further in vitro experiments are needed.

Broadband on-chip near-infrared spectroscopy based on a plasmonic grating filter array.

We demonstrate an ultra-compact, broadband on-chip near-infrared (NIR) spectroscopy system based on a narrow-band plasmonic filter array. The entire filter array, consisting of 28 individual subwavelength metallic gratings, was monolithically integrated in a thin gold film on a quartz substrate, covering a 270 nm spectra from 1510 nm to 1780 nm. In order to achieve a high spectral resolution, extremely narrow slits are created for the gratings with a polymer waveguide layer on top, generating narrow-band guided-mode resonances through coupling with the surface-plasmon resonances of the metallic gratings. Experimental results show that the transmission bands of the filter array have full width at half-maximum of only 7 nm-13 nm, which is sufficient for NIR spectroscopy. The NIR absorption spectroscopy of xylene using the on-chip plasmonic filter array matches very well with the results from conventional Fourier transform infrared spectroscopy, which proves the great potential for NIR sensing applications.

Prognostic Value of Expression of Cyclin E in Gastrointestinal Cancer: A Systematic Review and Meta-Analysis.

Cyclin E is a critical regulator in cell cycle and promotes the initiation of DNA replication and centrosome duplication in late G1. The overexpression of cyclin E is common in cancers of the digestive system. However, whether cyclin E represents a prognostic biomarker in gastrointestinal cancer remains controversial. We reviewed the published literatures to clarify the association between cyclin E determined by immunohistochemistry (IHC) and survival in gastrointestinal cancer. Literatures were searched in PubMed and Cochrane Library published up to December 1, 2014. A total of 282 articles were initially identified, and 14 articles were included in this study. Meta-analysis was performed for 10 studies with a total of 1300 patients. Combined hazard risk (HR) and corresponding 95% confidence interval (CI) were calculated by random-effect model due to the heterogeneity. The quality of included studies was assessed by the Newcastle-Ottawa Scale and the Methodological Index for Non-Randomized Studies (MINORS). We found that high level of cyclin E was a predicator of poor prognosis among patients with gastrointestinal cancer (HR = 1.67, 95% CI = 1.06-2.63, P = .028). In summary, overexpression of cyclin E is associated with poor prognosis in gastrointestinal cancer and expression of cyclin E determined by IHC might be a prognostic marker for gastrointestinal cancer in clinical practice.

Long noncoding RNAs in hepatocellular carcinoma: Novel insights into their mechanism.

Hepatocellular carcinoma (HCC) is the predominant subject of liver malignancies which arouse global concern. Advanced studies have found that long noncoding RNAs (lncRNAs) are differentially expressed in HCC and implicate they may play distinct roles in the pathogenesis and metastasis of HCC. However, the underlying mechanisms remain largely unclear. In this review, we summarized the functions and mechanisms of those known aberrantly expressed lncRNAs identified in human HCC tissues. We hope to enlighten more comprehensive researches on the detailed mechanisms of lncRNAs and their application in clinic, such as being used as diagnostic and prognostic biomarkers and the targets for potential therapy. Although studies on lncRNAs in HCC are still deficient, an improved understanding of the roles played by lncRNAs in HCC will lead to a much more effective utilization of those lncRNAs as novel candidates in early detection, diagnosis, prevention and treatment of HCC.

Slow-light effect via Rayleigh anomaly and the effect of finite gratings.

In this Letter, we investigate the slow-light effect of subwavelength diffraction gratings via the Rayleigh anomaly using a fully analytical approach without needing to consider specific grating structures. Our results show that the local group velocity of the transmitted light can be significantly reduced due to the optical vortex, which can inspire a new mechanism to enhance light-matter interactions for optical sensing and photodetection. However, the slow-light effect will diminish as the transmitted light propagates farther from the grating surface, and the slowdown factor decreases as the grating size shrinks.

Effect of finite metallic grating size on Rayleigh anomaly-surface plasmon polariton resonances.

Rayleigh anomalies (RAs) and surface plasmon polaritons (SPPs) on subwavelength metallic gratings play pivotal roles in many interesting phenomena such as extraordinary optical transmission. In this work, we present a theoretical analysis of the effect of finite metallic grating size on RA-SPP resonances based on the combination of rigorous coupled wave analysis and finite aperture diffraction. One-dimensional arrays of gold subwavelength gratings with different device sizes were fabricated and the optical transmission spectra were measured. As the grating size shrinks, the broadening of the RA-SPP resonances is predicted by the theoretical model. For the first order RA-SPP resonances, the results from this model are in good agreement with the spectra measured from the fabricated plasmonic gratings.

Prognostic value of Caspase-3 expression in cancers of digestive tract: a meta-analysis and systematic review.

Various studies have evaluated the relationship between Caspase-3 expression and cancers of digestive tract. However, the prognostic value of Caspase-3 expression remains unclear. Hence, a meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between Caspase-3 expression and survival of patients in gastrointestinal tract cancers. Electronic databases updated to April 12(th), 2015 were searched to obtain relevant primary articles. Twelve studies were finally included with 2402 patients of esophageal, gastric or colorectal cancers. The detection of Caspase-3 was performed by immunohistochemistry (IHC). Survival data were aggregated and quantitatively analyzed. Combined hazard ratios (HRs) suggested that Caspase-3 expression had no specific impact on the overall survival (OS) (HR=0.94, 95% CI (0.64-1.37), I(2)=79.6%, P<0.001) of cancers of digestive tract. When each subtype of gastrointestinal cancer was analyzed separately, the over-expression of Caspase-3 was associated with favorable prognosis of OS in esophageal cancer HR=0.31, 95% CI (0.09-1.09), I(2)=54.6%, P=0.138). On the contrary, high level of Caspase-3 was correlated with poor prognosis of OS in gastric cancer HR=1.53, 95% CI (0.93-2.50), I(2)=46.4%, P=0.172). However, the expression of Caspase-3 showed no relationship of OS for patients with colorectal cancer (HR=1.03, 95% CI (0.66-1.63), I(2)=0.0%, P=0.410). Furthermore, the Caspase-3 expression was an indicator of poor prognosis of recurrence-free survival (RFS) for digestive tract cancer (HR=1.65, 95% CI (1.12-2.41), I(2)=43.9%, P=0.148). More studies need to be carried out to certify the prognostic value of Caspase-3 expression for patients with digestive tract cancers.

Clinicopathological and prognostic significance of high Ki-67 labeling index in hepatocellular carcinoma patients: a meta-analysis.

BACKGROUND: The relationship between Ki-67 labeling index (LI) and clinical outcome in hepatocellular carcinoma (HCC) has been investigated by various studies, but no consistent result has been concluded. To define the prognostic significance of Ki-67 LI in patients with HCC, we performed a meta-analysis. METHODS: We searched for literatures in the following databases: PubMed, ISI Web of Science, EMBASE, Cochrane Central Register of Controlled Trials, Science Direct, Wiley Online Library, Google Scholar, China National Knowledge Infrastructure (CNKI), Chinese VIP and WanFang Databases. Our search ended on April 6th, 2015. Data were extracted from eligible studies and the correlation between Ki-67 LI and clinicopathological features of HCC was analyzed and pooled hazard ratios (HRs) for eligible studies were calculated by STATA 11.0 (STATA Corp., College, TX). RESULTS: In total, 54 studies involving 4996 patients were included in the current meta-analysis. The meta-analysis provided evidence that high Ki-67 LI was closely associated with histological grade, tumor size, number of tumor nodes, the status of metastasis, cirrhosis and vein invasion in HCC patients. The pooled HRs showed that high Ki-67 LI had an unfavorable impact on disease-free survival (DFS) (HR=1.626, 95% confidence interval (CI): 1.364-1.939, P<0.001), relapse-free survival (RFS) (HR=1.820, 95% CI: 1.215-2.725, P=0.004) and overall survival (OS) (HR=1.170, 95% CI: 1.102-1.243, P<0.001), respectively. Additionally, subgroup analysis indicated that high Ki-67 LI was related to poorer DFS, RFS and OS independent of regions, treatment strategies or statistical methods, except that no statistical significance was found on RFS (HR=2.413, 95% CI: 0.523-11.142, P=0.259) and OS (HR=1.998, 95% CI: 0.797-5.009, P=0.14) in patients with liver transplantation. CONCLUSIONS: Our meta-analysis suggests that higher Ki-67 LI confers a fast progression and poor prognosis for HCC patients.

Expression and clinicopathological significance of miR-193a-3p and its potential target astrocyte elevated gene-1 in non-small lung cancer tissues.

BACKGROUND: Aberrant expression of miR-193a-3p and astrocyte elevated gene-1 (AEG-1) have been revealed to be related to the tumorigenesis of various cancers, including non-small cell lung cancer (NSCLC). However, the significance of miR-193a-3p and its correlation with AEG-1 in NSCLC has not been explored. The purpose of this study was to evaluate the association between miR-193a-3p and AEG-1 and their relationship with the clinicopathological features in NSCLC patients. METHODS: Via online in silico prediction, complementary sequences were found between miR-193a-3p and the 3'-untranslated region of AEG-1. Three independent cohorts were applied in the current study. Firstly, miR-193a-3p level was detected in 125 cases of NSCLC with quantitative real-time PCR (qRT-PCR). Secondly, AEG-1 protein level was evaluated in 339 cases of lung cancers with immunohistochemistry. Finally, the relationship between miR-193a-3p and AEG-1 protein expression was verified in another group with 65 cases of NSCLC. RESULTS: The results showed that miR-193a-3p level was decreased in NSCLC tissues and significantly negatively related to tumor size (r = -0.277, P = 0.002), clinical TNM stage (r = -0.226, P = 0.011), lymph node metastasis (r = -0.186, P = 0.038), epidermal growth factor receptor (EGFR) protein level (r = -0.272, P = 0.041). On the contrary, AEG-1 protein expression was up-regulated in NSCLC and positively relative to tumor size (r = 0.240, P < 0.001), TNM stages (r = 0.164, P = 0.002) and lymph node metastasis (r = 0.232, P < 0.001) in NSCLC patients. In addition, miR-193a-3p was found to be inversely associated with AEG-1 protein expression in the third cohort (r = -0.564, P < 0.001). CONCLUSION: In conclusion, miR-193a-3p and AEG-1 might be responsible for the carcinogenesis and aggressiveness of NSCLC. AEG-1 has the potential to be one of the targeted genes of miR-193a-3p. However, future in vitro and in vivo experiments are needed to verify this hypothesis.