We used oxidative isotope-coded affinity tags (OxICAT) to investigate the global redox status of proteins in human papillomavirus (HPV)-related cervical cancer cells, in order to identify a potential target for gene therapy. Voltage-dependent anion channel 1 (VDAC1) was found to be highly oxidized in HPV-positive cervical cancer cells. VDAC1 expression correlated significantly with the invasion of cervical cancer, the grade of cervical intraepithelial neoplasia (CIN) and the expression of HPV16 E7 in CIN. Knockdown of VDAC1 in cell lines increased the rate of apoptosis, while overexpression of the VDAC1 (respectively) partly reversed the effect. Thus, VDAC1 may promote the malignant progression of HPV-related disease, and treatments designed to suppress VDAC1 could prevent the progression of HPV-induced cervical disease.

Intra-subject variation in reaction time (ISVRT) is a developmentally-important phenomenon that decreases from childhood through young adulthood in parallel with the development of executive functions and networks. Prior work has shown a significant association between trial-by-trial variations in reaction time (RT) and trial-by-trial variations in brain activity as measured by the blood-oxygenated level-dependent (BOLD) response in functional magnetic resonance imaging (fMRI) studies. It remains unclear, however, whether such "RT-BOLD" relationships vary with age. Here, we determined whether such trial-by-trial relationships vary with age in a cross-sectional design. We observed an association between age and RT-BOLD relationships in 11 clusters located in visual/occipital regions, frontal and parietal association cortex, precentral/postcentral gyrus, and thalamus. Some of these relationships were negative, reflecting increased BOLD associated with decreased RT, manifesting around the time of stimulus presentation and positive several seconds later. Critically for present purposes, all RT-BOLD relationships increased with age. Thus, RT-BOLD relationships may reflect robust, measurable changes in the brain-behavior relationship across development.

Macrophages have been recognized as an important inflammatory component in choroidal neovascularization (CNV). However, it is unclear how these cells are activated and polarized, how they affect angiogenesis and what the underlining mechanisms are during CNV. Notch signaling has been implicated in macrophage activation. Previously we have shown that inducible disruption of RBP-J, the critical transcription factor of Notch signaling, in adult mice results in enhanced CNV, but it is unclear what is the role of macrophage-specific Notch signaling in the development of CNV. In the current study, by using the myeloid specific RBP-J knockout mouse model combined with the laser-induced CNV model, we show that disruption of Notch signaling in macrophages displayed attenuated CNV growth, reduced macrophage infiltration and activation, and alleviated angiogenic response after laser induction. The inhibition of CNV occurred with reduced expression of VEGF and TNF-α in infiltrating inflammatory macrophages in myeloid specific RBP-J knockout mice. These changes might result in direct inhibition of EC lumen formation, as shown in an in vitro study. Therefore, clinical intervention of Notch signaling in CNV needs to pinpoint myeloid lineage to avoid the counteractive effects of global inhibition.

Most cervical cancer patients worldwide receive surgical treatments, and yet the current International Federation of Gynecology and Obstetrics (FIGO) staging system do not consider surgical-pathologic data. We propose a more comprehensive and prognostically valuable surgical-pathologic staging and scoring system (SPSs).

Endothelial progenitor cells (EPCs) can migrate to the tumor tissue and enhance the angiogenesis of hepatocellular carcinoma (HCC); thus, they are associated with a poor prognosis. However, the specific molecular mechanism underlying the homing of EPCs to the HCC neovasculature remains unrevealed.

Diabetes as a latent risk factor for cancer has been extensively investigated, while its postoperative prognosis for esophageal cancer is rarely reported. We therefore sought to assess whether the elevated fasting blood glucose before surgery was associated with poor survival in esophageal cancer patients by eliciting a subset of data from the ongoing Fujian prospective investigation of cancer (FIESTA) study. Over 15-year follow-up, 2535 patients receiving three-field lymphadenectomy were assessable. Only patients with esophageal squamous cell carcinoma (ESCC) (n=2396) were analyzed due to the lower prevalence of the other histological types. In ESCC patients, the follow-up duration ranged from 0.5 to 180 months (median 38.2 months). The median survival time (MST) was remarkably shorter in males than in females (80.7 vs. 180+ months, Log-rank test: P<0.001). In males, the survival was worse in patients with diabetes than those without (MST: 27.9 vs. 111.1 months, Log-rank test: P<0.001). In females, the survivor was improved in patients with diabetes (MST: 71.5 months), but was still worse than patients without diabetes (MST: 180+ months, Log-rank test: P<0.001). The overall multivariate hazard ratio for per unit increment in fasting blood glucose was 1.11 (95% confidence interval or CI: 1.09-1.14, P<0.001) and 1.08 (95% CI: 1.03-1.13, P=0.002) in males and females, respectively. Further survival tree analysis consolidated the discrimination ability of fasting blood glucose for the survival of ESCC patients. Taken together, our findings convincingly demonstrated that the elevated preoperative fasting blood glucose can predict poor survival of ESCC patients, especially in males.

The melanocortin-5 receptor (MC(5)) of the dogfish Squalus acanthias (SacMC(5) receptor) can be functionally expressed in CHO cells in the absence of the co-expression of an exogenous MRAP cDNA. Both human ACTH(1-24) and dogfish ACTH(1-25) were much better stimulators of the SacMC(5) receptor than any of the mammalian or dogfish MSH ligands that were tested. The order of ligand selectivity for the dogfish melanocortins was ACTH(1-25)>αMSH>γ-MSH=δ-MSH>β-MSH. Unlike mammalian MC(5) receptors, the functional expression of the SacMC(5) receptor was not negatively impacted when the receptor was co-expressed with a cartilaginous fish (Callorhinchus milii) MRAP2 cDNA. However, co-expression with either mouse mMRAP1 or zebrafish zfMRAP1 increased the sensitivity of SacMC(5) receptor for hACTH(1-24) by at least one order of magnitude. Hence, SacMC(5) receptor has the potential to interact with MRAP1 orthologs and in this regard behaved more like a melanocortin MC(2) receptor ortholog than a melanocortin MC(5) receptor ortholog. These observations are discussed in light of the evolution of the melanocortin receptor gene family in cartilaginous fish, and the physiological implications of these observations are considered.

It is well known that upon stress, the level of the tumor suppressor p53 is remarkably elevated. However, despite extensive studies, the underlying mechanism involving important inter-players for stress-induced p53 regulation is still not fully understood. We present evidence that the human lincRNA-RoR (RoR) is a strong negative regulator of p53. Unlike MDM2 that causes p53 degradation through the ubiquitin-proteasome pathway, RoR suppresses p53 translation through direct interaction with the heterogeneous nuclear ribonucleoprotein I (hnRNP I). Importantly, a 28-base RoR sequence carrying hnRNP I binding motifs is essential and sufficient for p53 repression. We further show that RoR inhibits p53-mediated cell cycle arrest and apoptosis. Finally, we demonstrate a RoR-p53 autoregulatory feedback loop where p53 transcriptionally induces RoR expression. Together, these results suggest that the RoR-hnRNP I-p53 axis may constitute an additional surveillance network for the cell to better respond to various stresses.

It has been suggested that excessive reactive oxygen species (ROS) and oxidative stress play an important role in ethanol-induced damage to both the developing and mature central nervous system (CNS). The mechanisms underlying ethanol-induced neuronal ROS, however, remain unclear. In this study, we investigated the role of NADPH oxidase (NOX) in ethanol-induced ROS generation. We demonstrated that ethanol activated NOX and inhibition of NOX reduced ethanol-promoted ROS generation. Ethanol significantly increased the expression of p47(phox) and p67(phox), the essential subunits for NOX activation in cultured neuronal cells and the cerebral cortex of infant mice. Ethanol caused serine phosphorylation and membrane translocation of p47(phox) and p67(phox), which were prerequisites for NOX assembly and activation. Knocking down p47(phox) with the small interfering RNA was sufficient to attenuate ethanol-induced ROS production and ameliorate ethanol-mediated oxidative damage, which is indicated by a decrease in protein oxidation and lipid peroxidation. Ethanol activated cell division cycle 42 (Cdc42) and overexpression of a dominant negative (DN) Cdc42 abrogate ethanol-induced NOX activation and ROS generation. These results suggest that Cdc42-dependent NOX activation mediates ethanol-induced oxidative damages to neurons.

The present study investigates the effect of pre-treatment with Salvia miltiorrhiza ethanol extracts (SMEE) on renal function markers, immunity and antioxidant activities in renal ischemia and reperfusion (IR) rats. Wistar rat kidneys were subjected to 60 min of global ischemia at 37 °C followed by 30 min of reperfusion, and were randomly assigned into the sham, IR model and three SMEE-treated groups (n = 8 per group). Results showed that high serum creatinin (Scr), blood urea nitrogen (BUN), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α) and malondialhehyde (MDA) levels, and low antioxidant enzyme activities were observed in IR rats compared to the sham rats. Pre-treatment of Salvia miltiorrhiza ethanol extracts for 20 days prior to IR operation improved renal function, reduced IR induced renal inflammatory and oxidative injury. It is concluded that Salvia miltiorrhiza ethanol extracts could be beneficial in the treatment of renal ischemic injury.

The treatment of cancer such as oligonucleotides or peptides requires efficient delivery systems. A novel peptide, TMTP1, previously derived and identified in our laboratory showed remarkable ability to target highly metastatic tumors both in vitro and in vivo, even at the early stage of occult metastasis foci. TMTP1 moderately inhibited tumor cell viability, although not enough to deem it an efficient killer of tumor cells. In this study, we sought to enhance the anti-tumor activity of TMTP1. To do this, we fused it to an antimicrobial peptide, (D)(KLAKLAK)(2), and termed the resulting peptide TMTP1-DKK. We found that TMTP1-DKK could trigger rapid apoptosis in human prostate and gastric cancer cells through both the mitochondrial-induced apoptosis pathway and the death receptor pathway. Furthermore, direct injection of TMTP1-DKK into mice with prostate and gastric xenograft cancers resulted in reduction of tumor volumes and a significant delay in tumor progression and metastasis in vivo. These results suggest that TMTP1-DKK may serve as a powerful therapeutic agent for metastatic tumors.

To develop reagents for early diagnosis and therapeutic drugs against SARS-associated coronavirus (SARS-CoV), a large (3 x 10(9)) immunized human antibody library was constructed from peripheral blood mononuclear cells from six SARS convalescent patients. A single chain variable fragment antibody (N18) with high affinity against N protein of SARS-CoV was isolated. Sequence analysis revealed that the VL gene was composed of VL3h (V lambda subgroup) and JL2 regions and the VH gene was composed of VH1-69 (VH1 subgroup), D2-15, D3-22 and JH6 regions. Soluble N18 antibody was expressed in Escherichia coli HB2151, purified by Ni-NTA affinity chromatography and verified by SDS-PAGE and Western blot. The potential application for early diagnosis was evaluated using N protein capture ELISA in which N18 antibody demonstrated high sensitive activity in detecting N protein of SARS-CoV. Finally, the potential usefulness of the N18 antibody in prophylaxis, vaccine design and therapy of SARS is discussed.

Tamoxifen (TAM) is an antiestrogen widely used in the treatment and prevention of breast cancer in women. One of the major mechanisms of metabolism of TAM and one of its major active metabolites, 4-hydroxytamoxifen (4-OH-TAM), is via glucuronidation. In the present study, the glucuronidating activities of three common variant isoforms encoded by the human UDP-glucuronosyltransferase (UGT) 1A4 gene were examined against TAM, trans-4-OH-TAM and cis-4-OH-TAM.

Background We evaluated the safety and efficiency of flow diverters (FDs) in treating small intracranial aneurysms (IAs). Materials and Methods We reviewed the literature published in PubMed and EMBASE. R for Project software was used to calculate the complete aneurysm occlusion rates, procedure-related neurologic mortality, procedure-related neurologic morbidity and procedure-related permanent morbidity. Results Ten observational studies were included in this analysis. The complete aneurysm occlusion rate was 84.23% (80.34%-87.76%), the procedure-related neurologic mortality was 0.87% (0.29%-1.74%), the procedure-related neurologic morbidity rate was 5.22% (3.62%-7.1%), the intracerebral haemorrhage rate was 1.42% (0.64%-2.49%), the ischemic rate was 2.35% (1.31%-3.68%), the subarachnoid haemorrhage rate was 0.03% (0%-0.32%) and the procedure-related permanent morbidity was 2.41% (0.81%-4.83%). Conclusions Treatment of small IAs with FDs may be correlated with high complete occlusion rates and low complication rates. Future long-term follow-up randomized trials will determine the optimal treatment for small IAs.

The downstream of tyrosine kinase 7 (DOK7) is an adaptor protein mediating signalling transduction between receptors and intracellular downstream molecules. Reduced expression of DOK7 has been observed in breast cancer. The present study aimed to investigate the role played by DOK7 in lung cancer. The expression of DOK7 at both mRNA and protein levels was evaluated in human lung cancer. A reduced expression of DOK7 transcripts was seen in lung cancers compared with normal lung tissues. Kaplan-Meier analyses showed that the reduced expression of DOK7 was associated with poorer overall survival and progression-free survival of patients with lung cancer. A further western blot analysis revealed a predominant expression of DOK7 isoform 1 (DOK7V1) in normal lung tissues, which was reduced in lung cancer. Forced overexpression of DOK7V1 in lung cancer cell lines, A549 and H3122 resulted in a decrease of in vitro cell proliferation and migration, while adhesion to extracellular matrix was enhanced following the expression. In conclusion, DOK7 was reduced in lung cancer and reduced DOK7 expression was associated with poorer survival. DOK7 isoform 1 plays an inhibitory role on the proliferation and migration of lung cancer cells in which Akt pathway may be involved.

Abnormal expression of microRNA (miR) is associated with the occurrence and progression of various types of cancers, including papillary thyroid carcinoma (PTC). In the present study, the aim was to explore miR‑486‑5p expression and its role in PTC, as well as to investigate the biological function of its potential target genes. The expression levels of miR‑486‑5p and its clinicopathological significance were examined in 507 PTC and 59 normal thyroid samples via The Cancer Genome Atlas (TCGA). Subsequently, the results were validated using data from Gene Expression Omnibus (GEO) and ArrayExpress. Receiver operating characteristic and summary receiver operating characteristic curves were used to assess the ability of miR‑486‑5p in distinguishing PTC from normal tissue. Furthermore, potential miR‑486‑5p mRNA targets were identified using 12 prediction tools and enrichment analysis was performed on the encoding genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The expression levels of miR‑486‑5p were consistently downregulated in PTC compared with in normal tissue across datasets from TCGA, GEO (GSE40807, GSE62054 and GSE73182) and ArrayExpress (E‑MTAB‑736). The results also demonstrated that miR‑486‑5p expression was associated with cancer stage (P=0.003), pathologic lymph node (P=0.047), metastasis (P=0.042), neoplasm (P=0.012) and recurrence (P=0.016) in patients with PTC. In addition, low expression of miR‑486‑5p in patients with PTC was associated with a worse overall survival. A total of 80 miR‑486‑5p‑related genes were observed from at least 9 of 12 prediction platforms, and these were involved in 'hsa05200: Pathways in cancer' and 'hsa05206: MicroRNAs in cancer'. Finally, three hub genes, CRK like proto‑oncogene, phosphatase and tensin homolog and tropomyosin 3, were identified as important candidates in tumorigenesis and progression of PTC. In conclusion, it may be hypothesized that miR‑486‑5p contributes towards PTC onset and progression, and may act as a clinical target. However, in vitro and in vivo experiments are required to validate the findings of the present study.

BACKGROUND microRNAs (miRNAs) have a role as biomarkers in human cancer. The aim of this study was to use bioinformatics data, and review of cases identified from the literature, to investigate the role of microRNA-99a-3p (miR-99a-3p) in prostate cancer, including the identification of its target genes and signaling pathways. MATERIAL AND METHODS Meta-analysis from a literature review included 965 cases of prostate cancer. Bioinformatics databases interrogated for miR-99a-3p in prostate cancer included The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and ArrayExpress. Twelve computational predictive algorithms were developed to integrate miR-99a-3p target gene prediction data. Bioinformatics analysis data from Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) network analysis were used investigate the possible pathways and target genes for miR-99a-3p in prostate cancer. RESULTS TCGA data showed that miR-99a was down-regulated in prostate cancer when compared with normal prostate tissue. Receiver-operating characteristic (ROC) curve area under the curve (AUC) for miR-99a-3p was 0.660 (95% CI, 0.587-0.732) or a moderate level of discriminations. Pathway analysis showed that miR-99a-3p was associated with the Wnt and vascular endothelial growth factor (VEGF) signaling pathways. The PPP3CA and HYOU1 genes, selected from the PPI network, were highly expressed in prostate cancer tissue compared with normal prostate tissue, and negatively correlated with the expression of miR-99a-3p. CONCLUSIONS In prostate cancer, miR-99a-3p expression was associated with the Wnt and VEGF signaling pathways, which might inhibit the expression of PPP3CA or HYOU1.

During our study on the bioactivities of natural flavonoids, we found that the total flavonoids (TFs) and the main constituent of it, licochalcone A (lico A), activated unfolded protein response (UPR) and induced autophagy and thereby apoptosis in H292 cells. MicroRNAs, such as the tumor repressor miR-144-3p, were reported to be differentially expressed in lung cancer cells and were linked to ER stress, autophagy, and apoptosis. However, the underlying miRNA-based mechanism for lico A modulating proliferation, autophagy and apoptosis in lung cancer cells is elusive. In this study, we found that miR-144-3p was down-regulated in H292 cells comparing to normal embryonic lung cells WI-38, and lico A (10 μM) could increase miR-144-3p level in H292 cells. Knockdown of miR-144-3p significantly abrogated the apoptosis and proliferation-inhibiting effects of lico A, and lico A could enhance the proliferation-inhibiting effect and apoptosis induced by miR-144-3p overexpression. Moreover, overexpression miR-144-3p could induce ER stress by down-regulating Nrf2, and lico A enhanced the Nrf2 down-regulation caused by miR-144-3p overexpression. Co-transfection experiments showed that lico A potentially increased the dicing of pre-miR-144 so as to increase the mature miR-144-3p level. Interestingly, high level of lico A (40 μM) up-regulated CHOP protein, but failed to increase the downstream genes levels of CHOP, including Bim and Bcl-2 in H292 cells. Docking studies indicated that CHOP-mediated pathway was potentially blocked by high dose of lico A. Our results suggested that lico A could cause UPR, autophagy and apoptosis, and the underlying mechanism involved up-regulation of miR-144-3p, and increased lico A level would also increase the potential for lico A inhibiting CHOP-dependent apoptosis in H292 cells.

To investigate whether unilateral pedicle screw fixation is superior than bilateral pedicle screw fixation for lumbar degenerative diseases.

Despite gemcitabine being the leading chemotherapeutic drug for pancreatic cancer, many patients still relapse due to the drug resistance. We previously reported the molecular link between FKBP51 mediated AKT inhibition and gemcitabine response in pancreatic cancers. However, the upstream regulator of this pathway, especially the involvement of non-coding RNAs in gemcitabine response is still not clear. Here we delineated the miRNA expression profile and key signaling pathways associated with gemcitabine response. Furthermore, we confirmed that miR-30a, one node of this network, regulated cellular response to gemcitabine through SNAI1-IRS1-AKT pathway. MiR-30a directly targeted SNAI1, which activates AKT and ERK through regulating IRS1 in vitro and in vivo. Clinically, miR-30a is downregulated in pancreatic cancer tissue and associated with overall patient survival. We also identified miR-30a as an AKT-FOXO3a-regulated gene that forms a feedback loop. Together, these results demonstrate that miR-30a is an upstream regulator of the Akt pathway with a critical role in cancer etiology and chemoresistance.