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1.  Elevated matrix metalloproteinase-7 expression promotes metastasis in human lung carcinoma 
Background
Matrix metalloproteinase 7 (MMP-7) promotes tumor invasion and metastasis in several cancers. However, its role in lung cancer progression is understudied. In this study, we investigated the correlation between MMP-7 expression and lung cancer pathology.
Methods
We searched the databases PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, China BioMedicine (CBM) and China National Knowledge Infrastructure (CNKI) for scientific literature relevant to MMP-7 and lung cancer. Carefully selected studies were pooled and ORs with 95% CI were calculated. Subgroup analyses and publication bias were analyzed to understand the retrieved data in greater detail. Version 12.0 STATA software was used for statistical analysis.
Results
We retrieved a total of 121 studies through database searches. Finally, 14 cohort studies satisfied our inclusion/exclusion criteria, and these 14 studies, published between 2004 and 2012, were selected for meta-analysis to understand the influence of MMP-7 expression in lung cancer progression. Our results showed consistent differences in MMP-7 expression when comparisons were made between TNM I-II versus III-IV (OR = 1.82, 95% CI: 1.19 to 2.78, P = 0.006); histologic grade 1 to 2 versus 3 to 4 (OR = 1.67, 95% CI: 1.14 to 2.42, P = 0.008); and lymph node-negative versus lymph node-positive samples (OR = 2.81, 95% CI: 1.73 to 4.58, P <0.001), with significantly higher MMP-7 expression levels found in the more advanced stages. Subgroup analysis showed that age was not the factor influencing the associations between histologic grade, LN metastasis and MMP-7 expression in lung cancer patients, as both under 60 and over 60 age groups showed strong correlations (all P <0.05). However, when TNM staging was analyzed for its association with MMP-7 expression, only patients under age 60 showed a statistically significant correlation.
Conclusions
Our meta-analysis results revealed that MMP-7 overexpression is associated with advanced TNM and histological grades, and is linked to aggressive LN metastasis in lung cancer patients; thus MMP-7 is a useful biomarker to assess the disease status in lung cancers.
doi:10.1186/1477-7819-13-5
PMCID: PMC4326471  PMID: 25588786
Matrix metalloproteinase 7; Protein expression; Lung cancer; Meta-analysis
2.  Inhibition of itch-related responses by selectively ablated serotonergic signals at the rostral ventromedial medulla in mice 
Descending control of nociceptive processing in the rostral ventromedial medulla (RVM) has been implicated in the inhibition and facilitation of spinal nociceptive transmission. Here we investigated the contribution of serotonergic (5-HT) pathway at the RVM to pruritic behavior. Selective lesion of the descending serotonergic pathway by intra-RVM injection of focal neurotoxin 5,7-dihydroxytryptamine (2 μg/0.5 μl) attenuated pruritic behavior at the 30-min observation period following an intradermal microinjection of compound 48/80 (100 μg/100 μl) in the nape of the neck. Intradermal microinjection of compound 48/80 resulted in a dramatic increase in itch behavior between naive group and saline group. 5,7-DHT-treated mice showed profound scratching deficits after intradermal injection of compound 48/80. 5,7-DHT treatment resulted in a significant decrease in the number of 5-HT positive neurons in the RVM by using intracisternal injection of the serotonin neurotoxin 5,7-DHT. These findings demonstrate that pruritic behavior is dependent in part on descending facilitation via the RVM, and identify a modulatory role of serotonergic pathway at the RVM for pruritic behavior.
PMCID: PMC4314012
Itch; serotonergic signals; the rostral ventromedial medulla
3.  Neural mechanisms and potential treatment of epilepsy and its complications 
The factors underlying epilepsy are multifaceted, but recent research suggests that the brain’s neural circuits, which play a key role in controlling the balance between epileptic and antiepileptic factors, may lie at the heart of epilepsy. This article provides a comprehensive review of the neural mechanisms and potential treatment of intractable epilepsy from neural inflammatory responses, melanocortin circuits in brain and pedunculopontine tegmental nucleus. Further studies should be undertaken to elucidate the nature of neural circuits so that we may more effectively apply these new preventive and symptomatic therapies to the patient suffering from medically refractory seizures and its complications.
PMCID: PMC4297332  PMID: 25628775
Intractable epilepsy; neural inflammatory responses; melanocortin circuits; pedunculopontine tegmental nucleus
4.  Pulsed radiofrequency to the great occipital nerve for the treatment of intractable postherpetic itch: a case report 
A patient with intractable postherpetic itch lasting for 1 year was reported. The itch was mainly from the left vertex, frontal and ophthalmic regions and extended to the left neck area. The patient had negative response to the ophthalmic nerve block. Under the initial positive response to the great occipital nerve block, pulsed radiofrequency (PRF) was performed on the position of the great occipital nerve. After 4 months treatment, the itch was completely vanished. This case study demonstrates the effectiveness of PRF for intractable postherpetic itch originating in the head and neck. However, more samples needed to verify this management.
PMCID: PMC4238490  PMID: 25419389
Postherpetic itch; pulse radiofrequency; great occipital nerve
5.  Inhibitory effects of intrathecal p38β antisense oligonucleotide on bone cancer pain in rats 
Objective: To evaluate the effects of intrathecal administration p38β antisense oligonucleotide on the development of bone cancer pain rats. Methods: Forty female SD rats weighing 180~220 g were randomly divided into 4 groups (n = 10 each): Group A (control group): intra-tibial injection of 3 μl Hank’s solution; group B (model group): intra-tibial injection of 3 μl MADB-106 mammary gland carcinoma cells of rats (4.8 × 103/μl); group C (p38β-SODN 20 μg); group D (p38β-ASODN 20 μg). The model procedures in group C and D were same to those in the group B. From the 14th day after operation, p38β-SODN 20 μg and p38β-ASODN 20 μg were respectively intrathecally administrated in group C and D once daily for 6 days whereas normal saline was for group A and B. Mechanical withdrawal threshold and radiant heat threshold of rat hind paws were measured before operation and every other day until 22 d of post-operation. The lumbar 4-6 spinal cord was removed on the 22nd day. The expression of spinal p38β protein was determined by Western blot. Results: No significant differences in mechanical withdrawal threshold and radiant heat threshold were found at all time points in control group. During the first 6 days after operation there were obvious differences in radiant heat stimulus between control group between the other groups (P < 0.05); During 14-22 days after operation, mechanical pain threshold and radiant heat threshold between p38β-SODN group and Model group were significantly changed compared with that in control group (P < 0.05). However, the differences were not remarkable between control group and p38β-ASODN group (P > 0.05). The expression of p38β protein in lumbar spinal cord was significantly higher between p38β-SODN group and Model group than that in control group (P < 0.05). There was no significant difference in p38β protein expression between p38β-ASODN group and control group (P > 0.05). Conclusions: Hyperalgesia induced by bone cancer can be inhibited by intrathecal administration of p38β antisense oligonucleotide, which is achieved by reducing expression of p38β protein.
PMCID: PMC4270575  PMID: 25550805
Bone cancer pain; antisense oligonucleotides; p38beta; hyperalgesia; spinal dorsal horn
6.  RNF26 Temporally Regulates Virus-Triggered Type I Interferon Induction by Two Distinct Mechanisms 
PLoS Pathogens  2014;10(9):e1004358.
Viral infection triggers induction of type I interferons (IFNs), which are critical mediators of innate antiviral immune response. Mediator of IRF3 activation (MITA, also called STING) is an adapter essential for virus-triggered IFN induction pathways. How post-translational modifications regulate the activity of MITA is not fully elucidated. In expression screens, we identified RING finger protein 26 (RNF26), an E3 ubiquitin ligase, could mediate polyubiquitination of MITA. Interestingly, RNF26 promoted K11-linked polyubiquitination of MITA at lysine 150, a residue also targeted by RNF5 for K48-linked polyubiquitination. Further experiments indicated that RNF26 protected MITA from RNF5-mediated K48-linked polyubiquitination and degradation that was required for quick and efficient type I IFN and proinflammatory cytokine induction after viral infection. On the other hand, RNF26 was required to limit excessive type I IFN response but not proinflammatory cytokine induction by promoting autophagic degradation of IRF3. Consistently, knockdown of RNF26 inhibited the expression of IFNB1 gene in various cells at the early phase and promoted it at the late phase of viral infection, respectively. Furthermore, knockdown of RNF26 inhibited viral replication, indicating that RNF26 antagonizes cellular antiviral response. Our findings thus suggest that RNF26 temporally regulates innate antiviral response by two distinct mechanisms.
Author Summary
Virus infection induces the host cells to produce type I interferons, which are secreted proteins important for the host to clear viruses. Previously, we identified a cellular protein called MITA, which is essential for virus-triggered induction of interferons. In this study, we found an enzyme called RNF26 could covalently modify MITA with one type of polypeptide, called polyubiquitin. This modification caused increased stability of MITA after viral infection. RNF26 also caused disability of IRF3, another important component required for virus-triggered interferon induction. Thus, RNF26 could temporally regulate virus-triggered interferon induction by two distinct mechanisms. This discovery helps to understand how the antiviral response is delicately regulated.
doi:10.1371/journal.ppat.1004358
PMCID: PMC4177927  PMID: 25254379
7.  Diagnostic Value of Mutation-Specific Antibodies for Immunohistochemical Detection of Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer: A Meta-Analysis 
PLoS ONE  2014;9(9):e105940.
Background
Various studies have assessed the diagnostic accuracy of EGFR mutation-specific antibodies in non-small cell lung cancer (NSCLC). We performed a meta-analysis of existing data to investigate the diagnostic value of mutation-specific antibodies for detection of EGFR mutations in NSCLC.
Methods
We systematically retrieved relevant studies from PubMed, Web of Knowledge, and Google Scholar. Data from studies that met the inclusion criteria were extracted for further exploration of heterogeneity, including calculation of the average sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and analysis of SROC(summary receiver operating characteristic) curves.
Results
Fifteen studies met our inclusion criteria. A summary of the meta-analysis of the efficacy of the anti-E746-A750 antibody was as follows: sensitivity, 0.60 (95% CI, 0.55–0.64); specificity, 0.98 (95% CI, 0.97–0.98); PLR, 33.50 (95% CI, 13.96–80.39); NLR, 0.39 (95% CI, 0.30–0.51) and DOR, 111.17 (95% CI, 62.22–198.63). A similar meta-analysis was performed for the anti-L858R antibody with results as follows: sensitivity, 0.76 (95% CI, 0.71–0.79); specificity, 0.96 (95% CI, 0.95–0.97); PLR, 24.42 (95% CI, 11.66–51.17); NLR, 0.22 (95% CI, 0.12–0.39) and DOR, 126.66 (95% CI, 54.60–293.82).
Conclusion
Immunohistochemistry alone is sufficient for the detection of EGFR mutations if the result is positive. Molecular-based analyses are necessary only if the anti-E746-A750 antibody results are negative. Immunohistochemistry seems more suitable for clinical screening for EGFR mutations prior to molecular-based analysis.
doi:10.1371/journal.pone.0105940
PMCID: PMC4159133  PMID: 25203004
8.  Pleiotropic Functions for Transcription Factor Zscan10 
PLoS ONE  2014;9(8):e104568.
The transcription factor Zscan10 had been attributed a role as a pluripotency factor in embryonic stem cells based on its interaction with Oct4 and Sox2 in in vitro assays. Here we suggest a potential role of Zscan10 in controlling progenitor cell populations in vivo. Mice homozygous for a Zscan10 mutation exhibit reduced weight, mild hypoplasia in the spleen, heart and long bones and phenocopy an eye malformation previously described for Sox2 hypomorphs. Phenotypic abnormalities are supported by the nature of Zscan10 expression in midgestation embryos and adults suggesting a role for Zscan10 in either maintaining progenitor cell subpopulation or impacting on fate choice decisions thereof.
doi:10.1371/journal.pone.0104568
PMCID: PMC4128777  PMID: 25111779
9.  Alteration of Th17 and Treg cells in patients with unexplained recurrent spontaneous abortion before and after lymphocyte immunization therapy 
Background
Several types of T cells have been associated with the pathogenesis of unexplained recurrent spontaneous abortion (URSA), including Th1/Th2/Th17/Tregs cell. It has been appreciated that immunotherapy with paternal or third party lymphocytes is an effective method of treatment for URSA patients. The balance of Th1/Th2 cells could be maintained and an increase of Treg cells would be beneficial after immunotherapy; however, the mechanism by which the Th17/Treg balance affects URSA has not yet been fully elucidated.
Methods
Here, we used flow cytometry, liquid chip technology and quantitative real-time PCR (qPCR) methods to characterize Th17/Treg cell populations after immunotherapy. We found that after immunotherapy in URSA patients, the percentage of Th17 cells decreased and the percentage of Treg cells in peripheral blood mononuclear cells (PBMC) increased, as detected by flow cytometry.
Results
Immunotherapy may induce a decrease in the Th17/Treg ratio and the Treg bias, which may be beneficial for the maintenance of pregnancy. The expression level of ROR gamma t, a transcription factor found in Th17 cells, decreased and the expression of the Treg-specific transcription factor Foxp3 increased in peripheral blood as detected by qPCR. Immunotherapy may induce a decrease in the ratio of ROR gamma t to Foxp3 and a Treg cell bias, which would be beneficial for pregnancy maintenance. The secretion of the Treg-associated cytokine TGF-beta, as well as Th2 cytokines, was increased in serum, while the secretion of Th17-associated cytokine IL-17A and Th1 cytokine production was decreased. The Th1/Th2 cytokine ratio significantly decreased. Similarly, the Th17/Treg ratio significantly decreased in the total patient after immunotherapy.
Conclusions
These results indicate that in patients with URSA, immunotherapy with mononuclear cells derived from the baby’s father could affect both Th1/Th2 and Th17/Treg balance, and we found that the Th2 and Treg bias would be beneficial for pregnancy, which may lead to a balancing of the Th17/Treg ratio in URSA patients after immunotherapy.
doi:10.1186/1477-7827-12-74
PMCID: PMC4237930  PMID: 25086467
Th17 cells; Treg cells; Unexplained recurrent spontaneous abortion; Lymphocyte immunization therapy
10.  Effects of SSd Combined with Radiation on Inhibiting SMMC-7721 Hepatoma Cell Growth 
Background
The aim of this study was to investigate the effects of Saikosaponin-d (SSd) combined with radiotherapy on SMMC-7721 hepatoma cell lines and its mechanism.
Material/Methods
SMMC-7721 hepatoma cell lines are selected in our research. With MTT (methylthiazolyldiphenyl-tetrazolium-bromide) method, the effects of SSd and radiation on inhibiting SMMC-7721 cell growth were investigated. We also used transmission electron microscopy (TEM) to observe ultrastructural changes of cells. Colorimetry methods were used to measure content changes of glutathione (GSH) and malondialdehyde (MDA) in cells.
Results
Both SSd and radiation inhibited the growth of SMMC-7721 cells. The combination of SSd and radiotherapy had a time-dependent synergistic effect. Radiation caused ultrastructural damage to cells, and the damage was enhanced in combination with SSd. Radiation decreased the GSH content and increased the MDA content in cells, and this effect was suppressed after the intervention of SSd.
Conclusions
SSd can inhibit the growth of SMMC-7721 hepatoma cell lines in vitro. Additionally, it significantly enhances the effects of radiation on inhibiting the growth of SMMC-7721 hepatoma cell lines, and up-regulates the antioxidant level after the radiotherapy. Thus, SSd could be an ideal radiotherapy sensitizer for the treatment of liver cancer.
doi:10.12659/MSM.891355
PMCID: PMC4136936  PMID: 25080219
Saikosaponin-d; Radiation; Hepatocellular Carcinoma; Glutathione
11.  Identification of neuroanatomic circuits from spinal cord to stomach in mouse: retrograde transneuronal viral tracing study 
To determine the spinal innervation and neuronal connections is important for studying gastric carbohydrate metabolism and motor responses. Neurons involved in the efferent control of the stomach were identified following visualization of pseudorabies virus (PRV)-614 retrograde tracing. PRV-614 was injected into the ventral stomach wall in 13 adult C57BL/6J strain male mice. On the fifth day postinjection, animals were humanely sacrificed, and spinal cords were removed and sectioned, and processed for PRV visualization. The virus injected into the ventral stomach wall was specifically transported to the thoracic spinal cord. At 5 d after injection of the PRV-614, stomach enlargement and tissue edema were found, and PRV-614 positive cells were found in the intermediolateral cell column, the intercalates nucleus or the central autonomic nucleus of spinal cord segments T3 to L1, and major PRV-614 labeled cells were focused in the T6-10 segment. Our results revealed neuroanatomical circuits between stomach and the spinal intermediolateral cell column neurons.
PMCID: PMC4152111  PMID: 25197421
Stomach; spinal cord; autonomic nervous system; pseudorabies virus; transsynaptic tracing
12.  Retrograde tracing of medial vestibular nuclei connections to the kidney in mice 
Vestibular nuclei have been identified as a uniform multifunctional structure in order to maintain physiological homeostasis, including the participation of renal sympathetic activity. In this study, the medial vestibular nuclei (MVe) of 10 adult male C57BL/6J strain mice were mapped retrograde using injections of pseudorabies virus (PRV)-614. The virus, injected into the kidney, was specifically transported to the medial vestibular nuclei (MVe). We used a fluorescence immunohistochemistry to characterize the chemical neuroanatomical substrate of MVe innervating the kidney in the mouse. At five days after PRV-614 injection in the kidney, PRV-614 infected neurons were retrogradely labeled in MVeMC and MVePC; PRV-614/tyrosine hydroxylase (TH) double-labeled neurons located predominantly in MVeMC and not in MVePC, whereas PRV-614/tryptophan hydroxylase (TPH) neurons were not localized in MVeMC and MVePC. Our results revealed direct neuroanatomical evidence to identify catecholaminergic projections from the MVeMC to the kidney, suggesting that medial vestibulo-renal pathway may be catecholaminergic.
PMCID: PMC4152112  PMID: 25197422
Kidney; medial vestibular nuclei; retrograde tracing; pseudorabies virus
13.  Increasing summer rainfall in arid eastern-Central Asia over the past 8500 years 
Scientific Reports  2014;4:5279.
A detailed and well-dated proxy record of summer rainfall variation in arid Central Asia is lacking. Here, we report a long-term, high resolution record of summer rainfall extracted from a peat bog in arid eastern-Central Asia (AECA). The record indicates a slowly but steadily increasing trend of summer rainfall in the AECA over the past 8500 years. On this long-term trend are superimposed several abrupt increases in rainfall on millennial timescales that correspond to rapid cooling events in the North Atlantic. During the last millennium, the hydrological climate pattern of the AECA underwent a major change. The rainfall in the past century has reached its highest level over the 8500-year history, highlighting the significant impact of the human-induced greenhouse effect on the hydrological climate in the AECA. Our results demonstrate that even in very dry eastern-Central Asia, the climate can become wetter under global warming.
doi:10.1038/srep05279
PMCID: PMC4055903  PMID: 24923304
14.  Conventional Hypoglycaemic Agents and the Risk of Lung Cancer in Patients with Diabetes: A Meta-Analysis 
PLoS ONE  2014;9(6):e99577.
Background
Accumulating evidence suggests that hypoglycaemic agents influence lung cancer risk in patients with diabetes. It remains to be fully elucidated whether conventional hypoglycaemic agents (metformin, sulfonylureas, thiazolidinediones [TZDs] or insulin) affect lung cancer incidence in patients with diabetes.
Methods
We performed a meta-analysis using EMBASE, MEDLINE and Web of Science to search randomised controlled trials (RCTs), cohort studies, and case-control studies published up to October 2013 that assessed the effects of metformin, sulfonylurea, TZDs or insulin on lung cancer risk in subjects with diabetes. Fixed and random effects meta-analysis models were used, and the effect size was expressed as a summary odds ratio (OR) with 95% confidence intervals (CI). The Grades of Research, Assessment, Development and Evaluation (GRADE) approach was applied to define the quality of the evidence.
Results
Analysis of 15 studies (11 cohort studies, 2 case-control studies, and 2 RCTs) showed that metformin use was associated with a 15% reduction in risk of lung cancer (OR 0.85, 95% CI 0.77 to 0.92), but this finding was not supported by sub-analysis of smoking-adjusted studies (OR 0.84, 95% CI 0.61 to 1.06). Moreover, sulfonylurea or TZDs use was not associated with increased or decreased lung cancer risk, respectively (OR 1.10, 95% CI 0.93 to 1.26), (OR 0.86, 95% CI 0.70 to 1.02). Higher lung cancer risk was related to insulin (OR 1.23, 95% CI 1.10 to 1.35). However, all data from RCTs failed to demonstrate a statistically significant effect.
Conclusions
This analysis demonstrated that metformin use may reduce lung cancer risk in patients with diabetes but not in a smoking-adjusted subgroup and that insulin use may be associated with an increased lung cancer risk in subjects with diabetes.
doi:10.1371/journal.pone.0099577
PMCID: PMC4055722  PMID: 24924771
15.  CD40 mutant expression and its clinical significance to prognosis in gastric cancer patients 
Background
We aimed to detect CD40 mutant expression and evaluate its clinical significance in gastric cancer.
Methods
CD40 mutant expression in 78 cases of gastric cancer tissues, 10 cases of normal gastric tissues, and 10 cases of gastric adenoma tissues by immunohistochemical test. Survival analyses were also performed.
Results
The positive CD40 mutant rate in gastric cancer was 55.1% (43/78). No positive CD40 mutant staining was observed in the normal gastric tissue or the gastric adenoma. CD40 mutants expression was significantly correlated with invasive depth, lymph metastasis, and TNM stage (P <0.05). Cases with negative CD40 mutant expression had a significantly longer median survival time than those with positive CD40 mutant expression (40 vs. 14 months, P <0.05). A lower death risk in negative CD40 mutant cases was observed comparing with positive CD40 mutant cases.
Conclusions
Positive CD40 mutant expression suggests a poorer prognosis of gastric cancer cases.
doi:10.1186/1477-7819-12-167
PMCID: PMC4050400  PMID: 24885116
Gastric cancer; CD40 mutant; Immunohistochemistry
16.  Central circuits regulating the sympathetic outflow to lumbar muscles in spinally transected mice by retrograde transsynaptic transport 
Despite considerable interest in the mechanisms that control the hyperalgesia associated with muscle inflammation, the CNS descending pathways that coordinate autonomic circuits regulating lumbar muscles are not adequately understood. Here we used both pseudorabies virus (PRV)-614 retrograde transsynaptic tracing and spinally transected method in 33 C57BL/6J mice to map the polysynaptic pathways between lumbar muscle and CNS. Tissues were processed for dual-label immunocytochemical detection between PRV-614 and tryptophan hydroxylase (TPH) or tyrosine hydroxylase (TH)-expressing neurons in CNS. In intact mice, PRV-614 was transported to the intermediolateral column (IML) and ventral horn (VH) of spinal cord, with subsequent transport to many brain regions, including the medullary raphe nuclei, rostral ventrolateral medulla (RVLM), A5 cell group regions (A5), locus coeruleus (LC), the medullary and pontine reticular formation nucleus (MRN and PRN), paraventricular nucleus of the hypothalamus (PVN), and other central sites. However, PRV-614 in spinally transected mice produced retrograde infection of IML, with subsequent transport to main brain regions that have been shown to contribute to regulating sympathetic circuits, including RVLM, Lateral paragigantocellular reticular nucleus (LPGi), A5, LC, and PVN, whereas PRV-614 labeling in VH and MRN was eliminated in almost every case. In above five brain regions, dual-labeling immunocytochemistry showed coexpression of PRV-614/TPH and PRV-614/TH immunoreactive (IR) neurons involved in these regulatory circuits. Our results reveal a hierarchical organization of central autonomic circuits controlling the lumbar muscles, thus providing neuroanatomical substrates for the central catecholaminergic and serotonergic system to regulate the lumbar muscles.
PMCID: PMC4097212  PMID: 25031717
Lumbar muscles; spinal transection; pseudorabies virus; tryptophan hydroxylase; tyrosine hydroxylase
17.  Death-associated protein kinase 1 is an IRF3/7-interacting protein that is involved in the cellular antiviral immune response 
Cellular and Molecular Immunology  2014;11(3):245-252.
Interferon regulatory factor (IRF) 7 has been demonstrated to be a master regulator of virus-induced type I interferon production (IFN), and it plays a central role in the innate immune response against viruses. Here, we identified death-associated protein kinase 1 (DAPK1) as an IRF7-interacting protein by tandem affinity purification (TAP). Viral infection induced DAPK1–IRF7 and DAPK1–IRF3 interactions and overexpression of DAPK1 enhanced virus-induced activation of the interferon-stimulated response element (ISRE) and IFN-β promoters and the expression of the IFNB1 gene. Knockdown of DAPK1 attenuated the induction of IFNB1 and RIG-I expression triggered by viral infection or IFN-β, and they were enhanced by viral replication. In addition, viral infection or IFN-β treatment induced the expression of DAPK1. IFN-β treatment also activated DAPK1 by decreasing its phosphorylation level at serine 308. Interestingly, the involvement of DAPK1 in virus-induced signaling was independent of its kinase activity. Therefore, our study identified DAPK1 as an important regulator of the cellular antiviral response.
doi:10.1038/cmi.2013.65
PMCID: PMC4085485  PMID: 24531619
DAPK1; innate antiviral response; IRF3/7; type I interferon
18.  Prognostic value of secreted phosphoprotein-1 in pleural effusion associated with non-small cell lung cancer 
BMC Cancer  2014;14:280.
Background
Malignant pleural effusion (MPE) is a common complication of advanced lung cancer. Research has shown that secreted phosphoprotein-1 (SPP1) is essential in MPE associated with lung cancer. This retrospective study was performed to evaluate the prognostic significance of SPP1 in the MPE of patients with non-small cell lung cancer (NSCLC).
Methods
MPE specimens were obtained from 85 NSCLC patients (study group), and pleural effusion specimens were obtained from 24 patients with benign lung disease (control group). Specimens were tested for SPP1 using enzyme-linked immunosorbent assay (ELISA). Based on the cutoff value of receiver operating characteristic (ROC) curve analysis, the study patients were divided into a high-SPP1-expression subgroup and a low-expression subgroup. The primary and secondary endpoints of this study were progression-free survival (PFS) and overall survival (OS).
Results
The SPP1 levels of the study group were significantly higher compared to those of the controls (Mann–Whitney U test, P = 0.017). The number of extrapulmonary metastases was significantly higher in the high-SPP1-expressing patients than in the low-expressing patients (P = 0.03). Kaplan-Meier survival analysis showed that SPP1 levels were negatively associated with OS and PFS in both subgroups of study patients (P = 0.026; P = 0.039, respectively). Cox regression analysis showed that SPP1 was an independent prognostic factor in patients with NSCLC (HR = 1.832, 95% confidence interval: 1.003–3.345; P = 0.049).
Conclusion
SPP1 in pleural effusion can be used for the auxiliary diagnosis of MPE and used to determine the prognosis of patients with NSCLC.
doi:10.1186/1471-2407-14-280
PMCID: PMC4014756  PMID: 24758329
Secreted phosphoprotein-1; Osteopontin; Wmalignant pleural effusion; Non-small cell lung cancer; Prognosis
19.  Improved Stabilization Method for Lurie Networked Control Systems 
The Scientific World Journal  2014;2014:789398.
The problem of stabilization of Lurie networked control systems (NCSs) is investigated in this paper. The network-induced delays in NCSs are assumed to be time-varying and bounded. By utilizing a reciprocally convex technique to consider the relationship between the network-induced delay and its varying interval, a new absolute stability condition is derived in terms of linear matrix inequalities (LMIs). Based on the obtained condition, an improved cone complementary linearisation (CCL) iteration algorithm is presented to design a state feedback controller. The effectiveness of the proposed method is verified by a numerical example.
doi:10.1155/2014/789398
PMCID: PMC4032754  PMID: 24892090
20.  Oocytes with a Dark Zona Pellucida Demonstrate Lower Fertilization, Implantation and Clinical Pregnancy Rates in IVF/ICSI Cycles 
PLoS ONE  2014;9(2):e89409.
The morphological assessment of oocytes is important for embryologists to identify and select MII oocytes in IVF/ICSI cycles. Dysmorphism of oocytes decreases viability and the developmental potential of oocytes as well as the clinical pregnancy rate. Several reports have suggested that oocytes with a dark zona pellucida (DZP) correlate with the outcome of IVF treatment. However, the effect of DZP on oocyte quality, fertilization, implantation, and pregnancy outcome were not investigated in detail. In this study, a retrospective analysis was performed in 268 infertile patients with fallopian tube obstruction and/or male factor infertility. In 204 of these patients, all oocytes were surrounded by a normal zona pellucida (NZP, control group), whereas 46 patients were found to have part of their retrieved oocytes enclosed by NZP and the other by DZP (Group A). In addition, all oocytes enclosed by DZP were retrieved from 18 patients (Group B). No differences were detected between the control and group A. Compared to the control group, the rates of fertilization, good quality embryos, implantation and clinical pregnancy were significantly decreased in group B. Furthermore, mitochondria in oocytes with a DZP in both of the two study groups (A and B) were severely damaged with several ultrastructural alterations, which were associated with an increased density of the zona pellucida and vacuolization. Briefly, oocytes with a DZP affected the clinical outcome in IVF/ICSI cycles and appeared to contain more ultrastructural alterations. Thus, DZP could be used as a potential selective marker for embryologists during daily laboratory work.
doi:10.1371/journal.pone.0089409
PMCID: PMC3933533  PMID: 24586757
21.  Improved Stability Criteria of Static Recurrent Neural Networks with a Time-Varying Delay 
The Scientific World Journal  2014;2014:391282.
This paper investigates the stability of static recurrent neural networks (SRNNs) with a time-varying delay. Based on the complete delay-decomposing approach and quadratic separation framework, a novel Lyapunov-Krasovskii functional is constructed. By employing a reciprocally convex technique to consider the relationship between the time-varying delay and its varying interval, some improved delay-dependent stability conditions are presented in terms of linear matrix inequalities (LMIs). Finally, a numerical example is provided to show the merits and the effectiveness of the proposed methods.
doi:10.1155/2014/391282
PMCID: PMC3988971  PMID: 25143974
22.  Motor Cortex-Periaqueductal Gray-Spinal Cord Neuronal Circuitry May Involve in Modulation of Nociception: A Virally Mediated Transsynaptic Tracing Study in Spinally Transected Transgenic Mouse Model 
PLoS ONE  2014;9(2):e89486.
Several studies have shown that motor cortex stimulation provided pain relief by motor cortex plasticity and activating descending inhibitory pain control systems. Recent evidence indicated that the melanocortin-4 receptor (MC4R) in the periaqueductal gray played an important role in neuropathic pain. This study was designed to assess whether MC4R signaling existed in motor cortex- periaqueductal gray- spinal cord neuronal circuitry modulated the activity of sympathetic pathway by a virally mediated transsynaptic tracing study. Pseudorabies virus (PRV)-614 was injected into the left gastrocnemius muscle in adult male MC4R-green fluorescent protein (GFP) transgenic mice (n = 15). After a survival time of 4–6 days, the mice (n = 5) were randomly assigned to humanely sacrifice, and spinal cords and brains were removed and sectioned, and processed for PRV-614 visualization. Neurons involved in the efferent control of the left gastrocnemius muscle were identified following visualization of PRV-614 retrograde tracing. The neurochemical phenotype of MC4R-GFP-positive neurons was identified using fluorescence immunocytochemical labeling. PRV-614/MC4R-GFP dual labeled neurons were detected in spinal IML, periaqueductal gray and motor cortex. Our findings support the hypothesis that MC4R signaling in motor cortex-periaqueductal gray-spinal cord neural pathway may participate in the modulation of the melanocortin-sympathetic signaling and contribute to the descending modulation of nociceptive transmission, suggesting that MC4R signaling in motor cortex- periaqueductal gray-spinal cord neural pathway may modulate the activity of sympathetic outflow sensitive to nociceptive signals.
doi:10.1371/journal.pone.0089486
PMCID: PMC3929690  PMID: 24586817
23.  Trs130 participates in autophagy through GTPases Ypt31/32 in Saccharomyces cerevisiae 
Traffic (Copenhagen, Denmark)  2012;14(2):233-246.
Trs130 is a specific component of the TRAPP II (Transport protein particle II) complex, which functions as a guanine exchange factor (GEF) for Rab GTPases Ypt31/32. Ypt31/32 is known to be involved in autophagy, although the precise mechanism has not been thoroughly studied. In this study, we investigated the potential involvement of Trs130 in autophagy and found that both the cytoplasm-to-vacuole targeting (Cvt) pathway and starvation-induced autophagy were defective in a trs130ts (trs130 temperature-sensitive) mutant. Mutant cells could not transport Atg8 and Atg9 to the preautophagosomal structure/ phagophore assembly site (PAS) properly, resulting in multiple Atg8 dots and Atg9 dots dispersed in the cytoplasm. Some dots were trapped in the trans-Golgi. Genetic studies showed that the effect of the Trs130 mutation was downstream of Atg5 and upstream of Atg1, Atg13, Atg9 and Atg14 on the autophagic pathway. Furthermore, overexpression of Ypt31 or Ypt32, but not of Ypt1, rescued autophagy defects in trs130ts and trs65ts (Trs130-HA Trs120-myc trs65Δ) mutants. Our data provide mechanistic insight into how Trs130 participates in autophagy and suggest that vesicular trafficking regulated by GTPases/GEFs is important in the transport of autophagy proteins from the trans-Golgi to the PAS.
doi:10.1111/tra.12024
PMCID: PMC3538905  PMID: 23078654
TRAPP II; GEF complex; Ypt31/32; Rab GTPases; autophagy
24.  A functional variant in the cystathionine β-synthase gene promoter significantly reduces congenital heart disease susceptibility in a Han Chinese population 
Cell Research  2012;23(2):242-253.
Homocysteine is an independent risk factor for various cardiovascular diseases. There are two ways to remove homocysteine from embryonic cardiac cells: remethylation to form methionine or transsulfuration to form cysteine. Cystathionine β-synthase (CBS) catalyzes the first step of homocysteine transsulfuration as a rate-limiting enzyme. In this study, we identified a functional variant −4673C>G (rs2850144) in the CBS gene promoter region that significantly reduces the susceptibility to congenital heart disease (CHD) in a Han Chinese population consisting of 2 340 CHD patients and 2 270 controls. Individuals carrying the heterozygous CG and homozygous GG genotypes had a 15% (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75-0.96, P = 0.011) and 40% (OR = 0.60, 95% CI = 0.49-0.73, P = 1.78 × 10−7) reduced risk to develop CHD than the wild-type CC genotype carriers in the combined samples, respectively. Additional stratified analyses demonstrated that CBS −4673C>G is significantly related to septation defects and conotruncal defects. In vivo detection of CBS mRNA levels in human cardiac tissues and in vitro luciferase assays consistently showed that the minor G allele significantly increased CBS transcription. A functional analysis revealed that both the attenuated transcription suppressor SP1 binding affinity and the CBS promoter hypomethylation specifically linked with the minor G allele contributed to the remarkably upregulated CBS expression. Consequently, the carriers with genetically increased CBS expression would benefit from the protection due to the low homocysteine levels maintained by CBS in certain cells during the critical heart development stages. These results shed light on unexpected role of CBS and highlight the importance of homocysteine removal in cardiac development.
doi:10.1038/cr.2012.135
PMCID: PMC3567826  PMID: 22986502
congenital heart disease; cystathionine β-synthase; non-coding variant; homocysteine
25.  ALK gene copy number gain and its clinical significance in hepatocellular carcinoma 
AIM: To examine the status and clinical significance of anaplastic lymphoma kinase (ALK) gene alterations in hepatocellular carcinoma (HCC) patients.
METHODS: A total of 213 cases of HCC were examined by fluorescent in situ hybridization using dual color break-apart ALK probes for the detection of chromosomal translocation and gene copy number gain. HCC tissue microarrays were constructed, and the correlation between the ALK status and clinicopathological variables was assessed by χ2 test or Fisher’s exact test. Survival analysis was estimated using the Kaplan-Meier approach with a Log-rank test. Univariate and multivariate analyses of clinical variables were performed using the Cox proportional hazards regression model.
RESULTS: ALK gene translocation was not observed in any of the HCC cases included in the present study. ALK gene copy number gain (ALK/CNG) (≥ 4 copies/cell) was detected in 28 (13.15%) of the 213 HCC patients. The 3-year progression-free-survival (PFS) rate for ALK/CNG-positive HCC patients was significantly poorer than ALK/CNG-negative patients (27.3% vs 42.5%, P = 0.048), especially for patients with advanced stage III/IV (0% vs 33.5%, P = 0.007), and patients with grade III disease (24.8% vs 49.9%, P = 0.023). ALK/CNG-positive HCC patients had a significantly poorer prognosis than ALK/CNG-negative patients in the subgroup that was negative for serum hepatitis B virus DNA, with significantly different 3-year overall survival rates (18.2% vs 63.6%, P = 0.021) and PFS rates (18.2% vs 46.9%, P = 0.019). Multivariate Cox proportional hazards regression analysis suggested that ALK/CNG prevalence can predict death in HCC (HR = 1.596; 95%CI: 1.008-2.526, P = 0.046).
CONCLUSION: ALK/CNG, but not translocation of ALK, is present in HCC and may be an unfavorable prognostic predictor.
doi:10.3748/wjg.v20.i1.183
PMCID: PMC3886007  PMID: 24415871
Anaplastic lymphoma kinase gene; Hepatocellular carcinoma; Prognostic predictor

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