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1.  Dopaminergic and cholinergic regulation of Fyn tyrosine kinase phosphorylation in the rat striatum in vivo 
Neuropharmacology  2015;99:491-499.
Src and Fyn are two Src family kinase (SFK) members that are expressed in mammalian brains and play important roles in the regulation of a variety of neuronal and synaptic substrates. Here we investigated the responsiveness of these SFKs to changing dopamine receptor signals in dopamine responsive regions of adult rat brains in vivo. Pharmacological activation of dopamine D1 receptors (D1Rs) by a systemic injection of the selective agonist SKF81297 increased phosphorylation of SFKs at a conserved and activation-associated autophosphorylation site (Y416) in the striatum, indicating activation of SFKs following SKF81297 injection. The dopamine D2 receptor (D2R) agonist quinpirole had no effect. Blockade of D1Rs with an antagonist SCH23390 did not alter striatal Y416 phosphorylation, while the D2R antagonist eticlopride elevated it. Between Src and Fyn, SKF81297 seemed to preferentially facilitate Fyn phosphorylation. Activation of muscarinic acetylcholine M4 receptors (M4Rs) with a positive allosteric modulator VU0152100 suppressed SFK Y416 responses to SKF81297. Additionally, SKF81297 induced a correlated increase in phosphorylation of N-methyl-D-aspartate (NMDA) receptor GluN2B subunits at a Fyn site (Y1472), which was attenuated by VU0152100. SKF81297 also enhanced synaptic recruitments of active Fyn and GluN1/GluN2B-containing NMDA receptors. These data demonstrate that D1Rs regulate Fyn and downstream NMDA receptors in striatal neurons in vivo. Acetylcholine through activating M4Rs inhibits Fyn and NMDA receptors in their sensitivity to D1R signaling.
doi:10.1016/j.neuropharm.2015.08.017
PMCID: PMC4655164  PMID: 26277342
Acetylcholine; glutamate; Fyn; D1 receptor; D2 receptor; muscarinic M4 receptor; NMDA; tyrosine phosphorylation
2.  Oncolytic adenovirus expressing interleukin-18 improves antitumor activity of dacarbazine for malignant melanoma 
Conditionally replicating adenoviruses have emerged as novel therapeutic agents for cancer. This study aimed to evaluate synergistic antitumor activity of replication-competent adenovirus armed with interleukin (IL)-18 (ZD55-IL-18) and dacarbazine (DTIC) against melanoma. Melanoma A375 cells or nude mouse tumor xenografts were treated with ZD55-IL-18 alone or together with DTIC. The results showed that ZD55-IL-18 competently replicated in A375 cells and expressed IL-18, and these were not affected by DTIC. ZD55-IL-18 enhanced the cytotoxicity of DTIC accompanied by increased apoptosis. Moreover, ZD55-IL-18 and DTIC synergistically inhibited the growth but promoted the apoptosis of A375 xenografts and inhibited vascular endothelial growth factor expression and lung metastasis in xenografts of nude mice. In conclusion, this is the first study to show synergistic anticancer activity of ZD55-IL-18 and DTIC for malignant melanoma. Our results provide evidence that chemo-gene-viro therapeutic approach has greater potential for malignant cancers than conventional chemotherapy or gene therapy.
doi:10.2147/DDDT.S115121
PMCID: PMC5117872  PMID: 27895465
melanoma; IL-18; dacarbazine; oncolytic adenovirus
3.  New DNA methylation markers and global DNA hypomethylation are associated with oral cancer development 
DNA promoter methylation of tumor suppressor genes and global DNA hypomethylation are common features of head and neck cancers. Our goal was to identify early DNA methylation changes in oral premalignant lesions (OPLs) that may serve as predictive markers of developing oral squamous cell carcinoma (OSCC). Using high-throughput DNA methylation profiles of 24 OPLs, we found that the top 86 genes differentially methylated between patients who did or did not develop OSCC were simultaneously hypermethylated, suggesting that a CpG island methylation phenotype may occur early during OSCC development. The vast majority of the 86 genes were non-methylated in normal tissues and hypermethylated in OSCC versus normal mucosa. We used pyrosequencing in a validation cohort of 44 patients to evaluate the degree of methylation of AGTR1, FOXI2, and PENK promoters CpG sites that were included in the top 86 genes, and of LINE1 repetitive element methylation, a surrogate of global DNA methylation. A Methylation Index (MI) was developed by averaging the percent methylation of AGTR1, FOXI2, and PENK promoters; patients with a high MI had a worse OCFS (P=0.0030). On the other hand, patients with low levels of LINE1 methylation had a significantly worse OCFS (P=0.0153). In conclusion, AGTR1, FOXI2 and PENK promoter methylation and LINE1 hypomethylation may be associated with an increased risk of OSCC development in patients with OPLs.
doi:10.1158/1940-6207.CAPR-14-0179
PMCID: PMC4777304  PMID: 26342026
oral leukoplakia; oral cancer; squamous cell carcinoma; DNA promoter methylation; DNA global hypomethylation; risk biomarker
4.  Metabotropic glutamate receptor 5 upregulates surface NMDA receptor expression in striatal neurons via CaMKII 
Brain research  2015;1624:414-423.
Metabotropic and ionotropic glutamate receptors are closely clustered in postsynaptic membranes and are believed to interact actively with each other to control excitatory synaptic transmission. Metabotropic glutamate receptor 5 (mGluR5), for example, has been well documented to potentiate ionotropic NMDA receptor activity, although underlying mechanisms are poorly understood. In this study, we investigated the role of mGluR5 in regulating trafficking and subcellular distribution of NMDA receptors in adult rat striatal neurons. We found that the mGluR1/5 agonist DHPG concentration-dependently increased NMDA receptor GluN1 and GluN2B subunit expression in the surface membrane. Meanwhile, DHPG reduced GluN1 and GluN2B levels in the intracellular compartment. The effect of DHPG was blocked by an mGluR5 selective antagonist MTEP but not by an mGluR1 selective antagonist 3-MATIDA. Pretreatment with an inhibitor or a specific inhibitory peptide for synapse-enriched Ca2+/calmodulin-dependent protein kinase II (CaMKII) also blocked the DHPG-stimulated redistribution of GluN1 and GluN2B. In addition, DHPG enhanced CaMKIIα activity and elevated GluN2B phosphorylation at a CaMKII-sensitive site (serine 1303). These results demonstrate that mGluR5 regulates trafficking of NMDA receptors in striatal neurons. Activation of mGluR5 appears to induce rapid trafficking of GluN1 and GluN2B to surface membranes through a signaling pathway involving CaMKII.
doi:10.1016/j.brainres.2015.07.053
PMCID: PMC4630094  PMID: 26256252
mGluR; striatum; GluN1; GluN2B; NR2B; G protein-coupled receptor; phosphorylation; DHPG
5.  Why Does 2,3,5,6-Tetrachlorophenol Generate the Strongest Intrinsic Chemiluminescence among All Nineteen Chlorophenolic Persistent Organic Pollutants during Environmentally-friendly Advanced Oxidation Process? 
Scientific Reports  2016;6:33159.
We found recently that intrinsic chemiluminescence (CL) could be produced by all 19 chlorophenolic persistent organic pollutants during environmentally-friendly advanced oxidation processes. Interestingly and unexpectedly, the strongest CL was produced not by the most-highly chlorinated pentachlorophenol (PCP), but rather by the less chlorinated 2,3,5,6-tetrachlorophenol (2,3,5,6-TeCP), one of the three tetrachlorophenol (TeCPs) isomers. However, it remains unclear what is the underlying molecular mechanism. Here we show that not only chlorinated quinoid intermediates, but more interestingly, semiquinone radicals were produced during the degradation of the three TeCPs and PCP by Fenton reagents, and the type and yield of which were found to be well correlated with CL generation. We propose that hydroxyl radical-dependent formation of more tetrachlorinated quinoids, quinone-dioxetanes and electronically excited carbonyl species might be responsible for the exceptionally strong CL production by 2,3,5,6-TeCP as compared to PCP and its two isomers. This is the first report showing the critical role of quinoid intermediates and semiquinone radicals in CL generation from polychlorinated phenols and Fenton system. These new findings may have broad chemical and environmental implications for future studies on remediation of other halogenated persistent aromatic pollutants by advanced oxidation processes.
doi:10.1038/srep33159
PMCID: PMC5066286  PMID: 27748358
6.  Dopamine D2 receptors are involved in the regulation of Fyn and mGluR5 phosphorylation in the rat striatum in vivo 
Journal of neuroscience research  2016;94(4):329-338.
Fyn, a major Src family kinase (SFK) member that is densely expressed in striatal neurons, is actively involved in the regulation of cellular and synaptic activities in local neurons. This SFK member is likely regulated by dopamine signaling through a receptor mechanism involving dopamine D2 receptors (D2Rs). In this study, we thus characterized the D2R-dependent regulation of Fyn in the rat striatum in vivo. Moreover, we explored whether D2Rs regulate metabotropic glutamate receptor 5 (mGluR5) in its tyrosine phosphorylation and whether the D2R-SFK pathway modulates trafficking of mGluR5. We found that blockade of D2Rs by a systemic administration of a D2R antagonist eticlopride substantially increased SFK phosphorylation in the striatum. This increase was a transient and reversible event. The eticlopride-induced SFK phosphorylation occurred predominantly in immunopurified Fyn but not another SFK member Src. Eticlopride also elevated tyrosine phosphorylation of mGluR5. In parallel, eticlopride enhanced synaptic delivery of active Fyn and mGluR5. Pretreatment with an SFK inhibitor blocked the eticlopride-induced tyrosine phosphorylation and synaptic trafficking of mGluR5. These results indicate that D2Rs inhibit SFK (mainly Fyn) phosphorylation in the striatum. D2Rs also inhibit tyrosine phosphorylation and synaptic recruitment of mGluR5 through a signaling mechanism likely involving Fyn.
Graphical Abstract
doi:10.1002/jnr.23713
PMCID: PMC4744551  PMID: 26777117
metabotropic glutamate receptor; non-receptor tyrosine kinase; Src; SFK; tyrosine phosphorylation; nucleus accumbens; eticlopride; PP2
7.  Regulation of synaptic MAPK/ERK phosphorylation in the rat striatum and medial prefrontal cortex by dopamine and muscarinic acetylcholine receptors 
Journal of neuroscience research  2015;93(10):1592-1599.
Dopamine and acetylcholine are two principal transmitters in the striatum and are usually balanced to modulate local neural activity and maintain striatal homeostasis. In this study, we investigated the role of dopamine and muscarinic acetylcholine receptors in the regulation of a central signaling protein, i.e., the mitogen-activated protein kinase (MAPK). We focused on the synaptic pool of MAPKs based on the fact that these kinases reside in peripheral synaptic structures in addition to their somatic locations. We found that a systemic injection of a dopamine D1 receptor (D1R) agonist SKF81297 enhanced phosphorylation of extracellular signal-regulated kinases (ERKs), a prototypic subclass of MAPKs, in the adult rat striatum. Similar results were observed in another dopamine responsive region, the medial prefrontal cortex (mPFC). The dopamine D2 receptor agonist quinpirole had no such effects. Pretreatment with a positive allosteric modulator (PAM) of muscarinic acetylcholine M4 receptors (M4Rs), VU0152100, attenuated the D1R agonist-stimulated ERK phosphorylation in the two regions, while the PAM itself did not alter basal ERK phosphorylation. All drug treatments had no effect on phosphorylation of c-Jun N-terminal kinases (JNKs), another MAPK subclass, in the striatum and mPFC. These results demonstrate that dopamine and acetylcholine are integrated to control synaptic ERK, although not JNK, activation in striatal and mPFC neurons in vivo. Activation of M4Rs exerts an inhibitory effect on the D1R-mediated upregulation of synaptic ERK phosphorylation.
Graphical Abstract
doi:10.1002/jnr.23622
PMCID: PMC4545715  PMID: 26153447
Basal ganglia; M4 receptor; D1 dopamine receptor; extracellular signal-regulated kinase; c-Jun N-terminal kinase; stress-activated protein kinase; RRID, AB_476693; RRID, AB_331646; RRID, AB_10695746; RRID, AB_2140557; RRID, AB_10693936; RRID, nif-0000-30467
8.  Super-elastic and fatigue resistant carbon material with lamellar multi-arch microstructure 
Nature Communications  2016;7:12920.
Low-density compressible materials enable various applications but are often hindered by structure-derived fatigue failure, weak elasticity with slow recovery speed and large energy dissipation. Here we demonstrate a carbon material with microstructure-derived super-elasticity and high fatigue resistance achieved by designing a hierarchical lamellar architecture composed of thousands of microscale arches that serve as elastic units. The obtained monolithic carbon material can rebound a steel ball in spring-like fashion with fast recovery speed (∼580 mm s−1), and demonstrates complete recovery and small energy dissipation (∼0.2) in each compress-release cycle, even under 90% strain. Particularly, the material can maintain structural integrity after more than 106 cycles at 20% strain and 2.5 × 105 cycles at 50% strain. This structural material, although constructed using an intrinsically brittle carbon constituent, is simultaneously super-elastic, highly compressible and fatigue resistant to a degree even greater than that of previously reported compressible foams mainly made from more robust constituents.
Low-density compressible materials often suffer from fatigue-induced failure or limited elasticity. Here, the authors create a hierarchical multi-arch carbon material that achieves high compressibility, superior elasticity and fatigue resistance simultaneously, inspired by properties of arches in daily life.
doi:10.1038/ncomms12920
PMCID: PMC5052633  PMID: 27676215
9.  Comparative genomic, transcriptomic and secretomic profiling of Penicillium oxalicum HP7-1 and its cellulase and xylanase hyper-producing mutant EU2106, and identification of two novel regulatory genes of cellulase and xylanase gene expression 
Background
The filamentous fungus Penicillium oxalicum is a potential alternative to Trichoderma reesei for industrial production of a complete cellulolytic enzyme system for a bio-refinery. Comparative omics approaches can support rational genetic engineering and/or breeding of filamentous fungi with improved cellulase production capacity. In this study, comparative genomic, transcriptomic and secretomic profiling of P. oxalicum HP7-1 and its cellulase and xylanase hyper-producing mutant EU2106 were employed to screen for novel regulators of cellulase and xylanase gene expression.
Results
The 30.62 Mb P. oxalicum HP7-1 genome was sequenced, and 9834 protein-coding genes were annotated. Re-sequencing of the mutant EU2106 genome identified 274 single nucleotide variations and 12 insertion/deletions. Comparative genomic, transcriptomic and secretomic profiling of HP7-1 and EU2106 revealed four candidate regulators of cellulase and xylanase gene expression. Deletion of these candidate genes and measurement of the enzymatic activity of the resultant mutants confirmed the identity of three regulatory genes. POX02484 and POX08522, encoding a putative Zn(II)2Cys6 DNA-binding domain and forkhead protein, respectively, were found to be novel, while PoxClrB is an ortholog of ClrB, a key transcriptional regulator of cellulolytic enzyme gene expression in filamentous fungi. ΔPOX02484 and ΔPOX08522 mutants exhibited significantly reduced β-glucosidase activity, increased carboxymethylcellulose cellulase and xylanase activities, and altered transcription level of cellulase and xylanase genes compared with the parent strain ΔPoxKu70, with Avicel as the sole carbon source.
Conclusions
Two novel genes, POX02484 and POX08522, were found and characterized to regulate the expression of cellulase and xylanase genes in P. oxalicum. These findings are important for engineering filamentous fungi to improve cellulase and xylanase production.
Electronic supplementary material
The online version of this article (doi:10.1186/s13068-016-0616-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13068-016-0616-9
PMCID: PMC5035457  PMID: 27688806
Penicillium oxalicum; Genomics; Transcriptomics; Secretomics; Transcription factor; Cellulase; Xylanase; Regulation
10.  Primary surveys on molecular epidemiology of bovine viral diarrhea virus 1 infecting goats in Jiangsu province, China 
BMC Veterinary Research  2016;12(1):181.
Background
Bovine viral diarrhea virus (BVDV) is a pathogen of domestic and wildlife animals worldwide and is associated with several diseases. In China, there are many reports about genotyping of BVDV strains originated from cattle and pigs, and some of them focused on the geographical distributions of BVDV. Currently, the goat industry in Jiangsu province of China is under going a rapid expansion. Most of these goat farms are backyard enterprises and in close proximity to pig and cattle farms. However, there was very limited information about BVDV infections in goats. The objective of this study was to assess the frequency of BVDV infections of goats, the relationship of these infections to clinical signs and determine what BVDV genotypes are circulating in Jiangsu province.
Results
From 236 goat sera collected from six regions in Jiangsu province between 2011 and 2013, BVDV-1 was identified in 29 samples from the five regions by RT-PCR. The BVDV-1 infections occurred with/without clinical signs. Eight different BVDV-1 strains were identified from these positive samples based on the 5′-untranslated region (5′-UTR) sequences, and further clustered into four BVDV-1 subtypes on the phylogenetic analysis. Three were BVDV-1b, two BVDV-1m, two BVDV-1o, and one BVDV-1p, respectively.
Conclusions
To our knowledge, this is the first report to investigate the occurrence of BVDV and the genotypes of BVDV infecting goats in China. The results indicated that BVDV-1 infections were indeed present and the viruses were with genetic variations in Chinese goat herds. The information would be very useful for prevention and control of BVDV-1 infections in China.
doi:10.1186/s12917-016-0820-7
PMCID: PMC5011786  PMID: 27596263
BVDV-1; Goats; Genotyping
11.  Trichoderma Biodiversity of Agricultural Fields in East China Reveals a Gradient Distribution of Species 
PLoS ONE  2016;11(8):e0160613.
We surveyed the Trichoderma (Hypocreales, Ascomycota) biodiversity in agricultural fields in four major agricultural provinces of East China. Trichoderma strains were identified based on molecular approaches and morphological characteristics. In three sampled seasons (spring, summer and autumn), 2078 strains were isolated and identified to 17 known species: T. harzianum (429 isolates), T. asperellum (425), T. hamatum (397), T. virens (340), T. koningiopsis (248), T. brevicompactum (73), T. atroviride (73), T. fertile (26), T. longibrachiatum (22), T. pleuroticola (16), T. erinaceum (16), T. oblongisporum (2), T. polysporum (2), T. spirale (2), T. capillare (2), T. velutinum (2), and T. saturnisporum (1). T. harzianum, T. asperellum, T. hamatum, and T. virens were identified as the dominant species with dominance (Y) values of 0.057, 0.052, 0.048, and 0.039, respectively. The species amount, isolate numbers and the dominant species of Trichoderma varied between provinces. Zhejiang Province has shown the highest diversity, which was reflected in the highest species amount (14) and the highest Shannon–Wiener diversity index of Trichoderma haplotypes (1.46). We observed that relative frequencies of T. hamatum and T. koningiopsis under rice soil were higher than those under wheat and maize soil, indicating the preference of Trichoderma to different crops. Remarkable seasonal variation was shown, with summer exhibiting the highest biodiversity of the studied seasons. These results show that Trichoderma biodiversity in agricultural fields varies by region, crop, and season. Zhejiang Province (the southernmost province in the investigated area) had more T. hamatum than Shandong Province (the northernmost province), not only in isolate amounts but also in haplotype amounts. Furthermore, at haplotype level, only T. hamatum showed a gradient distribution from south to north in correspondence analysis among the four dominant species. The above results would contribute to the application of Trichoderma biocontrol strains.
doi:10.1371/journal.pone.0160613
PMCID: PMC4970770  PMID: 27482910
12.  Maternal and cord blood adiponectin levels in relation to post-natal body size in infants in the first year of life: a prospective study 
Background
Adiponectin is an adipocyte hormone involved in energy homeostasis and metabolism. However, its role in early infancy is poorly understood.
Methods
We recruited a total of 443 pregnant women and their children in this prospective study. Cord blood samples were successfully obtained from 331 neonates. Maternal and umbilical blood serum adiponectin were measured. The weight-, height- and BMI-for-age Z scores of infants at birth and at 3, 6 and 12 months of age were assessed.
Results
Multiple linear regression analysis indicated that cord blood but not maternal serum adiponectin was positively associated with all of the anthropometric measures at birth (P < 0.01). Using Generalized Estimating Equation model after adjustment for sex, time, maternal age, gestational age, prepregnancy BMI, weight gain during pregnancy, maternal education, parity, history of miscarriage and mode of delivery, for every 1-μg/ml increment of maternal serum adiponectin, the height-for-age Z score during the first year of life increased by 0.026 (P =0.013) on average, and the height-for-age Z score of infants in the highest quartile of maternal serum adiponectin was 0.270 (95 % CI: 0.013–0.527) higher than those in the lowest quartile. The changes in weight-for-age Z score from birth decreased by 0.67 × 10−2 on average with every 1-μg/ml additional increase of cord blood adiponectin (P = 0.047). The infants in the highest quartile of cord blood adiponectin showed a −0.368 (95 % CI, −0.701–−0.035) decrease in weight-for-age Z score change from birth compared with those in the lowest quartile.
Conclusions
Cord blood adiponectin concentration is a determinant of infant birth size and weight gain in the first year of life. Circulating maternal adiponectin during pregnancy may predict postnatal height growth.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-016-0978-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12884-016-0978-9
PMCID: PMC4962456  PMID: 27459998
Adiponectin; Cord blood; Infant; Growth; Prospective study
13.  Dynamic increases in AMPA receptor phosphorylation in the rat hippocampus in response to amphetamine 
Journal of neurochemistry  2015;133(6):795-805.
Increasing evidence supports the critical role of AMPA glutamate receptors in psychostimulant action. These receptors are regulated via a phosphorylation-dependent mechanism in their trafficking, distribution and function. The hippocampus is a brain structure important for learning and memory and is emerging as a critical site for processing psychostimulant effects. To determine whether the hippocampal pool of AMPA receptors is regulated by stimulants, we investigated and characterized the impact of amphetamine (AMPH) on phosphorylation of AMPA receptors in the adult rat hippocampus in vivo. We found that AMPH markedly increased phosphorylation of AMPA receptor GluA1 subunits at serine 845 (S845) in the hippocampus. The effect of AMPH was dose-dependent. A single dose of AMPH induced a rapid and transient increase in S845 phosphorylation. Among different hippocampal subfields, AMPH primarily elevated S845 phosphorylation in the Cornu Ammonis area 1 and dentate gyrus. In contrast to S845, serine 831 phosphorylation of GluA1 and serine 880 phosphorylation of GluA2 were not altered by AMPH. In addition, surface expression of hippocampal GluA1 was upregulated, while the amount of intracellular GluA1 fraction was concurrently reduced in response to AMPH. GluA2 protein levels in either the surface or intracellular pool were insensitive to AMPH. These data demonstrate that the AMPA receptor in the hippocampus is sensitive to dopamine stimulation. Acute AMPH administration induces dose-, time-, site-, and subunit-dependent phosphorylation of AMPA receptors and facilitates surface trafficking of GluA1 AMPA receptors in hippocampal neurons in vivo.
doi:10.1111/jnc.13067
PMCID: PMC4464951  PMID: 25689263
CA1; dentate gyrus; GluA1; GluA2; glutamate; stimulant; S831; S845; S880
14.  Impact of central obesity on prognostic outcome of triple negative breast cancer in Chinese women 
SpringerPlus  2016;5:594.
Purpose
To evaluate the prognostic effect of central obesity on triple negative breast cancer (TNBC).
Methods
206 TNBC patients treated from June 2006 to June 2015 were enrolled retrospectively. Body mass index (BMI) ≥25 kg/m2 was the standard of obesity and waist circumference ≥80 cm was the standard of central obesity. Patient and tumor characteristics were compared between obesity categories. Survival differences between obesity categories were assessed with log-rank test in the univariate analysis and prognostic factors were then investigated by Cox regression analysis.
Results
81 cases were with obesity (39.3 %). 71 cases were with central obesity (34.5 %). Patients with obesity or central obesity tended to be older (P = 0.022 for obesity; P = 0.013 for central obesity) and to have larger tumor size (P = 0.027 for obesity; P = 0.027 for central obesity). By Cox regression analysis, central obesity (DFS: HR 1.759; 95 % CI 1.009–3.065; P = 0.046. OS: HR 2.297; 95 % CI 1.184–4.456; P = 0.014) was identified as an independent prognostic factor. For central obesity with BMI ≥ 25 kg/m2, the prognostic effect was more apparent (DFS: HR 1.845; 95 % CI 1.059–3.212; P = 0.031. OS: HR 2.377; 95 % CI 1.230–4.593; P = 0.010).
Conclusion
Central obesity, especially with high BMI, was an independent prognostic factor for TNBC.
doi:10.1186/s40064-016-2200-y
PMCID: PMC4864763  PMID: 27247890
Obesity; Central obesity; Triple negative breast cancer; Prognosis
15.  Pancreatic β-Cell Death due to Pdx-1 Deficiency Requires Multi-BH Domain Protein Bax but Not Bak* 
The Journal of Biological Chemistry  2016;291(26):13529-13534.
Diabetes develops in Pdx1-haploinsufficient mice due to an increase in β-cell death leading to reduced β-cell mass and decreased insulin secretion. Knockdown of Pdx1 gene expression in mouse MIN6 insulinoma cells induced apoptotic cell death with an increase in Bax activation and knockdown of Bax reduced apoptotic β-cell death. In Pdx1 haploinsufficient mice, Bax ablation in β-cells increased β-cell mass, decreased the number of TUNEL positive cells and improved glucose tolerance after glucose challenge. These changes were not observed with Bak ablation in Pdx1-haploinsufficient mice. These results suggest that Bax mediates β-cell apoptosis in Pdx1-deficient diabetes.
doi:10.1074/jbc.M115.705293
PMCID: PMC4919439  PMID: 27137932
apoptosis; Bax; beta cell (β-cell); cell death; diabetes
16.  Pulmonologist Involvement, Stage-Specific Treatment, and Survival in Adults with Non–Small Cell Lung Cancer and Chronic Obstructive Pulmonary Disease 
Rationale: Up to 80% of patients with lung cancer have comorbid chronic obstructive pulmonary disease (COPD). Many of them are poor candidates for stage-specific lung cancer treatment due to diminished lung function and poor functional status, and many forego treatment. The negative effect of COPD may be moderated by pulmonologist-guided management.
Objectives: This study examined the association between pulmonologist management and the probability of receiving the recommended stage-specific treatment modality and overall survival among patients with non-small cell lung cancer (NSCLC) with preexisting COPD.
Methods: Early- and advanced-stage NSCLC cases diagnosed between 2002 and 2005 with a prior COPD diagnosis (3–24 months before NSCLC diagnosis) were identified in Surveillance, Epidemiology, and End Results tumor registry data linked to Medicare claims. Study outcomes included receipt of recommended stage-specific treatment (surgical resection for early-stage NSCLC and chemotherapy for advanced-stage NSCLC [advNSCLC]) and overall survival. Pulmonologist management was considered present if one or more Evaluation and Management visit claims with pulmonologist specialty were observed within 6 months after NSCLC diagnosis. Stage-specific multivariate logistic regression tested association between pulmonologist management and treatment received. Cox proportional hazard models examined the independent association between pulmonologist care and mortality. Two-stage residual inclusion instrumental variable (2SRI-IV) analyses tested and adjusted for potential confounding based on unobserved factors or measurement error.
Measurements and Main Results: The cohorts included 5,488 patients with early-stage NSCLC and 6,426 patients with advNSCLC disease with preexisting COPD. Pulmonologist management was recorded for 54.9% of patients with early stage NSCLC and 35.7% of patients with advNSCLC. Of those patients with pulmonologist involvement, 58.5% of patients with early NSCLC received surgical resection, and 43.6% of patients with advNSCLC received chemotherapy. Pulmonologist management post NSCLC diagnosis was associated with increased surgical resection rates (odds ratio, 1.26; 95% confidence interval, 1.11–1.45) for early NSCLC and increased chemotherapy rates (odds ratio, 1.88; 95% confidence interval, 1.67–2.10) for advNSCLC. Pulmonologist management was also associated with reduced mortality risk for patients with early-stage NSCLC but not AdvNSCLC.
Conclusions: Pulmonologist management had a positive association with rates of stage-specific treatment in both groups and overall survival in early-stage NSCLC. These results provide preliminary support for the recently published guidelines emphasizing the role of pulmonologists in lung cancer management.
doi:10.1513/AnnalsATS.201406-230OC
PMCID: PMC4418342  PMID: 25760983
non–small cell lung carcinoma; pulmonology medicine; chronic obstructive pulmonary disease; survival
17.  Maternal hepatitis B virus carrier status and pregnancy outcomes: a prospective cohort study 
Background
Infection with hepatitis B virus (HBV) in pregnant women may be a threat for both mothers and fetuses. This study was performed to explore the impact of maternal HBV carrier status on pregnancy outcomes.
Methods
We conducted a prospective cohort study at the Obstetrics & Gynecology Hospital of Nantong University between January 1, 2012 and September 30, 2015. A consecutive sample of 21,004 pregnant women, 513 asymptomatic HBV carriers and 20,491 non-HBV controls, was included in this study. The main outcomes of interest were selected pregnancy outcomes including miscarriage, stillbirth, preterm birth (PTB), gestational diabetes (GDM), intrahepatic cholestasis of pregnancy (ICP), preterm premature rupture of the membrane (PPROM), low birth weight (LBW), small for gestational age (SGA) and Apgar scores. The incidence of adverse pregnancy outcomes between asymptomatic HBV carriers and non-HBV controls were compared using the chi-square test and logistic regression. P values were two sided, and P <0.05 was considered to indicate statistical significance.
Results
The incidences of stillbirth, PTB, GDM, ICP, PPROM, LBW, and SGA were similar between the HBV carrier and non-HBV groups. The proportion of miscarriage was significantly higher among the HBV carriers than the controls (9.36 % vs 5.70 %; P <0.001). After using multivariate modelling to adjust for possible socio-demographical variables and obstetric complications, women with HBV carrier status were still more likely to have miscarriage (adjusted OR 1.71, 95 % CI 1.23–2.38). In addition, the incidences of other maternal and neonatal outcomes were similar between the two groups.
Conclusion
Maternal HBV carrier status may be an independent risk factor for miscarriage and careful surveillance is warranted.
doi:10.1186/s12884-016-0884-1
PMCID: PMC4845477  PMID: 27113723
Pregnancy; Hepatitis B virus infection; Miscarriage
18.  Clinical Study on 136 Children with Sudden Sensorineural Hearing Loss 
Chinese Medical Journal  2016;129(8):946-952.
Background:
The prevalence of sudden sensorineural hearing loss in children (CSSNHL) is consistently increasing. However, the pathology and prognosis of CSSNHL are still poorly understood. This retrospective study evaluated clinical characteristics and possible associated factors of CSSNHL.
Methods:
One hundred and thirty-six CSSNHL patients treated in Department of Otolaryngology-Head and Neck Surgery and Institute of Otolaryngology at Chinese PLA General Hospital between July 2008 and August 2015 were included in this study. These patients were analyzed for clinical characteristics, audiological characteristics, laboratory examinations, and prognostic factors.
Results:
Among the 136 patients (151 ears), 121 patients (121 ears, 80.1%) were diagnosed with unilaterally CSSNHL, and 15 patients (30 ears, 19.9%) with bilateral CSSNHL. The complete recovery rate of CSSNHL was 9.3%, and the overall recovery rate was 37.7%. We found that initial degree of hearing loss, onset of treatment, tinnitus, the ascending type audiogram, gender, side of hearing loss, the recorded auditory brainstem response (ABR), and distortion product otoacoustic emissions (DPOAEs) had prognostic significance. Age, ear fullness, and vertigo had no significant correlation with recovery. Furthermore, the relevant blood tests showed 30.8% of the children had abnormal white blood cell (WBC) counts, 22.1% had elevated homocysteine levels, 65.8% had high alkaline phosphatase (ALP), 33.8% had high IgE antibody levels, and 86.1% had positive cytomegalovirus (CMV) IgG antibodies.
Conclusions:
CSSNHL commonly occurs unilaterally and results in severe hearing loss. Initial severe hearing loss and bilateral hearing loss are negative prognostic factors for hearing recovery, while positive prognostic factors include tinnitus, gender, the ascending type audiogram, early treatment, identifiable ABR waves, and DPOAEs. Age, vertigo, and ear fullness are not correlated with the recovery. Some serologic indicators, including the level of WBC, platelet, homocysteine, ALP, positive CMV IgG antibody, fibrinogen, and some immunologic indicators, are closely related to CSSNHL.
doi:10.4103/0366-6999.179791
PMCID: PMC4831530  PMID: 27064040
Audiological Characteristics; Children; Laboratory Examinations; Prognostic Factors; Sudden Hearing Loss
19.  Relationship between diagonal earlobe creases and coronary artery disease as determined via angiography 
BMJ Open  2016;6(2):e008558.
Objective
This study was designed to examine the prevalence of unilateral and bilateral diagonal earlobe creases (DELCs) with respect to the diagnosis of coronary heart disease (CHD).
Methods
A total of 558 consecutive participants (402 males and 156 females) aged 36–91 years who underwent coronary angiography were enrolled in this study. The participants were classified as being without a DELC, having a unilateral DELC and having bilateral DELCs; participants with either a unilateral DELC or bilateral DELCs were defined as participants with DELCs. Significant CHD was defined as at least one major vessel with >50% stenosis, and coronary atherosclerosis severity was defined using the Gensini scoring system.
Results
In the present study, bilateral DELCs were more frequently among male (p=0.001), CHD (p=0.000), older people (p=0.000) and those with more severe coronary artery atherosclerosis (p=0.000). The results of the multiple regression analyses indicated that DELCs (OR, 4.861; 95% CI 3.093 to 7.642, p=0.000) remained independently associated with a risk of CHD. It was assumed that participants without a DELC have a certain background risk for CHD (OR is assumed to be 1); the results of the multivariate logistic regression indicated that the relative risk of CHD among participants with bilateral DELCs was 5.690 among all participants (OR, 5.690; 95% CI 3.450 to 9.384, p=0.000), 5.436 among male participants (OR, 5.436; 95% CI 2.808 to 10.523, p=0.000) and 7.148 among female participants (OR, 7.148; 95% CI 3.184 to 16.049, p=0.000). Moreover, a positive association between DELC and age (SI=1.21, SIM=1.65, AP =0.132), gender (SI=2.09, SIM=0.81, AP=0.49) and smoking status (SI=1.49, SIM=0.73, AP=0.29) was found, respectively.
Conclusions
The results of the present study indicated that DELCs are a simple and a feasible means of identifying CHD. However, the exact mechanism underlying the relationship between DELCs and CHD warrants further study.
doi:10.1136/bmjopen-2015-008558
PMCID: PMC4762085  PMID: 26868940
CARDIOLOGY
21.  Antinociceptive effects of vitexin in a mouse model of postoperative pain 
Scientific Reports  2016;6:19266.
Vitexin, a C-glycosylated flavone present in several medicinal herbs, has showed various pharmacological activities including antinociception. The present study investigated the antinociceptive effects of vitexin in a mouse model of postoperative pain. This model was prepared by making a surgical incision on the right hindpaw and von Frey filament test was used to assess mechanical hyperalgesia. Isobolographical analysis method was used to examine the interaction between vitexin and acetaminophen. A reliable mechanical hyperalgesia was observed at 2 h post-surgery and lasted for 4 days. Acute vitexin administration (3–10 mg/kg, i.p.) dose-dependently relieved this hyperalgesia, which was also observed from 1 to 3 days post-surgery during repeated daily treatment. However, repeated vitexin administration prior to surgery had no preventive value. The 10 mg/kg vitexin-induced antinociception was blocked by the opioid receptor antagonist naltrexone or the GABAA receptor antagonist bicuculline. The doses of vitexin used did not significantly suppress the locomotor activity. In addition, the combination of vitexin and acetaminophen produced an infra-additive effect in postoperative pain. Together, though vitexin-acetaminophen combination may not be useful for treating postoperative pain, vitexin exerts behaviorally-specific antinociception against postoperative pain mediated through opioid receptors and GABAA receptors, suggesting that vitexin may be useful for the control of postoperative pain.
doi:10.1038/srep19266
PMCID: PMC4817219  PMID: 26763934
22.  Intracoronary Transplantation of Mesenchymal Stem Cells with Overexpressed Integrin-Linked Kinase Improves Cardiac Function in Porcine Myocardial Infarction 
Scientific Reports  2016;6:19155.
The effect of mesenchymal stem cell (MSCs)-based therapy on treating acute myocardial infarction (MI) is limited due to poor engraftment and limited regenerative potential. Here we engineered MSCs with integrin-linked kinase (ILK), a pleiotropic protein critically regulating cell survival, proliferation, differentiation, and angiogenesis. We firstly combined ferumoxytol with poly-L-lysine (PLL), and found this combination promisingly enabled MRI visualization of MSCs in vitro and in vivo with good safety. We provided visually direct evidence that intracoronary ILK-MSCs had substantially enhanced homing capacity to infarct myocardium in porcine following cardiac catheterization induced MI. Intracoronary transplantation of allogeneic ILK-MSCs, but not vector-MSCs, significantly enhanced global left ventricular ejection fraction (LVEF) by 7.8% compared with baseline, by 10.3% compared with vehicles, and inhibited myocardial remodeling compared with vehicles at 15-day follow-up. Compared with vector-MSCs, ILK-MSCs significantly improved regional LV contractile function, reduced scar size, fibrosis, cell apoptosis, and increased regional myocardial perfusion and cell proliferation. This preclinical study indicates that ILK-engineered MSCs might promote the clinical translation of MSC-based therapy in post-MI patients, and provides evidence that ferumoxytol labeling of cells combined with PLL is feasible in in vivo cell tracking.
doi:10.1038/srep19155
PMCID: PMC4707493  PMID: 26750752
23.  Glycoproteomic Approach Identifies KRAS as a Positive Regulator of CREG1 in Non-small Cell Lung Cancer Cells 
Theranostics  2016;6(1):65-77.
Protein glycosylation plays a fundamental role in a multitude of biological processes, and the associated aberrant expression of glycoproteins in cancer has made them attractive biomarkers and therapeutic targets. In this study, we examined differentially expressed glycoproteins in cell lines derived from three different states of lung tumorigenesis: an immortalized bronchial epithelial cell (HBE) line, a non-small cell lung cancer (NSCLC) cell line harboring a Kirsten rat sarcoma viral oncogene homolog (KRAS) activation mutation and a NSCLC cell line harboring an epidermal growth factor receptor (EGFR) activation deletion. Using a Triple SILAC proteomic quantification strategy paired with hydrazide chemistry N-linked glycopeptide enrichment, we quantified 118 glycopeptides in the three cell lines derived from 82 glycoproteins. Proteomic profiling revealed 27 glycopeptides overexpressed in both NSCLC cell lines, 6 glycopeptides overexpressed only in the EGFR mutant cells and 19 glycopeptides overexpressed only in the KRAS mutant cells. Further investigation of a panel of NSCLC cell lines found that Cellular repressor of E1A-stimulated genes (CREG1) overexpression was closely correlated with KRAS mutation status in NSCLC cells and could be down-regulated by inhibition of KRAS expression. Our results indicate that CREG1 is a down-stream effector of KRAS in a sub-type of NSCLC cells and a novel candidate biomarker or therapeutic target for KRAS mutant NSCLC.
doi:10.7150/thno.12350
PMCID: PMC4679355  PMID: 26722374
KRAS; non-small cell lung cancer (NSCLC); adenocarcinoma; quantitative glycoproteomics; glycoprotein
24.  The conservation and signatures of lincRNAs in Marek’s disease of chicken 
Scientific Reports  2015;5:15184.
Long intergenic non-coding RNAs (lincRNAs) associated with a number of cancers and other diseases have been identified in mammals, but they are still formidable to be comprehensively identified and characterized. Marek’s disease (MD) is a T cell lymphoma of chickens induced by Marek’s disease virus (MDV). Here, we used a MD chicken model to develop a precise pipeline for identifying lincRNAs and to determine the roles of lincRNAs in T cell tumorigenesis. More than 1,000 lincRNA loci were identified in chicken bursa. Computational analyses demonstrated that lincRNAs are conserved among different species such as human, mouse and chicken. The putative lincRNAs were found to be associated with a wide range of biological functions including immune responses. Interestingly, we observed distinct lincRNA expression signatures in bursa between MD resistant and susceptible lines of chickens. One of the candidate lincRNAs, termed linc-satb1, was found to play a crucial role in MD immune response by regulating a nearby protein-coding gene SATB1. Thus, our results manifested that lincRNAs may exert considerable influence on MDV-induced T cell tumorigenesis and provide a rich resource for hypothesis-driven functional studies to reveal genetic mechanisms underlying susceptibility to tumorigenesis.
doi:10.1038/srep15184
PMCID: PMC4608010  PMID: 26471251
25.  In vitro, ex vivo and in vivo anti-hypertensive activity of Chrysophyllum cainito L. extract 
Chrysophyllum cainito L., a traditional herbal medicine, could have the potential for management of hypertension due to presence of polyphenolic compounds. The extracts and fractions of the pulp of plant were evaluated for in vitro (inhibition of angiotensin I converting enzyme/ACE assay), ex vivo (isolated aorta relaxation assay) and in vivo (salt induced hypertensive rat assay). The alcoholic and aqueous extract (ALE and AQE respectively) of fruit of plant C. cainito was having 14.8 and 9.2% yield respectively. The fractionation with ethyl alcohol (EAF) and butanol (BTF) yielded 2.52 & 2.17% respectively from ALE and 0.46 & 0.31% respectively from AQE with respect to fruit pulp dry weight. More phenolic content was found in ALE (3.75±0.15 mg gallic acid equivalent or GAE g-1 of dry power of fruit pulp) compared to AQE and maximum in ethyl acetate fraction of ALE (ALE-EAF) (2.32±0.21 mg GAE g-1 of dry power of fruit pulp) among all fractions. ACE inhibition activity was found to be maximum in ALE-EAF 62.5±7.34%. While ex vivo study using isolated tissue of aorta showed again showed maximum activity (62.82±6.19 and 46.47±8.32% relaxation with 50 µg mL-1 and 10 µg mL-1 GAE concentration respectively). ALE-EAF reduced the elevated arterial pressure of salt induced hypertensive rat significantly to the level of normotensive animal group. Results of ALE-EAF have shown its potential as a source for novel constituent for the treatment hypertension and should further be studied for isolation of specific constituent for more effectiveness.
PMCID: PMC4694285  PMID: 26770385
ACE inhibition; aorta ring assay; chrysophyllum cainito; extracts; fraction hypertension; salt induced hypertensive rat model

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