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1.  Atherosclerotic plaque uptake of a novel integrin tracer 18F-Flotegatide in a mouse model of atherosclerosis 
Rupture of unstable atherosclerotic plaque is the primary event leading to stroke and myocardial infarction. Plaque vulnerability may be induced by macrophage infiltration, neovessel formation and intraplaque instability. A tracer that selectively binds to macrophages and neovascular endothelium may identify rupture prone plaque. The 18F-labeled “R-G-D” containing tripeptide (Flotegatide) is a click chemistry derived radiotracer that binds to integrin αvβ3, a protein present in vulnerable plaque. We now demonstrate that Flotegatide preferentially binds to aortic plaque in an ApoE knock out mouse model of atherosclerosis. The tracer's uptake is strongly associated with presence of histologic markers for macrophage infiltration and integrin expression. There is a weaker but detectable association between Flotegatide uptake and presence of an immunohistochemical marker for neovascularization. We hypothesize that Flotegatide may be a useful tracer for visualization of inflamed plaque in clinical subjects.
doi:10.1007/s12350-014-9879-3
PMCID: PMC4316660  PMID: 24627345
2.  Mutant β-III Spectrin Causes mGluR1α Mislocalization and Functional Deficits in a Mouse Model of Spinocerebellar Ataxia Type 5 
The Journal of Neuroscience  2014;34(30):9891-9904.
Spinocerebellar ataxia type 5 (SCA5), a dominant neurodegenerative disease characterized by profound Purkinje cell loss, is caused by mutations in SPTBN2, a gene that encodes β-III spectrin. SCA5 is the first neurodegenerative disorder reported to be caused by mutations in a cytoskeletal spectrin gene. We have developed a mouse model to understand the mechanistic basis for this disease and show that expression of mutant but not wild-type β-III spectrin causes progressive motor deficits and cerebellar degeneration. We show that endogenous β-III spectrin interacts with the metabotropic glutamate receptor 1α (mGluR1α) and that mice expressing mutant β-III spectrin have cerebellar dysfunction with altered mGluR1α localization at Purkinje cell dendritic spines, decreased mGluR1-mediated responses, and deficient mGluR1-mediated long-term potentiation. These results indicate that mutant β-III spectrin causes mislocalization and dysfunction of mGluR1α at dendritic spines and connects SCA5 with other disorders involving glutamatergic dysfunction and synaptic plasticity abnormalities.
doi:10.1523/JNEUROSCI.0876-14.2014
PMCID: PMC4107406  PMID: 25057192
long term potentiation; mGluR1α; mouse model; neurodegeneration; Purkinje cells; spinocerebellar ataxia type 5
3.  Decision-Making for Risky Gains and Losses among College Students with Internet Gaming Disorder 
PLoS ONE  2015;10(1):e0116471.
Individuals with Internet gaming disorder (IGD) tend to exhibit disadvantageous risky decision-making not only in their real life but also in laboratory tasks. Decision-making is a complex multifaceted function and different cognitive processes are involved in decision-making for gains and losses. However, the relationship between impaired decision-making and gain versus loss processing in the context of IGD is poorly understood. The main aim of the present study was to separately evaluate decision-making for risky gains and losses among college students with IGD using the Cups task. Additionally, we further examined the effects of outcome magnitude and probability level on decision-making related to risky gains and losses respectively. Sixty college students with IGD and 42 matched healthy controls (HCs) participated. Results indicated that IGD subjects exhibited generally greater risk taking tendencies than HCs. In comparison to HCs, IGD subjects made more disadvantageous risky choices in the loss domain (but not in the gain domain). Follow-up analyses indicated that the impairment was associated to insensitivity to changes in outcome magnitude and probability level for risky losses among IGD subjects. In addition, higher Internet addiction severity scores were associated with percentage of disadvantageous risky options in the loss domain. These findings emphasize the effect of insensitivity to losses on disadvantageous decisions under risk in the context of IGD, which has implications for future intervention studies.
doi:10.1371/journal.pone.0116471
PMCID: PMC4304794  PMID: 25615595
4.  Pretreatment platelet count as a predictor for survival and distant metastasis in nasopharyngeal carcinoma patients 
Oncology Letters  2015;9(3):1458-1466.
The aim of the present study was to investigate the prognostic value of different pretreatment platelet (PLT) counts on the treatment outcome in nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) alone. A total of 1,501 NPC patients, including 412 receiving CCRT and 1,089 receiving RT, were enrolled in the present study. The PLT count cut-off points for the CCRT and RT groups were 150 and 300×109/l, respectively, and the PLT counts were categorized it into three groups: Low (PLT≤150×109/l), moderate (150×109/l300×109/l). To identify independent predictors of overall survival (OS), the Cox proportional hazards model was used to determine local-regional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) rates in the CCRT and RT patients. Furthermore, univariate and multivariate analysis indicated that compared with a moderate PLT count, a low PLT count was an independent unfavorable prognostic factor for OS rate in CCRT patients [hazard ratio (HR), 2.024; 95% confidence interval (CI), 1.165–3.516], and a high PLT count was an independent unfavorable prognostic factor for OS and DMFS rates in CCRT (OS: HR, 1.742; 95% CI, 1.090–2.786; DFMS: HR, 2.110; 95%CI, 1.084–4.108) and RT (OS: HR, 1.740; 95%CI, 1.283–2.362; DMFS: HR, 2.819; 95% CI, 1.766–4.497) patients. Compared with a low PLT count, a high PLT count was significantly and independently associated with a poor DMFS rate in the RT patients (P=0.025; HR, 2.454; 95% CI, 1.121–5.372). Therefore, the present study indicates that low and high PLT counts may be useful indicators of survival and distant metastasis in NPC patients who have undergone radiation treatment.
doi:10.3892/ol.2015.2872
PMCID: PMC4314978  PMID: 25663931
platelet count; nasopharyngeal carcinoma; radiotherapy; concurrent chemoradiotherapy; predictor; prognosis
5.  Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden 
PLoS Pathogens  2015;11(1):e1004579.
Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg− mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.
Author Summary
Parasitic helminths, which infect an estimated two billion people worldwide, represent a significant global public health problem. Infection is associated with life-long morbidity including growth retardation and organ failure. Despite these debilitating conditions, there are currently no successful vaccines against helminths. Further, great variability in the host immune response to helminths exists, with the ability of some individuals to develop immunity, while others are susceptible when re-exposed or maintain life-long chronic infections. Identifying new factors that are differentially expressed in immune versus susceptible individuals could provide new targeting strategies for diagnosis or treatment of helminth infection. Here, we identify an important immunoregulatory function for human resistin in helminth infection. Employing transgenic mice in which the human resistin gene was inserted, we show that human resistin is induced by infection with the helminth Nippostrongylus brasiliensis, where it promotes excessive inflammation and impedes parasite killing. Moreover, analysis of clinical samples from two cohorts of individuals infected with filarial nematodes or soil-transmitted helminths revealed increased resistin and serum proinflammatory cytokines compared to putatively immune individuals. Together, these studies suggest that human resistin is a detrimental cytokine that is expressed in multiple helminth infections, mediates pathogenic inflammation, and delays parasite clearance.
doi:10.1371/journal.ppat.1004579
PMCID: PMC4287580  PMID: 25568944
6.  Distinct brain activity in processing negative pictures of animals and objects --- the role of human contexts 
NeuroImage  2013;84:10.1016/j.neuroimage.2013.09.064.
Previous studies have shown that the amygdala is important in processing not only animate entities but also social information. It remains to be determined to what extent the factors of category and social context interact to modulate the activities of the amygdala and cortical regions. In this study, pictures depicting animals and inanimate objects in negative and neutral levels were presented. The contexts of the pictures differed in whether they included human/human parts. The factors of valence, arousal, familiarity and complexity of pictures were controlled across categories. The results showed that the amygdala activity was modulated by category and contextual information. Under the nonhuman context condition, the amygdala responded more to animals than objects for both negative and neutral pictures. In contrast, under the human context condition, the amygdala showed stronger activity for negative objects than animals. In addition to cortical regions related to object action, functional and effective connectivity analyses showed that the anterior prefrontal cortex interacted with the amygdala more for negative objects (vs. animals) in the human context condition, by a top-down modulation of the anterior prefrontal cortex to the amygdala. These results highlighted the effects of category and human contexts on modulating brain activity in emotional processing.
doi:10.1016/j.neuroimage.2013.09.064
PMCID: PMC3849327  PMID: 24099847
Stimulus category; emotion; context; amygdala; prefrontal cortex
7.  Loss of p53 and altered miR15-a/16-1→MCL-1 pathway in CLL: insights from TCL1-Tg:p53−/− mouse model and primary human leukemia cells 
Leukemia  2013;28(1):118-128.
Chronic lymphocytic leukemia (CLL) patients with deletion of chromosome 17p, where the tumor suppressor p53 gene is located, often develop more aggressive disease with poor clinical outcomes. To investigate the underlying mechanisms responsible for the highly malignant phenotype of 17p- CLL and to facilitate the in vivo evaluation of potential drugs against CLL with p53 deletion, we have created a mouse model with TCL1-Tg:p53−/− genotype. The TCL1-Tg:p53−/− mice develop B-cell leukemia at very early age and follow an aggressive path of disease development that resembles human CLL with 17p deletion, with an early appearance of CD5+/IgM+ B cells in the peritoneal cavity, spleen and bone marrow. These TCL1-Tg:p53−/− leukemia cells exhibit higher survival capacity and are more resistant to drug treatment than the leukemia cells from the TCL1-Tg:p53wt (TCL1-Tg) mice. Analysis of microRNA expression reveals that the p53 deletion resulted in a significant decrease of miR-15a and miR-16-1, leading to a substantial elevated expression of Mcl-1. Primary leukemia cells from CLL patients with 17p deletion also show a decrease in miR-15a/miR-16-1 and an increase in Mcl-1 expression. Our study has created a novel CLL mouse model, and suggests that the p53/miR15a/16-Mcl-1 axis may contribute to the aggressive phenotype and drug resistance in CLL cells with loss of p53.
doi:10.1038/leu.2013.125
PMCID: PMC3806892  PMID: 23608884
Leukemia; p53; TCL1; mouse model; Drug resistance
8.  Infrared neural stimulation of primary visual cortex in non-human primates 
NeuroImage  2013;84:181-190.
Infrared neural stimulation (INS) is an alternative neurostimulation modality that uses pulsed infrared light to evoke spatially precise neural activity that does not require direct contact with neural tissue. With these advantages INS has the potential to increase our understanding of specific neural pathways and impact current diagnostic and therapeutic clinical applications. In order to develop this technique, we investigate the feasibility of INS (λ = 1.875 μm, fiber diameter = 100–400 μm) to activate and modulate neural activity in primary visual cortex (V1) of Macaque monkeys. Infrared neural stimulation was found to evoke localized neural responses as evidenced by both electrophysiology and intrinsic signal optical imaging (OIS). Single unit recordings acquired during INS indicated statistically significant increases in neuron firing rates that demonstrate INS evoked excitatory neural activity. Consistent with this, INS stimulation led to focal intensity-dependent reflectance changes recorded with OIS. We also asked whether INS is capable of stimulating functionally specific domains in visual cortex and of modulating visually evoked activity in visual cortex. We found that application of INS via 100 μm or 200 μm fiber optics produced enhancement of visually evoked OIS response confined to the eye column where INS was applied and relative suppression of the other eye column. Stimulating the cortex with a 400 μm fiber, exceeding the ocular dominance width, led to relative suppression, consistent with involvement of inhibitory surrounds. This study is the first to demonstrate that INS can be used to either enhance or diminish visual cortical response and that this can be done in a functional domain specific manner. INS thus holds great potential for use as a safe, non-contact, focally specific brain stimulation technology in primate brains.
doi:10.1016/j.neuroimage.2013.08.040
PMCID: PMC4120263  PMID: 23994125
9.  Role of microRNAs in diagnosis and treatment of the pathogenesis of gastric cancer 
We aim to detect the miRNAs that are correlated with the gastric cancer cell line SGC-7901 to provide theoretical basis for clinical application. We first analyzed miRNA expression profiles of gastric cancer patients compared with normal controls by microarray analysis and validated the results by real-time qPCR. We also determined the absolute copy numbers of these three miRNAs in normal adults. The results showed that three miRNAs (miR-150, miR-23a, and miR-130a) were identified to significantly decrease in expanded 38 gastric cancer patients compared with 90 normal controls. Molecular and statistical analysis showed that the decreased miRNAs were significant in clinical analysis. Generally speaking, this finding suggest vital roles of these miRNAs in human gastric cancer genesis and as potential biomarkers in gastric cancer diagnosis.
PMCID: PMC4307587  PMID: 25664140
microRNAs; gastric cancer; SGC-7901; diagnosis biomarker
10.  Interferon-Inducible Cholesterol-25-Hydroxylase Inhibits Hepatitis C Virus Replication via Distinct Mechanisms 
Scientific Reports  2014;4:7242.
Cholesterol 25-hydroxylase (CH25H) as an interferon-stimulated gene (ISG) has recently been shown to exert broad antiviral activity through the production of 25-hydroxycholesterol (25HC), which is believed to inhibit the virus-cell membrane fusion during viral entry. However, little is known about the function of CH25H on HCV infection and replication and whether antiviral function of CH25H is exclusively mediated by 25HC. In the present study, we have found that although 25HC produced by CH25H can inhibit HCV replication, CH25H mutants lacking the hydroxylase activity still carry the antiviral activity against HCV but not other viruses such as MHV-68. Further studies have revealed that CH25H can interact with the NS5A protein of HCV and inhibit its dimer formation, which is essential for HCV replication. Thus, our work has uncovered a novel mechanism by which CH25H restricts HCV replication, suggesting that CH25H inhibits viral infection through both 25HC-dependent and independent events.
doi:10.1038/srep07242
PMCID: PMC4252895  PMID: 25467815
11.  Decreased expression and clinical significance of miR-148a in hepatocellular carcinoma tissues 
Background
Aberrant expression of microRNA-148a (miR-148a) has been reported in several types of malignancies. However, its expression and clinicopathological significance in hepatocellular carcinoma (HCC) has not been entirely clarified. Our objective was to investigate the clinicopathological contribution of the miR-148a expression in HCC formalin-fixed paraffin-embedded (FFPE) tissues.
Methods
Eighty-nine HCC and their para-cancerous liver tissues were recruited. Total mRNA including miRNA was isolated and miR-148a expression was determined by using real time RT-qPCR. Furthermore, the relationship between the miR-148a level and clinicopathological features was explored.
Results
Significantly lower miR-148a expression in HCC tissues was observed than that in adjacent noncancerous hepatic tissues. miR-148a expression was also correlated to clinical TNM stage, metastasis, status of capsular infiltration and numbers of tumor nodes.
Conclusions
Underexpression of miR-148a might be associated with HCC tumorigenesis and deterioration of HCC. miR-148a might act as a suppressor miRNA of HCC and it therefore has a potential role in prognosis of HCC patients.
doi:10.1186/s40001-014-0068-2
PMCID: PMC4258268  PMID: 25444499
miR-148a; Hepatocellular carcinoma; Metastasis; Paraffin-embedded tissues; RT-qPCR
12.  The E3 Ubiquitin Ligase XIAP Restricts Anaplasma phagocytophilum Colonization of Ixodes scapularis Ticks 
The Journal of Infectious Diseases  2013;208(11):1830-1840.
Ubiquitination is a posttranslational modification that regulates protein degradation and signaling in eukaryotes. Although it is acknowledged that pathogens exploit ubiquitination to infect mammalian cells, it remains unknown how microbes interact with the ubiquitination machinery in medically relevant arthropods. Here, we show that the ubiquitination machinery is present in the tick Ixodes scapularis and demonstrate that the E3 ubiquitin ligase named x-linked inhibitor of apoptosis protein (XIAP) restricts bacterial colonization of this arthropod vector. We provide evidence that xiap silencing significantly increases tick colonization by the bacterium Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis. We also demonstrate that (i) XIAP polyubiquitination is dependent on the really interesting new gene (RING) catalytic domain, (ii) XIAP polyubiquitination occurs via lysine (K)-63 but not K-48 residues, and (iii) XIAP-dependent K-63 polyubiquitination requires zinc for catalysis. Taken together, our data define a role for ubiquitination during bacterial colonization of disease vectors.
doi:10.1093/infdis/jit380
PMCID: PMC3814841  PMID: 23901084
ticks; Rickettsia; Ehrlichia; insecta; ubiquitin
13.  The Tick Salivary Protein Sialostatin L2 Inhibits Caspase-1-Mediated Inflammation during Anaplasma phagocytophilum Infection 
Infection and Immunity  2014;82(6):2553-2564.
Saliva from arthropod vectors facilitates blood feeding by altering host inflammation. Whether arthropod saliva counters inflammasome signaling, a protein scaffold that regulates the activity of caspase-1 and cleavage of interleukin-1β (IL-1β) and IL-18 into mature molecules, remains elusive. In this study, we provide evidence that a tick salivary protein, sialostatin L2, inhibits inflammasome formation during pathogen infection. We show that sialostatin L2 targets caspase-1 activity during host stimulation with the rickettsial agent Anaplasma phagocytophilum. A. phagocytophilum causes macrophage activation and hemophagocytic syndrome features. The effect of sialostatin L2 in macrophages was not due to direct caspase-1 enzymatic inhibition, and it did not rely on nuclear factor κB or cathepsin L signaling. Reactive oxygen species from NADPH oxidase and the Loop2 domain of sialostatin L2 were important for the regulatory process. Altogether, our data expand the knowledge of immunoregulatory pathways of tick salivary proteins and unveil an important finding in inflammasome biology.
doi:10.1128/IAI.01679-14
PMCID: PMC4019176  PMID: 24686067
14.  Enhanced local bioavailability of single or compound drugs delivery to the inner ear through application of PLGA nanoparticles via round window administration 
In this paper, the potential of poly(d,l-lactide-co-glycolide acid) (PLGA) nanoparticles (NPs) for carrying single or compound drugs traversing the round window membrane (RWM) was examined after the round window (RW) administration of different NPs to guinea pigs. First, coumarin-6 was incorporated into PLGA NPs as a fluorescent probe to investigate its ability to cross the RWM. Then, PLGA NPs with salvianolic acid B (Sal B), tanshinone IIA (TS IIA), and total panax notoginsenoside (PNS) including notoginsenoside R1 (R1), ginsenoside Rg1 (Rg1), and ginsenoside Rb1 (Rb1) were developed to evaluate whether NPs loaded with compound drugs would pass through the RWM and improve the local bioavailability of these agents. PLGA NPs loaded with single or compound drugs were prepared by the emulsification solvent evaporation method, and their particle size distribution, particle morphology, and encapsulation efficiency were characterized. In vitro release study showed sustained-release profiles of Sal B, TS IIA, and PNS from the NPs. The pharmacokinetic results showed that NPs applied to the RWM significantly improved drug distribution within the inner ear. The AUC0–t of coumarin-6 in the perilymph (PL) following RW administration of NPs was 4.7-fold higher than that of coumarin-6 solution, and the Cmax was 10.9-fold higher. Furthermore, the AUC0–t of R1, Rg1, and Rb1 were 4.0-, 3.1-, and 7.1-fold greater, respectively, after the application of NPs compared to the compound solution, and the Cmax were, respectively, 14.4-, 10.0-, and 16.7-fold higher. These findings suggest that PLGA NPs with unique properties at the nanoscale dimensions have a powerful ability to transport single or compound drugs into the PL through the RWM and remarkably enhance the local bioavailability of the encapsulated drugs in the inner ear. The use of PLGA NPs as nanoscale delivery vehicles to carry drugs across the RWM may be a promising strategy for the treatment of inner ear diseases.
doi:10.2147/IJN.S72555
PMCID: PMC4257110  PMID: 25489245
inner ear administration; nanoparticles; perilymph; local bioavailability; poly(d,l-lactide-co-glycolide acid)
15.  Primary urinary bladder adenosquamous carcinoma complicated with lower limb deep venous thromboses: a case report 
Primary urinary bladder adenosquamous carcinoma is extremely rare and only a few cases have been reported in English literatures. Its biological behavior remains unclear. Here we reported a 60-year-old male patient with lower limb deep venous thromboses associated with primary urinary bladder adenosquamous carcinoma. A color ultrasonography showed right stock total venous thrombosis and right great saphenous vein thrombosis of lower limb. Contrast-enhanced computed tomography (CT) scan confirmed a 3.17 × 3.33 × 3.84 cm enhancing mass within the urinary bladder along the right lateral and posterior wall. Histopathological examination revealed adenosquamous carcinoma of urinary bladder, with extensive infiltration of the muscle layer. To the best of our knowledge, this is the first report of primary urinary bladder adenosquamous carcinoma complicated with deep venous thromboses in lower limb.
PMCID: PMC4314037
Urinary bladder adenosquamous carcinoma; deep venous thromboses; hypercoagulability; hematuria
16.  Characterization of a novel orthoreovirus isolated from fruit bat, China 
BMC Microbiology  2014;14(1):293.
Background
In recent years novel human respiratory disease agents have been described for Southeast Asia and Australia. The causative pathogens were classified as pteropine orthoreoviruses with a strong phylogenetic relationship to orthoreoviruses of bat origin.
Results
In this report, we isolated a novel Melaka-like reovirus (named “Cangyuan virus”) from intestinal content samples of one fruit bat residing in China’s Yunnan province. Phylogenetic analysis of the whole Cangyuan virus genome sequences of segments L, M and S demonstrated the genetic diversity of the Cangyuan virus. In contrast to the L and M segments, the phylogenetic trees for the S segments of Cangyuan virus demonstrated a greater degree of heterogeneity.
Conclusions
Phylogenetic analysis indicated that the Cangyuan virus was a novel orthoreovirus and substantially different from currently known members of Pteropine orthoreovirus (PRV) species group.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-014-0293-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12866-014-0293-4
PMCID: PMC4264558  PMID: 25433675
Bat Orthoreovirus; Prevalence; Viral genome reassortment
17.  Morphological factors differentiating between early lung adenocarcinomas appearing as pure ground-glass nodules measuring ≤10 mm on thin-section computed tomography 
Cancer Imaging  2014;14(1):33.
Background
We aimed to compare the morphological features of pure ground-glass nodules (GGNs; diameter, ≤10 mm) on thin-section computed tomography (TSCT) with their histopathological results in order to identify TSCT features differentiating between atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA).
Methods
Between January and December 2013, 205 pure GGNs with a diameter ≤10 mm on TSCT were pathologically confirmed as AAH (40), AIS (95) or MIA (70) lesions. The patients’ age and sex were recorded. The morphological features were evaluated, and maximum diameter and mean CT value were measured for each nodule. F test, Pearson χ2 test, Fisher exact test and multinomial logistic regression analysis were used to identify factors differentiating between AAH, AIS and MIA. Receiver operating characteristic (ROC) curve analysis was performed for maximum diameter and mean CT value.
Results
F test, Pearson χ2 test and Fisher exact test revealed that maximum diameter (P <0.00001), mean CT value (P =0.005), type of interface (P =0.005) and presence of air bronchograms (P =0.02, n =44) significantly differed among the AAH, AIS and MIA groups. Multinomial logistic regression analysis showed that maximum diameter ≥6.5 mm, a well-defined and coarse interface indicated AIS or MIA rather than AAH; air bronchograms differentiated MIA from AAH; but these parameters did not differentiate between AIS and MIA. A mean CT value less than −520 HU indicated AAH or AIS rather than MIA, but did not differentiate between AAH and AIS.
Conclusions
In the case of pure GGNs measuring ≤10 mm, a maximum diameter ≥6.5 mm, a well-defined and coarse interface indicate AIS or MIA rather than AAH; an air bronchogram can differentiate MIA from AAH. A mean CT value less than −520 HU indicates AAH or AIS rather than MIA.
doi:10.1186/s40644-014-0033-x
PMCID: PMC4331838  PMID: 25608623
Ground glass nodule; Computed tomography; Small lung lesion; Adenocarcinoma; Atypical adenomatous hyperplasia; Adenocarcinoma in situ; Minimally invasive adenocarcinoma
18.  Restorative effect and mechanism of mecobalamin on sciatic nerve crush injury in mice 
Neural Regeneration Research  2014;9(22):1979-1984.
Mecobalamin, a form of vitamin B12 containing a central metal element (cobalt), is one of the most important mediators of nervous system function. In the clinic, it is often used to accelerate recovery of peripheral nerves, but its molecular mechanism remains unclear. In the present study, we performed sciatic nerve crush injury in mice, followed by daily intraperitoneal administration of mecobalamin (65 μg/kg or 130 μg/kg) or saline (negative control). Walking track analysis, histomorphological examination, and quantitative real-time PCR showed that mecobalamin significantly improved functional recovery of the sciatic nerve, thickened the myelin sheath in myelinated nerve fibers, and increased the cross-sectional area of target muscle cells. Furthermore, mecobalamin upregulated mRNA expression of growth associated protein 43 in nerve tissue ipsilateral to the injury, and of neurotrophic factors (nerve growth factor, brain-derived nerve growth factor and ciliary neurotrophic factor) in the L4–6 dorsal root ganglia. Our findings indicate that the molecular mechanism underlying the therapeutic effect of mecobalamin after sciatic nerve injury involves the upregulation of multiple neurotrophic factor genes.
doi:10.4103/1673-5374.145379
PMCID: PMC4283280  PMID: 25598780
nerve regeneration; peripheral nerve injury; mecobalamin; sciatic nerve; nerve repair; neurotrophic factor; neuroprotective effect; vitamin B12; molecular mechanism; gene expression; neural regeneration
19.  Bisdemethoxycurcumin attenuates gastric adenocarcinoma growth by inducing mitochondrial dysfunction 
Oncology Letters  2014;9(1):270-274.
Bisdemethoxycurcumin (BDMC) is a demethoxy derivative of curcumin. In this study, a human gastric adenocarcinoma xenograft model was generated in vivo using nude mice and BDMC was observed to suppress the growth and activity of tumors, in addition to improving the physical and mental capacity of the mice. An increased number of apoptotic cells, decreased ratio of B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein and increased caspase-3 expression was also observed following treatment with BDMC, indicating that BDMC may promote apoptosis in tumors via mitochondrial modulation. The growth of SGC 7901 gastric cancer cells was inhibited and arrested at G1 phase. Specific indicators of mitochondrial dysfunction, a reduction in adenosine triphosphate generation, the inner mitochondrial membrane potential, augmentation of reactive oxygen species production and cytochrome c were also detected in the mitochondria following treatment with BDMC. These results indicate that BDMC attenuates gastric adenocarcinoma growth by inducing mitochondrial dysfunction.
doi:10.3892/ol.2014.2685
PMCID: PMC4246618  PMID: 25435973
bisdemethoxycurcumin; gastric adenocarcinoma; tumor growth inhibition; apoptosis; mitochondria
20.  Cigarette Smoking Promotes Inflammation in Patients with COPD by Affecting the Polarization and Survival of Th/Tregs through Up-Regulation of Muscarinic Receptor 3 and 5 Expression 
PLoS ONE  2014;9(11):e112350.
Background
CD4+ T cells in the lung are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD), although CD4+ T cell subsets and the direct effect of smoking on these cells, especially the expression of MRs, have not been comprehensively examined.
Methods
First, circulating CD4+ T cell subsets in healthy nonsmokers, patients with SCOPD and patients with AECOPD were evaluated by flow cytometry. Then, differentiation experiments were carried out using RT-PCR, and Ki-67/Annexin V antibodies were used to measure proliferation and apoptosis. We also explored the impact of CSE on the differentiation and survival of CD4+Th/Tregs and examined the expression of MRs in healthy nonsmokers and patients with SCOPD.
Results
We found the percentages of circulating Th1 and Th17 cells were increased in patients with AECOPD, while the percentage of Th2 cells was decreased in patients with SCOPD. The percentages of Th10 cells were decreased in both patients with SCOPD and patients with AECOPD, while the percentages of Tregs were increased. In addition, the percentages of CD4+α-7+ T cells were decreased in patients with SCOPD and patients with AECOPD. However, only the decrease observed in patients with AECOPD was significant. In vitro studies also revealed MR expression affected the polarization of T cells, with different CD4+ T cell subtypes acquiring different MR expression profiles. The addition of CSE facilitated CD4+ T cell polarization towards pro-inflammatory subsets (Th1 and Th17) and affected the survival of CD4+ T cells and Treg cells by up-regulating the expression of MR3 and 5, resulting in an imbalance of CD4+ T cell subsets.
Conclusions
Our findings suggest an imbalance of circulating CD4+ T cell subsets is involved in COPD pathogenesis in smokers. Cigarette smoking may contribute to this imbalance by affecting the polarization and survival of Th/Tregs through the up-regulation of MR3 and MR5.
doi:10.1371/journal.pone.0112350
PMCID: PMC4223024  PMID: 25375131
21.  Alloisoleucine differentiates the branched-chain aminoacidemia of obese Zucker and diet-induced obesity (DIO) rats 
Obesity (Silver Spring, Md.)  2014;22(5):1212-1215.
Objective
Circulating branched-chain amino acids (BCAAs) are elevated in obesity and this has been linked to obesity comorbidities. However it is unclear how obesity affects alloisoleucine, a BCAA and pathognomonic marker of branched-chain keto acid dehydrogenase complex (BCKDC) disorders. It has been previously established that obese Zucker rats exhibit BCKDC impairments in fat and other tissues, whereas BCKDC impairments in adipose tissue of DIO rats are compensated by increased hepatic BCKDC activity. Therefore, alloisoleucine was investigated in these two obesity models.
Design and Methods
Amino acids were extracted from plasma and measured using ultra performance liquid chromatography mass spectrometry (UPLC-MS).
Results
Plasma alloisoleucine was 238% higher in obese compared to lean Zucker rats. This elevation was greater than that of other BCAAs (107–124%). DIO rats had no significant change in alloisoleucine, despite elevations in other BCAAs (15–66%).
Conclusions
Alloisoleucine was elevated in obese Zucker but not DIO rats consistent with known global impairments of BCKDC in Zucker but not DIO rats. Cytotoxic branched-chain ketoacids (BCKAs) accumulate in genetic disorders affecting BCKDC. BCKAs increase reactive oxygen species, stress kinase activation and mitochondrial dysfunction. Inasmuch as these factors underlie obesity comorbidities, it may important to identify obese individuals with elevated alloisoleucine.
doi:10.1002/oby.20691
PMCID: PMC4008669  PMID: 24415721
branched-chain amino acids; isoleucine; branched-chain amino acid transaminase; maple syrup urine disease; alloisoleucine
22.  Treg/IL-17 Ratio and Treg Differentiation in Patients with COPD 
PLoS ONE  2014;9(10):e111044.
Background
Chronic obstructive pulmonary disease (COPD) is characterized by chronic pulmonary and systematic inflammation. An abnormal adaptive immune response leads to an imbalance between pro- and anti-inflammatory processes. T-helper (Th), T-cytotoxic (Tc) and T-regulatory (Treg) cells may play important roles in immune and inflammatory responses. This study was conducted to clarify the changes and imbalance of cytokines and T lymphocyte subsets in patients with COPD, especially during acute exacerbations (AECOPD).
Methods
Twenty-three patients with stable COPD (SCOPD) and 21 patients with AECOPD were enrolled in the present study. In addition, 20 age-, sex- and weight-matched non-smoking healthy volunteers were included as controls. The serum levels of selected cytokines (TGF-β, IL-10, TNF-α, IL-17 and IL-9) were measured by enzyme-linked immunosorbent assay (ELISA) kits. Furthermore, the T lymphocyte subsets collected from peripheral blood samples were evaluated by flow cytometry after staining with anti-CD3-APC, anti-CD4-PerCP, anti-CD8- PerCP, anti-CD25-FITC and anti-FoxP3-PE monoclonal antibodies. Importantly, to remove the confounding effects of inflammatory factors, the authors introduced a concept of “inflammation adjustment” and corrected each measured value using representative inflammatory markers, such as TNF-α and IL-17.
Results
Unlike the other cytokines, serum TGF-β levels were considerably higher in patients with AECOPD relative to the control group regardless of adjustment. There were no significant differences in the percentages of either CD4+ or CD8+ T cells among the three groups. Although Tregs were relatively upregulated during acute exacerbations, their capacities of generation and differentiation were far from sufficient. Finally, the authors noted that the ratios of Treg/IL-17 were similar among groups.
Conclusions
These observations suggest that in patients with COPD, especially during acute exacerbations, both pro-inflammatory and anti-inflammatory reactions are strengthened, with the pro-inflammatory reactions dominating. Although the Treg/IL-17 ratios were normal, the regulatory T cells were still insufficient to suppress the accompanying increases in inflammation. All of these changes suggest a complicated mechanism of pro- and anti-inflammatory imbalance which needs to be further investigated.
doi:10.1371/journal.pone.0111044
PMCID: PMC4199736  PMID: 25329073
23.  Expression of IRAK1 in lung cancer tissues and its clinicopathological significance: a microarray study 
The interleukin-1 receptor associated kinases 1 (IRAK1) is a down stream effector molecule of the toll like receptor (TLR) signaling pathway, which is involved in inflammation, autoimmunity and cancer. However, the role of IRAK1 in lung cancer remains unclarified. Herein, we investigated the protein expression and the clinicopathological significance of IRAK1 in 3 formalin-fixed paraffin-embedded lung cancer tissue microarrays by using immunohistochemistry, which included 365 tumor and 30 normal lung tissues. We found that the expression of IRAK1 in lung cancer was significantly higher compared with that in normal lung tissues (P=0.002). Receiver operating characteristic (ROC) curves were generated to evaluate the power of IRAK1 to distinguish lung cancer from non-cancerous lung tissue. The area under curve (AUC) of ROC of IRAK1 was 0.643 (95% CI 0.550~0.735, P=0.009). Additionally, IRAK1 expression was related to clinical TNM stage (r=0.241, P < 0.001), lymph node metastasis (r=0.279, P < 0.001) and tumor size (r=0.299, P < 0.001) in lung cancer. In the subgroup of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the positive rates of IRAK1 were both higher than that in the normal lung tissues (P=0.003, P=0.002, respectively). Further spearman analysis showed that IRAK1 protein in NSCLC was positive correlated with clinical TNM stage (r=0.222, P < 0.001), lymph node metastasis (r=0.277, P < 0.001), tumor size (r=0.292, P < 0.001) and distal metastasis (r=0.110, P=0.043). In conclusion, the expression of IRAK1 protein might be valuable in identifying patients with increased risks of lung cancer and might act as a target for diagnosis and gene therapy for lung cancer.
PMCID: PMC4270603  PMID: 25550857
Lung cancer; IRAK1; immunohistochemistry; tissue microarray
24.  Response to learned threat: an fMRI study in adolescent and adult anxiety 
The American journal of psychiatry  2013;170(10):1195-1204.
Objective
Poor threat-safety discrimination reflects prefrontal cortex dysfunction in adult anxiety disorders. While adolescent anxiety disorders are impairing and predict high risk for adult anxiety disorders, no prior study examines neural correlates of threat-safety discrimination in this group. The current study compares prefrontal cortex function in anxious and healthy adolescents and adults following conditioning and extinction, processes requiring threat-safety learning.
Method
Anxious and healthy adolescents and adults (n=114) completed fear conditioning and extinction in the clinic. Conditioned stimuli (CS+) were neutral faces, paired with an aversive scream. Physiological and subjective data were acquired. Several weeks later, 82 participants viewed the CS+ and morphed images resembling the CS+ in a magnetic resonance imaging (MRI) scanner. During scanning, participants made difficult threat-safety discriminations while appraising threat and explicit memory of the CS+.
Results
During conditioning and extinction, anxious groups reported more fear than healthy groups, but patient groups did not differ on physiology. During imaging, both anxious adolescents and adults exhibited lower sub-genual anterior cingulate (sgACC) activation than healthy peers, specifically when appraising threat. In ventromedial prefrontal cortex (vmPFC), relative to their age-matched peer groups, anxious adults exhibited reduced activation when appraising threat, whereas anxious adolescents exhibited a U-shaped pattern of activation, with greater activation to the most extreme CS and CS−.
Conclusions
Two regions of the prefrontal cortex are involved in anxiety disorders. Reduced sgACC engagement is a shared feature in adult and adolescent anxiety disorders, but vmPFC dysfunction is age-specific. The unique U-shaped pattern of vmPFC activation in many anxious adolescents could reflect heightened sensitivity to threat and safety conditions. How variations in the pattern relate to later risk for adult illness remains to be determined.
doi:10.1176/appi.ajp.2013.12050651
PMCID: PMC3790858  PMID: 23929092
25.  Overexpression of MMP-7 Increases Collagen 1A2 in the Aging Kidney 
Physiological reports  2013;1(5):e00090.
The percentage of the U.S. population over 65 is rapidly increasing, as is the incidence of chronic kidney disease (CKD). The kidney is susceptible to age-dependent alterations in structure, specifically tubulointerstitial fibrosis, that lead to CKD. Matrix metalloproteinases (MMPs) were initially characterized as extracellular matrix (ECM) proteinases; however it is clear that their biological role is much larger. We have observed increased gene expression of several MMPs in the aging kidney, including MMP-7. MMP-7 overexpression was observed starting at 16 months, and over a 500 fold up-regulation in 2 year-old animals. Overexpression of MMP-7 is not observed in age-matched, calorically restricted controls that do not develop fibrosis and renal dysfunction, suggesting a role in the pathogenesis. In order to delineate the contributions of MMP-7 to renal dysfunction, we overexpressed MMP-7 in NRK-52E cells. High-throughput sequencing of the cells revealed that two collagen genes, Col1a2 and Col3a1, were elevated in the MMP-7 overexpressing cells. These two collagen genes were also elevated in aging rat kidneys and temporally correlated with increased MMP-7 expression. Addition of exogenous MMP-7, or conditioned media from MMP-7 overexpressing cells also increased Col1A2 expression. Inhibition of PKA, src, and MAPK signaling at p38 and ERK was able to attenuate the MMP-7 up-regulation of Col1a2. Consistent with this finding, increased phosphorylation of PKA, src and ERK was seen in MMP-7 overexpressing cells and upon exogenous MMP-7 treatment of NRK-52E cells. These data suggest a novel mechanism by which MMP-7 contributes to the development of fibrosis leading to CKD.
doi:10.1002/phy2.90
PMCID: PMC3834982  PMID: 24273653
Aging; Collagen; Fibrosis; MMP-7

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