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1.  Mechanisms of Gefitinib-mediated reversal of tamoxifen resistance in MCF-7 breast cancer cells by inducing ERα re-expression 
Scientific Reports  2015;5:7835.
Estrogen receptor (ER)-positive breast cancer patients may turn ER-negative and develop acquired drug resistance, which compromises the efficacy of endocrine therapy. By investigating the phenomenon that gefitinib can re-sensitise tamoxifen (TAM)-resistant MCF-7 breast cancer cells (MCF-7/TAM) to TAM, the present study verified that gefitinib could reverse the acquired drug resistance in endocrine therapy and further explored the underlying mechanism.ERα-negative MCF-7/TAM cells were established. Upon treating the cells with gefitinib, the mRNA and protein levels of ERα and ERβ, as well as the expression of molecules involved in the MAPK pathway, were examined using the RT-PCR and immunocytochemistry. The RT-PCR results showed that the mRNA levels of ERα and ERβ in MCF-7/TAM cells were up-regulated following gefitinib treatment; specifically, ERα was re-expressed, and ERβ expression was up-regulated. The expression of molecules involved in the MAPK pathway, including RAS, MEK1/2, and p-ERK1/2, in MCF-7/TAM cells was significantly up-regulated, compared with MCF-7 cells. After the gefitinib treatment, the expression levels of MEK1/2 and p-ERK1/2 were significantly down-regulated. ERα loss is the primary cause for TAM resistance. Gefitinib reverses TAM resistance primarily by up-regulating the ERα mRNA level and inducing the re-expression of ERα. The MAPK pathway plays a key role in ERα re-expression.
PMCID: PMC4314651  PMID: 25644501
2.  Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains 
Acta neuropathologica  2014;129(2):221-237.
Filamentous tau pathologies are hallmark lesions of several neurodegenerative tauopathies including Alzheimer’s disease (AD) and corticobasal degeneration (CBD) which show cell type-specific and topographically distinct tau inclusions. Growing evidence supports templated transmission of tauopathies through functionally interconnected neuroanatomical pathways suggesting that different self-propagating strains of pathological tau could account for the diverse manifestations of neurodegenerative tauopathies. Here, we describe the rapid and distinct cell type-specific spread of pathological tau following intracerebral injections of CBD or AD brain extracts enriched in pathological tau (designated CBD-Tau and AD-Tau, respectively) in young human mutant P301S tau transgenic (Tg) mice (line PS19) ~6–9 months before they show onset of mutant tau transgene-induced tau pathology. At 1 month post-injection of CBD-Tau, tau inclusions developed predominantly in oligodendrocytes of the fimbria and white matter near the injection sites with infrequent intraneuronal tau aggregates. In contrast, injections of AD-Tau in young PS19 mice induced tau pathology predominantly in neuronal perikarya with little or no oligodendrocyte involvement 1 month post-injection. With longer post-injection survival intervals of up to 6 months, CBD-Tau- and AD-Tau-induced tau pathology spread to different brain regions distant from the injection sites while maintaining the cell type-specific pattern noted above. Finally, CA3 neuron loss was detected 3 months post-injection of AD-Tau but not CBD-Tau. Thus, AD-Tau and CBD-Tau represent specific pathological tau strains that spread differentially and may underlie distinct clinical and pathological features of these two tauopathies. Hence, these strains could become targets to develop disease-modifying therapies for CBD and AD.
PMCID: PMC4305460  PMID: 25534024
Alzheimer’s disease; Corticobasal degeneration; Seeded transmission of pathological tau; Frontotemporal degeneration
3.  Distributional Variations in Trabecular Architecture of the Mandibular Bone: An In Vivo Micro-CT Analysis in Rats 
PLoS ONE  2015;10(1):e0116194.
To evaluate the effect of trabecular thickness and trabecular separation on modulating the trabecular architecture of the mandibular bone in ovariectomized rats.
Materials and Methods
Fourteen 12-week-old adult female Wistar rats were divided into an ovariectomy group (OVX) and a sham-ovariectomy group (sham). Five months after the surgery, the mandibles from 14 rats (seven OVX and seven sham) were analyzed by micro-CT. Images of inter-radicular alveolar bone of the mandibular first molars underwent three-dimensional reconstruction and were analyzed.
Compared to the sham group, trabecular thickness in OVX alveolar bone decreased by 27% (P = 0.012), but trabecular separation in OVX alveolar bone increased by 59% (P = 0.005). A thickness and separation map showed that trabeculae of less than 100μm increased by 46%, whereas trabeculae of more than 200μm decreased by more than 40% in the OVX group compared to those in the sham group. Furthermore, the OVX separation of those trabecular of more than 200μm was 65% higher compared to the sham group. Bone mineral density (P = 0.028) and bone volume fraction (p = 0.001) were also significantly decreased in the OVX group compared to the sham group.
Ovariectomy-induced bone loss in mandibular bone may be related to the distributional variations in trabecular thickness and separation which profoundly impact the modulation of the trabecular architecture.
PMCID: PMC4307973  PMID: 25625431
4.  Increased gene copy number of the vesicle SNARE VAMP7 disrupts human male urogenital development through altered estrogen action 
Nature medicine  2014;20(7):715-724.
Vesicle transport is intimately connected with key nuclear functions and transcriptional regulation. Here, children born with congenital genitourinary tract masculinization disorders were analyzed by array-Comparative Genomic Hybridization, which revealed the presence of de novo copy number gains on Xq28 encompassing the VAMP7 gene encoding a vesicle-trafficking protein. Humanized VAMP7 BAC transgenic mice displayed cryptorchidism, urethral defects, and hypospadias. Mutant mice exhibited reduced penile length, focal spermatogenic anomalies, diminished sperm motility, and subfertility. VAMP7 colocalized with estrogen receptor alpha (ESR1) in the presence of ligand. Elevated levels of VAMP7 markedly intensified ESR1 transcriptional activity by increasing ESR1 protein cellular content upon ligand stimulation and up-regulated the expression of estrogen-responsive genes including ATF3, CYR61, and CTGF, all of which are implicated in human hypospadias. Hence, increased gene dosage of the SNARE protein, VAMP7, enhances estrogen receptor action in male genitourinary tissues, affects the virilization of the reproductive tract, and results in genitourinary birth defects in humans.
PMCID: PMC4283218  PMID: 24880616
5.  Cruciferous vegetables, glutathione S-transferase polymorphisms and the risk of colorectal cancer among Chinese men 
Annals of epidemiology  2013;24(1):10.1016/j.annepidem.2013.10.003.
To assess the associations between cruciferous vegetable (CV) intake, GST gene polymorphisms and colorectal cancer (CRC) in a population of Chinese men.
Using incidence density sampling, CRC cases (N = 340) diagnosed prior to December 31, 2010 within the Shanghai Men’s Health Study were matched to non-cases (N = 673). CV intake was assessed from a food frequency questionnaire and by isothiocyanate (ITC) levels from spot urine samples. GSTM1 and GSTT1 were categorized as null (0 copies) versus non-null (1 or 2 copies). Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between CV intake and GST gene variants with CRC and statistical interactions were evaluated.
CRC risk was not associated with CV intake, whether measured by self-report or by urinary ITC, nor with GST gene variants. No statistical interactions were detected between CV intake and GST gene variants on the odds of CRC. Stratifying by timing of urine sample collection and excluding CRC cases diagnosed in the first two years did not materially alter the results.
This study provides no evidence supporting the involvement of CV intake in the development of CRC in Chinese men.
PMCID: PMC3864981  PMID: 24238877
brassicaceae; China; colorectal neoplasms; glutathione S-transferase M1; glutathione S-transferase T1; men
6.  Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging: A potential utility for the evaluation of regional liver function impairment following transcatheter arterial chemoembolization 
Oncology Letters  2014;9(3):1191-1196.
The present study aimed to evaluate regional liver function impairment following transcatheter arterial chemoembolization (TACE), assessed by magnetic resonance imaging (MRI) enhanced by gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA). Additionally, this study evaluated the associations between signal intensity and various clinical factors. A prospective study was conducted between March 2012 and May 2013 with a total of 35 patients. Gd-EOB-DTPA-enhanced MRI was performed 3–5 days after TACE therapy. The signal to noise ratio (SNR) was subsequently calculated for healthy liver tissue regions and peritumoral regions, prior to and 20 min after Gd-EOB-DTPA administration. The correlation between clinical factors and relative SNR was assessed using Pearson’s correlation coefficient or Spearman’s rank correlation coefficient. Prior to Gd-EOB-DTPA administration, the SNR values showed no significant difference (t=1.341, P=0.191) in healthy liver tissue regions (50.53±15.99; range, 11.25–83.46) compared with peritumoral regions (49.81±15.85; range, 12.34–81.53). On measuring at 20 min following Gd-EOB-DTPA administration, the SNR in healthy liver tissue regions (82.55±33.33; range, 31.45–153.02) was significantly higher (t=3.732, P<0.001) compared with that in peritumoral regions (75.77±27.41; range, 31.42–144.49). The relative SNR in peritumoral regions correlated only with the quantity of iodized oil used during TACE therapy (r=0.528, P=0.003); the age, gender, diameter and blood supply of the tumor, or Child-Pugh class of the patient did not correlate with relative SNR. Gd-EOB-DTPA-enhanced MRI may be an effective way to evaluate regional liver function impairment following TACE therapy.
PMCID: PMC4315072  PMID: 25663880
magnetic resonance imaging; regional liver function; gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid; transcatheter arterial chemoembolization
7.  Function of a novel plakophilin-2 mutation in the abnormal expression of connexin43 in a patient with arrhythmogenic right ventricular cardiomyopathy 
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a desmosomal disease. Desmosomes and gap junctions are important structural components of cardiac intercalated discs. The proteins plakophilin-2 (PKP-2) and connexin43 (Cx43) are components of desmosomes and gap junctions, respectively. This study was conducted to determine whether Cx43 expression is affected by the mutation of the PKP-2 gene in patients with ARVC. A novel mutation was detected in a typical patient with ARVC. The mutated gene was transfected into rat mesenchymal stem cells expressing Cx43 through a pReversied-M-29 plasmid. Cx43 expression was detected using quantitative polymerase chain reaction analysis. Cx43 expression was significantly decreased in the mutant PKP-2 group compared with that in the wild-type PKP-2 group. In conclusion, PKP-2 affected Cx43 expression at the gene transcription level in the patient with ARVC.
PMCID: PMC4316957  PMID: 25667661
arrhythmogenic right ventricular cardiomyopathy; desmosome; connexin43; gap junction; plakophilin-2 gene
8.  Antiangiogenic and Antineuroinflammatory Effects of Kallistatin Through Interactions With the Canonical Wnt Pathway 
Diabetes  2013;62(12):4228-4238.
Kallistatin is a member of the serine proteinase inhibitor superfamily. Kallistatin levels have been shown to be decreased in the vitreous while increased in the circulation of patients with diabetic retinopathy (DR). Overactivation of the Wnt pathway is known to play pathogenic roles in DR. To investigate the role of kallistatin in DR and in Wnt pathway activation, we generated kallistatin transgenic (kallistatin-TG) mice overexpressing kallistatin in multiple tissues including the retina. In the oxygen-induced retinopathy (OIR) model, kallistatin overexpression attenuated ischemia-induced retinal neovascularization. In diabetic kallistatin-TG mice, kallistatin overexpression ameliorated retinal vascular leakage, leukostasis, and overexpression of vascular endothelial growth factor and intracellular adhesion molecule. Furthermore, kallistatin overexpression also suppressed Wnt pathway activation in the retinas of the OIR and diabetic models. In diabetic Wnt reporter (BAT-gal) mice, kallistatin overexpression suppressed retinal Wnt reporter activity. In cultured retinal cells, kallistatin blocked Wnt pathway activation induced by high glucose and by Wnt ligand. Coprecipitation and ligand-binding assays both showed that kallistatin binds to a Wnt coreceptor LRP6 with high affinity (Kd = 4.5 nmol/L). These observations suggest that kallistatin is an endogenous antagonist of LRP6 and inhibitor of Wnt signaling. The blockade of Wnt signaling may represent a mechanism for its antiangiogenic and antineuroinflammatory effects.
PMCID: PMC3837048  PMID: 23884893
9.  Elevated Circulation Levels of an Anti-angiogenic SERPIN in Patients with Diabetic Microvascular Complications Impairs Wound Healing through Suppression of Wnt Signaling 
Wound healing, angiogenesis and hair follicle maintenance are often impaired in the skin of diabetic patients, but the pathogenesis has not been well understood. Here, we report that circulation levels of kallistatin, a member of the serine proteinase inhibitor (SERPIN) superfamily with anti-angiogenic activities, were elevated in Type 2 diabetic patients with diabetic vascular complications. To test the hypothesis that elevated kallistatin levels could contribute to a wound healing deficiency via inhibition of Wnt/β-catenin signaling, we generated kallistatin-transgenic (KS-TG) mice. KS-TG mice had reduced cutaneous hair follicle density, microvascular density, and panniculus adiposus layer thickness as well as altered skin microvascular hemodynamics and delayed cutaneous wound healing. Using Wnt reporter mice, our results showed that Wnt/β-catenin signaling is suppressed in dermal endothelium and hair follicles in KS-TG mice. Lithium, a known activator of β-catenin via inhibition of glycogen synthase kinase-3β, reversed the inhibition of Wnt/β-catenin signaling by kallistatin and rescued the wound healing deficiency in KS-TG mice. These observations suggest that elevated circulating anti-angiogenic serpins in diabetic patients may contribute to impaired wound healing through inhibition of Wnt/β-catenin signaling. Activation of Wnt/β-catenin signaling, at a level downstream of Wnt receptors, may ameliorate the wound healing deficiency in diabetic patients.
PMCID: PMC4065799  PMID: 24463424
10.  Association of various risk factors with prognosis and hospitalization cost in Chinese patients with acute myocardial infarction: A clinical analysis of 627 cases 
Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality in the developed world and is becoming increasingly more common in developing countries. The risk factors affecting the prognosis of Chinese patients may differ from those in other populations. This study was conducted to investigate the potential risk factors that may correlate with prognosis and hospitalization costs of Chinese AMI patients. A total of 627 hospitalized AMI patients were recruited and their general information and relevant laboratory parameters were collected. Accordingly, the patients were grouped into different subgroups and potential risk factors and their correlations with prognosis and hospitalization costs were analyzed. Age, high blood pressure, infarct location and percutaneous coronary intervention (PCI) were the variables significantly associated with the differences in the prognosis of AMI patients (P<0.05), whereas times and duration of hospitalization, high blood pressure, infarct location and PCI treatment were found to be significantly associated with the cost of hospitalization (P<0.05). However, the AMI patients enrolled in this study may not be representative of all AMI patients in China. In addition, the prognosis of these patients was limited to their hospital stay. Therefore, long-term follow-up requires careful assessment.
PMCID: PMC4280932  PMID: 25574242
acute myocardial infarction; prognosis; hospitalization cost; risk factors; Chinese population
11.  Molecular Characterization and Expression Analysis of Triticum aestivum Squamosa-Promoter Binding Protein-Box Genes Involved in Ear Development 
Wheat (Triticum aestivum L.) is one of the most important crops in the world. Squamosa-promoter binding protein (SBP)-box genes play a critical role in regulating flower and fruit development. In this study, 10 novel SBP-box genes (TaSPL genes) were isolated from wheat ((Triticum aestivum L.) cultivar Yanzhan 4110). Phylogenetic analysis classified the TaSPL genes into five groups (G1–G5). The motif combinations and expression patterns of the TaSPL genes varied among the five groups with each having own distinctive characteristics: TaSPL20/21 in G1 and TaSPL17 in G2 mainly expressed in the shoot apical meristem and the young ear, and their expression levels responded to development of the ear; TaSPL6/15 belonging to G3 were upregulated and TaSPL1/23 in G4 were downregulated during grain development; the gene in G5 (TaSPL3) expressed constitutively. Thus, the consistency of the phylogenetic analysis, motif compositions, and expression patterns of the TaSPL genes revealed specific gene structures and functions. On the other hand, the diverse gene structures and different expression patterns suggested that wheat SBP-box genes have a wide range of functions. The results also suggest a potential role for wheat SBP-box genes in ear development. This study provides a significant beginning of functional analysis of SBP-box genes in wheat.
PMCID: PMC4239008  PMID: 24386921
Expression profile; grain yield; squamosa-promoter binding protein-box genes; Triticum aestivum
Cell host & microbe  2013;14(5):522-534.
Arenaviruses and hantaviruses cause severe and often fatal diseases in humans. Little is known regarding host proteins required for their propagation. We identified human proteins that interact with the glycoproteins (GPs) of a prototypic arenavirus and hantavirus and show that the lectin ERGIC-53 - a cargo receptor required for cellular glycoprotein trafficking within the early exocytic pathway - associates with arenavirus, hantavirus, coronavirus, orthomyxovirus, and filovirus GPs. ERGIC-53 binds to arenavirus GPs through a lectin-independent mechanism, traffics to arenavirus budding sites, and is incorporated into arenavirus particles. ERGIC-53 is required for arenavirus, coronavirus, and filovirus propagation; in its absence, GP-containing virus particles form, but are noninfectious due, in part, to their inability to attach to host cells. Thus, we have identified a class of pathogen-derived ERGIC-53 ligands, a lectin-independent basis for their association with ERGIC-53, and a role for ERGIC-53 in the propagation of several highly pathogenic RNA virus families.
PMCID: PMC3999090  PMID: 24237698
13.  TgMAPK1 is a Toxoplasma gondii MAP kinase that hijacks host MKK3 signals to regulate virulence and interferon-γ-mediated nitric oxide production 
Experimental parasitology  2013;134(3):389-399.
The parasite Toxoplasma gondii controls tissue-specific nitric oxide (NO), thereby augmenting virulence and immunopathology through poorly-understood mechanisms. We now identify TgMAPK1, a Toxoplasma mitogen-activated protein kinase (MAPK), as a virulence factor regulating tissue-specific parasite burden by manipulating host interferon (IFN)-γ-mediated inducible nitric oxide synthase (iNOS). Toxoplasma with reduced TgMAPK1 expression (TgMAPK1lo) demonstrated that TgMAPK1 facilitates IFN-γ-driven p38 MAPK activation, reducing IFN-γ-generated NO in an MKK3-dependent manner, blunting IFN-γ-mediated parasite control. TgMAPK1lo infection in wild type mice produced ≥ten-fold lower parasite burden versus control parasites with normal TgMAPK1 expression (TgMAPK1con). Reduced parasite burdens persisted in IFN-γ KO mice, but equalized in normally iNOS-replete organs from iNOS KO mice. Parasite MAPKs are far less studied than other parasite kinases, but deserve additional attention as targets for immunotherapy and drug discovery.
PMCID: PMC4226171  PMID: 23541881
iNOS; MAPK; Toxoplasma gondii; virulence
14.  Structural Controllability of Complex Networks Based on Preferential Matching 
PLoS ONE  2014;9(11):e112039.
Minimum driver node sets (MDSs) play an important role in studying the structural controllability of complex networks. Recent research has shown that MDSs tend to avoid high-degree nodes. However, this observation is based on the analysis of a small number of MDSs, because enumerating all of the MDSs of a network is a #P problem. Therefore, past research has not been sufficient to arrive at a convincing conclusion. In this paper, first, we propose a preferential matching algorithm to find MDSs that have a specific degree property. Then, we show that the MDSs obtained by preferential matching can be composed of high- and medium-degree nodes. Moreover, the experimental results also show that the average degree of the MDSs of some networks tends to be greater than that of the overall network, even when the MDSs are obtained using previous research method. Further analysis shows that whether the driver nodes tend to be high-degree nodes or not is closely related to the edge direction of the network.
PMCID: PMC4222963  PMID: 25375628
15.  Fruit and vegetable intake and the risk of colorectal cancer: Results from the Shanghai Men's Health Study 
Cancer causes & control : CCC  2013;24(11):1935-1945.
The observed associations of fruit and vegetable consumption with the risk of colorectal cancer have been inconsistent. Therefore, we aimed to evaluate the association of fruit and vegetable consumption with the risk of colorectal cancer within Chinese men.
61,274 male participants aged 40 to 74 years were included. A validated food frequency questionnaire was administered to collect information on usual dietary intake, including 8 fruits and 38 vegetables commonly consumed by residents of Shanghai. Follow-up for diagnoses of colon or rectal cancer were available through December 31, 2010. Dietary intakes were analyzed both as categorical (quintiles) and continuous variables. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated for colorectal, colon, and rectal cancer using Cox proportional hazards models.
After 390,688 person-years of follow-up, 398 cases of colorectal cancer (236 colon and 162 rectal) were observed in the cohort. Fruit consumption was inversely associated with the risk of colorectal cancer (5th vs. 1st quintile HR: 0.67; 95% CI: 0.48, 0.95; P trend = 0.03), whereas vegetable intake was not significantly associated with risk. The associations for sub-groups of fruits and legumes, but not other vegetable categories, were generally inversely associated with the risk of colon and rectal cancer.
Fruit intake was generally inversely associated with the risk of colorectal cancer while vegetable consumption was largely unrelated to risk among middle aged and older Chinese men.
PMCID: PMC3805771  PMID: 23913012
Colorectal cancer; fruits; vegetables; cohort study; Chinese men
16.  Requirement of NK cells for selective A2A receptor blockade to suppress CD73+ tumor metastasis 
Immunotherapy  2014;6(1):19-21.
CD73 is becoming an emerging therapeutic target for the prevention of tumor growth and metastasis. However, the mechanism by which CD73 promotes tumor metastasis is unclear. Beavis et al. evaluated the efficacy of A2A and A2B adenosine receptor antagonists in inhibiting the metastasis of tumors expressing CD73, either endogenously or ectopically. They demonstrate distinct mechanisms whereby A2A versus A2B adenosine receptors could contribute to CD73+ tumor metastasis. As A2Areceptor (R)/A2BR antagonists have been tested in clinical trials in other disease settings, this study highlights the potential therapeutic application of an A2AR/A2BR blockade strategy for treatment of CD73+ metastatic tumors.
PMCID: PMC3968679  PMID: 24341879
adenosine receptor; CD73; ecto-5′-nucleotidase; metastasis; NK cell
17.  A single institution experience using the LigaSure vessel sealing system in video-assisted thoracoscopic surgery for primary spontaneous pneumothorax 
Journal of Biomedical Research  2014;28(6):494-497.
This study sought to report our 6-year experience with the LigaSure vessel sealing system (LVSS) in video-assisted thoracoscopic surgery (VATS) for primary spontaneous pneumothorax. A series of 180 consecutive patients with primary spontaneous pneumothorax were operated on in our institution from May 2005 to December 2010. Intraoperatively, large lesions (bullae or blebs) with a diameter more than 2 cm were resected by staplers, and the residual lesions were treated by LVSS. LVSS was also used to ablate the apical area when no lesions were found. Conventional apical pleural abrasion was done in all cases. All patients were successfully treated using VATS with minimal perioperative bleeding. The mean operating time was 76 minutes (range, 43–160 minutes) for single-side procedures and 169 minutes (range, 135–195 minutes) for bilateral procedures, the mean number of applied staples was 1.93 per patient (range, 0–8 days), the duration of drainage was 3.8 days (range, 2–15 days), and the duration of hospital stay was 5.8 days (range, 3–16 days). Postoperative complications included persistent air leak (> 5 days) in 11 cases (6.1%) and residual pneumothorax in 6 (3.3%). None required reoperation. The mean duration of follow-up was 57 months (range, 24–105 months). Recurrence was seen in three cases (1.7%), and all underwent another operation thereafter. None of the lesions in the relapse cases received ablation with LVSS in the first operation. LVSS can optimize VATS for primary spontaneous pneumothorax and reduces the use of single-use staples. The method is safe, easy to use, and cost-effective and produces satisfactory results.
PMCID: PMC4250528  PMID: 25469119
LigaSure vessel sealing system; video-assisted thoracoscopic surgery (VATS); primary spontaneous pneumothorax
18.  Get Ready to Wnt: Prepatterning in Neuromuscular Junction Formation 
Developmental cell  2009;16(3):325-327.
Clustering of acetylcholine receptors (AChR) in muscle fibers prior to innervation by motor neurons is thought to be involved in neuromuscular junction formation. Jing et al. now report in Neuron that this prepatterning of AChRs, via a novel MuSK-dependent Wnt pathway, may guide motor axons to the central region of muscle fibers for synapse formation in zebrafish.
PMCID: PMC4214859  PMID: 19289078
19.  Evaluation of 18F-fluorodeoxyglucose uptake in enlarged mediastinal lymph nodes in patients with lung cancer 
Accurate lymph nodal staging of lung cancer is critical for determining the treatment options. With the help of 18F-fluorodeoxyglucose positron emission tomography/computer tomography (18F-FDG-PET/CT), the clinician can rule out/in the regional lymph nodes positive for metastasis in the patients with lung cancer in a majority of cases. However, a small proportion of cases with false positivity of metastasis have been reported. Transbronchial needle aspirations and mediastinoscopic biopsies are still necessary to determine whether enlarged hypermetabolic mediastinal lymph nodes are positive for lung cancer metastasis. Here we report three intricate cases showing hypermetabolic activity in the mediastinal lymph nodes in the patients with pathologically diagnosed lung cancer on PET/CT. The first patient had squamous cell carcinoma in the left upper lobe of the lung with surrounding necrotizing granulomas and concurrent with silicosis and granulomatous inflammation in the lymph nodes; the second presented with symptoms of viral pneumonia, which was pathologically diagnosed as a lung adenocarcinoma, stage IA, concurrent with sarcoidosis involving the lymph nodes; the last case was diagnosed as squamous cell carcinoma in the right upper lobe of the lung, but lymph nodes showed reactive hyperplasia. These cases suggest that some cases are so complex that avid 18F-FDG uptake in the mediastinal lymph nodes in the patients with pathologically diagnosed lung cancer should be carefully analyzed based on individual patients’ clinical background.
PMCID: PMC4270568  PMID: 25550877
FDG; PET-CT; hypermetabolic; mediastinal lymph nodes; lung cancer
20.  Assessment of tumor response to chemotherapy in patients with breast cancer using 18F-FLT: a meta-analysis 
To determine the diagnostic performance of 3'-deoxy-3'-18F-fluorothymidine positron emission tomography/computed tomography (FLT PET/CT) and FLT PET for evaluating response to chemotherapy in patients with breast cancer.
Databases such as PubMed (MEDLINE included) and excerpta medica database (EMBASE), were searched for relevant original articles. The included studies were assessed for methodological quality with quality assessment of diagnosis accuracy studies (QUADAS) score tool. Histopathological analysis and/or clinical and/or radiological follow-up for at least 6 months were used as the reference standard. The data were extracted by two reviewers independently to analyze the sensitivity, specificity, summary receiver operating characteristic (SROC) curve, area under the curve (AUC), and heterogeneity.
The present study analyzed a total of 4 selected articles. The pool sensitivity was 0.773 [95% confidence interval (CI): 0.594-0.900]. The pooled specificity was 0.685 (95% CI: 0.479-0.849) on basis of FEM. The pooled LR+, LR-, and DOR were 2.874 (1.492-5.538), 0.293 (0.146-0.589), and 14.891 (3.238-68.475), respectively. The AUC was 0.8636 (±0.0655), and the Q* index was 0.7942 (±0.0636).
Our results indicate that 18F-FLT PET/CT or PET is useful to predict chemotherapy response in breast cancer with reasonable sensitivity, specificity and DOR. However, future larger scale clinical trials will be needed to assess the regimen of 18F-FLT PET/CT or PET in monitoring the response to chemotherapy in breast cancer patients.
PMCID: PMC4220254  PMID: 25400416
Breast cancer; 18F-FLT PET; chemotherapy; meta-analysis
21.  Effect of Sperm Count on Success of Intrauterine Insemination in Couples Diagnosed with Male Factor Infertility 
Materia Socio-Medica  2014;26(5):321-323.
To exam semen parameters in predicting intrauterine insemination (IUI) outcomes in couples with male factor.
Study design:
This retrospective study was performed at department of infertility and sexual medicine from September 2007 to February 2014. 307 couples with male factor infertility were included and 672 IUI cycles were analyzed.
From 672 inseminations performed on 307 couples, there are 27.36% couples get pregnancy (84 out of 307) and the overall pregnancy rate was 12.95% (87 out of 672) of IUI. With the increase of post total progressive sperm count, the clinical pregnancy rate increased. When the initial progressive sperm count was lower than 5*106, there was no pregnant in the IUI cycle. At the end of the third cycle, 85 clinical pregnancies had been achieved (97.70%).
The initial total progressive sperm count lower than 5*106 means the poor outcome of IUI in the infertile couples with male factor. If the infertile couples with male factor don’t get pregnancy after three IUI cycles, the couples should receive re-assessment or other artificial reproductive technology.
PMCID: PMC4272842  PMID: 25568631
Intrauterine insemination; Male factor infertility; Semen analysis
22.  Isolation and Characterization of Canine Natural Killer Cells 
NK cells are non-T, non-B lymphocytes that kill target cells without previous activation. The immunophenotype and function of these cells in humans and mice are well defined, but canine NK cells remain incompletely characterized. Our objectives were to isolate and culture canine peripheral blood NK cells, and to define their immunophenotype and killing capability. PBMC were obtained from healthy dogs and T cells were depleted by immunomagnetic separation. The residual cells were cultured in media supplemented with IL-2, IL-15 or both, or with mouse embryonic liver (EL) feeder cells. Non-T, non-B lymphocytes survived and expanded in these cultures. IL-2 was necessary and sufficient for survival; the addition of IL-15 was necessary for expansion, but IL-15 alone did not support survival. Culture with EL cells and IL-2 also fostered survival and expansion. The non-T, non-B lymphocytes uniformly expressed CD45, MHC I, and showed significant cytotoxic activity against CTAC targets. Expression of MHC II, and of CD11/18 was restricted to subsets of these cells. The data show that cells meeting the criteria for NK cells in other species, i.e., non-T, non-B lymphocytes with cytotoxic activity, can be expanded from canine PBMC by T-cell depletion and culture with cytokines or feeder cells.
PMCID: PMC4019669  PMID: 23876304
canine; NK cells; interleukins
23.  Escherichia coli and TNF-α modulate macrophage phagocytosis of Candida glabrata1 
The Journal of surgical research  2008;155(2):217-224.
The incidence of systemic nonalbicans Candida (especially C. glabrata) infections is increasing dramatically in intensive care units, but relatively little is known about the pathogenesis or host defenses associated with these life threatening infections.
Materials and methods
The course of systemic C. glabrata infection was assessed as the fungal burden in the kidneys and livers of mice sacrificed 1, 8, and 15 days after intravenous C. glabrata. Sixteen hours before each sacrifice, half of the mice were injected intraperitoneally with intact viable or nonviable E. coli cells, or with E. coli lipopolysaccharide (LPS), or with tumor necrosis factor (TNF)-α. To clarify the effect of LPS and TNF-α on phagocytosis, resident (unstimulated) mouse peritoneal macrophages were harvested, cultivated ex vivo, and some cultures were treated with LPS or TNF-α prior to 30 min incubation with C. glabrata.
Compared to mice injected with vehicle, each agent (intact E. coli cells or E. coli LPS or TNF-α) was consistently associated with decreased numbers of tissue C. glabrata, and some of these decreases were significant (P<.05). Compared to untreated macrophages, phagocytosis of C. glabrata was increased with LPS-treated macrophages (P<.01), and phagocytosis was also increased in the presence of TNF-α (P<.01).
E. coli LPS and TNF-α may participate in host defense against C. glabrata by a mechanism involving increased macrophage phagocytosis, suggesting that stimulation of inflammatory cytokines may facilitate host clearance of C. glabrata.
PMCID: PMC4157574  PMID: 19482303
Candida glabrata; Escherichia coli; lipopolysaccharide; tumor necrosis factor-α; macrophage
24.  Prognostic Value Analysis of Mutational and Clinicopathological Factors in Non-Small Cell Lung Cancer 
PLoS ONE  2014;9(9):e107276.
Targeting activating oncogenic driver mutations in lung adenocarcinoma has led to prolonged survival in patients harboring these specific genetic alterations. The prognostic value of these mutations has not yet been elucidated. The prevalence of recently uncovered non-coding somatic mutation in promoter region of TERT gene is also to be validated in lung cancer. The purpose of this study is to show the prevalence, association with clinicalpathological features and prognostic value of these factors.
In a cohort of patients with non-small cell lung cancer (NSCLC) (n = 174, including 107 lung adenocarcinoma and 67 lung squamous cell carcinoma), EGFR, KRAS, HER2 and BRAF were directly sequenced in lung adeoncarcinoma, ALK fusions were screened using FISH (Fluorescence in situ Hybridization).TERT promoter region was sequenced in all of the 174 NSCLC samples. Associations of these somatic mutations and clinicopathological features, as well as prognostic factors were evaluated.
EGFR, KRAS, HER2, BRAF mutation and ALK fusion were mutated in 25.2%, 6.5%, 1.9%, 0.9% and 3.7% of lung adenocarcinomas. No TERT promoter mutation was validated by reverse-sided sequencing. Lung adenocarcinoma with EGFR and KRAS mutations showed no significant difference in Disease-free Survival (DFS) and Overall Survival (OS). Cox Multi-variate analysis revealed that only N stage and HER2 mutation were independent predictors of worse overall survival (HR = 1.653, 95% CI 1.219–2.241, P = 0.001; HR = 12.344, 95% CI 2.615–58.275, P = 0.002).
We have further confirmed that TERT promoter mutation may only exist in a very small fraction of NSCLCs. These results indicate that dividing lung adenocarcinoma into molecular subtypes according to oncogenic driver mutations doesn't predict survival difference of the disease.
PMCID: PMC4157862  PMID: 25198510
25.  Adsorption of Bisphenol A to a Carbon Nanotube Reduced Its Endocrine Disrupting Effect in Mice Male Offspring 
Soluble carbon nanotubes (CNTs) have shown promise as materials for adsorption of environmental contaminants such as Bisphenol A (BPA), due to the high adsorption capacity and strong desorption hysteresis of BPA on CNTs. The adsorption of BPA to CNTs may change the properties of both BPA and CNTs, and induce different toxicity to human and living systems from that of BPA and CNTs alone. Herein, we report that oral exposure of BPA/MWCNT–COOH (carboxylated multi-walled carbon nantubes) adduct to mice during gestation and lactation period decreased the male offspring reproductive toxicity compared with those induced by BPA alone. The adduct decreased malondialdehyde (MDA) level in testis and follicle-stimulating hormone (FSH) in serum, but increased the level of serum testosterone in male offspring in comparison to BPA alone. Our investigations broadened the knowledge of nanotoxicity and provided important information on the safe application of CNTs.
PMCID: PMC4200835  PMID: 25210847
carbon nanotubes (CNTs); Bisphenol A (BPA); contaminants adsorption; environmental endocrine disrupting effect; reproductive toxicity

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