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1.  The Emerging Duck Flavivirus Is Not Pathogenic for Primates and Is Highly Sensitive to Mammalian Interferon Antiviral Signaling 
Journal of Virology  2016;90(14):6538-6548.
Flaviviruses pose a significant threat to both animals and humans. Recently, a novel flavivirus, duck Tembusu virus (DTMUV), was identified to be the causative agent of a serious duck viral disease in Asia. Its rapid spread, expanding host range, and uncertain transmission routes have raised substantial concerns regarding its potential threats to nonavian hosts, including humans. Here, we demonstrate that DTMUV is not pathogenic for nonhuman primates and is highly sensitive to mammal type I interferon (IFN) signaling. In vitro assays demonstrated that DTMUV infected and replicated efficiently in various mammalian cell lines. Further tests in mice demonstrated high neurovirulence and the age-dependent neuroinvasiveness of the virus. In particular, the inoculation of DTMUV into rhesus monkeys did not result in either viremia or apparent clinical symptoms, although DTMUV-specific humoral immune responses were detected. Furthermore, we revealed that although avian IFN failed to inhibit DTMUV in avian cells, DTMUV was more sensitive to the antiviral effects of type I interferon than other known human-pathogenic flaviviruses. Knockout of the type I IFN receptor in mice caused apparent viremia, viscerotropic disease, and mortality, indicating a vital role of IFN signaling in protection against DTMUV infection. Collectively, we provide direct experimental evidence that this novel avian-origin DTMUV possesses a limited capability to establish infection in immunocompetent primates due to its decreased antagonistic activity in the mammal IFN system. Furthermore, our findings highlight the potential risk of DTMUV infection in immunocompromised individuals and warrant studies on the cross-species transmission and pathogenesis of this novel flavivirus.
IMPORTANCE Mosquito-borne flaviviruses comprise a large group of pathogenic and nonpathogenic members. The pathogenic flaviviruses include dengue, West Nile, and Japanese encephalitis viruses, and the nonpathogenic flaviviruses normally persist in a natural cycle and rarely cause disease in humans. A novel flavivirus, DTMUV (also known as duck egg drop syndrome flavivirus [DEDSV]) was identified in 2012 in ducks and then rapidly spread to several Asian countries. This new flavivirus was then shown to infect multiple avian species, resulting in neurological symptoms with unknown routes of transmission. There is public concern regarding its potential transmission from birds to humans and other nonavian hosts. Our present study shows that the mammalian IFN system can efficiently eliminate DTMUV infection and that the emergence of severe DTMUV-associated disease in mammals, especially humans, is unlikely. Currently, DTMUV infection mostly affects avian species.
PMCID: PMC4936123  PMID: 27147750
2.  Knocking Down the Expression of GMPase Gene OsVTC1-1 Decreases Salt Tolerance of Rice at Seedling and Reproductive Stages 
PLoS ONE  2016;11(12):e0168650.
Salinity is a severe environmental stress that greatly impairs production of crops worldwide. Previous studies have shown that GMPase plays an important role in tolerance of plants to salt stress at vegetative stage. However, the function of GMPase in plant responses to salt stress at reproductive stage remains unclear. Studies have shown that heterologous expression of rice GMPase OsVTC1-1 enhanced salt tolerance of tobacco seedlings, but the native role of OsVTC1-1 in salt stress tolerance of rice is unknown. To illustrate the native function of GMPase in response of rice to salt stress, OsVTC1-1 expression was suppressed using RNAi-mediated gene silencing. Suppressing OsVTC1-1 expression obviously decreased salt tolerance of rice varieties at vegetative stage. Intriguingly, grain yield of OsVTC1-1 RNAi rice was also significantly reduced under salt stress, indicating that OsVTC1-1 plays an important role in salt tolerance of rice at both seedling and reproductive stages. OsVTC1-1 RNAi rice accumulated more ROS under salt stress, and supplying exogenous ascorbic acid restored salt tolerance of OsVTC1-1 RNAi lines, suggesting that OsVTC1-1 is involved in salt tolerance of rice through the biosynthesis regulation of ascorbic acid. Altogether, results of present study showed that rice GMPase gene OsVTC1-1 plays a critical role in salt tolerance of rice at both vegetative and reproductive stages through AsA scavenging of excess ROS.
PMCID: PMC5167552  PMID: 27992560
3.  Increased Expressions of Plasma Galectin-3 in Patients with Amyotrophic Lateral Sclerosis 
Chinese Medical Journal  2016;129(23):2797-2803.
High expressions of galectin-3 were identified recently in the end stage of amyotrophic lateral sclerosis (ALS) patients, which suggested that immune reactivity and inflammatory mechanisms might play an important role in the pathogenesis of ALS. The purpose of this study was to investigate plasma galectin-3 levels in different groups and stages of ALS patients and the association with related clinical characteristics.
A total of 51 patients with ALS and 60 normal controls (NCs) were recruited in this study. Plasma galectin-3 levels were determined using the enzyme-linked immunosorbent assay. Patients with ALS were divided into several groups according to their clinical characteristics: gender, type of disease onset, duration of disease, and clinical conditions of disease. Statistical analyses of the differences of galectin-3 levels between groups and the association with the clinical characteristics of disease were performed.
As compared with the NCs (201.64 [22.35–401.63] ng/ml), plasma galectin-3 levels were significantly elevated in the patients with duration >12 months (341.17 [69.12–859.22] ng/ml, P < 0.05), and the patients with limb onset of disease (254.14 [69.12–859.22] ng/ml, P < 0.05); however, no difference was found in the patients with duration ≤12 months (250.62 [109.77–334.92] ng/ml, P > 0.05), and the patients with bulbar onset of disease (251.79 [109.20–404.76] ng/ml, P > 0.05). In addition, galectin-3 levels were significantly increased in the female patients (263.27 [123.32–859.22] ng/ml, P < 0.05) while no difference was found in the male patients (220.39 [69.12–748.73] ng/ml, P > 0.05). The further statistical analyses showed that plasma galectin-3 levels were positively correlated with the duration of disease (r = 0.293, P = 0.037).
Plasma galectin-3 levels were significantly increased in ALS patients with limb onset of disease, especially in ALS female patients, and positively correlated with the duration of disease, which suggested that plasma galectin-3 might be an interesting and useful factor associated with ALS.
PMCID: PMC5146785  PMID: 27900991
Amyotrophic Lateral Sclerosis; Galectin-3; Immune; Inflammatory
5.  Types of Renal Calculi and Management Regimen for Chinese Minimally Invasive Percutaneous Nephrolithotomy 
The Indian Journal of Surgery  2014;77(Suppl 3):872-876.
Strict selection of patients for minimally invasive percutaneous nephrolithotomy could effectively improve the success rate of surgery. This study aimed to understand the required skills and the efficacy of mini-PCNL in the treatment of five types of upper ureteral calculi. Data collected after X-ray analysis and B mode ultrasound from 633 patients with upper ureteral and renal pelvis calculi who underwent B ultrasound-guided lithotomy was reviewed, including the following: type I, upper ureteral or renal pelvis calculi with moderate hydronephrosis (154 cases); type II, upper ureteral or renal pelvis calculi with severe hydronephrosis (157 cases); type III, upper ureteral or renal pelvis calculi without hydronephrosis (61 cases); type IV, renal pelvis calculi, one or two renal calyx calculi (206 cases); and type V, renal staghorn calculi (55 cases). Operations on 611 cases were successful. The treatment method for five patients was converted to open surgery. Twelve cases were treated by indwelling double-J tube retro-catheterization and extracorporeal shock wave lithotripsy. Five patients gave up the treatment. The rate of calculus clearance was 82.3 %, and the rate of residual calculus was 17.6 %. Selective renal artery embolization was performed in nine cases. Hydropneumothorax occurred in nine cases. No intestinal fistula occurred, and no patient had to undergo nephrectomy. The difficulty and the curative effect of the operation were different because the types of calculi varied. Selection of the procedure based on the different types of calculi could effectively improve the success rate of the procedure, reduce complications, and shorten the learning curve.
PMCID: PMC4775614  PMID: 27011473
Minimally invasive nephrolithotomy; Types of calculus; Upper ureteral and renal calculi; Renal staghorn calculi; Hydronephrosis
6.  The effects for PM2.5 exposure on non-small-cell lung cancer induced motility and proliferation 
SpringerPlus  2016;5(1):2059.
Increasing urbanization and associated air pollution, including elevated levels of particulate matter (PM), are strongly correlated with the development of various respiratory diseases. In particular, PM2.5 has been implicated in promoting lung cancer initiation, growth and progression. Cell migration and proliferation are crucial for the progression of cancer. However, the molecular signatures and biological networks representing the distinct and shared features of non-small cell lung cancer (NSCLC) after PM2.5 exposure are unknown.
Functional assays demonstrated higher proliferation, migration and invasion of cancer cells stimulated with PM2.5. To investigate the complicated mechanisms, we performed global transcriptome profiling of the A549 cell line. Particularly, transcriptome sequencing revealed invasive characteristics reminiscent of cancer cells. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining the invasive and proliferative properties of PM2.5-exposed cells, respectively. Interestingly, under the PM2.5-stimulated condition, the A549 and H1299 cells strengthened obviously properties in motility and proliferation. Based on the network model reconstructing the shared protein–protein interactions, we selected the two most up-regulated genes, interleukin-1β (IL1β) and matrix metalloprotease 1 (MMP1), as key regulators responsible for the effects of PM2.5 exposure. Notably, IL1β and MMP1 expression was elevated in independent assays, which was further enhanced by PM2.5.
Taken together, our systems approach to investigating PM2.5 exposure provides a basis to identify key regulators responsible for the pathological features of NSCLC.
PMCID: PMC5133205  PMID: 27995036
Cell proliferation; Migration; Non-small cell lung cancer; PM2.5
7.  Usefulness of dynamic contrast-enhanced magnetic resonance imaging for predicting treatment response to vinorelbine-cisplatin with or without recombinant human endostatin in bone metastasis of non-small cell lung cancer 
American Journal of Cancer Research  2016;6(12):2890-2900.
Metastatic bone disease is a frequent complication of advanced non-small cell lung cancer (NSCLC) and causes skeletal-related events, which result in a poor prognosis. Currently, no standard method has been developed to precisely assess the therapeutic response of bone metastases (BM) and the early efficacy of anti-angiogenic therapy, which does not conform to the concept of precision medicine. This study aimed to investigate the usefulness of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for precise evaluation of the response to chemotherapy with anti-angiogenic agents in NSCLC patients with BM. Patients were randomly assigned to a treatment group (vinorelbine + cisplatin [NP] + recombinant human endostatin [rh-endostatin]) or a control group (NP + placebo). All patients were evaluated before treatment and after 2 cycles of treatment using DCE-MRI quantitative analysis technology for BM lesions and chest computed tomography (CT). Correlations between changes in the DCE-MRI quantitative parameters and treatment effect were analyzed. We enrolled 33 patients, of whom 28 were evaluable (20 in the treatment group and 8 in the control group). The results suggested a higher objective response rate (30% vs. 0%), better overall survival (21.44 ± 17.28 months vs. 7.71 ± 4.68 months), and a greater decrease in the transport constant (Ktrans) value (60% vs. 4.4%) in the treatment group than in the control group (P < 0.05). The Ktrans values in the “partial remission plus stable disease (PR + SD)” group were significantly lower after treatment (P < 0.05). Patients with a decrease of > 50% in the Ktrans value showed a significantly better overall survival than those with a decrease of ≤ 50% (13.2 vs. 9.8 months, P < 0.05). Ktrans as a DEC-MRI quantitative parameter could be used for the precise evaluation of BM lesions after anti-angiogenic therapy and as a predictor of survival. In addition, we reconfirmed the anti-angiogenic effect of rh-endostatin in NSCLC patients with BM.
PMCID: PMC5199762  PMID: 28042508
DCE-MRI; quantitative parameters; non-small cell lung cancer; bone metastases; anti-angiogenic therapy; recombinant human endostatin; therapeutic response
8.  Combination use of paclitaxel and avastin enhances treatment effect for the NSCLC patients with malignant pleural effusion 
Medicine  2016;95(47):e5392.
The current study is conducted to investigate efficacy of the chemotherapy drug paclitaxel in combination with Avastin (Roche Diagnostics GmbH., Mannheim, Germany) (antiangiogenic agent) in treatment of malignant pleural effusions (MPEs).
Twenty-four patients with non–small cell lung cancer were randomly assigned for 2 treatment approaches. Ten patients received paclitaxel (175 mg/m2) alone, and 14 patients took a combination therapy of paclitaxel and Avastin (5 mg/kg). Efficacy of the treatment approaches in the patients was validated with the change in the MPE volume. Pharmacokinetic (PK) profile and urinary excretion rate of paclitaxel were analyzed with serum vascular endothelial growth factor (VEGF) level, and adverse events were examined as well.
The combination therapy reduced the MPE level with a successful rate of 29% and a survival rate of 25% over the single paclitaxel treatment in the study cohort (both P < 0.05). PKs for the combined treatment displayed a rapid distribution of the anticancer drug paclitaxel with an obvious increase in its elimination half-life in the pleural fluid (both P < 0.01). Mean residence time of paclitaxel increased in the presence of Avastin (P < 0.01). Serum VEGF levels significantly reduced in the Avastin-treated patients as compared to the paclitaxel-treated ones (P < 0.01). The urinary excretion rate was similar in the study cohort. Incidence of adverse events for the 2 treatment approaches was similar in the patients.
Intervention of Avastin enhances potency of paclitaxel in treatment of MPEs with the increased survival rate of the patients through inhibiting VEGF production and prolonging time of ongoing interaction between the chemotherapy drug and the tumor tissues.
PMCID: PMC5134869  PMID: 27893676
Avastin; malignant pleural effusion; NSCLC; paclitaxel; pharmacokinetics; VEGF
9.  A Genome Sequence of Novel SARS-CoV Isolates: the Genotype, GD-Ins29, Leads to a Hypothesis of Viral Transmission in South China 
We report a complete genomic sequence of rare isolates (minor genotype) of the SARS-CoV from SARS patients in Guangdong, China, where the first few cases emerged. The most striking discovery from the isolate is an extra 29-nucleotide sequence located at the nucleotide positions between 27,863 and 27,864 (referred to the complete sequence of BJ01) within an overlapped region composed of BGI-PUP5 (BGI-postulated uncharacterized protein 5) and BGI-PUP6 upstream of the N (nucleocapsid) protein. The discovery of this minor genotype, GD-Ins29, suggests a significant genetic event and differentiates it from the previously reported genotype, the dominant form among all sequenced SARS-CoV isolates. A 17-nt segment of this extra sequence is identical to a segment of the same size in two human mRNA sequences that may interfere with viral genome replication and transcription in the cytosol of the infected cells. It provides a new avenue for the exploration of the virus-host interaction in viral evolution, host pathogenesis, and vaccine development.
PMCID: PMC5172408  PMID: 15626340
Severe Acute Respiratory Syndrome (SARS); genotype; GD-Ins29
10.  Neighboring-Nucleotide Effects on the Mutation Patterns of the Rice Genome 
DNA composition dynamics across genomes of diverse taxonomy is a major subject of genome analyses. DNA composition changes are characteristics of both replication and repair machineries. We investigated 3,611,007 single nucleotide polymorphisms (SNPs) generated by comparing two sequenced rice genomes from distant inbred lines (subspecies), including those from 242,811 introns and 45,462 protein-coding sequences (CDSs). Neighboring-nucleotide effects (NNEs) of these SNPs are diverse, depending on structural content-based classifications (genome-wide, intronic, and CDS) and sequence context-based categories (A/C, A/G, A/T, C/G, C/T, and G/T substitutions) of the analyzed SNPs. Strong and evident NNEs and nucleotide proportion biases surrounding the analyzed SNPs were observed in 1−3 bp sequences on both sides of an SNP. Strong biases were observed around neighboring nucleotides of protein-coding SNPs, which exhibit a periodicity of three in nucleotide content, constrained by a combined effect of codon-related rules and DNA repair mechanisms. Unlike a previous finding in the human genome, we found negative correlation between GC contents of chromosomes and the magnitude of corresponding bias of nucleotide C at −1 site and G at +1 site. These results will further our understanding of the mutation mechanism in rice as well as its evolutionary implications.
PMCID: PMC5172528  PMID: 16487081
CpG dinucleotides; methylation; SNP; transcription-coupled repair
11.  Reconstruction of auricular conchal defects with local flaps 
Medicine  2016;95(46):e5282.
Reconstruction of the auricular conchal cavity is relatively difficult because of its unique structure, shape, and location. We compared different methods of repair of the auricular concha to determine the method that would cause the least injury to the donor site.
The method selected was based on the location and size of the defect. If the defect was located in the upper part of the concha, or if the defect was >15 mm in diameter, we used a post-auricular subcutaneous pedicle island flap that was pulled through a post-auricular sulcus tunnel to cover the wound. If the defect was located in the lower part of the concha and was <15 mm in diameter, we used a pre-auricular translocation flap that was passed through the intertragic notch to cover the wound. The donor site was closed primarily. All flaps survived well and any scars associated with the surgery were unnoticeable. No tumor relapse or metastasis was observed over a mean follow-up period of 35 months. All patients were satisfied with the outcome.
The periauricular flap technique chosen for reconstruction of skin defects in the auricular concha depends on the size and location of the defect. With appropriate flap selection, excellent functional, and aesthetic outcomes are achieved.
PMCID: PMC5120910  PMID: 27861353
auricular conchal cavity; island flap; skin defect
12.  Topological Organization of Metabolic Brain Networks in Pre-Chemotherapy Cancer with Depression: A Resting-State PET Study 
PLoS ONE  2016;11(11):e0166049.
This study aimed to investigate the metabolic brain network and its relationship with depression symptoms using 18F-fluorodeoxyglucose positron emission tomography data in 78 pre-chemotherapy cancer patients with depression and 80 matched healthy subjects. Functional and structural imbalance or disruption of brain networks frequently occur following chemotherapy in cancer patients. However, few studies have focused on the topological organization of the metabolic brain network in cancer with depression, especially those without chemotherapy. The nodal and global parameters of the metabolic brain network were computed for cancer patients and healthy subjects. Significant decreases in metabolism were found in the frontal and temporal gyri in cancer patients compared with healthy subjects. Negative correlations between depression and metabolism were found predominantly in the inferior frontal and cuneus regions, whereas positive correlations were observed in several regions, primarily including the insula, hippocampus, amygdala, and middle temporal gyri. Furthermore, a higher clustering efficiency, longer path length, and fewer hubs were found in cancer patients compared with healthy subjects. The topological organization of the whole-brain metabolic networks may be disrupted in cancer. Finally, the present findings may provide a new avenue for exploring the neurobiological mechanism, which plays a key role in lessening the depression effects in pre-chemotherapy cancer patients.
PMCID: PMC5104370  PMID: 27832148
13.  CB2 cannabinoid receptor is a novel target for third-generation selective estrogen receptor modulators bazedoxifene and lasofoxifene 
The purpose of the current study was to investigate the ability of the third-generation selective estrogen receptor modulators (SERMs) bazedoxifene and lasofoxifene to bind and act on CB2 cannabinoid receptor. We have identified, for the first time, that CB2 is a novel target for bazedoxifene and lasofoxifene. Our results showed that bazedoxifene and lasofoxifene were able to compete for specific [3H]CP-55,940 binding to CB2 in a concentration-dependent manner. Our data also demonstrated that by acting on CB2, bazedoxifene and lasofoxifene concentration-dependently enhanced forskolin-stimulated cAMP accumulation. Furthermore, bazedoxifene and lasofoxifene caused parallel, rightward shifts of the CP-55,940, HU-210, and WIN55,212-2 concentration-response curves without altering the efficacy of these cannabinoid agonists on CB2, which indicates that bazedoxifene- and lasofoxifene-induced CB2 antagonism is most likely competitive in nature. Our discovery that CB2 is a novel target for bazedoxifene and lasofoxifene suggests that these third-generation SERMs can potentially be repurposed for novel therapeutic indications for which CB2 is a target. In addition, identifying bazedoxifene and lasofoxifene as CB2 inverse agonists also provides important novel mechanisms of actions to explain the known therapeutic effects of these SERMs.
PMCID: PMC5099082  PMID: 24275139
cannabinoid receptor; inverse agonist; selective estrogen receptor modulator; bazedoxifene; lasofoxifene
14.  In vivo Confocal Microscopy Evaluation of Meibomian Gland Dysfunction in Dry Eye Patients with Different Symptoms 
Chinese Medical Journal  2016;129(21):2617-2622.
Dry eye patients suffer from all kinds of symptoms. Sometimes, the clinical signs evaluation does not disclose any obvious difference in routine examination; in vivo confocal microscopy (IVCM) is a powerful tool for ocular surface disease. This study aimed to clarify meibomian gland (MG) alterations in dry eye patients with different symptoms and to compare the findings using IVCM.
A total of sixty patients were recruited, all subjected to Ocular Surface Disease Index (OSDI) and Salisbury Eye Evaluation Questionnaire (SEEQ), and questionnaires for the assessment of dry eye symptoms before clinical sign examinations were given to the patients. Finally, IVCM was applied to observe MG's structure. Statistical analysis was performed using the t-test, Mann-Whitney U-test and Spearman correlation analysis. The differences were statistically significant when P < 0.05.
In the severe symptom group, OSDI and SEEQ scores were significantly higher (P < 0.05) compared with the mild symptoms group. All other clinical sign examinations had no statistical difference in the two groups (P > 0.05). However, all the IVCM-observed data showed that patients with severe symptoms had more significant fibrosis in MG (acinar unit area 691.87 ± 182.01 μm2 for the severe, 992.17 ± 170.84 μm2 for the mild; P < 0.05) and severer decrease in the size of MG acinar units than those observed in patients with mild symptoms (MG acinar unit density [MGAUD] 70.08 ± 18.78 glands/mm2, MG acinar unit longest diameter [MGALD] 51.50 ± 15.51 μm, MG acinar unit shortest diameter [MGASD] 20.30 ± 11.85 μm for the severe, MGAUD 89.53 ± 39.88 glands/mm2, MGALD 81.57 ± 21.14 μm, MGASD 42.37 ± 14.55 μm for the mild; P < 0.05). Dry eye symptoms were negatively correlated with MG confocal microscopic parameters and positively correlated with conjunctival inflammatory cells and Langerhans cells (P < 0.05).
IVCM application provides a strong support to differentiate dry eye patients with different symptoms: meibomian gland dysfunction (MGD) plays a pivotal role in dry eye aggravation, and using IVCM to observe MG fibrosis, changes in size and density of MG as well as status of inflammation cells can help not only correctly diagnose the type and severity of dry eye, but also possibly prognosticate in routine eye examination in the occurrence of MGD.
PMCID: PMC5125342  PMID: 27779170
Confocal Microscopy; Dry Eye; Meibomian Gland
15.  Five endometrial cancer risk loci identified through genome-wide association analysis 
Cheng, Timothy HT | Thompson, Deborah J | O’Mara, Tracy A | Painter, Jodie N | Glubb, Dylan M | Flach, Susanne | Lewis, Annabelle | French, Juliet D | Freeman-Mills, Luke | Church, David | Gorman, Maggie | Martin, Lynn | Hodgson, Shirley | Webb, Penelope M | Attia, John | Holliday, Elizabeth G | McEvoy, Mark | Scott, Rodney J | Henders, Anjali K | Martin, Nicholas G | Montgomery, Grant W | Nyholt, Dale R | Ahmed, Shahana | Healey, Catherine S | Shah, Mitul | Dennis, Joe | Fasching, Peter A | Beckmann, Matthias W | Hein, Alexander | Ekici, Arif B | Hall, Per | Czene, Kamila | Darabi, Hatef | Li, Jingmei | Dörk, Thilo | Dürst, Matthias | Hillemanns, Peter | Runnebaum, Ingo | Amant, Frederic | Schrauwen, Stefanie | Zhao, Hui | Lambrechts, Diether | Depreeuw, Jeroen | Dowdy, Sean C | Goode, Ellen L | Fridley, Brooke L | Winham, Stacey J | Njølstad, Tormund S | Salvesen, Helga B | Trovik, Jone | Werner, Henrica MJ | Ashton, Katie | Otton, Geoffrey | Proietto, Tony | Liu, Tao | Mints, Miriam | Tham, Emma | Consortium, CHIBCHA | Jun Li, Mulin | Yip, Shun H | Wang, Junwen | Bolla, Manjeet K | Michailidou, Kyriaki | Wang, Qin | Tyrer, Jonathan P | Dunlop, Malcolm | Houlston, Richard | Palles, Claire | Hopper, John L | Peto, Julian | Swerdlow, Anthony J | Burwinkel, Barbara | Brenner, Hermann | Meindl, Alfons | Brauch, Hiltrud | Lindblom, Annika | Chang-Claude, Jenny | Couch, Fergus J | Giles, Graham G | Kristensen, Vessela N | Cox, Angela | Cunningham, Julie M | Pharoah, Paul D P | Dunning, Alison M | Edwards, Stacey L | Easton, Douglas F | Tomlinson, Ian | Spurdle, Amanda B
Nature genetics  2016;48(6):667-674.
We conducted a meta-analysis of three endometrial cancer GWAS and two replication phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five novel risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1 near SIVA1). A second independent 8q24.21 signal (rs17232730) was found. Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2=0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103-T endometrial cancer protective allele suppressed gene expression in vitro suggesting that regulation of KLF5 expression, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
PMCID: PMC4907351  PMID: 27135401
16.  Structure-activity relationships of fatty acid amide ligands in activating and desensitizing G protein-coupled receptor 119 
The purpose of the current study was to apply a high throughput assay to investigate the structure-activity relationships of fatty acid amides for activating and desensitizing G protein-coupled receptor 119, a promising therapeutic target for both type 2 diabetes and obesity. A cell-based, homogenous time resolved fluorescence (HTRF) method for measuring G protein-coupled receptor 119-mediated increase of cyclic adenosine monophosphate (cAMP) levels was validated and applied in this study. Using novel fatty acid amides and detailed potency and efficacy analyses, we have demonstrated that degree of saturation in acyl chain and charged head groups of fatty acid amides have profound effects on the ability of these compounds to activate G protein-coupled receptor 119. In addition, we have demonstrated for the first time that pretreatments with G protein-coupled receptor 119 agonists desensitize the receptor and the degrees of desensitization caused by fatty acid amides correlate well with their structure-activity relationships in activating the receptor.
PMCID: PMC5086809  PMID: 24184668
G protein-coupled receptor 119; Fatty acid amides; Structure-activity relationship
17.  Identification of Raloxifene as a Novel CB2 Inverse Agonist 
The purpose of the current study was to apply a high throughput assay to systematically screen a library of food and drug administration (FDA)-approved drugs as potential ligands for the cannabinoid receptor 2 (CB2). A cell-based, homogenous time resolved fluorescence (HTRF) method for measuring changes in intracellular cAMP levels was validated and found to be suitable for testing ligands that may act on CB2. Among the 640 FDA-approved drugs screened, raloxifene, a drug used to treat/prevent post-menopausal osteoporosis, was identified for the first time to be a novel CB2 inverse agonist. Our results demonstrated that by acting on CB2, raloxifene enhances forskolin-stimulated cAMP accumulation in a concentration-dependant manner. Furthermore, our data showed that raloxifene competes concentration-dependently for specific [3H]CP-55,940 binding to CB2. In addition, raloxifene pretreatment caused a rightward shift of the concentration-response curves of the cannabinoid agonists CP-55,940, HU-210, and WIN55,212-2. Raloxifene antagonism is most likely competitive in nature, as these rightward shifts were parallel and were not associated with any changes in the efficacy of cannabinoid agonists on CB2. Our discovery that raloxfiene is as an inverse agonist for CB2 suggests that it might be possible to repurpose this FDA-approved drug for novel therapeutic indications for which CB2 is a target. Furthermore, identifying raloxifene as a CB2 inverse agonist also provides important novel mechanisms of actions to explain the known therapeutic effects of raloxifene.
PMCID: PMC5084446  PMID: 23611779
cannabinoid receptor; inverse agonist; drug repurposing; raloxifene; osteoporosis
18.  Involvement of a non-CB1/CB2 cannabinoid receptor in the aqueous humor outflow-enhancing effects of abnormal-cannabidiol 
Experimental eye research  2012;100:59-64.
The purpose of this study was to investigate the effects of abnormal-cannabidiol (abn-cbd), a non-psychoactive cannabinoid agonist, on aqueous humor outflow via the trabecular meshwork (TM) of porcine eye, and to examine the involvement of a non-CB1/CB2 cannabinoid receptor and the p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathway. The effects of abn-cbd on aqueous humor outflow were measured using a porcine anterior segment perfused organ culture model. The activation of p42/44 MAPK by abn-cbd was determined in cultured TM cells with western blot analysis using an anti-phospho-p42/44 MAPK antibody. Administration of abn-cbd caused a concentration-dependent enhancement of aqueous humor outflow facility with a maximum effect (155.0 ± 11.7% of basal outflow facility) after administration of 30 nM abn-cbd. Pretreatment with 1 μM of O-1918, a cannabidiol analog that acts as a selective antagonist at the non-CB1/CB2 receptor, produced a full antagonism of 30 nM abn-cbd induced increase of aqueous humor outflow facility. Pretreatment with 1 μM of CB1 antagonist SR141716A partially blocked, whereas pretreatment with either 1 μM of CB1 antagonist AM251 or 1 μM of CB2 antagonist SR144528 had no effect on abn-cbd induced enhancement of outflow facility. Treatment of TM cells with 30 nM of abn-cbd activated p42/44 MAPK, which was blocked completely by pretreatment with O-1918, and partially by pretreatment with SR141716A, but not by either AM251 or SR144528. In addition, PD98059, an inhibitor of p42/44 MAPK pathway, blocked completely the abn-cbd induced p42/44 MAPK activation and blocked partially the abn-cbd induced enhancement of outflow facility. In conclusion, the results from this study demonstrate that abn-cbd increases aqueous humor outflow through the TM pathway of the eye, and this effect is mediated by a non-CB1/CB2 cannabinoid receptor, with an involvement of p42/44 MAPK signaling pathway.
PMCID: PMC5076473  PMID: 22580290
Abnormal-cannabidiol; Cannabinoid receptor; Intraocular pressure; Trabecular meshwork; Aqueous humor outflow; p42/44 mitogen-activated protein kinase
19.  Germline mutations of KIT in gastrointestinal stromal tumor (GIST) and mastocytosis 
Cell & Bioscience  2016;6:55.
Somatic mutations of KIT are frequently found in mastocytosis and gastrointestinal stromal tumor (GIST), while germline mutations of KIT are rare, and only found in few cases of familial GIST and mastocytosis. Although ligand-independent activation is the common feature of KIT mutations, the phenotypes mediated by various germline KIT mutations are different. Germline KIT mutations affect different tissues such as interstitial cells of Cajal (ICC), mast cells or melanocytes, and thereby lead to GIST, mastocytosis, or abnormal pigmentation. In this review, we summarize germline KIT mutations in familial mastocytosis and GIST and discuss the possible cellular context dependent transforming activity of KIT mutations.
PMCID: PMC5070372  PMID: 27777718
KIT; Cancer; Signal transduction; Targeted therapy
20.  α-Hydroxy coordination of mononuclear vanadyl citrate, malate and S-citramalate with N−heterocycle ligand, implying a new protonation pathway of iron-vanadium cofactor in nitrogenase 
Unlike the most of α-alkoxy coordination in α-hydroxycarboxylates to vanadium, novel α-hydroxy coordination to vanadium(IV) has been observed for a series of chiral and achiral monomeric α-hydroxycarboxylato vanadyl complexes [VO(H2cit)(bpy)]·2H2O (1), [VO(Hmal)(bpy)]·H2O (2), [VO(H2cit)(phen)]·1.5H2O (3), [VO(Hmal)(phen)]·H2O (4), and [ΔVO(S-Hcitmal)(bpy)]·2H2O (5), [VO(H2cit)(phen)]2·6.5H2O (6), which were isolated from the reactions of vanadyl sulfate with α-hydroxycarboxylates and N-heterocycle ligands in acidic solution. The complexes feature a tridentate citrate, malate or citramalate that chelates to vanadium atom through their α–hydroxy, α–carboxy and β–carboxy groups; while the other β–carboxylic acidic group of citrate is free to participate strong hydrogen bonds with lattice water molecule. The neutral α-hydroxy group also forms strong intermolecular hydrogen bonds with water molecule and the negatively-charged α-carboxy group in the environment. The inclusion of a hydrogen ion in α–alkoxy group results in the formation of a series of neutral complexes with one less positive charge. There are two different configurations of citrate with respect to the trans-position of axial oxo group, where the complex with trans-hydroxy configuration seems more stable with less hindrance. The average bond distances of V–Ohydroxy and V–Oα-carboxy are 2.196 and 2.003 Å respectively, which are comparable to the V–O distance (2.15 Å) of homocitrate in FeV–cofactor of V–nitrogenase. A new structural model is suggested for R-homocitrato iron vanadium cofactor as VFe7S9C(R-Hhomocit) (H4homocit = homocitric acid) with one more proton in homocitrate ligand.
PMCID: PMC5065718  PMID: 25240212
Citrate; malate; vanadyl; crystal structure; R-homocitrato iron vanadium cofactor; nitrogenase
21.  Sigmoid Sinus Wall Reconstruction for Pulsatile Tinnitus Caused by Sigmoid Sinus Wall Dehiscence: A Single-Center Experience 
PLoS ONE  2016;11(10):e0164728.
To evaluate clinical characteristics and present surgical outcomes of PT caused by sigmoid sinus wall dehiscence (SSWD)
This study retrospectively reviewed 34 patients with PT who were diagnosed with SSWD in our institution between December 2008 and July 2013. Among them, 27 patients underwent sigmoid sinus wall reconstruction (surgery group) and 7 patients refused surgery (non-surgery group). Preoperative data were obtained from the patients’ medical records. All patients were followed up regularly for at least 25 months. Preoperative and postoperative computed tomography angiography (CTA) images were compared. Student’s t-tests were used to compare age, body mass index (BMI) and preoperative Tinnitus Handicap Inventory (THI) scores between the surgery and the non-surgery groups and to compare pre- and follow-up THI scores.
There was no significant difference in age, body mass index, or preoperative THI scores between groups. Following surgery, 14 patients had complete resolution, 5 had partial resolution, 7 experienced no change and PT was aggravated in 1 patient. The difference between preoperative and postoperative THI scores was significant. No severe complications were found postoperatively. Comparison of the preoperative and postoperative CTA images revealed that remnant unrepaired dehiscences were the cause of unsatisfactory outcomes following surgery. In the non-surgery group, PT remained largely unchanged.
Sigmoid sinus wall reconstruction is an effective and safe treatment for PT caused by SSWD. It is imperative that all regions of the dehiscence are sufficiently exposed and resurfaced during surgery.
PMCID: PMC5088000  PMID: 27736970
22.  Magnetic Resonance Imaging Features of Extraocular Muscle Lymphoma in Five Cases 
Chinese Medical Journal  2016;129(19):2384-2385.
PMCID: PMC5040027  PMID: 27647200
Extraocular Muscles; Lymphatic; Lymphoma; Magnetic Resonance Imaging; Orbit
24.  Long non-coding RNA H19 regulates FOXM1 expression by competitively binding endogenous miR-342-3p in gallbladder cancer 
Long non-coding RNA (lncRNA) H19 has been reported to involve in many kinds of human cancers and functions as an oncogene. Our previous study found that H19 was over-expressed in gallbladder cancer (GBC) and was shown to promote tumor development in GBC. However, the competing endogenous RNA (ceRNA) regulatory network involving H19 in GBC progression has not been fully elucidated. We aim to detect the role of H19 as a ceRNA in GBC.
Methods and Results
In this study, the expression of H19 and miR-342-3p were analyzed in 35 GBC tissues and matched normal tissues by using quantitative polymerase chain reaction (qRT-PCR). We demonstrated H19 was overexpressed and negatively correlated with miR-342-3p in GBC. By dual-luciferase reporter assays, RNA-binding protein immunoprecipitation (RIP) and RNA pull-down assays, we verified that H19 was identified as a direct target of miR-342-3p. QRT-PCR and Western-blotting assays demonstrated that H19 silencing down-regulated, whereas over-expression enhanced the expression of miR-342-3p targeting FOXM1 through competitively ‘sponging’ miR-342-3p. Furthermore, transwell invasion assays and cell cycle assays indicated that H19 knockdown inhibited both cells invasion and proliferation, but this effects was attenuated by co-transfection of siRNA-H19 and miR-342-3p inhibitor in GBC cells. In vivo, tumor volumes were decreased significantly in H19 silenced group compared to the control group, but was attenuated by co-transfection of shRNA-H19 and miR-342-3p inhibitor, which were stablely constructed through lenti-virus vector.
Our results suggest a potential ceRNA regulatory network involving H19 regulates FOXM1 expression by competitively binding endogenous miR-342-3p in GBC. This mechanism may contribute to a better understanding of GBC pathogenesis and provides potential therapeutic strategy for GBC.
PMCID: PMC5048611  PMID: 27716361
H19; miR-342-3p; Competing endogenous RNA; FOXM1; Gallbladder cancer
25.  Viral RNA switch mediates the dynamic control of flavivirus replicase recruitment by genome cyclization 
eLife  null;5:e17636.
Viral replicase recruitment and long-range RNA interactions are essential for RNA virus replication, yet the mechanism of their interplay remains elusive. Flaviviruses include numerous important human pathogens, e.g., dengue virus (DENV) and Zika virus (ZIKV). Here, we revealed a highly conserved, conformation-tunable cis-acting element named 5′-UAR-flanking stem (UFS) in the flavivirus genomic 5′ terminus. We demonstrated that the UFS was critical for efficient NS5 recruitment and viral RNA synthesis in different flaviviruses. Interestingly, stabilization of the DENV UFS impaired both genome cyclization and vRNA replication. Moreover, the UFS unwound in response to genome cyclization, leading to the decreased affinity of NS5 for the viral 5′ end. Thus, we propose that the UFS is switched by genome cyclization to regulate dynamic RdRp binding for vRNA replication. This study demonstrates that the UFS enables communication between flavivirus genome cyclization and RdRp recruitment, highlighting the presence of switch-like mechanisms among RNA viruses.
eLife digest
Flaviviruses include a large family of viruses that are harmful to human health, such as dengue virus, West Nile virus and Zika virus. Understanding the details of the life cycle of these viruses is important for better controlling and treating the diseases that they cause.
The genetic information of flaviviruses is stored in single-stranded molecules of RNA. To form new copies of a virus, the RNA must be replicated in a process that involves two critical steps. First, an enzyme called viral RNA polymerase NS5 must be recruited to a specific end of the RNA strand (known as the 5′ end). Then, the ends of the RNA strand bind together to form a circular loop. However, little is known about whether these two processes are linked, or how they are regulated.
Using bioinformatics, biochemical and reverse genetics approaches, Liu et al. have now identified a new section of RNA in the 5′ end of the flavivirus RNA, named the 5′-UAR-flanking stem (or UFS for short), which is critical for viral replication. The UFS plays an important role in efficiently recruiting the NS5 viral RNA polymerase to the 5′ end of the flavivirus RNA.
After the RNA forms a circle, the UFS unwinds. This makes the NS5 polymerase less likely to bind to the 5′ end of the RNA. Stabilizing the structure of the UFS impairs the ability of the RNA strand to form a circle, and hence reduces the ability of the RNA to replicate. Thus, the UFS links and enables communication between the processes that form the flavivirus RNA into a circle and that recruit the viral RNA polymerase to the RNA.
The structural basis of the interaction between the flavivirus RNA 5′ end, including the UFS element, and the viral RNA polymerase now deserves further investigation. It will be also important to explore whether other types of viruses regulate their replication via a similar mechanism.
PMCID: PMC5101012  PMID: 27692070
flavivirus; genome cyclization; viral replicase recruitment; cis-acting element; viral RNA structure; Virus

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