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2.  A genetic contribution from the Far East into Ashkenazi Jews via the ancient Silk Road 
Scientific Reports  2015;5:8377.
Contemporary Jews retain a genetic imprint from their Near Eastern ancestry, but obtained substantial genetic components from their neighboring populations during their history. Whether they received any genetic contribution from the Far East remains unknown, but frequent communication with the Chinese has been observed since the Silk Road period. To address this issue, mitochondrial DNA (mtDNA) variation from 55,595 Eurasians are analyzed. The existence of some eastern Eurasian haplotypes in eastern Ashkenazi Jews supports an East Asian genetic contribution, likely from Chinese. Further evidence indicates that this connection can be attributed to a gene flow event that occurred less than 1.4 kilo-years ago (kya), which falls within the time frame of the Silk Road scenario and fits well with historical records and archaeological discoveries. This observed genetic contribution from Chinese to Ashkenazi Jews demonstrates that the historical exchange between Ashkenazim and the Far East was not confined to the cultural sphere but also extended to an exchange of genes.
doi:10.1038/srep08377
PMCID: PMC4323646  PMID: 25669617
3.  Down-Regulation of Human Enteric Antimicrobial Peptides by NOD2 during Differentiation of the Paneth Cell Lineage 
Scientific Reports  2015;5:8383.
Ileal Crohn's disease (CD) arising from the alteration of intestinal homeostasis is characterized by two features, namely a decrease in Paneth cell-produced antimicrobial peptides that play a key role in maintaining this balance and an increase in NOD2, an intracellular sensor. Although mutations in NOD2 are highly correlated with the incidence of CD, the physiological role of NOD2 in intestinal immunity remains elusive. Here, we show that NOD2 can down-regulate the expression of human enteric antimicrobial peptides during differentiation of the Paneth cell lineage. This finding, which links the decrease of human enteric antimicrobial peptides to increased NOD2 in ileal CD patients, provides a new view into the pathogenesis of ileal CD.
doi:10.1038/srep08383
PMCID: PMC4323657  PMID: 25670499
4.  Concurrent radiotherapy and weekly chemotherapy of 5-fluorouracil and platinum agents for postoperative locoregional recurrence of oesophageal squamous cell carcinoma 
Scientific Reports  2015;5:8071.
The most optimal management for postoperative locoregional recurrence of oesophageal squamous cell carcinoma is still controversial. Several studies have reported the feasibility and efficacy of concurrent chemoradiotherapy (CCRT), mostly with three-weekly or four-weekly schedule of chemotherapy. However, treatment compliance was not quite satisfactory, probably due to treatment-related toxicities. Since CCRT with weekly chemotherapy regimens have demonstrated a favorable toxicity profile as well as promising survival in certain types of cancer, we aimed to evaluate the efficacy and toxicity of radiotherapy concurrently with weekly chemotherapy with 5-fluorouracil (5-FU) and platinum agents for patients with postoperative locoregional recurrence of oesophageal squamous cell carcinoma in our center. Twenty-seven consecutive patients who were diagnosed with postoperative locoregional recurrence of oesophageal squamous cell carcinoma and received CCRT with weekly chemotherapy of 5-FU and platinum agents were retrospectively analyzed. Our data showed that the present protocol of radiotherapy combined concurrently with weekly chemotherapy of 5-FU and platinum agents was a safe and effective salvage treatment for postoperative locoregional recurrence of oesophageal squamous cell carcinoma.
doi:10.1038/srep08071
PMCID: PMC4308707  PMID: 25627119
5.  The Arabidopsis alkaline ceramidase TOD1 is a key turgor pressure regulator in plant cells 
Nature Communications  2015;6:6030.
Turgor pressure plays pivotal roles in the growth and movement of walled cells that make up plants and fungi. However, the molecular mechanisms regulating turgor pressure and the coordination between turgor pressure and cell wall remodelling for cell growth remain poorly understood. Here, we report the characterization of Arabidopsis TurgOr regulation Defect 1 (TOD1), which is preferentially expressed in pollen tubes and silique guard cells. We demonstrate that TOD1 is a Golgi-localized alkaline ceramidase. tod1 mutant pollen tubes have higher turgor than wild type and show growth retardation both in pistils and in agarose medium. In addition, tod1 guard cells are insensitive to abscisic acid (ABA)-induced stomatal closure, whereas sphingosine-1-phosphate, a putative downstream component of ABA signalling and product of alkaline ceramidases, promotes closure in both wild type and tod1. Our data suggest that TOD1 acts in turgor pressure regulation in both guard cells and pollen tubes.
Turgor pressure is critical for the growth of plant cells but the mechanisms regulating turgor are poorly understood. Here, Chen et al. identify TOD1, an alkaline ceramidase, involved in sphingosine metabolism that regulates turgor during pollen tube growth and stomatal closure.
doi:10.1038/ncomms7030
PMCID: PMC4309442  PMID: 25591940
6.  Negative Life Events and Attempted Suicide in Rural China 
PLoS ONE  2015;10(1):e0116634.
Objective
This study aimed to examine the association between negative life events (NLEs) and attempted suicide in rural China.
Methods
Six rural counties were selected from disease surveillance points in Shandong province, China. A total of 409 suicide attempters in rural areas between October 1, 2009, and March 31, 2011, and an equal number of matched controls were interviewed. We compared negative life events experienced within 1 month, 1–3 months, 3–6months, and 6–2 months prior to attempted suicide for cases and prior to interview for controls. We used multivariate logistic regression to examine the association between NLEs and attempted suicide.
Results
Suicide attempters experienced more NLEs within the last year prior to suicide attempt than controls prior to interview (83.1% vs. 33.5%). There was a significant dose-response relationship between NLEs experienced within the last year and increased risk of attempted suicide. Timing of NLEs analysis showed that NLEs experienced in the last month and 6–12 months prior to suicide attempt were significantly associated with elevated risk of attempted suicide, even after adjusting for mental disorders and demographic factors. Of NLEs, quarrelling with spouse, quarrelling with other family members, conflicting with friends or neighbors, family financial difficulty, and serious illness were independently related to attempted suicide.
Conclusion
NLEs are significantly associated with increased risk for attempted suicide in rural China. Stress management and intervention may be important to prevent suicidal behavior in rural China.
doi:10.1371/journal.pone.0116634
PMCID: PMC4303417  PMID: 25611854
7.  Leveraging Social Networks to Detect Anomalous Insider Actions in Collaborative Environments 
Collaborative information systems (CIS) enable users to coordinate efficiently over shared tasks. T hey are often deployed in complex dynamic systems that provide users with broad access privileges, but also leave the system vulnerable to various attacks. Techniques to detect threats originating from beyond the system are relatively mature, but methods to detect insider threats are still evolving. A promising class of insider threat detection models for CIS focus on the communities that manifest between users based on the usage of common subjects in the system. However, current methods detect only when a user’s aggregate behavior is intruding, not when specific actions have deviated from expectation. In this paper, we introduce a method called specialized network anomaly detection (SNAD) to detect such events. SNAD assembles the community of users that access a particular subject and assesses if similarities of the community with and without a certain user are sufficiently different. We present a theoretical basis and perform an extensive empirical evaluation with the access logs of two distinct environments: those of a large electronic health record system (6,015 users, 130,457 patients and 1,327,500 accesses) and the editing logs of Wikipedia (2,388,955 revisors, 55,200 articles and 6,482,780 revisions). We compare SNAD with several competing methods and demonstrate it is significantly more effective: on average it achieves 20–30% greater area under an ROC curve.
doi:10.1109/ISI.2011.5984061
PMCID: PMC4303584  PMID: 25621314
8.  Lower irritation microemulsion-based rotigotine gel: formulation optimization and in vitro and in vivo studies 
Background
Rotigotine is a potent and selective D1, D2, and D3 dopaminergic receptor agonist. Due to an extensive first-pass effect, it has a very low oral bioavailability (approximately 0.5% in rats).
Purpose
The present investigation aimed to develop a microemulsion-based hydrogel for transdermal rotigotine delivery with lower application site reactions.
Methods
Pseudoternary phase diagrams were constructed to determine the region of oil in water (o/w)-type microemulsion. Central composite design was used to support the pseudoternary phase diagrams and to select homogeneous and stable microemulsions with an optimal amount of rotigotine permeation within 24 hours. In vitro skin permeation experiments were performed, using Franz diffusion cells, to compare rotigotine-loaded microemulsions with rotigotine solutions in oil. The optimized formulation was used to prepare a microemulsion-based hydrogel, which was subjected to bioavailability and skin irritancy studies.
Results
The selected formulations of rotigotine-loaded microemulsions had enhanced flux and permeation coefficients compared with rotigotine in oil. The optimum microemulsion contained 68% water, 6.8% Labrafil®, 13.44% Cremophor® RH40, 6.72% Labrasol®, and 5.04% Transcutol® HP; the drug-loading rate was 2%. To form a microemulsion gel, 1% Carbomer 1342 was added to the microemulsion. The bioavailability of the rotigotine-loaded microemulsion gel was 105.76%±20.52% with respect to the marketed rotigotine patch (Neupro®). The microemulsion gel irritated the skin less than Neupro.
Conclusion
A rotigotine microemulsion-based hydrogel was successfully developed, and an optimal formulation for drug delivery was identified. This product could improve patient compliance and have broad marketability.
doi:10.2147/IJN.S74079
PMCID: PMC4298334  PMID: 25609965
pseudoternary phase diagrams; central composite design; transdermal
9.  Meta-analyses on prevalence of selected Parkinson’s nonmotor symptoms before and after diagnosis 
Background
Nonmotor symptoms are common among patients with Parkinson’s disease (PD) and some may precede disease diagnosis.
Methods
We conducted a meta-analysis on the prevalence of selected nonmotor symptoms before and after PD diagnosis, using random-effect models. We searched PubMed (1965 through October/November 2012) for the following symptoms: hyposmia, constipation, rapid eye movement sleep behavior disorder, excessive daytime sleepiness, depression, and anxiety. Eligible studies were publications in English with original data on one or more of these symptoms.
Results
The search generated 2,373 non-duplicated publications and 332 met the inclusion criteria, mostly (n = 320) on symptoms after PD diagnosis. For all symptoms, the prevalence was substantially higher in PD cases than in controls, each affecting over a third of the patients. Hyposmia was the most prevalent (75.5% in cases vs. 19.1% in controls), followed by constipation (50% vs. 17.7%), anxiety (39.9% vs. 19.1%), rapid eye movement sleep behavior disorder (37.0% vs. 7.0%), depression (36.6% vs. 14.9%), and excessive daytime sleepiness (33.9% vs. 10.5%). We observed substantial heterogeneities across studies and meta-regression analyses suggested that several factors might have contributed to this. However, the prevalence estimates were fairly robust in several sensitivity analyses. Only 20 studies had data on any symptoms prior to PD diagnosis, but still the analyses revealed higher prevalence in future PD cases than in controls.
Conclusion
These symptoms are common among PD patients both before and after diagnosis. Further studies are needed to understand the natural history of nonmotor symptoms in PD and their etiological and clinical implications.
Electronic supplementary material
The online version of this article (doi:10.1186/2047-9158-4-1) contains supplementary material, which is available to authorized users.
doi:10.1186/2047-9158-4-1
PMCID: PMC4322463  PMID: 25671103
Parkinson’s disease; Nonmotor symptoms; Meta-analysis; Prevalence; Natural history
10.  Placement of 125I seed strands and stents for a type IV Klatskin tumor 
Herein, we report a new technique that consists of placing two 125I seed strands and two stents in the right and left intrahepatic bile ducts for the treatment of hilar cholangiocarcinoma. A 75-year-old man presented with jaundice and was diagnosed with Bismuth type IV Klatskin tumor. Abdominal computed tomography (CT) showed intrahepatic and extrahepatic bile duct dilatation and a soft tissue mass in the hepatic hilum. Because curative surgical resection was not possible, we placed 125I seed strands and stents in the right and left intrahepatic bile ducts. Three months later, abdominal CT showed less intrahepatic and extrahepatic bile duct dilatation than before the procedure. This technique was feasible and could be considered for the treatment of patients with Bismuth type IV tumors.
doi:10.3748/wjg.v21.i1.373
PMCID: PMC4284358  PMID: 25574114
Cholangiocarcinoma; Klatskin tumor; 125I seed strands; Stent; Bismuth type IV; Bile duct
11.  Poor Lower Extremity Function Was Associated with Pre-Diabetes and Diabetes in Older Chinese People 
PLoS ONE  2014;9(12):e115883.
Objective
To determine whether a relationship exists between performance-based physical assessments and pre-diabetes/diabetes in an older Chinese population.
Methods
Our study population comprised 976 subjects (mean ± SD age: 67.6±6.0 years; 44.5% men) from the Hangu area of Tianjin, China. Diabetes was defined by self-reporting of a physician's diagnosis, or a fasting plasma glucose level ≥126 mg/dL; and pre-diabetes was defined as a fasting plasma glucose level ≥100 mg/dL and <126 mg/dL.
Results
When all other variables were adjusted for, men needing longer to finish a Timed Up and Go Test and a decreased usual walking speed had higher odds of pre-diabetes (P for trend = 0.007 and 0.008, respectively) and diabetes (P for trend = 0.012 and 0.014, respectively). However, women needing longer to finish the test and a decreased usual walking speed had a higher odds of diabetes (P for trend = 0.020 and 0.034, respectively) but not of pre-diabetes. There was no apparent association between grip strength and pre-diabetes/diabetes in both sexes.
Conclusions
In this study, poor lower extremity function was associated with pre-diabetes/diabetes in older people.
doi:10.1371/journal.pone.0115883
PMCID: PMC4274122  PMID: 25531769
12.  Arsenic exposure is associated with DNA hypermethylation of the tumor suppressor gene p16 
Background
Occupational and environmental exposure to inorganic arsenic leads to development of cancer and represents a significant health hazard in more than 70 countries. The underlying mechanism for arsenic-induced carcinogenesis remains unclear. Laboratory studies suggest that arsenic is a poor mutagen but may cause epigenetic silencing of key tumor suppressor genes such as p16 through DNA hypermethylation. However, the evidence for an association between human arsenic exposure and abnormal DNA methylation of tumor suppressor genes is lacking.
Findings
Paired case–control studies were conducted involving 40 individuals with high arsenic exposure and arsenicosis, 40 individuals with similarly high exposure to arsenic but without arsenicosis, and 40 individuals with normal exposure to arsenic. DNA methylation status of p16 was determined using methylation-specific PCR. Conditional logistic regression analysis showed that DNA hypermethylation of p16 gene was significantly associated with high arsenic exposure (Odds Ratio = 10.0, P = 0.0019) independently of the development of arsenicosis (Odds Ratio = 2.0, P = 0.1343).
Conclusions
High exposure of arsenic in human is positively linked to DNA hypermethylation of p16 gene, suggesting that epigenetic silencing of key tumor suppressor may be an important mechanism by which arsenic promotes cancer initiation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12995-014-0042-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12995-014-0042-5
PMCID: PMC4297462  PMID: 25598836
Arsenic; p16 gene; DNA methylation; Case–control study; Cancer
13.  Phase II study of weekly irinotecan and capecitabine treatment in metastatic colorectal cancer patients 
BMC Cancer  2014;14(1):986.
Background
The purpose of this phase II study was to evaluate the safety and efficacy of weekly irinotecan and capecitabine (wXELIRI) treatment in patients with metastatic colorectal cancer, specifically the rate of severe diarrhea.
Methods
Patients with unresectable histologically confirmed metastatic colorectal cancer with measurable disease received weekly irinotecan 90 mg/m2 on day 1 and capecitabine 1200 mg/m2 twice daily on days 1–5. Patients naïve to systemic chemotherapy for metastatic disease or who had failed FOLFOX (infusional 5-fluorouracil [5-FU], leucovorin, and oxaliplatin) or XELOX (capecitabine plus oxaliplatin) as first-line treatment were eligible. The primary endpoint was the rate of grade 3/4 diarrhea. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.
Results
A total of 52 patients were enrolled, 30 of whom received wXELIRI as first-line treatment and 22 as second-line treatment. Grade 4 diarrhea was observed in one patient and the rate of grade 3/4 diarrhea was 7.7%. The other common grade 3/4 toxicities included leukopenia (9.6%), neutropenia (17.3%), nausea (3.8%), vomiting (3.8%), fatigue (1.9%), and hand-foot syndrome (1.9%). The median progression-free survival and overall survival for the 30 patients treated in the first-line setting was 8.5 and 16.3 months, while those for the 22 patients treated in the second-line setting was 5.0 and 10.7 months, respectively.
Conclusions
The wXELIRI regimen resulted in a low rate of severe diarrhea with an acceptable toxicity profile. This study provides a basis for a subsequent randomized controlled study of wXELIRI versus FOLFIRI (irinotecan, 5-FU, and folinic acid) to further explore the efficacy and safety of this regimen.
Trial registration
ClinicalTrials.gov: NCT01322152.
doi:10.1186/1471-2407-14-986
PMCID: PMC4300831  PMID: 25527007
Colorectal neoplasms; Irinotecan; Capecitabine; Antineoplastic agents
14.  Reduction of Acute Rejection by Bone Marrow Mesenchymal Stem Cells during Rat Small Bowel Transplantation 
PLoS ONE  2014;9(12):e114528.
Background
Bone marrow mesenchymal stem cells (BMMSCs) have shown immunosuppressive activity in transplantation. This study was designed to determine whether BMMSCs could improve outcomes of small bowel transplantation in rats.
Methods
Heterotopic small bowel transplantation was performed from Brown Norway to Lewis rats, followed by infusion of BMMSCs through the superficial dorsal veins of the penis. Controls included rats infused with normal saline (allogeneic control), isogeneically transplanted rats (BN-BN) and nontransplanted animals. The animals were sacrificed after 1, 5, 7 or 10 days. Small bowel histology and apoptosis, cytokine concentrations in serum and intestinal grafts, and numbers of T regulatory (Treg) cells were assessed at each time point.
Results
Acute cellular rejection occurred soon after transplantation and became aggravated over time in the allogeneic control rats, with increase in apoptosis, inflammatory response, and T helper (Th)1/Th2 and Th17/Treg-related cytokines. BMMSCs significantly attenuated acute cellular rejection, reduced apoptosis and suppressed the concentrations of interleukin (IL)-2, IL-6, IL-17, IL-23, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ while upregulating IL-10 and transforming growth factor (TGF)-β expression and increasing Treg levels.
Conclusion
BMMSCs improve the outcomes of allogeneic small bowel transplantation by attenuating the inflammatory response and acute cellular rejection. Treatment with BMMSCs may overcome acute cellular rejection in small bowel transplantation.
doi:10.1371/journal.pone.0114528
PMCID: PMC4266507  PMID: 25500836
15.  Efficacy of EGFR Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Patients with/without EGFR-Mutation: Evidence Based on Recent Phase III Randomized Trials 
Background
EGFR mutation might be a predictive factor for applying EGFR-tyrosine kinase inhibitors (EGFR-TKIs, including gefitinib, erlotinib and afatinib) in non-small-cell lung cancer (NSCLS) patients. Thus, it is necessary to pool previous trials to compare the effect of EGFR-TKIs versus cytotoxic chemotherapy in EGFR mutation positive (mut+) and negative (mut−) patients.
Material/Methods
This study identified 8 first-line and 9 second-line phase III trials in databases. Hazard ratio (HR) was pooled to assess the risk of progression-free survival (PFS), and overall survival (OS), while odds ratio (OR) was pooled to assess objective response, disease control, and toxicity of EGFR-TKIs verses chemotherapy.
Results
In EGFR mut+ patients, EGFR-TKIs were associated with significantly lower risk of disease progression in the first-line setting, but this trend was only observed in the gefitinib group, not in the erlotinib group in the second-line setting. In EGFR mut− patients, gefitinib and erlotinib had significantly higher risk of disease progression in first-line and second-line setting, respectively. Compared with chemotherapy, the effects of EGFR-TKIs on OS in both first-line and second-line settings were not evident. Regarding toxicity, EGFR-TKIs had significantly higher risk of rash and lower hematological toxicity compared with chemotherapy.
Conclusions
All of the 3 EGFR-TKIs and gefitinib alone regimens had better effects in prolonging PFS in EGFR mut+ patients in first-line and second-line setting, respectively, but chemotherapy seemed more effective in EGFR mut− patients than EGFR-TKIs. Therefore, accurate identification of EGFR mutation status is useful to decide on an appropriate regimen for treatment of NSCLC patients.
doi:10.12659/MSM.892476
PMCID: PMC4271800  PMID: 25503781
Carcinoma, Non-Small-Cell Lung; Genes, erbB-1; Meta-Analysis
16.  Concerns of and coping strategies by parents of pediatric liver transplant recipients: a qualitative study from China 
Parents of liver transplant recipient children have to face complicated health issues of their children. Coping strategies of parents as major care providers not only impacts on their handling of stresses on themselves but also on the recipients’ quality of life. In this study, we sought to investigate the coping strategies of parents of Chinese pediatric liver transplant recipients at a single tertiary care institution in China. Twenty-five parents of liver transplant recipients were selected by the purposive sampling method and data was collected using qualitative semi-structured interview. Interviews were conducted until thematic saturation was achieved. We extracted 5 major themes: 1) guilt and self-blame for not giving a happy life to the sick child; 2) seeking social support for helping to treat the sick child; 3) standing firm by not giving up on treating the sick child; 4) cautious caretaking; 5) compromise: a helpless acceptance of truth. In summary, parents of transplant recipients present 5 major coping strategies. Proper assessment of stresses on parents of liver transplant recipient children and their coping strategies may help the medical staff and social services to provide more targeted support, and help and promote the balance of the family function.
PMCID: PMC4307545  PMID: 25664098
Liver transplant; children; parents; coping; qualitative study
17.  Analysis of risk factors for postoperative pancreatic fistula following pancreaticoduodenectomy 
World Journal of Gastroenterology : WJG  2014;20(46):17491-17497.
AIM: To explore the morbidity and risk factors of postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy.
METHODS: The data from 196 consecutive patients who underwent pancreaticoduodenectomy, performed by different surgeons, in the General Hospital of the People’s Liberation Army between January 1st, 2013 and December 31st, 2013 were retrospectively collected for analysis. The diagnoses of POPF and clinically relevant (CR)-POPF following pancreaticoduodenectomy were judged strictly by the International Study Group on Pancreatic Fistula Definition. Univariate analysis was performed to analyze the following factors: patient age, sex, body mass index (BMI), hypertension, diabetes mellitus, serum CA19-9 level, history of jaundice, serum albumin level, blood loss volume, pancreatic duct diameter, pylorus preserving pancreaticoduodenectomy, pancreatic drainage and pancreaticojejunostomy. Multivariate logistic regression analysis was used to determine the main independent risk factors for POPF.
RESULTS: POPF occurred in 126 (64.3%) of the patients, and the incidence of CR-POPF was 32.7% (64/196). Patient characteristics of age, sex, BMI, hypertension, diabetes mellitus, serum CA19-9 level, history of jaundice, serum albumin level, blood loss volume, pylorus preserving pancreaticoduodenectomy and pancreaticojejunostomy showed no statistical difference related to the morbidity of POPF or CR-POPF. Pancreatic duct diameter was found to be significantly correlated with POPF rates by univariate analysis and multivariate regression analysis, with a pancreatic duct diameter ≤ 3 mm being an independent risk factor for POPF (OR = 0.291; P = 0.000) and CR-POPF (OR = 0.399; P = 0.004). The CR-POPF rate was higher in patients without external pancreatic stenting, which was found to be an independent risk factor for CR-POPF (OR = 0.394; P = 0.012). Among the entire patient series, there were three postoperative deaths, giving a total mortality rate of 1.5% (3/196), and the mortality associated with pancreatic fistula was 2.4% (3/126).
CONCLUSION: A pancreatic duct diameter ≤ 3 mm is an independent risk factor for POPF. External stent drainage of pancreatic secretion may reduce CR-POPF mortality and POPF severity.
doi:10.3748/wjg.v20.i46.17491
PMCID: PMC4265610  PMID: 25516663
Pancreaticoduodenectomy; Pancreatic fistula; Complication; Pancreatic duct
18.  Inhibition of Survivin Reduces HIF-1α, TGF-β1 and TFE3 in Salivary Adenoid Cystic Carcinoma 
PLoS ONE  2014;9(12):e114051.
In the present study, we explored the expression and correlation of survivin with HIF-1α, TGF-β1 and TFE3 in adenoid cystic carcinoma (AdCC). The expression of survivin, HIF-1α, TGF-β1 and TFE3 was assessed by immunohistochemical staining of a tissue microarray containing tissue samples of normal salivary gland (NSG), pleomorphic adenoma (PA) and AdCC. Correlation analysis of these proteins revealed that increased survivin expression was associated with the overexpression of HIF-1α (P<0.001, r = 0.5599), TGF-β1 (P<0.001, r = 0.6616) and TFE3 (P<0.001, r = 0.7747). The expression of survivin, HIF-1α, TGF-β1 and TFE3 was not correlated with the pathological type of human AdCC (P>0.05). Selective inhibition of survivin by YM155 and siRNA significantly reduced human SACC-83 cell proliferation, with the corresponding decrease in expression of HIF-1α, TGF-β1 and TFE3. The data indicate that the overexpression of survivin in AdCC is related to HIF-1α, TGF-β1 and TFE3. We hypothesize from these findings that the inhibition of survivin may be a novel strategy for neoadjuvant chemotherapeutic and radiosensitive treatment of AdCC.
doi:10.1371/journal.pone.0114051
PMCID: PMC4259474  PMID: 25485635
19.  Genomes of the rice pest brown planthopper and its endosymbionts reveal complex complementary contributions for host adaptation 
Genome Biology  2014;15(12):521.
Background
The brown planthopper, Nilaparvata lugens, the most destructive pest of rice, is a typical monophagous herbivore that feeds exclusively on rice sap, which migrates over long distances. Outbreaks of it have re-occurred approximately every three years in Asia. It has also been used as a model system for ecological studies and for developing effective pest management. To better understand how a monophagous sap-sucking arthropod herbivore has adapted to its exclusive host selection and to provide insights to improve pest control, we analyzed the genomes of the brown planthopper and its two endosymbionts.
Results
We describe the 1.14 gigabase planthopper draft genome and the genomes of two microbial endosymbionts that permit the planthopper to forage exclusively on rice fields. Only 40.8% of the 27,571 identified Nilaparvata protein coding genes have detectable shared homology with the proteomes of the other 14 arthropods included in this study, reflecting large-scale gene losses including in evolutionarily conserved gene families and biochemical pathways. These unique genomic features are functionally associated with the animal’s exclusive plant host selection. Genes missing from the insect in conserved biochemical pathways that are essential for its survival on the nutritionally imbalanced sap diet are present in the genomes of its microbial endosymbionts, which have evolved to complement the mutualistic nutritional needs of the host.
Conclusions
Our study reveals a series of complex adaptations of the brown planthopper involving a variety of biological processes, that result in its highly destructive impact on the exclusive host rice. All these findings highlight potential directions for effective pest control of the planthopper.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0521-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-014-0521-0
PMCID: PMC4269174  PMID: 25609551
20.  Briarane Diterpenoids from the Gorgonian Dichotella gemmacea 
Marine Drugs  2014;12(12):6178-6189.
Seven new briarane diterpenoids, gemmacolides AS-AY (1–7), were isolated together with ten known analogues (8–17) from the South China Sea gorgonian Dichotella gemmacea. The structures of the new compounds were elucidated by the detailed analysis of spectroscopic data and comparison with reported data. The absolute configuration of compounds was determined based on electronic circular dichroism (ECD) experiments and genetic correlations as well. Compounds 15 and 16 were reported for the first time for the gorgonian. In the preliminary in vitro bioassays, compound 5 showed potential growth inhibitory activity against MG63 cells.
doi:10.3390/md12126178
PMCID: PMC4278224  PMID: 25528959
structure elucidation; briarane diterpenoids; tumor cell growth inhibitory activity; gorgonian; Dichotella gemmacea
21.  Spatiotemporal Transmission Dynamics of Hemorrhagic Fever with Renal Syndrome in China, 2005–2012 
Background
Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by many serotypes of hantaviruses. In China, HFRS has been recognized as a severe public health problem with 90% of the total reported cases in the world. This study describes the spatiotemporal dynamics of HFRS cases in China and identifies the regions, time, and populations at highest risk, which could help the planning and implementation of key preventative measures.
Methods
Data on all reported HFRS cases at the county level from January 2005 to December 2012 were collected from Chinese Center for Disease Control and Prevention. Geographic Information System-based spatiotemporal analyses including Local Indicators of Spatial Association and Kulldorff's space-time scan statistic were performed to detect local high-risk space-time clusters of HFRS in China. In addition, cases from high-risk and low-risk counties were compared to identify significant demographic differences.
Results
A total of 100,868 cases were reported during 2005–2012 in mainland China. There were significant variations in the spatiotemporal dynamics of HFRS. HFRS cases occurred most frequently in June, November, and December. There was a significant positive spatial autocorrelation of HFRS incidence during the study periods, with Moran's I values ranging from 0.46 to 0.56 (P<0.05). Several distinct HFRS cluster areas were identified, mainly concentrated in northeastern, central, and eastern of China. Compared with cases from low-risk areas, a higher proportion of cases were younger, non-farmer, and floating residents in high-risk counties.
Conclusions
This study identified significant space-time clusters of HFRS in China during 2005–2012 indicating that preventative strategies for HFRS should be particularly focused on the northeastern, central, and eastern of China to achieve the most cost-effective outcomes.
Author Summary
Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne viral disease caused by many serotypes of hantaviruses. In China, HFRS has been recognized as a severe public health problem and accounts for 90% of the reported cases in the world. We examined the spatiotemporal dynamics of HFRS cases in China during 2005–2012 and compared characteristics between cases from high-risk and low-risk counties. Several distinct HFRS cluster areas were identified, concentrated in northeastern, central, and eastern of China. Compared with cases from low-risk areas, a higher proportion of cases were younger, non-farmer, and floating residents in high-risk counties. These findings suggest preventative strategies for HFRS should be focused on the identified clusters in order to achieve the most cost-effective outcomes.
doi:10.1371/journal.pntd.0003344
PMCID: PMC4239011  PMID: 25412324
22.  Inhibition of mTOR reduce Stat3 and PAI related angiogenesis in salivary gland adenoid cystic carcinoma 
Angiogenesis is a complex biological process, which is involved in tumorigenesis and progression. However, the molecular mechanism of underlying angiogenesis remains largely unknown. In this study, we accessed the expression of proteins related angiogenesis by immunohistochemical staining of human tissue microarray which contains 72 adenoid cystic carcinoma (AdCC), 12 pleomorphic adenoma (PMA) and 18 normal salivary gland (NSG) using digital pathological scanner and scoring system. We found that the expression of p-S6S235/236 (a downstream molecule of mTOR), p-Stat3T705, PAI, EGFR, and HIF-1α was significantly increased in AdCC as compared with PMA and (or) NSG (p < 0.05). While, the expression of these proteins was not associated with pathological type of human AdCC (p > 0.05). Correlation analysis of these proteins revealed that p-S6S235/236 up-regulates the expression of EGFR/p-Stat3T705 (p < 0.05) and HIF-1α/PAI (p < 0.05). Moreover, the activation of p-S6S235/236, EGFR/p-Stat3T705 and HIF-1α/PAI associated with angiogenesis (CD34) and proliferation (Ki-67). In vitro, Rapamycin suppressed the expression of p-S6S235/236, EGFR, p-Stat3T705, HIF-1α and PAI. Further more, target inhibition of mTOR by rapamycin effectively reduced tumor growth of SACC-83 cells line nude mice xenograft and decreased the expression of p-S6S235/236, EGFR/p-Stat3T705 and HIF-1α/PAI. Taken together, these data revealed that mTOR signaling pathway regulates tumor angiogenesis by EGFR/p-Stat3T705 and HIF-1α/PAI. Inhibition of mTOR by rapamycin could effectively reduced tumor growth. It is likely that mTOR inhibitors may be a potential candidate for treatment of AdCC.
PMCID: PMC4266710  PMID: 25520866
Adenoid cystic carcinoma; angiogenesis; mTOR; Stat3; PAI; rapamycin
23.  Role of Moesin in Renal Fibrosis 
PLoS ONE  2014;9(11):e112936.
Background
Renal fibrosis is the final common pathway of chronic kidney disease (CKD). Moesin is a member of Ezrin/Radixin/Moesin (ERM) protein family but its role in renal fibrosis is not clear.
Method
Human proximal tubular cells (HK-2) were stimulated with or without TGF-β1. Moesin and downstream target genes were examined by real-time PCR and western blot. Phosphorylation of moesin and related signaling pathway was investigated as well. Rat model of unilateral ureteral obstruction (UUO) was established and renal moesin was examined by immunohistochemistry. Moesin in HK-2 cells were knocked down by siRNA and change of downstream genes in transfected HK-2 cells was studied. All animal experiments were reviewed and approved by the Ethics Committee for animal care of Ruijin Hospital.
Result
HK-2 cells stimulated with TGF-β1 showed up-regulated level of α-SMA and down-regulated level of E-Cadherin as well as elevated mRNA and protein level of moesin. In rat model of UUO, renal moesin expression increased in accordance with severity of tubulointerestital fibrosis in the kidneys with ureteral ligation while the contralateral kidneys were normal. Further study showed that TGF-β1 could induce phosphorylation of moesin which depended on Erk signaling pathway and Erk inhibitor PD98059 could block moesin phosphorylation. Effects of TGF-β1 on moesin phosphorylation was prior to its activation to total moesin. RNA silencing studies showed that knocking down of moesin could attenuate decrease of E-Cadherin induced by TGF-β1.
Conclusion
We find that moesin might be involved in renal fibrosis and its effects could be related to interacting with E-Cadherin.
doi:10.1371/journal.pone.0112936
PMCID: PMC4236084  PMID: 25406076
24.  Effect of (-)-epigallocatechin-3-gallate in preventing bone loss in ovariectomized rats and possible mechanisms 
Despite recent developments reported in studies of (-)-epigallocatechin-3-gallate (EGCG), its early preventive effect of mitigating bone loss is not well understood. We investigated the effect of EGCG in preventing bone loss in ovariectomized (OVX) female rats, and explored the possible underlying mechanisms. Twelve-week-old female Sprague-Dawley rats, were divided into 3 groups: group A received intraperitoneal EGCG for 12 consecutive weeks, begun 3 days after ovariectomy; group B received ovariectomy alone; group C, received a sham operation. At the end of the experiment, tibias and femurs were harvested for: (1) micro-CT scanning and measurement of bone mineral density (BMD) and bone morphological parameters; (2) a 3-point bending test; (3) HE staining and an immunohistological study investigating Sema4D expression. Results: The BMD and BV/TV of group A were significantly higher than for the OVX group. The trabecular separation (Tb.Sp) of group A was significantly lower than for group B. Results from the 3-point bending test showed no statistical significance among all the groups. Bone histological studies indicated that trabecular bone was denser in group C, while group B had less dense trabecular bone, and the bone morphological status of group A was intermediate between groups A and C. The immunohistological study demonstrated that Sema4D was more highly expressed as a percentage of the brown-stained area in group B than in the other 2 groups. Conclusion: EGCG had a positive effect on mitigating bone loss in ovariectomized rats, and it inhibited Sema4D expression in bone tissue. Early stage supplementation of EGCG at a dose of 10 mg/kg/day after the onset of ovariectomy did not entirely eliminate bone loss.
PMCID: PMC4276187  PMID: 25550929
EGCG; osteoporosis; bone loss; microarchitecture; BMD; Sema4D
25.  Association between Hemorrhagic Fever with Renal Syndrome Epidemic and Climate Factors in Heilongjiang Province, China 
The purpose of this study was to quantify the relationship between climate variation and transmission of hemorrhagic fever with renal syndrome (HFRS) in Heilongjiang Province, a highly endemic area for HFRS in China. Monthly notified HFRS cases and climatic data for 2001–2009 in Heilongjiang Province were collected. Using a seasonal autoregressive integrated moving average model, we found that relative humidity with a one-month lag (β = –0.010, P = 0.003) and a three-month lag (β = 0.008, P = 0.003), maximum temperature with a two-month lag (β = 0.082, P = 0.028), and southern oscillation index with a two-month lag (β = –0.048, P = 0.019) were significantly associated with HFRS transmission. Our study also showed that predicted values expected under the seasonal autoregressive integrated moving average model were highly consistent with observed values (Adjusted R2 = 83%, root mean squared error = 108). Thus, findings may help add to the knowledge gap of the role of climate factors in HFRS transmission in China and also assist national local health authorities in the development/refinement of a better strategy to prevent HFRS transmission.
doi:10.4269/ajtmh.12-0473
PMCID: PMC3820312  PMID: 24019443

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