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1.  Genome-wide association analysis identifies genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum from China-Myanmar border 
Scientific Reports  2016;6:33891.
Drug resistance has emerged as one of the greatest challenges facing malaria control. The recent emergence of resistance to artemisinin (ART) and its partner drugs in ART-based combination therapies (ACT) is threatening the efficacy of this front-line regimen for treating Plasmodium falciparum parasites. Thus, an understanding of the molecular mechanisms that underlie the resistance to ART and the partner drugs has become a high priority for resistance containment and malaria management. Using genome-wide association studies, we investigated the associations of genome-wide single nucleotide polymorphisms with in vitro sensitivities to 10 commonly used antimalarial drugs in 94 P. falciparum isolates from the China-Myanmar border area, a region with the longest history of ART usage. We identified several loci associated with various drugs, including those containing pfcrt and pfdhfr. Of particular interest is a locus on chromosome 10 containing the autophagy-related protein 18 (ATG18) associated with decreased sensitivities to dihydroartemisinin, artemether and piperaquine – an ACT partner drug in this area. ATG18 is a phosphatidylinositol-3-phosphate binding protein essential for autophagy and recently identified as a potential ART target. Further investigations on the ATG18 and genes at the chromosome 10 locus may provide an important lead for a connection between ART resistance and autophagy.
doi:10.1038/srep33891
PMCID: PMC5046179  PMID: 27694982
2.  Clinical Efficacy of Dihydroartemisinin–Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria at the China–Myanmar Border 
Artemisinin-based combination therapies (ACTs) are currently used as the first-line therapy for uncomplicated Plasmodium falciparum malaria. However, the recent emergence and/or spread of artemisinin resistance in parts of Greater Mekong Subregion (GMS) of southeast Asia requires close monitoring of the therapeutic efficacy of ACTs. This study was conducted from March 2012 to December 2013 in four clinics and seven villages along the China–Myanmar border. A total of 109 patients with uncomplicated falciparum malaria were treated with dihydroartemisinin–piperaquine (DP) and followed up on days 1, 2, 3, 7, 14, 21, 28, and 42 after treatment. A total of 71 patients (22 children and 49 adults) completed the 42-day follow-up. DP remained highly efficacious for treatment of uncomplicated falciparum malaria with an overall 42-day cure rate of 100%. The day 3 parasite-positive rate was 7.04% (5/71). Within 14 days of treatment, a total of 13 (18.31%) patients had detectable gametocytes and a large proportion of these were persistent from the first three days of treatment. The presence of gametocytes in patients through 14 days after DP treatment suggests that the incorporation of a single dose of primaquine for clearing gametocytemia should be considered for blocking parasite transmission.
doi:10.4269/ajtmh.15-0029
PMCID: PMC4720921  PMID: 26283743
3.  A prognostic risk model for patients with triple negative breast cancer based on stromal natural killer cells, tumor‐associated macrophages and growth‐arrest specific protein 6 
Cancer Science  2016;107(7):882-889.
The aim of this study was to establish a prognostic risk model for patients with triple negative breast cancer (TNBC). A total of 278 specimens of human TNBC tissues were investigated by immunohistochemistry for growth‐arrest specific protein 6 expression, infiltrations of stromal natural killer cells and tumor‐associated macrophages. According to their prognostic risk scores based on the model, patients were divided into three groups (score 0, 1–2, 3). Correlations of prognostic risk scores, clinicopathologic features and overall survival (OS) were analyzed. To study the clinical value of this stratification model in early disease recurrence or metastasis, 177 patients were screened out for further analysis. Based on disease free survival (DFS), 90 patients fell within the DFS ≤3 years group and 87 patients within the DFS ≥5 years group. We analyzed the differences in prognostic risk scores between the two groups. The prognostic risk scores were negatively related to tumor size, lymph node metastasis and P53 status (P < 0.001 for all). Patients with low prognostic risk scores had longer OS (P = 0.001). Using multivariate analysis, it was determined that TNM stage (HR = 0.432, 95% confidence interval [CI] = 0.281–0.665, P = 0.003), FOXP3 positive lymphocytes (HR = 1.712, 95% CI = 1.085–2.702, P = 0.021) and prognostic risk scores (HR = 1.340, 95% CI = 1.192–1.644, P = 0.005) were independent prognostic factors for OS. Compared with the DFS ≥5 years group, the DFS ≤3 years group patients had significantly higher prognostic risk scores (P < 0.001). In conclusion, the prognostic risk score of the model was a significant indicator of prognosis for patients with TNBC.
doi:10.1111/cas.12964
PMCID: PMC4946705  PMID: 27145494
Growth‐arrest specific gene 6; natural killer cell; prognostic predictor; triple negative breast cancer; tumor‐associated macrophages
4.  Therapeutic Responses of Plasmodium vivax Malaria to Chloroquine and Primaquine Treatment in Northeastern Myanmar 
Chloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure of Plasmodium vivax malaria. Emergence of CQ-resistant (CQR) P. vivax parasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ for P. vivax malaria in northeast Myanmar. We recruited 587 patients with P. vivax monoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28-day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3α gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine of P. vivax in northeastern Myanmar may be deteriorating.
doi:10.1128/AAC.04270-14
PMCID: PMC4335844  PMID: 25512415
5.  Decision-Making in Patients with Hyperthyroidism: A Neuropsychological Study 
PLoS ONE  2015;10(6):e0129773.
Introduction
Cognitive and behavioral impairments are common in patients with abnormal thyroid function; these impairments cause a reduction in their quality of life. The current study investigates the decision making performance in patients with hyperthyroidism to explore the possible mechanism of their cognitive and behavioral impairments.
Methods
Thirty-eight patients with hyperthyroidism and forty healthy control subjects were recruited to perform the Iowa Gambling Task (IGT), which assessed decision making under ambiguous conditions.
Results
Patients with hyperthyroidism had a higher score on the Zung Self-Rating Anxiety Scale (Z-SAS), and exhibited poorer executive function and IGT performance than did healthy control subjects. The patients preferred to choose decks with a high immediate reward, despite a higher future punishment, and were not capable of effectively using feedback information from previous choices. No clinical characteristics were associated with the total net score of the IGT in the current study.
Conclusions
Patients with hyperthyroidism had decision-making impairment under ambiguous conditions. The deficits may result from frontal cortex and limbic system metabolic disorders and dopamine dysfunction.
doi:10.1371/journal.pone.0129773
PMCID: PMC4474662  PMID: 26090955
6.  Refrigeration provides a simple means to synchronize in vitro cultures of Plasmodium falciparum 
Experimental parasitology  2014;140:18-23.
Plasmodium falciparum is usually asynchronous during in vitro culture. Highly synchronized cultures of Plasmodium falciparum are routinely used in malaria research. Here, we describe a simple synchronization procedure for P. falciparum asexual erythrocytic culture, which involves storage at 4°C for 8–24 h followed by routine culture. When cultures with 27–60% of ring stage were synchronized using this procedure, 70–93% ring stages were obtained after 48 h of culture and relative growth synchrony remained for at least two erythrocytic cycles. To test the suitability of this procedure for subsequent work, drug sensitivity assays were performed using four laboratory strains and four freshly adapted clinical P. falciparum isolates. Parasites synchronized by sorbitol treatment or refrigeration showed similar dose-response curves and comparable IC50 values to four antimalarial drugs. The refrigeration synchronization method is simple, inexpensive, time-saving, and should be especially useful when large numbers of P. falciparum culture are handled.
doi:10.1016/j.exppara.2014.03.010
PMCID: PMC4018460  PMID: 24632190
Synchronization; Plasmodium falciparum; Refrigeration; Drug susceptibility
7.  Prevalence of K13-propeller polymorphisms in Plasmodium falciparum from China-Myanmar border in 2007–2012 
Malaria Journal  2015;14:168.
Background
The recent emergence and spread of artemisinin resistance in the Greater Mekong Subregion poses a great threat to malaria control and elimination. A K13-propeller gene (K13), PF3D7_1343700, has been associated lately with artemisinin resistance both in vitro and in vivo. This study aimed to investigate the K13 polymorphisms in Plasmodium falciparum parasites from the China-Myanmar border area where artemisinin use has the longest history.
Methods
A total of 180 archived P. falciparum isolates containing 191 parasite clones, mainly collected in 2007–2012 from the China-Myanmar area, were used to obtain the full-length K13 gene sequences.
Results
Seventeen point mutations were identified in 46.1% (88/191) parasite clones, of which seven were new. The F446I mutation predominated in 27.2% of the parasite clones. The C580Y mutation that is correlated with artemisinin resistance was detected at a low frequency of 1.6%. Collectively, 43.1% of the parasite clones contained point mutations in the kelch domain of the K13 gene. Moreover, there was a trend of increase in the frequency of parasites carrying kelch domain mutations through the years of sample collection. In addition, a microsatellite variation in the N-terminus of the K13 protein was found to have reached a high frequency (69.1%).
Conclusions
This study documented the presence of mutations in the K13 gene in parasite populations from the China-Myanmar border. Mutations present in the kelch domain have become prevalent (>40%). A predominant mutation F446I and a prevalent microsatellite variation in the N-terminus were identified, but their importance in artemisinin resistance remains to be elucidated.
doi:10.1186/s12936-015-0672-9
PMCID: PMC4404080  PMID: 25927592
Malaria; Plasmodium falciparum; artemisinin resistance; K13 gene; F3D7_1343700
8.  Fabrication of thickness controllable free-standing sandwich-structured hybrid carbon film for high-rate and high-power supercapacitor 
Scientific Reports  2014;4:7050.
Hybrid carbon films composed of graphene film and porous carbon film may give full play to the advantages of both carbon materials, and have great potential for application in energy storage and conversion devices. Unfortunately, there are very few reports on fabrication of hybrid carbon films. Here we demonstrate a simple approach to fabricate free-standing sandwich-structured hybrid carbon film composed of porous amorphous carbon film and multilayer graphene film by chemical vapor deposition in a controllable and scalable way. Hybrid carbon films reveal good electrical conductivity, excellent flexibility, and good compatibility with substrate. Supercapacitors assembled by hybrid carbon films exhibit ultrahigh rate capability, wide frequency range, good capacitance performance, and high-power density. Moreover, this approach may provide a general path for fabrication of hybrid carbon materials with different structures by using different metals with high carbon solubility, and greatly expands the application scope of carbon materials.
doi:10.1038/srep07050
PMCID: PMC4231341  PMID: 25394410
9.  Plasmodium falciparum populations from northeastern Myanmar display high levels of genetic diversity at multiple antigenic loci 
Acta tropica  2012;125(1):53-59.
Levels of genetic diversity of the malaria parasites and multiclonal infections are correlated with transmission intensity. In order to monitor the effect of strengthened malaria control efforts in recent years at the China-Myanmar border area, we followed the temporal dynamics of genetic diversity of three polymorphic antigenic markers msp1, msp2, and glurp in the Plasmodium falciparum populations. Despite reduced malaria prevalence in the region, parasite populations exhibited high levels of genetic diversity. Genotyping 258 clinical samples collected in four years detected a total of 22 PCR size alleles. Multiclonal infections were detected in 45.7% of the patient samples, giving a minimum multiplicity of infection of 1.41. The majority of alleles experienced significant temporal fluctuations through the years. Haplotype diversity based on the three-locus genotypes ranged from the lowest in 2009 at 0.33 to the highest in 2010 at 0.80. Sequencing of msp1 fragments from 36 random samples of five allele size groups detected 13 different sequences, revealing an additional layer of genetic complexity. This study suggests that despite reduced prevalence of malaria infections in this region, the parasite population size and transmission intensity remained high enough to allow effective genetic recombination of the parasites and continued maintenance of genetic diversity.
doi:10.1016/j.actatropica.2012.09.008
PMCID: PMC3496066  PMID: 23000544
Plasmodium falciparum; antigenic diversity; border malaria; multiplicity of infection
10.  In Vitro Sensitivities of Plasmodium falciparum Isolates from the China-Myanmar Border to Piperaquine and Association with Polymorphisms in Candidate Genes 
The recent reports of resistance in Plasmodium falciparum to artemisinin derivatives and their partner drugs demand intensive studies toward understanding the molecular mechanisms of resistance. In this study, we examined the in vitro susceptibility of 63 P. falciparum field isolates collected from the China-Myanmar border area to chloroquine (CQ) and piperaquine (PPQ). Parasite isolates remained highly resistant to CQ, with the geometric mean 50% inhibitory concentration (IC50) of 252.7 nM and a range of 51.9 to 1,052.0 nM. In comparison, these parasites had a geometric mean IC50 of 28.4 nM for PPQ, with a fairly wide range of 5.3 to 132.0 nM, suggesting that certain parasite isolates displayed relatively high levels of resistance to PPQ. Interestingly, within the 4 years of study, the parasites exhibited a continuous decline in susceptibilities to both CQ and PPQ, and there was a significant correlation between responses to CQ and PPQ (Pearson correlation coefficient = 0.79, P < 0.0001). Consistent with the CQ-resistant phenotype, all parasites carried the pfcrt K76T mutation, and most parasites had the CVIET type that is prevalent in Southeast Asia. In contrast, pfmdr1 mutations were relatively rare, and no gene amplification was detected. Only the pfmdr1 N1042D mutation was associated with resistance to CQ. For the pfmrp1 gene, four substitutions reached relatively high prevalence of >22%, and the I876V mutation was associated with reduced sensitivity to CQ. However, we could not establish a link between PPQ responses and the polymorphisms in the three genes associated with quinoline drug resistance.
doi:10.1128/AAC.02306-12
PMCID: PMC3623367  PMID: 23357760
11.  Genetic Diversity and Lack of Artemisinin Selection Signature on the Plasmodium falciparum ATP6 in the Greater Mekong Subregion 
PLoS ONE  2013;8(3):e59192.
The recent detection of clinical Artemisinin (ART) resistance manifested as delayed parasite clearance in the Cambodia-Thailand border area raises a serious concern. The mechanism of ART resistance is not clear; but the P. falciparum sarco/endoplasmic reticulum Ca2+-ATPase (PfSERCA or PfATP6) has been speculated to be the target of ARTs and thus a potential marker for ART resistance. Here we amplified and sequenced pfatp6 gene (∼3.6 Kb) in 213 samples collected after 2005 from the Greater Mekong Subregion, where ART drugs have been used extensively in the past. A total of 24 single nucleotide polymorphisms (SNPs), including 8 newly found in this study and 13 nonsynonymous, were identified. However, these mutations were either uncommon or also present in other geographical regions with limited ART use. None of the mutations were suggestive of directional selection by ARTs. We further analyzed pfatp6 from a worldwide collection of 862 P. falciparum isolates in 19 populations from Asia, Africa, South America and Oceania, which include samples from regions prior to and after deployments ART drugs. A total of 71 SNPs were identified, resulting in 106 nucleotide haplotypes. Similarly, many of the mutations were continent-specific and present at frequencies below 5%. The most predominant and perhaps the ancestral haplotype occurred in 441 samples and was present in 16 populations from Asia, Africa, and Oceania. The 3D7 haplotype found in 54 samples was the second most common haplotype and present in nine populations from all four continents. Assessment of the selection strength on pfatp6 in the 19 parasite populations found that pfatp6 in most of these populations was under purifying selection with an average dN/dS ratio of 0.333. Molecular evolution analyses did not detect significant departures from neutrality in pfatp6 for most populations, challenging the suitability of this gene as a marker for monitoring ART resistance.
doi:10.1371/journal.pone.0059192
PMCID: PMC3608609  PMID: 23555629
12.  Factors associated with willingness to participate in free HIV test among general residents in Heilongjiang, Northeast China 
BMC Infectious Diseases  2012;12:256.
Background
The human immunodeficiency virus (HIV) is spreading from high-risk groups, such as men who have sex with men (MSM) and sex workers, to the general population in China. This study examined the willingness of general residents in Heilongjiang, Northeast China, to participate in free HIV testing in the nearest health care setting, and the factors that may affect participation, including demographic characteristics, HIV-related knowledge, and stigma.
Methods
A cross-sectional study was conducted in Heilongjiang Province. All residents aged 15–69 years in two communities in urban areas (September 2007) and four villages in rural areas (April 2008) were recruited using stratified cluster sampling. A total of 4050 residents were interviewed using an anonymous questionnaire. Univariate and multivariate log-binomial regression were used to analyze factors affecting willingness to undergo HIV testing.
Results
The proportions of participants who were willing to participate in free HIV testing was 73.0% in urban residents and 78.8% in rural residents. Multivariate regression analysis among urban participants showed that greater knowledge of HIV transmission misconceptions (relative risk (RR) = 1.02, 95% confidence interval (CI): 1.00–1.04, P = 0.021) and the awareness that an apparently healthy person can be an HIV carrier (RR = 1.12, 95%CI: 1.03–1.21, P = 0.007) was significantly associated with greater willingness to participate in free HIV testing. Among rural participants, greater knowledge of HIV transmission modes (RR = 1.03, 95%CI: 1.01–1.06 P = 0.001) and the awareness that an apparently healthy person can be an HIV carrier (RR = 1.07; 95%CI: 1.01–1.13 P = 0.019) was significantly associated with greater willingness to participate.
Conclusions
The overall level of willingness to accept free HIV testing is high, and is higher in rural residents than in urban residents in Heilongjiang. knowledge of HIV transmission misconceptions and that an apparently healthy person can be a carrier for HIV were associated with willingness to accept free HIV testing among urban residents, while knowledge of HIV transmission modes and that an apparently healthy person can be a carrier for HIV were associated with willingness to accept free HIV testing among rural residents.
doi:10.1186/1471-2334-12-256
PMCID: PMC3482579  PMID: 23057556
HIV; Knowledge; Public stigma; Willingness; General individuals

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