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1.  A variational Bayes discrete mixture test for rare variant association 
Genetic epidemiology  2014;38(1):21-30.
Recently, many statistical methods have been proposed to test for associations between rare genetic variants and complex traits. Most of these methods test for association by aggregating genetic variations within a predefined region, such as a gene. Although there is evidence that “aggregate” tests are more powerful than the single marker test, these tests generally ignore neutral variants and therefore are unable to identify specific variants driving the association with phenotype. We propose a novel aggregate rare-variant test that explicitly models a fraction of variants as neutral, tests associations at the gene-level, and infers the rare-variants driving the association. Simulations show that in the practical scenario where there are many variants within a given region of the genome with only a fraction causal our approach has greater power compared to other popular tests such as the Sequence Kernel Association Test (SKAT), the Weighted Sum Statistic (WSS), and the collapsing method of Morris and Zeggini (MZ). Our algorithm leverages a fast variational Bayes approximate inference methodology to scale to exome-wide analyses, a significant computational advantage over exact inference model selection methodologies. To demonstrate the efficacy of our methodology we test for associations between von Willebrand Factor (VWF) levels and VWF missense rare-variants imputed from the National Heart, Lung, and Blood Institute’s Exome Sequencing project into 2,487 African Americans within the VWF gene. Our method suggests that a relatively small fraction (~10%) of the imputed rare missense variants within VWF are strongly associated with lower VWF levels in African Americans.
PMCID: PMC4030763  PMID: 24482836
Exome sequencing study; approximate inference; von Willebrand Factor genetics
2.  MiR-23a Facilitates the Replication of HSV-1 through the Suppression of Interferon Regulatory Factor 1 
PLoS ONE  2014;9(12):e114021.
MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate gene expression. It has been reported that miRNAs are involved in host-virus interaction, but evidence that cellular miRNAs promote virus replication has been limited. Here, we found that miR-23a promoted the replication of human herpes simplex virus type 1 (HSV-1) in HeLa cells, as demonstrated by a plaque-formation assay and quantitative real-time PCR. Furthermore, interferon regulatory factor 1 (IRF1), an innate antiviral molecule, is targeted by miR-23a to facilitate viral replication. MiR-23a binds to the 3′UTR of IRF1 and down-regulates its expression. Suppression of IRF1 expression reduced RSAD2 gene expression, augmenting HSV-1 replication. Ectopic expression of IRF1 abrogated the promotion of HSV-1 replication induced by miR-23a. Notably, IRF1 contributes to innate antiviral immunity by binding to IRF-response elements to regulate the expression of interferon-stimulated genes (ISGs) and apoptosis, revealing a complex interaction between miR-23a and HSV-1. MiR-23a thus contributes to HSV-1 replication through the regulation of the IRF1-mediated antiviral signal pathway, which suggests that miR-23a may represent a promising target for antiviral treatments.
PMCID: PMC4252059  PMID: 25461762
3.  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.
PMCID: PMC4278224  PMID: 25528959
structure elucidation; briarane diterpenoids; tumor cell growth inhibitory activity; gorgonian; Dichotella gemmacea
4.  Patients’ expectations to dental implant: a systematic review of the literature 
To examine the current literature on the impact of patients’ expectations on treatment outcomes or final patient satisfaction and to identify the theoretical frameworks, study designs and measurement instruments which have been employed to assess patients’ expectations within implant dentistry.
A structured literature search of four databases Pubmed, Cochrane, Web of Science and PsychINFO was conducted following PRISMA guidelines. Any type of literature published in English discussing the topic of ‘patients expectations’ in oral health were identified and further screened. Studies reporting on expectations regarding dental implants were selected and a narrative review was conducted.
The initial search yielded 16707 studies, out of which 1051 ‘potentially effective studies’ were further assessed and final 41 ‘effective studies’ were included [Kappa = 0.76]. Ten observational studies, published from 1999 to 2013, dealt specifically with expectations of dental implants. There was a large degree of heterogeneity among studies in terms of assessment instruments. Expectations relating to aesthetics and function were primarily considered. Among the 10 studies, 8 were classified as quantitative research and 2 as qualitative research. The STROBE quality of reporting scores of the studies ranged from 13.5 to 18.0. Three of the 8 quantitative studies employed a before/after study design (prospective studies) and used visual analogue scales (VAS) to measure patient expectations.
There is a growing interest in patients’ expectations of dental implants. Most studies are cross sectional in nature and the quality of reporting varies considerably. Expectations with respect to aesthetics and function are key attributes considered. The use of visual analogue scales (VAS) provides quantitative assessments of patients’ expectations but the lack of standardization of measures prohibits meta- analyses.
PMCID: PMC4221691  PMID: 25358599
Dental implant; Patients’ expectations; Systematic review
5.  Complex interactions between microRNAs and hepatitis B/C viruses 
World Journal of Gastroenterology : WJG  2014;20(37):13477-13492.
MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate the expression of many target genes via mRNA degradation or translation inhibition. Many studies have shown that miRNAs are involved in the modulation of gene expression and replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) and play a pivotal role in host-virus interactions. Increasing evidence also demonstrates that viral infection leads to alteration of the miRNA expression profile in hepatic tissues or circulation. The deregulated miRNAs participate in hepatocellular carcinoma (HCC) initiation and progression by functioning as oncogenes or tumor suppressor genes by targeting various genes involved in cancer-related signaling pathways. The distinct expression pattern of miRNAs may be a useful marker for the diagnosis and prognosis of virus-related diseases considering the limitation of currently used biomarkers. Moreover, the role of deregulated miRNA in host-virus interactions and HCC development suggested that miRNAs may serve as therapeutic targets or as tools. In this review, we summarize the recent findings about the deregulation and the role of miRNAs during HBV/HCV infection and HCC development, and we discuss the possible mechanism of action of miRNAs in the pathogenesis of virus-related diseases. Furthermore, we discuss the potential of using miRNAs as markers for diagnosis and prognosis as well as therapeutic targets and drugs.
PMCID: PMC4188899  PMID: 25309078
MicroRNA; Hepatitis B/C virus; Host-virus interaction; Biomarker; Therapy
6.  The Association of the Vanin-1 N131S Variant with Blood Pressure Is Mediated by Endoplasmic Reticulum-Associated Degradation and Loss of Function 
PLoS Genetics  2014;10(9):e1004641.
High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)–rs2272996–in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P = 0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD) as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT) vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism.
Author Summary
Hypertension (HTN) or high blood pressure (BP) is common worldwide and a major risk factor for cardiovascular disease and all-cause mortality. Identification of genetic variants of consequence for HTN serves as the molecular basis for its treatment. Using admixture mapping analysis of the Family Blood Pressure Program data, we recently identified that the VNN1 gene (encoding the protein vanin-1), in particular SNP rs2272996 (N131S), was associated with BP in both African Americans and Mexican Americans. Vanin-1 was reported to act as an oxidative stress sensor using its pantetheinase enzyme activity. Because a linkage between oxidative stress and HTN has been hypothesized for many years, vanin-1's pantetheinase activity offers a physiologic rationale for BP regulation. Here, we first replicated the association of rs2272996 with BP in the Continental Origins and Genetic Epidemiology Network (COGENT), which included nearly 30,000 African Americans. We further demonstrated that the N131S mutation in vanin-1 leads to its rapid degradation in cells, resulting in loss of function on the plasma membrane. The loss of function of vanin-1 is associated with reduced BP. Therefore, our results indicate that vanin-1 is a new candidate to be manipulated to ameliorate HTN.
PMCID: PMC4169380  PMID: 25233454
7.  Relationship between TLR4 and NF-κB p65 protein expressions and clinical radiosensitivity of patients with esophageal squamous cell carcinoma 
Objective: To study the relationship between TLR4 and NF-κB p65 protein expressions in tumor tissues after radiotherapy and clinical radiosensitivity of patients with esophageal squamous cell carcinoma.
Methods: A total of 93 patients with esophageal squamous cell carcinoma first treated in our hospital by radiotherapy and surgeries from November 2010 to December 2013 were selected. They were then divided into a severe reaction group, a moderate reaction group and a mild reaction group according to the postoperative pathological examination results of tumor tissues. The expressions of TLR4 and NF-κB p65 in the tumor samples were detected by Western blotting.
Results: Compared with the severe reaction group, the expression levels of TLR4 and NF-κB p65 in the moderate reaction group significantly increased (P<0.05). Similarly, the expression levels of the mild reaction group were significantly higher than those of the moderate reaction group (P<0.05).
Conclusion: Reducing the expression levels of TLR4 and NF-κB p65 proteins may increase the radiosensitivity of patients with esophageal cancer.
PMCID: PMC4163217  PMID: 25225511
Esophageal cancer; Radiotherapy; TLR4; NF-κB
8.  Protein Kinase D Is Increased and Activated in Lung Epithelial Cells and Macrophages in Idiopathic Pulmonary Fibrosis 
PLoS ONE  2014;9(7):e101983.
Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and usually fatal lung disease of unknown etiology for which no effective treatments currently exist. Hence, there is a profound need for the identification of novel drugable targets to develop more specific and efficacious therapeutic intervention in IPF. In this study, we performed immunohistochemical analyses to assess the cell type-specific expression and activation of protein kinase D (PKD) family kinases in normal and IPF lung tissue sections. We also analyzed PKD activation and function in human lung epithelial cells. We found that PKD family kinases (PKD1, PKD2 and PKD3) were increased and activated in the hyperplastic and regenerative alveolar epithelial cells lining remodeled fibrotic alveolar septa and/or fibroblast foci in IPF lungs compared with normal controls. We also found that PKD family kinases were increased and activated in alveolar macrophages, bronchiolar epithelium, and honeycomb cysts in IPF lungs. Interestingly, PKD1 was highly expressed and activated in the cilia of IPF bronchiolar epithelial cells, while PKD2 and PKD3 were expressed in the cell cytoplasm and nuclei. In contrast, PKD family kinases were not apparently increased and activated in IPF fibroblasts or myofibroblasts. We lastly found that PKD was predominantly activated by poly-L-arginine, lysophosphatidic acid and thrombin in human lung epithelial cells and that PKD promoted epithelial barrier dysfunction. These findings suggest that PKD may participate in the pathogenesis of IPF and may be a novel target for therapeutic intervention in this disease.
PMCID: PMC4084945  PMID: 25000413
9.  Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network 
Human Molecular Genetics  2013;22(12):2529-2538.
Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ∼16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E−13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E − 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.
PMCID: PMC3658166  PMID: 23446634
10.  NF-κB-modulated miR-130a targets TNF-α in cervical cancer cells 
Nuclear factor-κB (NF-κB) induces a variety of biological processes through transcriptional gene control whose products are components in various signaling pathways. MicroRNAs are a small endogenous non-coding RNAs that regulate gene expression and are involved in tumorigenesis. Using human cervical cancer cell lines, this study aimed to investigate whether NF-κB could regulate miR-130a expression and the functions and targets of miR-130a.
We used the HeLa and C33A cervical cancer cell lines that were transfected with NF-κB or miR-130a overexpression plasmids to evaluate their effects on cell growth. We utilized bioinformatics, a fluorescent reporter assay, qRT-PCR and Western blotting to identify downstream target genes.
In HeLa and C33A cells, NF-κB and miR-130a overexpression promoted cell growth, but genetic knockdowns suppressed growth. TNF-α was identified as a target of miR-130a by binding in a 3’-untranslated region (3’UTR) EGFP reporter assay and by Western blot analysis. Furthermore, low TNF-α concentrations stimulated NF-κB activity and then induced miR-130a expression, and TNF-α overexpression rescued the effects of miR-130a on cervical cancer cells.
Our findings indicate that TNF-α can activate NF-κB activity, which can reduce miR-130a expression, and that miR-130a targets and downregulates TNF-α expression. Hence, we shed light on the negative feedback regulation of NF-κB/miR-130a/TNF-α/NF-κB in cervical cancer and may provide insight into the carcinogenesis of cervical cancer.
PMCID: PMC4084577  PMID: 24885472
miRNA; miRNA-130a; NF-κB; Cervical cancer; TNF-α
11.  Resistance to Botrytis cinerea in Solanum lycopersicoides involves widespread transcriptional reprogramming 
BMC Genomics  2014;15(1):334.
Tomato (Solanum lycopersicum), one of the world’s most important vegetable crops, is highly susceptible to necrotrophic fungal pathogens such as Botrytis cinerea and Alternaria solani. Improving resistance through conventional breeding has been hampered by a shortage of resistant germplasm and difficulties in introgressing resistance into elite germplasm without linkage drag. The goal of this study was to explore natural variation among wild Solanum species to identify new sources of resistance to necrotrophic fungi and dissect mechanisms underlying resistance against B. cinerea.
Among eight wild species evaluated for resistance against B. cinerea and A. solani, S. lycopersicoides expressed the highest levels of resistance against both pathogens. Resistance against B. cinerea manifested as containment of pathogen growth. Through next-generation RNA sequencing and de novo assembly of the S. lycopersicoides transcriptome, changes in gene expression were analyzed during pathogen infection. In response to B. cinerea, differentially expressed transcripts grouped into four categories: genes whose expression rapidly increased then rapidly decreased, genes whose expression rapidly increased and plateaued, genes whose expression continually increased, and genes with decreased expression. Homology-based searches also identified a limited number of highly expressed B. cinerea genes. Almost immediately after infection by B. cinerea, S. lycopersicoides suppressed photosynthesis and metabolic processes involved in growth, energy generation, and response to stimuli, and simultaneously induced various defense-related genes, including pathogenesis-related protein 1 (PR1), a beta-1,3-glucanase (glucanase), and a subtilisin-like protease, indicating a shift in priority towards defense. Moreover, cluster analysis revealed novel, uncharacterized genes that may play roles in defense against necrotrophic fungal pathogens in S. lycopersicoides. The expression of orthologous defense-related genes in S. lycopersicum after infection with B. cinerea revealed differences in the onset and intensity of induction, thus illuminating a potential mechanism explaining the increased susceptibility. Additionally, metabolic pathway analyses identified putative defense-related categories of secondary metabolites.
In sum, this study provided insight into resistance against necrotrophic fungal pathogens in the Solanaceae, as well as novel sequence resources for S. lycopersicoides.
Electronic supplementary material
The online version of this article (doi: 10.1186/1471-2164-15-334) contains supplementary material, which is available to authorized users.
PMCID: PMC4035065  PMID: 24885798
Necrotrophic pathogenesis; Botrydial; Phytoalexins
12.  Helicobacter pylori isolates from ethnic minority patients in Guangxi: Resistance rates, mechanisms, and genotype 
AIM: To investigate the rate of Helicobacter pylori (H. pylori) resistance to clarithromycin among ethnic minority patients in Guangxi, explore the underlying mechanisms, and analyze factors influencing genotype distribution of H. pylori isolates.
METHODS: H. pylori strains were isolated, cultured and subjected to drug sensitivity testing. The 23S rRNA gene of H. pylori isolates was amplified by PCR and analyzed by PCR-RFLP and direct sequencing to detect point mutations. REP-PCR was used for genotyping of H. pylori isolates, and NTsys_2 software was used for clustering analysis based on REP-PCR DNA fingerprints. Factors potentially influencing genotype distribution of H. pylori isolates were analyzed.
RESULTS: The rate of clarithromycin resistance was 31.3%. A2143G and A2144G mutations were detected in the 23S rRNA gene of all clarithromycin-resistant H. pylori isolates. At a genetic distance of 78%, clarithromycin-resistant H. pylori isolates could be divided into six groups. Significant clustering was noted among H. pylori isolates from patients with peptic ulcer or gastritis.
CONCLUSION: The rate of clarithromycin resistance is relatively high in ethnic minority patients in Guangxi. Main mechanisms of clarithromycin resistance are A2143G and A2144G mutations in the 23S rRNA gene. Clarithromycin-resistant H. pylori isolates can be divided into six groups based on REP-PCR DNA fingerprints. Several factors such as disease type may influence the genotype distribution of H. pylori isolates.
PMCID: PMC4000514  PMID: 24782630
Helicobacter pylori; Antibiotic resistance; Mechanism; Clarithromycin; Genotype
13.  Post-Esophagectomy Tube Feeding: A Retrospective Comparison of Jejunostomy and a Novel Gastrostomy Feeding Approach 
PLoS ONE  2014;9(3):e89190.
McKeown-type esophagectomy combined with retrosternal reconstruction is a common surgical treatment for esophageal cancer. Various enteral feeding options are available post-esophagectomy, but no definitive preference exists.
“Retrosternal Route Gastrostomy Feeding (RGF)” was developed as an alternative enteral feeding approach that requires few additional surgical interventions. RGF is based on McKeown-type esophagectomy. We retrospectively compared RGF (n = 121) to jejunostomy feeding (JF) (n = 153) in 274 patients at the Department of Cardiothoracic Surgery in Changzheng Hospital (Shanghai, China) between June 2008 and Sept. 2012. Data pertaining to efficacy and procedural complications were compared among patients.
RGF had a significantly shorter postoperative hospital stay (11 vs. 15 days, p<0.001) and time to removal of the feeding tube (9 vs. 14 days, p<0.001) compared to JF. Bowel obstruction (0.0% vs. 7.2% p = 0.003), abdominal distension (9.1% vs. 19% p = 0.022), and the occurrence of pneumonia (11.6% vs. 26.1% p = 0.003) were significantly lower in the RGF group. Feeding tube related complications and the associated morbidity rate were reduced in the RGF group. The two groups had similar tolerance to surgery.
Our data suggests that RGF is a safe post-esophagectomy enteral feeding alternative to JF.
PMCID: PMC3962330  PMID: 24658763
14.  Modeling 3D Facial Shape from DNA 
PLoS Genetics  2014;10(3):e1004224.
Human facial diversity is substantial, complex, and largely scientifically unexplained. We used spatially dense quasi-landmarks to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). Using bootstrapped response-based imputation modeling (BRIM), we uncover the relationships between facial variation and the effects of sex, genomic ancestry, and a subset of craniofacial candidate genes. The facial effects of these variables are summarized as response-based imputed predictor (RIP) variables, which are validated using self-reported sex, genomic ancestry, and observer-based facial ratings (femininity and proportional ancestry) and judgments (sex and population group). By jointly modeling sex, genomic ancestry, and genotype, the independent effects of particular alleles on facial features can be uncovered. Results on a set of 20 genes showing significant effects on facial features provide support for this approach as a novel means to identify genes affecting normal-range facial features and for approximating the appearance of a face from genetic markers.
Author Summary
The face is perhaps the most inherently fascinating and aesthetic feature of the human body. It is a principle subject of art throughout human history and across cultures and populations. It provides the most significant means by which we communicate our emotions and intentions in addition to health, sex, and age. And yet features such as the strength of the brow ridge, the spacing between the eyes, the width of the nose, and the shape of the philtrum are largely scientifically unexplained. Here, we use a novel method to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). We show that facial variation with regard to sex, ancestry, and genes can be systematically studied with our methods, allowing us to lay the foundation for predictive modeling of faces. Such predictive modeling could be forensically useful; for example, DNA left at crime scenes could be tested and faces predicted in order to help to narrow the pool of potential suspects. Further, our methods could be used to predict the facial features of descendants, deceased ancestors, and even extinct human species. In addition, these methods could prove to be useful diagnostic tools.
PMCID: PMC3961191  PMID: 24651127
15.  Reconstruction of large-size abdominal wall defect using biodegradable poly-p-dioxanone mesh: an experimental canine study 
Reconstruction of large-size abdominal wall defect (AWDs) is a huge challenge faced in current surgical practice. In this study, we aimed to evaluate the effectiveness and safety of biodegradable poly-p-dioxanone (PDO) mesh for reconstructing large-size AWDs in an experimental canine model.
Eighteen experimental canines were randomly and equally divided into three groups, namely, a PDO group, a Marlex group and a control group (n = 6 each). Following the creation of a 6 cm × 5.5 cm AWD, PDO mesh and Marlex mesh were used to reconstruct the defect in the PDO and Marlex groups, respectively. The defect was closed using relaxation sutures alone in the control group. Animals were killed 24 weeks after surgery, and reconstruction outcomes were evaluated using radiography, histology and biomechanical testing.
All animals except those in the control group survived the experiment. The PDO group showed no wound dehiscence, herniation or infection, whereas the animals in the Marlex group exhibited marked foreign body reactions. The PDO group had less intraabdominal adhesion than the Marlex group. As shown by radiography, histology and biomechanical testing, PDO mesh exhibited complete degradation and favorable biochemical strength at 24 weeks postsurgery.
PDO mesh implantation is an effective, safe treatment modality for reconstructing large-size AWDs.
PMCID: PMC3995574  PMID: 24625138
Abdominal wall defect; Canine model; Large size; Marlex; Mesh; Poly-p-dioxanone; Reconstruction
16.  Up-regulated MicroRNA-181a induces carcinogenesis in Hepatitis B virus-related hepatocellular carcinoma by targeting E2F5 
BMC Cancer  2014;14:97.
Accumulating evidence showed that microRNAs are involved in development and progression of multiple tumors. Recent studies have found that miR-181a were dysregulated in several types of cancers, however, the function of miR-181a in hepatocellular carcinoma (HCC) remains unclear. In this study we assessed the potential association between miR-181a, HBV and HCC.
The expression of miR-181a in HBV-expressing cells was determined by using qRT-PCR. Dual-Luciferase reporter Assay, qRT-PCR and western blot were performed to investigate the target genes of miR-181a. The effects of miR-181a on HCC proliferation were analyzed by MTS and colony formation assay. Tumor growth assay was used to analyze the effect of miR-181a on tumor formation.
HBV up-regulated miR-181a expression by enhancing its promoter activity. Overexpression of miR-181a in hepatoma cells promoted cell growth in vitro and tumor formation in vivo. Conversely, inhibition of miR-181a suppressed the proliferation of HBV-expressing cells. Mechanism investigation revealed that miR-181a inhibited the expression of transcription factor E2F5 by specifically targeting its mRNA 3′UTR. Moreover, E2F5 inhibition induced cell growth and rescued the suppressive effect of miR-181a inhibitor on the proliferation of SMMC-7721 cells. Interestingly, we also discovered that HBV could down-regulate E2F5 expression.
Those results strongly suggested that HBV down-regulated E2F5 expression, in part, by up-regulating the expression of miR-181a. Up-regulation of miR-181a by HBV in hepatoma cells may contribute to the progression of HCC possibly by targeting E2F5, suggesting miR-181a plays important role in HCC development.
PMCID: PMC3930291  PMID: 24529171
HCC; HBV; miR-181a; E2F5; Cell proliferation
17.  Briarane Diterpenes from the South China Sea Gorgonian Coral, Junceella gemmacea 
Marine Drugs  2014;12(2):589-600.
Four new briarane diterpenoids, junceellolides M–P (1–4), were isolated together with seven known analogs (5–11) from the South China Sea gorgonian, Junceella gemmacea. The structures of these compounds were elucidated by detailed spectroscopic analysis and comparison with the reported data. The absolute configuration of compounds 1–3 were determined based on an ECD experiment, while the absolute configuration of compound 4 was genetically determined. All the compounds were isolated for the first time from J. gemmacea. These compounds showed no growth inhibitory activity against A549, MG63 and SMMC-7721 cell lines in an in vitro bioassay.
PMCID: PMC3944505  PMID: 24473165
Junceella gemmacea; briarane; diterpenoid; junceellolide
19.  Variation and Genetic Control of Protein Abundance in Humans 
Nature  2013;499(7456):79-82.
Gene expression differs among both individuals and populations and is thought to be a major determinant of phenotypic variation. Although variation and genetic loci responsible for RNA expression levels have been analyzed extensively in human populations1–5, our knowledge is limited regarding the differences in human protein abundance and their genetic basis. Variation in mRNA expression is not a perfect surrogate for protein expression because the latter is influenced by a battery of post-transcriptional regulatory mechanisms, and, empirically, the correlation between protein and mRNA levels is generally modest6,7. Here we used isobaric tandem mass tag (TMT)-based quantitative mass spectrometry to determine relative protein levels of 5953 genes in lymphoblastoid cell lines (LCLs) from 95 diverse individuals genotyped in the HapMap Project8,9. We found that protein levels are heritable molecular phenotypes that exhibit considerable variation between individuals, populations, and sexes. Levels of specific sets of proteins involved in the same biological process co-vary among individuals, indicating that these processes are tightly regulated at the protein level. We identified cis-pQTLs (protein quantitative trait loci), including variants not detected by previous transcriptome studies. This study demonstrates the feasibility of high throughput human proteome quantification which, when integrated with DNA variation and transcriptome information, adds a new dimension to the characterization of gene expression regulation.
PMCID: PMC3789121  PMID: 23676674
21.  Is the Chronic Kidney Disease Epidemiology Collaboration creatinine–cystatin C equation useful for glomerular filtration rate estimation in the elderly? 
We aimed to evaluate the performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine–cystatin C equation in a cohort of elderly Chinese participants.
Materials and methods
Glomerular filtration rate (GFR) was measured in 431 elderly Chinese participants by the technetium-99m diethylene-triamine-penta-acetic acid (99mTc-DTPA) renal dynamic imaging method, and was calibrated equally to the dual plasma sample 99mTc-DTPA-GFR. Performance of the CKD-EPI creatinine–cystatin C equation was compared with the Cockcroft–Gault equation, the re-expressed 4-variable Modification of Diet in Renal Disease (MDRD) equation, and the CKD-EPI creatinine equation.
Although the bias of the CKD-EPI creatinine–cystatin C equation was greater than with the other equations (median difference, 5.7 mL/minute/1.73 m2 versus a range from 0.4–2.5 mL/minute/1.73 m2; P<0.001 for all), the precision was improved with the CKD-EPI creatinine–cystatin C equation (interquartile range for the difference, 19.5 mL/minute/1.73 m2 versus a range from 23.0–23.6 mL/minute/1.73 m2; P<0.001 for all comparisons), leading to slight improvement in accuracy (median absolute difference, 10.5 mL/minute/1.73 m2 versus 12.2 and 11.4 mL/minute/1.73 m2 for the Cockcroft–Gault equation and the re-expressed 4-variable MDRD equation, P=0.04 for both; 11.6 mL/minute/1.73 m2 for the CKD-EPI creatinine equation, P=0.11), as the optimal scores of performance (6.0 versus a range from 1.0–2.0 for the other equations). Higher GFR category and diabetes were independent factors that negatively correlated with the accuracy of the CKD-EPI creatinine–cystatin C equation (β=−0.184 and −0.113, P<0.001 and P=0.02, respectively).
Compared with the creatinine-based equations, the CKD-EPI creatinine–cystatin C equation is more suitable for the elderly Chinese population. However, the cost-effectiveness of the CKD-EPI creatinine–cystatin C equation for clinical use should be considered.
PMCID: PMC3797613  PMID: 24143084
elderly; equation; glomerular filtration rate; serum creatinine; cystatin C
22.  Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping 
Journal of hypertension  2012;30(10):1970-1976.
Genetic variants in 296 genes in regions identified through admixture mapping of hypertension, BMI, and lipids were assessed for association with hypertension, blood pressure, BMI, and HDL-C.
This study identified coding SNPs identified from HapMap2 data that were located in genes on chromosomes 5, 6, 8, and 21, where ancestry association evidence for hypertension, BMI or HDL-C was identified in previous admixture mapping studies. Genotyping was performed in 1,733 unrelated African-Americans from the National Heart, Lung and Blood Institute’s (NHLBI) Family Blood Pressure Project, and gene-based association analyses were conducted for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), BMI, and HDL-C. A gene score based on the number of minor alleles of each SNP in a gene was created and used for gene-based regression analyses, adjusting for age, age2, sex, local marker ancestry, and BMI, as applicable. An individual’s African ancestry estimated from 2,507 ancestry-informative markers was also adjusted for to eliminate any confounding due to population stratification.
CXADR (rs437470) on chromosome 21 was associated with SBP and DBP with or without adjusting for local ancestry (p < 0.0006). F2RL1 (rs631465) on chromosome 5 was associated with BMI (p = 0.0005). Local ancestry in these regions was associated with the respective traits as well.
This study suggests that CXADR and F2RL1 likely play important roles in blood pressure and obesity variation, respectively; and these findings are consistent with other studies, so replication and functional analyses are necessary.
PMCID: PMC3575678  PMID: 22914544
Blood pressure; Obesity; African Americans; Genetic Association Studies
23.  Inactivated Sendai virus strain Tianjin, a novel genotype of Sendai virus, inhibits growth of murine colon carcinoma through inducing immune responses and apoptosis 
Ultraviolet-inactivated, replication-defective Sendai virus particles (Z strain) have displayed antitumor effect through enhancing the immune responses or inducing apoptosis in a variety of carcinomas. Sendai virus strain Tianjin was isolated from the lungs of marmoset and proved to be a novel genotype of Sendai virus. In this study, we explored the antitumor effect and its mechanism of ultraviolet-inactivated, replication-defective Sendai virus strain Tianjin (UV-Tianjin) in mice bearing CT26 colon carcinoma.
Three injections of UV-Tianjin were delivered into CT26 tumors growing on the back of BALB/c mice. Tumor size was measured in a blinded manner and survival rate of mice was calculated. In order to make clear antitumor mechanism of UV-Tianjin, the maturation and interleukin-6 (IL-6) release from murine myeloid dendritic cells (DCs) was examined by flow cytometry or ELISA assay after induced by UV-Tianjin and compared with those of live virus. Moreover, real-time RT-PCR and immunohistochemistry was performed to identify whether UV-Tianjin could induce infiltration of DCs, CD4+ and CD8+ T cells into tumors. The TUNEL assay was done to observe the apoptosis of CT26 tumor cells after UV-Tianjin injection.
In animal model, UV-Tianjin could obviously inhibit the growth of CT26 tumors and prolong the survival of the tumor-bearing mice compared with control group (P < 0.01). In vitro murine DCs stimulated by UV-Tianjin underwent dose-dependent maturation, similar to that elicited by live virus. And the secretion amount of IL-6 from DCs induced by UV-Tianjin was a little lower than that released in the presence of live virus. Real-time RT-PCR and immunohistochemistry revealed that UV-Tianjin induced a remarkable infiltration of DCs, CD4+ and CD8+ T cells into tumors. The TUNEL assay showed that the apoptosis index of tumor tissues injected with UV-Tianjin was significantly higher than that of control group (P < 0.01).
Our results have demonstrated that UV-Tianjin alone could inhibit the growth of CT26 tumor in mice through enhancing host antitumor immunity and inducing apoptosis of tumor cells. Therefore, UV-Tianjin shows its prospect as a novel drug for carcinoma therapy.
PMCID: PMC3844535  PMID: 24007528
Sendai virus strain Tianjin; Murine colon carcinoma; Antitumor immunity; Dendritic cells; Apoptosis
24.  Toll-like receptor–mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway 
Nature immunology  2008;9(10):1157-1164.
Robust production of type I interferon (IFN-α/β) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) pathway in regulating interferon production by pDCs. Inhibition of mTOR or its ‘downstream’ mediators, the p70 ribosomal S6 protein kinases p70S6K1 and p70S6K2, during pDC activation by Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and subsequent activation of the interferon-regulatory factor IRF7, which resulted in impaired IFN-α/β production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed antiviral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in less IFN-α/β production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling is crucial in TLR-mediated IFN-α/β responses by pDCs.
PMCID: PMC3732485  PMID: 18758466
25.  The benefits of psychosocial interventions for cancer patients undergoing radiotherapy 
Many patients with cancer experience depression and anxiety, and an associated decrease in quality of life (QOL) during radiation therapy (RT). The main objective of the study was to determine the benefits of psychosocial interventions for cancer patients who received RT.
Patients with cancer (n = 178) who agreed to participate in the study were randomized to the intervention arm (n = 89) or the control arm (n = 89). Patients in the intervention group received psychosocial care during RT, whereas the control group received RT only. The benefits of the intervention were evaluated using the Zung Self-rating Depression Scale (SDS) to measure depression, the Self-rating Anxiety Scale (SAS) to assess anxiety, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) to survey health-related QOL. The association between intervention and survival was also assessed.
Patients randomly assigned to the intervention arm showed significant improvements on symptoms of depression (p < 0.05) and anxiety (p < 0.05), health-related QOL (p < 0.05) (i.e. better global health status, and physical and emotional functioning, and less insomnia) when compared with controls. In the subset analysis, female patients, those that received high dose irradiation, and those that underwent adjuvant chemotherapy could benefit more from psychosocial intervention. There was no difference between the two groups in disease-free survival (DFS) (2-year DFS 79.8% in the intervention arm and 76.4% in the control arm; p = 0.527) and overall survival (OS) (2-year OS 83.1% in the intervention arm and 84.3% in the control arm; p = 0.925)
Psychosocial intervention is a cost-effective approach that can improve a patient’s mood and QOL both during and after RT. However, the intervention was not found to reduce the risk of cancer recurrence and death.
Trial registration
PMCID: PMC3721996  PMID: 23866850
Cancer; Radiation oncology; Psychosocial intervention; Anxiety; Depression; Quality of life

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