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1.  Local administration of granulocyte macrophage colony-stimulating factor induces local accumulation of dendritic cells and antigen-specific CD8+ T cells and enhances dendritic cell cross-presentation 
Vaccine  2015;33(13):1549-1555.
Immunotherapy has emerged as a promising treatment strategy for the control of HPV-associated malignancies. Various therapeutic HPV vaccines have elicited potent antigen-specific CD8+ T cell mediated antitumor immune responses in preclinical models and are currently being tested in several clinical trials. Recent evidence indicates the importance of local immune activation, and higher number of immune cells in the site of lesion correlates with positive prognosis. Granulocyte macrophage colony-stimulating factor (GMCSF) has been reported to posses the ability to induce migration of antigen presentation cells and CD8+ T cells. Therefore, in the current study, we employ a combination of systemic therapeutic HPV DNA vaccination with local GMCSF application in the TC-1 tumor model. We show that intramuscular vaccination with CRT/E7 DNA followed by GMCSF intravaginal administration effectively controls cervicovaginal TC-1 tumors in mice. Furthermore, we observe an increase in the accumulation of E7-specific CD8+ T cells and dendritic cells in vaginal tumors following the combination treatment. In addition, we show that GMCSF induces activation and maturation in dendritic cells and promotes antigen cross-presentation. Our results support the clinical translation of the combination treatment of systemic therapeutic vaccination followed by local GMCSF administration as an effective strategy for tumor treatment.
PMCID: PMC4361388  PMID: 25701675
immunotherapy; GM-CSF; CRT/E7; dendritic cell
2.  Buccal injection of synthetic HPV long peptide vaccine induces local and systemic antigen-specific CD8+ T-cell immune responses and antitumor effects without adjuvant 
Cell & Bioscience  2016;6:17.
Human Papillomavirus is responsible for over 99 % of cervical cancers and is associated with cancers of the head and neck. The currently available prophylactic vaccines against HPV do not generate therapeutic effects against established HPV infections and associated lesions and disease. Thus, the need for a therapeutic vaccine capable of treating HPV-induced malignancies persists. Synthetic long peptides vaccination is a popular antigen delivery method because of its safety, stability, production feasibility, and its need to be processed by professional antigen presenting cells before it can be presented to cytotoxic CD8+ T lymphocytes. Cancers in the buccal mucosa have been shown to elicit cancer-related inflammations that are capable of recruiting inflammatory and immune cells to generate antitumor effects. In the current study, we evaluated the therapeutic potential of synthetic HPV long peptide vaccination in the absence of adjuvant in the TC-1 buccal tumor model.
We show that intratumoral vaccination with E7 long peptide alone effectively controls buccal TC-1 tumors in mice. Furthermore, we observed an increase in systemic as well as local E7-specific CD8+ T cells in buccal tumor-bearing mice following the vaccination. Finally, we show that induction of immune responses against buccal tumors by intratumoral E7 long peptide vaccination is independent of CD4+ T cells, and that the phenomenon may be related to the unique environment associated with mucosal tissues.
Our results suggest the possibility for clinical translation of the administration of adjuvant free therapeutic long peptide vaccine as a potentially effective and safe strategy for mucosal HPV-associated tumor treatment.
Electronic supplementary material
The online version of this article (doi:10.1186/s13578-016-0083-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4778350  PMID: 26949512
Immunotherapy; E7 long peptide; Adjuvant free; Buccal tumor
3.  The Effects of Creatine Supplementation on Explosive Performance and Optimal Individual Postactivation Potentiation Time 
Nutrients  2016;8(3):143.
Creatine plays an important role in muscle energy metabolism. Postactivation potentiation (PAP) is a phenomenon that can acutely increase muscle power, but it is an individualized process that is influenced by muscle fatigue. This study examined the effects of creatine supplementation on explosive performance and the optimal individual PAP time during a set of complex training bouts. Thirty explosive athletes performed tests of back squat for one repetition maximum (1RM) strength and complex training bouts for determining the individual optimal timing of PAP, height and peak power of a counter movement jump before and after the supplementation. Subjects were assigned to a creatine or placebo group and then consumed 20 g of creatine or carboxymethyl cellulose per day for six days. After the supplementation, the 1RM strength in the creatine group significantly increased (p < 0.05). The optimal individual PAP time in the creatine group was also significant earlier than the pre-supplementation and post-supplementation of the placebo group (p < 0.05). There was no significant difference in jump performance between the groups. This study demonstrates that creatine supplementation improves maximal muscle strength and the optimal individual PAP time of complex training but has no effect on explosive performance.
PMCID: PMC4808872  PMID: 26959056
complex training; counter movement jump; peak power; maximal muscle strength
4.  Fuzzy Stochastic Petri Nets for Modeling Biological Systems with Uncertain Kinetic Parameters 
PLoS ONE  2016;11(2):e0149674.
Stochastic Petri nets (SPNs) have been widely used to model randomness which is an inherent feature of biological systems. However, for many biological systems, some kinetic parameters may be uncertain due to incomplete, vague or missing kinetic data (often called fuzzy uncertainty), or naturally vary, e.g., between different individuals, experimental conditions, etc. (often called variability), which has prevented a wider application of SPNs that require accurate parameters. Considering the strength of fuzzy sets to deal with uncertain information, we apply a specific type of stochastic Petri nets, fuzzy stochastic Petri nets (FSPNs), to model and analyze biological systems with uncertain kinetic parameters. FSPNs combine SPNs and fuzzy sets, thereby taking into account both randomness and fuzziness of biological systems. For a biological system, SPNs model the randomness, while fuzzy sets model kinetic parameters with fuzzy uncertainty or variability by associating each parameter with a fuzzy number instead of a crisp real value. We introduce a simulation-based analysis method for FSPNs to explore the uncertainties of outputs resulting from the uncertainties associated with input parameters, which works equally well for bounded and unbounded models. We illustrate our approach using a yeast polarization model having an infinite state space, which shows the appropriateness of FSPNs in combination with simulation-based analysis for modeling and analyzing biological systems with uncertain information.
PMCID: PMC4766190  PMID: 26910830
5.  Efficiency of two nitrification inhibitors (dicyandiamide and 3, 4-dimethypyrazole phosphate) on soil nitrogen transformations and plant productivity: a meta-analysis 
Scientific Reports  2016;6:22075.
Dicyandiamide (DCD) and 3, 4-dimethypyrazole phosphate (DMPP) are often claimed to be efficient in regulating soil N transformations and influencing plant productivity, but the difference of their performances across field sites is less clear. Here we applied a meta-analysis approach to compare effectiveness of DCD and DMPP across field trials. Our results showed that DCD and DMPP were equally effective in altering soil inorganic N content, dissolve inorganic N (DIN) leaching and nitrous oxide (N2O) emissions. DCD was more effective than DMPP on increasing plant productivity. An increase of crop yield by DMPP was generally only observed in alkaline soil. The cost and benefit analysis (CBA) showed that applying fertilizer N with DCD produced additional revenues of $109.49 ha−1 yr−1 for maize farms, equivalent to 6.02% increase in grain revenues. In comparisons, DMPP application produced less monetary benefit of $15.67 ha−1 yr−1. Our findings showed that DCD had an advantage of bringing more net monetary benefit over DMPP. But this may be weakened by the higher toxicity of DCD than DMPP especially after continuous DCD application. Alternatively, an option related to net monetary benefit may be achieved through applying DMPP in alkaline soil and reducing the cost of purchasing DMPP products.
PMCID: PMC4763264  PMID: 26902689
6.  Fluorination Enables a Ligand-Controlled Regiodivergent Palladium-Catalyzed Decarboxylative Allylation Reaction to Access α,α-Difluoroketones 
α,α-Difluoroketones possess unique physicochemical properties that are useful for developing therapeutics and probes for chemical biology. In order to access the α-allyl-α,α-difluoroketone substructure, complementary Pd-catalyzed decarboxylative allylation reactions were developed to provide linear and branched α-allyl-α,α-difluoroketones. For these orthogonal processes, the regioselectivity was uniquely controlled by fluorination of the substrate and the structure of ligand.
PMCID: PMC4373536  PMID: 25581845
allylation; regioselectivity; synthetic methods; P ligands; palladium
7.  Genetic Investigation of Complement Pathway Genes in Type 2 Diabetic Retinopathy: An Inflammatory Perspective 
Mediators of Inflammation  2016;2016:1313027.
Diabetic retinopathy (DR) has complex multifactorial pathogenesis. This study aimed to investigate the association of complement pathway genes with susceptibility to DR. Eight haplotype-tagging SNPs of SERPING1 and C5 were genotyped in 570 subjects with type 2 diabetes: 295 DR patients (138 nonproliferative DR [NPDR] and 157 proliferative DR [PDR]) and 275 diabetic controls. Among the six C5 SNPs, a marginal association was first detected between rs17611 and total DR patients (P = 0.009, OR = 0.53 for recessive model). In stratification analysis, a significant decrease in the frequencies of G allele and GG homozygosity for rs17611 was observed in PDR patients compared with diabetic controls (Pcorr = 0.032, OR = 0.65 and Pcorr = 0.016, OR = 0.37, resp.); it was linked with a disease progression. A haplotype AA defined by the major alleles of rs17611 and rs1548782 was significantly predisposed to PDR with increased risk of 1.54 (Pcorr = 0.023). Regarding other variants in C5 and SERPING1, none of the tagging SNPs had a significant association with DR and its subgroups (all P > 0.05). Our study revealed an association between DR and C5 polymorphisms with clinical significance, whereas SERPING1 is not a major genetic component of DR. Our data suggest a link of complement pathway with DR pathogenesis.
PMCID: PMC4771919  PMID: 26989329
8.  The Klotho gene G-395A polymorphism and metabolic syndrome in very elderly people 
BMC Geriatrics  2016;16:46.
To investigate the possible association of the Klotho G-395A polymorphism and metabolic syndrome (MetS) among a population of Chinese nonagenarians and centenarians.
Subjects were from the Project of Longevity and Aging in Dujiangyan (PLAD). The genotyping of G-395A (rs1207568) in the promoter region of the Klotho gene was performed using the TaqMan allelic discrimination assay. MetS was diagnosed according to the International Diabetes Federation criteria.
We included 695 subjects aged 93.5 ± 3.2 years. G and A allele frequencies were 0.852 and 0.148, respectively. In the whole population, the frequency of MetS was 10.8 % and 5.9 % in the GG and GA + AA genotype group, respectively (p = 0.004). The -395A allele carriers had significantly lower risk of MetS in the whole population (odd ratio [OR] 0.50, 95 % confidential interval [CI] 0.25 to 0.98) and in women (OR 0.51, 95 % CI 0.24 to 0.97), but not in men (OR 0.42, 95 % CI 0.05 to 3.85). In the whole population and women, the relationship between the Klotho G-395A SNP and MetS might due to its influence on high blood pressure (OR 0.48, 95 % CI 0.34 to 0.67; OR 0.47, 95 % CI 0.31 to 0.71, respectively) and hypertriglyceridemia (OR 0.66, 95 % CI 0.39 to 0.95; OR 0.54, 95 % CI 0.31 to 0.98, respectively). In men, this relationship might due to its influence on high blood pressure (OR 0.47, 95 % CI 0.25 to 0.90) and low HDL-C (OR 0.69, 95 % CI 0.27 to 0.93).
The -395A allele carriers of the Klotho gene were correlated with lower risk of MetS among Chinese nonagenarians and centenarians, especially in women.
Electronic supplementary material
The online version of this article (doi:10.1186/s12877-016-0221-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4754834  PMID: 26880028
Klotho gene; Single nucleotide polymorphism; Metabolic syndrome; Nonagenarian; Centenarian
9.  Preclinical animal study and human clinical trial data of co-electrospun poly(l-lactide-co-caprolactone) and fibrinogen mesh for anterior pelvic floor reconstruction 
Synthetic and biological materials are commonly used for pelvic floor reconstruction. In this study, host tissue response and biomechanical properties of mesh fabricated from co-electrospun poly(l-lactide-co-caprolactone) (PLCL) and fibrinogen (Fg) were compared with those of polypropylene mesh (PPM) in a canine abdominal defect model. Macroscopic, microscopic, histological, and biomechanical evaluations were performed over a 24-week period. The results showed that PLCL/Fg mesh had similar host tissue responses but better initial vascularization and graft site tissue organization than PPM. The efficacy of the PLCL/Fg mesh was further examined in human pelvic floor reconstruction. Operation time, intraoperative blood loss, and pelvic organ prolapse quantification during 6-month follow-up were compared for patients receiving PLCL/Fg mesh versus PPM. According to the pelvic organ prolapse quantification scores, the anterior vaginal wall 3 cm proximal to the hymen point (Aa point), most distal edge of the cervix or vaginal cuff scar point (C point), and posterior fornix point (D point) showed significant improvement (P<0.01) at 1, 3, and 6 months for both groups compared with preoperatively. At 6 months, improvements at the Aa point in the PLCL/Fg group were significantly more (P<0.005) than the PPM group, indicating that, while both materials improve the patient symptoms, PLCL/Fg mesh resulted in more obvious improvement.
PMCID: PMC4745856  PMID: 26893556
anterior pelvic floor reconstruction; polypropylene mesh; poly(l-lactide-co-caprolactone); fibrinogen; pelvic organ prolapse quantification
10.  The N-terminal region of myelin basic protein reduces fibrillar amyloid-β deposition in Tg-5xFAD mice 
Neurobiology of aging  2014;36(2):801-811.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by extensive deposition of fibrillar amyloid β (Aβ) in the brain. Previously, myelin basic protein (MBP) was identified to be a potent inhibitor to Aβ fibril formation and this inhibitory activity was localized to the N-terminal residues 1–64, a fragment designated MBP1. Here we show that modest neuronal expression of a fusion protein of the biologically active MBP1 fragment and the enhanced green fluorescent protein (MBP1-EGFP) significantly improved the performance of spatial learning memory in Tg-5xFAD mice, a model of pathologic Aβ accumulation in brain. The levels of insoluble Aβ and fibrillar amyloid were significantly reduced in bigenic Tg-5xFAD/Tg-MBP1-EGFP mice. Quantitative stereological analysis revealed that the reduction in amyloid was due to a reduction in the size of fibrillar plaques, rather than a decrease in plaque numbers. The current findings support previous studies showing that MBP1 inhibits Aβ fibril formation in vitro, and demonstrate the ability of MBP1 to reduce Aβ pathology and improve behavioral performance.
PMCID: PMC4315736  PMID: 25457550
Alzheimer’s disease; myelin basic protein; transgenic mice; amyloid β-protein
11.  Autophagy in Ischemic Livers: A Critical Role of Sirtuin 1/Mitofusin 2 Axis in Autophagy Induction 
Toxicological Research  2016;32(1):35-46.
No-flow ischemia occurs during cardiac arrest, hemorrhagic shock, liver resection and transplantation. Recovery of blood flow and normal physiological pH, however, irreversibly injures the liver and other tissues. Although the liver has the powerful machinery for mitochondrial quality control, a process called mitophagy, mitochondrial dysfunction and subsequent cell death occur after reperfusion. Growing evidence indicates that reperfusion impairs mitophagy, leading to mitochondrial dysfunction, defective oxidative phosphorylation, accumulation of toxic metabolites, energy loss and ultimately cell death. The importance of acetylation/deacetylation cycle in the mitochondria and mitophagy has recently gained attention. Emerging data suggest that sirtuins, enzymes deacetylating a variety of target proteins in cellular metabolism, survival and longevity, may also act as an autophagy modulator. This review highlights recent advances of our understanding of a mechanistic correlation between sirtuin 1, mitophagy and ischemic liver injury.
PMCID: PMC4780240  PMID: 26977257
Autophagy; Mitochondria; Liver; Ischemia/Reperfusion; Acetylation
12.  Cytotoxic Rocaglate Derivatives from Leaves of Aglaia perviridis 
Scientific Reports  2016;6:20045.
Rocaglates are a series of structurally complex secondary metabolites with considerable cytotoxicity that have been isolated from plants of the Aglaia genus (Meliaceae). A new rocaglate (aglapervirisin A, 1) and its eight new biosynthetic precursors of rocaglate (aglapervirisins B-J, 2–9) together with five known compounds, were isolated from the leaves of Aglaia perviridis. Their structures were elucidated based on a joint effort of spectroscopic methods [IR, UV, MS, ECD, 1D- and 2D-NMR, HRESIMS], chemical conversion and single-crystal X-ray diffraction. Among these isolates, three (1, 10–11) were silvestrols, a rare subtype rocaglates, exhibiting notable cytotoxicity against four human tumor cell lines, with IC50 values between 8.0 and 15.0 nM. Aglapervirisin A (1) induces cell cycle arrest at the G2/M-phase boundary at concentration 10 nM accompanied by reductions in the expression levels of Cdc2 and Cdc25C in HepG2 cells after 72h co-incubation, and further induces the apoptosis of HepG2 cells at concentrations over 160 nM.
PMCID: PMC4730247  PMID: 26818797
13.  Involvement of the Hippo pathway in regeneration and fibrogenesis after ischaemic acute kidney injury: YAP is the key effector 
The Hippo pathway plays a stage-specific role in regeneration and fibrogenesis after ischaemia/reperfusion-induced acute kidney injury. The proper modulation of this pathway might be the key point of transition from acute kidney injury to chronic kidney disease.
Renal tubule cells can recover after they undergo AKI (acute kidney injury). An incomplete repair of renal tubules can result in progressive fibrotic CKD (chronic kidney disease). Studies have revealed the relationship between tubular epithelial cells and kidney fibrogenesis. However, the underlying mechanism remains unclear. Hippo pathway components were evaluated in complete/incomplete repair of I/R (ischaemia/reperfusion) AKI rat models, HK-2 cells and AKI human renal biopsy samples. We found that the expression levels of the Hippo pathway components changed dynamically during kidney regeneration and fibrogenesis in rat models of I/R-induced AKI and human renal biopsy samples. The transcription cofactor YAP (Yes-associated protein) might be a key effector of renal regeneration and fibrogenesis. Our results showed further that YAP might elicit both beneficial and detrimental effects on I/R AKI. After I/R injury occurred, YAP could promote the repair of the injured epithelia. The constant YAP increase and activation might be related to interstitial fibrosis and abnormal renal tubule differentiation. These results indicate that the proper modulation of the Hippo pathway, specifically the transcription cofactor YAP, during repair might be a potent therapeutic target in AKI–CKD transition after I/R injury.
PMCID: PMC4727597  PMID: 26574480
acute kidney injury; chronic kidney disease; fibrogenesis; Hippo pathway; repair; Yes-associated protein (YAP)
14.  Threshold Dependence of Deep- and Near-subwavelength Ripples Formation on Natural MoS2 Induced by Femtosecond Laser 
Scientific Reports  2016;6:19571.
Deep sub-wavelength ripples (DSRs) and near sub-wavelength ripples (NSRs) with uniform periods of ~160 nm and ~660 nm generated at the MoS2-vacuum interface is reported for the first time by the processing of femtosecond laser (800 nm, 120 fs, 1 kHz) in this paper. The DSRs and NSRs formation fluence thresholds are experimentally determined as 160 mJ/cm2 and 192 mJ/cm2, respectively. In addition, the ripple period is insensitive to the pulse number. Moreover, Raman analyses show that the MoS2 lattice in the irradiated area does not exhibit oxidation at room environment and the crystalline representation is well preserved in NSRs region. We attribute our result to the joint interactions of the spallation and sublimation of layered MoS2 together with the laser induced surface plasmon polaritons and propose an explanation to the threshold dependence of the ripple period. Our study provides some insights for ultrafast laser-matter interactions and indicates a simple effective method for future nano-fabrication of MoS2.
PMCID: PMC4726362  PMID: 26795074
15.  Protective effect of microRNA-138 against cerebral ischemia/reperfusion injury in rats 
MicroRNAs (miRs) serve a regulatory function in oxidative radical-mediated inflammation and apoptosis during ischemia/reperfusion (IR) injury. Lipocalin 2 (Lcn-2), a target protein of miR-138, is widely involved in the systemic response to IR injury. The aim of the present study was to investigate the association between miR-138 and Lcn-2 in a rat model of cerebral ischemia/reperfusion (CIR) injury and to verify the interaction between miR-138 and Lcn-2 in a PC12 cell model of hypoxia/reoxygenation injury. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the mRNA and protein expression levels of miR-138 and Lcn-2. Cell proliferation was determined by MTT assay. The results suggested that the expression of miR-138 was inversely correlated with the expression of Lcn-2 in the CIR rat model and the PC12 cells subjected to hypoxia and reoxygenation. The expression of Lcn-2 was inhibited by miR-138 mimics and enhanced by miR-138 inhibitors, thereby indicating that miR-138 functions as a negative regulator for Lcn-2 expression. This study provides an experimental basis for the further study of miR-138-based therapy for CIR injury.
PMCID: PMC4774489  PMID: 26998035
cerebral injury; ischemia/reperfusion; microRNA-138; lipocalin 2
16.  Possible introgression of the VRTN mutation increasing vertebral number, carcass length and teat number from Chinese pigs into European pigs 
Scientific Reports  2016;6:19240.
Vertnin (VRTN) variants have been associated with the number of thoracic vertebrae in European pigs, but the association has not been evidenced in Chinese indigenous pigs. In this study, we first performed a genome-wide association study in Chinese Erhualian pigs using one VRTN candidate causative mutation and the Illumina Porcine 60K SNP Beadchips. The VRTN mutation is significantly associated with thoracic vertebral number in this population. We further show that the VRTN mutation has pleiotropic and desirable effects on teat number and carcass (body) length across four diverse populations, including Erhualian, White Duroc × Erhualian F2 population, Duroc and Landrace pigs. No association was observed between VRTN genotype and growth and fatness traits in these populations. Therefore, testing for the VRTN mutation in pig breeding schemes would not only increase the number of vertebrae and nipples, but also enlarge body size without undesirable effects on growth and fatness traits, consequently improving pork production. Further, by using whole-genome sequence data, we show that the VRTN mutation was possibly introgressed from Chinese pigs into European pigs. Our results provide another example showing that introgressed Chinese genes greatly contributed to the development and production of modern European pig breeds.
PMCID: PMC4726066  PMID: 26781738
17.  Two newly recorded genera and species of Owlflies (Neuroptera: Ascalaphidae) from China 
The records of genus Bubopsis McLachlan, 1898 with species Bubopsis tancrei Weele, 1908 and the genus Nousera Navás, 1923 with species Nousera gibba Navás, 1923 have not been published in China.
New information
The genus Bubopsis McLachlan, 1898 with species Bubopsis tancrei Weele, 1908 and the genus Nousera Navás, 1923 with species Nousera gibba Navás, 1923 are recorded for the first time from China. We provide detailed descriptions and illlustrations of specimens and the collecting information of the specimens are also provided.
PMCID: PMC4759391  PMID: 26929716
Bubopsis ;  Nousera ;  Ascalaphidae ; China
18.  Synthesis and Application of an Aldazine-Based Fluorescence Chemosensor for the Sequential Detection of Cu2+ and Biological Thiols in Aqueous Solution and Living Cells 
A fluorescence chemosensor, 2-hydroxy-1-naphthaldehyde azine (HNA) was designed and synthesized for sequential detection of Cu2+ and biothiols. It was found that HNA can specifically bind to Cu2+ with 1:1 stoichiometry, accompanied with a dramatic fluorescence quenching and a remarkable bathochromic-shift of the absorbance peak in HEPES buffer. The generated HNA-Cu2+ ensemble displayed a “turn-on” fluorescent response specific for biothiols (Hcy, Cys and GSH) based on the displacement approach, giving a remarkable recovery of fluorescence and UV-Vis spectra. The detection limits of HNA-Cu2+ to Hcy, Cys and GSH were estimated to be 1.5 μM, 1.0 μM and 0.8 μM, respectively, suggesting that HNA-Cu2+ is sensitive enough for the determination of thiols in biological systems. The biocompatibility of HNA towards A549 human lung carcinoma cell, was evaluated by an MTT assay. The capability of HNA-Cu2+ to detect biothiols in live A549 cells was then demonstrated by a microscopy fluorescence imaging assay.
PMCID: PMC4732112  PMID: 26761012
aldazine; chemosensing ensemble; biothiols; detection; fluorescence imaging
19.  Comparison of Genetic Variants in Cancer-Related Genes between Chinese Hui and Han Populations 
PLoS ONE  2015;10(12):e0145170.
The Chinese Hui population, as the second largest minority ethnic group in China, may have a different genetic background from Han people because of its unique demographic history. In this study, we aimed to identify genetic differences between Han and Hui Chinese from the Ningxia region of China by comparing eighteen single nucleotide polymorphisms in cancer-related genes.
DNA samples were collected from 99 Hui and 145 Han people from the Ningxia Hui Autonomous Region in China, and SNPs were detected using an improved multiplex ligase detection reaction method. Genotyping data from six 1000 Genomes Project population samples (99 Utah residents with northern and western European ancestry (CEU), 107 Toscani in Italy (TSI), 108 Yoruba in Ibadan (YRI), 61 of African ancestry in the southwestern US (ASW), 103 Han Chinese in Beijing (CHB), and 104 Japanese in Tokyo (JPT)) were also included in this study. Differences in the distribution of alleles among the populations were assessed using χ2 tests, and FST was used to measure the degree of population differentiation.
We found that the genetic diversity of many SNPs in cancer-related genes in the Hui Chinese in Ningxia was different from that in the Han Chinese in Ningxia. For example, the allele frequencies of four SNPs (rs13361707, rs2274223, rs465498, and rs753955) showed different genetic distributions (p<0.05) between Chinese Ningxia Han and Chinese Ningxia Hui. Five SNPs (rs730506, rs13361707, rs2274223, rs465498 and rs753955) had different FST values (FST>0.000) between the Hui and Han populations.
These results suggest that some SNPs associated with cancer-related genes vary among different Chinese ethnic groups. We suggest that population differences should be carefully considered in evaluating cancer risk and prognosis as well as the efficacy of cancer therapy.
PMCID: PMC4684198  PMID: 26683024
20.  Discovery of novel INK4C small-molecule inhibitors to promote human and murine hematopoietic stem cell ex vivo expansion 
Scientific Reports  2015;5:18115.
Hematopoietic stem cells (HSCs) have emerged as promising therapeutic cell sources for high-risk hematological malignancies and immune disorders. However, their clinical use is limited by the inability to expand these cells ex vivo. Therefore, there is an urgent need to identify specific targets and effective probes that can expand HSCs. Here we report a novel class of INK4C (p18INK4C or p18) small molecule inhibitors (p18SMIs), which were initially found by in silico 3D screening. We identified a lead p18 inhibitor, XIE18-6, confirmed its p18-targeting specificity and bioactivity of promoting HSCs expansion, and then performed structure-activity relationship (SAR) studies by synthesizing a series of analogs of XIE18–6. Among these, compound 40 showed the most potent bioactivity in HSCs expansion (ED50 = 5.21 nM). We confirmed that compound 40 promoted expansion of both murine and human HSCs, and also confirmed its p18-targeting specificity. Notably, compound 40 did not show significant cytotoxicity toward 32D cells or HSCs, nor did it augment leukemia cell proliferation. Taken together, our newly discovered p18SMIs represent novel chemical agents for murine and human HSCs ex vivo expansion and also can be used as valuable chemical probes for further HSC biology research towards promising utility for therapeutic purposes.
PMCID: PMC4683533  PMID: 26681454
21.  Effects of Low-Protein Diets Supplemented with Ketoacid on Expression of TGF-β and Its Receptors in Diabetic Rats 
BioMed Research International  2015;2015:873519.
TGF-β1 has been recognized as a key mediator in DN. This study aimed to observe the effects of low-protein diets supplemented with ketoacid on mRNA and protein expression of TGF-β and TβRI and t TβRII receptors in the renal tissue of diabetic rats. A diabetes model was established in 72 male SD rats. They were then equally randomized to three groups: NPD group, LPD group, and LPD + KA group. Additional 24 male SD rats receiving normal protein diets were used as the control. Eight rats from each group were sacrificed at weeks 4, 8, and 12 after treatment, from which SCr, BUN, serum albumin, and 24 h urinary protein excretion were collected. The expressions of TGF-β1, TβRI, and TβRII in LPD and LPD + KA groups were significantly lower than those in NPD group and lower in LPD + KA group than those in LPD group. Low-protein diets supplemented with ketoacid have been demonstrated to provide a protective effect on the renal function as represented by reduced SCr, BUN, and urinary protein excretion, probably through downregulating the gene expression of TGF-β1 and its receptors in LPD + KA group.
PMCID: PMC4693005  PMID: 26788514
22.  Analysis of the prognostic risk factors of idiopathic membranous nephropathy using a new surrogate end-point 
Biomedical Reports  2015;4(2):147-152.
Idiopathic membranous nephropathy (IMN) is one of the most common causes of nephrotic syndrome (NS) in adults. The latest study of the chronic kidney disease-prognosis consortium showed that a 30% decrease in the estimated glomerular filtration rate (eGFR) within 2 years could cover more patients and showed a better correlation with end-stage renal disease (ESRD), as compared with serum creatinine (SCr). The aim of the present study was to analyze prognostic factors of ESRD using a 30% decrease in eGFR within 2 years as the end-point. The medical records of patients who were diagnosed as having IMN by clinical pathology between February 2011 and August 2012 and had been followed up for ≥24 months were analyzed retrospectively. A 30% decrease in eGFR or the occurrence of ESRD were the end-points. Factors affecting the prognosis were analyzed by the χ2 test and multivariate logistic regression analysis, and the cumulative risk of risk factors was analyzed by Kaplan-Meier curve. A total of 73 patients with IMN were confirmed by clinical pathology. Blood pressure, tubulointerstitial injury area (TIA), glomerular sclerosis ratio, SCr, blood urea nitrogen, cystatin C, serum albumin and 24-h urine protein. In total, 28 patients (38.4%) reached the observation end-point. Multivariate logistic regression analysis showed that only age ≥60 years, serum albumin <25 g/l and TIA >25% were independent risk factors for predicting the occurrence of end-point events in the two groups (P<0.05), which increased the risk of the occurrence of end-point events in IMN patients by 3.471-, 3.195- and 6.724-fold, respectively. Kaplan-Meier curve showed that the occurrence of end-point events within 2 years was significantly higher in IMN patients whose age was ≥60 years, serum albumin <25 g/l and TIA >25% (log-rank P=0.004, P=0.024 and P=0.001). The results of the present study revealed that age ≥60 years, low serum albumin concentrations and severe tubulointerstitial injury are independent risk factors for the occurrence of ESRD in IMN patients.
PMCID: PMC4734144  PMID: 26893829
idiopathic membranous glomerulonephritis; glomerular filtration rate; outcome; risk factors; Chinese population
23.  Joining the patient on the path to customized prophylaxis: one hemophilia team explores the tools of engagement 
The relationship between hemophilia team interventions and achievement of optimal clinical outcomes remains to be elucidated. The British Columbia Hemophilia Adult Team has previously reported results of a comprehensive approach to individualize prophylaxis that has resulted in substantially reduced bleeding rates. In order to facilitate knowledge exchange and potential replication, it was important to gain a thorough understanding of the team’s approach.
A focus group of the British Columbia Hemophilia Adult Team was conducted to identify specific roles and processes that might be contributing to the prophylaxis regimen outcomes in this clinic. The focus group consisted of two workshops; one to describe the individual and collective roles of the clinic team in providing clinical care and guiding patients toward individualized prophylaxis; and the other to describe the patient journey from initial contact through reaching a successful engagement with the clinic.
Analysis of the results revealed team roles and processes that underpinned a shared decision-making relationship with the patient with a particular focus on supporting the patient’s autonomy. Within this relationship, team focus shifts away from “adherence” toward the process whereby patients design and implement prophylaxis regimens resulting in reduction or elimination of bleeding episodes.
Using the current methodology, it is not possible to demonstrate a causal link between specific team processes and improved bleeding rates in patients.
Through the active support of patient autonomy in all aspects of decisions related to hemophilia management, the British Columbia Hemophilia Adult Team approach de-emphasizes “adherence” as the primary goal, and focuses on a prophylaxis plan that is customized by the patient and aligned with his priorities. Adoption of this comprehensive team approach facilitates shared goals between the patient and the team that may optimize treatment adherence, but more importantly, reduce bleeding rates.
PMCID: PMC4676616  PMID: 26675989
individiualized prophylaxis; shared decision-making; autonomy support; comprehensive care team
24.  Crystal structure of an antigenic outer-membrane protein from Salmonella Typhi suggests a potential antigenic loop and an efflux mechanism 
Scientific Reports  2015;5:16441.
ST50, an outer-membrane component of the multi-drug efflux system from Salmonella enterica serovar Typhi, is an obligatory diagnostic antigen for typhoid fever. ST50 is an excellent and unique diagnostic antigen with 95% specificity and 90% sensitivity and is used in the commercial diagnosis test kit (TYPHIDOTTM). The crystal structure of ST50 at a resolution of 2.98 Å reveals a trimer that forms an α-helical tunnel and a β-barrel transmembrane channel traversing the periplasmic space and outer membrane. Structural investigations suggest significant conformational variations in the extracellular loop regions, especially extracellular loop 2. This is the location of the most plausible antibody-binding domain that could be used to target the design of new antigenic epitopes for the development of better diagnostics or drugs for the treatment of typhoid fever. A molecule of the detergent n-octyl-β-D-glucoside is observed in the D-cage, which comprises three sets of Asp361 and Asp371 residues at the periplasmic entrance. These structural insights suggest a possible substrate transport mechanism in which the substrate first binds at the periplasmic entrance of ST50 and subsequently, via iris-like structural movements to open the periplasmic end, penetrates the periplasmic domain for efflux pumping of molecules, including poisonous metabolites or xenobiotics, for excretion outside the pathogen.
PMCID: PMC4643347  PMID: 26563565
25.  Rapid whole genome sequencing of Miyazaki-Bali/2007 Pteropine orthoreovirus by modified rolling circular amplification with adaptor ligation – next generation sequencing 
Scientific Reports  2015;5:16517.
The emergence of orthoreoviruses as the causative agent of human respiratory illness over the past few years has led to a demand to determine their viral genome sequences. The whole genome sequencing of such RNA viruses using traditional methods, such as Sanger dideoxy sequencing following rapid amplification of cDNA ends presents a laborious challenge due to the numerous preparatory steps required before sequencing can commence. We developed a practical, time-efficient novel combination method capable of reducing the total time required from months to less than a week in the determination of whole genome sequence of Pteropine orthoreoviruses (PRV); through a combination of viral RNA purification and enrichment, adaptor ligation, reverse transcription, cDNA circularization and amplification, and next generation sequencing. We propose to call the method “modified rolling circular amplification with adaptor ligation – next generation sequencing (mRCA-NGS)”. Here, we describe the technological focus and advantage of mRCA-NGS and its expansive application, exemplified through the phylogenetic understanding of the Miyazaki-Bali/2007 PRV.
PMCID: PMC4642344  PMID: 26558341

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