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1.  Transmitted Antiretroviral Drug Resistance in the Men Who Have Sex with Men HIV Patient Cohort, Beijing, China, 2008–2011 
Viral Immunology  2014;27(8):392-397.
Transmitted drug resistance (TDR) is an ongoing public health problem in HIV disease treatment. However, little is known about TDR among men who have sex with men (MSM) patients in China. In addition, TDR prevalence among patients with acute HIV infection (AHI) or early HIV infection (EHI) was believed higher than that of patients with chronic HIV infection (CHI), but as AHI is typically either unidentified or crudely defined in large populations, very few direct comparisons have been made. We did a retrospective analysis of TDR in 536 antiretroviral-naive MSM patients from our immunodeficiency clinics at You'an Hospital, Capital Medical University (CMU), in Beijing, China, 2008–2011. The cohort included 266 patients with AHI/EHI and 270 patients with CHI. We analyzed the subtype, estimated the TDR prevalence, and characterized the model of TDR and the predicted drug sensitivity. Additionally, we made a comparison of TDR between the patients with AHI/EHI and patients with CHI.
Our results indicated that among the 536 patients, HIV-1 subtype CRF01_AE accounted for 52.1%, subtype B accounted for 24.8%, CRF07_BC/ CRF08_BC accounted for 21.6% (116/536), and 1.3% were denoted as unique recombinant forms (URFs). A total of 7.8% patients had one or more transmitted HIV-1 drug resistance mutations, representing 6.2% for PI-related mutations, 0.9% for NRTI-related mutations, and 1.7% for NNRTI-related mutations. Although patients with AHI/EHI had a higher TDR prevalence as compared to that of patients with CHI, the difference was not statistically significant. There was no significant difference in TDR model and predicted drug susceptibility between the two groups of patients either.
This study provides important strategic information for public health planning by healthcare officials in China and warrants a comprehensive study with larger patient cohorts from various healthcare centers within China.
PMCID: PMC4183911  PMID: 25084305
2.  The BCL2L1 and PGAM5 axis defines hypoxia-induced receptor-mediated mitophagy 
Autophagy  2014;10(10):1712-1725.
Receptor-mediated mitophagy is one of the major mechanisms of mitochondrial quality control essential for cell survival. We previously have identified FUNDC1 as a mitophagy receptor for selectively removing damaged mitochondria in mammalian systems. A critical unanswered question is how receptor-mediated mitophagy is regulated in response to cellular and environmental cues. Here, we report the striking finding that BCL2L1/Bcl-xL, but not BCL2, suppresses mitophagy mediated by FUNDC1 through its BH3 domain. Mechanistically, we demonstrate that BCL2L1, but not BCL2, interacts with and inhibits PGAM5, a mitochondrially localized phosphatase, to prevent the dephosphorylation of FUNDC1 at serine 13 (Ser13), which activates hypoxia-induced mitophagy. Our results showed that the BCL2L1-PGAM5-FUNDC1 axis is critical for receptor-mediated mitophagy in response to hypoxia and that BCL2L1 possesses unique functions distinct from BCL2.
PMCID: PMC4198357  PMID: 25126723
BCL2L1/Bcl-xL; FUNDC1; hypoxia; mitophagy; PGAM5 phosphatase
4.  Distortion of memory Vδ2 γδ T cells contributes to immune dysfunction in chronic HIV infection 
Cellular and Molecular Immunology  2014;12(5):604-614.
γδ T cells play important roles in innate immunity as the first-line of defense against infectious diseases. Human immunodeficiency virus (HIV) infection disrupts the balance between Vδ1 T cells and Vδ2 T cells and causes dysfunction among γδ T cells. However, the biological mechanisms and clinical consequences of this disruption require further investigation. In this study, we performed a comprehensive analysis of phenotype and function of memory γδ T cells in cohorts of Chinese individuals with HIV infection. We found a dynamic change in memory Vδ2 γδ T cells, skewed toward an activated and terminally differentiated effector memory phenotype TEMRA Vδ2 γδ T cell, which may account for the dysfunction of Vδ2 γδ T cells in HIV disease. In addition, we found that IL-17-producing γδ T cells were significantly increased in HIV-infected patients with fast disease progression and positively correlated with HLA-DR+ γδ T cells and CD38+HLA-DR+ γδ T cells. This suggests the IL-17 signaling pathway is involved in γδ T-cell activation and HIV pathogenesis. Our findings provide novel insights into the role of Vδ2 T cells during HIV pathogenesis and represent a sound basis on which to consider immune therapies with these cells.
PMCID: PMC4579648  PMID: 25220734
γδ T cell; HIV; IL-17; immune activation; memory Vδ2 γδ T cells
5.  Low prevalence of human leukocyte antigen-B*5701 in HIV-1-infected Chinese subjects: a prospective epidemiological investigation 
Human leukocyte antigen (HLA)-B*5701 is strongly associated with developing a hypersensitivity reaction to abacavir (ABC). Limited data exist on HLA-B*5701 prevalence in HIV-1-infected subjects in China. We investigated HLA-B*5701 prevalence in HIV-1-infected population including Han and non-Han ethnic groups.
A prospective multi-centre study was designed to determine status of HLA-B*5701 in HIV-1-infected adults at six sites across China. HLA-B*5701 was tested by the method of PCR-SSP.
From six centers, 3,000 HIV-infected patients [2,452 (81.7%) Han, 548 (18.3%) Non-Han] were recruited with a mean age of 36.7 years old. The overall HLA-B*5701 prevalence was 0.86% [95% confidence interval (CI) 0.55–1.26%]. The prevalence of HLA-B*5701 among Han subjects was similar to that among non-Han subjects, which was 0.88% (95% CI 0.54–1.34%) and 0.76% (95% CI 0.19–1.93%), respectively (p value = 0.787). There were no differences in prevalence of HLA-B*5701 between subjects born in Henan, Yunnan, Shanxi, Guangdong, Hebei, Beijing and other provinces (p = 0.999).
HLA-B*5701 prevalence is very low in HIV-infected Chinese subjects, both in the Han and Non-Han nationalities. And there are no differences among different birthplaces across China.
PMCID: PMC4543466  PMID: 26300948
HLA-B*5701; HIV; Prevalence
6.  Structural Study of the RIPoptosome Core Reveals a Helical Assembly for Kinase Recruitment 
Biochemistry  2014;53(33):5424-5431.
Receptor interaction protein kinase 1 (RIP1) is a molecular cell-fate switch. RIP1, together with Fas-associated protein with death domain (FADD) and caspase-8, forms the RIPoptosome that activates apoptosis. RIP1 also associates with RIP3 to form the necrosome that triggers necroptosis. The RIPoptosome assembles through interactions between the death domains (DDs) of RIP1 and FADD and between death effector domains (DEDs) of FADD and caspase-8. In this study, we analyzed the overall structure of the RIP1 DD/FADD DD complex, the core of the RIPoptosome, by negative-stain electron microscopy and modeling. The results show that RIP1 DD and FADD DD form a stable complex in vitro similar to the previously described Fas DD/FADD DD complex, suggesting that the RIPoptosome and the Fas death-inducing signaling complex share a common assembly mechanism. Both complexes adopt a helical conformation that requires type I, II, and III interactions between the death domains.
PMCID: PMC4148139  PMID: 25119434
7.  Somatostatin Improved B Cells Mature in Macaques during Intestinal Ischemia-Reperfusion 
PLoS ONE  2015;10(7):e0133692.
Intestinal ischemia-reperfusion has been taken as an important pathophysiological process for multiple organ dysfunctions in critical patients. Recent studies reported that dual expression programs of the B cells receptors and Toll-like receptors on B-lymphocytes permit these ubiquitous cells to integrate both adaptive and innate immune functions. Our previous studies found that somatostatin inhibited the intestinal inflammatory injury after ischemia-reperfusion in macaques. However, the changes of B cells and the effects of somatostatin on B cells after intestinal ischemia-reperfusion were unclear.
15 macaques were divided into control, intestinal ischemia-reperfusion and somatostatin pretreatment groups. Immunohistochemistry was performed to identify the distributions of adaptive and innate immunity markers in the iliac mucosa. Hmy2.cir B lymphoblastoid cell line was cultured in vitro study. Enzyme-linked immunosorbent assay was used to measure IgM, IL-6 and SIgA, and the expressions of B cells transcription factors, PAX-5 and BLIMP-1, were detected by Western blotting.
B2 lymphocytes in normal Peyer’s patches were presented the phenotype of PAX-5+CD20+CD5-. Ischemia-reperfusion increased the numbers and sizes of Peyer’s patches but with PAX-5+CD20-CD5- B cells, an unmatured set of B cells. Somatostatin partly kept the phenotype of mature B cells during ischemia-reperfusion. The innate immunity of B cells was inhibited whereas the adaptive immunity was increased in the intestinal mucosa in the somatostatin group, compared to the ischemia-reperfusion group. In vitro, somatostatin significantly inhibited IL-6 and promoted IgM by increasing the expression of both PAX-5 and BLIMP-1 in the proinflammatory condition.
Intestinal ischemia-reperfusion resulted in the proliferation of unmatured B cells which were involved in the augmentation of innate immunity. Somatostatin, with a bi-directional regulation function on innate as well as adaptive immunity of B cells, greatly improved B cells mature in macaques during ischemia-reperfusion. Preventive supplements of somatostatin may greatly limit intestinal injury and bacterial translocation during ischemia-reperfusion.
PMCID: PMC4519283  PMID: 26222793
9.  MTDH-SND1 Interaction is Essential for the Expansion and Activity of Tumor-Initiating Cells in Diverse Oncogene- and Carcinogen-Induced Mammary Tumors 
Cancer cell  2014;26(1):92-105.
The Metadherin gene (MTDH) is prevalently amplified in breast cancer and associated with poor prognosis but its functional contribution to tumorigenesis is poorly understood. Using mouse models representing different subtypes of breast cancer, we demonstrated that MTDH plays a critical role in mammary tumorigenesis by regulating oncogene-induced expansion and activities of tumor-initiating cells (TICs), whereas it is largely dispensable for normal development. Mechanistically, MTDH supports the survival of mammary epithelial cells (MECs) under oncogenic/stress conditions by interacting with and stabilizing Staphylococcal nuclease domain-containing 1 (SND1). Silencing MTDH or SND1 individually or disrupting their interaction compromises tumorigenenic potential of TICs in vivo. Finally, this functional significance of MTDH-SND1 interaction is supported by clinical analysis of human breast cancer samples.
PMCID: PMC4101059  PMID: 24981741
10.  Assessments of Drought Impacts on Vegetation in China with the Optimal Time Scales of the Climatic Drought Index 
Drought is expected to increase in frequency and severity due to global warming, and its impacts on vegetation are typically extensively evaluated with climatic drought indices, such as multi-scalar Standardized Precipitation Evapotranspiration Index (SPEI). We analyzed the covariation between the SPEIs of various time scales and the anomalies of the normalized difference vegetation index (NDVI), from which the vegetation type-related optimal time scales were retrieved. The results indicated that the optimal time scales of needle-leaved forest, broadleaf forest and shrubland were between 10 and 12 months, which were considerably longer than the grassland, meadow and cultivated vegetation ones (2 to 4 months). When the optimal vegetation type-related time scales were used, the SPEI could better reflect the vegetation’s responses to water conditions, with the correlation coefficients between SPEIs and NDVI anomalies increased by 5.88% to 28.4%. We investigated the spatio-temporal characteristics of drought and quantified the different responses of vegetation growth to drought during the growing season (April–October). The results revealed that the frequency of drought has increased in the 21st century with the drying trend occurring in most of China. These results are useful for ecological assessments and adapting management steps to mitigate the impact of drought on vegetation. They are helpful to employ water resources more efficiently and reduce potential damage to human health caused by water shortages.
PMCID: PMC4515678  PMID: 26184243
drought; SPEI; optimal time scales; NDVI; ecological assessment; China
11.  Pullulanase and Starch Synthase III Are Associated with Formation of Vitreous Endosperm in Quality Protein Maize 
PLoS ONE  2015;10(6):e0130856.
The opaque-2 (o2) mutation of maize increases lysine content, but the low seed density and soft texture of this type of mutant are undesirable. Lines with modifiers of the soft kernel phenotype (mo2) called “Quality Protein Maize” (QPM) have high lysine and kernel phenotypes similar to normal maize. Prior research indicated that the formation of vitreous endosperm in QPM might involve changes in starch granule structure. In this study, we focused on analysis of two starch biosynthetic enzymes that may influence kernel vitreousness. Analysis of recombinant inbred lines derived from a cross of W64Ao2 and K0326Y revealed that pullulanase activity had significant positive correlation with kernel vitreousness. We also found that decreased Starch Synthase III abundance may decrease the pullulanase activity and average glucan chain length given the same Zpu1 genotype. Therefore, Starch Synthase III could indirectly influence the kernel vitreousness by affecting pullulanase activity and coordinating with pullulanase to alter the glucan chain length distribution of amylopectin, resulting in different starch structural properties. The glucan chain length distribution had strong positive correlation with the polydispersity index of glucan chains, which was positively associated with the kernel vitreousness based on nonlinear regression analysis. Therefore, we propose that pullulanase and Starch Synthase III are two important factors responsible for the formation of the vitreous phenotype of QPM endosperms.
PMCID: PMC4482715  PMID: 26115014
12.  Network-based survival-associated module biomarker and its crosstalk with cell death genes in ovarian cancer 
Scientific Reports  2015;5:11566.
Ovarian cancer remains a dismal disease with diagnosing in the late, metastatic stages, therefore, there is a growing realization of the critical need to develop effective biomarkers for understanding underlying mechanisms. Although existing evidences demonstrate the important role of the single genetic abnormality in pathogenesis, the perturbations of interactors in the complex network are often ignored. Moreover, ovarian cancer diagnosis and treatment still exist a large gap that need to be bridged. In this work, we adopted a network-based survival-associated approach to capture a 12-gene network module based on differential co-expression PPI network in the advanced-stage, high-grade ovarian serous cystadenocarcinoma. Then, regulatory genes (protein-coding genes and non-coding genes) direct interacting with the module were found to be significantly overlapped with cell death genes. More importantly, these overlapping genes tightly clustered together pointing to the module, deciphering the crosstalk between network-based survival-associated module and cell death in ovarian cancer.
PMCID: PMC4477367  PMID: 26099452
13.  IL-17A G197A gene polymorphism contributes to susceptibility for liver cirrhosis development from patients with chronic hepatitis B infection in Chinese population 
Background: IL-17A G197A and IL-17F A7488G gene polymorphisms are found to be associated with the risk of several diseases, however few studies have focused on their correlation with risk of liver cirrhosis (LC). Aims: The aim of this study was to assess the impact of IL-17A G197A and IL-17F A7488G gene polymorphisms on development of LC from chronic hepatitis B (CHB) in Chinese patients. Methods: A total of 163 HBV-related LC patients and 168 CHB patients were enrolled in the present study. IL-17A and IL-17F gene polymorphisms were analyzed using a polymerase chain reaction (PCR) restriction fragment length polymorphism assay (PCR-RFLP). Results: Frequencies of IL-17A G197A genotype AA and allele A were significantly higher in LC patients compared with that in CHB patients (AA 42.33% vs 27.98%, P = 0.032; A 56.34% vs 46.15%, P=0.011, respectively); While no significant difference in frequencies of genotypes and alleles of IL-17F A7488G was found between the two groups. The AA genotype of IL-17A G197A significantly increased LC risk (OR 4.186, 95% CI: 1.479-11.844), while A allele carriers were also associated with an increased LC risk (OR 1.856, 95% CI: 1.161-2.967). Conclusion: IL-17A G197A is a candidate gene that confers the genetic susceptibility for LC development from CHB in Chinese population.
PMCID: PMC4537967  PMID: 26309658
IL-17; liver cirrhosis; gene polymorphisms
14.  Testicular metastasis from gastric carcinoma: A case report 
Gastric cancer (GC) is the most prevalent malignancy in the world, especially in China. GC has been postulated to spread via several different routes, including through hematogenous channels, lymphatic vessels, the seeding of peritoneal surfaces, direct extension through the gastric wall, and retrograde extension through the vas deferens or lymphatics. Testicular metastasis is rare. We show here a 53-year-old patient with GC who underwent a radical total gastrectomy approximately 22 mo ago after he presented with a sensation of heaviness and swelling of the right hemiscrotum. The diagnosis of metastatic adenocarcinoma was made after a right-side orchiectomy. We report the first case of testicular metastasis from gastric adenocarcinoma in mainland China and summarize the clinicopathologic features of the disease based on previously published papers.
PMCID: PMC4458788  PMID: 26074716
Testicular cancer; Gastric carcinoma; Orchiectomy; Gastrectomy; Signet ring cell carcinoma
15.  Genome-Wide Association Studies of HIV-1 Host Control in Ethnically Diverse Chinese Populations 
Scientific Reports  2015;5:10879.
Genome-wide association studies (GWASs) have revealed several genetic loci associated with HIV-1 outcome following infection (e.g., HLA-C at 6p21.33) in multi-ethnic populations with genetic heterogeneity and racial/ethnic differences among Caucasians, African-Americans, and Hispanics. To systematically investigate the inherited predisposition to modulate HIV-1 infection in Chinese populations, we performed GWASs in three ethnically diverse HIV-infected patients groups (i.e., HAN, YUN, and XIN, N = 538). The reported loci at 6p21.33 was validated in HAN (e.g., rs9264942, P = 0.0018). An independent association signal (rs2442719, P = 7.85 × 10−7, HAN group) in the same region was observed. Imputation results suggest that haplotype HLA-B*13:02/C*06:02, which can partially account for the GWAS signal, is associated with lower viral load in Han Chinese. Moreover, several novel loci were identified using GWAS approach including the top association signals at 6q13 (KCNQ5, rs947612, P = 2.15 × 10−6), 6p24.1 (PHACTR1, rs202072, P = 3.8 × 10−6), and 11q12.3 (SCGB1D4, rs11231017, P = 7.39 × 10−7) in HAN, YUN, and XIN groups, respectively. Our findings imply shared or specific mechanisms for host control of HIV-1 in ethnically diverse Chinese populations, which may shed new light on individualized HIV/AIDS therapy in China.
PMCID: PMC4454153  PMID: 26039976
16.  Modeling Parkinson’s Disease in Monkeys for Translational Studies, a Critical Analysis 
Experimental neurology  2013;0:133-143.
The non-human primate MPTP model of Parkinson’s disease is an essential tool for translational studies. However, the currently used methodologies to produce parkinsonian monkeys do not follow unified criteria, and the applied models may often fall short of reproducing the characteristics of patients in clinical trials. Pooling of data from the parkinsonian monkeys produced in our Centers provided the opportunity to evaluate thoroughly the behavioral outcomes that may be considered for appropriate modeling in preclinical studies. We reviewed records from 108 macaques including rhesus and cynomolgus species used to model moderate to advanced parkinsonism with systemic MPTP treatment. The attained motor disability and the development of levodopa-induced dyskinesias, as primary outcomes, and the occurrence of clinical complications and instability of symptoms were all analyzed for correlations with the parameters of MPTP administration and for estimation of sample sizes. Results showed that frequently the MPTP-treated macaque can recapitulate the phenotype of patients entering clinical trials, but to produce this model consistently it is important to adapt the MPTP exposure tightly according to individual animal responses. For studies of reduced animal numbers it is also important to produce stable models, and stability of parkinsonism in macaques critically depends on reaching “marked” motor disability. The analyzed data also led to put forward recommendations for successfully producing the primate MPTP model of Parkinson’s disease for translational studies.
PMCID: PMC3962841  PMID: 24070854
Parkinson’s disease; MPTP; non-human primate; model; dyskinesia
17.  HMMR Maintains the Stemness and Tumorigenicity of Glioblastoma Stem-like Cells 
Cancer research  2014;74(11):3168-3179.
Glioblastoma (GBM) stem cells (GSC) are a subpopulation of tumor cells that display stem-like characteristics (stemness) and play unique roles in tumor propagation, therapeutic resistance and tumor recurrence. Therapeutic targets in GSC are a focus of increasing interest to improve GBM therapy. Here we report that the hyaluronan-mediated motility receptor (HMMR) is highly expressed in GBM tumors where it supports the self-renewal and tumorigenic potential of GSC. HMMR silencing impairs GSC self-renewal and inhibits the expression of GSC markers and regulators. Furthermore, HMMR silencing suppresses GSC-derived tumor growth and extends the survival of mice bearing GSC xenografts. Conversely, HMMR overexpression promotes GSC self-renewal and intracranial tumor propagation. In human GBM tumor specimens, HMMR expression is correlated positively with the expression of stemness-associated markers and regulators. Our findings identify HMMR as a candidate therapeutic target to GSC as a GBM treatment strategy.
PMCID: PMC4059010  PMID: 24710409
Cancer stem cell; brain tumor; oncogene; self-renewal; RNA interference
18.  Hydrolysis of 2′3′-cGAMP by ENPP1 and design of non-hydrolyzable analogs 
Nature chemical biology  2014;10(12):1043-1048.
Agonists of mouse STING (TMEM173) shrink and even cure solid tumor by activating innate immunity; human STING agonists are needed to test this therapeutic hypothesis in man. The endogenous STING agonist is 2′3′-cGAMP, a 2nd messenger that signals the presence of cytosolic dsDNA. We report activity-guided partial purification and identification of ENPP1 as the dominant 2′3′-cGAMP hydrolyzing activity in cultured cells. The hydrolysis activity of ENPP1 was confirmed using recombinant protein and was depleted in tissue extracts and plasma from Enpp1-/- mice. We synthesized a hydrolysis-resistant bis-phosphothioate analog of 2′3′-cGAMP (2′3′-cGsAsMP) with similar affinity for human STING in vitro and 10 times more potent at inducing IFN-β secretion from human THP1 monocytes. Studies in mouse Enpp1-/- lung fibroblasts indicate that resistance to hydrolysis contributes significantly to its higher potency. 2′3′-cGsAsMP is therefore improved over natural 2′3′-cGAMP as a model agonist, and has potential as a vaccine adjuvant and cancer therapeutic.
PMCID: PMC4232468  PMID: 25344812
19.  Single-base resolution analysis of active DNA demethylation using methylase-assisted bisulfite sequencing 
Nature biotechnology  2014;32(12):1231-1240.
Active DNA demethylation in mammals involves TET-mediated iterative oxidation of 5-methylcytosine (5mC)/5-hydroxymethylcytosine (5hmC) and subsequent excision repair of highly oxidized cytosine bases 5-formylcytosine (5fC)/5-carboxylcytosine (5caC) by Thymine DNA glycosylase (TDG). However, quantitative and high-resolution analysis of active DNA demethylation activity remains challenging. Here we describe M.SssI methylase-assisted bisulfite sequencing (MAB-seq), a method that directly maps 5fC/5caC at single-base resolution. Genome-wide MAB-seq allows systematic identification of 5fC/5caC in Tdg-depleted embryonic stem cells, thereby generating a base-resolution map of active DNA demethylome. A comparison of 5fC/5caC and 5hmC distribution maps indicates that catalytic processivity of TET enzymes correlates with local chromatin accessibility. MAB-seq also reveals strong strand asymmetry of active demethylation within palindromic CpGs. Integrating MAB-seq with other base-resolution mapping methods enables quantitative measurement of cytosine modification states at key transitioning steps of active demethylation pathway, and reveals a regulatory role of 5fC/5caC excision repair in active DNA demethylation cascade.
PMCID: PMC4269366  PMID: 25362244
20.  Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity 
Oncostatin M (OSM) exhibits many unique biological activities by activating Oβ receptor. However, its role in myocardial I/R injury in diabetic mice remains unknown. The involvement of OSM was assessed in diabetic mice which underwent myocardial I/R injury by OSM treatment or genetic deficiency of OSM receptor Oβ. Its mechanism on cardiomyocyte apoptosis, mitochondrial biogenesis and insulin sensitivity were further studied. OSM alleviated cardiac I/R injury by inhibiting cardiomyocyte apoptosis through inhibition of inositol pyrophosphate 7 (IP7) production, thus activating PI3K/Akt/BAD pathway, decreasing Bax expression while up-regulating Bcl-2 expression and decreasing the ratio of Bax to Bcl-2 in db/db mice. OSM enhanced mitochondrial biogenesis and mitochondrial function in db/db mice subjected to cardiac I/R injury. On the contrary, OSM receptor Oβ knockout exacerbated cardiac I/R injury, increased IP7 production, enhanced cardiomyocyte apoptosis, impaired mitochondrial biogenesis, glucose homoeostasis and insulin sensitivity in cardiac I/R injured diabetic mice. Inhibition of IP7 production by TNP (IP6K inhibitor) exerted similar effects of OSM. The mechanism of OSM on cardiac I/R injury in diabetic mice is partly associated with IP7/Akt and adenine mononucleotide protein kinase/PGC-1α pathway. OSM protects against cardiac I/R Injury by regulating apoptosis, insulin sensitivity and mitochondrial biogenesis in diabetic mice through inhibition of IP7 production.
PMCID: PMC4459845  PMID: 25752217
oncostatin M; ischaemia/Reperfusion injury; inositol pyrophosphate 7; diabetes
21.  Expression of ribosome-binding protein 1 correlates with shorter survival in Her-2 positive breast cancer 
Cancer Science  2015;106(6):740-746.
The aim of this study is to investigate the expression of ribosome-binding protein 1 (RRBP1) in invasive breast cancer and to analyze its relationship to clinical features and prognosis. RRBP1 expression was studied using real-time quantitative PCR and western blotting using pair-matched breast samples and immunohistochemical staining using a tissue microarray. Then the correlation between RRBP1 expression and clinicopathologic features was analyzed. RRBP1 mRNA and protein expression were significantly increased in breast cancer tissues compared with normal tissues. The protein level of RRBP1 is proved to be positively related to histological grade (P = 0.02), molecular subtype (P = 0.048) and status of Her-2 (P = 0.026) and P53 (P = 0.015). We performed a grade-stratified analysis of all patients according to the level of RRBP1 expression and found that RRBP1 overexpression highly affected overall survival in patients with early-stage (I and II) tumors (P = 0.042). Furthermore, Her-2 positive patients with negative RRBP1 expression had longer overall survival rates than those with positive RRBP1 expression (P = 0.031). Using multivariate analysis, it was determined that lymph node metastasis (LNM, P = 0.002) and RRBP1 expression (P = 0.005) were independent prognosis factors for overall survival. RRBP1 is a valuable prognostic factor in Her-2-positive breast cancer patients, indicating that RRBP1 is a potentially important target for the prediction of prognosis.
PMCID: PMC4471791  PMID: 25845758
Breast cancer; Her-2; histological grade; prognosis; RRBP1
22.  Targeted Next-Generation Sequencing in Uyghur Families with Non-Syndromic Sensorineural Hearing Loss 
PLoS ONE  2015;10(5):e0127879.
The mutation spectrum of deafness genes may vary in different ethnical groups. In this study, we investigated the genetic etiology of nonsyndromic deafness in four consanguineous and two multiplex Uyghur families in which mutations in common deafness genes GJB2, SLC26A4 and MT-RNR1 were excluded. Targeted next-generation sequencing of 97 deafness genes was performed in the probands of each family. Novel pathogenic mutations were identified in four probands including the p.L416R/p.A438T compound heterozygous mutations in TMC1, the homozygous p.V1880E mutation in MYO7A, c.1238delT frameshifting deletion in PCDH15 and c.9690+1G>A splice site mutation in MYO15A. Co-segregation of the mutations and the deafness were confirmed within each family by Sanger sequencing. No pathogenic mutations were identified in one multiplex family and one consanguineous family. Our study provided a useful piece of information for the genetic etiology of deafness in Uyghurs.
PMCID: PMC4444116  PMID: 26011067
23.  Interferon-induced transmembrane protein-3 rs12252-C is associated with rapid progression of acute HIV-1 infection in Chinese MSM cohort 
AIDS (London, England)  2015;29(8):889-894.
The interferon-inducible transmembrane protein-3 (IFITM3) is a protein that restricts multiple pathogenic viruses such as influenza virus. The single-nucleotide polymorphism rs12252-C, which is rare in Caucasian populations, but much more common in the Han Chinese population, has been found in much higher homozygous frequency in patients with severe acute influenza. Until now, there has been no study on the effect of this genetic variant on the clinical control of other viral infections.
To investigate the impact of IFITM3-rs12252 genotypes on primary HIV-1 infection progression in an acute HIV-1-infected cohort in Beijing (PRIMO), China.
Design and methods:
We identified IFITM3-rs12252 genotypes of 178 acute HIV-1-infected patients and 196 HIV-negative candidates from the PRIMO cohort. HIV-1 viral load and CD4+ T-cell counts were monitored at multiple time points during the first year of infection, and the association between IFITM3-rs12252 genotype and disease progression was evaluated.
The current study shows that the IFITM3-rs12252 genetic variant affects the progression of HIV-1 infection, but not the acquisition. A significantly higher frequency of the CC/CT genotypes was found in rapid progressors compared to nonprogressors. Patients with CC/CT genotypes showed an elevated peak viremia level and significantly lower CD4+ T-cell count at multiple time points during the first year of primary infection, and a significantly higher risk of rapid decline of the CD4+ T-cell count to below 350 cells/μl.
A novel association between IFITM3 gene polymorphism and rapid disease progression is reported in an acute HIV-1-infected MSM cohort in China.
PMCID: PMC4442129  PMID: 25784441
acute infection; CD4+ T-cell count; HIV-1; interferon-inducible transmembrane protein 3; rs12252-C allele
24.  HIV-associated memory B cell perturbations 
Vaccine  2015;33(22):2524-2529.
Memory B-cell depletion, hyperimmunoglobulinemia, and impaired vaccine responses are the hallmark of B cell perturbations inhuman immunodeficiency virus (HIV) disease. Although B cells are not the targets for HIV infection, there is evidence for B cell, especially memory B cell dysfunction in HIV disease mediated by other cells or HIV itself. This review will focus on HIV-associated phenotypic and functional alterations in memory B cells. Additionally, we will discuss the mechanism underlying these perturbations and the effect of anti-retroviral therapy (ART) on these perturbations.
PMCID: PMC4420662  PMID: 25887082
Memory B cells; HIV; anti-retroviral therapy; vaccination
25.  A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration 
This study aimed to investigate the sustained drug release properties and hearing protection effect of polyethylene glycol-coated polylactic acid (PEG-PLA) stealth nanoparticles loaded with dexamethasone (DEX). DEX was fabricated into PEG-PLA nanoparticles using an emulsion and evaporation technique, as previously reported. The DEX-loaded PEG-PLA nanoparticles (DEX-NPs) had a hydrodynamic diameter of 130±4.78 nm, and a zeta potential of −26.13±3.28 mV. The in vitro release of DEX from DEX-NPs lasted 24 days in phosphate buffered saline (pH 7.4), 5 days in artificial perilymph (pH 7.4), and 1 day in rat plasma. Coumarin 6-labeled NPs placed onto the round window membrane (RWM) of guinea pigs penetrated RWM quickly and accumulated to the organs of Corti, stria vascularis, and spiral ganglion cells after 1 hour of administration. The DEX-NPs locally applied onto the RWM of guinea pigs by a single-dose administration continuously released DEX in 48 hours, which was significantly longer than the free DEX that was cleared out within 12 hours after administration at the same dose. Further functional studies showed that locally administrated single-dose DEX-NPs effectively preserved outer hair cells in guinea pigs after cisplatin insult and thus significantly attenuated hearing loss at 4 kHz and 8 kHz frequencies when compared to the control of free DEX formulation. Histological analyses indicated that the administration of DEX-NPs did not induce local inflammatory responses. Therefore, prolonged delivery of DEX by PEG-PLA nanoparticles through local RWM diffusion (administration) significantly protected the hair cells and auditory function in guinea pigs from cisplatin toxicity, as determined at both histological and functional levels, suggesting the potential therapeutic benefits in clinical applications.
PMCID: PMC4437605  PMID: 25999718
stealth nanoparticles; dexamethasone; single-dose administration; cisplatin-induced hearing loss

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