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1.  Kinetic analysis of the immunity in a pregnant patient infected with avian influenza H7N9 
Background: Human infection with avian influenza A H7N9 has emerged in China since February, 2013. The immunologic changes in pregnant women infected with H7N9 are not known. Objective: To report the clinical data and kinetic changes of immunity in a pregnant woman infected with H7N9 virus in Zhenjiang, Jiangsu, China. Methods: The clinical data were collected and immunity status was monitored in this patient. Results: H7N9 virus became undetectable in sputum from 14 days since onset of symptoms after effective antiviral therapy with oseltamivir and symptomatic/supporting treatments. The symptoms and signs in this patient gradually improved from 15 days since onset of symptoms. Peripheral lymphocytes initially decreased and gradually increased. The percentage of CD4+ T cells increased since 16 days after onset of symptoms. The kinetic changes of cytokines including IFN-γ, IFN-α, TNF-α, IL-10 and TGF-β1 matched the development and recovery of illness. Her family members, including her parents exposed to H7N9 positive materials in poultry market, were H7N9 negative. Conclusions: Our results indicate that pregnant women are susceptible to H7N9 virus and H7N9 infection in pregnant women is curable without significant impact on fetus. Kinetic changes of pro-inflammatory and anti-inflammatory cytokines play a role in the pathogenesis and clinical outcome in the pregnant patient with H7N9 infection.
PMCID: PMC4132142  PMID: 25126178
H7N9; cytokine; pregnancy
2.  Risk factors for venous thromboembolism of total hip arthroplasty and total knee arthroplasty: a systematic review of evidences in ten years 
Risk factors for venous thromboembolism (VTE) of total joint arthroplasty (TJA) have been examined by many studies. A comprehensive systematic review of recent findings of high evidence level in this topic is needed.
We conducted a PubMed search for papers published between 2003 and 2013 that provided level-I and level-II evidences on risk factors for VTE of TJA. For each potential factors examined in at least three papers, we summarize the the number of the papers and confirmed the direction of statistically significant associations, e.g. “risk factor” “protective factor” or “controversial factor”.
Fifty-four papers were included in the systematic review. Risk factors found to be associated with VTE of both total hip arthroplasty and total knee arthroplasty included older age, female sex, higher BMI, bilateral surgery, surgery time > 2 hours. VTE history was found as a VTE risk factor of THA but an controversial factor of TKA. Cemented fixation as compared to cementless fixation was found as a risk factor for VTE only of TKA. TKA surgery itself was confirmed as a VTE risk factor compared with THA surgery.
This systematic review of high level evidences published in recent ten years identified a range of potential factors associated with VTE risk of total joint arthroplasty. These results can provide informations in this topic for doctors, patients and researchers.
PMCID: PMC4328702
Total hip arthroplasty; Total knee arthroplasty; Venous thromboembolism; Risk factor; Systematic review
3.  Combination therapy of ursodeoxycholic acid and budesonide for PBC–AIH overlap syndrome: a meta-analysis 
In this study, a meta-analysis of randomized controlled trials comparing ursodeoxycholic acid (UDCA) monotherapy with combination therapies utilizing UDCA and budesonide was performed. We found that combination therapy with UDCA and budesonide was more effective than UDCA monotherapy for primary biliary cirrhosis–autoimmune hepatitis overlap syndrome. Moreover, compared to prednisone, budesonide has fewer side effects.
PMCID: PMC4304592  PMID: 25632224
meta-analysis; UDCA; budesonide; combination therapy; PBC–AIH overlap syndrome
4.  Immunoproteomic profile of Trichinella spiralis adult worm proteins recognized by early infection sera 
Parasites & Vectors  2015;8:20.
Trichinellosis, a widespread zoonosis, is regarded as an emerging or reemerging disease. Effective treatment and prognosis of trichinellosis depends on early diagnosis of the infection. The objective of this study was to identify sensitive and specific antigens for early diagnosis or effective vaccine antigens for preventing infection.
The somatic proteins of T. spiralis adult worms were separated by two-dimensional gel electrophoresis (2-DE). The separated proteins were probed with early infection sera from swine or mice infected with T. spiralis for 7 days. The primary immunoreactive spots were characterized by MALDI-TOF/TOF-MS analysis in combination with bioinformatics. The identified proteins were annotated using WEGO based on their functions. The immunodominant protein was chosen for expression as recombinant protein in E. coli and the purified recombinant protein was used to confirm its antigenicity by Western blot with the same infection sera.
Approximately 300 spots were separated by 2-DE, with molecular weights ranging from 10 to 130 kDa, and pI values ranging from pH 4 to 10. The sera from swine and mice infected with T. spiralis for 7 days recognized 64 proteins. MALDI-TOF/TOF-MS analysis identified 55 proteins, some with different isoforms. Finally, 40 individual immunoreactive proteins were obtained with a wide range of biological functions. Several proteins, such as heat shock protein 70, 14-3-3 protein, and cysteine protease could be used as immunodiagnostic or vaccine antigens. Among these identified proteins, the highly immunodominant Ts14-3-3 was chosen for expression in E. coli and purified recombinant Ts14-3-3 was able to be strongly recognized by the same T. spiralis infected sera used for identifying these antigens, therefore the most promising antigen for early immunodiagnosis of Trichinella infection.
A total of 64 proteins from the adult worm were recognized by early infection sera from swine and mice infected with T. spiralis for 7 days. Several proteins, are of particular interest as immunodiagnostic or vaccine antigens, especially with Ts14-3-3 as most promising due to its highly immunogenicity during early infection, expressed protein can be recognized by Trichinella early infection sera and the native Ts14-3-3 expression in both adult and larval stages.
PMCID: PMC4299305  PMID: 25582511
Trichinella spiralis; Adult worm; Mass spectrometry; Immunoproteomics; Diagnosis
5.  Establishment and ultrasound characteristics of atherosclerosis in rhesus monkey 
BioMedical Engineering OnLine  2015;14(Suppl 1):S13.
Atherosclerosis is one of the main risk factors cause acute cerebral-cardio vascular diseases. It's of great significance to establish an atherosclerosis animal model that can mimic the characteristics and nature course of human patients. Therefore, a rhesus monkey model was induced by high-fat diet to monitor their lipid profile and intima-media thickness (IMT) of artery walls and study atherosclerosis progression.
Fifty male rhesus monkeys were enrolled in this study. All of these monkeys were aged 7 to 14 years with BMI >30 kg/m2. They were fed with high-fat diet containing 10% of fat for the first 48 weeks. Use ultrasound to measure the IMT at bilateral common carotid arteries and their bifurcations and aorta (AO) of the monkeys, and screen out the individuals with thickened IMT for the next phase. In the next 48 weeks, some of these monkeys (n = 4) were fed with standard diet containing 3% fat. Meanwhile the other monkeys (n = 5) were fed with high-fat diet for another 48 weeks. Their serum lipid level was monitored and arterial IMT was also determined periodically.
Serum lipid level of all 50 monkeys elevated after fed with high-fat diet for the first 48 weeks. IMT thickening at right common carotid bifurcation and aorta (AO) was thickened in 9 monkeys. Furthermore, 4 of these 9 monkeys were fed with standard diet and other 5 monkeys were fed with high-fat diet in the following 48 weeks. The serum lipid level of the 4 monkeys recovered and their IMT at RBIF and AO did not progress. However, the lipid level of other 5 monkeys remained high, and their IMT thickening of AO progressed, and plaques and calcification focuses were found at the anterior wall of aorta near the bifurcation of common iliac artery.
After high-fat diet induction for 96 weeks, serum lipid levels of rhesus monkeys elevated significantly, which subsequently caused IMT thickening and plaques formation. When IMT thickening occurred, further vascular injury may be prevented by reducing diet fat content. Our study indicates that vascular injury of high-fat diet induced rhesus monkey is similar to that of human in position and progression.
PMCID: PMC4306102  PMID: 25602196
6.  Detection of SRSF2-P95 Mutation by High-Resolution Melting Curve Analysis and Its Effect on Prognosis in Myelodysplastic Syndrome 
PLoS ONE  2014;9(12):e115693.
Hotspot mutations of serine/arginine-rich splicing factor 2 (SRSF2) gene have been identified in a proportion of hematologic malignancies including myelodysplastic syndrome (MDS). The aim of the present study was to develop a new approach to screen SRSF2 mutation and analyze the clinical relevance of SRSF2 mutations in Chinese MDS. A protocol based on high-resolution melting analysis (HRMA) was established to screen SRSF2-P95 mutation in 108 MDS patients and was compared with Sanger sequencing. The clinical relevance of SRSF2 mutations was further evaluated. HRMA identified five (4.6%) cases with SRSF2 mutation, completely validated by Sanger sequencing without false positive or negative results. The sensitivities of HRMA and Sanger sequencing were 10% and 25% for the detection of SRSF2-P95H mutation, respectively, against the background of wild-type DNA. Patients with SRSF2 mutation had shorter overall survival time than those with wild-type SRSF2 in both the whole cohort of cases and those with normal karyotype (P = 0.069 and 0.023, respectively). Multivariate analysis confirmed SRSF2 mutation as an independent risk factor in both patient populations. We established a fast, high-throughput, and inexpensive HRMA-based method to screen SRSF2 mutation, which could be used in clinical diagnostic laboratories. SRSF2 mutations were significantly associated with mortality rate in the MDS affected Chinese.
PMCID: PMC4277410  PMID: 25541999
7.  p38 MAPK-inhibited dendritic cells induce superior antitumor immune responses and overcome regulatory T cell-mediated immunosuppression 
Nature communications  2014;5:4229.
Dendritic cell (DC)-based cancer immunotherapy is a promising method but so far has demonstrated limited clinical benefits. Regulatory T cells (Treg) represent a major obstacle to cancer immunotherapy approaches. Here we show that inhibiting p38 MAPK during DC differentiation enables DCs to activate tumor-specific effector T cells (Teff), inhibiting the conversion of Treg and compromising Treg inhibitory effects on Teff. Inhibition of p38 MAPK in DCs lowers expression of PPARγ, activating p50 and upregulation of OX40L expression in DCs. OX40L/OX40 interactions between DCs and Teff and/or Treg are critical for priming effective and therapeutic antitumor responses. Similarly, p38 MAPK inhibition also augments the T cell-stimulatory capacity of human monocyte-derived DCs in the presence of Treg. These findings contribute to ongoing efforts to improve DC-based immunotherapy in human cancers.
PMCID: PMC4249595  PMID: 24957461
8.  Meta-analysis of the efficacy of probiotics in Helicobacter pylori eradication therapy 
World Journal of Gastroenterology : WJG  2014;20(47):18013-18021.
AIM: To evaluate the role of probiotics in the standard triple Helicobacter pylori therapy.
METHODS: In this meta-analysis, we investigated the efficacy of probiotics in a standard triple H. pylori therapy in adults. Searches were mainly conducted in MEDLINE/PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Fourteen studies met our criteria, and the quality of these studies was assessed using the Jadad scale. We used STATA version 12.0 to extract data and to calculate the odds ratios (ORs), which are presented with the corresponding 95% confidence intervals (CIs). The data are presented as forest plots.
RESULTS: The pooled ORs for the eradication rates calculated by intention-to-treat analysis and per-protocol analysis in the probiotic group vs the control group were 1.67 (95%CI: 1.38-2.02) and 1.68 (95%CI: 1.35-2.08), respectively, using the fixed-effects model. The sensitivity of the Asian studies was greater than that of the Caucasian studies (Asian: OR = 1.78, 95%CI: 1.40-2.26; Caucasian: OR = 1.48, 95%CI: 1.06-2.05). The pooled OR for the incidence of total adverse effects was significantly lower in the probiotic group (OR = 0.49, 95%CI: 0.26-0.94), using the random effects model, with significant heterogeneity (I2 = 85.7%). The incidence of diarrhea was significantly reduced in the probiotic group (OR = 0.21, 95%CI: 0.06-0.74), whereas the incidence of taste disorders, metallic taste, vomiting, nausea, and epigastric pain did not differ significantly between the probiotic group and the control group.
CONCLUSION: Supplementary probiotic preparations during standard triple H. pylori therapy may improve the eradication rate, particularly in Asian patients, and the incidence of total adverse effects.
PMCID: PMC4273153  PMID: 25548501
Helicobacter pylori; Eradication; Probiotics; Meta-analysis; Adult
9.  Effect of Zhuyun recipe on endometrial pinopode expression in mice with embryonic implantation dysfunction and ovulation stimulation 
Zhuyun recipe (ZYR) is a traditional Chinese medicine that has been widely used as an infertility treatment for a number of years. Although the therapeutic effects are desirable and satisfactory, the therapeutic mechanism of ZYR remains poorly understood. In the present study, pinopodes were investigated as an important morphological marker of endometrial receptivity, in order to further investigate the therapeutic mechanism of ZYR. The expression of pinopodes during the implantation window was observed using scanning electron microscopy in mice with induced ovarian stimulation (OS) and embryo implantation dysfunction (EID). A marked decrease in the number of fully developed pinopodes was observed on the endometrial surface in the OS and EID model mice, which was in accordance with the decreased pregnancy rate and number of embryonic implantation sites when compared with the control. Following treatment with ZYR, the spatial and temporal expression of pinopodes in the OS and EID mice was found to be similar to the control mice. In conclusion, ZYR was demonstrated to improve endometrial receptivity in OS and EID mice through significant improvements in the spatial and temporal expression of pinopodes.
PMCID: PMC4280920  PMID: 25574221
ovarian stimulation; embryo implantation dysfunction; traditional Chinese medicine; endometrial receptivity; pinopodes; mouse
10.  Functional Upregulation of Nav1.8 Sodium Channels on the Membrane of Dorsal Root Ganglia Neurons Contributes to the Development of Cancer-Induced Bone Pain 
PLoS ONE  2014;9(12):e114623.
We have previously reported that enhanced excitability of dorsal root ganglia (DRG) neurons contributes to the development of bone cancer pain, which severely decreases the quality of life of cancer patients. Nav1.8, a tetrodotoxin-resistant (TTX-R) sodium channel, contributes most of the sodium current underlying the action potential upstroke and accounts for most of the current in later spikes in a train. We speculate that the Nav1.8 sodium channel is a potential candidate responsible for the enhanced excitability of DRG neurons in rats with bone cancer pain. Here, using electrophysiology, Western blot and behavior assays, we documented that the current density of TTX-R sodium channels, especially the Nav1.8 channel, increased significantly in DRG neurons of rats with cancer-induced bone pain. This increase may be due to an increased expression of Nav1.8 on the membrane of DRG neurons. Accordantly, blockade of Nav1.8 sodium channels by its selective blocker A-803467 significantly alleviated the cancer-induced mechanical allodynia and thermal hyperalgesia in rats. Taken together, these results suggest that functional upregulation of Nav1.8 channels on the membrane of DRG neurons contributes to the development of cancer-induced bone pain.
PMCID: PMC4263726  PMID: 25503076
11.  Counseling Role of Primary Care Physicians in Preventing Early Childhood Caries in Children with Congenital Heart Disease 
The dental health of preschool children with congenital heart disease (CHD) is usually poor, which may contribute to the development of infective endocarditis (IE). Primary care physicians play an important role in providing access to preventive dental services, particularly for preschool children. The object of this study was to provide epidemiologic evidence for the impact of primary care physicians’ (PCP’s) counseling role on early childhood caries in children with CHD in Guangzhou, China, which might guide future caries prevention to decrease the risk of IE in children with CHD. A hospital-based, case-control study was performed, which contained 100 children with newly diagnosed early childhood caries and 100 matched (sex and age) children without dental caries. All of the subjects were diagnosed with CHD at birth and recruited from Guangdong Cardiovascular Institute from 2012 through 2013. A conditional multivariate logistic-regression model was used to assess the associations between PCPs’ role and early childhood caries with a significance level of 5%. Our findings revealed that mother’s education level (OR = 0.36, CL = 0.14–0.92) and knowledge, being educated on the relationship between CHD and infective endocarditis (OR = 0.48, CL = 0.25–0.94) and the impact of oral health on infective endocarditis (OR = 0.37, CL = 0.18–0.79) by the PCP were associated with early childhood caries. PCPs played an important role in preventing early childhood caries among preschool children with CHD in Guangzhou, China.
PMCID: PMC4276642  PMID: 25500998
primary care physician; counseling role; early childhood caries; congenital heart disease
13.  Stem cell and endometriosis: new knowledge may be producing novel therapies 
The human endometrium is a dynamic tissue, which undergoes cycles of growth and regression with each menstrual cycle. Adult progenitor stem cells are likely responsible for this remarkable regenerative capacity; these same progenitor stem cells may also have an enhanced capacity to generate endometriosis if shed in a retrograde fashion. The progenitor stem cells reside in the uterus, and, however, may also travel from other tissues such as bone marrow to repopulate the progenitor population. Mesenchymal stem cells are also involved in the pathogenesis of endometriosis and may be the principle source of endometriosis outside of the peritoneal cavity when they differentiate into endometriosis in ectopic locations. The present short review mainly summarizes the latest observations contributing to the current knowledge regarding the presence and the potential contribution of stem cells in the etiology of endometriosis. All these data can have clinical implications and provide a basis for new potential therapeutic applications.
PMCID: PMC4276151  PMID: 25550893
Endometriosis; endometrial progenitor/stem cells; etiology; therapeutic applications; telomerase
14.  Hyperbaric oxygen therapy reduces apoptosis after spinal cord injury in rats 
Hyperbaric oxygen therapy (HBOT) protects brain tissue from inflammatory injury by suppressing mitochondrial apoptotic pathways. However, its neuroprotective mechanism via anti-apoptosis in spinal cord injury (SCI) is still unclear. In our study, Male Sprague-Dawley rats were randomly divided into three groups: sham-operated (SH), SCI model, and SCI + HBOT. Rats in each group were randomly divided into four sub-groups in a time-dependent manner (1 day, 3 days, 7 days and 14 days after surgery). Expression of adaptor molecule apoptosis-associated speck-like protein (ASC) and caspase-3 was evaluated at the indicated time after injury. Our data showed that HBOT downregulated expression of ASC in SCI rats at the mRNA and protein levels. HBOT mitigated caspase-3 release in injured spinal cord tissue. We conclude that HBOT prevents inflammation apoptosis after SCI, likely through suppression of ASC and caspase-3.
PMCID: PMC4276174  PMID: 25550916
Hyperbaric oxygen therapy; spinal cord injury; apoptosis-associated speck-like protein; caspase-3
15.  Clinical significance of epigenetic silencing and re-expression of O6-methylguanine-DNA methyltransferase using epigenetic agents in laryngeal carcinoma 
Oncology Letters  2014;9(1):35-42.
The aim of the present study was to investigate the association between O6-methylguanine-DNA methyltransferase (MGMT) gene expression levels, and DNA methylation status and histone modifications in laryngeal squamous cell carcinoma (LSCC). Chromatin immunoprecipitation, methylation-specific polymerase chain reaction (PCR), and reverse transcription-quantitative PCR were performed to analyze histone modifications, DNA methylation status and mRNA expression levels in the promoter region of the MGMT gene in laryngeal carcinoma HEp-2 cells, as well as in 50 paired healthy and LSCC tissue samples. The present study demonstrated that treatment of HEp-2 cells with 5-aza-2′-deoxycytidine (Aza), a DNA methyltransferase inhibitor, significantly upregulated MGMT mRNA expression levels, reduced MGMT DNA methylation, reduced MGMT histone H3 lysine 9 (H3K9) di-methylation, and increased MGMT histone H3 lysine 4 di-methylation without a significant change in H3K9 acetylation. Trichostatin A (TSA), a histone deacetylase inhibitor, marginally upregulated MGMT mRNA expression levels without affecting the DNA methylation status, or H3K9 or H3K4 di-methylation, however, TSA treatment caused a significant increase in H3K9 acetylation. Furthermore, Aza and TSA combination treatment produced a synergistic effect. In the LSCC samples, the rate of DNA methylation in the MGMT gene was 54%, compared with 24% in the healthy control group (P<0.05). Therefore, data from the present study indicates that MGMT may serve as a novel therapeutic target in the treatment of LSCC.
PMCID: PMC4247240  PMID: 25452816
laryngeal carcinoma; O6-methylguanine-DNA methyltransferase gene; DNA methylation; histone modification; 5-aza-2′-deoxycytidine; trichostatin A
16.  Temporal changes in soil bacterial and archaeal communities with different fertilizers in tea orchards* #  
It is important to understand the effects of temporal changes in microbial communities in the acidic soils of tea orchards with different fertilizers. A field experiment involving organic fertilizer (OF), chemical fertilizer (CF), and unfertilized control (CK) treatments was arranged to analyze the temporal changes in the bacterial and archaeal communities at bimonthly intervals based on the 16S ribosomal RNA (rRNA) gene using terminal restriction fragment length polymorphism (T-RFLP) profiling. The abundances of total bacteria, total archaea, and selected functional genes (bacterial and archaeal amoA, bacterial narG, nirK, nirS, and nosZ) were determined by quantitative polymerase chain reaction (qPCR). The results indicate that the structures of bacterial and archaeal communities varied significantly with time and fertilization based on changes in the relative abundance of dominant T-RFs. The abundancy of the detected genes changed with time. The total bacteria, total archaea, and archaeal amoA were less abundant in July. The bacterial amoA and denitrifying genes were less abundant in September, except the nirK gene. The OF treatment increased the abundance of the observed genes, while the CF treatment had little influence on them. The soil temperature significantly affected the bacterial and archaeal community structures. The soil moisture was significantly correlated with the abundance of denitrifying genes. Of the soil chemical properties, soil organic carbon was the most important factor and was significantly correlated with the abundance of the detected genes, except the nirK gene. Overall, this study demonstrated the effects of both temporal alteration and organic fertilizer on the structures of microbial communities and the abundance of genes involved in the nitrogen cycle.
PMCID: PMC4228508  PMID: 25367788
Bacterial and archaeal communities; Fertilizer; Soil; Temporal changes; Tea orchard; Functional genes
17.  A new potential risk factor in patients with erectile dysfunction and premature ejaculation: folate deficiency 
Asian Journal of Andrology  2014;16(6):902-906.
We investigated serum folic acid (FA) levels in patients with erectile dysfunction (ED) and/or premature ejaculation (PE). Fasting serum samples were obtained from 42 patients with ED, 36 with PE, 25 ED patients with PE, and 30 healthy men; the mean intravaginal ejaculation latency time (IELT) was measured during a 4 weeks baseline period. Levels of sex hormones (follicle-stimulating hormone, luteinizing hormone, total testosterone), homocysteine (Hcys), and FA were measured using chemiluminescent immunoassays. The sexual functions of PE patients and normal control men were evaluated using the Chinese Index of Premature Ejaculation (CIPE). The abridged International Index of Erectile Function-5 (IIEF-5) questionnaire was used to gauge erectile quality for ED patients and for normal controls. Serum FA concentrations were lower in ED (7.61 ± 3.97 ng ml−1), PE (9.37 ± 3.40 ng ml−1), and ED/PE (8.84 ± 4.28 ng ml−1) patients than in healthy men (12.23 ± 5.76 ng ml−1, P < 0.05). No significant differences in sex hormone levels were found between patients with sexual dysfunction and healthy controls (P > 0.05). There were positive correlations between serum FA concentrations and CIPE scores (r = 0.530, P < 0.01), IIEF-5 scores (r = 0.589, P < 0.01), and IELT (r = 0.445, P < 0.01); negative correlations with Hcys concentrations (r = −0.487, P < 0.01) were found in all participants. These findings showed a strong relationship between serum FA levels and sexual dysfunction, possibly due to an effect of FA on the metabolism of nitric oxide, Hcys, and 5-hydroxytryptamine.
PMCID: PMC4236337  PMID: 25080932
5-hydroxytryptamine; erectile dysfunction; folic acid; homocysteine; nitric oxide; premature ejaculation
18.  ITEPE: A Source Tracing Algorithm for the Microblog 
PLoS ONE  2014;9(10):e111380.
Finding the true source of a social network is a crucial component of social network information tracing. Using the new media microblog as an example, this paper provides a source tracing algorithm ITEPE (Initiators and Early Participants Extraction) to solve this problem. First, the cascade (session tree) is built according to the retweeting of a microblog, after which the cascade set (session forest) is clustered by topical relevance. Second, real initiators are identified through the user relationship network and information cascade network. The influence index and conformity index of every node is then iteratively calculated according to text sentiment analysis and information cascades and the early important participants are extracted. Finally, the real initiators and early participants are evaluated through an experiment.
PMCID: PMC4216087  PMID: 25360751
19.  Novel phosphatidylinositol 3-kinase inhibitor NVP-BKM120 induces apoptosis in myeloma cells and shows synergistic anti-myeloma activity with dexamethasone 
NVP-BKM120 is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor and is currently being investigated in phase I clinical trials in solid tumors. This study aimed to evaluate the therapeutic efficacy of BKM120 in multiple myeloma (MM). BKM120 induces cell growth inhibition and apoptosis in both MM cell lines and freshly isolated primary MM cells. However, BKM120 only shows limited cytotoxicity toward normal lymphocytes. The presence of MM bone marrow stromal cells, insulin-like growth factor, or interleukin-6 does not affect BKM120-induced tumor cell apoptosis. More importantly, BKM120 treatment significantly inhibits tumor growth in vivo and prolongs the survival of myeloma-bearing mice. In addition, BKM120 shows synergistic cytotoxicity with dexamethasone in dexamethasone-sensitive MM cells. Low doses of BKM120 and dexamethasone, each of which alone has limited cytotoxicity, induce significant cell apoptosis in MM.1S and ARP-1. Mechanistic study shows that BKM120 exposure causes cell cycle arrest by upregulating p27 (Kip1) and downregulating cyclin D1 and induces caspase-dependent apoptosis by downregulating antiapoptotic XIAP and upregulating expression of cytotoxic small isoform of Bim, BimS. In summary, our findings demonstrate the in vitro and in vivo anti-MM activity of BKM120 and suggest that BKM120 alone or together with other MM chemotherapeutics, particularly dexamethasone, may be a promising treatment for MM.
PMCID: PMC4212830  PMID: 22207485
Multiple myeloma; PI3K; BKM120; Apoptosis; Chemotherapy
20.  Toll-Like Receptor-4 Signaling in Mantle Cell Lymphoma: Effects on Tumor Growth and Immune Evasion 
Cancer  2012;119(4):782-791.
Mantle cell lymphoma (MCL) is an incurable B-cell malignancy with the poorest prognosis among B-cell lymphoma patients. The signal pathways that trigger MCL escape from immune surveillance are unclear. As Toll-like receptors (TLRs) initiate innate and adaptive immune responses against invading pathogens, we investigated the impact of TLR signaling in MCL cells.
We examined TLR expression on MCL cell lines and primary tumor cells from patients. We focused on TLR4 and its ligand lipopolysacharide (LPS) on MCL cells and their function on MCL proliferation and immune evasion.
MCL cells expressed multiple TLRs and TLR4 was among the highest-expressed molecules. Activation of TLR4 signaling in MCL cells by LPS induced MCL proliferation, and upregulated the secretion of cytokines such as interleukin (IL)-6 and IL-10, and vascular endothelial growth factor (VEGF). LPS-pretreated MCL cells inhibited the proliferation and cytolytic activity of T cells by secreted IL-10 and VEGF, and neutralizing antibodies against these cytokines restored their functions. Similar results were also observed in TLR4+MyD88+ but not in TLR4+MyD88− primary lymphoma cells from MCL patients. Knockdown of TLR4 on MCL cells abrogated the effect of LPS on MCLs in term of cell growth or secretion of the cytokines, and evasion of the immune system.
Our study indicates that TLR4 signaling triggers a cascade leading to MCL growth and evasion from the immune surveillance. Thus, TLR4 signaling molecules could be novel therapeutic targets for cancer therapy in MCL.
PMCID: PMC4211879  PMID: 22915070
Mantle cell lymphoma; Toll-like receptor-4; Lipopolysacharide; Cytotoxic T lymphocytes; Immune evasion
21.  Laser Hybrid Micro/nano-structuring of Si Surfaces in Air and its Applications for SERS Detection 
Scientific Reports  2014;4:6657.
Surface enhanced Raman spectroscopy (SERS) has been widely investigated as an effective technique for low-concentration bio-chemical molecules detection. A rapid two-step approach to fabricate SERS substrates with high controllability in ambient air is developed. Dynamic laser ablation directly creates microgroove on the Si substrate. Meanwhile, nanoparticles are synthesized via the nucleation of laser induced plasma species and the air molecules. It configures the Si surface into four different regions decorated with nanoparticles at different sizes. With Ag film coating, these nanoparticles function as hotspots for SERS. Microsquare arrays are fabricated on the Si surface as large-area SERS substrates by the laser ablation in horizontal and vertical directions. In each microsquare, it exhibits quasi-3D structures with randomly arranged and different shaped nanoparticles aggregated in more than one layer. With Ag film deposition, uniform SERS signals are obtained by detecting the 4-methylbenzenethiol molecules. The SERS signal intensity is determined by the size and shape distributions of the nanoparticles, which depend on the laser processing parameters. With the optimal laser fluence, the SERS signals show a uniform enhancement factor up to 5.5 × 106. This provides a high-speed and low-cost method to produce SERS substrates over a large area.
PMCID: PMC4200404  PMID: 25324167
22.  High-accuracy prediction of transmembrane inter-helix contacts and application to GPCR 3D structure modeling 
Bioinformatics  2013;29(20):2579-2587.
Motivation: Residue–residue contacts across the transmembrane helices dictate the three-dimensional topology of alpha-helical membrane proteins. However, contact determination through experiments is difficult because most transmembrane proteins are hard to crystallize.
Results: We present a novel method (MemBrain) to derive transmembrane inter-helix contacts from amino acid sequences by combining correlated mutations and multiple machine learning classifiers. Tested on 60 non-redundant polytopic proteins using a strict leave-one-out cross-validation protocol, MemBrain achieves an average accuracy of 62%, which is 12.5% higher than the current best method from the literature. When applied to 13 recently solved G protein-coupled receptors, the MemBrain contact predictions helped increase the TM-score of the I-TASSER models by 37% in the transmembrane region. The number of foldable cases (TM-score >0.5) increased by 100%, where all G protein-coupled receptor templates and homologous templates with sequence identity >30% were excluded. These results demonstrate significant progress in contact prediction and a potential for contact-driven structure modeling of transmembrane proteins.
Contact: or
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3789543  PMID: 23946502
23.  Function and subsets of dendritic cells and natural killer cells were decreased in gastric cancer 
Dendritic cells (DCs) and natural killer (NK) cells initiate specific immune responses against tumor cells. The aim of the present study was to determine the cytotoxicity and the subsets of the DC and NK cells and the cytokines level of DC and NK cells from cancer tissue and peripheral blood in the gastric cancer patients. Cytotoxicity of DC and NK was determined using the Cytotox non-radioactive assay. The cytotoxic activity of DC or NK isolated from cancer tissue and peripheral blood was attenuated in gastric cancer patients. CD11c, CD80, CD83, CD16, CD57 and CD69 were decreased in the cancer tissue and peripheral blood in the gastric cancer patients. CD86, CCR7 and CD59 were no significance in the cancer tissue and peripheral blood from gastric cancer patients. Tumor necrosis factor (TNF)-α, interleukin (IL)-2, T-bet and IL-15Rβ levels were decreased in DC and NK from the gastric cancer tissue and peripheral blood in the gastric cancer patients. IL-15 and IL-15Rα level were no significance in DC and NK in the gastric cancer tissue and peripheral blood in the gastric cancer patients. These results indicate that the cytotoxic activity and subsets and cytokines of DC and NK cells in the cancer tissue and peripheral blood in the gastric cancer patients were decreased. The decrease of subsets content and cytokines of DC and NK may contribute to a decrease in the function of DC and NK in the tissue and peripheral blood in the gastric cancer patients.
PMCID: PMC4270606  PMID: 25550889
Dendritic cell; natural killer cell; cytotoxicity; cytokine
24.  Cetrotide administration in the early luteal phase in patients at high risk of ovarian hyperstimulation syndrome: A controlled clinical study 
The aim of the present pilot study was to assess the feasibility and efficacy of Cetrotide administration in the early luteal phase in patients at high risk of ovarian hyperstimulation syndrome (OHSS), undergoing embryo cryopreservation following superovulation. A total of 135 patients at high risk of OHSS and undergoing embryo cryopreservation were divided into two groups. In the treatment group (n=39), the patients received daily subcutaneous injections of 0.25 mg Cetrotide between days 1 and 5 following ooctye retrieval, and volume expansion and symptomatic treatment were also provided. In the control group (n=96), the patients received routine treatments, including volume expansion therapy. The serum steroid hormone concentrations of the patients were measured on days 2, 5 and 8 following ooctye retrieval, while the incidence of moderate or severe OHSS, self-evaluated clinical symptoms and various clinical indicators were recorded. The serum estradiol (E2), luteinizing hormone and progesterone levels in the treatment group on days 2, 5 and 8 following oocyte retrieval were not found to differ significantly when compared with the patients in the control group (P>0.05). The incidence of severe OHSS did not differ significantly between the two groups (P>0.05). The average length of hospital stay and length of luteal phase were not found to be significantly different between the treatment and control groups (P>0.05). In conclusion, Cetrotide injections in the early luteal phase did not alter the serum steroid levels of patients at high risk of OHSS undergoing embryo cryopreservation, and were unable to reduce the incidence of severe early OHSS. However, further randomized studies are required to evaluate the effectiveness of Cetrotide in the prevention of OHSS.
PMCID: PMC4217764  PMID: 25371744
gonadotropin-releasing hormone antagonist; ovarian hyperstimulation syndrome; in vitro fertilization; luteal phase; prevention
25.  Peroxidase-Like Catalytic Activity of Ag3PO4 Nanocrystals Prepared by a Colloidal Route 
PLoS ONE  2014;9(10):e109158.
Nearly monodispersed Ag3PO4 nanocrystals with size of 10 nm were prepared through a colloidal chemical route. It was proven that the synthesized Ag3PO4 nanoparticles have intrinsic peroxidase-like catalytic activity. They can quickly catalyze oxidation of the peroxidase substrate 3, 3, 5, 5-tetramethylbenzidine (TMB) in the presence of H2O2, producing a blue color. The catalysis reaction follows Michaelis-Menten kinetics. The calculated kinetic parameters indicate a high catalytic activity and the strong affinity of Ag3PO4 nanocrystals to the substrate (TMB). These results suggest the potential applications of Ag3PO4 nanocrystals in fields such as biotechnology, environmental chemistry, and medicine.
PMCID: PMC4182944  PMID: 25271632

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