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1.  The Cancer Associated FGFR4-G388R Polymorphism Enhances Pancreatic Insulin Secretion and Modifies the Risk of Diabetes 
Cell metabolism  2013;17(6):929-940.
The fibroblast growth factor receptor 4 (FGFR4)-R388 single nucleotide polymorphism has been associated with cancer risk and prognosis. Here we show that the FGFR4-R388 allele yields a receptor variant which preferentially promotes STAT3/5 signaling. This STAT activation induces Grb14 transcription in pancreatic endocrine cells to modulate insulin receptor (IR) signaling and enhance insulin secretion. Knock-in mice with the FGFR4 variant allele develop pancreatic islets that secrete more insulin, a feature that is reversed through Grb14 deletion. We also show in humans that the FGFR4-R388 allele enhances islet function and may protect against type 2 diabetes. These data support a common genetic link between cancer and hyperinsulinemia.
PMCID: PMC4005358  PMID: 23747250
FGF receptors; FGFR4; Grb14; insulin receptor; diabetes; breast cancer
2.  Role of Immune Cells and Immune-Based Therapies in Pancreatitis and Pancreatic Ductal Adenocarcinoma 
Gastroenterology  2013;144(6):1230-1240.
Immune cells are important in pathogenesis of acute pancreatitis (AP) and determine disease severity. Results from cytokine-based clinical trials for AP have been disappointing, so strategies that target and alter the behavior of infiltrating immune cells require consideration. Recurrent AP can progress to chronic pancreatitis (CP). CP is a well-described risk factor for pancreatic ductal adenocarcinoma (PDA). However, most patients with CP do not develop PDA, and most patients with PDA do not have history of pancreatitis. Interestingly, CP and PDA tissues have similarities in their desmoplasia and inflammatory infiltrates, indicating overlapping inflammatory responses. Further studies are needed to determine the differences and similarities of these responses, improve our understanding of PDA pathogenesis, and develop specific immune-based therapies. Immune cells in PDA produce immunosuppressive signals that allow tumors to evade the immune response. Unlike single therapeutic agent studies that block immunosuppressive mechanisms, studies of combination therapies that include therapeutic vaccines have provided promising results.
PMCID: PMC3641650  PMID: 23622132
acute pancreatitis; chronic pancreatitis; pancreatic ductal adenocarcinoma
3.  Mutant Tristetraprolin: a Potent Inhibitor of Malignant Glioma Cell Growth 
Journal of neuro-oncology  2013;113(2):195-205.
Malignant gliomas rely on the production of certain critical growth factors including VEGF, interleukin (IL)-6 and IL-8, to fuel rapid tumor growth, angiogenesis, and treatment resistance. Post-transcriptional regulation through adenine and uridine-rich elements (ARE) of the 3′ untranslated region (UTR) is one mechanism for upregulating these and other growth factors. In glioma cells, we have shown that the post-transcriptional machinery is optimized for growth factor upregulation secondary to overexpression of the mRNA stabilizer, HuR. The negative regulator, tristetraprolin (TTP), on the other hand, may be suppressed because of extensive phosphorylation. Here we test that possibility by analyzing the phenotypic effects of a mutated form of TTP (mt-TTP) in which 8 phosphoserine residues were converted to alanines. We observed a significantly enhanced negative effect on growth factor expression in glioma cells at the post-transcriptional and transcriptional levels. The protein became stabilized and displayed significantly increased antiproliferative effects compared to wild-type TTP. Macroautophagy was induced with both forms of TTP, but inhibition of autophagy did not affect cell viability. We conclude that glioma cells suppress TTP function through phosphorylation of critical serine residues which in turn contributes to growth factor upregulation and tumor progression.
PMCID: PMC3679321  PMID: 23525947
4.  A unified intermediate and mechanism for soot combustion on potassium-supported oxides 
Scientific Reports  2014;4:4725.
The soot combustion mechanism over potassium-supported oxides (MgO, CeO2 and ZrO2) was studied to clarify the active sites and discover unified reaction intermediates in this typical gas-solid-solid catalytic reaction. The catalytically active sites were identified as free K+ rather than K2CO3, which can activate gaseous oxygen. The active oxygen spills over to soot and forms a common intermediate, ketene, before it was further oxidized into the end product CO2. The existence of ketene species was confirmed by density functional theory (DFT) calculations. The oxygen spillover mechanism is proposed, which is explained as an electron transfer from soot to gaseous oxygen through the active K+ sites. The latter mechanism is confirmed for the first time since it was put forward in 1950, not only by ultraviolet photoelectron spectroscopy (UPS) results but also by semi-empirical theoretical calculations.
PMCID: PMC3989558  PMID: 24740213
5.  An Agomir of miR-144-3p Accelerates Plaque Formation through Impairing Reverse Cholesterol Transport and Promoting Pro-Inflammatory Cytokine Production 
PLoS ONE  2014;9(4):e94997.
ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins, which then form nascent HDL, a key step in the mechanism of reverse cholesterol transport (RCT). While a series of microRNAs (miRNAs) have been identified as potent post-transcriptional regulators of lipid metabolism, their effects on ABCA1 function and associated mechanisms remain unclear.
Methods and Results
ABCA1 was identified as a potential target of miR-144-3p, based on the results of bioinformatic analysis and the luciferase reporter assay, and downregulated after transfection of cells with miR-144-3p mimics, as observed with real-time PCR and western blot. Moreover, miR-144-3p mimics (agomir) enhanced the expression of inflammatory factors, including IL-1β, IL-6 and TNF-α, in vivo and in vitro, inhibited cholesterol efflux in THP-1 macrophage-derived foam cells, decreased HDL-C circulation and impaired RCT in vivo, resulting in accelerated pathological progression of atherosclerosis in apoE−/− mice. Clinical studies additionally revealed a positive correlation of circulating miR-144-3p with serum CK, CK-MB, LDH and AST in subjects with AMI.
Our findings clearly indicate that miR-144-3p is essential for the regulation of cholesterol homeostasis and inflammatory reactions, supporting its utility as a potential therapeutic target of atherosclerosis and a promising diagnostic biomarker of AMI.
PMCID: PMC3986368  PMID: 24733347
6.  Incremental Learning with SVM for Multimodal Classification of Prostatic Adenocarcinoma 
PLoS ONE  2014;9(4):e93600.
Robust detection of prostatic cancer is a challenge due to the multitude of variants and their representation in MR images. We propose a pattern recognition system with an incremental learning ensemble algorithm using support vector machines (SVM) tackling this problem employing multimodal MR images and a texture-based information strategy. The proposed system integrates anatomic, texture, and functional features. The data set was preprocessed using B-Spline interpolation, bias field correction and intensity standardization. First- and second-order angular independent statistical approaches and rotation invariant local phase quantization (RI-LPQ) were utilized to quantify texture information. An incremental learning ensemble SVM was implemented to suit working conditions in medical applications and to improve effectiveness and robustness of the system. The probability estimation of cancer structures was calculated using SVM and the corresponding optimization was carried out with a heuristic method together with a 3-fold cross-validation methodology. We achieved an average sensitivity of 0.844±0.068 and a specificity of 0.780±0.038, which yielded superior or similar performance to current state of the art using a total database of only 41 slices from twelve patients with histological confirmed information, including cancerous, unhealthy non-cancerous and healthy prostate tissue. Our results show the feasibility of an ensemble SVM being able to learn additional information from new data while preserving previously acquired knowledge and preventing unlearning. The use of texture descriptors provides more salient discriminative patterns than the functional information used. Furthermore, the system improves selection of information, efficiency and robustness of the classification. The generated probability map enables radiologists to have a lower variability in diagnosis, decrease false negative rates and reduce the time to recognize and delineate structures in the prostate.
PMCID: PMC3974761  PMID: 24699716
7.  High-Resolution Melting Curve Analysis for Rapid Detection of Rifampin Resistance in Mycobacterium tuberculosis: a Meta-Analysis 
Journal of Clinical Microbiology  2013;51(10):3294-3299.
A rapid, simple, accurate, and affordable method for the detection of drug-resistant tuberculosis is very critical for the selection of antimicrobial therapy and management of patient treatment. High-resolution melting curve analysis has been used for the detection of rifampin resistance in Mycobacterium tuberculosis and has shown promise. We did a systematic review and meta-analysis of published studies to evaluate the accuracy of high-resolution melting curve analysis for the detection of rifampin resistance in clinical M. tuberculosis isolates. We searched the PubMed, BIOSIS Previews, and Web of Science databases to identify studies and included them according to predetermined criteria. We used the DerSimonian-Laird random-effects model to calculate pooled measures and applied Moses' constant for linear models to fit the summary receiver operating characteristic curve. According to the selection criteria, most of the identified studies were excluded, and only seven studies were included in the final analysis. The overall sensitivity of the high-resolution melting curve analysis was 94% (95% confidence interval [CI], 92% to 96%), and the overall specificity was very high at 99% (95% CI, 98% to 100%). The values for the pooled positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 63.39 (95% CI, 30.21 to 133.00), 0.06 (95% CI, 0.04 to 0.09), and 892.70 (95% CI, 385.50 to 2,067.24), respectively. There was no significant heterogeneity across all included studies for the measurements we evaluated. The summary receiver operating characteristic curve for the same data shows an area of 0.99 and a Q* value of 0.97. High-resolution melting curve analysis has high sensitivity and specificity for the detection of rifampin resistance in clinical M. tuberculosis isolates. This method might be a good alternative to conventional drug susceptibility tests in clinical practice.
PMCID: PMC3811634  PMID: 23885006
8.  Immunohistochemical Staining of B7-H1 (PD-L1) on Paraffin-embedded Slides of Pancreatic Adenocarcinoma Tissue 
B7-H1/PD-L1, a member of the B7 family of immune-regulatory cell-surface proteins, plays an important role in the negative regulation of cell-mediated immune responses through its interaction with its receptor, programmed death-1 (PD-1) 1,2. Overexpression of B7-H1 by tumor cells has been noted in a number of human cancers, including melanoma, glioblastoma, and carcinomas of the lung, breast, colon, ovary, and renal cells, and has been shown to impair anti-tumor T-cell immunity3–8.
Recently, B7-H1 expression by pancreatic adenocarcinoma tissues has been identified as a potential prognostic marker9,10. Additionally, blockade of B7-H1 in a mouse model of pancreatic cancer has been shown to produce an anti-tumor response11. These data suggest the importance of B7-H1 as a potential therapeutic target. Anti-B7-H1 blockade antibodies are therefore being tested in clinical trials for multiple human solid tumors including melanoma and cancers of lung, colon, kidney, stomach and pancreas12.
In order to eventually be able to identify the patients who will benefit from B7-H1 targeting therapies, it is critical to investigate the correlation between expression and localization of B7-H1 and patient response to treatment with B7-H1 blockade antibodies. Examining the expression of B7-H1 in human pancreatic adenocarcinoma tissues through immunohistochemistry will give a better understanding of how this co-inhibitory signaling molecule contributes to the suppression of antitumor immunity in the tumor’s microenvironment. The anti-B7-H1 monoclonal antibody (clone 5H1) developed by Chen and coworkers has been shown to produce reliable staining results in cryosections of multiple types of human neoplastic tissues4,8, but staining on paraffin-embedded slides had been a challenge until recently13–18. We have developed the B7-H1 staining protocol for paraffin-embedded slides of pancreatic adenocarcinoma tissues. The B7-H1 staining protocol described here produces consistent membranous and cytoplasmic staining of B7-H1 with little background.
PMCID: PMC3582653  PMID: 23328703
Cancer Biology; Issue 71; Medicine; Immunology; Biochemistry; Molecular Biology; Cellular Biology; Chemistry; Oncology; immunohistochemistry; B7-H1 (PD-L1); pancreatic adenocarcinoma; pancreatic cancer; pancreas; tumor; T-cell immunity; cancer
9.  Dihydrocapsaicin down-regulates apoM expression through inhibiting Foxa2 expression and enhancing LXRα expression in HepG2 cells 
Apolipoprotein M (apoM), as a novel apolipoprotein which is mainly expressed in liver and kidney tissues, is associated with development and progression of atherosclerosis and diabetes. Our group have recently shown that Dihydrocapsaicin(DHC)can significantly decrease atherosclerotic plaque formation in apoE−/− mice. However, the effect and possible mechanism of DHC on apoM expression remain unclear.
HepG2 cells were treated with 0 μM, 25 μM, 50 μM and 100 μM DHC for 24 h or were treated with 100 μM DHC for 0, 6, 12, and 24 h, respectively. The mRNA levels and protein levels were measured by real-time quantitative PCR and western blot analysis, respectively.
We found that DHC markedly decreased expression of apoM at both mRNA and protein level in HepG2 cells in a dose-dependent and time-dependent manner. Expression of Foxa2 was decreased while expression of LXRα was increased by DHC treatment in HepG2 cells. In addittion, overexpression of Foxa2 markedly compensated the inhibition effect induced by DHC on apoM expression. LXRα small interfering RNA significantly abolished the inhibition effect which induced by DHC on apoM expression. The liver of C57BL/6 mice treated with DHC had significantly lower expression of apoM. Furthermore, the liver had lower expression of Foxa2 while had higher expression of LXRα.
DHC could down-regulate apoM expression through inhibiting Foxa2 expression and enhancing LXRα expression in HepG2 cells.
PMCID: PMC3999941  PMID: 24642298
DHC; ApoM; Foxa2; LXRα
10.  The Insulin Resistance Grb14 Adaptor Protein Promotes Thyroid Cancer Ret Signaling and Progression 
Oncogene  2011;31(36):4012-4021.
The growth factor receptor-bound protein (Grb) 14 is an adapter molecule of the Grb7/10/14 family with characteristic BPS domains serving to avidly bind tyrosine kinases. Grb14 inhibits insulin receptor (IR) catalytic activity through interaction with the BPS domain and impedes peptide substrate binding. Members of this Grb family have also been shown to interact with other kinases through their SH2 domain. Here we examined the functional role of Grb14 in thyroid cancer using loss- and gain-of-function approaches. Stable knockdown of Grb14 in thyroid cancer cells facilitated insulin receptor signaling. In contrast, RET phosphorylation was diminished in concert with reduced activation of Akt and STAT3. Loss of Grb14 also resulted in diminished cell proliferation and invasion both in vitro and in mouse flank xenografts. In complementary studies, forced expression of Grb14 interrupted insulin receptor signaling but facilitated RET activation, STAT3, and Akt phosphorylation. Consistent with these findings Grb14 over-expression enhanced cell invasion and resulted in striking metastases in an orthotopic thyroid cancer mouse xenograft model. Primary human thyroid cancer microarrays revealed a positive correlation between Grb14 expression and invasive behavior. Our findings uncover a new role for Grb14 in finely tuning receptor signaling and modulating thyroid cancer progression.
PMCID: PMC3954818  PMID: 22158039 CAMSID: cams4095
Grb14; RET; thyroid cancer; cancer progression
11.  BEX1 Promotes Imatinib-Induced Apoptosis by Binding to and Antagonizing BCL-2 
PLoS ONE  2014;9(3):e91782.
An enhanced anti-apoptotic capacity of tumor cells plays an important role in the process of breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL)-independent imatinib resistance. We have previously demonstrated that brain expressed X-linked 1 (BEX1) was silenced in secondary imatinib-resistant K562 cells and that re-expression of BEX1 can restore imatinib sensitivity resulting in the induction of apoptosis. However, the mechanism by which BEX1 executes its pro-apoptotic function remains unknown. We identified B-cell lymphoma 2 (BCL-2) as a BEX1-interacting protein using a yeast two-hybrid screen. The interaction between BEX1 and BCL-2 was subsequently confirmed by co-immunoprecipitation assays. Like BCL-2, BEX1 was localized to the mitochondria. The region between 33K and 64Q on BEX1 is important for its localization to the mitochondria and its ability to interact with BCL-2. Additionally, we found that this region is essential for BEX1-regulated imatinib-induced apoptosis. Furthermore, we demonstrated that the interaction between BCL-2 and BEX1 promotes imatinib-induced apoptosis by suppressing the formation of anti-apoptotic BCL-2/BCL-2-associated X protein (BAX) heterodimers. Our results revealed an interaction between BEX1 and BCL-2 and a novel mechanism of imatinib resistance mediated by the BEX1/BCL-2 pathway.
PMCID: PMC3953594  PMID: 24626299
12.  Pancreatic cancer stroma: Understanding biology leads to new therapeutic strategies 
Pancreatic ductal adenocarcinoma (PDA) is among the deadliest cancers in the United States and in the world. Late diagnosis, early metastasis and lack of effective therapy are among the reasons why only 6% of patients diagnosed with PDA survive past 5 years. Despite development of targeted therapy against other cancers, little progression has been made in the treatment of PDA. Therefore, there is an urgent need for the development of new treatments. However, in order to proceed with treatments, the complicated biology of PDA needs to be understood first. Interestingly, majority of the tumor volume is not made of malignant epithelial cells but of stroma. In recent years, it has become evident that there is an important interaction between the stromal compartment and the less prevalent malignant cells, leading to cancer progression. The stroma not only serves as a growth promoting source of signals but it is also a physical barrier to drug delivery. Understanding the tumor-stroma signaling leading to development of desmoplastic reaction and tumor progression can lead to the development of therapies to decrease stromal activity and improve drug delivery. In this review, we focus on how the current understanding of biology of the pancreatic tumor microenvironment can be translated into the development of targeted therapy.
PMCID: PMC3942829  PMID: 24605023
Pancreatic ductal adenocarcinoma; Stroma; Tumor microenvironment; Pancreatic stellate cells; Cancer associated fibroblast; Sonic hedgehog; Hepatic growth factor; Fibroblast activation protein
13.  Application of Multispectral Imaging to Determine Quality Attributes and Ripeness Stage in Strawberry Fruit 
PLoS ONE  2014;9(2):e87818.
Multispectral imaging with 19 wavelengths in the range of 405–970 nm has been evaluated for nondestructive determination of firmness, total soluble solids (TSS) content and ripeness stage in strawberry fruit. Several analysis approaches, including partial least squares (PLS), support vector machine (SVM) and back propagation neural network (BPNN), were applied to develop theoretical models for predicting the firmness and TSS of intact strawberry fruit. Compared with PLS and SVM, BPNN considerably improved the performance of multispectral imaging for predicting firmness and total soluble solids content with the correlation coefficient (r) of 0.94 and 0.83, SEP of 0.375 and 0.573, and bias of 0.035 and 0.056, respectively. Subsequently, the ability of multispectral imaging technology to classify fruit based on ripeness stage was tested using SVM and principal component analysis-back propagation neural network (PCA-BPNN) models. The higher classification accuracy of 100% was achieved using SVM model. Moreover, the results of all these models demonstrated that the VIS parts of the spectra were the main contributor to the determination of firmness, TSS content estimation and classification of ripeness stage in strawberry fruit. These results suggest that multispectral imaging, together with suitable analysis model, is a promising technology for rapid estimation of quality attributes and classification of ripeness stage in strawberry fruit.
PMCID: PMC3913704  PMID: 24505317
14.  Nur77 Decreases Atherosclerosis Progression in apoE−/− Mice Fed a High-Fat/High-Cholesterol Diet 
PLoS ONE  2014;9(1):e87313.
It is clear that lipid disorder and inflammation are associated with cardiovascular diseases and underlying atherosclerosis. Nur77 has been shown to be involved in inflammatory response and lipid metabolism.
Here, we explored the role of Nur77 in atherosclerotic plaque progression in apoE−/− mice fed a high-fat/high cholesterol diet.
Methods and Results
The Nur77 gene, a nuclear hormone receptor, was highly induced by treatment with Cytosporone B (Csn-B, specific Nur77 agonist), recombinant plasmid over-expressing Nur77 (pcDNA-Nur77), while inhibited by treatment with siRNAs against Nur77 (si-Nur77) in THP-1 macrophage-derived foam cells, HepG2 cells and Caco-2 cells, respectively. In addition, the expression of Nur77 was highly induced by Nur77 agonist Csn-B, lentivirus encoding Nur77 (LV-Nur77), while silenced by lentivirus encoding siRNA against Nur77 (si-Nur77) in apoE−/− mice fed a high-fat/high cholesterol diet, respectively. We found that increased expression of Nur77 reduced macrophage-derived foam cells formation and hepatic lipid deposition, downregulated gene levels of inflammatory molecules, adhesion molecules and intestinal lipid absorption, and decreases atherosclerotic plaque formation.
These observations provide direct evidence that Nur77 is an important nuclear hormone receptor in regulation of atherosclerotic plaque formation and thus represents a promising target for the treatment of atherosclerosis.
PMCID: PMC3909091  PMID: 24498071
15.  Re-irradiation with stereotactic body radiation therapy as a novel treatment option for isolated local recurrence of pancreatic cancer after multimodality therapy: experience from two institutions 
Limited treatment options exist for isolated local recurrence of pancreatic ductal adenocarcinoma (PDA) following surgical resection accompanied by neoadjuvant or adjuvant chemoradiation therapy (CRT). While select patients are eligible for re-resection, recurrent lesions are often unresectable. Stereotactic body radiation therapy (SBRT) represents a possible minimally invasive treatment option for these patients, although published data in this setting are currently lacking. This study examines the safety, efficacy, and palliative capacity of re-irradiation with SBRT for isolated local PDA recurrence.
All patients undergoing SBRT at two academic centers from 2008-2012 were retrospectively reviewed to identify those who received re-irradiation with SBRT for isolated local recurrence or progression of PDA after previous conventionally fractionated CRT. Information regarding demographics, clinicopathologic characteristics, therapies received, survival, symptom palliation, and toxicity was obtained from patient charts. Kaplan-Meier statistics were used to analyze survival and the log-rank test was used to compare survival among patient subgroups.
Eighteen patients were identified. Fifteen had previously undergone resection with neoadjuvant or adjuvant CRT, while 3 received definitive CRT for locally advanced disease. Median CRT dose was 50.4 Gy [interquartile range (IQR), 45.0-50.4 Gy] in 28 fractions. All patients subsequently received gemcitabine-based maintenance chemotherapy, but developed isolated local disease recurrence or progression without evidence of distant metastasis. Locally recurrent or progressive disease was treated with SBRT to a median dose of 25.0 Gy (range, 20.0-27.0 Gy) in 5 fractions. Median survival from SBRT was 8.8 months (95% CI, 1.2-16.4 months). Despite having similar clinicopathologic disease characteristics, patients who experienced local progression greater than vs. less than 9 months after surgery/definitive CRT demonstrated superior median survival (11.3 vs. 3.4 months; P=0.019) and progression-free survival (10.6 vs. 3.2 months; P=0.030) after SBRT. Rates of freedom from local progression at 6 and 12 months after SBRT were 78% (14 of 18 patients) and 62% (5 of 8 patients), respectively. Effective symptom palliation was achieved in 4 of 7 patients (57%) who reported symptoms of abdominal or back pain prior to SBRT. Five patients (28%) experienced grade 2 acute toxicity; none experienced grade ≥3 acute toxicity. One patient (6%) experienced grade 3 late toxicity in the form of small bowel obstruction.
In conclusion, re-irradiation with hypofractionated SBRT in this salvage scenario appears to be a safe and reasonable option for palliation of isolated local PDA recurrence or progression following previous conventional CRT. Patients with a progression-free interval of greater than 9 months prior to isolated local recurrence or progression may be most suitable for re-irradiation with SBRT, as they appear to have a better prognosis with survival that is long enough for local control to be of potential benefit.
PMCID: PMC3819776  PMID: 24294505
Stereotactic body radiation therapy (SBRT); pancreatic cancer; local recurrence; re-irradiation
16.  A New Biomarkers Feature Pattern Consisting of TNF-α, IL-10, and IL-8 for Blood Stasis Syndrome with Myocardial Ischemia 
Objective. To explore new diagnostic patterns for syndromes to overcome the insufficiency of obtainable macrocharacteristics and specific biomarkers. Methods. Chinese miniswines were subjected to Ameroid constrictor, placed around the proximal left anterior descending branch. On the 4th week, macrocharacteristics, coronary angiography, echocardiography, and hemorheology indices were detected for diagnosis. IL-1, IL-6, IL-8, IL-10, TNF-α, and hsCRP in serum were detected, and Decision Tree was built. Results. According to current official-issued standard, model animals matched the diagnosis of blood stasis syndrome with myocardial ischemia based on findings, including >90% occlusion, attenuated left ventricular segmental motion, dark red or purple tongues, and higher blood viscosity. Significant decrease of IL-10 and increase of TNF-α were found in model animals. However, in the Decision Tree, besides IL-10 and TNF-α, IL-8 helped to increase the accuracy of classification to 86%. Conclusions. The Decision Tree building with TNF-α, IL-10, and IL-8 is helpful for the diagnosis of blood stasis syndrome in myocardial ischemia animals. What is more is that our data set up a new path to the differentiation of syndrome by feature patterns consisting of multiple biomarkers not only for animals but also for patients. We believe that it will contribute to the standardization and international application of syndromes.
PMCID: PMC3859256  PMID: 24371451
17.  Expanding the Product Profile of a Microbial Alkane Biosynthetic Pathway 
ACS synthetic biology  2012;2(1):10.1021/sb300061x.
Microbially produced alkanes are a new class of biofuels that closely match the chemical composition of petroleum-based fuels. Alkanes can be generated from the fatty acid biosynthetic pathway by the reduction of acyl-ACPs followed by decarbonylation of the resulting aldehydes. A current limitation of this pathway is the restricted product profile, which consists of n-alkanes of 13, 15, and 17 carbons in length. To expand the product profile, we incorporated a new part, FabH2 from Bacillus subtilis, an enzyme known to have a broader specificity profile for fatty acid initiation than the native FabH of Escherichia coli. When provided with the appropriate substrate, the addition of FabH2 resulted in an altered alkane product profile in which significant levels of n-alkanes of 14 and 16 carbons in length are produced. The production of even chain length alkanes represents initial steps toward the expansion of this recently discovered microbial alkane production pathway to synthesize complex fuels. This work was conceived and performed as part of the 2011 University of Washington international Genetically Engineered Machines (iGEM) project.
PMCID: PMC3818147  PMID: 23656326
alkane biosynthesis; biofuels; fatty acid biosynthesis; synthetic biology
18.  Vaccines for Pancreatic Cancer 
Cancer journal (Sudbury, Mass.)  2012;18(6):642-652.
Pancreatic ductal adenocarcinoma (PDA) remains a highly lethal disease; new therapeutic modalities are urgently needed. A number of immunotherapies tested in pre-clinical models have shown promise. Early phase clinical trials have demonstrated evidence of immune activation that in some cases correlates with clinical response. Moreover, recent evidence delineates inflammation’s intricate role in PDA, even at its earliest stages. PDA is thus ripe for immunotherapy; however, significant challenges remain before success can be realized. Future studies will need to focus on the discovery of novel PDA antigens, and the identification of the multiple immune suppressive pathways within the PDA tumor microenvironment that inhibit an effective PDA targeted immune response. Technologies are now available to rapidly advance discovery. Rapid translation of new discoveries into scientifically driven clinical trials testing combinations of immune agents will likely continue to shift the procarcinogenic tumor environment towards the most potent anticancer response.
PMCID: PMC3539747  PMID: 23187853
pancreatic cancer; immune therapy; cancer vaccine
20.  Comparison Analysis of Coal Biodesulfurization and Coal's Pyrite Bioleaching with Acidithiobacillus ferrooxidans 
The Scientific World Journal  2013;2013:184964.
Acidithiobacillus ferrooxidans (A. ferrooxidans) was applied in coal biodesulfurization and coal's pyrite bioleaching. The result showed that A. ferrooxidans had significantly promoted the biodesulfurization of coal and bioleaching of coal's pyrite. After 16 days of processing, the total sulfur removal rate of coal was 50.6%, and among them the removal of pyritic sulfur was up to 69.9%. On the contrary, after 12 days of processing, the coal's pyrite bioleaching rate was 72.0%. SEM micrographs showed that the major pyrite forms in coal were massive and veinlets. It seems that the bacteria took priority to remove the massive pyrite. The sulfur relative contents analysis from XANES showed that the elemental sulfur (28.32%) and jarosite (18.99%) were accumulated in the biotreated residual coal. However, XRD and XANES spectra of residual pyrite indicated that the sulfur components were mainly composed of pyrite (49.34%) and elemental sulfur (50.72%) but no other sulfur contents were detected. Based on the present results, we speculated that the pyrite forms in coal might affect sulfur biooxidation process.
PMCID: PMC3826568  PMID: 24288464
21.  Vaccine therapy for pancreatic cancer 
Oncoimmunology  2013;2(12):e26662.
Pancreatic cancer is a lethal disease and currently available therapies have significant limitations. Pancreatic cancer is thus an ideal setting for the development of novel treatment modalities such as immunotherapy. However, relevant obstacles must be overcome for immunotherapeutic regimens against pancreatic cancer to be successful. Vaccine therapy relies on the administration of biological preparations that include an antigen that (at least ideally) is specifically expressed by malignant cells, boosting the natural ability of the immune system to react against neoplastic cells. There are a number of ways to deliver anticancer vaccines. Potent vaccines stimulate antigen presentation by dendritic cells, hence driving the expansion of antigen-specific effector and memory T cells. Unlike vaccines given as a prophylaxis against infectious diseases, anticancer vaccines require the concurrent administration of agents that interfere with the natural predisposition of tumors to drive immunosuppression. The safety and efficacy of vaccines against pancreatic cancer are nowadays being tested in early phase clinical trials.
PMCID: PMC3912009  PMID: 24498551
pancreatic cancer; immunotherapy; cancer vaccine; clinical trials; immune checkpoint
23.  The bZIP protein from Tamarix hispida, ThbZIP1, is ACGT elements binding factor that enhances abiotic stress signaling in transgenic Arabidopsis 
BMC Plant Biology  2013;13:151.
Tamarix spp. are woody halophyte, which are very tolerant to abiotic stresses such as salinity and drought, but little is known about their specific stress response systems. Basic leucine zipper proteins (bZIPs) play important roles in the ability of plants to withstand adverse environmental conditions. However, their exact roles in abiotic stress tolerance are still not fully known. In the current study, we functionally characterized a bZIP gene (ThbZIP1) from Tamarix hispida in response to abiotic stresses.
We addressed the regulatory network of ThbZIP1 in three levels, i.e. its upstream regulators, the cis-acting elements recognized by ThbZIP1, and its downstream target genes. Two MYCs were found to bind to E-box, in the promoter of ThbZIP1 to activate its expression. Expression of ThbZIP1 is induced by ABA, salt, drought, methyl viologen and cold. ThbZIP1 can specifically bind to ACGT elements, with the highest binding affinity to the C-box, followed by the G-box and lastly the A-box. Compared with wild-type (Col-0) Arabidopsis, transgenic plants expressing ThbZIP1 had an increased tolerance to drought and salt, but had an increased sensitivity to ABA during seed germination and root growth; meanwhile, ROS level, cell death and water loss rate in transgenic plants were significantly reduced. Microarray analyses showed that many ROS scavenging genes were up-regulated by ThbZIP1 under salt stress conditions.
Based on these data, we suggest that ThbZIP1 confers abiotic stress tolerance through activating stress tolerance genes to modulate ROS scavenging ability and other physiological changes involved in stress tolerance, and plays an important role in the ABA-mediated stress response of T. hispida.
PMCID: PMC3852707  PMID: 24093718
Abiotic stress; bZIP transcription factor; Arabidopsis thaliana; Gene expression regulation; Tamarix hispida; Yeast one-hybrid
24.  Genetic Characterization of the Hemagglutinin Genes of Wild-Type Measles Virus Circulating in China, 1993–2009 
PLoS ONE  2013;8(9):e73374.
China experienced several large measles outbreaks in the past two decades, and a series of enhanced control measures were implemented to achieve the goal of measles elimination. Molecular epidemiologic surveillance of wild-type measles viruses (MeV) provides valuable information about the viral transmission patterns. Since 1993, virologic surveillnace has confirmed that a single endemic genotype H1 viruses have been predominantly circulating in China. A component of molecular surveillance is to monitor the genetic characteristics of the hemagglutinin (H) gene of MeV, the major target for virus neutralizing antibodies.
Principal Findings
Analysis of the sequences of the complete H gene from 56 representative wild-type MeV strains circulating in China during 1993–2009 showed that the H gene sequences were clustered into 2 groups, cluster 1 and cluster 2. Cluster1 strains were the most frequently detected cluster and had a widespread distribution in China after 2000. The predicted amino acid sequences of the H protein were relatively conserved at most of the functionally significant amino acid positions. However, most of the genotype H1 cluster1 viruses had an amino acid substitution (Ser240Asn), which removed a predicted N-linked glycosylation site. In addition, the substitution of Pro397Leu in the hemagglutinin noose epitope (HNE) was identified in 23 of 56 strains. The evolutionary rate of the H gene of the genotype H1 viruses was estimated to be approximately 0.76×10−3 substitutions per site per year, and the ratio of dN to dS (dN/dS) was <1 indicating the absence of selective pressure.
Although H genes of the genotype H1 strains were conserved and not subjected to selective pressure, several amino acid substitutions were observed in functionally important positions. Therefore the antigenic and genetic properties of H genes of wild-type MeVs should be monitored as part of routine molecular surveillance for measles in China.
PMCID: PMC3779233  PMID: 24073194
25.  Mesenchymal stem cells modified with angiopoietin-1 gene promote wound healing 
Treatment of chronic skin wounds is difficult and largely ineffective. Little improvement has been shown in promoting the healing of these wounds in the past few decades. Innovative treatments to enhance chronic wound healing process are therefore needed.
In this study, we examined the efficacy of angiopoietin-1 gene-modified bone marrow mesenchymal stem cells (Ang1-MSCs) on the promotion of cutaneous wound healing in rats. Excisional full-thickness wounds were treated with Ang1-MSCs, a recombinant adenovirus encoding angiopoietin-1 (Ad-Ang1), unmodified bone marrow mesenchymal stem cells (MSCs), or vehicle medium (sham).
The results showed that Ang1-MSCs significantly promoted wound healing with increased epidermal and dermal regeneration, and enhanced angiogenesis compared with MSCs, Ad-Ang1 or sham treatment. Moreover, Ang1-MSCs expressed CD31 in the wound, suggesting a direct contribution of Ang1-MSCs to angiogenesis.
Here we show that Ang1-MSCs accelerate wound healing by promoting skin regeneration and angiogenesis, compared with MSCs or Ad-Ang1 alone.
PMCID: PMC3854694  PMID: 24477049

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