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1.  Draft Genome Sequence of Stenotrophomonas maltophilia Strain B418, a Promising Agent for Biocontrol of Plant Pathogens and Root-Knot Nematode 
Genome Announcements  2015;3(1):e00015-15.
Stenotrophomonas maltophilia strain B418 was isolated from a barley rhizosphere in China. This bacterium exhibits broad-spectrum inhibitory activities against plant pathogens and root-knot nematode along with growth-promoting effects. Here, we present the draft genome sequence of S. maltophilia B418.
doi:10.1128/genomeA.00015-15
PMCID: PMC4335322
2.  The association between expressions of Ras and CD68 in the angiogenesis of breast cancers 
Cancer Cell International  2015;15(1):17.
Objective
Angiogenesis is a critical step of breast cancer metastasis. Oncogenic Ras promotes the remodeling of cancer microenviroment. Tumor-associated macrophages (TAMs) are a prominent inflammatory cell population emerging in the microenviroment and facilitating the angiogenesis and metastasis. In the present study, we tried to investigate the relationship between the expression of Ras and infiltration of TAM, both of which could further promote angiogenesis.
Methods
Expressions of Ras, CD68 and CD34 were assessed by immunohistochemistry. The infiltration of macrophages was evaluated by counting the number of CD68+ cells. Vessel endothelial cells were defined as CD34+ cells. Angiogenesis vascularity was defined by microvessel density (MVD) assay through counting the number of vessels per field counted in the area of highest vascular density. The Kaplan–Meier survival analysis was used to estimate the overall survival (OS). Macrophages were derived from monocytes in the presence of macrophage colony-stimulating-factor (MCSF). Breast cancer cells were treated with macrophage-conditioned medium (MCM) and tested the expressions of K-, H- and N-Ras by using realtime-PCR.
Results
Ras positive status was correlated with ER, PR and Her-2 positivity, larger tumour size and lymph node metastasis, as well as higher TNM stages. A higher number of CD68+ cells was correlated with larger tumour size, higher TNM stages and Her-2 positivity. Both Ras positivity and infiltration of CD68+ macrophages correlated with poor OS. The number of CD68+ cells was positively correlated with the expression of Ras. Treatment with MCM did not up-regulate but repressed the expression of Ras. Both up-regulation of Ras and infiltration of TAMs correlated with increased MVD.
Conclusion
Expression of Ras and infiltration of TAM were positively correlated, and both participated in angiogenesis. Elevated Ras could be responsible for the infiltration of TAM.
doi:10.1186/s12935-015-0169-1
PMCID: PMC4326448
Breast cancer; Ras; TAM; CD34; Angiogenesis
3.  A concise synthesis of Fingolimod: an orally available drug for treating multiple sclerosis 
A concise route for the synthesis of Fingolimod is reported. Starting from n-octylbenzene and 3-nitropropionic acid, a sequence of reactions consisting of Friedel-Crafts acylation, reduction, and double Henry reaction, followed by hydrogenation were applied to prepare Fingolimod with a yield of 31%, and an overall atom economy of 82.7%.
Graphical AbstractStarting from 3-nitropropanyl chloride, Fingolimod was obtained in 4 steps with an overall yield of 31%.
doi:10.1186/s13065-015-0081-8
PMCID: PMC4317520  PMID: 25657817
Fingolimod; 3-nitropropionic acid; Immunosuppressant
4.  A concise synthesis of Fingolimod: an orally available drug for treating multiple sclerosis 
A concise route for the synthesis of Fingolimod is reported. Starting from n-octylbenzene and 3-nitropropionic acid, a sequence of reactions consisting of Friedel-Crafts acylation, reduction, and double Henry reaction, followed by hydrogenation were applied to prepare Fingolimod with a yield of 31%, and an overall atom economy of 82.7%.
Graphical AbstractStarting from 3-nitropropanyl chloride, Fingolimod was obtained in 4 steps with an overall yield of 31%.
doi:10.1186/s13065-015-0081-8
PMCID: PMC4317520  PMID: 25657817
Fingolimod; 3-nitropropionic acid; Immunosuppressant
5.  A Bio-Inspired Spatial Patterning Circuit 
Lateral Inhibition (LI) is a widely conserved patterning mechanism in biological systems across species. Distinct from better-known Turing patterns, LI depend on cell-cell contact rather than diffusion. We built an in silico genetic circuit model to analyze the dynamic properties of LI. The model revealed that LI amplifies differences between neighboring cells to push them into opposite states, hence forming stable 2-D patterns. Inspired by this insight, we designed and implemented an electronic circuit that recapitulates LI patterning dynamics. This biomimetic system serve as a physical model to elucidate the design principle of generating robust patterning through spatial feedback, regardless of the underlying devices being biological or electrical.
doi:10.1109/EMBC.2014.6943535
PMCID: PMC4304701  PMID: 25569903
6.  A Metabolic Signature of Colon Cancer Initiating Cells 
Colon cancer initiating cells (CCICs) are more tumorigenic and metastatic than the majority of colorectal cancer (CRC) cells. CCICs have also been associated with stem cell-like properties. However, there is a lack of system-level understanding of what mechanisms distinguish CCICs from common CRC cells. We compared the transcriptomes of CD133+ CCICs and CD133− CRC cells from multiple sources, which identified a distinct metabolic signature for CD133high CCICs. High-resolution unbiased metabolomics was then performed to validate this CCIC metabolic signature. Specifically, levels of enzymes and metabolites involved in glycolysis, the citric acid (TCA) cycle, and cysteine and methionine metabolism are altered in CCICs. Analyses of the alterations further suggest an epigenetic link. This metabolic signature provides mechanistic insights into CCIC phenotypes and may serve as potential biomarkers and therapeutic targets for future CRC treatment.
doi:10.1109/EMBC.2014.6944688
PMCID: PMC4302416  PMID: 25571056
7.  The Clinical Significance of DC-SIGN and DC-SIGNR, which Are Novel Markers Expressed in Human Colon Cancer 
PLoS ONE  2014;9(12):e114748.
Background
Colon cancer has always been diagnosed at a late stage, which is associated with poor prognosis. The currently used serum tumor markers CEA and CA19-9 display low sensitivity and specificity and may not have diagnostic value in early stage colon cancer. Thus, there is an urgent need to identify novel serum biomarkers for use in the early detection of colon cancer.
Methods
In this study, the expression of DC-SIGN and DC-SIGNR in serum was detected by enzyme-linked immunosorbent assay (ELISA). DC-SIGN and DC-SIGNR expression was detected in cancer tissues by immunohistochemistry (IHC).
Results
The level of sDC-SIGN was lower in patients than in the healthy controls, while the level of sDC-SIGNR in patients was higher than in the healthy controls. Both sDC-SIGN and sDC-SIGNR had diagnostic significances for cancer patients, and the combined diagnosis of these two markers was higher than both of them alone. Furthermore, there were significant differences between both sDC-SIGN and sDC-SIGNR in stage I/II patients and the healthy controls. Moreover, high sDC-SIGN level was accompanied with the long survival time. Additionally, DC-SIGNR was negative in the cancer foci and matched normal colon tissues but was weakly positive between the cancer foci. DC-SIGN staining was faint in matched normal colon tissues, strong in the tumor stroma and the invasive margin of colon cancer tissues, and negatively correlated with the sDC-SIGN level in serum from the same patient. Interestingly, the percent survival of patients with a DC-SIGN mean density of>0.001219 (the upper 95% confidence interval of matched normal colon tissues) was higher than for all other patients.
Conclusion
DC-SIGN and DC-SIGNR are blood-based molecular markers that can potentially be used for the diagnosis of early stage patients. Moreover, expression of DC-SIGN in serum and cancer tissues may affect the survival time for colon cancer patients.
doi:10.1371/journal.pone.0114748
PMCID: PMC4264775  PMID: 25504222
8.  Paused Pol II Coordinates Tissue Morphogenesis in the Drosophila Embryo 
Cell  2013;153(5):976-987.
Summary
Paused RNA Polymerase (Pol II) is a pervasive feature of Drosophila embryos and mammalian stem cells, but its role in development is uncertain. Here, we demonstrate that there is a spectrum of paused Pol II, which determines the “time to synchrony”--the time required to achieve coordinate gene expression across the different cells of a tissue. To determine whether synchronous patterns of gene activation are significant in development, we manipulated the timing of snail expression, which controls the coordinated invagination of ∼1000 mesoderm cells during gastrulation. Replacement of the strongly paused snail promoter with moderately paused or nonpaused promoters results in stochastic activation of snail expression and the progressive loss of mesoderm invagination. Computational modeling of the dorsal-ventral patterning network recapitulates these variable and bistable gastrulation profiles, and emphasizes the importance of timing of gene activation in development. We conclude that paused Pol II and transcriptional synchrony are essential for coordinating cell behavior during morphogenesis.
doi:10.1016/j.cell.2013.04.045
PMCID: PMC4257494  PMID: 23706736
Pol II pausing; promoter; Drosophila; transcription; synchrony; morphogenesis; temporal coordination; gastrulation; timing
9.  Tamoxifen enhances the anticancer effect of cantharidin and norcantharidin in pancreatic cancer cell lines through inhibition of the protein kinase C signaling pathway 
Oncology Letters  2014;9(2):837-844.
Cantharidin is an active constituent of mylabris, a traditional Chinese therapeutic agent. Cantharidin is a potent and selective inhibitor of protein phosphatase 2A (PP2A). Cantharidin has been previously reported to efficiently repress the growth of pancreatic cancer cells. However, excessively activated protein kinase C (PKC) has been shown to improve cell survival following the adminstration of cantharidin. Tamoxifen is widely used in the treatment of estrogen receptor-positive breast cancer. In addition, an increasing number of studies have found that tamoxifen selectively inhibits PKC and represses growth in estrogen receptor-negative cancer cells. Administration of a combination of PKC inhibitor and PP2A inhibitors has been demonstrated to exert a synergistic anticancer effect. The proliferation of pancreatic cancer cells was analyzed by 3-(4,5-dimethyltiazol-2-yl]2, 5-diphenyltetrazo-lium bromide assay. The expression levels of ERα and ERβ in various pancreatic cancer cell lines were determined by reverse transcription polymerase chain reaction. In addition, the protein levels of PKCα and phosphorylated PKCα in pancreatic cell lines were analyzed by western blot analysis. In the present study, tamoxifen was found to exert a cytotoxic effect against pancreatic cancer cells independent of the hormone receptor status. Tamoxifen repressed the phosphorylation of PKC, and amplified the anticancer effect induced by cantharidin and norcantharidin. The findings reveal a novel potential strategy against pancreatic cancer using co-treatment with tamoxifen plus cantharidin or cantharidin derivatives.
doi:10.3892/ol.2014.2711
PMCID: PMC4301527  PMID: 25624908
pancreactic cancer; cantharidin; protein phosphatase 2A; tamoxifen; protein kinase C
10.  Discovery and Analysis of MicroRNAs in Leymus chinensis under Saline-Alkali and Drought Stress Using High-Throughput Sequencing 
PLoS ONE  2014;9(11):e105417.
Leymus chinensis (Trin.) Tzvel. is a perennial rhizome grass of the Poaceae (also called Gramineae) family, which adapts well to drought, saline and alkaline conditions. However, little is known about the stress tolerance of L. chinensis at the molecular level. microRNAs (miRNAs) are known to play critical roles in nutrient homeostasis, developmental processes, pathogen responses, and abiotic stress in plants. In this study, we used Solexa sequencing technology to generate high-quality small RNA data from three L. chinensis groups: a control group, a saline-alkaline stress group (100 mM NaCl and 200 mM NaHCO3), and a drought stress group (20% polyethylene glycol 2000). From these data we identified 132 known miRNAs and 16 novel miRNAs candidates. For these miRNAs we also identified target genes that encode a broad range of proteins that may be correlated with abiotic stress regulation. This is the first study to demonstrate differentially expressed miRNAs in L. chinensis under saline-alkali and drought stress. These findings may help explain the saline-alkaline and drought stress responses in L. chinensis.
doi:10.1371/journal.pone.0105417
PMCID: PMC4219666  PMID: 25369004
11.  microPET of Tumor Integrin αvβ3 Expression Using 18F-Labeled PEGylated Tetrameric RGD Peptide (18F-FPRGD4) 
In vivo imaging of αvβ3 expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin αvβ3–binding affinity due to the polyvalency effect. Here we report an example of 18F-labeled tetrameric RGD peptide for PET of αvβ3 expression in both xenograft and spontaneous tumor models.
Methods
The tetrameric RGD peptide E{E[c(RGDyK)]2}2 was derived with amino-3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate α-amino group. NH2-mini-PEG-E{E[c(RGDyK)]2}2 (PRGD4) was labeled with 18F via the N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer 18F-FPRGD4 were evaluated in vitro by a cell-binding assay and in vivo by quantitative microPET imaging studies.
Results
The decay-corrected radiochemical yield for 18F-FPRGD4 was about 15%, with a total reaction time of 180 min starting from 18F-F−. The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. 18F-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of 18F-FPRGD4 in vivo was confirmed by effective blocking of the uptake in both tumors and normal organs or tissues with excess c(RGDyK).
Conclusion
The tetrameric RGD peptide tracer 18F-FPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin αvβ3 expression in cancer and other angiogenesis related diseases.
doi:10.2967/jnumed.107.040816
PMCID: PMC4183663  PMID: 17704249
microPET; integrin αvβ3; tetrameric RGD peptide; PEGylation; 18F
12.  Click Chemistry for 18F-Labeling of RGD Peptides and microPET Imaging of Tumor Integrin αvβ3 Expression 
Bioconjugate chemistry  2007;18(6):1987-1994.
The cell adhesion molecule integrin αvβ3 plays a key role in tumor angiogenesis and metastasis. A series of 18F-labeled RGD peptides have been developed for PET of integrin expression based on primary amine reactive prosthetic groups. In this study, we report the use of the Cu(I)-catalyzed Huisgen cycloaddition, also known as a click reaction, to label RGD peptides with 18F by forming 1,2,3-triazoles. Nucleophilic fluorination of a toluenesulfonic alkyne provided 18F-alkyne in high yield (nondecay-corrected yield: 65.0 ± 1.9%, starting from the azeotropically dried 18F-fluoride), which was then reacted with an RGD azide (nondecay-corrected yield: 52.0 ± 8.3% within 45 min including HPLC purification). The 18F-labeled peptide was subjected to microPET studies in murine xenograft models. Murine microPET experiments showed good tumor uptake (2.1 ± 0.4%ID/g at 1 h postinjection (p.i.)) with rapid renal and hepatic clearance of 18F-fluoro-PEG-triazoles-RGD2 (18F-FPTA-RGD2) in a subcutaneous U87MG glioblastoma xenograft model (kidney 2.7 ± 0.8%ID/g; liver 1.9 ± 0.4%ID/g at 1 h p.i.). Metabolic stability of the newly synthesized tracer was also analyzed (intact tracer ranging from 75% to 99% at 1 h p.i.). In brief, the new tracer 18F-FPTA-RGD2 was synthesized with high radiochemical yield and high specific activity. This tracer exhibited good tumor-targeting efficacy and relatively good metabolic stability, as well as favorable in vivo pharmacokinetics. This new 18F labeling method based on click reaction may also be useful for radiolabeling of other biomolecules with azide groups in high yield.
doi:10.1021/bc700226v
PMCID: PMC4183694  PMID: 18030991
13.  HER-2 positive breast cancer is associated with an increased risk of positive cavity margins after initial lumpectomy 
Background
The effect of breast cancer subtype on margin status after lumpectomy remains unclear. This study aims to determine whether approximated breast cancer subtype is associated with positive margins after lumpectomy, which could be used to determine if there is an increased risk of developing local recurrence (LR) following breast-conserving surgery.
Methods
We studied 1,032 consecutive patients with invasive cancer who received lumpectomies and cavity margin (CM) assessments from January 2003 to November 2012. The following data were collected: patient age, cT stage, pT stage, grade, status of CM, lymph node status, menopausal status, ER, PR, HER-2, and Ki67, as well as the presence of extensive intraductal component (EIC) and lymphovascular invasion (LVI). A χ2 test was used to compare categorical baseline characteristics. Univariate and multivariate logistic regression analyses were performed to evaluate associations between pathologic features of CM status. Kaplan-Meier actuarial cumulative rates of LR (ipsilateral in-breast) were calculated.
Results
A total of 7,884 pieces of marginal tissue were collected from 1,032 patients, and 209 patients had positive CMs. Of the patients tested, 52.3% had luminal A subtype, 14.9% were luminal B, 12.8% were luminal-HER-2, 8.1% were HER-2 enriched, and 11.8% were triple negative. Univariate analysis showed that EIC (P <0.001), LVI (P = 0.026), pN stage (N1 vs. N0: P = 0.018; N3 vs. N0: P <0.001), and luminal B (P = 0.001) and HER-2 (P <0.001) subtypes were associated with positive CMs. Multivariable analysis indicated that only EIC (P <0.001), pN stage (P = 0.003), and HER-2 subtype (P <0.001) were significantly correlated with positive CMs. On multivariable analysis, HER-2 subtype was an independent prognostic factor in LR (P = 0.031).
Conclusions
The HER-2 subtype was the predictive factor most associated with positive CMs and an independent prognostic factor for LR. This result suggests that the increased risk of LR in HER-2 breast cancer is due to an increased microscopic invasive tumor burden, which is indicated by margin status after lumpectomy.
Electronic supplementary material
The online version of this article (doi:10.1186/1477-7819-12-289) contains supplementary material, which is available to authorized users.
doi:10.1186/1477-7819-12-289
PMCID: PMC4190445  PMID: 25241216
Breast cancer subtype; Breast-conserving surgery; Cavity margin; HER-2
14.  Mechanisms of action for 2-phenylethanol isolated from Kloeckera apiculata in control of Penicillium molds of citrus fruits 
BMC Microbiology  2014;14(1):242.
Background
Green and blue mold decay, caused by Penicillium digitatum and P. italicum, respectively, are important postharvest diseases of citrus. Biocontrol by microbes is an alternative to synthetic fungicide application. In this study, the antagonistic yeast strain Kloeckera apiculata 34–9 was used to investigate the action mechanisms involved in the biocontrol of postharvest diseases.
Results
An antifungal substance, 2-phenylethanol (PEA), was isolated from K. apiculata and demonstrated to have antimicrobial activity against selected phytopathogenic fungi. Experiments on P. italicum cells identified the mitochondria and the nucleus as particularly sensitive to inhibition. Regulation of P. italicum gene expression was investigated using RNA-Seq. PEA up-regulated genes involved with the peroxisome, regulation of autophagy, phosphatidylinositol signaling system, protein processing in endoplasmic reticulum, fatty acid metabolism, and inhibited ribosome, RNA polymerase, DNA replication, amino acid biosynthesis, aminoacyl-tRNA biosynthesis and cell cycle. Inhibitory responses revealed by RNA-Seq suggest that PEA might compete for attachment on the active site of phenylalanyl-tRNA synthetase (PheRS).
Conclusion
This study provided new insight on the mode of action of biocontrol yeast agents in controlling postharvest pathogenic fungi.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-014-0242-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12866-014-0242-2
PMCID: PMC4177429  PMID: 25230758
Biological control; Penicillium; Kloeckera apiculata; Antifungal compound; 2-phenylethanol (PEA); Postharvest
15.  Uncoupling Protein 2 Impacts Endothelial Phenotype via p53-Mediated Control of Mitochondrial Dynamics 
Circulation research  2013;113(7):10.1161/CIRCRESAHA.113.301319.
Rationale
Mitochondria, although required for cellular ATP production, are also known to have other important functions that may include modulating cellular responses to environmental stimuli. However, the mechanisms whereby mitochondria impact cellular phenotype are not yet clear.
Objective
To determine how mitochondria impact endothelial cell function.
Methods and Results
We report here that stimuli for endothelial cell proliferation evoke strong upregulation of mitochondrial uncoupling protein 2 (UCP2). Analysis in silico indicated increased UCP2 expression is common in highly proliferative cell types, including cancer cells. Upregulation of UCP2 was critical for controlling mitochondrial membrane potential (Δψ) and superoxide production. In the absence of UCP2, endothelial growth stimulation provoked mitochondrial network fragmentation and premature senescence via a mechanism involving superoxide-mediated p53 activation. Mitochondrial network fragmentation was both necessary and sufficient for the impact of UCP2 on endothelial cell phenotype.
Conclusions
These data identify a novel mechanism whereby mitochondria preserve normal network integrity and impact cell phenotype via dynamic regulation of UCP2.
doi:10.1161/CIRCRESAHA.113.301319
PMCID: PMC3869454  PMID: 23819990
Endothelium; mitochondria; superoxide; uncoupling proteins; angiogenesis; endothelial function; ischemia
16.  Prevention Effect of Allopurinol on Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: A Meta-Analysis of Prospective Randomized Controlled Trials 
PLoS ONE  2014;9(9):e107350.
Background
Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP) which can be severe and cause death in approximately 10% of cases. Up to now, six randomized controlled trials (RCTs) have been found relevant to the effect of allopurinol on prevention of Post-ERCP pancreatitis (PEP). However, these results remained controversial.
Objective
To conduct a meta-analysis with RCTs published in full text to determine the effectiveness of prophylactic allopurinol of different dosages and administration time in the incidence and severity of PEP.
Methods
Literature search was performed in PubMed, Embase, Web of Science and Cochrane Library from databases inception to May 2014. RCTs comparing the effect of allopurinol with placebo on prevention of PEP were included. Statistical heterogeneity was quantitatively evaluated byχ2 test with the significance set P<0.10 or I2>50%.
Results
Six RCTs consisting of 1974 participants were eventually included. The incidences of PEP in allopurinol group and placebo group were 8.4%(83/986) and 9.9%(98/988) respectively. Meta-analysis showed no evident prevention effect of allopurinol on the incidence of PEP (RR 0.75, 95%CI 0.39–1.42) with significant heterogeneity (I2 = 70.4%, P = 0.005). When studies were stratified according to the dosages and administration time of allopurinol they applied, there was still no evident prevention effect of allopurinol on mild, moderate or severe PEP. However, statistically substantial heterogeneity was presented in the subgroup of moderate PEP when the effect of high dose of allopurinol was analyzed (Imoderate2 = 82.3%, Pmoderate = 0.018). Statistically significant heterogeneity was also observed in subgroup of mild PEP, when the effect of long adminstration time of allopurinol was investigated (Imild2 = 62.8%, Pmild = 0.068).
Conclusion
The prophylactic use of allopurinol in different dosages and administration time had no effect in preventing incidence and severity of PEP.
doi:10.1371/journal.pone.0107350
PMCID: PMC4159328  PMID: 25202907
17.  Monitoring of the Biological Response to Murine Hindlimb Ischemia With 64Cu-Labeled Vascular Endothelial Growth Factor-121 Positron Emission Tomography 
Circulation  2008;117(7):915-922.
Background
Vascular endothelial growth factor-121 (VEGF121), an angiogenic protein secreted in response to hypoxic stress, binds to VEGF receptors (VEGFRs) overexpressed on vessels of ischemic tissue. The purpose of this study was to evaluate 64Cu-VEGF121 positron emission tomography for noninvasive spatial, temporal, and quantitative monitoring of VEGFR2 expression in a murine model of hindlimb ischemia with and without treadmill exercise training.
Methods and Results
64Cu-labeled VEGF121 and a VEGF mutant were tested for VEGFR2 binding specificity in cell culture. Mice (n=58) underwent unilateral ligation of the femoral artery, and postoperative tissue ischemia was assessed with laser Doppler imaging. Longitudinal VEGFR2 expression in exercised and nonexercised mice was quantified with 64Cu-VEGF121 positron emission tomography at postoperative day 8, 15, 22, and 29 and correlated with postmortem γ-counting. Hindlimbs were excised for immunohistochemistry, Western blotting, and microvessel density measurements. Compared with the VEGF mutant, VEGF121 showed specific binding to VEGFR2. Perfusion in ischemic hindlimbs fell to 9% of contralateral hindlimb on postoperative day 1 and recovered to 82% on day 29. 64Cu-VEGF121 uptake in ischemic hindlimbs increased significantly (P<0.001) from a control level of 0.61 ±0.17% ID/g (percentage of injected dose per gram) to 1.62±0.35% ID/g at postoperative day 8, gradually decreased over the following 3 weeks (0.59±0.14% ID/g at day 29), and correlated with γ-counting (R2=0.99). Compared with nonexercised mice, 64Cu-VEGF121 uptake was increased significantly (P≤0.0001) in exercised mice (at day 15, 22, and 29) and correlated with VEGFR2 levels as obtained by Western blotting (R2=0.76). Ischemic hindlimb tissue stained positively for VEGFR2. In exercised mice, microvessel density was increased significantly (P<0.001) compared with nonexercised mice.
Conclusions
64Cu-VEGF121 positron emission tomography allows longitudinal spatial and quantitative monitoring of VEGFR2 expression in murine hindlimb ischemia and indirectly visualizes enhanced angiogenesis stimulated by treadmill exercise training.
doi:10.1161/CIRCULATIONAHA.107.733220
PMCID: PMC4157592  PMID: 18250264
imaging; arteriosclerosis; exercise; angiogenesis; tomography; peripheral vascular disease; growth substances
18.  US Imaging of Tumor Angiogenesis with Microbubbles Targeted to Vascular Endothelial Growth Factor Receptor Type 2 in Mice1 
Radiology  2008;246(2):508-518.
Purpose
To prospectively evaluate contrast material–enhanced ultrasonography (US) with microbubbles targeted to vascular endothelial growth factor receptor type 2 (VEGFR2) for imaging tumor angiogenesis in two murine tumor models.
Materials and Methods
Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. A US contrast agent, consisting of encapsulated gaseous microbubbles, was developed specifically to bind to VEGFR2 (by using anti-VEGFR2 antibodies and biotin-streptavidin interaction) which is up-regulated on endothelial cells of tumor blood vessels. VEGFR2-targeted microbubbles (MBV), control microbubbles (MBC), and nonlabeled microbubbles (MBN) were tested for binding specificity on cells expressing VEGFR2 (mouse angiosarcoma SVR cells) and control cells (mouse skeletal myoblast C2C12 cells). Expression of mouse VEGFR2 in culture cells was tested with immunocytochemical and Western blot analysis. Contrast-enhanced US imaging with MBV and MBC was performed in 28 tumor-bearing nude mice (mouse angiosarcoma, n = 18; rat malignant glioma, n = 10). Differences were calculated by using analysis of variance.
Results
In cell culture, adherence of MBV on SVR cells (2.1 microbubbles per SVR cell) was significantly higher than adherence of control microbubbles (0.01– 0.10 microbubble per SVR cell; P < .001) and significantly more MBV attached to SVR cells than to C2C12 cells (0.15 microbubble per C2C12 cell; P < .001). In vivo, contrast-enhanced US imaging showed significantly higher average video intensity when using MBV compared with MBC for angiosarcoma and malignant glioma tumors (P < .001). Results of immunohistochemical analysis confirmed VEGFR2 expression on vascular endothelial cells of both tumor types.
Conclusion
US imaging with contrast microbubbles targeted to VEGFR2 allows noninvasive visualization of VEGFR2 expression in tumor vessels in mice.
doi:10.1148/radiol.2462070536
PMCID: PMC4157631  PMID: 18180339
19.  Future of the Particle Replication in Nonwetting Templates (PRINT) Technology 
Particle replication in nonwetting templates (PRINT) is a continuous, roll-to-roll, high-resolution molding technology which allows the design and synthesis of precisely defined micro- and nanoparticles. This technology adapts the lithographic techniques from the microelectronics industry and marries these with the roll-to-roll processes from the photographic film industry to enable researchers to have unprecedented control over particle size, shape, chemical composition, cargo, modulus, and surface properties. In addition, PRINT is a GMP-compliant (GMP = good manufacturing practice) platform amenable for particle fabrication on a large scale. Herein, we describe some of our most recent work involving the PRINT technology for application in the biomedical and material sciences.
doi:10.1002/anie.201209145
PMCID: PMC4157646  PMID: 23670869
colloids; drug delivery; nanomedicine; nano-particles; soft lithography
20.  Pulmonary arteriovenous malformations presenting as refractory heart failure 
Journal of Thoracic Disease  2014;6(9):E169-E172.
A 22-year-old young man with a history of idiopathic dilated cardiomyopathy (IDC) was admitted to our hospital due to difficult-to-control heart failure. A thoracic X-ray showed multiple nodules at the both pulmonary hilus and upper lobe of the right lung. Computed tomography (CT) angiography of the thorax confirmed arteriovenous malformation (AVM). However, effective treatment was impossible due to the poor physical condition; he died a few days later. Here we reported on the case of pulmonary arteriovenous malformations (PAVMs) being misdiagnosed as refractory heart failure.
doi:10.3978/j.issn.2072-1439.2014.07.39
PMCID: PMC4178099  PMID: 25276390
Pulmonary arteriovenous malformations (PAVMs); heart failure; idiopathic dilated cardiomyopathy (IDC)
21.  Potential role of NADPH oxidase in pathogenesis of pancreatitis 
Studies have demonstrated that reactive oxygen species (ROS) are closely related to inflammatory disorders. Nicotinamide adenine dinucleotide phosphate oxidase (NOX), originally found in phagocytes, is the main source of ROS in nonphagocytic cells. Besides directly producing the detrimental highly reactive ROS to act on biomolecules (lipids, proteins, and nucleic acids), NOX can also activate multiple signal transduction pathways, which regulate cell growth, proliferation, differentiation and apoptosis by producing ROS. Recently, research on pancreatic NOX is no longer limited to inflammatory cells, but extends to the aspect of pancreatic acinar cells and pancreatic stellate cells, which are considered to be potentially associated with pancreatitis. In this review, we summarize the literature on NOX protein structure, activation, function and its role in the pathogenesis of pancreatitis.
doi:10.4291/wjgp.v5.i3.169
PMCID: PMC4133516  PMID: 25133019
Nicotinamide adenine dinucleotide phosphate oxidase; Reactive oxygen species; Pancreatitis; Pancreatic acinar cells; Pancreatic stellate cells
22.  Recent advances in diagnosis and treatment of gliomas using chlorotoxin-based bioconjugates 
Malignant gliomas, especially glioblastoma multiforme, are the most widely distributed and deadliest brain tumors because of their resistance to surgical and medical treatment. Research of glioma-specific bioconjugates for diagnosis and therapy developed rapidly during the past several years. Many studies have demonstrated that chlorotoxin (CTX) and Buthus martensii Karsch chlorotoxin (BmK CT) specifically inhibited glioma cells growth and metastasis, and accelerated tumor apoptosis. The bioconjugates of CTX or BmK CT with other molecules have played an increasing role in diagnostic imaging and treatment of gliomas. To date, CTX-based bioconjugates have achieved great success in phase I/II clinical trials about safety profiles. Here, we will provide a review on the important role of ion channels in the underlying mechanisms of gliomas invasive growth and how CTX suppresses gliomas proliferation and migration. We will summarize the recent advances in the applications of CTX bioconjugates for gliomas diagnosis and treatment. In addition, we will review recent studies on BmK CT bioconjugates and compare their efficacies with CTX derivatives. Finally, we will address advantages and challenges in the use of CTX or BmK CT bioconjugates as specific agents for theranostic applications in gliomas.
PMCID: PMC4138135  PMID: 25143859
Chlorotoxin (CTX); Buthus martensii Karsch chlorotoxin (BmK CT); glioma; imaging; therapy
23.  A comparative analysis of EGFR mutation status in association with the efficacy of TKI in combination with WBRT/SRS/surgery plus chemotherapy in brain metastasis from non-small cell lung cancer 
Journal of Neuro-Oncology  2014;120(2):423-430.
We proposed to identify the efficacy of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) using whole brain radiotherapy (WBRT)/stereotactic radiosurgery (SRS)/surgery in brain metastases from patients with non-small cell lung cancer (NSCLC) and clarify the association between treatment outcome and EGFR gene mutation status. A total of 282 patients with NSCLC brain metastases who underwent WBRT/SRS/surgery alone or in combination with TKI were enrolled in our study from 2003–2013. Amplification mutation refractory system technology was used to determine the EGFR mutation status in 109 tissue samples. EGFR mutation detection was performed in 109 patients with tumor tissues. The EGFR positive rate was 50 % (55/109), including 26 exon 19 deletions and 24 L858R mutations. The median follow-up time was 28 months. The median overall survival, median progression-free survival of intracranial disease, and median progression-free survival of extracranial disease was significantly longer for patients with TKI treatment (31.9 vs 17.0 months, P < 0.0001; 19.8 vs 12.0 months, P < 0.0001; and 19.6 vs 12.3 months, P < 0.0001; respectively). In subgroup analysis within the TKI group, patients harboring EGFR mutations had better extracranial disease control (20.4 vs 14.1 months, P = 0.032). Administration of TKI agents with conventional therapy compared with conventional therapy alone might be beneficial for overall survival, progression-free survival of intracranial disease and progression-free survival of extracranial disease in patients with brain metastases from NSCLC independent of EGFR mutations.
doi:10.1007/s11060-014-1570-7
PMCID: PMC4206296  PMID: 25098700
EGFR mutation; TKI; Brain metastasis; Non-small cell lung cancer
24.  Novel Bayesian classification models for predicting compounds blocking hERG potassium channels 
Acta Pharmacologica Sinica  2014;35(8):1093-1102.
Aim:
A large number of drug-induced long QT syndromes are ascribed to blockage of hERG potassium channels. The aim of this study was to construct novel computational models to predict compounds blocking hERG channels.
Methods:
Doddareddy's hERG blockage data containing 2644 compounds were used, which divided into training (2389) and test (255) sets. Laplacian-corrected Bayesian classification models were constructed using Discovery Studio. The models were internally validated with the training set of compounds, and then applied to the test set for validation. Doddareddy's experimentally validated dataset with 60 compounds was used for external test set validation.
Results:
A Bayesian classification model considering the effects of four molecular properties (Mw, PPSA, ALogP and pKa_basic) as well as extended-connectivity fingerprints (ECFP_14) exhibited a global accuracy (91%), parameter sensitivity (90%) and specificity (92%) in the test set validation, and a global accuracy (58%), parameter sensitivity (61%) and specificity (57%) in the external test set validation.
Conclusion:
The novel model is better than those in the literatures for predicting compounds blocking hERG channels, and can be used for large-scale prediction.
doi:10.1038/aps.2014.35
PMCID: PMC4125710  PMID: 24976154
hERG; potassium channels; long QT syndrome; pharmacophore; modeling; Laplacian-modified Bayesian; extended-connectivity fingerprints; QSAR

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