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1.  Mutations of C-Reactive Protein (CRP) -286 SNP, APC and p53 in Colorectal Cancer: Implication for a CRP-Wnt Crosstalk 
PLoS ONE  2014;9(7):e102418.
C-reactive protein (CRP) is an established marker of inflammation with pattern-recognition receptor-like activities. Despite the close association of the serum level of CRP with the risk and prognosis of several types of cancer, it remains elusive whether CRP contributes directly to tumorigenesis or just represents a bystander marker. We have recently identified recurrent mutations at the SNP position -286 (rs3091244) in the promoter of CRP gene in several tumor types, instead suggesting that locally produced CRP is a potential driver of tumorigenesis. However, it is unknown whether the -286 site is the sole SNP position of CRP gene targeted for mutation and whether there is any association between CRP SNP mutations and other frequently mutated genes in tumors. Herein, we have examined the genotypes of three common CRP non-coding SNPs (rs7553007, rs1205, rs3093077) in tumor/normal sample pairs of 5 cancer types (n = 141). No recurrent somatic mutations are found at these SNP positions, indicating that the -286 SNP mutations are preferentially selected during the development of cancer. Further analysis reveals that the -286 SNP mutations of CRP tend to co-occur with mutated APC particularly in rectal cancer (p = 0.04; n = 67). By contrast, mutations of CRP and p53 or K-ras appear to be unrelated. There results thus underscore the functional importance of the -286 mutation of CRP in tumorigenesis and imply an interaction between CRP and Wnt signaling pathway.
PMCID: PMC4099363  PMID: 25025473
2.  A Comparative Study on Inhibition of Total Astragalus Saponins and Astragaloside IV on TNFR1-Mediated Signaling Pathways in Arterial Endothelial Cells 
PLoS ONE  2014;9(7):e101504.
Both total astragalus saponins (AST) and it’s main component astragaloside IV (ASIV) have been used in China as cardiovascular protective medicines. However, the anti-inflammatory activities that are beneficial for cardiovascular health have never been compared directly and the molecular mechanisms remain unresolved. This study was conducted to compare the inhibitory effects of these drugs on TNFα-induced cell responses, related signaling pathways, and the underlying mechanisms in mouse arterial endothelial cells.
Methodology/Principal Findings
Real-time qRT-PCR was performed to determine the expression of cell adhesion molecule (CAM) genes. Immunofluorescent staining was used to detect the nuclear translocation of transcription factor NF-κB-p65. Western Blot analysis was used to identify TNFα-induced NF-κB-p65 phosphorylation, IκBα degradation, and caspase-3 cleavage. Cell surface proteins were isolated and TNFα receptor-1(TNFR1) expression was determined. The results suggest that both AST and ASIV attenuate TNFα-induced up-regulation of CAMs mRNA and upstream nuclear translocation and phosphorylation of NF-κB-p65. However, TNFR1-mediated IκBα degradation, cleavage of caspase-3 and apoptosis were inhibited only by AST. These differences in the actions of AST and ASIV could be explained by the presence of other components in AST, such as ASII and ASIII, which also had an inhibitory effect on TNFR1-induced IκBα degradation. Moreover, AST, but not ASIV, was able to reduce TNFR1 protein level on the cell surface. Furthermore, mechanistic investigation demonstrated that TNFR1-mediated IκBα degradation was reversed by the use of TAPI-0, an inhibitor of TNFα converting enzyme (TACE), suggesting the involvement of TACE in the modulation of surface TNFR1 level by AST.
ASIV was not a better inhibitor than AST, at least on the inhibition of TNFα-induced inflammatory responses and TNFR1-mediated signaling pathways in AECs. The inhibitory effect of AST was caused by the reduction of cell surface TNFR1 level, and TACE could be involved in this action.
PMCID: PMC4081628  PMID: 24991819
3.  Artery Buckling: New Phenotypes, Models, and Applications 
Annals of biomedical engineering  2012;41(7):1399-1410.
Arteries are under significant mechanical loads from blood pressure, flow, tissue tethering, and body movement. It is critical that arteries remain patent and stable under these loads. This review summarizes the common forms of buckling that occur in blood vessels including cross-sectional collapse, longitudinal twist buckling, and bent buckling. The phenomena, model analyses, experimental measurements, effects on blood flow, and clinical relevance are discussed. It is concluded that mechanical buckling is an important issue for vasculature, in addition to wall stiffness and strength, and requires further studies to address the challenges. Studies of vessel buckling not only enrich vascular biomechanics but also have important clinical applications.
PMCID: PMC3618579  PMID: 23192265
instability; collapsible tube; bent buckling; twist buckling; kinking; folding; blood flow; arteries; veins; blood vessels
4.  β1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1 
Journal of cellular physiology  2013;228(7):1601-1609.
This study was carried out to dissect the mechanism by which β1 integrins promote resistance to radiation. For this purpose, we conditionally ablated β1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of β1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to β1, AIIB2, in a xenograft model. The role of β1 integrins and of a β1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that β1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, β1 integrins are shown here to suppress activation of JNK1 and, consequently apoptosis, in response to irradiation. Downregulation of JNK1 is necessary to preserve the effect of β1 on resistance to radiation in vitro and in vivo. Finally, given the established cross-talk between β1 integrins and type 1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate β1 integrin levels. We report that IGF-IR regulates the expression of β1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that β1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation.
PMCID: PMC3749928  PMID: 23359252
TRAMP mice; Prostate cancer; Apoptosis; Insulin-like growth factor receptor
5.  Epidermal Growth Factor-Like Domain-Containing Protein 7 (EGFL7) Enhances EGF Receptor−AKT Signaling, Epithelial−Mesenchymal Transition, and Metastasis of Gastric Cancer Cells 
PLoS ONE  2014;9(6):e99922.
Epidermal growth factor-like domain-containing protein 7 (EGFL7) is upregulated in human epithelial tumors and so is a potential biomarker for malignancy. Indeed, previous studies have shown that high EGFL7 expression promotes infiltration and metastasis of gastric carcinoma. The epithelial–mesenchymal transition (EMT) initiates the metastatic cascade and endows cancer cells with invasive and migratory capacity; however, it is not known if EGFL7 promotes metastasis by triggering EMT. We found that EGFL7 was overexpressed in multiple human gastric cancer (GC) cell lines and that overexpression promoted cell invasion and migration as revealed by scratch wound and transwell migration assays. Conversely, shRNA-mediated EGFL7 knockdown reduced invasion and migration. Furthermore, EGFL7-overexpressing cells grew into larger tumors and were more likely to metastasize to the liver compared to underexpressing CG cells following subcutaneous injection in mice. EGFL7 overexpression protected GC cell lines against anoikis, providing a plausible mechanism for this enhanced metastatic capacity. In excised human gastric tumors, expression of EGFL7 was positively correlated with expression levels of the mesenchymal marker vimentin and the EMT-associated transcription repressor Snail, and negatively correlated with expression of the epithelial cell marker E-cadherin. In GC cell lines, EGFL7 knockdown reversed morphological signs of EMT and decreased both vimentin and Snail expression. In addition, EGFL7 overexpression promoted EGF receptor (EGFR) and protein kinase B (AKT) phospho-activation, effects markedly suppressed by the EGFR tyrosine kinase inhibitor AG1478. Moreover, AG1478 also reduced the elevated invasive and migratory capacity of GC cell lines overexpressing EGFL7. Collectively, these results strongly suggest that EGFL7 promotes metastasis by activating EMT through an EGFR−AKT−Snail signaling pathway. Disruption of EGFL7−EGFR−AKT−Snail signaling may a promising therapeutic strategy for gastric cancer.
PMCID: PMC4063792  PMID: 24945379
6.  Detection of piroplasms infection in sheep, dogs and hedgehogs in Central China 
Piroplasms are kinds of tick-borne parasitic apicomplexan protozoa, which are detrimental to humans and animals in tropical and subtropical areas around the world. Up until now, there has been a limited amount of reliable information available about the prevalence of piroplasms infections in wild animals in China. Therefore, we have investigated the infections of Babesia and Theileria species in both domestic and wild animals in Xinyang city, Henan province, where tick-borne diseases have recently been reported. This study aims to analyze the distribution patterns of piroplasms infections in animals, and assess their potential threat to humans in Central China.
Blood samples were collected from sheep, dogs and hedgehogs in two regions, including Shihe District and Luoshan County, of Xinyang city, Henan province from August to December 2012. Babesia spp. and Theileria spp. were detected by polymerase chain reaction (PCR) and identified by sequencing and phylogenetic analysis. Moreover, the characteristics of detected piroplasms in different animal hosts were compared between the two study regions.
A total of 227 blood samples were collected from 73 sheep, two dogs and 152 hedgehogs. Babesia spp. was only detected in the two dogs. Theileria spp. was detected both in the sheep and the hedgehogs, and the total positive rate of Theileria spp. in the sheep and the hedgehogs was 57.53% and 13.82%, respectively. Sequencing and phylogenetic analysis revealed that the Theileria spp. detected in the sheep and the hedgehogs were very close to T. lunwenshuni cloned from a small ruminant and Theileria spp. isolated from a febrile hospitalized patient in China.
Babesia and Theileria infections were detected in both domestic and wild animals in Xinyang city, Henan province in Central China, thus warranting further studies in these regions.
PMCID: PMC4051148  PMID: 24917932
Babesia spp; Theileria spp; Dogs; Sheep; Hedgehogs; China
7.  Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2 
Cancer discovery  2013;3(12):1378-1393.
An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the non-canonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Further, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In melanoma patients treated with the BRAF inhibitor, Vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance.
PMCID: PMC3918498  PMID: 24104062
8.  Tick-borne pathogens and associated co-infections in ticks collected from domestic animals in central China 
Parasites & Vectors  2014;7:237.
Ticks can transmit a number of pathogens to humans and domestic animals. Tick borne diseases (TBDs), which may lead to organ failure and death have been recently reported in China. 98.75% of the total cases (>1000) in Henan provinces have been reported in Xinyang city. Therefore, the aims of this study were to investigate the fauna of ticks and detect the potential pathogens in ticks in Xinyang, the region of central China.
Ticks were collected from 10 villages of Xinyang from April to December 2012, from domestic animals including sheep, cattle and dogs. Then identification of ticks and detection of tick-borne pathogens, including Babesia spp., Theileria spp., Anaplasma spp., Ehrlichia spp., Rickettsia spp., tick-borne encephalitis virus (TBEV), Borrelia burgdorferi sensu lato, Leishmania infantum, were undertaken by using polymerase chain reaction assay (PCR) and sequence analysis. Moreover, the co-infection patterns of various pathogens were compared among locations where ticks were collected.
A total of 308 ticks were collected. Two species of Ixodidae were found, namely Haemaphysalis longicornis (96.75%) and Rhipicephalus microplus (3.25%). Five genera of pathogens, namely Theileria spp. (3.25%), Anaplasma spp. (2.92%), Babesia spp. (1.95%), Ehrlichia spp. (2.92%) and Rickettsia spp. (0.65%), were detected in 7 villages. Co-infections by two pathogens were diagnosed in 11.11% of all infected ticks.
Both human and animal pathogens were abundant in ticks in the study areas. Humans and animals in these regions were at a high risk of exposure to piroplasmosis, since piroplasm had the highest rates of infection and co-infection in positive ticks.
PMCID: PMC4045914  PMID: 24886497
Ticks; Domestic animals; Tick-borne pathogens; Co-infections; China
9.  Trop-2 promotes prostate cancer metastasis by modulating β1 integrin functions 
Cancer research  2013;73(10):3155-3167.
The molecular mechanisms underlying metastatic dissemination are still not completely understood. We have recently shown that β1 integrin-dependent cell adhesion to fibronectin (FN) and signaling are affected by a transmembrane molecule, Trop-2, which is frequently upregulated in human carcinomas. Here we report that Trop-2 promotes metastatic dissemination of prostate cancer cells in vivo and is abundantly expressed in metastasis from human prostate cancer. We also show here that Trop-2 promotes prostate cancer cell migration on FN, a phenomenon dependent on β1 integrins. Mechanistically, we demonstrate that Trop-2 and the α5β1 integrin associate through their extracellular domains, causing relocalization of α5β1 and the β1-associated molecule talin from focal adhesions to the leading edges. Trop-2 effect is specific since this molecule does not modulate migration on vitronectin (VN), does not associate with the major VN receptor, αvβ3 integrin, and does not affect localization of αvβ3 integrin as well as vinculin in focal adhesions. We show that Trop-2 enhances directional prostate cancer cell migration, through modulation of Rac1 GTPase activity. Finally, we demonstrate that Trop-2 induces activation of PAK4, a kinase that has been reported to mediate cancer cell migration. In conclusion, we provide the first evidence that β1 integrin-dependent migratory and metastatic competence of prostate cancer cells is enhanced by Trop-2.
PMCID: PMC3655712  PMID: 23536555
10.  Enhancement of radiotherapy efficacy by miR-200c-loaded gelatinase-stimuli PEG-Pep-PCL nanoparticles in gastric cancer cells 
Radiotherapy is the main locoregional control modality for many types of unresectable tumors, including gastric cancer. However, many patients fail radiotherapy due to intrinsic radioresistance of cancer cells, which has been found to be strongly associated with cancer stem cell (CSC)-like properties. In this study, we developed a nanoparticle formulation to deliver miR-200c, which is reported to inhibit CSC-like properties, and then evaluated its potential activity as a radiosensitizer. miR-200c nanoparticles significantly augmented radiosensitivity in three gastric cancer cell lines (sensitization enhancement ratio 1.13–1.25), but only slightly in GES-1 cells (1.06). In addition to radioenhancement, miR-200c nanoparticles reduced the expression of CD44, a putative CSC marker, and the percentage of CD44+ BGC823 cells. Meanwhile, other CSC-like properties, including invasiveness and resistance to apoptosis, could be suppressed by miR-200c nanoparticles. CSC-associated radioresistance mechanisms, involving reactive oxygen species levels and DNA repair capacity, were also attenuated. We have demonstrated that miR-200c nanoparticles are an effective radiosensitizer in gastric cancer cells and induce little radiosensitization in normal cells, which suggests that they are as a promising candidate for further preclinical and clinical evaluation.
PMCID: PMC4026568  PMID: 24872697
radiosensitizer; miR-200c; gelatinase-stimuli nanoparticles; cancer stem cell-like properties; gastric cancer
11.  Perchlorate Exposure and Thyroid Function in Ammonium Perchlorate Workers in Yicheng, China 
The impact of low level dust on the thyroid function of workers chronically exposed to ammonium perchlorate (AP) is uncertain and controversial. The aim of this study was to examine whether workers in China with long-term (>3 years) occupational exposure to low levels of AP dust had affected thyroid homeostasis. Mean occupational exposures to AP dust ranged from 0.43 to 1.17 mg/m3. Geometric means of post-shift urinary perchlorate levels were 20.5 µg/L for those exposed and 12.8 µg/L for the controls. No significant differences were found for thyroid function parameters of FT3, FT4, or log TSH or for TPO prevalence or thyroglobulin levels. Additionally, no differences in findings were observed for complete blood count (CBC), serum biochemical profile, or pulmonary function test. Median urinary iodine levels of 172 and 184 µg/L showed that the workers had sufficient iodine intake. This study found no effect on thyroid function from long term, low-level documented exposure to ammonium perchlorate. It is the first study to report both thyroid status parameters and urinary perchlorate, a biomarker of internal perchlorate exposure, in occupationally exposed workers in China.
PMCID: PMC4053892  PMID: 24810578
ammonium perchlorate; thyroid; occupational exposure; biomarker
12.  Effects of Immunosuppression on Circulating Adeno-Associated Virus Capsid-Specific T cells in Humans 
Human Gene Therapy  2013;24(4):431-442.
In humans adeno-associated virus (AAV)-mediated gene transfer is followed by expansion of AAV capsid-specific T cells, evidence of cell damage, and loss of transgene product expression, implicating immunological rejection of vector-transduced cells, which may be prevented by immunosuppressive drugs. We undertook this study to assess the effect of immunosuppression (IS) used for organ transplantation on immune responses to AAV capsid antigens. Recipients of liver or kidney transplants were tested before and 4 weeks after induction of IS in comparison with matched samples from healthy human adults and an additional cohort with comorbid conditions similar to those of the transplant patients. Our data show that transplant patients and comorbid control subjects have markedly higher frequencies of circulating AAV capsid-specific T cells compared with healthy adults. On average, IS resulted in a reduction of AAV-specific CD4+ T cells, whereas numbers of circulating CD8+ effector and central memory T cells tended to increase. Independent of the type of transplant or the IS regimens, the trend of AAV capsid-specific T cell responses after drug treatment varied; in some patients responses were unaffected whereas others showed decreases or even pronounced increases, casting doubt on the usefulness of prophylactic IS for AAV vector recipients.
Parzych and colleagues assess the effect of immunosuppression (IS) when used for organ transplantation on immune responses to adeno-associated virus (AAV) capsid antigens. Transplant patients and comorbid control subjects had markedly higher frequencies of circulating AAV capsid–specific T cells compared with healthy adults. IS treatment resulted in a reduction of AAV-specific CD4+ T cells, whereas numbers of circulating CD8+ effector and central memory T cells tended to increase.
PMCID: PMC3631016  PMID: 23461589
13.  The Marine Fungal Metabolite, Dicitrinone B, Induces A375 Cell Apoptosis through the ROS-Related Caspase Pathway 
Marine Drugs  2014;12(4):1939-1958.
Dicitrinone B, a rare carbon-bridged citrinin dimer, was isolated from the marine-derived fungus, Penicillium citrinum. It was reported to have antitumor effects on tumor cells previously; however, the details of the mechanism remain unclear. In this study, we found that dicitrinone B inhibited the proliferation of multiple tumor types. Among them, the human malignant melanoma cell, A375, was confirmed to be the most sensitive. Morphologic evaluation, cell cycle arrest and apoptosis rate analysis results showed that dicitrinone B significantly induced A375 cell apoptosis. Subsequent observation of reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) reduction revealed that the apoptosis induced by dicitrinone B may be triggered by over-producing ROS. Further studies indicated that the apoptosis was associated with both intrinsic and extrinsic apoptosis pathways under the regulation of Bcl-2 family proteins. Caspase-9, caspase-8 and caspase-3 were activated during the process, leading to PARP cleavage. The pan-caspase inhibitor, Z-VAD-FMK, could reverse dicitrinone B-induced apoptosis, suggesting that it is a caspase-dependent pathway. Our data for the first time showed that dicitrinone B inhibits the proliferation of tumor cells by inducing cell apoptosis. Moreover, compared with the first-line chemotherapy drug, 5-fluorouracil (5-Fu), dicitrinone B showed much more potent anticancer efficacy, suggesting that it might serve as a potential antitumor agent.
PMCID: PMC4012433  PMID: 24699111
dicitrinone B; marine-derived fungus; human malignant melanoma cell A375; anticancer activity; apoptosis
14.  Hypertriglyceridemic Waist Phenotype and Chronic Kidney Disease in a Chinese Population Aged 40 Years and Older 
PLoS ONE  2014;9(3):e92322.
To examine the relationship between the HW phenotype and risk for CKD in a community population aged 40 years and older.
A cross-sectional study was conducted in Zhuhai from June to October 2012. The participants were divided into three groups: Group 1, Waist circumference >90 cm in men or >85 cm in women and triglycerides ≥2 mmol/l; Group 3, Waist circumference ≤90 cm in men or ≤85 cm in women and triglycerides <2 mmol/l; Group 2, The remaining participants. The prevalence of the three subgroups and CKD were determined. The association between HW phenotype and CKD was then analyzed using SPSS (version 13.0).
After adjusting for age and sex, Group 1 was associated with CKD (OR 3.08, 95% CI 2.01, 4.73, P<0.001), when compared with Group 3. Further adjustment for factors which were potential confounders and unlikely to be in the causal pathway between the HW phenotype and CKD, Group 1 was still significantly associated with CKD. The OR for CKD was 2.65 (95% CI 1.65, 4.26, P<0.001). When adjusted for diabetes and hypertension, the association of Group 1 and CKD was still significant (OR 2.09, 95% CI 1.26, 3.45, P = 0.004). Group 2 was associated with CKD (OR 1.81, 95% CI 1.29, 2.53, P = 0.001), when compared with Group 3. Further adjustment for factors which were potential confounders, Group 2 was still significantly associated with CKD. The OR for CKD was 1.75 (95% CI 1.22, 2.51, P = 0.002). When adjusted for diabetes and hypertension, the association between Group 2 and CKD still existed. The OR for CKD was 1.48 (95% CI 1.01, 2.16, P = 0.046).
Our results showed that HW phenotype was associated with CKD in the population aged 40 years and older.
PMCID: PMC3963886  PMID: 24663403
15.  Association of Uric Acid with Metabolic Syndrome in Men, Premenopausal Women and Postmenopausal Women 
Objective: To explore the relationship between serum uric acid (SUA) and metabolic syndrome (MS) in men, premenopausal women and postmenopausal women. Methods: A cross-sectional study was conducted in 1,834 community-based Southern Chinese participants from June to October 2012. Sex-specific SUA quartiles were used as follows: <345, 345–<400, 400–<468, ≥468 µmol/L in males; and <248, 248–<288, 288–<328, ≥328 µmol/L in females. MS was defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) Criteria. The association between SUA and MS was then analyzed using the STATA software. Results: The odds ratio (OR) for having MS in the highest versus lowest quartiles of SUA levels was 2.46 (95% confidence interval [CI], 1.39 to 4.34, p = 0.002) in men after adjusting for age, sex, history of coronary heart disease, history of stroke, current current smoking, current alcohol use, physical inactivity, education status, and BMI. Further adjusting for above confounders, hypertension and diabetes, the OR for having MS in the highest versus lowest quartiles of SUA was 3.06 (95% CI, 1.64 to 5.70, p < 0.001). The OR for having MS in the highest versus lowest quartiles of SUA was 3.45 (95% CI, 1.38 to 8.64, p = 0.008) and 1.98 (95% CI, 1.16 to 3.37, p = 0.08) in premenopausal women and postmenopausal women after adjusting for age, sex, history of coronary heart disease, history of stroke, current smoking, current alcohol use, physical inactivity, education status, and BMI. Further adjusting for above confounders, hypertension and diabetes, the OR for having MS in the highest versus lowest quartiles of SUA was 3.42 (95% CI, 1.15 to 10.18, p = 0.03) and 1.87 (95% CI, 1.05 to 3.33, p = 0.03) in premenopausal women and postmenopausal women. Conclusions: Higher SUA levels are positively associated with the presence of MS in males and females. Higher SUA levels had a higher risk of having MS in premenopausal women than in postmenopausal women.
PMCID: PMC3987011  PMID: 24619122
uric acid; metabolic syndrome; premenopausal women and postmenopausal women
16.  Smooth Muscle Cell Contraction Increases the Critical Buckling Pressure of Arteries 
Journal of biomechanics  2012;46(4):841-844.
Recent in vitro experiments demonstrated that arteries under increased internal pressure or decreased axial stretch may buckle into the tortuous pattern that is commonly observed in aging or diseased arteries in vivo. It suggests that buckling is a possible mechanism for the development of artery tortuosity. Vascular tone has significant effects on arterial mechanical properties but its effect on artery buckling is unknown. The objective of this study was to determine the effects of smooth muscle cell contraction on the critical buckling pressure of arteries. Porcine common carotid arteries were perfused in an ex vivo organ culture system overnight under physiological flow and pressure. The perfusion pressure was adjusted to determine the critical buckling pressure of these arteries at in vivo and reduced axial stretch ratios (1.5 and 1.3) at baseline and after smooth muscle contraction and relaxation stimulated by norepinephrine and sodium nitroprusside, respectively. Our results demonstrated that the critical buckling pressure was significantly higher when the smooth muscle was contracted compared with relaxed condition (97.3mmHg versus 72.9mmHg at axial stretch ratio of 1.3 and 93.7mmHg vs 58.6mmHg at 1.5, p<0.05). These results indicate that arterial smooth muscle cell contraction increased artery stability.
PMCID: PMC3568186  PMID: 23261241
critical buckling pressure; mechanical instability; smooth muscle cell contraction; vascular tone; stability
17.  The Autographa californica Multiple Nucleopolyhedrovirus ORF78 Is Essential for Budded Virus Production and General Occlusion Body Formation 
Journal of Virology  2013;87(15):8441-8450.
ORF78 (ac78) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is a baculovirus core gene of unknown function. To determine the role of ac78 in the baculovirus life cycle, an AcMNPV mutant with ac78 deleted, Ac78KO, was constructed. Quantitative PCR analysis revealed that ac78 is a late gene in the viral life cycle. After transfection into Spodoptera frugiperda cells, Ac78KO produced a single-cell infection phenotype, indicating that no infectious budded viruses (BVs) were produced. The defect in BV production was also confirmed by both viral titration and Western blotting. However, viral DNA replication was unaffected, and occlusion bodies were formed. An analysis of BVs and occlusion-derived viruses (ODVs) revealed that AC78 is associated with both forms of the virions and is an envelope structural protein. Electron microscopy revealed that AC78 also plays an important role in the embedding of ODV into the occlusion body. The results of this study demonstrate that AC78 is a late virion-associated protein and is essential for the viral life cycle.
PMCID: PMC3719795  PMID: 23698311
18.  Immune history shapes specificity of pandemic H1N1 influenza antibody responses 
The Journal of Experimental Medicine  2013;210(8):1493-1500.
The specificity of H1N1 antibody responses can be shifted to epitopes near the HA receptor–binding domain after sequential infections with viral strains that share homology in this region.
Human antibody responses against the 2009 pandemic H1N1 (pH1N1) virus are predominantly directed against conserved epitopes in the stalk and receptor-binding domain of the hemagglutinin (HA) protein. This is in stark contrast to pH1N1 antibody responses generated in ferrets, which are focused on the variable Sa antigenic site of HA. Here, we show that most humans born between 1983 and 1996 elicited pH1N1 antibody responses that are directed against an epitope near the HA receptor–binding domain. Importantly, most individuals born before 1983 or after 1996 did not elicit pH1N1 antibodies to this HA epitope. The HAs of most seasonal H1N1 (sH1N1) viruses that circulated between 1983 and 1996 possess a critical K133 amino acid in this HA epitope, whereas this amino acid is either mutated or deleted in most sH1N1 viruses circulating before 1983 or after 1996. We sequentially infected ferrets with a 1991 sH1N1 virus and then a pH1N1 virus. Sera isolated from these animals were directed against the HA epitope involving amino acid K133. These data suggest that the specificity of pH1N1 antibody responses can be shifted to epitopes near the HA receptor–binding domain after sequential infections with sH1N1 and pH1N1 viruses that share homology in this region.
PMCID: PMC3727314  PMID: 23857983
19.  Effect of bowel obstruction on stage IV colorectal cancer 
Molecular and Clinical Oncology  2014;2(2):308-312.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with a high mortality rate, particularly among patients with advanced-stage disease complicated by bowel obstruction. The present study aimed to investigate the value of different surgical procedures and potential predictors of survival for patients with stage IV CRC, with or without bowel obstruction. Between August, 1994 and December, 2005, a total of 2,950 CRC patients were diagnosed and treated at our hospital. Among these, 381 patients had stage IV disease and were divided into two groups according to the presence (n=295) or absence (n=86) of bowel obstruction. The clinical data of all the patients with stage IV CRC were retrospectively analyzed and all the patients were followed up. Our results demonstrated statistically significant differences in gender, radical resection, histological type, ascites, tumor location, peritoneal and liver metastases between the obstruction and non-obstruction groups. We also observed that hepatic metastases and radical resection were factors associated with prognosis according to the univariate and multivariate analyses. Furthermore, the mean/median survival time was 49.4/21.6 and 37.2/17.1 months in the non-obstruction and obstruction groups, respectively. In conclusion, obstruction was not found to be an independent indicator of survival for patients with stage IV CRC, with patients in the obstruction group exhibiting a worse overall survival compared to those in the non-obstruction group, whereas active radical surgery significantly improved the prognosis of patients with stage IV CRC.
PMCID: PMC3917774  PMID: 24649353
colorectal cancer; stage IV; radical resection; obstruction
20.  Mechanical Buckling of Arterioles in Collateral Development 
Collateral arterioles enlarge in both diameter and length, and develop corkscrew-like tortuous patterns during remodeling. Recent studies showed that artery buckling could lead to tortuosity. The objective of this study was to determine arteriole critical buckling pressure and buckling pattern during arteriole remodeling. Arterioles were modeled as elastic cylindrical vessels with an elastic matrix support and underwent axial and radial growth. Our results demonstrated that arteriole critical buckling pressure decreased with increasing axial growth ratio and radius growth ratio, but increased with increasing wall thickness. Arteriole buckling mode number increased (wave length decreased) with increasing axial growth ratio, but decreased with increasing radius growth ratio and wall thickness. Our study suggests that axial growth in arterioles makes them prone to buckling and that buckling leads to tortuous collaterals. These results shed light on the mechanism of collateral arteriole tortuosity.
PMCID: PMC3498525  PMID: 23034307
arteriole buckling; tortuosity; critical pressure; remodeling; axial growth ratio; radius growth ratio; artery; modeling
21.  Comparison of one-level microendoscopy laminoforaminotomy and cervical arthroplasty in cervical spondylotic radiculopathy: a minimum 2-year follow-up study 
This study aims to compare the perioperative parameters and clinical results between microendoscopy laminoforaminotomy (MELF) and cervical arthroplasty (CA) in the treatment of one-level cervical spondylotic radiculopathy in a retrospective study.
From 2003 to 2007, a total of 97 patients with one-level cervical spondylotic radiculopathy were treated. Forty-five patients underwent CA. Fifty-two patients underwent MELF. Patient demographics and operative data were collected with a minimum 2-year follow-up. Perioperative parameters were compared. Clinical assessment in terms of neck disability index (NDI), short form (SF)-36, and visual analogue scale (VAS) of arm pain and neck pain was performed prior to surgery and at 1.5, 3, 6, 12, and 24 months after surgery.
Fluoroscopy time (CA, 60.3 s; MELF, 12.1 s; P < 0.01) and surgical time (CA, 95.1 min; MELF, 24.0 min; P < 0.01) were significantly longer in the CA cases. Shorter hospitalized days (CA, 1.1 days; MELF, 0.13 days; P < 0.01) and less estimated blood loss (EBL; CA, 75.8 ml; MELF, 31.9 ml; P < 0.01) were observed in the MELF group. Both CA and MELF groups showed significant improvement in NDI, VAS of neck pain and arm pain, and SF-36 (P < 0.05 for each) at 1.5, 3, 6, 12, and 24 months after surgery, but there was no significant difference between them (P > 0.05).
As alternatives of anterior cervical decompression and fusion (ACDF), both CA and MELF can produce satisfactory clinical outcomes. MELF has the additional benefits of less blood loss, less surgical time, less X-ray time, and shorter hospital stay.
PMCID: PMC3868414  PMID: 24341633
Microendoscopy; Laminoforaminotomy; Arthroplasty; Cervical spondylotic radiculopathy
22.  Prevention of infection in immunosuppressive patients with autoimmune nephrosis by using an immunostimulating bacterial lysate Broncho-vaxom 
Human Vaccines & Immunotherapeutics  2012;8(12):1802-1807.
The utilization of immunosuppressive agents presents patients with autoimmune nephrosis at a high risk of infection. The present trial was to investigate the efficacy and safety of Broncho-Vaxom on preventing infection in immunosuppressive patients with autoimmune nephrosis.
Methods: 40 patients with autoimmune nephrosis were randomly divided into two groups. The control group (20 cases) routinely received corticosteroid and (or) immunosuppressive therapy, while the treatment group (20 cases) received a capsule containing 7 mg Broncho-Vaxom daily for the first 10 d of each month for 3 consecutive months on the basis of conventional corticosteroid and (or) immunosuppressive therapy. The condition of infection and blood lymphocyte were assessed.
Results: 4 patients in the treatment group and 5 patients in the control group were lost during the follow-up period. 25% of patients in the treatment group and 40% of patients in the control group suffered infection. There was no difference in the incidence of infection between the two groups (p > 0.05), while Broncho-Vaxom treated patients suffered a shorter infection period and of which fewer patients need to receive antibiotics therapy (p < 0.05). After the treatment with Broncho-Vaxom, the total number of blood T lymphocyte, proportion of CD4+ T lymphocyte, CD4+/CD8+ reduced less and the serum IgG rose more obviously (p < 0.05), but the blood lymphocyte, B lymphocyte, CD8+ T lymphocyte, IgA and IgM have no differences between the two groups (p > 0.05).
Conclusion: Broncho-Vaxom might be a good choice for preventing the respiratory infection in nephrosis, especially in the patients under the therapy of immunosuppressive agents.
PMCID: PMC3656069  PMID: 22922768
Glomerulonephritis; Immunostimulating Bacterial Lysate; Nephrotic Syndrome; Respiratory infection; T lymphocyte subsets; glomerulonephritis
23.  Systematic Comparison of Fractionation Methods for In-depth Analysis of Plasma Proteomes 
Journal of proteome research  2012;11(6):3090-3100.
Discovery and validation of plasma biomarkers are quite challenging due to the high complexity and wide dynamic range of the plasma proteome. Current plasma protein profiling strategies usually use major protein immunodepletion and nanoLC-MS/MS as the first and final analytical steps, respectively, but additional fractionation is needed to detect and quantify low-abundant disease biomarkers. In this study, the performance of 1-D SDS-PAGE, peptide isoelectrofocusing, and peptide high pH reverse-phase chromatography for fractionation of immunodepleted human plasma were systematically compared by evaluating protein coverage, peptide resolution, and capacity to detect known low-abundant proteins. Trade-offs between increasing the number of fractions to improve proteome coverage and resulting decreases in throughput also were assessed. High pH reverse-phase HPLC exhibited the highest peptide resolution and yielded the best depth of analysis with detection of the largest number of known low-abundant proteins for a given level of fractionation. Another advantage of using high pH reverse-phase fractionation rather than 1-D SDS gels is that all fractionation steps except for abundant protein depletion occur at the peptide level, making this strategy more compatible with quantitative biomarker validation methods such as stable isotope dilution multiple reaction monitoring.
PMCID: PMC3430803  PMID: 22536952
plasma proteome; proteome fractionation; protein profiling; biomarkers; human plasma; biomarker discovery; biomarker validation
24.  A Novel Measure of Dietary Change in a Prostate Cancer Dietary Program Incorporating Mindfulness Training 
Diet may represent a modifiable prostate cancer (CaP) risk factor, but a vegetable-based prostate-healthy diet is a major change for most men. We used a ratio of animal:vegetable proteins (A:V ratio) to evaluate whether a comprehensive dietary change was self-sustaining following completion of 11 weekly dietary and cooking classes that integrated mindfulness training (MT). Thirty-six men with recurring CaP were randomized to the intervention or wait-list control. Assessments were at baseline, three months and six months. Of the 17 men randomized to the intervention, 14 completed the requirements. Nineteen were randomized to control and 17 completed requirements. Compared to controls, a significant post-intervention (3 months) decrease in A:V ratio in the intervention group (p=.01) was self-maintained 3 months post-intervention (p=0.049). At each assessment, the A:V ratio was correlated with lycopene, fiber, saturated fat, and dietary cholesterol; four dietary components linked to clinically relevant outcomes in CaP. Change in A:V ratio was also significantly correlated with changes in fiber, saturated fat and dietary cholesterol intake. Participants reported regular MT practice and there was a significant correlation between MT practice and changes in both initiation and maintenance of the change in the A:V ratio. These pilot results provide encouraging evidence for the feasibility of a dietary program that includes MT in supporting dietary change for men with recurrent CaP and invite further study to explore the possible role of MT as a means of supporting both initiation of dietary changes and maintenance of those changes over time.
PMCID: PMC3483420  PMID: 22853988
diet; maintenance; prostate cancer; clinical trial; mindfulness
25.  CD20-Targeted T Cells after Stem Cell Transplantation for High Risk and Refractory Non-Hodgkin’s Lymphoma 
A phase I trial of infusing anti-CD3 × anti-CD20 bispecific antibody (CD20Bi) armed activated T cells (aATC) was conducted in high-risk/refractory non-Hodgkin’s lymphoma patients to determine whether aATC infusions are safe, affect immune recovery, and induce an antilymphoma effect. Ex vivo expanded ATC from 12 patients were armed with anti-CD20 bispecific antibody, cryopreserved, and infused after autologous stem cell transplantation (SCT). Patients underwent SCT after high-dose chemotherapy, and aATC infusions were started on day +4. The patients received 1 infusion of aATC per week for 4 weeks after SCT with doses of 5,10,15, and 20 × 109. aATC infusions were safe and did not impair engraftment. The major side effects were chills, fever, hypotension, and fatigue. The mean number of IFN-γ Enzyme-linked Immunosorbent Spots (ElSpots) directed at CD20 positive lymphoma cells (DAUDI, P = .0098) and natural killer cell targets (K562, P < .0051) and the mean specific cytotoxicity directed at DAUDI (P = .037) and K562 (P = .002) from pre-SCT to post-SCT were significantly higher. The increase in IFN-γ EliSpots from pre-SCT to post-SCT in patients who received armed ATC after SCT were significantly higher than those in patients who received SCT alone (P = .02). Serum IL-7, IL-15, Macrophage inflammatory protein (MIP)-1 beta, IP-10, MIP-1α, and Monokine induced by gamma interferone increased within hours after infusion. Polyclonal and specific antibodies were near normal 3 months after SCT. aATC infusions were safe and increased innate and specific antilymphoma cell immunity without impairing antibody recovery after SCT.
PMCID: PMC3794673  PMID: 23529012
Non-Hodgkin lymphoma; Activated T cells; Bispecific antibody; Autologous stem cell; transplantation

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