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1.  Common Variants Related to Serum Uric Acid Concentrations Are Associated with Glucose Metabolism and Insulin Secretion in a Chinese Population 
PLoS ONE  2015;10(1):e0116714.
Background
Elevated serum uric acid concentration is an independent risk factor and predictor of type 2 diabetes (T2D). Whether the uric acid-associated genes have an impact on T2D remains unclear. We aimed to investigate the effects of the uric acid-associated genes on the risk of T2D as well as glucose metabolism and insulin secretion.
Method
We recruited 2,199 normal glucose tolerance subjects from the Shanghai Diabetes Study I and II and 2,999 T2D patients from the inpatient database of Shanghai Diabetes Institute. Fifteen single nucleotide polymorphisms (SNPs) mapped in or near 11 loci (PDZK1, GCKR, LRP2, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC17A3, SLC22A11, SLC22A12 and SF1) were genotyped and serum biochemical parameters related to uric acid and T2D were determined.
Results
SF1 rs606458 showed strong association to T2D in both males and females (p = 0.034 and 0.0008). In the males, LRRC16A was associated with 2-h insulin and insulin secretion (p = 0.009 and 0.009). SLC22A11 was correlated with HOMA-B and insulin secretion (p = 0.048 and 0.029). SLC2A9 rs3775948 was associated with 2-h glucose (p = 0.043). In the females, LRP2 rs2544390 and rs1333049 showed correlations with fasting insulin, HOMA-IR and insulin secretion (p = 0.028, 0.033 and 0.052 and p = 0.034, 0.047 and 0.038, respectively). SLC2A9 rs11722228 was correlated with 2-h glucose, 2-h insulin and insulin secretion (p = 0.024, 0.049 and 0.049, respectively).
Conclusions
Our results indicated that the uric acid-associated genes have an impact on the risk of T2D, glucose metabolism and insulin secretion in a Chinese population.
doi:10.1371/journal.pone.0116714
PMCID: PMC4305305  PMID: 25617895
2.  Intrinsic Topological Insulator Bi1.5Sb0.5Te3-xSex Thin Crystals 
Scientific Reports  2015;5:7931.
The quaternary topological insulator (Bi,Sb)2(Te,Se)3 has demonstrated topological surface states with an insulating bulk. Scientists have identified an optimized composition of Bi1.5Sb0.5Te1.7Se1.3 with the highest resistivity reported. But the physics that drive to this composition remains unclear. Here we report the crystal structure and the magneto-transport properties of Bi1.5Sb0.5Te3-xSex (BSTS) series. A correlation between the structure and the physical properties has been revealed. We found out that within the rhombohedral structure, the composition with most Te substituting Se has the highest resistivity. On the other hand, segregation of other composition phases will introduce much higher bulk concentration.
doi:10.1038/srep07931
PMCID: PMC4300459  PMID: 25604579
3.  Elevated CNS inflammation in patients with preclinical Alzheimer's disease 
Alzheimer's disease (AD) is a progressive, neurodegenerative disease that may involve inflammatory responses in the central nervous system (CNS). Our objective was to determine whether patients with amnestic mild cognitive impairment (aMCI), a preclinical stage of AD, have inflammatory characteristics similar to patients with multiple sclerosis (MS), a known CNS inflammatory disease. The frequency of lymphocytes and levels of pro-inflammatory cytokines in the cerebrospinal fluid of aMCI patients was comparable to MS patients or patients at high risk to develop MS. Thus, brain inflammation occurs early at the preclinical stage of AD and may have an important role in pathology.
doi:10.1038/jcbfm.2013.183
PMCID: PMC3887357  PMID: 24149932
Alzheimer's disease; dementia; inflammation; leukocytes; T cells
4.  Reduced pulmonary function and increased pro-inflammatory cytokines in nanoscale carbon black-exposed workers 
Background
Although major concerns exist regarding the potential consequences of human exposures to nanoscale carbon black (CB) particles, limited human toxicological data is currently available. The purpose of this study was to evaluate if nanoscale CB particles could be responsible, at least partially, for the altered lung function and inflammation observed in CB workers exposed to nanoscale CB particles.
Methods
Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and Brunauer-Emmett-Teller were used to characterize CB. Eighty-one CB-exposed male workers and 104 non-exposed male workers were recruited. The pulmonary function test was performed and pro-inflammatory cytokines were evaluated. To further assess the deposition and pulmonary damage induced by CB nanoparticles, male BALB/c mice were exposed to CB for 6 hours per day for 7 or 14 days. The deposition of CB and the pathological changes of the lung tissue in mice were evaluated by paraffin sections and TEM. The cytokines levels in serum and lung tissue of mice were evaluated by ELISA and immunohistochemical staining (IHC).
Results
SEM and TEM images showed that the CB particles were 30 to 50 nm in size. In the CB workplace, the concentration of CB was 14.90 mg/m3. Among these CB particles, 50.77% were less than 0.523 micrometer, and 99.55% were less than 2.5 micrometer in aerodynamic diameter. The reduction of lung function parameters including FEV1%, FEV/FVC, MMF%, and PEF% in CB workers was observed, and the IL-1β, IL-6, IL-8, MIP-1beta, and TNF- alpha had 2.86-, 6.85-, 1.49-, 3.35-, and 4.87-folds increase in serum of CB workers, respectively. In mice exposed to the aerosol CB, particles were deposited in the lung. The alveolar wall thickened and a large amount of inflammatory cells were observed in lung tissues after CB exposure. IL-6 and IL-8 levels were increased in both serum and lung homogenate.
Conclusions
The data strongly suggests that nanoscale CB particles could be responsible for the lung function reduction and pro-inflammatory cytokines secretion in CB workers. These results, therefore, provide the first evidence of a link between human exposure to CB and long-term pulmonary effects.
Electronic supplementary material
The online version of this article (doi:10.1186/s12989-014-0073-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12989-014-0073-1
PMCID: PMC4318129  PMID: 25497989
Carbon black; Nanoparticles; Occupational exposure; Pro-inflammatory cytokines; Pulmonary function
5.  Clinical in vestigation of misdiagnosis of invasive pulmonary aspergillosis in 26 immunocompetent patients 
The clinical features of invasive pulmonary aspergillosis (IPA) in immunocompromised patients is well studied in the past decades. While the manifestations of IPA in immunocompetent patients remain unclear.The purpose of this study was to determine the clinical and radiological manifestations of invasive pulmonary aspergillosis (IPA) in patients without immunosuppression, as well as the reasons for the misdiagnosis of IPA. We retrieved and retrospectively reviewed the records of 102 patients from whom surgical lung specimens of chronic inflammatory granulomas were harvested. 26 patients were eventually diagnosed with pulmonary aspergillosis on Grocott methenamine silver staining. We investigated these patients in detail. We found that the rate of misdiagnosis before the lung surgery was as high as 73%. The most common symptom was hemoptysis, and the main feature in radiology was nodule or mass lesion. Air crescent sign or Halo sign were not common in our study. The atypical radiological manifestations and non-specific clinical findings make the diagnosis of IPA difficult and lead to a high misdiagnosis rate.
PMCID: PMC4276182  PMID: 25550924
Invasive pulmonary aspergillosis; immunocompetent; radiological features; clinical characteristics
6.  An Interaction between a FNDC5 Variant and Obesity Modulates Glucose Metabolism in a Chinese Han Population 
PLoS ONE  2014;9(11):e109957.
Background
To investigate the impact of common variants of FNDC5 on type 2 diabetes and clinical traits related to glucose metabolism in a large Chinese population sample.
Methods
Three tagging single nucleotide polymorphisms within the region of the FNDC5 gene were selected and genotyped in 6822 participants. Detailed clinical investigations and biochemistry measurements were carried out in all of the participants. Subjects without diabetes were classified into normal weight and overweight/obese subgroups according to body mass index (BMI).
Results
None of the SNPs were associated with either the risk of type 2 diabetes in all of the participants or with any of the clinical quantitative traits in the controls with normal glucose regulation. Subgroup analysis showed that in controls with normal weight (BMI <25 kg/m2), the rs16835198 major allele G was significantly associated with fasting insulin levels, and that each additional copy of the allele resulted in a 0.0178 mU/L increment of the values (p = 0.046). Moreover, after adjusting for confounding variables, there were trends towards correlation of rs16835198 with HOMA-insulin resistance (HOMA-IR) (p = 0.057) and low-density lipoprotein cholesterol (LDL-C) levels (p = 0.083). In overweight/obese subjects (BMI ≥25 Kg/m2), we noted rs16835198 showed trends towards association with fasting insulin (p = 0.057) and HOMA-IR levels (p = 0.091), both of which declined with additional copies of the major allele G. Moreover, rs16835198 was significantly associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 0.013), and HOMA-β cell function (p = 0.028) in the overweight/obese subjects. Finally, we observed a significant interaction between BMI-rs16835198 and fasting insulin levels in the control group (p = 0.003).
Conclusions
Our data indicate that the effect of the common FNDC5 SNP rs16835198 on fasting insulin was significantly modified by BMI in the Chinese Han population.
doi:10.1371/journal.pone.0109957
PMCID: PMC4219676  PMID: 25369206
7.  Life-long aerobic exercise preserved baseline cerebral blood flow but reduced vascular reactivity to CO2 
Journal of magnetic resonance imaging : JMRI  2013;38(5):10.1002/jmri.24090.
Purpose
To examine the potential benefits of life-long aerobic exercise on brain health, in particular cerebrovascular function.
Materials and Methods
Ten Masters Athletes (MA) (7 males/3 females; 74.5±5.8 yrs.) and ten sedentary elderly individuals (SE) (8 males/2 females; 75.4±5.6 yrs.) were recruited, and baseline Cerebral Blood Flow (CBF) and Cerebral Vascular Reactivity (CVR) to CO2 were measured on a 3 Tesla MRI scanner. Nine sedentary young subjects were also recruited to serve as a control group to verify the age-effect.
Results
When compared to the SE group, MA showed higher CBF in posterior cingulate cortex/precuneus, which are key regions of the default-mode-network and are known to be highly sensitive to age and dementia. CVR in the MA brain were paradoxically lower than that in SE. This effect was present throughout the brain. Within the MA group, individuals with higher Vo2max had an even lower CVR, suggesting a dose-response relationship.
Conclusion
Life-long aerobic exercise preserved blood supply in the brain’s default-mode-network against age-related degradation. On the other hand, its impact on cerebral vascular system seems to be characterized by a dampening of CO2 reactivity, possibly because of desensitization effects due to a higher lifetime exposure.
doi:10.1002/jmri.24090
PMCID: PMC3695025  PMID: 23526811
masters athletes; cerebral vascular reactivity; cerebral blood flow; BOLD MRI; Arterial-Spin-Labeling; CO2
8.  Masters Athletes Exhibit Larger Regional Brain Volume and Better Cognitive Performance than Sedentary Older Adults 
Journal of magnetic resonance imaging : JMRI  2013;38(5):10.1002/jmri.24085.
Purpose
To investigate differences in the age-related decline in brain tissue concentration between Masters athletes and sedentary older adults.
Materials and Methods
Twelve Masters athletes (MA) (3 females, age=72.4±5.6yrs, endurance training>15yrs), 12 sedentary elderly (SE) similar in age and educational level (4 females, age=74.6±4.3yrs), and 9 young controls (YC)(4 females, age=27.2±3.6yrs) participated. T1-weighted-high-resolution (1×1×1mm3) images were acquired. Voxel-based analysis was conducted to identify clusters showing tissue concentration differences with t-tests. Cognitive function was assessed using a standard clinical battery focused on executive function and memory.
Results
Two Masters athletes and 2 sedentary elderly were unable to complete MRI study. Both SE and MA showed lower GM concentrations than YC in the superior, inferior and middle frontal gyrus, superior temporal gyrus, postcentral gyrus and the cingulate gyrus (PFDR-corrected<0.001) and lower WM concentrations in the inferior frontal gyrus and precentral gyrus (PFDR-corrected<0.005). Notably, MA showed higher GM and WM concentrations than SE in the sub-gyral, cuneus, and precuneus regions related to visuospatial function, motor control, and working memory (PFDR-corrected<0.005). After controlling for estimated intelligence, MA outperformed SE on tasks of letter (p<0.01) and category (p<0.05) fluency.
Conclusion
Life-long exercise may confer benefits to some aspects of executive function and age-related brain tissue loss in the regions related to visuospatial function, motor control, and working memory in older adults.
doi:10.1002/jmri.24085
PMCID: PMC3812419  PMID: 23908143
Aging; brain; cognition; exercise; MRI
9.  Cerebral Autoregulation of Blood Velocity and Volumetric Flow during Steady-State Changes in Arterial Pressure RR 
Hypertension  2013;62(5):973-979.
The validity of using transcranial Doppler (TCD) measurement of cerebral blood flow velocity (CBFV) to assess cerebral autoregulation (CA) still is a concern. This study measured CBFV in the middle cerebral artery (MCA) using TCD and volumetric cerebral blood flow (CBF) in the internal carotid artery (ICA) using color-coded duplex ultrasonography to assess CA during steady-state changes in mean arterial pressure (MAP). Twenty-one healthy adults participated. MAP was changed stepwise by intravenous infusion of sodium nitroprusside and phenylephrine. Changes in CBFV, CBF, cerebrovascular resistance (CVR = MAP/CBF) or resistance index (CVRi = MAP/CBFV) were measured to assess CA by linear regression analysis. The relationship between changes in ICA diameter and MAP was assessed. All values were normalized as percentage changes from baseline. Drug induced changes in MAP were from −26% to 31%. Changes in CBFV and CVRi in response to MAP were linear and the regresssion slopes were similar between MCA and ICA. However, CBF in ICA remained unchanged despite large changes in MAP. Consistently, a steeper slope of changes in CVR relative to CVRi was observed (0.991 vs. 0.804, P < 0.05). The ICA diameter changed inversely in response to MAP (r = −0.418, P < 0.05). These findings indicate that CA can be assessed with TCD mesurements of CBFV and CVRi in MCA. However, it is likely to be underestimated when compared to the measurements of CBF and CVR in ICA. The inverse relationship between changes in ICA diameter and MAP suggests that large cerebral arteries are involved in CA.
doi:10.1161/HYPERTENSIONAHA.113.01867
PMCID: PMC3893684  PMID: 24041946
cerebral autoregulation; blood pressure; cerebral blood flow; transcranial Doppler; ultrasonography; middle cerebral artery; internal carotid artery
10.  A 2-Helix Small Protein Labeled with 68Ga for PET Imaging of HER2 Expression 
Affibody molecules are a class of scaffold proteins being developed into a generalizable approach to targeting tumors. Many 3-helix–based Affibody proteins have shown excellent in vivo properties for tumor imaging and therapy. By truncating one a-helix that is not responsible for receptor recognition in the Affibody and maturating the protein affinity through synthetic strategies, we have successfully identified in our previous research several small 2-helix proteins with excellent binding affinities to human epidermal growth factor receptor type 2 (HER2). With preferential properties such as faster blood clearance and tumor accumulation, lower immunogenic potential, and facile and economically viable synthetic schemes, we hypothesized that these 2-helix protein binders could become excellent molecular imaging probes for monitoring HER2 expression and modulation.
Methods
In this study, a 2-helix small protein, MUT-DS, was chemically modified with a metal chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). DOTA-MUTDS was then site-specifically radiolabeled with an important PET radionuclide, 68Ga. The resulting radiolabeled anti-HER2 2-helix molecule was further evaluated as a potential molecular probe for small-animal PET HER2 imaging in a SKOV3 tumor mouse model.
Results
The 2-helix DOTA-MUT-DS showed high HER2-binding affinity (dissociation constant, 4.76 nM). The radiolabeled probe displayed high stability in mouse serum and specificity toward HER2 in cell cultures. Biodistribution and small-animal PET studies further showed that 68Ga-DOTAMUT-DS had rapid and high SKOV3 tumor accumulation and quick clearance from normal organs. The specificity of 68Ga-DOTA-MUT-DS for SKOV3 tumors was confirmed by monitoring modulation of HER2 protein on treatment of tumor mice with heat shock protein 90 inhibitor 17-N,N-dimethyl ethylene diaminegeldanamycin in vivo.
Conclusion
This proof-of-concept research clearly demonstrated that synthetic 2-helix 68Ga-DOTA-MUT-DS is a promising PET probe for imaging HER2 expression in vivo. The Affibody-derived small 2-helix protein scaffold has great potential for developing targeting agents for a variety of tumor-associated biomarkers.
doi:10.2967/jnumed.109.064287
PMCID: PMC4216181  PMID: 19690041
HER2; Affibody; PET; imaging; 68Ga
11.  Salinity anomaly as a trigger for ENSO events 
Scientific Reports  2014;4:6821.
According to the classical theories of ENSO, subsurface anomalies in ocean thermal structure are precursors for ENSO events and their initial specification is essential for skillful ENSO forecast. Although ocean salinity in the tropical Pacific (particularly in the western Pacific warm pool) can vary in response to El Niño events, its effect on ENSO evolution and forecasts of ENSO has been less explored. Here we present evidence that, in addition to the passive response, salinity variability may also play an active role in ENSO evolution, and thus important in forecasting El Niño events. By comparing two forecast experiments in which the interannually variability of salinity in the ocean initial states is either included or excluded, the salinity variability is shown to be essential to correctly forecast the 2007/08 La Niña starting from April 2007. With realistic salinity initial states, the tendency to decay of the subsurface cold condition during the spring and early summer 2007 was interrupted by positive salinity anomalies in the upper central Pacific, which working together with the Bjerknes positive feedback, contributed to the development of the La Niña event. Our study suggests that ENSO forecasts will benefit from more accurate salinity observations with large-scale spatial coverage.
doi:10.1038/srep06821
PMCID: PMC4212239  PMID: 25352285
12.  A Novel Method of Object Detection from a Moving Camera Based on Image Matching and Frame Coupling 
PLoS ONE  2014;9(10):e109809.
A new method based on image matching and frame coupling to handle the problems of object detection caused by a moving camera and object motion is presented in this paper. First, feature points are extracted from each frame. Then, motion parameters can be obtained. Sub-images are extracted from the corresponding frame via these motion parameters. Furthermore, a novel searching method for potential orientations improves efficiency and accuracy. Finally, a method based on frame coupling is adopted, which improves the accuracy of object detection. The results demonstrate the effectiveness and feasibility of our proposed method for a moving object with changing posture and with a moving camera.
doi:10.1371/journal.pone.0109809
PMCID: PMC4212968  PMID: 25354301
13.  Genomewide Analysis of Rat Periaqueductal Gray-Dorsal Horn Reveals Time-, Region- and Frequency-Specific mRNA Expression Changes in Response to Electroacupuncture Stimulation 
Scientific Reports  2014;4:6713.
Electroacupuncture (EA) has been widely applied for illness prevention, treatment or rehabilitation in the clinic, especially for pain management. However, the molecular events that induce these changes remain largely uncharacterized. The periaqueductal gray (PAG) and the spinal dorsal horn (DH) have been verified as two critical regions in the response to EA stimulation in EA analgesia. In this study, a genetic screen was conducted to delineate the gene expression profile in the PAG-DH regions of rats to explore the molecular events of the analgesic effect induced by low-frequency (2-Hz) and high-frequency (100-Hz) EAs. Microarray analysis at two different time points after EA stimulation revealed time-, region- and frequency-specific gene expression changes. These expression differences suggested that modulation of neural-immune interaction in the central nervous system played an important role during EA analgesia. Furthermore, low-frequency EA could regulate gene expression to a greater degree than high-frequency EA. Altogether, the present study offers, for the first time, a characterized transcriptional response pattern in the PAG-DH regions followed by EA stimulation and, thus, provides a solid experimental framework for future in-depth analysis of the mechanisms underlying EA-induced effects.
doi:10.1038/srep06713
PMCID: PMC4209446  PMID: 25346229
14.  Molecular and Morphological Analysis Reveals Five New Species of Zygophiala Associated with Flyspeck Signs on Plant Hosts from China 
PLoS ONE  2014;9(10):e110717.
Species in the genus Zygophiala are associated with sooty blotch and flyspeck disease on a wide range of hosts. In this study, 63 Zygophiala isolates collected from flyspeck colonies on a range of plants from several regions of China were used for phylogeny, host range and geographic distribution analysis. Phylogenetic trees were constructed on four genes - internal transcribed spacer (ITS), partial translation elongation factor 1-alpha (TEF), β-tubulin (TUB2), and actin (ACT) – both individually and in combination. Isolates were grouped into 11 clades among which five new species, Z. emperorae, Z. trispora, Z. musae, Z. inaequalis and Z. longispora, were described. Species of Zygophiala differed in observed host range and geographic distribution. Z. wisconsinensis and Z. emperorae were the most prevalent throughout the sampled regions of China, whereas Z. trispora, Z. musae, Z. inaequalis and Z. longispora were collected only in southern China. The hosts of Z. wisconsinensis and Z. emperorae were mainly in the family Rosaceae whereas Z. trispora, Z. musae, Z. inaequalis and Z. longispora were found mainly on banana (Musa spp.). Cross inoculation tests provided evidence of host specificity among SBFS species.
doi:10.1371/journal.pone.0110717
PMCID: PMC4203821  PMID: 25329930
15.  Expression of vascular endothelial growth factor C and anti-angiogenesis therapy in endometriosis 
Angiogenesis is an important pathogenesis of Endometriosis. Vascular endothelial growth factor C (VEGF-C) is one of the most important factor in the regulation of both normal and abnormal angiogenesis. Anti-angiogenic treatment of endometriosis is still in the exploratory stage. In this study, we investigate the relationship between VEGF-C and endometriosis, the therapeutic effects of Endostar in the rat endometriosis model. We then demonstrated that Immunohistochemical expression of VEGF-C was higher in endometriotic tissues than in control normal ovary tissues (P < 0.01) and higher in the endomertriosis grade III-IV than in endomertriosis grade I-II (P=0.013). In rat endometriosis model, we observed a significant reduction in the mean volume and weight of the endometriotic implants per rat in the treatment group as compared with the control group. By immunohistochemical evaluation, there was a significant reduction in VEGF-C expression after treatment in all areas examined. VEGF-C may be involved in the pathogenesis of endomertriosis by regulating the angiogenesis. Endostar has therapeutic effects of endometriosis lesions in the rat endometriosis model.
PMCID: PMC4270624  PMID: 25550812
Endomertriosis; VEGF-C; angiogenesis; rat; Endostar
16.  Streptomyces coelicolor SCO4226 Is a Nickel Binding Protein 
PLoS ONE  2014;9(10):e109660.
The open reading frame SCO4226 of Streptomyces coelicolor A3(2) encodes an 82-residue hypothetical protein. Biochemical assays revealed that each SCO4226 dimer binds four nickel ions. To decipher the molecular function, we solved the crystal structures of SCO4226 in both apo- and nickel-bound (Ni-SCO4226) forms at 1.30 and 2.04 Å resolution, respectively. Each subunit of SCO4226 dimer adopts a canonical ferredoxin-like fold with five β-strands flanked by two α-helices. In the structure of Ni-SCO4226, four nickel ions are coordinated at the surface of the dimer. Further biochemical assays suggested that the binding of Ni2+ triggers the self-aggregation of SCO4226 in vitro. In addition, RT-qPCR assays demonstrated that the expression of SCO4226 gene in S. coelicolor is specifically up-regulated by the addition of Ni2+, but not other divalent ions such as Cu2+, Mn2+ or Co2+. All these results suggested that SCO4226 acts as a nickel binding protein, probably required for nickel sequestration and/or detoxification.
doi:10.1371/journal.pone.0109660
PMCID: PMC4186839  PMID: 25285530
17.  Diagnosis of 25 genotypes of human papillomaviruses for their physical statuses in cervical precancerous/cancerous lesions: a comparison of E2/E6E7 ratio-based vs. multiple E1-L1/E6E7 ratio-based detection techniques 
Background
Cervical lesions caused by integrated human papillomavirus (HPV) infection are highly dangerous because they can quickly develop into invasive cancers. However, clinicians are currently hampered by the lack of a quick, convenient and precise technique to detect integrated/mixed infections of various genotypes of HPVs in the cervix. This study aimed to develop a practical tool to determine the physical status of different HPVs and evaluate its clinical significance.
Methods
The target population comprised 1162 women with an HPV infection history of > six months and an abnormal cervical cytological finding. The multiple E1-L1/E6E7 ratio analysis, a novel technique, was developed based on determining the ratios of E1/E6E7, E2/E6E7, E4E5/E6E7, L2/E6E7 and L1/E6E7 within the viral genome. Any imbalanced ratios indicate integration. Its diagnostic and predictive performances were compared with those of E2/E6E7 ratio analysis. The detection accuracy of both techniques was evaluated using the gold-standard technique “detection of integrated papillomavirus sequences” (DIPS). To realize a multigenotypic detection goal, a primer and probe library was established.
Results
The integration rate of a particular genotype of HPV was correlated with its tumorigenic potential and women with higher lesion grades often carried lower viral loads. The E1-L1/E6E7 ratio analysis achieved 92.7% sensitivity and 99.0% specificity in detecting HPV integration, while the E2/E6E7 ratio analysis showed a much lower sensitivity (75.6%) and a similar specificity (99.3%). Interference due to episomal copies was observed in both techniques, leading to false-negative results. However, some positive results of E1-L1/E6E7 ratio analysis were missed by DIPS due to its stochastic detection nature. The E1-L1/E6E7 ratio analysis is more efficient than E2/E6E7 ratio analysis and DIPS in predicting precancerous/cancerous lesions, in which both positive predictive values (36.7%-82.3%) and negative predictive values (75.9%-100%) were highest (based on the results of three rounds of biopsies).
Conclusions
The multiple E1-L1/E6E7 ratio analysis is more sensitive and predictive than E2/E6E7 ratio analysis as a triage test for detecting HPV integration. It can effectively narrow the range of candidates for colposcopic examination and cervical biopsy, thereby lowering the expense of cervical cancer prevention.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0282-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-014-0282-2
PMCID: PMC4192431  PMID: 25269554
Human papillomavirus; Physical status; Integration; E1; E2; E6; E7; L1; Polymerase chain reaction; Cervical cancer
18.  A modified method for locating parapharyngeal space neoplasms on magnetic resonance images: implications for differential diagnosis 
Chinese Journal of Cancer  2014;33(10):511-520.
The parapharyngeal space (PPS) is an inverted pyramid-shaped deep space in the head and neck region, and a variety of tumors, such as salivary gland tumors, neurogenic tumors, nasopharyngeal carcinomas with parapharyngeal invasion, and lymphomas, can be found in this space. The differential diagnosis of PPS tumors remains challenging for radiologists. This study aimed to develop and test a modified method for locating PPS tumors on magnetic resonance (MR) images to improve preoperative differential diagnosis. The new protocol divided the PPS into three compartments: a prestyloid compartment, the carotid sheath, and the areas outside the carotid sheath. PPS tumors were located in these compartments according to the displacements of the tensor veli palatini muscle and the styloid process, with or without blood vessel separations and medial pterygoid invasion. This protocol, as well as a more conventional protocol that is based on displacements of the internal carotid artery (ICA), was used to assess MR images captured from a series of 58 PPS tumors. The consequent distributions of PPS tumor locations determined by both methods were compared. Of all 58 tumors, our new method determined that 57 could be assigned to precise PPS compartments. Nearly all (13/14; 93%) tumors that were located in the pre-styloid compartment were salivary gland tumors. All 15 tumors within the carotid sheath were neurogenic tumors. The vast majority (18/20; 90%) of trans-spatial lesions were malignancies. However, according to the ICA-based method, 28 tumors were located in the pre-styloid compartment, and 24 were located in the post-styloid compartment, leaving 6 tumors that were difficult to locate. Lesions located in both the pre-styloid and the post-styloid compartments comprised various types of tumors. Compared with the conventional ICA-based method, our new method can help radiologists to narrow the differential diagnosis of PPS tumors to specific compartments.
doi:10.5732/cjc.014.10017
PMCID: PMC4198754  PMID: 25104280
Parapharyngeal space; neoplasm; magnetic resonance imaging (MRI); differential diagnosis; location
19.  Multifrequency Excitation Method for Rapid and Accurate Dynamic Test of Micromachined Gyroscope Chips 
Sensors (Basel, Switzerland)  2014;14(10):19507-19516.
A novel multifrequency excitation (MFE) method is proposed to realize rapid and accurate dynamic testing of micromachined gyroscope chips. Compared with the traditional sweep-frequency excitation (SFE) method, the computational time for testing one chip under four modes at a 1-Hz frequency resolution and 600-Hz bandwidth was dramatically reduced from 10 min to 6 s. A multifrequency signal with an equal amplitude and initial linear-phase-difference distribution was generated to ensure test repeatability and accuracy. The current test system based on LabVIEW using the SFE method was modified to use the MFE method without any hardware changes. The experimental results verified that the MFE method can be an ideal solution for large-scale dynamic testing of gyroscope chips and gyroscopes.
doi:10.3390/s141019507
PMCID: PMC4239857  PMID: 25330052
micromachined gyroscope chip; dynamic test; multifrequency excitation
20.  The effects of dexamethasone on the proliferation and apoptosis of human ovarian cancer cells induced by paclitaxel 
Background
Dexamethasone (DEX) has been routinely used as a pre-treatment in the clinical application of paclitaxel (PTX) to treat ovarian cancer. However, PTX-induced apoptosis might be inhibited by DEX. This study was undertaken to investigate the effects of DEX on the apoptosis induced by PTX.
Methods
Both of SKOV-3 and HO-8910 human ovarian cancer cells were divided into four groups: (1) untreated (Con); (2) treated with DEX (0.1 μM) alone; (3) treated with PTX (50 nM); and (4) pre-treated with DEX (0.1 μM), and 24 h later, treated with PTX (DEX + PTX). Cell proliferation was determined by the 3-(4,5)-dimethylthiahiazo (−z-y1)-3,5-di- phenytetrazoliumromide (MTT) dye uptake method, while cell apoptosis was analyzed by propidium iodide (PI) staining and flow cytometry. Then, reverse transcription polymerase chain reactions (RT-PCRs) were applied to semi-quantitative analysis, followed by western blot analysis. Statistical analysis was performed, with Fisher’s least significant difference test.
Results
Our results demonstrated that DEX can differentially inhibit SKOV-3 and HO-8910 cell proliferation induced by PTX and decrease the apoptosis rates in cancer cells. Pre-treatment with DEX could up-regulate the expressions of members of anti-apoptotic Bcl-2 family (Bcl-2 and Bcl-XL) and members of IAP family (survivin). The expression of cleaved caspase-3 was down-regulated by DEX, shown by semi-quantitative RT-PCRs and western blot analysis.
Conclusions
Our data gained invaluable insights of the antagonistic mechanisms of DEX on PTX-induced cancer cell death and may provide new methods of using DEX as antineoplastic drugs or agents in the clinical treatment for ovarian cancer patients.
doi:10.1186/s13048-014-0089-z
PMCID: PMC4200216  PMID: 25297825
Bcl-XL; Cleaved caspase-3; Dexamethasone; Ovarian cancer; Paclitaxel; Survivin
21.  In vivo targeting of HER2-positive tumor using 2-helix affibody molecules 
Amino acids  2011;43(1):405-413.
Molecular imaging of human epidermal growth factor receptor type 2 (HER2) expression has drawn significant attention because of the unique role of the HER2 gene in diagnosis, therapy and prognosis of human breast cancer. In our previous research, a novel cyclic 2-helix small protein, MUT-DS, was discovered as an anti-HER2 Affibody analog with high affinity through rational protein design and engineering. MUT-DS was then evaluated for positron emission tomography (PET) of HER2-positive tumor by labeling with two radionuclides, 68Ga and 18F, with relatively short half-life (t1/2 < 2 h). In order to fully study the in vivo behavior of 2-helix small protein and demonstrate that it could be a robust platform for labeling with a variety of radionuclides for different applications, in this study, MUT-DS was further radiolabeled with 64Cu or 111In and evaluated for in vivo targeting of HER2-positive tumor in mice. Design 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid (DOTA) conjugated MUT-DS (DOTA–MUT-DS) was chemically synthesized using solid phase peptide synthesizer and I2 oxidation. DOTA–MUTDS was then radiolabeled with 64Cu or 111In to prepare the HER2 imaging probe (64Cu/111In-DOTA–MUT-DS). Both biodistribution and microPET imaging of the probe were evaluated in nude mice bearing subcutaneous HER2-positive SKOV3 tumors. DOTA–MUT-DS could be successfully synthesized and radiolabeled with 64Cu or 111In. Biodistribution study showed that tumor uptake value of 64Cu or 111In-labeled DOTA–MUT-DS was 4.66 ± 0.38 or 2.17 ± 0.15%ID/g, respectively, in nude mice bearing SKOV3 xenografts (n = 3) at 1 h post-injection (p.i.). Tumor-to-blood and tumor-to-muscle ratios for 64Cu-DOTA-MUT-DS were attained to be 3.05 and 3.48 at 1 h p.i., respectively, while for 111In-DOTA–MUT-DS, they were 2.04 and 3.19, respectively. Co-injection of the cold Affibody molecule ZHER2:342 with 64Cu-DOTA-MUT-DS specifically reduced the SKOV3 tumor uptake of the probe by 48%. 111In-DOTA–MUT-DS displayed lower liver uptake at all the time points investigated and higher tumor to blood ratios at 4 and 20 h p.i., when compared with 64Cu-DOTA–MUT-DS. This study demonstrates that the 2-helix protein based probes, 64Cu/111In DOTA–MUT-DS, are promising molecular probes for imaging HER2-positive tumor. Two-helix small protein scaffold holds great promise as a novel and robust platform for imaging and therapy applications.
doi:10.1007/s00726-011-1096-7
PMCID: PMC4172459  PMID: 21984380
Affibody; HER2; PET; Molecular imaging; 111In; 64Cu
22.  Effects of vagus nerve stimulation via cholinergic anti-inflammatory pathway activation on myocardial ischemia/reperfusion injury in canine 
Background: Acute myocardial infarction (AMI) was a type of disease with high mortality rate and high disability rate. And about 50% of the final area of myocardial infarction after AMI was led by ischemia/reperfusion (I/R) injury. The I/R injury was a kind of systemic inflammatory response, in which the main performance laid in the release of the large quantity of inflammatory cytokines. The basic experiments, clinical studies and the large scaled epidemiology investigations found that the low functions of vagus nerves had close relevance with the occurrence, development and prognosis of the cardiovascular diseases. This study investigate the effects of cholinergic anti-inflammatory pathway with with vagus never stimulation I/R injury in canine. Methods: 18 adult mongrel dogs were randomly divided into 3 groups (n = 6): sham operation group (sham Group), ischemia/reperfusion group (I/R group), right vagus nerve stimulation and ischemia/reperfusion group (STM group). The hemodynamic indexes were measured after reperfusion 120 min. Through internal jugular venous blood, serum acetylcholine (Ach), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) concentrations were detected by ELISA. Alpha 7 subunit Ach acetylcholine receptor (α7nAchR) expression level was detected with immunohistochemical method. HE staining was used to observe the degree of neutrophil infiltration. Results: After ischemia/reperfusion 120 min, compared with sham group, TNF-α and IL-6 were significantly decreased, Ach content increased, the expression of α7nAchR protein was significantly reduced in I/R group (P < 0.05). Expression of α7nAchR protein, Ach content, TNF-α and IL-6 level had no significant difference in STM group (P < 0.05). Compared with I/R group, the expression of Ach and α7nAchR protein significantly increased the TNF- and IL-6 levels decreased in STM group (P < 0.05). Compared with the baseline, TNF-α and IL-6 levels significantly increased Ach content decreased in I/R group after ischemia /reperfusion 120 min (P < 0.05). Ach, TNF-α and IL-6 levels had no significant change in sham group and STM group of (P < 0.05). TNF-α and IL-6 were negatively correlated with Ach in I/R group (P < 0.05), and TNF-α, IL-6 were negatively correlated with Ach in group STM (P < 0.05). Massive infiltration of neutrophils were detected in myocardial tissue of I/R group, and a small number of neutrophils infiltration were detected in STM group. Conclusion: Right vagus nerve stimulation could activate anti-inflammatory pathway and inhibit the systemic and local inflammatory reaction to relieve myocardial I/R injury.
PMCID: PMC4211767  PMID: 25356117
Myocardial ischemia/reperfusion injury; cholinergic anti-inflammatory pathway; vagus nerve; acetylcholine
23.  Between-centre variability in transfer function analysis, a widely used method for linear quantification of the dynamic pressure–flow relation: The CARNet study 
Medical engineering & physics  2014;36(5):620-627.
Transfer function analysis (TFA) is a frequently used method to assess dynamic cerebral autoregulation (CA) using spontaneous oscillations in blood pressure (BP) and cerebral blood flow velocity (CBFV). However, controversies and variations exist in how research groups utilise TFA, causing high variability in interpretation. The objective of this study was to evaluate between-centre variability in TFA outcome metrics. 15 centres analysed the same 70 BP and CBFV datasets from healthy subjects (n = 50 rest; n = 20 during hypercapnia); 10 additional datasets were computer-generated. Each centre used their in-house TFA methods; however, certain parameters were specified to reduce a priori between-centre variability. Hypercapnia was used to assess discriminatory performance and synthetic data to evaluate effects of parameter settings. Results were analysed using the Mann–Whitney test and logistic regression. A large non-homogeneous variation was found in TFA outcome metrics between the centres. Logistic regression demonstrated that 11 centres were able to distinguish between normal and impaired CA with an AUC > 0.85. Further analysis identified TFA settings that are associated with large variation in outcome measures. These results indicate the need for standardisation of TFA settings in order to reduce between-centre variability and to allow accurate comparison between studies. Suggestions on optimal signal processing methods are proposed.
doi:10.1016/j.medengphy.2014.02.002
PMCID: PMC4155942  PMID: 24725709
Cerebral autoregulation; Transfer function analysis; Method comparison; Standardisation
24.  Direct Site-Specific Radiolabeling of an Affibody Protein with 4-[18F]Fluorobenzaldehyde via Oxime Chemistry 
Purpose
In this study, we introduce a methodology for preparing 18F-labeled Affibody protein, specifically 18F-Anti-HER2 dimeric Affibody (14 kDa), for in vivo imaging of HER2neu with positron emission tomography (PET).
Procedures
We have used 4-[18F]fluorobenzaldehyde as a synthon to prepare 18F-Anti-HER2 Affibody. Aminooxy-functionalized Affibody (Anti-HER2-ONH2) was incubated with 4-[18F] fluorobenzaldehyde in ammonium acetate buffer at pH 4 in the presence of methanol at 70°C for 15 min. The resulting 18F-labeled Affibody molecule was evaluated as a PET probe in xenograft models expressing HER2.
Results
We have successfully prepared 18F-Anti-HER2 dimeric Affibody (14 kDa), N-(4-[18F] fluorobenzylidine)oxime-Anti-HER2 Affibody, [18F]FBO-Anti-HER2, in 26–30% radiochemical yields (decay corrected). High-contrast small-animal PET images with relatively moderate tumor uptake (1.79±0.40% ID/g) were observed for the 18F-Anti-HER2 Affibody.
Conclusion
Site-specific 18F-labeled Affibody against HER2 has been synthesized via chemo-selective oxime formation between an aminooxy-functionalized Affibody and 18F-fluorobenzaldehyde. The results have implications for radiolabeling of other affibodies and macromolecules and should also be important for advancing Affibody imaging with PET.
doi:10.1007/s11307-008-0142-7
PMCID: PMC4155982  PMID: 18481153
Affibody; HER2; Positron emission tomography (PET); Imaging; 18F
25.  64Cu-Labeled Affibody Molecules for Imaging of HER2 Expressing Tumors 
Introduction
The development of molecular probes based on novel engineered protein constructs is under active investigation due to the great potential of this generalizable strategy for imaging a variety of tumor targets.
Discussion
In this report, human epidermal growth factor receptor type 2 (HER2)-binding Affibody molecules were radiolabeled with 64Cu and their imaging ability was further evaluated in tumor mice models to understand the promise and limitations of such probes. The anti-HER2 Affibody molecules in monomeric (ZHER2:477) and dimeric [(ZHER2:477)2] forms were site specifically modified with the maleimide-functionalized chelator, 1,4,7,10-tetraazacyclodode-cane-1,4,7-tris(acetic acid)-10-acetate mono (N-ethylmaleimide amide) (Mal-DOTA). The resulting DOTA–Affibody conjugates were radiolabeled with 64Cu and evaluated in nude mice bearing subcutaneous SKOV3 tumors. Biodistribution experiments showed that tumor uptake values of 64Cu-DOTA-ZHER2:477 and 64Cu-DOTA-(ZHER2:477)2 were 6.12±1.44% and 1.46±0.50% ID/g, respectively, in nude mice (n=3 each) at 4 h postinjection. Moreover, 64Cu-labeled monomer exhibited significantly higher tumor/blood ratio than that of radiolabeled dimeric counterpart at all time points examined in this study. MicroPET imaging of 64Cu-DOTA-ZHER2:477 in SKOV3 tumor mice clearly showed good and specific tumor localization. This study demonstrates that 64Cu-labeled ZHER2:477 is a promising targeted molecular probe for imaging HER2 receptor expression in living mice. Further work is needed to improve the excretion properties, hence dosimetry and imaging efficacy, of the radiometal-based probe.
doi:10.1007/s11307-009-0256-6
PMCID: PMC4155984  PMID: 19779897
Affibody; HER2; PET; Imaging; 64Cu

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