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1.  A computer aided measurement method for unstable pelvic fractures based on standardized radiographs 
BMC Medical Imaging  2015;15:41.
To set up a method for measuring radiographic displacement of unstable pelvic ring fractures based on standardized X-ray images and then test its reliability and validity using a software-based measurement technique.
Twenty-five patients that were diagnosed as AO/OTA type B or C pelvic fractures with unilateral pelvis fractured and dislocated were eligible for inclusion by a review of medical records in our clinical centre. Based on the input pelvic preoperative CT data, the standardized X-ray images, including inlet, outlet, and anterior-posterior (AP) radiographs, were simulated using Armira software (Visage Imaging GmbH, Berlin, Germany). After representative anatomic landmarks were marked on the standardized X-ray images, the 2-dimensional (2D) coordinates of these points could be revealed in Digimizer software (Model: Mitutoyo Corp., Tokyo, Japan). Subsequently, we developed a formula that indicated the translational and rotational displacement patterns of the injured hemipelvis. Five separate observers calculated the displacement outcomes using the established formula and determined the rotational patterns using a 3D-CT model based on their overall impression. We performed 3D reconstruction of all the fractured pelvises using Mimics (Materialise, Haasrode, Belgium) and determined the translational and rotational displacement using 3-matic suite. The interobserver reliability of the new method was assessed by comparing the continuous measure and categorical outcomes using intraclass correlation coefficient (ICC) and kappa statistic, respectively.
The interobserver reliability of the new method for translational and rotational measurement was high, with both ICCs above 0.9. Rotational outcome assessed by the new method was the same as that concluded by 3-matic software. The agreement for rotational outcome among orthopaedic surgeons based on overall impression was poor (kappa statistic, 0.250 to 0.426). Compared with the 3D reconstruction outcome, the interobserver reliability of the formula method for translational and rotational measures was perfect with both ICCs more than 0.9.
The new method for measuring displacement using a formula was reliable, and could minimise the measurement errors and maximise the precision of pelvic fracture description. Furthermore, this study was useful for standardising the operative plan and establishing a theoretical basis for robot-assisted pelvic fracture surgery based on 2-D radiographs.
PMCID: PMC4588254  PMID: 26423682
Unstable pelvic fractures; Radiographic assessment; Software-based measurement; Reliability study
2.  Effect of Negative Pressure on Proliferation, Virulence Factor Secretion, Biofilm Formation, and Virulence-Regulated Gene Expression of Pseudomonas aeruginosa In Vitro 
BioMed Research International  2016;2016:7986234.
Objective. To investigate the effect of negative pressure conditions induced by NPWT on P. aeruginosa. Methods. P. aeruginosa was cultured in a Luria–Bertani medium at negative pressure of −125 mmHg for 24 h in the experimental group and at atmospheric pressure in the control group. The diameters of the colonies of P. aeruginosa were measured after 24 h. ELISA kit, orcinol method, and elastin-Congo red assay were used to quantify the virulence factors. Biofilm formation was observed by staining with Alexa Fluor® 647 conjugate of concanavalin A (Con A). Virulence-regulated genes were determined by quantitative RT-PCR. Results. As compared with the control group, growth of P. aeruginosa was inhibited by negative pressure. The colony size under negative pressure was significantly smaller in the experimental group than that in the controls (p < 0.01). Besides, reductions in the total amount of virulence factors were observed in the negative pressure group, including exotoxin A, rhamnolipid, and elastase. RT-PCR results revealed a significant inhibition in the expression level of virulence-regulated genes. Conclusion. Negative pressure could significantly inhibit the growth of P. aeruginosa. It led to a decrease in the virulence factor secretion, biofilm formation, and a reduction in the expression level of virulence-regulated genes.
PMCID: PMC5198154  PMID: 28074188
3.  Evaluation of Elastic Stiffness in Healing Achilles Tendon After Surgical Repair of a Tendon Rupture Using In Vivo Ultrasound Shear Wave Elastography 
There has been no published report assessing the mechanical properties of a repaired Achilles tendon after surgery using shear wave elastography (SWE). The aim of this study was to investigate the changes in mechanical properties of the healing Achilles tendon after surgical repair of a tendon rupture using ultrasound SWE and how these changes correlate with tendon function.
Twenty-six patients who underwent surgical repair for Achilles tendon rupture were examined with ultrasound SWE coupled with a linear array transducer (4–15 MHz). The elasticity values of the repaired Achilles tendon in a longitudinal view were measured at 12, 24, and 48 weeks postoperatively. Functional outcomes were assessed with the American Orthopedic Foot and Ankle Society (AOFAS) rating system at 12, 24, and 48 weeks postoperatively. General linear regression analysis and correlation coefficients were used to analyze the relationship between elasticity and the AOFAS score.
There were significant differences with respect to the mean elasticity values and functional scores of the repaired Achilles tendon at 12, 24, and 48 weeks postoperatively (all P<0.05). Tendon function was positively correlated with the elasticity of the repaired Achilles tendon (P=0.0003).
Our findings suggest that SWE can provide biomechanical information for evaluating the mechanical properties of healing Achilles tendon and predict Achilles tendon function.
PMCID: PMC4835154  PMID: 27072885
Achilles Tendon; Elasticity Imaging Techniques; Foot Injuries; Ultrasonography
4.  Experimental study on treatment of acetabular anterior column fractures: applyment of a minimally invasive percutaneous lag screw guide apparatus 
The aim of this study was to design a new minimally invasive percutaneous lag screw guide apparatus and to verify its adjuvant treatment of acetabular anterior column fracture on pelvis specimens.
This guide apparatus was self-developed based on the principles of “two points form a line” and “Rectangle”. Using C-arm fluoroscopy, this guide apparatus was used to conduct minimally invasive percutaneous lag screw internal fixation of acetabular anterior column fractures. Ten hollow lag screws were placed into 5 pelvis specimens.
Result showed no sign of any screws puncturing the cortex or entering into the hip joint on radiological assessment. The cross-section reconstructed vertical distance to the screw, on the cross-section acetabular notch and the cross-section of the screw where the distance of between the screw and the iliopectineal line’s arc roof was at its shortest, indicate that at all points (T, R-r) under the line with an inclination of 1 (namely T = R-r) the screw is within the cortex and does not puncture the acetabula anterior column or enter into the hip joint.
We may conclude that this self-developed guide apparatus solves the screw precision problem during the treatment of acetabular anterior column fractures through a minimally invasive percutaneous lag screw.
PMCID: PMC4714437  PMID: 26769591
Acetabula anterior column; Fracture; Minimally invasive; Percutaneous; Lag screw; Guide apparatus
5.  The Efficacy and Safety of Icotinib in Patients with Advanced Non-Small Cell Lung Cancer Previously Treated with Chemotherapy: A Single-Arm, Multi-Center, Prospective Study 
PLoS ONE  2015;10(11):e0142500.
Icotinib is a small molecule targeting epidermal growth factor receptor tyrosine kinase, which shows non-inferior efficacy and better safety comparing to gefitinib in previous phase III trial. The present study was designed to further evaluate the efficacy and safety of icotinib in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.
Patients with NSCLC progressing after one or two lines of chemotherapy were enrolled to receive oral icotinib (125mg tablet, three times per day). The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, time to progression, quality of life and safety.
From March 16, 2010 to October 9, 2011, 128 patients from 15 centers nationwide were enrolled, in which 124 patients were available for efficacy evaluation and 127 patients were evaluable for safety. The median progression-free survival and time to progression were 5.0 months (95%CI 2.9–6.6 m) and 5.4 months (95%CI 3.1–7.9 m), respectively. The objective response rate and disease control rate were 25.8% and 67.7% respectively. Median overall survival exceeded 17.6 months (95%CI 14.2 m-NA) according to censored data. Further follow-up of overall survival is ongoing. The most frequent treatment-related adverse events were rash (26%, 33/127), diarrhea (12.6%, 16/127) and elevation of transaminase (15.7%, 20/127).
In general, this study showed similar efficacy and numerically better safety when compared with that in ICOGEN trial, further confirming the efficacy and safety of icotinib in treating patients with advanced NSCLC previously treated with chemotherapy.
Trial Registration NCT02486354
PMCID: PMC4657981  PMID: 26599904
6.  Hyperbaric Oxygen and Ginkgo Biloba Extract Ameliorate Cognitive and Memory Impairment via Nuclear Factor Kappa-B Pathway in Rat Model of Alzheimer's Disease 
Chinese Medical Journal  2015;128(22):3088-3093.
Hyperbaric oxygen (HBO) and Ginkgo biloba extract (e.g., EGB 761) were shown to ameliorate cognitive and memory impairment in Alzheimer's disease (AD). However, the exact mechanism remains elusive. The aim of the present study was to investigate the possible mechanisms of HBO and EGB 761 via the function of nuclear factor kappa-B (NF-κB) pathway.
AD rats were induced by injecting β-amyloid 25–35 into the hippocampus. All animals were divided into six groups: Normal, sham, AD model, HBO (2 atmosphere absolute; 60 min/d), EGB 761 (20 mg·kg−1·d−1), and HBO/EGB 761 groups. Morris water maze tests were used to assess cognitive, and memory capacities of rats; TdT-mediated dUTP Nick-End Labeling staining and Western blotting were used to analyze apoptosis and NF-κB pathway-related proteins in hippocampus tissues.
Morris water maze tests revealed that EGB 761 and HBO significantly improved the cognitive and memory ability of AD rats. In addition, the protective effect of combinational therapy (HBO/EGB 761) was superior to either HBO or EGB 761 alone. In line, reduced apoptosis with NF-κB pathway activation was observed in hippocampus neurons treated by HBO and EGB 761.
Our results suggested that HBO and EGB 761 improve cognitive and memory capacity in a rat model of AD. The protective effects are associated with the reduced apoptosis with NF-κB pathway activation in hippocampus neurons.
PMCID: PMC4795254  PMID: 26608991
Ginkgo Biloba Extract 761; Hyperbaric Oxygen; Nuclear Factor Kappa-B; Rats; Alzheimer's Disease
7.  Delay of the Onset of Puberty in Female Rats by Prepubertal Exposure to T-2 Toxin 
Toxins  2015;7(11):4668-4683.
Growing evidence has revealed the deleterious influence of environmental and food contaminants on puberty onset and development in both animals and children, provoking an increasing health concern. T-2 toxin, a naturally-produced Type A trichothecene mycotoxin which is frequently found in cereal grains and products intended for human and animal consumption, has been shown to impair the reproduction and development in animals. Nevertheless, whether this trichothecene mycotoxin can disturb the onset of puberty in females remains unclear. To clarify this point, infantile female rats were given a daily intragastric administration of vehicle or 187.5 μg/kg body weight of T-2 toxin for five consecutive days from postnatal day 15 to 19, and the effects on puberty onset were evaluated in the present study. The results revealed that the days of vaginal opening, first dioestrus, and first estrus in regular estrous cycle were delayed following prepubertal exposure to T-2 toxin. The relative weights of reproductive organs uterus, ovaries, and vagina, and the incidence of corpora lutea were all diminished in T-2 toxin-treated rats. Serum levels of gonadotropins luteinizing hormone, follicle-stimulating hormone, and estradiol were also reduced by T-2 toxin treatment. The mRNA expressions of hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary GnRH receptor displayed significant reductions following exposure to T-2 toxin, which were consistent with the changes of serum gonadotropins, delayed reproductive organ development, and delayed vaginal opening. In conclusion, the present study reveals that prepubertal exposure to T-2 toxin delays the onset of puberty in immature female rats, probably by the mechanism of disturbance of hypothalamic-pituitary-gonadal (HPG) axis function. Considering the vulnerability of developmental children to food contaminants and the relative high level of dietary intake of T-2 toxin in children, we think the findings of the present study provide valuable information for the health risk assessment in children.
PMCID: PMC4663527  PMID: 26569305
T-2 toxin; female rat; puberty onset; delay; HPG axis; GnRH
8.  Three-Dimensional Analysis of the Curvature of the Femoral Canal in 426 Chinese Femurs 
BioMed Research International  2015;2015:318391.
Purpose. The human femur has long been considered to have an anatomical anterior curvature in the sagittal plane. We established a new method to evaluate the femoral curvature in three-dimensional (3D) space and reveal its influencing factors in Chinese population. Methods. 3D models of 426 femurs and the medullary canal were constructed using Mimics software. We standardized the positions of all femurs using 3ds Max software. After measuring the anatomical parameters, including the radius of femoral curvature (RFC) and banking angle, of the femurs using the established femur-specific coordinate system, we analyzed and determined the relationships between the anatomical parameters of the femur and the general characteristics of the population. Results. Pearson's correlation analyses showed that there were positive correlations between the RFC and height (r = 0.339, p < 0.001) and the femoral length and RFC (r = 0.369, p < 0.001) and a negative correlation between the femoral length and banking angle (r = −0.223, p < 0.001). Stepwise linear regression analyses showed that the most relevant factors for the RFC and banking angle were the femoral length and gender, respectively. Conclusions. This study concluded that the banking angle of the femur was significantly larger in female than in male.
PMCID: PMC4657382  PMID: 26640785
9.  Three-Dimensional Analysis of the Characteristics of the Femoral Canal Isthmus: An Anatomical Study 
BioMed Research International  2015;2015:459612.
Purpose. To establish a new approach for measuring and locating the femoral intramedullary canal isthmus in 3-dimensional (3D) space. Methods. Based on the computed tomography data from 204 Chinese patients, 3D models of the whole femur and the corresponding femoral isthmus tube were reconstructed using Mimics software (Materialise, Haasrode, Belgium). The anatomical parameters of the femur and the isthmus, including the femur length and radius, and the isthmus diameter and height, were measured accordingly. Results. The mean ratio of the isthmus height versus the femoral height was 55 ± 4.8%. The mean diameter of the isthmus was 10.49 ± 1.52 mm. The femoral length, the isthmus diameter, and the isthmus tube length were significantly larger in the male group. Significant correlations were observed between the femoral length and the isthmus diameter (r = 0.24, p < 0.01) and between the femoral length and the isthmus height (r = 0.6, p < 0.01). Stepwise linear regression analyses demonstrated that the femoral length and radius were the most important factors influencing the location and dimension of the femoral canal isthmus. Conclusion. The current study developed a new approach for measuring the femoral canal and for optimization of customer-specific femoral implants.
PMCID: PMC4475546  PMID: 26137483
10.  Experimental and clinical study of influence of high-frequency electric surgical knives on healing of abdominal incision 
AIM: To study the influence of high-frequency electric surgical knives on healing of abdominal incision.
METHODS: Two hundred and forty white rats were divided into 100, 102, 105, and 108 groups and rat models of abdominal operation were induced by using electric surgical knives and common lancets respectively. Then they were respectively given hypodermic injections of normal saline and 0.2 mL quantitative mixture of Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa at a concentration of 102, 105 and 108. On the basis of the animal experiment, 220 patients undergoing abdominal operations (above type II) were randomly allocated into one of following three groups: electric knife (EK, 93 cases), electro-coagulation (EC, 55 cases) and control (72 cases). High-frequency electric surgical knives were used to dissect abdominal tissues and electro-coagulation for hemostasis in EK group. Common lancets and electro-coagulation were applied in EC group. Common lancets and tieing silk suture were used in the controls.
RESULTS: In all the groups except group 100, infection rate of incisional wounds made by electric surgical knives were remarkably higher than that with common lancets. Furthermore, there were significant differences in groups 102, 105, and 108 (P < 0.05), but not in group 100 (P > 0.05) between EK and EC groups. Clinical studies showed a delayed wound healing in 16 cases (17.20%) in EK, 11 cases (16.36%) in EC and 2 cases (2.86%) in the control groups. A significant difference between EK and the control groups (χ2 = 8.57, P < 0.01), and between EC and the control groups (χ2 = 5.66, P < 0.05) was observed, but not between EK and EC (χ2 = 0.017, P > 0.05).
CONCLUSION: High-frequency electric knives may remarkably delay abdominal incision healing. Its application should be minimized so as to reduce the possibility of postoperative complications.
PMCID: PMC4087727  PMID: 16810765
High-frequency electric surgical knives; Abdominal incision; Healing; Infection
11.  Plasma Amino Acid Profile in Patients with Aortic Dissection 
Scientific Reports  2017;7:40146.
Aortic dissection (AD), a severe cardiovascular disease with the characteristics of high mortality, is lack of specific clinical biomarkers. In order to facilitate the diagnosis of AD, we investigated plasma amino acid profile through metabolomics approach. Total 33 human subjects were enrolled in the study: 11 coronary heart disease (CHD) patients without aortic lesion and 11 acute AD and 11 chronic AD. Amino acids were identified in plasma using liquid chromatography and mass spectrometry (LC-MS/MS), and were further subjected to multiple logistic regression analysis. The score plots of principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) showed clear discrimination of CHD patients with AD, acute AD or chronic AD patients, respectively. The contents of histidine, glycine, serine, citrate, ornithine, hydroxyproline, proline and sarcosine were significant different in acute AD patients comparing with CHD patients. The levels of citrate, GABA, glutamate and cysteine were significant different in chronic AD patients comparing with CHD patients. The contents of glutamate and phenylalanine were significant changed in acute AD patients comparing with chronic AD patients. Plasma aminograms were significantly altered in patients with AD comparing with CHD, especially in acute AD, suggesting amino acid profile is expected to exploit a novel, non-invasive, objective diagnosis for AD.
PMCID: PMC5223271  PMID: 28071727
12.  Predictive Value of Serum IFN-γ inducible Protein-10 and IFN-γ/IL-4 Ratio for Liver Fibrosis Progression in CHB Patients 
Scientific Reports  2017;7:40404.
Noninvasive serum markers for assessment of liver fibrosis in chronic hepatitis B (CHB) patients have not been well-studied. The present study was to evaluate the predictive value of serum interferon gamma-inducible protein-10 (IP-10/CXCL10) and the interferon (IFN)-γ/interleukin (IL)-4 ratio for liver fibrosis progression in CHB patients. A total of 180 CHB patients were categorized into four groups: no fibrosis, mild fibrosis, moderate fibrosis, and severe fibrosis. Serum and intrahepatic levels of IP-10, IFN-γ, and IL-4 were examined, from which the IFN-γ/IL-4 ratio was calculated. We found that the serum IP-10 levels were positively correlated with the severity of liver fibrosis, whereas the IFN-γ/IL-4 ratio was negatively associated with the progression of hepatic fibrosis. Multivariate logistic regression analysis revealed that the serum IP-10 was an independent predictor for significant fibrosis. For predicting significant fibrosis, the IP-10 cut-off value of 300 ng/mL had a sensitivity of 92.7% and a specificity of 68.6%. When the IP-10 level was combined with the IFN-γ/IL-4 ratio, the specificity and positive predictive value were 93.8% and 94.6%, respectively; thus, the discriminatory ability was much improved. In conclusion, the serum IP-10 level and the IFN-γ/IL-4 ratio have great potential to predict significant fibrosis among CHB patients.
PMCID: PMC5220308  PMID: 28067328
14.  Screening of Candidate Leaf Morphology Genes by Integration of QTL Mapping and RNA Sequencing Technologies in Oilseed Rape (Brassica napus L.) 
PLoS ONE  2017;12(1):e0169641.
Leaf size and shape play important roles in agronomic traits, such as yield, quality and stress responses. Wide variations in leaf morphological traits exist in cultivated varieties of many plant species. By now, the genetics of leaf shape and size have not been characterized in Brassica napus. In this study, a population of 172 recombinant inbred lines (RILs) was used for quantitative trait locus (QTL) analysis of leaf morphology traits. Furthermore, fresh young leaves of extreme lines with more leaf lobes (referred to as ‘A’) and extreme lines with fewer lobes (referred to as ‘B’) selected from the RIL population and leaves of dissected lines (referred to as ‘P’) were used for transcriptional analysis. A total of 31 QTLs for the leaf morphological traits tested in this study were identified on 12 chromosomes, explaining 5.32–39.34% of the phenotypic variation. There were 8, 6, 2, 5, 8, and 2 QTLs for PL (petiole length), PN (lobe number), LW (lamina width), LL (Lamina length), LL/LTL (the lamina size ratio) and LTL (leaf total length), respectively. In addition, 74, 1,166 and 1,272 differentially expressed genes (DEGs) were identified in ‘A vs B’, ‘A vs P’ and ‘B vs P’ comparisons, respectively. The Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to predict the functions of these DEGs. Gene regulators of leaf shape and size, such as ASYMMETRIC LEAVES 2, gibberellin 20-oxidase 3, genes encoding gibberellin-regulated family protein, genes encoding growth-regulating factor and KNOTTED1-like homeobox were also detected in DEGs. After integrating the QTL mapping and RNA sequencing data, 33 genes, including a gene encoding auxin-responsive GH3 family protein and a gene encoding sphere organelles protein-related gene, were selected as candidates that may control leaf shape. Our findings should be valuable for studies of the genetic control of leaf morphological trait regulation in B. napus.
PMCID: PMC5222374  PMID: 28068426
15.  ITS non-concerted evolution and rampant hybridization in the legume genus Lespedeza (Fabaceae) 
Scientific Reports  2017;7:40057.
The internal transcribed spacer (ITS) as one part of nuclear ribosomal DNA is one of the most extensively sequenced molecular markers in plant systematics. The ITS repeats generally exhibit high-level within-individual homogeneity, while relatively small-scale polymorphism of ITS copies within individuals has often been reported in literature. Here, we identified large-scale polymorphism of ITS copies within individuals in the legume genus Lespedeza (Fabaceae). Divergent paralogs of ITS sequences, including putative pseudogenes, recombinants, and multiple functional ITS copies were sometimes detected in the same individual. Thirty-seven ITS pseudogenes could be easily detected according to nucleotide changes in conserved 5.8S motives, the significantly lower GC contents in at least one of three regions, and the lost ability of 5.8S rDNA sequence to fold into a conserved secondary structure. The distribution patterns of the putative functional clones were highly different between the traditionally recognized two subgenera, suggesting different rates of concerted evolution in two subgenera which could be attributable to their different extents/frequencies of hybridization, confirmed by our analysis of the single-copy nuclear gene PGK. These findings have significant implications in using ITS marker for reconstructing phylogeny and studying hybridization.
PMCID: PMC5209741  PMID: 28051161
16.  Iron Status in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis 
PLoS ONE  2017;12(1):e0169145.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children. However, the pathogenesis of ADHD remains unclear. Iron, an important trace element, is implicated in brain function and dopaminergic activity. Recent studies have investigated the association between iron deficiency and ADHD, but the results are inconsistent.
A systemic search of MEDLINE, EMBASE, Web of Science and Cochrane Library databases was supplemented by manual searches of references of key retrieved articles. Study quality was evaluated using the Newcastle-Ottawa Scale. The standardised mean difference (SMD) and 95% confidence intervals (CIs) were calculated using a random-effects model. H2 and I2 were used to evaluate the heterogeneity, and sensitivity, subgroup and meta-regression analyses were conducted to explore the reason of heterogeneity.
The search yielded 11 studies published before July 25, 2016. Of these, 10 studies, comprising 2191 participants and 1196 ADHD cases, reported serum ferritin levels, and six studies, comprising 617 participants and 369 ADHD cases, reported serum iron levels. Serum ferritin levels were lower in ADHD cases (SMD = -0.40, 95% CI = -0.66 to -0.14). However, we found no correlation between serum iron levels and ADHD (SMD = -0.026, 95% CI = -0.29 to 0.24). Meta-regression analysis indicated that publication year, age, gender, sample size, and Hb levels did not significantly influence the pooled estimates of serum ferritin.
Lower serum ferritin rather than serum iron is associated with ADHD in children.
PMCID: PMC5207676  PMID: 28046016
17.  Hematopoietic stem and multipotent progenitor cells produce IL-17, IL-21 and other cytokines in response to TLR signals associated with late apoptotic products and augment memory Th17 and Tc17 cells in the bone marrow of normal and lupus mice 
We studied effects of early and late apoptotic (necroptotic) cell products, related damage associated alarmins and TLR agonists, on hematopoietic stem and progenitor cells (HSPC).1 Surprisingly, normal HSPC themselves produced IL-17 and IL-21 after 1½ days of stimulation, and the best stimulators were TLR7/8 agonist; HMGB1-DNA; TLR9 agonist, and necroptotic B cells. The stimulated HSPC expressed additional cytokines/mediators, directly causing rapid expansion of IL-17+ memory CD4 T (Th17), and CD8 T (Tc17) cells, and antigen-experienced IL-17+ T cells with “naïve” phenotype. In lupus marrow, HSPC were spontaneously pre-stimulated by endogenous signals to produce IL-17 and IL-21. In contrast to HSPC, megakaryocyte progenitors (MKP) did not produce IL-17, and unlike HSPC, they could process and present particulate apoptotic autoantigens to augment autoimmune memory Th17 response. Thus abnormally stimulated primitive hematopoietic progenitors augment expansion of IL-17 producing immune and autoimmune memory T cells in the bone marrow, which may affect central tolerance.
PMCID: PMC4698105  PMID: 26521071
Hematopoietic progenitors; Memory Th17/Tc17 cells; Apoptosis; TLR signals; Cytokines; Lupus; Bone marrow
Individuals with cerebral palsy tend to have altered muscle architecture and composition, but little is known about the muscle material properties, specifically stiffness. Shear wave ultrasound elastography allows shear wave speed, which is related to stiffness, to be measured in vivo in individual muscles. Our aim was to evaluate the material properties, specifically stiffness, as measured by shear wave speed of the medial gastrocnemius and tibialis anterior muscles in children with hemiplegic cerebral palsy across a range of ankle torques and positions, and fascicle strains.
Shear wave speed was measured bilaterally in the medial gastrocnemius and tibialis anterior over a range of ankle positions and torques using shear wave ultrasound elastography in eight individuals with hemiplegic cerebral palsy. B-mode ultrasound was used to measure muscle thickness and fascicle strain.
Shear waves traveled faster in the medial gastrocnemius and tibialis anterior of the more-affected limb by 14% (p=0.024) and 20% (p=0.03), respectively, when the ankle was at 90°. Shear wave speed in the medial gastrocnemius increased as the ankle moved from plantarflexion to dorsiflexion (less affected: r2=0.82,p<0.001; more-affected: r2=0.69,p<0.001) and as ankle torque increased (less affected: r2=0.56,p<0.001; more-affected: r2=0.45,p<0.001). In addition, shear wave speed was strongly correlated with fascicle strain (less affected: r2=0.63,p<0.001; more-affected: r2=0.53,p<0.001).
The higher shear wave speed in the more-affected limb of individuals with cerebral palsy indicates greater muscle stiffness, and demonstrates the clinical potential of shear wave elastography as a non-invasive tool for investigating mechanisms of altered muscle properties and informing diagnosis and treatment.
PMCID: PMC4729598  PMID: 26490641
cerebral palsy; muscle; ultrasound; shear wave elastography
19.  T1ρ relaxation time in brain regions increases with ageing: an experimental MRI observation in rats 
The British Journal of Radiology  2015;89(1057):20140704.
T1ρ variation is associated with neurodegenerative diseases. This study aims to observe T1ρ relaxation time changes in rat brains associated with normal ageing in Sprague–Dawley (SD) rats, Wistar Kyoto (WKY) rats and spontaneously hypertension rats (SHRs).
18 male SD rats, 11 male WKY rats and 11 male SHRs were used. T1ρ measurement was performed at 3-T MR with a spin-lock frequency of 500 Hz. SD rats were scanned at the ages of 5, 8, 10 and 15 months. SHRs and WKY rats were scanned at the ages of 6, 9 and 12 months.
For SD rats, T1ρ at the thalamus, hippocampus and frontal cortices increased significantly from 5 to 15 months (p < 0.05). For the WKY rats and SHRs, the T1ρ values in the thalamus, hippocampus and frontal cortices also increased significantly from 6 to 12 months (p < 0.05). Furthermore, T1ρ in the thalamus, hippocampus and frontal cortices of SHRs were consistently higher than those of WKY rats at the ages of 6, 9 and 12 months (p < 0.05). The percentage regional T1ρ differences between WKY rats and SHRs did not change during ageing.
An increase in T1ρ was associated with age-related changes of the rat brain.
Advances in knowledge:
An age-related and hypertension-related T1ρ increase in rat brain regions was observed in the thalamus, hippocampus and frontal cortical regions of the rat brain.
PMCID: PMC4985938  PMID: 26529226
20.  Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction 
Theranostics  2017;7(1):51-66.
Hypoxia-inducible factor 1α (HIF-1α) plays a critical protective role in ischemic heart disease. Under normoxic conditions, HIF-1α was degraded by oxygen-dependent prolyl hydroxylase-2 (PHD2). Gene therapy has become a promising strategy to inhibit the degradation of HIF-1α and to improve cardiac function after ischemic injury. However, conventional gene delivery systems are difficult to achieve a targeted and localized gene delivery into the ischemic myocardia. Here, we report the localized myocardial delivery of shRNA against PHD2 through ultrasound-targeted microbubble destruction (UTMD) for protection the heart from acute myocardial infarction. In this study, a novel cationic microbubble was fabricated by using of the thin-film hydration and sonication method. The resulting microbubbles had a 28.2 ± 2.21 mV surface zeta potential and could greatly improve DNA binding performance, achieving 17.81 ± 1.46 μg of DNA loading capacity per 5 × 108 microbubbles. Combined with these cationic microbubbles, UTMD-mediated gene delivery was evaluated and the gene transfection efficiency was optimized in the H9C2 cardiac cells. Knockdown of PHD2 gene was successfully realized by UTMD-mediated shPHD2 transfection, resulting in HIF-1α-dependent protective effects on H9C2 cells through increasing the expression of HIF-1α, VEGF and bFGF. We further employed UTMD-mediated shPHD2 transfection into the localized ischemic myocardia in a rat ischemia model, demonstrating significantly reduced infarct size and greatly improved the heart function. The silencing of PHD2 and the up-regulation of its downstream genes in the treated myocardia were confirmed. Histological analysis further revealed numbers of HIF-1α- and VEGF-, and CD31-positive cells/mm2 in the shPHD2-treated group were significantly greater than those in the sham or control vector groups (P < 0.05). In conclusion, our study provides a promising strategy to realize ultrasound-mediated localized myocardial shRNA delivery to protect the heart from acute myocardial infarction via cationic microbubbles.
PMCID: PMC5196885  PMID: 28042316
Prolyl hydroxylase-2; Ischemic myocardial disease; Gene delivery; Ultrasound; Cationic microbubbles.
21.  Inhibition by Multifunctional Magnetic Nanoparticles Loaded with Alpha-Synuclein RNAi Plasmid in a Parkinson's Disease Model 
Theranostics  2017;7(2):344-356.
Lewy bodies are considered as the main pathological characteristics of Parkinson's disease (PD). The major component of Lewy bodies is α-synuclein (α-syn). The use of gene therapy that targeting and effectively interfere with the expression of α-syn in neurons has received tremendous attention. In this study, we used magnetic Fe3O4 nanoparticles coated with oleic acid molecules as a nano-carrier. N-isopropylacrylamide derivative (NIPAm-AA) was photo-immobilized onto the oleic acid molecules, and shRNA (short hairpin RNA) was absorbed. The same method was used to absorb nerve growth factor (NGF) to NIPAm-AA to specifically promote neuronal uptake via NGF receptor-mediated endocytosis. Additionally, shRNA plasmid could be released into neurons because of the temperature and pH sensitivity of NIPAm-AA interference with α-syn synthesis. We investigated apoptosis in neurons with abrogated α-syn expression in vitro and in vivo. The results demonstrated that multifunctional superparamagnetic nanoparticles carrying shRNA for α-syn could provide effective repair in a PD model.
PMCID: PMC5197069  PMID: 28042339
Fe3O4 nanoparticles; shRNA; RNAi; α-synuclein; Parkinson's disease.
22.  Metabolism and excretion of novel pulmonary-targeting docetaxel liposome in rabbits 
Our study aims to determine the metabolism and excretion of novel pulmonary-targeting docetaxel liposome (DTX-LP) using the in vitro and in vivo animal experimental models. The metabolism and excretion of DTX-LP and intravenous DTX (DTX-IN) in New Zealand rabbits were determined with ultraperformance liquid chromatography tandem mass spectrometry. We found DTX-LP and DTX-IN were similarly degraded in vitro by liver homogenates and microsomes, but not metabolized by lung homogenates. Ultra-performance liquid chromatography tandem mass spectrometry identified two shared DTX metabolites. The unconfirmed metabolite Mun differed structurally from all DTX metabolites identified to date. DTX-LP likewise had a similar in vivo metabolism to DTX-IN. Conversely, DTX-LP showed significantly diminished excretion in rabbit feces or urine, approximately halving the cumulative excretion rates compared to DTX-IN. Liposomal delivery of DTX did not alter the in vitro or in vivo drug metabolism. Delayed excretion of pulmonary-targeting DTX-LP may greatly enhance the therapeutic efficacy and reduce the systemic toxicity in the chemotherapy of non-small cell lung cancer. The identification of Mun may further suggest an alternative species-specific metabolic pathway.
PMCID: PMC5214910  PMID: 28066140
Animal model; Chemotherapy; Cumulative excretion rate; Liquid chromatography; Lung cancer; Mass spectrometry
23.  Jagged1 upregulation in prostate epithelial cells promotes formation of reactive stroma in the Pten null mouse model for prostate cancer 
Oncogene  2016;10.1038/onc.2016.232.
The role of Notch signaling in prostate cancer has not been defined definitively. Several large scale tissue microarray studies revealed that the expression of some Notch signaling components including the Jagged1 ligand are upregulated in advanced human prostate cancer specimens. Jagged1 expressed by tumor cells may activate Notch signaling in both adjacent tumor cells and cells in tumor microenvironment. However, it remains undetermined whether increased Jagged1 expression reflects a cause for or a consequence of tumor progression in vivo. To address this question, we generated a novel R26-LSL-JAG1 mouse model that enables spatiotemporal Jagged1 expression. Prostate specific upregulation of Jagged1 neither interferes with prostate epithelial homeostasis nor significantly accelerates tumor initiation or progression in the prostate-specific Pten deletion mouse model for prostate cancer. However, Jagged1 upregulation results in increased inflammatory foci in tumors and incidence of intracystic adenocarcinoma. In addition, Jagged1 overexpression upregulates Tgfβ signaling in prostate stromal cells and promotes progression of a reactive stromal microenvironment in the Pten null prostate cancer model. Collectively, Jagged1 overexpression does not significantly accelerate prostate cancer initiation and progression in the context of loss-of-function of Pten, but alters tumor histopathology and microenvironment. Our study also highlights an understudied role of Notch signaling in regulating prostatic stromal homeostasis.
PMCID: PMC5192002  PMID: 27345403
Notch; Jagged1; Pten; prostate cancer; reactive stroma
24.  Ginsenoside Rg3 Improves Cardiac Function after Myocardial Ischemia/Reperfusion via Attenuating Apoptosis and Inflammation 
Objectives. Ginsenoside Rg3 is one of the ginsenosides which are the main constituents isolated from Panax ginseng. Previous study demonstrated that ginsenoside Rg3 had a protective effect against myocardial ischemia/reperfusion- (I/R-) induced injury. Objective. This study was designed to evaluate the effect of ginsenoside Rg3 on cardiac function impairment induced by myocardial I/R in rats. Methods. Sprague-Dawley rats were subjected to myocardial I/R. Echocardiographic and hemodynamic parameters and histopathological examination were carried out. The expressions of P53, Bcl-2, Bax, and cleaved caspase-3 and the levels of TNF-α and IL-1β in the left ventricles were measured. Results. Ginsenoside Rg3 increased a left ventricular fractional shortening and left ventricular ejection fraction. Treatment with ginsenoside Rg3 also alleviated increases of left ventricular end diastolic pressure and decreases of left ventricular systolic pressure and ±dp/dt in myocardial I/R-rats. Ginsenoside Rg3 decreased apoptosis cells through inhibiting the activation of caspase-3. Ginsenoside Rg3 also caused significant reductions of the contents of TNF-α and IL-1β in left ventricles of myocardial I/R-rats. Conclusion. The findings suggested that ginsenoside Rg3 possessed the effect of improving myocardial I/R-induced cardiac function impairment and that the mechanism of pharmacological action of ginsenoside Rg3 was related to its properties of antiapoptosis and anti-inflammation.
PMCID: PMC5220470
25.  Targeting Triple Negative Breast Cancer with a Small-sized Paramagnetic Nanoparticle 
There is no available targeted therapy or imaging agent for triple negative breast cancer (TNBC). We developed a small-sized dendrimer-based nanoparticle containing a clinical relevant MRI contrast agent, GdDOTA and a NIR fluorescent dye, DL680. Systemic delivery of dual-modal nanoparticles led to accumulation of the agents in a flank mouse model of TNBC that were detected by both optical and MR imaging. In-vivo fluorescence images, as well as ex-vivo fluorescence images of individual organs, demonstrated that nanoparticles accumulated into tumor selectively. A dual modal strategy resulted in a selective delivery of a small-sized (GdDOTA)42-G4-DL680 dendrimeric agent to TNBC tumors, avoiding other major organs.
PMCID: PMC5180609  PMID: 28018751
Triple negative breast cancer; Dual modality; MRI; Optical imaging

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