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1.  Study on In-Vivo Anti-Tumor Activity of Verbena Officinalis Extract 
We investigated the anti-tumor effects of Verbena officinalis extract on H22 tumor-bearing mice and its effect on immune function. Mice model of H22 solid tumor was established, the mice were divided into five groups and administered the extract, later, tumors were removed and inhibition rates were calculated; spleens were removed and spleen indices were calculated, and the sheep red blood cell-delayed-type hypersensitivity (SRBC-DTH) and the serum hemolysin level were determined. The Verbena officinalis extract had anti-tumor effect, with the inhibition rate reaching 38.78%, it also increased the spleen index to a certain extent, in addition, the changes in DTA and HA were not obvious compared with the model group. The Verbena officinalis extract had in vivo anti-tumor effect, while causing no damage on the immune function.
PMCID: PMC3777594  PMID: 24146482
Verbena officinalis extract; H22 mouse; tumor inhibition; immune function
2.  Reduced growth and proliferation dynamics of nasal epithelial stem/progenitor cells in nasal polyps in vitro 
Scientific Reports  2014;4:4619.
Basal cells in nasal epithelium have stemness/progenitor characters and play essential roles in the epithelial remodeling in nasal polyps (NP). We investigate whether the human nasal epithelial stem/progenitor cells (hNESPCs) from patients with NP are inherently distinct from those obtained from healthy controls. Epithelial basal cells were isolated and cultured for four passages from NP tissues and control nasal mucosa. hNESPCs from controls were stained positively with stem cell marker p63 and KRT5 and presented a consistent high Ki67 expression level over four passages. In contrast, hNESPCs from NP patients showed: i). a reduced growth and proliferation rate at each passage by evaluating colony-forming efficiency and doubling time; ii). a lower percentage of Ki67+ cells among p63+ cells in the colonies in late passages, which was also confirmed by immunostaining in the NP tissues. Thus reduced growth/proliferation dynamics in hNESPCs from NP could be an important pathological phenomenon in NP development.
doi:10.1038/srep04619
PMCID: PMC3980221  PMID: 24714674
3.  Personal electronics printing via tapping mode composite liquid metal ink delivery and adhesion mechanism 
Scientific Reports  2014;4:4588.
Printed electronics is becoming increasingly important in a variety of newly emerging areas. However, restricted to the rather limited conductive inks and available printing strategies, the current electronics manufacture is usually confined to industry level. Here, we show a highly cost-effective and entirely automatic printing way towards personal electronics making, through introducing a tapping-mode composite fluid delivery system. Fundamental mechanisms regarding the reliable printing, transfer and adhesion of the liquid metal inks on the substrate were disclosed through systematic theoretical interpretation and experimental measurements. With this liquid metal printer, a series of representative electronic patterns spanning from single wires to desired complex configurations such as integrated circuit (IC), printed-circuits-on-board (PCB), electronic paintings, or more do-it-yourself (DIY) devices, were demonstrated to be printed out with high precision in a moment. And the total machine cost already reached personally affordable price. This is hard to achieve by a conventional PCB technology which generally takes long time and is material, water and energy consuming, while the existing printed electronics is still far away from the real direct printing goal. The present work opens the way for large scale personal electronics manufacture and is expected to generate important value for the coming society.
doi:10.1038/srep04588
PMCID: PMC3975221  PMID: 24699375
4.  Prevalence of Serological Markers for Hepatitis B and C Viruses in Brazilian Blood Donors, and Incidence and Residual Risk of Transfusion-Transmission of Hepatitis C Virus 
Transfusion  2012;53(4):827-834.
Background
We evaluate the current prevalence of serological markers for HBV and HCV in blood donors and estimated HCV incidence and residual transfusion-transmitted risk at three large Brazilian blood centers.
Material and Methods
Data on whole blood and platelet donations were collected from January through December 2007 and analyzed by center, donor type (replacement vs. community), age, sex, donation status (first-time vs. repeat), and serological results for HBsAg, anti-HBc and anti-HCV. HBV (HBsAg+/anti-HBc+) and HCV (anti-HCV) prevalence rates were calculated for all first time donations. HCV incidence was derived including inter-donation intervals that preceded first repeat donations given during the study and HCV residual risk was estimated for transfusions derived from repeat donors.
Results
There were 307,354 donations from January through December 2007. Overall prevalence of concordant HBsAg and anti-HBc reactivity was 289 per 100,000 donations and of anti-HCV confirmed reactivity 191 per 100,000 donations. There were significant associations between older age and hepatitis markers, especially for HCV. HCV incidence was 3.11 (95% CI 0.77-7.03) per 100,000 person-years, and residual risk of HCV window-phase infections was estimated at 5.0 per million units transfused.
Conclusion
Improvement in blood donor selection, socioeconomic conditions and preventive measures, implemented over time, may have helped to decrease prevalence of hepatitis B and C viruses, relative to previous reports. Incidence and residual risk of HCV are also diminishing. Ongoing monitoring of hepatitis B and C viral markers among Brazilian blood donors should help guide improved recruitment procedures, donor selection, laboratory screening methods and counseling strategies.
doi:10.1111/j.1537-2995.2012.03840.x
PMCID: PMC3499633  PMID: 22882510
Blood donors; Brazil; Residual Risk; Hepatitis B; Hepatitis C; Prevalence; Incidence
5.  Value of Serum Procalcitonin in Evaluating the Prognosis of Sepsis in Elderly Patients with Colorectal Cancer Undergoing Emergency Colorectal Surgery 
The Indian Journal of Surgery  2012;75(2):86-93.
Serum procalcitonin (PCT) levels may have predictive value in the prognosis of postoperative sepsis in elderly patients who have undergone colorectal surgery for colorectal cancer in intensive care units (ICUs). A prospective study involving 90 critically ill patients who underwent colorectal surgery for colorectal cancer in ICUs was performed. Twenty-eight patients were diagnosed with sepsis, in accordance with the American College of Chest Physicians/Society of Critical Care Medicine consensus criteria, and these patients were included in the sepsis group. Sixty-two patients, who were without evidence of sepsis, were enrolled in the control group. We measured the serum PCT concentrations preoperatively (immediately before induction of anesthesia), upon arrival in the ICU (ICU day 0), on the morning of the first postoperative day (postoperative day 1), and on the morning of the third postoperative day (postoperative day 3). The C-reactive protein (CRP) index, acute physiology and chronic health evaluation II (APACHE II) score, mechanical duration of ventilation, mortality rate, incidence of multiple organ failure, and usage of continuous renal replacement therapy were evaluated. The area under the curve for the receiver operating characteristic curve (AUC-ROCC) was measured to explore the association between the serum PCT and the prognosis. In the sepsis group, 12/28 patients died (mortality rate 43 %). In the control group, 6/62 patients died (mortality rate 9.7 %). On the first postoperative day, the serum PCT level was dramatically higher in the sepsis group than in the control group (2.71 ± 1.13 vs. 1.37 ± 0.57, P ≤ 0.05). The PCT level on the first postoperative day was distinctly higher than that measured upon arrival in the ICU (2.71 ± 1.13 vs. 1.31 ± 0.58, P ≤ 0.05). In the two groups, the CRP concentrations were both markedly higher on the first postoperative day than upon arrival in the ICU (138.89 ± 45.12 vs. 70.43 ± 23.54 in the sepsis group, and 133.13 ± 44.91 vs. 69.65 ± 24.98 in the control group, P ≤ 0.05). Linear regression analysis was performed. The results suggest that the PCT and APACHE-II scores were not significantly associated. On the first and third postoperative days, the PCT levels were associated with increased odds of sepsis (AUC-ROCC, 95 % confidence interval 0.817–0.973, P = 0.000, and 0.755–0.944, P = 0.000, respectively). The outcomes of patients in the sepsis group were worse than those in the control group. PCT levels appear to be early markers of postoperative sepsis in elderly patients undergoing colorectal surgery for colorectal cancer during the ICU course. These findings could allow for early identification of postoperative septic complications and be used for prognostic evaluation of these patients.
doi:10.1007/s12262-012-0631-4
PMCID: PMC3644167  PMID: 24426400
Elderly patients; Sepsis; Emergency colorectal surgery; Procalcitonin; Prognosis
6.  A Novel MRI-compatible Tactile Stimulator for Cortical Mapping of Foot Sole Pressure Stimuli with fMRI 
Foot sole somatosensory feedback is critical to motor control and declines with aging and disease. To enable study of cortical networks underlying foot sole somatosensation we developed a pneumatic tactile stimulator capable of producing 1-DOF oscillations with preset waveform, frequency (≤10 Hz), force magnitude (5-500 N), duty cycle (20%-100%) and contacted surface area over which pressures are applied to the foot sole. Image tests (anatomical/functional/field map) of a phantom demonstrated that the device is compatible with 3T MRI. GRE-EPI images of seven healthy young adults using a typical block-designed 1Hz sinusoidal stimulation protocol revealed significant activation contralaterally within the primary somatosensory cortex and paracentral gyrus, and bilaterally within the secondary somatosensory cortex. The stimulation system may therefore serve as a research tool to study functional brain networks involved in the perception and modulation of foot sole somatosensation and its relationship to motor control.
doi:10.1002/mrm.24330
PMCID: PMC3704153  PMID: 22678849
Plantar; somatosensory; gait; feedback; pneumatic
7.  A Fungal Insecticide Engineered for Fast Per Os Killing of Caterpillars Has High Field Efficacy and Safety in Full-Season Control of Cabbage Insect Pests 
Applied and Environmental Microbiology  2013;79(20):6452-6458.
Fungal insecticides developed from filamentous pathogens of insects are notorious for their slow killing action through cuticle penetration, depressing commercial interest and practical application. Genetic engineering may accelerate their killing action but cause ecological risk. Here we show that a Beauveria bassiana formulation, HV8 (BbHV8), engineered for fast per os killing of caterpillars by an insect midgut-acting toxin (Vip3Aa1) overexpressed in conidia has both high field efficacy and safety in full-season protection of cabbage from the damage of an insect pest complex dominated by Pieris rapae larvae, followed by Plutella xylostella larvae and aphids. In two fields repeatedly sprayed during summer, BbHV8 resulted in overall mean efficacies of killing of 71% and 75%, which were similar or close to the 70% and 83% efficacies achieved by commercially recommended emamectin benzoate but much higher than the 31% and 48% efficacies achieved by the same formulation of the parental wild-type strain (WT). Both BbHV8 and WT sprays exerted no adverse effect on a nontarget spider community during the trials, and the sprays did not influence saprophytic fungi in soil samples taken from the field plots during 4 months after the last spray. Strikingly, BbHV8 and the WT showed low fitness when they were released into the environment because both were decreasingly recovered from the field lacking native B. bassiana strains (undetectable 5 months after the spray), and the recovered isolates became much less tolerant to high temperature and UV-B irradiation. Our results highlight for the first time that a rationally engineered fungal insecticide can compete with a chemical counterpart to combat insect pests at an affordable cost and with low ecological risk.
doi:10.1128/AEM.01594-13
PMCID: PMC3811226  PMID: 23956386
8.  Unusual Compression Behavior of Nanocrystalline CeO2 
Scientific Reports  2014;4:4441.
The x-ray diffraction study of 12 nm CeO2 was carried out up to ~40 GPa using an angle dispersive synchrotron-radiation in a diamond-anvil cell with different pressure transmitting medium (PTM) (4:1 methanol: ethanol mixture, silicone oil and none) at room temperature. While the cubic fluorite-type structure CeO2 was retained to the highest pressure, there is progressive broadening and intensity reduction of the reflections with increasing pressure. At pressures above 12 GPa, an unusual change in the compression curve was detected in all experiments. Significantly, apparent negative volume compressibility was observed at P = 18–27 GPa with silicone oil as PTM, however it was not detected in other circumstances. The expansion of the unit cell volume of cubic CeO2 was about 1% at pressures of 15–27 GPa. To explain this abnormal phenomenon, a dual structure model (hard amorphous shell and relatively soft crystalline core) has been proposed.
doi:10.1038/srep04441
PMCID: PMC3963033  PMID: 24658049
9.  The Epidemic Characteristics and Changing Trend of Hemorrhagic Fever with Renal Syndrome in Hubei Province, China 
PLoS ONE  2014;9(3):e92700.
Background
Hemorrhagic fever with renal syndrome (HFRS) is caused by different hantaviruses within the Bunyaviridae family. HFRS is a fulminant, infectious disease that occurs worldwide and is endemic in all 31 provinces of China. Since the first HFRS case in Hubei Province was reported in 1957, the disease has spread across the province and Hubei has become one of the seriously affected areas in China with the greatest number of reported HFRS cases in the 1980's. However, the epidemic characteristics of HFRS in Hubei are still not entirely clear and long-term, systematic investigations of this epidemic area have been very limited.
Methods
The spatiotemporal distribution of HFRS was investigated using data spanning the years 1980 to 2009. The annual HFRS incidence, fatality rate and seasonal incidence between 1980 and 2009 were calculated and plotted. GIS-based spatial analyses were conducted to detect the spatial distribution and seasonal pattern of HFRS. A spatial statistical analysis, using Kulldorff's spatial scan statistic, was performed to identify clustering of HFRS.
Results
A total of 104,467 HFRS cases were reported in Hubei Province between 1980 and 2009. Incidence of and mortality due to HFRS declined after the outbreak in 1980s and HFRS cases have been sporadic in recent years. The locations and scale of disease clusters have changed during the three decades. The seasonal epidemic pattern of HFRS was characterized by the shift from the unimodal type (autumn/winter peak) to the bimodal type.
Conclusions
Socioeconomic development has great influence on the transmission of hantaviruses to humans and new epidemic characteristics have emerged in Hubei Province. It is necessary to reinforce preventative measures against HFRS according to the newly-presented seasonal variation and to intensify these efforts especially in the urban areas of Hubei Province.
doi:10.1371/journal.pone.0092700
PMCID: PMC3962441  PMID: 24658382
10.  Association of PKCζ Expression with Clinicopathological Characteristics of Breast Cancer 
PLoS ONE  2014;9(3):e90811.
The protein kinase C (PKC) family has been functionally linked to cancer. It has been suggested that atypical PKCs contribute to cell proliferation and cancer progression. With respect to breast cancer, PKCζ has been found to play a key role in intracellular transduction of mitogenic and apoptotic signals using mammary cell lines. However, little is known about its function in vivo. Here we examined the correlation between PKCζ protein levels and important clinicopathologic factors in breast cancer using patient samples. To conduct the study, 30 invasive ductal carcinoma cases and their paired normal tissues were used for tissue microarray analysis (TMA) and 16 were used for western blot analysis. In addition, the correlation between PKCζ expression levels and clinicopathologic characteristics was determined in 176 cases with relevant clinical data. Finally, the correlation between PKCζ and epithelial growth factor receptor 2 (HER2) expressions was determined using three breast cancer cell lines by western blot analysis. Both TMA and western blot results showed that PKCζ protein was highly expressed in primary tumors but not in paired normal tissue. The correlation study indicated that high PKCζ levels were associated with premenopausal patients (p = 0.019) and worse prognostic factors, such as advanced clinical stage, more lymph node involvement and larger tumor size. Both disease-free survival and overall survival rates were lower in the high PKCζ group than those in the low PKCζ group. No correlation was observed between PKCζ levels and age, histological grade, or estrogen or progesterone receptor expression status. A positive correlation between PKCζ and HER2 levels was observed in both tumor samples and cell lines. Our observations link PKCζ expression with factors pointing to worse prognosis, higher HER2 levels and a lower survival rate. This suggests that PKCζ protein levels may serve as a prognostic marker of breast cancer.
doi:10.1371/journal.pone.0090811
PMCID: PMC3946230  PMID: 24603690
11.  p62/SQSTM1 Accumulation in Squamous Cell Carcinoma of Head and Neck Predicts Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitors 
PLoS ONE  2014;9(3):e90171.
The phosphoinositol-3 kinase (PI3K) pathway is highly dysregulated in squamous cell carcinoma of the head and neck (SCCHN). While inhibitors of the PI3K/AKT pathway are being developed in cancer, their efficacy does not appear to be related to the presence of mutations or amplification in pathway genes. The PI3K pathway is a major regulator of macro-autophagy, an evolutionarily conserved catabolic process that degrades cellular materials to promote cellular homeostasis and survival under stress. Employing a panel of SCCHN cell lines, we observed a significant correlation between the activity of PI3K/AKT inhibitors and their ability to induce autophagy. More specifically, resistance to these inhibitors was associated with accumulation of p62/SQSTM1, a pleotropic protein that is consumed during autophagy, while loss of autophagy was, for the first time, found to be due to silencing of an essential autophagy gene, ATG7. Moreover, modulating ATG7 and p62/SQSTM1 could regulate sensitivity to PI3K/AKT inhibitors, underscoring a mechanistic link between autophagy and drug sensitivity. Analysis of human tissues revealed progressive accumulation of p62/SQSTM1 in a significant proportion of cancer samples compared to normal tissue, suggesting that defective autophagy has relevance to SCCHN. These findings are further validated by analysis of TCGA data confirming homozygous deletion and mRNA down-regulation of ATG7 in 10.0% of SCCHN samples. Taken together, these data indicate that p62/SQSTM1 levels modulate sensitivity to PI3K/AKT inhibitors; cancers vary in their capacity to undergo autophagy through epigenetic modification and, when deficient, accumulate p62/SQSTM1; and expression of autophagy-related proteins may serve as markers for resistance to PI3K/AKT inhibitors in SCCHN.
doi:10.1371/journal.pone.0090171
PMCID: PMC3943907  PMID: 24599075
12.  The Severe Adverse Reaction to Vitamin K1 Injection Is Anaphylactoid Reaction but Not Anaphylaxis 
PLoS ONE  2014;9(3):e90199.
The severe adverse reaction to vitamin K1 injection is always remarkable and is thought to result from anaphylaxis. Paradoxically, however, some patients administered vitamin K1 injection for the first time have adverse reactions. Using beagle dogs, the present study tested the hypothesis that the response to vitamin K1 is an anaphylactoid reaction. The results showed that serious anaphylaxis-like symptoms appeared in beagle dogs after the administration of vitamin K1 injection for the first time. The plasma histamine concentration increased, and blood pressure decreased sharply. After sensitization, dogs were challenged with vitamin K1 injection and displayed the same degree of symptoms as prior to sensitization. However, when the vitamin K1 injection-sensitized dogs were challenged with a vitamin K1-fat emulsion without solubilizers such asTween-80, the abnormal reactions did not occur. Furthermore, there was no significant change in the plasma immunoglobulin E concentration after vitamin K1 challenge. Following treatment with vitamin K1 injection, the release of histamine and β-hexosaminidase by rat basophilic leukemia-2H3 cells as well as the rate of apoptosis increased. The Tween-80 group displayed results similar to those observed following vitamin K1 injection in vivo. However, the dogs in the vitamin K1-fat emulsion group did not display any abnormal behavior or significant change in plasma histamine. Additionally, degranulation and apoptosis did not occur in rat basophilic leukemia-2H3 cells. Our results indicate that the adverse reaction induced by vitamin K1 injection is an anaphylactoid reaction, not anaphylaxis. Vitamin K1 injection induces the release of inflammatory factors via a non-IgE-mediated immune pathway, for which the trigger may be the solubilizer.
doi:10.1371/journal.pone.0090199
PMCID: PMC3942416  PMID: 24594861
13.  Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling 
Nature chemical biology  2013;9(9):557-564.
Oxysterols bind the seven-spanner transmembrane protein Smoothened and potently activate vertebrate Hedgehog signaling, a pathway essential in embryonic development, adult stem cell maintenance and cancer. It is unknown, however, if oxysterols are important for normal vertebrate Hedgehog signaling, and whether antagonizing oxysterols can inhibit the Hedgehog pathway. We developed azasterols that block Hedgehog signaling by binding the oxysterol-binding site of Smoothened. We show that the binding site for oxysterols and azasterols maps to the extracellular, cysteine-rich domain of Smoothened, and is completely separable from the site bound by other small molecule modulators, located within the heptahelical bundle of Smoothened. Smoothened mutants in which oxysterol binding is abolished no longer respond to oxysterols, and cannot be maximally activated by the Hedgehog ligand. Our results show that oxysterol binding to vertebrate Smoothened is required for normal Hedgehog signaling, and that targeting the oxysterol binding site is an effective strategy to inhibit Smoothened.
doi:10.1038/nchembio.1290
PMCID: PMC3749252  PMID: 23831757
14.  The Interaction Effects of pri-let-7a-1 rs10739971 with PGC and ERCC6 Gene Polymorphisms in Gastric Cancer and Atrophic Gastritis 
PLoS ONE  2014;9(2):e89203.
Background
The aim of this study was to investigate the interaction effects of pri-let-7a-1 rs10739971 with pepsinogen C (PGC) and excision repair cross complementing group 6 (ERCC6) gene polymorphisms and its association with the risks of gastric cancer and atrophic gastritis. We hoped to identify miRNA polymorphism or a combination of several polymorphisms that could serve as biomarkers for predicting the risk of gastric cancer and its precancerous diseases.
Methods
Sequenom MassARRAY platform method was used to detect polymorphisms of pri-let-7a-1 rs10739971 G→A, PGC rs4711690 C→G, PGC rs6458238 G→A, PGC rs9471643 G→C, and ERCC6 rs1917799 in 471 gastric cancer patients, 645 atrophic gastritis patients and 717 controls.
Results
An interaction effect of pri-let-7a-1 rs10739971 polymorphism with ERCC6 rs1917799 polymorphism was observed for the risk of gastric cancer (Pinteraction = 0.026); and interaction effects of pri-let-7a-1 rs10739971 polymorphism with PGC rs6458238 polymorphism (Pinteraction = 0.012) and PGC rs9471643 polymorphism (Pinteraction = 0.039) were observed for the risk of atrophic gastritis.
Conclusion
The combination of pri-let-7a-1 rs10739971 polymorphism and ERCC6 and PGC polymorphisms could provide a greater prediction potential than a single polymorphism on its own. Large-scale studies and molecular mechanism research are needed to confirm our findings.
doi:10.1371/journal.pone.0089203
PMCID: PMC3934903  PMID: 24586594
15.  Cell-specific translational profiling in acute kidney injury 
The Journal of Clinical Investigation  2014;124(3):1242-1254.
Acute kidney injury (AKI) promotes an abrupt loss of kidney function that results in substantial morbidity and mortality. Considerable effort has gone toward identification of diagnostic biomarkers and analysis of AKI-associated molecular events; however, most studies have adopted organ-wide approaches and have not elucidated the interplay among different cell types involved in AKI pathophysiology. To better characterize AKI-associated molecular and cellular events, we developed a mouse line that enables the identification of translational profiles in specific cell types. This strategy relies on CRE recombinase–dependent activation of an EGFP-tagged L10a ribosomal protein subunit, which allows translating ribosome affinity purification (TRAP) of mRNA populations in CRE-expressing cells. Combining this mouse line with cell type–specific CRE-driver lines, we identified distinct cellular responses in an ischemia reperfusion injury (IRI) model of AKI. Twenty-four hours following IRI, distinct translational signatures were identified in the nephron, kidney interstitial cell populations, vascular endothelium, and macrophages/monocytes. Furthermore, TRAP captured known IRI-associated markers, validating this approach. Biological function annotation, canonical pathway analysis, and in situ analysis of identified response genes provided insight into cell-specific injury signatures. Our study provides a deep, cell-based view of early injury-associated molecular events in AKI and documents a versatile, genetic tool to monitor cell-specific and temporal-specific biological processes in disease modeling.
doi:10.1172/JCI72126
PMCID: PMC3938273  PMID: 24569379
16.  Self-Gated Free-Breathing 3D Coronary CINE Imaging with Simultaneous Water and Fat Visualization 
PLoS ONE  2014;9(2):e89315.
The aim of this study was to develop a novel technique for acquiring 3-dimensional (3D) coronary CINE magnetic resonance images with both water and fat visualization during free breathing and without external respiratory or cardiac gating. The implemented multi-echo hybrid 3D radial balanced Steady-State Free Precession (SSFP) sequence has an efficient data acquisition and is robust against motion. The k-space center along the slice encoding direction was repeatedly acquired to derive both respiratory and cardiac self-gating signals without an increase in scan time, enabling a free-breathing acquisition. The multi-echo acquisition allowed image reconstruction with water-fat separation, providing improved visualization of the coronary artery lumen. Ten healthy subjects were imaged successfully at 1.5 T, achieving a spatial resolution of 1.0×1.0×3.0 mm3 and scan time of about 5 minutes. The proposed imaging technique provided coronary vessel depiction comparable to that obtained with conventional breath-hold imaging and navigator gated free-breathing imaging.
doi:10.1371/journal.pone.0089315
PMCID: PMC3930724  PMID: 24586682
17.  Targeted Delivery of Anti-coxsackievirus siRNAs Using Ligand-conjugated Packaging RNAs 
Antiviral research  2009;83(3):307-316.
Coxsackievirus B3 (CVB3) is a common pathogen of myocarditis. We previously synthesized a siRNA targeting the CVB3 protease 2A (siRNA/2A) gene and achieved reduction of CVB3 replication by 92% in vitro. However, like other drugs under development, CVB3 siRNA faces a major challenge of targeted delivery. In this study, we investigated a novel approach to deliver CVB3 siRNAs to a specific cell population (e.g. HeLa cells containing folate receptor) using receptor ligand (folate)-linked packaging RNA (pRNA) from bacterial phage phi29. pRNA monomers can spontaneously form dimers and multimers under optimal conditions by base-pairing between their stem loops. By covalently linking a fluorescence-tag to folate, we delivered the conjugate specifically to HeLa cells without the need of transfection. We further demonstrated that pRNA covalently conjugated to siRNA/2A achieved an equivalent antiviral effect to that of the siRNA/2A alone. Finally, the drug targeted delivery was further evaluated by using pRNA monomers or dimers, which carried both the siRNA/2A and folate ligand and demonstrated that both of them strongly inhibited CVB3 replication. These data indicate that pRNA as a siRNA carrier can specifically deliver the drug to target cells via its ligand and specific receptor interaction and inhibit virus replication effectively.
doi:10.1016/j.antiviral.2009.07.005
PMCID: PMC3909712  PMID: 19616030
packaging RNA; Coxsackievirus B3; drug delivery; gene therapy; folate receptor; siRNA
18.  Enhanced Control of In Vivo Bone Formation with Surface Functionalized Alginate Microbeads Incorporating Heparin and Human Bone Morphogenetic Protein-2 
Tissue Engineering. Part A  2012;19(3-4):350-359.
In this study, we tested the hypothesis that a surface functionalization delivery platform incorporating heparin onto strontium alginate microbeads surfaces would convert this “naive carriers” into “mini-reservoirs” for localized in vivo delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2) that will induce functional bone regeneration. In vitro evaluation confirmed that (1) heparin incorporation could immobilize and prolong rhBMP-2 release for approximately 3 weeks; (2) a significant decrease (p<0.01) in rhBMP-2 burst release is attainable depending on initial protein load; and (3) rhBMP-2 released from surface functionalized microbeads retained bioactivity and stimulated higher alkaline phosphatase activity in cultured C2C12 cells when compared with daily administration of fresh bolus rhBMP-2. Subsequently, surface functionalized microbeads were used for in vivo delivery of rhBMP-2 at local sites of posterolateral spinal fusion surgery in rats. The microbeads were loaded into the pores of medical-grade polyepsilone caprolactone-tricalcium phosphate scaffolds before implantation. Results revealed robust bone formation and a biomechanically solid fusion after 6 weeks. When compared with a control group consisting of an equivalent amount of rhBMP-2 that was directly adsorbed onto bare-surfaced microbeads with no heparin, a 5.3-fold increase in bone volume fraction and a 2.6-fold increase in bending stiffness (flexion/extension) were observed. When compared with collagen sponge carriers of rhBMP-2, a 1.5-fold and a 1.3-fold increase in bone volume fraction and bending stiffness were observed, respectively. More importantly, 3D micro-computed tomography images enabled the visualization of a well-contained newly formed bone at ipsilateral implant sites with surface functionalized rhBMP-2 delivery. This was absent with collagen sponge carriers where newly formed bone tissue was poorly contained and crossed over the posterior midline to contralateral implants. These findings are important because of complications with current rhBMP-2 delivery method, including excessive, uncontrolled bone formation.
doi:10.1089/ten.tea.2012.0274
PMCID: PMC3542875  PMID: 22894570
19.  The Impact of Policies to Restrict the Use of Plasma Containing Products and Apheresis Platelets from Female Donors to Mitigate Transfusion Related Acute Lung Injury (TRALI) in Brazil 
Background and Objectives
Although the incidence of TRALI is unknown in Brazil, some blood centers have adopted strategies to prevent TRALI. We evaluated the impact of three policies to mitigate TRALI on the supply of blood products: to divert the production of whole blood-derived plasma from female donors; to defer all female donors from apheresis platelet collections, and to defer only multiparous female donors from apheresis platelet collections.
Materials and Methods
Data from allogeneic whole blood and apheresis platelet donations from April 2008 to December 2009 were collected in three Brazilian blood centers and the impact of the aforementioned strategies was evaluated.
Results
Of 544,814 allogeneic blood donations, 30.8% of whole blood plasma and 24.1% of apheresis platelet donations would be reduced if only male donor plasma was issued for transfusion and all female donors were deferred from apheresis donation, respectively. If only multiparous donors were deferred from apheresis donation, there would be a 5% decrease of all apheresis platelet collections.
Conclusion
Restricting the use of whole blood derived plasma to male-only donors and deferring all female apheresis platelet donors would impact two out of three Brazilian blood centers. A deferral policy on multiparous apheresis platelet donors may be acceptable as a temporary measure, but may cause more stress on a system that is already working at its limit.
doi:10.1016/j.transci.2012.07.010
PMCID: PMC3547161  PMID: 22985535
TRALI; multiparous donors; apheresis platelets; leukocyte antibodies; Brazil; transfusion reactions
20.  Accelerated MRI with CIRcular Cartesian UnderSampling (CIRCUS): a variable density Cartesian sampling strategy for compressed sensing and parallel imaging 
Purpose
This study proposes and evaluates a novel method for generating efficient undersampling patterns for 3D Cartesian acquisition with compressed sensing (CS) and parallel imaging (PI).
Methods
Image quality achieved with schemes that accelerate data acquisition, including CS and PI, are sensitive to the design of the specific undersampling scheme used. Ideally random sampling is required to recover MR images from undersampled data with CS. In practice, pseudo-random sampling schemes are usually applied. Radial or spiral sampling either for Cartesian or non-Cartesian acquisitions has been using because of its favorable features such as interleaving flexibility. In this study, we propose to undersample data on the ky-kz plane of the 3D Cartesian acquisition by circularly selecting sampling points in a way that maintains the features of both random and radial or spiral sampling.
Results
The proposed sampling scheme is shown to outperform conventional random and radial or spiral samplings for 3D Cartesian acquisition and is found to be comparable to advanced variable-density Poisson-Disk sampling (vPDS) while retaining interleaving flexibility for dynamic imaging, based on the results with retrospective undersampling. Our preliminary results with the prospective implementation of the proposed undersampling strategy demonstrated its favorable features.
Conclusions
The proposed undersampling patterns for 3D Cartesian acquisition possess the desirable properties of randomization and radial or spiral trajectories. It provides easy implementation, flexible sampling, and high accuracy of image reconstruction with CS and PI.
doi:10.3978/j.issn.2223-4292.2014.02.01
PMCID: PMC3947985  PMID: 24649436
Undersampling; acceleration; random; variable-density; compressed sensing (CS); parallel imaging (PI)
21.  Insight into Conformational Change for 14-3-3σ Protein by Molecular Dynamics Simulation 
14-3-3σ is a member of a highly conserved family of 14-3-3 proteins that has a double-edged sword role in human cancers. Former reports have indicated that the 14-3-3 protein may be in an open or closed state. In this work, we found that the apo-14-3-3σ is in an open state compared with the phosphopeptide bound 14-3-3σ complex which is in a more closed state based on our 80 ns molecular dynamics (MD) simulations. The interaction between the two monomers of 14-3-3σ in the open state is the same as that in the closed state. In both open and closed states, helices A to D, which are involved in dimerization, are stable. However, large differences are found in helices E and F. The hydrophobic contacts and hydrogen bonds between helices E and G in apo-14-3-3σ are different from those in the bound 14-3-3σ complex. The restrained and the mutated (Arg56 or Arg129 to alanine) MD simulations indicate that the conformation of four residues (Lys49, Arg56, Arg129 and Tyr130) may play an important role to keep the 14-3-3σ protein in an open or closed state. These results would be useful to evaluate the 14-3-3σ protein structure-function relationship.
doi:10.3390/ijms15022794
PMCID: PMC3958882  PMID: 24552877
conformational change; 14-3-3σ protein; molecular dynamics simulation
22.  Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs 
Biological chemistry  2011;392(4):315-325.
Spinocerebellar ataxia-3 (SCA3) (also known as Machado Joseph Disease) is an incurable neurodegenerative disorder caused by expression of a mutant variant of ataxin-3 protein (ATX3). Inhibiting expression of ATX-3 would provide a therapeutic strategy, but indiscriminant inhibition of both wild-type and mutant ATX3 might lead to undesirable side-effects. An ideal silencing agent would block expression of mutant ATX3 while leaving expression of wild-type ATX3 intact. We have previously observed that peptide nucleic acid (PNA) conjugates targeting the expanded CAG repeat within ATX3 mRNA block expression of both alleles. We now identify additional PNAs capable of inhibiting ATX3 expression that vary in length and in the nature of the conjugated cation chain. We can also achieve potent and selective inhibition using duplex RNAs containing one or more mismatches relative to the CAG repeat. Anti-CAG antisense bridged nucleic acid (BNA) oligonucleotides that lack a cationic domain are potent inhibitors but are not allele-selective. Allele-selective inhibitors of ATX-3 expression provide insights into the mechanism of selectivity and promising lead compounds for further development and in vivo investigation.
doi:10.1515/BC.2011.045
PMCID: PMC3908450  PMID: 21294677
Ataxin-3; Spinocerebellar ataxia-3; allele-selective; siRNA; peptide nucleic acid
23.  Therapeutic efficacy comparison of radiofrequency ablation in hepatocellular carcinoma and metastatic liver cancer 
The aim of this study was to evaluate the effect of radiofrequency ablation (RFA) on malignant hepatic tumors and compare its therapeutic efficacy in hepatocellular carcinoma (HCC) and metastatic liver cancer (MLC). A total of 56 patients with malignant hepatic tumors (34 patients with HCC and 22 patients with MLC) underwent RFA treatment. Two weeks following the RFA treatment, contrast-enhanced abdominal computed tomography scans were used to investigate whether the ablation of the tumors was complete. The patients were followed up for a period ranging from 1 to 93 months, to compare recurrence rates, distant recurrence rates and survival rates. The HCC group exhibited an initial complete ablation rate of 94.1% compared with 95.4% for the MLC group; the difference in ablation rates was not identified to be statistically significant. The recurrence and distant recurrence rates were 14.7% and 11.8%, respectively, for the HCC group and 9.1% and 36.4%, respectively, for the MLC group. The 1-, 3- and 5-year survival rates of the patients with HCC were 86.2, 71.4 and 60.0%, respectively, whereas those for the patients with MLC were 73.9%, 45.4% and 37.5%, respectively. The survival rates of the two groups were identified to be significantly different (P=0.002). RFA treatment was therefore shown to be effective in treating small (<5 cm) malignancies, which is clinically significant.
doi:10.3892/etm.2014.1505
PMCID: PMC3961118  PMID: 24669247
radiofrequency ablation; hepatocellular carcinoma; metastatic liver cancer; survival rate
24.  Conditioned medium of human adipose-derived mesenchymal stem cells mediates protection in neurons following glutamate excitotoxicity by regulating energy metabolism and GAP-43 expression 
Metabolic Brain Disease  2014;29:193-205.
Glutamate excitotoxicity has been implicated as one of the pathological mechanisms contributing to neuronal cell death and is involved in many neurological disorders. Stem cell transplantation is a promising approach for the treatment of nervous system damage or diseases. Previous studies have shown that mesenchymal stem cells (MSCs) have important therapeutic effects in experimental animal and preclinical disease model of central nervous system pathology. However, it is not well understood whether neurogenesis of MSCs or MSC conditioned-medium (CM) containing microparticles mediates therapeutic effects. Here, we investigated the neuroprotective effects of human adipose-derived MSCs (AMSCs) on cortical neurons using models of glutamate excitotoxicity. Following exposure to glutamate (100 μM, 15 min), cortical neurons were co-cultured with either AMSCs separated by a semiporous membrane (prohibiting direct cell-cell contact) or with AMSC-CM for 18 h. Compared to untreated control groups, AMSCs and AMSC-CM partially and similarly reduced neuronal cell damages, as indicated by reduced LDH release, a decreased number of trypan-positive cells and a decline in the number of apoptotic nuclei. Protection by CM was associated with increased GAP-43 expression and an elevated number of GAP-43-positive neurites. Furthermore, CM increased levels of ATP, NAD+ and NADH and the ratio of NAD+/NADH, while preventing a glutamate-induced decline in mitochondrial membrane potential. These results demonstrate that AMSC-CM mediates direct neuroprotection by inhibiting neuronal cell damage/apoptosis, promoting nerve regeneration and repair, and restoring bioenergy following energy depletion caused by glutamate excitotoxicity.
doi:10.1007/s11011-014-9490-y
PMCID: PMC3930846  PMID: 24458787
Excitotoxicity; Cortical neurons; AMSCs; Neuroprotection; GAP-43; Energy metabolism
25.  Effect of Mixed Transplantation of Autologous and Allogeneic Microskin Grafts on Wound Healing in a Rat Model of Acute Skin Defect 
PLoS ONE  2014;9(1):e85672.
The treatment of extensive thermal injuries with insufficient autologous skin remains a great challenge to burn surgeons. In this study, we investigated the influence of the ratio of autologous and allogeneic tissue in mixed microskin grafts on wound healing in order to develop an effective method for using limited donor skin to cover a large open wound. Four different mixtures were tested: autologous microskin at an area expansion ratio of 10∶1 with allogeneic microskin at an area expansion ratio of 10∶1 or 10∶3 and autologous microskin at an expansion ratio of 20∶1 with allogeneic microskin at an expansion ratio of 20∶3 or 20∶6. Wound healing, wound contraction, and integrin β1 expression were measured. Mixed microskin grafting facilitated wound healing substantially. The mixture of autologous microskin at an expansion ratio of 10∶1 with the same amount of allogeneic microskin achieved the most satisfactory wound healing among the 4 tested mixtures. Histological examination revealed the presence of obviously thickened epidermis and ectopic integrin β1 expression. Keratinocytes expressing integrin β1 were scattered in the suprabasal layer. Higher levels of integrin β1 expression were associated with faster wound healing, implying that ectopic expression of integrin β1 in keratinocytes may play a pivotal role in wound healing. In conclusion, this study proves that this new skin grafting technique may improve wound healing.
doi:10.1371/journal.pone.0085672
PMCID: PMC3897459  PMID: 24465646

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