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1.  Protective Macroautophagy Is Involved in Vitamin E Succinate Effects on Human Gastric Carcinoma Cell Line SGC-7901 by Inhibiting mTOR Axis Phosphorylation 
PLoS ONE  2015;10(7):e0132829.
Vitamin E succinate (VES), a potential cancer therapeutic agent, potently induces apoptosis and inhibits the growth of various cancer cells. Autophagy has been supposed to promote cancer cell survival or trigger cell death, depending on particular cancer types and tumor microenvironments. The role of autophagy in the growth suppressive effect of VES on gastric cancer cell is basically unknown. We aimed to determine whether and how autophagy affected the VES-induced inhibition of SGC-7901 human gastric carcinoma cell growth. SGC-7901 cells were treated with VES or pre-treated with autophagy inhibitor, chloroquine (CQ) and 3-methyladenine (3-MA). Electron microscopy, fluorescence microscopy and Western blot were used to study whether VES induced autophagy reaction in SGC-7901 cells. Western blot evaluated the activities of the mammalian target of rapamycin (mTOR) axis. Then we used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry to detect the level of cell viability and apoptosis. Collectively, our data indeed strongly support our hypothesis that VES treatment produced cytological variations that depict autophagy, increased the amount of intracellular green fluorescent protein—microtubule associated protein 1 light chain 3 (GFP-LC3) punctate fluorescence and the number of autophagic vacuoles. It altered the expression of endogenous autophagy marker LC3. VES activated the suppression of mTOR through inhibiting upstream regulators p38 MAPK and Akt. mTOR suppression consequently inhibited the activation of mTOR downstream targets p70S6K and 4E-BP-1. The activation of the upstream mTOR inhibitor AMPK had been up-regulated by VES. The results showed that pre-treatment SGC-7901 with autophagy inhibitors before VES treatment could increase the capacity of VES to reduce cell viability and to provoke apoptosis. In conclusion, VES-induced autophagy participates in SGC-7901 cell protection by inhibiting mTOR axis phosphorylation. Our findings not only strengthen our understanding of the roles of autophagy in cancer biology, but may also be useful for developing new treatments for gastric cancer patients.
PMCID: PMC4500415  PMID: 26168048
2.  Measurement of mitral leaflet and annular geometry and stress after repair of posterior leaflet prolapse: Virtual repair using a patient specific finite element simulation 
The Annals of thoracic surgery  2014;97(5):1496-1503.
Recurrent mitral regurgitation after mitral valve (MV) repair for degenerative disease occurs at a rate of 2.6% per year and re-operation rate progressively reaches 20% at 19.5 years. We believe that MV repair durability is related to initial post-operative leaflet and annular geometry with subsequent leaflet remodeling due to stress. We tested the hypothesis that MV leaflet and annular stress is increased after MV repair.
Magnetic resonance imaging was performed before and intra-operative 3D trans-esophageal echocardiography was performed before and after repair of posterior leaflet (P2) prolapse in a single patient. The repair consisted of triangular resection and annuloplasty band placement. Images of the heart were manually co-registered. The left ventricle and MV were contoured, surfaced and a 3D finite element (FE) model was created. Elements of the P2 region were removed to model leaflet resection and virtual sutures were used to repair the leaflet defect and attach the annuloplasty ring.
The principal findings of the current study are 1) FE simulation of MV repair is able to accurately predict changes in MV geometry including changes in annular dimensions and leaflet coaptation, 2) average posterior leaflet stress is increased, and 3) average anterior leaflet and annular stress are reduced after triangular resection and mitral annuloplasty.
We successfully conducted virtual mitral valve prolapse repair using FE modeling methods. Future studies will examine the effects of leaflet resection type as well as annuloplasty ring size and shape.
PMCID: PMC4121378  PMID: 24630767
Mitral prolapse; mitral regurgitation; cardiac surgery; valve repair; annuloplasty; finite element; modeling
3.  Association between LMP2 and LMP7 gene polymorphisms and the risk of gastric cancer: A case-control study 
Oncology Letters  2015;10(1):509-517.
The integrality of low molecular weight protein (LMP)2/LMP7 function plays an important role in the processing of GC cell antigens. The purpose of the present hospital-based case-control study was to estimate the effect of polymorphisms in the LMP2 and LMP7 genes on the risk of GC. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to distinguish the Arg to His substitution at codon 60 of LMP2 (LMP2-60) and the Gln to Lys substitution at codon 145 of LMP7 (LMP7-145) in 502 gastric cancer patients and 502 age and gender-matched cancer-free control individuals. The Lys allele of the LMP7-145 variant was more frequent in GC patients compared with control individuals [P=0.004; adjusted odds ratio (OR), 1.39; 95% confidence interval (CI), 1.11–1.74]. The Gln/Lys and Lys/Lys genotypes increased the risk of GC compared with the Gln/Gln genotype (P=0.049 and P=0.041, respectively; adjusted OR, 1.32 and 2.13, respectively; 95% CI, 1.00–1.73 and 1.03–4.39, respectively). Compared with the Gln/Gln genotype, the LMP7-145 Gln/Lys and Lys/Lys variants of the LMP7 gene were also associated with increased susceptibility to GC (P=0.017; adjusted OR, 1.38; 95% CI, 1.06–1.80). Haplotype analysis revealed that the LMP2 (Arg)-LMP7 (Lys) haplotype was associated with increased risk of GC (P=0.013, adjusted OR=1.34, 95% CI=1.06–1.70). Stratified analysis revealed that the association between the risk of GC and the variant genotypes of LMP7-145 was stronger in older individuals (>59 years), males and non-smokers. However, no association between the LMP2-60 polymorphism and the risk of GC was observed. The present results suggest that the LMP7-145 genetic variant contributes to increased susceptibility to GC, and the Lys allele is an independent risk factor for GC.
PMCID: PMC4487101  PMID: 26171060
gastric cancer; LMP2/LMP7; gene polymorphism
4.  EGF-reduced Wnt5a transcription induces epithelial-mesenchymal transition via Arf6-ERK signaling in gastric cancer cells 
Oncotarget  2015;6(9):7244-7261.
Wnt5a, a ligand for activating the non-canonical Wnt signaling pathway, is commonly associated with Epithelial-to-mesenchymal transition (EMT) in cancer cell metastasis. Here, we show that downregulation of Wnt5a mRNA and protein by EGF is necessary for EGF-induced EMT in gastric cancer SGC-7901 cells. To further explore the mechanisms, we investigated the effect of EGF signaling on Wnt5a expression. EGF increased Arf6 and ERK activity, while blockade of Arf6 activation repressed ERK activity, up-regulated Wnt5a expression and repressed EMT in response to EGF. We also demonstrate that EGF inactivated Wnt5a transcription by direct recruitment of ERK to the Wnt5a promoter. On the other hand, inhibition of ERK phosphorylation resulted in decreased movement of ERK from the cytoplasm to the nucleus, following rescued Wnt5a mRNA and protein expression and favored an epithelial phenotype of SGC-7901 cells. In addition, we notice that kinase-dead, nuclear-localised ERK has inhibitory effect on Wnt5a transcription. Analysis of gastric cancer specimens revealed an inverse correlation between P-ERK and Wnt5a protein levels and an association between Wnt5a expression and better prognosis. These findings indicate that Wnt5a is a potential suppressor of EMT and identify a novel Arf6/ERK signaling pathway for EGF-regulated Wnt5a expression at transcriptional level of gastric cancer cells.
PMCID: PMC4466682  PMID: 25779663
EGF; Arf6; ERK; Wnt5a; EMT
5.  Shift Work and the Relationship with Metabolic Syndrome in Chinese Aged Workers 
PLoS ONE  2015;10(3):e0120632.
Shift work is indicated to be associated with adverse metabolic disorders. However, potential effects of shift work on metabolic syndrome (MetS) and its components have not been well established.
In total, 26,382 workers from Dongfeng-Tongji Cohort were included in this study. Information on shift work history was gathered through questionnaires and metabolic traits were measured. Logistic regression models were used to calculate the odds ratio (OR) and 95% confidence interval (CI) for long-term shift work related with MetS and each component, respectively. Further stratification analysis was performed to detect the differences on MetS between female and male shift workers.
Long-term shift work was associated with MetS without adjusting for any confounders. Compared with the group of non-shift work, the multivariate-adjusted ORs (95%CI) of MetS associated with 1–10, 11−20, and ≥20y of shift work were 1.05 (0.95−1.16), 1.14 (1.03−1.26), 1.16 (1.01−1.31), respectively. In female workers, we found a dose-response relationship that every 10 years increase in shift work was associated with a 10% (95% CI: 1%−20%) elevated OR of MetS, while no significant dose-response trend was found among male workers. Furthermore, shift work duration was significantly associated with ORs of high blood pressure (1.07, 1.01−1.13), long waist circumference (1.10, 1.01−1.20) and high glucose levels (1.09, 1.04−1.15). No significant association was observed between shift work and low HDL cholesterol) and raised triglyceride levels.
Long-term shift work was associated with metabolic syndrome and the association might differ by gender in retired workers. Applicable intervention strategies are needed for prevention of metabolic disorders for shift workers.
PMCID: PMC4356508  PMID: 25761114
6.  Comparison of 2 synthetically generated recombinant prions 
Prion  2014;8(2):215-220.
Prion is a protein-conformation-based infectious agent causing fatal neurodegenerative diseases in humans and animals. Our previous studies revealed that in the presence of cofactors, infectious prions can be synthetically generated in vitro with bacterially expressed recombinant prion protein (PrP). Once initiated, the recombinant prion is able to propagate indefinitely via serial protein misfolding cyclic amplification (sPMCA). In this study, we compared 2 separately initiated recombinant prions. Our results showed that these 2 recombinant prions had distinct biochemical properties and caused different patterns of spongiosis and PrP deposition in inoculated mice. Our findings indicate that various recombinant prions can be initiated in vitro and potential reasons for this variability are discussed.
PMCID: PMC4189893  PMID: 24721728
prion; sPMCA; recombinant PrP; recombinant prion; bioassay; histopathology; GuHCl denaturation assay
7.  Reg3α Overexpression Protects Pancreatic β Cells from Cytokine-Induced Damage and Improves Islet Transplant Outcome 
Molecular Medicine  2015;20(1):548-558.
The process of islet transplantation for treating type 1 diabetes has been limited by the high level of graft failure. This may be overcome by locally delivering trophic factors to enhance engraftment. Regenerating islet-derived protein 3α (Reg3α) is a pancreatic secretory protein which functions as an antimicrobial peptide in control of inflammation and cell proliferation. In this study, to investigate whether Reg3α could improve islet engraftment, a marginal mass of syngeneic islets pretransduced with adenoviruses expressing Reg3α or control EGFP were transplanted under the renal capsule of streptozotocin-induced diabetic mice. Mice receiving islets with elevated Reg3α production exhibited significantly lower blood glucose levels (9.057 ± 0.59 mmol/L versus 13.48 ± 0.35 mmol/L, P < 0.05) and improved glucose-stimulated insulin secretion (1.80 ± 0.17 ng/mL versus 1.16 ± 0.16 ng/mL, P < 0.05) compared with the control group. The decline of apoptotic events (0.57% ± 0.15% versus 1.06% ± 0.07%, P < 0.05) and increased β-cell proliferation (0.70% ± 0.10% versus 0.36% ± 0.14%, P < 0.05) were confirmed in islet grafts overexpressing Reg3α by morphometric analysis. Further experiments showed that Reg3α production dramatically protected cultured islets and pancreatic β cells from cytokine-induced apoptosis and the impairment of glucose-stimulated insulin secretion. Moreover, exposure to cytokines led to the activation of MAPKs in pancreatic β cells, which was reversed by Reg3α overexpression in contrast to control group. These results strongly suggest that Reg3α could enhance islet engraftments through its cytoprotective effect and advance the therapeutic efficacy of islet transplantation.
PMCID: PMC4365059  PMID: 25826674
8.  Nonlinear optical microscopy for immunoimaging: a custom optimized system of high-speed, large-area, multicolor imaging 
The nonlinear optical microscopy has become the current state-of-the-art for intravital imaging. Due to its advantages of high resolution, superior tissue penetration, lower photodamage and photobleaching, as well as intrinsic z-sectioning ability, this technology has been widely applied in immunoimaging for a decade. However, in terms of monitoring immune events in native physiological environment, the conventional nonlinear optical microscope system has to be optimized for live animal imaging. Generally speaking, three crucial capabilities are desired, including high-speed, large-area and multicolor imaging. Among numerous high-speed scanning mechanisms used in nonlinear optical imaging, polygon scanning is not only linearly but also dispersion-freely with high stability and tunable rotation speed, which can overcome disadvantages of multifocal scanning, resonant scanner and acousto-optical deflector (AOD). However, low frame rate, lacking large-area or multicolor imaging ability make current polygonbased nonlinear optical microscopes unable to meet the requirements of immune event monitoring.
We built up a polygon-based nonlinear optical microscope system which was custom optimized for immunoimaging with high-speed, large-are and multicolor imaging abilities.
Firstly, we validated the imaging performance of the system by standard methods. Then, to demonstrate the ability to monitor immune events, migration of immunocytes observed by the system based on typical immunological models such as lymph node, footpad and dorsal skinfold chamber are shown. Finally, we take an outlook for the possible advance of related technologies such as sample stabilization and optical clearing for more stable and deeper intravital immunoimaging.
This study will be helpful for optimizing nonlinear optical microscope to obtain more comprehensive and accurate information of immune events.
PMCID: PMC4312289  PMID: 25694951
Nonlinear optical microscopy; immunoimaging; high-speed; large-area; multicolor
9.  Comparison of two different standards of care in detecting malignant thyroid nodules using thyroid fine-needle aspiration 
Molecular and Clinical Oncology  2015;3(3):682-686.
The aim of the present study was to verify the optimal method to obtain enough fine-needle aspiration (FNA) materials for detecting thyroid malignancy. A prospective study was performed by comparing two different regional standards of care. In one group a traditional FNA method mainly used in Asian countries, including China, was performed in which a single pass of a 22-G needle was applied with or without aspiration. In the other group, the method mainly used in Western countries was performed in which three passes of a 25-G needle with non-aspiration were undertaken for thyroid nodules. The study included 718 thyroid nodules from 695 patients. These nodules were allocated for three different methods of performing thyroid FNA. There were 332 thyroid nodules subjected to the traditional Asian FNA method using a 22-G needle with aspiration for 142 nodules and non-aspiration for 190 nodules. FNA using the Western method was performed with three passes of non-aspiration using 25 G for 386 nodules. All the FNAs were performed with the guidance of ultrasound. The components of the nodules were documented. All the samples were reported using the Bethesda System for Reporting Thyroid Cytopathology. Among the 22 G group, the non-diagnostic rate in the aspiration group was as high as 76.76%, which was significantly higher than 44.21% in the non-aspiration group (P<0.01). For the non-aspiration group, the non-diagnostic rate in the 25 G group was 34.97%, which was significantly lower than 44.21% in the 22 G group. In general, the non-diagnostic rate for the 25-G needle was 34.97%, which was significantly lower than 58.13% in all the 22 G groups. For the solid and mixed nodules, the non-diagnostic rate was lower in the 25-G needle group compared to the 22 G groups with statistical significance. The non-aspiration method using a 25-G needle with multiple passes can result in a higher diagnostic rate for thyroid FNA.
PMCID: PMC4471588  PMID: 26137287
thyroid nodule; fine-needle aspiration; techniques; Bethesda System; standards of care
10.  Zigzag Generalized Lévy Walk: the In Vivo Search Strategy of Immunocytes 
Theranostics  2015;5(11):1275-1290.
Immune responses are based on the coordinated searching behaviors of immunocytes that are aimed at tracking down specific targets. The search efficiency of immunocytes significantly affects the speed of initiation and development of immune responses. Previous studies have shown that not only the intermittent walk but also the zigzag turning preference of immunocytes contributes to the search efficiency. However, among existing models describing immunocytes' search strategy, none has captured both features. Here we propose a zigzag generalized Lévy walk model to describe the search strategy of immunocytes more accurately and comprehensively by considering both the intermittent and the zigzag-turning walk features. Based on the analysis of the searching behaviors of typical immune cell types, dendritic cells and leukocytes, in their native physiological environment, we demonstrate that the model can describe the in vivo search strategy of immunocytes well. Furthermore, by analyzing the search efficiency, we find that this type of search strategy enables immunocytes to capture rare targets in approximately half the time than the previously proposed generalized Lévy walk. This study sheds new light on the fundamental mechanisms that drive the efficient initiation and development of immune responses and in turn may lead to the development of novel therapeutic approaches for diseases ranging from infection to cancer.
PMCID: PMC4568454  PMID: 26379792
Search strategy; dendritic cell; leukocyte; amoeboid-manner crawling; zigzag walk; Lévy walk
11.  A general strategy for developing cell-permeable photo-modulatable organic fluorescent probes for live-cell super-resolution imaging 
Nature Communications  2014;5:5573.
Single-molecule localization microscopy (SMLM) achieves super-resolution imaging beyond the diffraction limit but critically relies on the use of photo-modulatable fluorescent probes. Here we report a general strategy for constructing cell-permeable photo-modulatable organic fluorescent probes for live-cell SMLM by exploiting the remarkable cytosolic delivery ability of a cell-penetrating peptide (rR)3R2. We develop photo-modulatable organic fluorescent probes consisting of a (rR)3R2 peptide coupled to a cell-impermeable organic fluorophore and a recognition unit. Our results indicate that these organic probes are not only cell permeable but can also specifically and directly label endogenous targeted proteins. Using the probes, we obtain super-resolution images of lysosomes and endogenous F-actin under physiological conditions. We resolve the dynamics of F-actin with 10 s temporal resolution in live cells and discern fine F-actin structures with diameters of ~80 nm. These results open up new avenues in the design of fluorescent probes for live-cell super-resolution imaging.
Single-molecule localization microscopy depends on the use of photo-modulatable fluorescent probes; however, many cannot be used in live-cell studies due to poor cell permeability. Pan et al. present a strategy for constructing cell-permeable probes and use it to image actin filament dynamics and lysosomes.
PMCID: PMC4263135  PMID: 25410769
12.  Coexistence of Histologically Confirmed Hashimoto's Thyroiditis with Different Stages of Papillary Thyroid Carcinoma in a Consecutive Chinese Cohort 
Purpose. To determine the relationship between Hashimoto's thyroiditis (HT) and all stages of papillary thyroid carcinoma (PTC) with or without local lymph node metastasis (LNM). Methods. We conducted a retrospective study of thyroidectomies from 2008–2013 in First Affiliated Hospital of Nanjing Medical University. We categorized patients according to the presence of histopathologically proven HT. The prevalence of mPTC (maximum diameter ≤ 10 mm) and crPTC (clinical relevant PTC) and local LNM rates were compared. Results. We evaluated 6,432 consecutive thyroidectomies. In total, 1,328 specimens were confirmed as HT. The prevalence of PTC in this HT cohort was 43.8%, significantly higher than non-HT group. After adjustment of gender and age, the prevalence of PTC was still higher in HT group. HT was a risk factor for PTC in multivariate analysis with odds ratio 2.725 (95% CI, 2.390–3.109) (P < 0.001). However, no correlation was found between HT and LNM of PTC. Conclusion. HT was associated with an increased prevalence of all stages of PTC, independent of tumor size, gender, and age. In contrast, locally advanced disease defined by LNM was unrelated to HT. These data suggest an association of HT with low risk PTC and a potential protective immunologic effect from further disease progression.
PMCID: PMC4255062  PMID: 25505911
13.  Cancer stem cells, epithelial-mesenchymal transition, and drug resistance in high-grade ovarian serous carcinoma 
Human pathology  2013;44(11):2373-2384.
Although epithelial ovarian cancer cells are eliminated by debulking surgery and chemotherapy during initial treatment, it is believed that only a subset of cancer cells, that is, cancer stem cells, may be an important source of tumor recurrence and drug resistance. This review highlights our current understanding of high-grade serous carcinoma, ovarian cancer stem cells, common methods for enrichment of ovarian cancer stem cells, mechanisms involved in drug resistance, and potential strategies for overcoming drug resistance, with associated potential controversies and pitfalls. We also review the potential relationship between epithelial-to-mesenchymal transition and cancer stem cells and how we can induce cancer cells to differentiate into benign stromal fibroblasts in response to certain chemotherapy drugs.
PMCID: PMC3797876  PMID: 23850493
High-grade ovarian serous cancer; Cancer stem cell; Epithelial-mesenchymal transition
14.  Algisyl-LVR™ with coronary artery bypass grafting reduces left ventricular wall stress and improves function in the failing human heart☆,☆☆ 
International journal of cardiology  2013;168(3):2022-2028.
Left ventricular (LV) wall stress reduction is a cornerstone in treating heart failure. Large animal models and computer simulations indicate that adding non-contractile material to the damaged LV wall can potentially reduce myofiber stress. We sought to quantify the effects of a novel implantable hydrogel (Algisyl-LVR™) treatment in combination with coronary artery bypass grafting (i.e. Algisyl-LVR™+CABG) on both LV function and wall stress in heart failure patients.
Methods and results
Magnetic resonance images obtained before treatment (n=3), and at 3 months (n=3) and 6 months (n=2) afterwards were used to reconstruct the LV geometry. Cardiac function was quantified using end-diastolic volume (EDV), end-systolic volume (ESV), regional wall thickness, sphericity index and regional myofiber stress computed using validated mathematical modeling. The LV became more ellipsoidal after treatment, and both EDV and ESV decreased substantially 3 months after treatment in all patients; EDV decreased from 264±91 ml to 146±86 ml and ESV decreased from 184±85 ml to 86±76 ml. Ejection fraction increased from 32±8% to 47±18% during that period. Volumetric-averaged wall thickness increased in all patients, from 1.06±0.21 cm (baseline) to 1.3±0.26 cm (3 months). These changes were accompanied by about a 35% decrease in myofiber stress at end-of-diastole and at end-of-systole. Post-treatment myofiber stress became more uniform in the LV.
These results support the novel concept that Algisyl-LVR™+CABG treatment leads to decreased myofiber stress, restored LV geometry and improved function.
PMCID: PMC3748222  PMID: 23394895
Congestive heart failure; Dilated cardiomyopathy; Coronary artery bypass grafting; Left ventricular wall stress; Mathematical modeling; Magnetic resonance imaging
15.  The Wuhan-Zhuhai (WHZH) cohort study of environmental air particulate matter and the pathogenesis of cardiopulmonary diseases: study design, methods and baseline characteristics of the cohort 
BMC Public Health  2014;14:994.
Particulate air pollution has been recognized to be associated with a wide range of adverse health effects, including increased mortality, morbidity, exacerbation of respiratory conditions. However, earlier physiological or pathological changes or long-term bodies’ reaction to air pollutants have not been studied in depth in China. The Wuhan-Zhuhai (WHZH) cohort study is designed to investigate the association between air pollutants exposure and physiological or pathological reactions on respiratory and cardiovascular system.
The cohort is a community-based prospective study that includes 4812 individuals aged 18–80 years. The collections of data were conducted from April to May 2011 in Wuhan city and in May 2012 in Zhuhai city. At baseline, data on demographic and socioeconomic information, occupational history, family disease history, lifestyle, cooking mode, daily travel mode, physical activity and living condition have been collected by questionnaires. Participants underwent an extensive physical examination, including anthropometry, spirometry, electrocardiography, and measurements of blood pressure, heart rate, exhaled nitric oxide and carbon monoxide. Potential conditions in the lung, heart, liver, spleen, and skin were synchronously performed. In addition, samples of morning urine, fasting blood serum and plasma were collected during physical health examination. DNA were extracted and were stored at -80°C. Environment concentrations of particulate matter and chemicals were determined for 15 days in each of four seasons. Participants are followed for physiological or pathological changes or incidence of cardiopulmonary diseases every 3 years.
The results obtained in WHZH cohort study may increase a better understanding of the relationship between particulate air pollution and its components and possible health damages. And the potential mechanisms underlying the development of cardiopulmonary diseases has implications for the development of prevention and treatment strategies.
PMCID: PMC4247123  PMID: 25252923
Cohort study; Air pollutants; Particulate matter; Pulmonary function; Respiratory diseases; Cardiovascular diseases
16.  A Coupled Biventricular Finite Element and Lumped Parameter Circulatory System Model of Heart Failure 
Numerical modeling of the cardiovascular system is becoming an important tool for assessing the influence of heart disease and treatment therapies. In the current study we present an approach for modeling the interaction between the heart and circulatory system. This was accomplished by creating animal specific biventricular finite element models, which characterize the mechanical response of the heart, and coupling them to a lumped parameter model that represents the systemic and pulmonic circulatory system. In order to minimize computation time, the coupling was enforced in a weak (one-way) manner, where the ventricular pressure-volume relationships were generated by the finite element models and then passed into the circulatory system model to ensure volume conservation and physiological pressure changes. The models were first validated by tuning the parameters, such that the output of the models matched experimentally measured pressures and volumes. Then the models were used to examine cardiac function and the myofiber stress in a healthy canine heart and a canine heart with dilated cardiomyopathy. The results show good agreement with experimental measurements. The stress in the case of cardiomyopathy was found to increase significantly, while the pump function was decreased, compared to the healthy case. The total run time of the simulations is less than many fully-coupled models presented in the literature. This will allow for a much quicker evaluation of possible treatment strategies for combating the effects of heart failure, especially in optimization schemes that require numerous finite element simulations.
PMCID: PMC3367128  PMID: 22248290
Finite Element; Lumped Parameter; Cardiac Mechanics
17.  Patient-specific finite element modeling of the Cardiokinetix Parachute® device: Effects on left ventricular wall stress and function 
The Parachute® (Cardiokinetix, Inc., Menlo Park, California) is a catheter-based device intended to reverse left ventricular (LV) remodeling after antero-apical myocardial infarction. When deployed, the device partitions the LV into upper and lower chambers. To simulate its mechanical effects, we created a finite element LV model based on computed tomography (CT) images from a patient before and 6 months after Parachute® implantation. Acute mechanical effects were determined by in-silico device implantation (VIRTUAL-Parachute). Chronic effects of the device were determined by adjusting the diastolic and systolic material parameters to better match the 6-month post-implantation CT data and LV pressure data at end-diastole (ED) (POST-OP). Regional myofiber stress and pump function were calculated in each case. The principal finding is that VIRTUAL-Parachute was associated with a 61.2% reduction in the lower chamber myofiber stress at ED. The POST-OP model was associated with a decrease in LV diastolic stiffness, and a larger reduction in myofiber stress at the upper (27.1%) and lower chamber (78.4%) at ED. Myofiber stress at end-systole and stroke volume were little changed in the POST-OP case. These results suggest that the primary mechanism of Parachute® is a reduction in ED myofiber stress, which may reverse eccentric post-infarct LV hypertrophy.
PMCID: PMC4118670  PMID: 24793158
Myocardial Infarction; Remodeling; Finite element method; Surgical ventricular restoration
18.  Fungal Small RNAs Suppress Plant Immunity by Hijacking Host RNA Interference Pathways 
Science (New York, N.Y.)  2013;342(6154):118-123.
Botrytis cinerea, the causative agent of gray mold disease, is an aggressive fungal pathogen that infects more than 200 plant species. Here, we show that some B. cinerea small RNAs (Bc-sRNAs) can silence Arabidopsis and tomato genes involved in immunity. These Bc-sRNAs hijack the host RNA interference (RNAi) machinery by binding to Arabidopsis Argonaute 1 (AGO1) and selectively silencing host immunity genes. The Arabidopsis ago1 mutant exhibits reduced susceptibility to B. cinerea, and the B. cinerea dcl1 dcl2 double mutant that can no longer produce these Bc-sRNAs displays reduced pathogenicity on Arabidopsis and tomato. Thus, this fungal pathogen transfers “virulent” sRNA effectors into host plant cells to suppress host immunity and achieve infection, which demonstrates a naturally occurring cross-kingdom RNAi as an advanced virulence mechanism.
PMCID: PMC4096153  PMID: 24092744
19.  C-kit and PDGFRA gene mutations in triple negative breast cancer 
In this study, we evaluated C-kit immunohistochemical expression and C-kit and platelet derived growth factor receptor A (PDGFRA) gene mutations in triple negative breast cancer. 171 cases were analyzed by immunohistochemical staining for the expression of C-kit and 45 cases, including 10 C-kit negative cases and 35 C-kit positive cases, were performed for C-kit gene mutations in exons 9, 11, 13 and 17 and PDGFRA gene mutations in exons 12 and 18. C-kit expression was detected in 42.1% of triple negative breast cancers. Only 1 activating mutation was detected in exon 11 of C-kit gene in 1 case. No activating mutations were found in the other 44 cases. C-kit expression is a frequent finding in triple negative breast cancers; 1 activating mutation which was also found in gastrointestinal stromal tumors was detected; a few cases might benefit from imatinib.
PMCID: PMC4129045  PMID: 25120810
C-KIT; PDGFRA; mutation; triple negative breast cancer; immunohistochemical expression
20.  The Proteasome Inhibitor, MG132, Attenuates Diabetic Nephropathy by Inhibiting SnoN Degradation In Vivo and In Vitro 
BioMed Research International  2014;2014:684765.
Transforming growth factor-β (TGF-β) has been shown to be involved in diabetic nephropathy (DN). The SnoN protein can regulate TGF-β signaling through interaction with Smad proteins. Recent studies have shown that SnoN is mainly degraded by the ubiquitin-proteasome pathway. However, the role of SnoN in the regulation of TGF-β/Smad signaling in DN is still unclear. In this study, diabetic rats were randomly divided into a diabetic control group (DC group) and a proteasome inhibitor (MG132) diabetes therapy group (DT group). Kidney damage parameters and the expression of SnoN, Smurf2, and TGF-β were observed. Simultaneously, we cultured rat glomerular mesangial cells (GMCs) stimulated with high glucose, and SnoN and Arkadia expression were measured. Results demonstrated that 24-hour urine protein, ACR, BUN, and the expression of Smurf2 and TGF-β were significantly increased (P < 0.05), whereas SnoN was significantly decreased in the DC group (P < 0.05). However, these changes diminished after treatment with MG132. SnoN expression in GMCs decreased significantly (P < 0.05), but Arkadia expression gradually increased due to high glucose stimulation (P < 0.05), which could be almost completely reversed by MG132 (P < 0.05). The present results support the hypothesis that MG132 may alleviate kidney damage by inhibiting SnoN degradation and TGF-β activation, suggesting that the ubiquitin-proteasome pathway may become a new therapeutic target for DN.
PMCID: PMC4070544  PMID: 25003128
21.  Biventricular Finite Element Modeling of the Acorn CorCap Cardiac Support Device on a Failing Heart 
The Annals of thoracic surgery  2013;95(6):2022-2027.
The Acorn CorCap Cardiac Support Device (CSD; Acorn Cardiovascular Inc, St. Paul, MN) is a woven polyester jacket that is placed around the heart and designed to reverse the progressive remodeling associated with dilated cardiomyopathy. However, the effects of the Acorn CSD on myofiber stress and ventricular function remain unknown. We tested the hypothesis that the Acorn CSD reduces end-diastolic (ED) myofiber stress.
A previously described weakly coupled biventricular finite element (FE) model and circulatory model based on magnetic resonance images of a dog with dilated cardiomyopathy was used. Virtual applications of the CSD alone (Acorn), CSD with rotated fabric fiber orientation (rotated), CSD with 5% prestretch (tight), and CSD wrapped only around the left ventricle (LV; LV-only) were performed, and the effect on myofiber stress at ED and pump function was calculated.
The Acorn CSD has a large effect on ED myofiber stress in the LV free wall, with reductions of 55%, 79%, 92%, and 40% in the Acorn, rotated, tight, and LV-only cases, respectively. However, there is a tradeoff in which the Acorn CSD reduces stroke volume at LV end-diastolic pressure of 8 mm Hg by 23%, 25%, 30%, and 7%, respectively, in the Acorn, rotated, tight, and LV-only cases.
The Acorn CSD significantly reduces ED myofiber stress. However, CSD wrapped only around the LV was the only case with minimal negative effect on pump function. Findings suggest that LV-only CSD and Acorn fabric orientation should be optimized to allow maximal myofiber stress reduction with minimal reduction in pump function.
PMCID: PMC3702266  PMID: 23643546
22.  The Molecular Architecture of the Bacteriophage T4 Neck 
Journal of molecular biology  2013;425(10):1731-1744.
A hexamer of the bacteriophage T4 tail terminator protein, gp15, attaches to the top of the phage tail stabilizing the contractile sheath and forming the interface for binding of the independently assembled head. Here we report the crystal structure of the gp15 hexamer, describe its interactions in T4 virions that have either an extended tail or a contracted tail, and discuss its structural relationship to other phage proteins. The neck of T4 virions is decorated by the “collar” and “whiskers”, made of fibritin molecules. Fibritin acts as a chaperone helping to attach the long tail fibers to the virus during the assembly process. The collar and whiskers are environment-sensing devices, regulating the retraction of the long tail fibers under unfavorable conditions, thus preventing infection. Cryo-electron microscopy analysis suggests that twelve fibritin molecules attach to the phage neck with six molecules forming the collar and six molecules forming the whiskers.
PMCID: PMC3746776  PMID: 23434847
bacteriophage T4; fibritin; gpwac; T4 collar and whiskers; tail terminator protein, gp15
23.  LC3 fluorescent puncta in autophagosomes or in protein aggregates can be distinguished by FRAP analysis in living cells 
Autophagy  2013;9(5):756-769.
LC3 is a marker protein that is involved in the formation of autophagosomes and autolysosomes, which are usually characterized and monitored by fluorescence microscopy using fluorescent protein-tagged LC3 probes (FP-LC3). FP-LC3 and even endogenous LC3 can also be incorporated into intracellular protein aggregates in an autophagy-independent manner. However, the dynamic process of LC3 associated with autophagosomes and autolysosomes or protein aggregates in living cells remains unclear. Here, we explored the dynamic properties of the two types of FP-LC3-containing puncta using fluorescence microscopy techniques, including fluorescence recovery after photobleaching (FRAP) and fluorescence resonance energy transfer (FRET). The FRAP data revealed that the fluorescent signals of FP-LC3 attached to phagophores or in mature autolysosomes showed either minimal or no recovery after photobleaching, indicating that the dissociation of LC3 from the autophagosome membranes may be very slow. In contrast, FP-LC3 in the protein aggregates exhibited nearly complete recovery (more than 80%) and rapid kinetics of association and dissociation (half-time < 1 sec), indicating a rapid exchange occurs between the aggregates and cytoplasmic pool, which is mainly due to the transient interaction of LC3 and SQSTM1/p62. Based on the distinct dynamic properties of FP-LC3 in the two types of punctate structures, we provide a convenient and useful FRAP approach to distinguish autophagosomes from LC3-involved protein aggregates in living cells. Using this approach, we find the FP-LC3 puncta that adjacently localized to the phagophore marker ATG16L1 were protein aggregate-associated LC3 puncta, which exhibited different kinetics compared with that of autophagic structures.
PMCID: PMC3669184  PMID: 23482084
autophagosome; protein aggregate; inclusion body; LC3; FRAP; FRET
24.  Incidence of Microscopically Positive Proximal Margins in Adenocarcinoma of the Gastroesophageal Junction 
PLoS ONE  2014;9(2):e88010.
To investigate the incidence and risk factors of microscopically positive proximal margins in Chinese patients with adenocarcinoma of the gastroesophageal junction.
The medical records of 483 patients, who underwent surgical treatment with curative intent for adenocarcinoma of the gastroesophageal junction in a single high-volume tertiary medical center, were reviewed. Demographic, radiographic, endoscopic, pathologic, and treatment-related variables were evaluated. All proximal margins were re-evaluated by two experienced pathologists, and a positive proximal margin was defined as the microscopic presence of invasive tumor cells seen at the esophageal transaction margin submitted en face on final paraffin sections.
The incidence of positive proximal margins was 23.81% in this series. Siewert type, depth of tumor invasion, lymph node involvement, presence of vascular or lymphatic invasion, and presence of perineural invasion were significantly associated with positive proximal margins. On multivariate analysis, the presence of vascular or lymphatic invasion and advanced-stage disease were independent risk factors for positive proximal margins in patients with adenocarcinoma of the gastroesophageal junction.
Residual cancer at proximal resection margins remains a major issue for the surgical treatment of adenocarcinoma of the gastroesophageal junction in China.
PMCID: PMC3914864  PMID: 24505353
25.  ATM impacts IGF-1 signaling in skeletal muscle 
Experimental physiology  2012;98(2):526-535.
Reports that ataxia telangiectasia mutated (ATM) is required for full activation of Akt raise the hypothesis that ATM plays a role in IGF-1 signaling through the Akt/mTOR pathway. Differentiated C2C12 cells harboring either ATM-targeting shRNA or non-targeting shRNA and myotubes from a C2C12 lineage previously exposed to empty vector lentivirus were incubated in the presence or absence of 10 nM IGF-1 followed by western blot analysis. Parallel experiments were performed in isolated soleus muscles from mice expressing only one functional ATM allele (ATM+/−) compared to muscles from wild-type (ATM+/+) mice. IGF-1 increased phosphorylation of Akt S473, Akt T308, and p70 S6 kinase (S6K) in myotubes expressing non-targeting shRNA and in empty vector controls, but the IGF-1 effects were significantly reduced in myotubes with shRNA-mediated ATM knockdown. Likewise, IGF-1-stimulated phosphorylation of Akt S473, Akt T308, mTOR, and S6K was lower in isolated soleus muscles from ATM+/− mice compared to muscles from ATM+/+ mice. The ATM inhibitor KU55933 prevented stimulation of S6K phosphorylation in C2C12 myotubes exposed to IGF-1, suggesting that decreased IGF-1 action is not limited to chronic conditions of decreased ATM function. Stimulation of IRS-1 tyrosine 612 phosphorylation by IGF-1 was unaffected by ATM deficiency, though IGF-1 phosphatidylinositol 3-kinase activity tended to be lower in muscle from ATM haploinsufficient mice compared to wild type muscle. The data suggest that ATM is a modulator of IGF-1 signaling downstream of IRS-1 in skeletal muscle.
PMCID: PMC3553258  PMID: 22941977
Akt; IGF-1; mTOR

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