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1.  The p38 MAPK stress pathway as a tumor suppressor or more? 
p38 mitogen-activated protein kinases (p38 MAPKs) are a group of serine/threonine protein kinases that together with ERK (extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinases) MAPKs act to convert different extracellular signals into specific cellular responses through interacting with and phosphorylating downstream targets. In contrast to the mitogenic ERK pathway, mammalian p38 MAPK family proteins (alpha, beta, gamma, and delta), with and without JNK participation, predominantly regulate inflammatory and stress response. Recent emerging evidence suggests that the p38 stress MAPK pathway may function as a tumor suppressor through regulating Ras-dependent and -independent proliferation, transformation, invasion and cell death by isoform-specific mechanisms. A selective activation of a stress pathway to block tumorigenesis may be a novel strategy to control human malignancies.
PMCID: PMC4758212  PMID: 18508457
The p38 MAPK pathway; Ras; Tumor Suppressor; isoform-specific; Oncogenesis; Review
2.  Altered Autophagy-Associated Genes Expression in T Cells of Oral Lichen Planus Correlated with Clinical Features 
Mediators of Inflammation  2016;2016:4867368.
Oral lichen planus (OLP) is a T cell-mediated inflammatory autoimmune disease. Autophagy has emerged as a fundamental trafficking event in mediating T cell response, which plays crucial roles in innate and adaptive immunity. The present study mainly investigated the mRNA expression of autophagy-associated genes in peripheral blood T cells of OLP patients and evaluated correlations between their expression and the clinical features of OLP. Five differentially expressed autophagy-associated genes were identified by autophagy array. Quantitative real-time RT-PCR results confirmed that IGF1 expression in the peripheral blood T cells of OLP patients was significantly higher than that in controls, especially in female and middle-aged (30–50 years old) OLP patients. In addition, ATG9B mRNA levels were significantly lower in nonerosive OLP patients. However, no significant differences were found in the expression of HGS, ESR1, and SNCA between OLP patients and controls. Taken together, dysregulation of T cell autophagy may be involved in immune response of OLP and may be correlated with clinical patterns.
PMCID: PMC4770128  PMID: 26980945
3.  Strong Ion Regulatory Abilities Enable the Crab Xenograpsus testudinatus to Inhabit Highly Acidified Marine Vent Systems 
Hydrothermal vent organisms have evolved physiological adaptations to cope with extreme abiotic conditions including temperature and pH. To date, acid-base regulatory abilities of vent organisms are poorly investigated, although this physiological feature is essential for survival in low pH environments. We report the acid-base regulatory mechanisms of a hydrothermal vent crab, Xenograpsus testudinatus, endemic to highly acidic shallow-water vent habitats with average environment pH-values ranging between 5.4 and 6.6. Within a few hours, X. testudinatus restores extracellular pH (pHe) in response to environmental acidification of pH 6.5 (1.78 kPa pCO2) accompanied by an increase in blood HCO3- levels from 8.8 ± 0.3 to 31 ± 6 mM. Branchial Na+/K+-ATPase (NKA) and V-type H+-ATPase (VHA), the major ion pumps involved in branchial acid-base regulation, showed dynamic increases in response to acidified conditions on the mRNA, protein and activity level. Immunohistochemical analyses demonstrate the presence of NKA in basolateral membranes, whereas the VHA is predominantly localized in cytoplasmic vesicles of branchial epithelial- and pillar-cells. X. testudinatus is closely related to other strong osmo-regulating brachyurans, which is also reflected in the phylogeny of the NKA. Accordingly, our results suggest that the evolution of strong ion regulatory abilities in brachyuran crabs that allowed the occupation of ecological niches in euryhaline, freshwater, and terrestrial habitats are probably also linked to substantial acid-base regulatory abilities. This physiological trait allowed X. testudinatus to successfully inhabit one of the world's most acidic marine environments.
PMCID: PMC4734175  PMID: 26869933
hydrothermal vent; V-type H+-ATPase; Na+/K+-ATPase; hypercapnia; invertebrate physiology; gill; crustacean
4.  MicroRNA-155-IFN-γ Feedback Loop in CD4+T Cells of Erosive type Oral Lichen Planus 
Scientific Reports  2015;5:16935.
Oral lichen planus (OLP) is a T cell-mediated immune disorder, and we have indicated a Th1-dominated immune response in OLP. MicroRNA-155 (miR-155) could promote Th1 cells polarization. The present study aims to determine the role of miR-155 in immune response of OLP. The expression of miR-155 and the target mRNA was tested by Real-Time PCR. The serum levels of IL-2, 4, 10 and IFN-γ were examined with ELISA. Furthermore, in vitro study was built to observe the function of miR-155 in erosive-type OLP (EOLP). Finally, we determined the expression and correlation of miR-155 and SOCS1 in EOLP CD4+ T cells. The results showed miR-155 was high related with the disease severities. Besides, serum IFN-γ was specifically increased in EOLP group, while IL-4 was decreased. In vitro studies showed miR-155 could reinforce IFN-γ signal transducer, and the induction of IFN-γ could also promote miR-155 expression in EOLP CD4+ T cells. In addition, miR-155 levels were negatively related with SOCS1 mRNA expression in EOLP CD4+ T cells. Our study revealed a positive miR-155- IFN-γ feedback loop in EOLP CD4+ T cell, which might contribute to the Th1-dominated immune response. Furthermore, miR-155 could be used for the evaluation and treatment of OLP.
PMCID: PMC4655359  PMID: 26594049
5.  Anxious/Depressed Symptoms are Linked to Right Ventromedial Prefrontal Cortical Thickness Maturation in Healthy Children and Young Adults 
Ducharme, Simon | Albaugh, Matthew D. | Hudziak, James J. | Botteron, Kelly N. | Nguyen, Tuong-Vi | Truong, Catherine | Evans, Alan C. | Karama, Sherif | Ball, William S. | Byars, Anna Weber | Schapiro, Mark | Bommer, Wendy | Carr, April | German, April | Dunn, Scott | Rivkin, Michael J. | Waber, Deborah | Mulkern, Robert | Vajapeyam, Sridhar | Chiverton, Abigail | Davis, Peter | Koo, Julie | Marmor, Jacki | Mrakotsky, Christine | Robertson, Richard | McAnulty, Gloria | Brandt, Michael E. | Fletcher, Jack M. | Kramer, Larry A. | Yang, Grace | McCormack, Cara | Hebert, Kathleen M. | Volero, Hilda | Botteron, Kelly | McKinstry, Robert C. | Warren, William | Nishino, Tomoyuki | Almli, C. Robert | Todd, Richard | Constantino, John | McCracken, James T. | Levitt, Jennifer | Alger, Jeffrey | O'Neil, Joseph | Toga, Arthur | Asarnow, Robert | Fadale, David | Heinichen, Laura | Ireland, Cedric | Wang, Dah-Jyuu | Moss, Edward | Zimmerman, Robert A. | Bintliff, Brooke | Bradford, Ruth | Newman, Janice | Evans, Alan C. | Arnaoutelis, Rozalia | Pike, G. Bruce | Collins, D. Louis | Leonard, Gabriel | Paus, Tomas | Zijdenbos, Alex | Das, Samir | Fonov, Vladimir | Fu, Luke | Harlap, Jonathan | Leppert, Ilana | Milovan, Denise | Vins, Dario | Zeffiro, Thomas | Van Meter, John | Lange, Nicholas | Froimowitz, Michael P. | Botteron, Kelly | Almli, C. Robert | Rainey, Cheryl | Henderson, Stan | Nishino, Tomoyuki | Warren, William | Edwards, Jennifer L. | Dubois, Diane | Smith, Karla | Singer, Tish | Wilber, Aaron A. | Pierpaoli, Carlo | Basser, Peter J. | Chang, Lin-Ching | Koay, Chen Guan | Walker, Lindsay | Freund, Lisa | Rumsey, Judith | Baskir, Lauren | Stanford, Laurence | Sirocco, Karen | Gwinn-Hardy, Katrina | Spinella, Giovanna | McCracken, James T. | Alger, Jeffry R. | Levitt, Jennifer | O'Neill, Joseph
Cerebral Cortex (New York, NY)  2013;24(11):2941-2950.
The relationship between anxious/depressed traits and neuromaturation remains largely unstudied. Characterizing this relationship during healthy neurodevelopment is critical to understanding processes associated with the emergence of child/adolescent onset mood/anxiety disorders. In this study, mixed-effects models were used to determine longitudinal cortical thickness correlates of Child Behavior Checklist (CBCL) and Young Adult Self Report Anxious/Depressed scores in healthy children. Analyses included 341 subjects from 4.9 to 22.3 year-old with repeated MRI at up to 3 time points, at 2-year intervals (586 MRI scans). There was a significant “CBCL Anxious/Depressed by Age” interaction on cortical thickness in the right ventromedial prefrontal cortex (vmPFC), including the medial orbito-frontal, gyrus rectus, and subgenual anterior cingulate areas. Anxious/Depressed scores were negatively associated with thickness at younger ages (<9 years), but positively associated with thickness at older ages (15–22 years), with the shift in polarity occurring around age 12. This was secondary to a slower rate of vmPFC cortical thinning in subjects with higher scores. In young adults (18–22 years), Anxious/Depressed scores were also positively associated with precuneus/posterior cingulate cortical thickness. Potential neurobiological mechanisms underlying this maturation pattern are proposed. These results demonstrate the dynamic impact of age on relations between vmPFC and negative affect in the developing brain.
PMCID: PMC4193463  PMID: 23749874
anxiety; brain development; Child Behavior Checklist; depression; magnetic resonance imaging
6.  A Study of the Preparation and Properties of Antioxidative Copper Inks with High Electrical Conductivity 
Conductive ink using copper nanoparticles has attracted much attention in the printed electronics industry because of its low cost and high electrical conductivity. However, the problem of easy oxidation under heat and humidity conditions for copper material limits the wide applications. In this study, antioxidative copper inks were prepared by dispersing the nanoparticles in the solution, and then conductive copper films can be obtained after calcining the copper ink at 250 °C in nitrogen atmosphere for 30 min. A low sheet resistance of 47.6 mΩ/□ for the copper film was measured by using the four-point probe method. Importantly, we experimentally demonstrate that the electrical conductivity of copper films can be improved by increasing the calcination temperature. In addition, these highly conductive copper films can be placed in an atmospheric environment for more than 6 months without the oxidation phenomenon, which was verified by energy-dispersive X-ray spectroscopy (EDS). These observations strongly show that our conductive copper ink features high antioxidant properties and long-term stability and has a great potential for many printed electronics applications, such as flexible display systems, sensors, photovoltaic cells, and radio frequency identification.
PMCID: PMC4569602  PMID: 26370132
Conductive ink; Stability; Resistivity; Antioxidant
7.  Development of biodegradable radiopaque microsphere for arterial embolization-a pig study 
World Journal of Radiology  2015;7(8):212-219.
AIM: To develop a new type of calibrated, biodegradable, and imaging detectable microsphere and evaluated its embolization safety and efficacy on pig’s liver and spleen.
METHODS: Six kinds of pharmaceutical excipient were combined and atomized to form our microsphere. Twenty-four male Lanyu pigs weighing 25-30 kg were used. The arteries of spleen and liver were embolized with Gelfoam, Embosphere, or our microsphere. The serum biochemical tests, computed tomography (CT), liver perfusion scan, and tissue microscopy examination were done to evaluate the safety and efficacy of embolization.
RESULTS: Radiopaque microspheres with a size ranging from 300 to 400 μm were produced. Embolization of hepatic and splenic artery of pigs with our microsphere significantly reduced the blood flow of liver and resulted in splenic infarction. The follow-up CT imaging and the microscopic examination showed intraarterial degradation of Gelfoam and microsphere. The blood tests demonstrated insignificant changes with regards to liver and renal functions.
CONCLUSION: Our microspheres, with the unique characteristics, can be used for transcatheter arterial embolization with effects equivalent to or better than Gelfoam and Embosphere in pigs.
PMCID: PMC4553253  PMID: 26339465
Atomization; Pharmaceutical excipient; Microsphere; Arterial embolization
8.  Virtual-Reality Simulator System for Double Interventional Cardiac Catheterization Using Fractional-Order Vascular Access Tracker and Haptic Force Producer 
The Scientific World Journal  2015;2015:697569.
This study proposes virtual-reality (VR) simulator system for double interventional cardiac catheterization (ICC) using fractional-order vascular access tracker and haptic force producer. An endoscope or a catheter for diagnosis and surgery of cardiovascular disease has been commonly used in minimally invasive surgery. It needs specific skills and experiences for young surgeons or postgraduate year (PGY) students to operate a Berman catheter and a pigtail catheter in the inside of the human body and requires avoiding damaging vessels. To improve the training in inserting catheters, a double-catheter mechanism is designed for the ICC procedures. A fractional-order vascular access tracker is used to trace the senior surgeons' consoled trajectories and transmit the frictional feedback and visual feedback during the insertion of catheters. Based on the clinical feeling through the aortic arch, vein into the ventricle, or tortuous blood vessels, haptic force producer is used to mock the elasticity of the vessel wall using voice coil motors (VCMs). The VR establishment with surgeons' consoled vessel trajectories and hand feeling is achieved, and the experimental results show the effectiveness for the double ICC procedures.
PMCID: PMC4485928  PMID: 26171419
9.  Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER) 
Oncotarget  2015;6(15):13320-13333.
Protein-protein interactions can increase or decrease its therapeutic target activity and the determining factors involved, however, are largely unknown. Here, we report that tyrosine-dephosphorylation of epidermal growth factor receptor (EGFR) increases its therapeutic target activity by disrupting its interaction with estrogen receptor (ER). Protein tyrosine phosphatase H1 (PTPH1) dephosphorylates the tyrosine kinase EGFR, disrupts its interaction with the nuclear receptor ER, and increases breast cancer sensitivity to small molecule tyrosine kinase inhibitors (TKIs). These effects require PTPH1 catalytic activity and its interaction with EGFR, suggesting that the phosphatase may increase the sensitivity by dephosphorylating EGFR leading to its dissociation with ER. Consistent with this notion, a nuclear-localization defective ER has a higher EGFR-binding activity and confers the resistance to TKI-induced growth inhibition. Additional analysis show that PTPH1 stabilizes EGFR, stimulates the membranous EGFR accumulation, and enhances the growth-inhibitory activity of a combination therapy of TKIs with an anti-estrogen. Since EGFR and ER both are substrates for PTPH1 in vitro and in intact cells, these results indicate that an inhibitory EGFR-ER protein complex can be switched off through a competitive enzyme-substrate binding. Our results would have important implications for the treatment of breast cancer with targeted therapeutics.
PMCID: PMC4537017  PMID: 26079946
protein tyrosine phosphatase H1 (PTPH1); EGFR; ER; protein-protein-interactions; therapeutic target activity
10.  Electroacupuncture Prevents Cognitive Impairments by Regulating the Early Changes after Brain Irradiation in Rats 
PLoS ONE  2015;10(4):e0122087.
Cognitive impairments severely affect the quality of life of patients who undergo brain irradiation, and there are no effective preventive strategies. In this study, we examined the therapeutic potential of electroacupuncture (EA) administered immediately after brain irradiation in rats. We detected changes in cognitive function, neurogenesis, and synaptic density at different time points after irradiation, but found that EA could protect the blood-brain barrier (BBB), inhibit neuroinflammatory cytokine expression, upregulate angiogenic cytokine expression, and modulate the levels of neurotransmitter receptors and neuropeptides in the early phase. Moreover, EA protected spatial memory and recognition in the delayed phase. At the cellular/molecular level, the preventative effect of EA on cognitive dysfunction was not dependent on hippocampal neurogenesis; rather, it was related to synaptophysin expression. Our results suggest that EA applied immediately after brain irradiation can prevent cognitive impairments by protecting against the early changes induced by irradiation and may be a novel approach for preventing or ameliorating cognitive impairments in patients with brain tumors who require radiotherapy.
PMCID: PMC4382177  PMID: 25830357
11.  Flexible Bronchoscopy with Multiple Modalities for Foreign Body Removal in Adults 
PLoS ONE  2015;10(3):e0118993.
Aspiration of the lower airways due to foreign body is rare in adults. This study aimed to determine the outcome of patients who received flexible bronchoscopy with different modalities for foreign body removal in the lower airways.
Patients and Methods
Between January 2003 and January 2014, 94 patients diagnosed with foreign body in the lower airways underwent flexible bronchoscopy with different modalities, which included forceps, loop, basket, knife, electromagnet, and cryotherapy. The clinical presentation, foreign body location and characteristics, and applications of flexible bronchoscopy were analyzed.
Forty (43%) patients had acute aspiration, which developed within one week of foreign body entry and 54 (57%) had chronic aspiration. The most common foreign bodies were teeth or bone. More patients with chronic aspiration than those with acute aspiration were referred from the out-patient clinic (48% vs. 28%), but more patients with acute aspiration were referred from the emergency room (35% vs. 6%) and intensive care unit (18% vs. 2%). Flexible bronchoscopy with different modalities was used to remove the foreign bodies (85/94, 90%). Electromagnet or cryotherapy was used in nine patients to eliminate the surrounding granulation tissue before foreign body removal. In the nine patients with failed flexible bronchoscopy, eight underwent rigid bronchoscopy instead and one had right lower lung lobectomy for lung abscess.
Flexible bronchoscopy with multiple modalities is effective for diagnosing and removing foreign bodies in the lower respiratory airways in adults, with a high success rate (90%) and no difference between acute and chronic aspirations.
PMCID: PMC4358882  PMID: 25768933
12.  Gene transfection mediated by polyethyleneimine-polyethylene glycol nanocarrier prevents cisplatin-induced spiral ganglion cell damage 
Neural Regeneration Research  2015;10(3):425-431.
Polyethyleneimine-polyethylene glycol (PEI-PEG), a novel nanocarrier, has been used for transfection and gene therapy in a variety of cells. In our previous study, we successfully carried out PEI-PEG-mediated gene transfer in spiral ganglion cells. It remains unclear whether PEI-PEG could be used for gene therapy with X-linked inhibitor of apoptosis protein (XIAP) in the inner ear. In the present study, we performed PEI-PEG-mediated XIAP gene transfection in the cochlea of Sprague-Dawley rats, via scala tympani fenestration, before daily cisplatin injections. Auditory brainstem reflex tests demonstrated the protective effects of XIAP gene therapy on auditory function. Immunohistochemical staining revealed XIAP protein expression in the cytoplasm of cells in the spiral ganglion, the organ of Corti and the stria vascularis. Reverse transcription-PCR detected high levels of XIAP mRNA expression in the cochlea. The present findings suggest that PEI-PEG nanocarrier-mediated XIAP gene transfection results in XIAP expression in the cochlea, prevents damage to cochlear spiral ganglion cells, and protects hearing.
PMCID: PMC4396105  PMID: 25878591
nerve regeneration; polyethyleneimine-polyethylene glycol; spiral ganglion cells; X-linked inhibitor of apoptosis protein; gene therapy; nanocarrier; cisplatin; neural regeneration; ototoxicity; cochlea
13.  Passivation ability of graphene oxide demonstrated by two-different-metal solar cells 
The study on graphene oxide (GO) grows rapidly in recent years. We find that graphene oxide could act as the passivation material in photovoltaic applications. Graphene oxide has been applied on Si two-different-metal solar cells. The suitable introduction of graphene oxide could result in obvious enhancement on the efficiency. The simple chemical process to deposit graphene oxide makes low thermal budget, large-area deposition, and fast production of surface passivation possible. The different procedures to incorporate graphene oxide in Si two-different-metal solar cells are compared, and 21% enhancement on the efficiency is possible with a suitable deposition method.
PMCID: PMC4493844  PMID: 26088990
Passivation; Solar cell; Graphene oxide; Two-different-metal; Hummers method
14.  Developmental Changes in Organization of Structural Brain Networks 
Khundrakpam, Budhachandra S. | Reid, Andrew | Brauer, Jens | Carbonell, Felix | Lewis, John | Ameis, Stephanie | Karama, Sherif | Lee, Junki | Chen, Zhang | Das, Samir | Evans, Alan C. | Ball, William S. | Byars, Anna Weber | Schapiro, Mark | Bommer, Wendy | Carr, April | German, April | Dunn, Scott | Rivkin, Michael J. | Waber, Deborah | Mulkern, Robert | Vajapeyam, Sridhar | Chiverton, Abigail | Davis, Peter | Koo, Julie | Marmor, Jacki | Mrakotsky, Christine | Robertson, Richard | McAnulty, Gloria | Brandt, Michael E. | Fletcher, Jack M. | Kramer, Larry A. | Yang, Grace | McCormack, Cara | Hebert, Kathleen M. | Volero, Hilda | Botteron, Kelly | McKinstry, Robert C. | Warren, William | Nishino, Tomoyuki | Robert Almli, C. | Todd, Richard | Constantino, John | McCracken, James T. | Levitt, Jennifer | Alger, Jeffrey | O'Neil, Joseph | Toga, Arthur | Asarnow, Robert | Fadale, David | Heinichen, Laura | Ireland, Cedric | Wang, Dah-Jyuu | Moss, Edward | Zimmerman, Robert A. | Bintliff, Brooke | Bradford, Ruth | Newman, Janice | Evans, Alan C. | Arnaoutelis, Rozalia | Bruce Pike, G. | Louis Collins, D. | Leonard, Gabriel | Paus, Tomas | Zijdenbos, Alex | Das, Samir | Fonov, Vladimir | Fu, Luke | Harlap, Jonathan | Leppert, Ilana | Milovan, Denise | Vins, Dario | Zeffiro, Thomas | Van Meter, John | Lange, Nicholas | Froimowitz, Michael P. | Botteron, Kelly | Robert Almli, C. | Rainey, Cheryl | Henderson, Stan | Nishino, Tomoyuki | Warren, William | Edwards, Jennifer L. | Dubois, Diane | Smith, Karla | Singer, Tish | Wilber, Aaron A. | Pierpaoli, Carlo | Basser, Peter J. | Chang, Lin-Ching | Koay, Chen Guan | Walker, Lindsay | Freund, Lisa | Rumsey, Judith | Baskir, Lauren | Stanford, Laurence | Sirocco, Karen | Gwinn-Hardy, Katrina | Spinella, Giovanna | McCracken, James T. | Alger, Jeffry R. | Levitt, Jennifer | O'Neill, Joseph
Cerebral Cortex (New York, NY)  2012;23(9):2072-2085.
Recent findings from developmental neuroimaging studies suggest that the enhancement of cognitive processes during development may be the result of a fine-tuning of the structural and functional organization of brain with maturation. However, the details regarding the developmental trajectory of large-scale structural brain networks are not yet understood. Here, we used graph theory to examine developmental changes in the organization of structural brain networks in 203 normally growing children and adolescents. Structural brain networks were constructed using interregional correlations in cortical thickness for 4 age groups (early childhood: 4.8–8.4 year; late childhood: 8.5–11.3 year; early adolescence: 11.4–14.7 year; late adolescence: 14.8–18.3 year). Late childhood showed prominent changes in topological properties, specifically a significant reduction in local efficiency, modularity, and increased global efficiency, suggesting a shift of topological organization toward a more random configuration. An increase in number and span of distribution of connector hubs was found in this age group. Finally, inter-regional connectivity analysis and graph-theoretic measures indicated early maturation of primary sensorimotor regions and protracted development of higher order association and paralimbic regions. Our finding reveals a time window of plasticity occurring during late childhood which may accommodate crucial changes during puberty and the new developmental tasks that an adolescent faces.
PMCID: PMC3729193  PMID: 22784607
adolescence; connectivity; connector hub; cortical thickness; maturation
15.  SIRT1 expression is associated with lymphangiogenesis, lymphovascular invasion and prognosis in pN0 esophageal squamous cell carcinoma 
Cell & Bioscience  2014;4:48.
Sirtuin1 (SIRT1) is an NAD+-dependent type III histone deacetylase (HDAC). This research investigated the prevalence of SIRT1 protein expression and its prognostic influence with the aim of validating its potential role in lymphangiogenesis and lymphovascular invasion (LVI) in pN0 esophageal squamous cell carcinoma (ESCC).
A total of 206 patients were enrolled in this retrospective study. SIRT1 and VEGF-C protein expression was detected by immunohistochemical staining. Peritumoral lymphatic microvessel density (LVD) and LVI were evaluated by immunostaining for D2-40. Statistical analysis was then preformed to investigate the relevance of SIRT1 expression and various clinicopathologic features and to examine the effect of SIRT1 on tumor-induced lymphangiogenesis, LVI and prognosis.
SIRT1 positive expression was identified in 95 cases in the nucleus and was significantly correlated with T status (P < 0.001), disease stage (P = 0.001), VEGF-C positive expression (P = 0.015), high LVD (P = 0.013) and positive LVI (P = 0.015). Patients with SIRT1 positive expression, high LVD and positive LVI had a significantly unfavorable 5-year disease free survival (P < 0.001, P = 0.030, and P < 0.001, respectively) and overall survival (P < 0.001, P = 0.017, and P < 0.001, respectively). However, based on multivariate Cox regression analysis, only SIRT1 positive expression and positive LVI were significant independent prognosticators of poor disease-free survival (P = 0.029 and 0.018, respectively) and overall survival (P = 0.045 and 0.031, respectively).
SIRT1 positive expression was significantly associated with tumor progression, lymphangiogenesis, LVI and poor survival in pN0 ESCC patients. Our research shows a utilization of SIRT1 in prognosing poor survival and providing possible target for ESCC patients through inhibiting its lymphangiogenesis activity.
PMCID: PMC4412293  PMID: 25922660
Esophageal squamous cell carcinoma; Lymphangiogenesis; Lymphatic metastasis; Prognosis; SIRT1
16.  Ultrasound Image Enhancement Using Structure-Based Filtering 
Ultrasound images are prone to speckle noises. Speckles blur features which are essential for diagnosis and assessment. Thus despeckling is a necessity in ultrasound image processing. Linear filters can suppress speckles, but they smooth out features. Median filter based despeckling algorithms produce better results. However, they may produce artifact patterns in the resulted images and oversmooth nonuniform regions. This paper presents an innovative despeckle procedure for ultrasound images. In the proposed method, the diffusion tensor of intensity is computed at each pixel at first. Then the eigensystem of the diffusion tensor is calculated and employed to detect and classify the underlying structure. Based on the classification result, a feasible filter is selected to suppress speckles and enhance features. Test results show that the proposed despeckle method reduces speckles in uniform areas and enhances tissue boundaries and spots.
PMCID: PMC4089207  PMID: 25110515
17.  Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer 
Oncotarget  2014;5(12):4269-4282.
A cancer phenotype is driven by several proteins and targeting a cluster of functionally interdependent molecules should be more effective for therapeutic intervention. This is specifically important for Ras-dependent cancer, as mutated (MT) Ras is non-druggable and targeting its interaction with effectors may be essential for therapeutic intervention. Here, we report that a protein-complex activated by the Ras effector p38γ MAPK is a novel therapeutic target for K-Ras-dependent colon cancer. Unbiased proteomic screening and immune-precipitation analyses identified p38γ interaction with heat shock protein 90 (Hsp90) and K-Ras in K-Ras MT, but not wild-type (WT), colon cancer cells, indicating a role of this complex in Ras-dependent growth. Further experiments showed that this complex requires p38γ and Hsp90 activity to maintain MT, but not WT, K-Ras protein expression. Additional studies demonstrated that this complex is activated by p38γ-induced Hsp90 phosphorylation at S595, which is important for MT K-Ras stability and for K-Ras dependent growth. Of most important, pharmacologically inhibition of Hsp90 or p38γ activity disrupts the complex, decreases K-Ras expression, and selectively inhibits the growth of K-Ras MT colon cancer in vitro and in vivo. These results demonstrated that the p38γ-activated ternary complex is a novel therapeutic target for K-Ras-dependent colon cancer.
PMCID: PMC4147322  PMID: 24962213
p38γ MAPK; Hsp90; K-Ras; ternary complex; therapeutic target; and colon cancer
18.  Circulating MicroRNAs in gynecological malignancies: from detection to prediction 
MicroRNAs (miRNAs) have been demonstrated to play critical roles in many physiological and pathophysiological processes. The presence of altered miRNA profiles in human body fluids has been reported for a number of diseases including gynecological malignancies. In this review, we summarized the current progresses of circulating miRNAs associated with malignancies in gynecology, with an emphasizing on the circulating miRNAs as diagnostic and prognostic biomarkers in ovarian cancer, endometrial carcinoma and cervical cancer.
PMCID: PMC4047546  PMID: 24910811
19.  Terrestrial Origin of Viviparity in Mesozoic Marine Reptiles Indicated by Early Triassic Embryonic Fossils 
PLoS ONE  2014;9(2):e88640.
Viviparity in Mesozoic marine reptiles has traditionally been considered an aquatic adaptation. We report a new fossil specimen that strongly contradicts this traditional interpretation. The new specimen contains the oldest fossil embryos of Mesozoic marine reptile that are about 10 million years older than previous such records. The fossil belongs to Chaohusaurus (Reptilia, Ichthyopterygia), which is the oldest of Mesozoic marine reptiles (ca. 248 million years ago, Early Triassic). This exceptional specimen captures an articulated embryo in birth position, with its skull just emerged from the maternal pelvis. Its headfirst birth posture, which is unlikely to be a breech condition, strongly indicates a terrestrial origin of viviparity, in contrast to the traditional view. The tail-first birth posture in derived ichthyopterygians, convergent with the conditions in whales and sea cows, therefore is a secondary feature. The unequivocally marine origin of viviparity is so far not known among amniotes, a subset of vertebrate animals comprising mammals and reptiles, including birds. Therefore, obligate marine amniotes appear to have evolved almost exclusively from viviparous land ancestors. Viviparous land reptiles most likely appeared much earlier than currently thought, at least as early as the recovery phase from the end-Permian mass extinction.
PMCID: PMC3922983  PMID: 24533127
20.  In Vivo Analysis of Trapeziometacarpal Joint Kinematics during Pinch Tasks 
BioMed Research International  2014;2014:157295.
This study investigated how the posture of the thumb while performing common pinch movements and the levels of pinch force applied by the thumb affect the arthrokinematics of the trapeziometacarpal joint in vivo. Fifteen subjects performed the pinch tasks at the distal phalange (DP), proximal interphalangeal (PIP) joint, and metacarpophalangeal (MP) joint of the index finger with 0%, 50%, and 80% of maximal pinch forces by a single-axis load cell. 3D images of the thumb were obtained using the computed tomography. The results show that the reference points moved from the central region to the dorsal-radial region when changing from pinching the DP to the MP joint without pinching force being applied. Pinching with 80% of the maximum pinching force resulted in reference points being the closest to the volar-ulnar direction. Significant differences were seen between 0% and 50% of maximum pinch force, as well as between 0% and 80%, when pinching the MP joint in the distal-proximal direction. The effects of posture of the thumb and applied pinch force on the arthrokinematics of the joint were investigated with a 3D model of the trapeziometacarpal joint. Pinching with more than 50% of maximum pinch force might subject this joint to extreme displacement.
PMCID: PMC3934769  PMID: 24683540
21.  The Role of the High-Sensitivity C-Reactive Protein in Patients with Stable Non-Cystic Fibrosis Bronchiectasis 
Pulmonary Medicine  2013;2013:795140.
Study Objectives. The aim of this study is to investigate the correlation between serum high-sensitivity C-reactive protein (hs-CRP) and other clinical tools including high-resolution computed tomography (HRCT) in patients with stable non-CF bronchiectasis. Design. A within-subject correlational study of a group of patients with stable non-CF bronchiectasis, who were recruited from our outpatient clinic, was done over a two-year period. Measurements. Sixty-nine stable non-CF bronchiectasis patients were evaluated in terms of hs-CRP, 6-minute walk test, pulmonary function tests, and HRCT. Results. Circulating hs-CRP levels were significantly correlated with HRCT scores (n = 69, r = 0.473, P < 0.001) and resting oxygenation saturation (r = −0.269, P = 0.025). HRCT severity scores significantly increased in patients with hs-CRP level of 4.26 mg/L or higher (mean ± SD 28.1 ± 13.1) compared to those with hs-CRP level less than 4.26 mg/L (31.7 ± 9.8, P = 0.004). Oxygenation saturation at rest was lower in those with hs-CRP level of 4.26 mg/L or higher (93.5 ± 4.4%) compared to those with hs-CRP level less than 4.26 mg/L (96.4 ± 1.6%, P = 0.001). Conclusion. There was a good correlation between serum hs-CRP and HRCT scores in the patients with stable non-CF bronchiectasis.
PMCID: PMC3870862  PMID: 24381758
22.  Neuropathic pain in hereditary coproporphyria 
Acute porphyrias are rare diseases with varying incidences worldwide. These diseases are disorders of heme biosynthesis characterized by acute attacks of neurological symptoms. Acute porphyria should be considered in patients with unexplained abdominal pain or neurological damage. Clinical manifestations of acute porphyria are nonspecific and are associated with multiple organ systems. This report examines a rare case of an uncommon type of acute porphyria in a patient with an initial presentation of abdominal pain and progressive polyneuropathy.
PMCID: PMC3809238  PMID: 24353603
Hereditary coproporphyria; Polyneuropathy; Neuropathic pain; Photosensitivity
23.  Metabolomic Analysis of Complex Chinese Remedies: Examples of Induced Nephrotoxicity in the Mouse from a Series of Remedies Containing Aristolochic Acid 
Aristolochic acid nephropathy is caused by aristolochic acid (AA) and AA-containing herbs. In traditional Chinese medicine, a principle called “Jun-Chen-Zou-Shi” may be utilized to construct a remedial herbal formula that attempts to mitigate the toxicity of the main ingredient. This study used Bu-Fei-A-Jiao-Tang (BFAJT) to test if the compound remedy based on a principle of “Jun-Chen-Zou-Shi” can decrease the toxicity of AA-containing herbs. We compared the three toxicities of AA standard, Madouling (an Aristolochia herb), and a herbal formula BFAJT. AA standard was given for BALB/c mice at a dose of 5 mg/kg bw/day or 7.5 mg/kg bw/day for 10 days. Madouling and BFAJT were given at an equivalence of AA 0.5 mg/kg bw/day for 21 days. Nephrotoxicity was evaluated by metabolomics and histopathology. The urinary metabolomics profiles were characterized by 1H NMR spectroscopy. The spectral data was analyzed with partial least squares discriminant analysis, and the significant differential metabolites between groups were identified. The result showed different degrees of acute renal tubular injuries, and metabolomics analysis found that the kidney injuries were focused in proximal renal tubules. Both metabolomics and pathological studies revealed that AA standard, Madouling, and BFAJT were all nephrotoxicants. The compositions of the compound remedy did not diminish the nephrotoxicity caused by AA.
PMCID: PMC3626396  PMID: 23606874
24.  Novel Application of a Multiscale Entropy Index as a Sensitive Tool for Detecting Subtle Vascular Abnormalities in the Aged and Diabetic 
Although previous studies have shown the successful use of pressure-induced reactive hyperemia as a tool for the assessment of endothelial function, its sensitivity remains questionable. This study aims to investigate the feasibility and sensitivity of a novel multiscale entropy index (MEI) in detecting subtle vascular abnormalities in healthy and diabetic subjects. Basic anthropometric and hemodynamic parameters, serum lipid profiles, and glycosylated hemoglobin levels were recorded. Arterial pulse wave signals were acquired from the wrist with an air pressure sensing system (APSS), followed by MEI and dilatation index (DI) analyses. MEI succeeded in detecting significant differences among the four groups of subjects: healthy young individuals, healthy middle-aged or elderly individuals, well-controlled diabetic individuals, and poorly controlled diabetic individuals. A reduction in multiscale entropy reflected age- and diabetes-related vascular changes and may serve as a more sensitive indicator of subtle vascular abnormalities compared with DI in the setting of diabetes.
PMCID: PMC3590579  PMID: 23509600
25.  Defective Antiviral Responses of Induced Pluripotent Stem Cells to Baculoviral Vector Transduction 
Journal of Virology  2012;86(15):8041-8049.
Genetic engineering of induced pluripotent stem cells (iPSCs) is important for their clinical applications, and baculovirus (BV) holds promise as a gene delivery vector. To explore the feasibility of using BV for iPSCs transduction, in this study we first examined how iPSCs responded to BV. We determined that BV transduced iPSCs efficiently, without inducing appreciable negative effects on cell proliferation, apoptosis, pluripotency, and differentiation. BV transduction slightly perturbed the transcription of 12 genes involved in the Toll-like receptor (TLR) signaling pathway, but at the protein level BV elicited no well-known cytokines (e.g., interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-α], and beta interferon [IFN-β]) except for IP-10. Molecular analyses revealed that iPSCs expressed no TLR1, -6, -8, or -9 and expressed merely low levels of TLR2, -3, and -4. In spite of evident expression of such RNA/DNA sensors as RIG-I and AIM2, iPSCs barely expressed MDA5 and DAI (DNA-dependent activator of IFN regulatory factor [IRF]). Importantly, BV transduction of iPSCs stimulated none of the aforementioned sensors or their downstream signaling mediators (IRF3 and NF-κB). These data together confirmed that iPSCs responded poorly to BV due to the impaired sensing and signaling system, thereby justifying the transduction of iPSCs with the baculoviral vector.
PMCID: PMC3421682  PMID: 22623765

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