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2.  Rapid and sustained GluA1 S845 phosphorylation in synaptic and extrasynaptic locations in the rat forebrain following amphetamine administration 
Neurochemistry international  2013;64:10.1016/j.neuint.2013.11.001.
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is a major ionotropic glutamate receptor subtype in the mammalian brain. Like other glutamate receptors, the AMPA receptor is regulated by phosphorylation. By phosphorylating specific serine resides in AMPA receptor subunits (GluA1 and GluA2), various protein kinases regulate subcellular/subsynaptic expression and function of the receptor. In this study, we conducted a time course study to evaluate the temporal property of responses of phosphorylation at those sites to dopamine stimulation with the psychostimulant amphetamine in the adult rat striatum and medial prefrontal cortex (mPFC) in vivo. We focused on biochemically-enriched AMPA receptors from synaptic and extrasynaptic compartments. We found that acute injection of amphetamine induced a rapid and relatively sustained increase in GluA1 S845 phosphorylation at both synaptic and extrasynaptic sites in the striatum. Similar results were observed in the mPFC. In contrast to S845, amphetamine did not induce a significant change in GluA1 S831 phosphorylation in synaptic and extrasynaptic pools in the striatum and mPFC. GluA2 S880 phosphorylation in synaptic and extrasynaptic fractions in the two brain regions also remained stable in response to amphetamine. These results support S845 to be a principal site on AMPA receptors sensitive to acute stimulant exposure. Its phosphorylation levels are rapidly upregulated by amphetamine in the two defined subsynaptic microdomains (synaptic versus extrasynaptic locations) in striatal and cortical neurons.
PMCID: PMC3880017  PMID: 24231469
Striatum; basal ganglia; prefrontal cortex; dopamine; glutamate; GluR; excitatory amino acid; addiction
3.  Differential Regulation of CaMKIIα Interactions with mGluR5 and NMDA Receptors by Ca2+ in Neurons 
Journal of neurochemistry  2013;127(5):620-631.
Two glutamate receptors, metabotropic glutamate receptor 5 (mGluR5) and ionotropic NMDA receptors (NMDAR), functionally interact with each other to regulate excitatory synaptic transmission in the mammalian brain. In exploring molecular mechanisms underlying their interactions, we found that Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) may play a central role. The synapse-enriched CaMKIIα directly binds to the proximal region of intracellular C terminal tails of mGluR5 in vitro. This binding is state-dependent: inactive CaMKIIα binds to mGluR5 at a high level whereas the active form of the kinase (following Ca2+/calmodulin binding and activation) loses its affinity for the receptor. Ca2+ also promotes calmodulin to bind to mGluR5 at a region overlapping with the CaMKIIα-binding site, resulting in a competitive inhibition of CaMKIIα binding to mGluR5. In rat striatal neurons, inactive CaMKIIα constitutively binds to mGluR5. Activation of mGluR5 Ca2+-dependently dissociates CaMKIIα from the receptor and simultaneously promotes CaMKIIα to bind to the adjacent NMDAR GluN2B subunit, which enables CaMKIIα to phosphorylate GluN2B at a CaMKIIα-sensitive site. Together, the long intracellular C-terminal tail of mGluR5 seems to serve as a scaffolding domain to recruit and store CaMKIIα within synapses. The mGluR5-dependent Ca2+ transients differentially regulate CaMKIIα interactions with mGluR5 and GluN2B in striatal neurons, which may contribute to crosstalk between the two receptors.
PMCID: PMC3933469  PMID: 24032403
striatum; nucleus accumbens; calcium; calmodulin; glutamate; mGluR; GluN2B; NR2B; G protein-coupled receptor
4.  Group III metabotropic glutamate receptors and drug addiction 
Frontiers of medicine  2013;7(4):445-451.
Neuroadaptations of glutamatergic transmission in the limbic reward circuitry are linked to persistent drug addiction. Accumulating data have demonstrated roles of ionotropic glutamate receptors and group I and II metabotropic glutamate receptors (mGluRs) in this event. Emerging evidence also identifies Gαi/o-coupled group III mGluRs (mGluR4/7/8 subtypes enriched in the limbic system) as direct substrates of drugs of abuse and active regulators of drug action. Auto- and heteroreceptors of mGluR4/7/8 reside predominantly on nerve terminals of glutamatergic corticostriatal and GABAergic striatopallidal pathways, respectively. These presynaptic receptors regulate basal and/or phasic release of respective transmitters to maintain basal ganglia homeostasis. In response to operant administration of common addictive drugs, such as psychostimulants (cocaine and amphetamine), alcohol and opiates, limbic group III mGluRs undergo drastic adaptations to contribute to the enduring remodeling of excitatory synapses and to usually suppress drug seeking behavior. As a result, a loss-of-function mutation (knockout) of individual group III receptor subtypes often promotes drug seeking. This review summarizes the data from recent studies on three group III receptor subtypes (mGluR4/7/8) expressed in the basal ganglia and analyzes their roles in the regulation of dopamine and glutamate signaling in the striatum and their participation in the addictive properties of three major classes of drugs (psychostimulants, alcohol, and opiates).
PMCID: PMC3973399  PMID: 24078068
group III metabotropic glutamate receptors; cocaine; amphetamine; alcohol; opiate
5.  Human epidermal growth factor receptor 2 testing in gastric cancer: Recommendations of an Asia-Pacific Task Force 
Human epidermal growth factor receptor 2 (HER2) testing in gastric and gastroesophageal junction cancer is an evolving area in clinical practice that has particular relevance to Asia-Pacific countries, which face a high incidence of these diseases. A growing body of evidence demonstrates that HER2-targeted therapy improves survival for patients with HER2-positive advanced disease, and drives the need for high-quality testing procedures to identify patients who will respond to treatment. However, various factors challenge day-to-day testing of gastric specimens in these countries, to a degree greater than that observed for breast specimens. Recommendations for HER2 testing of gastric cancer specimens were published as a result of the Trastuzumab for Gastric Cancer (ToGA) trial. The guidelines proposed in this manuscript build on these recommendations and emphasize local testing environments, particularly in Asia-Pacific countries. A multidisciplinary task force comprising experts from Asia-Pacific who actively work and provide education in the area was convened to assess the applicability of existing recommendations in the Asia-Pacific region. The resulting recommendations reported here highlight and clarify aspects of testing that are of particular relevance to the region, and notably emphasize multidisciplinary collaborations to optimize HER2 testing quality.
PMCID: PMC4241045  PMID: 25227602
gastric cancer; human epidermal growth factor receptor 2; immunohistochemistry; in situ hybridization; quality control
6.  Generation and dynamics of an endogenous, self-generated signaling gradient across a migrating tissue 
Cell  2013;155(3):10.1016/j.cell.2013.09.046.
In animals, many cells reach their destinations by migrating towards higher concentrations of an attractant. However, the nature, generation and interpretation of attractant gradients are poorly understood. Using a GFP fusion and a signaling sensor, we analyzed the distribution of the attractant chemokine Sdf1 during migration of the zebrafish posterior lateral line primordium, a cohort of about 200 cells that migrates over a stripe of cells uniformly expressing sdf1. We find that a small fraction of the total Sdf1 pool is available to signal and induces a linear Sdf1-signaling gradient across the primordium. This signaling gradient is initiated at the rear of the primordium, equilibrates across the primordium within 200 minutes, and operates near steady-state. The rear of the primordium generates this gradient through continuous sequestration of Sdf1 protein by the alternate Sdf1-receptor Cxcr7. Modeling shows that this is a physically plausible scenario.
PMCID: PMC3842034  PMID: 24119842
7.  Primary lymph node gastrinoma. A diagnosis of exclusion. A case for duodenotomy in the setting of a negative imaging for primary tumor: A case report and review of the literature 
Zollinger–Ellison syndrome (ZES) is caused by uninhibited secretion of gastrin from a gastrinoma. Gastrinomas most commonly arise within the wall of the duodenum followed by the pancreas. Primary lymph node gastrinomas have also been reported in the literature. This is a case of ZES where preoperative localization revealed a gastrinoma in a solitary portacaval lymph node, presumed to be a primary lymph node gastrinoma.
The patient is a 57 year old female diagnosed with ZES, suspected of having a primary lymph node gastrinoma. The patient underwent an exploratory laparotomy and excision of a portacaval lymph node with a frozen section which was positive for gastrinoma. Intraoperative sonography of the pancreas, upper endoscopy with transillumination of the duodenum, and a duodenotomy with bimanual examination of the duodenal wall were also performed. The patient was found to have a 4 mm duodenal mass near the pylorus, which was excised.
Pathology showed that the duodenal mass was primary gastrinoma. Serum gastrin levels taken four months postoperatively were normal and the repeat octreotide scan did not show any evidence of recurrence.
Primary lymph node gastrinoma is a diagnosis of exclusion. The duodenum and pancreas must be fully explored to rule out a primary gastrinoma that may be occult.
PMCID: PMC4245667  PMID: 25462049
Gastrinoma; Pancreas; Duodenum; Duodenotomy; Zollinger–Ellison syndrome
8.  Extension of the Germinal Center Stage of B-cell Development Promotes Autoantibodies in BXD2 Mice 
Arthritis and rheumatism  2013;65(10):2703-2712.
Regulator of G-protein Signaling (RGS) proteins inhibit chemokine signaling by desensitizing G-protein coupled receptor signals. The mechanisms by which RGS13 promotes the generation of pathogenic autoantibodies in germinal centers (GC) were determined using BXD2-Rgs13−/− mice.
Confocal and light microscopy imaging was used to determine the location of cells that express RGS13 and activation-induced cytidine deaminase (AID) in the spleen and the number of plasmablasts. The levels of GC and plasma cell program transcripts in GC B cells were determined by quantitative real-time PCR. Differential IL-17-mediated expression of Rgs13 in GC versus non-GC B cells was analyzed using A20 versus 70Z/3 B cells.
In spleens of BXD2 mice, RGS13 was mainly expressed by GC B cells and was stimulated by IL-17 but not IL-21. IL-17 upregulated Rgs13 in A20 GC but not 70Z/3 non-GC B cells. BXD2-Rgs13−/− mice exhibited smaller GCs, lower AID levels, suggesting lower somatic hypermutation and affinity maturation. There were, however, increased IgMbright plasmablasts, upregulation of plasma program genes Irf4, Blimp1, Xbp1 and pCREB target genes Fosb and Obf1, with down-regulation of GC program genes Aicda, Pax5 and Bach2 in GC B cells of BXD2-Rgs13−/− mice. BXD2-Rgs13−/− mice showed lower titers of IgG autoantibodies and IgG deposits in the glomeruli, suggesting reduced autoantibody pathogenicity.
RGS13 deficiency is associated with reduction in GC program genes and exit of less pathogenic IgM plasmablasts in BXD2 mice. Prolonged GC program, mediated by upregulation RGS13, enhanced AID expression and enabled generation of pathogenic autoantibodies in autoreactive GCs.
PMCID: PMC3979745  PMID: 23818250
9.  Regulation of phosphorylation of synaptic and extrasynaptic GluA1 AMPA receptors in the rat forebrain by amphetamine 
European journal of pharmacology  2013;715(0):164-171.
The AMPA receptor is regulated by phosphorylation. Two major phosphorylation sites (S831 and S845) are located in the intracellular C-terminal tail of GluA1 subunits. The phosphorylation on these sites controls receptor expression and function and is subject to the regulation by psychostimulants. In this study, we further characterized the regulation of S831 and S845 phosphorylation by amphetamine (AMPH) in the adult rat striatum and medial prefrontal cortex (mPFC) in vivo. We focused on the specific fraction of GluA1/AMPA receptors enriched from synaptic and extrasynaptic membranes, using a pre-validated biochemical fractionation procedure. We found that acute AMPH administration elevated GluA1 S845 phosphorylation in the defined synaptic membrane from the striatum in a dose-dependent manner. AMPH also induced a comparable increase in S845 phosphorylation in the extrasynaptic fraction of striatal GluA1. Similar increases in S845 phosphorylation in both synaptic and extrasynaptic pools were observed in the mPFC. In contrast, S831 phosphorylation was not altered in synaptic and extrasynaptic GluA1 in striatal neurons and synaptic GluA1 in mPFC neurons in response to AMPH, although a moderate increase in S831 phosphorylation was seen in extrasynaptic GluA1 after an AMPH injection at a high dose. Total synaptic and extrasynaptic GluA1 expression remained stable in the two regions after AMPH administration. Our data demonstrate the differential sensitivity of S845 and S831 phosphorylation to dopamine stimulation. S845 is a primary site where phosphorylation of GluA1 is upregulated by AMPH in striatal and mPFC neurons at both synaptic and extrasynaptic compartments.
PMCID: PMC3763922  PMID: 23747591
Striatum; basal ganglia; striatum; prefrontal cortex; dopamine; glutamate; GluR1; excitatory amino acid; addiction
10.  Dynamic downregulation of Nogo receptor expression in the rat forebrain by amphetamine 
Neurochemistry international  2013;63(3):195-200.
Nogo receptors (NgR) are a family of cell surface receptors that are broadly expressed in the mammalian brain. These receptors could serve as an inhibitory element in the regulation of activity-dependent axonal growth and spine and synaptic formation in the adult animal brain. Thus, through balancing the structural response to changing cellular and synaptic inputs, NgRs participate in constructing activity-dependent morphological plasticity. Psychostimulants have been well documented to induce morphological plasticity critical for addictive properties of stimulants, although underlying molecular mechanisms are poorly understood. In this study, we initiated a study to investigate the response of NgRs to a stimulant. We tested the effect of acute administration of amphetamine on protein expression of two principal NgR subtypes (NgR1 and NgR2) in the rat striatum, medial prefrontal cortex (mPFC) and hippocampus. We found that a single injection of amphetamine induced a rapid and time-dependent decrease in NgR1 and NgR2 expression in the striatum and mPFC. A relatively delayed and time-dependent decrease in expression of the two receptors was seen in the hippocampus. The drug-induced decrease in NgR1 and NgR2 expression in the three forebrain regions was dose-dependent. A behaviorally active dose of the drug was required to trigger a significant reduction in NgR1 and NgR2 expression. These data indicate that NgRs are subject to the regulation by the stimulant. Amphetamine exposure exerts the inhibitory modulation of basal NgR1 and NgR2 expression in the key structures of reward circuits in vivo.
PMCID: PMC3735811  PMID: 23770273
NgR; reticulon 4 receptor; Nogo-66; stimulant; addiction; spine density; striatum; prefrontal cortex; hippocampus
11.  The surgical learning curve for robotic-assisted laparoscopic radical prostatectomy: experience of a single surgeon with 500 cases in Taiwan, China 
Asian Journal of Andrology  2014;16(5):728-734.
To analyze the learning curve for cancer control from an initial 250 cases (Group I) and subsequent 250 cases (Group II) of robotic-assisted laparoscopic radical prostatectomy (RALP) performed by a single surgeon. Five hundred consecutive patients with clinically localized prostate cancer received RALP and were evaluated. Surgical parameters and perioperative complications were compared between the groups. Positive surgical margin (PSM) and biochemical recurrence (BCR) were assessed as cancer control outcomes. Patients in Group II had significantly more advanced prostate cancer than those in Group I (22.2% vs 14.2%, respectively, with Gleason score 8–10, P= 0.033; 12.8% vs 5.6%, respectively, with clinical stage T3, P= 0.017). The incidence of PSM in pT3 was decreased significantly from 49% in Group I to 32.6% in Group II. A meaningful trend was noted for a decreasing PSM rate with each consecutive group of 50 cases, including pT3 and high-risk patients. Neurovascular bundle (NVB) preservation was significantly influenced by the PSM in high-risk patients (84.1% in the preservation group vs 43.9% in the nonpreservation group). The 3-year, 5-year, and 7-year BCR-free survival rates were 79.2%, 75.3%, and 70.2%, respectively. In conclusion, the incidence of PSM in pT3 was decreased significantly after 250 cases. There was a trend in the surgical learning curve for decreasing PSM with each group of 50 cases. NVB preservation during RALP for the high-risk group is not suggested due to increasing PSM.
PMCID: PMC4215670  PMID: 24830691
cancer control; learning curve; prostate cancer; prostatectomy; robotics; surgical margin
12.  14-3-3σ induces heat shock protein 70 expression in hepatocellular carcinoma 
BMC Cancer  2014;14:425.
14-3-3σ is implicated in promoting tumor development of various malignancies. However, the clinical relevance of 14-3-3σ in hepatocellular carcinoma (HCC) tumor progression and modulation and pathway elucidation remain unclear.
We investigated 14-3-3σ expression in 109 HCC tissues by immunohistochemistry. Overexpression and knockdown experiments were performed by transfection with cDNA or siRNA. Protein expression and cell migration were determined by Western blot and Boyden chamber assay.
In this study, we found that 14-3-3σ is abundantly expressed in HCC tumors. Stable or transient overexpression of 14-3-3σ induces the expression of heat shock factor-1α (HSF-1α) and heat shock protein 70 (HSP70) in HCC cells. Moreover, expression of 14-3-3σ significantly correlates with HSF-1α/HSP70 in HCC tumors and both 14-3-3σ and HSP70 overexpression are associated with micro-vascular thrombi in HCC patients, suggesting that 14-3-3σ/HSP70 expression is potentially involved in cell migration/invasion. Results of an in vitro migration assay indicate that 14-3-3σ promotes cell migration and that 14-3-3σ-induced cell migration is impaired by siRNA knockdown of HSP70. Finally, 14-3-3σ-induced HSF-1α/HSP70 expression is abolished by the knockdown of β-catenin or activation of GSK-3β.
Our findings indicate that 14-3-3σ participates in promoting HCC cell migration and tumor development via β-catenin/HSF-1α/HSP70 pathway regulation. Thus, 14-3-3σ alone or combined with HSP70 are potential prognostic biomarkers for HCC.
PMCID: PMC4061114  PMID: 24923353
14-3-3σ; β-catenin; Hepatocellular carcinoma; HSF-1; HSP70
13.  Spectrum of Epstein-Barr virus-associated T-cell lymphoproliferative disorder in adolescents and young adults in Taiwan 
Epstein-Barr Virus (EBV) is a herpesvirus usually infecting B-cells but may occasionally infect T- or natural killer (NK)-cells. EBV-associated T- or NK-cell lymphoproliferations represent a continuous spectrum of diseases ranging from asymptomatic infection, infectious mononucleosis (IM), to clonal and malignant lymphoproliferations including systemic EBV-positive T/NK-cell lymphoproliferative disease (EBV-T/NK-LPD) of childhood and hydroa-vacciniforme-like lymphoma of the skin. The clonal diseases are more prevalent in East Asia and exhibit overlapping clinical and pathological features with chronic active EBV infection. Here we report our experience on 10 cases of EBV-associated T-cell lymphoproliferation from Taiwan including five males and five females with a median age of 18 years old (range, 15-28). The most common clinical symptoms were fever, neck mass and hepatosplenomegaly. Eight of these patients showed elevated lactate dehydrogenase level and half of the patients had cytopenia. All patients had either elevated EBV antibody titers or increased serum EBV DNA levels. Five cases were clinically IM-like with polyclonal (3 cases) or clonal (2 cases) T-cell lymphoproliferation. Two patients each had chronic active EBV infection (CAEBV) and hemophagocytic lymphohistiocytosis (HLH). One patient had both CAEBV and HLH. One of the HLH patients with marrow infiltration by intra-sinusoidal large atypical lymphocytes experienced a fulminant course. In a median follow-up time of 21.5 months, seven patients were free of disease, one was alive with disease, and two died of disease in 31 and 3 months, respectively, despite chemotherapy. We confirmed a wide clinicopathological range of EVB-associated T-cell lymphoproliferation in Taiwan. Furthermore, monomorphic LPD and the single case with fulminant course as defined by Ohshima et al (Pathol Int 2018) as categories A3 and B, respectively, died of disease despite chemotherapy. Our report, the largest series in the recent decade from Taiwan, adds to the understanding of these rare diseases with variable clinical and histopathological presentations.
PMCID: PMC4069894  PMID: 24966953
Epstein-Barr virus; hemophagocytic lymphohistiocytosis; infectious mononucleosis; systemic T/natural killer-cell lymphoproliferative disease; T/natural killer-cell lymphoproliferation; Taiwan
14.  Structural Instability of Epitaxial (001) BiFeO3 Thin Films under Tensile Strain 
Scientific Reports  2014;4:4631.
We explore BiFeO3 under tensile strain using first-principles calculations. We find that the actual structures are more complex than what had been previously thought, and that there is a strong shear deformation type structural instability which modifies the properties. Specifically, we find that normal tensile strain leads to structural instabilities with a large induced shear deformation in (001) BiFeO3 thin films. These induced shear deformations in (001) BiFeO3 thin films under tension stabilize the (001) BiFeO3 thin films and lead to Cc and Ima2 phases that are more stable than the Pmc21 phase at high tensile strain. The induced shear deformation shifts the Cc to Ima2 phase transition towards lower tensile strain region (~1% less), prevents monoclinic tilt and oxygen octahedral tilts, and increases the ferroelectric polarization. The induced shear deformation also strongly affects the electronic structure. The results are discussed in relation to growth of BiFeO3 thin films on cubic and tetragonal substrates involving high levels of tensile strain.
PMCID: PMC3982161  PMID: 24717537
15.  Investigation of amygdala volume in men with the fragile X premutation 
Brain imaging and behavior  2011;5(4):285-294.
Premutation fragile X carriers have a CGG repeat expansion (55 to 200 repeats) in the promoter region of the fragile X mental retardation 1 (FMR1) gene. Amygdala dysfunction has been observed in premutation symptomatology, and recent research has suggested the amygdala as an area susceptible to the molecular effects of the premutation. The current study utilizes structural magnetic resonance imaging (MRI) to examine the relationship between amygdala volume, CGG expansion size, FMR1 mRNA, and psychological symptoms in male premutation carriers without FXTAS compared with age and IQ matched controls. No significant between group differences in amygdala volume were found. However, a significant negative correlation between amygdala volume and CGG was found in the lower range of CGG repeat expansions, but not in the higher range of CGG repeat expansions.
PMCID: PMC3982607  PMID: 21786216
Fragile X premutation; Amygdala; FMR1; mRNA; Structural MRI
16.  Prostate cancer-derived CCN3 induces M2 macrophage infiltration and contributes to angiogenesis in prostate cancer microenvironment 
Oncotarget  2014;5(6):1595-1608.
Tumor-associated macrophages (TAMs) are M2-polarized macrophages that infiltrate the tumor microenvironment and promote tumorigenesis. However, the mechanisms by which TAMs modulate prostate cancer (PCa) growth are poorly understood. Here, we found that expression of Nephroblastoma Overexpressed (NOV/CCN3) is upregulated in PCa cells and correlated with M2 macrophage infiltration. RAW264.7 macrophage migration was induced by conditioned media (CM) from various PCa cells in proportion to the cellular level of CCN3 expression and was inhibited by an anti-CCN3 neutralizing antibody. CCN3 and PCaCM treatment skewed RAW264.7 cell differentiation from an M1 phenotype to an M2 phenotype. PCa-derived CCN3 induced focal adhesion kinase (FAK)/Akt/NF-κB signaling in RAW264.7 cells, which resulted in VEGF expression and subsequently increased tube formation in endothelial progenitor cells. Finally, PCa-secreted CCN3 stimulated RAW264.7 cells and promoted angiogenesis in the chick chorioallantoic membrane assay (CAM), and increased tumor growth and tumor-associated angiogenesis in a PCa xenograft mouse model. Our results indicate that PCa-secreted CCN3 can recruit macrophages and skew their differentiation to an M2 phenotype. In turn, CCN3-stimulated macrophages contribute to VEGF-dependent angiogenesis. This study reveals a novel mechanism by which TAMs enhance PCa angiogenesis and identifies a potential therapeutic target for PCa.
PMCID: PMC4039234  PMID: 24721786
CCN3; VEGF; Prostate cancer; M2 macrophage; angiogenesis
17.  Regulation of hERG and hEAG Channels by Src and by SHP-1 Tyrosine Phosphatase via an ITIM Region in the Cyclic Nucleotide Binding Domain 
PLoS ONE  2014;9(2):e90024.
Members of the EAG K+ channel superfamily (EAG/Kv10.x, ERG/Kv11.x, ELK/Kv12.x subfamilies) are expressed in many cells and tissues. In particular, two prototypes, EAG1/Kv10.1/KCNH1 and ERG1/Kv11.1/KCNH2 contribute to both normal and pathological functions. Proliferation of numerous cancer cells depends on hEAG1, and in some cases, hERG. hERG is best known for contributing to the cardiac action potential, and for numerous channel mutations that underlie ‘long-QT syndrome’. Many cells, particularly cancer cells, express Src-family tyrosine kinases and SHP tyrosine phosphatases; and an imbalance in tyrosine phosphorylation can lead to malignancies, autoimmune diseases, and inflammatory disorders. Ion channel contributions to cell functions are governed, to a large degree, by post-translational modulation, especially phosphorylation. However, almost nothing is known about roles of specific tyrosine kinases and phosphatases in regulating K+ channels in the EAG superfamily. First, we show that tyrosine kinase inhibitor, PP1, and the selective Src inhibitory peptide, Src40-58, reduce the hERG current amplitude, without altering its voltage dependence or kinetics. PP1 similarly reduces the hEAG1 current. Surprisingly, an ‘immuno-receptor tyrosine inhibitory motif’ (ITIM) is present within the cyclic nucleotide binding domain of all EAG-superfamily members, and is conserved in the human, rat and mouse sequences. When tyrosine phosphorylated, this ITIM directly bound to and activated SHP-1 tyrosine phosphatase (PTP-1C/PTPN6/HCP); the first report that a portion of an ion channel is a binding site and activator of a tyrosine phosphatase. Both hERG and hEAG1 currents were decreased by applying active recombinant SHP-1, and increased by the inhibitory substrate-trapping SHP-1 mutant. Thus, hERG and hEAG1 currents are regulated by activated SHP-1, in a manner opposite to their regulation by Src. Given the widespread distribution of these channels, Src and SHP-1, this work has broad implications in cell signaling that controls survival, proliferation, differentiation, and other ERG1 and EAG1 functions in many cell types.
PMCID: PMC3938566  PMID: 24587194
18.  Pigmented villous nodular synovitis mimicking metastatic melanoma on PET-CT 
Positron Emission Tomography – Computed Tomography (PET-CT) is routinely utilized in the management of melanoma, either as a part of staging workup or during surveillance. Since melanomas have a high metastatic potential, any FDG avid lesion is considered suspicious for recurrence. We report a case of a FDG avid lesion, diagnosed during melanoma surveillance, its management and review of literature.
A 58 year-old-male underwent wide local excision for melanoma of the left cheek, and one year post-operatively a PET-CT that revealed a hypermetabolic focus in his right subscapularis muscle, which upon resection was diagnosed as Pigmented Villonodular Synovitis (PVNS).
PVNS is a rare benign giant cell tumor that requires no additional treatment in asymptomatic individuals. PET-CT is used for staging and surveillance of numerous malignancies, including melanoma. A hypermetabolic lesion on a PET-CT scan in the setting of malignancy is always suspicious for recurrence.
The surgeon is reminded of a uncommon benign FDG avid lesion. Typical location, nonspecific symptoms and characteristic imaging findings help cue in the diagnosis of PVNS and a tissue diagnosis will establish the diagnosis, thus avoiding unnecessarily aggressive surgical management.
PMCID: PMC4008855  PMID: 24705190
Metastatic melanoma; Pigmented villous nodular synovitis
19.  Amphetamine increases phosphorylation of MAPK/ERK at synaptic sites in the rat striatum and medial prefrontal cortex 
Brain research  2012;1494:101-108.
Mitogen-activated protein kinases (MAPKs) play a central role in cell signaling. Extracellular signal-regulated kinase (ERK) is a prototypic subclass of MAPKs and is densely expressed in postmitotic neurons of adult mammalian brains. Active ERK translocates into the nucleus to regulate gene expression. Additionally, ERK is visualized in neuronal peripheries, such as distal synaptic structures. While nuclear ERK is a known sensitive target of psychostimulants, little is known about the responsiveness of synaptic ERK to stimulants. In this study, we focused on ERK at synaptic versus extrasynaptic sites and investigated its responses to the psychostimulant amphetamine in the adult rat striatum and medial prefrontal cortex (mPFC) in vivo. We used a pre-validated biochemical fractionation procedure to isolate synapse- and extrasynapse-enriched membranes. We found that two common ERK isoforms (ERK1 and ERK2) were concentrated more in extrasynaptic fractions than in synaptic fractions in striatal and cortical neurons under normal conditions. At synaptic sites, ERK2 was noticeably more abundant than ERK1. Acute injection of amphetamine induced an increase in ERK2 phosphorylation in the synaptic fraction of striatal neurons, while the drug did not alter extrasynaptic ERK2 phosphorylation. Similar results were observed in the mPFC. In both synaptic and extrasynaptic compartments, total ERK1/2 proteins remained stable in response to amphetamine. Our data establish the subsynaptic distribution pattern of MAPK/ERK in striatal and cortical neurons. Moreover, the synaptic pool of ERK2 in these neurons can be selectively activated by amphetamine.
PMCID: PMC3546198  PMID: 23201445
Striatum; basal ganglia; dopamine; stimulant; postsynaptic density; extrasynaptic membrane; addiction
20.  Molecular Epidemiology of Enterovirus 71 Infection in the Central Region of Taiwan from 2002 to 2012 
PLoS ONE  2013;8(12):e83711.
Enterovirus 71 (EV71), a causative agent of hand, foot, and mouth disease can be classified into three genotypes and many subtypes. The objectives of this study were to conduct a molecular epidemiological study of EV71 in the central region of Taiwan from 2002–2012 and to test the hypothesis that whether the alternative appearance of different EV71 subtypes in Taiwan is due to transmission from neighboring countries or from re-emergence of pre-existing local strains. We selected 174 EV71 isolates and used reverse transcription-polymerase chain reaction to amplify their VP1 region for DNA sequencing. Phylogenetic analyses were conducted using Neighbor-Joining, Maximum Likelihood and Bayesian methods. We found that the major subtypes of EV71 in Taiwan were B4 for 2002 epidemic, C4 for 2004–2005 epidemic, B5 for 2008–2009 epidemic, C4 for 2010 epidemic and B5 for 2011–2012 epidemic. Phylogenetic analysis demonstrated that the 2002 and 2008 epidemics were associated with EV71 from Malaysia and Singapore; while both 2010 and 2011–2012 epidemics originated from different regions of mainland China including Shanghai, Henan, Xiamen and Gong-Dong. Furthermore, minor strains have been identified in each epidemic and some of them were correlated with the subsequent outbreaks. Therefore, the EV71 infection in Taiwan may originate from pre-existing minor strains or from other regions in Asia including mainland China. In addition, 101 EV71 isolates were selected for the detection of new recombinant strains using the nucleotide sequences spanning the VP1-2A-2B region. No new recombinant strain was found. Analysis of clinical manifestations showed that patients infected with C4 had significantly higher rates of pharyngeal vesicles or ulcers than patients infected with B5. This is the first study demonstrating that different EV 71 genotypes may have different clinical manifestations and the association of EV71 infections between Taiwan and mainland China.
PMCID: PMC3877097  PMID: 24391812
21.  Cocaine and HIV-1 Interplay in CNS: Cellular and Molecular Mechanisms 
Current HIV research  2012;10(5):425-428.
Although antiretrovirals are the mainstay of therapy against HIV infection, neurological complications associated with the virus continue to hamper quality of life of the infected individuals. Drugs of abuse in the infected individuals further fuel the epidemic. Epidemiological studies have demonstrated that abuse of cocaine resulted in acceleration of HIV infection and the progression of NeuroAIDS. Cocaine has not only been shown to play a crucial role in promoting virus replication, but also has diverse but often deleterious effects on various cell types of the CNS. In the neuronal system, cocaine exposure results in neuronal toxicity and also potentiates gp120-induced neurotoxicity. In the astroglia and microglia, cocaine exposure leads to up-regulation of pro-inflammatory mediators such as cytokines and chemokines. These in turn, can lead to neuroinflammation and transmission of toxic responses to the neurons. Additionally, cocaine exposure can also lead to leakiness of the blood-brain barrier that manifests as enhanced transmigraiton of leukocytes/monocytes into the CNS. Both in vitro and in vivo studies have provided valuable tools in exploring the role of cocaine in mediating HIV-associated neuropathogenesis. This review summarizes previous studies on the mechanism(s) underlying the interplay of cocaine and HIV as it relates to the CNS.
PMCID: PMC3824955  PMID: 22591366
HIV; AIDS; cocaine; Glial cell; neuron; HIV-1-associated neurocognitive disorders
22.  Quantitative physiology and immunohistochemistry of oral lesions 
Biomedical Optics Express  2013;4(11):2696-2709.
Angiogenesis and hypoxia are reported to correlate with tumor aggressiveness. In this study, we investigated the potential of optically measured total hemoglobin concentration (THC) and blood oxygen saturation (StO2) as a quantitative measure of angiogenesis and hypoxia in oral lesions with an immunohistochemical comparison. 12 normal subjects and 40 oral patients (22 oral squamous cell carcinoma (SCC), 18 benign/premalignant lesions including 11 verrucous hyperplasia (VH) and 7 hyperkeratosis/parakeratosis (HK)) were studied. The results showed that the THC measurement was consistent with vascular endothelial growth factor (VEGF) and microvessel staining in the stromal area, but StO2 was not associated with HIF-1α. We observed inflammation induced neovascular formation in the stromal area of VH and HK that were likely attributed to higher-than-control THC and StO2 and resulted in no difference in optical measurements between all lesions. However, we found that in majority of SCC, the ratio of THC and StO2 levels between lesions and the surrounding tissues provide potential distinguishing characteristics from VH, which are not visually differentiable from SCC, with a sensitivity, specificity, and accuracy of 91%, 68%, and 76%, respectively.
PMCID: PMC3829562  PMID: 24298427
(170.1610) Clinical applications; (170.1850) Dentistry; (170.5280) Photon migration; (300.0300) Spectroscopy
23.  Upregulation of Npas4 protein expression by chronic administration of amphetamine in rat nucleus accumbens in vivo 
Neuroscience letters  2012;528(2):210-214.
The neuronal PAS domain protein 4 (Npas4) is a transcription factor that is almost exclusively expressed in the mammalian brain. As an activity-dependent transcription factor, Npas4 regulates the transcription of discrete genes and transcriptionally controls the experience-dependent learning and memory. In this study, we explored the impact of the psychostimulant amphetamine (AMPH) on Npas4 protein expression in the rat striatum. We found that acute systemic injection of AMPH had a minimal effect on protein levels of Npas4 in the caudate putamen (CPu) and nucleus accumbens (NAc), while AMPH readily increased protein products of the immediate early gene c-Fos in these regions. In contrast, repeated administration of AMPH (5 mg/kg, once daily for 5 days) triggered a significant increase in Npas4 expression in the NAc, although repeated AMPH did not alter Npas4 in the CPu. These data demonstrate that Npas4 is an AMPH-sensitive transcription factor. It is inducible selectively in the NAc in response to repeated AMPH administration.
PMCID: PMC3478397  PMID: 22884934
Immediate early gene; transcription factor; c-Fos; Le-PAS; NXF; PASD10; striatum; caudate
24.  Developing ultraviolet illumination of gillnets as a method to reduce sea turtle bycatch 
Biology Letters  2013;9(5):20130383.
Fisheries bycatch of marine animals has been linked to population declines of multiple species, including many sea turtles. Altering the visual cues associated with fishing gear may reduce sea turtle bycatch. We examined the effectiveness of illuminating gillnets with ultraviolet (UV) light-emitting diodes for reducing green sea turtle (Chelonia mydas) interactions. We found that the mean sea turtle capture rate was reduced by 39.7% in UV-illuminated nets compared with nets without illumination. In collaboration with commercial fishermen, we tested UV net illumination in a bottom-set gillnet fishery in Baja California, Mexico. We did not find any difference in overall target fish catch rate or market value between net types. These findings suggest that UV net illumination may have applications in coastal and pelagic gillnet fisheries to reduce sea turtle bycatch.
PMCID: PMC3971673  PMID: 23883577
sea turtles; bycatch; gillnets; UV vision
25.  Chronic Inhibition, Self-Control and Eating Behavior: Test of a ‘Resource Depletion’ Model 
PLoS ONE  2013;8(10):e76888.
The current research tested the hypothesis that individuals engaged in long-term efforts to limit food intake (e.g., individuals with high eating restraint) would have reduced capacity to regulate eating when self-control resources are limited. In the current research, body mass index (BMI) was used as a proxy for eating restraint based on the assumption that individuals with high BMI would have elevated levels of chronic eating restraint. A preliminary study (Study 1) aimed to provide evidence for the assumed relationship between eating restraint and BMI. Participants (N = 72) categorized into high or normal-range BMI groups completed the eating restraint scale. Consistent with the hypothesis, results revealed significantly higher scores on the weight fluctuation and concern for dieting subscales of the restraint scale among participants in the high BMI group compared to the normal-range BMI group. The main study (Study 2) aimed to test the hypothesized interactive effect of BMI and diminished self-control resources on eating behavior. Participants (N = 83) classified as having high or normal-range BMI were randomly allocated to receive a challenging counting task that depleted self-control resources (ego-depletion condition) or a non-depleting control task (no depletion condition). Participants then engaged in a second task in which required tasting and rating tempting cookies and candies. Amount of food consumed during the taste-and-rate task constituted the behavioral dependent measure. Regression analyses revealed a significant interaction effect of these variables on amount of food eaten in the taste-and-rate task. Individuals with high BMI had reduced capacity to regulate eating under conditions of self-control resource depletion as predicted. The interactive effects of BMI and self-control resource depletion on eating behavior were independent of trait self-control. Results extend knowledge of the role of self-control in regulating eating behavior and provide support for a limited-resource model of self-control.
PMCID: PMC3798321  PMID: 24146942

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