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1.  Estimation of Genetic Parameters for Pork Belly Components in Yorkshire Pigs 
This study was conducted to estimate the genetic parameters for pork belly traits and muscles in Yorkshire pigs. Each pork belly was cut into nine parts perpendicular to the thoracic vertebrae (6th to 14th). Traits of belly muscles including the deep pectoral, latissimus dorsi, cutaneous trunci, rectus abdominis, external and internal abdominal oblique from 382 purebred pigs were recorded and analyzed using SAS Package (9.1) and Derivative-free restricted maximum likelihood methods. Heritability estimates for belly traits ranged from 0.27 to 0.49, while they were 0.12 to 0.66 for belly muscles. Moderate to high heritability estimates were noted in belly weight (0.33), belly length (0.28), and belly width (0.49). In belly muscles, the latissimus dorsi and deep pectoral, which are located only in the 6th to 9th vertebrae sections, were found to have heritability estimates ranging from 0.21 to 0.29 and 0.23 to 0.35, respectively. Strong heritability estimates were observed in the 7th to 13th sections of cutaneous trunci muscle ranging from 0.42 to 0.66. Genetic correlations of latissimus dorsi m. with belly length were positive (0.50), while cutaneous trunci m. with belly weight also revealed a positive relationship that ranged from 0.35 to 0.47. The estimated genetic parameters indicate that belly weight can be improved by genetic selection. Differences in the levels of heritability occurred among various parameters of Yorkshire pork belly, which should be considered when performing selection to improve pork belly quality. Moreover, these results can provide valuable information that can be used as the basis for further investigations to improve pork belly.
doi:10.5713/ajas.14.0678
PMCID: PMC4478500  PMID: 26104395
Genetic Parameters; Pork Belly; Yorkshire Pigs
2.  Neuritin can normalize neural deficits of Alzheimer's disease 
Cell Death & Disease  2014;5(11):e1523-.
Reductions in hippocampal neurite complexity and synaptic plasticity are believed to contribute to the progressive impairment in episodic memory and the mild cognitive decline that occur particularly in the early stages of Alzheimer's disease (AD). Despite the functional and therapeutic importance for patients with AD, intervention to rescue or normalize dendritic elaboration and synaptic plasticity is scarcely provided. Here we show that overexpression of neuritin, an activity-dependent protein, promoted neurite outgrowth and maturation of synapses in parallel with enhanced basal synaptic transmission in cultured hippocampal neurons. Importantly, exogenous application of recombinant neuritin fully restored dendritic complexity as well as spine density in hippocampal neurons prepared from Tg2576 mice, whereas it did not affect neurite branching of neurons from their wild-type littermates. We also showed that soluble recombinant neuritin, when chronically infused into the brains of Tg2576 mice, normalized synaptic plasticity in acute hippocampal slices, leading to intact long-term potentiation. By revealing the protective actions of soluble neuritin against AD-related neural defects, we provide a potential therapeutic approach for patients with AD.
doi:10.1038/cddis.2014.478
PMCID: PMC4260736  PMID: 25393479
3.  Clinical impacts of tumor cell contamination of hematopoietic stem cell products in metastatic breast cancer patients undergoing autologous peripheral blood stem cell transplantation: multicenter trial. 
Journal of Korean Medical Science  2001;16(2):175-182.
To determine whether the tumor cell contamination of peripheral blood stem cells influences clinical impacts on high-dose chemotherapy in patients with metastatic breast cancer, we analyzed carcinoembryonic antigen (CEA) mRNA in the apheresis products by nested RT-PCR (reverse transcriptase-polymerase chain reaction). A total of 38 metastatic breast cancer patients and ten normal healthy subjects as a negative control were included. Twenty out of 38 (51.3%) apheresis products from patients with metastatic breast cancer were positive for CEA mRNA. CEA mRNA was noted in 54.8% (17/31) of patients mobilized with chemotherapy plus G-CSF and 42.8% (3/7) of patients with G-CSF alone. There was no significant difference in age, estrogen receptor, menopausal status, mobilization method, disease free interval, or number of metastasis sites (1 vs > or = 2) between positive and negative groups. The presence of CEA mRNA in apheresis products did not influence the time to progression and overall survival in both groups. However, both the univariate and the multivariate analysis disclosed that the number of metastasis was associated with survival significantly. We suggest that the tumor cell contamination does not predict poor treatment outcome in patients with metastatic breast cancer.
PMCID: PMC3054721  PMID: 11306743
4.  G0/G1 switch gene 2 has a critical role in adipocyte differentiation 
Cell Death and Differentiation  2014;21(7):1071-1080.
Mouse 3T3-L1 preadipocytes differentiate into adipocytes when treated with 3-isobutyl-1-methylxanthine, dexamethasone, and insulin. Although mechanisms of adipogenesis, including transcriptional cascades, are understood, it is still unclear how clonally expanded cells eventually enter the terminal differentiation program. From gene expression profile studies, we identified G0/G1 switch gene 2 (G0s2) as a novel regulator of adipogenesis. The gene was found to be expressed at a higher level in white and brown adipose tissues, and it was induced in 3T3-L1 cells by hormonal treatment. Importantly, G0s2 expression was closely associated with the transition from mitotic clonal expansion to terminal differentiation. Knockdown of G0s2 expression with siRNA inhibited adipocyte differentiation, whereas constitutive overexpression of G0s2 accelerated differentiation of preadipocytes to mature adipocytes. Expression of G0s2 was found to be regulated by peroxisome proliferator-activated receptor γ (PPARγ), which is a well-known regulator of adipocyte differentiation. Absence of either PPARγ or G0s2 expression resulted in apoptotic pathway activation before terminal differentiation. To determine whether G0s2 has a role in vivo, G0s2-knockout mice were generated. The knockout mice were normal in appearance, but they had less adipose mass than wild-type littermates. Mouse embryonic fibroblast cells from G0s2-deficient mice exhibited impaired adipogenesis and contained unusually small intracellular lipid droplets, suggesting that G0s2 has a role in lipid droplet formation. Our studies demonstrate that G0s2 has an important role in adipogenesis and accumulation of triacylglycerol.
doi:10.1038/cdd.2014.26
PMCID: PMC4207475  PMID: 24583640
5.  Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures 
Cell Death and Differentiation  2014;21(7):1095-1106.
Kainic acid (KA)-induced seizures followed by neuronal death are associated with neuroinflammation and blood–brain barrier (BBB) leakage. Tonicity-responsive enhancer binding protein (TonEBP) is known as a transcriptional factor activating osmoprotective genes, and in brain, it is expressed in neuronal nuclei. Thus dysregulation of TonEBP may be involved in the pathology of KA-induced seizures. Here we used TonEBP heterozygote (+/−) mice to study the roles of TonEBP. Electroencephalographic study showed that TonEBP (+/−) mice reduced seizure frequency and severity compared with wild type during KA-induced status epilepticus. Immunohistochemistry and western blotting analysis showed that KA-induced neuroinflammation and BBB leakage were dramatically reduced in TonEBP (+/−) mice. Similarly, TonEBP-specific siRNA reduced glutamate-induced death in HT22 hippocampal neuronal cells. TonEBP haplodeficiency prevented KA-induced nuclear translocation of NF-κB p65 and attenuated inflammation. Our findings identify TonEBP as a critical regulator of neuroinflammation and BBB leakage in KA-induced seizures, which suggests TonEBP as a good therapeutic target.
doi:10.1038/cdd.2014.29
PMCID: PMC4207478  PMID: 24608792
6.  Laughter and Stress Relief in Cancer Patients: A Pilot Study 
The purpose of this study was to examine the effect of a therapeutic laughter program and the number of program sessions on anxiety, depression, and stress in breast cancer patients. A randomized controlled trial was conducted involving 31 patients who received four sessions of therapeutic laughter program comprised and 29 who were assigned to the no-program control group. Scores for anxiety, depression, and stress were measured using an 11-point numerical rating scale. While no change was detected in the control group, the program group reported reductions of 1.94, 1.84, and 2.06 points for anxiety, depression, and stress, respectively (p < 0.01, p < 0.01, and p < 0.01). Scores decreased significantly after the first therapeutic laughter session (p < 0.05, p < 0.01, and p < 0.01). As the therapeutic laughter program was effective after only a single session in reducing anxiety, depression, and stress in breast cancer patients, it could be recommended as a first-line complementary/alternative therapy.
doi:10.1155/2015/864739
PMCID: PMC4439472  PMID: 26064177
7.  Risk and prognosis of ovarian cancer in women with endometriosis: a meta-analysis 
British Journal of Cancer  2014;110(7):1878-1890.
Background:
The risk and prognosis of ovarian cancer have not been well established in women with endometriosis. Thus, we investigated the impact of endometriosis on the risk and prognosis for ovarian cancer, and evaluated clinicopathologic characteristics of endometriosis-associated ovarian cancer (EAOC) in comparison with non-EAOC.
Methods:
After we searched an electronic search to identify relevant studies published online between January 1990 and December 2012, we found 20 case–control and 15 cohort studies including 444 255 patients from 1 625 potentially relevant studies. In the meta-analysis, ovarian cancer risk by endometriosis and clinicopathologic characteristics were evaluated using risk ratio (RR) or standard incidence ratio (SIR), and prognosis was investigated using hazard ratio (HR) with 95% confidence interval (CI). Heterogeneity was evaluated using Higgins I2 to select fixed-effect (I2 ⩽50%) or random effects models (I2>50%), and found no publication bias using funnel plots with Egger's test (P>0.05). Furthermore, we performed subgroup analyses based on study design, assessment of endometriosis, histology, disease status, quality of study and adjustment for potential confounding factors to minimise bias.
Results:
Endometriosis increased ovarian cancer risk in case–control or two-arm cohort studies (RR, 1.265; 95% CI, 1.214–1.318) and single-arm cohort studies (SIR, 1.797; 95% CI, 1.276–2.531), which were similar in subgroup analyses. Although progression-free survival was not different between EAOC and non-EAOC (HR, 1.023; 95% CI, 0.712–1.470), EAOC was associated with better overall survival than non-EAOC in crude analyses (HR, 0.778; 95% CI, 0.655–0.925). However, progression-free survival and overall survival were not different between the two groups in subgroup analyses. Stage I–II disease, grade 1 disease and nulliparity were more common in EAOC (RRs, 1.959, 1.319 and 1.327; 95% CIs, 1.367–2.807, 1.149–1.514 and 1.245–1.415), whereas probability of optimal debulking surgery was not different between the two groups (RR, 1.403; 95% CI, 0.915–2.152). Furthermore, endometrioid and clear cell carcinomas were more common in EAOC (RRs, 1.759 and 2.606; 95% CIs, 1.551–1.995 and 2.225–3.053), whereas serous carcinoma was less frequent in EAOC than in non-EAOC (RR, 0.733; 95% CI, 0.617–0.871), and there was no difference in the risk of mucinous carcinoma between the two groups (RR, 0.805; 95% CI, 0.584–1.109). These clinicopathologic characteristics were also similar in subgroup analyses.
Conclusions:
Endometriosis is strongly associated with the increased risk of ovarian cancer, and EAOC shows favourable characteristics including early-stage disease, low-grade disease and a specific histology such as endometrioid or clear cell carcinoma. However, endometriosis may not affect disease progression after the onset of ovarian cancer.
doi:10.1038/bjc.2014.29
PMCID: PMC3974076  PMID: 24518590
endometriosis; ovarian cancer; risk; prognosis; meta-analysis
8.  Activated STING in a Vascular and Pulmonary Syndrome 
The New England journal of medicine  2014;371(6):507-518.
BACKGROUND
The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation.
METHODS
We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-β, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls.
RESULTS
We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mono-nuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibro-blasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients’ lymphocytes was reduced by JAK inhibitors.
CONCLUSIONS
STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173.
doi:10.1056/NEJMoa1312625
PMCID: PMC4174543  PMID: 25029335
9.  hnRNP Q regulates translation of p53 in normal and stress conditions 
Cell Death and Differentiation  2012;20(2):226-234.
The responses to numerous stress signals are important for cellular growth and survival. The p53 tumor-suppressor protein is stabilized under stress conditions and induces transcription of several genes to regulate cell cycle and apoptosis. Regarding p53 protein accumulation, inhibition of proteasomal degradation of p53 protein, which is mainly mediated by Mdm2, has received much attention. Here, we demonstrate that regulation of translation initiation is also crucial for p53 protein accumulation. Furthermore, we report that heterogeneous nuclear ribonucleoprotein (hnRNP) Q binds to the 5′-untranslated region (UTR) of mouse p53 mRNA and regulates translation efficiency of p53 and apoptosis progression. We also suggest that changes in cytosolic hnRNP Q levels contribute to cell cycle-dependent translational differences in p53 mRNA.
doi:10.1038/cdd.2012.109
PMCID: PMC3554343  PMID: 22935615
hnRNP Q; IRES; p53; translation
10.  Mycobacterial HBHA induces endoplasmic reticulum stress-mediated apoptosis through the generation of reactive oxygen species and cytosolic Ca2+ in murine macrophage RAW 264.7 cells 
Cell Death & Disease  2013;4(12):e957-.
Mycobacterial heparin-binding haemagglutinin antigen (HBHA) is a virulence factor that induces apoptosis of macrophages. Endoplasmic reticulum (ER) stress-mediated apoptosis is an important regulatory response that can be utilised to study the pathogenesis of tuberculosis. In the present study, HBHA stimulation induced ER stress sensor molecules in a caspase-dependent manner. Pre-treatment of RAW 264.7 cells with an IκB kinase 2 inhibitor reduced not only C/EBP homology protein expression but also IL-6 and monocyte chemotactic protein-1 (MCP-1) production. BAPTA-AM reduced both ER stress responses and caspase activation and strongly suppressed HBHA-induced IL-6 and MCP-1 production in RAW 264.7 cells. Enhanced reactive oxygen species (ROS) production and elevated cytosolic [Ca2+]i levels were essential for HBHA-induced ER stress responses. Collectively, our data suggest that HBHA induces cytosolic [Ca2+]i, which influences the generation of ROS associated with the production of proinflammatory cytokines. These concerted and complex cellular responses induce ER stress-associated apoptosis during HBHA stimulation in macrophages. These results indicate that the ER stress pathway has an important role in the HBHA-induced apoptosis during mycobacterial infection.
doi:10.1038/cddis.2013.489
PMCID: PMC3877560  PMID: 24336077
ER stress; macrophage; mycobacteria
11.  (ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson's disease 
Cell Death & Disease  2013;4(11):e919-.
Genetic and epidemiologic evidence suggests that cellular energy homeostasis is critically associated with Parkinson's disease (PD) pathogenesis. Here we demonstrated that genetic deletion of Poly (ADP-ribose) polymerase 1 completely blocked 6-hydroxydopamine-induced dopaminergic neurodegeneration and related PD-like symptoms. Hyperactivation of PARP-1 depleted ATP pools in dopaminergic (DA) neurons, thereby activating AMP-activated protein kinase (AMPK). Further, blockade of AMPK activation by viral infection with dominant-negative AMPK strongly inhibited DA neuronal atrophy with moderate suppression of nuclear translocation of apoptosis-inhibiting factor (AIF), whereas overactivation of AMPK conversely strengthened the 6-OHDA-induced DA neuronal degeneration. Collectively, these results suggest that manipulation of PARP-1 and AMPK signaling is an effective therapeutic approach to prevent PD-related DA neurodegeneration.
doi:10.1038/cddis.2013.447
PMCID: PMC3847323  PMID: 24232095
PARP-1; ATP; AMPK; 6-OHDA; Parkinson's disease
12.  A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells 
Cell Death & Disease  2013;4(8):e750-.
Compound K (20-O-(β-D-glucopyranosyl)-20(S)-protopanaxadiol) is an active metabolite of ginsenosides and induces apoptosis in various types of cancer cells. This study investigated the role of autophagy in compound K-induced cell death of human HCT-116 colon cancer cells. Compound K activated an autophagy pathway characterized by the accumulation of vesicles, the increased positive acridine orange-stained cells, the accumulation of LC3-II, and the elevation of autophagic flux. Whereas blockade of compound K-induced autophagy by 3-methyladenein and bafilomycin A1 significantly increased cell viability. In addition, compound K augmented the time-dependent expression of the autophagy-related proteins Atg5, Atg6, and Atg7. However, knockdown of Atg5, Atg6, and Atg7 markedly inhibited the detrimental impact of compound K on LC3-II accumulation and cell vitality. Compound K-provoked autophagy was also linked to the generation of intracellular reactive oxygen species (ROS); both of these processes were mitigated by the pre-treatment of cells with the antioxidant N-acetylcysteine. Moreover, compound K activated the c-Jun NH2-terminal kinase (JNK) signaling pathway, whereas downregulation of JNK by its specific inhibitor SP600125 or by small interfering RNA against JNK attenuated autophagy-mediated cell death in response to compound K. Compound K also provoked apoptosis, as evidenced by an increased number of apoptotic bodies and sub-G1 hypodiploid cells, enhanced activation of caspase-3 and caspase-9, and modulation of Bcl-2 and Bcl-2-associated X protein expression. Notably, compound K-stimulated autophagy as well as apoptosis was induced by disrupting the interaction between Atg6 and Bcl-2. Taken together, these results indicate that the induction of autophagy and apoptosis by compound K is mediated through ROS generation and JNK activation in human colon cancer cells.
doi:10.1038/cddis.2013.273
PMCID: PMC3763435  PMID: 23907464
apoptosis; autophagy; compound K; reactive oxygen species; colon cancer
13.  High TOP2B/TOP2A expression ratio at diagnosis correlates with favourable outcome for standard chemotherapy in acute myeloid leukaemia 
British Journal of Cancer  2012;107(1):108-115.
Background:
Cytosine arabinoside-based chemotherapy coupled with anthracycline is currently the first-line treatment for acute myeloid leukaemia (AML), but diverse responses to the regimen constitute obstacles to successful treatment. Therefore, outcome prediction to chemotherapy at diagnosis is believed to be a critical consideration.
Methods:
The mRNA expression of 12 genes closely involved in the actions of cytosine arabinoside and anthracycline was evaluated by real-time reverse transcriptase PCR (RT–PCR), in 54 diagnostic bone marrow specimens of M2-subtype AML.
Results:
Low expression levels of ribonucleotide reductase M2 (RRM2) and high expression levels of topoisomerase 2 beta (TOP2B) were correlated with longer survival in a univariate analysis. Another interesting finding is that high ratios of TOP2B/RRM2 and TOP2B/TOP2 alpha (TOP2A) in a combined analysis were also shown to have a prognostic impact for longer survival with improved accuracy. Among the four markers, when adjusted for the influence of other clinical factors in multivariate analysis, the TOP2B/TOP2A ratio was significantly correlated with treatment outcomes; patients with high ratios trended toward longer disease-free survival (HR, 0.24; P=0.002) and overall survival (HR, 0.29; P=0.005).
Conclusion:
Genes with distinct expression profiles such as TOP2B/TOP2A expression ratio at diagnosis can be employed for outcome prediction after the treatment with standard regimens in AML patients with M2 subtype.
doi:10.1038/bjc.2012.206
PMCID: PMC3389410  PMID: 22627319
AML; standard chemotherapy; prognosis; topoisomerase 2
14.  Molecular Mechanisms of Large-Conductance Ca2+-Activated Potassium Channel Activation by Ginseng Gintonin 
Gintonin is a unique lysophosphatidic acid (LPA) receptor ligand found in Panax ginseng. Gintonin induces transient [Ca2+]i through G protein-coupled LPA receptors. Large-conductance Ca2+-activated K+ (BKCa) channels are expressed in blood vessels and neurons and play important roles in blood vessel relaxation and attenuation of neuronal excitability. BKCa channels are activated by transient [Ca2+]i and are regulated by various Ca2+-dependent kinases. We investigated the molecular mechanisms of BKCa channel activation by gintonin. BKCa channels are heterologously expressed in Xenopus oocytes. Gintonin treatment induced BKCa channel activation in oocytes expressing the BKCa channel α subunit in a concentration-dependent manner (EC50 = 0.71 ± 0.08 µg/mL). Gintonin-mediated BKCa channel activation was blocked by a PKC inhibitor, calphostin, and by the calmodulin inhibitor, calmidazolium. Site-directed mutations in BKCa channels targeting CaM kinase II or PKC phosphorylation sites but not PKA phosphorylation sites attenuated gintonin action. Mutations in the Ca2+ bowl and the regulator of K+ conductance (RCK) site also blocked gintonin action. These results indicate that gintonin-mediated BKCa channel activations are achieved through LPA1 receptor-phospholipase C-IP3-Ca2+-PKC-calmodulin-CaM kinase II pathways and calcium binding to the Ca2+ bowl and RCK domain. Gintonin could be a novel contributor against blood vessel constriction and over-excitation of neurons.
doi:10.1155/2013/323709
PMCID: PMC3638619  PMID: 23662129
15.  Correlation between mammographic and sonographic findings and prognostic factors in patients with node-negative invasive breast cancer 
The British Journal of Radiology  2011;84(997):19-30.
Objectives
The purpose of this study was to correlate sonographic and mammographic findings with prognostic factors in patients with node-negative invasive breast cancer.
Methods
Sonographic and mammographic findings in 710 consecutive patients (age range 21–81 years; mean age 49 years) with 715 node-negative invasive breast cancers were retrospectively evaluated. Pathology reports relating to tumour size, histological grade, lymphovascular invasion (LVI), extensive intraductal component (EIC), oestrogen receptor (ER) status and HER-2/neu status were reviewed and correlated with the imaging findings. Statistical analysis was performed using logistic regression analysis and intraclass correlation coefficient (ICC).
Results
On mammography, non-spiculated masses with calcifications were associated with all poor prognostic factors: high histological grade, positive LVI, EIC, HER-2/neu status and negative ER. Other lesions were associated with none of these poor prognostic factors. Hyperdense masses on mammography, the presence of mixed echogenicity, posterior enhancement, calcifications in-or-out of masses and diffusely increased vascularity on sonography were associated with high histological grade and negative ER. Associated calcifications on both mammograms and sonograms were correlated with EIC and HER-2/neu overexpression. The ICC value for the disease extent was 0.60 on mammography and 0.70 on sonography.
Conclusion
Several sonographic and mammographic features can have a prognostic value in the subsequent treatment of patients with node-negative invasive breast cancer. Radiologists should pay more attention to masses that are associated with calcifications because on both mammography and sonography associated calcifications were predictors of positive EIC and HER-2/neu overexpression.
doi:10.1259/bjr/92960562
PMCID: PMC3473801  PMID: 20682592
16.  Involvement of the BLT2 receptor in the itch-associated scratching induced by 12-(S)-lipoxygenase products in ICR mice 
British Journal of Pharmacology  2008;154(5):1073-1078.
Background and purpose:
Recently, we reported that 12(S)-HPETE (12(S)-hydroperoxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid) induces scratching in ICR mice. We hypothesized that 12(S)-HPETE might act as an agonist of the low-affinity leukotriene B4 receptor BLT2. To confirm the involvement of the BLT2 receptor in 12(S)-HPETE-induced scratching, we studied the scratch response using the BLT2 receptor agonists compound A (4′-{[pentanoyl (phenyl) amino]methyl}-1,1′-biphenyl-2-carboxylic acid) and 12(S)-HETE (12(S)-hydroxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid).
Experimental approach:
A video recording was used to determine whether the BLT2 receptor agonists caused itch-associated scratching in ICR mice. Selective antagonists and several chemicals were used.
Key results:
Both 12(S)-HETE and compound A dose dependently induced scratching in the ICR mice. The dose–response curve for compound A showed peaks at around 0.005–0.015 nmol per site. Compound A- and 12(S)-HETE-induced scratching was suppressed by capsaicin and naltrexon. We examined the suppressive effects of U75302 (6-[6-(3-hydroxy-1E,5Z-undecadienyl)-2-pyridinyl]-1,5-hexanediol, the BLT1 receptor antagonist) and LY255283 (1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5-yl)heptyl]oxy]phenyl]-ethanone, the BLT2 receptor antagonist) on the BLT2 agonist-induced scratching. LY255283 suppressed compound A- and 12(S)-HETE-induced scratching, but U75302 did not. LY255283 required a higher dose to suppress the compound A-induced scratching than it did to suppress the 12(S)-HETE-induced scratching. One of the BLT2 receptor agonists, 12(R)-HETE (12(R)-hydroxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid), also induced scratching in the ICR mice.
Conclusions and implications:
Our present results corroborate the hypothesis that the BLT2 receptor is involved in 12(S)-lipoxygenase-product-induced scratching in ICR mice. We also confirmed that this animal model could be a valuable means of evaluating the effects of BLT2 receptor antagonists.
doi:10.1038/bjp.2008.220
PMCID: PMC2451041  PMID: 18536755
12(S,R)-HETE; compound A; 12(R)-HETE; scratching; BLT2 receptor; LY255283
17.  Epidermal growth factor increases insulin secretion and lowers blood glucose in diabetic mice 
Abstract
Epidermal growth factor (EGF) is synthesized in the pancreas and diabetic animals have low levels of EGF. However, the role of EGF in regulating the major function of the pancreas, insulin secretion, has not been studied. Here, we show that EGF rapidly increased insulin secretion in mouse pancreatic islets, as well as in a pancreatic β-cell line. These events were dependent on a Ca2+ influx and phospholipase D (PLD) activity, particularly PLD2, as determined using pharmacological blockers and molecular manipulations such as over-expression and siRNA of PLD isozymes. In addition, EGF also increased plasma insulin levels and mediated glucose lowering in normal and diabetic mice. Here, for the first time, we provide evidence that EGF is a novel secretagogue that regulates plasma glucose levels and a candidate for the development of therapeutics for diabetes.
doi:10.1111/j.1582-4934.2007.00169.x
PMCID: PMC3918075  PMID: 18053093
epidermal growth factor; insulin secretion; phospholipase D2; glucose homeostasis
18.  Association of the CD14 gene –159C polymorphism with progression of IgA nephropathy 
Yoon, H | Shin, J | Yang, S | Chae, D | Kim, H | Lee, D | Kim, H | Kim, S | Lee, J | Kim, Y
Journal of Medical Genetics  2003;40(2):104-108.
The risk factors associated with the progression of IgA nephropathy (IgAN), the most common form of glomerulonephritis, are unclear. It has been suggested that CD14 signalling in response to various microbes affects the natural history of chronic inflammatory conditions. It has been hypothesised that variants in the promoter region of the CD14 gene might alter the expression of CD14, and this in turn could influence the progressive nature of IgAN.
PCR-RFLP was used to determine the polymorphism at the -159 site (T to C). The distribution of the CD14/-159 polymorphism was no different in patients with IgAN (n=216) compared to 171 healthy controls. After follow up for 86 months, it was found that an excess of the C genotype occurred in patients with progressive disease (p=0.03) and the risk of disease progression increased as the number of C alleles increased (p for trend = 0.002). The hazard ratio for progression in the patients with the CC genotype was 3.2 (p=0.025) compared with the patients possessing the TT genotype. After LPS stimulation, sCD14 was released more abundantly from the PBMCs of the TT subjects than from that of the CC subjects (p=0.006), even though mCD14 expression level was no different. In addition, the TT subjects released less IL-6 than the CC subjects after stimulation (p=0.0003). These results suggest that the CD14/-159 polymorphism is an important marker for the progression of IgAN and may modulate the level of the inflammatory responses.
doi:10.1136/jmg.40.2.104
PMCID: PMC1735366  PMID: 12566518
19.  BRAF mutations in non-Hodgkin's lymphoma 
British Journal of Cancer  2003;89(10):1958-1960.
doi:10.1038/sj.bjc.6601371
PMCID: PMC2394455  PMID: 14612909
mutation; BRAF; RAS; non-Hodgkin's lymphoma; oncogene
20.  Expression of multidrug resistance-associated protein1,P-glycoprotein, and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection 
British Journal of Cancer  2002;86(10):1578-1585.
Both 5-fluorouracil and doxorubicin are commonly used agents in chemotherapy of gastric cancer in adjuvant setting as well as metastatic disease. In a variety of malignancies, high expression of multidrug resistance-associated protein1 and P-glycoprotein has been associated with resistance to doxorubicin, whereas 5-fluorouracil resistance has correlated with the level of thymidylate synthase expression. We evaluated the expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase using immunohistochemistry in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection and investigated the association between their expression and clinicopathologic characteristics including prognosis of the patients. While high expression (⩾5% of tumour cells positive) of multidrug resistance-associated protein1 and P-glycoprotein was observed in 70 patients (68%) and 42 patients (41%), respectively, 65 patients (63%) had primary tumours with high expression (⩾25% of tumour cells positive) of thymidylate synthase. There was a significant association between multidrug resistance-associated protein1 and P-glycoprotein expression (P<0.0001) as well as P-glycoprotein and thymidylate synthase expression (P<0.0001). High multidrug resistance-associated protein1 and P-glycoprotein expressions were associated with well and moderately differentiated histology (P<0.0001 and P=0.03, respectively) and intestinal type (P<0.0001 and P=0.009, respectively). High multidrug resistance-associated protein1 expression correlated with lymph node metastasis (P=0.037), advanced stage (P=0.015), and older age (P=0.021). Five-year disease-free survival and overall survival of total patients were 55.2% and 56.2%, respectively, with a median follow-up of 68 months. There were no significant differences in disease-free survival and overall survival according to the expression of multidrug resistance-associated protein1 (P=0.902 and P=0.975, respectively), P-glycoprotein (P=0.987 and P=0.955, respectively), and thymidylate synthase (P=0.604 and P=0.802, respectively). Concurrent high expression of these proteins (high multidrug resistance-associated protein1/P-glycoprotein, high multidrug resistance-associated protein1/thymidylate synthase, high P-glycoprotein/thymidylate synthase) did not correlate with disease-free survival or overall survival. Even high expression of all three proteins was not associated with poor disease-free survival (P=0.919) and overall survival (P=0.852). In conclusion, high expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase did not predict poor prognosis of gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy. A larger study including patients treated with surgical resection alone would be necessary.
British Journal of Cancer (2002) 86, 1578–1585. DOI: 10.1038/sj/bjc/6600305 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600305
PMCID: PMC2746581  PMID: 12085207
gastric cancer; multidrug resistance-associated protein1; P-glycoprotein; thymidylate synthase; adjuvant chemotherapy; prognosis
21.  Enhancement of 1α,25-dihydroxyvitamin D3-induced differentiation of human leukaemia HL-60 cells into monocytes by parthenolide via inhibition of NF-κB activity 
British Journal of Pharmacology  2002;135(5):1235-1244.
Transcription factors such as NF-κB provide powerful targets for drugs to use in the treatment of cancer. In this report parthenolide (PT), a sesquiterpene lactone of herbal remedies such as feverfew (Tanacetum parthenium) with NF-κB inhibitory activity, markedly increased the degree of human leukaemia HL-60 cell differentiation when simultaneously combined with 5 nM 1α,25-dihydroxyvitamin D3 (1,25-(OH)2D3). PT by itself did not induce HL-60 cell differentiation.Cytofluorometric analysis indicated that PT stimulated 1,25-(OH)2D3-induced differentiation of HL-60 cells predominantly into monocytes.Pretreatment of HL-60 cells with PT before the 1,25-(OH)2D3 addition also potentiated the 1,25-(OH)2D3-induced HL-60 cell differentiation in both a dose- and a time-dependent manner, in which the enhanced levels of cell differentiation closely correlated with the inhibitory levels of NF-κB binding activity by PT.In contrast, santonin, a sesquiterpene lactone without an inhibitory activity of NF-κB binding to the κB sites, did not enhance the 1,25-(OH)2D3-induced HL-60 cell differentiation.In transfection experiments, PT enhanced 1,25-(OH)2D3-induced VDRE-dependent promoter activity. Furthermore, PT restored 1,25-(OH)2D3-induced VDRE-dependent promoter activity inhibited by TNF-α, an activator of NF-κB signalling pathway.These results indicate that PT strongly potentiates the 1,25-(OH)2D3-induced HL-60 cell differentiation into monocytes via the inhibition of NF-κB activity and provide evidence that inhibition of NF-κB activation can be a pre-requisite to the efficient entry of promyelocytic leukaemia cells into a differentiation pathway.
doi:10.1038/sj.bjp.0704573
PMCID: PMC1573237  PMID: 11877332
Differentiation; nuclear factor-κB; parthenolide; sesquiterpene lactone; 1α,25-dihydroxyvitamin D3
22.  Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection 
British Journal of Cancer  2001;84(2):186-192.
We evaluated the expression of thymidylate synthase (TS) in locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection and investigated the association between TS expression and clinicopathologic characteristics including prognosis of the patients. TS expression was evaluated by immunohistochemical staining using TS106 monoclonal antibody in 103 locally advanced gastric cancer patients (stage IB–IV) who underwent 5-fluorouracil (5-FU) and doxorubicin-based adjuvant chemotherapy after curative resection. 65 patients (63%) had primary tumours with high TS expression (≥ 25% of tumour cells positive), and 38 patients (37%) demonstrated low TS expression (< 25% of tumour cells positive or no staining). High TS expression was associated with male gender (P = 0.002), poorly differentiated histology (P = 0.015), and mixed type in Lauren’s classification (P = 0.027). There were no statistically significant differences in 4-year disease-free survival (60.0% vs 57.2%, P = 0.548) and overall survival (59.6% vs 59.3%, P = 0.792) between high-TS group and low-TS group. In conclusion, although high TS expression was associated with poorly differentiated histology and mixed type in Lauren's classification, it did not predict poor disease-free and overall survival in gastric cancer patients treated with 5-FU and doxorubicin-based adjuvant chemotherapy after curative resection. Further prospective studies including the evaluation of other biological markers associated with the resistance to 5-FU and doxorubicin are necessary. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2000.1553
PMCID: PMC2363711  PMID: 11161374
gastric cancer; thymidylate synthase; adjuvant chemotherapy; drug resistance; prognosis
23.  Spinocerebellar ataxia type 6 and episodic ataxia type 2 in a Korean family. 
Journal of Korean Medical Science  2001;16(6):809-813.
Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine (FHM) have been known as allelic disorders, which are caused by the alteration of the alpha1A voltage-dependent calcium channel subunit. Expansions of the CAG repeat in the CACNA1A gene on the short arm of the chromosome 19 induce SCA6, and point mutations in the same gene are responsible for EA2 and FHM. In recent studies, both SCA6 and EA2 have been concurrently found in families with 26 CAG repeats without previously reported point mutations either in coding sequences or in intron-exon junctions. We describe a Korean family with CAG26 repeats in the CACNA1A gene. Some of the affected family members had progressive ataxia typical of SCA6 whereas others had episodic vertigo responsive to acetazolamide typical of EA2. Our family support that SCA6 and EA2 are allelic disorders with a high phenotypic variability.
PMCID: PMC3054805  PMID: 11748369
24.  Effect of graded running on esophageal motility and gastroesophageal reflux in fed volunteers. 
Journal of Korean Medical Science  2001;16(2):183-187.
The effects of different grades of running on esophageal motility and gastroesophageal reflux in the fed state were evaluated. We studied healthy volunteers (male: 12, age: 27 +/- 5 yr) using ambulatory esophageal manometry, pH catheter and portable digital data recorder. Each exercise was performed 30 min after meal, with 20 min of rest between exercises. Subjects exercised on a treadmill at 40% and 70% maximal heart rate. The number of gastroesophageal reflux episodes, the duration of esophageal acid exposure and percent time pH below 4 were significantly (p < 0.01) increased during exercise at 70% maximal heart rate. The frequency of contraction (contraction/min) (p < 0.05), frequency of repetition (p < 0.01), percent of simultaneous contraction (p < 0.01), percent of above 100 mmHg amplitude (p < 0.05), and frequency of 2-peak contraction (p < 0.01) were significantly increased during exercise at 70% maximal heart rate. However, median amplitude and median duration showed no significant changes between each exercise session. Postprandial running exercises induce gastroesophageal reflux, which correlates with exercise intensity. These effects are mediated by disorganized esophageal motility.
PMCID: PMC3054723  PMID: 11306744
25.  Role of Hck in the Pathogenesis of Encephalomyocarditis Virus-Induced Diabetes in Mice 
Journal of Virology  2001;75(4):1949-1957.
Soluble mediators such as interleukin-1β, tumor necrosis factor alpha (TNF-α), and inducible nitric oxide synthase (iNOS) produced from activated macrophages play an important role in the destruction of pancreatic β cells in mice infected with a low dose of the D variant of encephalomyocarditis (EMC-D) virus. The tyrosine kinase signaling pathway was shown to be involved in EMC-D virus-induced activation of macrophages. This investigation was initiated to determine whether the Src family of kinases plays a role in the activation of macrophages, subsequently resulting in the destruction of β cells, in mice infected with a low dose of EMC-D virus. We examined the activation of p59/p56Hck, p55Fgr, and p56/p53Lyn in macrophages from DBA/2 mice infected with the virus. We found that p59/p56Hck showed a marked increase in both autophosphorylation and kinase activity at 48 h after infection, whereas p55Fgr and p56/p53Lyn did not. The p59/p56Hck activity was closely correlated with the tyrosine phosphorylation level of Vav. Treatment of EMC-D virus-infected mice with the Src kinase inhibitor, PP2, resulted in the inhibition of p59/p56Hck activity and almost complete inhibition of the production of TNF-α and iNOS in macrophages and the subsequent prevention of diabetes in mice. On the basis of these observations, we conclude that the Src kinase, p59/p56Hck, plays an important role in the activation of macrophages and the subsequent production of TNF-α and nitric oxide, leading to the destruction of pancreatic β cells, which results in the development of diabetes in mice infected with a low dose of EMC-D virus.
doi:10.1128/JVI.75.4.1949-1957.2001
PMCID: PMC115141  PMID: 11160694

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