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1.  Multidetector CT imaging features of solid pseudopapillary tumours of the pancreas in male patients: distinctive imaging features with female patients 
The British Journal of Radiology  2014;87(1035):20130513.
To describe multidetector CT imaging features of solid pseudopapillary tumours (SPTs) in male patients and to compare these imaging features with those found in female patients.
The institutional review board approved this retrospective study. We included the CT images of 72 patients (M:F = 12:60; mean age, 35.0 years) diagnosed with SPT by histology. CT images were reviewed on the following: location of the tumour, maximal diameter, shape, margin and the fraction of the tumour composition. Statistical differences in CT imaging features were analysed.
Male patients with SPTs were significantly older than female patients (42.4 years vs 33.4 years, p = 0.0408) and the mean size of the SPTs in male patients was larger (6.3 cm vs 4.6 cm, p = 0.0413) than that of SPTs in female patients. Lobulated shape of the SPTs was most frequent in male patients, whereas oval shape was most frequent in female patients (p = 0.0133). SPTs in male patients tended to have a solid component (p = 0.0434). Progressive enhancement in the solid portion of the tumour was seen in 9 (81.8%) of 11 SPTs in male patients and in 30 (79.0%) of 38 SPTs in female patients on multiphasic CT.
The imaging features of SPTs in male patients usually appeared as a somewhat large-sized solid mass with a lobulated margin and progressive enhancement. These imaging features may help to differentiate SPTs from other pancreatic tumours for their proper management.
Advances in knowledge:
SPTs in male patients appear as somewhat large-sized solid masses with lobulated margins, and this form occurs more frequently in older male patients than in female patients.
PMCID: PMC4064602  PMID: 24472726
2.  Lesional location of lateral medullary infarction presenting hiccups (singultus) 
Park, M | Kim, B | Koh, S | Park, M | Park, K | Lee, D
Background: Hiccups are an infrequent result of lateral medullary infarction. Their importance may be underestimated and they can cause distress, exhaustion, and aspiration. Hiccups in lateral medullary infarction remain poorly understood
Objective: To evaluate the relation between the lesional loci of lateral medullary infarction and hiccups.
Methods: 51 patients with lateral medullary infarction were investigated by magnetic resonance imaging within three days of the onset of infarction. Seven of the 51 patients developed hiccup.
Results: All patients with hiccups had middle level lateral medullary lesions, including two with lower level lesions and four with upper level lesions. In the middle level lateral medullary lesions, dorsolateral lesions were most often involved. All patients with lateral medullary infarction presenting with hiccups also had vertigo, dizziness, nausea, vomiting, and dysphagia.
Conclusions: The observations suggest that middle level and dorsolateral lesion locations in lateral medullary infarction frequently induce hiccups.
PMCID: PMC1739304  PMID: 15608002
3.  Novel signaling axis for ROS generation during K-Ras-induced cellular transformation 
Cell Death and Differentiation  2014;21(8):1185-1197.
Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47phox, a subunit of NOX1 to plasma membrane. Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47phox and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47phox C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47phox-NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCδ, p47phox and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCδ, p47phox or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/PDPK1/PKCδ/p47phox/NOX1 for ROS generation and consequent malignant cellular transformation.
PMCID: PMC4085525  PMID: 24632950
4.  Consensus of Nonlinear Complex Systems with Edge Betweenness Centrality Measure under Time-Varying Sampled-Data Protocol 
The Scientific World Journal  2015;2015:493907.
This paper proposes a new consensus criterion for nonlinear complex systems with edge betweenness centrality measure. By construction of a suitable Lyapunov-Krasovskii functional, the consensus criterion for such systems is established in terms of linear matrix inequalities (LMIs) which can be easily solved by various effective optimization algorithms. One numerical example is given to illustrate the effectiveness of the proposed methods.
PMCID: PMC4489014  PMID: 26167526
5.  Impaired T cell survival promotes mucosal inflammatory disease in SHIP1-deficient mice 
Mucosal immunology  2014;7(6):1429-1439.
T cells play a critical role in immune surveillance at mucosal surfaces. SHIP1−/− mice succumb to mucosal inflammatory disease that afflicts the lung and small intestine. The basis of this condition has not been defined. Here we show that SHIP1 is required for the normal persistence and survival of T cells in mucosal tissues. We find that CD4 and CD8 effector T cells are reduced, but Treg cells increased in the SI and lungs of SHIP1−/− and CD4CreSHIPflox/flox mice. Furthermore, a subset of T cells in the SI of SHIP1−/− mice are FasL+ and are more susceptible to extrinsic cell death. Mechanistic analyses showed that SHIP1 associates with the death receptor CD95/Fas and treatment with a Caspase8 inhibitor prevents SHIP1 inhibitor mediated T cell death. Notably, mucosal inflammation in SHIP1−/− mice is reduced by treatment with a Caspase8 inhibitor. We also find that the incidence of CD and pneumonia are significantly increased in mice with dual T and myeloid lineage SHIP1 deletion, but not in single lineage deleted mice. Thus, by promoting survival of protective T cells, thereby preventing an inflammatory myeloid response, SHIP1 maintains an appropriate balance of innate immune function at mucosal surfaces necessary for immune homeostasis.
PMCID: PMC4205272  PMID: 24781051
SHIP1; pneumonia; ileitis; Crohn's disease; T cells; adoptive T cell transfer (ACT); SHIP1 inhibitor; 3-α-aminocholestane (3AC); caspase 8; apoptosis
6.  Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells 
Cell Death & Disease  2014;5(5):e1231-.
Lymphangioleiomyomatosis (LAM) is a female-predominant interstitial lung disease that can lead to respiratory failure. LAM cells typically have inactivating TSC2 mutations, leading to mTORC1 activation. The gender specificity of LAM suggests that estradiol contributes to disease development, yet the underlying pathogenic mechanisms are not completely understood. Using metabolomic profiling, we identified an estradiol-enhanced pentose phosphate pathway signature in Tsc2-deficient cells. Estradiol increased levels of cellular NADPH, decreased levels of reactive oxygen species, and enhanced cell survival under oxidative stress. Mechanistically, estradiol reactivated Akt in TSC2-deficient cells in vitro and in vivo, induced membrane translocation of glucose transporters (GLUT1 or GLUT4), and increased glucose uptake in an Akt-dependent manner. 18F-FDG-PET imaging demonstrated enhanced glucose uptake in xenograft tumors of Tsc2-deficient cells from estradiol-treated mice. Expression array study identified estradiol-enhanced transcript levels of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway. Consistent with this, G6PD was abundant in xenograft tumors and lung metastatic lesions of Tsc2-deficient cells from estradiol-treated mice. Molecular depletion of G6PD attenuated estradiol-enhanced survival in vitro, and treatment with 6-aminonicotinamide, a competitive inhibitor of G6PD, reduced lung colonization of Tsc2-deficient cells. Collectively, these data indicate that estradiol promotes glucose metabolism in mTORC1 hyperactive cells through the pentose phosphate pathway via Akt reactivation and G6PD upregulation, thereby enhancing cell survival under oxidative stress. Interestingly, a strong correlation between estrogen exposure and G6PD was also found in breast cancer cells. Targeting the pentose phosphate pathway may have therapeutic benefit for LAM and possibly other hormonally dependent neoplasms.
PMCID: PMC4047866  PMID: 24832603
tuberin; Akt; pentose phosphate pathway; glucose transporters; glucose uptake; 6-aminonicotinamide
7.  Attenuation of noise-induced hearing loss using methylene blue 
Cell Death & Disease  2014;5(4):e1200-.
The overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) has been known to contribute to the pathogenesis of noise-induced hearing loss. In this study, we discovered that in BALB/c mice pretreatment with methylene blue (MB) for 4 consecutive days significantly protected against cochlear injury by intense broad-band noise for 3 h. It decreased both compound threshold shift and permanent threshold shift and, further, reduced outer hair cell death in the cochlea. MB also reduced ROS and RNS formation after noise exposure. Furthermore, it protected against rotenone- and antimycin A-induced cell death and also reversed ATP generation in the in vitro UB-OC1 cell system. Likewise, MB effectively attenuated the noise-induced impairment of complex IV activity in the cochlea. In addition, it increased the neurotrophin-3 (NT-3) level, which could affect the synaptic connections between hair cells and spiral ganglion neurons in the noise-exposed cochlea, and also promoted the conservation of both efferent and afferent nerve terminals on the outer and inner hair cells. These findings suggest that the amelioration of impaired mitochondrial electron transport and the potentiation of NT-3 expression by treatment with MB have a significant therapeutic value in preventing ROS-mediated sensorineural hearing loss.
PMCID: PMC4001318  PMID: 24763057
noise-induced hearing loss; cochlea; mitochondrial respiratory chain; reactive oxygen species; methylene blue; neurotrophin-3
9.  Differentiation of early hepatocellular carcinoma from benign hepatocellular nodules on gadoxetic acid-enhanced MRI 
The British Journal of Radiology  2012;85(1018):e837-e844.
To test new diagnostic criteria for the discrimination of early hepatocellular carcinoma (HCC) from benign hepatocellular nodules on gadoxetic acid-enhanced MRI (Gd-EOB-MRI).
We retrospectively analysed 34 patients with 29 surgically diagnosed early HCCs and 31 surgically diagnosed benign hepatocellular nodules. Two radiologists reviewed Gd-EOB-MRI, including diffusion-weighted imaging (DWI), and the signal intensity at each sequence, presence of arterial enhancement and washout were recorded. We composed new diagnostic criteria based on the lesion size and MRI findings, and then the diagnostic performance was compared with that of conventional imaging criteria with logistic regression and a generalised estimating equation method.
A size cut-off value (≥1.5 cm diameter) and MRI findings of T1 hypointensity, T2 hyperintensity, DWI hyperintensity on both low and high b-value images (b=50 and 800 s mm−2, respectively), arterial enhancement, late washout and hepatobiliary hypointensity were selected as the diagnostic criteria. When lesions were considered malignant if they satisfied three or more of the above criteria, the sensitivity was significantly higher than when making a diagnosis based on arterial enhancement and washout alone (58.6% vs 13.8%, respectively; p=0.0002), while the specificity was 100.0% for both criteria.
Our new diagnostic criteria on Gd-EOB-MRI may help to improve the discrimination of early HCC from benign hepatocellular nodules.
PMCID: PMC3474012  PMID: 22553295
10.  Pathological correlation with diffusion restriction on diffusion-weighted imaging in patients with pathological complete response after neoadjuvant chemoradiation therapy for locally advanced rectal cancer: preliminary results 
The British Journal of Radiology  2012;85(1017):e566-e572.
The objective of this study was to assess causative pathological factors associated with diffusion restriction on diffusion-weighted imaging (DWI) in patients who achieved pathological complete response (pCR) after treatment with neoadjuvant chemoradiation therapy (CRT) for locally advanced rectal cancer.
In total, 43 patients with locally advanced rectal cancer (≥T3 or lymph node positive) who underwent neoadjuvant CRT, subsequent surgery and ultimately achieved pCR were enrolled. All patients underwent pre- and post-CRT 3.0 T rectal MRI with DWI. Two radiologists blinded to pathological staging reviewed pre- and post-CRT 3.0 T rectal MRI for the presence of diffusion restriction in the corresponding tumour areas on post-CRT DWI, with a third radiologist arbitrating any disagreement. The consensus of these findings was then correlated with pathological data such as intramural mucin and the degree of proctitis and mural fibrosis seen on surgical specimen. Additionally, the pre-CRT tumour volume was measured to define the effect of this variable on the degree of radiation proctitis and fibrosis, as well as the presence of intramural mucin.
Diffusion restriction occurred in 18 subjects (41.9%), while 25 subjects remained diffusion restriction-free (58.1%). The diffusion restriction group tended to have more severe proctitis and mural fibrosis when compared with non-diffusion restriction group (p<0.001). Intramural mucin was also more common in the diffusion restriction group (p=0.052). Higher pre-CRT tumour volumes were significantly predictive of the degree of proctitis (p=0.0247) and fibrosis (p=0.0445), but not the presence of intramural mucin (p=0.0944). Proctitis and mural fibrosis severity were also identified as independent pathological risk factors for diffusion restriction on multivariate analysis (p=0.0073 and 0.0011, respectively).
Both radiation-induced proctitis and fibrosis were significant and independent predictors of diffusion restriction in patients achieving pCR after treatment with neoadjuvant CRT for locally advanced rectal cancer, and pre-CRT tumour volume significantly affects both variables.
PMCID: PMC3487069  PMID: 22422387
11.  Contrast-enhanced MR cholangiography: comparison of Gd-EOB-DTPA and Mn-DPDP in healthy volunteers 
The British Journal of Radiology  2012;85(1017):1250-1254.
The purpose of this study was to compare the biliary enhancement dynamics of gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic-acid (Gd-EOB-DTPA) and mangafodipir trisodium (Mn-DPDP) for contrast-enhanced MR cholangiography (MRC) in healthy subjects.
15 healthy volunteers underwent MRI at 1.5 T with volumetric interpolated breath-hold examination sequence. Each volunteer was scanned once for each contrast agent. The signal-to-noise ratio (SNR) of the liver parenchyma and common hepatic duct (CHD) and the contrast-to-noise ratio (CNR) of CHD to liver parenchyma were evaluated and compared before and at several time points (5, 15, 30, 45, 60, 90, and 120 min) after injection of each agent.
SNR was significantly higher for Gd-EOB-DTPA than for Mn-DPDP in liver parenchyma after 5 min and in CHD after 15 min (p<0.05). CNR of CHD to liver parenchyma using Gd-EOB-DTPA showed an initial decrease at 5 min post-injection followed by a steep increase to a peak at 15 min post-injection. CNR using Mn-DPDP showed a steady increase to a peak at 15 min post-injection without an initial decrease. At 15 min, the value of CNR was significantly higher for Gd-EOB-DTPA than for Mn-DPDP (p<0.05).
For both contrast agents, CNR reached a peak at 15 min after contrast injection. At this time point, CNR of Gd-EOB-DTPA was significantly higher than that of Mn-DPDP. Therefore, Gd-EOB-DTPA may provide better contrast-enhanced MRC than Mn-DPDP at 15 min after contrast administration.
PMCID: PMC3487056  PMID: 22553292
12.  Decay of Impact after Self-Management Education for People with Chronic Illnesses: Changes in Anxiety and Depression over One Year 
PLoS ONE  2013;8(6):e65316.
In people with chronic illnesses, self-management education can reduce anxiety and depression. Those benefits, however, decay over time. Efforts have been made to prevent or minimize that “decay of impact”, but they have not been based on information about the decay’s characteristics, and they have failed. Here we show how the decay’s basic characteristics (prevalence, timing, and magnitude) can be quantified. Regarding anxiety and depression, we also report the prevalence, timing, and magnitude of the decay.
Adults with various chronic conditions participated in a self-management educational program (n = 369). Data were collected with the Hospital Anxiety and Depression Scale four times over one year. Using within-person effect sizes, we defined decay of impact as a decline of ≥0.5 standard deviations after improvement by at least the same amount. We also interpret the results using previously-set criteria for non-cases, possible cases, and probable cases.
Prevalence: On anxiety, decay occurred in 19% of the participants (70/369), and on depression it occurred in 24% (90/369). Timing: In about one third of those with decay, it began 3 months after the baseline measurement (6 weeks after the educational program ended). Magnitude: The median magnitudes of decay on anxiety and on depression were both 4 points, which was about 1 standard deviation. Early in the follow-up year, many participants with decay moved into less severe clinical categories (e.g., becoming non-cases). Later, many of them moved into more severe categories (e.g., becoming probable cases).
Decay of impact can be identified and quantified from within-person effect sizes. This decay occurs in about one fifth or more of this program’s participants. It can start soon after the program ends, and it is large enough to be clinically important. These findings can be used to plan interventions aimed at preventing or minimizing the decay of impact.
PMCID: PMC3681854  PMID: 23785418
13.  Association between Endocrine Disrupting Phenols in Colostrums and Maternal and Infant Health 
Bisphenol A (BPA) and alkylphenols (APs) are well-known endocrine disrupting chemicals (EDCs) which may threat the next generations' health. We performed biomonitoring of these phenols in colostrums to assess risk of the phenols in breast-fed neonates. Study subjects were the lactating mothers who delivered babies within 2 weeks (N = 325; 30.67 ± 3.45 years) and their neonates (N = 326; embryonic period, 39.1 ± 1.5 weeks). BPA, nonylphenol (NP), and octylphenol (OP) in colostrums were quantified with LC/MS/MS. Information for environmental exposure sources of the phenols was obtained by questionnaires. As results, median level of BPA in colostrums was 7.8 ng/mL, while most NP or OP was not detected. Regarding health risks of phenols, levels of total NP in colostrums were elevated among sick mothers with toxemia, thyroid disorders, gastritis, and so forth than health mothers (3.51 ± 4.98 versus 2.04 ± 3.71 ng/mL, P = 0.02). Dairy products intake and detergents use were positively correlated with total BPA levels (Ps < 0.05). In conclusion, we estimate most neonates who are exposed to BPA rather than NP or OP via colostrums and recommend continuous biomonitoring of the phenols to clarify their suspected health risk on neonates and pregnant or gestation mothers.
PMCID: PMC3662185  PMID: 23737772
14.  MRI features of serous oligocystic adenoma of the pancreas: differentiation from mucinous cystic neoplasm of the pancreas 
The British Journal of Radiology  2012;85(1013):571-576.
The purpose of this study was to describe the MRI features of the benign pancreatic neoplasm serous oligocystic adenoma (SOA) that differ from those of mucinous cystic neoplasm (MCN), a neoplasm with the potential for malignant degeneration.
Seven patients with SOA (seven women; mean age 36.6 years) and eight patients with MCN (eight women: mean age 39.9 years) were included. Several imaging features were reviewed: mass size, location, shape, wall thickness, cyst configuration (Type I, unilocular; Type II, multiple clustered cyst; Type III, cyst with internal septation) and signal intensity of the lesion with heterogeneity.
SOA lesions were smaller (3.4 cm) than those of MCN (9.3 cm) (p=0.023). The commonest lesion shape was lobulated (85.7%) for SOA, but oval (50.0%) or lobulated (37.5%) for MCN (p=0.015). The most common cyst configuration was Type II (85.7%) for SOA and Type III (75.0%) for MCN (p=0.008). Heterogeneity of each locule in T1 weighted images was visible in all cases of MCN, but in no case for SOA (p=0.004).
SOA could be differentiated from MCN by identifying the imaging features of lobulated contour with multiple clustered cyst configurations and homogeneity of each locule in T1 weighted MR images.
PMCID: PMC3479889  PMID: 21304008
16.  eIF5A isoforms and cancer: two brothers for two functions? 
Amino acids  2011;44(1):103-109.
Eukaryotic translation initiation factor 5A (eIF5A) is the only cellular protein that contains the unusual amino acid hypusine [Nε-(4-amino-2-hydroxybutyl)lysine]. The role of hypusine formation in the eIF5A protein in the regulation of cell proliferation and apoptosis is addressed in the present review. Moreover, vertebrates carry two genes that encode two eIF5A isoforms, eIF5A-1 and eIF5A-2, which, in humans, are 84% identical. However, the biological functions of these two isoforms may be significantly different. In fact, eIF5A-1 is demonstrable in most cells of different histogenesis, whereas eIF5A-2 protein is detectable only in certain human cancer cells or tissues, suggesting its role as a potential oncogene. In this review we focus our attention on the involvement of eIF5A-1 in the triggering of an apoptotic program and in the regulation of cell proliferation. In addition, the potential oncogenic role and prognostic significance of eIF5A-2 in the prediction of the survival of cancer patients is described. eIF5A-1 and/or the eIF5A-2 isoform may serve as a new molecular diagnostic or prognostic marker or as a molecular target for anti-cancer therapy.
PMCID: PMC3536922  PMID: 22139412
eIF5A isoform; Hypusine; Tissue transglutaminase; Cancer; Apoptosis; Prognostic markers; Hypusine synthesis inhibitors
17.  Acinar cell carcinoma with fatty change arising from the pancreas 
The British Journal of Radiology  2011;84(1008):e226-e228.
Acinar cell carcinoma of the pancreas is a rare malignant tumour developing from acinar cells, accounting for approximately 1% of pancreatic exocrine tumours. We experienced a case of an acinar cell carcinoma with fatty change. To the best of our knowledge, this is the first case report of an acinar cell carcinoma with fatty change in the clinical literature.
PMCID: PMC3473822  PMID: 22101587
18.  A Whole Genome Association Study on Meat Quality Traits Using High Density SNP Chips in a Cross between Korean Native Pig and Landrace 
A whole genome association (WGA) study was performed to detect significant polymorphisms for meat quality traits in an F2 cross population (N = 478) that were generated with Korean native pig sires and Landrace dams in National Livestock Research Institute, Songwhan, Korea. The animals were genotyped using Illumina porcine 60k SNP beadchips, in which a set of 46,865 SNPs were available for the WGA analyses on ten carcass quality traits; live weight, crude protein, crude lipids, crude ash, water holding capacity, drip loss, shear force, CIE L, CIE a and CIE b. Phenotypes were regressed on additive and dominance effects for each SNP using a simple linear regression model, after adjusting for sex, sire and slaughter stage as fixed effects. With the significant SNPs for each trait (p<0.001), a stepwise regression procedure was applied to determine the best set of SNPs with the additive and/or dominance effects. A total of 106 SNPs, or quantitative trait loci (QTL) were detected, and about 32 to 66% of the total phenotypic variation was explained by the significant SNPs for each trait. The QTL were identified in most porcine chromosomes (SSCs), in which majority of the QTL were detected in SSCs 1, 2, 12, 13, 14 and 16. Several QTL clusters were identified on SSCs 12, 16 and 17, and a cluster of QTL influencing crude protein, crude lipid, drip loss, shear force, CIE a and CIE b were located between 20 and 29 Mb of SSC12. A pleiotropic QTL for drip loss, CIE L and CIE b was also detected on SSC16. These QTL need to be validated in commercial pig populations for genetic improvement in meat quality via marker-assisted selection.
PMCID: PMC4093033  PMID: 25049513
Whole Genome Association; SNP; Meat Quality; Korean Native Pig; Landrace
19.  Reprogramming of the Tumor Microenvironment by Stromal Pten-regulated miR-320 
Nature Cell Biology  2011;14(2):159-167.
Phosphatase and tensin homolog deleted on chromosome ten (Pten) in stromal fibroblasts suppresses epithelial mammary tumors, but the underlying molecular mechanisms remain unknown. Using proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2, are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumor angiogenesis and tumor cell invasion. Expression of the Pten-miR-320-Ets2 regulated secretome distinguished human normal breast stroma from tumor stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumor suppressor axis that acts in stromal fibroblasts to reprogram the tumor microenvironment and curtail tumor progression.
PMCID: PMC3271169  PMID: 22179046
21.  PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation 
Cell Death and Differentiation  2010;18(4):666-677.
Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) has frequently been observed in human gliomas, conferring AKT activation and resistance to ionizing radiation (IR) and drug treatments. Recent reports have shown that PTEN loss or AKT activation induces premature senescence, but many details regarding this effect remain obscure. In this study, we tested whether the status of PTEN determined fate of the cell by examining PTEN-deficient U87, U251, and U373, and PTEN-proficient LN18 and LN428 glioma cells after exposure to IR. These cells exhibited different cellular responses, senescence or apoptosis, depending on the PTEN status. We further observed that PTEN-deficient U87 cells with high levels of both AKT activation and intracellular reactive oxygen species (ROS) underwent senescence, whereas PTEN-proficient LN18 cells entered apoptosis. ROS were indispensable for inducing senescence in PTEN-deficient cells, but not for apoptosis in PTEN-proficient cells. Furthermore, transfection with wild-type (wt) PTEN or AKT small interfering RNA induced a change from premature senescence to apoptosis and depletion of p53 or p21 prevented IR-induced premature senescence in U87 cells. Our data indicate that PTEN acts as a pivotal determinant of cell fate, regarding senescence and apoptosis in IR-exposed glioma cells. We conclude that premature senescence could have a compensatory role for apoptosis in the absence of the tumor suppressor PTEN through the AKT/ROS/p53/p21 signaling pathway.
PMCID: PMC3131905  PMID: 21072054
premature senescence; apoptosis; PTEN; glioma
23.  Effect of Dietary Antimicrobials on Immune Status in Broiler Chickens 
This study evaluated the effects of dietary anticoccidial drugs plus antibiotic growth promoters (AGPs) on parameters of immunity in commercial broiler chickens. Day-old chicks were raised on used litter from a farm with endemic gangrenous dermatitis to simulate natural pathogen exposure and provided with diets containing decoquinate (DECX) or monensin (COBN) as anticoccidials plus bacitracin methylene disalicylate and roxarsone as AGPs. As a negative control, the chickens were fed with a non-supplemented diet. Immune parameters examined were concanavalin A (ConA)-stimulated spleen cell proliferation, intestine intraepithelial lymphocyte (IEL) and spleen cell subpopulations, and cytokine/chemokine mRNA levels in IELs and spleen cells. ConA-induced proliferation was decreased at 14 d post-hatch in DECX-treated chickens, and increased at 25 and 43 d in COBN-treated animals, compared with untreated controls. In DECX-treated birds, increased percentages of MHC2+ and CD4+ IELS were detected at 14 d, but decreased percentages of these cells were seen at 43 d, compared with untreated controls, while increased TCR2+ IELs were evident at the latter time. Dietary COBN was associated with decreased fractions of MHC2+ and CD4+ IELs and reduced percentages of MHC2+, BU1+, and TCR1+ spleen cells compared with controls. The levels of transcripts for interleukin-4 (IL-4), IL-6, IL-17F, IL-13, CXCLi2, interferon-γ (IFN-γ), and transforming growth factorβ4 were elevated in IELs, and those for IL-13, IL-17D, CXCLi2, and IFN-γ were increased in spleen cells, of DECX- and/or COBN-treated chickens compared with untreated controls. By contrast, IL-2 and IL-12 mRNAs in IELs, and IL-4, IL-12, and IL-17F transcripts in spleen cells, were decreased in DECX- and/or COBN-treated chickens compared with controls. These results suggest that DECX or COBN, in combination with bacitracin and roxarsone, modulate the development of the chicken post-hatch immune system.
PMCID: PMC4092964  PMID: 25049577
Decoquinate; Monensin; Bacitracin; Roxarsone; Immunity; Broiler
24.  Sphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagy 
Cell Death and Differentiation  2010;18(2):350-361.
The sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) have recently been implicated in autophagy. In this study, we report that depletion of sphingosine-1-phosphate phosphohydrolase-1 (SPP1), an endoplasmic reticulum (ER)-resident enzyme that specifically dephosphorylates S1P, induced autophagy. Although the mammalian target of rapamycin and class III phosphoinositide 3-kinase/Beclin-1 pathways were not involved and this autophagy was p53 independent, C/EBP homologous protein, BiP, and phospho-eucaryotic translation initiation factor-2α, and cleavage of procaspases 2 and 4, downstream targets of ER stress, were increased after SPP1 depletion. Autophagy was suppressed by depletion of protein kinase regulated by RNA-like ER kinase (PERK), inositol-requiring transmembrane kinase/endonuclease-1α, or activating transcription factor 6, three sensors of the unfolded protein response (UPR) to ER stress. Autophagy triggered by downregulation of SPP1 did not lead to apoptosis but rather stimulated, in a PERK dependent manner, the survival signal Akt, whose inhibition then sensitized cells to apoptosis. Although depletion of SPP1 increased intracellular levels of S1P and its secretion, activation of cell surface S1P receptors did not induce autophagy. Nevertheless, increases in intracellular pools of S1P, but not dihydro-S1P, induced autophagy and ER stress. Thus, SPP1, by regulating intracellular S1P homeostasis, can control the UPR and ER stress-induced autophagy.
PMCID: PMC3131882  PMID: 20798685
sphingosine-1-phosphate phosphatase-1; autophagy; ER stress; apoptosis; Akt
25.  Antibody Colocalization Microarray: A Scalable Technology for Multiplex Protein Analysis in Complex Samples* 
Molecular & Cellular Proteomics : MCP  2011;11(4):M111.011460.
DNA microarrays were rapidly scaled up from 256 to 6.5 million targets, and although antibody microarrays were proposed earlier, sensitive multiplex sandwich assays have only been scaled up to a few tens of targets. Cross-reactivity, arising because detection antibodies are mixed, is a known weakness of multiplex sandwich assays that is mitigated by lengthy optimization. Here, we introduce (1) vulnerability as a metric for assays. The vulnerability of multiplex sandwich assays to cross-reactivity increases quadratically with the number of targets, and together with experimental results, substantiates that scaling up of multiplex sandwich assays is unfeasible. We propose (2) a novel concept for multiplexing without mixing named antibody colocalization microarray (ACM). In ACMs, both capture and detection antibodies are physically colocalized by spotting to the same two-dimensional coordinate. Following spotting of the capture antibodies, the chip is removed from the arrayer, incubated with the sample, placed back onto the arrayer and then spotted with the detection antibodies. ACMs with up to 50 targets were produced, along with a binding curve for each protein. The ACM was validated by comparing it to ELISA and to a small-scale, conventional multiplex sandwich assay (MSA). Using ACMs, proteins in the serum of breast cancer patients and healthy controls were quantified, and six candidate biomarkers identified. Our results indicate that ACMs are sensitive, robust, and scalable.
PMCID: PMC3322566  PMID: 22171321

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