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1.  Radiological findings and clinical features of thoracic immunoglobulin G4-positive plasma cell granuloma: two cases 
The British Journal of Radiology  2010;83(991):e150-e153.
Plasma cell granulomas, inflammatory pseudotumours and myofibroblastomas are synonymous with characteristic plasma cell infiltration in various body organs including the pancreas, liver, retroperitoneum and mediastinal structures causing idiopathic fibrosclerosis. Recently, a new concept has arisen regarding the relationship between immunoglobulin (Ig)G4-positive cell infiltration and idiopathic systemic fibrosclerosis. We report two cases showing IgG4-positive cell infiltration in the lung presenting as lung nodules with or without extrapulmonary manifestations.
PMCID: PMC3473664  PMID: 20603401
2.  Genetic susceptibility to COPD 
Thorax  2000;55(8):722.
PMCID: PMC1745824  PMID: 10950722
3.  Epidemiologic and clinical survey of Behcet's disease in Korea: the first multicenter study. 
Journal of Korean Medical Science  2001;16(5):615-618.
The prevalence of Behcet's disease is the highest in the East Asian and the Mediterranean countries. Behcet's disease is also distributed in the Asian countries, but the nationwide survey has not been performed in Korea yet. The Korean Study Group for Behcet's Disease, founded in 1999, conducted a multicenter, retrospective survey on epidemiologic and clinical features of the patients with Behcet's disease from 20 hospitals around the nation from 1997 to 1999. Of 3,497 patients, 1,527 were classified into complete or incomplete type of Behcet's disease according to the revised Shimizu's classification. The sex ratio was 1:1.75 with the female predominance. Geographical distribution showed the highest frequency in Seoul (38.5%). Clinically, 98.8% had oral ulcers, 83.2% had genital ulcers, 84.3% had skin lesions and 50.9% had ocular lesions. As for the minor clinical manifestations, articular symptoms were the most frequent. The pathergy test showed positive in 15.4% of patients and revealed a higher positive rate in males (20.2%) than in females (12.7%). In conclusion, we performed the first multicenter study on Behcet's disease in Korea and revealed the female predominance, higher frequency of ocular lesions, and lower positivity of pathergy test in the patients.
PMCID: PMC3057606  PMID: 11641532
4.  Epinephrine-induced arrhythmias: effects of thoracic epidural anesthesia and vagotomy during enflurane anesthesia in rabbits. 
Journal of Korean Medical Science  1999;14(2):133-137.
For evaluating the effects of thoracic epidural anesthesia, with or without bilateral vagotomy, epinephrine-induced arrhythmias were studied in 31 rabbits anesthetized with 1 minimum alveolar concentration of enflurane. We divided the rabbits into 5 groups: Group I (epidural saline as control group; n=6), Group II (epidural lidocaine without vagotomy; n=6), Group III (intravenous lidocaine; n=7), Group IV (epidural saline with vagotomy; n=6), and Group V (epidural lidocaine with vagotomy; n=6). Using logdose protocol, epinephrine was infused at an initial rate of 0.67 microg/kg/min and increased by Exp[0.4] until arrhythmias occurred; if arrhythmias occurred at any of these doses, a smaller dose, divided by Exp[0.2], was tested. Arrhythmic dose of epinephrine was defined as the smallest infusion rate needed to produce four or more arrhythmias within 15 sec during epinephrine infusion. Arrhythmic dose of epinephrine and its plasma concentration in epidural lidocaine group were significantly higher than control (p<0.05). Similarity of results was also noted amongst the intravenous lidocaine group, vagotomy only group, and vagotomized epidural lidocaine group with respect to the control. These results suggest that thoracic epidural anesthesia raises the threshold for enflurane-epinephrine induced arrhythmias in rabbits and that this effect is eliminated by bilateral vagotomy.
PMCID: PMC3054358  PMID: 10331557
5.  Arthritic manifestations of inflammatory bowel disease. 
Inflammatory bowel disease (IBD) is commonly associated with arthritic manifestations. They are divided into three clinical categories; peripheral arthritis, spondylitis, and sacroiliitis. To evaluate the incidence of arthritis associated with IBD in Korea, we retrospectively reviewed one hundred and twenty-nine patients with IBD, 77 with ulcerative colitis (UC) and 52 with Crohn's disease (CD). Arthritis occurred in twenty-two patients (17.1%); 15 with UC(19.6%), 7 with CD (13.5%). Patients with arthritis had more active inflammations and all were seronegative except one patient. Peripheral arthritis was found in twenty patients (15.5%) and more common in UC (19.6%) than in CD (9.6%). Joint involvements tended to be monoarticular or pauciarticular, and most frequently developed in the knee and ankle. Spondylitis was diagnosed in one patient (1.6%) who showed HLA B27 positivity. Radiographic sacroiliitis was observed in eight patients (6.2%) who revealed HLA B27 negativity. Both peripheral arthritis and sacroiliitis were found in six patients (4.6%). In CD, arthritis occurred in 20% of the patients with colonic involvement but in none of the patients without colonic involvement. In conclusion, arthritis was frequent in patients with IBD. Peripheral arthritis was more common in patients with UC than CD. All the patients with CD and arthritis had colonic involvement.
PMCID: PMC3054342  PMID: 9539317
6.  The activity of the high-affinity K+ uptake system Kdp sensitizes cells of Escherichia coli to methylglyoxal. 
Journal of Bacteriology  1996;178(13):3957-3961.
Expression of the Kdp system sensitizes cells to methylglyoxal (MG) whether this electrophile is added externally or is synthesized endogenously. The basis of this enhanced sensitivity is the maintenance of a higher cytoplasmic pH (pHi) in cells expressing Kdp. In such cells, MG elicits rapid cytoplasmic acidification via KefB and KefC, but the steady-state pHi attained is still too high to confer protection Lowering pHi further by incubation with acetate increases the sensitivity of cells to MG.
PMCID: PMC232660  PMID: 8682804
7.  Incidence estimation of genitourinary cancer in Korea. 
A nation-wide study was performed to estimate the incidence of bladder, kidney, renal pelvis and ureter, prostate, testicular and other genitourinary cancer among Koreans in Korea using medical records of the inpatients of the beneficiaries of the Korea Medical Insurance Corporation (KMIC) from Jan. 1, 1989 to Dec. 31, 1989. The crude incidence rate of bladder cancer (ICD-9 188) is estimated to be 4.43 and 0.98 per 100,000 in males and females, respectively. Around 1,093 new cases of bladder cancer (895 male and 198 female) are estimated to occur in a year. The adjusted rate for the world population is 7.76 in males and 1.19 in females which is similar to that of Japanese in Osaka and Chinese in Shanghai, but lower than in American whites and blacks. The crude incidence of kidney, renal pelvis and ureteral cancer (ICD-9 189) is estimated to be 1.61 and 0.87 in males and females, respectively. Around 507 new cases of kidney, renal pelvis and ureteral cancer (332 male and 175 female) are estimated to occur in a year. The adjusted rate for the world population is 2.69 in males and 1.04 in females. In the prostate (ICD-9 185), the crude incidence rate of cancer is estimated to be 1.36. Around 274 new cases of prostate cancer are occurring in a year. The adjusted rate for the world population is 2.98 which is similar to the Chinese rate. The incidence of genitourinary cancer continuously increases with age.
PMCID: PMC3053813  PMID: 1524728
8.  Insulin Clearance and the Incidence of Type 2 Diabetes in Hispanics and African Americans 
Diabetes Care  2013;36(4):901-907.
We aimed to identify factors that are independently associated with the metabolic clearance rate of insulin (MCRI) and to examine the association of MCRI with incident type 2 diabetes in nondiabetic Hispanics and African Americans.
We investigated 1,116 participants in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study with baseline examinations from 2000 to 2002 and follow-up examinations from 2005 to 2006. Insulin sensitivity (SI), acute insulin response (AIR), and MCRI were determined at baseline from frequently sampled intravenous glucose tolerance tests. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin. Incident diabetes was defined as fasting glucose ≥126 mg/dL or antidiabetic medication use by self-report.
We observed that SI and HDL cholesterol were independent positive correlates of MCRI, whereas fasting insulin, fasting glucose, subcutaneous adipose tissue, visceral adipose tissue, and AIR were independent negative correlates (all P < 0.05) at baseline. After 5 years of follow-up, 71 (6.4%) participants developed type 2 diabetes. Lower MCRI was associated with a higher risk of incident diabetes after adjusting for demographics, lifestyle factors, HDL cholesterol, indexes of obesity and adiposity, and insulin secretion (odds ratio 2.01 [95% CI 1.30–3.10], P = 0.0064, per one-SD decrease in loge-transformed MCRI).
Our data showed that lower MCRI predicts the incidence of type 2 diabetes.
PMCID: PMC3609510  PMID: 23223351
9.  CT findings of pulmonary non-tuberculous mycobacterial infection in non-AIDS immunocompromised patients: a case-controlled comparison with immunocompetent patients 
The British Journal of Radiology  2013;86(1024):20120209.
To describe CT findings of non-tuberculous mycobacteria (NTM) pulmonary infection in non-AIDS immunocompromised patients (ICPs) and to compare these findings with those in immunocompetent patients.
From July 2000 to August 2007, 369 patients (mean age 58.3 years; 169 males and 200 females) with pulmonary NTM infection were retrospectively reviewed. Of these 369 patients, 24 ICPs (mean age 64.8 years; 15 males and 9 females) were identified. 16 patients had diabetes mellitus, and 6 patients had received long-term steroid therapy. One had received solid organ transplantation and one had received high-dose chemotherapy for haematological disease. 24 age- and sex-matched immunocompetent patients (mean age 64.6 years; 15 males and 9 females) were selected as the control group from the same registry. CT images were reviewed in consensus by three chest radiologists, who were blinded to immune status. Each lung lobe was evaluated in terms of extent of the lesion, bronchiectasis, parenchymal opacity and the presence of ancillary findings.
A total of 287 lobes were evaluated in ICPs and the control group. The ICPs showed a higher prevalence of ill-defined nodules, with cavities and large opacity >2 cm with/without cavity (p=0.03, 0.04 and 0.02, respectively). Regardless of the immune status, the most common CT findings were bronchiectasis and ill-defined nodules without cavity.
The most common CT findings of pulmonary NTM infection in ICPs were bronchiectasis and ill-defined nodules, similar to those in the control group. Ill-defined nodules with cavity and large opacity >2 cm with/without cavity were more frequently found in ICPs.
Advances in knowledge:
In patients affected by NTM infection, large opacities and cavitation in pulmonary nodules are more frequent in ICPs than in immunocompetent patients.
PMCID: PMC3635784  PMID: 23440166
10.  Prevalence and risk factors for Staphylococcus aureus colonization in individuals entering maximum-security prisons 
Epidemiology and infection  2013;142(3):484-493.
To assess the prevalence and risk factors for colonization with Staphylococcus aureus in inmates entering two maximum-security prisons in New York State, USA, inmates (N=830) were interviewed and anterior nares and oropharyngeal samples collected. Isolates were characterized using spa typing. Overall, 50·5% of women and 58·3% of men were colonized with S. aureus and 10·6% of women and 5·9% of men were colonized with MRSA at either or both body sites. Of MSSA isolates, the major subtypes were spa type 008 and 002. Overall, risk factors for S. aureus colonization varied by gender and were only found in women and included younger age, fair/poor self-reported general health, and longer length of prior incarceration. Prevalence of MRSA colonization was 8·2%, nearly 10 times greater than in the general population. Control of epidemic S. aureus in prisons should consider the constant introduction of strains by new inmates.
PMCID: PMC3874074  PMID: 23806331
Estimating; methicillin-resistant Staphylococcus aureus (MRSA); molecular epidemiology; prevalence of disease; risk assessment; Staphylococcus aureus
11.  Overexpression of Aurora-C interferes with the spindle checkpoint by promoting the degradation of Aurora-B 
Cell Death & Disease  2014;5(3):e1106-.
The chromosomal passenger complex (CPC) plays a pivotal role in controlling accurate chromosome segregation and cytokinesis during cell division. Aurora-B, one of the chromosomal passenger proteins, is important for the mitotic spindle assembly checkpoint (SAC). Previous reports noted that Aurora-C is predominantly expressed in male germ cells and has the same subcellular localization as Aurora-B. Increasing evidence indicates that Aurora-C is overexpressed in many somatic cancers, although its function is uncertain. Our previous study showed that the aberrant expression of Aurora-C increases the tumorigenicity of cancer cells. Here, we demonstrate that overexpressed Aurora-C displaces the centromeric localization of CPCs, including INCENP, survivin, and Aurora-B. When cells were treated with nocodazole to turn on SAC, both the Aurora-B protein stability and kinase activity were affected by overexpressed Aurora-C. As a result, the activation of spindle checkpoint protein, BubR1, and phosphorylation of histone H3 and MCAK were also eliminated in Aurora-C-overexpressing cells. Thus, our results suggest that aberrantly expressed Aurora-C in somatic cancer cells may impair SAC by displacing the centromeric localization of CPCs.
PMCID: PMC3973241  PMID: 24603334
Aurora-C; Aurora-B; spindle assembly checkpoint; chromosomal passenger proteins
12.  Pilot- and bench-scale testing of faecal indicator bacteria survival in marine beach sand near point sources 
Journal of applied microbiology  2009;107(1):72-84.
Factors affecting faecal indicator bacteria (FIB) and pathogen survival/persistence in sand remain largely unstudied. This work elucidates how biological and physical factors affect die-off in beach sand following sewage spills.
Methods and Results
Solar disinfection with mechanical mixing was pilot-tested as a disinfection procedure after a large sewage spill in Los Angeles. Effects of solar exposure, mechanical mixing, predation and/or competition, season, and moisture were tested at bench scale. First-order decay constants for Escherichia coli ranged between −0·23 and −·102 per day, and for enterococci between −0·5 and −1·0 per day. Desiccation was a dominant factor for E. coli but not enterococci inactivation. Effects of season were investigated through a comparison of experimental results from winter, spring, and fall.
Moisture was the dominant factor controlling E. coli inactivation kinetics. Initial microbial community and sand temperature were also important factors. Mechanical mixing, common in beach grooming, did not consistently reduce bacterial levels.
Significance and Impact of the Study
Inactivation rates are mainly dependent on moisture and high sand temperature. Chlorination was an effective disinfection treatment in sand microcosms inoculated with raw influent.
PMCID: PMC3938294  PMID: 19302327
degradation; detection; disinfection; indicators; soil; water quality
13.  Whole-Genome Array CGH Evaluation for Replacing Prenatal Karyotyping in Hong Kong 
PLoS ONE  2014;9(2):e87988.
To evaluate the effectiveness of whole-genome array comparative genomic hybridization (aCGH) in prenatal diagnosis in Hong Kong.
Array CGH was performed on 220 samples recruited prospectively as the first-tier test study. In addition 150 prenatal samples with abnormal fetal ultrasound findings found to have normal karyotypes were analyzed as a ‘further-test’ study using NimbleGen CGX-135K oligonucleotide arrays.
Array CGH findings were concordant with conventional cytogenetic results with the exception of one case of triploidy. It was found in the first-tier test study that aCGH detected 20% (44/220) clinically significant copy number variants (CNV), of which 21 were common aneuploidies and 23 had other chromosomal imbalances. There were 3.2% (7/220) samples with CNVs detected by aCGH but not by conventional cytogenetics. In the ‘further-test’ study, the additional diagnostic yield of detecting chromosome imbalance was 6% (9/150). The overall detection for CNVs of unclear clinical significance was 2.7% (10/370) with 0.9% found to be de novo. Eleven loci of common CNVs were found in the local population.
Whole-genome aCGH offered a higher resolution diagnostic capacity than conventional karyotyping for prenatal diagnosis either as a first-tier test or as a ‘further-test’ for pregnancies with fetal ultrasound anomalies. We propose replacing conventional cytogenetics with aCGH for all pregnancies undergoing invasive diagnostic procedures after excluding common aneuploidies and triploidies by quantitative fluorescent PCR. Conventional cytogenetics can be reserved for visualization of clinically significant CNVs.
PMCID: PMC3914896  PMID: 24505343
14.  Identification of factors that function in Drosophila salivary gland cell death during development using proteomics 
Cell Death and Differentiation  2012;20(2):218-225.
Proteasome inhibitors induce cell death and are used in cancer therapy, but little is known about the relationship between proteasome impairment and cell death under normal physiological conditions. Here, we investigate the relationship between proteasome function and larval salivary gland cell death during development in Drosophila. Drosophila larval salivary gland cells undergo synchronized programmed cell death requiring both caspases and autophagy (Atg) genes during development. Here, we show that ubiquitin proteasome system (UPS) function is reduced during normal salivary gland cell death, and that ectopic proteasome impairment in salivary gland cells leads to early DNA fragmentation and salivary gland condensation in vivo. Shotgun proteomic analyses of purified dying salivary glands identified the UPS as the top category of proteins enriched, suggesting a possible compensatory induction of these factors to maintain proteolysis during cell death. We compared the proteome following ectopic proteasome impairment to the proteome during developmental cell death in salivary gland cells. Proteins that were enriched in both populations of cells were screened for their function in salivary gland degradation using RNAi knockdown. We identified several factors, including trol, a novel gene CG11880, and the cop9 signalsome component cop9 signalsome 6, as required for Drosophila larval salivary gland degradation.
PMCID: PMC3554341  PMID: 22935612
autophagy; programmed cell death; ubiquitin proteasome system; proteomics; cop9 signalsome; trol/perlecan
15.  Association of LIPC and advanced age-related macular degeneration 
Eye  2013;27(2):265-271.
To determine whether there is an association between hepatic lipase (LIPC) and age-related macular degeneration (AMD) in two independent Caucasian cohorts.
A discovery cohort of 1626 patients with advanced AMD and 859 normal controls and a replication cohort of 2159 cases and 1150 controls were genotyped for two single-nucleotide polymorphisms (SNPs) in the promoter region of LIPC. The associations between the SNPs and AMD were examined by χ2 tests.
In the discovery cohort, rs493258 and rs10468017 were both associated with advanced AMD (P=9.63E−3 and P=0.048, respectively). The association was corroborated in the replication cohort (P=4.48E−03 for rs493258 and P=0.015 for rs10468017). Combined analysis resulted in even more significant associations (P=1.21E−04 for rs493258 and P=1.67E−03 for rs10468017).
The LIPC promoter variants rs493258 and rs10468017 were associated with advanced AMD in two independent Caucasian populations, confirming that LIPC polymorphisms may be a genetic risk factor for AMD in the Caucasian population.
PMCID: PMC3574263  PMID: 23348725
LIPC; hepatic lipase; advanced age-related macular degeneration; genetics
16.  CCN3/NOV gene expression in human prostate cancer is directly suppressed by the androgen receptor 
Wu, L | Runkle, C | Jin, H-J | Yu, J | Li, J | Yang, X | Kuzel, T | Lee, C | Yu, J
Oncogene  2013;33(4):504-513.
Androgen receptor (AR) has essential roles during prostate cancer progression. With genome-wide AR-binding sites mapped to high resolution, studies have recently reported AR as a transcriptional repressor. How AR inhibits gene expression and how this contributes to prostate cancer, however, are incompletely understood. Through meta-analysis of microarray data, here we nominate nephroblastoma overexpressed (NOV) as a top androgen-repressed gene. We show that NOV is directly suppressed by androgen through the AR. AR occupies the NOV enhancer and communicates with the NOV promoter through DNA looping. AR activation recruits the polycomb group protein EZH2, which subsequently catalyzes histone H3 lysine 27 tri-methylation around the NOV promoter, thus leading to repressive chromatin remodeling and epigenetic silencing. Concordantly, AR and EZH2 inhibition synergistically restored NOV expression. NOV is downregulated in human prostate cancer wherein AR and EZH2 are upregulated. Functionally, NOV inhibits prostate cancer cell growth in vitro and in vivo. NOV reconstitution reverses androgen-induced cell growth and NOV knockdown drives androgen-independent cell growth. In addition, NOV expression is restored by hormone-deprivation therapies in mice and prostate cancer patients. Therefore, using NOV as a model gene we gained further understanding of the mechanisms underlying AR-mediated transcriptional repression. Our findings establish a tumor-suppressive role of NOV in prostate cancer and suggest that one important, but previously underestimated, manner by which AR contributes to prostate cancer progression is through inhibition of key tumor-suppressor genes.
PMCID: PMC3796014  PMID: 23318417
androgen receptor; polycomb EZH2; NOV; CCN3
17.  Lessons Learned from an Osteoporosis Clinical Trial in Frail Long Term Care Residents 
Although osteoporosis affects women of all ages, the impact is most pronounced in frail residents in long term care. Nevertheless, few interventional trials have been performed in this population and few data on therapeutic alternatives are available in this cohort.
We describe the challenges and lessons learned in developing and carrying out a trial in frail long term care residents.
The ZEST (Zoledronic acid in frail Elders to STrengthen bone) study was designed to examine the safety and efficacy of a single-dose therapy for osteoporosis in frail residents in long term care in the Pittsburgh area. Women with osteoporosis who were 65 years of age and older and currently not on therapy, were randomized in a blinded fashion to intravenous zoledronic acid or placebo. Follow-up of each participant was planned for 2 years. All participants received appropriate calcium and vitamin D supplementation.
Seven hundred and thirty-three contacts were made with long term care residents of 9 participating facilities. Of 252 women screened, 181 women were eligible, enrolled, and were randomized. Multiple barriers to research in long term care facilities were encountered but overcome with direct communication, information sessions, in-service trainings and social events. Lessons learned included designing the study in a manner that avoided placing an additional burden on an already overcommitted facility staff, a two-stage consent process to separate screening from randomization, and a flexible examination schedule to accommodate residents while obtaining the necessary outcome measurements. Furthermore, a mobile unit accessible to participants containing state-of-the-art dual x-ray absorptiometry, assessment for vertebral fractures, and phlebotomy equipment allows all assessments to be performed on-site at each facility. Serious adverse events are collected from affiliated hospitals in real time with a novel electronic surveillance system.
The major limitation is selection of outcomes that can be assessed at participating facilities and do not require transport of participants to hospitals or clinics.
Clinical research for osteoporosis can be successfully and safely performed with frail residents in long term care facilities. Lessons learned from this study may inform future investigations among frail elderly residents of these facilities.
PMCID: PMC3889110  PMID: 22157987
osteoporosis; long term care; frail elderly
18.  CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence 
Cell Death and Differentiation  2012;19(12):2015-2028.
Transforming growth factor-α (TGF-α)-induced proliferation and transforming growth factor-β (TGF-β)-mediated quiescence are intricately balanced in normal lung-tissue homeostasis but are deregulated during neoplastic progression of lung cancer. Here, we show that Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a novel MYC-interacting transcriptional modulator, responds to TGF-α induction and TGF-β suppression to orchestrate cellular proliferation and quiescence, respectively. Upon TGF-α induction, CITED2 was induced by MYC and further modulated MYC-mediated transcription in a feed-forward manner. CITED2 recruited p300 to promote MYC-p300-mediated transactivation of E2F3, leading to increased G1/S cell cycle progression. Moreover, CITED2 inhibited cellular quiescence by enhancing MYC-mediated suppression of p21CIP1. CITED2 interacted with histone deacetylase 1 (HDAC1) and potentiated MYC–HDAC1 complex formation. TGF-β stimulation provoked downregulation of CITED2, which abrogated MYC-HDAC1-mediated p21CIP1 suppression, causing cellular quiescence. Ectopic CITED2 expression enhanced tumor growth in nude mice; furthermore, CITED2 knockdown caused tumor shrinkage and increased overall host mouse survival rates. Expression of CITED2/MYC/E2F3/p21CIP1 signaling molecules was associated with poor prognosis of lung cancer patients. Thus, CITED2 functions as a molecular switch of TGF-α and TGF-β-induced growth control, and MYC-CITED2 signaling axis provides a new index for predicting clinical outcome.
PMCID: PMC3504715  PMID: 22814619
CITED2; MYC; cytokine; transcriptional modulator; lung cancer
19.  Cystatin SN neutralizes the inhibitory effect of cystatin C on cathepsin B activity 
Cell Death & Disease  2013;4(12):e974-.
Cystatin SN (CST1) is one of the several salivary cystatins that form tight equimolar complexes with cysteine proteases, such as the cathepsins. High expression of CST1 is correlated with advanced pTNM stage in gastric cancer. However, the functional role of CST1 in tumorigenesis has not been elucidated. In this study, we showed that CST1 was highly expressed in colon tumor tissues, compared with nontumor regions. Increased cell proliferation and invasiveness were observed in HCT116 cell lines stably transfected with CST1 cDNA (HCT116-CST1) but not in CST3-transfected cells. We also demonstrated that CST1-overexpressing cell lines exhibited increased tumor growth as well as metastasis in a xenograft nude mouse model. Interestingly, CST1 interacted with cystatin C (CST3), a potent cathepsin B (CTSB) inhibitor, with a higher affinity than the interaction between CST3 and CTSB in the extracellular space of HCT116 cells. CTSB-mediated cellular invasiveness and proteolytic activities were strongly inhibited by CST3, but in the presence of CST1 CTSB activities recovered significantly. Furthermore, domain mapping of CST1 showed that the disulfide-bonded conformation, or conserved folding, of CST1 is important for its secretion and for the neutralization of CST3 activity. These results suggest that CST1 upregulation might be involved in colorectal tumorigenesis and acts by neutralizing the inhibition of CTSB proteolytic activity by CST3.
PMCID: PMC3877556  PMID: 24357805
cystatin SN; Cystatin C; Cathepsin B; colon cancer; invasion
20.  Developmental Role of Anoctamin-1/TMEM16A in Ca2+-Dependent Volume Change in Supporting Cells of the Mouse Cochlea 
Experimental Neurobiology  2013;22(4):322-329.
Mammalian cochlea undergoes morphological and functional changes during the postnatal period, around the hearing onset. Major changes during the initial 2 postnatal weeks of mouse include maturation of sensory hair cells and supporting cells, and acquisition of afferent and efferent innervations. During this period, supporting cells in the greater epithelial ridge (GER) of the cochlea exhibit spontaneous and periodic activities which involves ATP, increase in intracellular Ca2+, and cell volume change. This Ca2+-dependent volume change has been proposed to involve chloride channels or transporters. We found that the spontaneous volume changes were eliminated by anion channel blocker, 100 µM NPPB. Among candidates, expression of Anoctamin-1 (Ano1 or TMEM16A), bestriphin-1 and NKCC1 were investigated in whole-mount cochlea of P9-10 mice. Immunolabeling indicated high level of Ano1 expression in the GER, but not of betrophin-1 or NKCC1. Double-labeling with calretinin and confocal image analysis further elucidated the cellular localization of Ano1 immunoreactivity in supporting cells. It was tested if the Ano1 expression exhibits similar time course to the spontaneous activities in postnatal cochlear supporting cells. Cochlear preparations from P2-3, P5-6, P9-10, P15-16 mice were subjected to immunolabeling. High level of Ano1 immunoreactivity was observed in the GER of P2-3, P5-6, P9-10 cochleae, but not of P15-17 cochleae. Taken together, the localization and time course in Ano1 expression pattern correlates with the spontaneous, periodic volume changes recorded in postnatal cochlear supporting cells. From these results we propose that Ano1 is the pacemaker of spontaneous activities in postnatal cochlea.
PMCID: PMC3897694  PMID: 24465148
Anoctamin-1 (Ano1)/TMEM16A; cochlea; greater epithelial ridge; cell volume change; Ca2+-activated chloride channel; supporting cell
21.  Urinary tuberculosis is associated with the development of urothelial carcinoma but not renal cell carcinoma: a nationwide cohort study in Taiwan 
British Journal of Cancer  2013;109(11):2933-2940.
Obstructive uropathy and chronic urinary tract infection increase the risk of urinary tract cancer. Urinary tuberculosis (UTB) can cause chronic urinary tract inflammation, lead to obstructive uropathy, and potentially contribute to the development of urinary tract cancer. However, the association between UTB and urinary tract cancer has not been studied.
This study enrolled 135 142 tuberculosis (TB) cases (male, 69%) from a nationwide health insurance research database in Taiwan and investigated the risk factors for urinary tract cancer, with emphasis on a history of UTB. The incidence of urinary tract cancer in the general population without TB was also calculated for comparison.
The TB patients had a mean age of 57.5±19.5 years. Of the 1287 UTB and 133 855 non-UTB patients, 15 (1.2%) and 396 (0.3%) developed urothelial carcinoma, respectively (P<0.001); and 2 (0.2%) and 96 (0.1%) developed renal cell carcinoma, respectively (P=0.240). Cox regression analysis revealed that age, male sex, end-stage renal disease, obstructive uropathy, arsenic intoxication, organ transplantation, and UTB (hazard ratio: 3.38 (2.01–5.69)) were independent risk factors for urothelial carcinoma. The hazard ratio of UTB was higher among female patients (5.26 (2.12–13.06)) than that among male patients (2.96 (1.57–5.60)).
Urinary tuberculosis had a strong association with urothelial carcinoma, but not with renal cell carcinoma. In TB endemic areas, the urinary tract of TB patients should be scrutinised. It is also imperative that these patients be followed-up carefully in the post-treatment period, and urinalysis, ultrasonography or endoscopy should be an integral part of the follow-up.
PMCID: PMC3844900  PMID: 24129236
cohort study; obstructive uropathy; Taiwan; tuberculosis; urinary tract cancer; National Health Insurance Research Database
22.  Jun dimerization protein 2 is a critical component of the Nrf2/MafK complex regulating the response to ROS homeostasis 
Cell Death & Disease  2013;4(11):e921-.
Oxidative stress and reactive oxygen species (ROS) are associated with diseases such as cancer, cardiovascular complications, inflammation and neurodegeneration. Cellular defense systems must work constantly to control ROS levels and to prevent their accumulation. We report here that the Jun dimerization protein 2 (JDP2) has a critical role as a cofactor for transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and small Maf protein family K (MafK) in the regulation of the antioxidant-responsive element (ARE) and production of ROS. Chromatin immunoprecipitation–quantitative PCR (qPCR), electrophoresis mobility shift and ARE-driven reporter assays were carried out to examine the role of JDP2 in ROS production. JDP2 bound directly to the ARE core sequence, associated with Nrf2 and MafK (Nrf2–MafK) via basic leucine zipper domains, and increased DNA-binding activity of the Nrf2–MafK complex to the ARE and the transcription of ARE-dependent genes. In mouse embryonic fibroblasts from Jdp2-knockout (Jdp2 KO) mice, the coordinate transcriptional activation of several ARE-containing genes and the ability of Nrf2 to activate expression of target genes were impaired. Moreover, intracellular accumulation of ROS and increased thickness of the epidermis were detected in Jdp2 KO mice in response to oxidative stress-inducing reagents. These data suggest that JDP2 is required to protect against intracellular oxidation, ROS activation and DNA oxidation. qPCR demonstrated that several Nrf2 target genes such as heme oxygenase-1, glutamate–cysteine ligase catalytic and modifier subunits, the notch receptor ligand jagged 1 and NAD(P)H dehydrogenase quinone 1 are also dependent on JDP2 for full expression. Taken together, these results suggest that JDP2 is an integral component of the Nrf2–MafK complex and that it modulates antioxidant and detoxification programs by acting via the ARE.
PMCID: PMC3847324  PMID: 24232097
JDP2; Nrf2–MafK; ROS regulation; antioxidant enzymes; antioxidation
23.  Radiolabeling Human Peripheral Blood Stem Cells for Positron Emission Tomography (PET) Imaging in Young Rhesus Monkeys 
PLoS ONE  2013;8(10):e77148.
These studies focused on a new radiolabeling technique with copper (64Cu) and zirconium (89Zr) for positron emission tomography (PET) imaging using a CD45 antibody. Synthesis of 64Cu-CD45 and 89Zr-CD45 immunoconjugates was performed and the evaluation of the potential toxicity of radiolabeling human peripheral blood stem cells (hPBSC) was assessed in vitro (viability, population doubling times, colony forming units). hPBSC viability was maintained as the dose of 64Cu-TETA-CD45 increased from 0 (92%) to 160 µCi/mL (76%, p>0.05). Radiolabeling efficiency was not significantly increased with concentrations of 64Cu-TETA-CD45 >20 µCi/mL (p>0.50). Toxicity affecting both growth and colony formation was observed with hPBSC radiolabeled with ≥40 µCi/mL (p<0.05). For 89Zr, there were no significant differences in viability (p>0.05), and a trend towards increased radiolabeling efficiency was noted as the dose of 89Zr-Df-CD45 increased, with a greater level of radiolabeling with 160 µCi/mL compared to 0–40 µCi/mL (p<0.05). A greater than 2,000 fold-increase in the level of 89Zr-Df-CD45 labeling efficiency was observed when compared to 64Cu-TETA-CD45. Similar to 64Cu-TETA-CD45, toxicity was noted when hPBSC were radiolabeled with ≥40 µCi/mL (p<0.05) (growth, colony formation). Taken together, 20 µCi/mL resulted in the highest level of radiolabeling efficiency without altering cell function. Young rhesus monkeys that had been transplanted prenatally with 25×106 hPBSC expressing firefly luciferase were assessed with bioluminescence imaging (BLI), then 0.3 mCi of 89Zr-Df-CD45, which showed the best radiolabeling efficiency, was injected intravenously for PET imaging. Results suggest that 89Zr-Df-CD45 was able to identify engrafted hPBSC in the same locations identified by BLI, although the background was high.
PMCID: PMC3789702  PMID: 24098579
24.  Mechanistic correlations between two itch biomarkers, IL-31 cytokine and beta-endorphin neuropeptide, via STAT3/calcium axis in atopic dermatitis 
The British journal of dermatology  2012;167(4):794-803.
Itch is the cardinal symptom of atopic dermatitis (AD). Beta-endorphin, a neuropeptide, is increased in both AD skin and sera. IL-31, an itch-relevant cytokine, activates IL-31 receptors in keratinocytes. However, how IL-31 and beta-endorphin interact in AD skin remains elusive.
This study investigated the mechanistic interaction of IL-31 and beta-endorphin in AD.
This is a prospective cross sectional study. We recruited adult patients of AD and controls according to Hanifin's AD criteria. Serum levels of IL-31 and beta-endorphin were measured by ELISA. Expressions of IL-31RA and beta-endorphin in the skin were accessed by immunohistochemistry. Their expressions in the skin and blood were compared and correlated in AD patients and in controls. We also treated primary keratinocytes with IL-31 and measured calcium influx, beta-endorphin production, and signaling pathways to define their mechanistic interactions.
We found beta-endorphin to be increased in supernatant from IL-31-treated keratinocytes. IL-31 receptor activation resulted in calcium influx and STAT3 activation; pretreatment with STAT3 inhibitor stopped the increase of beta-endorphin. Notably, either replacement of extracellular calcium or treatment with 2-APB, an inhibitor for the store-operated channel, blocked STAT3 activation. We found higher levels of blood beta-endorphin and IL-31, that are significantly correlated, in AD patients. Moreover, IL-31RA and beta-endorphin was increased and colocalized both in AD human skin and TPA-painted mouse skin.
We concluded IL-31R activation in keratinocytes induced calcium influx and STAT3-dependent production of beta-endorphin. These results might contribute to an understanding of regulatory mechanisms underlying peripheral itch.
PMCID: PMC3482403  PMID: 22578170
atopic dermatitis; calcium; beta-endorphin; IL-31; itch
25.  miR-125b transcriptionally increased by Nrf2 inhibits AhR repressor, which protects kidney from cisplatin-induced injury 
Cell Death & Disease  2013;4(10):e899-.
MicroRNAs (miRNAs) have a role in the cellular defense mechanism. Nuclear factor erythroid-2-related factor 2 (Nrf2) increases antioxidant enzyme capacity. However, miRNA transcriptionally controlled by Nrf2 had been uncharacterized. Here we report that miR-125b is transactivated by Nrf2 and inhibits aryl hydrocarbon receptor (AhR) repressor (AhRR). Bioinformatic approaches enabled us to extract six candidate miRNAs. Of them, only miR-125b was increased in the kidney of mice treated with oltipraz. Nrf2 overexpression enhanced primary, precursor and mature miR-125b levels. Functional assays revealed MIR125B1 is a bona fide target gene of Nrf2. Oltipraz treatment protected the kidney from cisplatin toxicity with increase of miR-125b. Consistently, Nrf2 knockout abrogated an adaptive increase of miR-125b elicited by cisplatin, augmenting kidney injury. An integrative network of miRNA and messenger RNA changes enabled us to predict miR-125b as an inhibitor of AhRR for the control of AhR activity and cell survival. In our molecular study, miR-125b inhibited AhRR and thereby activated AhR, leading to the induction of mdm2. Consistently, p53 activation by cisplatin was diminished by either miR-125b or oltipraz treatment. The results of experiments using miR-125b mimic or small interfering RNA of AhRR verified the role of miR-125b in AhRR regulation for kidney protection. In conclusion, miR-125b is transcriptionally activated by Nrf2 and serves as an inhibitor of AhRR, which contributes to protecting kidney from acute injury.
PMCID: PMC3920955  PMID: 24176857
miR-125b; Nrf2; AhRR; acute kidney injury; cisplatin

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