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1.  Absence of BRCA/FMR1 Correlations in Women with Ovarian Cancers 
PLoS ONE  2014;9(7):e102370.
Previously reported findings in Austrian BRCA1/2 mutation carriers suggested a possible dependency of embryos with BRCA1/2 mutations on so-called low alleles of the fragile X mental retardation 1 (FMR1) gene, characterized by less than 26 CGG repeats (CGGn<26). The hypothesis arose from a study reporting highly statistically significant enrichment of low FMR1 alleles, significantly exceeding low allele prevalence in a general population, suggesting embryo lethality of BRCA1/2 mutations, “rescued” by presence of low FMR1 alleles. Such a dependency would also offer an explanation for the so-called “BRCA-paradox,” characterized by BRCA1/2 deficient embryonic tissues being anti-proliferative (thereby potentially causing embryo-lethality) but proliferative in malignant tumors, including breast and ovarian cancers. Follow up investigations by other investigators, however, at most demonstrated trends towards enrichment but, mostly, no enrichment at all, raising questions about the original observation and hypothesis. We in this study, therefore, investigated CGGn of the FMR1 gene of 86 anonymized DNA samples from women with various forms of ovarian cancer, and were unable to demonstrate differences in prevalence of low FMR1 alleles either between positive and negative ovarian cancer patients for BRCA1/2 or between ovarian cancer patients and reported rates in non-cancer populations. This raises further questions about a suggested dependency between BRCA1/2 and FMR1, but also raises the possibility that investigated Austrian BRCA1/2 carrier populations differ from those in other countries. Either only selected BRCA1/2 mutations, therefore, interact with low FMR1 alleles or the Austrian data reflect only coincidental observations.
doi:10.1371/journal.pone.0102370
PMCID: PMC4103842  PMID: 25036526
2.  Clinical Characteristics of Q Fever and Etiology of Community-Acquired Pneumonia in a Tropical Region of Southern Taiwan: A Prospective Observational Study 
PLoS ONE  2014;9(7):e102808.
Background
The clinical characteristics of Q fever are poorly identified in the tropics. Fever with pneumonia or hepatitis are the dominant presentations of acute Q fever, which exhibits geographic variability. In southern Taiwan, which is located in a tropical region, the role of Q fever in community-acquired pneumonia (CAP) has never been investigated.
Methodology/Principal Findings
During the study period, May 2012 to April 2013, 166 cases of adult CAP and 15 cases of acute Q fever were prospectively investigated. Cultures of clinical specimens, urine antigen tests for Streptococcus pneumoniae and Legionella pneumophila, and paired serologic assessments for Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Q fever (Coxiella burnetii) were used for identifying pathogens associated with CAP. From April 2004 to April 2013 (the pre-study period), 122 cases of acute Q fever were also included retrospectively for analysis. The geographic distribution of Q fever and CAP cases was similar. Q fever cases were identified in warmer seasons and younger ages than CAP. Based on multivariate analysis, male gender, chills, thrombocytopenia, and elevated liver enzymes were independent characteristics associated with Q fever. In patients with Q fever, 95% and 13.5% of cases presented with hepatitis and pneumonia, respectively. Twelve (7.2%) cases of CAP were seropositive for C. burnetii antibodies, but none of them had acute Q fever. Among CAP cases, 22.9% had a CURB-65 score ≧2, and 45.8% had identifiable pathogens. Haemophilus parainfluenzae (14.5%), S. pneumoniae (6.6%), Pseudomonas aeruginosa (4.8%), and Klebsiella pneumoniae (3.0%) were the most common pathogens identified by cultures or urine antigen tests. Moreover, M. pneumoniae, C. pneumoniae, and co-infection with 2 pathogens accounted for 9.0%, 7.8%, and 1.8%, respectively.
Conclusions
In southern Taiwan, Q fever is an endemic disease with hepatitis as the major presentation and is not a common etiology of CAP.
doi:10.1371/journal.pone.0102808
PMCID: PMC4102556  PMID: 25033402
3.  Utilizing FMR1 Gene Mutations as Predictors of Treatment Success in Human In Vitro Fertilization 
PLoS ONE  2014;9(7):e102274.
Context
Mutations of the fragile X mental retardation 1 (FMR1) gene are associated with distinct ovarian aging patterns.
Objective
To confirm in human in vitro fertilization (IVF) that FMR1 affects outcomes, and to determine whether this reflects differences in ovarian aging between FMR1 mutations, egg/embryo quality or an effect on implantation.
Design, Setting, Patients
IVF outcomes were investigated in a private infertility center in reference to patients' FMR1 mutations based on a normal range of CGGn = 26–34 and sub-genotypes high (CGGn>34) and low (CGG<26). The study included 3 distinct sections and study populations: (i) A generalized mixed-effects model of morphology (777 embryos, 168 IVF cycles, 125 infertile women at all ages) investigated whether embryo quality is associated with FMR1; (ii) 1041 embryos in 149 IVF cycles in presumed fertile women assessed whether the FMR1 gene is associated with aneuploidy; (iii) 352 infertile patients (< age 38; in 1st IVF cycles) and 179 donor-recipient cycles, assessed whether the FMR1 gene affects IVF pregnancy chances via oocyte/embryo quality or non-oocyte maternal factors.
Interventions
Standardized IVF protocols.
Main Outcome Measures
Morphologic embryo quality, ploidy and pregnancy rates.
Results
(i) Embryo morphology was reduced in presence of a low FMR1 allele (P = 0.032). In absence of a low allele, the odds ratio (OR) of chance of good (vs. fair/poor) embryos was 1.637. (ii) FMR1 was not associated with aneuploidy, though aneuploidy increased with female age. (iii) Recipient pregnancy rates were neither associated with donor age or donor FMR1. In absence of a low FMR1 allele, OR of clinical pregnancy (vs. chemical or no pregnancy) was 2.244 in middle-aged infertility patients.
Conclusions
A low FMR1 allele (CGG<26) is associated with significantly poorer morphologic embryo quality and pregnancy chance. As women age, low FMR1 alleles affect IVF pregnancy chances by reducing egg/embryo quality by mechanisms other than embryo aneuploidy.
doi:10.1371/journal.pone.0102274
PMCID: PMC4096763  PMID: 25019151
4.  Ethanol Extract of Lycopus lucidus Elicits Positive Inotropic Effect Via Activation of Ca2+ Entry and Ca2+ Release in Beating Rabbit Atria 
Journal of Medicinal Food  2013;16(7):633-640.
Abstract
Lycopus lucidus Turcz has been widely used as a traditional Oriental medicine (TOM) in Korea and China and prescribed for the enhancement of heart function. However, the precise effects have yet to be defined. The purpose of the present study was, therefore, to address whether the ethanol extract of Lycopus lucidus Turcz (ELT) has a positive inotropic effect. ELT-induced changes in atrial mechanical dynamics (pulse pressure, dp/dt, and stroke volume), and cAMP efflux were measured in perfused beating rabbit atria. Three active components, rosmarinic acid, betulinic acid, and oleanolic acid were identified in ELT by high performance liquid chromatography analysis. ELT increased atrial dynamics in a concentration-dependent manner without changes in atrial cAMP levels and cAMP efflux. The ELT-induced positive inotropic effect was blocked by inhibition of the L-type Ca2+ channels and sarcoplasmic reticulum (SR). Inhibitors of β-adrenoceptors had no effect on the ELT-induced positive inotropic effect. The results suggest that ELT exerts a positive inotropic effect via activation of Ca2+ entry through L-type Ca2+ channel and Ca2+ release from the SR in beating rabbit atria.
doi:10.1089/jmf.2012.2487
PMCID: PMC3719484  PMID: 23875903
inotropic effect; L-type Ca2+ channel; Lycopus lucidusTurcz; sarcoplasmic reticulum
5.  Hesperidin Induces Paraptosis Like Cell Death in Hepatoblatoma, HepG2 Cells: Involvement of ERK1/2 MAPK 
PLoS ONE  2014;9(6):e101321.
Hesperidin, a natural flavonoid abundantly present in Citrus is known for its anti-cancer, anti-oxidant and anti-inflammatory properties. In this study we examined the effect of hesperidin on HepG2 cells. HepG2 cells treated with various concentration of hesperidin undergo a distinct type of programed cell death. Cytoplasmic vacuolization, mitochondria and endoplasmic reticulum swelling and uncondensed chromatin were observed in hesperidin treated cells. DNA electrophoresis show lack of DNA fragmentation and western blot analysis demonstrates lack of caspase activation and PARP cleavage. It was observed that hesperidin induced cell death is nonautophagic and also activate mitogen activated protein kinase ERK1/2. Taken together, the data indicate that hesperidin induces paraptosis like cell death in HepG2 cells with the activation of ERK1/2. Thus our finding suggests that hesperidin inducing paraptosis may offer an alternative tool in human liver carcinoma therapy.
doi:10.1371/journal.pone.0101321
PMCID: PMC4076305  PMID: 24977707
6.  Efficacy of Ketamine in Improving Pain after Tonsillectomy in Children: Meta-Analysis 
PLoS ONE  2014;9(6):e101259.
Background and objectives
The goal of this meta-analysis study was to perform a systematic review of the literature on the effects of ketamine on postoperative pain following tonsillectomy and adverse effects in children.
Subjects and Methods
Two authors independently searched three databases (MEDLINE, SCOPUS, Cochrane) from their inception of article collection to February 2014. Studies that compared preoperative ketamine administration (ketamine groups) with no treatment (control group) or opioid administration (opioid group) where the outcomes of interest were postoperative pain intensity, rescue analgesic consumption, or adverse effects (sedation, nausea and vomiting, bad dream, worsening sleep pattern, and hallucination) 0–24 hours after leaving the operation room were included in the analysis.
Results
The pain score reported by the physician during first 4 hours and need for analgesics during 24 hours postoperatively was significantly decreased in the ketamine group versus control group and was similar with the opioid group. In addition, there was no significant difference between ketamine and control groups for adverse effects during 24 hours postoperatively. In the subgroup analyses (systemic and local administration) regarding pain related measurements, peritonsillar infiltration of ketamine was more effective in reducing the postoperative pain severity and need for analgesics.
Conclusion
Preoperative administration of ketamine systemically or locally could provide pain relief without side-effects in children undergoing tonsillectomy. However, considering the insufficient evaluation of efficacy of ketamine according to the administration methods and high heterogeneity in some parameters, further clinical trials with robust research methodology should be conducted to confirm the results of this study.
doi:10.1371/journal.pone.0101259
PMCID: PMC4076328  PMID: 24979227
7.  Structural insights into the role of the Smoothened cysteine-rich domain in Hedgehog signalling 
Nature communications  2013;4:2965.
Smoothened (Smo) is a member of the Frizzled (FzD) class of G-protein-coupled-receptors (GPCRs), and functions as the key transducer in the Hedgehog (Hh) signalling pathway. Smo has an extracellular cysteine-rich domain (CRD), indispensable for its function and downstream Hh signalling. Despite its essential role, the functional contribution of the CRD to Smo signalling has not been clearly elucidated. However, given that the FzD CRD binds to the endogenous Wnt ligand, it has been proposed that the Smo CRD may bind its own endogenous ligand. Here we present the NMR solution structure of the Drosophila Smo CRD, and describe interactions between the glucocorticoid budesonide (Bud) and the Smo CRDs from both Drosophila and human. Our results highlight a function of the Smo CRD, demonstrating its role in binding to small molecule modulators.
doi:10.1038/ncomms3965
PMCID: PMC3890372  PMID: 24351982
8.  Therapeutic use of PDZ protein-protein interaction antagonism 
Drug news & perspectives  2008;21(3):137-141.
PDZ domains are important interaction modules in many intracellular pathways and abnormal activations of many of those pathways lead to diseases, including several types of cancer. The domains are characterized by the ability to recognize the extreme COOH-terminus of target proteins, such as G protein-coupled receptors and ion channels. Because PDZ protein-protein interaction is a key factor in the function of cellular pathways and signal transmission in those pathways, developing small-molecule inhibitors to compete with PDZ targets is very attractive in dissecting molecular mechanisms and formulating pharmaceutical agents. Moreover, there is a growing interest in developing small-molecule drugs to block signaling within cells. The modulation of PDZ-involved interactions in cells might be an approach to target the G protein-coupled receptors and ion channels, which are among the most important classes of drug targets in the pharmaceutical industry today. Here, we review recent progress in the development of small-molecule PDZ inhibitors, and especially focus on two PDZ domain-containing target proteins, postsynaptic density 95 and dishevelled.
PMCID: PMC4055467  PMID: 18560611
9.  Clinical Factors Associated with Response or Survival after Chemotherapy in Patients with Waldenström Macroglobulinemia in Korea 
BioMed Research International  2014;2014:253243.
Waldenström's macroglobulinemia (WM) is a B-cell proliferative malignancy characterized by immunoglobulin M monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells. Clinical features and cytogenetics of WM in Asia including Republic of Korea remain unclear. Moreover, no study has reported treatment outcomes in patients with WM treated with novel agent combined with conventional chemotherapy. This study investigated clinical features and assessed treatment outcomes with novel agent and conventional chemotherapy in Republic of Korea. Data from all (n = 71) patients with newly diagnosed WM at 17 hospitals who received chemotherapy between January 2005 and December 2012 were collected retrospectively. The median age of patients was 66 years (range: 37–92 years) and male to female ratio was 5 : 1. Patients treated with novel agent combined chemotherapy displayed higher overall response rate (ORR) compared to conventional chemotherapy alone (92.9% versus 52.6%, P = 0.006). The 5-year overall survival rate was 62.6% (95% confidence interval: 34.73–111.07). Use of novel agents produced higher ORR but survival benefit was not apparent due to the small number of patients and short follow-up duration. Further studies are needed to confirm the efficacy of novel agents in patients with WM.
doi:10.1155/2014/253243
PMCID: PMC4065725  PMID: 24995279
10.  Total Talar Extrusion without Soft Tissue Attachments 
Clinics in Orthopedic Surgery  2014;6(2):236-241.
Total talar extrusion without a soft tissue attachment is an extremely rare injury and is rarely reported. Appropriate treatment remains controversial. We describe the long-term outcomes of two patients who had complete talar extrusion without remaining soft tissue attachment treated with arthrodesis. Both of our patients had complications such as infection and progressive osteolysis. We suggest reimplantation of the extruded talus after thorough debridement as soon as possible as a reasonable option unless the talus is contaminated or missing, because an open wound may arise from inside to outside.
doi:10.4055/cios.2014.6.2.236
PMCID: PMC4040387  PMID: 24900908
Talus; Extrusion; Missing talus; Arthrodesis
11.  99mTc-Labeled RBC Scan in a Patient with Blue Rubber Bleb Nevus Syndrome: A Case Report 
Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder characterized by cutaneous and gastrointestinal vascular malformations. We report here the case of a 13-year-old patient with BRBNS who was suffering from chronic anemia. His chief complaint was melena. Contrast-enhanced abdominal computed tomography showed multiple hemangiomas in the small bowel. 99mTc-labeled red blood cell (RBC) scan identified the bleeding sites in the small bowel. The patient underwent exploratory laparotomy with segmental resection and multiple wedge resection of the small bowel. The pathological results confirmed the multiple cavernous hemangiomas. This case confirms the critical role of the 99mTc-labeled RBC scan in localizing the bleeding sites in patients with BRBNS.
doi:10.1007/s13139-013-0199-3
PMCID: PMC4041976  PMID: 24900091
Blue rubber bleb nevus syndrome; 99mTc-labeled red blood cell scan; Venous malformation; Chronic anemia
12.  Dexamethasone Induces Apoptosis of Nasal Polyp-Derived Tissue Cultures Through JNK and p38 MAPK Activation 
Objectives
Glucocorticoids, such as dexamethasone (DEX), increase apoptosis in a variety of white cells in nasal polyps and apoptosis is an important factor in the resolution of inflammation. However, the mechanism of glucocorticoids induced apoptosis in nasal polyp remains unclear. In this study the authors evaluated which pathways were engaged in apoptosis induced by DEX in an ex vivo model of nasal polyps.
Methods
Nasal polyp tissues were cultured using an air-liquid interface method. Cultures were maintained in the absence or presence of DEX (10 or 100 µM) for 24 hours. To investigate the involvement of the apoptotic signaling pathways in nasal polyp, such as caspase cascades, Fas-FasL signaling pathway, mitochondrial pathway and p38 mitogen-activated protein kinase (MAPK)/JNK pathway, the authors performed reverse transcription-polymerase chain reaction and Western blotting.
Results
The expression ratios of FasL, activated form of caspase-8, caspase-9, and caspase-3 were significantly higher in DEX-treated polyps (P<0.01). In the Bcl-2 family expression, the anti-apoptotic molecules, Bcl-2 and Bcl-XL decreased, but pro-apoptotic molecules, Bax increased, and Bid and Bad were activated. In the conventional MAPKs, JNK, and the phospho-p38 MAPK were significantly higher, but phospho-extracellular signal-regulated kinase (ERK)1/2 was significantly lower in DEX-treated polyps (P<0.01).
Conclusion
DEX induces apoptosis of nasal polyp via caspase cascades, Fas-FasL signaling pathway, mitochondrial pathway and p38 MAPK/JNK pathway.
doi:10.3342/ceo.2014.7.2.112
PMCID: PMC4050082  PMID: 24917907
Apoptosis; Glucocorticoids; Nasal polyps; Organ culture; Ex vivo; MAPKs
13.  Advantages of Binaural Amplification to Acceptable Noise Level of Directional Hearing Aid Users 
Objectives
The goal of the present study was to examine whether Acceptable Noise Levels (ANLs) would be lower (greater acceptance of noise) in binaural listening than in monaural listening condition and also whether meaningfulness of background speech noise would affect ANLs for directional microphone hearing aid users. In addition, any relationships between the individual binaural benefits on ANLs and the individuals' demographic information were investigated.
Methods
Fourteen hearing aid users (mean age, 64 years) participated for experimental testing. For the ANL calculation, listeners' most comfortable listening levels and background noise level were measured. Using Korean ANL material, ANLs of all participants were evaluated under monaural and binaural amplification with a counterbalanced order. The ANLs were also compared across five types of competing speech noises, consisting of 1- through 8-talker background speech maskers. Seven young normal-hearing listeners (mean age, 27 years) participated for the same measurements as a pilot testing.
Results
The results demonstrated that directional hearing aid users accepted more noise (lower ANLs) with binaural amplification than with monaural amplification, regardless of the type of competing speech. When the background speech noise became more meaningful, hearing-impaired listeners accepted less amount of noise (higher ANLs), revealing that ANL is dependent on the intelligibility of the competing speech. The individuals' binaural advantages in ANLs were significantly greater for the listeners with longer experience of hearing aids, yet not related to their age or hearing thresholds.
Conclusion
Binaural directional microphone processing allowed hearing aid users to accept a greater amount of background noise, which may in turn improve listeners' hearing aid success. Informational masking substantially influenced background noise acceptance. Given a significant association between ANLs and duration of hearing aid usage, ANL measurement can be useful for clinical counseling of binaural hearing aid candidates or unsuccessful users.
doi:10.3342/ceo.2014.7.2.94
PMCID: PMC4050094  PMID: 24917904
Acceptable noise level; Binaural amplification; Directional microphone hearing aids
14.  Prevalence of Chronic Sputum and Associated Factors in Korean Adults 
Journal of Korean Medical Science  2014;29(6):825-830.
Chronic sputum is a troublesome symptom in many respiratory diseases. The prevalence of chronic sputum varies from 1.2% to 13% according to the country. The purpose of this study was to estimate the prevalence of chronic sputum and to find its associated factors in a general Korean population. We analyzed the data of the Korea National Health and Nutrition Examination Survey 2010 and 2011. A total number of 6,783 subjects aged 40 yr or more were enrolled in this study with 3,002 men and 3,781 women. As a result, the prevalence of chronic sputum was 6.3% (n=430). Significant risk factors for chronic sputum by multivariate analysis were: age (≥70 yr) (odds ratio [OR], 1.954; 95% confidence interval [CI], 1.308-2.917), current smoking (OR, 4.496; 95% CI, 3.001-6.734), chronic obstructive pulmonary disease (COPD) (OR, 1.483; 95% CI, 1.090-2.018), and tuberculosis (OR, 1.959; 95% CI, 1.307-2.938). In conclusion, the prevalence of chronic sputum in Korea was in the intermediate range compared with other countries. Smoking is a preventable risk factor identified in this study, and major respiratory diseases, such as COPD and tuberculosis, should be considered in subjects with chronic sputum.
Graphical Abstract
doi:10.3346/jkms.2014.29.6.825
PMCID: PMC4055817  PMID: 24932085
Chronic Sputum; Prevalence; Associated Factor
15.  R-CHOP chemoimmunotherapy followed by autologous transplantation for the treatment of diffuse large B-cell lymphoma 
Blood research  2014;49(2):107-114.
Background
We investigated factors that influence outcomes in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab combined with the CHOP regimen (R-CHOP) followed by upfront autologous stem cell transplantation (Auto-SCT).
Methods
We retrospectively evaluated survival differences between subgroups based on the age-adjusted International Prognostic Index (aaIPI) and revised-IPI (R-IPI) at diagnosis, disease status, and positron emission tomographic/computerized tomographic (PET/CT) status at transplantation in 51 CD20-positive DLBCL patients treated with R-CHOP followed by upfront Auto-SCT.
Results
Patients had either stage I/II bulky disease (5.9%) or stage III/IV disease (94.1%). The median patient age at diagnosis was 47 years (range, 22-66 years); 53.3% and 26.7% had high-intermediate and high risks according to aaIPI, respectively. At the time of Auto-SCT, 72.5% and 27.5% experienced complete (CR) and partial remission (PR) after R-CHOP, respectively. The median time from diagnosis to Auto-SCT was 7.27 months (range, 3.4-13.4 months). The 5-year overall (OS) and progression-free survival (PFS) were 77.3% and 72.4%, respectively. The 5-year OS and PFS rates according to aaIPI, R-IPI, and PET/CT status did not differ between the subgroups. More importantly, the 5-year OS and PFS rates of the patients who achieved PR at the time of Auto-SCT were not inferior to those of the patients who achieved CR (P=0.223 and 0.292, respectively).
Conclusion
Survival was not influenced by the aaIPI and R-IPI at diagnosis, disease status, or PET/CT status at transplantation, suggesting that upfront Auto-SCT might overcome unfavorable outcomes attributed to PR after induction chemoimmunotherapy.
doi:10.5045/br.2014.49.2.107
PMCID: PMC4090331  PMID: 25025012
Diffuse large B-cell lymphoma; Hematopoietic stem cell transplantation; Autologous transplantation; Rituximab; Survival analysis
16.  Pulmonary metastasectomy for colorectal cancer: How many nodules, how many times? 
Colorectal cancer (CRC) is one of the most common cancers worldwide, with 5%-15% of CRC patients eventually developing lung metastasis (LM). Despite doubts about the role of locoregional therapy in the management of systemic disease, many surgeons have performed pulmonary metastasectomy (PM) for CRC in properly selected patients. However, the use of pulmonary metastasectomy remains controversial due to the lack of randomized controlled studies. This article reviews the results of surgical treatment of pulmonary metastases for CRC, focusing on (1) current treatment guidelines and surgical techniques of PM in patients with LM from CRC; (2) outcomes of PM and its prognostic factors; and (3) controversial issues in PM, focusing on repeated metastasectomy, bilateral multiple metastases, and combined liver and lung metastasectomy.
doi:10.3748/wjg.v20.i20.6133
PMCID: PMC4033452  PMID: 24876735
Colorectal cancer; Pulmonary metastasectomy; Surgery; Metastases
17.  FIZZ2/RELM-β Induction and Role in Pulmonary Fibrosis 
Found in inflammatory zone (FIZZ) 2, also known as resistin-like molecule (RELM)-β, belongs to a novel cysteine-rich secreted protein family named FIZZ/RELM. Its function is unclear, but a closely related family member, FIZZ1, has profibrotic activities. The human ortholog of rodent FIZZ1 has not been identified, but human FIZZ2 has significant sequence homology to both rodent FIZZ2 (59%) and FIZZ1 (50%). Given the greater homology to rodent FIZZ2, analyzing the role of FIZZ2 in a rodent model of bleomycin-induced pulmonary fibrosis would be of greater potential relevance to human fibrotic lung disease. The results showed that FIZZ2 was highly induced in lungs of rodents with bleomycin-induced pulmonary fibrosis and of human patients with idiopathic pulmonary fibrosis. FIZZ2 expression was induced in rodent and human lung epithelial cells by Th2 cytokines, which was mediated via STAT6 signaling. The FIZZ2 induction in murine lungs was found to be essential for pulmonary fibrosis, as FIZZ2 deficiency significantly suppressed pulmonary fibrosis and associated enhanced extracellular matrix and cytokine gene expression. In vitro analysis indicated that FIZZ2 could stimulate type I collagen and α-smooth muscle actin expression in lung fibroblasts. Furthermore, FIZZ2 was shown to have chemoattractant activity for bone marrow (BM) cells, especially BM-derived CD11c+ dendritic cells. Notably, lung recruitment of BM-derived cells was impaired in FIZZ2 knockout mice. These findings suggest that FIZZ2 is a Th2-associated multifunctional mediator with potentially important roles in the pathogenesis of fibrotic lung diseases.
doi:10.4049/jimmunol.1000964
PMCID: PMC4030639  PMID: 21602491
18.  Negative impact of sedation on esophagogastric junction evaluation during esophagogastroduodenoscopy 
AIM: To compare the esophagogastric junction (EGJ) areas observed in sedated and non-sedated patients during esophagogastroduodenoscopy (EGD).
METHODS: Data were collected prospectively from consecutive patients who underwent EGD for various reasons. The patients were divided into three groups according to the sedation used: propofol, midazolam, and control (no sedation). The EGJ was observed during both insertion and withdrawal of the endoscope. The extent of the EGJ territory observed was classified as excellent, good, fair, or poor. In addition, the time the EGJ was observed was estimated.
RESULTS: The study included 103 patients (50 males; mean age 58.44 ± 10.3 years). An excellent observation was achieved less often in the propofol and midazolam groups than in the controls (27.3%, 28.6% and 91.4%, respectively, P < 0.001). There was a significant difference in the time at which EGJ was observed among the groups (propofol 20.7 ± 11.7 s vs midazolam 16.3 ± 7.3 s vs control 11.6 ± 5.8 s, P < 0.001). Multivariate analysis showed that sedation use was the only independent risk factor for impaired EGJ evaluation (propofol, OR = 24.4, P < 0.001; midazolam, OR = 25.3, P < 0.001). Hiccoughing was more frequent in the midazolam group (propofol 9% vs midazolam 25.7% vs control 0%, P = 0.002), while hypoxia (SaO2 < 90%) tended to occur more often in the propofol group (propofol 6.1% vs midazolam 0% vs control 0%, P = 0.101).
CONCLUSION: Sedation during EGD has a negative effect on evaluation of the EGJ.
doi:10.3748/wjg.v20.i18.5527
PMCID: PMC4017068  PMID: 24833883
Esophagogastric junction; Endoscopy; Esophagus; Propofol; Midazolam
19.  A novel antitumor activity of deguelin targeting the insulin-like growth factor (IGF) receptor pathway via up-regulation of IGF-binding protein-3 expression in breast cancer 
Cancer letters  2013;332(1):102-109.
In this study, we investigated the antitumor effects of deguelin in several human breast cancer cells in vitro and in vivo. Deguelin inhibited cell viability and the anchorage-dependent and anchorage-independent colony formation of triple-negative (MDA-MB-231 and MDA-MB-468) and triple-positive (MCF-7) breast cancer cells, and it significantly reduced the growth of MCF-7 cell xenograft tumors. The induction of apoptosis, inhibition of insulin-like growth factor-1 receptor (IGF-1R) signaling activation, and up-regulation of IGF-binding protein-3 (IGFBP-3) expression may be associated with deguelin-mediated antitumor effects. Our findings suggest a potential therapeutic use for deguelin in patients with triple-negative breast cancer and for those with breast cancers who are sensitive to endocrine- and HER2-targeted therapies.
doi:10.1016/j.canlet.2013.01.022
PMCID: PMC3638119  PMID: 23348700
Deguelin; Breast cancer; Apoptosis; IGFR signaling; IGFBP-3
20.  Embryonic Stem Cell–Derived Granulosa Cells Participate in Ovarian Follicle Formation In Vitro and In Vivo 
Reproductive Sciences  2013;20(5):524-535.
Differentiating embryonic stem cells (ESCs) can form ovarian follicle-like structures in vitro, consisting of an oocyte-like cell surrounded by somatic cells capable of steroidogenesis. Using a dual-fluorescence reporter system in which mouse ESCs express green fluorescent protein (GFP) under the control of a germ cell–specific Pou5f1 gene promoter and red fluorescent protein (Discosoma sp red [DsRed]) driven by the granulosa cell–specific Forkhead box L2 (Foxl2) gene promoter, we first confirmed in vitro formation of follicle-like structures containing GFP-positive cells surrounded by DsRed-positive cells. Isolated DsRed-positive cells specified from ECSs exhibited a gene expression profile consistent with granulosa cells, as revealed by the detection of messenger RNAs (mRNAs) for Foxl2, follistatin (Fst), anti-Müllerian hormone (Amh), and follicle-stimulating hormone receptor (Fshr) as well as by production of both progesterone and estradiol. In addition, treatment of isolated DsRed-expressing cells with follicle-stimulating hormone (FSH) significantly increased estradiol production over basal levels, confirming the presence of functional FSH receptors in these cells. Last, ESC-derived DsRed-positive cells injected into neonatal mouse ovaries became incorporated within the granulosa cell layer of immature follicles. These studies demonstrate that Foxl2-expressing ovarian somatic cells derived in vitro from differentiating ESCs express granulosa cell markers, actively associate with germ cells in vitro, synthesize steroids, respond to FSH, and participate in folliculogenesis in vivo.
doi:10.1177/1933719113483017
PMCID: PMC3635068  PMID: 23536570
granulosa cells; Foxl2; embryonic stem cell; oocyte; follicle; ovary
21.  Multidrug-Resistant Tuberculosis Presenting as Miliary Tuberculosis without Immune Suppression: A Case Diagnosed Rapidly with the Genotypic Line Probe Assay Method 
Miliary tuberculosis (TB) is a rare extrapulmonary form of TB, and there have been only two reports of miliary TB associated with infection with multidrug-resistant (MDR)-TB pathogen in an immunocompetent host. A 32-year-old woman was referred to our hospital because of abnormal findings on chest X-ray. The patient was diagnosed with MDR-TB by a line probe assay and was administered proper antituberculous drugs. After eight weeks, a solid-media drug sensitivity test revealed that the pathogen was resistant to ethambutol and streptomycin in addition to isoniazid and rifampicin. The patient was then treated with effective antituberculous drugs without delay after diagnosis of MDR-TB. To the best of our knowledge, this is the first case of miliary TB caused by MDR-TB pathogen in Korea.
doi:10.4046/trd.2014.76.5.245
PMCID: PMC4050074  PMID: 24920953
Tuberculosis, Multidrug-Resistant; Tuberculosis, Miliary; Molecular Probe Techniques
22.  Suppression of Colorectal Cancer Liver Metastasis by Apolipoprotein(a) Kringle V in a Nude Mouse Model through the Induction of Apoptosis in Tumor-Associated Endothelial Cells 
PLoS ONE  2014;9(4):e93794.
The formation of liver metastases in colorectal cancer patients is the primary cause of patient death. Current therapies directed at liver metastasis from colorectal cancer have had minimal impact on patient outcomes. Therefore, the development of alternative treatment strategies for liver metastasis is needed. In the present study, we demonstrated that recombinant human apolipoprotein(a) kringle V, also known as rhLK8, induced the apoptotic turnover of endothelial cells in vitro through the mitochondrial apoptosis pathway. The interaction of rhLK8 with glucose-regulated protein 78 (GRP78) may be involved in the induction of apoptosis because the inhibition of GRP78 by GRP78-specific antibodies or siRNA knockdown inhibited the rhLK8-mediated apoptosis of human umbilical vein endothelial cells in vitro. Next, to evaluate the effects of rhLK8 on angiogenesis and metastasis, an experimental model of liver metastasis was established by injecting a human colorectal cancer cell line, LS174T, into the spleens of BALB/c nude mice. The systemic administration of rhLK8 significantly suppressed liver metastasis from human colorectal cancer cells and improved host survival compared with controls. The combination of rhLK8 and 5-fluorouracil substantially increased these survival benefits compared with either therapy alone. Histological observation showed significant induction of apoptosis among tumor-associated endothelial cells in liver metastases from rhLK8-treated mice compared with control mice. Collectively, these results suggest that the combination of rhLK8 with conventional chemotherapy may be a promising approach for the treatment of patients with life-threatening colorectal cancer liver metastases.
doi:10.1371/journal.pone.0093794
PMCID: PMC3974802  PMID: 24699568
23.  PTEN loss and HOXA10 expression are associated with ovarian endometrioid adenocarcinoma differentiation and progression 
Carcinogenesis  2012;34(4):893-901.
Epithelial ovarian cancer is a heterogeneous disease that is subdivided into five major histotypes but the mechanisms driving their differentiation are not clear. Mutations in adenomatous polyposis coli (APC) and β-catenin are commonly observed in the human ovarian endometrioid adenocarcinoma (OEA) patients. However, the mechanisms subsequent to APC deletion in ovarian tumorigenesis have not been well characterized. We have conditionally deleted APC in the murine ovarian surface epithelium (OSE) and showed that its loss leads to development of epithelial inclusion cysts. High-grade OEAs with tightly packed villoglandular histology were observed in older APC-deleted mice. Phosphatase and tensin homolog (PTEN) expression was elevated in the early lesions but lost after progression to the more advanced tumors. Knockdown of APC or expression of a gain-of-function β-catenin similarly induced human OSE cells to develop tumors with endometrioid histology in xenografts. Expression of HOXA10 was induced in both the advanced APC-deleted murine tumors and in the tumor xenografts of human OSE cells with knocked-down APC. These results show that reduced APC activity is sufficient to induce formation of epithelial inclusion cysts and support OEA development and suggest that induced HOXA10 expression and loss of PTEN are key mechanisms driving endometrioid histotype differentiation and progression.
doi:10.1093/carcin/bgs405
PMCID: PMC3616672  PMID: 23276799
24.  Comparison of laparoscopy and laparotomy for the management of early-stage ovarian cancer: surgical and oncological outcomes 
Journal of Gynecologic Oncology  2014;25(2):111-117.
Objective
To investigate the surgical and oncological outcomes of laparoscopic surgery compared with laparotomy for the treatment of early-stage ovarian cancer.
Methods
Data from patients who underwent surgical management for early-stage ovarian cancer between 2006 and 2012 were retrospectively reviewed. All patients presented with stage I or II disease, and underwent comprehensive staging surgery consisting of a total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, omentectomy, and peritoneal cytology.
Results
Seventy-seven patients who underwent laparoscopic surgery (24 patients) or laparotomy (53 patients) were identified. Surgery for none of the patients was converted from laparoscopy to laparotomy. The mean operation time was shorter and the estimated blood loss was lower in the laparoscopy group than in the laparotomy group, though the differences were not statistically significant (193 min vs. 224 min, p=0.127; 698 mL vs. 973 mL, p=0.127). There were no differences in the intraoperative or postoperative complications. During a mean follow-up period of 31 months, tumor recurrence occurred in 4 patients: 2 (8.3%) in the laparoscopy group and 2 (3.8%) in the laparotomy group. The mean disease-free survival was 59 months after laparoscopy and 66 months after laparotomy (p=0.367).
Conclusion
Laparoscopic surgery seems to be adequate and feasible for the treatment of early-stage ovarian cancer with comparable results to laparotomy in terms of the surgical outcomes and oncological safety.
doi:10.3802/jgo.2014.25.2.111
PMCID: PMC3996260  PMID: 24761214
Early-stage ovarian cancer; Laparoscopy surgery; Laparotomy staging
25.  Metronomic oral paclitaxel shows anti-tumor effects in an orthotopic mouse model of ovarian cancer 
Journal of Gynecologic Oncology  2014;25(2):130-135.
Objective
The purpose of this study was to compare the in vivo anti-tumor efficacy of a mucoadhesive, lipid-based, oral paclitaxel formulation (DHP107) with traditional, intraperitoneal (IP) paclitaxel using an orthotopic mouse model of chemotherapy-sensitive SKOV3ip1 ovarian cancer.
Methods
To determine the optimal therapeutic dose of oral paclitaxel, DHP107 was administered per os to female athymic nude mice at 0, 25, or 50 mg/kg twice per week. Control mice received 100 µL saline once per week. IP injections of paclitaxel at 5 mg/kg once per week were used for comparison. To evaluate the potential therapeutic effect of metronomic DHP107 chemotherapy, mice received DHP107 50 mg/kg once per week per os, which was compared with 25 mg/kg twice per week and with vehicle-treated controls.
Results
Low-dose DHP107 (25 mg/kg) twice per week was as effective as IP paclitaxel (5 mg/kg once a week) but high-dose DHP107 (50 mg/kg once per week) was less effective at inhibiting tumor growth in an orthotopic mouse model (88%, 82%, and 36% decrease in tumor weight, respectively). Mice that received 25 mg/kg DHP107 twice per week or 50 mg/kg DHP107 once per week per os had a significant decrease in tumor weight compared with vehicle-treated controls (p<0.01, both doses).
Conclusion
Metronomic oral chemotherapy with DHP107 showed anti-tumor efficacy in vivo similar to IP paclitaxel in an orthotopic mouse model.
doi:10.3802/jgo.2014.25.2.130
PMCID: PMC3996263  PMID: 24761217
Chemotherapy; DHP107; Oral paclitaxel; Ovarian cancer

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