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1.  The prevalence and clinical characteristics of cancer among anemia patients treated at an outpatient clinic 
Blood research  2013;48(1):46-50.
Background
Anemia is the most common hematologic condition encountered in outpatient clinics. It is often overlooked because it is common among patients; however, anemia is one of the leading indicators of cancer. This study examined the prevalence and characteristics of cancer among anemia patients who visited an outpatient clinic.
Methods
The data were collected by reviewing the records of an outpatient clinic from January 2007 to December 2011.
Results
In total, 502 patients (52 males, 450 females) were diagnosed with anemia. Cancer prevalence among anemia patients was 5.57% (25.0%, men; 3.3%, women); further, the most frequently diagnosed cancer was colorectal cancer (22.5%), followed by advanced gastric cancer (16.1%), breast cancer (9.6%), myelodysplastic syndrome (9.6%), cervical cancer (6.4%), renal-cell carcinoma (6.4%), and thyroid cancer (6.4%). The prevalence of cancer was 4.1% in those aged 40-49 years, 4.2% in the subjects in their fifties, 8.0% in those in their sixties, 21.6% in those in their seventies, and 55.6% in those aged over 80 years. The cancer prevalence among iron deficiency anemia (IDA) patients was 6.18% (28.8%, men; 3.5%, women). The cancer prevalence in postmenopausal and premenopausal female IDA patients was 16.0% and 1.6%, respectively.
Conclusion
Among anemia patients, male patients aged over 40 years and female patients aged over 60 years, along with postmenopausal female patients, were more likely to be diagnosed with cancer. Consequently, male IDA patients, and female patients aged over 60 years must be carefully evaluated for the possibility of malignancy.
doi:10.5045/br.2013.48.1.46
PMCID: PMC3624994  PMID: 23589795
Anemia; Prevalence; Cancer; Outpatient clinic
2.  A Case of Typhlitis Developed after Chemotherapy with Irinotecan and Cisplatin in a Patient with Small Cell Lung Carcinoma 
Typhlitis is a necrotizing colitis that usually occurs in neutropenic patients and develops most often in patients with hematologic malignancies such as leukemia and lymphoma. Typhlitis may proceed to bowel perforation, peritonitis and sepsis, which requires immediate treatment. Irinotecan is a semisynthetic analogue of the natural alkaloid camptothecin which prevents DNA from unwinding by inhibition of topoisomerase I. It is mainly used in colon cancer and small cell lung carcinoma (SCLC), of which the most common adverse effects are gastrointestinal toxicities. To the best of our knowledge, no case of typhlitis after chemotherapy with a standard dose of irinotecan in a solid tumor has been reported in the literature. We, herein, report the first case of typhlitis developed after chemotherapy combining irinotecan and cisplatin in a patient with SCLC.
doi:10.4046/trd.2012.73.5.288
PMCID: PMC3517949  PMID: 23236322
Typhlitis; Irinotecan; Small Cell Lung Carcinoma
3.  Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait 
Biological psychiatry  2013;74(8):576-584.
BACKGROUND
Brain development follows a different trajectory in children with Autism Spectrum Disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort.
METHODS
We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters.
RESULTS
Gender, age, height, weight, genetic ancestry and ASD status were significant predictors of HC (estimate of the ASD effect=0.2cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC.
CONCLUSIONS
Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait and population norms for HC would be far more accurate if covariates including genetic ancestry, height and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.
doi:10.1016/j.biopsych.2013.04.018
PMCID: PMC3772969  PMID: 23746936
head circumference; body metrics; genetic ancestry; IQ; autism spectrum disorder; ASD
4.  Undiagnosed Borrmann type II gastric cancer due to necrosis and regenerative epithelium 
Endoscopic biopsy is essential to the proper diagnosis and treatment of gastric cancer. Unfortunately, the results of endoscopic biopsy are not always the same as what is expected based on gross endoscopic findings. The results of endoscopic biopsy can be negative for malignancy in Borrmann type IV advanced gastric cancer (AGCa) or gastric lymphoma. However, in the case of type II AGCa, repeated biopsies negative for malignancy have not been reported. A 49-year-old male patient underwent esophagogastroduodenoscopy three times due to large gastric ulcer suspected to be Borrmann type II cancer. However, three repeat endoscopic biopsies with multiple specimens showed necrosis and superficial regenerative epithelium without malignant findings. The patient underwent laparoscopic distal gastrectomy with D2 lymph node dissection. The surgical specimen revealed that the mucosal layer was completely replaced with regenerative epithelium without cancer cells.
doi:10.3748/wjg.v20.i28.9621
PMCID: PMC4110598  PMID: 25071361
Endoscopy; Biopsy; Stomach neoplasm; Stomach ulcer; Regeneration
6.  Primary Benign Intraosseous Meningioma on 18F-FDG PET/CT Mimicking Malignancy 
We present a case of primary benign intraosseous meningioma in the sphenoid bone mimicking malignancy. A 44-year-old female patient who had a protruding right eye and headache came to our hospital. MRI showed a large, destructive, heterogeneously well-enhancing soft tissue mass in the right sphenoid bone suggesting malignancy. 18F-FDG PET/CT showed a hypermetabolic mass in the same site with an SUVmax of 9.1 The pathological diagnosis by surgery revealed that this tumor was a WHO grade I transitional meningioma. This case suggests that primary benign intraosseous meningioma may show high 18F-FDG uptake mimicking a malignancy.
doi:10.1007/s13139-013-0259-8
PMCID: PMC4028472  PMID: 24900156
Benign meningioma; Sphenoid bone; PET/CT; 18F-Fluorodeoxyglucose
7.  Primary renal aspergillosis and renal stones in both kidneys associated with hematopoietic stem cell transplant 
The Korean Journal of Hematology  2010;45(4):275-278.
Invasive aspergillosis (IA) is a leading cause of infectious mortality in patients who have undergone a hematopoietic stem cell transplant (HSCT); the mortality due to IA ranges from 70% to 93% in HSCT patients. Early diagnosis and treatment are the cornerstones for the good prognosis of IA. Primary renal aspergillosis is an extremely rare presentation in patients who have undergone HSCT, and the risk factor for this uncommon presentation is not well known. We report a patient who developed primary renal aspergillosis and renal stones in both the kidneys after HSCT. Invasive renal aspergillosis was diagnosed after a nephrectomy, which was performed to treat massive renal hematoma.
doi:10.5045/kjh.2010.45.4.275
PMCID: PMC3023055  PMID: 21253431
Primary renal aspergillosis; Hematopoietic stem cell transplant; Renal stones
8.  The Modified Glasgow Prognostic Scores as a Predictor in Diffuse Large B Cell Lymphoma Treated with R-CHOP Regimen 
Yonsei Medical Journal  2014;55(6):1568-1575.
Purpose
The modified Glasgow Prognostic Score (mGPS) consisting of serum C-reactive protein and albumin levels, shows significant prognostic value in several types of tumors. We evaluated the prognostic significance of mGPS in 285 patients with diffuse large B cell lymphoma (DLBCL), retrospectively.
Materials and Methods
According to mGPS classification, 204 patients (71.5%) had an mGPS of 0, 57 (20%) had an mGPS of 1, and 24 (8.5%) had an mGPS of 2.
Results
Our study found that high mGPS were associated with poor prognostic factors including older age, extranodal involvement, advanced disease stage, unfavorable International Prognostic Index scores, and the presence of B symptoms. The complete response (CR) rate after 3 cycles of R-CHOP chemotherapy was higher in patients with mGPS of 0 (53.8%) compared to those with mGPS of 1 (33.3%) or 2 (25.0%) (p=0.001). Patients with mGPS of 0 had significantly better overall survival (OS) than those with mGPS=1 and those with mGPS=2 (p=0.036). Multivariate analyses revealed that the GPS score was a prognostic factor for the CR rate of 3 cycle R-CHOP therapy (p=0.044) as well as OS (p=0.037).
Conclusion
mGPS can be considered a potential prognostic factor that may predict early responses to R-CHOP therapy in DLBCL patients.
doi:10.3349/ymj.2014.55.6.1568
PMCID: PMC4205696  PMID: 25323893
Modified Glasgow Prognostic Score; diffuse large B cell lymphoma; prognostic factor
9.  Tumorigenesis of Papillary Thyroid Cancer Is Not BRAF-Dependent in Patients with Acromegaly 
PLoS ONE  2014;9(10):e110241.
Introduction
Several studies have reported a high frequency of papillary thyroid cancer (PTC) in patients with acromegaly. The aim of this study was to determine the prevalence and predictors of thyroid cancer in patients with acromegaly and to investigate the frequency of the BRAFV600E mutation in PTC patients with and without acromegaly.
Materials and Methods
We conducted a retrospective study of 60 patients with acromegaly. Thyroid ultrasonography (US) and US-guided fine needle aspiration were performed on nodules with sonographic features of malignancy. We selected 16 patients with non-acromegalic PTC as a control group. The BRAFV600E mutation was analyzed in paraffin-embedded surgical specimens of PTC by real-time polymerase chain reaction, and tumor specimens from patients with PTC were stained immunohistochemically with an antibody against insulin-like growth factor-1 receptor β (IGF-1Rβ).
Results
Thyroid cancer was found in 15 (25.0%) patients. No differences in age, sex, initial growth hormone (GH) and IGF-1 percentage of the upper limit of normal values or treatment modalities were observed between patients with and without PTC. Acromegaly was active in 12 of 15 patients at the time of PTC diagnosis; uncontrolled acromegaly had a significantly higher frequency in the PTC group (60%) than in the non-PTC group (28.9%) (p = 0.030). The BRAFV600E mutation was present in only 9.1% (1/11) of PTC patients with acromegaly, although 62.5% (10/16) of control patients with PTC had the mutation (p = 0.007). IGF-1Rβ immunostaining showed moderate-to-strong staining in all malignant PTC cells in patients with and without acromegaly. Significantly less staining for IGF-1Rβ was observed in normal adjacent thyroid tissues of PTC patients with acromegaly compared with those without (p = 0.014).
Conclusion
The prevalence of PTC in acromegalic patients was high (25%). An uncontrolled hyperactive GH-IGF-1 axis may play a dominant role in the development of PTC rather than the BRAFV600E mutation in patients with acromegaly.
doi:10.1371/journal.pone.0110241
PMCID: PMC4201528  PMID: 25329702
10.  Transmission disequilibrium testing of the chromosome 15q11-q13 region in autism 
Evidence implicates the serotonin transporter gene (SLC6A4) and the 15q11-q13 genes as candidates for autism as well as restricted repetitive behavior (RRB).
We conducted dense transmission disequilibrium mapping of the 15q11-q13 region with 93 single nucleotide polymorphisms (SNPs) in 86 strictly defined autism trios and tested association between SNPs and autism using the transmission disequilibrium test (TDT). As exploratory analyses, parent-of-origin effects were examined using likelihood-ratio tests (LRT) and genotype-phenotype associations for specific RRB using the Family-Based Association Test (FBAT). Additionally, gene-gene interactions between nominally associated 15q11-q13 variants and 5-HTTLPR, the common length polymorphism of SLC6A4, were examined using conditional logistic regression (CLR).
TDT revealed nominally significant transmission disequilibrium between autism and five SNPs, three of which are located within close proximity of the GABAA receptor subunit gene clusters. Three SNPs in the SNRPN/UBE3A region had marginal imprinting effects. FBAT for genotype-phenotype relations revealed nominally significant association between two SNPs and one ADI-R sub-domain item. However, both TDT and FBAT were not statistically significant after correcting for multiple comparisons. Gene-gene interaction analyses by CLR revealed additive genetic effect models, without interaction terms, fit the data best.
Lack of robust association between the 15q11-q13 SNPs and RRB phenotypes may be due to a small sample size and absence of more specific RRB measurement. Further investigation of the 15q11-q13 region with denser genotyping in a larger sample set may be necessary to determine whether this region confers risk to autism, indicated by association, or to specific autism phenotypes.
doi:10.1002/ajmg.b.30733
PMCID: PMC4095800  PMID: 18361419
Autism; 15q11-q13; restricted repetitive behavior; 5-HTTLPR; association
11.  Primary Benign Intraosseous Meningioma on 18F-FDG PET/CT Mimicking Malignancy 
We present a case of primary benign intraosseous meningioma in the sphenoid bone mimicking malignancy. A 44-year-old female patient who had a protruding right eye and headache came to our hospital. MRI showed a large, destructive, heterogeneously well-enhancing soft tissue mass in the right sphenoid bone suggesting malignancy. 18F-FDG PET/CT showed a hypermetabolic mass in the same site with an SUVmax of 9.1 The pathological diagnosis by surgery revealed that this tumor was a WHO grade I transitional meningioma. This case suggests that primary benign intraosseous meningioma may show high 18F-FDG uptake mimicking a malignancy.
doi:10.1007/s13139-013-0259-8
PMCID: PMC4028472  PMID: 24900156
Benign meningioma; Sphenoid bone; PET/CT; 18F-Fluorodeoxyglucose
12.  Effects of Smoking Cessation on Gene Expression in Human Leukocytes of Chronic Smoker 
Psychiatry Investigation  2014;11(3):290-296.
Objective
The risks of cigarette smoking concerning higher systemic disease mortality are lessened by smoking cessation.
Methods
Microarray analysis compared the expression profiles of smokers who were successful and not successful at smoking cessation, with the goal of identifying genes that might serve as potential biomarkers or that might be valuable in elucidating distinct biological mechanisms. The mRNAs were isolated and compared from peripheral leukocytes of six smokers who were successful in cessation and six smokers who failed in smoking cessation.
Results
Two hundred ninety nine genes displayed significantly different expression; 196 genes were up-regulated and 103 genes were down-regulated in the success group compared to the failure group. Twenty four of these genes were identified with biological processes including immunity, cytoskeleton and cell growth/cycle. Real-time PCR confirmed the differential gene expression. The mRNA levels of HEPACAM family member 2 (HEPACAM2) and tropomodulin 1 (TMOD1) were significantly more expressed in the success group, while the mRNA ubiquitin specific peptides 18 (USP18) were significantly less expressed in the success group compared to the failure group.
Conclusion
The results suggest that smoking cessation can modulate cell adhesion and immune response by regulating expression levels of genes, especially HEPACAM2, TMOD1 and USP18, which have an important relationship with smoking cessation.
doi:10.4306/pi.2014.11.3.290
PMCID: PMC4124188  PMID: 25110502
Nicotine cessation; Microarray; Leucocytes; Real time PCR
13.  Diffuse Metastasis to the Thyroid: Unique Ultrasonographic Finding and Clinical Correlation 
Journal of Korean Medical Science  2014;29(6):818-824.
Cases of metastases to the thyroid gland seem to be increasing in recent years. The clinical and ultrasonographic findings of diffuse metastases have been sparsely reported. Thirteen cases of diffuse metastases to the thyroid gland were documented by thyroid ultrasonography-guided fine needle aspiration cytology between 2004 and 2013. We retrospectively reviewed the patients with diffuse thyroid metastases. The most common primary site was the lung (n=9), followed by unknown origin cancers (n=2), cholangiocarcinoma (n=1), and penile cancer (n=1). Eleven patients were incidentally found to have thyroid metastases via surveillance or staging FDG-PET. Other 2 patients were diagnosed during work-up for hypothyroidism and palpable cervical lymph nodes. On ultrasonography, the echogenicity of the enlarged thyroid gland was heterogeneously hypoechoic or isoechoic, and reticular pattern internal hypoechoic lines were observed without increased vascularity found by power Doppler ultrasonography (3 right lobe, 2 left lobe, and 8 both lobes). In the 8 patients who had involvement of both lobes, 3 had hypothyroidism. In conclusion, ultrasonographic finding of diffuse metastasis is a diffusely enlarged heterogeneous thyroid with reticular pattern internal hypoechoic lines. Thyroid function testing should be performed in all patients with diffuse thyroid metastases, especially those with bilateral lobe involvement.
Graphical Abstract
doi:10.3346/jkms.2014.29.6.818
PMCID: PMC4055816  PMID: 24932084
Thyroid; Diffuse; Metastasis; Ultrasonography; Fine Needle Aspiration Cytology
14.  Absence of CCL2 is sufficient to restore hippocampal neurogenesis following cranial irradiation 
Cranial irradiation for the treatment of brain tumors causes a delayed and progressive cognitive decline that is pronounced in young patients. Dysregulation of neural stem and progenitor cells is thought to contribute to these effects by altering early childhood brain development. Earlier work has shown that irradiation creates a chronic neuroinflammatory state that severely and selectively impairs postnatal and adult neurogenesis. Here we show that irradiation induces a transient non-classical cytokine response with selective upregulation of CCL2/monocyte chemoattractant protein–1(MCP-1). Absence of CCL2 signaling in the hours after irradiation is alone sufficient to attenuate chronic microglia activation and allow the recovery of neurogenesis in the weeks following irradiation. This identifies CCL2 signaling as a potential clinical target for moderating the long-term defects in neural stem cell function following cranial radiation in children.
doi:10.1016/j.bbi.2012.09.010
PMCID: PMC3556199  PMID: 23041279
CCL2/MCP1; radiation; neurogenesis; inflammation; hippocampus
15.  Exposure–Response Relationship Between Aircraft Noise and Sleep Quality: A Community-based Cross-sectional Study 
Objectives
Exposure to aircraft noise has been shown to have adverse health effects, causing annoyance and affecting the health-related quality of life, sleep, and mental states of those exposed to it. This study aimed to determine sleep quality in participants residing near an airfield and to evaluate the relationship between the levels of aircraft noise and sleep quality.
Methods
Neighboring regions of a military airfield were divided into three groups: a high exposure group, a low exposure group, and a control group. A total of 1082 participants (aged 30–79 years) completed a comprehensive self-administered questionnaire requesting information about demographics, medical history, lifestyle, and the Pittsburgh Sleep Quality Index.
Results
Of the 1082 participants, 1005 qualified for this study. The prevalence of sleep disturbance was 45.5% in the control group, 71.8% in the low exposure group, and 77.1% in the high exposure group (p for trend < 0.001). After adjusting for potential confounding factors, we determined the exposure–response relationship between the degree of aircraft noise and sleep quality. Of the participants with a normal mental status, the prevalence of sleep disturbance was 2.61-fold higher in the low exposure group and 3.52-fold higher in the high exposure group than in the control group.
Conclusion
The relationship between aircraft noise and health should be further evaluated through a large-scale follow-up study.
doi:10.1016/j.phrp.2014.03.004
PMCID: PMC4064632  PMID: 24955321
aircraft noise; anxiety; depression; sleep quality; stress
16.  Serum microRNA-21 as a Potential Biomarker for Response to Hypomethylating Agents in Myelodysplastic Syndromes 
PLoS ONE  2014;9(2):e86933.
Identification of biomarkers that predict responses to hypomethylating agents (HMAs) will allow optimal strategies for epigenetic therapy in myelodysplastic syndromes (MDS) to be established. Serum miR-21 was quantitatively measured in 58 MDS patients treated with HMAs and 14 healthy controls. Serum miR-192 was an internal control, and diagnostic performance was evaluated according to receiver operating characteristics (ROCs). ROC analysis indicated that serum miR-21 levels differentiated responders from non-responders with an area under the curve of 0.648 (95% confidence, 0.49 to 0.72). The baseline level of serum miR-21 was significantly lower in the responder group than in the non-responder group (P = 0.041). The overall response rate (ORR) of the high miR-21 group was significantly lower than that of the low miR-21 group (41.2 vs. 73.2%, P = 0.021). Progression-free survival (PFS) was significantly inferior in the high group versus the low group (14.0 vs. 44.5 months, P = 0.001). Multivariate analyses revealed that the initial serum miR-21 level (P = 0.001) and circulating blasts (P = 0.007) were prognostic factors for PFS. Serum miR-21 level was significantly associated with ORR and PFS in MDS patients treated with HMAs. Although validation with a large prospective study is required, serum miR-21 is a potential biomarker of epigenetic therapy in MDS patients.
doi:10.1371/journal.pone.0086933
PMCID: PMC3913572  PMID: 24503739
17.  Tempol Attenuates Renal Fibrosis in Mice with Unilateral Ureteral Obstruction: The Role of PI3K-Akt-FoxO3a Signaling 
Journal of Korean Medical Science  2014;29(2):230-237.
This study investigated whether tempol, an anti-oxidant, protects against renal injury by modulating phosphatidylinositol 3-kinase (PI3K)-Akt-Forkhead homeobox O (FoxO) signaling. Mice received unilateral ureteral obstruction (UUO) surgery with or without administration of tempol. We evaluated renal damage, oxidative stress and the expression of PI3K, Akt, FoxO3a and their target molecules including manganese superoxide dismutase (MnSOD), catalase, Bax, and Bcl-2 on day 3 and day 7 after UUO. Tubulointerstitial fibrosis, collagen deposition, α-smooth muscle actin-positive area, and F4/80-positive macrophage infiltration were significantly lower in tempol-treated mice compared with control mice. The expression of PI3K, phosphorylated Akt, and phosphorylated FoxO3a markedly decreased in tempol-treated mice compared with control mice. Tempol prominently increased the expressions of MnSOD and catalase, and decreased the production of hydrogen peroxide and lipid peroxidation in the obstructed kidneys. Significantly less apoptosis, a lower ratio of Bax to Bcl-2 expression and fewer apoptotic cells in TUNEL staining, and decreased expression of transforming growth factor-β1 were observed in the obstructed kidneys from tempol-treated mice compared with those from control mice. Tempol attenuates oxidative stress, inflammation, and fibrosis in the obstructed kidneys of UUO mice, and the modulation of PI3K-Akt-FoxO3a signaling may be involved in this pathogenesis.
Graphical Abstract
doi:10.3346/jkms.2014.29.2.230
PMCID: PMC3924002  PMID: 24550650
FoxO3a Protein, Mouse; Oxidative Stress; Apoptosis; Renal Fibrosis; Unilateral Ureteral Obstruction
18.  Community-Based Risk Communication Survey: Risk Prevention Behaviors in Communities during the H1N1 crisis, 2010 
Objectives
The present study aimed to investigate the prevalence of and factors associated with H1N1 preventive behaviors in a community-based population.
Methods
A cross-sectional study was conducted in three urban and two rural communities in Korea. Interviews were conducted with 3462 individuals (1608 men and 1854 women) aged ≥ 19 years during February–March 2010. Influenza-related information including anxiety, preventive behaviors and their perceived effectiveness, vaccination status, past influenza-like illness symptoms, and sources of and trust in information was obtained.
Results
Among 3462 participants, 173 reported experiencing influenza-like illness symptoms within the past 12 months. The mean H1N1 preventive behavior score was 25.5 ± 5.5 (out of a possible 40). The percent of participants reporting high perceived effectiveness and high anxiety was 46.2% and 21.4%, respectively. After controlling for potential confounders, H1N1 preventive behavior scores were predicted by a high (β = 3.577, p < 0.001) or moderate (β = 2.529, p < 0.001) perception of their effectiveness. Similarly, moderate (β = 1.516, p < 0.001) and high (β = 4.103, p < 0.001) anxiety scores predicted high preventive behavior scores.
Conclusion
Effective methods of promoting population behavior change may be nationwide campaigns through mass media, as well as education and promotion by health care providers and broadcasters.
doi:10.1016/j.phrp.2013.12.001
PMCID: PMC4064644  PMID: 24955307
anxiety; behavior; cross-sectional survey; H1N1 virus; self-efficacy
19.  Oleanolic acid attenuates renal fibrosis in mice with unilateral ureteral obstruction via facilitating nuclear translocation of Nrf2 
Background
Renal interstitial fibrosis is a common final pathological process in the progression of kidney disease. This is primarily due to oxidative stress, which contributes to renal inflammation and fibrosis. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is known to coordinate induction of genes that encode antioxidant enzymes. We investigated the effects of oleanolic acid, a known Nrf2 activator, on oxidative stress-induced renal inflammation and fibrosis.
Methods
One day before unilateral ureteral obstruction (UUO) performed in C57BL/6 mice, oleanolic acid treatment was initiated and was continued until 3 and 7 days after UUO. Renal inflammation and fibrosis, markers of oxidative stress, and changes in Nrf2 expression were subsequently evaluated.
Results
In the obstructed kidneys of UUO mice, oleanolic acid significantly attenuated UUO-induced collagen deposition and fibrosis on day 7. Additionally, significantly less inflammatory cell infiltration, a lower ratio of Bax to Bcl-2 expression, and fewer apoptotic cells on TUNEL staining were observed in the obstructed kidneys of oleanolic acid-treated mice. Oleanolic acid increased the expression of nuclear Nrf2, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and heat shock protein 70, and decreased lipid peroxidation in the obstructed kidney of UUO mice. There were no changes in the expression of total Nrf2 and Kelch-like ECH-associated protein 1, indicating that oleanolic acid enhanced nuclear translocation of Nrf2.
Conclusions
These results suggest that oleanolic acid may exert beneficial effects on renal fibrosis by increasing nuclear translocation of Nrf2 and subsequently reducing renal oxidative stress.
doi:10.1186/1743-7075-11-2
PMCID: PMC3896758  PMID: 24393202
20.  Success Rate and Risk Factors for Failure of Empirical Antifungal Therapy with Itraconazole in Patients with Hematological Malignancies: A Multicenter, Prospective, Open-Label, Observational Study in Korea 
We assessed the success rate of empirical antifungal therapy with itraconazole and evaluated risk factors for predicting the failure of empirical antifungal therapy. A multicenter, prospective, observational study was performed in patients with hematological malignancies who had neutropenic fever and received empirical antifungal therapy with itraconazole at 22 centers. A total of 391 patients who had abnormal findings on chest imaging tests (31.0%) or a positive result of enzyme immunoassay for serum galactomannan (17.6%) showed a 56.5% overall success rate. Positive galactomannan tests before the initiation of the empirical antifungal therapy (P=0.026, hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.10-4.69) and abnormal findings on the chest imaging tests before initiation of the empirical antifungal therapy (P=0.022, HR, 2.03; 95% CI, 1.11-3.71) were significantly associated with poor outcomes for the empirical antifungal therapy. Eight patients (2.0%) had premature discontinuation of itraconazole therapy due to toxicity. It is suggested that positive galactomannan tests and abnormal findings on the chest imaging tests at the time of initiation of the empirical antifungal therapy are risk factors for predicting the failure of the empirical antifungal therapy with itraconazole. (Clinical Trial Registration on National Cancer Institute website, NCT01060462)
doi:10.3346/jkms.2014.29.1.61
PMCID: PMC3890478  PMID: 24431907
Hematological Malignancy; Itraconazole; Empirical Antifungal Therapy; Galactomannan Test
21.  Electroacupuncture Analgesia Is Improved by Adenoviral Gene Transfer of Dopamine Beta-hydroxylase into the Hypothalamus of Rats 
Electroacupuncture (EA) is a modified form of acupuncture that utilizes electrical stimulation. We previously showed that EA stimulated rats were divided into responders that were sensitive to EA and non-responders that were insensitive to EA based on the tail flick latency (TFL) test. The dopamine beta-hydroxylase (DBH) gene was more abundantly expressed in the hypothalamus of responder rats than non-responder rats. To determine whether overexpression of DBH gene expression in the hypothalamus modulate EA analgesia, we constructed a DBH encoding adenovirus and which was then injected into the hypothalamus of SD rats. Microinjection of DBH or control GFP virus into the hypothalamus had no changes on the basal pain threshold measured by a TFL test without EA treatment. However, the analgesic effect of EA was significantly enhanced from seven days after microinjection of the DBH virus, but not after injection of the control GFP virus. DBH expression was significantly higher in the hypothalamus of DBH virus injected rat than control GFP virus or PBS injected rats. Moreover, expression of the DBH gene did not affect the body core temperature, body weight, motor function or learning and memory ability. Although the functional role of DBH in the hypothalamus in the analgesic effect of EA remains unclear, our findings suggest that expression of the DBH gene in the hypothalamus promotes EA analgesia without obvious side-effects.
doi:10.4196/kjpp.2013.17.6.505
PMCID: PMC3874437  PMID: 24381499
Adenovirus; Analgesia; Dopamine-beta-hydroxylase; Electroacupuncture; Hypothalamus
22.  Neuroprotective Effects of AMP-Activated Protein Kinase on Scopolamine Induced Memory Impairment 
AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, is activated in response to cellular stress when intracellular levels of AMP increase. We investigated the neuroprotective effects of AMPK against scopolamine-induced memory impairment in vivo and glutamate-induced cytotoxicity in vitro. An adenovirus expressing AMPK wild type alpha subunit (WT) or a dominant negative form (DN) was injected into the hippocampus of rats using a stereotaxic apparatus. The AMPK WT-injected rats showed significant reversal of the scopolamine induced cognitive deficit as evaluated by escape latency in the Morris water maze. In addition, they showed enhanced acetylcholinesterase (AChE)-reactive neurons in the hippocampus, implying increased cholinergic activity in response to AMPK. We also studied the cellular mechanism by which AMPK protects against glutamate-induced cell death in primary cultured rat hippocampal neurons. We further demonstrated that AMPK WT-infected cells increased cell viability and reduced Annexin V positive hippocampal neurons. Western blot analysis indicated that AMPK WT-infected cells reduced the expression of Bax and had no effects on Bcl-2, which resulted in a decreased Bax/Bcl-2 ratio. These data suggest that AMPK is a useful cognitive impairment treatment target, and that its beneficial effects are mediated via the protective capacity of hippocampal neurons.
doi:10.4196/kjpp.2013.17.4.331
PMCID: PMC3741490  PMID: 23946693
Adenovirus; AMPK; Apoptosis; Learning and memory; Scopolamine
23.  Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes 
Prader–Willi syndrome (PWS) is a multisystem, contiguous gene disorder caused by an absence of paternally expressed genes within the 15q11.2-q13 region via one of the three main genetic mechanisms: deletion of the paternally inherited 15q11.2-q13 region, maternal uniparental disomy and imprinting defect. The deletion class is typically subdivided into Type 1 and Type 2 based on their proximal breakpoints (BP1–BP3 and BP2–BP3, respectively). Despite PWS being a well-characterized genetic disorder the role of the specific genes contributing to various aspects of the phenotype are not well understood. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is a recently developed technique that detects copy number changes and aberrant DNA methylation. In this study, we initially applied MS-MLPA to elucidate the deletion subtypes of 88 subjects. In our cohort, 32 had a Type 1 and 49 had a Type 2 deletion. The remaining seven subjects had unique or atypical deletions that were either smaller (n=5) or larger (n=2) than typically described and were further characterized by array-based comparative genome hybridization. In two subjects both the PWS region (15q11.2) and the newly described 15q13.3 microdeletion syndrome region were deleted. The subjects with a unique or an atypical deletion revealed distinct phenotypic features. In conclusion, unique or atypical deletions were found in ∼8% of the deletion subjects with PWS in our cohort. These novel deletions provide further insight into the potential role of several of the genes within the 15q11.2 and the 15q13.3 regions.
doi:10.1038/ejhg.2011.187
PMCID: PMC3283188  PMID: 22045295
Prader–Willi syndrome; 15q11.2-q13; MS-MLPA; array CGH; genotype–phenotype; seizures
24.  Methylation-Specific Multiplex Ligation-Dependent Probe Amplification and Identification of Deletion Genetic Subtypes in Prader-Willi Syndrome 
Purpose: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are complex neurodevelopmental disorders caused by loss of expression of imprinted genes from the 15q11-q13 region depending on the parent of origin. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) kits from MRC-Holland (Amsterdam, The Netherlands) were used to detect PWS and AS deletion subtypes. We report our experience with two versions of the MS-MLPA-PWS/AS kit (original A1 and newer B1) in determining methylation status and deletion subtypes in individuals with PWS. Methods: MS-MLPA analysis was performed on DNA isolated from a large cohort of PWS subjects with the MS-MLPA-PWS/AS-A1 and -B1 probe sets. Results: Both MS-MLPA kits will identify deletions in the 15q11-q13 region but the original MS-MLPA-A1 kit has a higher density of probes at the telomeric end of the 15q11-q13 region, which is more useful for identifying individuals with atypical deletions. The newer B1 kit contains more probes in the imprinting center (IC) and adjoining small noncoding RNAs useful in identifying small microdeletions. Conclusion: The A1 kit identified the typical deletions and smaller atypical deletions, whereas the B1 kit was more informative for identifying microdeletions including the IC and SNORD116 regions. Both kits should be made available for accurate characterization of PWS/AS deletion subtypes as well as evaluating for IC and SNORD116 microdeletions.
doi:10.1089/gtmb.2011.0115
PMCID: PMC3306590  PMID: 21977908
25.  Karyotypic change between diagnosis and relapse as a predictor of salvage therapy outcome in AML patients 
Blood research  2013;48(1):24-30.
Background
Only a few patients who experience AML relapse derive lasting benefit from re-induction therapy. The utility of reassessing the disease karyotype at relapse is unclear. The main goals of this study were to identify prognostic factors for AML relapse and to determine the prognostic utility of karyotypic change between diagnosis and relapse as a variable for predicting response to salvage therapy for relapsed AML.
Methods
This retrospective study included 58 patients with relapsed AML treated at the Yonsei University College of Medicine between 2005 and 2010. Karyotypes at both diagnosis and relapse were available for 45 patients (77%). A change in karyotype at relapse was observed in 17 of 45 cases (37%), and no change was noted in 28 of 45 cases (62%).
Results
Karyotypic changes between diagnosis and relapse were associated with the response rate (RR) to salvage therapy (P=0.016). Overall survival (OS) and event-free survival (EFS) in the group with karyotypic changes between diagnosis and relapse were significantly different from those with no karyotypic changes (P=0.004 and P=0.010, respectively). We applied multiple multivariate Cox regression analyses to identify independent prognostic factors for overall response (OR), OS, and EFS. A change in karyotype between diagnosis and relapse was significantly associated with OS (P=0.023; RR=2.655) and EFS (P=0.033; RR=2.831).
Conclusion
Karyotypic changes between the diagnosis and relapse of AML could be used to predict outcomes and tailor clinical and biological therapeutic strategies for relapsed AML patients.
doi:10.5045/br.2013.48.1.24
PMCID: PMC3624999  PMID: 23589791
Karyotype; Prognosis; Salvage therapy; Acute myeloid leukemia

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