Publications by authors named "Sun A Kim"

101 Publications

Hierarchical structured Component Analysis for Microbiome Data Using Taxonomy Assignments.

IEEE/ACM Trans Comput Biol Bioinform 2020 Nov 19;PP. Epub 2020 Nov 19.

The advent of high-throughput sequencing technology has enabled us to study the associations between human microbiome and diseases. The DNA sequences of microbiome samples are clustered as operational taxonomic units (OTUs) according to their similarity. The OTU table is used to measure correlations between OTUs and disease status and find key microbes for prediction of the disease status. Various statistical methods have been proposed for such microbiome data analysis. However, none of these methods reflects the hierarchy of taxonomy information. Here, we propose a hierarchical structural component model for microbiome data (HisCoM-microb) using taxonomy information as well as OTU table data. The proposed HisCoM-microb consists of two layers: one for OTUs and the other for taxa at the higher taxonomy level. Then we calculate simultaneously coefficient estimates of OTUs and taxa of the two layers inserted in the hierarchical model. Through this analysis, we can infer the association between taxa or OTUs and disease status, considering the impact of taxonomic structure on disease status. Both simulation study and real microbiome data analysis show that HisCoM-microb can successfully reveal the relations between each taxon and disease status and identify the key OTUs of the disease at the same time.
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http://dx.doi.org/10.1109/TCBB.2020.3039326DOI Listing
November 2020

Relationship of breastfeeding duration with joint pain and knee osteoarthritis in middle-aged Korean women: a cross-sectional study using the Korea National Health and Nutrition Examination Survey.

BMC Womens Health 2020 09 24;20(1):213. Epub 2020 Sep 24.

Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, 3F JS tower, 538 Gangnam-daero, Gangnam-gu, Seoul, 06110, Republic of Korea.

Background: The effect of joint health on the quality of life of middle-aged and older women is becoming more widely recognized with the aging of the world's population. However, the association of long-term breastfeeding with joint pain and knee osteoarthritis has not been fully examined. The aim of this study was to determine the association of prior breastfeeding duration with current joint pain and knee osteoarthritis in middle-aged Korean women.

Methods: This cross-sectional study was conducted among 3454 women aged ≥50 years who underwent knee radiography and answered a questionnaire on breastfeeding and joint pain for the 5th Korea National Health and Nutrition Examination Survey (2010-2011). After adjusting for confounding sociodemographic, medical history, and obstetric and gynecologic variables, logistic regression analysis was conducted to analyze the prevalence of joint pain and knee osteoarthritis according to breastfeeding and its duration.

Results: Among the 3454 participants, 298 had not breastfed and 1042, 815, and 1299 had breastfed for 1-24, 25-48, and ≥ 49 months, respectively. Of all participants, 1731 had joint pain and 739 were diagnosed with knee osteoarthritis after radiography. Using the non-breastfeeding group as a reference, the odds ratio (OR) for joint pain among women who breastfed ≥1 month was 1.49 (95% confidence interval [CI] 1.01-2.21). As the breastfeeding duration increased, the OR of joint pain prevalence also increased (p for trend; p = 0.002). For knee osteoarthritis, the OR was 2.30 in the 25-48 months group (95% CI 1.09-4.86). The OR of knee osteoarthritis in the ≥49 months group was 2.17 (95% CI 1.01-4.64). Sensitivity analysis after selecting only participants aged ≥60 years showed that the prevalence of joint pain and knee osteoarthritis was more positively correlated with extended breastfeeding duration (joint pain, p for trend; p = 0.005) (knee osteoarthritis, p for trend; p = 0.012).

Conclusions: Long-term feeding for more than 25 months was associated with an increased prevalence of joint pain and degenerative arthritis in Korean women aged ≥50 years.
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http://dx.doi.org/10.1186/s12905-020-01078-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517693PMC
September 2020

Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer.

J Pathol 2020 04 3;250(4):397-408. Epub 2020 Feb 3.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Fusobacterium nucleatum (F. nucleatum), which has been associated with colorectal carcinogenesis, can impair anti-tumour immunity, and actively invade colon epithelial cells. Considering the critical role of autophagy in host defence against microorganisms, we hypothesised that autophagic activity of tumour cells might influence the amount of F. nucleatum in colorectal cancer tissue. Using 724 rectal and colon cancer cases within the Nurses' Health Study and the Health Professionals Follow-up Study, we evaluated autophagic activity of tumour cells by immunohistochemical analyses of BECN1 (beclin 1), MAP1LC3 (LC3), and SQSTM1 (p62) expression. We measured the amount of F. nucleatum DNA in tumour tissue by quantitative polymerase chain reaction (PCR). We conducted multivariable ordinal logistic regression analyses to examine the association of tumour BECN1, MAP1LC3, and SQSTM1 expression with the amount of F. nucleatum, adjusting for potential confounders, including microsatellite instability status; CpG island methylator phenotype; long-interspersed nucleotide element-1 methylation; and KRAS, BRAF, and PIK3CA mutations. Compared with BECN1-low cases, BECN1-intermediate and BECN1-high cases were associated with lower amounts of F. nucleatum with odds ratios (for a unit increase in three ordinal categories of the amount of F. nucleatum) of 0.54 (95% confidence interval, 0.29-0.99) and 0.31 (95% confidence interval, 0.16-0.60), respectively (P  < 0.001 across ordinal BECN1 categories). Tumour MAP1LC3 and SQSTM1 levels were not significantly associated with the amount of F. nucleatum (P  > 0.06). Tumour BECN1, MAP1LC3, and SQSTM1 levels were not significantly associated with patient survival (P  > 0.10). In conclusion, tumour BECN1 expression is inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting a possible role of autophagy in the elimination of invasive microorganisms. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282529PMC
April 2020

Highly differentiated follicular carcinoma of ovary: Use of imprint cytology at intraoperative consultation.

Diagn Cytopathol 2020 Apr 2;48(4):360-363. Epub 2019 Dec 2.

Department of pathology, Pennsylvania Hospital, University of Pennsylvania Health System, Philadelphia, Pennsylvania.

Highly differentiated follicular carcinoma of ovary (HDFCO) is a rare entity known to arise in struma ovarii. Clinical presentation and radiological features mimic other cystic ovarian neoplasm. Thus, intraoperative diagnosis of this entity can be challenging. We hereby report a HDFCO case of a 52-year-old woman, who presented with significant abdominal bloating for 3 months. Imaging showed a 11.7 cm left adnexal-mixed cystic and solid mass, adhering to the bowel with ascites. The mass was examined intraoperatively and showed multilocular cysts filled with straw or red brown-colored gelatinous fluid. Microscopically, the tumor consisted of small and large follicles with proteinous material and bland-looking cuboidal cells, suspicious for struma ovarii or granulosa cell tumor with extensive cystic changes, while imprint cytology slides showed watery colloid with cracking artifact favoring the former. However, the adherence to the bowel suggested HDFCO, and prompted surgical staging. The histology of the ovarian mass in the permanent section resembled goiterous thyroid tissue with invasion of endocervical stroma, uterine wall and colonic serosa, and presence of tumor nodules in omentum leading to the diagnosis of HDFCO. Due to striking resemblance of HDFCO to benign thyroid goiter, searching for invasive and metastatic foci is crucial for correct diagnosis. In addition, intraoperative imprint cytology revealing colloid with cracking artifact is helpful for differentiating struma ovarii and/or HDFCO from other ovarian lesions.
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http://dx.doi.org/10.1002/dc.24360DOI Listing
April 2020

The iron deficiency response in requires the phosphorylated transcription factor URI.

Proc Natl Acad Sci U S A 2019 12 27;116(50):24933-24942. Epub 2019 Nov 27.

Department of Biological Sciences, Dartmouth College, Hanover, NH 03755;

Iron is an essential nutrient for plants, but excess iron is toxic due to its catalytic role in the formation of hydroxyl radicals. Thus, iron uptake is highly regulated and induced only under iron deficiency. The mechanisms of iron uptake in roots are well characterized, but less is known about how plants perceive iron deficiency. We show that a basic helix-loop-helix (bHLH) transcription factor Upstream Regulator of IRT1 (URI) acts as an essential part of the iron deficiency signaling pathway in The mutant is defective in inducing Iron-Regulated Transporter1 (IRT1) and Ferric Reduction Oxidase2 (FRO2) and their transcriptional regulators FER-like iron deficiency-induced transcription factor (FIT) and bHLH38/39/100/101 in response to iron deficiency. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) reveals direct binding of URI to promoters of many iron-regulated genes, including but not While URI transcript and protein are expressed regardless of iron status, a phosphorylated form of URI only accumulates under iron deficiency. Phosphorylated URI is subject to proteasome-dependent degradation during iron resupply, and turnover of phosphorylated URI is dependent on the E3 ligase BTS. The subgroup IVc bHLH transcription factors, which have previously been shown to regulate bHLH38/39/100/101, coimmunoprecipitate with URI mainly under Fe-deficient conditions, suggesting that it is the phosphorylated form of URI that is capable of forming heterodimers in vivo. We propose that the phosphorylated form of URI accumulates under Fe deficiency, forms heterodimers with subgroup IVc proteins, and induces transcription of These transcription factors in turn heterodimerize with FIT and drive the transcription of and to increase Fe uptake.
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http://dx.doi.org/10.1073/pnas.1916892116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911256PMC
December 2019

Night-Shift Work Duration and Risk of Colorectal Cancer According to and Expression.

Cancer Epidemiol Biomarkers Prev 2020 01 30;29(1):133-140. Epub 2019 Oct 30.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Background: We hypothesized that the risk of colorectal cancer in night-shift workers might be different according to insulin receptor substrate status.

Methods: Among 77,470 eligible women having night work assessed in the Nurses' Health Study, we documented a total of 1,397 colorectal cancer cases, of which 304 or 308 had available data on and , respectively. We used duplication-method Cox proportional hazards regression analysis for competing risks to calculate HRs and 95% confidence intervals (CI) for each colorectal cancer subtype. We measured tumor or expression by immunohistochemistry (IHC).

Results: Compared with women who never worked night shifts, those working ≥15 years night shifts had a marginal trend of increased overall risk of colorectal cancer ( = 0.06; multivariable HR = 1.20; 95% CI, 0.99-1.45). Longer duration of night-shift work was associated with a higher risk of -positive tumors (multivariable HR = 2.69; 95% CI, 1.48-4.89; = 0.001, ≥15 years night shifts vs. never) but not with -negative tumors (multivariable HR = 0.90; 95% CI, 0.54-1.51; = 0.72; for = 0.008). Similarly, the corresponding multivariable HRs were 1.81 for -positive tumors (95% CI, 0.94-3.48; = 0.06) and 1.13 for -negative tumors (95% CI, 0.71-1.80; = 0.56; for = 0.02).

Conclusions: Our molecular pathologic epidemiology data suggest a potential role of in mediating carcinogenesis induced by night-shift work.

Impact: Although these findings need validation, rotating night shift might increase colorectal cancer risk in women with abnormal insulin receptor pathways.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954315PMC
January 2020

Physical Activity and Colorectal Cancer Prognosis According to Tumor-Infiltrating T Cells.

JNCI Cancer Spectr 2018 Oct 9;2(4):pky058. Epub 2019 Jan 9.

Department of Oncologic Pathology.

Background: Evidence suggests that high-level physical activity may potentially reduce cancer mortality through its immune enhancement effect. We therefore hypothesized that survival benefits associated with physical activity might be stronger in colorectal carcinomas with lower immune reaction at diagnosis.

Methods: Using molecular pathological epidemiology databases of 470 colon and rectal carcinoma cases in the Nurses' Health Study and the Health Professionals Follow-up Study, we assessed the prognostic association of postdiagnosis physical activity in strata of densities of CD3 cells, CD8 cells, CD45RO (PTPRC) cells, or FOXP3 cells in tumor tissue. Cox proportional hazards regression model was used to adjust for potential confounders, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, , , and mutations, and expression of CTNNB1 (beta-catenin), PTGS2 (cyclooxygenase-2), and .

Results: The association of postdiagnosis physical activity with colorectal cancer-specific mortality differed by CD3 cell density ( < .001). Multivariable-adjusted colorectal cancer-specific mortality hazard ratios for a quartile-unit increase in physical activity were 0.56 (95% confidence interval = 0.38 to 0.83) among cases with the lowest quartile of CD3 cell density compared with 1.14 (95% confidence interval = 0.79 to 1.65) in cases with the highest quartile. We observed no differential survival association of physical activity by densities of CD8 cells, CD45RO cells, or FOXP3 cells.

Conclusions: The association between postdiagnosis physical activity and colorectal cancer survival appeared stronger for carcinomas with lower T cell infiltrates, suggesting an interactive effect of exercise and immunity on colorectal cancer progression.
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http://dx.doi.org/10.1093/jncics/pky058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591576PMC
October 2018

Non-linear Relationship Between Body Mass Index and Lower Urinary Tract Symptoms in Korean Males.

J Prev Med Public Health 2019 May 29;52(3):147-153. Epub 2019 Mar 29.

Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Korea.

Objectives: The purpose of this study was to evaluate the association between body mass index (BMI) and severe lower urinary tract symptoms (LUTS) in Korean males.

Methods: This study was conducted on males aged ≥50 years who participated in the 2011 Korean Community Health Survey. LUTS severity was assessed using the Korean version of the International Prostate Symptom Score (IPSS) questionnaire, and was dichotomized as severe (IPSS >19) and non-severe (IPSS ≤19). BMI was divided into 6 categories: <18.5, 18.5-22.9, 23.0-24.9, 25.0-27.4, 27.5-29.9, and ≥30.0 kg/m2. To evaluate the relationship between BMI and LUTS, a survey-weighted multivariate Poisson regression analysis was performed to estimate prevalence rate ratios (PRRs). Age, smoking status, alcohol intake, physical activity, educational level, household income, and comorbidities were adjusted for in the multivariate model.

Results: A U-shaped relationship was detected between BMI and severe LUTS. Compared with a BMI of 23.0-24.9 kg/m2, the PRR for a BMI <18.5 kg/m2 was 1.65 (95% confidence interval [CI], 1.35 to 2.02), that for a BMI of 18.5-22.9 kg/m2 was 1.25 (95% CI, 1.09 to 1.44), that for a BMI of 25.0-27.4 kg/m2 was 1.20 (95% CI, 1.00 to 1.45), that for a BMI of 27.5-29.9 kg/m2 was 1.11 (95% CI, 0.83 to 1.47), and that for a BMI ≥30.0 kg/m2 was 1.85 (95% CI, 1.18 to 2.88).

Conclusions: This study showed that both high and low BMI were associated with severe LUTS.
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http://dx.doi.org/10.3961/jpmph.18.259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549014PMC
May 2019

Association of Falls and Fear of Falling with Mortality in Korean Adults: The Dong-gu Study.

Chonnam Med J 2019 May 23;55(2):104-108. Epub 2019 May 23.

Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea.

This study evaluated the association between falls and the fear of falling (FOF) with the risk of all-cause mortality in Korean adults. The study enrolled 4,386 subjects aged 50 years and over who participated in the Dong-gu Study. Falls in the past year were categorized as yes or no. Injurious falls were defined as falls that resulted in fractures, head injuries, sprains or strains, bruising or bleeding, or other unspecified injuries. FOF was classified as low or high. The associations of falls and fall-related characteristics with mortality were assessed using Cox proportional hazards models. The average follow-up was 7.8 years. During this period, 255 men and 146 women died. In a fully adjusted model, falls in the past year were not associated with an increased risk of all-cause mortality (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.85-1.58), but a history of injurious falls was associated with an increased risk of mortality (HR 1.36, 95% CI 1.04-1.79). Compared with subjects without a FOF, subjects who were moderately or very afraid of falling had a higher mortality rate (HR 1.26, 95% CI 0.97-1.63). In conclusion, injurious falls and a high FOF increased the risk of all-cause mortality in Koreans. This study suggests that injurious falls and FOF can predict mortality in the general population.
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http://dx.doi.org/10.4068/cmj.2019.55.2.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536433PMC
May 2019

25-Hydroxyvitamin D Is Associated with Kidney Function: The Dong-gu Study.

J Nutr Sci Vitaminol (Tokyo) 2018 ;64(6):385-390

Department of Preventive Medicine, Chonnam National University Medical School.

Although the kidneys play a leading part in the biosynthesis of vitamin D, there is no consensus regarding the relationship of the vitamin D concentration with kidney function. Thus, we aimed to estimate the correlation among 25-hydroxyvitamin D (25(OH)D), estimated glomerular filtration rate (eGFR), and albumin/creatinine ratio (ACR) in participants aged ≥50 y in Korea. This study consisted of 9,166 people who participated in a basic survey of the Dong-gu Study. Following an overnight fast, the blood and urine sample were assessed. The serum 25(OH)D, eGFR, ACR of each subject were measured. When adjusting for covariates and log-transformed ACR (Model III), the lower eGFR value was significantly associated with increasing 25(OH)D levels (<10.0: 71.5[70.5-72.4]; 10.0-14.9: 70.0 [69.5-70.4]; 15.0-19.9: 68.7 [68.3-69.2]; ≥20.0: 67.4 [66.8-67.9] mL/min/1.73 m, p<0.001). When adjusted for the same covariates and log-transformed eGFR (Model III), the lower ACR value was significantly associated with increasing 25(OH)D levels (<10.0: 57.4 [48.0-66.9]; 10.0-14.9: 40.8 [36.5-45.2]; 15.0-19.9: 34.0 [29.5-38.5]; ≥20.0: 34.3 [28.8-39.8] μg/mg creatinine, p<0.001). In conclusion, the mean values of eGFR were significantly decreased with increasing 25(OH)D levels independent of ACR. In additon, the mean values of ACR were significantly decreased with increasing 25(OH)D levels independent of eGFR in participants aged ≥50 y in Korea.
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http://dx.doi.org/10.3177/jnsv.64.385DOI Listing
April 2019

Serum level vitamin D and parathyroid hormone, and mortality, with or without chronic kidney disease.

J Bone Miner Metab 2019 Sep 7;37(5):825-834. Epub 2018 Dec 7.

Department of Preventive Medicine, Chonnam National University Medical School, 264, Seoyang-ro Hwasun-eup, Hwasun, 58128, Jeollanam-do, Korea.

Levels of vitamin D and parathyroid hormone (PTH) are closely associated with renal function. We evaluated the associations among 25-hydroxyvitamin D (25OHD) levels, PTH levels, and mortality, and whether these associations varied by renal function. We used data from the Dong-gu Study, a population-based cohort in Korean adults. We analyzed the associations among intact PTH, 25OHD levels and mortality in 8580 participants. Hazard ratios (HRs) for mortality were calculated using Cox proportional hazards regression after adjusting for age, sex, month of sampling, lifestyle, and comorbidities. We also evaluated the effects of chronic kidney disease (CKD). A total of 860 deaths occurred during the follow-up period of 7.6 years. Compared to the first 25OHD quartile, the HRs of the second, third, and fourth quartiles were 0.96 [95% confidence interval (CI) 0.79-1.16], 0.84 (95% CI 0.68-1.02), and 0.71 (95% CI 0.57-0.89), respectively. The association between intact PTH levels and mortality varied by renal function, and was both nonlinear and significant only in subjects with CKD. Compared to the second intact PTH quartile in such subjects, the HRs for the first, third, and fourth quartiles were 1.61 (95% CI 0.92-2.81), 1.97 (95% CI 1.17-3.31), and 2.19 (95% CI 1.33-3.59), respectively. In conclusion, we demonstrated that low serum levels of 25OHD are associated with an increased risk of mortality. Serum levels of intact PTH are nonlinearly associated with mortality only in subjects with CKD, with the lowest risk for mortality being evident in the second quartile.
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http://dx.doi.org/10.1007/s00774-018-0979-zDOI Listing
September 2019

Characterization of the hepatosplenic and portal venous findings in patients with Proteus syndrome.

Am J Med Genet A 2018 12 22;176(12):2677-2684. Epub 2018 Oct 22.

Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

Proteus syndrome (PS) is a rare disorder caused by a mosaic AKT1 variant that comprises patchy overgrowth of tissues derived from all three germinal layers affecting multiple viscera. We sought to delineate the extent of hepatoportal manifestations in patients with PS. We identified patients with PS who had abdominal imaging from 1989 to 2015 in a natural history study. Imaging was characterized for evidence of focal findings in the liver, spleen, and portal vasculature and for organomegaly. Relevant clinical and laboratory data were compared among those with or without organomegaly. Abdominal imaging was available on 38 patients including 20 who had serial studies. Nine patients had focal hepatic lesions including vascular malformations (VMs). Focal splenic abnormalities were noted in seven patients. Patients without cutaneous VMs did not have visceral VMs. Nine patients had splenomegaly, 12 had portal vein dilation, and 4 had hepatomegaly. There was a weak correlation of portal vein dilation to spleen height ratio (r = 0.18, p < .05). On laboratory evaluation, hepatic function was normal but there was thrombocytopenia in those with splenomegaly; platelet counts were 179 ± 87K/μL compared to those with normal spleen size at 253 ± 57K/μL (p < .05). Overall, focal hepatosplenic abnormalities occurred in 11 of 38 (29%) patients with PS. Splenomegaly and portal venous dilation were both found in 8 of 38 (21%) patients; however, other than relative thrombocytopenia, there was no evidence of portal hypertension. Although the AKT1-E17K somatic variant is a suspected oncogene, there were no malignant lesions identified in this study.
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http://dx.doi.org/10.1002/ajmg.a.40636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020299PMC
December 2018

Association between Smoking and Unintentional Injuries among Korean Adults.

Chonnam Med J 2018 Sep 27;54(3):184-189. Epub 2018 Sep 27.

Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Korea.

Using a cross-sectional representative national survey, we evaluated the relationship between cigarette smoking and unintentional injuries among Korean adults. We used data from the 2009 Korean Community Health Survey. Smoking status was defined as never smokers, ex-smokers, and current smokers. Current smokers were categorized into light daily smokers (1-10 cigarettes/day), moderate daily smokers (11-20 cigarettes/day), or heavy daily smokers (≥21 cigarettes/day). We used the Poisson regression model with a robust variance estimation to estimate prevalence rate ratios (PRR) and corresponding 95% confidence interval (95% CI). After adjusting for demographic characteristics, socioeconomic variables, lifestyle variables, and health status variables, former smokers (PRR, 1.19, 95% CI 1.11-1.28), light daily smokers (PRR 1.22, 95% CI 1.13-1.32), moderate daily smokers (PRR 1.33, 95% CI 1.24-1.42), and heavy daily smokers (PRR 1.40, 95% CI 1.25-1.57) had an increased risk for unintentional injuries compared with non-smokers. In conclusion, cigarette smoking is associated with unintentional injuries in a dose-response manner in Korean adults. The findings suggest that community smoking cessation programs may reduce morbidity and mortality from unintentional injuries.
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http://dx.doi.org/10.4068/cmj.2018.54.3.184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165918PMC
September 2018

Association of Coffee and Tea with Ferritin: Data from the Korean National Health and Nutrition Examination Survey (IV and V).

Chonnam Med J 2018 Sep 27;54(3):178-183. Epub 2018 Sep 27.

Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Korea.

There have been few studies that have evaluated the association between coffee intake and iron in Korean population. Data from the Korean National Health and Nutrition Examination Survey (IV and V; 2007-2012) was used to investigate the association between coffee and green tea intake and serum ferritin levels in Korean adults. Beverage intake was assessed using a food frequency questionnaire. Multivariate linear regression was performed to evaluate the relationship between coffee and tea intake and serum ferritin levels, after adjusting for age, body mass index, education level, smoking status, alcohol consumption, physical activity, hypertension, diabetes mellitus, and daily iron intake. Coffee intake was negatively related to serum ferritin levels in both sexes. The multivariate-adjusted geometric mean of serum ferritin level was 100.7 ng/mL (95% confidence interval [CI]: 98.2-103.4) in men drinking <1 coffee/day, and 92.2 ng/mL (95% CI: 89.7-94.8) in those drinking ≥3 coffees/day. In women, the equivalent serum ferritin levels were 35.6 ng/mL (95% CI: 34.8-36.4) and 28.9 ng/mL (95% CI: 27.8-30.1). However, green tea intake was not related to serum ferritin levels. In conclusion, coffee consumption was associated with lower serum ferritin levels in Korean adults.
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http://dx.doi.org/10.4068/cmj.2018.54.3.178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165914PMC
September 2018

Increased number of arginase 1-positive cells in the stroma of carcinomas compared to precursor lesions and nonneoplastic tissues.

Pathol Res Pract 2018 Aug 28;214(8):1179-1184. Epub 2018 Jun 28.

Department of Pathology, Dongguk University College of Medicine, Gyeongju, Republic of Korea.

Arginase 1 (Arg1) is involved in dampening the response of antitumor T lymphocytes. Arg1 expression has been reported in a variety of cancer cell lines and tumor-associated myeloid-derived cells. However, its examination in situ in tumor microenvironment is poorly investigated. We examined the Arg1-positive cells in tumor microenvironment of gastric carcinomas (GCs), colorectal carcinomas (CRCs) and prostate carcinomas (PCs), and analyzed their clinicopathological significance. Immunohistochemical staining for Arg1 was done in 60 GCs, 38 gastric adenomas, 40 CRCs, 10 colonic adenomas, 36 PCs, and 15 benign prostatic hyperplasia (BPH). Arg1 expression was predominantly localized in tumor microenvironment and the stroma of nonneoplastic tissues. Cells with Arg1 expression were mostly leukocytes, morphologically resembling polymorphonuclear neutrophils, and showed CD15 expression. Arg1 expression was focally expressed in cancer cells of 6 PCs, but not in those of GCs and CRCs. Arg1-positive cells were significantly more infiltrated in tumors than adenomas and nonneoplastic tissues, such as BPH, intestinal metaplasia and adjacent tissues. There were no significant findings between them and clinicopathological parameters, except for the relationship to gender and tumor differentiation in CRCs. These findings suggest that Arg1-positive cells in tumor microenvironment is involved in the occurrence of GCs, CRCs, and PCs. More expansive studies are necessary to better elucidate their clinicopathological significance in carcinomas.
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http://dx.doi.org/10.1016/j.prp.2018.06.016DOI Listing
August 2018

Parathyroid Hormone Levels Are Independently Associated with eGFR and Albuminuria: The Dong-gu Study.

J Nutr Sci Vitaminol (Tokyo) 2018 ;64(1):18-25

Department of Preventive Medicine, Chonnam National University Medical School.

Increased parathyroid hormone (PTH) was associated with cardiovascular mortality and morbidity in CKD patients. Our aim was to investigate the associations among estimated glomerular filtration rate (eGFR), albumin/creatinine ratio (ACR) and PTH independent of 25-hydroxyvitamin D (25(OH)D). This study included 9,162 individuals who completed the baseline survey of the Dong-gu Study, which was conducted in Korea from 2007 to 2010. The eGFR, ACR, PTH and 25(OH)D were measured in participants who met the detailed inclusion criteria. After being adjusting for covariates (sex, age, waist circumference, smoking, alcohol intake, physical activity, hypertension medications, diabetes medication, total cholesterol, triglyceride, HDL cholesterol) and log-ACR, the PTH value stratified by 25(OH)D level significantly decreased with increasing eGFR levels in each 25(OH)D stratum. Moreover, after adjustment for the same covariates and log-eGFR, the PTH value stratified by 25(OH)D level significantly increased with increasing ACR levels in each 25(OH)D stratum. In conclusion, the PTH values significantly decreased with increasing eGFR levels and increased with increasing ACR levels independently of 25(OH)D in an adult Korean population ≥50 y of age.
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http://dx.doi.org/10.3177/jnsv.64.18DOI Listing
October 2018

Combined use of CEMIP and CA 19-9 enhances diagnostic accuracy for pancreatic cancer.

Sci Rep 2018 02 21;8(1):3383. Epub 2018 Feb 21.

Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Carbohydrate antigen (CA) 19-9 is the only diagnostic marker used in pancreatic cancer despite its limitations. Here, we aimed to identify the diagnostic role of CEMIP (also called KIAA1199) combined with CA 19-9 in patients with pancreatic cancer. A retrospective analysis of prospectively collected patient samples was performed to determine the benefit of diagnostic markers in the diagnosis of pancreatic cancer. We investigated CEMIP and CA 19-9 levels in 324 patients with pancreatic cancer and 49 normal controls using serum enzyme-linked immunosorbent assay. Median CA 19-9 and CEMIP levels were 410.5 U/ml (40.8-3342.5) and 0.67 ng/ml (0.40-1.08), respectively, in patients with pancreatic cancer. The AUROC for CA 19-9 and CEMIP were 0.847 (95% confidence interval [CI]: 0.806-0.888) and 0.760 (95% CI: 0.689-0.831), respectively. Combination of CA 19-9 with CEMIP showed markedly improved AUROC over CA 19-9 alone in pancreatic cancer diagnosis (0.94 vs. 0.89; P < 0.0001). CEMIP showed a diagnostic yield of 86.1% (68/79) in CA 19-9 negative pancreatic cancer. Combined use with CEMIP showed significantly improved diagnostic value compared with CA 19-9 alone in pancreatic cancer. Especially, CEMIP may be a complementary marker in pancreatic cancer patients with normal CA 19-9 levels.
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http://dx.doi.org/10.1038/s41598-018-21823-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821821PMC
February 2018

Thymic epithelial tumors and metastasis to the brain: a case series and systematic review.

Transl Lung Cancer Res 2017 Oct;6(5):588-599

Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Thymic epithelial tumors (TETs) rarely metastasize to the brain. Clinico-pathologic features of TET patients with brain metastasis are not well described.

Methods: TET patients referred for consultation or screening for clinical trials are included. Imaging to evaluate for brain metastases was performed when clinically indicated or if required for screening. Tumor tissue from brain metastases was obtained for analysis, when available. Clinical characteristics and survival was evaluated and a systematic review of the literature on brain metastases associated with TETs was performed.

Results: Fourteen TET patients with brain metastasis were identified. Median age at TET diagnosis was 53 years (range: 31-71 years). Twelve patients had thymic carcinoma and two patients had World Health Organization B3 thymoma. Median time from TET diagnosis to discovery of brain metastases was 2.5 years (range: 9 months-8.3 years). Eleven patients had extracranial, extrathoracic metastases during presentation with brain metastases. Three patients underwent surgery and radiation therapy, eight patients received radiation therapy alone, and one patient had surgery alone. One patient with thymoma died 11 months after diagnosis of brain metastases and another patient died but with unknown date of diagnosis of brain metastases. Among 12 patients with thymic carcinoma, 11 of whom had a known date of brain metastases diagnosis, the median potential follow-up is 35.8 months, and median overall survival (OS) from diagnosis of brain metastases is 13.1 months.

Conclusions: Although uncommon, patients with advanced thymic carcinoma can develop brain metastases. Appropriate imaging and aggressive treatment should be considered for these patients.
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http://dx.doi.org/10.21037/tlcr.2017.08.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653528PMC
October 2017

Suppression of pancreatic adenocarcinoma upregulated factor (PAUF) increases the sensitivity of pancreatic cancer to gemcitabine and 5FU, and inhibits the formation of pancreatic cancer stem like cells.

Oncotarget 2017 Sep 22;8(44):76398-76407. Epub 2017 Jul 22.

Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

Pancreatic cancer stem cells (CSCs) play a crucial role in tumorigenesis and chemoresistance of pancreatic ductal adenocarcinoma. Pancreatic adenocarcinoma up-regulated factor (PAUF), a novel secretory protein, has been shown to contribute to cancer progression and metastasis. Because the clinical relationship between PAUF and pancreatic CSCs is largely unknown, we investigated the associations between the functional role of PAUF and pancreatic CSCs. Pancreatic cancer sphere cultured from the CFPAC-1 cells showed elevated expression of PAUF and pluripotent stemness genes (Oct4, Nanog, Stat3, and Sox2), and the mRNA of PAUF were increased in CD44CD24ESA pancreatic CSCs. PAUF knockdown (shPAUF) CFPAC-1 diminished the number of spheres and decreased stemness genes and CSC surface markers (CD133, c-MET and ALDH1). In addition, siPAUF CFPAC-1 decreased the mRNA expression of multidrug resistant protein 5 (MRP5) and ribonucleotide reductase M2 (RRM2) and were more vulnerable to gemcitabine and 5-FU than negative control (p<0.05). In conclusion, PAUF was increased in pancreatic CSCs and the suppression of PAUF enhances chemotherapeutic response to gemcitabine and 5FU by decreasing MRP5 and RRM2 in pancreatic cancer cells.
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http://dx.doi.org/10.18632/oncotarget.19458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652714PMC
September 2017

A Gender-Specific Association between Self-Reported Snoring and Hemoglobin A1c Levels in a General Population without Type 2 Diabetes Mellitus.

Yonsei Med J 2017 Nov;58(6):1152-1159

Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Korea.

Purpose: We explored whether a gender difference was evident in terms of the associations of snoring with hemoglobin A1c (HbA1c) and homeostatic model assessment-insulin resistance (HOMA-IR) levels in a healthy population without type 2 diabetes mellitus (DM).

Materials And Methods: We analyzed 2706 males and 4080 females who participated in the baseline survey of the Namwon Study. In terms of self-reported snoring frequency, participants were classified as non-snorers or occasional (1-3 days/week), frequent (4-6 days/week), or constant (7 days/week) snorers. Participants with DM, defined as a fasting blood glucose level ≥126 mg/dL and/or use of insulin or hypoglycemic medication, were excluded from the analysis.

Results: In females, the fully adjusted mean (95% confidence interval) HbA1c levels in non-snorers and in occasional, frequent, and constant snorers were 5.53% (5.47-5.59%), 5.53% (5.47-5.59%), 5.57% (5.49-5.64%), and 5.57% (5.51-5.64%), respectively, reflecting a dose-response relationship (p trend=0.004). Compared with female non-snorers, the risk of an elevated HbA1c level (top quintile, ≥5.9%) in constant snorers remained significant (odds ratio 1.30, 95% confidence interval 1.02-1.66) after full adjustment. In addition, in females, a significant linear trend in HbA1c level odds ratio by increased snoring frequency was apparent (p trend=0.019 in model 3). In contrast, no significant association between snoring frequency and HbA1c level was identified in males. No significant association between snoring frequency and HOMA-IR was detected in either gender.

Conclusion: We discovered a gender-specific association between snoring and HbA1c level in a healthy, community-dwelling population free of DM.
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http://dx.doi.org/10.3349/ymj.2017.58.6.1152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653480PMC
November 2017

Glycated Hemoglobin and All-Cause Mortality in Korean Type 2 Diabetes.

Chonnam Med J 2017 Sep 25;53(3):223-228. Epub 2017 Sep 25.

Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea.

The purpose of this study was to evaluate the association between glycated hemoglobin (HbA1c) and all-cause mortality in type 2 diabetes mellitus. We conducted a community-based prospective cohort study of 352 type 2 diabetic patients aged 30-92 who participated in a community diabetes complications screening program in Gokseng-gun, Jeollanamdo, Korea. HbA1c levels were categorized as <6.5%, 6.5-6.9%, 7.0-7.9%, 8.0-8.9% and ≥9.0%. Patients were followed up on for a mean of 6.9 years. The Cox proportional hazards model was used to evaluate the relationship between HbA1c levels and all-cause mortality. During the mean follow-up period of 6.9 years, 77 patients (21.9%) died. A J-shaped association was found between HbA1c and all-cause mortality, with the lowest mortality at 6.5-6.9% of HbA1c levels. Compared to patients with HbA1c of 6.5-6.9%, patients with <6.5%, 7.0-7.9%, 8.0-8.9% and ≥9.0% had an adjusted hazard ratio (95% confidence interval) for all-cause mortality of 1.71 (0.76-3.84), 1.23 (0.53-2.82), 1.32(0.51-3.44) and 2.66 (1.01-7.02), respectively. We found a J-shaped association between glycated hemoglobin and all-cause mortality in Korean type 2 diabetic patients.
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http://dx.doi.org/10.4068/cmj.2017.53.3.223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636762PMC
September 2017

Tumor SQSTM1 (p62) expression and T cells in colorectal cancer.

Oncoimmunology 2017;6(3):e1284720. Epub 2017 Jan 31.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Evidence suggests that activation of autophagy in neoplastic cells potentiates antitumor immunity through cross-presentation of tumor-associated antigens to T cells and release of immune mediators. The SQSTM1 (sequestosome 1, p62) protein is degraded by activated autophagy, and might enhance immune response to tumor cells. We hypothesized that tumor SQSTM1 expression level might be inversely associated with T-cell densities in colorectal carcinoma tissue. We evaluated tumor SQSTM1 expression by immunohistochemistry in 601 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study. Ordinal logistic regression analyses were conducted to assess the association of tumor SQSTM1 expression with CD3, CD8, CD45RO (PTPRC), or FOXP3 cell density in tumor tissue, controlling for potential confounders, including tumor status of microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation level, and , and mutations. Tumor SQSTM1 expression level was inversely associated with FOXP3 cell density ( = 0.006), but not with CD3, CD8, or CD45RO cell density (with the adjusted α level of 0.01 for multiple hypothesis testing). For a unit increase in quartile categories of FOXP3 cell density, multivariable odds ratios were 0.66 [95% confidence interval (CI), 0.45-0.98] for intermediate-level SQSTM1 expression, and 0.55 (95% CI, 0.36-0.83) for high-level SQSTM1 expression, compared with low-level SQSTM1 expression. Tumor SQSTM1 expression is inversely associated with FOXP3 cell density in colorectal cancer tissue, suggesting a possible role of SQSTM1-expressing carcinoma cells on regulatory T cells in the tumor microenvironment.
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http://dx.doi.org/10.1080/2162402X.2017.1284720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384412PMC
January 2017

Association between Serum 25-hydroxyvitamin D Levels and Type 2 Diabetes in Korean Adults.

Chonnam Med J 2017 Jan 25;53(1):73-77. Epub 2017 Jan 25.

Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea.

Previous studies have suggested that a vitamin D deficiency increases the risk of type 2 diabetes. This study evaluated the association between serum vitamin D levels and type 2 diabetes in Korean adults. This study included 9,014 subjects (3,600 males and 5,414 females) aged ≥50 years who participated in the Dong-gu Study. The subjects were divided into groups in whom the serum vitamin D level was severely deficient (<10 ng/mL), deficient (10 to <20 ng/mL), insufficient (20 to <30 ng/mL) and sufficient (≥30 ng/mL). Type 2 diabetes was defined by a fasting blood glucose level of ≥126 mg/dL and/or an HbA1c proportion of ≥6.5% and/or self-reported current use of diabetes medication. Multiple logistic regression was performed to evaluate the association between vitamin D status and type 2 diabetes. The age- and sex-adjusted prevalence of type 2 diabetes was 22.6%, 22.5% and 18.4% and 12.7% for severely deficient, deficient, insufficient, and sufficient, respectively. Multivariate modeling revealed that subjects with insufficient or sufficient vitamin D levels were at a lower risk of type 2 diabetes than were subjects with deficient vitamin D levels [odds ratio (OR), 0.82; 95% confidence interval (CI), 0.71-0.94 and OR, 0.51; 95% CI, 0.35-0.74, respectively]. Higher serum vitamin D levels were associated with a reduced risk of diabetes in Korean adults, suggesting that vitamin D may play a role in the pathogenesis of diabetes.
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http://dx.doi.org/10.4068/cmj.2017.53.1.73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299133PMC
January 2017

A novel HDAC inhibitor, CG200745, inhibits pancreatic cancer cell growth and overcomes gemcitabine resistance.

Sci Rep 2017 01 30;7:41615. Epub 2017 Jan 30.

Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Pancreatic cancer is predominantly lethal, and is primarily treated using gemcitabine, with increasing resistance. Therefore, novel agents that increase tumor sensitivity to gemcitabine are needed. Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents, since HDAC plays an important role in cancer initiation and progression. We evaluated the antitumor effect of a novel HDAC inhibitor, CG200745, combined with gemcitabine/erlotinib on pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells. Three pancreatic cancer-cell lines were used to evaluate the antitumor effect of CG200745 combined with gemcitabine/erlotinib. CG200745 induced the expression of apoptotic proteins (PARP and caspase-3) and increased the levels of acetylated histone H3. CG200745 with gemcitabine/erlotinib showed significant growth inhibition and synergistic antitumor effects in vitro. In vivo, gemcitabine/erlotinib and CG200745 reduced tumor size up to 50%. CG200745 enhanced the sensitivity of gemcitabine-resistant pancreatic cancer cells to gemcitabine, and decreased the level of ATP-binding cassette-transporter genes, especially multidrug resistance protein 3 (MRP3) and MRP4. The novel HDAC inhibitor, CG200745, with gemcitabine/erlotinib had a synergistic anti-tumor effect on pancreatic cancer cells. CG200745 significantly improved pancreatic cancer sensitivity to gemcitabine, with a prominent antitumor effect on gemcitabine-resistant pancreatic cancer cells. Therefore, improved clinical outcome is expected in the future.
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http://dx.doi.org/10.1038/srep41615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278546PMC
January 2017

Sorafenib inhibits 5-fluorouracil-resistant gastric cancer cell growth.

Scand J Gastroenterol 2017 May 22;52(5):577-584. Epub 2017 Jan 22.

a Division of Gastroenterology, Department of Internal Medicine and Yonsei Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Republic of Korea.

Background: Sorafenib is a multi-kinase inhibitor used in the treatment of various cancers. This study investigated the inhibitory effect of sorafenib on xenograft models of gastric cancer cells and 5-fluorouracil (5-FU)-resistant cells.

Methods: The half-maximal inhibitory concentration (IC) of sorafenib in NCI-N87 cells was determined. Xenograft models were established using BALB/c nude mice and were divided into four groups treated with vehicle, sorafenib (20 mg kg day), 5-FU (50 mg kg week), or a combination of sorafenib (20 mg kg day) plus 5-FU (50 mg kg week). 5-FU-resistant NCI-N87 cells were established by repeated exposure to 5-FU.

Results: Sorafenib inhibited NCI-N87 cell growth in a concentration-dependent manner with a mean IC of 16.345 ± 5.391 μM. Phosphorylation levels of mitogen-activated protein kinase kinase and extracellular signal-regulated kinase in these cells decreased in a dose-dependent manner after exposure to sorafenib. Sorafenib induced the activation of caspase-3, and its combination with 5-FU more effectively inhibited the growth of xenograft tumors than either sorafenib or 5-FU alone (p < 0.05). Sorafenib markedly inhibited 5-FU-resistant NCI-N87 cell growth as well as sphere formation in both parental and 5-FU-resistant NCI-N87 cells.

Conclusions: The sorafenib and 5-FU combination exhibited enhanced antitumor effects in a gastric cancer xenograft model and inhibited 5-FU-resistant cell proliferation and sphere formation. These findings suggest that sorafenib is useful in overcoming gastric cancer resistance to conventional chemotherapy.
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http://dx.doi.org/10.1080/00365521.2017.1278786DOI Listing
May 2017

Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors.

Pancreas 2016 11;45(10):1386-1393

From the *Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; †Department of Geriatric Gastroenterology, Chinese PLA General Hospital, Beijing, China; ‡Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA; §Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China; ∥IPSEN Bioscience Inc, Global Drug Discovery Department, Cambridge, MA; ¶IPSEN Innovation, Global Drug Discovery Department, Les Ulis, France; Departments of #Biostatistics, and **Epidemiology, Harvard T.H. Chan School of Public Health, ††Massachusetts General Hospital, ‡‡Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, §§Department of Radiology, Massachusetts General Hospital, and ∥∥Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Objective: Somatostatin receptors (SSTRs), products of gene superfamily SSTR1-5, are commonly expressed in neuroendocrine tumors (NETs). Somatostatin analogs (SSAs) bind to SSTRs and are used as therapeutic agents in patients with advanced NETs. We hypothesized that tumor SSTR expression status would be associated with clinical outcomes in NET.

Methods: Expression of the 5 SSTRs was evaluated by immunohistochemistry, using tissue microarrays comprising 173 primary NETs, 24 matched metastases, and 22 metastatic NETs from 195 patients. Cox proportional hazards regression analysis was used to assess the association of SSTR expression status (high vs low) with clinical outcomes, adjusting for potential confounders.

Results: High expression of SSTR2 was associated with longer overall survival (OS) in the cohort overall (multivariate hazard ratio, 0.42; 95% confidence interval, 0.21-0.84; P = 0.013). In a subgroup of patients with metastatic small intestine NET treated with SSAs and evaluable for progression, SSTR2 expression was associated with both longer progression-free survival (PFS) and OS. No associations with PFS or OS were observed with expression of other SSTRs.

Conclusions: Our study demonstrated that expression of SSTR2, but not other SSTRs, is associated with longer OS. In patients treated with SSAs, expression of SSTR2 is associated with longer PFS survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067972PMC
http://dx.doi.org/10.1097/MPA.0000000000000700DOI Listing
November 2016

Optical Imaging of Mesenchymal Epithelial Transition Factor (MET) for Enhanced Detection and Characterization of Primary and Metastatic Hepatic Tumors.

Theranostics 2016 9;6(12):2028-2038. Epub 2016 Sep 9.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School.

To assess optical imaging of Mesenchymal-Epithelial Transition factor (MET) for delineation and characterization of intrahepatic models of human hepatocellular carcinoma (HCC) and metastatic colorectal cancer (CRC), and thereby demonstrate its potential use in precision oncology. MET expression in human CRC and HCC was assessed in tissue microarrays. We used GE-137, a modified cyanine 5-tagged peptide for MET targeting. HepG2 and Huh-7 (HCC) and HT-29 (CRC) cells with MET overexpression, and LNCaP cells (negative control) with minimal MET expression were incubated with the probe. Correlation between the relative fluorescence signal intensity and cellular MET expression level was assessed. Flow cytometry was used to assess probe specific binding and dissociation constant (K). Orthotopic xenograft models of human HCC and metastatic CRC were generated in nu/nu mice by subcapsular implantation of cells. Epifluorescence imaging was performed to capture the changes in deferential probe accumulation at different time points after injection. Target-to-liver background ratio (TBR) was calculated and the probe biodistribution within different organs was assessed. Histopathologic analysis of extracted xenografts was performed to correlate the tumors MET expression with probe uptake by cancer cells. Approximately 91.5% of HCC and 81% of CRC microarray cores showed MET expression. HCC and CRC cells incubated with the probe showed substantial fluorescence compared to control LNCaP, with strong correlation between fluorescence signal and MET expression (R = 0.99, p < 0.001). Probe binding affinity to MET (K) was measured to be 2.9 ± 0.36 nM. Epifluorescence imaging showed intense uptake in subcapsular tumors with peak TBR of 5.46 ± 0.46 in Huh-7, 3.55 ± 0.38 in HepG2, and 15.93 ± 0.61 in HT-29 orthotopic xenografts at 4 hours post-injection (mean ± standard deviation). We demonstrated that probe uptake in xenografts is specific and can be blocked when co-injected with unlabeled peptide; for instance the epifluorescence TBR is reduced from 13.5 ± 1.2 to 1.7 ± 0.3 (p 0.05) in HT-29 and from 5.3 ± 0.8 to 1.4 ± 0.2 (p 0.05) in Huh-7 xenografts after co-injection with unlabeled peptides. Biodistribution studies showed predominantly renal clearance of the probe. Optical imaging of MET resulted in high TBR in animal models of primary and metastatic hepatic tumors suggesting its utility for procedural guidance.
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http://dx.doi.org/10.7150/thno.15718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039678PMC
October 2017

Elevated cortisol content in dog hair with atopic dermatitis.

Jpn J Vet Res 2016 May;64(2):123-9

Canine atopic dermatitis (CAD) is a chronic relapsing inflammatory skin disease occurring in 10% of the canine population. Although most studies have focused on the pathophysiological mechanism involved in CAD, the detrimental impact of CAD on quality of life has received only little attention. Hair cortisol analysis is becoming a valuable tool in monitoring chronic stress. To further validate this approach in CAD, we compared the hair cortisol concentration of atopic dogs with that of healthy conditioned dogs. The extent and severity of cutaneous lesions of atopic dermatitis were assessed according to modified CADESI-03 scores. In addition, skin barrier function was evaluated by measuring transepidermal water loss (TEWL) and stratum corneum conductance. The correlation between CAD severity and hair cortisol concentration was evaluated. The level of hair cortisol evaluated by ELISA assay showed that the atopic dermatitis group had significantly increased cortisol levels compared to that of the healthy control group. A significant positive correlation was identified between hair cortisol level and the CADESI score in CAD patients. The TEWL value of the cubital flexor of the forelimb in the atopic group was significantly higher compared to the healthy controls. These findings imply that the hair cortisol analysis can be an effective and objective biomarker in assessment of long-term stress of CAD patients.
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May 2016

Natural Killer Cell Deficits Aggravate Allergic Rhinosinusitis in a Murine Model.

ORL J Otorhinolaryngol Relat Spec 2016 7;78(4):199-207. Epub 2016 Jul 7.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Objective: Defective innate immune functions can contribute to chronic rhinosinusitis (RS). Recently, it has been reported that chronic RS patients show impaired function of natural killer (NK) cells. We investigated the role of NK cells in eosinophilic inflammation in an allergic RS mouse model.

Methods: Mice sensitized to ovalbumin (OVA) by intraperitoneal injection received nasal challenges with OVA for 5 weeks. NK cell depletion was achieved by intraperitoneal injections of anti-asialo ganglio-N-tetraosylceramide (ASGM1) antibodies 10 days before OVA sensitization and every 5 days thereafter until sacrifice. Sinonasal complex samples were evaluated histologically, and IL-4, IL-5, IL-13, IFN-γ, MIP-2, and eotaxin levels were measured in the nasal lavage fluid. Differential white blood cell counts were also obtained.

Results: Allergic RS mice showed significantly more eosinophilic inflammation in the sinonasal mucosa, elevated levels of IL-4, IL-5, IL-13, and eotaxin in the nasal lavage fluid, and peripheral blood eosinophilia compared to control mice. The depletion of NK cells by anti-ASGM1 treatment induced more prominent eosinophilic inflammation and increased secretion of IL-5 and peripheral blood eosinophilia in allergic RS mice.

Conclusion: The depletion of NK cells aggravates allergen-induced sinonasal eosinophilic inflammation, suggesting that impaired NK cell activity may be an exacerbating factor in eosinophilic chronic RS.
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http://dx.doi.org/10.1159/000445775DOI Listing
March 2017

Sensitization to and Challenge with Gliadin Induce Pancreatitis and Extrapancreatic Inflammation in HLA-DQ8 Mice: An Animal Model of Type 1 Autoimmune Pancreatitis.

Gut Liver 2016 Sep;10(5):842-50

Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background/aims: The aim of this study was to establish a pathogenetic mechanism of pancreatitis in celiac disease and IgG4-related disease using gluten-sensitive human leukocyte antigen (HLA)-DQ8 transgenic mice.

Methods: Transgenic mice expressing HLA-DQ8 genes were utilized. Control mice were not sensitized but were fed gliadin-free rice cereal. Experimental groups consisted of gliadin-sensitized and gliadin-challenged mice; nonsensitized mice with cerulein hyperstimulation; and gliadin-sensitized and gliadinchallenged mice with cerulein hyperstimulation.

Results: Gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation showed significant inflammatory cell infiltrates, fibrosis and acinar atrophy compared with the control mice and the other experimental groups. The immunohistochemical analysis showed greater IgG1-positive plasma cells in the inflammatory infiltrates of gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation compared with the control mice and the other experimental groups. Gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation or gliadin-sensitized and gliadinchallenged mice showed IgG1-stained inflammatory cell infiltrates in the extrapancreatic organs, including the bile ducts, salivary glands, kidneys, and lungs.

Conclusions: Gliadinsensitization and cerulein hyperstimulation of gluten-sensitive HLA-DQ8 transgenic mice resulted in pancreatitis and extrapancreatic inflammation. This animal model suggests that chronic gliadin ingestion in a susceptible individual with the HLA-DQ8 molecule may be associated with pancreatitis and extrapancreatic inflammation.
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http://dx.doi.org/10.5009/gnl15484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003210PMC
September 2016