Effects of caloric restriction on the expression of lipocalin-2 and its receptor in the brown adipose tissue of high-fat diet-fed mice

Obesity causes inflammation and impairs thermogenic functions in brown adipose tissue (BAT). The adipokine lipocalin 2 (LCN2) has been implicated in inflammation and obesity. Herein, we investigated the protective effects of caloric restriction (CR) on LCN2-mediated inflammation and oxidative stress in the BAT of high-fat diet (HFD)-fed mice. Mice were fed a HFD for 20 weeks and then either continued on the HFD or subjected to CR for the next 12 weeks. CR led to the browning of the white fat-like phenotype in HFD-fed mice. Increased expressions of LCN2 and its receptor in the BAT of HFD-fed mice were significantly attenuated by CR. Additionally, HFD+CR-fed mice had fewer neutrophils and macrophages expressing LCN2 and iron-positive cells than HFD-fed mice. Further, oxidative stress and mitochondrial fission induced by a HFD were also significantly attenuated by CR. Our findings indicate that the protective effects of CR on inflammation and oxidative stress in the BAT of obese mice may be associated with regulation of LCN2.

Magnetization-tagged MRI is a simple method for predicting liver fibrosis

BACKGROUND/AIMS: To assess the usefulness of magnetization-tagged magnetic resonance imaging (MRI) in quantifying cardiac-induced liver motion and deformation in order to predict liver fibrosis. METHODS: This retrospective study included 85 patients who underwent liver MRI including magnetization-tagged sequences from April 2010 to August 2010. Tagged images were acquired in three coronal and three sagittal planes encompassing both the liver and heart. A Gabor filter bank was used to measure the maximum value of displacement (MaxDisp) and the maximum and minimum values of principal strains (MaxP1 and MinP2, respectively). Patients were divided into three groups (no fibrosis, mild-to-moderate fibrosis, and significant fibrosis) based on their aspartate-aminotransferase-to-platelet ratio index (APRI) score. Group comparisons were made using ANOVA tests. RESULTS: The patients were divided into three groups according to APRI scores: no fibrosis (≤0.5; n=41), moderate fibrosis (0.5-1.5; n=23), and significant fibrosis (>1.5; n=21). The values of MaxDisp were 2.9±0.9 (mean±SD), 2.3±0.7, and 2.1±0.6 in the no fibrosis, moderate fibrosis, and significant fibrosis groups, respectively (P<0.001); the corresponding values of MaxP1 were 0.05±0.2, 0.04±0.02, and 0.03±0.01, respectively (P=0.002), while those of MinP2 were -0.07±0.02, -0.05±0.02, and -0.04±0.01, respectively (P<0.001). CONCLUSIONS: Tagged MRI to quantify cardiac-induced liver motion can be easily incorporated in routine liver MRI and may represent a helpful complementary tool in the diagnosis of early liver fibrosis.

Field Cancerization in Sporadic Colon Cancer

BACKGROUND/AIMS: Aberrant DNA methylation has a specific role in field cancerization. Certain molecular markers, including secreted frizzled-related protein 2 (SFRP2), tissue factor pathway inhibitor 2 (TFPI2), N-Myc downstream-regulated gene 4 (NDRG4) and bone morphogenic protein 3 (BMP3), have previously been shown to be hypermethylated in colorectal cancer (CRC). We aim to examine field cancerization in CRC based on the presence of aberrant DNA methylation in normal-appearing tissue from CRC patients. METHODS: We investigated promoter methylation in 34 CRC patients and five individuals with normal colonoscopy results. CRC patients were divided into three tissue groups: tumor tissue, adjacent and nonadjacent normal-appearing tissue. The methylation status (positive: methylation level >20%) of SFRP2, TFPI2, NDRG4, and BMP3 promoters was investigated using methylation-specific PCR. RESULTS: The methylation frequencies of the SFRP2, TFPI2, NDRG4 and BMP3 promoters in tumor/adjacent/nonadjacent normal-appearing tissue were 79.4%/63.0%/70.4%, 82.4%/53.6%/60.7%, 76.5%/61.5%/69.2%, 41.2%/35.7%/50.0%, respectively. The methylation levels of the SFRP,TFPI2, NDRG4 and BMP3 promoters in tumor tissues were significantly higher than those in normal-appearing tissue (SFRP2, p=0.013; TFPI2, p<0.001; NDRG4, p=0.003; BMP3, p=0.001). No significant correlation was observed between the methylation levels of the promoters and the clinicopathological variables. CONCLUSIONS: The field effect is present in CRC and affects both the adjacent and nonadjacent normal-appearing mucosa.

Microsatellite Instability Status of Interval Colorectal Cancers in a Korean Population

BACKGROUND/AIMS: A subset of patients may develop colorectal cancer after a colonoscopy that is negative for malignancy. These missed or de novo lesions are referred to as interval cancers. The aim of this study was to determine whether interval colon cancers are more likely to result from the loss of function of mismatch repair genes than sporadic cancers and to demonstrate microsatellite instability (MSI). METHODS: Interval cancer was defined as a cancer that was diagnosed within 5 years of a negative colonoscopy. Among the patients who underwent an operation for colorectal cancer from January 2013 to December 2014, archived cancer specimens were evaluated for MSI by sequencing microsatellite loci. RESULTS: Of the 286 colon cancers diagnosed during the study period, 25 (8.7%) represented interval cancer. MSI was found in eight of the 25 patients (32%) that presented interval cancers compared with 22 of the 261 patients (8.4%) that presented sporadic cancers (p=0.002). In the multivariable logistic regression model, MSI was associated with interval cancer (OR, 3.91; 95% confidence interval, 1.38 to 11.05). CONCLUSIONS: Interval cancers were approximately four times more likely to show high MSI than sporadic cancers. Our findings indicate that certain interval cancers may occur because of distinct biological features.

Erratum: Field Cancerization in Sporadic Colon Cancer

In the version of this article initially published, the first affiliation (affiliation number 1) was incorrectly stated as "Division of Gastroentorology, Department of Internal Medicine." The correct affiliation is "Department of Internal Medicine."

Myeloid-specific SIRT1 Deletion Aggravates Hepatic Inflammation and Steatosis in High-fat Diet-fed Mice

Sirtuin 1 (SIRT1) is a mammalian NAD+-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-kappaB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (alpha-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.

Engagement of CD99 Reduces AP-1 Activity by Inducing BATF in the Human Multiple Myeloma Cell Line RPMI8226

CD99 signaling is crucial to a diverse range of biological functions including survival and proliferation. CD99 engagement is reported to augment activator protein-1 (AP-1) activity through mitogen-activated protein (MAP) kinase pathways in a T-lymphoblastic lymphoma cell line Jurkat and in breast cancer cell lines. In this study, we report that CD99 differentially regulated AP-1 activity in the human myeloma cell line RPMI8226. CD99 was highly expressed and the CD99 engagement led to activation of the MAP kinases, but suppressed AP-1 activity by inducing the expression of basic leucine zipper transcription factor, ATF-like (BATF), a negative regulator of AP-1 in RPMI8226 cells. By contrast, engagement of CD99 enhanced AP-1 activity and did not change the BATF expression in Jurkat cells. CD99 engagement reduced the proliferation of RPMI8226 cells and expression of cyclin 1 and 3. Overall, these results suggest novel CD99 functions in RPMI8226 cells.

A Case of Acute Pancreatitis Caused by Distal Migration of a Pyloric Covered Self-Expandable Metal Stent / 대한내과학회지

Endoscopic metal stent insertion has been widely performed to palliatively treat gastrointestinal (GI) tract obstruction in patients with cancer. The use of metal stents for benign strictures of the GI tract is increasing due to the low risk of major complications other than stent migration. The incidence of acute pancreatitis after placing a GI tract metal stent is rare. Herein, we report a case of acute pancreatitis caused by a covered metal stent that was initially inserted for a benign stricture of a gastroduodenal anastomosis that developed after the operation, then distally migrated, bent into a U-shape, and impacted into the second portion of the duodenum in a 56-year-old female who underwent a Billroth-I gastrectomy due to gastric cancer.

18F-Fluorodeoxyglucose Positron Emission Tomography for Primary Thyroid Cancer: Correlation with the Clinical, Pathologic and Sonographic Findings

PURPOSE: We wanted to investigate the incidence and the clinicopathologic and sonographic characteristics of thyroid cancers that exhibit positive PET scans. MATERIALS AND METHODS: From January 2007 to February 2008, 156 patients with thyroid cancer underwent both sonography and FDG-PET for the purpose of staging the cancer. We conducted a retrospective review of their clinical, radiologic and pathologic records and we evaluated the incidence of PET-positive thyroid cancer, as well as the associated clinicopathologic aggressiveness and the sonographic features. RESULTS: The incidence of PET-positive thyroid carcinoma was 78.2% (122/156). On univariate analysis, PET-positive thyroid cancer was significantly associated with tumor size, extracapsular invasion and central lymph node metastasis, but there was no association between the sonographic features of the thyroid cancer or the sonographic features of the 2 groups of tumor (1. probably benign and 2. suspicious for malignancy) and the FDG uptake. Multivariate logistic regression analysis showed a significant association between PET positivity and both extrathyroidal extension and a higher cancer stage (III/IV) (p < 0.05). CONCLUSION: The incidence of PET positive thyroid carcinoma is high (78.2%) and PET positivity is significantly associated with tumor size, extracapsular extension and a higher stage. However, there is no significant association between PET positivity and the sonographic features of thyroid carcinoma.

A Rare Case of Acute Lymphoblastic Leukemia with t(12;17)(p13;q21) / 대한진단검사의학회지

Patients with ALL rarely present with t(12;17)(p13;q21) as the primary clonal abnormality; this abnormality is associated with the expression of myeloid antigens. In this study, we have reported presumably the first case of this chromosomal abnormality in Korea, thereby facilitating the delineation of a distinct subtype of ALL. A 57-yr-old woman was referred to our hospital because of pancytopenia. Peripheral blood examination showed 55% blasts. The bone marrow was markedly hypercellular, and about 82.4% of all nucleated cells were blasts. The results of immunophenotyping and cytochemical staining suggested early precursor B-ALL. Cytogenetic analysis of the bone marrow cells showed a complex karyotype, including a reciprocal translocation between the short arm of chromosome 12 and the long arm of chromosome 17, t(12;17)(p13;q21). Data from array comparative genomic hybridization were almost consistent with the cytogenetic findings.

Evaluation of the Clinical Performance of an Automated Procalcitonin Assay for the Quantitative Detection of Bloodstream Infection / 대한진단검사의학회지

BACKGROUND: Bloodstream infection (BSI) is associated with a high mortality rate. Since the origin of infection is demonstrated in approximately 2/3rds of cases, early and established biomarkers are warranted. We evaluated the clinical performances of automated procalcitonin (PCT) and C-reactive protein (CRP) assays for the quantitative detection of BSI. Analytical performance of the VIDAS(R) B.R.A.H.M.S PCT assay (bioMerieux, France) was assessed and also compared with the semi-quantitative PCT-Q test (B.R.A.H.M.S Aktiengesellschaft, Germany). METHODS: We prospectively included consecutive patients divided into 3 groups at the Dong-A University Medical Center. Patients were categorized according to the criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference (ACCP/SCCM), and also on the basis of catheter-associated bacteremia. RESULTS: A total 77 patients were enrolled. All mean values of PCT and PCT-Q were consistent with the reference value. Measured PCT concentrations showed good linearity (r=0.983). The between-run, within-run, and total imprecisions were below 5%. The PCT levels in gram-negative bacteremia were significantly higher than those in gram-positive bacteremia. Furthermore, the PCT concentrations were significantly different among non-infection, bacteremia, sepsis, severe sepsis, and septic shock groups. Our study showed that PCT >0.3 ng/mL had 95.0% sensitivity and 97.3% specificity, whereas CRP >5.46 mg/dL had 85.0% sensitivity and 86.5% specificity for diagnosing sepsis. CONCLUSIONS: We suggest that, compared with CRP, PCT is a better diagnostic and discriminative biomarker of sepsis categorized according to the ACCP/SCCM. Moreover, catheter-associated bacteremia could be discriminated from sepsis using PCT concentration.

Relationship between the Levels of Holotranscobalamin and Vitamin B12 / 대한진단검사의학회지

To date, the determination of serum vitamin B12 levels has been the most common laboratory test for the assessment of vitamin B12 status; however, the diagnostic accuracy of this test is low. To obtain a more sensitive marker, a new test to measure holotranscobalamin (holoTC) levels has been introduced. In this study, we assessed 45 patients for whom a vitamin B12 test had been requested and 139 anemic patients. We investigated the associations between the levels of homocysteine (Hcy) and those of holoTC, serum vitamin B12, and folate and assessed the diagnostic value of holoTC levels as a marker for vitamin B12 deficiency. We also determined the precision of the AxSYM holoTC assay by calculating the coefficient of variance (CV). The within-run and between-run precision values were excellent, as all CV values were less than 3.5%. The holoTC levels were low (12 micromol/L) indicated vitamin B12 deficiency. Thus, the holoTC levels were more sensitive than the serum vitamin B12 levels for indicating vitamin B12 status. If the serum vitamin B12 level is 151-300 pmol/L, the levels of holoTC alone or in combination with serum vitamin B12 levels are likely to be more useful markers than serum vitamin B12 levels alone.

Prevalence and Clinical Associations of Lupus Anticoagulant, Anticardiolipin Antibodies, and Anti-beta2-glycoprotein I Antibodies in Patients with Systemic Lupus Erythematosus / 대한진단검사의학회지

BACKGROUND: The presence of antiphospholipid antibodies (aPLs) is associated with the clinical features of antiphospholipid syndrome (APS), which comprises venous and arterial thrombosis and pregnancy loss, and systemic lupus erythematosus (SLE). The prevalence of aPLs has been reported to be different in patient populations affected by either of these conditions. We performed a retrospective study to evaluate the prevalence and clinical associations of aPLs, including lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-beta2-glycoprotein I antibodies (anti-beta2-GPI) in a cohort of Korean patients with SLE. METHODS: This study included samples from 88 SLE patients for whom aPL testing had been advised between June 2006 and July 2009 at the Dong-A University Hospital. Serum and plasma samples were tested for LAC, aCL (IgG, IgM), and anti-beta2-GPI (IgG, IgM) antibodies. Clinical data from patients were obtained from a review of medical records. RESULTS: LAC was the most common (34.1% of total patients, 30/88) antibody, followed by IgM aCL (31.8%, 28/88), IgG aCL (18.2%, 16/88), and IgM and IgG anti-beta2-GPI (both 5.7%, 5/88 each). Positivity for LAC was strongly associated with venous/arterial thrombosis (P=0.002). CONCLUSIONS: LAC was the most common antibody detected in Korean SLE patients and is shown to have a significant association with the presence of venous/arterial thrombosis. The measurement of LAC may be clinically useful in identifying patients with SLE who are at a high risk for venous/arterial thrombosis.

A de novo Proximal 6q Deletion Confirmed by Array Comparative Genomic Hybridization / 대한진단검사의학회지

Deletions of chromosome 6q, particularly in the proximal region, are relatively rare. Here, we report on a de novo interstitial deletion of (6)(q13q16.2) in a girl with facial dysmorphism, congenital hip dislocation, porencephaly, and brain atrophy. Array comparative genomic hybridization analysis showed arr 6q13q16.2(73,378,824-99,824,130), demonstrating higher resolution than the conventional cytogenetic findings, del(6)(q12q15). The clinical data were analyzed and compared with those of similar patients previously reported in the literature.

Comparison between Conventional Cytogenetics and Interphase Fluorescence in situ Hybridization (FISH) for Patients with Multiple Myeloma

BACKGROUND: For patients with multiple myeloma (MM), different strategies are used to detect chromosomal abnormalities (CA). There have been a few studies that have directly compared FISH with conventional cytogenetics (CC) for the detection of CA. In this study, we employed a combined approach of metaphase cytogenetics and interphase FISH to investigate the genetic basis for the great heterogeneity observed in the clinical behavior of 28 MM patients. METHODS: Cytogenetic analysis was performed via traditional metaphase karyotype analysis. The FISH studies were done using DNA probes to detect translocations involving the immunoglobulin heavy chain gene (IGH) at 14q32 and deletions of 17p13.1 and 13q14. RESULTS: CA were detected by CC in 16 patients (57.1%) and by FISH in 14 patients (50.0%) of the 28 patients we studied. 14q32 abnormalities and deletion abnormalities of 13q14 and 17p13.1 were detected by CC in five patients (17.9%), three patients (10.7%) and no patients (0%), respectively and these were detected by FISH in 12 (42.8%), four (14.3%) and five (17.8%), respectively, of the 28 patients we studied. The median follow-up timefor the patients was 23.85 months (range: 0.3~58.13 months). On the univariate and multivariate analyses, none of the abnormalities detected by cytogenetics and interphase FISH affected survival. CONCLUSION: On comparing the cytogenetics and interphase FISH results, we can suggest that both studies should be an essential part of the workup for the diagnosis of patients with MM. Also, both studies may complement each other to predict the prognosis.

Effect of ABO-incompatibility on Allogeneic Hematopoietic Stem Cell Transplantation: A Single Institute Study / 대한수혈학회지

No abstract available.

Primary anti-D Immunization by DEL Red Blood Cells / 대한진단검사의학회지

Extremely weak D variants called DEL are serologically detectable only by adsorption-elution techniques. A nucleotide change of exon 9 in RHD gene, RHD (K409K, 1227G>A) allelic variant is present in almost all the DEL individuals of East Asians. No DEL phenotype has yet been shown to induce a primary alloanti-D immunization in East Asia. A 68-yr-old D-negative Korean man was negative for anti-D at admission, and he developed alloanti-D after transfusion of red blood cells (RBC) from 4 apparently D-negative donors. Four donors who typed D-negative by routine serologic test were analyzed by real-time PCR for RHD gene and RHD (K409K). One donor was found to have RHD (K409K). This is the first case in which DEL RBCs with RHD (K409K) induced a primary alloanti-D immunization in Asian population. Because the DEL phenotype can induce an anti-D immunization in D-negative recipients, further discussion is needed whether RhD negative donors should be screened by molecular method and what an efficient genotyping method is for detecting the RHD gene carriers in Korea.

Cytogenetic Characterizations of Central Nervous System Tumors: The First Comprehensive Report from a Single Institution in Korea

The World Health Organization (WHO) classification of central nervous system (CNS) tumors incorporates morphology, cytogenetics, molecular genetics, and immunologic markers. Despite the relatively large number of CNS tumors with clonal chromosome abnormalities, only few studies have investigated cytogenetic abnormalities for CNS tumors in Korea. Thus, we investigated 119 CNS tumors by conventional G-banded karyotypes to characterize patterns of chromosomal abnormalities involving various CNS tumors, and 92.4% of them were cultured and karyotyped successfully. Totally, 51.8% of karyotypable CNS tumors showed abnormal cytogenetic results, including neuroepithelial tumors (75.0%), meningeal tumors (71.1%), pituitary adenomas (4.2%), schwannomas (44.4%), and metastatic tumors (100.0%). Glioblastomas had hyperdiploid, complex karyotypes, mainly involving chromosomes Y, 1, 2, 6, 7, 10, 12, 13, and 14. Monosomy 22 was observed in 56.4% of meningiomas. There was a significant increase in the frequencies of karyotypic complexity according to the increase of WHO grade between grades I and II (P=0.0422) or IV (P=0.0101). Abnormal karyotypes were more complex at high-grade tumors, suggesting that the karyotype reflects the biologic nature of the tumor. More detailed cytogenetic and molecular characterizations of CNS tumors contribute to better diagnostic criteria and deeper insights of tumorigenesis, eventually resulting in development of novel therapeutic strategies.

Cytogenetic Characterizations of Central Nervous System Tumors: The First Comprehensive Report from a Single Institution in Korea

The World Health Organization (WHO) classification of central nervous system (CNS) tumors incorporates morphology, cytogenetics, molecular genetics, and immunologic markers. Despite the relatively large number of CNS tumors with clonal chromosome abnormalities, only few studies have investigated cytogenetic abnormalities for CNS tumors in Korea. Thus, we investigated 119 CNS tumors by conventional G-banded karyotypes to characterize patterns of chromosomal abnormalities involving various CNS tumors, and 92.4% of them were cultured and karyotyped successfully. Totally, 51.8% of karyotypable CNS tumors showed abnormal cytogenetic results, including neuroepithelial tumors (75.0%), meningeal tumors (71.1%), pituitary adenomas (4.2%), schwannomas (44.4%), and metastatic tumors (100.0%). Glioblastomas had hyperdiploid, complex karyotypes, mainly involving chromosomes Y, 1, 2, 6, 7, 10, 12, 13, and 14. Monosomy 22 was observed in 56.4% of meningiomas. There was a significant increase in the frequencies of karyotypic complexity according to the increase of WHO grade between grades I and II (P=0.0422) or IV (P=0.0101). Abnormal karyotypes were more complex at high-grade tumors, suggesting that the karyotype reflects the biologic nature of the tumor. More detailed cytogenetic and molecular characterizations of CNS tumors contribute to better diagnostic criteria and deeper insights of tumorigenesis, eventually resulting in development of novel therapeutic strategies.

Detection of PML/RARA Rearrangement by Reverse Transcriptase-PCR and Sequencing in a Case of Microgranular Acute Promyelocytic Leukemia Lacking t(15;17) on Karyotype and FISH / 대한진단검사의학회지

We report a case of morphologically microgranular acute promyelocytic leukemia with PML/RARA fusion transcripts demonstrated by reverse transcriptase-PCR and cDNA sequencing, and no PML/RARA fusion detected by karyotype and FISH analyses. Karyotype was 47,XX,+8[19]/46,XX[1]. Although the newer FISH probes provide more accurate detections of t(15;17), it would be necessary to perform other molecular tests to further identify the masked PML/RARA fusions.