Silencing of homeobox B9 is associated with down-regulation of CD56 and extrathyroidal extension of tumor in papillary thyroid carcinoma

Kim, J.H.,Kim, Y.H.,Han, J.H.,Lee, K.B.,Sheen, S.S.,Lee, J.,Soh, E.Y.,Park, T.J. W. B. Saunders Co ; Centrum Philadelphia 2012 Human pathology Vol.43 No.8

Papillary thyroid carcinoma is the most common type of thyroid malignancy, and CD56, a neural cell adhesion molecule, is typically down-regulated in almost all cases of papillary thyroid carcinoma. Homeobox B9 is a transcription factor, belongs to the products of the homeobox transcription factor gene family, and has been known to regulate transcription of CD56 and to promote tumorigenicity and metastasis in some malignancies. In this study, we investigated the expression and relation of homeobox B9 to reduced expression of CD56 in papillary thyroid carcinomas and also a relationship between their expression and clinicopathologic parameters. Therefore, we performed CD56 and homeobox B9 immunohistochemical staining on 72 papillary thyroid carcinomas and Western blotting on 31 papillary thyroid carcinomas. CD56 protein staining revealed that it was reduced or absent in 65 papillary thyroid carcinomas (90.3%) and was related to silencing of homeobox B9 (77.8%) (P = .003). The loss of homeobox B9 expression was associated with extrathyroidal extension (P = .002), pathologic stage of tumor (P = .01), and age older than 45 years (P = .032). However, the CD56 staining did not reveal any significant relationship with clinicopathologic features (P > .05). In conclusion, reduced expression of CD56 is associated with homeobox B9 in papillary thyroid carcinomas. Furthermore, silencing of homeobox B9 is more common in older age and is linked to extrathyroidal extension and advanced pathologic stage of papillary thyroid carcinoma.

Sonoelastographic strain index for differentiation of benign and malignant nonpalpable breast masses.

Cho, Nariya,Moon, Woo Kyung,Kim, Ha Young,Chang, Jung Min,Park, Sang Hee,Lyou, Chae Yeon W.B. Saunders 2010 Journal of ultrasound in medicine Vol.29 No.1

<P>OBJECTIVE: The purpose of this study was to evaluate the diagnostic potential of the sonoelastographic strain index for differentiation of nonpalpable breast masses. METHODS: Ninety-nine nonpalpable breast masses (79 benign and 20 malignant) in 94 women (mean age, 45 years; range, 21-68 years) who had been scheduled for a sonographically guided core biopsy were examined with B-mode sonography and sonoelastography. Radiologists who had performed the biopsies analyzed the B-mode sonograms and provided American College of Radiology Breast Imaging Reporting and Data System categories. The strain index (fat to lesion strain ratio) was calculated by dividing the strain value of the subcutaneous fat by that of the mass. The histologic result from the sonographically guided core biopsy was used as a reference standard. The diagnostic performance of the strain index and that of B-mode sonography were compared by receiver operating characteristic (ROC) curve analysis. RESULTS: The mean strain index values +/- SD were 6.57 +/- 6.62 (range, 1.29-28.69) in malignant masses and 2.63 +/- 4.57 (range, 0.54-38.76) in benign masses (P = .019). The area under the ROC curve values were 0.835 (95% confidence interval [CI], 0.747-0.902) for B-mode sonography and 0.879 (95% CI, 0.798-0.936) for the strain index (P = .490). The sensitivity, specificity, positive predictive value, and negative predictive value were 95% (19 of 20), 75% (59 of 79), 48% (19 of 39), and 98% (59 of 60), respectively, when a best cutoff point of 2.24 was used. CONCLUSIONS: The strain index based on the fat to lesion strain ratio has diagnostic performance comparable with that of B-mode sonography for differentiation of benign and malignant breast masses.</P>

Implications of infiltrating immune cells within bone marrow of patients with diffuse large B-cell lymphoma

Jeong, J.,Oh, E.J.,Yang, W.I.,Kim, S.J.,Yoon, S.O. W. B. Saunders Co ; Centrum Philadelphia 2017 Human pathology Vol.64 No.-

<P>The implications of infiltrating immune cells, especially T cells and macrophages, in the bone marrow (BM) microenvironment of patients with diffuse large B-cell lymphoma (DLBCL) have rarely been studied. We aimed to investigate the significance of infiltrating immune cells in the BM microenvironment as a prognostic factor for DLBCL patients. Using the initial pretreatment BM biopsy obtained from 198 DLBCL patients, we semiquantitatively evaluated CD3+ T cells, CD8+ T cells, and CD163+ macrophages that infiltrate into the paratrabecular and interstitial areas of BM by immunohistochemistry and analyzed their clinicopathological and prognostic implications. Levels of infiltrating CD3+ T cells, CD8+ T cells, and CD163+ macrophages were significantly higher in BM with DLBCL involvement (BMI-positive group) than in that without DLBCL involvement (BMI-negative group). Infiltration of CD8+ T cells significantly increased in cases with advanced Ann Arbor stage, elevated lactate dehydrogenase level, extranodal site involvement >= 2 sites, higher Eastern Cooperative Oncology Group performance status, and higher International Prognostic Index (IPI) risk. High levels of CD3+ T cells were significantly associated with age <= 60, and high levels of CD163+ macrophages were associated with advanced Ann Arbor stage and higher IPI risk. High infiltration of CD8+ T cells was significantly related to inferior overall and recurrence-free survival rate, even in the BMI-negative group. High infiltration of CD8+ T cells within the pretreatment BM was related to poor prognosis, and might be a useful prognostic factor of DLBCL patients. Therefore, evaluation of CD8+ T cells is helpful for predicting prognosis in initial pretreatment BM biopsy of DLBCL patients. (C) 2017 Elsevier Inc. All rights reserved.</P>

Cytokine secreted by S100A9 via TLR4 in monocytes delays neutrophil apoptosis by inhibition of caspase 9/3 pathway

Lee, N.R.,Park, B.S.,Kim, S.Y.,Gu, A.,Kim, D.H.,Lee, J.S.,Kim, I.S. Saunders Scientific Publications, W.B. Saunders ; 2016 Cytokine Vol.86 No.-

Dysregulation of neutrophil apoptosis causes pathogenesis and aggravation of allergy. S100A9 exists as one of the proteins in the neutrophils, triggering inflammatory responses by activating the immune cells. In this study, we investigated whether S100A9 affects constitutive neutrophil apoptosis by activating the monocytes in normal and allergic subjects. Supernatant from human monocytic THP-1 cells after treatment with S100A9 suppressed normal neutrophil apoptosis by inhibiting the activations of caspase 9 and caspase 3. S100A9 upregulated the release of MCP-1, IL-6, and IL-8 in THP-1 cells. An increase in cytokine was suppressed by CLI-095, a Toll-like receptor (TLR) 4 inhibitor, PP2, a Src inhibitor, rottlerin, a PKCδ inhibitor, MAP kinase inhibitors, including PD98059, SB202190, and SP600125, and BAY-11-7085, an NF-κB inhibitor. Src, PKCδ, ERK½, p38 MAPK, and JNK were phosphorylated by S100A9. The phosphorylation of Src and PKCδ was suppressed by CLI-095, and the activation of ERK½, p38 MAPK, and JNK was inhibited by CLI-095, PP2, and rottlerin. S100A9 induced NF-κB activity, and the activation was suppressed by CLI-095, PP2, rottlerin, and MAPK kinase inhibitors. In normal and allergic subjects, supernatant from normal and allergic monocytes after stimulation with S100A9 suppressed normal and allergic neutrophil apoptosis, respectively; MCP-1, IL-6, and IL-8 in the supernatant was increased by S100A9. The cytokine secretion induced by S100A9 is related to TLR4, Src, PKCδ, ERK½, p38 MAPK, JNK, and NF-κB. Taken together, S100A9 induces anti-apoptotic effect on normal and allergic neutrophils by increasing cytokine secretion of monocytes. These findings may help us to better understand neutrophil apoptosis regulated by S100A9 and pathogenesis of allergic diseases.

Therapeutic effect of Active Hexose-Correlated Compound (AHCC) combined with CpG-ODN (oligodeoxynucleotide) in B16 melanoma murine model

Ignacio, R.M.,Kim, C.S.,Kim, Y.D.,Lee, H.M.,Qi, X.F.,Kim, S.K. Saunders Scientific Publications, W.B. Saunders ; 2015 Cytokine Vol.76 No.2

While Active Hexose Correlated Compound (AHCC) and CpG oligodeoxynucleotide (ODN) are separately known to modulate oxidative stress and immune responses in cancer patients, the combined effect of these two compounds is unknown. To clarify this, we investigated whether AHCC plus KSK-CpG ODN would be therapeutic in B16 melanoma mouse model, if so, and how in reduction-oxidation (redox) balance and cytokines network. We found that treatment groups (AHCC only, KSK-CpG ODN only and AHCC/KSK-CpG ODN) markedly reduced (p<0.001) tumor size when compared to the positive control (PC) group. The total white blood cell (WBC) of AHCC only and KSK-CpG ODN only-treated groups showed significant lower counts than that of PC group. Next, the production of nitric oxide (NO) was significantly increased (p<0.01) in AHCC/KSK-CpG ODN group compared to the PC group. Further, the redox balance was improved in AHCC/KSK-CpG ODN group through significantly low (p<0.001) reactive oxygen species (ROS) production and significantly high (p<0.05) glutathione peroxidase (GPx) activity compared to the PC group. Finally, AHCC/KSK-CpG ODN (p<0.01) and KSK-CpG ODN (p<0.001)-treated groups augmented tumor immune surveillance as shown by significantly increased level of anti-inflammatory cytokine (IL-10) and significantly decreased (p<0.05) level of pro-tumorigenic IL-6 of AHCC/KSK-CpG ODN treated group as compared to the PC group. Collectively, our study indicates therapeutic effect of Active Hexose-Correlated Compound (AHCC) combined with KSK-CpG ODN in B16 melanoma murine model via balancing redox and cytokines network.

Increased postprandial apolipoprotein B-48 level after a test meal in diabetic patients: A multicenter, cross-sectional study

Park, C.Y.,Park, J.Y.,Choi, J.,Kim, D.J.,Park, K.S.,Yoon, K.H.,Lee, M.K.,Park, S.W. W.B.Saunders [etc.] 2016 clinical and experimental Vol.65 No.6

Objective: To evaluate plasma apolipoprotein B (ApoB)-48 concentrations among Korean diabetic subjects with normal to moderately high levels of low-density-lipoprotein cholesterol (LDL-C). Methods: This multicenter, cross-sectional study included subjects with LDL-C levels between 100 and 160mg/dL who had not been treated with a lipid-lowering agent for over 6weeks prior to baseline. Blood tests to assess lipid-profile parameters were conducted in both fasting and postprandial states. This study compared ApoB-48 and other lipid-profile parameters in diabetic and nondiabetic subjects. Results: Of the 93 subjects enrolled, 88 (42 diabetic; 46 nondiabetic) completed the study. Significantly higher mean incremental area under curve (0-6h; iAUC<SUB>0-6h</SUB>) of postprandial ApoB-48 levels was noted among diabetic subjects than nondiabetic subjects (p=0.0078). The mean postprandial ApoB-48 peak level was higher in diabetic subjects; however, the difference was not statistically significant. The fasting ApoB-48 level was similar in both groups: 5.9 (3.5) in diabetics and 7.3 (5.8) in nondiabetics (p=0.18). The iAUC<SUB>0-6h</SUB> of postprandial total cholesterol (TC), triglyceride (TG), LDL-C, non-high-density-lipoprotein cholesterol (non-HDL-C), ApoB-100, and remnant cholesterol was similar in both groups. The ApoB-48 level was moderately correlated with TG and non-HDL-C for both groups (p<0.05). Conclusion: Without lipid-lowering treatment, the postprandial increment in ApoB-48 level was significantly higher in Korean diabetic subjects compared with nondiabetic subjects, irrespective of similar LDL-C levels.

Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients With Chronic Hepatitis

Boni, Carolina,Janssen, Harry L.A.,Rossi, Marzia,Yoon, Seung Kew,Vecchi, Andrea,Barili, Valeria,Yoshida, Eric M.,Trinh, Huy,Rodell, Timothy C.,Laccabue, Diletta,Alfieri, Arianna,Brillo, Federica,Fisic W.B. Saunders Co. 2019 Gastroenterology Vol.157 No.1

<P><B>Background & Aims</B></P> <P>One strategy to treat chronic hepatitis B virus (HBV) infection could be to increase the functions of virus-specific T cells. We performed a multicenter phase 2 study to evaluate the safety and efficacy of GS-4774, a yeast-based therapeutic vaccine engineered to express HBV antigens, given with tenofovir disoproxil fumarate (TDF) to untreated patients with chronic HBV infection.</P> <P><B>Methods</B></P> <P>We performed an open-label study at 34 sites in Canada, Italy, New Zealand, Romania, South Korea, and United States from July 2014 to August 2016. Adults who were positive for HB surface antigen (HBsAg) > 6 months and levels of HBV DNA ≥2000 IU/mL who had not received antiviral treatment for HBV within 3 months of screening were randomly assigned (1:2:2:2) to groups given oral TDF 300 mg daily alone (n = 27; controls) or with 2, 10, or 40 yeast units GS-4774 (n = 168), administered subcutaneously every 4 weeks until week 20 for a total of 6 doses. Blood samples were collected and analyzed and patients received regular physical examinations. Efficacy was measured by decrease in HBsAg from baseline to week 24. Specific responses to HBV (production of interferon gamma [IFNG], tumor necrosis factor [TNF], interleukin 2 [IL2], and degranulation) were measured in T cells derived from 12 HBeAg-negative patients with genotype D infections, after overnight or 10 days of stimulation of peripheral blood mononuclear cells with peptides from the entire HBV proteome. T-regulatory cells were analyzed for frequency and phenotype. Data from studies of immune cells were compared with data on reductions in HBsAg, HBV DNA, and alanine aminotransferase in blood samples from patients.</P> <P><B>Results</B></P> <P>GS-4774 was safe and well tolerated but did not produce significant decreases in levels of HBsAg. Production of IFNG, TNF, and IL2 increased significantly at weeks 24 and 48, compared with baseline, in HBV-specific CD8+ T cells from patients given GS-4774 but not from controls. GS-4774 had greater effects on CD8+ than CD4+ T cells, which were not affected at all or very weakly by TDF with or without GS-4774. GS-4774 did not affect responses of T cells to other viruses tested. HBV core peptides induced the greatest production of IFNG by T cells following overnight stimulation, whereas HBV envelope antigens did not induce a response. Following 10 days of stimulation, production of IFNG and TNF increased with time of exposure to GS-4774; the greatest levels of responses were to HBV envelope antigens followed by core and polymerase peptides. We observed a correlation in patients given GS-4774 between increased T-cell functions and reductions in numbers of T-regulatory cells.</P> <P><B>Conclusions</B></P> <P>In a phase 2 study of patients with chronic HBV infection given TDF with or without GS-4774, we found that vaccination can increase production of IFNG, TNF, and IL2 by CD8+ T cells exposed to antigenic peptides, with little effect on CD4+ T cells. Although GS-4774 did not reduce levels of HBsAg in patients, its strong immune stimulatory effect on CD8+ T cells might be used in combination with other antiviral agents to boost the antivirus immune response. Clinicaltrials.gov no: NCT02174276.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Association study of hypoxia inducible factor 1α (<i>HIF1α</i>) with osteonecrosis of femoral head in a Korean population

Hong, J. Min,Kim, T.-H.,Chae, S.-C.,Koo, K.-H.,Lee, Y. Jong,Park, E. Kyun,Choi, J.-Y.,Ryoo, H.-M.,Kim, S.-Y. W.B. SAUNDERS COMPANY 2007 OSTEOARTHRITIS AND CARTILAGE Vol.15 No.6

<P><B>Summary</B></P><P><B>Objective</B></P><P>Disruption of the vascular supply to the bone and subsequent hypoxia has been implicated in the pathogenesis of osteonecrosis (ON) of the femoral head (ONFH). To evaluate the genetic effect of <I>HIF1α</I>, a key transcription factor in controlling hypoxia condition, on ONFH, we analyzed <I>HIF1α</I> polymorphism and its genetic association with ONFH.</P><P><B>Methods</B></P><P>We directly sequenced the <I>HIF1α</I> gene in 24 Korean individuals and identified four sequence variants. Four polymorphisms (−2755C>A, +41224T>C, +45319C>T, +51610C>T) were genotyped in ONFH (<I>n</I>=384). ONFH patients were divided into three subgroups based on etiological factors: idiopathic (129 cases), steroid (59 cases) and alcohol (196 cases) ON groups.</P><P><B>Results</B></P><P>We found that the allele frequency of −2755C>A and the genotype frequencies of +41224T>C and +51610C>T were significantly associated with idiopathic ONFH in men (<I>P</I>=0.0409, 0.0113, 0.0269, respectively). In addition, haplotype (CTCC) of <I>HIF1α</I> was also significantly associated with idiopathic ONFH in men (<I>P</I>=0.017).</P><P><B>Conclusions</B></P><P>We found that <I>HIF1α</I> polymorphisms are associated with idiopathic ONFH in men. These results suggest that variations in <I>HIF1α</I> may play an important role in the pathogenesis and risk factor for ONFH.</P>

Chitinase-3-like-1 deficiency attenuates ethanol-induced liver injury by inhibition of sterol regulatory element binding protein 1-dependent triglyceride synthesis

Lee, Dong Hun,Han, Ji Hye,Lee, Yong Sun,Jung, Young Suk,Roh, Yoon Seok,Yun, Jae Suk,Han, Sang Bae,Hong, Jin Tae W.B. Saunders Co. [etc.] 2019 Metabolism, clinical and experimental Vol.95 No.-

<P><B>Abstract</B></P> <P><B>Objective</B></P> <P>Alcohol overconsumption and abuse lead to alcoholic liver disease (ALD), which is a major chronic liver disease worldwide. Chitinase-3-like protein 1 (CHI3L1) have an important role in the pathogenesis of inflammatory disease. However, the role of CHI3L1 in ALD has not yet been reported. In the present study, we investigated the effect of CHI3L1 on chronic plus binge ethanol-induced liver injury.</P> <P><B>Methods</B></P> <P>CHI3L1 knock out (KO) mice and their littermate control mice based on C57BL/6 (10–12 weeks old) were fed on a Lieber-DeCarli diet containing 6.6% ethanol for 10 days. And, CHI3L1 siRNA or CHI3L1 expressing vector was transfected HepG2 cells were treated with ethanol or without.</P> <P><B>Results</B></P> <P>Ethanol-induced hepatic triglyceride (TG) levels and the mRNA levels of TG synthesis-related genes such as acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1) were decreased in the liver of CHI3L1 knock out (KO) mice and the HepG2 cells transfected with CHI3L1 siRNA. Increased mRNA level and activation of SREBP1 which is transcription factor of ACC, FAS and SCD1 by ethanol feeding were reduced in the liver of ethanol-fed CHI3L1 KO mice. Moreover, ethanol-induced SREBP1 luciferase activity and mRNA level of SREBP1, ACC, FAS and SCD1 were also decreased in the HepG2 cells transfected with CHI3L1 siRNA, while those were further increased in the HepG2 cells treated with recombinant human CHI3L1. Furthermore, oxidative stress and up-regulated pro-inflammatory cytokines by ethanol were recovered in the liver of ethanol-fed CHI3L1 KO mice.</P> <P><B>Conclusion</B></P> <P>Our finding suggest that inhibition of CHI3L1 suppressed ethanol-induced liver injury through inhibition of TG synthesis, and the blocking of oxidative stress and hepatic inflammation induced SREBP1 activity could be significant.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Ethanol-induced liver injury was ameliorated in CHI3L1 KO mice. </LI> <LI> Ethanol-induced oxidative stress and inflammation in the liver were attenuated in CHI3L1 KO mice. </LI> <LI> CHI3L1 KO mice showed inhibition of ethanol-induced SREBP1 in the liver. </LI> <LI> Ethanol-induced oxidative stress and inflammation were inhibited in HepG2 cells by CHI3L1 si-RNA transfection. </LI> </UL> </P>

Frameshift mutations of chromosome cohesion-related genes SGOL1 and PDS5B in gastric and colorectal cancers with high microsatellite instability

Kim, M.S.,An, C.H.,Yoo, N.J.,Lee, S.H. W. B. Saunders Co ; Centrum Philadelphia 2013 Human pathology Vol.44 No.10

Cohesin is a protein complex that regulates chromatid cohesion and plays a role in preventing aneuploidy and maintaining chromosomal stability. SGOL1 encodes a cohesin protector, and PDS5B encodes a regulatory cohesion factor. Both SGOL1 and PDS5B are considered putative tumor suppressor genes. The aim of this study was to explore whether SGOL1 and PDS5B genes are mutated and expressionally altered in gastric and colorectal cancers. A genome database indicated that both genes possessed mononucleotide repeats in coding sequences, which could be mutation targets in cancers with microsatellite instability. We analyzed mutations in 91 gastric cancers and 100 colorectal cancers with high microsatellite instability or stable/low microsatellite instability by single-strand conformation polymorphism analysis and DNA sequencing. We also analyzed SGOL1 and PDS5B expression by immunohistochemistry. Overall, we found 21 SGOL1 frameshift mutations in 21 cases and 18 PDS5B frameshift mutations in 16 cases. SGOL1 and PDS5B frameshift mutations were detected in 26.6% and 20.3%, respectively, of high microsatellite instability but not in stable/low microsatellite instability (0/112). By immunohistochemistry, losses of SGOL1 and PDS5B were identified in 19% to 47% of the gastric and colorectal cancers irrespective of microsatellite instability status. The losses were more common in those with frameshift mutations or high microsatellite instability than those without mutations or high microsatellite instability. The data indicate that frameshift mutations of SGOL1 and PDS5B and the loss of their expression may be a feature of gastric and colorectal cancers with high microsatellite instability. In addition, the data suggest that these alterations might contribute to cancer pathogenesis by deregulating cohesin-related functions.