Search

Supplementary Figure 1. Gating strategies for flow cytometry data analysis. Supplementary Figure 2. Co-staining of mPGES1 and S100 in human melanoma tissues. Supplementary Figure 3. Chemokines/cytokines related to COX2 or mPGES1 in melanoma. Supplementary Figure 4. Effect of COX2 or mPGES1 inhibitors on surface expression of PD-L1. Supplementary Figure 5. Comparison of PGE2 level and cell viability in scramble, PTGES KO and PTGS1/PTGS2 double KO mouse melanoma cell lines. Supplementary Figure 6. Prognostic effect of mPGES1 in Stage IV melanoma. Supplementary Figure 7. Association between mPGES1 levels and response of anti-PD-1 therapy.

Purpose:Microsomal prostaglandin E2 synthase 1 (mPGES1) was evaluated as an important downstream effector of the COX2 pathway responsible for tumor-mediated immunosuppression in melanoma.Experimental Design:The analysis of a stage III melanoma tissue microarray (n = 91) was performed to assess the association between mPGES1, COX2, CD8, and patient survival. Pharmacologic inhibitors and syngeneic mouse models using PTGES-knockout (KO) mouse melanoma cell lines were used to evaluate the mPGES1-mediated immunosuppressive function.Results:We observed correlations in expression and colocalization of COX2 and mPGES1, which are associated with increased expression of immunosuppressive markers in human melanoma. In a syngeneic melanoma mouse model, PTGES KO increased melanoma expression of PD-L1, increased infiltration of CD8a+ T cells, and CD8a+ dendritic cells into tumors and suppressed tumor growth. Durable tumor regression was observed in mice bearing PTGES KO tumors that were given anti–PD-1 therapy. Analysis of a stage III melanoma tissue microarray revealed significant associations between high mPGES1 expression and low CD8+ infiltration, which correlated with a shorter patient survival.Conclusions:Our results are the first to illustrate a potential role for mPGES1 inhibition in melanoma immune evasion and selective targeting in supporting the durability of response to PD-1 checkpoint immunotherapy. More research effort in this drug development space is needed to validate the use of mPGES1 inhibitors as safe treatment options.

PDF file - 249K, Expression of PR protein and its target genes in Wnt7acre+ Mig-6f/f mice after P4 treatment.

PDF file - 250K, Steroid hormone regulation of epithelial Mig-6 in the murine uterus.

Endometrial cancer is preceded by endometrial hyperplasia, unopposed estrogen exposure, and genetic alterations, but the precise causes of endometrial cancer remain uncertain. Mig-6, mainly known as a negative regulator of the EGF receptor, is an important mediator of progesterone signaling in the uterus, where it mediates tumor suppression by modulating endometrial stromal–epithelial communications. In this study, we investigated the function of Mig-6 in the uterine epithelium using a tissue-specific gene knockout strategy, in which floxed Mig-6 (Mig-6f/f) mice were crossed to Wnt7a-Cre mice (Wnt7acre+Mig-6f/f). Wnt7acre+Mig-6f/f mice developed endometrial hyperplasia and estrogen-dependent endometrial cancer, exhibiting increased proliferation in epithelial cells as well as apoptosis in subepithelial stromal cells. We documented increased expression of NOTCH1 and BIRC3 in epithelial cells of Wnt7acre+Mig-6f/f mice and decreased expression of the progesterone receptor (PR) in stromal cells. Progesterone therapy controls endometrial growth and prevents endometrial cancer, but the effectiveness of progesterone as a treatment for women with endometrial cancer is less clear. We noted that the hyperplasic phenotype of Wnt7acre+Mig-6f/f mice was prevented by progesterone treatment, whereas this treatment had no effect in PRcre/+Mig-6f/f mice where Mig-6 was deleted in both the epithelial and stromal compartments of the uterus. In contrast, activation of progesterone signaling in the stroma regulated proliferation and apoptosis in the epithelium via suppression of ERα signaling. In summary, our results establish that epithelial Mig-6 functions as a critical tumor suppressor that mediates the ability of progesterone to prevent the development of endometrial cancer. Cancer Res; 73(16); 5090–9. ©2013 AACR.

Objective Stimulant use instigates abstinence syndrome in humans. miRNAs are a critical component for the pathophysiology of stimulant abstinence. Here we sought to identify a miRNA marker of methamphetamine abstinence in the circulating extracellular vesicles (cEVs). Methods miR-137 in the cEVs was quantified by qPCR in thirty-seven patients under methamphetamine abstinence and thirty-five age-matched healthy controls recruited from 2014 to 2016 from the general adult population in a hospital setting, Seoul, South Korea. Diagnostic power was evaluated by area under curve in the receiver-operating characteristics curve and other multiple statistical parameters. Results Patients under methamphetamine abstinence exhibited a significant reduction in cEV miR-137. Overall, cEV miR-137 had high potential as a blood-based marker of methamphetamine abstinence. cEV miR-137 retained the diagnostic power irrespective of the duration of methamphetamine abstinence or methamphetamine use. Interestingly, cEV miR-137 interacted with age: Control participants displayed an aging-dependent reduction of cEV miR-137, while methamphetamine-abstinent patients showed an aging-dependent increase in cEV miR-137. Accordingly, cEV miR-137 had variable diagnostic power depending on age, in which cEV miR-137 more effectively discriminated methamphetamine abstinence in the younger population. Duration of methamphetamine use or abstinence, cigarette smoking status, depressive disorder, or antidepressant treatment did not interact with the methamphetamine abstinence-induced reduction of cEV miR-137. Conclusion Our data collectively demonstrated that miR-137 in the circulating extracellular vesicles held high potential as a stable and accurate diagnostic marker of methamphetamine abstinence syndrome.

Purpose: Microsomal prostaglandin E2 synthase 1 (mPGES1) was evaluated as an important downstream effector of the COX2 pathway responsible for tumor-mediated immunosuppression in melanoma. Experimental Design: The analysis of a stage III melanoma tissue microarray (n = 91) was performed to assess the association between mPGES1, COX2, CD8, and patient survival. Pharmacologic inhibitors and syngeneic mouse models using PTGES-knockout (KO) mouse melanoma cell lines were used to evaluate the mPGES1-mediated immunosuppressive function. Results: We observed correlations in expression and colocalization of COX2 and mPGES1, which are associated with increased expression of immunosuppressive markers in human melanoma. In a syngeneic melanoma mouse model, PTGES KO increased melanoma expression of PD-L1, increased infiltration of CD8a+ T cells, and CD8a+ dendritic cells into tumors and suppressed tumor growth. Durable tumor regression was observed in mice bearing PTGES KO tumors that were given anti–PD-1 therapy. Analysis of a stage III melanoma tissue microarray revealed significant associations between high mPGES1 expression and low CD8+ infiltration, which correlated with a shorter patient survival. Conclusions: Our results are the first to illustrate a potential role for mPGES1 inhibition in melanoma immune evasion and selective targeting in supporting the durability of response to PD-1 checkpoint immunotherapy. More research effort in this drug development space is needed to validate the use of mPGES1 inhibitors as safe treatment options.

Somatic mutations can promote malignant transformation of airway epithelial cells and induce inflammatory responses directed against resultant tumors. Tumor-infiltrating T lymphocytes (TIL) in early-stage non–small cell lung cancer (NSCLC) secrete distinct proinflammatory cytokines, but the contribution of these TILs to tumor development and metastasis remains unknown. We show here that TILs in early-stage NSCLC are biased toward IL17A expression (Th17) when compared with adjacent tumor-free tissue, whereas Th17 cells are decreased in tumor infiltrating locoregional lymph nodes in advanced NSCLC. Mice in which Pten and Smad4 (Pts4d/d) are deleted from airway epithelial cells develop spontaneous tumors, that share genetic signatures with squamous- (SQ.2b), and adeno- (AD.1) subtypes of human NSCLC. Pts4d/d mice globally lacking in IL17a (Pts4d/dIl17a–/–) showed decreased tumor latency and increased metastasis. Th17 cells were required for recruitment of CD103+ dendritic cells, and adoptive transfer of IL17a-sufficient CD4+ T cells reversed early tumor development and metastasis in Pts4d/dIl17a–/– mice. Together, these findings support a key role for Th17 cells in TILs associated with the Pts4d/d model of NSCLC and suggest therapeutic and biomarker strategies for human SQ2b and AD1 lung cancer. Cancer Immunol Res; 6(6); 645–57. ©2018 AACR.

Objectives Lung cancer is the leading cause of cancer related deaths worldwide and mutation activating KRAS is one of the most frequent mutations found in lung adenocarcinoma. Identifying regulators of KRAS may aid in the development of therapies to treat this disease. The mitogen-induced gene 6, MIG-6, is a small adaptor protein modulating signaling in cells to regulate the growth and differentiation in multiple tissues. Here, we investigated the role of Mig-6 in regulating adenocarcinoma progression in the lungs of genetically engineered mice with activation of Kras. Materials and methods Using the CCSPCre mouse to specifically activate expression of the oncogenic KrasG12D in Club cells, we investigated the expression of Mig-6 in CCSPCreKrasG12D-induced lung tumors. To determine the role of Mig-6 in KrasG12D-induced lung tumorigenesis, Mig-6 was conditionally ablated in the Club cells by breeding Mig6f/f mice to CCSPCreKrasG12D mice, yielding CCSPCreMig-6d/dKrasG12D mice (Mig-6d/dKrasG12D). Results We found that Mig-6 expression is decreased in CCSPCreKrasG12D-induced lung tumors. Ablation of Mig-6 in the KrasG12D background led to enhanced tumorigenesis and reduced life expectancy. During tumor progression, there was increased airway hyperplasia, a heightened inflammatory response, reduced apoptosis in KrasG12D mouse lungs, and an increase of total and phosphorylated ERBB4 protein levels. Mechanistically, Mig-6 deficiency attenuates the cell apoptosis of lung tumor expressing KRASG12D partially through activating the ErbB4 pathway. Conclusions In summary, Mig-6 deficiency promotes the development of KrasG12D-induced lung adenoma through reducing the cell apoptosis in KrasG12D mouse lungs partially by activating the ErbB4 pathway.

Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC. LKB1 is frequently mutated in lung squamous cell carcinomas. Here, the authors show that sole LKB1 depletion is sufficient to drive the development of this cancer, where downstream defective MKK7-JNK1/2 signalling activates the ∆Np63/p63 pathway to induce subsequent epithelial cells transformation and tumour progression.

COX-2 and its product PGE2 enhance carcinogenesis and tumor progression, which has been previously reported in melanoma. As most COX inhibitors cause much toxicity, the downstream microsomal PGE2 synthase-1 (mPGES1) is a consideration for targeting. Human melanoma TMAs were employed for testing mPGES1 protein staining intensity and percentage levels, and both increased with clinical stage; employing a different Stage III TMA, mPGES1 intensity (not percentage) associated with reduced patient survival. Our results further show that iNOS was also highly expressed in melanoma tissues with high mPGES1 levels, and iNOS-mediated NO promoted mPGES1 expression and PGE2 production. An mPGES1-specific inhibitor (CAY10526) as well as siRNA attenuated cell survival and increased apoptosis. CAY10526 significantly suppressed tumor growth and increased apoptosis in melanoma xenografts. Our findings support the value of a prognostic and predictive role for mPGES1, and suggest targeting this molecule in the PGE2 pathway as another avenue toward improving melanoma therapy.

Korea is a country in which journal industry is rapidly increasing recently. KoreaScience is a typical Korean scientific and technical journal database that may be used to analyze Korean journals. A set of journal attributes reflecting the requirements in view of submitting authors was derived and some characteristics of KoreaScience journals such as subject distribution, launch year, publication frequency, publication language, and open access were quantitatively analyzed according to the journal attributes. As a result, it was found that Korean journals are published in almost all subject categories except some subject categories under Physics. The number of journal has been increased rapidly during the period between 1980s and 1990s. Journals published quarterly are 45%. Journals published in English are 31%. Open access journals are 26% while 72% free access.

Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC., LKB1 is frequently mutated in lung squamous cell carcinomas. Here, the authors show that sole LKB1 depletion is sufficient to drive the development of this cancer, where downstream defective MKK7-JNK1/2 signalling activates the ∆Np63/p63 pathway to induce subsequent epithelial cells transformation and tumour progression.

SUMMARY Lung cancer remains the leading cause of cancer death. Genome sequencing of lung tumors from patients with squamous cell carcinoma has identified SMAD4 to be frequently mutated. Here, we use a mouse model to determine the molecular mechanisms by which Smad4 loss leads to lung cancer progression. Mice with ablation of Pten and Smad4 in airway epithelium develop metastatic adenosquamous tumors. Comparative transcriptomic and in vivo cistromic analyses determine that loss of PTEN and SMAD4 results in ELF3 and ErbB2 pathway activation due to decreased expression of ERRFI1, a negative regulator of ERBB2 in mouse and human cells. The combinatorial inhibition of ErbB2 and Akt signaling attenuate tumor progression and cell invasion, respectively. Expression profile analysis of human lung tumors substantiated the importance of the ErbB2/Akt/ELF3 signaling pathway as both a prognostic biomarker and a therapeutic drug target for treating lung cancer., Graphical Abstract, In Brief Liu et al. now show that ablation of Smad4 and Pten in the pulmonary epithelium results in the development of metastatic adenosquamous lung tumors through activation of the ErbB2/ELF3/AKT pathway. ErbB2 activation in mice is due to downregulation of Errfi1 expression, a direct target of SMAD4.

Objective A genome-wide association study and several replication studies have shown significant association between BTBD9 gene single nucleotide polymorphisms and restless legs syndrome (RLS). The aim of this study is to investigate the association between the BTBD9 gene polymorphisms and antipsychotic-induced RLS in schizophrenic patients. Methods Restless legs syndrome symptoms were evaluated using the diagnostic criteria of the International Restless Legs Syndrome Study Group in 190 Korean schizophrenic patients. We genotyped the rs9357271 and rs3923809 polymorphisms of the BTBD9 gene in schizophrenic patients with (n = 96) and without (n = 94) RLS symptoms. Results There was a significant difference in the allele frequency (χ2 = 8.14, p = 0.004) of the rs9357271 polymorphism between schizophrenic patients with and without RLS symptoms. Significant genotypic association of this single nucleotide polymorphisms with RLS symptoms was also observed for the dominant model (χ2 = 10.32, p = 0.001) and heterozygous model (χ2 = 10.9, p = 0.001). When we compared the frequencies of the rs3923809–rs9357271 haplotypes between the two groups, the overall haplotype frequencies were significantly different (permuted p = 0.037), and the A-T haplotype was significantly more frequent in the RLS symptom group than in the no RLS symptom group (0.112 vs. 0.041, permuted p = 0.007). Conclusions These data suggest that the BTBD9 gene is associated with antipsychotic-induced RLS symptoms in schizophrenic patients. Copyright © 2013 John Wiley & Sons, Ltd.

Objective This study aimed to investigate whether the monoamine oxidase (MAO) A and B genes are associated with antipsychoticinduced restless legs syndrome (RLS) in schizophrenia. Methods We assessed antipsychotic-induced RLS symptoms in 190 Korean schizophrenic patients and divided the subjects into two groups: thosewith RLS symptoms (n ¼96) and thosewithout RLS symptoms (n ¼94). Genotyping was performed for thevariable number of tandem repeat (VNTR) polymorphism of the MAOA gene and A644G polymorphism of the MAOB gene. Results There was no significant difference in the genotype and allele frequencies of all polymorphisms investigated between these two groups. However, the result of global haplotype analysis showed a significant difference in haplotype frequencies between male subjects with and without RLS symptoms (p ¼0.013). The interaction between two polymorphisms had a significant effect on the RLS scores of both male (p ¼0.047) and female (p ¼0.028) patients. Conclusions These data do not suggest that the MAOA gene VNTR and MAOB gene A644G polymorphisms are associated with antipsychotic-induced RLS symptoms in schizophrenia. However, we found that the haplotype frequencies differed between the male schizophrenic patients with and without RLS symptom and the interaction between the two polymorphisms had a significant influence on the RLS scores of patients with schizophrenia. Copyright # 2010 John Wiley & Sons, Ltd. key words—restless legs syndrome; antipsychotics; schizophrenia; monoamine A and B genes; polymorphism; gene‐gene interaction

Mitogen-inducible gene 6 [Mig-6; Errfi1 (ErbB receptor feedback inhibitor 1); RALT (receptor-associated late transducer); gene 33] is a ubiquitously expressed adaptor protein containing CRIB, SH3 and 14-3-3 interacting domains and has been shown to negatively regulate EGF signaling. Ablation of Mig-6 results in a partial lethal phenotype in which surviving mice acquire degenerative joint diseases and tumors in multiple organs. We have determined that the early lethality in Mig-6-/- mice occurs in the perinatal period, with mice displaying abnormal lung development. Histological examination of Mig-6-/- lungs (E15.5-P3) revealed reduced septation, airway over-branching, alveolar type II cell hyperplasia, and disturbed vascular formation. In neonatal Mig-6-/- lungs, cell proliferation increased in the airway epithelium but apoptosis increased in the blood vessels. Adult Mig-6-/- mice developed features of chronic obstructive pulmonary disease (COPD); however, when Mig-6 was inducibly ablated in adult mice (Mig-6d/d), the lungs were normal. Knockdown of MIG-6 in H441 human bronchiolar epithelial cells increased phospho-EGFR and phospho-AKT levels as well as cell proliferation, whereas knockdown of MIG-6 in human lung microvascular endothelial (HMVEC-L) cells promoted their apoptosis. These results demonstrate that Mig-6 is required for prenatal and perinatal lung development, in part through the regulation of EGF signaling, as well as for maintaining proper pulmonary vascularization.

Objective This study examined whether the manganese superoxide dismutase (MnSOD) gene Ala–9Val single-nucleotide polymorphism (SNP) is associated with neuroleptic-induced tardive dyskinesia (TD) and the severity of the abnormal involuntary movements in Korean schizophrenic patients. Method We investigated whether the MnSOD gene Ala–9Val SNP is associated with TD in Korean schizophrenic patients with ( n = 83) and without ( n = 126) TD who were matched for exposure to antipsychotics and other relevant variables. Results Logistic regression analysis revealed that being older ( p = 0.026) was a risk factor for TD, but that there was no significant association between MnSOD gene and TD. Abnormal involuntary movements were more severe in carriers of the Ala allele than in noncarriers ( p = 0.044). Conclusion These findings do not support that the MnSOD gene Ala–9Val SNP is associated with TD in Korean schizophrenic patients. However, this polymorphism might be related to the severity of abnormal involuntary movements in this population.

Although intravenous drug users are a well-known route of hepatitis C virus (HCV) and hepatitis B virus (HBV) transmission, there is no data on the prevalence of HBV and HCV infection among intravenous drug users in Korea. In order to describe the prevalence of HBV and HCV infection, and to determine HCV genotypes in the population, serum samples were collected from 107 intravenous drug users during 2005–2006. Fifty-seven percent (n = 61) were HCV RNA positive and 51% (n = 55) were HBV DNA positive. Co-infection of HBV and HCV were found in 23% (n = 25). HCV genotypes 1b, 2a/2c, 2, 2b, and 3a were found in 38% (n = 23), 44% (n = 27), 8% (n = 5), 2% (n = 1), and 3% (n = 2), respectively. Moreover, mixed infections of genotypes 1b and 2a/2c were found in 5% (n = 3). When the number of patients with HCV genotype 1b compared with that of patients with genotype 2a/2c, HBV DNA titer was not significantly different by independent t-test (t = −0.881, P = 0.392 > 0.05) between the two patient groups. These results suggest that the prevalence of HBV and HCV infection among intravenous drug users is high showing over 50% in Korea and a strategic prevention program should be performed in this group to prevent further infection into local community. J. Med. Virol. 80:1570–1575, 2008. © 2008 Wiley-Liss, Inc.

Objective This study investigated whether the brain-derived neurotrophic factor ( BDNF ) gene Val66Met single-nucleotide polymorphism (SNP) is associated with antipsychotic-induced tardive dyskinesia (TD) in schizophrenia. Methods Genotyping was performed for the BDNF gene Val66Met SNP in Korean schizophrenic patients with ( n = 83) and without TD ( n = 126) who were matched for antipsychotic drug exposure and other relevant variables. Results The frequencies of genotypes ( χ 2 = 2.37, p = 0.306) and alleles ( χ 2 = 0.03, p = 0.867) did not differ significantly between these two groups. Conclusion These findings suggest that the BDNF polymorphism does not play a major role in the susceptibility to TD in schizophrenic patients.

The dopaminergic neurotransmission system is one of the major factors in development of alcoholism and also contributes to anxiety and depression. In this study, the associations of the dopamine receptor type 2 (DRD2) polymorphisms with the symptoms of anxiety were analyzed. A total of 573 alcoholics and 273 controls were enrolled in the study from the Korean population. Five DRD2 SNPs, including -32869 A>G, -32768 insdel C, +11890 C>G, +11915 C>T, and +32806 C>T, were genotyped using a TaqMan assay and analyzed with various alcoholic phenotypes. Although no DRD2 polymorphisms were associated with the risk of alcoholism, +32806C>T and Block2-ht1 showed associations (in dominant models) with both the state anxiety level scale (STAI-S) and the trait anxiety level scale (STAI-T) (P=0.004 and P=0.003, and P=0.01 and P=0.005, respectively). In addition, the -32768 insdel C also showed positive association with both anxiety level scales in recessive models (P=0.01 and P=0.02, respectively).

Multiple dopamine receptors in the dopaminergic system may be prime candidates for genetic influence on alcohol abuse and dependence due to their involvement in reward and reinforcing mechanisms. Genetic polymorphisms in dopamine receptor genes are believed to influence the development and/or severity of alcoholism. To examine the genetic effects of the Dopamine Receptor D1 (DRD) gene family (DRD1-DRD5) in the Korean population, 11 polymorphisms in the DRD gene family were genotyped and analyzed in 535 alcohol-dependent subjects and 273 population controls. Although none of the polymorphisms of DRD1-5 genes were found to be associated with the risk of alcoholism, one 5' UTR polymorphism in the DRD1 (DRD1-48A>G) gene was significantly associated with severity of alcohol-related problem, as measured by the Alcohol Use Disorders Identification Test (AUDIT) in a gene dose-dependent manner, i.e., 24.37 (+/-8.19) among patients with -48A/A genotype, 22.37 (+/-9.49) among those with -48A/G genotype, and 17.38 (+/-8.28) among those with -48G/G genotype (P=0.002). The genetic effects of DRD1-48A>G were further analyzed with other phenotypes among alcohol-dependent subjects. Interestingly, the DRD1-48A>A genotype was also found to be associated with novelty seeking (NC), harm avoidance (HA), and persistence (P) (P =0.01, 0.02, and 0.003, respectively). The information derived from this study could be valuable for understanding the genetic factors involved in alcoholic phenotypes and genetic distribution of the DRD gene family, and could facilitate further investigation in other ethnic groups.

We investigated the therapeutic effect of oculo-acupuncture on dogs induced with acute hepatic injury. Hepatic injury was induced by intraperitoneal injection with carbon tetrachloride ( CCl4) in 8 mongrel dogs (4 females and 4 males, aged 2 to 4 years). The dogs were divided into the control group (4 dogs) and the experimental group (4 dogs). The experimental group was treated with oculo-acupuncture at the liver/gallbladder regions plus the zhong jiao region of the eye after the induction of hepatic injury. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transpeptidase (GGT) activities were measured in both control and experimental groups. The serum AST, ALT, and GGT activities in the experimental group were decreased as compared to those in the control group. The significant differences were detected on the third day (AST, p < 0.05), second day (ALT, p < 0.05) and third day (GGT, p < 0.05) in the experimental group, respectively. Oculo-acupuncture alleviated acute liver damage induced by carbon tetrachloride in dogs was also confirmed by histopathological examination. We concluded that oculo-acupuncture at the liver/gallbladder regions plus the zhong jiao region was effective in the recovery of dogs from hepatic injury in a CCl4-induced model.

International marriage has increased drastically in South Korea in recent years, and by 2005, 13.6 per cent of marriages involved a foreign spouse. The purpose of this study is twofold: to explore the demographic demand and supply of foreign spouses in the marriage market in South Korea, and to examine how social positions of foreign wives vary by their place in the marriage market as determined by their nationality and ethnicity. Data show that the demand for foreign spouses is particularly strong among rural never-married and urban divorced Korean men. Among foreign wives, Chinese, especially Korean Chinese, tend to marry divorced Koreans, partly because many of them have also been married before. The Korean Chinese are the most autonomous among five groups of foreign wives examined, showing the highest rates of Korean citizenship, divorce-separation, and employment. Southeast Asian women tend to marry rural never-married men, and they are the most adaptive to the host society in the way they show among the highest rates of Korean citizenship and employment (after controlling for their poor Korean proficiency and short duration in Korea). Their divorce-separation rate is the lowest regardless of such control. This study demonstrates that marriage migrants adaptation to the host society differs significantly by nationality and ethnic origin.

The systematic shape control of colloidal nanocrystals including one-dimensional (1D) nanorods remains a key issue in the “bottom–up” approach of nanoscience. Here, we examine the anisotropic structural evolution of various semiconductor nanocrystals and systematically elucidate the key growth parameters for their shape control. The crystalline phase of nucleating seeds and kinetic growth regimes controlled by changing growth parameters are crucial for the determination of the 1D nanocrystal geometry.

Lymphangioleiomyomatosis (LAM) is a rare disease characterized by proliferation of abnormal smooth-muscle cells in the lungs, leading to functional loss and sometimes lung transplantation. Although the origin of LAM cells is unknown, several features of LAM provide clues. First, LAM cells contain inactivating mutations in genes encoding Tsc1 or Tsc2, proteins that limit mTORC1 activity. Second, LAM tumors recur after lung transplantation, suggesting a metastatic pathogenesis. Third, LAM is found almost exclusively in women. Finally, LAM shares features with uterine leiomyomas, benign tumors of myometrial cells. From these observations, we proposed that LAM cells might originate from uterine leiomyomas containing Tsc mutations. To test our hypothesis, and to develop mouse models for leiomyoma and LAM, we targeted Tsc2 deletion primarily in uterine cells. In fact, nearly 100% of uteri from uterine-specific Tsc2 knockout mice developed myometrial proliferation and uterine leiomyomas by 12 and 24 weeks, respectively. Myometrial proliferation and mTORC1/S6 activity were abrogated by the mTORC1 inhibitor rapamycin or by elimination of sex steroid production through ovariectomy or aromatase inhibition. In ovariectomized Tsc2 null mice, mTORC1/S6 activity and myometrial growth were restored by estrogen but not progesterone. Thus, even without Tsc2, estrogen appears to be required for myometrial mTORC1/S6 signaling and proliferation. Finally, we found Tsc2 null myometrial tumors in lungs of older Tsc2 uterine-specific knockout females, suggesting that lung LAM-like myometrial lesions may indeed originate from the uterus. This mouse model may improve our understanding of LAM and leiomyomas and might lead to novel therapeutic strategies for both diseases.

Endometrial cancer is preceded by endometrial hyperplasia, unopposed estrogen exposure, and genetic alterations, but the precise causes of endometrial cancer remain uncertain. Mig-6, mainly known as a negative regulator of the EGF receptor, is an important mediator of progesterone signaling in the uterus, where it mediates tumor suppression by modulating endometrial stromal–epithelial communications. In this study, we investigated the function of Mig-6 in the uterine epithelium using a tissue-specific gene knockout strategy, in which floxed Mig-6 (Mig-6f/f) mice were crossed to Wnt7a-Cre mice (Wnt7acre+Mig-6f/f). Wnt7acre+Mig-6f/f mice developed endometrial hyperplasia and estrogen-dependent endometrial cancer, exhibiting increased proliferation in epithelial cells as well as apoptosis in subepithelial stromal cells. We documented increased expression of NOTCH1 and BIRC3 in epithelial cells of Wnt7acre+Mig-6f/f mice and decreased expression of the progesterone receptor (PR) in stromal cells. Progesterone therapy controls endometrial growth and prevents endometrial cancer, but the effectiveness of progesterone as a treatment for women with endometrial cancer is less clear. We noted that the hyperplasic phenotype of Wnt7acre+Mig-6f/f mice was prevented by progesterone treatment, whereas this treatment had no effect in PRcre/+Mig-6f/f mice where Mig-6 was deleted in both the epithelial and stromal compartments of the uterus. In contrast, activation of progesterone signaling in the stroma regulated proliferation and apoptosis in the epithelium via suppression of ERα signaling. In summary, our results establish that epithelial Mig-6 functions as a critical tumor suppressor that mediates the ability of progesterone to prevent the development of endometrial cancer. Cancer Res; 73(16); 5090–9. ©2013 AACR.

Foreign wives were never a visible social group in Korea until recently. Korean society has experienced a fast-growth in international cross-border marriage during the past few decades. Marriage migration across borders has come to be pervasive in Asia and other regions. A large group of young women from Southeast Asian countries, who reside in Korea as workers and brides, have also received increasing attention from scholars and policy-makers because marriage immigrants have emerged as an important social issue in contemporary Korean society. From the 1990s, a steady increase in the visibility of immigrant foreign spouses and immigrant laborers in Korea has had an unsettling effect on the long-held image of the perceived homogeneity of Korean society. This study tries to analyze important phenomena current in the upsurge of international marriages in South Korea. First, it examines the recent trend in the state of marriage-based immigrants and their families. Second, the study seeks to delineate their basic socio-cultural needs by analyzing data collected by a nationwide sample survey conducted in 2006 by three sociologists, Drs. Seol, D.H., Lee, H.K. and Cho, S.N. under a grant from the Ministry of Gender Equalities in South Korea. The study thus tries to capture actual living conditions of marriage-based immigrants and their families in Korea, focusing on those factors deemed to be a prerequisite for long-term policy measures towards their successful social integration.

Tardive dyskinesia (TD) is a potential adverse effect of long-term treatment with antipsychotics. Previous studies have suggested a link between brain serotonergic systems and TD vulnerability. A recent report described that a serotonin 3 receptor (5-HTR3) agonist induced rhythmic movements in mice with complete paraplegia. Furthermore, it has been reported that the 5-HTR3 antagonist ondansetron is efficacious in the treatment of Gilles de la Tourette syndrome (GTS).The aim of the present study was to determine whether the 5-HTR3A gene C178T polymorphism is associated with antipsychotic-induced TD in Korean schizophrenia patients.We investigated 280 Korean schizophrenia patients. Subjects with TD (n = 105) and without TD (n = 175) were matched for antipsychotic drug exposure and other relevant variables.The distributions of genotypic (chi-squared = 3.55, p = 0.169) and allelic (chi-squared = 0.40, p = 0.528) frequencies did not differ between patients with and without TD. The total score on the Abnormal Involuntary Movement Scale also did not differ between the two genotype groups (F = 0.94, p = 0.391).The findings of the present study do not support the involvement of the 5-HTR3A gene C178T polymorphism in TD in Korean schizophrenia subjects.

Krüppel-like factor 12 (KLF12) is a transcription factor that plays a role in normal kidney development and repression of decidualization. KLF12 is frequently elevated in esophageal adenocarcinoma and has been reported to promote gastric cancer progression. Here, we examined the role of KLF12 in colorectal cancer (CRC). Indeed, KLF12 promotes tumor growth by directly activating early growth response protein 1 (EGR1). The levels of KLF12 and EGR1 correlate synergistically with a poor prognosis. These results indicate that KLF12 likely plays an important role in CRC and could serve as a potential prognostic marker and therapeutic target.

Lung tumorigenesis is a stochastic multistep process, during which different gene mutations accumulate, and Kras is an oncogene with the most frequent mutation in the Caucasian lung adenocarcinoma. Although Mig-6 (mitogen-inducible gene 6) has been shown to be a tumor suppressor gene in lung, skin and uterus, the interplay between Mig-6 and Kras in lung tumorigenesis remains elusive. Here, we found Mig-6 expression was down-regulated in oncogenic KrasG12D-induced lung tumors and Mig-6d/dKrasG12D mice showed an earlier onset of pulmonary tumor development and a significantly reduced life span as compared to KrasG12D mice though no obvious lung phenotype was observed in Mig-6d/d mice. Meanwhile, ablation of Mig-6 can change the lung epithelial cell fate in KrasG12D mice. Furthermore, lung tumor tissues of Mig-6d/dKrasG12D mice showed decreased cellular apoptosis, elevated EGF/Akt signaling and increased severity of inflammation as compared to those of KrasG12D mice. Thus, ablation of Mig-6 cooperated with oncogenic Kras in promoting lung tumorigenesis and this novel murine model of lung cancer can be applied for future study. Citation Format: Jian Liu, Sung-Nam Cho, Nili Jin, Seyed Javad Moghaddam, Jennifer Gilbert, Ignacio Wistuba, Francesco J. DeMayo. Mig-6 ablation cooperates with oncogenic Kras in promoting mouse lung tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4168.