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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.

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.

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).

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.

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.

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.

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.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.There was a significant difference in the allele frequency (χ(2) = 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 (χ(2) = 10.32, p = 0.001) and heterozygous model (χ(2) = 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).These data suggest that the BTBD9 gene is associated with antipsychotic-induced RLS symptoms in schizophrenic patients.

Objective The cause of restless legs syndrome (RLS) has not yet been ascertained, but one of the most promising theories involves dopaminergic deficiency. In accordance with this theory, we assumed that the prevalence of RLS would be higher among schizophrenics treated with antipsychotics than in the normal population. The purpose of this study was to establish the prevalence, characteristics, and clinical correlates of RLS in schizophrenic patients undergoing treatment with antipsychotics. Methods A total of 182 hospitalized schizophrenic patients and 108 age- and sex-matched normal controls were enrolled. The presence of RLS and its severity were assessed using the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria and the IRLSSG rating scale, respectively. The Athens Insomnia Scale (AIS), Brief Psychiatric Rating Scale (BPRS), and Barnes Akathisia Rating Scale (BARS) were used to evaluate insomnia, global psychiatric symptoms, and akathisia, respectively, in schizophrenic patients. Results Of the 182 schizophrenic patients, 39 (21.4%) were found to have RLS and 87 (47.8%) met at least one of the RLS diagnostic criteria. The prevalence of RLS was significantly higher in the schizophrenia group than in the control group (p = 0.009), as were the RLS scores (p

Major depressive disorder and alcohol dependence are common and serious mental illnesses. There is a great interest in discovering useful treatments for both mood symptoms and alcohol abuse in those patients with depressive disorders and comorbid alcohol dependence. The primary purpose of this study was to evaluate the effectiveness and tolerability of mirtazapine for the treatment of patients with alcohol dependence comorbid with a depressive disorder in an open label, naturalistic multicentre treatment setting. The 17-item Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS) and the Clinical Global Impression-Severity (CGI-S) scale were measured at baseline and at weeks 4 and 8 for the assessment of treatment effectiveness. Alcohol craving was measured using the Obsessive Compulsive Drinking Scale (OCDS) and the Visual Analog Scale for Craving (VAS). This study showed a statistically significant reduction of the scores on the HDRS (13.9+/-7.3, p

Background The aim of the current study was to explore changes of relative regional cerebral blood flow (rCBF) in short-term and long-term abstinent methamphetamine (MA) users. Methods Relative rCBF in 40 abstinent MA users and 23 healthy comparison subjects was compared by the technetium-99m-hexamethyl-propylene amine oxime ( 99m Tc-HMPAO) single photon emission computed tomography (SPECT). Relative rCBF in areas that were found to differ significantly was also compared in groups of MA users with short-term ( Results MA users showed decreased relative rCBF in the right anterior cingulate cortex (Brodmann area 32) relative to healthy comparison subjects. Long-term abstinent MA users had significantly greater rCBF than short-term abstinent MA users. Conclusions We report that abstinent MA users have decreased rCBF in the anterior cingulate cortex with smaller relative decreases in subjects with prolonged abstinence.

Persistent endometriosis after total hysterectomy and both salpingo-oophorectomy (TH with BSO) is a rare condition and the etiology is uncertain. The exact incidence of persistent endometriosis after definitive surgery is not known. In addition, the treatment of persistent endometriosis after complete surgical excision is controversial. We report a case of persistent endometriosis with vaginal and sigmoid-colonic invasion after TH with BSO. The lesions were not responsive to hormonal therapy. The patient was managed successfully by therapeutic pelvic radiation.