Use of cutting-edge RNA-sequencing technology to identify biomarkers and potential therapeutic targets in canine and feline cancers and other diseases.

With the growing interest in companion animals and the rapidly expanding animal healthcare and pharmaceuticals market worldwide. With the advancements in RNA-sequencing (RNA-seq) technology, it has become a valuable tool for understanding biological processes in companion animals and has multiple applications in animal healthcare. Historically, veterinary diagnoses and treatments relied solely on clinical symptoms and drugs used in human diseases. However, RNA-seq has emerged as an effective technology for studying companion animals, providing insights into their genetic information. The sequencing technology has revealed that not only messenger RNAs (mRNAs) but also non-coding RNAs (ncRNAs) such as long ncRNAs and microRNAs can serve as biomarkers. Based on the examination of RNA-seq applications in veterinary medicine, particularly in dogs and cats, this review concludes that RNA-seq has significant potential as a diagnostic and research tool. It has enabled the identification of potential biomarkers for cancer and other diseases in companion animals. Further research and development are required to maximize the utilization of RNA-seq for improved disease diagnosis and therapeutic targeting in companion animals.

Occupational Risk Factors for Stroke: A Comprehensive Review.

For primary prevention, it is important for public health and clinical medicine to identify and characterize modifiable risk factors of stroke. In existing literature, the impact of occupational variables on ischemic and hemorrhagic stroke has been extensively studied. This review summarizes the available data on the significance of occupational variables in stroke. The results of this review suggest that there is sufficient evidence for the relationship between increased risk of stroke and job stress, working in extreme temperatures, long working hours, and/or shift work. The association between long working hours and occupational exposure to noise and chemicals remains inconclusive although several studies have reported this finding. This review will act as a step toward future research and provide information that may serve as a baseline for developing targeted interventions to prevent stroke in the working population.

Suaeda glauca Attenuates Liver Fibrosis in Mice by Inhibiting TGFß1-Smad2/3 Signaling in Hepatic Stellate Cells.

Chronic liver injury due to various hepatotoxic stimuli commonly leads to fibrosis, which is a crucial factor contributing to liver disease-related mortality. Despite the potential benefits of Suaeda glauca (S. glauca) as a natural product, its biological and therapeutic effects are barely known. This study investigated the effects of S. glauca extract (SGE), obtained from a smart farming system utilizing LED lamps, on the activation of hepatic stellate cells (HSCs) and the development of liver fibrosis. C57BL/6 mice received oral administration of either vehicle or SGE (30 or 100 mg/kg) during CCl4 treatment for 6 weeks. The supplementation of SGE significantly reduced liver fibrosis induced by CCl4 in mice as evidenced by histological changes and a decrease in collagen accumulation. SGE treatment also led to a reduction in markers of HSC activation and inflammation as well as an improvement in blood biochemical parameters. Furthermore, SGE administration diminished fibrotic responses following acute liver injury. Mechanistically, SGE treatment prevented HSC activation and inhibited the phosphorylation and nuclear translocation of Smad2/3, which are induced by transforming growth factor (TGF)-ß1 in HSCs. Our findings indicate that SGE exhibits anti-fibrotic effects by inhibiting TGFß1-Smad2/3 signaling in HSCs.

Genetically engineered neural stem cells expressing cytosine deaminase and interferon-beta enhanced T cell-mediated antitumor immunity against gastric cancer in a humanized mouse model.

AIMS: Gastric cancer (GC) is an invasive, fatal disease with a poor prognosis. Gene-directed enzyme prodrug therapy via genetically engineered neural stem cells (GENSTECs) has been widely studied in various malignancies, such as breast, ovarian, and renal cancer. In this study, the human neural stem cells expressing cytosine deaminase and interferon beta (HB1.F3.CD.IFN-ß) cells were applied to convert non-toxic 5-fluorocytosine to cytotoxic 5-fluorouracil and secrete IFN-ß. MATERIALS AND METHODS: Human lymphokine-activated killer cells (LAKs) were generated by stimulating human peripheral blood mononuclear cells (PBMCs) by interleukin-2, and we evaluated the cytotoxic activity and migratory ability of LAKs co-cultured with GNESTECs or their conditioned media in vitro. A GC-bearing human immune system (HIS) mouse model was generated by transplanting human PBMCs followed by subcutaneous engraftment of MKN45 cells in NSG-B2m mice to evaluate the involvement of T cell-mediated anti-cancer immune activity of GENSTECs. KEY FINDINGS: In vitro studies showed the presence of HB1.F3.CD.IFN-ß cells facilitated the migration ability of LAKs to MKN45 cells and activated their cytotoxic potential. In MKN45-xenografted HIS mice, treatment with HB1.F3.CD.IFN-ß cells resulted in increased cytotoxic T lymphocyte (CTL) infiltration throughout the tumor, including the central area. Moreover, the group treated to HB1.F3.CD.IFN-ß showed increased granzyme B expression in the tumor, eventually enhancing the tumor-killing potential of CTLs and significantly delaying tumor growth. SIGNIFICANCE: These results indicate that the HB1.F3.CD.IFN-ß cells exert anti-cancer effects on GC by facilitating the T cell-mediated immune response, and GENSTECs are a promising therapeutic strategy for GC.

Effects of CCN6 overexpression on the cell motility and activation of p38/bone morphogenetic protein signaling pathways in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancer types that is highly resistant to conventional treatments, such as chemotherapy and radiotherapy. As the demand for more effective therapeutics for PDAC treatment increases, various approaches have been studied to develop novel targets. The cellular communication network (CCN) family is a matricellular protein that modulates various cellular functions, including cell adhesion, proliferation, migration, and invasiveness. Despite this, little is known about the role of CCN6 in PDAC. The current study investigated the role of CCN6 in PDAC by generating CCN6-overexpressing PANC-1 cells (PANC-1-CCN6) by infecting lentivirus particles containing CCN6. PANC-1-CCN6 induces cell viability and tumorigenesis than PANC-1 cells with empty vector (control). The PANC-1-CCN6 formed more colonies, and the size of spheroids increased compared to the control. The upregulation of CCN6 enhances the expression of bone morphogenetic proteins (BMPs) genes and the upregulation of p38 mitogen-activated protein kinases (MAPKs). In PANC-1-CCN6 cells, the levels of N-cadherin, VEGF, and Snail expression were higher than the control, while E-cadherin expression was lower, which is associated with upregulation of epithelial-to-mesenchymal transition (EMT). Consistent with the changes in EMT-related proteins in PANC-1-CCN6, the migratory ability and invasiveness were enhanced in PANC-1-CCN6. Xenografted PANC-1-CCN6 in immunocompromised mice exhibited accelerated tumor growth than the control group. In immunohistochemistry (IHC), the PANC-1-CCN6 xenografted tumor showed an increased positive area of PCNA and Ki-67 than the control. These results suggest that CCN6 plays a tumorigenic role and induces the metastatic potential by the p38 MAPK and BMPs signaling pathways. Although the role of CCN6 has been introduced as an antitumor factor, there was evidence of CCN6 acting to cause tumorigenesis and invasion in PANC-1.

The association between shift work and the incidence of reflux esophagitis in Korea: a cohort study.

Shift work has adverse health effects such as diabetes, cardiovascular disease, sleep disturbance, depression, and breast cancer. Gastro-esophageal reflux disease (GERD) results in lesions such as reflux esophagitis (RE) and Barrett's esophagus. This study investigated the association between shift work and RE. A cohort study was conducted with 140,553 participants who were followed up at least once from 2012 to 2018. Type of working and shift types were collected using standardized questionnaires. Esophagogastroduodenoscopy (EGD) was performed by experienced endoscopists who were blinded to the aims of this study. According to the Los Angeles classification, RE was categorized based on the extent of esophageal mucosal breaks. During the 469,217.2 person-years of follow-up, 35,185 participants developed incident cases of RE. The multivariable adjusted hazard ratio (95% confidence intervals) for incident cases comparing shift work to fixed day work was 1.09 (1.04-1.13). This association was more strongly observed in the younger age group (18-39 years old) and the female group. In conclusion, shift work was significantly associated with the incidence of RE. Particularly, the results were more significant in the younger and female groups.

TGF-ß2 antisense oligonucleotide enhances T-cell mediated anti-tumor activities by IL-2 via attenuation of fibrotic reaction in a humanized mouse model of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with high mortality and recurrence rate. In this study, we generated a human immune system mouse model by transplanting human peripheral blood mononuclear cells into NSG-B2m mice followed by xenografting AsPC-1 cells, after which we assessed the role of transforming growth factor-ß2 (TGF-ß2) in T-cell-mediated anti-tumor immunity. We observed that inhibiting the TGF-ß2 production by TGF-ß2 antisense oligonucleotide (TASO) combined with IL-2 delays pancreatic cancer growth. Co-treatment of TASO and IL-2 had little effect on the SMAD-dependent pathway, but significantly inhibited the Akt phosphorylation and sequentially activated GSK-3ß. Activation of GSK-3ß by TASO subsequently suppressed ß-catenin and α-SMA expression and resulted in attenuated fibrotic reactions, facilitating the infiltration of CD8 + cytotoxic T lymphocytes (CTLs) into the tumor. TGF-ß2 inhibition suppressed the Foxp3 + regulatory T-cells in peripheral blood and tumors, thereby enhancing the tumoricidal effects of CTLs associated with increased granzyme B and cleaved caspase-3. Moreover, changes in the T-cell composition in peripheral blood and at the tumor site by TASO and IL-2 induced the increase of pro-inflammatory cytokines such as IFN-γ and TNF-α and the decrease of anti-inflammatory cytokines such as TGF-ßs. These results indicate that the TGF-ß2 inhibition by TASO combined with IL-2 enhances the T-cell mediated anti-tumor immunity against SMAD4-mutated PDAC by modulating the tumor-associated fibrosis, suggesting that TASO in combination with IL-2 may be a promising immunotherapeutic intervention for PDAC.

Characteristics of workers' compensation claim applications for COVID-19 infections in South Korea.

This study aimed to identify the major industries and jobs with the highest proportion of workers' compensation (WC) claims for COVID-19, characterize COVID-19 WC claims in terms of their demographic properties and disease severity, and identify factors influencing the approval of COVID-19 WC claims as occupational disease. A total of 488 workers who submitted COVID-19-related claims to the Korea Workers' Compensation and Welfare Service (KWCWS) from January 2020 to July 2021 were analyzed. A Fisher's exact test was employed to associate the severity of COVID-19 infection with demographic properties. The highest proportion of all COVID-19 WC claims compensated as occupational disease (N=462) were submitted by healthcare workers (HCW=233, 50%), while only 9% (N=41) of the total originated from manufacturing industries. The 5% (N=26) of the COVID-19 WC claims accepted were evaluated as severe (N=15) and acute respiratory distress syndrome (N=9). A total of 71% (N=329) of the COVID-19 patients compensated (N=462) were from workplaces with infection clusters. A total of 26 WC cases were rejected for various reasons, including unclear infection routes, infection at private gatherings (including within families), no diagnosis, and more. Given our findings, we suggest an official system should be established to detect and compensate more job-associated infectious diseases like COVID-19.

Overexpression of KiSS1 Induces the Proliferation of Hepatocarcinoma and Increases Metastatic Potential by Increasing Migratory Ability and Angiogenic Capacity.

Liver cancer has a high prevalence, with majority of the cases presenting as hepatocellular carcinoma (HCC). The prognosis of metastatic HCC has hardly improved over the past decade, highlighting the necessity for liver cancer research. Studies have reported the ability of the KiSS1 gene to inhibit the growth or metastasis of liver cancer, but contradictory research results are also emerging. We, therefore, sought to investigate the effects of KiSS1 on growth and migration in human HCC cells. HepG2 human HCC cells were infected with lentivirus particles containing KiSS1. The overexpression of KiSS1 resulted in an increased proliferation rate of HCC cells. Quantitative polymerase chain reaction and immunoblotting revealed increased Akt activity, and downregulation of the G1/S phase cell cycle inhibitors. A significant increase in tumor spheroid formation with upregulation of ß-catenin and CD133 was also observed. KiSS1 overexpression promoted the migratory, invasive ability, and metastatic capacity of the hepatocarcinoma cell line, and these effects were associated with changes in the expressions of epithelial mesenchymal transition (EMT)-related genes such as E-cadherin, N-cadherin, and slug. KiSS1 overexpression also resulted in dramatically increased tumor growth in the xenograft mouse model, and upregulation of proliferating cell nuclear antigen (PCNA) and Ki-67 in the HCC tumors. Furthermore, KiSS1 increased the angiogenic capacity by upregulation of the vascular endothelial growth factor A (VEGF-A) and CD31. Based on these observations, we infer that KiSS1 not only induces HCC proliferation, but also increases the metastatic potential by increasing the migratory ability and angiogenic capacity.

The role of KiSS1 gene on the growth and migration of prostate cancer and the underlying molecular mechanisms.

Metastatic prostate cancers have a high mortality rate. KiSS1 was originally identified as a metastasis suppressor gene in metastatic melanoma and breast cancer, but its role in prostate cancer has been contradictory. This study was therefore undertaken to investigate the effects of KiSS1 overexpression on the growth and migration of human metastatic prostate cancer cells. We first tested the effect of KiSS1 overexpression on the growth and migration of DU145 human metastatic prostate cancer cells in vitro. DU145 cells were infected with the culture medium of 293T cells, which produce lentivirus particles containing KiSS1. A 2.5-fold increase in proliferation of KiSS1-overexpressing cancer cells was observed, and these cells formed tumor spheroids about 3 times larger than the vector control group. qPCR and immunoblotting revealed the association between increased cell growth and regulation of the PI3K/Akt and cell cycle genes, and also that increases in ß-catenin and CD133 contribute to tumor aggregation. KiSS1 overexpression resulted in upregulation of the ß-arrestin1/2 and Raf-MEK-ERK-NF-κB pathways via KiSS1R. Moreover, the migration and invasion of KiSS1-overexpressing cells were determined to be faster than the control group, along with 1.6-fold increased metastatic colonization of the KiSS1-overexpressing cancer cells. These were associated to the regulation of EMT gene expressions, such as E-cadherin and N-cadherin, and the upregulation of MMP9. In a xenograft mouse model inoculated with DU145 cells infected GFP or KiSS1 via a lentiviral vector, KiSS1 statistically significantly increased the tumor growth, with upregulation of PCNA and Ki-67 in the tumor tissues. In addition, KiSS1 increased the angiogenic capacity by upregulating VEGF-A and CD31, both in vitro and in vivo. Taken together, our results indicate that KiSS1 not only induces prostate cancer proliferation, but also promotes metastasis by increasing the migration, invasion, and angiogenesis of malignant cells.

The association between prolonged sedentary time and coronary artery calcification in young healthy men in Korea: a cohort study.

Coronary artery calcium score (CACS) is a useful method for predicting coronary artery disease in asymptomatic adults. In this study, we investigated the association between prolonged sedentary time and CACS. A cohort study was conducted in 14949 men with negative CACS (CACS = 0) at baseline who were followed up at least once. Sedentary time was categorized into < 7, 7-8, and ≥ 9 h/day. CACS was calculated by cardiac tomography. During 60,112.1 person-years of follow-up, 569 participants developed positive CACS. The multivariable adjusted hazard ratios (95% confidence intervals) for incident positive CACS comparing sedentary times of 7-8 h/day and ≥ 9 h/day to sedentary time of < 7 h/day were 1.25 (0.97-1.62) and 1.28 (1.03-1.59), respectively. This association was more strongly observed in the non-obese group (BMI < 25 kg/m2). In contrast, in the obese group (BMI ≥ 25 kg/m2), there was no significant association between sedentary time and incidence of positive CACS. Prolonged sedentary time was significantly associated with incidence of positive CACS in the study. CACS is also an effective screening tool for predicting future cardiovascular events in asymptomatic patients. Therefore, CACS can be an effective screening method for predicting coronary artery diseases in people with prolonged sedentary time, especially in metabolically healthy people.

Epithelial-Mesenchymal Transition-Inducing Factors Involved in the Progression of Lung Cancers.

Although there have been advances in cancer therapy and surgical improvement, lung cancer has the lowest survival rate (19%) at all stages. This is because most patients are diagnosed with concurrent metastasis, which occurs due to numerous related reasons. Especially, lung cancer is one of the most common and malignant cancers in the world. Although there are advanced therapeutic strategies, lung cancer remains one of the main causes of cancer death. Recent work has proposed that epithelialmesenchymal transition (EMT) is the main cause of metastasis in most cases of human cancers including lung cancer. EMT involves the conversion of epithelial cells, wherein the cells lose their epithelial abilities and become mesenchymal cells involved in embryonic development, such as gastrulation and neural crest formation. In addition, recent research has indicated that EMT contributes to altering the cancer cells into cancer stem cells (CSCs). Although EMT is important in the developmental stages, this process also activates lung cancer progression, including complicated and diverse signaling pathways. Despite the numerous investigations on signaling pathways involved in the progression of lung cancer, this malignancy is considered critical for treatment. EMT in lung cancer involves many transcription factors and inducers, for example, Snail, TWIST, and ZEB are the master regulators of EMT. EMT-related factors and signaling pathways are involved in the progression of lung cancer, proposing new approaches to lung cancer therapy. In the current review, we highlight the signaling pathways implicated in lung cancer and elucidate the correlation of these pathways, indicating new insights to treat lung cancer and other malignancies.

Cross-sectional association between long working hours and liver function: the Kangbuk Samsung Health Study.

OBJECTIVES: Although the effects of long working hours on liver function remain unclear, in South Korea, there is a social perception that long working hours are associated with poor liver function. Thus, long working hours have recently become a major issue. This study aimed to determine the association between long working hours and liver function, as indicated by the alanine transaminase (ALT) levels. DESIGN: Cross-sectional study. SETTING: Large university hospitals in Seoul and Suwon, South Korea. PARTICIPANTS: Workers in formal employment who underwent a comprehensive health examination at the Kangbuk Samsung Hospital Total Healthcare Centre clinics in Seoul and Suwon, South Korea, between January 2011 and December 2018. Of the 386 488 participants, 212 421 met the inclusion criteria and were included in the analysis. PRIMARY OUTCOME MEASURE: ALT elevation. RESULTS: The participants were predominantly well-educated (86.1%), male (69.3%) and in their 30s (49.6%). In total, 13.4% of the participants presented ALT elevation (>40 IU/L). There was no significant association between working hours and ALT elevation in the general population and in the hepatitis B surface antigen (HBsAg)-negative group. Conversely, in the HBsAg-positive group, working >60 hours per week compared with 35-40 hours per week was significantly associated with ALT elevation. The association was more pronounced in those with ALT levels >80 IU/L (OR 1.94, 95% CI 1.24 to 3.01) than in those with ALT levels >40 IU/L (OR: 1.45, 95% CI 1.20 to 1.75). The p values for trend were <0.05. CONCLUSIONS: Long working hours were associated with ALT elevation only in hepatitis B virus carriers and not in the general population. Provided that there is adherence to the legal working hours, there is no need to further restrict working hours for liver health, irrespective of HBsAg status.

Mental health impact on a humidifier disinfectant disaster victim: a case report.

In Korea, the cause of lung disease of unknown origin was identified as humidifier disinfectants in November 2011. In February 2017, the 'Special Act on Remedy for Damage Caused by Humidifier Disinfectants' was promulgated. Even though emotional and mental injuries caused by humidifier disinfectants have been reported, the focus of the special act has been on physical injury only, and criteria for recognizing mental health impact have not been considered. This case considers emotional and mental injury caused by humidifier disinfectants. After a humidifier disinfectant was used from January 2005 to April 2006, the patient's son aged 20 months was hospitalized with respiratory symptoms, and he died within two weeks. Also, the patient was hospitalized for a month with the same symptoms, and then she led a normal life with no symptoms. After both mother and son were diagnosed with definite (level 1) humidifier disinfectant lung injury (HDLI) in 2017, she took to drinking alcohol because of extreme guilt over her son's death. In March 2018 she died from acute liver failure due to alcohol use disorder. The patient's death was caused by continuous alcoholism, due to emotional and mental trauma caused by her son's death after HDLI was revealed as the cause. The government did not acknowledge her death was due to humidifier disinfectants, but the company that sold the humidifier disinfectants recognized her as a victim and compensated the family of the victim. There are still lots of psychological responses among humidifier disinfectant disaster victims. Mental health impact on humidifier disinfectant victims should be considered more carefully, and institutional improvements should be made into establish psychological interventions and measures.

Problems with diagnostic criteria for humidifier disinfectant lung injury (HDLI): two cases of radiologically improved HDLI.

BACKGROUND: In Korea, to investigate the casual relationship between humidifier disinfectant and lung disease, four rounds of investigation and judgment were conducted. During this investigation, two adults who performed lung biopsy were recognized for their relevance between humidifier disinfectants and lung disease. At first, we did not think of the relationship to humidifier disinfectant because chest computed tomography (CT) finding of 2 cases were improved. However, they performed lung biopsy and it showed typical humidifier disinfectant lung injury (HDLI) pathologic findings, they could be recognized as HDLI. We report these cases here. CASE PRESENTATION: We selected 2 cases from the fourth-round investigation at Kangbuk Samsung Hospital. Patient of case 1 used humidifier disinfectants since September 2010. The patient was admitted 6 months later to the intensive care unit (ICU) due to severe dyspnea. Pathology following a lung biopsy revealed typical HDLI finding which was determined to be due to humidifier disinfectant exposure. Patient of case 2 used humidifier disinfectant from 2001 to 2008 for about 3 months each winter. The patient's cough and sputum production symptoms began in December of 2007. The patient was admitted to the respiratory medicine department due to worsening dyspnea. Pathology following a lung biopsy revealed typical HDLI finding. This was determined to have been caused by humidifier disinfectant exposure. CONCLUSIONS: Because the typical radiologic findings associated with HDLI can improve over time, it is necessary to consider the revision of current diagnostic criteria that the presence of radiologic findings is important.

Relationship between working hours and probability to take alopecia medicine among Korean male workers: a 4-year follow-up study.

BACKGROUND: Many studies have reported the negative effects of long working hours on various health problems. However, whether hair loss is associated with working hours has been rarely investigated so far. The main purpose of this study is to explore the relationship between long working hours and the development of alopecia among Korean male workers. METHODS: A total of 13,391 male workers not to take alopecia medicine in 2013 were followed up to see if they have alopecia medicine after 4 years, and that was used to confirm the alopecia development. Weekly working hours were categorized into three groups: reference working hours (RWH; < 40 hours/week), long working hours (LWH, 40-52 hours/week), and much longer working hours (MLWH; > 52 hours/week). Multiple logistic regression analyses were conducted to investigate the relationship between long working hours and the development of alopecia after adjusting age, marital status, education, monthly household income, smoking, and work schedule within strata of the covariates. RESULTS: Long working hours was significantly related to the development of alopecia. The adjusted odds ratios (ORs) for the development of alopecia were 1.57 (95% confidence interval [CI]: 1.21-2.05) for LWH group and 1.74 (95% CI: 1.23-2.47) for MLWH group relative to RWH group. CONCLUSIONS: Our findings suggest that unintentional development of alopecia is another potential health consequence of long working hours among Korean male workers. Preventive interventions to promote appropriate and reasonable working hours are required in our society.

The association between long working hours and marital status change: middle-aged and educated Korean in 2014-2015.

BACKGROUND: We investigated the association between long workhours and marital status change from married to divorced or separated status that might have bad health effects. METHODS: A total of 40,654 participants with married status in 2014 were followed up in 2015. Weekly workhours were categorized into four groups: ≤ 40, 41-52, 53-60, and > 60 hours per week. Univariate and multivariate logistic regression analyses were performed to determine the relationship between groups of workhours and marital status change after adjusting for age, total monthly household income, working type, and depression with sex stratification. RESULTS: The study populations consisted of 8,346 (20.5%) females and 32,308 (79.5%) males. Odd ratios (ORs) of marital status change for females working for more than 60 hours per week was 4.26 (95% confidence interval [CI]: 1.25-14.5), when working less than or equal to 40 hours per week was used as reference in the crude model. ORs of working more than 60 hours per week was 4.57 (95% CI: 1.02-20.5) in female workers when considering age, total household earning per month, working type of daytime, and depression in a dose-response manner. However, for male workers, long workhours were not significantly related to change of marriage status. CONCLUSIONS: Long workhours for more than 60 hours per week had significantly higher risk of divorce or separation in females, but not in males. Further follow-up studies are needed to evaluate long term effects of long workhours on divorce risk.

RORα suppresses interleukin-6-mediated hepatic acute phase response.

Acute liver failure (ALF) is characterized by loss of liver function in response to sustained augmentation of the acute-phase response (APR) in the liver, which can progress even to death. Although the inflammatory interleukin-6 (IL-6)-axis is a crucial factor that drives the hepatic APR by releasing diverse acute-phase proteins (APPs), therapeutic strategies to block the IL-6-STAT3-mediated APR are not well developed. Here, we show that the nuclear receptor retinoic acid-related orphan receptor α (RORα) limits APR-mediated liver injury by inhibiting the hepatic IL-6-STAT3 signaling pathway. Administration of JC1-40, an RORα activator, diminished diethylnitrosamine-induced acute liver injury and repressed transcriptional expression of APPs such as CXCL1 and LCN2 in mice. IL-6-mediated activation of STAT3 was repressed after RORα activation by either adenoviral infusion of RORα or JC1-40 treatment in primary hepatocytes. Activation of RORα decreased transcriptional expression of IL-6 receptor α, an upstream activator of STAT3, both in vitro and in vivo. This may be one mechanism underlying the RORα-mediated inhibition of STAT3. Taken together, our results suggest that RORα is a regulator of the hepatic IL-6-STAT3 signaling pathway and may be a new therapeutic target for treating APR-associated inflammatory ALF.

Paradoxical relationship between body mass index and bone mineral density in patients with non-small cell lung cancer with brain metastasis.

BACKGROUND AND PURPOSE: Low body mass index (BMI) at presentation has been reported to be associated with higher incidence and mortality of lung cancer, but studies on the relationship between brain metastasis and BMI at presentation are lacking. This study aimed to evaluate the association between brain metastasis and BMI and bone mineral density (BMD) in NSCLC. METHODS: We retrospectively enrolled patients with non-small cell lung cancer who underwent brain magnetic resonance imaging with contrast within 3 months of diagnosis. The BMI was collected, and the BMD was measured in Hounsfield unit (HU) on initial staging computed tomography scans. The independent relationship between BMI and BMD was assessed using multivariable linear regression according to the presence of brain metastasis. RESULTS: A total of 356 consecutive NSCLC patients were enrolled in the study over a 8-year period in a single institution. Lower BMI with higher BMD was an independent predictive factor for brain metastasis in patients with NSCLC, relative to the other group (HR, 2.03; 95% CI, 1.21 to 3.40; P = 0.007). We also found a significant negative correlation between BMI and BMD among patients with NSCLC with brain metastases (B, -3.343; 95% confidence interval, -6.352 to -0.333; P = 0.030). CONCLUSIONS: Brain metastasis may possibly be associated with lower BMI and higher BMD in NSCLC patients. We expect that these results may facilitate future predictions of brain metastases during the clinical course of NSCLC and enhance our understanding of the underlying mechanisms that link brain metastases and lung cancer.

Standardized Seed Extract of Quisqualis indica (HU-033) Attenuates Testosterone Propionate-Induced Benign Prostatic Hyperplasia via α1-Adrenergic Receptors and Androgen/Estrogen Signaling.

Benign prostatic hyperplasia (BPH) is an age-related disease characterized by prostatic enlargement and is the most common urologic symptoms in elderly men 60 years of age and older. Previously, we documented that 70% ethanol (EtOH) seed extract of Quisqualis indica (QI) attenuates pathological condition of testosterone propionate (TP)-induced BPH rat model via modulation of proliferation and apoptosis of prostate cells. Based on this potential of QI, we produced standardized seed extract of QI (HU-033) in order to prove further mechanisms. In this study, we aimed to suggest further mechanisms underlying the relationship between BPH and HU-033. Through not only cellular and nuclear receptor functional assays, but TP-mediated BPH rat model treated with HU-033, we demonstrated that HU-033 exerted antagonist effect on α1A- and α1D-adrenergic receptors in vitro and inhibitory effect on protein expression of androgen receptor and estrogen receptor alpha in vivo. Taken together, these results suggest that HU-033 is a novel candidate for the management of BPH.