Hemoglobin Subunit Theta 1 Promotes Proliferation by Reducing Reactive Oxygen Species in Lung Adenocarcinoma.

Lung adenocarcinoma is a crucial contributor to cancer-related mortality; however, effective treatments remain challenging. The present study aimed to investigate the role of hemoglobin subunit theta 1 (HBQ1), an α subunit of hemoglobin whose expression has recently been reported in non-erythroid cells, in lung adenocarcinoma. Comparative analysis showed that HBQ1 expression was significantly higher in lung adenocarcinoma tissues compared to normal lung tissues. Moreover, high HBQ1 expression was correlated with unfavorable overall survival and progression-free survival in patients, highlighting its potential as a prognostic marker. Our functional experiments revealed that when overexpressed, HBQ1 acts as an oncogene, enhancing cell proliferation, whereas HBQ1 knockdown inhibits it. Additionally, HBQ1 exhibited antioxidant properties by reducing basal reactive oxygen species levels, playing a crucial role in lung adenocarcinoma progression. These findings emphasize the critical role of HBQ1 in driving tumor growth and progression in lung adenocarcinoma. Our in vivo studies further supported the role of HBQ1 in lung adenocarcinoma. HBQ1 knockdown resulted in the inhibition of lung adenocarcinoma growth, demonstrating the potential of HBQ1 as a therapeutic target. Our findings highlight the importance of HBQ1 in lung adenocarcinoma and suggest its potential as both a diagnostic marker and a molecular target for therapeutic interventions.

Engineered Human Antibody with Improved Endothelin Receptor Type A Binding Affinity, Developability, and Serum Persistence Exhibits Excellent Antitumor Potency.

Endothelin receptor A (ETA), a class A G protein-coupled receptor (GPCR), is a promising tumor-associated antigen due to its close association with the progression and metastasis of many types of cancer, such as colorectal, breast, lung, ovarian, and prostate cancer. However, only small-molecule drugs have been developed as ETA antagonists with anticancer effects. In a previous study, we identified an antibody (AG8) with highly selective binding to human ETA through screening of a human naïve immune antibody library. Although both in vitro and in vivo experiments indicated that the identified AG8 had anticancer effects, there is a need for improvement in biochemical and physicochemical properties such as the ETA binding affinity, thermostability, and productivity. In this study, we engineered the framework regions of AG8 and isolated an anti-ETA antibody (MJF1) exhibiting significantly improved thermostability and ETA binding affinity. Subsequently, our previously isolated PFc29, an Fc variant with an enhanced pH-dependent human FcRn binding profile, was introduced to MJF1, and the resulting Fc-engineered anti-ETA antibody (MJF1-PFc29) inhibited the proliferation of tumor cells comparably to MJF1 and showed a 4.2-fold increased serum half-life in human FcRn transgenic mice. Moreover, MJF1-PFc29 elicited higher tumor growth inhibition in colorectal cancer xenograft mice compared to MJF1. Our results demonstrate that the engineered human anti-ETA antibody MJF1-PFc29 has great therapeutic potential and high antitumor potency against various types of cancers including colorectal cancer.

A human antibody against human endothelin receptor type A that exhibits antitumor potency.

Endothelin receptor A (ETA), a class A G-protein-coupled receptor (GPCR), is involved in the progression and metastasis of colorectal, breast, lung, ovarian, and prostate cancer. We overexpressed and purified human endothelin receptor type A in Escherichia coli and reconstituted it with lipid and membrane scaffold proteins to prepare an ETA nanodisc as a functional antigen with a structure similar to that of native GPCR. By screening a human naive immune single-chain variable fragment phage library constructed in-house, we successfully isolated a human anti-ETA antibody (AG8) exhibiting high specificity for ETA in the ß-arrestin Tango assay and effective inhibitory activity against the ET-1-induced signaling cascade via ETA using either a CHO-K1 cell line stably expressing human ETA or HT-29 colorectal cancer cells, in which AG8 exhibited IC50 values of 56 and 51 nM, respectively. In addition, AG8 treatment repressed the transcription of inhibin ßA and reduced the ETA-induced phosphorylation of protein kinase B and extracellular regulated kinase. Furthermore, tumor growth was effectively inhibited by AG8 in a colorectal cancer mouse xenograft model. The human anti-ETA antibody isolated in this study could be used as a potential therapeutic for cancers, including colorectal cancer.

GPR87 Promotes Metastasis through the AKT-eNOS-NO Axis in Lung Adenocarcinoma.

Lung adenocarcinoma is one of the leading causes of cancer-related deaths. Despite the availability of advanced anticancer drugs for lung cancer treatment, the prognosis of patients still remains poor. There is a need to explore novel oncogenic mechanisms to overcome these therapeutic limitations. The functional experiments in vitro and in vivo were performed to evaluate the role of GPR87 expression on lung adenocarcinoma metastasis. The public lung adenocarcinoma dataset was used to determine the clinical relevance of GPR87 expression in patients with lung adenocarcinoma. GPR87 is upregulated in various cancer; however, the biological function of GPR87 has not yet been established in lung adenocarcinoma. In this study, we found that GPR87 expression is upregulated in lung adenocarcinoma and is associated with poor patient prognosis. Additionally, we showed that GPR87 overexpression promotes invasiveness and metastasis of lung adenocarcinoma cells. Furthermore, we demonstrated that AKT-eNOS-NO signaling is a novel downstream pathway of GPR87 in lung adenocarcinoma. Conversely, we confirmed that silencing of GPR87 expression suppressed these phenotypes. Our results reveal the oncogenic function of GPR87 in cancer progression and metastasis through the activation of eNOS as a key mediator. Therefore, we propose that targeting eNOS could be a novel therapeutic strategy to improve the clinical treatment of lung adenocarcinoma.

Blockade of endothelin receptor A enhances the therapeutic efficacy of gemcitabine in pancreatic cancer cells.

Pancreatic adenocarcinoma is currently one of the leading causes of cancer-related death worldwide. The high rate of mortality in pancreatic cancer patients is due to the inability to detect early-stage disease and the disease being highly refractory to therapy. Gemcitabine has been the standard chemotherapy for advanced pancreatic cancer patients for the last two decades. However, gemcitabine resistance develops within a few weeks of treatment, and the associated mechanism remains poorly understood. Therefore, a novel therapeutic strategy is needed to overcome the limited clinical efficacy of gemcitabine in pancreatic adenocarcinoma. In this study, we demonstrated that ET-1/ETAR axis gene expression was upregulated in pancreatic cancer cells after treatment with gemcitabine. Additionally, ETAR expression was significantly higher in tumor tissues than in normal tissues, and patients with high ETAR expression had a notably worse overall survival rate than those with low ETAR expression. Furthermore, our results revealed that bosentan, an ETAR antagonist, enhanced the growth-inhibiting and proapoptotic effects of gemcitabine on pancreatic cancer cells. Thus, our findings indicate that blockade of the ET-1/ETAR axis signaling pathway promotes the antiproliferative effect of gemcitabine on pancreatic cancer. Therefore, combination of ETAR blockade and gemcitabine serves as an effective therapeutic approach to achieve clinical benefits in pancreatic adenocarcinoma patients.

Non-Heme Iron Catalysts for Olefin Epoxidation: Conformationally Rigid Aryl-Aryl Junction To Support Amine/Imine Multidentate Ligands.

Atom-transfer chemistry represents an important class of reactions catalyzed by metalloenzymes. As a functional mimic of non-heme iron enzymes that deliver oxygen atoms to olefins, we have designed monoiron complexes supported by new N-donor chelates. These ligands take advantage of heme-like conformational rigidity of the π-conjugated molecular backbone, and synthetic flexibility of tethering non-heme donor groups for additional steric and electronic control. Iron complexes generated in situ can be used to carry out catalytic epoxidation of a wide range of olefin substrates by using mCPBA as a terminal oxidant. The fate of initial iron-peracid adduct and the involvement of iron-oxo species in this process were investigated further by mechanistic probes and isotope exchange studies. Our findings suggest that anilidopyridyl-derived [N,N]-bidentate motif could serve as a versatile structural platform to build non-heme ligands for catalytic oxidation chemistry.

Medical visits, antihypertensive prescriptions and medication adherence among newly diagnosed hypertensive patients in Korea.

OBJECTIVES: The objective of this study was to assess the antihypertensive medication adherence in patients who were newly diagnosed with hypertension in Korea. METHODS: Study subjects were diagnosed with hypertension for the first time by the General Health Screening in 2012 and were 65,919. As indices, visiting rate to medical institution, the antihypertensive prescription rate, medication possession ratio and the rate of appropriate medication adherence were used. The qualification data, the General Health Screening data and the health insurance claims data were used. RESUTLS: Visiting rate to medical institution within one-year was 42.3%. Gender, age, family history of hypertension, smoking status, drinking frequency, insurance type, BMI, hypertension status, blood glucose level and LDL-cholesterol level were significant variables for visiting a medical institution. Of the study subjects who visited a medical institution, the antihypertensive prescription rate was 89.1%. Medication possession ratio was 70.9% and the rate of appropriate medication adherence was 60.6%. Age, family history of hypertension, smoking status, BMI level, hypertension level, blood glucose level, status, and LDL-cholesterol level were significant variables for the antihypertensive prescription and gender, age, family history of hypertension, smoking status, BMI, hypertension status, and the time of the first visit to a medical institution were significant variables for appropriate medication adherence. CONCLUSIONS: This study showed that the antihypertensive medication adherence in patients who were newly diagnosed with hypertension was not relatively high in Korea. National Health Insurance Service should support an environment in which medical institutions and those diagnosed with hypertension can fulfill their roles.

Synthesis, Characterization, and Efficient Catalytic Activities of a Nickel(II) Porphyrin: Remarkable Solvent and Substrate Effects on Participation of Multiple Active Oxidants.

A new nickel(II) porphyrin complex, [NiII (porp)] (1), has been synthesized and characterized by 1 H NMR, 13 C NMR and mass spectrometry analysis. This NiII porphyrin complex 1 quantitatively catalyzed the epoxidation reaction of a wide range of olefins with meta-chloroperoxybenzoic acid (m-CPBA) under mild conditions. Reactivity and Hammett studies, H218 O-exchange experiments, and the use of PPAA (peroxyphenylacetic acid) as a mechanistic probe suggested that participation of multiple active oxidants NiII -OOC(O)R 2, NiIV -Oxo 3, and NiIII -Oxo 4 within olefin epoxidation reactions by the nickel porphyrin complex is markedly affected by solvent polarity, concentration, and type of substrate. In aprotic solvent systems, such as toluene, CH2 Cl2 , and CH3 CN, multiple oxidants, NiII -(O)R 2, NiIV -Oxo 3, and NiIII -Oxo 4, operate simultaneously as the key active intermediates responsible for epoxidation reactions of easy-to-oxidize substrate cyclohexene, whereas NiIV -Oxo 3 and NiIII -Oxo 4 species become the common reactive oxidant for the difficult-to-oxidize substrate 1-octene. In a protic solvent system, a mixture of CH3 CN and H2 O (95:5), the NiII -OOC(O)R 2 undergoes heterolytic or homolytic O-O bond cleavage to afford NiIV -Oxo 3 and NiIII -Oxo 4 species by general acid catalysis prior to direct interaction between 2 and olefin, regardless of the type of substrate. In this case, only NiIV -Oxo 3 and NiIII -Oxo 4 species were the common reactive oxidant responsible for olefin epoxidation reactions.

Peroxiredoxin 5 overexpression enhances tumorigenicity and correlates with poor prognosis in gastric cancer.

Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Despite the advanced surgical resection techniques and anticancer drugs currently available to treat early stage gastric cancer, the prognosis of patients with gastric cancer remains poor. The epithelial to mesenchymal transition (EMT) is an important process for the initiation of tumorigenesis. Recent studies suggested that reactive oxygen species (ROS) can promote cell migration and invasion. Thus, an imbalance of redox homeostasis can result in cancer cells exhibiting EMT properties. PRXs are upregulated in various tumors in the breast, bladder, lung, cervical, ovarian, prostate, esophageal, and hepatocellular. However, PRX expression and its impact on disease prognosis, patient survival rate, and EMT are rarely studied in the context of human gastric cancer. The expression of PRX5 was significantly correlated with tumor size, depth of tumor, lymphatic invasion in patients of gastric cancer. In addition, overexpression of PRX5 enhanced carcinogenicity by increasing the proliferation and invasiveness of gastric cancer cells via upregulation of Snail. Taken together, we suggest that PRX5 may be a potential factor that may contribute to poor prognosis of gastric cancer through enhancing the mesenchymal phenotype. Finally, PRX5 is a putative therapeutic target and clinical strategy for various cancers overexpressing PRX5.

Peroxiredoxin 5 promotes the epithelial-mesenchymal transition in colon cancer.

Globally, colorectal cancer (CRC) is common cause of cancer-related deaths. The high mortality rate of patients with colon cancer is due to cancer cell invasion and metastasis. Initiation of the epithelial-to-mesenchymal transition (EMT) is essential for the tumorigenesis. Peroxiredoinxs (PRX1-6) have been reported to be overexpressed in various tumor tissues, and involved to be responsible for tumor progression. However, the exact role of PRX5 in colon cancer remains to be investigated enhancing proliferation and promoting EMT properties. In this study, we constructed stably overexpressing PRX5 and suppressed PRX5 expression in CRC cells. Our results revealed that PRX5 overexpression significantly enhanced CRC cell proliferation, migration, and invasion. On the other hand, PRX5 suppression markedly inhibited these EMT properties. PRX5 was also demonstrated to regulate the expression of two hallmark EMT proteins, E-cadherin and Vimentin, and the EMT-inducing transcription factors, Snail and Slug. Moreover, in the xenograft mouse model, showed that PRX5 overexpression enhances tumor growth of CRC cells. Thus, our findings first provide evidence in CRC that PRX5 promotes EMT properties by inducing the expression of EMT-inducing transcription factors. Therefore, PRX5 can be used as a predictive biomarker and serves as a putative therapeutic target for the development of clinical treatments for human CRC.

Anti-cancer Activity of Novel TM4SF5-Targeting Antibodies through TM4SF5 Neutralization and Immune Cell-Mediated Cytotoxicity.

The transmembrane four L6 family member 5 (TM4SF5) protein is a novel molecular target for the prevention and treatment of hepatocellular carcinoma. TM4SF5 is highly expressed in liver, colon, esophageal, and pancreatic cancers and is implicated in tumor progression. Here, we screened monoclonal antibodies that specifically bound to the extracellular loop 2 (EC2) of TM4SF5 from a phage-displayed murine antibody (single-chain variable fragment; scFv) library. We constructed and characterized chimeric antibodies, Ab27 and Ab79, of scFv fused with Fc domain of human IgG1. The affinity (KD) of Ab27 and Ab79 for soluble EC2 was approximately 9.2 nM and 16.9 nM, respectively, as determined by surface plasmon resonance analysis. Ab27 and Ab79 efficiently bound to native TM4SF5 on the cell surface were internalized into the cancer cells, leading to a decrease in cell surface TM4SF5. Ab27 and Ab79 inhibited the proliferation and invasion of TM4SF5-positive liver and colon cancer cells and reduced FAK and c-Src phosphorylation. Ab27 and Ab79 also enhanced anoikis sensitivity and reduced survivin. Ab27 mediated antibody-dependent cell-mediated cytotoxicity in vitro. Ab27 and Ab79 efficiently inhibited tumor growth in a liver cancer xenograft model. These results strongly support the further development of Ab27 as a novel anti-cancer agent in the clinic.

Defining the activities of publicness for Korea's public community hospitals using the Delphi method.

This study aims to identify which activities of a public community hospital (PHC) should be included in their definition of publicness and tries to achieve a consensus among experts using the Delphi method. We conduct 2 rounds of the Delphi process with 17 panel members using a developed draft of tentative activities for publicness including 5 main categories covering 27 items. The questions remain the same in both rounds and the applicability of each of the 27 items to publicness is measured on a 9-point scale. If the participants believe government funding is needed, we ask how much they think the government should support each item on a 0% to 100% scale. After conducting 2 rounds of the Delphi process, 22 out of the 27 items reached a consensus as activities defining the publicness of the PHCs. Among the 5 major categories, in category C, activities preventing market failure, all 10 items were considered activities of publicness. Nine of these were evaluated as items that should be compensated at 100% of total financial loss by the Korean government. Throughout results, we were able to define the activities of the PCH that encompassed its publicness and confirm that there are "good deficits" in the context of the PCHs. Thus, some PCH deficits are unavoidable and not wasted as these monies support a necessary role and function in providing public health. The Korean government should therefore consider taking actions such as exempting such "good deficits" or providing additional financial aid to reimburse the PHCs for "good deficits."

Synthesis, Characterization, and Catalytic Activities of A Nickel(II) Monoamido-Tetradentate Complex: Evidence For NiIII -Oxo and NiIV -Oxo Species.

A new mononuclear nickel(II) complex, [NiII (dpaq)Cl] (1), containing a tetradentate monoamido ligand, dpaq (dpaq=2-[bis(pyridin-2-ylmethyl)amino]-N-(quinolin-8-yl)acetamide), has been synthesized and characterized by IR spectroscopy, elemental analysis, and UV/Vis spectroscopy. The structure of the nickel complex has been determined by X-ray crystallography. This nonheme NiII complex 1 catalyzed the epoxidation reaction of a wide range of olefins with meta-chloroperoxybenzoic acid (m-CPBA) under mild conditions. Olefin epoxidation using this catalytic system has been proposed to involve a new reactive NiIV -oxo (4) species, based on the evidence from a PPAA (peroxyphenylacetic acid) probe, Hammett studies, H218 O exchange experiments, and ESI mass spectroscopic analysis. Moreover, the nature of solvent significantly influenced partitioning between heterolytic and homolytic O-O bond cleavage of the Ni-acylperoxo intermediate (2). The O-O bond of 2 proceeded predominantly through heterolytic cleavage in a protic solvent, such as CH3 OH. These results suggest that possibly a NiIV -oxo species is a common reactive intermediate in protic solvents. The two active oxidants, namely NiIV -oxo (3) and NiIII -oxo (4), which are responsible for stereospecific olefin epoxidation and radical-type oxidations, respectively, operate in aprotic solvents.

A Colorimetric and Fluorescent Chemosensor for the Selective Detection of Cu2+ and Zn2+ Ions.

A new bi-functional chemosensor 1 based on 3,5-dichlorosalicylaldehyde and 2-(methylthio)aniline has been synthesized. It can detect Cu2+ with a color change from pale yellow to dark yellow in aqueous solution. The selective mechanism of 1 for Cu2+ was proposed to be the enhancement of the intramolecular charge transfer (ICT) band, which was explained by theoretical calculations. The sensor 1 could be used to detect and quantify Cu2+ in water samples. In addition, the sensor 1 displayed "turn-on" fluorescence response only to Zn2+, based on an effect of chelation-enhanced fluorescence (CHEF). Therefore, 1 can serve as a 'single sensor for two different targets' with dual modes.

Development of Models for Regional Cardiac Surgery Centers.

BACKGROUND: This study aimed to develop the models for regional cardiac surgery centers, which take regional characteristics into consideration, as a policy measure that could alleviate the concentration of cardiac surgery in the metropolitan area and enhance the accessibility for patients who reside in the regions. METHODS: To develop the models and set standards for the necessary personnel and facilities for the initial management plan, we held workshops, debates, and conference meetings with various experts. RESULTS: After partitioning the plan into two parts (the operational autonomy and the functional comprehensiveness), three models were developed: the 'independent regional cardiac surgery center' model, the 'satellite cardiac surgery center within hospitals' model, and the 'extended cardiac surgery department within hospitals' model. Proposals on personnel and facility management for each of the models were also presented. A regional cardiac surgery center model that could be applied to each treatment area was proposed, which was developed based on the anticipated demand for cardiac surgery. The independent model or the satellite model was proposed for Chungcheong, Jeolla, North Gyeongsang, and South Gyeongsang area, where more than 500 cardiac surgeries are performed annually. The extended model was proposed as most effective for the Gangwon and Jeju area, where more than 200 cardiac surgeries are performed annually. CONCLUSION: The operation of regional cardiac surgery centers with high caliber professionals and quality resources such as optimal equipment and facility size, should enhance regional healthcare accessibility and the quality of cardiac surgery in South Korea.

Public Perception of the Concentration of Cardiac and Cerebrovascular Surgery to Metropolitan Hospitals.

BACKGROUND: This study investigates the perception of the general public regarding the concentration to metropolitan, hospitals of cardiac and cerebrovascular surgeries, and the perceived public need for government policies to resolve this issue. METHODS: A total of 800 participants were recruited for our telephone interview survey. Quota sampling was performed, adjusting for age and sex, to select by various geographic regions. Sampling with random digit dialing was performed; we called the randomly generated telephone numbers and made three attempts for non-responders before moving on to a different telephone number. RESULTS: Our sample population was 818 participants, 401 men (49.0%) and 417 women (51.0%). Our data showed that 85.5% of participants thought that cardiac surgery and neurosurgery patients are concentrated in large hospitals in Seoul. The principle reason for regional patients to want to receive surgery at major hospitals in Seoul was because of poor medical standards associated with regional hospitals (87.7%). We found that a vast majority of participants (97.5%) felt that government policies are needed to even out the clustering of cardiac surgery and neurosurgery patients, and that this clustering may be alleviated if policies that can specifically enhance the quality and the capacity of regional hospitals to carry out surgeries are adopted (98.3%). CONCLUSION: Government policy making must reflect public desiderata, and we suggest that these public health needs may be partially resolved through government-designated cardiac and neurosurgery specialist hospitals in regional areas.

Thoracic and Cardiovascular Surgeons' Perception of the Concentration of Cardiovascular Operations in Seoul Metropolitan Area's Hospitals.

BACKGROUND: The purpose of this study is to evaluate the concentration of cardiovascular surgical procedures in a metropolitan area and investigate the perception of specialists regarding governmental policies to resolve this imbalance. METHODS: From March to May 2015, surveys were distributed to members of the Thoracic and Cardiovascular Surgery Association. The final pool of research subjects consisted of 75 respondents. Subjects were queried regarding the concentration of cardiovascular operations in metropolitan areas, alternatives to the imbalance, and governmental policies to resolve the inequalities. RESULTS: Survey participants responded that South Korea needs governmental policies to alleviate the concentration of cardiovascular surgery patients in large metropolitan hospitals. Participants agreed that the freedom to choose medical institutions and improved accessibility to metropolitan hospitals due to advanced transportation systems were some of the causes for the concentration. A majority (98.7%) of respondents thought establishing thoracic and cardiovascular surgery centers in provinces was an appropriate solution to alleviate the concentration. Thoracic and cardiovascular surgery specialists were ranked as the number one group on which to focus development. CONCLUSION: Developing and carrying out policies to establish thoracic and cardiovascular surgery centers in provinces will alleviate the regional imbalance in available heart surgery services and an overall improvement in cardiovascular disease treatment in South Korea.

Trends in Percutaneous Coronary Intervention and Coronary Artery Bypass Surgery in Korea.

BACKGROUND: Coronary angioplasty has been replacing coronary artery bypass grafting (CABG) because of the relative advantage in terms of recovery time and noninvasiveness of the procedure. Compared to other Organization for Economic Cooperation and Development (OECD) countries, Korea has experienced a rapid increase in coronary angioplasty volumes. METHODS: We analyzed changes in procedure volumes of CABG and of percutaneous coronary intervention (PCI) from three sources: the OECD Health Data, the National Health Insurance Service (NHIS) surgery statistics, and the National Health Insurance claims data. RESULTS: We found the ratio of procedure volume of PCI to that of CABG per 100,000 population was 19.12 in 2014, which was more than triple the OECD average of 5.92 for the same year. According to data from NHIS statistics, this ratio was an increase from 11.4 to 19.3 between 2006 and 2013. CONCLUSION: We found that Korea has a higher ratio of total procedure volumes of PCI with respect to CABG and also a more rapid increase of volumes of PCI than other countries. Prospective studies are required to determine whether this increase in absolute volumes of PCI is a natural response to a real medical need or representative of medical overuse.

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1.

TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, and metastasis. We also found that TMPRSS4 activates the transcription factor activating protein-1 (AP-1) to induce cancer cell invasion. Here, we explored TMPRSS4-mediated cellular functions and the underlying mechanisms. TMPRSS4 induced Slug, an epithelial-mesenchymal transition (EMT)-inducing transcription factor, and cyclin D1 through activation of AP-1, composed of c-Jun and activating transcription factor (ATF)-2, which resulted in enhanced invasion and proliferation of PC3 prostate cancer cells. In PC3 cells, not only c-Jun but also Slug was required for TMPRSS4-mediated proliferation and invasion. Interestingly, Slug induced phosphorylation of c-Jun and ATF-2 to activate AP-1 through upregulation of Axl, establishing a positive feedback loop between Slug and AP-1, and thus induced cyclin D1, leading to enhanced proliferation. Using data from The Cancer Genome Atlas, we found that Slug expression positively correlated with that of c-Jun and cyclin D1 in human prostate cancers. Expression of Slug was positively correlated with that of cyclin D1 in various cancer cell lines, whereas expression of other EMT-inducing transcription factors was not. This study demonstrates that TMPRSS4 modulates both invasion and proliferation via Slug and cyclin D1, which is a previously unrecognized pathway that may regulate metastasis and cancer progression.

[Hospital Arrival Rate within Golden Time and Factors Influencing Prehospital Delays among Patients with Acute Myocardial Infarction].

PURPOSE: This research was done to identify the hospital arrival rate and factors related to prehospital delay in arriving at an emergency medical center within the golden time after symptom onset in patients with acute myocardial infarction (AMI). METHODS: Data used in the research was from the National Emergency Department Information System of the National Emergency Medical Center which reported that in 2014, 9,611 patients went to emergency medical centers for acute myocardial infarction. Prehospital time is the time from onset to arrival at an emergency medical center and is analyzed by subdividing arrival and delay based on golden time of 2 hour. RESULTS: After onset of acute myocardial infarction, arrival rate to emergency medical centers within the golden time was 44.0%(4,233), and factors related to prehospital delay were gender, age, region of residence, symptoms, path to hospital visit, and method of transportation. CONCLUSION: Results of this study show that in 2014 more than half of AMI patients arrive at emergency medical centers after the golden time for proper treatment of AMI. In order to reduce prehospital delay, new policy that reflects factors influencing prehospital delay should be developed. Especially, public campaigns and education to provide information on AMI initial symptoms and to enhance utilizing EMS to get to the emergency medical center driectly should be implemented for patients and/or caregivers.