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Background Particulate matter (PM) is one of the principal causes of human respiratory disabilities resulting from air pollution. Animal models have been applied to discover preventive and therapeutic drugs for lung diseases caused by PM. However, the induced severity of lung injury in animal models using PM varies from study to study due to disparities in the preparation of PM, and the route and number of PM administrations. In this study, we established an in vivo model to evaluate PM-induced lung injury in mice. Results PM dispersion was prepared using SRM2975. Reactive oxygen species were increased in MLE 12 cells exposed to this PM dispersion. In vivo studies were conducted in the PM single challenge model, PM multiple challenge model, and PM challenge with ovalbumin-induced asthma using the PM dispersion. No histopathological changes were observed in lung tissues after a single injection of PM, whereas mild to moderate lung inflammation was obtained in the lungs of mice exposed to PM three times. However, fibrotic changes were barely seen, even though transmission electron microscopy (TEM) studies revealed the presence of PM particles in the alveolar macrophages and alveolar capillaries. In the OVA-PM model, peribronchial inflammation and mucous hypersecretion were more severe in the OVA+PM group than the OVA group. Serum IgE levels tended to increase in OVA+PM group than in OVA group. Conclusions In this study, we established a PM-induced lung injury model to examine the lung damage induced by PM. Based on our results, repeated exposures of PM are necessary to induce lung inflammation by PM alone. PM challenge, in the presence of underlying diseases such as asthma, can also be an appropriate model for studying the health effect of PM.

Leaky gut is a condition of increased paracellular permeability of the intestine due to compromised tight junction barriers. In recent years, this affliction has drawn the attention of scientists from different fields, as a myriad of studies prosecuted it to be the silent culprit of various immune diseases. Due to various controversies surrounding its culpability in the clinic, approaches to leaky gut are restricted in maintaining a healthy lifestyle, avoiding irritating factors, and practicing alternative medicine, including the consumption of supplements. In the current study, we investigate the tight junction-modulating effects of processed Aloe vera gel (PAG), comprising 5–400-kD polysaccharides as the main components. Our results show that oral treatment of 143 mg/kg PAG daily for 10 days improves the age-related leaky gut condition in old mice, by reducing their individual urinal lactulose/mannitol (L/M) ratio. In concordance with in vivo experiments, PAG treatment at dose 400 μg/mL accelerated the polarization process of Caco-2 monolayers. The underlying mechanism was attributed to enhancement in the expression of intestinal tight junction-associated scaffold protein zonula occludens (ZO)-1 at the translation level. This was induced by activation of the MAPK/ERK signaling pathway, which inhibits the translation repressor 4E-BP1. In conclusion, we propose that consuming PAG as a complementary food has the potential to benefit high-risk patients.

Tachykinin NK

Chemical upcycling of poly(bisphenol A carbonate) (PC) was achieved in this study with hydroxamic acid nucleophiles, giving rise to synthetically valuable 1,4,2-dioxazol-5-ones and bisphenol A. Using 1,5,7-triazabicyclo[4.4.0]-dec-5-ene (TBD), non-green carbodiimidazole or phosgene carbonylation agents used in conventional dioxazolone synthesis were successfully replaced with PC, and environmentally harmful bisphenol A was simultaneously recovered. Assorted hydroxamic acids exhibited good-to-excellent efficiencies and green chemical features, promising broad synthetic application scope. In addition, a green aryl amide synthesis process was developed, involving one-pot depolymerization from polycarbonate to dioxazolone followed by rhodium-catalyzed C-H amidation, including gram-scale examples with used compact discs.

Autophagy in the proximal tubules may promote fibrosis by activating tubular cell death, interstitial inflammation, and the production of pro-fibrotic factors. The signal transducer and activator of transcription 3 (STAT3) is activated as a potential transcription factor, which mediates the stimulation of renal fibrosis. We investigated the role of the STAT3 in autophagy and its effect on the prevention of interstitial renal fibrosis. In this study, we use synthesized STAT3 decoy oligonucleotides (ODN), which were injected into the tail veins of unilateral ureteral obstruction (UUO) mice, to explore the regulation of autophagy in UUO-induced renal fibrosis. The expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and collagen were decreased by STAT3 decoy ODN. The autophagy markers microtubule-associated protein light chain 3 (LC3) and fibronectin, were identified through immunofluorescent staining, indicating that they were reduced in the group injected with ODN. The expressions of LC3, Beclin1, p62, and autophagy-related 5–12 (Atg5–12) and hypoxia inducible factor-1α (HIF-1α) were inhibited in the ODN injection group. We determined the inhibitory effect of autophagy in chronic kidney disease and confirmed that STAT3 decoy ODN effectively inhibited autophagy by inhibiting the expression of STAT3 transcription factors in the UUO group.

Acetaminophen (APAP) is one of the most frequently prescribed analgesic and anti-pyretic drugs. However, APAP-induced hepatotoxicity is a major cause of acute liver failure globally. While the therapeutic dose is safe, an overdose of APAP produces an excess of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), subsequently resulting in hepatotoxicity. Allyl isothiocyanate (AITC), a bioactive molecule in cruciferous plants, is reported to exert various biological effects, including anti-inflammatory, anti-cancer, and anti-microbial effects. Notably, AITC is known for activating nuclear factor erythroid 2-related factor 2 (NRF2), but there is limited evidence supporting the beneficial effects on hepatocytes and liver, where AITC is mainly metabolized. We applied a mouse model in the current study to investigate whether AITC protects the liver against APAP-induced injury, wherein we observed the protective effects of AITC. Furthermore, NRF2 nuclear translocation and the increase of target genes by AITC treatment were confirmed by in vitro experiments. APAP-induced cell damage was attenuated by AITC via an NRF2-dependent manner, and rapid NRF2 activation by AITC was attributed to the elevation of NRF2 stability by decreasing its spontaneous degradation. Moreover, liver tissues from our mouse experiment revealed that AITC increases the expression of heme oxygenase-1 (HO-1), an NRF2 target gene, confirming the potential of AITC as a hepatoprotective agent that induces NRF2 activation. Taken together, our results indicate the potential of AITC as a natural-product-derived NRF2 activator targeting the liver.

Background Intratumoral fibrosis (ITF) is a frequent histologic finding in solid organ tumors. Renal cell carcinoma (RCC) is a highly vascularized tumor with different shapes and degrees of ITF and inflammation. ITF is a poor prognostic factor, especially in breast cancer, and is related to intratumoral necrosis (ITN) and intratumoral inflammation (ITI). However, the significance of ITF in RCC has not been fully studied. In this study, we evaluate the relationships between ITF and other clinicopathologic parameters associated with RCC prognosis. Methods ITF was evaluated in 204 clear cell renal cell carcinoma (CCRCC) specimens according to presence and grade of fibrosis, degree of ITI, and presence of ITN. Lysyl oxidase (LOX) expression in tumor cells was also evaluated with clinicopathologic parameters. Results Among 204 CCRCC cases, 167 (81.7%) showed ITF, 71 (34.8%) showed ITI, 35 (17.2%) showed ITN, and 111 (54.4%) showed LOX expression. ITF correlated with Fuhrman nuclear grade (p = .046), lymphovascular invasion (LVI) (p = .027), and ITN (p = .036). Patients with ITF had a poor five-year overall survival rate (p = .104). Conclusions ITF is related to other poor prognostic factors in CCRCC, such as Fuhrman nuclear grade, ITN, and LVI, but ITF itself had no significant correlation with prognosis of CCRCC.

Tachykinin NK2 receptors are distributed in periphery, in the smooth muscle of the respiratory, gastrointestinal, genitourinary tract, and within the brain. Substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) are endogenous ligands for NK2 receptors and are active in the peripheral and central nervous systems. NK2 antagonists have the potential to reduce airway motor responses and prevent hyperactivity by inhibiting NKA-induced bronchoconstriction in asthmatic patients. Due to its abundance, peripherally and centrally, tachykinin NK2 receptor antagonists have high potential in treating various disease states ranging from asthma to irritable bowel syndrome, to detrusor hyperactivity, to anxiety. This review is an evaluation of NK2 receptor antagonists as possible therapeutics for a myriad of pharmacological treatments.

Sustainable and efficient hydrogen production from biomass resources have been highly desired. Here, we report a low-temperature hydrogen production process from lignocellulosic biomass passing through formic acid (the biomass-formic acid-hydrogen conversion process) with improved sustainability and formic acid yield. In the biomass oxidation/hydrolysis step, toxic sulfuric acid has been replaced by sustainable citric acid. In addition, mechanocatalytic depolymerization of biomass has been applied to the biomass pretreatment step, resulting in the remarkable improvement in formic acid yield. In the first step, the citric-acid-impregnated biomass was subjected to a mechanocatalytic depolymerization process for facilitating contact between the substrate and catalysts (MD-CIB). In the second step, the crude formic acid (CF) solution was obtained via combined hydrolysis-oxidation process of the MD-CIB in the presence of dimethyl sulfoxide (DMSO), and hydrogen peroxide (H2O2). The yield of formic acid were measured up to be 50.03%. In the third step, the lignin-free crude formic acid (LCF) solution was recovered by filtration, or distilled formic acid (DF) solution was obtained by distillation of the CF solution. In the final step, hydrogen was generated from LCF or DF solutions through dehydrogenation of formic acid over Pd catalysts supported on amine-functionalized mesoporous silica (KIE-6) with a sodium formate. The turnover frequency (TOF) at 10 min were measured up to be 279.24 mol H2 mol Pd-1h−1. The clean hydrogen, which is produced from biomass passing through formic acid, could be directly applied in fuel cell as an energy source. Our hydrogen production process is expected to be much more efficient, sustainable and economical process for hydrogen production from biomass. In addition, organic acids as a byproduct could be utilized as a platform chemical.

Ethnopharmacological relevance Pharbitis Nil (PN) is used as a main component of the existing drug, DA-9701, which was developed to treat functional dyspepsia (FD) in Korea. PN extracts isolated from its seeds have been reported to have anticancer effects. Aim of the study The purpose of this study was to investigate the underlying mechanism of the chemotherapeutic effects of PN in lung cancer cells. Materials and methods We performed MTT assays, colony formation assays, flow cytometry assays, Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence analysis, and cell counting assays to study the molecular mechanism of chemotherapeutic effects of PN in lung cancer cells. Results Our results indicate that PN induced autophagy as well as apoptosis. PN inhibited cell proliferation and survival by inducing apoptosis in several lung cancer cell lines. PN-treated cells also exhibited induction of autophagy, as evidenced by increased protein expression levels and punctuate patterns of LC3 II. Moreover, activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which plays an important role in autophagy activation, was shown to be related with PN-induced autophagy. Interestingly, pharmacological blockade of autophagy activation with wortmannin and inhibition of ERK1/2 phosphorylation by U0126 markedly enhanced PN-induced apoptosis and reduced cell viability, suggesting that autophagy induced by PN may have a cytoprotective effect by suppressing apoptosis. PN- induced apoptosis was regulated by signal transducer and activator of transcription 3 (STAT3) deactivation. Moreover, decrease of STAT3 activation in PN-treated cells was associated with reduced survivin expression, further demonstrating that PN-induced apoptosis was regulated by STAT3 deactivation. Conclusion We believe that PN, which is already proven to treat human patients with FD, might be a potential anticancer drug for human lung cancer. In addition, our data suggest that the combination of PN treatment with an autophagy inhibitor or traditional anticancer agents may be an effective anticancer therapy.

// Jong Kyu Woo 1, 2 , Hyun Jin Jung 2 , Ji-Youn Park 1 , Ju-Hee Kang 1 , Byung Il Lee 3 , DongYun Shin 1 , Chu Won Nho 4 , Soo-Young Cho 3 , Je Kyung Seong 2, * and Seung Hyun Oh 1, * 1 Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea 2 Korea Mouse Phenotyping Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea 3 National Cancer Center, Goyang-si, Republic of Korea 4 Korea Institute of Science and Technology (KIST), Gangneung Institute, Gangneung-si, Republic of Korea * These are authors contributed equally to this work Correspondence to: Seung Hyun Oh, email: eyeball@hanmail.net , eyeball@gachon.ac.kr Keywords: daurinol, breast cancer, lung cancer, FAK, metastasis Received: January 16, 2017 Accepted: June 18, 2017 Published: July 04, 2017 ABSTRACT FAK overexpression has been reported in diverse primary and metastatic tumor tissues, supporting its pro-tumorigenic and pro-metastatic roles. Therefore, we have developed a neo-treatment strategy using daurinol to effectively treat cancer metastasis. Daurinol blocked cancer cell migration and invasion in vitro and exhibited anti-metastatic activity in an experimental metastasis model of breast and lung cancer. Daurinol selectively inhibited phosphorylation of FAK at Tyr925, Tyr576/577, and Tyr397 sites in a dose- and time-dependent manner. Daurinol effectively suppressed migration and invasion of MDA-MB-231 and A549 cancer cells. These data were associated with inhibition of expression and secretion of invasion factors, including matrix metalloproteinase (MMP) 2, MMP9, and urokinase plasminogen activator (uPA). Consistent with these in vitro results, daurinol (10 mg/kg; Oral gavage) effectively inhibited breast and lung cancer metastasis in a mouse model. In addition, daurinol showed strong suppressive activity of cell survival as revealed by colony formation assays. Analysis of cellular phenotypes revealed that inhibition of FAK phosphorylation in cancer cells limited colony formation, cell migration, and invasion, thereby reducing the cell proliferation rate. Furthermore, daurinol significantly reduced tumor development in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)/benzo(a)pyrene (BaP)-treated A/J mice. Our results suggest that daurinol suppresses lung metastasis through inhibition of migration and survival via blockade of FAK activity.

Juvenile Oncorhynchus mykiss (average weight: 22.3 g) were fed one of five selenomethionine diets (1.09, 8.79, 15.37, 30.79, or 61.58 mg Se/kg diet). After 4 weeks, hepatic catalase activity over 15.37 mg Se/kg diets was significantly decreased, and the glutathione peroxidase activity over 30.79 mg Se/kg diets was elevated compared to the controls. In the brain, the dopamine levels at 61.58 mg Se/kg diet and the serotonin levels over 15.37 mg Se/kg diets were significantly increased, whereas the 3,4-dihydroxyphenylacetic acid, homovanillic acid, and dopamine turnover, and the 5-hydroxyindoleacetic acid and serotonin turnover over 30.79 mg Se/kg diets were decreased. In muscle, the 3-nitrotyrosine level over 15.37 mg Se/kg diets, acetylcholine esterase activity over 30.79 mg Se/kg diets, and histological alterations over 8.79 mg Se/kg diets were increased. Our current results showed that selenomethionine disrupted dopamine and serotonin metabolism in the brain and damaged the neuromuscular system in skeletal muscle.

Nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a cell-surface adhesion molecule that regulates cell migration and attachment. This study demonstrates the increase in Ninj1 protein expression during development of intestinal inflammation. Ninj1-deficient mice exhibited significantly attenuated bodyweight loss, shortening of colon length, intestinal inflammation, and lesser pathological lesions than wild-type mice. Although more severe inflammation and serious lesions are observed in wild-type mice than Ninj1-deficient mice, there were no changes in the numbers of infiltrating macrophages in the inflamed tissues obtained from WT and Ninj1-deficient mice. Ninj1 expression results in activation of macrophages, and these activated macrophages secrete more cytokines and chemokines than Ninj1-deficient macrophages. Moreover, mice with conditional deletion of Ninj1 in myeloid cells (Ninj1fl/fl, Lyz-Cre+) alleviated experimental colitis compared with wild-type mice. In summary, we propose that the Ninj1 in myeloid cells play a pivotal function in intestinal inflammatory conditions.

Neuronal morphogenesis requires multiple regulatory pathways to appropriately determine axonal and dendritic structures, thereby to enable the functional neural connectivity. Yet, however, the precise mechanisms and components that regulate neuronal morphogenesis are still largely unknown. Here, we newly identified the sequential phosphorylation of NDEL1 critical for neuronal morphogenesis through the human kinome screening and phospho-proteomics analysis of NDEL1 from mouse brain lysate. DYRK2 phosphorylates NDEL1 S336 to prime the phosphorylation of NDEL1 S332 by GSK3β. TARA, an interaction partner of NDEL1, scaffolds DYRK2 and GSK3β to form a tripartite complex and enhances NDEL1 S336/S332 phosphorylation. This dual phosphorylation increases the filamentous actin dynamics. Ultimately, the phosphorylation enhances both axonal and dendritic outgrowth and promotes their arborization. Together, our findings suggest the NDEL1 phosphorylation at S336/S332 by the TARA-DYRK2-GSK3β complex as a novel regulatory mechanism underlying neuronal morphogenesis.

Liver fibrosis is characterized by formation of scar tissue in the liver. The role of STAT3 signaling has been implicated on activating hepatic stellate cells (HSC) to myofibroblast-like cells in liver fibrosis. Major factors that activate STAT3 signaling are TGF-β1 and IL-6, which are upregulated in the liver in patients afflicted with liver fibrosis. Recent reports indicate that not only IL-6, but also the non-canonical signaling pathway of TGF-β1 is associated with STAT3 signaling. In this study, we demonstrate a new function of the STAT3 inhibitor, STX-0119, in liver fibrosis. STX-0119 is an inhibitor of STAT3 dimerization, which is required for nuclear localization of STAT3. We first investigated the anti-fibrotic effect of STX-0119 in in vitro experiments. Exposure to STX-0119 inhibited the nuclear localization of STAT3 in HSCs, resulting in decreased expression of its target genes, such as col1a1 and αSMA. In addition, STX-0119 also inhibited the TGF-β1/IL-6-induced activation of HSCs. Next, we examined the in vivo effect of STX-0119 in the liver fibrosis mouse model using thioacetamide (TAA) and carbon tetrachloride (CCl4). STX-0119 attenuated the TAA-induced liver fibrosis by inhibiting activation of HSCs to myofibroblast-like cells. Consistent with the in vivo results using TAA-induced liver fibrosis model, treatment of STX-0119 similarly attenuated CCl4-induced liver fibrosis. In conclusion, we believe that STX-0119 inhibits the development of liver fibrosis by blocking the activation of hepatic stellate cells. These results indicate that STX-0119 is a potential new therapeutic strategy to prevent disease progression to cirrhosis.

Purpose: Histone deacetylase inhibitors (HDI) are promising anticancer therapies; however, drug resistance limits their efficacy. Here, we investigated the molecular mechanisms underlying HDI resistance, focusing on the mechanism of HDI-mediated induction of insulin-like growth factor 2 (IGF2) based on our previous study. Experimental Design: The methylation status of CCCTC-binding factor (CTCF)-binding sites in the IGF2/H19 imprinting control region (ICR) were determined by methylation-specific PCR and bisulfite sequencing. The effectiveness of single or combinatorial blockade of DNA methyltransferase 1 (DNMT1) and histone deacetylase (HDAC) was evaluated using cell viability assay and patient-derived tumor xenograft (PDX) model. Results: HDAC inhibition by vorinostat increased acetylated STAT3 (K685), resulting in transcriptional upregulation of DNMT1. DNMT1-mediated hypermethylation of CTCF-binding sites in the IGF2/H19 ICR decreased CTCF insulator activity, leading to a transcriptional upregulation of IGF2 and activation of the insulin-like growth factor 1 receptor (IGF-1R) pathway in cells with acquired or de novo vorinostat resistance. Strategies targeting DNMT1 diminished the IGF2 expression and potentiated vorinostat sensitivity in preclinical models of lung cancer with hypermethylation in the H19/IGF2 ICR. The degree of ICR hypermethylation correlated with vorinostat resistance in patient-derived lung tumors and in patients with hematologic malignancies. Conclusions: DNMT1-mediated transcriptional upregulation of IGF2 is a novel mechanism of resistance to HDIs, highlighting the role of epigenetic deregulation of IGF2 in HDI resistance and the potential value of the H19/IGF2 ICR hypermethylation and DNMT1 expression as predictive biomarkers in HDI-based anticancer therapies. Clin Cancer Res; 23(5); 1299–311. ©2016 AACR.

Purpose: We aimed to evaluate the effect of testosterone replacement therapy (TRT) on cognitive function and depression in men with testosterone deficiency syndrome. Materials and Methods: We carried out a prospective, placebo-controlled trial involving 106 men with total testosterone levels ＜3.3 ng/mL and symptoms of hypogonadism. Based on whether the patients received TRT (injection with 1,000 mg testosterone undecanoate) or a placebo (advice to modify lifestyle), the study population was divided into a TRT group (n=54) and a control group (n=52). Results: The age among patients in the TRT and control groups was 56.7±12.6 years and 57.8±11.4 years, respectively (p＞ 0.05). At baseline, no significant differences between the TRT and control groups were noted regarding serum testosterone or prostate-specific antigen levels, or regarding the scores for aging symptoms (Aging Males’ Symptoms scale), erectile function (5-item International Index of Erectile Function questionnaire), cognitive function (Korean Mini-Mental State Examination), and depression (Beck Depression Inventory). At 8 months after intervention total serum testosterone levels and erectile function scores had significantly increased (p＜0.05), whereas the scores for aging symptoms and depression had significantly decreased (p＜0.05) in the TRT group; no significant improvement in any parameters was noted for the control group. Notably, significant improvement in cognitive function was noted among patients with cognitive impairment at baseline (cognitive function score ＜25) who received TRT. Conclusions: TRT may be considered in men with testosterone deficiency syndrome if low testosterone levels are associated with depression or cognitive impairment.

Joo Hee Han, Sohyeon Yun, Sang Min Lee, Ram Hwangbo, Hyun Jin Jung, and Geon Ho Bahn Ifamilylove Clinic, Seoul, Korea School of Medicine, Kyung Hee University, Seoul, Korea Department of Psychiatry, Konyang University College of Medicine, Konyang University Hospital, Daejeon, Korea Department of Psychiatry, Graduate School, Kyung Hee University, Seoul, Korea Department of Psychiatry, Chuncheon National Hospital, Chuncheon, Korea Department of Psychiatry, Kyung Hee University School of Medicine, Seoul, Korea

The parameters of the alkaline fractionation process were investigated and optimized using a statistical analysis method to simultaneously remove hemicellulose and ash from rice husk (RH) concomitantly. After the alkaline fractionation process, the residual solid contained high cellulose, and the recovery yield of hemicellulose was enhanced in the fractionated liquid hydrolyzate. The hemicellulosic sugar recovery yield (71.6%), de-ashing yield (&gt, 99%), and lignin removal (&gt, 80%) were obtained at the reaction conditions of 150 °C of temperature, 40 min of reaction time, and 6% (w/v) of NaOH concentration. Subsequently, nano-structured silica was synthesized using black liquor obtained as a by-product of this fractionation process. For the production of nano-structured silica, it was observed that the pH of a black liquor and the heat treatment temperature significantly influenced the textural properties of silica product. In addition, the two-stage bleaching of solid residue followed by colloid milling for the production of high value-added CNF with was attempted. As a result, in addition to 119 g of fermentable sugar, 143 g of high-purity (&gt, 98%) silica with a surface area of 328 m2g−1 and 273.1 g of high-functional CNF with cellulose content of 80.1% were simultaneously obtained from 1000 g of RH.

Cancer-associated fibroblasts (CAF), as one of the major components of tumor microenvironment, have a significant role in cancer development and progression. CAF also supports the survival and chemo-induced resistance of cancer cells. Among various signaling pathways involved in cancer cell and CAF interaction, the signal transducers and activators of transcription (STAT3) pathway has been investigated a lot, but its own role in CAF itself is not yet clearly defined. In this paper, we established CAF using MRC5, which is a stable lung fibroblast cell line, by culturing with conditioned medium from lung cancer cells. Then, by using a STAT3 inhibitor, STX-0119, and STAT3 siRNA, we examined whether the blocking of STAT3 pathway in MRC5 affects chemotherapeutic resistance or invasiveness of A549 lung cancer cells. We found out that STAT3 inhibition in fibroblasts did not prevent CAF-induced resistance of A549 cells on proliferation, but it did attenuate the invasiveness and migration of A549 cells. These results suggest that the combination of a low dose of a STAT3 inhibitor, which would be high enough to inactivate the CAF around the tumor cells, and an anticancer drug can be taken as an approach to cancer treatment. Citation Format: Ju-Hee Kang, Ha Jung Lee, Hyun Jin Jung, Min Woo Kim, Seung Hyun Oh. STAT3 pathway in fibroblasts aggravates invasiveness of lung cancer cells in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B48.

Betula platyphylla (BP) is frequently administered in the treatment of various human diseases, including cancers. This study was undertaken to investigate the pharmacological function of the active components in BP and the underlying mechanism of its chemotherapeutic effects in human lung cancer cells. We observed that BP extracts and 1,7-bis(4-hydroxyphenyl)-4-hepten-3-one (BE1), one of the components of BP, effectively decreased the cell viability of several lung cancer cell lines. BE1-treated cells exhibited apoptosis induction and cell cycle arrest at the G2/M phase. Further examination demonstrated that BE1 treatment resulted in suppression of autophagy, as evidenced by increased protein expression levels of both LC3 II and p62/SQSTM1. Interestingly, the pharmacological induction of autophagy with rapamycin remarkably reduced the BE1-induced apoptosis, indicating that apoptosis induced by BE1 was associated with autophagy inhibition. Our data also demonstrated that BE1 exposure activated the p38 pathway resulting in regulation of the pro-apoptotic activity. Taken together, we believe that BE1 is a potential anticancer agent for human lung cancer, which exerts its effect by enhancing apoptosis via regulating autophagy and the p38 pathway.

Many studies have made clear that most of the genome is transcribed into noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), both of which can affect different cell features. LncRNAs are long heterogeneous RNAs that regulate gene expression and a variety of signaling pathways involved in cellular homeostasis and development. Several studies have demonstrated that lncRNA is an important class of regulatory molecule that can be targeted to change cellular physiology and function. The expression or dysfunction of lncRNAs is closely related to various hereditary, autoimmune, and metabolic diseases, and tumors. Specifically, recent work has shown that lncRNAs have an important role in kidney pathogenesis. The effective roles of lncRNAs have been recognized in renal ischemia, injury, inflammation, fibrosis, glomerular diseases, renal transplantation, and renal-cell carcinoma. The present review focuses on the emerging role and function of lncRNAs in the pathogenesis of kidney inflammation and fibrosis as novel essential regulators. Although lncRNAs are important players in the initiation and progression of many pathological processes, their role in renal fibrosis remains unclear. This review summarizes the current understanding of lncRNAs in the pathogenesis of kidney fibrosis and elucidates the potential role of these novel regulatory molecules as therapeutic targets for the clinical treatment of kidney inflammation and fibrosis.

The study was designed to assess and predict patient-reported goal achievement after treatment of benign prostatic hyperplasia (BPH) patients with tamsulosin.From November 2013 to October 2015, 272 patients initially diagnosed with BPH were prospectively enrolled in nine different centers. Before the treatment, subjective final goals were recorded by all patients. Every four weeks, the treatment outcomes were evaluated using international prostate symptom score (IPSS) and uroflowmetry, and adverse events were recorded. Patient-reported goal achievements were assessed after 12 weeks of treatment.Of the enrolled patients, 179 patients completed the study. The pretreatment patients' goals included the frequency improvement, nocturia improvement, residual urine sense improvement, well voiding, hesitancy improvement, weak urine stream improvement, urgency improvement, and voiding-related discomfort improvement. Of the 179 patients, 129 patients (72.1%) reported that they achieved their primary goals after three months of medical therapy. Logistic regression analysis revealed that pretreatment quality of life (OR = 8.621, 95% CI: 2.154-9.834), and improvement of quality of life (OR = 6.740, 95% CI: 1.908-11.490) were independent predictors of patient-reported goal achievement after tamsulosin monotherapy.Overall patient-reported goal achievement after medical therapy for BPH was high and the scores of pretreatment quality of life and improvement of quality of life can be important factors to predict the achievement of treatment goals.

A field experiment was performed to evaluate the effects of tillage systems and fertilizer management on the growth and nutrient uptake in soybean. The plant height, fresh weight and dry weight of conventional tillage (CT) were much higher those observed for no-tillage (NT). The highest plant height (128.47 cm) was observed in CT with chemical fertilizer. The plant nitrate concentration was higher (2.29%) in NT with green manure than chemical fertilization. However, nitrogen increased steadily in all treatments, and the highest quantity of total nitrogen (476.7 Kg/ha) was observed in NT with green manure. The NO3-N content in the soil decreased gradually just after the vegetative stage. Tillage practices and additional fertilizer application was less effective on the uptake of N, P and K in soybean seeds as compared to NT with green manure. The results postulated that NT strategies with fertilizers might influence the growth characteristics and mineral uptake in soybean.

Along with the increase of railway catenary system operation speed to 400 km/h, there have been growing demands for good quality current collection systems that satisfy quality standards as well as criteria for safe working. Retaining uniform elasticity tension of contact wires is essential in maintaining high quality contact between pantograph and OCL (Overhead Contact Line) of current collection systems in high speed railways. Therefore, the tension of contact wire must be kept within tight tolerance limits in both working conditions and adverse weather conditions of catenary system. In accordance with these conditions, this paper presents a real time monitoring system for the tensioning device of the newly installed catenary system on the special route of Honam high speed line for 400 km/h operation. For the verification of the true value of tension of contact wires, we have developed ring-type tensioning sensors which were installed on supporting points of mast which compose the catenary system. According to the field test performed on the Honam high speed line catenary system, variation of tension was measured accurately in real-time.Key Words : Arc detector, Loss-of-contact, Current collection, Contact wire, Pantograph†Corresponding Author : Dept. of High-Speed Railroad ResearchCenter, Korea Railroad Research Institute, KoreaE-mail : ypark@krri.re.kr* Dept. of High-Speed Railroad Research Center, Korea RailroadResearch Institute, Korea** DahyunCNI Co., Ltd, KoreaReceived : May 21, 2015; Accepted : July 7, 2015

The influence of stacking faults (SFs) and triangular defects (TDs) on the electrical properties of 4H-SiC Schottky barrier diode (SBD) were investigated. The SF types and locations were distinguished and mapped by using room-temperature photoluminescence (PL) and optical microscope. SBDs were fabricated including the location of SF’s and TD’s. The effects of the types of defects and its area portion in the fabricated SBDs were also investigated. Based on the present data, 3C-TD has more harmful effect rather than the other SFs. The fabricated SBDs including SFs showed that increase of area portion of SF’s also resulted increase of specific on resistance of SBDs.

A large set of Bacillus megaterium CYP102A1 mutants are known to metabolize various drugs to form human metabolites. Omeprazole (OMP), a proton pump inhibitor, has been widely used as an acid inhibitory agent for the treatment of gastric acid hypersecretion disorders. It is primarily metabolized by human CYP2C19 and CYP3A4 to 5'-OH OMP and a sulfone product, respectively. It was recently reported that several CYP102A1 mutants can oxidize racemic and S-OMP to 5'-OH OMP and that these mutants can further oxidize 5'-OH racemic OMP to 5'-COOH OMP. Here, we report that the S- and R-enantiomers of OMP are hydroxylated by 26 mutants of CYP102A1 to produce 1 major metabolite (5'-OH OMP) regardless of the chirality of the parent substrates. Although the binding of R-OMP to the CYP102A1 active site caused a more apparent change of heme environment compared with binding of S-OMP, there was no correlation between the spectral change upon substrate binding and catalytic activity of either enantiomer. The 5'-OH OMP produced from racemic, S-, and R-OMP could be obtained with a high conversion rate and high selectivity when the triple R47L/F87V/L188Q mutant was used. These results suggest that bacterial CYP102A1 mutants can be used to produce the human metabolite 5'-OH OMP from both the S- and R-enantiomers of OMP.

Objective During the last decade laparoscopy has increasingly been advocated as the primary investigative procedure for the management of the non-palpable testis. We reviewed the medical records in a consecutive series of boys with non-palpable testis to examine the contribution of the initial inguinal approach in the management of unilateral non-palpable testis. Materials and methods Among the 183 consecutive patients with cryptorchidism from 2003 to 2012, there were 21 patients with unilateral and three with bilateral non-palpable testes. All unilateral patients then underwent inguinal and scrotal exploration through an inguinal incision. For those patients with an intra-abdominal peeping testis, the gonad was placed into the scrotum after meticulous cranial mobilization of the spermatic cord. Results Patient age ranged from 11 months to 144 months (mean age: 23 months). Among the 21 unilateral cases, testicular absence or atrophy was confirmed in seven patients with a scrotal nubbin in six, and blind-ending vas and vessels at the external inguinal ring in one patient. Among the remaining 14 patients with sizeable testes, 12 testes were intra-abdominal peeping testes and two testicles were seen within the distal inguinal canal, which may be missed on physical examination owing to patient obesity. The intra-abdominal peeping testicle had the opened processus vaginalis entering the internal ring in which testicle was found. These were fixed into the scrotum successfully by cranial mobilization of spermatic vessel sometimes cutting the internal oblique muscle and by Prentiss and Fowler-Stephen's maneuver. Diagnostic laparoscopy was done on three patients with bilateral cases. Conclusions Given the result that most of nubbins are within the scrotum and testes with intra-abdominal peeping testes are fixed down safely into the scrotum, the inguinal approach may suffice for the management of unilateral non-palpable testis. Laparoscopy should be reserved for patients with bilateral non-palpable undescended testes.

Aim of the Study: Betula platyphylla (BP) is a representative medicinal herb used in the treatment of various inflammatory diseases in East Asia. The purpose of this study was to identify the active components of BP extracts and examine the cytotoxic effect of constituents through specific biological mechanisms that regulate the chemotherapeutic activity in lung cancer cells. Materials and Methods: We performed MTT assays, colony formation assays, flow cytometry assays, western blot analysis, and used fluorescence microscopy after transfection with plasmids to study the molecular mechanisms and chemotherapeutic effects of BP extracts and its active components. Results: We observed that BP extracts and 1,7-Bis(4-hydroxyphenyl)-4-hepten-3-one (BE1), one of the components of BP, effectively decreased the cell viability of several lung cancer cell lines. BE1-treated cells exhibited apoptosis induction and cell cycle arrest at the G2/M phase. Further examination demonstrated that BE1 treatment resulted in suppression of autophagy, as evidenced by increased protein expression levels of both LC3 II and p62/SQSTM1. Interestingly, the pharmacological induction of autophagy with rapamycin remarkably reduced the BE1-induced apoptosis, indicating that apoptosis induced by BE1 was associated with autophagy inhibition. Our data also demonstrated that BE1 exposure activated the p38 pathway resulting in regulation of the pro-apoptotic activity. Conclusion: Taken together, we believe that BE1 is a potential anticancer agent for human lung cancer, which exerts its effect by enhancing apoptosis via regulating autophagy and the p38 pathway. Citation Format: Hyun Jin Jung, Ju-Hee Kang, Seung Hyun Oh. 1,7-Bis(4-hydroxyphenyl)-4-hepten-3-one from Betula platyphylla impairs autophagy and induces apoptosis in lung cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A020. doi:10.1158/1535-7163.TARG-19-A020

Objective To report our experience with the diagnosis and management of coexisting ureteropelvic junction obstruction (UPJO) and ureterovesical junction obstruction (UVJO). Materials and Methods Among the pediatric patients who underwent pyeloplasty or ureteroneocystostomy from 2003-2012, 15 patients were diagnosed with coexisting UPJO and UVJO. We retrospectively analyzed their medical records. Results Of the 15 patients with coexisting UPJO and UVJO, the correct diagnosis was made preoperatively in 10 patients (66.7%). In 4 other patients, only UPJO was diagnosed, and in 1 patient, only UVJO was diagnosed. The decision of where to initially operate was determined from the combined results of the preoperative antegrade evaluation and retrograde ureteropyelography. Pyeloplasty was the initial surgical management choice for 9 patients, and ureteroneocystostomy was the initial surgical approach in 5 patients. In 1 patient, both pyeloplasty and ureteroneocystostomy were performed simultaneously. Of the 9 patients who underwent initial pyeloplasty, additional ureteroneocystostomy was required in 2. Additional pyeloplasty was required in 2 of the 5 patients who initially underwent ureteroneocystostomy. Conclusion It is often difficult to correctly diagnose coexisting UPJO and UVJO. In patients with UPJO, it is highly recommended that retrograde ureteropyelography be performed before pyeloplasty to evaluate the distal ureter–ureterovesical junction. Initial pyeloplasty is not always recommended as a first-line therapy.

Urothelium lined seromuscular colocystoplasty is an ideal method of augmentation cystoplasty that avoids various complications caused by the use of gastrointestinal segments. We reviewed the long-term outcomes using this technique at a single institution.We retrospectively analyzed 34 patients who underwent urothelium lined seromuscular colocystoplasty between January 1996 and December 2007. A total of 33 patients, excluding 1 who had previously undergone artificial urinary sphincter implantation, were included in the study. Changes in urodynamic parameters, duration of anticholinergic use, incontinence and surgical complications were analyzed.Mean±SD age at surgery was 10.0±5.7 years (range 3.0 to 26.0) and duration of followup was 6.0±2.3 years (2.7 to 13.4). A total of 17 patients (51.5%) underwent simultaneous anti-incontinence surgery and urothelium lined seromuscular colocystoplasty. Mean bladder capacity increased by a factor of 2.96 and mean percentage of expected bladder capacity for age increased by a factor of 1.96 postoperatively. Of patients who underwent anti-incontinence surgery 4 of 10 whose abdominal leak point pressure was less than 40 cm H2O required additional surgery, whereas none whose abdominal leak point pressure was 40 to 60 cm H2O required reoperation. Two of 16 patients who did not undergo anti-incontinence surgery eventually required continence surgery. A total of 13 patients (39.4%) were able to discontinue anticholinergics at 47.3 months postoperatively. There were no bladder perforations, bowel obstructions or metabolic abnormalities.Urothelium lined seromuscular colocystoplasty can be primarily considered in patients without prior bladder mucosal injury. Constant high bladder outlet pressure to facilitate adhesion of bladder mucosa and seromuscular patch is critical for the best results. We recommend abdominal leak point pressure 60 cm H2O or less as an indication for simultaneous anti-incontinence surgery and urothelium lined seromuscular colocystoplasty.