IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis.

Rationale: Nab-paclitaxel (Abx) is widely employed in malignant tumor therapy. In tumor cells and pro-tumoral M2-type macrophages, the IL4 receptor (IL4R) is upregulated. This study aimed to elucidate the selective delivery of Abx to M2-type macrophages by targeting IL4R and reprogramming them into an anti-tumoral M1-type. Methods: Abx was conjugated with the IL4R-binding IL4RPep-1 peptide using click chemistry (IL4R-Abx). Cellular internalization, macrophage reprogramming and signal pathways, and tumor growth and metastasis by IL4R-Abx were examined. Results: IL4R-Abx was internalized into M2 macrophages more efficiently compared to the unmodified Abx and control peptide-conjugated Abx (Ctrl-Abx), which was primarily inhibited using an anti-IL4R antibody and a receptor-mediated endocytosis inhibitor compared with a macropinocytosis inhibitor. IL4R-Abx reprogrammed the M2-type macrophages into M1-like phenotype and increased reactive oxygen species (ROS) levels and extracellular release of high mobility group box 1 (HMGB1) in M2 macrophages at higher levels than Abx and Ctrl-Abx. The conditioned medium of IL4R-Abx-treated M2 macrophages skewed M2 macrophages into the M1-like phenotype, in which an anti-HMGB1 antibody and a toll-like receptor 4 (TLR4) inhibitor induced a blockade. IL4R-Abx accumulated at tumors, heightened immune-stimulatory cells while reducing immune-suppressing cells, and hampered tumor growth and metastasis in mice more efficiently than Abx and Ctrl-Abx. Conclusions: These results indicate that IL4R-targeting allows enhancement of M2-macrophage shaping into M1-like phenotype by Abx through the ROS-HMGB1-TLR4 axis, improvement of antitumor immunity, and thereby inhibition of tumor growth and metastasis, presenting a new approach to cancer immunotherapy.

TM-MC 2.0: an enhanced chemical database of medicinal materials in Northeast Asian traditional medicine.

BACKGROUND: As chromatographic techniques have advanced, many articles that analyze the constituting compounds of medicinal materials have been published in relation to Northeast Asian traditional medicine, including traditional Chinese medicine (TCM). TM-MC was launched in 2015, providing information about the chemical compounds in medicinal materials from chromatographic articles in PubMed. Since 2015, through continuous curation efforts, we have now released TM-MC 2.0 with significant improvements to the quantity and quality of the data ( https://tm-mc.kr ). DESCRIPTION: TM-MC 2.0 contains 635 medicinal materials, 34,107 chemical compounds (21,306 identified and de-duplicated), 13,992 targets, 27,997 diseases, and 5,075 prescriptions (2,393 de-duplicated by name). The database provides the largest number of identified compounds for medicinal materials listed in the pharmacopoeia compared to all TCM databases. In particular, marker compounds of medicinal materials and many newly discovered compounds were added through the manual curation of recent chromatographic articles. CONCLUSION: TM-MC 2.0 provides the largest collection of information about the chemical compounds of the medicinal materials listed in the Korean, Chinese, and Japanese pharmacopoeias. Our database can be utilized for network pharmacology in traditional medicine and for the compound screening of medicinal materials for modern drug discovery.

Comparative studies on vertical-channel charge-trap memory thin-film transistors using In-Ga-Zn-O active channels deposited by sputtering and atomic layer depositions.

Vertical-channel charge-trap memory thin film-transistors (V-CTM TFTs) using oxide semiconductors were fabricated and characterized, in which In-Ga-Zn-O (IGZO) channels were prepared by sputtering and atomic-layer deposition (ALD) methods to elucidate the effects of deposition process. The vertical-channel gate stack of the fabricated device was verified to be well implemented on the vertical sidewall of the spacer patterns due to excellent step-coverage and self-limiting mechanisms of ALD process. The V-CTM TFTs using ALD-IGZO channel exhibited a wide memory window (MW) of 15.0 V at a VGS sweep of ±20 V and a large memory margin of 1.6 × 102 at a program pulse duration as short as 5 ms. The programmed memory margin higher than 105 did not experience any degradation with time evolution for 104 s. The mechanical durability was also evaluated after the delamination process of polyimide (PI) film. There were no marked variations in charge-trap-assisted MW even at a curvature radius of 1 mm and programmed memory margin even after repeated program operations of 104 cycles. The introduction of ALD process for the formation of IGZO active channel was suggested as a main process parameter to ensure the excellent memory device characteristics of the V-CTM TFTs.

Regional characteristics of NO2 column densities from Pandora observations during the MAPS-Seoul campaign.

Vertical column density (VCD) of nitrogen dioxide (NO2) was measured using Pandora spectrometers at six sites on the Korean Peninsula during the Megacity Air Pollution Studies-Seoul (MAPS-Seoul) campaign from May to June 2015. To estimate the tropospheric NO2 VCD, the stratospheric NO2 VCD from the Ozone Monitoring Instrument (OMI) was subtracted from the total NO2 VCD from Pandora. European Centre for Medium-Range Weather Forecasts (ECMWF) reanalysis wind data was used to analyze variations in tropospheric NO2 VCD caused by wind patterns at each site. The Yonsei/SEO site was found to have the largest tropospheric NO2 VCD (1.49 DU on average) from a statistical analysis of hourly tropospheric NO2 VCD measurements. At rural sites, remarkably low NO2 VCDs were observed. However, a wind field analysis showed that trans-boundary transport and emissions from domestic sources lead to an increase in tropospheric NO2 VCD at NIER/BYI and KMA/AMY, respectively. At urban sites, high NO2 VCD values were observed under conditions of low wind speed, which were influenced by local urban emissions. Tropospheric NO2 VCD at HUFS/Yongin increases under conditions of significant transport from urban area of Seoul according to a correlation analysis that considers the transport time lag. Significant diurnal variations were found at urban sites during the MAPS-Seoul campaign, but not at rural sites, indicating that it is associated with diurnal patterns of NO2 emissions from dense traffic.

A systems pharmacology approach to investigate the mechanism of Oryeong-san formula for the treatment of hypertension.

ETHNOPHARMACOLOGICAL RELEVANCE: Oryeong-san (ORS) is a traditional formula that has long been used for the treatment of dysfunctions of body fluids and electrolyte homeostasis in Korea, China and Japan. Recent reports have shown that ORS may suppress hypertension by controlling the renin-angiotensin-aldosterone system (RAAS) in the kidney, but its action mechanism has not been well defined. AIM OF THE STUDY: The aim of this study was to decipher the ORS mechanisms in the treatment of hypertension using a systems pharmacology approach. MATERIALS AND METHODS: The compounds of ORS were obtained from the TM-MC (database of medicinal materials and chemical compounds in Northeast Asian traditional medicine), and the drug-likeness (DL) and oral bioavailability (OB) of the compounds were evaluated. The potential targets of the compounds were identified using various pharmacology databases. To analyze the mechanisms of the ORS for hypertension, a Compound-Target-Disease (C-T-D) network was established with respect to the genes related to hypertension. RESULTS: A screening evaluation of the DL and OB of the ORS compounds identified a list of 232 active compounds. The pharmacological activity of the targets was investigated by exploring the interaction network between the compounds and the targets. Analysis of the interactions between the compounds and the hypertension-related targets revealed that 14 ORS compounds regulate the RAAS and vasoconstrictors in the kidney. CONCLUSIONS: This study used the systems pharmacology approach to decipher the mechanisms of action of ORS for the treatment of hypertension. When hypertension drugs and ORS are used in combination for treatment, possible side effects should be considered because most hypertension drugs are related to the RAAS. The results of this study may provide clues to not only analyze the pharmacological activity of ORS for the treatment of hypertension but other diseases as well.

Research trends in Korean medicine based on temporal and network analysis.

BACKGROUND: Much research on Korean medicine has been recently published in Korea. The aim of this study was to determine the research trends in Korean medicine by performing a comprehensive analysis of articles that have been published in Korea using temporal and network analysis methods. METHODS: A total of 29,876 articles from 1963 to 2018 were prepared from OASIS (Oriental Medicine Advanced Searching Integrated System), the largest portal for Korean medicine. After the keywords and years were extracted from the metadata of the articles, an annual frequency matrix was obtained for the keywords. By using the matrix, the temporal trends of the keywords were analyzed by comparing the changes in similarity between the lists of keywords by year. Moreover, to analyze the relationship among research topics, a clustered network was constructed in which a node was a keyword and an edge was a similarity between two keywords. RESULTS: The temporal trend of the keywords was classified into six chronological phases. The appearance frequency of most keywords tended to increase gradually, but only the keywords "mibyeong," "systems biology" and "korean medicine hospital" appeared in the most recent phase. The network of keywords was clustered and visualized into thirteen groups with the Gephi software. The main keywords in each group were related to effects such as "anti-inflammation" and "antioxidant," to diseases such as "allergic rhinitis" and "diabetes" and to therapies such as "herbal acupuncture" and "herbal formula." CONCLUSIONS: The analysis of the trends determined in this study provides a systematic understanding as well as future research directions in Korean medicine to researchers. In the future, an overall analysis of the research trends in Korean medicine will be done by analyzing articles published in Korea and other countries.

DisArticle: a web server for SVM-based discrimination of articles on traditional medicine.

BACKGROUND: Much research has been done in Northeast Asia to show the efficacy of traditional medicine. While MEDLINE contains many biomedical articles including those on traditional medicine, it does not categorize those articles by specific research area. The aim of this study was to provide a method that searches for articles only on traditional medicine in Northeast Asia, including traditional Chinese medicine, from among the articles in MEDLINE. RESULTS: This research established an SVM-based classifier model to identify articles on traditional medicine. The TAK + HM classifier, trained with the features of title, abstract, keywords, herbal data, and MeSH, has a precision of 0.954 and a recall of 0.902. In particular, the feature of herbal data significantly increased the performance of the classifier. By using the TAK + HM classifier, a total of about 108,000 articles were discriminated as articles on traditional medicine from among all articles in MEDLINE. We also built a web server called DisArticle ( http://informatics.kiom.re.kr/disarticle ), in which users can search for the articles and obtain statistical data. CONCLUSIONS: Because much evidence-based research on traditional medicine has been published in recent years, it has become necessary to search for articles on traditional medicine exclusively in literature databases. DisArticle can help users to search for and analyze the research trends in traditional medicine.

Structuralizing biomedical abstracts with discriminative linguistic features.

OBJECTIVE: Nearly 75% of the abstracts in MEDLINE papers present in an unstructured format. This study aims to automate the reformatting of unstructured abstracts into the Introduction, Methods, Results, and Discussion (IMRAD) format. The quality of this reformatting relies on the features used in sentence classification. Therefore, we explored the most effective linguistic features in MEDLINE papers. METHODS: We constructed a feature set consisting of bag of words, linguistic features, grammatical features, and structural features. In order to evaluate the effectiveness, which is the capability of the sentence classification with the features, three datasets from PubMed Central Open Access Subset were selected and constructed: (1) structured abstract (SA) for training, (2) unstructured RCT abstract (UA-1) and (3) unstructured general abstract (UA-2). F-score and accuracy were used to measure the effectiveness on IMRAD section level and the overall classification. RESULTS: Adding linguistic features improves the classification of the abstract sentence from 1.2% to 35.8% in terms of accuracy in three abstract datasets. The highest accuracies achieved were 91.7% in SA, 86.3% in UA-1, and 77.9% in UA-2. Linguistic features (dimensions=15) had fewer dimensions than bag-of-words (dimensions= 1541). All representative linguistic features (n-gram and verb phrase, and noun phrase) for each section are identified in our system (available at http://abstract.bike.re.kr). CONCLUSION: Linguistic features can be used to effectively classify sentence with low computation burden in MEDLINE abstract.

TM-MC: a database of medicinal materials and chemical compounds in Northeast Asian traditional medicine.

BACKGROUND: In traditional medicine, there has been a great deal of research on the effects exhibited by medicinal materials. To study the effects, resources that can systematically describe the chemical compounds in medicinal materials are necessary. In recent years, numerous databases on medicinal materials and constituent compounds have been constructed. However, because these databases provide differing information and the sources of such information are unclear or difficult to verify, it is difficult to decide which database to use. Moreover, there is much overlapping information. The aim of this study was to construct a database of medicinal materials and chemical compounds in Northeast Asian traditional medicine (TM-MC), for which medicinal materials are listed in the Korean, Chinese, and Japanese pharmacopoeias and information on the compound names of medicinal materials can easily be confirmed online. DESCRIPTION: To provide information on the chemical compounds of medicinal materials, chromatography articles from MEDLINE and PubMed Central were searched. After chemical compounds of medicinal materials were extracted by manually investigating the full-text of articles, a database of information on about 14,000 compounds from 536 medicinal materials was built. The database also provides links to the articles from which each medicinal material and chemical compound were extracted. CONCLUSION: TM-MC database provides information on medicinal materials and their chemical compounds from chromatography articles in MEDLINE and PubMed Central. Researchers can easily check relevant information through the links to articles.

A mathematical model for the deficiency-excess mechanism of yin-yang in five viscera.

To raise traditional medicine to a higher level of scientific research, a mathematical model has been proposed using symbolic notations and operators to describe several disease symptoms generally recognized in traditional medicine. Even though this model to a certain degree offers a mathematical approach to identify the relationships between yin-yang and the five viscera, it is not an efficient means of explaining the pathology in traditional medicine due to its use of superfluous notations and definitions. In this paper, we introduce two concise operators, a self-development operator and an action operator: the former describes the effect of a viscus in the unbalanced state on other viscera: the latter explains the engendering and restraining relationships between the two viscera. These tools are useful to elucidate the interactions among the states of the five viscera based on yin-yang and the five elements theory. Our mathematical model with these two operators facilitates description for the scheme of deficiency-excess of yin-yang in the five viscera. Accordingly, we have mathematically refined the existing results and shown clinical applications as well.

Tribody: robust self-assembled trimeric targeting ligands with high stability and significantly improved target-binding strength.

The C-terminal coiled-coil region of mouse and human cartilage matrix protein (CMP) self-assembles into a parallel trimeric complex. Here, we report a general strategy for the development of highly stable trimeric targeting ligands (tribodies), against epidermal growth factor receptor (EGFR) and prostate-specific membrane antigen (PSMA) as examples, by fusing a specific target-binding moiety with a trimerization domain derived from CMP. The resulting fusion proteins can efficiently self-assemble into a well-defined parallel homotrimer with high stability. Surface plasmon resonance (SPR) analysis of the trimeric targeting ligands demonstrated significantly enhanced target-binding strength compared with the corresponding monomers. Cellular-binding studies confirmed that the trimeric targeting ligands have superior binding strength toward their respective receptors. Significantly, the EGFR-binding tribody was considerably accumulated in the tumor of mice bearing xenografted EGFR-positive tumors, indicating its effective cancer-targeting feature under in vivo conditions. Our results demonstrate that CMP-based self-assembly of tribodies can be a general strategy for the facile and robust generation of trivalent targeting ligands for a wide variety of in vitro and in vivo applications.

Ontology for medicinal materials based on traditional Korean medicine.

UNLABELLED: We are constructing an ontology for traditional Korean medicine, and we started with medicinal materials to express the relationships between patients' symptoms, diseases and treatments. Biological materials and mineral resources have been used traditionally for patient treatments. The ontology includes various data related to these materials, such as their scientific names, parts of materials used, effectiveness and related oriental organ of the human body. AVAILABILITY: http://tkm.kiom.re.kr/ontology/TraditionalKoreanMedicine.rdf-xml.owl (10-20 s using Internet Explorer.)

[Occurrence of diabetic ketoacidosis and autoimmune thyroiditis in a patient treated with pegylated interferon-alpha 2b and ribavirin for chronic hepatitis C].

Combined pegylated interferon and ribavirin therapy for chronic hepatitis C infection cause a wide range of side effects, including flu-like syndrome, hematological abnormalities, cardiovascular symptoms, gastrointestinal symptoms, pulmonary dysfunction, depression, and retinopathy. Interferon-alpha has been shown to be related to the development of various autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroid disease, and type 1 diabetes mellitus (DM). Type 1 DM and thyroid disease respectively develop in 0.08-2.61% and 10-15% of patients treated with combined interferon-alpha and ribavirin for chronic hepatitis C. The coexistence of type 1 DM and autoimmune thyroiditis was rarely reported. We report a case of a 33-year-old female patient with chronic hepatitis C who simultaneously developed diabetic ketoacidosis and autoimmune thyroiditis after treatment with pegylated interferon-alpha 2b and ribavirin.

Atypical acute syphilitic posterior placoid chorioretinitis.

A 48-year-old man presented with visual dimness in the right eye that had developed 2 weeks previously. Dilated fundus examination showed few vitreous cells and numerous yellow, placoid lesions in both eyes. His right eye had more severe serous retinal detachment involving the macula. Fluorescein angiography demonstrated early irregular hypofluorescence with late staining in the areas of the yellow placoid lesions. He started a regimen of 60 mg of oral prednisone daily. Two weeks later, a serologic fluorescent treponemal antigen absorption test was positive for Ig G and Ig M. He was referred to an infectious disease specialist for antibiotic therapy. A week later, he returned, having stayed on prednisone only and not having taken the internist's antibiotic prescription. Meanwhile, the chorioretinitis in his right eye, which had initially been at a more advanced stage, was resolved with the use of steroids. The chorioretinitis in his left eye, which was aggravated at an earlier stage, ultimately recovered. Our case had atypical courses such that one eye improved and the other worsened during the same steroid treatment period. This result was inconsistent with that of previous reports showing that oral steroid influences the clinical course of acute syphilitic posterior placoid chorioretinitis.

Multidetector row computed tomographic gastrography findings after endoscopic submucosal dissection for early gastric cancer: emphasis on time evolution and factors for predicting residual tumor.

PURPOSE: To retrospectively investigate multidetector row computed tomographic (CT) gastrography (CTG) findings after endoscopic submucosal dissection (ESD) of the stomach and to analyze the time evolution and factors for predicting residual tumor. MATERIALS AND METHODS: During an 18-month period, ESD was performed for 92 early gastric cancers (EGCs) in 86 patients. All patients were followed up with CTG, and 6 patients underwent CTG 2times. A total of 98 CTGs were analyzed by 2 radiologists for the presence of mucosal break, overlying enhancing layer and the attenuation of the lesion on 2-dimensional (2D) images, and malignant-looking fold convergence on 3D volume-rendered images. Multidetector row computed tomographic gastrography findings were categorized into 5 types: deep benign ulcer (BU), deformed BU, shallow depressed ulcer, EGC, and advanced gastric cancer (AGC). To analyze the time evolution of CTG findings, the mean time interval between the procedure and CT was calculated and compared among the 5 types using the Kruskal-Wallis test. The chi test or Fisher exact test was used to determine significant CT findings for predicting residual tumor after ESD. RESULTS: Tumor involvement was found at the resection margin in 7 lesions (6 radial and 1 deep). Of 98 lesions, 5 (5.1%) were not visualized on either 2D or 3D images. Most lesions had mucosal break (82/93) and showed intermediate low attenuation (67/93) on 2D images. Prominent enhancement of overlying layer above ESD site was seen in 23 lesions. Malignant-looking fold convergence was observed in 11 lesions. Sixty-five lesions appeared as shallow depressed ulcers, 13 as deformed BUs, 8 as EGCs, 4 AGCs, and 3 deep BUs. Among them, deep BUs appeared first (average, 0.2 month after ESD; P < 0.05), followed by deformed BUs (5.3 months), then AGCs (6.0 months), EGCs (7.3 months), and shallow depressed ulcers (7.7 months). However, the only significant time interval difference was between the deep BUs and the other types (P < 0.05). There was no correlation between the presence of marginal tumor involvement and any CT findings. CONCLUSIONS: Immediately after ESD, lesions appear as deep BUs then evolve over time into shallow depressed ulcers. The presence of malignant-looking fold convergence and enhancing layer above the mucosal break on CT do not indicate tumor involvement at the ESD margin.

Crystalline structure of ceria particles controlled by the oxygen partial pressure and STI CMP performances.

The effect of the crystalline structures of nano-sized ceria particles on shallow trench isolation (STI) chemical mechanical planarization (CMP) performance was investigated. The ceria particles were synthesized via a solid-state displacement reaction method, and their crystalline structure was controlled by regulating the oxygen partial pressure at the reaction site on the precursor. The crystalline structures of ceria particles were analyzed by the high-resolution TEM nano-beam diffraction pattern. In a calcination process with a high oxygen concentration, the synthesized ceria particles had a cubic fluorite structure (CeO(2)), because of the decarbonation of the cerium precursor. However, a low oxygen concentration results in a hexagonal phase cerium oxide (Ce(2)O(3)) rather than the cubic phase due to the insufficient oxidation of Ce(3+) to Ce(4+). In the STI CMP evaluation, the ceria slurry prepared with the cubic CeO(2) shows enhanced performances of the oxide-to-nitride removal selectivity.

[Long-term results of endoscopic histoacryl (N-butyl-2-cyanoacrylate) injection for treatment of gastric varices--a 10-year experience].

BACKGROUND/AIMS: Gastric variceal bleeding is an infrequent but serious complication of portal hypertension. Endoscopic injection of Histoacryl (N-butyl-2-cyanoacrylate) has been approved as an effective treatment for gastric variceal bleeding. The aim of this study was to evaluate the long-term efficacy and safety of the endoscopic injection of Histoacryl for the treatment of gastric varices. METHODS: Between January 1994 and January 2005, eighty-five patients with gastric varices received endoscopic injections of Histoacryl. Among these 85 patients, 65 received the procedure within 1 week after gastric variceal bleeding, and 13 received as a prophylactic procedure. According to the Sarin classification, 32 patients were GOV1 and 53 were GOV2. Most of the varices were large (F2 or F3, 75 patients). The average volume of Histoacryl per each session was 1.43 ml. Among 85 patients, 72 patients were followed-up and the median duration was 24.5 months. RESULTS: The rate of initial hemostasis was 98.6% and recurrent bleeding occurred in 29.2% (21 of 72). When rebleeding occurred, 76.2% was within 1 year after the initial injection. Treatment failure-related mortality rate was 1.4% (1 of 85). Twenty-seven patients died, mostly due to hepatocelluar carcinoma or liver failure. Two patients experienced pulmonary embolism and one experienced splenic infarction. They recovered without specific treatment. Rebleeding rate had a tendency to increase in patients with hepatocelluar carcinoma (p=0.051) and GOV2 (p=0.061). CONCLUSIONS: Histoacryl injection therapy is a effective treatment method for gastric varices with high initial hemostasis rate and low major complications.