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Introduction: DPP4 is thought to be involved in certain immune processes and plays an important role in allergic reactions in the lungs. The effect of the DPP4 inhibitor sitagliptin on the effector phase of allergic rhinitis (AR) in ovalbumin (OVA)-sensitized mice and on mast cell degranulation in vitro was assessed. Methods: The AR mouse model was established by intraperitoneal injection combined with OVA intranasal method. OVA was injected intraperitoneally 3 times for the first 2 weeks, and the mice were subsequently given DPP4 inhibitors by oral gavage, accompanied by an OVA intranasal challenge. The impacts of DPP4 inhibitors on DPP4 levels in mouse model were determined. Nasal mucosa tissue was collected for H&E staining and toluidine blue staining. Immunoglobulin E (IgE) levels and histamine levels were analyzed, and IL-4, IL-5, and IL-12 as well as IFN-γ levels were assessed. Following the treatment of dinitrophenol (DNP)-IgE or DNP-IgE plus sitagliptin in RBL-2H3 cells, β-hexosaminidase activity was analyzed and toluidine blue staining was performed. Results: DPP4 level was reduced in AR patients, as well as in AR mouse models. Nasal allergic symptoms such as sneezing and nose-scratching showed high frequency in OVA-induced mice. Sitagliptin treatment during the intranasal challenge of OVA decreased DPP4 levels, suppressed allergic symptoms, eosinophil infiltration, IgE levels, mast cell infiltration, as well as the levels of inflammatory cytokines. We further found that sitagliptin inhibited mast cell activation and histamine levels in vitro. Conclusion: Sitagliptin suppresses the effector phase of AR, and this mechanism is partly attributed to the suppression of inflammatory response and mast cell degranulation.

PDF file 70K, This table contains the IC50 values of in vitro cell survival assay for crizotinib or ceritinib in engineered EML4-ALK mutant Ba/F3 cells corresponding to Fig 4A

PDF file 135K, Figure S1 contains data about Ceritinib specificity and potency on crizotinib na?ve EML4-ALK wild-type cells. Figure S2 contains the Cell survival curves of H3122 CR1, MGH021-4 and MGH045 cells following treatment with Crizotinib or ceritinib corresponding to Fig2A. Figure S3 contains the Cell survival curves of Ba/F3 cells following treatment with Crizotinib or ceritinib corresponding to Fig4A. Figure S4 contains tumor growth curves corresponding to the Development of crizotinib resistant H2228 xenograft tumor models used in Fig 5A-D

PDF file 100K, Legends for the supplementary figures

Targeted therapy is an important therapeutic strategy currently, however, the development of targeted therapy for nasopharyngeal carcinoma (NPC) is relatively lagging. Cullin 4A (CUL4A) was reported to be overexpressed in NPC; nevertheless, the specific role of CUL4A remains unrevealed. NPC cells and tumor-bearing mice were cultivated to explore the role and mechanism of CUL4A in NPC. After evaluating CUL4A levels in NPC cells, functional experiments were carried out to investigate the effects of CUL4A knockdown and overexpression on cell proliferative, invasive and migratory aptitude as well as NF-κB signaling. Following the GeneMANIA database predicted that protein arginine methyltransferase 5 (PRMT5) was downstream of CUL4A, the mediated role of PRMT5 in the regulation of CUL4A on cells was then determined. Moreover, the tumor volumes and weights of tumor-bearing mice were recorded, and the levels of proliferation-, migration-, and NF-κB signaling-related proteins in the tumor were determined. Herein, CUL4A was enhanced in NPC cells, and its knockdown and overexpression separately suppressed and promoted cell proliferative, invasive, and migratory aptitude as well as NF-κB signal activation. Novelty, PRMT5 knockdown reversed the influences of CUL4A overexpression on these aspects. In addition, its knockdown likewise reversed the facilitating impact of CUL4A expression on tumor growth and declined the expression levels of proliferation-, migration-, and NF-κB signaling-related protein in the tumor. Together, this paper indicated that CUL4A promoted the proliferative, invasive, and migratory aptitude of NPC cells as well as tumor growth by promoting PRMT5 to activate NF-κB signaling.

Alginate (Alg) hydrogels have attracted extensive attention in the biomedical field due to their biocompatibility. However, single Alg hydrogels exhibit weak mechanical strength, poor stability and cell adhesion, which severely restricts their biomedical application. For this reason, we designed alginate/gelatin/cellulose nanocrystals (Alg/G/CNCs) composite hydrogels by combining interpenetrating network (IPN) technology, cellulose nanocrystals (CNCs) reinforcement and in situ cross-linking method to improve the functional defects of Alg hydrogels. The structure and properties of the resultant Alg/G/CNCs composite hydrogels were comprehensively evaluated by FT-IR, TGA, XRD, swelling and degradability measurements, and cytocompatibility experiments. Alg/G/CNCs composite hydrogels with regular three-dimensional porous network (3D) structures was successfully fabricated through the ionic cross-linking of alginate and the covalent cross-linking of gelatin, followed by the reinforcement of colloidal cellulose nanocrystals (CNCs) that were prepared by sulfuric acid hydrolysis of microcrystalline cellulose (MCC). The addition of CNCs could generate interaction force with the polymer in the IPN matrix, which was able to regulate the physicochemical properties of the composite hydrogel to a certain extent. Moreover, with the increase of gelatin (G) content, the compressive strength of Alg/G/CNCs composite hydrogels gradually increased, while the swelling property decreased gradually. Meanwhile, Alg/G/CNCs composite hydrogels exhibited good cell adhesion, proliferation and differentiation properties. In particular, Alg/0.5G/CNCs composite hydrogels displayed the best cell proliferation effect, while Alg/2G/CNCs composite hydrogels revealed the most significant cell differentiation effect. Therefore, Alg/G/CNCs composite hydrogels could exhibit good mechanical properties and biocompatibility, which possessed great application potential in the field of tissue engineering.

Background CPT-11 (irinotecan) is one of the most efficient agents used for colorectal cancer chemotherapy. However, as for many other chemotherapeutic drugs, how to minimize the side effects of CPT-11 still needs to be thoroughly described. Objectives This study aimed to develop the CPT-11-loaded DSPE-PEG 2000 targeting EGFR liposomal delivery system and characterize its targeting specificity and therapeutic effect on colorectal cancer (CRC) cells in vitro and in vivo. Results The synthesized liposome exhibited spherical shapes (84.6 ± 1.2 nm to 150.4 nm ± 0.8 nm of estimated average sizes), good stability, sustained release, and enough drug loading (55.19%). For in vitro experiments, SW620 cells treated with CPT-11-loaded DSPE-PEG2000 targeting EGFR liposome showed lower survival extended level of intracellular ROS production. In addition, it generated an enhanced apoptotic cell rate by upregulating the protein expression of both cleaved-caspase-3 and cleaved-caspase-9 compared with those of SW620 cells treated with free CPT-11. Importantly, the xenograft model showed that both the non-target and EGFR-targeted liposomes significantly inhibited tumor growth compared to free CPT-11. Conclusions Compared with the non-target CPT-11-loaded DSPE-PEG2000 liposome, CPT-11-loaded DSPE-PEG2000 targeting EGFR liposome treatment showed much better antitumor activity in vitro in vivo. Thus, our findings provide new assets and expectations for CRC targeting therapy.

Oxidized sodium alginate (OSA) is selected as an appropriate material to be extensively applied in regenerative medicine, 3D-printed/composite scaffolds, and tissue engineering for its excellent physicochemical properties and biodegradability. However, few literatures have systematically investigated the structure and properties of the resultant OSA and the effect of the oxidation degree (OD) of alginate on its biodegradability and gelation ability. Herein, we used NaIO4 as the oxidant to oxidize adjacent hydroxyl groups at the C-2 and C-3 positions on alginate uronic acid monomer to obtain OSA with various ODs. The structure and physicochemical properties of OSA were evaluated by Fourier transform infrared spectroscopy (FT-IR), 1H nuclear magnetic resonance (1H NMR), X-ray Photoelectron Spectroscopy (XPS), X-ray Diffraction (XRD), and thermogravimetric analysis (TGA). At the same time, gel permeation chromatography (GPC) and a rheometer were used to determine the hydrogel-forming ability and biodegradation performance of OSA. The results showed that the two adjacent hydroxyl groups of alginate uronic acid units were successfully oxidized to form the aldehyde groups; as the amount of NaIO4 increased, the OD of OSA gradually increased, the molecular weight decreased, the gelation ability continued to weaken, and degradation performance obviously rose. It is shown that OSA with various ODs could be prepared by regulating the molar ratio of NaIO4 and sodium alginate (SA), which could greatly broaden the application of OSA-based hydrogel in tissue engineering, controlled drug release, 3D printing, and the biomedical field.

The development of information technology and information systems is changing rapidly, and advanced information systems are applied to all walks of life. In the field of environmental protection, because pollution has brought a lot of trouble to social life, as well as the inherent characteristics of pollution sources, as the source of pollution information needs of environmental protection institutions and individuals, from a large number of pollution source information to find their own concern of the information is often not an easy thing; The recommendation system is the main tool to solve this contradiction. By establishing the model of analyzing user preferences, UFTB algorithm is used to analyze the type of pollution source information and scoring data that users have seen. In establishing the recommendation model for analyzing pollution source information, the modified cosine similarity is calculated by using the co-filter algorithm, and the default value is predicted to optimize the algorithm. In order to prevent over-optimization, we should take the information of eliminating the user’s non-preferred type of pollution source, get the optimization default prediction matrix, bring the similarity data into the recommended formula to get the value and use the sort, find the N user with the highest similarity to the target user, and recommend the target user the pollution source information according to their preferences. Analysis based on collaborative filtering and association-based rules based on the recommendation of pollution source information number, we can find that the affinity is not high, because the two recommended rules are based on different, so the final results will be different, but both are practical. So in practice, we can design a combination recommendation system based on a variety of recommended methods.

Based on the Platform effect of polydopamine (PDA), the distribution of metal catalyst on the surface of carbon fiber was investigated in this study. Through PDA-based carbon coating, directional Carbon nanotubes (CNTs) are grown on the high strength carbon fiber body without damaging the interface structure and properties of Carbon fiber reinforced plastic (CFRP) by Chemical vapor deposition (CVD) approach. The results indicated that the PDA coating endows CNTs with a uniform distribution on the fiber surface, which effectively mitigate the corrosion of the fiber body by the high temperature and metal catalyst during the CVD process, thus augmenting the mechanical properties of the carbon fibers and their composites. The failure mechanism of the composite under stress was clarified by the transverse and longitudinal fracture morphology, which further developed the interface theory of CFRP.

Background Colorectal cancer (CRC) is a common cancer with high morbidity and mortality. However, its molecular mechanism is not clear, nor the genes related to CRC stages. Methods Gene expression data in CRC and healthy colorectal tissues were obtained from gene expression omnibus. Limma package was used to identify the differentially expressed genes (DEGs) between control and CRC (stage I, II, III, and IV), obtaining 4 DEG sets. VennPlex was utilized to find all DEGs and intersection DEGs. Functional interactions between all DEGs and protein-protein interactions (PPIs) between intersection DEGs were analyzed using ReactomeFIViz and STRING, respectively, and networks were visualized. Known CRC-related genes were down-loaded from Comparative Toxicogenomics Database and mapped to PPI network. Results Totally, 851, 760, 729, and 878 DEGs were found between control and CRC stage I, II, III, and IV, respectively. Taken together, 1235 DEGs were found, as well as 128 up-regulated intersection DEGs, 365 down-regulated intersection DEGs, and 0 contra-regulated DEG. A functional interaction network of all DEGs and a PPI network of intersection DEGs were constructed, in which CDC20, PTTG1, and MAD2L1 interacted with BUB1B; UGT2B17 interacted with ADH1B; MCM7 interacted with MCM2. BUB1B, ADH1B, and MCM2 were known CRC-related genes. Gradually upregulated expressions of CDC20, PTTG1, MAD2L1, UGT2B17, and MCM7 in stage I, II, III, and IV CRC were confirmed by using quantitative PCR. Besides, up-regulated intersection DEGs enriched in pathways about Cell cycle, DNA replication, and p53 signaling. Conclusion CDC20, PTTG1, MAD2L1, UGT2B17, and MCM7 might be CRC stage-related genes.

Inspired by the composition of adhesive proteins in mussels, polydopamine (PDA) has been widely utilized in interface modification fields to fabricate high performance composites with designable interfacial bonding strength. Nevertheless, not much attention has been taken to the changes of chemical structure and adhesion state of PDA on the material properties with varying temperature. Herein, we have done the corresponding work with carbon fiber as a case to understanding the chemical composition and adhesion state of PDA on its mechanical properties. The results shed light on that annealing treatment could promote the further polymerization of monomers and polymeric oligomers, resulting in the increase of C O content and the degree of cross-linking of PDA chains in the coating. The ILSS value (80.04 MPa) of annealed CF-PDA based composites were improved by 38.73 %. Furthermore, ILSS retention rate of annealed CF-PDA based composites after hydrothermal aging treatment reached 92.61 %. The simple strategy provides a fundamental understanding of the formation mechanism for interface improvement of PDA, which is believed to be beneficial for engineering applications.

Objective This study aims to investigate the molecular mechanism of injury development in the cortex and the striatum after cerebral ischemia/reperfusion (I/R). Methods Gene expression data (GSE23160) in the cortex and the striatum of an intraluminal middle cerebral artery occlusion–I/R mouse model (N = 12) and sham controls (N = 4) were downloaded from the Gene Expression Omnibus. Limma package was used to identify the differentially expressed genes (DEGs) between the I/R (2, 8, and 24 hours) and control groups. Correlation analysis was then performed to identify the highly correlated differentially expressed genes (HCDEGs). STRING and Cytoscape software were used to construct a protein–protein interaction (PPI) network of HCDEGs. Furthermore, Venny 2.0 was used to identify common overlapped DEGs whose transcription factors (TFs) were predicted using iRegulon in Cytoscape. Results For the cortex and the striatum, 2295 and 2282 DEGs were respectively identified between the I/R group and the controls, and were classified into 3 and 2 correlation modules. For each module, a PPI network was constructed, and Toll-like receptor 2 (Tlr2, degree = 25), interleukin 1β (Il1b, degree = 21), and heme oxygenase-1 (Hmox1, degree = 17) had high connective degrees. Furthermore, 29 common overlapped DEGs were found across time and tissue, which might be targeted by 13 TFs. Especially, Tlr2, Il1b, and Hmox1 were targeted by myeloblastosis protein (Myb, target count = 16) and FBJ osteosarcoma protein (Fos, target count = 15). Moreover, plasminogen activator urokinase receptor (Plaur) was targeted by Fos, and it was an HCDEG in correlation modules of both cortex and striatum. Upregulation of Tlr2, Il1b, Hmox1, and Plaur in I/R injury was confirmed using quantitative polymerase chain reaction and immunohistochemical staining. Conclusion Tlr2, Il1b, Hmox1, and Plaur regulated by Myb and Fos might participate in cortex and striatum injury after cerebral I/R.

Telaprevir is a potent, selective, peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3-4A serine protease. it is used for the treatment of HCV infection in combination with peginterferon alfa and ribavirin. In the present work, the E-Z isomerization process of telaprevir in solution was revealed by online HPLC-DAD (diode array detector)-MS, variable-temperature and variable-gradient experiments. The molecular geometry information of the two isomers was established by molecular mechanics calculations, and good correlation between the two isomers' UV-vis spectra and their molecular geometry information was also discovered. In addition, it was revealed by molecular docking that the two isomers have different affinities to HCV NS3•4A protease, and the Z isomer, the minor form of telaprevir in solution, is the more effective inhibitor of HCV NS3•4A protease. The investigation can provide more structure information about telaprevir in solution and in the binding process of HCV NS3•4A protease.

Background Abnormal lipid metabolism has been reported in patients with idiopathic pulmonary arterial hypertension (IPAH); however, the prognostic value of plasma free fatty acids (FFAs) for these patients is unclear. The present study aimed to determine whether FFA can play a role in predicting the survival of patients with IPAH. Methods A total of 69 blood samples from patients with IPAH were subjected to liquid chromatography-mass spectrometry (LC-MS). According to the classification criteria for pulmonary hypertension in the European Society of Cardiology (ESC) guidelines, patients were divided into low-risk, intermediate-risk, and high-risk groups. The FFA expression levels of patients in the three groups were compared, and the indicators with significant differences were selected. Cox regression analysis was performed to examine the associations between survival and different factors. Receiver operator characteristic (ROC) curves were used to assess the predictive effect of plasma lipids in assessing patients' risk of morbidity, including area under the curve (AUC), sensitivity, specificity and the best cutoff value. Kaplan-Meier curves were used to predict survival. Results A total of 24 FFA molecules were detected in the patients with IPAH. Among them, FFA (20:4), FFA (20:5), FFA (22:5), FFA (22:6), FFA (24:0) and FFA (30:4) showed significant differences between the low-risk and the intermediate-risk or high-risk patients with IPAH. These six FFAs were significantly correlated with hemodynamic parameters. FFA (22:6), named docosahexaenoic acid (DHA), displayed significant negative correlations with World Health Organization functional classification (WHO FC), mean right atrial pressure (mRAP), and pulmonary vascular resistance (PVR), and significant positive correlations with 6-minute walking distance (6MWD) and cardiac index (CI). Cox regression analyses demonstrated that total bilirubin (TBIL) and DHA were independent risk factors for survival of IPAH. Receiver operating characteristic curve analysis revealed that DHA had a cut-off value of 77.55, which had a sensitivity of 96.7% and a specificity of 62.5% for predicting survival. Kaplan-Meier curve analysis showed that a lower level of DHA predicted a poor outcome in patients with IPAH. Conclusions Our study suggested that FFA levels were correlated with disease severity. Lower levels of DHA predict poor survival in patients with IPAH.

Non–small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378), in the setting of crizotinib resistance. An interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of patients with crizotinib-resistant NSCLC, revealed that ceritinib potently overcomes crizotinib-resistant mutations. In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T, and S1206Y mutations, and a cocrystal structure of ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations was identified in 5 of 11 biopsies from patients with acquired resistance to ceritinib. Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease. Significance: The second-generation ALK inhibitor ceritinib can overcome several crizotinib-resistant mutations and is potent against several in vitro and in vivo laboratory models of acquired resistance to crizotinib. These findings provide the molecular basis for the marked clinical activity of ceritinib in patients with ALK-positive NSCLC with crizotinib-resistant disease. Cancer Discov; 4(6); 662–73. ©2014 AACR. See related commentary by Ramalingam and Khuri, p. 634 This article is highlighted in the In This Issue feature, p. 621

ALK (anaplastic lymphoma kinase) is an RTK (receptor tyrosine kinase) of the IRK (insulin receptor kinase) superfamily, which share an YXXXYY autophosphorylation motif within their A-loops (activation loops). A common activation and regulatory mechanism is believed to exist for members of this superfamily typified by IRK and IGF1RK (insulin-like growth factor receptor kinase-1). Chromosomal translocations involving ALK were first identified in anaplastic large-cell lymphoma, a subtype of non-Hodgkin's lymphoma, where aberrant fusion of the ALK kinase domain with the NPM (nucleophosmin) dimerization domain results in autophosphosphorylation and ligand-independent activation. Activating mutations within the full-length ALK kinase domain, most commonly R1275Q and F1174L, which play a major role in neuroblastoma, were recently identified. To provide a structural framework for understanding these mutations and to guide structure-assisted drug discovery efforts, the X-ray crystal structure of the unphosphorylated ALK catalytic domain was determined in the apo, ADP- and staurosporine-bound forms. The structures reveal a partially inactive protein kinase conformation distinct from, and lacking, many of the negative regulatory features observed in inactive IGF1RK/IRK structures in their unphosphorylated forms. The A-loop adopts an inhibitory pose where a short proximal A-loop helix (αAL) packs against the αC helix and a novel N-terminal β-turn motif, whereas the distal portion obstructs part of the predicted peptide-binding region. The structure helps explain the reported unique peptide substrate specificity and the importance of phosphorylation of the first A-loop Tyr1278 for kinase activity and NPM–ALK transforming potential. A single amino acid difference in the ALK substrate peptide binding P−1 site (where the P-site is the phosphoacceptor site) was identified that, in conjunction with A-loop sequence variation including the RAS (Arg-Ala-Ser)-motif, rationalizes the difference in the A-loop tyrosine autophosphorylation preference between ALK and IGF1RK/IRK. Enzymatic analysis of recombinant R1275Q and F1174L ALK mutant catalytic domains confirms the enhanced activity and transforming potential of these mutants. The transforming ability of the full-length ALK mutants in soft agar colony growth assays corroborates these findings. The availability of a three-dimensional structure for ALK will facilitate future structure–function and rational drug design efforts targeting this receptor tyrosine kinase.

Introduction: In this paper, we report a novel VMD2 gene mutation in a Chinese family with Best vitelliform macular dystrophy. Materials and Methods: Ophthalmologic examination and optical coherence tomography (OCT) were performed in 2 members of this family. Mutational screening was performed by single-strand conformation polymorphism (SSCP) and direct sequencing of PCR-amplified DNA fragments, corresponding to the 11 exons of the gene. Results: Sequence analysis identified a previously unreported C to G change, predicting a Phe-113-Leu substitution. Both the proband and his sister harboured this novel mutation. Each had bilateral vitelliform lesions. Conclusions: A novel mutation in the VMD2 gene (C427G) was found in Chinese patients with Best vitelliform macular dystrophy. Key words: Best macular dystrophy, Bestrophin, Retinal pigment epithelium

Background Hand hygiene compliance is generally assessed by observation of adherence to the “WHO five moments” using numbers of opportunities as the denominator. The quality of the activity is usually not monitored since there is no established methodology for the routine assessment of hand hygiene technique. The aim of this study was to objectively assess hand rub coverage of staff using a novel imaging technology and to look for patterns and trends in missed areas after the use of WHO’s 6 Step technique. Methods A hand hygiene education and assessment program targeted 5200 clinical staff over 7 days at the National University Hospital, Singapore. Participants in small groups were guided by professional trainers through 5 educational stations, which included technique-training and UV light assessment supported by digital photography of hands. Objective criteria for satisfactory hand hygiene quality were defined a priori. The database of images created during the assessment program was analyzed subsequently. Patterns of poor hand hygiene quality were identified and linked to staff demographic. Results Despite the assessment taking place immediately after the training, only 72% of staff achieved satisfactory coverage. Failure to adequately clean the dorsal and palmar aspects of the hand occurred in 24% and 18% of the instances, respectively. Fingertips were missed by 3.5% of subjects. The analysis based on 4642 records showed that nurses performed best (77% pass), and women performed better than men (75% vs. 62%, p Conclusion Ongoing education and training has a vital role in improving hand hygiene compliance and technique of clinical staff. Identification of typical sites of failure can help to develop improved training.

The plant growth promoting rhizobacterium Pseudomonas putida GR12-2 was originally isolated from the rhizosphere of plants growing in the Canadian High Arctic. Here we report that this bacterium was able to grow and promote root elongation of both spring and winter canola at 5 °C, a temperature at which only a relatively small number of bacteria are able to proliferate and function. In addition, the bacterium survived exposure to freezing temperatures, i.e., −20 and −50 °C. In an effort to determine the mechanistic basis for this behaviour, it was discovered that following growth at 5 °C, P. putida GR12-2 synthesized and secreted to the growth medium a protein with antifreeze activity. Analysis of the spent growth medium, following concentration by ultrafiltration, by SDS-polyacrylamide gel electrophoresis revealed the presence of one major protein with a molecular mass of approximately 32–34 kDa and a number of minor proteins. However, at this point it is not known which of these proteins contains the antifreeze activity.Key words: plant growth promoting rhizobacteria, PGPR, bacterial fertilizer, soil bacteria, antifreeze protein.

Formal Concept Analysis is a branch of applied mathematics, it comes from the philosophy of understanding of the concept. According to the field with a binary relation expressed in the form of background, to extract the concept hierarchy, that concept lattice. The paper puts forward the construction and application of search engine system in e-commerce based on FCA. Therefore, the system has to narrow the search to expand content. This system can be expanded and narrow the search results reveal the contents of the scope of this class, either browse the knowledge they want to discover new knowledge can reveal deeply hidden content.

Ontology is a formal, explicit specification of a shared conceptual model and provides a way for computers to exchange, search and identify characteristics. Data mining is a drawing work from areas including database technology, machine learning, statistics, pattern recognition, neural networks, artificial intelligence, and data visualization. As a branch of applied mathematics, formal concept analysis comes of the understanding of concept in philosophical domain. Finally, data mining information management system in E- Commerce is proposed based on integrating of ontology and formal concept analysis. The experimental results indicate that this method has great promise.

E-commerce websites analyze the interests and habits of users and recommend products by recommendation systems now. But the traditional recommendation systems have some shortcomings, such as data sparsity and digging out the potential demand. Ontology is a formal, explicit specification of a shared conceptual model. The aim of ontology is to obtain, describe and express the knowledge of related domain. Ontology model is proposed based on integrating of ontology model, formal concept analysis, and is used to reduce formal context. This type of recommendation has better results in comparison with other type of recommendation. The experimental results have shown our suggested recommender system will increase precision and performance.

A smart material using piezoelectric ceramics to have the function of both the sensor and actuator is developed for such a vibration suppression system. This ontology is a guide, which provides a vocabulary for the visual description of domain classes. But traditional smart material system construction is time-consuming and costly procedure. This paper present a novel smart material system construction method based on ontology Bayesian network and grid model. The experimental results indicate that the Bayesian network building smart material algorithm achieves significant performance improvement.

Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active.

Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements are sensitive to the ALK tyrosine kinase inhibitor (TKI) crizotinib. However, these cancers invariably relapse due to the development of resistance, and approximately 1/3 of such cancers develop resistance mutations within the ALK tyrosine kinase domain. Here we report the preclinical evaluation of the next-generation ALK TKI, LDK378 in the setting of crizotinib resistance. Using EML4-ALK mutant Ba/F3 cellular models, in vivo models of acquired resistance to crizotinib, and novel cell lines established from biopsies of crizotinib-resistant NSCLC patients, we have examined the efficacy of LDK378 in crizotinib-naïve and -resistant ALK-positive cancers. These studies reveal that LDK378 is more potent than crizotinib and effectively overcomes resistance in vitro and in vivo. In particular, LDK378 inhibits ALK harboring crizotinib resistance mutations, including L1196M, G1269A, I1171T and S1206Y. Cell lines derived from crizotinib-resistant biopsies were sensitive to LDK378, including one that did not harbor an ALK resistance mutation and was also sensitive to crizotinib, suggesting that some crizotinib-resistant cancers with wildtype ALK are still sensitive to complete ALK inhibition. We observed that LDK378 did not effectively overcome two crizotinib-resistant ALK mutations, G1202R and F1174C ALK, and mutations in one of these residues was identified in 5 out of 11 biopsies from patients with acquired resistance to LDK378. Altogether our results demonstrate that LDK378 can overcome many mechanisms of crizotinib resistance, consistent with emerging clinical data showing marked efficacy of LDK378 in patients with crizotinib-resistant disease. Citation Format: Luc Friboulet, Nanxin Li, Ryohei Katayama, Christian C. Lee, Justin F. Gainor, Adam S. Crystal, Pierre-Yves Michellys, Mark M. Awad, Noriko Yanagitani, Sungjoon Kim, AnneMarie Pferdekamper, Jie Li, Shailaja Kasibhatla, Frank Sun, Xiuying Sun, Su Hua, Peter McNamara, Sidra Mahmood, Elizabeth L. Lockerman, Naoya Fujita, Makoto Nishio, Jennifer L. Harris, Alice T. Shaw, Jeffrey A. Engelman. The ALK inhibitor LDK378 overcomes crizotinib resistance in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 957. doi:10.1158/1538-7445.AM2014-957

A c-MET/ALK kinase inhibitor crizotinib has demonstrated significant activity in lung cancer patients with EML4-ALK in clinical studies. However relapse (or acquired resistance) has also been reported. We have developed crizotinib resistant tumor models and used the models to evaluate the ALK inhibitor LDK378. LDK378 is a potent and selective ALK inhibitor that does not cross react with c-MET. In a mouse xenograft tumor model derived from the EML4-ALK+ lung cancer cell line NCI-H2228, LDK378 caused complete tumor regression when dosed orally at 25 mg/kg/day. After tumor bearing animals had been treated with LDK378 at 50 mg/kg/day for 14 days, remission was maintained for more than 4 months. In several NCI-H2228 tumor models that were induced to become resistant to crizotinib, LDK378 demonstrated efficacy at 50 mg/kg/day. Based on 4-wk GLP toxicology studies the drug exposure associated with this dose is predicted to be below the exposure at the MTD in humans. ALK resistance mutations reported in crizotinib relapsed patients were also found in the crizotinib resistant NCI-H2228 tumor models. The results from these preclinical studies suggest that LDK378 may be active in crizotinib-relapsed patients. A phase I clinical study of LDK378 has recently begun in both crizotinib-relapsed and crizotinib-naïve patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B232.