Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 477

Search results for: EGFR kinase inhibitor

477 Synthesis of Some 1h-Benzimidazoles as Inhibitors of EGFR Tyrosine Kinase

Authors: İsmail Çeli̇k, Gülgün Ayhan-Kılcıgi̇l, Arzu Onay-Beşi̇kçi̇

Abstract:

In this study, some 2-(2-phenyl/substitutedphenyl)- lH-benzo[d]'imidazol-l-yl)-N'-(alkylthiosemicarbazide were designed and prepared. Firstly, 2-phenyl/ suhstitutedphenyl-lH-Benzo[d]imidazole was prepared via oxidative condensation of o-phenylenediamine, benzaldehyde and sodium metabisulfite. Treatment of the benzimidazole compound with ethyl chloroacetate in KOH/DMSO gave the ester compound ethyl 2-(2-substitutedphenyl)-1H-benzo[d]imidazol-l-yl)acetate. Hydrazine hydrate and the ester in ethanol were refluxed for 4 h to give 2-(2-phenyl/substitutedphenyl)-1H-benzo[d]imidazol-l-yl)acetohydrazide. Thiosemicarbazides were obtained by condensing acyl hydrazide with the alkylisothiocyanate in ethanol. Following the structure elucidation, benzimidazole compounds were tested for their EGFR kinase inhibitory activities by using ADP-GloTM Kinase Assay.

Keywords: benzimidazole, EGFR kinase inhibitor, synthesis, thiosemicarbazide

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476 Synthesis and in-vitro Evaluation of Quinozolines as Potent EGFR Inhibitor

Authors: Vinaya Kambappa, Chinnadurai Mani, Komaraiah Palle

Abstract:

Non-small cell-lung cancer (NSCLC) cells have increased expression of EGFR, which makes them a potential target for cancer therapy. Based on molecular docking and previous reports, we designed and synthesized quinazoline derivatives as potent EGFR inhibitors. Among the derivatives, three compounds showed good antiproliferative activity against A-549 and H-1299 cells. Furthermore, these compounds inhibited EGFR signaling exhibiting diminishing p-EGFR and its downstream proteins like p-Akt, p-Erk1/2, and p-mTOR; however, it did not alter the levels of EGFR, Akt, Erk1/2 and mTOR proteins. Flow cytometric analysis indicated the accumulation of cells at G1 phase suggesting induction of apoptosis, which was further confirmed by annexin V/propidium iodide staining. Our study suggested that quinazoline scaffold can be developed as novel EGFR kinase inhibitors for cancer therapy.

Keywords: apoptosis, non-small cell-lung cancer cells, EGFR, quinazoline

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475 Design and Synthesis of Some Oxadiazole Bearing Benzimidazole Derivatives as Potential Epidermal Growth Factor Receptor Inhibitors

Authors: Ismail Celik, Gulgun Ayhan Kilcigil, Berna Guven, Zumra Kara, Arzu Onay-Besikci

Abstract:

Epidermal Growth Factor Receptor is the cell-surface receptor of the ErbB (erythroblastic leukemia viral oncogene homologue receptors) family of tyrosine kinases. It plays a vital role in regulating the proliferation and differentiation of cells. However, a variety of mechanisms, such as EGFR expression, mutation, and ligand-dependent receptor dimerization, are associated with the development of various activated EGFR tumors. EGFR is highly expressed in most solid tumors, including breast, head and neck cancer, non-small cell lung cancer (NSCLC), renal, ovarian, and colon cancers. Thus, specific EGFR inhibition plays one of the key roles in cancer treatment. The compounds used in the treatment as tyrosine kinase inhibitors are known to contain the benzimidazole isosterium indole, pazopanib, and axitinibin indazole rings. In addition, benzimidazoles have been shown to exhibit protein kinase inhibitory activity in addition to their different biological activities.Based on these data, it was planned and synthesized of some oxadiazole bearing benzimidazole derivatives [N-cyclohexyl-5-((2-phenyl/substitutedphenyl-1H-benzo[d]imidazole-1-yl) methyl)-1,3,4-oxadiazole-2-amine]. EGFR kinase inhibitory efficiency of the synthesized compounds was determined by comparing them with a known kinase inhibitor erlotinib in vitro, and two of the compounds bearing phenyl (19a) and 3,4-dibenzyloxyphenyl (21a) ring exhibited significant activities.

Keywords: benzimidazole, EGFR kinase inhibitory, oxadiazole, synthesis

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474 Sensing of Cancer DNA Using Resonance Frequency

Authors: Sungsoo Na, Chanho Park

Abstract:

Lung cancer is one of the most common severe diseases driving to the death of a human. Lung cancer can be divided into two cases of small-cell lung cancer (SCLC) and non-SCLC (NSCLC), and about 80% of lung cancers belong to the case of NSCLC. From several studies, the correlation between epidermal growth factor receptor (EGFR) and NSCLCs has been investigated. Therefore, EGFR inhibitor drugs such as gefitinib and erlotinib have been used as lung cancer treatments. However, the treatments result showed low response (10~20%) in clinical trials due to EGFR mutations that cause the drug resistance. Patients with resistance to EGFR inhibitor drugs usually are positive to KRAS mutation. Therefore, assessment of EGFR and KRAS mutation is essential for target therapies of NSCLC patient. In order to overcome the limitation of conventional therapies, overall EGFR and KRAS mutations have to be monitored. In this work, the only detection of EGFR will be presented. A variety of techniques has been presented for the detection of EGFR mutations. The standard detection method of EGFR mutation in ctDNA relies on real-time polymerase chain reaction (PCR). Real-time PCR method provides high sensitive detection performance. However, as the amplification step increases cost effect and complexity increase as well. Other types of technology such as BEAMing, next generation sequencing (NGS), an electrochemical sensor and silicon nanowire field-effect transistor have been presented. However, those technologies have limitations of low sensitivity, high cost and complexity of data analyzation. In this report, we propose a label-free and high-sensitive detection method of lung cancer using quartz crystal microbalance based platform. The proposed platform is able to sense lung cancer mutant DNA with a limit of detection of 1nM.

Keywords: cancer DNA, resonance frequency, quartz crystal microbalance, lung cancer

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473 A Platform to Screen Targeting Molecules of Ligand-EGFR Interactions

Authors: Wei-Ting Kuo, Feng-Huei Lin

Abstract:

Epidermal growth factor receptor (EGFR) is often constitutively stimulated in cancer owing to the binding of ligands such as epidermal growth factor (EGF), so it is necessary to investigate the interaction between EGFR and its targeting biomolecules which were over ligands binding. This study would focus on the binding affinity and adhesion force of two targeting products anti-EGFR monoclonal antibody (mAb) and peptide A to EGFR comparing with EGF. Surface plasmon resonance (SPR) was used to obtain the equilibrium dissociation constant to evaluate the binding affinity. Atomic force microscopy (AFM) was performed to detect adhesion force. The result showed that binding affinity of mAb to EGFR was higher than that of EGF to EGFR, and peptide A to EGFR was lowest. The adhesion force between EGFR and mAb that was higher than EGF and peptide A to EGFR was lowest. From the studies, we could conclude that mAb had better adhesion force and binding affinity to EGFR than that of EGF and peptide A. SPR and AFM could confirm the interaction between receptor and targeting ligand easily and carefully. It provide a platform to screen ligands for receptor targeting and drug delivery.

Keywords: adhesion force, binding affinity, epidermal growth factor receptor, target molecule

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472 Downregulation of Epidermal Growth Factor Receptor in Advanced Stage Laryngeal Squamous Cell Carcinoma

Authors: Sarocha Vivatvakin, Thanaporn Ratchataswan, Thiratest Leesutipornchai, Komkrit Ruangritchankul, Somboon Keelawat, Virachai Kerekhanjanarong, Patnarin Mahattanasakul, Saknan Bongsebandhu-Phubhakdi

Abstract:

In this globalization era, much attention has been drawn to various molecular biomarkers, which may have the potential to predict the progression of cancer. Epidermal growth factor receptor (EGFR) is the classic member of the ErbB family of membrane-associated intrinsic tyrosine kinase receptors. EGFR expression was found in several organs throughout the body as its roles involve in the regulation of cell proliferation, survival, and differentiation in normal physiologic conditions. However, anomalous expression, whether over- or under-expression is believed to be the underlying mechanism of pathologic conditions, including carcinogenesis. Even though numerous discussions regarding the EGFR as a prognostic tool in head and neck cancer have been established, the consensus has not yet been met. The aims of the present study are to assess the correlation between the level of EGFR expression and demographic data as well as clinicopathological features and to evaluate the ability of EGFR as a reliable prognostic marker. Furthermore, another aim of this study is to investigate the probable pathophysiology that explains the finding results. This retrospective study included 30 squamous cell laryngeal carcinoma patients treated at King Chulalongkorn Memorial Hospital from January 1, 2000, to December 31, 2004. EGFR expression level was observed to be significantly downregulated with the progression of the laryngeal cancer stage. (one way ANOVA, p = 0.001) A statistically significant lower EGFR expression in the late stage of the disease compared to the early stage was recorded. (unpaired t-test, p = 0.041) EGFR overexpression also showed the tendency to increase recurrence of cancer (unpaired t-test, p = 0.128). A significant downregulation of EGFR expression was documented in advanced stage laryngeal cancer. The results indicated that EGFR level correlates to prognosis in term of stage progression. Thus, EGFR expression might be used as a prevailing biomarker for laryngeal squamous cell carcinoma prognostic prediction.

Keywords: downregulation, epidermal growth factor receptor, immunohistochemistry, laryngeal squamous cell carcinoma

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471 The Second Generation of Tyrosine Kinase Inhibitor Afatinib Controls Inflammation by Regulating NLRP3 Inflammasome Activation

Authors: Shujun Xie, Shirong Zhang, Shenglin Ma

Abstract:

Background: Chronic inflammation might lead to many malignancies, and inadequate resolution could play a crucial role in tumor invasion, progression, and metastases. A randomised, double-blind, placebo-controlled trial shows that IL-1β inhibition with canakinumab could reduce incident lung cancer and lung cancer mortality in patients with atherosclerosis. The process and secretion of proinflammatory cytokine IL-1β are controlled by the inflammasome. Here we showed the correlation of the innate immune system and afatinib, a tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR) in non-small cell lung cancer. Methods: Murine Bone marrow derived macrophages (BMDMs), peritoneal macrophages (PMs) and THP-1 were used to check the effect of afatinib on the activation of NLRP3 inflammasome. The assembly of NLRP3 inflammasome was check by co-immunoprecipitation of NLRP3 and apoptosis-associated speck-like protein containing CARD (ASC), disuccinimidyl suberate (DSS)-cross link of ASC. Lipopolysaccharide (LPS)-induced sepsis and Alum-induced peritonitis were conducted to confirm that afatinib could inhibit the activation of NLRP3 in vivo. Peripheral blood mononuclear cells (PBMCs) from non-small cell lung cancer (NSCLC) patients before or after taking afatinib were used to check that afatinib inhibits inflammation in NSCLC therapy. Results: Our data showed that afatinib could inhibit the secretion of IL-1β in a dose-dependent manner in macrophage. Moreover, afatinib could inhibit the maturation of IL-1β and caspase-1 without affecting the precursors of IL-1β and caspase-1. Next, we found that afatinib could block the assembly of NLRP3 inflammasome and the ASC speck by blocking the interaction of the sensor protein NLRP3 and the adaptor protein ASC. We also found that afatinib was able to alleviate the LPS-induced sepsis in vivo. Conclusion: Our study found that afatinib could inhibit the activation of NLRP3 inflammasome in macrophage, providing new evidence that afatinib could target the innate immune system to control chronic inflammation. These investigations will provide significant experimental evidence in afatinib as therapeutic drug for non-small cell lung cancer or other tumors and NLRP3-related diseases and will explore new targets for afatinib.

Keywords: inflammasome, afatinib, inflammation, tyrosine kinase inhibitor

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470 Biflavonoids from Selaginellaceae as Epidermal Growth Factor Receptor Inhibitors and Their Anticancer Properties

Authors: Adebisi Adunola Demehin, Wanlaya Thamnarak, Jaruwan Chatwichien, Chatchakorn Eurtivong, Kiattawee Choowongkomon, Somsak Ruchirawat, Nopporn Thasana

Abstract:

The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein involved in cellular signalling processes and, its aberrant activity is crucial in the development of many cancers such as lung cancer. Selaginellaceae are fern allies that have long been used in Chinese traditional medicine to treat various cancer types, especially lung cancer. Biflavonoids, the major secondary metabolites in Selaginellaceae, have numerous pharmacological activities, including anti-cancer and anti-inflammatory. For instance, amentoflavone induces a cytotoxic effect in the human NSCLC cell line via the inhibition of PARP-1. However, to the best of our knowledge, there are no studies on biflavonoids as EGFR inhibitors. Thus, this study aims to investigate the EGFR inhibitory activities of biflavonoids isolated from Selaginella siamensis and Selaginella bryopteris. Amentoflavone, tetrahydroamentoflavone, sciadopitysin, robustaflavone, robustaflavone-4-methylether, delicaflavone, and chrysocauloflavone were isolated from the ethyl-acetate extract of the whole plants. The structures were determined using NMR spectroscopy and mass spectrometry. In vitro study was conducted to evaluate their cytotoxicity against A549, HEPG2, and T47D human cancer cell lines using the MTT assay. In addition, a target-based assay was performed to investigate their EGFR inhibitory activity using the kinase inhibition assay. Finally, a molecular docking study was conducted to predict the binding modes of the compounds. Robustaflavone-4-methylether and delicaflavone showed the best cytotoxic activity on all the cell lines with IC50 (µM) values of 18.9 ± 2.1 and 22.7 ± 3.3 on A549, respectively. Of these biflavonoids, delicaflavone showed the most potent EGFR inhibitory activity with an 84% relative inhibition at 0.02 nM using erlotinib as a positive control. Robustaflavone-4-methylether showed a 78% inhibition at 0.15 nM. The docking scores obtained from the molecular docking study correlated with the kinase inhibition assay. Robustaflavone-4-methylether and delicaflavone had a docking score of 72.0 and 86.5, respectively. The inhibitory activity of delicaflavone seemed to be linked with the C2”=C3” and 3-O-4”’ linkage pattern. Thus, this study suggests that the structural features of these compounds could serve as a basis for developing new EGFR-TK inhibitors.

Keywords: anticancer, biflavonoids, EGFR, molecular docking, Selaginellaceae

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469 A Microfluidic Biosensor for Detection of EGFR 19 Deletion Mutation Targeting Non-Small Cell Lung Cancer on Rolling Circle Amplification

Authors: Ji Su Kim, Bo Ram Choi, Ju Yeon Cho, Hyukjin Lee

Abstract:

Epidermal growth factor receptor (EGFR) 19 deletion mutation gene is over-expressed in carcinoma patient. EGFR 19 deletion mutation is known as typical biomarker of non-small cell lung cancer (NSCLC), which one section in the coding exon 19 of EGFR is deleted. Therefore, there have been many attempts over the years to detect EGFR 19 deletion mutation for replacing conventional diagnostic method such as PCR and tissue biopsy. We developed a simple and facile detection platform based on Rolling Circle Amplification (RCA), which provides highly amplified products in isothermal amplification of the ligated DNA template. Limit of detection (~50 nM) and a faster detection time (~30 min) could be achieved by introducing RCA.

Keywords: EGFR19, cancer, diagnosis, rolling circle amplification (RCA), hydrogel

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468 Immunohistochemical Expression of β-catenin and Epidermal Growth Factor Receptor in Adamantinomatous Craniopharyngioma

Authors: Ghada Esheba, Fatimah Alturkistani, Arwa Obaid, Ahdab Bashehab, Moayad Alturkistani

Abstract:

Introduction: Craniopharyngiomas (CPs) are rare epithelial tumors located mainly in the sellar/parasellar region. CPs have been classified histopathologically, genetically, clinically and prognostically into two distinctive subtypes: adamantinomatous and papillary variants. Aim: To examine the pattern of expression of both the β-catenin and epidermal growth factor receptor (EGFR) in surgically resected samples of adamantinomatous CP, and to asses for the possibility of using anti-EGFR in the management of ACP patients. Materials and methods: β-catenin and EGFR immunostaining was performed on paraffin-embedded tissue sections of 18 ACP cases. Result: 17 out of 18 cases (94%) of ACP exhibited strong nuclear/cytoplasmic expression of β-catenin, 15 (83%) of APC cases were positive for EGFR. Conclusion: Nuclear accumulation of β-catenin is a diagnostic hallmark of ACP. EGFR positivity in most cases of ACP could qualify the use of anti-EGFR therapy. 

Keywords: craniopharyngioma, adamantinomatous, papillary, epidermal growth factor receptor, B-catenin

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467 Discovery, Design and Synthesis of Some Novel Antitumor 1,2,4-Triazine Derivatives as C-Met Kinase Inhibitors

Authors: Ibrahim M. Labouta, Marwa H. El-Wakil, Hayam M. Ashour, Ahmed M. Hassan, Manal N. Saudi

Abstract:

The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. Among the wide variety of heterocycles that have been explored for developing c-Met kinase inhibitors, the 1,2,4-triazines have been rarely investigated, although they are well known in the literature to possess antitumor activities. Herein we describe the design and synthesis of a novel series of 1,2,4-triazine derivatives possessing N-acylarylhydrazone moiety and another series combining the 1,2,4-triazine scaffold to the well-known anticancer drug 6-MP in order to explore their “double-drug” effect. The synthesized compounds were evaluated for their in vitro antitumor activity against three c-Met addicted cancer cell lines (A549, HT-29 and MKN-45). Most compounds showed moderate to excellent antiproliferative activity and four compounds showed potent inhibitory activity more than the reference drug Foretinib against one or more cancer cell lines. The obtained results revealed that the potent compounds are highly selective to A549 (lung adenocarcinoma) cancer cell line. The c-Met kinase inhibitory activity of the potent derivatives is still under investigation. The present study clearly demonstrates that the 1,2,4-triazine core ring exhibits promising antitumor activity with potential c-Met kinase inhibitory activity.

Keywords: 1, 2, 4-triazine, antitumor, c-Met inhibitor, double-drug

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466 Effect of Removing Hub Domain on Human CaMKII Isoforms Sensitivity to Calcium/Calmodulin

Authors: Ravid Inbar

Abstract:

CaMKII (calcium-calmodulin dependent protein kinase II) makes up 2% of the protein in our brain and has a critical role in memory formation and long-term potentiation of neurons. Despite this, research has yet to uncover the role of one of the domains on the activation of this kinase. The following proposes to express the protein without the hub domain in E. coli, leaving only the kinase and regulatory segment of the protein. Next, a series of kinase assays will be conducted to elucidate the role the hub domain plays on CaMKII sensitivity to calcium/calmodulin activation. The hub domain may be important for activation; however, it may also be a variety of domains working together to influence protein activation and not the hub alone. Characterization of a protein is critical to the future understanding of the protein's function, as well as for producing pharmacological targets in cases of patients with diseases.

Keywords: CaMKII, hub domain, kinase assays, kinase + reg seg

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465 Role of Imaging in Predicting the Receptor Positivity Status in Lung Adenocarcinoma: A Chapter in Radiogenomics

Authors: Sonal Sethi, Mukesh Yadav, Abhimanyu Gupta

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The upcoming field of radiogenomics has the potential to upgrade the role of imaging in lung cancer management by noninvasive characterization of tumor histology and genetic microenvironment. Receptor positivity like epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genotyping are critical in lung adenocarcinoma for treatment. As conventional identification of receptor positivity is an invasive procedure, we analyzed the features on non-invasive computed tomography (CT), which predicts the receptor positivity in lung adenocarcinoma. Retrospectively, we did a comprehensive study from 77 proven lung adenocarcinoma patients with CT images, EGFR and ALK receptor genotyping, and clinical information. Total 22/77 patients were receptor-positive (15 had only EGFR mutation, 6 had ALK mutation, and 1 had both EGFR and ALK mutation). Various morphological characteristics and metastatic distribution on CT were analyzed along with the clinical information. Univariate and multivariable logistic regression analyses were used. On multivariable logistic regression analysis, we found spiculated margin, lymphangitic spread, air bronchogram, pleural effusion, and distant metastasis had a significant predictive value for receptor mutation status. On univariate analysis, air bronchogram and pleural effusion had significant individual predictive value. Conclusions: Receptor positive lung cancer has characteristic imaging features compared with nonreceptor positive lung adenocarcinoma. Since CT is routinely used in lung cancer diagnosis, we can predict the receptor positivity by a noninvasive technique and would follow a more aggressive algorithm for evaluation of distant metastases as well as for the treatment.

Keywords: lung cancer, multidisciplinary cancer care, oncologic imaging, radiobiology

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464 EGFR Signal Induced-Nuclear Translocation of Beta-catenin and PKM2 Promotes HCC Malignancy and Indicates Early Recurrence After Curative Resection

Authors: Fangtian Fan, Zhaoguo Liu, Yin Lu

Abstract:

Early recurrence (ER) (< 1 year) after liver resection is one of the most important factors that impacts the prognosis of patients with hepatocellular carcinoma (HCC). However, the molecular mechanisms and predictive indexes of ER after curative resection remain largely unknown. The present study aimed to exploit the role of EGFR signaling in EMT and early recurrence of HCC after curative resection and elucidate the molecular mechanisms. Our results showed that nuclear beta-catenin / PKM2 was a independent predictor of early recurrence after curative resection in EGFR-overexpressed HCC. Mechanistic investigation indicated that nuclear accumulation of beta-catenin and PKM2 induced by EGFR signal promoted HCC cell invasion and proliferation, which were required for early recurrence of HCC. These effects were mediated by PI3K/AKT and ERK pathways rather than the canonical Wnt signaling. In conclusions, EGFR signal induced-nuclear translocation of beta-catenin and PKM2 promotes HCC malignancy and indicates early recurrence after curative resection.

Keywords: beta-catenin, early recurrence, hepatocellular carcinoma, malignancy, PKM2

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463 Anticancer Lantadene Derivatives: Synthesis, Cytotoxic and Docking Studies

Authors: A. Monika, Manu Sharma, Hong Boo Lee, Richa Dhingra, Neelima Dhingra

Abstract:

Nuclear factor-κappa B serve as a molecular lynchpin that links persistent infections and chronic inflammation to increased cancer risk. Inflammation has been recognized as a hallmark and cause of cancer. Natural products present a privileged source of inspiration for chemical probe and drug design. Herbal remedies were the first medicines used by humans due to the many pharmacologically active secondary metabolites produced by plants. Some of the metabolites like Lantadene (pentacyclic triterpenoids) from the weed Lantana camara has been known to inhibit cell division and showed anti-antitumor potential. The C-3 aromatic esters of lantadenes were synthesized, characterized and evaluated for cytotoxicity and inhibitory potential against Tumor necrosis factor alpha-induced activation of Nuclear factor-κappa B in lung cancer cell line A549. The 3-methoxybenzoyloxy substituted lead analogue inhibited kinase activity of the inhibitor of nuclear factor-kappa B kinase in a single-digit micromolar concentration. At the same time, the lead compound showed promising cytotoxicity against A549 lung cancer cells with IC50 ( half maximal inhibitory concentration) of 0.98l µM. Further, molecular docking of 3-methoxybenzoyloxy substituted analogue against Inhibitor of nuclear factor-kappa B kinase (Protein data bank ID: 3QA8) showed hydrogen bonding interaction involving oxygen atom of 3-methoxybenzoyloxy with the Arginine-31 and Glutamine-110. Encouraging results indicate the Lantadene’s potential to be developed as anticancer agents.

Keywords: anticancer, lantadenes, pentacyclic triterpenoids, weed

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462 Thiosemicarbazone Derived from 4-Aminoantipyrine as Corrosion Inhibitor

Authors: Ahmed A. Al-Amiery, Yasmin K. Al-Majedy, Abdul Amir H. Kadhum, Abu Bakar Mohamad

Abstract:

The efficiency of synthesized thiosemicarbazone namely 2-(1,5-dimethyl-4-(2-methylbenzylidene)amino)-2-phenyl-1H-pyrazol-3(2H)-ylidene) hydrazinecarbothioamide investigated as corrosion inhibitor of mild steel in 1N H2SO4 using electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization (PD) in addition of scanning electron microscopy (SEM). The results showed that this inhibitor behaved as a good corrosion inhibitor even at low concentration with a mean efficiency of 93%. Polarization technique and EIS were tested in different concentrations reveal that this compound is adsorbed on the mild steel, therefore blocking the active sites and the adsorption follows the Langmuir adsorption isotherm model. SEM shows that mild steel surface is nearly perfect for mild steel which was immersed in a solution of H2SO4 with corrosion inhibitor.

Keywords: corrosion inhibitor, thiosemicarbazide, electrochemical impedance, electrochemical impedance spectroscopy

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461 Identification of Potential Small Molecule Regulators of PERK Kinase

Authors: Ireneusz Majsterek, Dariusz Pytel, J. Alan Diehl

Abstract:

PKR-like ER kinase (PERK) is serine/threonie endoplasmic reticulum (ER) transmembrane kinase activated during ER-stress. PERK can activate signaling pathways known as unfolded protein response (UPR). Attenuation of translation is mediated by PERK via phosphorylation of eukaryotic initiation factor 2α (eIF2α), which is necessary for translation initiation. PERK activation also directly contributes to activation of Nrf2 which regulates expression of anti-oxidant enzymes. An increased phosphorylation of eIF2α has been reported in Alzheimer disease (AD) patient hippocampus, indicating that PERK is activated in this disease. Recent data have revealed activation of PERK signaling in non-Hodgkins lymphomas. Results also revealed that loss of PERK limits mammary tumor cell growth in vitro and in vivo. Consistent with these observations, activation of UPR in vitro increases levels of the amyloid precursor protein (APP), the peptide from which beta-amyloid plaques (AB) fragments are derived. Finally, proteolytic processing of APP, including the cleavages that produce AB, largely occurs in the ER, and localization coincident with PERK activity. Thus, we expect that PERK-dependent signaling is critical for progression of many types of diseases (human cancer, neurodegenerative disease and other). Therefore, modulation of PERK activity may be a useful therapeutic target in the treatment of different diseases that fail to respond to traditional chemotherapeutic strategies, including Alzheimer’s disease. Our goal will be to developed therapeutic modalities targeting PERK activity.

Keywords: PERK kinase, small molecule inhibitor, neurodegenerative disease, Alzheimer’s disease

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460 Investigation of the Corrosion Inhibition Mechanism of Tagetes erecta Extract for Mild Steel in Nitric Acid: Gravimetric Studies

Authors: Selvam Noyel Victoria, Kavita Yadav, Manivannan Ramachandran

Abstract:

The extract of Tagetes erecta (marigold flower) was used as a green corrosion inhibitor for mild steel (MS) in nitric acid medium. The weight loss measurements were performed to understand the inhibition mechanism. The effect of temperature on the behaviour of mild steel corrosion without and with inhibitor was studied. The temperature studies revealed that the activation energy increased from 12 kJ/mol to 28.8 kJ/mol with the addition of 500 ppm inhibitor concentration. The thermodynamic analysis and the adsorption isotherm studies revealed that the molecules of inhibitor show physical adsorption on the surface of mild steel. Based on weight loss measurements, adsorption of the inhibitor on the surface of mild steel follows Langmuir isotherm.

Keywords: Tagetes erecta, corrosion, adsorption, inhibitor

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459 Nanoparticle Based Green Inhibitor for Corrosion Protection of Zinc in Acidic Medium

Authors: Neha Parekh, Divya Ladha, Poonam Wadhwani, Nisha Shah

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Nano scaled materials have attracted tremendous interest as corrosion inhibitor due to their high surface area on the metal surfaces. It is well known that the zinc oxide nanoparticles have higher reactivity towards aqueous acidic solution. This work presents a new method to incorporate zinc oxide nanoparticles with white sesame seeds extract (nano-green inhibitor) for corrosion protection of zinc in acidic medium. The morphology of the zinc oxide nanoparticles was investigated by TEM and DLS. The corrosion inhibition efficiency of the green inhibitor and nano-green inhibitor was determined by Gravimetric and electrochemical impedance spectroscopy (EIS) methods. Gravimetric measurements suggested that nano-green inhibitor is more effective than green inhibitor. Furthermore, with the increasing temperature, inhibition efficiency increases for both the inhibitors. In addition, it was established the Temkin adsorption isotherm fits well with the experimental data for both the inhibitors. The effect of temperature and Temkin adsorption isotherm revealed Chemisorption mechanism occurring in the system. The activation energy (Ea) and other thermodynamic parameters for inhibition process were calculated. The data of EIS showed that the charge transfer controls the corrosion process. The surface morphology of zinc metal (specimen) in absence and presence of green inhibitor and nano-green inhibitor were performed using Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) techniques. The outcomes indicated a formation of a protective layer over zinc metal (specimen).

Keywords: corrosion, green inhibitor, nanoparticles, zinc

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458 MAGE-A3 and PRAME Gene Expression and EGFR Mutation Status in Non-Small-Cell Lung Cancer

Authors: Renata Checiches, Thierry Coche, Nicolas F. Delahaye, Albert Linder, Fernando Ulloa Montoya, Olivier Gruselle, Karen Langfeld, An de Creus, Bart Spiessens, Vincent G. Brichard, Jamila Louahed, Frédéric F. Lehmann

Abstract:

Background: The RNA-expression levels of cancer-testis antigens MAGE A3 and PRAME were determined in resected tissue from patients with primary non-small-cell lung cancer (NSCLC) and related to clinical outcome. EGFR, KRAS and BRAF mutation status was determined in a subset to investigate associations with MAGE A3 and PRAME expression. Methods: We conducted a single-centre, uncontrolled, retrospective study of 1260 tissue-bank samples from stage IA-III resected NSCLC. The prognostic value of antigen expression (qRT-PCR) was determined by hazard-ratio and Kaplan-Meier curves. Results: Thirty-seven percent (314/844) of tumours expressed MAGE-A3, 66% (723/1092) expressed PRAME and 31% (239/839) expressed both. Respective frequencies in squamous-cell tumours and adenocarcinomas were 43%/30% for MAGE A3 and 80%/44% for PRAME. No correlation with stage, tumour size or patient age was found. Overall, no prognostic value was identified for either antigen. A trend to poorer overall survival was associated with MAGE-A3 in stage IIIB and with PRAME in stage IB. EGFR and KRAS mutations were found in 10.1% (28/311) and 33.8% (97/311) of tumours, respectively. EGFR (but not KRAS) mutation status was negatively associated with PRAME expression. Conclusion: No clear prognostic value for either PRAME or MAGE A3 was observed in the overall population, although some observed trends may warrant further investigation.

Keywords: MAGE A3, PRAME, cancer-testis gene, NSCLC, survival, EGFR

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457 Single-Molecule Optical Study of Cholesterol-Mediated Dimerization Process of EGFRs in Different Cell Lines

Authors: Chien Y. Lin, Jung Y. Huang, Leu-Wei Lo

Abstract:

A growing body of data reveals that the membrane cholesterol molecules can alter the signaling pathways of living cells. However, the understanding about how membrane cholesterol modulates receptor proteins is still lacking. Single-molecule tracking can effectively probe into the microscopic environments and thermal fluctuations of receptor proteins in a living cell. In this study we applies single-molecule optical tracking on ligand-induced dimerization process of EGFRs in the plasma membranes of two cancer cell lines (HeLa and A431) and one normal endothelial cell line (MCF12A). We tracked individual EGFR and dual receptors, diffusing in a correlated manner in the plasma membranes of live cells. We developed an energetic model by integrating the generalized Langevin equation with the Cahn-Hilliard equation to help extracting important information from single-molecule trajectories. From the study, we discovered that ligand-bound EGFRs move from non-raft areas into lipid raft domains. This ligand-induced motion is a common behavior in both cancer and normal cells. By manipulating the total amount of membrane cholesterol with methyl-β-cyclodextrin and the local concentration of membrane cholesterol with nystatin, we further found that the amount of cholesterol can affect the stability of EGFR dimers. The EGFR dimers in the plasma membrane of normal cells are more sensitive to the local concentration changes of cholesterol than EGFR dimers in the cancer cells. Our method successfully captures dynamic interactions of receptors at the single-molecule level and provides insight into the functional architecture of both the diffusing EGFR molecules and their local cellular environment.

Keywords: membrane proteins, single-molecule tracking, Cahn-Hilliard equation, EGFR dimers

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456 Immunoliposomes for Co-Delivery of Doxorubicin and Ribonucleotide Reductase M2 Sirna Inhibit of Gastric Cancer Growth

Authors: Jie Gao

Abstract:

The combination of chemotherapy with gene therapy is highly effective in cancer therapy. To achieve combined therapeutic effects in human gastric cancer over expressing EGFR, we developed targeted LPD (liposome-polycation-DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab’ for co-delivery of doxorubicin (DOX) and ribonucleotide reductase M2 (RRM2) siRNA (DOX-RRM2-TLPD). The results showed that EGFR was over expressed in several gastric cancer cell lines and gastric cancer tissues. Gene Expression Omnibus (GEO) results showed that RRM2 expression was significantly higher in gastric cancer than in non-gastric cancer tissue, and RRM2 siRNA inhibited the proliferation of several gastric cancer cells, indicating that RRM2 is a candidate target for gastric cancer therapy. Confocal studies and flow cytometry showed that DOX-RRM2-TLPD delivered DOX and RRM2 siRNA to EGFR over expressing gastric cancer cells specifically and efficiently both in vitro and in vivo, resulting in enhanced therapeutic effects (cytotoxicity and apoptosis) compared with single-drug loaded or non-targeted controls, including DOX-NC-TLPD (targeted LPD co-delivering DOX and negative control siRNA), RRM2-TLPD (targeted LPD delivering RRM2 siRNA) and DOX-RRM2-NTLPD (non-targeted LPD co-delivering DOX and RRM2 siRNA). The in vivo antitumor assay showed that the average weight of the gastric cancer in mice treated with DOX-RRM2-TLPD was significantly lighter than that of mice treated with other controls. DOX-RRM2-TLPD represents an effective approach for combined therapy of gastric cancer over expressing EGFR.

Keywords: gene therapy, chemotherapy, immunoliposomes, gastric cancer

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455 Camptothecin Promotes ROS-Mediated G2/M Phase Cell Cycle Arrest, Resulting from Autophagy-Mediated Cytoprotection

Authors: Rajapaksha Gedara Prasad Tharanga Jayasooriya, Matharage Gayani Dilshara, Yung Hyun Choi, Gi-Young Kim

Abstract:

Camptothecin (CPT) is a quinolone alkaloid which inhibits DNA topoisomerase I that induces cytotoxicity in a variety of cancer cell lines. We previously showed that CPT effectively inhibited invasion of prostate cancer cells and also combined treatment with subtoxic doses of CPT and TNF-related apoptosis-inducing ligand (TRAIL) potentially enhanced apoptosis in a caspase-dependent manner in hepatoma cancer cells. Here, we found that treatment with CPT caused an irreversible cell cycle arrest in the G2/M phase. CPT-induced cell cycle arrest was associated with a decrease in protein levels of cell division cycle 25C (Cdc25C) and increased the level of cyclin B and p21. The CPT-induced decrease in Cdc25C was blocked in the presence of proteasome inhibitor MG132, thus reversed the cell cycle arrest. In addition to that treatment of CPT-increased phosphorylation of Cdc25C was the resulted of activation of checkpoint kinase 2 (Chk2), which was associated with phosphorylation of ataxia telangiectasia-mutated. Interestingly CPT induced G2/M phase of the cell cycle arrest is reactive oxygen species (ROS) dependent where ROS inhibitors NAC and GSH reversed the CPT-induced cell cycle arrest. These results further confirm by using transient knockdown of nuclear factor-erythroid 2-related factor 2 (Nrf2) since it regulates the production of ROS. Our data reveal that treatment of siNrf2 increased the ROS level as well as further increased the CPT induce G2/M phase cell cycle arrest. Our data also indicate CPT-enhanced cell cycle arrest through the extracellular signal-regulated kinase (ERK) and the c-Jun N-terminal kinase (JNK) pathway. Inhibitors of ERK and JNK more decreased the Cdc25C expression and protein expression of p21 and cyclin B. These findings indicate that Chk2-mediated phosphorylation of Cdc25C plays a major role in G2/M arrest by CPT.

Keywords: camptothecin, cell cycle, checkpoint kinase 2, nuclear factor-erythroid 2-related factor 2, reactive oxygen species

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454 Study of Demographic, Hematological Profile and Risk Stratification in Chronic Myeloid Leukemia Patients

Authors: Rajandeep Kaur, Rajeev Gupta

Abstract:

Background: Chronic myeloid leukemia (CML) is the most common leukaemia in India. The annual incidence of chronic myeloid leukemia in India was originally reported to be 0.8 to 2.2 per 1,00,000 population. CML is a clonal disorder that is usually easily diagnosed because the leukemic cells of more than 95% of patients have a distinctive cytogenetic abnormality, the Philadelphia chromosome (Ph1). The approval of tyrosine kinase inhibitors (TKIs), which target BCR-ABL1 kinase activity, has significantly reduced the mortality rate associated with chronic myeloid leukemia (CML) and revolutionized treatment. Material and Methods: 80 diagnosed cases of CML were taken. Investigations were done. Bone marrow and molecular studies were also done and with EUTOS, patients were stratified into low and high-risk groups and then treatment with Imatinib was given to all patients and the molecular response was evaluated at 6 months and 12 months follow up with BCR-ABL by RT-PCR quantitative assay. Results: In the study population, out of 80 patients in the study population, 40 were females and 40 were males, with M: F is 1:1. Out of total 80 patients’ maximum patients (54) were in 31-60 years age group. Our study showed a most common symptom of presentation is abdominal discomfort followed by fever. Out of the total 80 patients, 25 (31.3%) patients had high EUTOS scores and 55 (68.8%) patients had low EUTOS scores. On 6 months follow up 36.3% of patients had Complete Molecular Response, 16.3% of patients had Major Molecular Response and 47.5% of patients had No Molecular Response but on 12 months follow up 71.3% of patients had Complete Molecular Response, 16.25% of patients had Major Molecular Response and 12.5% patients had No Molecular Response. Conclusion: In this study, we found a significant correlation between EUTOS score and Molecular response at 6 months and 12 months follow up after Imatinib therapy.

Keywords: chronic myeloid leukemia, European treatment and outcome study score, hematological response, molecular response, tyrosine kinase inhibitor

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453 The Nutritional Status and the Kidney Function in Older Patients

Authors: Magdalena Barbara Kaziuk, Waldemar Kosiba

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Background: Obesity, particularly abdominal type, lead to accelerated progress of atherosclerosis and thus affects the functioning of various human organs. Non-HDL cholesterol includes residual risk of the cardiovascular diseases which persists in patients after achieved recommended level of LDL cholesterol. The maintenance of normal body mass index plays a particularly important role in both the prevention and treatment of chronic diseases. Materials and Methods: The study covered 96 patients (55 females, 42 males, age 66,9 +/-10,2 years). The nutritional status was determined with the Waist to Height Ratio (WHtR) and the Waist to Hip Ratio (WHR). A function of the kidney was evaluated by calculating the estimated glomerular filtration rate (eGFR) using the MDRD formula. Non-high-density lipoprotein cholesterol (non-HDL) is simply the difference between the total cholesterol concentration and the HDL cholesterol concentration. Results: The higher was level of non-HDL cholesterol, the lower eGFR had studied subjects (p<0.001). Significant correlation was found between higher WHtR and lower the eGFR (p=0.002). Also underweight (30% of patient) led to obtaining lower values of eGFR in subjects over 65 years old. The poorer nutrition the lower was glomerular filtration rate. Conclusions: Nutritional statuses of patients have a significant impact on the level of kidney function. Not only accumulated excess fat in the abdominal area, but also its deficiency affects the deterioration in renal filtration. Higher level of non-HDL not only raises the residual risk of the heart disease but also influences on kidney by worsening eGFR. Proper diet in connection with physical activity should lead to achieving good nutrition in these patients and protect their kidney function.

Keywords: nutrition, non-HDL cholesterol, glomerular filtration rate, lifestyle

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452 Neuroprotective Effect of Vildagliptin against Cerebral Ischemia in Rats

Authors: Salma A. El-Marasy, Rehab F. Abdel-Rahman, Reham M. Abd-Elsalam

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The burden of stroke is intensely increasing worldwide. Brain injury following transient or permanent focal cerebral ischemia develops ischemic stroke as a consequence of a complex series of pathophysiological events. The aim of this study is to evaluate the possible neuroprotective effect of a dipeptidyl peptidase-4 inhibitor, vildagliptin, independent on its insulinotropic properties in non-diabetic rats subjected to cerebral ischemia. Anaesthetized Wistar rats were subjected to either left middle cerebral artery occlusion (MCAO) or sham operation followed by reperfusion after 30 min of MCAO. The other three groups were orally administered vildagliptin at 3 dose levels (2.5, 5, 10 mg/kg) for 3 successive weeks before subjected to left focal cerebral ischemia/reperfusion and till the end of the study. Neurological deficit scores and motor activity were assessed 24h following reperfusion. 48h following reperfusion, rats were euthanized and their left brain hemispheres were harvested and used in the biochemical, histopathological, and immunohistochemical investigations. Vildagliptin pretreatment improved neurological score deficit, locomotor activity and motor coordination in MCAO rats. Moreover, vildagliptin reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), phosphotylinosital 3 kinase (PI3K), phosphorylated of protein kinase B (p-AKT), and mechanistic target of rapamycin (mTOR) brain contents in addition to reducing protein expression of caspase-3. Also, vildagliptin showed a dose-dependent attenuation in neuronal cell loss and histopathological alterations in MCAO rats. This study proves that vildagliptin exerted the neuroprotective effect in a dose-dependent manner as shown in amelioration of neuronal cell loss and histopathological damage in MCAO rats, which may be mediated by attenuating neuronal and motor deficits, it’s anti-oxidant property, activation of PI3K/AKT/mTOR pathway and its anti-apoptotic effect.

Keywords: caspase-3, cerebral ischemia, dipeptidyl peptidase-4 inhibitor, oxidative stress, PI3K/AKT/mTOR pathway, rats, vildagliptin

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451 A Comprehensive Analysis of LACK (Leishmania Homologue of Receptors for Activated C Kinase) in the Context of Visceral Leishmaniasis

Authors: Sukrat Sinha, Abhay Kumar, Shanthy Sundaram

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The Leishmania homologue of activated C kinase (LACK) is known T cell epitope from soluble Leishmania antigens (SLA) that confers protection against Leishmania challenge. This antigen has been found to be highly conserved among Leishmania strains. LACK has been shown to be protective against L. donovani challenge. A comprehensive analysis of several LACK sequences was completed. The analysis shows a high level of conservation, lower variability and higher antigenicity in specific portions of the LACK protein. This information provides insights for the potential consideration of LACK as a putative candidate in the context of visceral Leishmaniasis vaccine target.

Keywords: bioinformatics, genome assembly, leishmania activated protein kinase c (lack), next-generation sequencing

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450 Deep Learning Approach for Chronic Kidney Disease Complications

Authors: Mario Isaza-Ruget, Claudia C. Colmenares-Mejia, Nancy Yomayusa, Camilo A. González, Andres Cely, Jossie Murcia

Abstract:

Quantification of risks associated with complications development from chronic kidney disease (CKD) through accurate survival models can help with patient management. A retrospective cohort that included patients diagnosed with CKD from a primary care program and followed up between 2013 and 2018 was carried out. Time-dependent and static covariates associated with demographic, clinical, and laboratory factors were included. Deep Learning (DL) survival analyzes were developed for three CKD outcomes: CKD stage progression, >25% decrease in Estimated Glomerular Filtration Rate (eGFR), and Renal Replacement Therapy (RRT). Models were evaluated and compared with Random Survival Forest (RSF) based on concordance index (C-index) metric. 2.143 patients were included. Two models were developed for each outcome, Deep Neural Network (DNN) model reported C-index=0.9867 for CKD stage progression; C-index=0.9905 for reduction in eGFR; C-index=0.9867 for RRT. Regarding the RSF model, C-index=0.6650 was reached for CKD stage progression; decreased eGFR C-index=0.6759; RRT C-index=0.8926. DNN models applied in survival analysis context with considerations of longitudinal covariates at the start of follow-up can predict renal stage progression, a significant decrease in eGFR and RRT. The success of these survival models lies in the appropriate definition of survival times and the analysis of covariates, especially those that vary over time.

Keywords: artificial intelligence, chronic kidney disease, deep neural networks, survival analysis

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449 Identifying the Host Substrates for the Mycobacterial Virulence Factor Protein Kinase G

Authors: Saha Saradindu, Das Payel, Somdeb BoseDasgupta

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Tuberculosis caused by Mycobacteria tuberculosis is a dreadful disease and more so with the advent of extreme and total drug-resistant species. Mycobacterial pathogenesis is an ever-changing paradigm from phagosome maturation block to phagosomal escape into macrophage cytosol and finally acid tolerance and survival inside the lysosome. Mycobacteria are adept at subverting the host immune response by highjacking host cell signaling and secreting virulence factors. One such virulence factor is a ser/thr kinase; Protein kinase G (PknG), which is known to prevent phagosome maturation. The host substrates of PknG, allowing successful pathogenesis still remain an enigma. Hence we carried out a comparative phosphoproteomic screen and identified a number of substrates phosphorylated by PknG. We characterized some of these substrates in vivo and in vitro and observed that PknG mediated phosphorylation of these substrates leads to reduced TNFa production as well as decreased response to TNFa induced macrophage necroptosis, thus enabling mycobacterial survival and proliferation.

Keywords: mycobacteria, Protein kinase G, phosphoproteomics, necroptosis

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448 Zamzam Water as Corrosion Inhibitor for Steel Rebar in Rainwater and Simulated Acid Rain

Authors: Ahmed A. Elshami, Stephanie Bonnet, Abdelhafid Khelidj

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Corrosion inhibitors are widely used in concrete industry to reduce the corrosion rate of steel rebar which is present in contact with aggressive environments. The present work aims to using Zamzam water from well located within the Masjid al-Haram in Mecca, Saudi Arabia 20 m (66 ft) east of the Kaaba, the holiest place in Islam as corrosion inhibitor for steel in rain water and simulated acid rain. The effect of Zamzam water was investigated by electrochemical impedance spectroscopy (EIS) and Potentiodynamic polarization techniques in Department of Civil Engineering - IUT Saint-Nazaire, Nantes University, France. Zamzam water is considered to be one of the most important steel corrosion inhibitor which is frequently used in different industrial applications. Results showed that zamzam water gave a very good inhibition for steel corrosion in rain water and simulated acid rain.

Keywords: Zamzam water, corrosion inhibitor, rain water, simulated acid rain

Procedia PDF Downloads 307