80 results on '"Ercan D"'
Search Results
2. Burnout Syndrome Among Dentists in Turkey
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Abdullah Kalaycı, Ercan Durmuş, Ahmet Aktı, Şeyma Koyuncu, and Gökhan Gürses
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burnout syndrome ,copenhagen burnout inventory ,dentist ,title ,workplace ,diş hekimi ,işyeri ,kophenag tükenmişlik envanteri ,tükenmişlik sendromu ,unvan ,Dentistry ,RK1-715 - Abstract
Background: The simple explanation of burnout syndrome is exhaustion from work and work-related factors. It is more common in work that requires face-to-face contact with people, such as dentists. In this study, we researched the burnout levels of dentists working in Turkey and evaluated them according to gender, title, place of work and experience. Methods: Burnout scores were determined by the Copenhagen Burnout Inventory. This questionnaire was delivered to dentists online through various social media applications. We analyzed data via SigmaPlot Software. Results: The answers of a total of 477 dentists were considered valid. We observed that 73,5% of them had high burnout scores. A statistically significant difference was found in the evaluations according to the title and workplace. Experience and gender do not statistically affect burnout scores. Conclusion: It has been observed that dentists working in Turkey are more likely to face burnout syndrome at high levels. It has been predicted that patient burden may be closely related to burnout syndrome.
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- 2023
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3. Türkiye'deki Diş Hekimlerinin Antibiyotik ve Profilaksi Bilgilerinin Değerlendirilmesi
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Ercan Durmuş, Hasan Küçükkolbaşı, Ahmet Aktı, Rabia Gür, and Gökhan Gürses
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antibiotic knowledge ,antibiotic prophylaxis ,antibiotic resistance ,dentistry ,online survey ,antibiyotik bilgisi ,antibiyotik profilaksisi ,antibiyotik direnci ,diş hekimliği ,çevrimiçi anket ,Dentistry ,RK1-715 - Abstract
Introduction: Inappropriately prescribed antibiotics accelerate the formation of antibiotic-resistant bacteria. This circumstance creates a problematic situation in terms of public health. This study aims to measure dentists' antibiotic/prophylaxis knowledge and awareness of antibiotic resistance in Turkey based on two case scenarios. Materials Methods: Dentists in Turkey are invited by open invitation posts on various social media applications for our twelve-question online survey. The scoring was shaped based on answers to measure antibiotic/prophylaxis knowledge. The collected data were statistically analyzed by SPSS Statistics 22. Results: 321 participants answered all questions included in the study. The statistical analyses showed a significant difference in the evaluations according to gender, title, graduation time, and workplace. Conclusion: Inappropriate antibiotic prescription by dentists is common in Turkey. Dentists should receive more undergraduate lessons, and taking reminder antibiotic courses at regular intervals after graduation can contribute to keeping their knowledge up to date.
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- 2023
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4. Osteoproductivity of Injectable Bone Grafts with and without Ostrich Eggshell Membrane Protein in Rabbit Femur
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Ziya Ozan Cengiz, Ercan Durmus, Ilhami Celik, and Ahmet Aktı
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bone graft material ,dental implant ,eggshell powder ,Biotechnology ,TP248.13-248.65 ,Medicine (General) ,R5-920 - Abstract
Background: The aim of this study was to evaluate the biocompatibility and effectiveness in terms of osseointegration of dental implants composed of novel injectable bone grafts with and without ostrich eggshell particles and membrane protein in rabbit femur. Methods: Sixteen adult male New Zealand rabbits were used in this study. A bone defect was created in each animal’s right and left femur, and a dental implant was placed adjacent to the defect. Two graft materials were prepared, one containing the membrane protein and the other not. In two groups, the defects were filled with these materials. In the negative control group (NC, (n:8)), the defects were left empty. A commercial product of biphasic calcium sulfate was used as a positive control material (PC, n = 8). The graft groups were defined as the group with the membrane protein (MP+, (n:8)), and without the membrane protein (MP−, n:8). The animals were euthanized at the 12th week after surgery. The samples were investigated using histology, histomorphometry, and micro-computed tomography. Data were statistically analyzed using one-way ANOVA and Tukey’s tests (p = 0.05). Results: Both the PC and MP+ groups had similar newly formed bone areas, and the mean values of these groups were significantly (p < 0.05) higher than those of the MP− and NC groups. The PC group had the highest amount of unresorbed material, while the MP− group had the lowest amount of unresorbed material. The bone–implant contact (BIC) scores of the PC and MP+ groups were significantly higher (p < 0.05) than that of the NC group. The connective tissue area of the PC group was the lowest, which was significantly lower than the other groups (p < 0.05). Conclusions: The grafts produced are highly biocompatible and also showed osteoproductivity. Their cost-effectiveness and osteoproductive activity require further investigation.
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- 2024
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5. DENTOALVEOLAR YARALANMALARDA ERKEN TEDAVİ UYGULAMASININ PROGNOZ AÇISINDAN ÖNEMİ: OLGU SUNUMU
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Abdullah Kalaycı, Ercan Durmuş, Hasan Küçükkolbaşı, and Gizem Doğan
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dentoalveolar yapı ,erken tedavi ,travma ,Dentistry ,RK1-715 - Abstract
AMAÇ Dentoalveolar ve perioral yumuşak doku yaralanmaları çeşitli travmalara bağlı olarak genellikle kavga, düşme, trafik kazası ve spor yaralanmaları sonucunda meydana gelir. Diş yaralanmalarının çoğu ön dişleri, özellikle de maksiller santral dişleri etkiler. Konküzyon, sublüksasyon ve lüksasyon süt dişlerinde en sık görülen yaralanmalar iken, daimi dişlerde en sık komplike olmayan kron kırıkları görülür. Üç olgu içeren bu serinin amacı çocuklarda görülebilen travmatik yaralanmalara erken müdahale edildiğinde dentoalveolar yapılarda gözlenen olumlu iyileşme sürecinin aktarılması bununla beraber müdahaleye geç kalındığında dentoalveolar yapı kayıplarının gösterilmesidir. OLGU İlk iki olguda benzer yaştaki çocuk hastalarda görülen dentoalveolar yaralanmalara, hastaların kliniğimize erken başvurması sonucu uyguladığımız tedavilerin olumlu sonuçlar verdiği yapılan takipler sonrasında gözlemlenmiştir. Bir diğer olguda ise travma alan hasta aradan uzun zaman geçtikten sonra kliniğimize ağrı ve şişlik şikayetiyle başvurmuştur. Gelişen olumsuz durum hastada diş ve kemik kayıplarına neden olmuştur. BULGU Bahsedilen olgulardaki travma hastalarından kliniğimize erken başvuranlar için tedavi süreci olumlu sonuçlanmış ve uzun dönemde başarı sağlanmıştır. Ancak üzerinden zaman geçen olguda hastada kemik ve diş kaybıyla sonuçlanan, hastayı estetik, psikolojik ve de fonksiyonel olarak etkileyen bir süreç ortaya çıkmıştır. SONUÇ Dental travmalar genellikle komplikedir ve yaralanmaların erken tedavisi uzun vadeli sonuç elde etmek için oldukça önemlidir. Hekimin bilgisi ve tedaviye yaklaşımı aynı zamanda hasta ve ailesinin yaralanma konusunda bilinç düzeyi, travma sonrası sağlık kuruluşuna başvurma süresi gibi birçok faktör prognozu önemli ölçüde etkilemektedir. Anahtar Kelimeler: Dentoalveolar yapı, erken tedavi, travma
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- 2023
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6. MST2 kinase suppresses rDNA transcription in response to DNA damage by phosphorylating nucleolar histone H2B
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Pefani, D.E. Tognoli, M.L. Pirincci Ercan, D. Gorgoulis, V. O'Neill, E.
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The heavily transcribed rDNA repeats that give rise to the ribosomal RNA are clustered in a unique chromatin structure, the nucleolus. Due to its highly repetitive nature and transcriptional activity, the nucleolus is considered a hotspot of genomic instability. Breaks in rDNA induce a transient transcriptional shut down to conserve energy and promote rDNA repair; however, how nucleolar chromatin is modified and impacts on rDNA repair is unknown. Here, we uncover that phosphorylation of serine 14 on histone H2B marks transcriptionally inactive nucleolar chromatin in response to DNA damage. We identified that the MST2 kinase localises at the nucleoli and targets phosphorylation of H2BS14p in an ATM-dependent manner. We show that establishment of H2BS14p is necessary for damage-induced rDNA transcriptional shut down and maintenance of genomic integrity. Ablation of MST2 kinase, or upstream activators, results in defective establishment of nucleolar H2BS14p, perturbed DNA damage repair, sensitisation to rDNA damage and increased cell lethality. We highlight the impact of chromatin regulation in the rDNA damage response and targeting of the nucleolus as an emerging cancer therapeutic approach. © 2018 The Authors. Published under the terms of the CC BY 4.0 license
- Published
- 2018
7. Origin and invasion of the emerging infectious pathogen Sphaerothecum destruens
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Sana, S., Hardouin, E. A., Gozlan, Rodolphe, Ercan, D., Tarkan, A. S., Zhang, T. T., and Andreou, D.
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aquaculture ,biological invasion ,fungal pathogens ,invasive - Abstract
Non-native species are often linked to the introduction of novel pathogens with detrimental effects on native biodiversity. Since Sphaerothecum destruens was first discovered as a fish pathogen in the United Kingdom, it has been identified as a potential threat to European fish biodiversity. Despite this parasite's emergence and associated disease risk, there is still a poor understanding of its origin in Europe. Here, we provide the first evidence to support the hypothesis that S. destruens was accidentally introduced to Europe from China along with its reservoir host Pseudorasbora parva via the aquaculture trade. This is the first study to confirm the presence of S. destruens in China, and it has expanded the confirmed range of S. destruens to additional locations in Europe. The demographic analysis of S. destruens and its host P. parva in their native and invasive range further supported the close association of both species. This research has direct significance and management implications for S. destruens in Europe as a non-native parasite.
- Published
- 2017
8. KOMPLEKS VE KOMPOUND ODONTOMA, 22 VAKA SUNUMU
- Author
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Ercan Durmuş, Abdullah Kalaycı, Ahmet Aktı, Gökhan Gürses, and Aslı Ataseven
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odontoma ,gömülü diş ,odontojenik tümör ,Dentistry ,RK1-715 - Abstract
Amaç Odontomalar çenelerde en sık görülen odontojenik kökenli iyi huylu tümörlerdir. Yavaş büyürler ve agresif davranış göstermezler. Genellikle asemptomatiktirler ve sıklıkla rutin radyografi sırasında bulunurlar. Kompleks ve kompaund odontoma olarak ikiye ayrılmaktadır. Bu vaka serisinde 8’i komplex 14'ü kompaund, toplam 22 odontoma vakasının cerrahi tedavisinin anlatılması amaçlanmıştır. Olgular Sunumu Yaş aralığı 10-34 arası olan 14’ü kadın 8’i erkek toplam 22 hasta, bölümümüzde gerekli klinik ve radyolojik muayenelerden sonra cerrahi olarak opere edilmiştir. Çıkarılan dokuların histopatalojilerinin, radyolojik ve klinik bulgularla değerlendirilmesi ile 8’inin komplex 14’ünün kompound odontoma olduğu tespit edilmiştir. Bazı vakalarda odontoma ile birlikte gömülü diş alınırken bazı vakalarda diş sürmesinin takibi amacıyla veya çene fraktürü riski sebebiyle etken gömülü dişler bırakılmıştır. İyileşme süresince hastalarda herhangi bir komplikasyon görülmemiştir. Sonuç Odontomalar genellikle asemptomatik görüldükleri için hastaların diş hekimlerine rutin kontrollere gelmeleri, erken teşhiste çok önemlidir. Erken teşhis ile morbidite ve maliyet azaltılabilir.
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- 2022
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9. Mapping and performance evaluation of mathematics education research in Turkey: A bibliometric analysis from 2005 to 2021
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Ercan Dede and Ercan Ozdemir
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bibliometric analysis ,science mapping ,mathematics education ,co-citation analysis ,VOSviewer ,SSCI ,Education ,Education (General) ,L7-991 - Abstract
Different types of in-depth literature reviews were conducted to identify, evaluate or summarize the findings, common themes, trends, gaps, and used methods in mathematics education research. In recent decades, technological advances have enabled us to evaluate mathematics education literature in a more reliable, powerful, and objective manner. This study aims to present a complete description of Turkey-addressed mathematics education research using bibliometric methods. In other words, the current study aims to identify the most influential and/or productive authors, institutions, and publications in the field of mathematics education in Turkey. This study also aims to visualize and uncover the dynamic of the conceptual and intellectual structure of the field. For this purpose, citation analysis, co-occurrence analysis, co-citation analysis, and science mapping were performed using 416 highly-qualified and SSCI-indexed articles obtained from the WoS database. The results of citation analysis indicate the most influential authors are A. Baki, B. Guven, and D. Akyuz, respectively while the most productive ones are M. Isıksal-Bostan, A. Kursat Erbas, and O. Birgin. The most effective and leading institutions in the field are METU, Karadeniz Technical, and Hacettepe Universities. Additionally, co-occurrence analysis indicates mathematical achievement, mathematical modelling, and attitude are the most commonly used author keywords. Co-citation mapping visualizes the knowledge base of the mathematics education research and uncover which subjects the scholars in the field benefited from the research studies of seminal authors. Based on the findings, the current study makes suggestions for the research topics that could be influential and needed further research in the field.
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- 2022
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10. Low-Dose Dietary Phytoestrogen Abrogates Tamoxifen-Associated Mammary Tumor Prevention
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Liu, B., Edgerton, S., Yang, X., Kim, A., Ordonez-Ercan, D., Mason, T., Alvarez, K., Mckimmey, C., Liu, N., and Thor, A.
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Cancer Research ,Dose-Response Relationship, Drug ,Mammary Neoplasms, Experimental ,Breast Neoplasms ,Mice, Transgenic ,Phytoestrogens ,Isoflavones ,Mice ,Tamoxifen ,Oncology ,Cell Line, Tumor ,Animals ,Humans ,Drug Interactions ,Female - Abstract
Wild-type erbB-2/neu transgenic mice were used to study the interactions between tamoxifen and dietary phytoestrogens (or isoflavones) by dose and form in vivo. Mice were randomized to one of four dietary formulas and implanted with an 8-week continuous-release tamoxifen or placebo pellet at 8 weeks of age. In placebo-treated mice, soy meal diet (but not diets supplemented with low-dose or high-dose isoflavones or a casein diet) resulted in prolongation of tumor latency. In tamoxifen-treated mice fed the soy meal, casein, or high-dose isoflavone enriched diets, the majority (>80%) showed no tumor formation by 60 weeks of age. Of the mice that developed tumors, latency was significantly prolonged. In tamoxifen-treated mice fed the low-dose isoflavone enriched diet, a much higher rate of mammary tumor development (>50%; P < 0.002) and a shorter tumor latency were observed. In vitro studies of human and mouse mammary tumor cell lines confirm that low doses of genistein, co-administered with tamoxifen, promote cell proliferation. This is in contrast to tamoxifen alone or tamoxifen with higher doses of genistein that are growth inhibitory. In summary, low-dose dietary isoflavones abrogated tamoxifen-associated mammary tumor prevention in vivo. These interactions are supported by in vitro data from human and mouse mammary tumor cell lines. These dose-associated interactions likely have relevance to the human use of tamoxifen for prevention or treatment of breast cancer.
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- 2005
11. Fronto-striatal structures related with model-based control as an endophenotype for obsessive–compulsive disorder
- Author
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Meltem I. Kasal, Lutfullah Besiroglu, Nabi Zorlu, Nur Dikmeer, Aslıhan Bilge, Ercan Durmaz, Serap Polat, Fazil Gelal, Michael Rapp, Andreas Heinz, and Miriam Sebold
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Medicine ,Science - Abstract
Abstract Recent theories suggest a shift from model-based goal-directed to model-free habitual decision-making in obsessive–compulsive disorder (OCD). However, it is yet unclear, whether this shift in the decision process is heritable. We investigated 32 patients with OCD, 27 unaffected siblings (SIBs) and 31 healthy controls (HCs) using the two-step task. We computed behavioral and reaction time analyses and fitted a computational model to assess the balance between model-based and model-free control. 80 subjects also underwent structural imaging. We observed a significant ordered effect for the shift towards model-free control in the direction OCD > SIB > HC in our computational parameter of interest. However less directed analyses revealed no shift towards model-free control in OCDs. Nonetheless, we found evidence for reduced model-based control in OCDs compared to HCs and SIBs via 2nd stage reaction time analyses. In this measure SIBs also showed higher levels of model-based control than HCs. Across all subjects these effects were associated with the surface area of the left medial/right dorsolateral prefrontal cortex. Moreover, correlations between bilateral putamen/right caudate volumes and these effects varied as a function of group: they were negative in SIBs and OCDs, but positive in HCs. Associations between fronto-striatal regions and model-based reaction time effects point to a potential endophenotype for OCD.
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- 2021
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12. Two Practical Methods for the Forward Kinematics of 3-3 Type Spatial and 3-RRR Planar Parallel Manipulators
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Ercan Düzgün and Osman Kopmaz
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Stewart platform ,planar manipulators ,forward kinematics ,Bezout method ,polynomials ,Technology ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Biology (General) ,QH301-705.5 ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
The forward kinematics in parallel manipulators is a mathematically challenging issue, unlike serial manipulators. Kinematic constraint equations are non-linear transcendental equations that can be reduced to algebraic equations with appropriate transformations. For this reason, sophisticated and time-consuming methods such as the Bezout method, the Groebner bases method, and the like, are used. In this paper, we demonstrate that these equations can be solved by non-complicated mathematical methods for some special types of manipulators such as the 3-3 and 6-3 types of Stewart platforms, and the 3-RRR planar parallel manipulator. Our first method is an analytical approach that exploits the special structure of kinematic constraint equations and yields polynomials of 32nd and 16th order, as mentioned in the previous works. In the second method, an error function is defined. This error function is employed to find the most appropriate initial values for the non-linear equation solver which is used for solving kinematic constraint equations. Determining the initial values in this manner saves computation time and guarantees fast convergence to real solutions.
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- 2022
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13. The effect of swim-up and gradient sperm preparation techniques 0n deoxyribinucleic acid (DNA) fragmentation in subfertile patients
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Erdem, A., primary, Oguz, Y., additional, Erdem, M., additional, Oktem, M., additional, Ercan, D., additional, and Gumuslu, S., additional
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- 2013
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14. Corrosion Inhibition of Mild Steel by 4-Allyl-5-pyridin-4-yl-4H-1,2,4-triazole-3-thiol
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ORHAN, A., primary, ERCAN, D., additional, KOPARIR, P., additional, and SOYLEMEZ, A., additional
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- 2012
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15. Physicochemical, textural, volatile, and sensory profiles of traditional Sepet cheese
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Ercan, D., primary, Korel, F., additional, Karagül Yüceer, Y., additional, and Kınık, Ö., additional
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- 2011
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16. Neuroticism and introversion mediates the relationship between probable ADHD and symptoms of Internet gaming disorder: results of an online survey
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Bilge Evren, Cuneyt Evren, Ercan Dalbudak, Merve Topcu, and Nilay Kutlu
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ADHD ,extraversion ,Internet gaming disorder ,neuroticism ,online survey ,university students ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
OBJECTIVES: The aim of the present study was to evaluate relationship of probable attention deficit hyperactivity disorder (ADHD) with severity of the Internet gaming disorder (IGD), neuroticism and extraversion. METHODS: The study was conducted with online survey among 457 volunteered university students in Ankara and people who play games on the Internet and who are in the e-mail database of a company located in Istanbul that organizes e-sports tournaments. Participants were evaluated by applying the Adult ADHD Self-Report Scale (ASRS-v1.1), the 9-item Internet Gaming Disorder Scale (IGDS) and the Eysenck Personality Questionnaire Revised-Abbreviated Form (EPQR-A). RESULTS: Age was lower among those with the probable ADHD (n = 102, 22.3%) and those without (n = 355, 77.7%). Gender, educational status, and type of the participants did not differ between the groups. Severity of IGD symptoms and neuroticism were higher among those with the probable ADHD, whereas extraversion was lower. In logistic regression analysis, severity of IGD symptoms predicted the probable ADHD in the first Step, whereas when extraversion and neuroticism were included in the analysis as independent variables, low extraversion (introversion) and high neuroticism predicted the probable ADHD and severity of IGD symptoms was no longer a predictor. CONCLUSION: These findings suggest that the severity of IGD symptoms is related with the probable ADHD and low extraversion (introversion) and high neuroticism may have mediator effect on this relationship.
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- 2019
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17. The relationship of internet addiction symptom severity with posttraumatic stress disorder symptoms and impulsivity among Turkish university students
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Bilge Evren, Ercan Dalbudak, Cuneyt Evren, and Secil Ozen
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Hyperarousal ,impulsivity ,internet addiction ,posttraumatic stress disorder ,university students ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
OBJECTIVES: The first aim of this study was to investigate the relationship of impulsivity with Internet addiction symptom severity (IASS), and the second aim was to evaluate the mediator effect of posttraumatic stress disorder (PTSD) symptoms on this relationship among Turkish university students. METHODS: A total of 314 Turkish university students participated in this study. However, 268 students who answered “YES” to the any question concerning various traumatic experiences were included in the study. The students were assessed through sociodemographic questionnaire, the Internet Addiction Scale (IAS), the Posttraumatic Stress Disorder Checklist – Civilian Version (PCL-C) and the Barratt Impulsiveness Scale 11 – Short Form (BIS-11-SF). RESULTS: According to Internet addiction risk severity (IARS), the participants were classified into the three groups as high (25.0%, n = 67), mild (33.6%, n = 90), and no risk (41.4%, n = 111) of IA. Total score of BIS-11-SF and subscale scores (non-planning impulsivity [NPI], motor impulsivity [MI], and attention impulsivity [AI]) were higher in the group with high IARS. Scale scores were mildly correlated with each other. Finally, hierarchical regression analysis indicated that severity of MI, AI, and PTSD symptoms, especially hyperarousal symptoms, were the main predictors for IASS. CONCLUSIONS: There was strong relationship between impulsivity and IASS and this relationship persist even after severity of PTSD symptoms was entered in the analysis among Turkish university students. Severity of PTSD symptoms especially hyperarousal symptoms, may partially mediate the relationship between severity of impulsivity (especially MI and AI) and IASS.
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- 2019
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18. Nicotine induces cell proliferation by -arrestin-mediated activation of Src and Rb-Raf-1 pathways
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Dasgupta, P., primary, Rastogi, S., additional, Pillai, S., additional, Ordonez-Ercan, D., additional, Morris, M., additional, Haura, E., additional, and Chellappan, S., additional
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- 2006
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19. Ortaöğretim Öğrencilerinin Yazma Eğilimi Algıları
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Ercan Deniz and Mehmet Çeçen
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ortaöğretim ,yazma ,yazma eğilimi ,yazma becerisi ,Education - Abstract
Bu araştırmanın amacı, ortaöğretim öğrencilerinin yazma eğilimi algılarının genel düzeyini tespit ederek yazma eğilimi algısını cinsiyet, sınıf düzeyi, öğrenim alanı, anne eğitim durumu, baba eğitim durumu, kitap okuma sıklığı, facebook ve e-mail kullanma durumlarına göre incelemektir. Araştırma 2013-2014 eğitim-öğretim yılında tesadüfi örnekleme yoluyla seçilen resmi bir okuldaki 317 öğrenci üzerinde yürütülmüştür. Elde edilen veriler SPSS 20.0 paket programı kullanılarak analiz edilmiştir. Verilerin analizinde ilişkisiz örneklem t testi, tek yönlü varyans analizi ve pearson momentler çarpımı korelasyonu kullanılmıştır. Araştırmada elde edilen bulgulara göre ortaöğretim öğrencilerinin yazma eğilimi algılarının “orta düzeyde” olduğu sonucuna ulaşılmıştır. Öğrencilerin yazma eğilimi algılarının cinsiyet, sınıf düzeyi, öğrenim alanı ve kitap okuma sıklığı değişkenlerine göre anlamlı bir farlılık gösterdiği tespit edilmiştir. Anne ve baba eğitim durumuyla facebook ve e-mail kullanma değişkenlerinin yazma eğilimi algısıyla istatiksel olarak anlamlı bir ilişkisi bulunmamaktadır.
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- 2015
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20. Severity of Internet gaming disorder symptoms might be related with the body mass index
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Cuneyt Evren, Bilge Evren, Ercan Dalbudak, Merve Topcu, and Nilay Kutlu
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2018
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21. Hip fracture risk and different gene polymorphisms in the turkish population
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Ercan Dinçel, Aylin Sepici-Dinçel, Vesile Sepici, Hakan Özsoy, and Behçet Sepici
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Hip fractures risk ,Osteoporosis ,Gene polymorphism ,Medicine (General) ,R5-920 - Abstract
BACKGROUND: We aimed to discuss the risk assessments for both patients with hip fractures due to fall-related, low energy traumas and non-fractured control patients by examining bone mineral density and genetic data, two features associated with femoral strength and hip fracture risk. METHODS: Twenty-one osteoporotic patients with proximal femur fractures and non-fractured, osteoporotic, age- and gender-matched controls were included in the study. Bone mineral density measurements were performed with a Lunar DXA. The COL1A1, ESR, VDR, IL-6, and OPG genes were amplified, and labeling of specific gene sequences was performed in a multiplex polymerase chain reaction using the osteo/check PCR kit from the whole blood of all subjects. RESULTS: The bone mineral density (trochanteric and total bone mineral density values) of the fracture group was significantly decreased relative to the control group. We were not able to conduct statistical tests for the polymorphisms of the COL1A1, ESR, and VDR genes because our results were expressed in terms of frequency. Although they were not significant, we did examine differences in the IL-6 and OPG genes polymorphisms between the two groups. We concluded that increasing the number of cases will allow us to evaluate racial differences in femoral hip fracture risk by genotypes.
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- 2008
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22. Evidence of threat to European economy and biodiversity following the introduction of an alien pathogen on the fungal–animal boundary
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Ercan, D., Andreou, Demetra, Sana, S., Öntaş, C., Baba, E., Top, N., Karakuş, U., Tarkan, A.S., Gozlan, Rodolphe Elie, Ercan, D., Andreou, Demetra, Sana, S., Öntaş, C., Baba, E., Top, N., Karakuş, U., Tarkan, A.S., and Gozlan, Rodolphe Elie
- Abstract
Recent years have seen a global and rapid resurgence of fungal diseases with direct impact on biodiversity and local extinctions of amphibian, coral, or bat populations. Despite similar evidence of population extinction in European fish populations and the associated risk of food aquaculture due to the emerging rosette agent Sphaerothecum destruens, an emerging infectious eukaryotic intracellular pathogen on the fungal–animal boundary, our understanding of current threats remained limited. Long-term monitoring of population decline for the 8-year post-introduction of the fungal pathogen was coupled with seasonal molecular analyses of the 18S rDNA and histological work of native fish species organs. A phylogenetic relationship between the existing EU and US strains using the ribosomal internal transcribed spacer sequences was also carried out. Here, we provide evidence that this emerging parasite has now been introduced via Pseudorasbora parva to sea bass farms, an industry that represents over 400 M€ annually in a Mediterranean region that is already economically vulnerable. We also provide for the first time evidence linking S. destruens to disease and severe declines in International Union for Conservation of Nature threatened European endemic freshwater fishes (i.e. 80% to 90 % mortalities). Our findings are thus of major economic and conservation importance.
23. A VIDICON SYSTEM FOR REAL TIME DIFFRACTION STUDIES
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BÖSECKE, P., primary, ERCAN, D., additional, and RIEKEL, C., additional
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- 1986
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24. Comparison of Depth of Anesthesia in Different Parts of Maxilla When Only Buccal Anesthesia Was Done for Maxillary Teeth Extraction
- Author
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Kubilay Isik, Abdullah Kalayci, and Ercan Durmus
- Subjects
Dentistry ,RK1-715 - Abstract
Objective. Recently, some authors reported that maxillary teeth could be extracted without using palatal anesthesia, but they did not clearly specify the extracted teeth. This is important, because apparently the local anesthetic solution infiltrates the maxilla and achieves a sufficient anesthesia in the palatal side. Thus, thickness of the bone may affect the depth of anesthesia. The aim of this study was to compare the depth of anesthesia in different parts of the maxilla when only a buccal infiltration anesthesia was done. Patients and Method. The maxilla was divided into anterior, premolar, and molar regions. In each region, 15 teeth were extracted with a single buccal infiltration. The patient marked the pain level on a numerical rating scale. Results. Anesthesia depth was sufficient and was not significantly different (𝑃>0.05) among three maxillary regions. Conclusion. Except for surgical interventions, all maxillary teeth can be extracted using only a buccal infiltration anesthesia.
- Published
- 2011
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25. Investigation of the effects of clinical parameters on mortality in patients with necrotizing fasciitis.
- Author
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Aydın SY, Ercan A, and Ercan D
- Subjects
- Humans, Retrospective Studies, Risk Factors, Anti-Bacterial Agents therapeutic use, Fasciitis, Necrotizing diagnosis, Fasciitis, Necrotizing surgery, Soft Tissue Infections diagnosis
- Abstract
Background: Necrotizing fasciitis is a rapidly progressing, potentially fatal soft-tissue infection that spreads through the fascia. Due to the late onset of diagnostic signs during the disease's advanced stage and its rapid progression, it can be challenging to make a prompt diagnosis. However, with a rapid and accurate diagnosis, the progression of the disease can be halted through appropriate early surgical intervention. Even with correct and timely treatment, the mortality rate for necrotizing fasciitis is higher compared to other soft-tissue infections. This study aims to investigate the effects of clinical parameters in patients with necrotizing fasciitis on mortality., Methods: The study included 37 patients with a necrotizing fasciitis diagnosis between 2009 and 2018. Demographic characteristics of the patients (age, gender, comorbid conditions), duration from diabetes diagnosis if present, blood glucose level at the time of diagnosis, microorganisms isolated from wound cultures, presence of positive blood cultures, administered antibiotic therapy, laboratory risk indicator for necrotizing fasciitis (LRINEC) score at presentation, number and types of surgical procedures performed, length of hospital stay, and mortality rates were retrospectively recorded. Statistical analysis of dependent and independent variables was conducted using t-tests, Mann-Whitney U test, Chi-square test, and Fisher's exact test., Results: Age was found to be an average of 70 in the mortality group, and it is significantly higher compared to the non-mortality group. A high LRINEC score, the presence of comorbidity, and a positive blood culture were also found to be significant in the mortal-ity group. The low number of surgical procedures performed is significantly lower in the mortality group., Conclusion: This study highlights the conditions associated with high mortality in patients with necrotizing fasciitis, which is a treatable disease through timely and accurate diagnosis followed by appropriate antibiotic therapy and surgical intervention. It emphasizes the importance of updating the approach for high-risk group patients and aims to provide information that will help lower the threshold for diagnosing necrotizing fasciitis.
- Published
- 2023
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26. An Assessment of the Penile Squamous Cell Carcinoma Surfaceome for Biomarker and Therapeutic Target Discovery.
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Grass GD, Ercan D, Obermayer AN, Shaw T, Stewart PA, Chahoud J, Dhillon J, Lopez A, Johnstone PAS, Rogatto SR, Spiess PE, and Eschrich SA
- Abstract
Penile squamous cell carcinoma (PSCC) is a rare malignancy in most parts of the world and the underlying mechanisms of this disease have not been fully investigated. About 30-50% of cases are associated with high-risk human papillomavirus (HPV) infection, which may have prognostic value. When PSCC becomes resistant to upfront therapies there are limited options, thus further research is needed in this venue. The extracellular domain-facing protein profile on the cell surface (i.e., the surfaceome) is a key area for biomarker and drug target discovery. This research employs computational methods combined with cell line translatomic (n = 5) and RNA-seq transcriptomic data from patient-derived tumors (n = 18) to characterize the PSCC surfaceome, evaluate the composition dependency on HPV infection, and explore the prognostic impact of identified surfaceome candidates. Immunohistochemistry (IHC) was used to validate the localization of select surfaceome markers. This analysis characterized a diverse surfaceome within patient tumors with 25% and 18% of the surfaceome represented by the functional classes of receptors and transporters, respectively. Significant differences in protein classes were noted by HPV status, with the most change being seen in transporter proteins (25%). IHC confirmed the robust surface expression of select surfaceome targets in the top 85% of expression and a superfamily immunoglobulin protein called BSG /CD147 was prognostic of survival. This study provides the first description of the PSCC surfaceome and its relation to HPV infection and sets a foundation for novel biomarker and drug target discovery in this rare cancer.
- Published
- 2023
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27. Inhibitory effect of whey protein concentrate on SARS-CoV-2-targeted furin activity and spike protein-ACE2 binding in methotrexate-induced lung damage.
- Author
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Tufan E, Sivas GG, Gürel-Gökmen B, Yılmaz-Karaoğlu S, Ercan D, Özbeyli D, Şener G, and Tunali-Akbay T
- Subjects
- Angiotensin-Converting Enzyme 2, Animals, Furin chemistry, Furin metabolism, Lung, Methotrexate adverse effects, Peptidyl-Dipeptidase A chemistry, Rats, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus metabolism, Whey Proteins, SARS-CoV-2, COVID-19 Drug Treatment
- Abstract
This study aims to investigate the effects of whey proteins on SARS CoV-2 in methotrexate-induced lung tissue damage in rats. To determine the possible effects, rats were divided into four groups as control, control + whey, methotrexate (20 mg/kg, i.p.) and methotrexate + whey. Whey protein concentrate (2 g/kg, oral gavage) was administered for 10 days. Cytokine levels were measured and protein electrophoresis was carried out in serum samples. Lipid peroxidation, nitric oxide and glutathione level, and superoxide dismutase and glutathione S transferase activities were determined in lung samples. Inhibition of SARS CoV-2-targeted lung furin activity and SARS CoV-2 spike protein-angiotensin converting enzyme binding with whey protein concentrate were also measured in each group. In conclusion, whey protein concentrate improved methotrexate-induced lung damage and inhibited lung furin activity targeting SARS-CoV-2 S1/S2 site cleavage and SARS CoV-2 spike protein-angiotensin converting enzyme binding. Whey proteins are potential protective candidates that inhibit SARS CoV-2-related interactions, even in methotrexate-induced lung injury. PRACTICAL APPLICATIONS: Whey proteins have anticarcinogenic, antihypertensive, antioxidant, antibacterial, antiviral, and immunomodulating properties due to the protein, bioactive peptide, and essential amino acid content. Methotrexate is a folate antagonist and inhibits cell proliferation and purine synthesis. The combined use of whey protein concentrate and methotrexate may be an alternative in the development of new strategies to the treatment approaches against COVID-19. In addition, according to the results of this study, it is thought that the protective effect of whey proteins in healthy conditions before encountering the SARS CoV-2 may be higher than those who have never used it., (© 2022 Wiley Periodicals LLC.)
- Published
- 2022
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28. Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of EGFR -mutant lung cancer.
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Eser PÖ, Paranal RM, Son J, Ivanova E, Kuang Y, Haikala HM, To C, Okoro JJ, Dholakia KH, Choi J, Eum Y, Ogino A, Missios P, Ercan D, Xu M, Poitras MJ, Wang S, Ngo K, Dills M, Yanagita M, Lopez T, Lin M, Tsai J, Floch N, Chambers ES, Heng J, Anjum R, Santucci AD, Michael K, Schuller AG, Cross D, Smith PD, Oxnard GR, Barbie DA, Sholl LM, Bahcall M, Palakurthi S, Gokhale PC, Paweletz CP, Daley GQ, and Jänne PA
- Subjects
- Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Humans, Mutation genetics, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, ErbB Receptors genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
The clinical efficacy of epidermal growth factor receptor (EGFR)–targeted therapy in EGFR -mutant non–small cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR inhibitor resistance occurs through amplification of the human growth factor receptor ( MET ) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent EGFR mutation and MET amplification are historically thought to be codependent on the activation of both oncogenes. Hence, patients whose tumors harbor both alterations are commonly treated with a combination of EGFR and MET tyrosine kinase inhibitors (TKIs). Here, we identify and characterize six patient-derived models of EGFR -mutant, MET -amplified lung cancer that have switched oncogene dependence to rely exclusively on MET activation for survival. We demonstrate in this MET-driven subset of EGFR TKI-refractory cancers that canonical EGFR downstream signaling was governed by MET, even in the presence of sustained mutant EGFR expression and activation. In these models, combined EGFR and MET inhibition did not result in greater efficacy in vitro or in vivo compared to single-agent MET inhibition. We further identified a reduced EGFR:MET mRNA expression stoichiometry as associated with MET oncogene dependence and single-agent MET TKI sensitivity. Tumors from 10 of 11 EGFR inhibitor–resistant EGFR -mutant, MET -amplified patients also exhibited a reduced EGFR:MET mRNA ratio. Our findings reveal that a subset of EGFR -mutant, MET -amplified lung cancers develop dependence on MET activation alone, suggesting that such patients could be treated with a single-agent MET TKI rather than the current standard-of-care EGFR and MET inhibitor combination regimens.
- Published
- 2021
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29. Budding yeast relies on G 1 cyclin specificity to couple cell cycle progression with morphogenetic development.
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Pirincci Ercan D, Chrétien F, Chakravarty P, Flynn HR, Snijders AP, and Uhlmann F
- Abstract
Two models have been put forward for cyclin-dependent kinase (Cdk) control of the cell cycle. In the qualitative model, cell cycle events are ordered by distinct substrate specificities of successive cyclin waves. Alternatively, in the quantitative model, the gradual rise of Cdk activity from G
1 phase to mitosis leads to ordered substrate phosphorylation at sequential thresholds. Here, we study the relative contributions of qualitative and quantitative Cdk control in Saccharomyces cerevisiae All S phase and mitotic cyclins can be replaced by a single mitotic cyclin, albeit at the cost of reduced fitness. A single cyclin can also replace all G1 cyclins to support ordered cell cycle progression, fulfilling key predictions of the quantitative model. However, single-cyclin cells fail to polarize or grow buds and thus cannot survive. Our results suggest that budding yeast has become dependent on G1 cyclin specificity to couple cell cycle progression to essential morphogenetic events., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)- Published
- 2021
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30. Analysis of Cell Cycle Progression in the Budding Yeast S. cerevisiae.
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Pirincci Ercan D and Uhlmann F
- Subjects
- Cell Cycle, Electrophoretic Mobility Shift Assay, Flow Cytometry, Models, Biological, Pheromones pharmacology, Phosphorylation, Saccharomyces cerevisiae Proteins metabolism, Cyclin-Dependent Kinases metabolism, Cyclins metabolism, Saccharomyces cerevisiae physiology
- Abstract
The cell cycle is an ordered series of events by which cells grow and divide to give rise to two daughter cells. In eukaryotes, cyclin-cyclin-dependent kinase (cyclin-Cdk) complexes act as master regulators of the cell division cycle by phosphorylating numerous substrates. Their activity and expression profiles are regulated in time. The budding yeast S. cerevisiae was one of the pioneering model organisms to study the cell cycle. Its genetic amenability continues to make it a favorite model to decipher the principles of how changes in cyclin-Cdk activity translate into the intricate sequence of substrate phosphorylation events that govern the cell cycle. In this chapter, we introduce robust and straightforward methods to analyze cell cycle progression in S. cerevisiae. These techniques can be utilized to describe cell cycle events and to address the effects of perturbations on accurate and timely cell cycle progression.
- Published
- 2021
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31. MST2 kinase suppresses rDNA transcription in response to DNA damage by phosphorylating nucleolar histone H2B.
- Author
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Pefani DE, Tognoli ML, Pirincci Ercan D, Gorgoulis V, and O'Neill E
- Subjects
- Ataxia Telangiectasia Mutated Proteins metabolism, Chromatin genetics, DNA Damage genetics, DNA Repair genetics, DNA, Ribosomal genetics, Humans, Phosphorylation, Serine-Threonine Kinase 3, Transcription, Genetic genetics, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, DNA Breaks, Double-Stranded radiation effects, DNA, Ribosomal biosynthesis, Histones metabolism, Nucleolus Organizer Region genetics, Protein Serine-Threonine Kinases metabolism
- Abstract
The heavily transcribed rDNA repeats that give rise to the ribosomal RNA are clustered in a unique chromatin structure, the nucleolus. Due to its highly repetitive nature and transcriptional activity, the nucleolus is considered a hotspot of genomic instability. Breaks in rDNA induce a transient transcriptional shut down to conserve energy and promote rDNA repair; however, how nucleolar chromatin is modified and impacts on rDNA repair is unknown. Here, we uncover that phosphorylation of serine 14 on histone H2B marks transcriptionally inactive nucleolar chromatin in response to DNA damage. We identified that the MST2 kinase localises at the nucleoli and targets phosphorylation of H2BS14p in an ATM-dependent manner. We show that establishment of H2BS14p is necessary for damage-induced rDNA transcriptional shut down and maintenance of genomic integrity. Ablation of MST2 kinase, or upstream activators, results in defective establishment of nucleolar H2BS14p, perturbed DNA damage repair, sensitisation to rDNA damage and increased cell lethality. We highlight the impact of chromatin regulation in the rDNA damage response and targeting of the nucleolus as an emerging cancer therapeutic approach., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2018
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32. Origin and invasion of the emerging infectious pathogen Sphaerothecum destruens.
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Sana S, Hardouin EA, Gozlan RE, Ercan D, Tarkan AS, Zhang T, and Andreou D
- Subjects
- Animals, Aquaculture, China epidemiology, Communicable Diseases, Emerging epidemiology, Communicable Diseases, Emerging parasitology, Europe epidemiology, Fish Diseases epidemiology, Mesomycetozoea isolation & purification, Mesomycetozoea Infections epidemiology, United Kingdom epidemiology, Communicable Diseases, Emerging veterinary, Cyprinidae parasitology, Fish Diseases parasitology, Introduced Species, Mesomycetozoea pathogenicity, Mesomycetozoea Infections parasitology
- Abstract
Non-native species are often linked to the introduction of novel pathogens with detrimental effects on native biodiversity. Since Sphaerothecum destruens was first discovered as a fish pathogen in the United Kingdom, it has been identified as a potential threat to European fish biodiversity. Despite this parasite's emergence and associated disease risk, there is still a poor understanding of its origin in Europe. Here, we provide the first evidence to support the hypothesis that S. destruens was accidentally introduced to Europe from China along with its reservoir host Pseudorasbora parva via the aquaculture trade. This is the first study to confirm the presence of S. destruens in China, and it has expanded the confirmed range of S. destruens to additional locations in Europe. The demographic analysis of S. destruens and its host P. parva in their native and invasive range further supported the close association of both species. This research has direct significance and management implications for S. destruens in Europe as a non-native parasite.
- Published
- 2017
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33. Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors.
- Author
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Kosaka T, Tanizaki J, Paranal RM, Endoh H, Lydon C, Capelletti M, Repellin CE, Choi J, Ogino A, Calles A, Ercan D, Redig AJ, Bahcall M, Oxnard GR, Eck MJ, and Jänne PA
- Subjects
- Adult, Amino Acid Substitution, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Codon, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm genetics, ErbB Receptors chemistry, Female, Gene Expression, Humans, Lung Neoplasms diagnosis, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Male, Mice, Middle Aged, Models, Molecular, Molecular Conformation, Protein Binding, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors therapeutic use, Receptor, ErbB-2 chemistry, Tomography, X-Ray Computed, Treatment Outcome, Xenograft Model Antitumor Assays, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Exons, Mutagenesis, Insertional, Protein Kinase Inhibitors pharmacology, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-2 genetics
- Abstract
Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline-based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors. Cancer Res; 77(10); 2712-21. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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34. Identification of Existing Drugs That Effectively Target NTRK1 and ROS1 Rearrangements in Lung Cancer.
- Author
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Chong CR, Bahcall M, Capelletti M, Kosaka T, Ercan D, Sim T, Sholl LM, Nishino M, Johnson BE, Gray NS, and Jänne PA
- Subjects
- Animals, Antineoplastic Agents chemistry, Cell Line, Tumor, Humans, Lung Neoplasms diagnosis, Lung Neoplasms drug therapy, Mice, Models, Molecular, Molecular Conformation, Molecular Targeted Therapy, Mutation, Phosphorylation, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins chemistry, Receptor Protein-Tyrosine Kinases chemistry, Receptor, trkA chemistry, Signal Transduction drug effects, Small Molecule Libraries, Structure-Activity Relationship, Tomography, X-Ray Computed, Treatment Outcome, Antineoplastic Agents pharmacology, Drug Screening Assays, Antitumor, Gene Rearrangement, Lung Neoplasms genetics, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases genetics, Receptor, trkA antagonists & inhibitors, Receptor, trkA genetics
- Abstract
Purpose: Efforts to discover drugs that overcome resistance to targeted therapies in patients with rare oncogenic alterations, such as NTRK1 and ROS1 rearrangements, are complicated by the cost and protracted timeline of drug discovery., Experimental Design: In an effort to identify inhibitors of NTRK1 and ROS1, which are aberrantly activated in some patients with non-small cell lung cancer (NSCLC), we created and screened a library of existing targeted drugs against Ba/F3 cells transformed with these oncogenes., Results: This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1-transformed Ba/F3, including the crizotinib-resistant mutants G2032R and L2026M (IC
50 = 9, 26, and 11 nmol/L, respectively). Cabozantinib inhibited CD74-ROS1-transformed Ba/F3 cells more potently than brigatinib (wild-type/G2032R/L2026M IC50 = 30/170/200 nmol/L, respectively), entrectinib (IC50 = 6/2,200/3,500 nmol/L), and PF-06463922 (IC50 = 1/270/2 nmol/L). Cabozantinib inhibited ROS1 autophosphorylation and downstream ERK activation in transformed Ba/F3 cells and in patient-derived tumor cell lines. The IGF-1R inhibitor BMS-536924 potently inhibited CD74-NTRK1-transformed compared with parental Ba/F3 cells (IC50 = 19 nmol/L vs. > 470 nmol/L). A patient with metastatic ROS1-rearranged NSCLC with progression on crizotinib was treated with cabozantinib and experienced a partial response., Conclusions: While acquired resistance to targeted therapies is challenging, this study highlights that existing agents may be repurposed to overcome drug resistance and identifies cabozantinib as a promising treatment of ROS1-rearranged NSCLC after progression on crizotinib. Clin Cancer Res; 23(1); 204-13. ©2016 AACR., (©2016 American Association for Cancer Research.)- Published
- 2017
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35. Recent advances for the production and recovery methods of lysozyme.
- Author
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Ercan D and Demirci A
- Subjects
- Animals, Anti-Infective Agents metabolism, Anti-Infective Agents pharmacology, Bacteria metabolism, Humans, Muramidase pharmacology, Muramidase metabolism
- Abstract
Lysozyme is an antimicrobial peptide with a high enzymatic activity and positive charges. Therefore, it has applications in food and pharmaceutical industries as an antimicrobial agent. Lysozyme is ubiquitous in both animal and plant kingdoms. Currently, egg-white lysozyme is the most commercially available form of lysozyme. The main concerns of egg-white lysozyme are high recovery cost, low activity and most importantly the immunological problems to some people. Therefore, human lysozyme production has gained importance in recent years. Scientists have developed transgenic plants, animals and microorganisms that can produce human lysozyme. Out of these, microbial production has advantages for commercial productions, because high production levels are achievable in a relatively short time. It has been reported that fermentation parameters, such as pH, temperature, aeration, are key factors to increase the effectiveness of the human lysozyme production. Moreover, purification of the lysozyme from the fermentation broth needs to be optimized for the economical production. In conclusion, this review paper covers the mechanism of lysozyme, its sources, production methods and recovery of lysozyme.
- Published
- 2016
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36. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors.
- Author
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Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, Xu C, Rhee K, Chen T, Zhang H, Palakurthi S, Jang J, Lelais G, DiDonato M, Bursulaya B, Michellys PY, Epple R, Marsilje TH, McNeill M, Lu W, Harris J, Bender S, Wong KK, Jänne PA, and Eck MJ
- Subjects
- Allosteric Regulation drug effects, Allosteric Site drug effects, Animals, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Proliferation drug effects, Cetuximab pharmacology, Disease Models, Animal, Drug Resistance, Multiple drug effects, Drug Resistance, Multiple genetics, Drug Resistance, Neoplasm drug effects, Drug Synergism, ErbB Receptors antagonists & inhibitors, ErbB Receptors chemistry, ErbB Receptors metabolism, Lung Neoplasms drug therapy, Lung Neoplasms enzymology, Lung Neoplasms pathology, Mice, Mutant Proteins chemistry, Mutant Proteins genetics, Mutant Proteins metabolism, Protein Conformation drug effects, Protein Multimerization drug effects, Antineoplastic Agents pharmacology, Benzeneacetamides pharmacology, Drug Resistance, Neoplasm genetics, ErbB Receptors genetics, Mutant Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Thiazoles pharmacology
- Abstract
The epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harbouring activating mutations in the EGFR kinase, but resistance arises rapidly, most frequently owing to the secondary T790M mutation within the ATP site of the receptor. Recently developed mutant-selective irreversible inhibitors are highly active against the T790M mutant, but their efficacy can be compromised by acquired mutation of C797, the cysteine residue with which they form a key covalent bond. All current EGFR TKIs target the ATP-site of the kinase, highlighting the need for therapeutic agents with alternative mechanisms of action. Here we describe the rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor. The crystal structure shows that the compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. The compound inhibits L858R/T790M-mutant EGFR with low-nanomolar potency in biochemical assays. However, as a single agent it is not effective in blocking EGFR-driven proliferation in cells owing to differential potency on the two subunits of the dimeric receptor, which interact in an asymmetric manner in the active state. We observe marked synergy of EAI045 with cetuximab, an antibody therapeutic that blocks EGFR dimerization, rendering the kinase uniformly susceptible to the allosteric agent. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR(L858R/T790M) and by EGFR(L858R/T790M/C797S), a mutant that is resistant to all currently available EGFR TKIs. More generally, our findings illustrate the utility of purposefully targeting allosteric sites to obtain mutant-selective inhibitors.
- Published
- 2016
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37. Arterial disease and vascular access in diabetic patients.
- Author
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Baktiroglu S, Yanar F, Ozata IH, Oner G, and Ercan D
- Subjects
- Diabetic Angiopathies diagnosis, Diabetic Angiopathies physiopathology, Diabetic Nephropathies complications, Diabetic Nephropathies diagnosis, Humans, Kidney Failure, Chronic complications, Kidney Failure, Chronic diagnosis, Risk Factors, Treatment Outcome, Vascular Calcification diagnosis, Vascular Calcification physiopathology, Arteriovenous Shunt, Surgical adverse effects, Diabetic Angiopathies complications, Diabetic Nephropathies therapy, Kidney Failure, Chronic therapy, Renal Dialysis, Vascular Calcification complications, Vascular Stiffness
- Abstract
Purpose: There are conflicting reports on the effects of diabetes on the outcomes of hemodialysis access procedures. While some found no negative effects, others reported deleterious effects of diabetes on vascular access outcomes. Why is there concern about diabetes and related vascular problems on vascular access procedures? What are the differences of diabetic patients and their vasculature from that of nondiabetics? Do they have an effect on hemodialysis vascular access outcomes? We will try to find answers to these questions in light of the available evidence., Methods: Recent literature on arterial disease in diabetes and end-stage renal disease (ESRD), and the effects on vascular access outcomes were searched in order to find answers to above questions., Results: There are conflicting and controversial reports on the effects of preexisting vascular problems due to diabetes and chronic kidney disease (CKD) on the outcomes of hemodialysis access procedures. Diabetic vasculature, especially in patients with ESRD, has some specific problems, the most important of which seem to be the calcification and stiffening of the arteries., Conclusions: Although some authors report inferior outcomes of vascular access procedures in diabetic patients, there is evidence that most of the problems encountered can be dealt with by careful patient selection, surgical skill, and experience.
- Published
- 2016
- Full Text
- View/download PDF
38. Effects of fed-batch and continuous fermentations on human lysozyme production by Kluyveromyces lactis K7 in biofilm reactors.
- Author
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Ercan D and Demirci A
- Subjects
- Biomass, Humans, Biofilms, Bioreactors, Fermentation, Kluyveromyces metabolism, Muramidase biosynthesis
- Abstract
Lysozyme is a lytic enzyme, which has antimicrobial activity. It has been used for food and pharmaceutical applications. This study was undertaken to evaluate fed-batch and continuous fermentations for the human lysozyme production in biofilm reactor. Results showed that addition of lactose the mid-log phase to make the concentration back to the initial level generates higher lysozyme production (177 U/ml) compared with lactose addition in late-log phase (174 U/ml) (p < 0.05). Moreover, fed-batch fermentation with glucose as initial carbon source and continuous addition of lactose with 0.6 ml/min for 10 h demonstrated significantly higher lysozyme production (187 U/ml) compared to the batch fermentation (173 U/ml) (p < 0.05). In continuous fermentation, biofilm reactor provided significantly higher productivity (7.5 U/ml/h) compared to the maximum productivity in suspended cell bioreactor (4 U/ml/h), because the biofilm reactor provided higher cell density at higher dilution rate compared to suspended cell reactor (p < 0.05).
- Published
- 2015
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39. Evidence of threat to European economy and biodiversity following the introduction of an alien pathogen on the fungal-animal boundary.
- Author
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Ercan D, Andreou D, Sana S, Öntaş C, Baba E, Top N, Karakuş U, Tarkan AS, and Gozlan RE
- Subjects
- Animals, Aquaculture, Base Sequence, Biodiversity, Europe epidemiology, Fish Diseases economics, Fish Diseases parasitology, Fish Diseases pathology, Introduced Species, Mesomycetozoea genetics, Molecular Sequence Data, Phylogeny, Prevalence, Seasons, Sequence Analysis, DNA, Bass parasitology, Cyprinidae parasitology, Fish Diseases epidemiology, Mesomycetozoea isolation & purification
- Abstract
Recent years have seen a global and rapid resurgence of fungal diseases with direct impact on biodiversity and local extinctions of amphibian, coral, or bat populations. Despite similar evidence of population extinction in European fish populations and the associated risk of food aquaculture due to the emerging rosette agent Sphaerothecum destruens, an emerging infectious eukaryotic intracellular pathogen on the fungal-animal boundary, our understanding of current threats remained limited. Long-term monitoring of population decline for the 8-year post-introduction of the fungal pathogen was coupled with seasonal molecular analyses of the 18S rDNA and histological work of native fish species organs. A phylogenetic relationship between the existing EU and US strains using the ribosomal internal transcribed spacer sequences was also carried out. Here, we provide evidence that this emerging parasite has now been introduced via Pseudorasbora parva to sea bass farms, an industry that represents over 400 M€ annually in a Mediterranean region that is already economically vulnerable. We also provide for the first time evidence linking S. destruens to disease and severe declines in International Union for Conservation of Nature threatened European endemic freshwater fishes (i.e. 80% to 90 % mortalities). Our findings are thus of major economic and conservation importance.
- Published
- 2015
- Full Text
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40. EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors.
- Author
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Ercan D, Choi HG, Yun CH, Capelletti M, Xie T, Eck MJ, Gray NS, and Jänne PA
- Subjects
- Acrylamides chemistry, Afatinib, Amino Acid Substitution, Animals, Cell Line, Tumor, Cell Proliferation drug effects, Codon, ErbB Receptors chemistry, Humans, Inhibitory Concentration 50, Mice, Models, Molecular, Molecular Conformation, Protein Kinase Inhibitors chemistry, Pyrimidines chemistry, Quinazolines administration & dosage, Quinazolines pharmacology, Acrylamides pharmacology, Drug Resistance, Neoplasm genetics, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Mutation, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology
- Abstract
Purpose: Mutant selective irreversible pyrimidine-based EGFR kinase inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models and in lung cancer patients harboring the EGFR T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired resistance to this class of EGFR inhibitors. We sought to identify and study EGFR mutations that confer resistance to this class of agents., Experimental Design: We performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen in EGFR-mutant (sensitizing alone or with concurrent EGFR T790M) Ba/F3 cells and selected drug-resistant clones. We evaluated the sensitivity of EGFR inhibitors in models harboring drug-resistant EGFR mutations., Results: We identified 3 major drug resistance mutations. EGFR L718Q, L844V, and C797S cause resistance to both WZ4002 and CO-1686 while, in contrast, only EGFR C797S leads to AZD9291 resistance. Cells containing an EGFR-sensitizing mutation, Del 19 or L858R, in conjunction with L718Q, L844V, or C797S retain sensitivity to quinazoline-based EGFR inhibitors, gefitinib and afatinib. The C797S mutation, in the presence of Del 19 or L858R and T790M, causes resistance to all current EGFR inhibitors, but L858R/T790M/C797S remains partially sensitive to cetuximab which leads to disruption of EGFR dimerization., Conclusions: Our findings provide insights into resistance mechanisms to irreversible pyrimidine-based EGFR inhibitors and identify specific genomic contexts in which sensitivity is retained to existing clinical EGFR inhibitors. These findings will guide the development of new strategies to inhibit EGFR., (©2015 American Association for Cancer Research.)
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- 2015
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41. Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer.
- Author
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Tricker EM, Xu C, Uddin S, Capelletti M, Ercan D, Ogino A, Pratilas CA, Rosen N, Gray NS, Wong KK, and Jänne PA
- Subjects
- Animals, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Disease Models, Animal, Humans, Lung Neoplasms drug therapy, Lung Neoplasms mortality, Mice, Mice, Transgenic, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Protein Kinase Inhibitors therapeutic use, Ribosomal Protein S6 Kinases metabolism, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm genetics, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Lung Neoplasms genetics, Lung Neoplasms metabolism, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Mutation, Protein Kinase Inhibitors pharmacology
- Abstract
Unlabelled: Irreversible pyrimidine-based EGFR inhibitors, including WZ4002, selectively inhibit both EGFR-activating and EGFR inhibitor-resistant T790M mutations more potently than wild-type EGFR. Although this class of mutant-selective EGFR inhibitors is effective clinically in lung cancer patients harboring EGFR(T790M), prior preclinical studies demonstrate that acquired resistance can occur through genomic alterations that activate ERK1/2 signaling. Here, we find that ERK1/2 reactivation occurs rapidly following WZ4002 treatment. Concomitant inhibition of ERK1/2 by the MEK inhibitor trametinib prevents ERK1/2 reactivation, enhances WZ4002-induced apoptosis, and inhibits the emergence of resistance in WZ4002-sensitive models known to acquire resistance via both T790M-dependent and T790M-independent mechanisms. Resistance to WZ4002 in combination with trametinib eventually emerges due to AKT/mTOR reactivation. These data suggest that initial cotargeting of EGFR and MEK could significantly impede the development of acquired resistance in EGFR-mutant lung cancer., Significance: Patients with EGFR-mutant lung cancer develop acquired resistance to EGFR and mutant-selective EGFR tyrosine kinase inhibitors. Here, we show that cotargeting EGFR and MEK can prevent the emergence of a broad variety of drug resistance mechanisms in vitro and in vivo and may be a superior therapeutic regimen for these patients., (©2015 American Association for Cancer Research.)
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- 2015
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42. Identification of Oncogenic and Drug-Sensitizing Mutations in the Extracellular Domain of FGFR2.
- Author
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Tanizaki J, Ercan D, Capelletti M, Dodge M, Xu C, Bahcall M, Tricker EM, Butaney M, Calles A, Sholl LM, Hammerman PS, Oxnard GR, Wong KK, and Jänne PA
- Subjects
- Adult, Animals, Carcinoma, Non-Small-Cell Lung genetics, Endoplasmic Reticulum metabolism, Glycosylation, Golgi Apparatus metabolism, Humans, Lung Neoplasms genetics, Male, Mice, Mice, Nude, NIH 3T3 Cells, Protein Kinase Inhibitors pharmacology, Protein Multimerization, Protein Structure, Tertiary, Receptor, Fibroblast Growth Factor, Type 2 antagonists & inhibitors, Receptor, Fibroblast Growth Factor, Type 2 metabolism, Signal Transduction drug effects, Signal Transduction genetics, Mutation, Receptor, Fibroblast Growth Factor, Type 2 genetics
- Abstract
The discovery of oncogenic driver mutations and the subsequent developments in targeted therapies have led to improved outcomes for subsets of lung cancer patients. The identification of additional oncogenic and drug-sensitive alterations may similarly lead to new therapeutic approaches for lung cancer. We identify and characterize novel FGFR2 extracellular domain insertion mutations and demonstrate that they are both oncogenic and sensitive to inhibition by FGFR kinase inhibitors. We demonstrate that the mechanism of FGFR2 activation and subsequent transformation is mediated by ligand-independent dimerization and activation of FGFR2 kinase activity. Both FGFR2-mutant forms are predominantly located in the endoplasmic reticulum and Golgi but nevertheless can activate downstream signaling pathways through their interactions with fibroblast growth factor receptor substrate 2 (FRS2). Our findings provide a rationale for therapeutically targeting this unique subset of FGFR2-mutant cancers as well as insight into their oncogenic mechanisms., (©2015 American Association for Cancer Research.)
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- 2015
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43. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M.
- Author
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Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, Ercan D, Matthews SE, Cantarini M, Barrett JC, Jänne PA, and Oxnard GR
- Subjects
- Adult, Aged, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Drug Resistance, Neoplasm, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation, Acrylamides administration & dosage, Aniline Compounds administration & dosage, Carcinoma, Non-Small-Cell Lung drug therapy, ErbB Receptors genetics
- Abstract
Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.
- Published
- 2015
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44. Current and future trends for biofilm reactors for fermentation processes.
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Ercan D and Demirci A
- Subjects
- Fermentation, Biofilms growth & development, Bioreactors
- Abstract
Biofilms in the environment can both cause detrimental and beneficial effects. However, their use in bioreactors provides many advantages including lesser tendencies to develop membrane fouling and lower required capital costs, their higher biomass density and operation stability, contribution to resistance of microorganisms, etc. Biofilm formation occurs naturally by the attachment of microbial cells to the support without use of any chemicals agent in biofilm reactors. Biofilm reactors have been studied and commercially used for waste water treatment and bench and pilot-scale production of value-added products in the past decades. It is important to understand the fundamentals of biofilm formation, physical and chemical properties of a biofilm matrix to run the biofilm reactor at optimum conditions. This review includes the principles of biofilm formation; properties of a biofilm matrix and their roles in the biofilm formation; factors that improve the biofilm formation, such as support materials; advantages and disadvantages of biofilm reactors; and industrial applications of biofilm reactors.
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- 2015
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45. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy.
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Montero J, Sarosiek KA, DeAngelo JD, Maertens O, Ryan J, Ercan D, Piao H, Horowitz NS, Berkowitz RS, Matulonis U, Jänne PA, Amrein PC, Cichowski K, Drapkin R, and Letai A
- Subjects
- Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Female, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Mitochondria metabolism, Neoplasms pathology, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, Precision Medicine, Cell Death, Neoplasms drug therapy, Signal Transduction
- Abstract
There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
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46. Tivantinib (ARQ 197) efficacy is independent of MET inhibition in non-small-cell lung cancer cell lines.
- Author
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Calles A, Kwiatkowski N, Cammarata BK, Ercan D, Gray NS, and Jänne PA
- Subjects
- Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Crizotinib, Humans, Indoles pharmacology, Lung Neoplasms enzymology, Lung Neoplasms genetics, Lung Neoplasms pathology, MAP Kinase Signaling System genetics, Mitogen-Activated Protein Kinase 1 genetics, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 genetics, Mitogen-Activated Protein Kinase 3 metabolism, Phosphorylation drug effects, Phosphorylation genetics, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-met genetics, Proto-Oncogene Proteins c-met metabolism, Pyrazoles pharmacology, Pyridines pharmacology, Sulfones pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, MAP Kinase Signaling System drug effects, Proto-Oncogene Proteins c-met antagonists & inhibitors, Pyrrolidinones pharmacology, Quinolines pharmacology
- Abstract
MET targeted therapies are under clinical evaluation for non-small-cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKI) against MET have varying degrees of specificity. Tivantinib (ARQ 197) is reported to be a non-ATP competitive selective MET inhibitor. We aimed to compare the activity of tivantinib to established MET TKIs in a panel of NSCLC cell lines characterized by their MET dependency and by different relevant genotypes. A549, H3122, PC9 and HCC827, their respective resistant clones PC9 GR4 and HCC827 GR6 and the MET amplified cell lines H1993 and EBC-1 were treated in vitro with tivantinib, crizotinib or PHA-665752. Crizotinib and PHA-665752 showed growth inhibition restricted to MET dependent cell lines. The pattern of activity was related to MET inhibition and downstream signaling inhibition of AKT and ERK1/2, resulting in G0/G1 cycle arrest and apoptosis. In contrast, tivantinib possessed more potent anti-proliferative activity that was not restricted to only MET dependent cell lines. Tivantinib did not inhibit cellular MET activity or phosphorylation of downstream signaling proteins AKT or ERK1/2 in either MET dependent or independent cell lines. Cell cycle analysis demonstrated that tivantinib induced a G2/M arrest and induced apoptosis. Tivantinib but not crizotinib effected microtubule dynamics, disrupting mitotic spindles by a mechanism consistent with it functioning as a microtubule depolymerizer. Tivantinib activity is independent of MET signaling in NSCLC and suggests alternative mechanisms of action that should be considered when interpreting the results from on-going clinical studies., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
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- 2015
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47. Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma.
- Author
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Capelletti M, Dodge ME, Ercan D, Hammerman PS, Park SI, Kim J, Sasaki H, Jablons DM, Lipson D, Young L, Stephens PJ, Miller VA, Lindeman NI, Munir KJ, Richards WG, and Jänne PA
- Subjects
- Adenocarcinoma pathology, Adenocarcinoma of Lung, Antineoplastic Agents pharmacology, Cell Transformation, Neoplastic genetics, Computational Biology, Drug Resistance, Neoplasm, ErbB Receptors antagonists & inhibitors, Female, Gene Frequency, Genomics, Humans, Lung Neoplasms pathology, Male, Neoplasm Staging, Phenylurea Compounds pharmacology, Pyrimidines pharmacology, Risk Factors, Translocation, Genetic, Adenocarcinoma genetics, Lung Neoplasms genetics, Microtubule-Associated Proteins genetics, Oncogene Proteins, Fusion genetics, Receptor, Fibroblast Growth Factor, Type 3 genetics
- Abstract
Purpose: Targetable oncogenic alterations are detected more commonly in patients with non-small cell lung cancer (NSCLC) who never smoked cigarettes. For such patients, specific kinase inhibitors have emerged as effective clinical treatments. However, the currently known oncogenic alterations do not account for all never smokers who develop NSCLC. We sought to identify additional oncogenic alterations from patients with NSCLC to define additional treatment options., Experimental Design: We analyzed 576 lung adenocarcinomas from patients of Asian and Caucasian ethnicity. We identified a subset of cancers that did not harbor any known oncogenic alteration. We performed targeted next-generation sequencing (NGS) assay on 24 patients from this set with >75% tumor cell content., Results: EGFR mutations were the most common oncogenic alteration from both Asian (53%) and Caucasian (41.6%) patients. No known oncogenic alterations were present in 25.7% of Asian and 31% of Caucasian tumor specimens. We identified a FGFR3-TACC3 fusion event in one of 24 patients from this subset using targeted NGS. Two additional patients harboring FGFR3-TACC3 were identified by screening our entire cohort (overall prevalence, 0.5%). Expression of FGFR3-TACC3 led to IL3 independent growth in Ba/F3 cells. These cells were sensitive to pan-fibroblast growth factor receptor (pan-FGFR) inhibitors but not the epidermal growth factor (EGFR) inhibitor gefitinib., Conclusions: FGFR3-TACC3 rearrangements occur in a subset of patients with lung adenocarcinoma. Such patients should be considered for clinical trials featuring FGFR inhibitors., (©2014 American Association for Cancer Research.)
- Published
- 2014
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48. Pharmacological targeting of the pseudokinase Her3.
- Author
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Xie T, Lim SM, Westover KD, Dodge ME, Ercan D, Ficarro SB, Udayakumar D, Gurbani D, Tae HS, Riddle SM, Sim T, Marto JA, Jänne PA, Crews CM, and Gray NS
- Subjects
- Acrylamides chemical synthesis, Adamantane chemistry, Adenine chemical synthesis, Adenine pharmacology, Adenosine Triphosphate chemistry, Adenosine Triphosphate metabolism, Antineoplastic Agents chemical synthesis, Catalytic Domain, Cell Line, Tumor, Cell Proliferation drug effects, Cysteine chemistry, Humans, Hydrophobic and Hydrophilic Interactions, Molecular Docking Simulation, Molecular Targeted Therapy, Protein Kinase Inhibitors chemical synthesis, Protein Multimerization, Proteolysis, Proto-Oncogene Proteins c-met genetics, Proto-Oncogene Proteins c-met metabolism, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Receptor, ErbB-3 chemistry, Receptor, ErbB-3 genetics, Signal Transduction, Acrylamides pharmacology, Adenine analogs & derivatives, Antineoplastic Agents pharmacology, Gene Expression Regulation, Neoplastic, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met chemistry, Receptor, ErbB-2 chemistry, Receptor, ErbB-3 antagonists & inhibitors
- Abstract
Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines. Subsequent derivatization with a hydrophobic adamantane moiety demonstrates that the resultant bivalent ligand (TX2-121-1) enhances inhibition of Her3-dependent signaling. Treatment of cells with TX2-121-1 results in partial degradation of Her3 and serendipitously interferes with productive heterodimerization between Her3 with either Her2 or c-Met. These results suggest that small molecules will be capable of perturbing the biological function of Her3 and ∼60 other pseudokinases found in human cells.
- Published
- 2014
- Full Text
- View/download PDF
49. Hepatitis B virus e antigen (HBeAg) may have a negative effect on dendritic cell generation.
- Author
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Hatipoglu I, Ercan D, Acilan C, Basalp A, Durali D, and Baykal AT
- Subjects
- Animals, Antigens, Ly metabolism, CD11c Antigen metabolism, Cell Count, Cell Differentiation, Cell Survival drug effects, Dendritic Cells cytology, Hepatitis B e Antigens toxicity, Hepatitis B virus immunology, Humans, Mice, Myeloid Cells cytology, Myeloid Cells immunology, Myeloid Cells metabolism, Proteome, Proteomics, Dendritic Cells immunology, Dendritic Cells metabolism, Hepatitis B e Antigens immunology
- Abstract
Hepatitis B virus (HBV) continues to be a serious worldwide health problem despite the use of protective HBV vaccines and therapeutic regimens against chronic HBV infection. Chronic HBV patients cannot induce sufficient immune responses against the virus. HBV and its antigens are believed to suppress immune responses during chronic infection. Hence, studying the role of HBV in immune suppression is very important for the development of alternative therapeutic strategies for HBV infections. In the present study, we investigated the effect of Hepatitis B virus e antigen (HBeAg) on the generation of bone marrow derived dendritic cells (BMDCs) and the stimulation of plasmacytoid DCs (pDCs). In the presence of HBeAg, the ratio of BMDCs was decreased, but the ratio of CD11b(+)Ly6G(+) immature myeloid cells was increased. The expression of 47 proteins was also changed during HBeAg treatment; however, CpG-induced MHC-II expression on pDCs was not affected. Our results indicate that HBeAg may have a negative effect on the generation of DCs from bone morrow precursors., (Copyright © 2014 Elsevier GmbH. All rights reserved.)
- Published
- 2014
- Full Text
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50. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.
- Author
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Tan L, Wang J, Tanizaki J, Huang Z, Aref AR, Rusan M, Zhu SJ, Zhang Y, Ercan D, Liao RG, Capelletti M, Zhou W, Hur W, Kim N, Sim T, Gaudet S, Barbie DA, Yeh JR, Yun CH, Hammerman PS, Mohammadi M, Jänne PA, and Gray NS
- Subjects
- Amino Acid Substitution, Binding Sites, Cell Line, Tumor, Crystallography, X-Ray, Drug Resistance, Neoplasm genetics, ErbB Receptors antagonists & inhibitors, ErbB Receptors chemistry, ErbB Receptors genetics, ErbB Receptors metabolism, Humans, Mutation, Missense, Neoplasms enzymology, Neoplasms genetics, Neoplasms pathology, Structure-Activity Relationship, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm drug effects, Neoplasms drug therapy, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Receptor, Fibroblast Growth Factor, Type 1 antagonists & inhibitors, Receptor, Fibroblast Growth Factor, Type 1 chemistry, Receptor, Fibroblast Growth Factor, Type 1 genetics, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Receptor, Fibroblast Growth Factor, Type 2 antagonists & inhibitors, Receptor, Fibroblast Growth Factor, Type 2 chemistry, Receptor, Fibroblast Growth Factor, Type 2 genetics, Receptor, Fibroblast Growth Factor, Type 2 metabolism, Receptor, Fibroblast Growth Factor, Type 4 antagonists & inhibitors, Receptor, Fibroblast Growth Factor, Type 4 chemistry, Receptor, Fibroblast Growth Factor, Type 4 genetics, Receptor, Fibroblast Growth Factor, Type 4 metabolism
- Abstract
The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.
- Published
- 2014
- Full Text
- View/download PDF
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