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Taha Toros Arşivi, Dosya No: 52-Cahit Sıtkı Tarancıİstanbul Kalkınma Ajansı (TR10/14/YEN/0033) İstanbul Development Agency (TR10/14/YEN/0033

Genomic and Transcriptomic Investigation of Endemic Burkitt Lymphoma and Epstein Barr Virus

Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein-Barr virus (EBV), unlike sporadic Burkitt Lymphoma (sBL) that occurs with a lower incidence in developed countries. Despite this increased burden the study of eBL has lagged. Additionally, while EBV was isolated from an African Burkitt lymphoma tumor 50 years ago, however, the impact of viral variation in oncogenesis is just beginning to be fully explored. In my thesis research, I focused on investigating molecular genetics of the endemic form of this lymphoma with a particular emphasis on the role of the virus and its variation in pathogenesis using novel sequencing and bioinformatic strategies. First, we sought to understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from 30 primary eBL tumors and compared to sBL tumors. BL tumor samples were prospectively obtained from 2009 until 2012 in Kenya. Within eBL tumors, minimal expression differences were found based on anatomical presentation site, in-hospital survival rates, and EBV genome type; suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding difference detected using surrogate variable analysis was the significantly decreased expression of key genes in the immunoproteasome complex in eBL tumors carrying type 2 EBV compared to type 1 EBV. Secondly, in comparison to previously published pediatric sBL specimens, the majority of the expression and pathway differences were related to the PTEN/PI3K/mTOR signaling pathway and was correlated most strongly with EBV status rather than the geographic designation. Moreover, the common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies similar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, we identified a set of new genes mutated in BL. Overall, these suggested that EBV, particularly EBV type 1, supports BL oncogenesis alleviating the need for particular driver mutations in the human genome. Second, we sought to comprehensively define sequence variations of EBV across the viral genome in eBL tumor cells and normal infections, and correlate variations with clinical phenotypes and disease risk. We investigated the whole genome sequence of EBV from primary tumors (N=41) and plasma from eBL patients (N=21) as well as EBV in the blood of healthy children (N=29) within the same malaria endemic region. We conducted a genome wide association analysis study with viral genomes of healthy kids and BL kids. Furthermore, we found that the frequencies of EBV types among healthy kids were at equal levels while they were skewed in favor of type 1 (70%) among eBL kids. To pinpoint the fundamental divergence between viral genome subtypes, type 1 and type 2, we constructed phylogenetic trees comparing to all public EBV genomes. The pattern of variation defined the substructures correlated with the subtypes. This investigation not only deciphers the puzzling pathogenic differences between subtypes but also helps to understand how these two EBV types persist in the population at the same time. Overall, this research provides insight into the molecular underpinning of eBL and the role of EBV. It further provides the groundwork and means to unravel the complexity of EBV population structure and provide insight into the viral variation that may influence oncogenesis and outcomes in eBL and other EBV-associated diseases. In addition, genomic and mutational analyses of Burkitt lymphoma tumors identify key differences based on viral content and clinical outcomes suggesting new avenues for the development of prognostic molecular biomarkers and therapeutic interventions

A mixed-integer programming model for cycle time minimization in assembly line balancing: Using rework stations for performing parallel tasks

[EN] In assembly lines, rework stations are generally used for reprocessing defective items. On the other hand, using rework stations for this purpose only might cause inefficient usage of the resources in this station especially in an assembly line with a low defective rate. In this study, a mixed-integer programming model for cycle time minimization is proposed by considering the use of rework stations for performing parallel tasks. By linearizing the non-linear constraint about parallel tasks using a variate transformation, the model is transformed to a linear-mixed-integer form. In addition to different defective rates, different rework station positions are also considered using the proposed model. The performance of the model is analyzed on several test problems from the related literature.Cavdur, F.; Kaymaz, E. (2020). A mixed-integer programming model for cycle time minimization in assembly line balancing: Using rework stations for performing parallel tasks. International Journal of Production Management and Engineering. 8(2):111-121. https://doi.org/10.4995/ijpme.2020.12368OJS11112182Altekin, F. T., Bayindir, Z. P., & Gümüskaya, V. (2016). Remedial actions for disassembly lines with stochastic task times. Computers & Industrial Engineering, 99, 78-96. https://doi.org/10.1016/j.cie.2016.06.027Anderson, E. J., & Ferris, M. C. (1994). Genetic algorithms for combinatorial optimization: the assemble line balancing problem. ORSA Journal on Computing, 6(2), 161-173. https://doi.org/10.1287/ijoc.6.2.161Askin, R. G., & Zhou, M. (1997). A parallel station heuristic for the mixed-model production line balancing problem. International Journal of Production Research, 35(11), 3095-3106. https://doi.org/ 10.1080/002075497194309Bard, J. F. (1989). Assembly line balancing with parallel workstations and dead time. The International Journal of Production Research, 27(6), 1005-1018. https://doi.org/10.1080/00207548908942604Bartholdi, J. J. (1993). Balancing two-sided assembly lines: a case study. International Journal of Production Research, 31(10), 2447-2461. https://doi.org/10.1080/00207549308956868Battaia, O., & Dolgui, A. (2013). A taxonomy of line balancing problems and their solution approaches. International Journal of Production Economics, 142(2), 259-277. https://doi.org/10.1016/j.ijpe.2012.10.020Baybars, I. (1986). A survey of exact algorithms for the simple assembly line balancing problem. Management science, 32(8), 909-932. https://doi.org/10.1287/mnsc.32.8.909Baykasoglu, A., & Demirkol Akyol, S. (2014). Ergonomic assembly line balancing. Journal of the Faculty of Engineering and Architecture of Gazi University, 29(4), 785-792. https://doi.org/10.17341/gummfd.00296Becker, C., & Scholl, A. (2006). A survey on problems and methods in generalized assembly line balancing. European journal of operational research, 168(3), 694-715. https://doi.org/10.1016/j.ejor.2004.07.023Boysen, N., Fliedner, M., & Scholl, A. (2007). A classification of assembly line balancing problems. European journal of operational research, 183(2), 674-693. https://doi.org/10.1016/j.ejor.2006.10.010Bryton, B. (1954). Balancing of a continuous production line. Master's Thesis, Northwestern University, Evanston.Cercioglu, H., Ozcan, U., Gokcen, H., & Toklu, B. (2009). A simulated annealing approach for parallel assembly line balancing problem. Journal of the Faculty of Engineering and Architecture of Gazi University, 24(2), 331-341.Efe, B., Kremer, G. E. O., & Kurt, M. (2018). Age and gender-based workload constraint for assembly line worker assignment and balancing problem in a textile firm. International Journal of Industrial Engineering, 25(1), 1-17.Ghosh, S., & Gagnon, R. J. (1989). A comprehensive literature review and analysis of the design, balancing and scheduling of assembly systems. The International Journal of Production Research, 27(4), 637-670. https://doi.org/10.1080/00207548908942574Gokcen, H., & Baykoc, Ö. F. (1999). A new line remedial policy for the paced lines with stochastic task times. International Journal of Production Economics, 58(2), 191-197. https://doi.org/10.1016/S0925-5273(98)00123-6Gokcen, H., Agpak, K., & Benzer, R. (2006). Balancing of parallel assembly lines. International Journal of Production Economics, 103(2), 600-609. https://doi.org/10.1016/j.ijpe.2005.12.001Guner, B., & Hasgul, S. (2012). U-Type assembly line balancing with ergonomic factors for balance stability. Journal of the Faculty of Engineering and Architecture of Gazi University, 27(2), 407-415.Kaplan, O. (2004). Assembly line balancing with task paralleling. Master's Thesis, METU, Ankara.Kara, Y., Ozguven, C., Yalcın, N., & Atasagun, Y. (2011). Balancing straight and U-shaped assembly lines with resource dependent task times. International Journal of Production Research, 49(21), 6387-6405. https://doi.org/10.1080/00207543.2010.535039Kara, Y., Atasagun, Y., Gokcen, H., Hezer, S., & Demirel, N. (2014). An integrated model to incorporate ergonomics and resource restrictions into assembly line balancing. International Journal of Computer Integrated Manufacturing, 27(11), 997-1007. https://doi.org/10.1080/0951192X.2013.874575Kazemi, S. M., Ghodsi, R., Rabbani, M., & Tavakkoli-Moghaddam, R. (2011). A novel two-stage genetic algorithm for a mixed-model U-line balancing problem with duplicated tasks. The International Journal of Advanced Manufacturing Technology, 55(9-12), 1111-1122. https://doi.org/10.1007/s00170-010-3120-6Kim, Y. K., Kim, Y., & Kim, Y. J. (2000). Two-sided assembly line balancing: a genetic algorithm approach. Production Planning & Control, 11(1), 44-53. https://doi.org/10.1080/095372800232478Kottas, J. F., & Lau, H. S. (1976). A total operating cost model for paced lines with stochastic task times. AIIE Transactions, 8(2), 234-240. https://doi.org/10.1080/05695557608975072Lau, H. S., & Shtub, A. (1987). An exploratory study on stopping a paced line when incompletions occur. IIE transactions, 19(4), 463-467. https://doi.org/10.1080/07408178708975421Lee, T. O., Kim, Y., & Kim, Y. K. (2001). Two-sided assembly line balancing to maximize work relatedness and slackness. Computers & Industrial Engineering, 40(3), 273-292. https://doi.org/10.1016/S0360-8352(01)00029-8Mutlu, O., & Ozgormus, E. (2012). A fuzzy assembly line balancing problem with physical workload constraints. International Journal of Production Research, 50(18), 5281-5291. https://doi.org/10.1080/00207543.2012.709647Ozcan, U., & Toklu, B. (2010). Balancing two-sided assembly lines with sequence-dependent setup times. International Journal of Production Research, 48(18), 5363-5383. https://doi.org/10.1080/00207540903140750Pinto, P., Dannenbring, D. G., & Khumawala, B. M. (1975). A branch and bound algorithm for assembly line balancing with paralleling. The International Journal of Production Research, 13(2), 183-196. https://doi.org/10.1080/00207547508942985Sabuncuoglu, I., Erel, E., & Alp, A. (2009). Ant colony optimization for the single model U-type assembly line balancing problem. International Journal of Production Economics, 120(2), 287-300. https://doi.org/10.1016/j.ijpe.2008.11.017Salveson, M. E. (1955). The assembly line balancing problem. The Journal of Industrial Engineering, 18-25.Scholl, A., & Becker, C. (2006). State-of-the-art exact and heuristic solution procedures for simple assembly line balancing. European Journal of Operational Research, 168(3), 666-693. https://doi.org/10.1016/j.ejor.2004.07.022Shtub, A. (1984). The effect of incompletion cost on line balancing with multiple manning of work stations. The International Journal of Production Research, 22(2), 235-245. https://doi.org/10.1080/00207548408942450Silverman, F. N., & Carter, J. C. (1986). A cost-based methodology for stochastic line balancing with intermittent line stoppages. Management Science, 32(4), 455-463. https://doi.org/10.1287/mnsc.32.4.455Simaria, A. S., & Vilarinho, P. M. (2001). The simple assembly line balancing problem with parallel workstations-a simulated annealing approach. Int J Ind Eng-Theory, 8(3), 230-240.Sivasankaran, P., & Shahabudeen, P. (2014). Literature review of assembly line balancing problems. The International Journal of Advanced Manufacturing Technology, 73(9-12), 1665-1694. https://doi.org/10.1007/s00170-014-5944-ySuer, G. A. (1998). Designing parallel assembly lines. Computers & industrial engineering, 35(3-4), 467-470. https://doi.org/10.1016/S0360-8352(98)00135-1Suwannarongsri, S., & Puangdownreong, D. (2008). Optimal assembly line balancing using tabu search with partial random permutation technique. 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An uncommon cause of anterior knee pain in a child: Osteoid Osteoma of the patella and a review of the literature

Introduction: Osteoid osteoma (OO) is a small, benign bone neoplasm that has a well demarcated nidus surrounded by a reactive zone of sclerosis. It is most common in the long bones and only rarely in the patella.Case Presentation: An eight-year-old girl was admitted to the outpatient clinic with the complaint of anterior knee pain. She had been suffering from pain for approximately one year. The patient had a patellar osteoid osteoma. Surgical curettage of the lesion was performed, and the patient was free of pain the day after the surgery.Conclusions: Although Patellar OO is rare, it should be included in the differential diagnosis of persistent knee pain in children and young adults.Keywords: Osteoid Osteoma, patella, knee pain, curettage, delayed diagnosis, bone neoplasm

How does Concept Transform into Product? An Appraisal of Analogy-based Design Practices in Architecture Education

AbstractWhen defining the concept of ‘metaphor’ as ‘an intuitive abstraction of uniqueness in diversities’, Aristoteles also creates a common-sense in comprehending analogy-based design processes. Therefore, as in all design practices, drawing analogies -with/to/between- by generating metaphors is also an important tuition for learners/students in architectural design education. Starting from the question of ‘how a designer's initial concept is transformed into an architectural product’, this study generates a discussion on architectural thinking and designing practices based on analogies, aiming at creating perspectives with regard to architectural design education which primarily intends to improve students’ designing abilities by providing the sustainability of current environmental data through the subsequent designs. In this education, the students are firstly directed to reveal metaphors in their specific studying areas by gathering inspiration from directly formal and physical environmental data or from indirectly informal and contextual data; and secondly expected to transform analogies into spatial decisions with architectural programs. In this sense, this study is methodologically carried out in two sections. The first part analyses the stages of the process that lead students from concept to product in the education of architectural design by emphasizing the relational potential of design by considering analogies/metaphors. In the second section, six student studies/products selected from design education studios are appraised in context of the metaphors they captured in their study areas and the analogies they created –or in other words, the reasons they asked for to design-. Among the consequences of the study are the inferences to be made on how to transform design practices, in which the students interrelates between environmental data, into architectural products