59 research outputs found
Abstract PR05: Lineage specifiers SOX2 and NKX2-1 inversely regulate lung tumor immune microenvironment
No full textAbstract
The tumor microenvironment is a critical effector of therapeutic response to diverse stimuli including immunotherapies. Lineage-specific drivers of cancer are known to dictate tumor differentiation and response to therapy, but how they influence the tumor immune microenvironment is largely unknown. SOX2 and NKX2-1 are critical regulators of lung development and cancer, with SOX2 amplifications associated with squamous lung cancer and NKX2-1 amplifications associated with lung adenocarcinoma. Here we employ and develop new genetically engineered mouse models (GEMMs) of lung cancer to interrogate the impact of SOX2 and NKX2-1 on innate immune infiltration. Squamous and adenocarcinoma GEMMs accurately recapitulate features of their human counterparts, including an enrichment of tumor-associated neutrophils (TANs) specifically in squamous lung cancer. We show that SOX2 recruits TANs, whereas NKX2-1 suppresses TANs, in the absence of histopathologic changes. SOX2 and NKX2-1 inversely regulate the neutrophil chemoattractant, Cxcl5, which is also upregulated in human squamous lung tumors. Using a novel GEMM of squamous lung cancer with a rapid latency of 3-4 months, preliminary data suggest that neutrophils can regulate adeno- to squamous transdifferentiation in vivo. Together these data reveal how lineage specifiers influence the tumor immune microenvironment, which in turn may regulate cancer cell fate.
This abstract is also being presented as Poster B19.
Citation Format: Gurkan Mollaoglu, Alex Jones, Anandaroop Mukhopadhyay, Jason Gertz, Kevin Jones, Eric Snyder, Trudy G. Oliver. Lineage specifiers SOX2 and NKX2-1 inversely regulate lung tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR05.</jats:p
Doctor of Philosophy
No full textdissertationThe clinical management of small cell lung cancer (SCLC) has primarily relied on chemotherapy for the last 40 years where all tumors are treated the same way regardless of their mutational status. MYC family member genes are frequently amplified in small cell lung tumors and cell lines in a mutually exclusive way. We developed a novel genetically engineered mouse model, in which we combined Myc ectopic expression with deletions of Trp53 and Rb1, two tumor-suppressor genes orthologs of which (i.e., TP53 and RB1) are almost universally lost together in human SCLC. For the first time, we demonstrated that MYC drives a neuroendocrine-low variant subtype of SCLC. In addition to the aggressive nature of these tumors such as rapid tumor growth and metastasis, we found that MYC-driven SCLC is specifically sensitive to Aurora kinase inhibition. Therefore, our findings not only revealed that MYC family oncogenes are responsible for tumor heterogeneity but also that SCLC should be stratified based on their genetics for subtype-specific targeted therapies. The majority of non-small cell lung cancers (NSCLC) are classified as lung adenocarcinoma (LADC) or lung squamous cell carcinoma (LSCC). SOX2 and NKX2-1 are the most frequently amplified genes in LSCC and LADC, respectively. SOX2 is a wellknown oncogene for LSCC while NKX2-1 has context-dependent oncogenic and tumorsuppressive functions in LADC. We report that SOX2-driven squamous mouse tumors recapitulate cellular and molecular features of human lung squamous tumors faithfully, iv including the tumor immune microenvironment (TIME). We found that NKX2-1 is a tumorsuppressor gene for LSCC, and deletion of Nkx2-1 significantly accelerates squamous tumorigenesis. Importantly, we discovered the genetic mechanism behind differential neutrophil recruitment in lung cancer. Specifically, SOX2 and NKX2-1 inversely regulate neutrophil chemotaxis to lung cancer, partly through transcriptional regulation of the chemokine Cxcl5. We identified that a subset of tumor-associated neutrophils in LSCC is protumorigenic and surprisingly provides preferential support to squamous tumors over adenocarcinomas. These findings provide a novel example of the emerging paradigm of how cancer cell intrinsic genetic programs can shape the TIME in addition to the unexpected biology of how the modified TIME, in turn, can influence cancer cell fate
Deletion of macro domain containing 2(MACRO D2) associated with transient hydrops fetalis
No full textCilingir, I. Uzun (Trakya Author)
Sayin, Niyazi Cenk (Trakya Author)
Gurkan, H.(Trakya Author)
Ciftdemir, N. A. (Trakya Author)
Atli, E. (Trakya Author)
Inan, C. (Trakya Author)
Erzincan, S. (Trakya Author)
Sutcu, H. (Trakya Author)
Vatansever, U. (Trakya Author)
Varol, Fusun (Trakya Author)Macro Domain Containing 2 (MACRO D2) gene is a gene from macro family which is highly expressed in the ventriculer zone of the brain during embryonic development. Association between Autism spectrum disorders and MACRO D2 gene polymorphisms has been reported before [1] . Deletion in MACRO D2 gene has also been associated with Kabuki Syndrome which is a well described congential anomaly syndrome [2]
Spatial genomics uncovers cytokines promoting ovarian tumour heterogeneity and immunotherapy resistance
No full textStrength-based design of a sunflower stalk cutter machine design using finite element analysis and experimental validation
No full textIn this study, the total algorithm of the strength-based design of the system for mass production has been developed. The proposed algorithm, which includes numerical, analytical, and experimental studies, was implemented through a case study on the strength-based structural design and fatigue analysis of a tractor-mounted sunflower stalk cutting machine (SSCM). The proposed algorithm consists of a systematic engineering approach, material selection and testing, design of the mass criteria suitability, structural stress analysis, computer-aided engineering (CAE), prototype production, experimental validation studies, fatigue calculation based on an FE model and experimental studies (CAE-based fatigue analysis), and an optimization process aimed at minimum weight. Approximately 85% of the system was designed using standard commercially available cross-section beams and elements using the proposed algorithm. The prototype was produced, and an HBM data acquisition system was used to collect the strain gage output. The prototype produced was successful in terms of functionality. Two- and three-dimensional mixed models were used in the structural analysis solution. The structural stress analysis and experimental results with a strain gage were 94.48% compatible in this study. It was determined using nCode DesignLife software that fatigue damage did not occur in the system using the finite element analysis (FEA) and experimental data. The SSCM design adopted a multi-objective genetic algorithm (MOGA) methodology for optimization with ANSYS. With the optimization solved from 422 iterations, a maximum stress value of 57.65 MPa was determined, and a 97.72 kg material was saved compared to the prototype. This study provides a useful methodology for experimental and advanced CAE techniques, especially for further study on complex stress, strain, and fatigue analysis of new systematic designs desired to have an optimum weight to strength ratio.Trakya University Scientific Research Projects Coordination Unit (TURKEY) [2019/158, 2019/47, 2180668, 1512]; Becan Makine Co.; Irtem Agricultural Machinery Industry. Ltd. Co. (Hayrabolu/Tekirdag TURKEY); Bias Engineering Co. Ltd.; SENSOR TEK Engineering and Measurement Systems Co. Ltd. (Hottinger Bruel & Kjaer representative of Turkey)The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Trakya University Scientific Research Projects Coordination Unit (TURKEY) by TUBAP 2019/158 and 2019/47; TUBITAK 1512 program and 2180668 project number; Becan Makine Co. Irtem Agricultural Machinery Industry. Ltd. Co. (Hayrabolu/Tekirdag TURKEY), Bias Engineering Co. Ltd. and SENSOR TEK Engineering and Measurement Systems Co. Ltd. (Hottinger Bruel & Kjaer representative of Turkey). The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gurkan IRSEL has patent #Turk Patent Institute: 2020/14499
Compression of ECG signals using variable-length classifıed vector sets and wavelet transforms
Get PDFIn this article, an improved and more efficient algorithm for the compression of the electrocardiogram (ECG) signals is presented, which combines the processes of modeling ECG signal by variable-length classified signature and envelope vector sets (VL-CSEVS), and residual error coding via wavelet transform. In particular, we form the VL-CSEVS derived from the ECG signals, which exploits the relationship between energy variation and clinical information. The VL-CSEVS are unique patterns generated from many of thousands of ECG segments of two different lengths obtained by the energy based segmentation method, then they are presented to both the transmitter and the receiver used in our proposed compression system. The proposed algorithm is tested on the MIT-BIH Arrhythmia Database and MIT-BIH Compression Test Database and its performance is evaluated by using some evaluation metrics such as the percentage root-mean-square difference (PRD), modified PRD (MPRD), maximum error, and clinical evaluation. Our experimental results imply that our proposed algorithm achieves high compression ratios with low level reconstruction error while preserving the diagnostic information in the reconstructed ECG signal, which has been supported by the clinical tests that we have carried out.ISIK University [06B302]The author would like to special thank Prof. Siddik Yarman who is Board of Trustees Chairman of the ISIK University and Umit Guz, Assistant Professor at the ISIK University for their valuable contributions and continuous interest in this article. The author also would like to thank Prof. Osman Akdemir who is a cardiologist in the Department of Cardiology at the T. C. Maltepe University and Dr. Ruken Bengi Bakal who is a cardiologist in the Department of Cardiology at the Kartal Kosuyolu Yuksek Ihtisas Education and Research Hospital for their valuable clinical contributions and suggestions and the reviewers for their constructive comments which improved the technical quality and presentation of the article. The present work was supported by the Scientific Research Fund of ISIK University, Project number 06B302.Publisher's Versio
Experimental, analytical, and numerical investigations on the flexural and fatigue behavior of steel thin-walled X-section beam
No full textThin-walled hollow shapes are of great interest in many industries with weight constraints, due to their availability, low price, and strength-to-weight ratio. This paper presents the development, calculation, and production of a thin-walled X-section beam design with a unique section geometry. This hollow X-section beam geometry is a beam that has been developed to use shape-connected jaws on the beam and to use less bolts and mounting elements, and to easily change the positions of the parts mounted on the beam. The bending strength of this unique beam section was investigated, and the fatigue damage of the beam was also handled with technological methods. Using both experimental stress measurements and finite element solution, the static and fatigue strength of the beam were calculated with computer-aided engineering software. The FEM solution was performed nonlinearly by defining the linear elastic and plasticity properties of the material. Validation studies were carried out in the laboratory using three-point and four-point bending tests. These traditional experiments were supported by strain gauge technology that measures strain with 0.05% accuracy. The weight and bending strength of the X-section beam were compared with the hollow section square beam. X-section beam (S355J0H) has 13% lower bending strength than 120 x 120 x 8 mm (S355J0H) beam; however, it is 37% lighter. ANSYS-analytical test results of difference are 3.95%, and ANSYS-experimental test results of difference are 0.85%. Experiments showed that a similar to 22% increase in strength is found in these corners depending on the production method. The fatigue behavior of the X-section beam was determined with the nCode DesignLife software using validated FEM solutions and fatigue curves of the materials. X-section beam developed for shape-connected assembly systems can be used especially in the formation of chassis with its superior assembly ability and bending strength, increasing functionality, and production speed.Trakya University Scientific Research Projects Coordination Unit (TURKEY) [TUBAP 2019/158, 2019/47, 2019/286]; Becan Makine Co. Ltd.; Irtem Agricultural Machinery Industry. Co. Ltd. (Hayrabolu/Tekirdag Turkey); Bias Engineering Co. Ltd.; Matil Material Testing and Innovation Laboratories Co.; Numesys Co.; Inan Makina Industry and Trade Inc.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Trakya University Scientific Research Projects Coordination Unit (TURKEY) by T U BAP 2019/158, 2019/47, 2019/286, Becan Makine Co. Ltd.,.Irtem Agricultural Machinery Industry. Co. Ltd. (Hayrabolu/Tekirdag Turkey), Bias Engineering Co. Ltd. and Matil Material Testing and Innovation Laboratories Co., Numesys Co.,.Inan Makina Industry and Trade Inc
Design of a precision planter chassis using computer-aided engineering and experimental validation
No full textThe application of X-section beams in the modular and strength-based design of a precision planter chassis was investigated numerically and experimentally in a case study. This study deals with the feasibility of a special section design with a systematic engineering approach. Mechanical tests were performed for the beam evaluated in a mounting system. The X-section beam model and the mounting elements on this beam were created using computer-aided engineering software, and the compatibility of the design with the mass criterion was investigated. This model was edited as a 2D and 3D mixed model and analyzed with the finite element method to analyzing studies of the system. Stress measurement was conducted using strain gauges at specified points in the system whose prototype was produced. These strain data were processed with nCode DesignLife software, and nonlinear FEA analyses were validated using these stress measurements. The fatigue damage of the X-section beam under dynamic loading conditions was investigated using the FE model solution and experimental measurement data (CAE-based fatigue analysis) with nCode software. The X-section beam design adopted a multiple-objective genetic algorithm technique for optimization by means of ANSYS. The maximum stress value was 121.83 MPa, and a 7.77 kg material was saved correlated to the prototype with the help of optimization solved 400 iterations. It has been determined that the X-section beam is safe by 1.06 x 10(6) cycles under these loading conditions and can carry a load of 1600 kg. The X-section beam can be successfully applied in similar systems owing to its assemblability and functionality.Trakya University Scientific Research Projects Coordination Unit (TURKEY) [TUBAP 2019/158, 2019/47]; Irtem Agricultural Machinery Industry. Co. Ltd. (Hayrabolu/Tekirdag Turkey); Bias Engineering Co. Ltd.; Inan Makina Industry; Trade Inc.The author disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Trakya University Scientific Research Projects Coordination Unit (TURKEY) by TUBAP 2019/158 and 2019/47, Irtem Agricultural Machinery Industry. Co. Ltd. (Hayrabolu/Tekirdag Turkey), Bias Engineering Co. Ltd., Inan Makina Industry and Trade Inc
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