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        PLK2 Single Nucleotide Variant in Gastric Cancer Patients Affects miR-23b-5p Binding

        Dominkus, Pia Puzar,Mesic, Aner,Hudler, Petra The Korean Gastric Cancer Association 2022 Journal of gastric cancer Vol.22 No.-

        Purpose: Chromosomal instability is a hallmark of gastric cancer (GC). It can be driven by single nucleotide variants (SNVs) in cell cycle genes. We investigated the associations between SNVs in candidate genes, PLK2, PLK3, and ATM, and GC risk and clinicopathological features. Materials and Methods: The genotyping study included 542 patients with GC and healthy controls. Generalized linear models were used for the risk and clinicopathological association analyses. Survival analysis was performed using the Kaplan-Meier method. The binding of candidate miRs was analyzed using a luciferase reporter assay. Results: The PLK2 C<sub>rs15009</sub>-C<sub>rs963615</sub> haplotype was under-represented in the GC group compared to that in the control group (P<sub>corr</sub>=0.050). Male patients with the PLK2 rs963615 CT genotype had a lower risk of GC, whereas female patients had a higher risk (P=0.023; P=0.026). The PLK2 rs963615 CT genotype was associated with the absence of vascular invasion (P=0.012). The PLK3 rs12404160 AA genotype was associated with a higher risk of GC in the male population (P=0.015). The ATM T<sub>rs228589</sub>-A<sub>rs189037</sub>-G<sub>rs4585</sub> haplotype was associated with a higher risk of GC (P<0.001). The ATM rs228589, rs189037, and rs4585 genotypes TA+AA, AG+GG, and TG+GG were associated with the absence of perineural invasion (P=0.034). In vitro analysis showed that the cancer-associated miR-23b-5p mimic specifically bound to the PLK2 rs15009 G allele (P=0.0097). Moreover, low miR-23b expression predicted longer 10-year survival (P=0.0066) in patients with GC. Conclusions: PLK2, PLK3, and ATM SNVs could potentially be helpful for the prediction of GC risk and clinicopathological features. PLK2 rs15009 affects the binding of miR-23b-5p. MiR-23b-5p expression status could serve as a prognostic marker for survival in patients with GC.

      • KCI등재

        PLK2 Single Nucleotide Variant in Gastric Cancer Patients Affects miR-23b-5p Binding

        Dominkuš Pia Pužar,Mesic Aner,Hudler Petra 대한위암학회 2022 Journal of gastric cancer Vol.22 No.4

        Purpose Chromosomal instability is a hallmark of gastric cancer (GC). It can be driven by single nucleotide variants (SNVs) in cell cycle genes. We investigated the associations between SNVs in candidate genes, PLK2, PLK3, and ATM, and GC risk and clinicopathological features. Materials and Methods The genotyping study included 542 patients with GC and healthy controls. Generalized linear models were used for the risk and clinicopathological association analyses. Survival analysis was performed using the Kaplan-Meier method. The binding of candidate miRs was analyzed using a luciferase reporter assay. Results The PLK2 Crs15009-Crs963615 haplotype was under-represented in the GC group compared to that in the control group (Pcorr=0.050). Male patients with the PLK2 rs963615 CT genotype had a lower risk of GC, whereas female patients had a higher risk (P=0.023; P=0.026). The PLK2 rs963615 CT genotype was associated with the absence of vascular invasion (P=0.012). The PLK3 rs12404160 AA genotype was associated with a higher risk of GC in the male population (P=0.015). The ATM Trs228589-Ars189037-Grs4585 haplotype was associated with a higher risk of GC (P<0.001). The ATM rs228589, rs189037, and rs4585 genotypes TA+AA, AG+GG, and TG+GG were associated with the absence of perineural invasion (P=0.034). In vitro analysis showed that the cancer-associated miR-23b-5p mimic specifically bound to the PLK2 rs15009 G allele (P=0.0097). Moreover, low miR-23b expression predicted longer 10-year survival (P=0.0066) in patients with GC. Conclusions PLK2, PLK3, and ATM SNVs could potentially be helpful for the prediction of GC risk and clinicopathological features. PLK2 rs15009 affects the binding of miR-23b-5p. MiR-23b-5p expression status could serve as a prognostic marker for survival in patients with GC. Purpose Chromosomal instability is a hallmark of gastric cancer (GC). It can be driven by single nucleotide variants (SNVs) in cell cycle genes. We investigated the associations between SNVs in candidate genes, PLK2, PLK3, and ATM, and GC risk and clinicopathological features. Materials and Methods The genotyping study included 542 patients with GC and healthy controls. Generalized linear models were used for the risk and clinicopathological association analyses. Survival analysis was performed using the Kaplan-Meier method. The binding of candidate miRs was analyzed using a luciferase reporter assay. Results The PLK2 Crs15009-Crs963615 haplotype was under-represented in the GC group compared to that in the control group (Pcorr=0.050). Male patients with the PLK2 rs963615 CT genotype had a lower risk of GC, whereas female patients had a higher risk (P=0.023; P=0.026). The PLK2 rs963615 CT genotype was associated with the absence of vascular invasion (P=0.012). The PLK3 rs12404160 AA genotype was associated with a higher risk of GC in the male population (P=0.015). The ATM Trs228589-Ars189037-Grs4585 haplotype was associated with a higher risk of GC (P<0.001). The ATM rs228589, rs189037, and rs4585 genotypes TA+AA, AG+GG, and TG+GG were associated with the absence of perineural invasion (P=0.034). In vitro analysis showed that the cancer-associated miR-23b-5p mimic specifically bound to the PLK2 rs15009 G allele (P=0.0097). Moreover, low miR-23b expression predicted longer 10-year survival (P=0.0066) in patients with GC. Conclusions PLK2, PLK3, and ATM SNVs could potentially be helpful for the prediction of GC risk and clinicopathological features. PLK2 rs15009 affects the binding of miR-23b-5p. MiR-23b-5p expression status could serve as a prognostic marker for survival in patients with GC.

      • Coupled testing-modeling approach to ultimate state computation of steel structure with connections for statics and dynamics

        Imamovic, Ismar,Ibrahimbegovic, Adnan,Mesic, Esad Techno-Press 2018 Coupled systems mechanics Vol.7 No.5

        The moment-resistant steel frames are frequently used as a load-bearing structure of buildings. Global response of a moment-resistant frame structure strongly depends on connections behavior, which can significantly influence the response and load-bearing capacity of a steel frame structure. The analysis of a steel frame with included joints behavior is the main focus of this work. In particular, we analyze the behavior of two connection types through experimental tests, and we propose numerical beam model capable of representing connection behavior. The six experimental tests, under monotonic and cyclic loading, are performed for two different types of structural connections: end plate connection with an extended plate and end plate connection. The proposed damage-plasticity model of Reissner beam is able to capture both hardening and softening response under monotonic and cyclic loading. This model has 18 constitutive parameters, whose identification requires an elaborate procedure, which we illustrate in this work. We also present appropriate loading program and arrangement of measuring equipment, which is crucial for successful identification of constitutive parameters. Finally, throughout several practical examples, we illustrate that the steel structure connections are very important for correct prediction of the global steel frame structure response.

      • Plasticity-damage model parameters identification for structural connections

        Imamovic, Ismar,Ibrahimbegovic, Adnan,Knopf-Lenoir, Catherine,Mesic, Esad Techno-Press 2015 Coupled systems mechanics Vol.4 No.4

        In this paper we present methodology for parameters identification of constitutive model which is able to present behavior of a connection between two members in a structure. Such a constitutive model for frame connections can be cast in the most general form of the Timoshenko beam, which can present three failure modes. The first failure mode pertains to the bending in connection, which is defined as coupled plasticity-damage model with nonlinear softening. The second failure mode is seeking to capture the shearing of connection, which is defined as plasticity with linear hardening and nonlinear softening. The third failure mode pertains to the diffuse failure in the members; excluding it leads to linear elastic constitutive law. Theoretical formulation of this Timoshenko beam model and its finite element implementation are presented in the second section. The parameter identification procedure that will allow us to define eighteen unknown parameters is given in Section 3. The proposed methodology splits identification in three phases, with all details presented in Section 4 through three different examples. We also present the real experimental results. The conclusions are stated in the last section of the paper.

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