Objectives: This study evaluates the combined effects of protocatechuic acid (PCA) and 5fluorouracil (5-FU) on gastric adenocarcinoma (AGS) cells. Materials and Methods: MTT assay test, colony formation assay, flow cytometry technique, Real-Time qPCR, and western blotting were used to investigate cytotoxic effects, colony formation, apoptosis, p53 gene expression, and Bcl-2 level in AGS cells co-treated with 5-FU and PCA, respectively. Results: Our results demonstrated that PCA alone, or in combination with 5-FU (10 µM, 5-FU and 500 µM, PGA) inhibited AGS cell proliferation, forms a colony, and increased apoptosis compared with untreated control cells. Also, the combined 5-FU/PCA led to up-regulation of p53 and down-regulation of Bcl-2 protein as compared to untreated control cells. Conclusion: The results demonstrate that the combined 5-FU/PCA may promote anti-proliferative and pro-apoptotic effects with the inhibition of colony formation in AGS cells. The mechanisms by which the combined 5-FU/PCA exerts its effects are associated with the up-regulation of p53 gene expression and down-regulation of Bcl-2 level. Therefore, the combination of 5-FU with PCA not only could be a promising approach to potentially reduce the dose requirements of 5-FU but also it can promote apoptosis via p53 and Bcl-2 signaling pathways.

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The ErbB family of tyrosine kinase receptors is composed of four homologous members, including EGFR (ErbB1/HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). Since the ErbB proteins play vital roles in various developmental processes, their mutation or overexpression leads to severe abnormalities such as cancer. The general mechanism of ErbB receptors activity is binding to growth factors via their extracellular domain followed by tyrosine phosphorylation intracellularly. Yet the EGFR and ErbB4 are the only two members that keep their ligand-binding domain and the tyrosine kinase activated. In contrast, ErbB2 and ErbB3 are incapable of keeping their ligand-binding and kinase domains activated, respectively. Active ErbB receptors form homo and heterodimers by binding of two similar or different family members together, respectively. Ligands and intracellular pathways that could be activated through heterodimerization are more diverse compared to homodimers. Moreover, it is known that Nglycosylation is critical for stabilizing and activating the ErbB receptors. In this study, atomistic molecular dynamics simulations were used on one of the most potentiated ErbB heterodimers (EGFR-ErbB4) in the glycosylated and unglycosylated states. It was shown that the EGFR-ErbB4 heterodimer is highly stabilized by glycosylation. The increased stability is most signi cant at the dimeric interfaces. Regulated by packing of three glycans attached to EGFR (Asn337) and ErbB4 (Asn333, Asn523) at the dimeric interface. Finally, it is proposed that heterodimerization is the persistent key player of the ErbB receptors activation. Thus, targeting the heterodimers in future therapeutic designs could be a promising approach against drug resistance ErbB positive cancers.

This paper studies capacitated facility location problem by considering green management perspectives. The proposed study considers reverse logistic problem as an alternative strategy for facility location in an attempt to take care of environmental characteristics. The resulted problem is formulated as mixed integer programming and it is classified as an NP-Hard problem. Therefore, a Lagrangian relaxation methodology is presented to reduce the complexity of the proposed problem and the solution has been implemented for some instances to examine the performance of the proposed study.

This study proposes six novel strategies on the customer's priority while addressing the conventional hub location issue. Each strategy assigns a value to every customer based on distance and demand parameters, in which customers are prioritized based on this value. Then, the vehicle fleet is scheduled according to the customer's priority. A new mixed-integer linear programming model is presented and applied for each strategy in a new hub location-scheduling problem solved by three approaches. Then, by using the CAB dataset, extensive experiments are designed to evaluate each strategy. The strategies are evaluated with statistical and nonstatistical analyses and ranked accordingly. In each case, a comparison of the non-priority strategy with the best customer's prioritization strategy shows that the non-priority strategy has an adverse effect on the delivery time (i.e., 129.7%, 171.68%, and 161.33% than the best strategy in the case of near, medium, and far nodes, respectively). In addition to the above tests, other tests are conducted to evaluate the optimum number of vehicles for different conditions. The results show that as the distance between customers and hubs increases, reducing the number of vehicles while increasing their capacity is preferable. Also, each strategy requires using a certain number of vehicles.