Association of RARRES2 rs17173608 gene polymorphism and serum Chemerin with acute myocardial infarction and its risk factors: A case-control study in an Iranian population.

OBJECTIVE: The adipokine Chemerin and the retinoic acid receptor responder 2 (RARRES2) gene have been associated with an increased incidence of obesity, insulin resistance, endothelial dysfunction, type 2 diabetes mellitus, and coronary artery disease. The impact of RARRES2 rs17173608 gene polymorphism on acute myocardial infarction and Chemerin levels has not yet been entirely elucidated. This study aimed to assess the association of RARRES2 rs17173608 gene polymorphism and serum Chemerin with acute myocardial infarction (AMI) and its risk factors in an Iranian population. METHODS: In this case-control study, 134 AMI patients and 100 healthy controls were recruited from tertiary referral hospitals in Zanjan, Iran. Whole blood samples were collected for DNA extraction and Chemerin level determination. An enzyme-linked immunosorbent assay was used to quantify plasma levels of Chemerin. Tetra-primer amplification refractory mutation system-polymerase chain reaction and agarose gel electrophoresis techniques were used to detect gene polymorphism of Chemerin rs17173608 from DNA samples. RESULTS: Serum Chemerin levels were higher in the control group than in the AMI group. However, after adjusting for age, sex, and other risk factors, there was no significant association between serum Chemerin level and AMI occurrence. In the genotype analysis, 21.6% of patients had the TT genotype, and 78.4% had the TG genotype. The GG genotype was not detected in any patient. The genotype distribution of the healthy control group was 19.0% TT genotype, 80.0% TG genotype, and 1.0% GG genotype. Serum Chemerin levels in participants with TG genotype were statistically different between case and control groups. CONCLUSION: Serum Chemerin levels and RARRES2 rs17173608 gene polymorphism were not correlated with AMI occurrence after adjusting for AMI risk factors in Iranian patients. More research with a larger sample size and diverse ethnicities is needed to corroborate our findings.

Apoptosis induction by siRNA targeting integrin-ß1 and regorafenib/DDAB-mPEG-PCL hybrid nanoparticles in regorafenib-resistant colon cancer cells.

Colorectal cancer (CRC) is regarded as the third most common cancer worldwide. Although Regorafenib as a receptor tyrosine kinase inhibitor (RTKI) disrupts tumor growth and angiogenesis in metastatic CRC (mCRC) patients, drug resistance leads to poor prognosis and survival. Integrin-ß1 overexpression has been proposed to be the major player in this regard. Herein, the Regorafenib-resistant human colon cancer cell line (SW-48) was induced, and the Integrin-ß1 gene expression, as well as apoptosis, was assessed through the combination of small interfering RNA (siRNA) targeting Integrin-ß1 and Regorafenib/Dimethyldioctadecylammonium bromide (DDAB)-methoxy poly (ethylene glycol) (mPEG)-poly-ε-caprolactone (PCL) hybrid nanoparticles (HNPs). In the current study, Regorafenib-resistant SW-48 cell line was generated in which the Regorafenib half-maximal inhibitory concentration (IC50) for non-resistant and resistant cells was 13.5±1.5 µM and 55.1±0.8 µM, respectively. The results of DLS also demonstrated that the size and the charge of the HNPs were equal to 66.56±0.5 nm and +29.5±1.2 mv, respectively. In addition, the Integrin-ß1 gene expression was significantly higher in resistant cells than in non-resistant ones (P<0.05). The siRNA/HNP complexes in combination with Regorafenib/HNPs were accordingly identified as the most effective treatment to decrease the Integrin-ß1 gene expression and to enhance the apoptosis rate in resistant cells (P<0.001). Overall, the study indicated that combination therapy using siRNA/HNP and Regorafenib/HNPs complex could down-regulate the Integrin-ß1 gene expression and consequently trigger apoptosis, and this may potentially induce drug sensitivity.

Multidirectional Strategies for Targeted Delivery of Oncolytic Viruses by Tumor Infiltrating Immune Cells.

Oncolytic virus (OV) immunotherapy has demonstrated to be a promising approach in cancer treatment due to tumor-specific oncolysis. However, their clinical use so far has been largely limited due to the lack of suitable delivery strategies with high efficacy. Direct 'intratumoral' injection is the way to cross the hurdles of systemic toxicity, while providing local effects. Progress in this field has enabled the development of alternative way using 'systemic' oncolytic virotherapy for producing better results. One major potential roadblock to systemic OV delivery is the low virus persistence in the face of hostile immune system. The delivery challenge is even greater when attempting to target the oncolytic viruses into the entire tumor mass, where not all tumor cells are equally exposed to exactly the same microenvironment. The microenvironment of many tumors is known to be massively infiltrated with various types of leucocytes in both primary and metastatic sites. Interestingly, this intratumoral immune cell heterogeneity exhibits a degree of organized distribution inside the tumor bed as evidenced, for example, by the hypoxic tumor microenviroment where predominantly recruits tumor-associated macrophages. Although in vivo OV delivery seems complicated and challenging, recent results are encouraging for decreasing the limitations of systemically administered oncolytic viruses and an improved efficiency of oncolytic viral therapy in targeting cancerous tissues in vitro. Here, we review the latest developments of carrier cell-based oncolytic virus delivery using tumor-infiltrating immune cells with a focus on the main features of each cellular vehicle.

Crosstalk between Epidermal Growth Factor Receptors (EGFR) and integrins in resistance to EGFR tyrosine kinase inhibitors (TKIs) in solid tumors.

Cell adhesion to the extracellular matrix (ECM) is important in a variety of physiological and pathologic processes, including development, tumor invasion, and metastasis. Integrin-mediated attachment to ECM proteins has emerged to cue events primitively important for the transformed phenotype of human cancer cells. Cross-talk between integrins and growth factor receptors takes an increasingly prominent role in defining adhesion, motility, and cell growth. This functional interaction has expanded beyond to link integrins with resistance to Tyrosine kinase inhibitors (TKIs) of Epidermal Growth Factor Receptors (EGFRs). In this regard, integrin-mediated adhesion has two separate functions one as a clear collaborator with growth factor receptor signaling and the second as a basic mechanism contributing in Epithelial to Mesenchymal Transition (EMT) which affects response to chemotherapy. This review provides an overview of these mechanisms and describes treatment options for selectively targeting and disrupting integrin interaction to EGFR for cancer therapy.