CRISPER/CAS System, a Novel Tool of Targeted Therapy of Drug-Resistant Lung Cancer.

Lung cancer (LC) is the most common cause of cancer-related death worldwide. Patients with LC are usually diagnosed at advanced phases. Five-year survival rate in LC patients is approximately 16%. Despite decades of research on LC treatments, clinical outcomes are still very poor, necessitating to develop novel technologies to manage the disease. Considering the role of genetic and epigenetic changes in oncogenes and tumor-suppressor genes in cancer progression, gene therapy provides a hot spot in cancer treatment research. Gene therapy offers less side effects compared to conventional methods such as chemotherapy. Unlike the traditional approaches of gene therapy that have temporary effects, using genetic modification tools can offer persistent cure. Over the past a few years, many studies have effectively used the CRISPR-Cas9 approach to modify gene expression in cells. This system is applied to induce site-specific mutagenesis and epigenetic modifications and regulate gene expression. In this review, we discuss recent applications of the CRISPR-Cas9 technology in treating LC.

Improved risk assessment of coronary artery disease by substituting paraoxonase 1 activity for HDL-C: Novel cardiometabolic biomarkers based on HDL functionality.

BACKGROUND AND AIMS: Developing laboratory assays to evaluate HDL functions and improve cardiovascular disease (CVD) risk assessment has recently emerged as a challenge. The present study was conducted to help predict the risk of coronary artery disease (CAD) by investigating new cardiometabolic risk factors based on substituting paraoxonase 1 (PON1) as a critical enzyme in the functionality of HDL for that of HDL-C. METHODS AND RESULTS: The present study recruited 274 subjects undergoing diagnostic coronary angiography, 92 without significant CAD (non-CAD), and 182 with a severe CAD. The diagnostic accuracy of the new biomarkers in non-CAD versus multi-vessel disease was obtained in descending order of AUC as 0.72 (P < 0.001) for log (TG/PON1), 0.70 (P < 0.001) for nonHDL-C/PON1, and 0.67 (P < 0.001) for LDL-C/PON1. After performing a multivariate adjustment for age, gender, BMI, statin therapy, and diabetes mellitus, the increased odds of CAD remained significant for the new cardiometabolic ratios as independent variables [adjusted OR = 1.47 (1.15-1.88), p = 0.002 for LDL-C/PON1; adjusted OR = 2.15 (1.41-3.5), p = 0.009 for nonHDL-C/PON1; adjusted OR = 5.03 (2.14-13.02), p = 0.004 for log (TG/PON1)]. CAD was diagnosed with an optimal discriminating cutoff of 1.84 for LDL-C/PON1, 2.8 for nonHDL-C/PON1, and 0.48 for log (TG/PON1). CONCLUSIONS: To improve CAD's risk assessment, the PON1 activity was proposed as an alternative to HDL-C in the commonly used atherogenic lipid ratios. Substituting the PON1 activity for the HDL-C concentration can provide an index of the HDL activity. The present study sought to exploit the lipoprotein-related risk factors of CAD from a more effective perspective.

Importance of paraoxonase 1 (PON1) as an antioxidant and antiatherogenic enzyme in the cardiovascular complications of type 2 diabetes: Genotypic and phenotypic evaluation.

Oxidant-antioxidant imbalance is involved in the etiology of different diseases, including cardiovascular diseases (CVDs), liver disorders, kidney diseases, cancers and diabetes mellitus. Antioxidant enzymes play a key role in striking an oxidant-antioxidant balance. Moreover, paraoxonase 1 (PON1) is an antioxidant enzyme that binds with high-density lipoprotein (HDL) in the circulation, and antioxidant and antiaterogenic properties of this lipoprotein are significantly associated with PON1. Research suggests PON1 contributes to the pathogenesis of certain human diseases such as type 2 diabetes (T2D). The association between PON1 and T2D appear to be reciprocal so that the disease significantly decreases PON1 levels and in turn, the genetics of PON1 may have a role the risk of susceptibility to T2D. Several factors that reduce the activity and concentration of PON1 in patients with T2D include increased glycation and loss-of-function polymorphisms. The genotypic and phenotypic evaluations of PON1 are therefore crucial for assessing the risk of cardiovascular complications in these patients, and strategies for increasing or restoring PON1 levels are useful for reducing or preventing their cardiovascular complications as their main cause of mortality. The present review aimed at discussing and emphasizing the key role of PON1 in T2D as a silent and dangerous disease.

The combined utility of myeloperoxidase (MPO) and paraoxonase 1 (PON1) as two important HDL-associated enzymes in coronary artery disease: Which has a stronger predictive role?

BACKGROUND AND AIMS: Serum paraoxonase 1 (PON1) and myeloperoxidase (MPO) are HDL-associated enzymes that contribute significantly to the formation of dysfunctional HDL. The present study thus seeks to comparatively analyze the predictive role of PON1, MPO and the MPO/PON1 ratio and to also evaluate which one has a stronger predictive role in their combined utility as an MPO/PON1 ratio in coronary artery disease (CAD). METHODS: PON1 activity and MPO concentrations were determined in patients with established CAD and those without significant CAD. Receiver operating characteristic (ROC) curves were drawn by plotting true positivity versus false positivity. RESULTS: The ROC curve analyses showed that PON1 (AUC = 61%, p = 0.003) and MPO/PON1 (AUC = 60%, p = 0.01) have a better diagnostic performance than MPO (AUC = 50%, p = 0.42) in detecting patients with CAD. PON1 and MPO/PON1 were found to have a significantly stronger discriminatory power for the age range ≥52 and < 60 years (AUC = 69%, p = 0.008 for PON1; AUC = 66%, p = 0.022 for MPO/PON1). The multivariate analysis revealed PON1 as an independent variable that was significantly associated with the multi-vessel disease [odds ratio (OR) = 0.98; p = 0.017]. At the cutoff point of 30 µmol/mL/min for PON1 and 1.85 for MPO/PON1, specificities were 97% and 73% and sensitivities 30% and 54% for discriminating patients with single-vessel disease from non-CAD subjects. CONCLUSIONS: The diagnostic performance of PON1 alone was comparable to that of the MPO/PON1 ratio for CAD risk assessment; however, MPO may increase the true positive rate. A larger number of blocked vessels seems to be associated with an increased predictive power for both PON1 and MPO/PON1. Recent data support the fact that PON1 and MPO may potentially be appropriate therapeutic targets for preventing CAD.