Study on the correlation between red cell distribution width, homocysteine, lipoprotein(a), and left atrial diameter in newly diagnosed nonvalvular atrial fibrillation patients.

OBJECTIVE: This study aims to investigate the correlations between red cell distribution width (RDW), homocysteine (Hcy), lipoprotein(a) [Lp(a)], and left atrial diameter (LAD) measured by echocardiography in newly diagnosed nonvalvular atrial fibrillation (NVAF) (referred to as "new-onset AF") patients and their predictive value for new-onset AF. The findings of this study provide a basis for early clinical identification of the risk of new-onset AF. PATIENTS AND METHODS: Eighty-nine newly diagnosed NVAF patients (46 males and 43 females) admitted to the Department of Cardiology, First Affiliated Hospital of Nanchang University, from January 2017 to January 2023 were included in the new-onset AF group. Over the same time, 88 sinus rhythm patients (44 males and 44 females) were included in the control group. Data, including demographic information, routine blood test parameters, biochemical indicators, and relevant values from cardiac color Doppler ultrasound, were recorded for all study subjects. Logistic regression analysis was used to explore the clinical characteristics of the indicators mentioned above in patients with new-onset AF. Receiver operating characteristic (ROC) curves were drawn to assess the predictive ability of these indicators for new-onset AF. RESULTS: Univariate analysis of biochemical indicators revealed differences between the two groups (p<0.05) in RDW, Hcy, and Lp(a). The univariate analysis also revealed differences (p<0.05) in RDW, Lp(a), Hcy, left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDD), interventricular septal thickness (IVST), and left ventricular ejection fraction (LVEF). Multivariable logistic regression analysis identified RDW (OR=2.38, 95% CI: 1.65-3.67), Hcy (OR=1.57, 95% CI: 1.37-1.86), and Lp(a) (OR=1.01, 95% CI: 1.00-1.01) as independent risk factors for the new-onset AF. In the subgroup analysis dichotomizing patients around the LAD cutoff value, the high-LAD group had higher RDW, Hcy, and Lp(a) (13.4 vs. 12.7, 15.0 vs. 10.9, 144.0 vs. 101.3, respectively). CONCLUSIONS: RDW, Hcy, and Lp(a) are elevated in patients with new-onset AF. They are positively correlated with LAD in these patients, indicating their role as risk factors for new-onset AF.

EGFR mutants found in non-small cell lung cancer show different levels of sensitivity to suppression of Src: implications in targeting therapy.

Mutations in epidermal growth factor receptor (EGFR) kinase domain associate with clinical responses to EGFR inhibitors and are frequently observed in non-small cell lung cancer (NSCLC) patients in East Asian populations. Clinically identified EGFR mutations cause constitutive receptor activation. The activating mechanisms were unclear but appeared to be different among EGFR mutants. We found that EGFR mutants had different sensitivity to an Src inhibitor PP2. S768I and L861Q mutants were less sensitive to Src suppression than others. Mutation at tyrosine 869 (845) residue, an Src phosphorylation site, decreased the phosphorylation levels of wild-type EGFR and other mutants, but not that of S768I and L861Q mutants, suggesting that S768I and L861Q mutants became Src independent for their activation and biological functions. In contrast, cells expressing EGFR-L858R or exon 19 deletion mutants were more sensitive to PP2 than cells expressing wild-type EGFR. Interestingly, EGFR with exon 19-deletion/T790M double mutations, which was resistant to gefitinib, remained sensitive to PP2. Taken together, our data indicate that Src inhibitors might be effective in treating NSCLC harboring specific types of EGFR mutations.

Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants.

Mutations in the kinase domain of epidermal growth factor receptor (EGFR) are associated with clinical responsiveness to gefitinib in patients with non-small-cell lung cancers (NSCLC). Recently, we have identified many novel EGFR mutations in NSCLC tissues. In this study, we found that gefitinib could suppress the tyrosine phosphorylation of most EGFR mutants better than the wild-type receptor. However, gefitinib had quite variable growth-suppressive effects on different EGFR mutant-expressing cells. All tested EGFR mutants have high basal phosphorylation at multiple tyrosine residues. Upon EGF stimulation, the mutated EGFRs did not have apparently stronger phosphorylation at tyrosines 845, 992, 1,068, and 1,173 than the wild-type receptor. However, stronger phosphorylation at tyrosine 1,045 was observed in the S768I, L861Q, E709G, and G719S mutants. The E746-A750 deletion mutant was less responsive to EGF than the wild-type and other mutant receptors. The S768I, L861Q, E709G, and G719S mutants were refractory to EGF-induced ubiquitination and had more sustained tyrosine phosphorylation. E709G and G719S also lacked EGF-induced receptor downregulation. Our results indicate that, in addition to sensitivity to gefitinib, EGFR mutations also caused various changes in EGFR's regulatory mechanisms, which may contribute to the constitutive activation of EGFR mutants and oncogenesis in NSCLC.