Combining a CDK4/6 Inhibitor With Pemetrexed Inhibits Cell Proliferation and Metastasis in Human Lung Adenocarcinoma.

Background: Recent clinical trials of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in human lung adenocarcinoma (LUAD) have not achieved satisfactory results. The disappointing results of single-drug treatments have prompted studies about synergistic therapies of CDK4/6i with other drugs. We aimed to test the anti-tumor effect of ribociclib (a CDK4/6i) combined with pemetrexed on LUAD and the potential mechanisms. Methods: Cell lines were exposed to ribociclib and pemetrexed at different doses. Antitumor effects were measured using growth inhibition. Cell cycle distribution and apoptosis were evaluated using flow cytometry. Cell migration and invasion were measured using wound healing and transwell invasion assays, respectively. The expression levels of proteins were analyzed using western blotting. Mice xenograft models were used for validation in vivo. Results: Synergism was associated with a combination of cell cycle effects from both agents. Cell cycle analysis revealed that pemetrexed blocked cells in the S phase, whereas ribociclib arrested cells in the G1 phase. Concomitant treatment with pemetrexed and ribociclib resulted in a significantly stronger antitumor ability than treatment alone. We also found that ribociclib strongly enhanced the pro-apoptotic activity of pemetrexed via the caspase/bcl-2 signaling pathway. In addition, we report for the first time that combination treatment with ribociclib and pemetrexed significantly inhibits the migration and invasion of LUAD cells. Conclusions: Combining ribociclib and pemetrexed showed a powerful ability to inhibit cancer proliferation, invasion, and metastasis, and it holds potential as a novel effective combinative therapy for patients with LUAD.

Extra pulmonary vein driver mapping and ablation in paroxysmal atrial fibrillation by electrogram dispersion analysis.

BACKGROUND: The adjunctive approach is still unknown for atrial fibrillation (AF), which cannot be terminated after pulmonary vein isolation (PVI). We hypothesized that the driver ablation plus PVI was superior to PVI alone. METHODS AND RESULTS: A total of 98 patients with paroxysmal AF were enrolled in this study and were divided into two groups, with one group undergoing PVI (n = 49) and the other group undergoing PVI + driver ablation (n = 49). The driver regions were defined as clusters of bipolar electrograms that displayed spatial dispersion spread over mean AF cycle length at a minimum of three adjacent bipolars of a PentaRay catheter. During the procedure, the most prominent driver regions before PVI were the roof (n = 27; 55.1%), PV antrum (n = 23; 46.9%), and the inferoposterior wall (n = 11; 22.4%). PVI can eliminate all drivers at PV antrum, but only terminate 30.4% of AF in the driver group. The AF termination rate in the driver ablation group was significantly higher than that in conventional ablation (93.9% vs 40.6%; P < 0.001). The rate of freedom from atrial tachyarrhythmia episodes by a single procedure at 6 months was significantly higher in the driver group than in the conventional group (91.6% vs 72.4%; P = 0.02). CONCLUSION: The present method is effective for AF driver identification. It guided ablation adjunctive to PVI increasing the rate of AF termination and improving the outcomes in patients with paroxysmal AF.

A Low-Normal Free Triiodothyronine Level Is Associated with Adverse Prognosis in Euthyroid Patients with Heart Failure Receiving Cardiac Resynchronization Therapy.

Thyroid dysfunction is prevalent in patients with heart failure (HF) and hypothyroidism is related to the adverse prognosis of HF subjects receiving cardiac resynchronization therapy (CRT). We aim to investigate whether low-normal free triiodothyronine (fT3) level is related to CRT response and the prognosis of euthyroid patients with HF after CRT implantation.One hundred and thirteen euthyroid patients who received CRT therapy without previous thyroid disease and any treatment affecting thyroid hormones were enrolled. All of patients were evaluated for cardiac function and thyroid hormones (serum levels of fT3, free thyroxine [fT4] and thyroid-stimulating hormone [TSH]). The end points were overall mortality and hospitalization for HF worsening. During a follow-up period of 39 ± 3 weeks, 36 patients (31.9%) died and 45 patients (39.8%) had hospitalization for HF exacerbation. A higher rate of NYHA III/IV class and a lower fT3 level were both observed in death group and HF event group. Multivariate Cox regression analyses disclosed that a lower-normal fT3 level (HR = 0.648, P = 0.009) and CRT response (HR = 0.441, P = 0.001) were both independent predictors of overall mortality. In addition, they were also both related to HF re-hospitalization event (P < 0.01 for both). Patients with fT3 < 3.00 pmol/L had a significantly higher overall mortality than those with fT3 ≥ 3.00 pmol/L (P = 0.027). Meanwhile, a higher HF hospitalization event rate was also found in patients with fT3 < 3.00 pmol/L (P < 0.001).A lower-normal fT3 level is correlated with a worse cardiac function an adverse prognosis in euthyroid patients with HF after CRT implantation.

Role of Circulating Fibrocytes in Cardiac Fibrosis.

OBJECTIVE: It is revealed that circulating fibrocytes are elevated in patients/animals with cardiac fibrosis, and this review aims to provide an introduction to circulating fibrocytes and their role in cardiac fibrosis. DATA SOURCES: This review is based on the data from 1994 to present obtained from PubMed. The search terms were "circulating fibrocytes " and "cardiac fibrosis ". STUDY SELECTION: Articles and critical reviews, which are related to circulating fibrocytes and cardiac fibrosis, were selected. RESULTS: Circulating fibrocytes, which are derived from hematopoietic stem cells, represent a subset of peripheral blood mononuclear cells exhibiting mixed morphological and molecular characteristics of hematopoietic and mesenchymal cells (CD34+/CD45+/collagen I+). They can produce extracellular matrix and many cytokines. It is shown that circulating fibrocytes participate in many fibrotic diseases, including cardiac fibrosis. Evidence accumulated in recent years shows that aging individuals and patients with hypertension, heart failure, coronary heart disease, and atrial fibrillation have more circulating fibrocytes in peripheral blood and/or heart tissue, and this elevation of circulating fibrocytes is correlated with the degree of fibrosis in the hearts. CONCLUSIONS: Circulating fibrocytes are effector cells in cardiac fibrosis.