Daily exercise improves the long-term prognosis of patients with acute coronary syndrome.

Objective: To demonstrate the effect of daily exercise on the incidence of major adverse cardiovascular events (MACE) for patients with acute coronary syndrome (ACS). Methods: A cohort of 9,636 patients with ACS were consecutively enrolled in our retrospective study between November 2015 and September 2017, which were used for model development. 6,745 patients were assigned as the derivation cohort and 2,891 patients were assigned as the validation cohort. The least absolute shrinkage and selection operator (LASSO) regression and COX regression were used to screen out significant variables for the construction of the nomogram. Multivariable COX regression analysis was employed for the development of a model represented by a nomogram. The nomogram was then evaluated for performance traits such as discrimination, calibration, and clinical efficacy. Results: Among 9,636 patients with ACS (mean [SD] age, 60.3 [10.4] years; 7,235 men [75.1%]), the 5-year incidence for MACE was 0.19 at a median follow-up of 1,747 (1,160-1,825) days. Derived from the LASSO regression and COX regression, the nomogram has included 15 factors in total including age, previous myocardial infarction (MI), previous percutaneous coronary intervention (PCI), systolic pressure, N-terminal Pro-B-type natriuretic peptide (NT-proBNP), high-density lipoprotein cholesterol (HDL), serum creatinine, left ventricular end-diastolic diameter (LVEDD), Killip class, the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score, left anterior descending (LAD) stenosis (≥50%), circumflex (LCX) stenosis (≥50%), right coronary artery (RCA) stenosis (≥50%), exercise intensity, cumulative time. The 5-year area under the ROC curve (AUC) of derivation and validation cohorts were 0.659 (0.643-0.676) and 0.653 (0.629-0.677), respectively. The calibration plots showed the strong concordance performance of the nomogram model in both two cohorts. Moreover, decision curve analysis (DCA) also showed the usefulness of nomogram in clinical practice. Conclusion: The present work provided a prediction nomogram predicting MACE for patients with ACS after incorporating the already known factors and the daily exercise, which demonstrated the effectiveness of daily exercise on the improvement of prognosis for patients with ACS.

Design, Synthesis, and Anticancer Activity of Cinnamoylated Barbituric Acid Derivatives.

This work deals with the design and synthesis of 18 barbituric acid derivatives bearing 1,3-dimethylbarbituric acid and cinnamic acid scaffolds to find potent anticancer agents. The target molecules were obtained through Knoevenagel condensation and acylation reaction. The cytotoxicity was assessed by the MTT assay. Flowcytometry was performed to determine the cell cycle arrest, apoptosis, ROS levels and the loss of MMP. The ratios of GSH/GSSG and the MDA levels were determined by using UV spectrophotometry. The results revealed that introducing substitutions (CF3 , OCF3 , F) on the meta- of the benzyl ring of barbituric acid derivatives led to a considerable increase in the antiproliferative activities compared with that of corresponding ortho- and para-substituted barbituric acid derivatives. Mechanism investigation implied that the 1c could increase the ROS and MDA level, decrease the ratio of GSH/GSSG and MMP, and lead to cell cycle arrest. Further research is needed for structural optimization to enhance hydrophilicity, thereby improve the biological activity of these compounds.

Piperlongumine Analogs Promote A549 Cell Apoptosis through Enhancing ROS Generation.

Chemotherapeutic agents, which contain the Michael acceptor, are potent anticancer molecules by promoting intracellular reactive oxygen species (ROS) generation. In this study, we synthesized a panel of PL (piperlongumine) analogs with chlorine attaching at C2 and an electron-withdrawing/electron-donating group attaching to the aromatic ring. The results displayed that the strong electrophilicity group at the C2-C3 double bond of PL analogs plays an important role in the cytotoxicity whereas the electric effect of substituents, which attached to the aromatic ring, partly contributed to the anticancer activity. Moreover, the protein containing sulfydryl or seleno, such as TrxR, could be irreversibly inhibited by the C2-C3 double bond of PL analogs, and boost intracellular ROS generation. Then, the ROS accumulation could disrupt the redox balance, induce lipid peroxidation, lead to the loss of MMP (Mitochondrial Membrane Potential), and ultimately result in cell cycle arrest and A549 cell line death. In conclusion, PL analogs could induce in vitro cancer apoptosis through the inhibition of TrxR and ROS accumulation.

The first competing risk survival nomogram in patients with papillary renal cell carcinoma.

There is still a lack of competing risk analysis of patients with papillary renal cell carcinoma (pRCC) following surgery. We performed the cumulative incidence function (CIF) to estimate the absolute risks of cancer-specific mortality (CSM) and other-cause mortality (OCM) of pRCC over time, and constructed a nomogram predicting the probability of 2-, 3- and 5-year CSM based on competing risk regression. A total of 5993 pRCC patients who underwent nephrectomy between 2010 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The 2-, 3-, 5-year CSM rates were 3.2%, 4.4% and 6.5%, respectively, and that of OCM were 3.2%, 5.0% and 9.3%, respectively. The estimates of 5-year cumulative mortality were most pronounced among patients aged > 75 years in OCM (17.0%). On multivariable analyses, age, tumor grade, T stage, N stage, and with or without bone, liver and lung metastases were identified as independent predictors of CSM following surgery and were integrated to generate the nomogram. The nomogram achieved a satisfactory discrimination with the AUCt of 0.730 at 5-year, and the calibration curves presented impressive agreements. Taken together, age-related OCM is a significant portion of all-cause mortality in elderly patients and our nomogram can be used for decision-making and patient counselling.

The potential role of the 5,6-dihydropyridin-2(1H)-one unit of piperlongumine on the anticancer activity.

Piperlongumine (PL), a potent anticancer agent from the plant long pepper (Piper longum), contains the 5,6-dihydropyridin-2(1H)-one heterocyclic scaffold and cinnamoyl unit. In this paper, we synthesized a series of PL analogs and evaluated their cytotoxicity against cancer cells for the sake of exploring which pharmacophore plays a more potent role in enhancing the anticancer activities of PL. These results illustrated that the position effect, not the electronic effect, of substituents plays a certain role in the cytotoxicity of PL and its analogs. More important, the 5,6-dihydropyridin-2(1H)-one unit, a potent pharmacophore in enhancing the antiproliferative activities of PL, could react with cysteamine and lead to ROS generation, and then bring about the occurrence of ROS-induced downstream events, followed by cell cycle arrest and apoptosis. This work suggests that introducing a lactam unit containing Michael acceptors may be a potent strategy to enhancing the anticancer activity of drugs.