Methylsulfonylmethane Suppresses Breast Cancer Growth by Down-Regulating STAT3 and STAT5b Pathways

Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1α, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA-binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90α, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers

C2 HEST Score and Prediction of Incident Atrial Fibrillation in Poststroke Patients: A French Nationwide Study.

Background The C2HEST score (coronary artery disease or chronic obstructive pulmonary disease [1 point each]; hypertension [1 point]; elderly [age ≥75 years, 2 points]; systolic heart failure [2 points]; thyroid disease [hyperthyroidism, 1 point]) was initially proposed for predicting incident atrial fibrillation (AF) in the general population. Its performance in poststroke patients remains to be established, especially because patients at high risk for incident AF should be targeted for more comprehensive screening. This study aimed to evaluate this newly established incident AF prediction risk score in a post-ischemic stroke population. Methods and Results Validation was based on a hospital-based nationwide cohort with 240 459 French post-ischemic stroke patients. Kaplan-Meier curves for incident rate of AF depict differences between varying risk categories. Discrimination of the C2HEST score was evaluated using the C index, the net reclassification index, integrated discriminatory improvement, and decision curve analysis. During 7.9±11.5 months of follow-up, 14 095 patients developed incident AF. The incidence of AF increased from 23.5 per 1000 patient-years in patients with a C2HEST score of 0 to 196.8 per 1000 patient-years in patients with a C2HEST score ≥6. Kaplan-Meier curves showed a clear difference among different risk strata (log-rank P<0.0001). The C2HEST score had good discrimination with a C index of 0.734 (95% CI, 0.732-0.736), which was better than the Framingham risk score and the CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 [doubled], diabetes mellitus, stroke [doubled], vascular disease, age 65 to 74 years, and female sex) ( P<0.0001, respectively). The C2HEST score was also superior to the Framingham risk score and the CHA2DS2-VASc score as shown by the net reclassification index, integrated discriminatory improvement ( P<0.0001, respectively) and decision curve analysis. Conclusions The C2HEST score performed well in discriminating the individual risk of developing incident AF in a white European population hospitalized with previous ischemic stroke. This simple score may potentially be used as a risk stratification tool for decision making in relation to a screening strategy for AF in post-ischemic stroke patients

Association of proteinuria and hypertension with incident atrial fibrillation in an elderly population: nationwide data from a community-based elderly cohort

ObjectiveThe excess risk of atrial fibrillation in relation to the presence of proteinuria associated with hypertension has not been well elucidated. We aimed to determine the effect of hypertension and/or proteinuria on the incidence of atrial fibrillation. Second, we evaluated whether the associations with temporal changes in proteinuria status on the incidence of atrial fibrillation.Methods and resultsA total of 85 434 participants with hypertension and 125 912 participants without hypertension with age at least 60 years from the Korea National Health Insurance Service-Senior cohort were included. Amongst controls (participants without proteinuria and hypertension), hypertension only, proteinuria only, and hypertension with proteinuria groups, the adjusted incidences of atrial fibrillation were 0.51, 0.69. 0.78 and 0.99 per 100 person-years, respectively after inverse probability of treatment weighting. Compared with controls, the weighted risks of atrial fibrillation in the hypertension only, proteinuria only and hypertension with proteinuria groups were increased by 37% (hazard ratio 1.37, 95% confidence interval, CI 1.30-1.44, P = 0.001), 55% (hazard ratio 1.55, 95% CI 1.28-1.88, P ConclusionIn conclusion, hypertension and/or proteinuria were associated with increased risk of atrial fibrillation, with the greatest risks when both are present. Proteinuria could be a useful factor for predicting atrial fibrillation development

Association of proteinuria and incident atrial fibrillation in patients with diabetes mellitus: a population-based senior cohort study (vol 11, 17013, 2021)

The original version of this Article contained an error in the Funding section. “This study was supported by a research grant from the Korean Healthcare Technology R&D project funded by the Ministry of Health and Welfare (HI15C1200, HC19C0130) and a CMB-Yuhan research grant of Yonsei University College of Medicine (6-2019-0124).” now reads: “This study was supported by a research grant from the Korean Healthcare Technology R&D project funded by the Ministry of Health and Welfare (HI15C1200, HC19C0130, HI19C0622) and a CMB-Yuhan research grant of Yonsei University College of Medicine (6-2019-0124).” The original Article has been corrected

Association of proteinuria and incident atrial fibrillation in patients with diabetes mellitus: a population-based senior cohort study

Diabetes mellitus (DM) is considered an independent risk factor for atrial fibrillation (AF). The excess risk in relation to the presence of proteinuria has not been well elucidated. Our aim was to determine the association between the incidence of AF and proteinuria in diabetic population. A total of 240,499 individuals aged ≥ 60 years from the Korea National Health Insurance Service-Senior cohort from 2004 to 2014 were included. 4.2% of individuals with DM and 3.7% of controls were diagnosed with AF during a median follow-up period of 7.2 years. Amongst controls (participants without proteinuria and DM), DM only, proteinuria only, and DM with proteinuria groups, the crude incidences of AF were 0.58, 0.70, 0.96, 1.24 per 100 person-years respectively. Compared with controls, the weighted risk of AF was increased by 11% (hazard ratio = 1.11, 95% confidence interval = 1.02-1.20, P = .001), 48% (hazard ratio = 1.48, 95% confidence interval = 1.30-1.69, P < .001), and 66% (hazard ratio = 1.66, 95% confidence interval = 1.26-2.18, P < .001) in the DM only, proteinuria only, and DM with proteinuria groups, respectively (P for trend < .001). Degree of proteinuria in diabetic patients was associated with a significantly higher rate of incident AF in dose dependent manner. Thus, assessing proteinuria by a simple urine dipstick test could provide a useful adjunct to risk assessment for AF in elderly population with DM

Impact of Physical Activity on All-Cause Mortality According to Specific Cardiovascular Disease

BackgroundPatients with cardiovascular disease (CVD) tend to have higher mortality rates and reduced physical activity (PA). We aimed to evaluate the effect of PA on mortality in older adults with specific CVD.MethodsWe enrolled 68,223 participants (n = 23,871 with CVD, n = 44,352 without CVD) aged ≥65 years with available physical activity data between 2005 and 2012 from the Korean National Health Insurance Service of Korea-Senior database. CVD was defined as a history of ischemic stroke, transient ischemic attack, heart failure, myocardial infarction, and peripheral artery disease.ResultsPatients with CVD were older than those without CVD. Compared with the sedentary group, the physically active groups with and without CVD had a lower incidence and risk of all-cause death during a median follow up period of 42 (interquartile range 30-51) months. A 500 metabolic equivalent task-min/week increase in PA resulted in an 11% and 16% reduction in the risk of mortality in the non-CVD and CVD groups, respectively. With regard to specific CVDs, the risk of mortality progressively reduced with increasing PA in patients with heart failure or myocardial infarction. However, the reduction reached a plateau in patients with stroke or peripheral artery disease, but was significantly greater in patients with stroke (20% vs. without stoke, 11%, Pint = 0.006) or heart failure (13% vs. without heart failure, 11%; Pint = 0.045).ConclusionsPA was associated with a reduced risk of all-cause mortality in older adults with and without CVD. The benefits of PA in patients with CVD, especially patients with stroke or heart failure, were greater than those without

The Effect of Integrated Care Management on Dementia in Atrial Fibrillation

Clinical outcomes of patients with atrial fibrillation (AF) can be improved by an integrated care approach. We analyzed whether adherence with the AF Better Care (ABC) pathway for integrated care management would reduce the risk of dementia in a nationwide AF cohort. Using the National Health Insurance Service database of Korea, 228,026 non-valvular AF patients were retrospectively evaluated between 2005 and 2015. Patients meeting all criteria of the ABC pathway were classified as the “ABC” group and those not classified as the “non-ABC” group. During a median (25th, 75th percentiles) follow-up of 6.0 (3.3, 9.5) years, the ABC group had lower rates and risk of overall dementia (0.17 vs. 1.11 per 100 person-years, p < 0.001; hazard ratio (HR) 0.80; 95% CI 0.73–0.87) and both Alzheimer’s (HR 0.79, 95% CI 0.71–0.88) and vascular dementia (HR 0.76, 95% CI 0.59–0.98) than the non-ABC group. The stratified analysis showed that the ABC pathway reduced the risk of dementia regardless of sex, comorbidities, and in patients with high stroke risk. Adherence with the ABC pathway is associated with a reduced risk of dementia in AF patients. Due to the high medical burden of AF, it is necessary to implement integrated AF management to reduce the risk of dementia

Role of Cyclin B1/Cdc2 Up-Regulation in the Development of Mitotic Prometaphase Arrest in Human Breast Cancer Cells Treated with Nocodazole

Background: During a normal cell cycle, the transition from G 2 phase to mitotic phase is triggered by the activation of the cyclin B1-dependent Cdc2 kinase. Here we report our finding that treatment of MCF-7 human breast cancer cells with nocodazole, a prototypic microtubule inhibitor, results in strong up-regulation of cyclin B1 and Cdc2 levels, and their increases are required for the development of mitotic prometaphase arrest and characteristic phenotypes. Methodology/Principal Findings: It was observed that there was a time-dependent early increase in cyclin B1 and Cdc2 protein levels (peaking between 12 and 24 h post treatment), and their levels started to decline after the initial increase. This early up-regulation of cyclin B1 and Cdc2 closely matched in timing the nocodazole-induced mitotic prometaphase arrest. Selective knockdown of cyclin B1or Cdc2 each abrogated nocodazole-induced accumulation of prometaphase cells. The nocodazole-induced prometaphase arrest was also abrogated by pre-treatment of cells with roscovitine, an inhibitor of cyclin-dependent kinases, or with cycloheximide, a protein synthesis inhibitor that was found to suppress cyclin B1 and Cdc2 up-regulation. In addition, we found that MAD2 knockdown abrogated nocodazole-induced accumulation of cyclin B1 and Cdc2 proteins, which was accompanied by an attenuation of nocodazole-induced prometaphase arrest. Conclusions/Significance: These observations demonstrate that the strong early up-regulation of cyclin B1 and Cdc2 contributes critically to the rapid and selective accumulation of prometaphase-arrested cells, a phenomenon associate