Background and Purpose-The association of total and high-density lipoprotein (HDL) cholesterol with stroke risk is unclear, especially regarding hemorrhagic stroke. Methods-We prospectively investigated the associations of serum total and HDL cholesterol and total/HDL cholesterol ratio with total and type-specific stroke incidence among 58 235 Finnish people aged 25 to 74 years and free of coronary heart disease and stroke at baseline. Results-During a mean follow-up period of 20.1 years, 3914 participants developed stroke events (3085 ischemic, 497 intracerebral hemorrhage, and 332 subarachnoid hemorrhage). The multivariable-adjusted hazard ratios at different levels of total cholesterol (Ͻ5 [reference], 5-5.9, 6 -6.0, Ն7.0 mmol/L) were 1.00, 1.05, 1.16, and 1.22 for total stroke (P trend ϭ0.036) and 1.00, 1.06, 1.19, and 1.27 for ischemic stroke (P trend ϭ0.02) in men and 1.00, 0.58, 0.61, and 0.50 for intracerebral hemorrhagic stroke (P trend ϭ0.02) in women, respectively. Low levels of HDL cholesterol and high total/HDL cholesterol ratio were associated with increased risks of total and ischemic stroke in both men and women. These associations disappeared in men but remained significant in women after further adjustment for body mass index, blood pressure, and history of diabetes. Conclusions-The study showed a positive association between total cholesterol and total and ischemic stroke risks in men and an inverse association between total cholesterol and intrahemorrhagic stroke risk in women. The inverse association of HDL cholesterol and a positive association of total/HDL cholesterol ratio with total and ischemic stroke risks were found in men and women. These associations attenuated after adjustment for body mass index, blood pressure, and history of diabetes.

Chemoresistance in breast cancer has been of great interest in past studies. However, the development of rational therapeutic strategies targeting chemoresistant cells is still a challenge in clinical oncology. By integrating data from global differences of gene expression and phospho-receptor tyrosine kinases between sensitive parental cells (MCF-7) and doxorubicin-resistant cells (MCF-7/ADR), we identified Axl as a potential target for chemoresistance and metastasis in multidrug resistant breast cancer cells. We analyzed Axl expression in 57 breast cancer cell lines and detected a dramatic increase in its expression level in mesenchymal breast cancer cell lines. Axl silencing suppressed invasive and metastatic potentials of chemoresistant breast cancer cells as well as increased elimination of cancer cells when combined with doxorubicin. Furthermore, in preclinical assays, an Axl inhibitor R428 showed increased cell death upon doxorubicin treatment. Additionally, using phospho-kinase array based proteomic analysis, we identified that Akt/GSK-3β/β-catenin cascade was responsible for Axl-induced cell invasion. Nuclear translocation of β-catenin then induced transcriptional upregulation of ZEB1, which in turn regulated DNA damage repair and doxorubicin-resistance in breast cancer cells. Most importantly, Axl was correlated with its downstream targets in tumor samples and was associated with poor prognosis in breast cancer patients. These results demonstrate that Gas6/Axl axis confers aggressiveness in breast cancer and may represent a therapeutic target for chemoresistance and metastasis.

BackgroundChronic hyperglycemia in type 2 diabetes increases the risk of microvascular events. However, there is continuing uncertainty about its effect on macrovascular outcomes and death. We conducted a meta-analysis of prospective studies to estimate the association of glycosylated hemoglobin level with the risk of all-cause mortality and cardiovascular outcomes among patients with type 2 diabetes.Methodology/Principal FindingsWe systematically searched the MEDLINE database through April 2011 by using Medical Subject Heading search terms and a standardized protocol. We included prospective cohort studies that reported data of glycosylated hemoglobin level on the risk of incident cardiovascular events and all-cause mortality. Relative risk estimates (continuous and categorical variables) were derived or abstracted from each cohort study. Twenty six studies were included in this analysis with a mean follow-up rang of 2.2–16 years. The pooled relative risk associated with a 1% increase in glycosylated hemoglobin level among patients with type 2 diabetes was 1.15 (95% CI, 1.11 to 1.20) for all-cause mortality, 1.17 (95% CI, 1.12 to 1.23) for cardiovascular disease, 1.15 (95% CI, 1.10 to 1.20) for coronary heart disease, 1.11 (95% CI, 1.05 to 1.18) for heart failure, 1.11 (95% CI, 1.06 to 1.17) for stroke, and 1.29 (95% CI, 1.18 to 1.40) for peripheral arterial disease, respectively. In addition, a positive dose-response trend existed between glycosylated hemoglobin level and cardiovascular outcomes.Conclusions/SignificanceChronic hyperglycemia is associated with an increased risk for cardiovascular outcomes and all-cause mortality among patients with type 2 diabetes, likely independently from other conventional risk factors.

Healthy lifestyle factors are associated with a lower risk of stroke, and there is a graded inverse association between the number of healthy lifestyle indicators and the risks of total, ischemic, and hemorrhagic stroke.