Reduced levels of high-density lipoprotein cholesterol (HDL) are associated with a substantially increased risk of coronary disease and cardiovascular events. Furthermore, numerous studies have ...suggested that HDL may exert several potentially important antiatherosclerotic and endothelial-protective effects. In particular, the promotion of reverse cholesterol transport, i.e. cholesterol efflux from lipid-loaded macrophages in atherosclerotic lesions and the subsequent cholesterol transport back to the liver, has been proposed as an anti-atherogenic effect of HDL that may promote regression of atherosclerotic lesions. Moreover, endothelial dysfunction is thought to play a critical role in development and progression of atherosclerosis and several recent studies have suggested that HDL exerts direct endothelial-protective effects, such as stimulation of endothelial production of the anti-atherogenic molecule nitric oxide, anti-oxidant, anti-inflammatory and anti-thrombotic effects. Furthermore, it has been observed that HDL may stimulate endothelial repair processes, involving mobilisation and promotion of endothelial repair capacity of endothelial progenitor cells. The relative significance of these different potential anti-atherosclerotic effects of HDL remains still unclear at present. Importantly, at the same time it has been recognized that the vascular effects of HDL may be variable, i.e. the capacity of HDL to stimulate macrophage cholesterol efflux and endothelial-protective effects may be altered in patients with inflammatory or cardiovascular disease. The further characterisation of underlying mechanisms and the identification of the clinical relevance of this "HDL dysfunction" are currently an active field of research. HDL-targeted treatment strategies are at present intensely evaluated and may lead to increased HDL plasma levels and/or HDL-stimulated anti-atherosclerotic effects. The cardiovascular protection provided by such approaches may likely depend on HDL function or quality, i.e. the anti-atherosclerotic and endothelial-protective properties of the on-treatment HDL. Currently, several HDL-raising treatment strategies are examined in clinical trials, i.e. extended-release niacin, the CETP inhibitors dalcetrapib and anacetrapib, reconstituted forms of HDL (i.e. CSL-111) or apoA-I mimetics, and some of these are already in large clinical outcome studies on top of statin therapy to determine their efficacy and safety for cardiovascular prevention.
Primary tumor sidedness (left vs. right) has prognostic and predictive impact on anti-EGFR agent efficacy and thus management of metastatic colorectal cancer (mCRC). This analysis evaluates the ...relevance of primary tumor location (PTL) in
wild-type mCRC patients, when dividing the colorectal frame into six segments. This pooled analysis, performed on a single-patient basis of five randomized first-line therapy trials, evaluates the impact of exact PTL classification on baseline characteristics, prognosis and prediction of anti-EGFR antibody efficacy by chi-square and log-rank tests, the Kaplan-Meier method, Cox and logistic regressions. The PTL was significantly associated with metastatic spread: liver (
= 0.001), lung (
= 0.047), peritoneal (
< 0.001) and lymph nodes (
= 0.048). A multivariate analysis indicated an impact on anti-EGFR agent efficacy in terms of overall survival depending on the exact primary tumor location: from detrimental in caecal (HR 2.63), rather neutral effects in the ascending colon (HR 1.24), right flexure/transverse colon (HR 0.99) and left flexure/descending colon (HR 0.91) to clear benefit in sigmoid (HR 0.71) and rectal (HR 0.58) primaries. Exact primary tumor location affects anti-EGFR antibody efficacy in a rather continuous than a dichotomous fashion in
wild-type mCRC patients. This perspective might help to support clinical decisions when anti-EGFR antibodies are considered.
The speed and spread of the COVID-19 pandemic has been affecting the entire world for the past several months.
is a social media network made up of more than 140 oncology stakeholders: oncologists ...(medical, radiation, and surgical), oncology nurses, and patient advocates who share the mission of fighting cancer by means of education and dissemination of information. As a response to the COVID-19 pandemic, OncoAlert hosted
We have documented this effort along with further discussion about the COVID-19 pandemic and the consequences on patients living with cancer to disseminate this information to our colleagues worldwide.
Quo vadis precision oncology? Heinrich, Kathrin; Westphalen, C. Benedikt
Journal of cancer research and clinical oncology,
2023/1, Letnik:
149, Številka:
1
Journal Article
Endothelial dysfunction and injury are thought to play an important role in the progression of coronary artery disease (CAD). High-density lipoprotein from healthy subjects (HDL(Healthy)) has been ...proposed to exert endothelial antiapoptotic effects that may represent an important antiatherogenic property of the lipoprotein. The present study therefore aimed to compare effects of HDL(CAD) and HDL(Healthy) on the activation of endothelial anti- and proapoptotic pathways and to determine which changes of the lipoprotein are relevant for these processes.
HDL was isolated from patients with stable CAD (HDL(sCAD)), an acute coronary syndrome (HDL(ACS)), and healthy subjects. HDL(Healthy) induced expression of the endothelial antiapoptotic Bcl-2 protein Bcl-xL and reduced endothelial cell apoptosis in vitro and in apolipoprotein E-deficient mice in vivo. In contrast, HDL(sCAD) and HDL(ACS) did not inhibit endothelial apoptosis, failed to activate endothelial Bcl-xL, and stimulated endothelial proapoptotic pathways, in particular, p38-mitogen-activated protein kinase-mediated activation of the proapoptotic Bcl-2 protein tBid. Endothelial antiapoptotic effects of HDL(Healthy) were observed after inhibition of endothelial nitric oxide synthase and after delipidation, but not completely mimicked by apolipoprotein A-I or reconstituted HDL, suggesting an important role of the HDL proteome. HDL proteomics analyses and subsequent validations and functional characterizations suggested a reduced clusterin and increased apolipoprotein C-III content of HDL(sCAD) and HDL(ACS) as mechanisms leading to altered effects on endothelial apoptosis.
The present study demonstrates for the first time that HDL(CAD) does not activate endothelial antiapoptotic pathways, but rather stimulates potential endothelial proapoptotic pathways. HDL-proteome remodeling plays an important role for these altered functional properties of HDL. These findings provide novel insights into mechanisms leading to altered vascular effects of HDL in coronary disease.
PDF
