8 research outputs found
beta-adrenoceptor subtypes involved in myocardial preconditioning and postconditioning.
Ischaemia and reperfusion in the heart leads to necrotic cell death (infarction) and contractile dysfunction (stunning). Ischaemic preconditioning (non-lethal periods of ischaemia prior to a longer ischaemic episode) and postconditioning (modified reperfusion) both reduce infarct size and are thought to act via activation of reperfusion injury salvage kinase (RISK) pathways to prevent the opening of the mitochondrial permeability transition pore (MPTP) at reperfusion. Catecholamines are released centrally and locally during myocardial ischaemia and activate adrenoceptors. This investigation was concerned with the roles of beta-adrenoceptor activation in preconditioning and postconditioning. Studies utilising isolated paced atrial and ventricular tissues demonstrated that preconditioning against stunning could be achieved by ischaemic preconditioning, or pre-treatment of tissues with isoprenaline, a beta-adrenoceptor agonist. Both forms of protection were blocked by propranolol, a beta-adrenoceptor antagonist. Postconditioning was not protective in this model. A Langendorff model of regional ischaemia was used to determine effects of beta-adrenoceptor agonists and antagonists on infarct size. In this model, ischaemic postconditioning was blocked by timolol, a non-selective p-adrenoceptor antagonist. Formoterol, a beta2-adrenoceptor agonist, given at reperfusion, mimicked postconditioning. The non-selective adrenoceptor agonist, adrenaline, when applied at reperfusion, worsened reperfusion contracture but had no effect on infarct size. The application of a selective beta1-adrenoceptor antagonist (CGP-20712A) at reperfusion led to a reduction of infarct size whereas beta2 (ICI-118,551) and beta3 (SR-59230A) antagonists had the opposite effect. If the results are replicable in man in vivo they would be of clinical relevance because a commonly used class of drugs (beta-adrenoceptor antagonists) have the potential to abrogate the protection of postconditioning. Another widely available class of drugs (beta-adrenoceptor agonists) can have cardioprotective effects at reperfusion
Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017
Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri
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Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.
Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease