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https://www.readbyqxmd.com/read/28448040/determination-of-high-affinity-antibody-antigen-binding-kinetics-using-four-biosensor-platforms
#1
Danlin Yang, Ajit Singh, Helen Wu, Rachel Kroe-Barrett
Label-free optical biosensors are powerful tools in drug discovery for the characterization of biomolecular interactions. In this study, we describe the use of four routinely used biosensor platforms in our laboratory to evaluate the binding affinity and kinetics of ten high-affinity monoclonal antibodies (mAbs) against human proprotein convertase subtilisin kexin type 9 (PCSK9). While both Biacore T100 and ProteOn XPR36 are derived from the well-established Surface Plasmon Resonance (SPR) technology, the former has four flow cells connected by serial flow configuration, whereas the latter presents 36 reaction spots in parallel through an improvised 6 x 6 crisscross microfluidic channel configuration...
April 17, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28447578/proprotein-convertase-subtilisin-kexin-type-9-affects-insulin-but-not-lipid-metabolism-in-cystic-fibrosis
#2
Adèle Coriati, Elizabeth Arslanian, Guillaume F Bouvet, Annik Prat, Nabil G Seidah, Rémi Rabasa-Lhoret, Yves Berthiaume
PURPOSE: Cystic Fibrosis (CF) is the most common genetic disorder and, with improved survival, glucose abnormalities have emerged as a major comorbidity. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of plasma LDL-cholesterol homeostasis, is associated with lipid and glucose metabolism in healthy individuals. Here we report on the link between PCSK9 and markers of metabolism in CF. METHODS: Cross-sectional analysis was performed on CF patients (≥ 18 years, N=94) from the Montreal Cohort, without known diabetes, and on healthy individuals (N=19)...
April 26, 2017: Clinical and Investigative Medicine. Médecine Clinique et Experimentale
https://www.readbyqxmd.com/read/28446516/access-to-non-statin-lipid-lowering-therapies-in-patients-at-high-risk-of-atherosclerotic-cardiovascular-disease
#3
Joshua W Knowles, William B Howard, Lala Karayan, Seth J Baum, Katherine A Wilemon, Christie M Ballantyne, Kelly D Myers
High-intensity statins are recommended for all patients with familial hypercholesterolemia (FH) and non-statin lipid lowering therapies (LLTs) are indicated when there is an inadequate response to statins(1, 2) In the pre-PCSK9 inhibitor (PCSK9i) era only about 40% of FH patients achieved an LDL-C level <100.(3) Partly based on the need for additional therapeutic options in high-risk FH patients, PCSK9 inhibitors were approved for treatment of heterozygous and homozygous FH in 2015. Nevertheless, emerging anecdotal data suggest that access to non-statin LLTs has been a challenge for FH patients though this has not been systematically evaluated...
April 26, 2017: Circulation
https://www.readbyqxmd.com/read/28445176/novel-lipid-modifying-drugs-to-lower-ldl-cholesterol
#4
Arjen J Cupido, Laurens F Reeskamp, John J P Kastelein
PURPOSE OF REVIEW: Statins have long been the cornerstone for the prevention of cardiovascular disease (CVD). However, because of perceived adverse effects and insufficient efficacy in certain groups of patients, considerable interest exists in the search for alternatives to lower LDL-cholesterol (LDL-C), and the recent approvals of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors underlines the success of this quest. Here, we give an updated overview on the most recent developments in the area of LDL-C lowering agents...
April 25, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28444187/modelling-the-cost-effectiveness-pcsk9-inhibitors-vs-ezetimibe-through-ldl-c-reductions-in-a-norwegian-setting
#5
Max Korman, Torbjørn Wisløff
Aims: Despite the success of statins, there remains unmet clinical need in cardiovascular disease (CVD) prevention. New proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce low-density lipoprotein cholesterol (LDL-C) by 55-65%. Two PCSK9 inhibitors, evolocumab and alirocumab, were approved for use in Norway but not yet for reimbursement through public national insurance. We aim to explore the cost-effectiveness of these compared to available treatments in a Norwegian setting...
April 21, 2017: European Heart Journal. Cardiovascular Pharmacotherapy
https://www.readbyqxmd.com/read/28442922/inhibition-of-pcsk9-protects-against-radiation-induced-damage-of-prostate-cancer-cells
#6
Si-Shun Gan, Jian-Qing Ye, Lei Wang, Fa-Jun Qu, Chuan-Min Chu, Yi-Jun Tian, Wei Yang, Xin-Gang Cui
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein expressed primarily in the liver, formerly known to maintain plasma lipid homeostasis by regulating low-density lipoprotein receptor levels, and its exact role in the radioresistance of prostate cancer (PCa) remains unclear. We aim to investigate the function of PCSK9 in the radioresistance of PCa cells. METHODS: PCSK9 small interfering RNA (siRNA) was introduced into the PCa cells by transient transfection...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28439730/physiological-and-therapeutic-regulation-of-pcsk9-activity-in-cardiovascular-disease
#7
REVIEW
Simon Glerup, Rainer Schulz, Ulrich Laufs, Klaus-Dieter Schlüter
Ischemic heart disease is the main cause of death worldwide and is accelerated by increased levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL-C through its ability to induce degradation of the LDL receptor (LDLR) in the lysosome of hepatocytes. Only in the last few years, a number of breakthroughs in the understanding of PCSK9 biology have been reported illustrating how PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance...
May 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28438747/low-ldl-cholesterol-pcsk9-and-hmgcr-genetic-variation-and-risk-of-alzheimer-s-disease-and-parkinson-s-disease-mendelian-randomisation-study
#8
Marianne Benn, Børge G Nordestgaard, Ruth Frikke-Schmidt, Anne Tybjærg-Hansen
Objective To test the hypothesis that low density lipoprotein (LDL) cholesterol due to genetic variation in the genes responsible for LDL cholesterol metabolism and biosynthesis(PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), respectively) is associated with a high risk of Alzheimer's disease, vascular dementia, any dementia, and Parkinson's disease in the general population.Design Mendelian randomisation study.Setting Copenhagen General Population Study and Copenhagen City Heart Study.Participants 111 194 individuals from the Danish general population...
April 24, 2017: BMJ: British Medical Journal
https://www.readbyqxmd.com/read/28437620/american-association-of-clinical-endocrinologists-and-american-college-of-endocrinology-guidelines-for-management-of-dyslipidemia-and-prevention-of-cardiovascular-disease
#9
Paul S Jellinger, Yehuda Handelsman, Paul D Rosenblit, Zachary T Bloomgarden, Vivian A Fonseca, Alan J Garber, George Grunberger, Chris K Guerin, David S H Bell, Jeffrey I Mechanick, Rachel Pessah-Pollack, Kathleen Wyne, Donald Smith, Eliot A Brinton, Sergio Fazio, Michael Davidson
OBJECTIVE: The development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). METHODS: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols...
April 2017: Endocrine Practice
https://www.readbyqxmd.com/read/28436724/circulating-proprotein-convertase-subtilisin-kexin-type-9-all-cause-mortality-and-cardiovascular-mortality-the-ludwigshafen-risk-and-cardiovascular-health-study
#10
Günther Silbernagel, Hubert Scharnagl, Marcus E Kleber, Tatjana Stojakovic, Winfried März
Background It is unclear whether proprotein convertase subtilisin-kexin type 9 (PCSK9) concentrations may be useful for cardiovascular risk stratification. Design The LUdwigshafen RIsk and Cardiovascular health (LURIC) study is a prospective observational registry of patients who were referred for coronary angiography. Methods Circulating PCSK9 was measured in 2139 participants of the LURIC study. There was a follow-up for all-cause and cardiovascular mortality with a median (interquartile range) duration of 10...
January 1, 2017: European Journal of Preventive Cardiology
https://www.readbyqxmd.com/read/28434484/practical-aspects-in-the-management-of-statin-associated-muscle-symptoms-sams
#11
Ulrich Laufs, Krysztof J Filipiak, Ioanna Gouni-Berthold, Alberico L Catapano
BACKGROUND AND AIMS: Statin-associated muscle symptoms (SAMS) frequently cause statin non-adherence, switching and discontinuation, contributing to adverse cardiovascular (CV) outcomes. Therefore, the management of SAMS is key in the effective treatment of patients with cardiovascular disease (CVD), through achievement of maximum-tolerated statin dosing and other practical aspects. The aim of this article is to provide practical, focused advice for healthcare professionals on the management of patients with SAMS...
April 2017: Atherosclerosis. Supplements
https://www.readbyqxmd.com/read/28434482/how-to-implement-clinical-guidelines-to-optimise-familial-hypercholesterolaemia-diagnosis-and-treatment
#12
Michel Farnier, Fernando Civeira, Olivier Descamps
BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is a genetic disorder associated with significantly elevated plasma low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease (CHD). Optimal management of FH relies on early identification and treatment with statins alone or in combination with other lipid-lowering therapies. A lack of awareness of FH and its manifestations among primary care physicians and specialists has led to many individuals being misdiagnosed in the early stages of the disease, further increasing the risk of CHD and requiring much more intensive lipid-lowering strategies...
April 2017: Atherosclerosis. Supplements
https://www.readbyqxmd.com/read/28430919/non-coding-rnas-in-cardiovascular-diseases-diagnostic-and-therapeutic-perspectives
#13
Wolfgang Poller, Stefanie Dimmeler, Stephane Heymans, Tanja Zeller, Jan Haas, Mahir Karakas, David-Manuel Leistner, Philipp Jakob, Shinichi Nakagawa, Stefan Blankenberg, Stefan Engelhardt, Thomas Thum, Christian Weber, Benjamin Meder, Roger Hajjar, Ulf Landmesser
Recent research has demonstrated that the non-coding genome plays a key role in genetic programming and gene regulation during development as well as in health and cardiovascular disease. About 99% of the human genome do not encode proteins, but are transcriptionally active representing a broad spectrum of non-coding RNAs (ncRNAs) with important regulatory and structural functions. Non-coding RNAs have been identified as critical novel regulators of cardiovascular risk factors and cell functions and are thus important candidates to improve diagnostics and prognosis assessment...
April 18, 2017: European Heart Journal
https://www.readbyqxmd.com/read/28429242/genetics-of-dyslipidemia-and-ischemic-heart-disease
#14
REVIEW
Kavita Sharma, Ragavendra R Baliga
PURPOSE OF REVIEW: Genetic dyslipidemias contribute to the prevalence of ischemic heart disease. The field of genetic dyslipidemias and their influence on atherosclerotic heart disease is rapidly developing and accumulating increasing evidence. The purpose of this review is to describe the current state of knowledge in regard to inherited atherogenic dyslipidemias. The disorders of familial hypercholesterolemia (FH) and elevated lipoprotein(a) will be detailed. Genetic technology has made rapid advancements, leading to new discoveries in inherited atherogenic dyslipidemias, which will be explored in this review, as well as a description of possible future developments...
May 2017: Current Cardiology Reports
https://www.readbyqxmd.com/read/28424973/pcsk9-inhibitors-in-hyperlipidemia-current-status-and-clinical-outlook
#15
Belinda Di Bartolo, Daniel J Scherer, Alex Brown, Peter J Psaltis, Stephen J Nicholls
The clinical reality of residual risk despite statin (HMG-CoA reductase inhibitor) therapy and emergence of statin intolerance support the need to develop additional lipid-lowering strategies. Proprotein convertase subtilisin kexin type 9 (PCSK9) has received considerable attention by virtue of genetic and clinical studies that have revealed its pivotal role in the regulation of cholesterol homeostasis. Monoclonal antibodies have been developed targeting PCSK9, which have been demonstrated to produce profound low-density lipoprotein cholesterol (LDL-C) lowering when provided as monotherapy or in combination with statins...
April 19, 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/28424373/statins-pcsk9-inhibitors-and-cholesterol-homeostasis-a-view-from-within-the-hepatocyte
#16
EDITORIAL
Allan D Sniderman, Robert Scott Kiss, Thomas Reid, George Thanassoulis, Gerald F Watts
Statins and PCSK9 inhibitors dramatically lower plasma LDL levels and dramatically increase LDL receptor number within hepatocyte cell membranes. It seems self-evident that total clearance of LDL particles from plasma and total delivery of cholesterol to the liver must increase in consequence. However, based on the results of stable isotope tracer studies, this analysis demonstrates the contrary to be the case. Statins do not change the production rate of LDL particles. Accordingly, at steady state, the clearance rate cannot change...
May 1, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28418263/systematic-bias-in-predictions-of-new-drugs-budget-impact-analysis-of-a-sample-of-recent-us-drug-launches
#17
Michael S Broder, Jenelle M Zambrano, Jackie Lee, Richard S Marken
OBJECTIVE: Expectations about the budget impact of new drug launches may affect payer behavior and ultimately consumer costs. Therefore, we evaluated the accuracy of pre-launch US budget impact estimates for a sample of new drugs. METHODS: We searched for publicly available budget impact estimates made pre-launch for drugs approved in the US from 1(st) September 2010 to 1(st) September 2015 and compared them to actual sales. Accuracy was calculated as the ratio of pre-launch estimate to actual sales...
April 18, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28413188/circulating-proprotein-convertase-subtilisin-kexin-type-9-pcsk9-concentration-and-risk-of-cardiovascular-events%C3%A3-systematic-review-and-meta-analysis-of-prospective-studies
#18
Yunjun Xiao, Chaoqiong Peng, Wei Huang, Jinzhou Zhang, Yang Gao, Jean H Kim, Eng-Kiong Yeoh, Xuefen Su
BACKGROUND: Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) and the risk of cardiovascular events. The aim of this meta-analysis was to evaluate this association in prospective studies.Methods and Results:A systematic search of prospective studies published through October 2016 was carried out in order to identify studies that met pre-specified inclusion criteria. After independent data extraction, summary relative risks were calculated using random-effects models...
April 11, 2017: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/28408313/preventing-cardiovascular-heart-disease-promising-nutraceutical-and-non-nutraceutical-treatments-for-cholesterol-management
#19
REVIEW
T P Johnston, T A Korolenko, M Pirro, A Sahebkar
Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease. Atherosclerosis resulting from hypercholesterolemia causes many serious cardiovascular diseases. Statins are generally accepted as a treatment of choice for lowering low-density lipoprotein (LDL) cholesterol, which reduces coronary heart disease morbidity and mortality. Since statin use can be associated with muscle problems and other adverse symptoms, non-adherence and discontinuation of statin therapy often leads to inadequate control of plasma cholesterol levels and increased cardiovascular risk...
April 10, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28405938/genetic-architecture-of-familial-hypercholesterolaemia
#20
REVIEW
Mahtab Sharifi, Marta Futema, Devaki Nair, Steve E Humphries
PURPOSE OF REVIEW: Familial hypercholesterolaemia (FH) is an inherited disorder of low-density lipoprotein cholesterol (LDL-C) which is characterised by a raised cholesterol level from birth and a high risk of premature coronary heart disease. In this paper, we review the genetic basis of FH and its impact on the clinical presentation. RECENT FINDINGS: Mutations in any of three genes (LDLR, APOB and PCSK9) are known to cause autosomal dominant FH, but a mutation can be found in only ∼40% of patients with a clinical diagnosis of FH...
May 2017: Current Cardiology Reports
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