Update on the use of fibrates: focus on bezafibrate

Low-density lipoprotein-cholesterol (LDL-C) is a well established coronary heart disease (CHD) risk factor. However, the ability of this metabolic risk factor alone to identify individuals at rigk for future CHD events is limited. The raised triglycerides-low high-density lipoprotein-cholesterol (HDL-C) dyslipidaemia was shown to be an important cardiovascular risk factor independently of LDL-C levels. Fibric acid derivatives (fibrates) have been used in clinical practice for more than 2 decades as a class of agents known to decrease triglyceride levels while substantially increasing HDL-C levels. Through peroxisome proliferator-activated α-receptors, fibrates have a significant impact on the synthesis of several apolipoproteins and enzymes of lipoprotein metabolism as well as on the expression of several genes involved in fibrinolysis and inflammation. Data from recent primary and secondary prevention clinical trials demonstrate the efficacy of fibrate therapy in patients with the raised triglycerides-low HDL-C dyslipidaemia. This review summarizes current data regarding mechanism of action and the metbolic effects of fibrates, as well as results from major clinical trials on the efficacy of this mode of lipid lowering therapy. In addition, recent data from subgroup analyses of the Bezafibrate Infarction Prevention trial, demonstrating several important metabolic and long-term cardiovascular effects of bezafibrate therapy, are detailed

Aversion vs. Abstinence: Conceptual Distinctions for the Receptivity Toward Algorithmic Decision-Making Systems Within Value-laden Contexts

Whilst algorithmic decision-making systems (ADMS) become increasingly pertinent across several contexts, many remain reluctant to adopt such systems, preferring human alternatives – often explored as “Algorithm Aversion”. However, the associated literature primarily frames this tendency in a utility-focused fashion, based on users’ perceptions of efficacy or accuracy. This framing offers a narrow scope of “aversion” that neglects emotional and experiential elements that may be at play, as well as especially prominent in “value-laden contexts” (e.g., medicine). This study uses an inductive approach to identifying various concepts and themes emerging from open-ended responses to the potential use of a future ADMS in such a context. Different reactions (both reluctant and receptive) of ADMS are then discussed and offered conceptual distinctions that may inform future examinations of the resulting biases. In doing so, we start to respond to the call for qualitative research examining the underlying motives related to Algorithm Aversion

Bezafibrate treatment is associated with a reduced rate of re-hospitalization in smokers after acute coronary syndrome

Background: Significantly increased rate of hospitalizations in current smokers is a major smoking-related problem which is associated with a heavy economic burden, whereas car­diovascular disease accounted for nearly half of hospitalizations. The effect of bezafibrate on the rate of re-hospitalization in smokers already treated with statin immediately post-acute coronary syndrome (ACS) is unknown. The aim of this study was to investigate 30-day rate of re-hospitalization in current smokers participating in the ACS Israeli Surveys (ACSIS) and who were treated on discharge with a bezafibrate/statin combination vs. statin alone. Methods: The study population comprised 3392 patients with confirmed current smoking status from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 3189 (94%) were discharged with statin alone, 203 (6%) with a combination of a statin and bezafibrate. Results: Thirty-day re-hospitalization rate was significantly lower in patients from the com­bination group than in their counterparts from the statin monotherapy group: 12.8% vs. 19%, p = 0.028. Multivariable analysis identified the combined bezafibrate/statin treatment as an independent predictor of reduced risk of 30-day re-hospitalization rate with odds ratio (OR) 0.53 (95% confidence interval [CI] 0.31–0.91), and it corresponded to 47% risk reduction. Other significant variables in our model associated with independent risk of 30-day re-hospi­talization rate during the follow-up were female gender (OR 1.43, CI 1.05–1.95, p = 0.03) and age > 65 years (OR 1.49, CI 1.13–1.95, p = 0.004). Conclusions: Adding bezafibrate to statin in smokers was associated with a significantly reduced 30-day rate of re-hospitalization after ACS.

Mechanism based heparanase inhibitors reduce cancer metastasis in vivo

Heparan sulfate proteoglycans (HSPGs) mediate essential interactions throughout the extracellular matrix (ECM), providing signals that regulate cellular growth and development. Altered HSPG composition during tumorigenesis strongly aids cancer progression. Heparanase (HPSE) is the principal enzyme responsible for extracellular heparan sulfate catabolism and is markedly up-regulated in aggressive cancers. HPSE overactivity degrades HSPGs within the ECM, facilitating metastatic dissemination and releasing mitogens that drive cellular proliferation. Reducing extracellular HPSE activity reduces cancer growth, but few effective inhibitors are known, and none are clinically approved. Inspired by the natural glycosidase inhibitor cyclophellitol, we developed nanomolar mechanism-based, irreversible HPSE inhibitors that are effective within physiological environments. Application of cyclophellitol-derived HPSE inhibitors reduces cancer aggression in cellulo and significantly ameliorates murine metastasis. Mechanism-based irreversible HPSE inhibition is an unexplored anticancer strategy. We demonstrate the feasibility of such compounds to control pathological HPSE-driven malignancies.NWO"Endoglycoprobe”714.018.002Bio-organic Synthesi

Inferring plant–plant interactions using remote sensing

Rapid technological advancements and increasing data availability have improved the capacity to monitor and evaluate Earth's ecology via remote sensing. However, remote sensing is notoriously ‘blind’ to fine-scale ecological processes such as interactions among plants, which encompass a central topic in ecology. Here, we discuss how remote sensing technologies can help infer plant–plant interactions and their roles in shaping plant-based systems at individual, community and landscape levels. At each of these levels, we outline the key attributes of ecosystems that emerge as a product of plant–plant interactions and could possibly be detected by remote sensing data. We review the theoretical bases, approaches and prospects of how inference of plant–plant interactions can be assessed remotely. At the individual level, we illustrate how close-range remote sensing tools can help to infer plant–plant interactions, especially in experimental settings. At the community level, we use forests to illustrate how remotely sensed community structure can be used to infer dominant interactions as a fundamental force in shaping plant communities. At the landscape level, we highlight how remotely sensed attributes of vegetation states and spatial vegetation patterns can be used to assess the role of local plant–plant interactions in shaping landscape ecological systems. Synthesis. Remote sensing extends the domain of plant ecology to broader and finer spatial scales, assisting to scale ecological patterns and search for generic rules. Robust remote sensing approaches are likely to extend our understanding of how plant–plant interactions shape ecological processes across scales—from individuals to landscapes. Combining these approaches with theories, models, experiments, data-driven approaches and data analysis algorithms will firmly embed remote sensing techniques into ecological context and open new pathways to better understand biotic interactions

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival