To review recent developments in the field of cholesteryl ester transfer protein (CETP) inhibition from clinical trials and genomic analyses which have the potential to impact future clinical ...programs.
CETP plays an important role in remodelling of lipoproteins. A large body of evidence suggests that the presence of low CETP activity should have favourable effects on lipid profiles and cardiovascular risk. However, a number of clinical development programs of pharmacological CETP inhibitors have been disappointing with reports of toxicity and clinical futility. These findings have led many to consider abandoning CETP inhibition as a potential strategy for cardiovascular prevention. However, recent observations from genomic analyses and post hoc observations of prior clinical trials have given greater insights into the potential relationship between CETP inhibition and cardiovascular risk. This has highlighted the importance of lowering levels of atherogenic lipoproteins.
These findings provide a pathway for ongoing clinical development of CETP inhibitors, where the potential to play an important role in the prevention of cardiovascular disease may still be possible. The lessons learned and pathway forward for new CETP inhibitors will be reviewed.
The American Society for Preventive Cardiology (ASPC) "Ten things to know about ten cardiovascular disease risk factors – 2022" is a summary document regarding cardiovascular disease (CVD) risk ...factors. This 2022 update provides summary tables of ten things to know about 10 CVD risk factors and builds upon the foundation of prior annual versions of "Ten things to know about ten cardiovascular disease risk factors” published since 2020. This 2022 version provides the perspective of ASPC members and includes updated sentinel references (i.e., applicable guidelines and select reviews) for each CVD risk factor section. The ten CVD risk factors include unhealthful dietary intake, physical inactivity, dyslipidemia, pre-diabetes/diabetes, high blood pressure, obesity, considerations of select populations (older age, race/ethnicity, and sex differences), thrombosis (with smoking as a potential contributor to thrombosis), kidney dysfunction and genetics/familial hypercholesterolemia. Other CVD risk factors may be relevant, beyond the CVD risk factors discussed here. However, it is the intent of the ASPC "Ten things to know about ten cardiovascular disease risk factors – 2022” to provide a tabular overview of things to know about ten of the most common CVD risk factors applicable to preventive cardiology and provide ready access to applicable guidelines and sentinel reviews.
Elevated levels of low-density lipoprotein (LDL) cholesterol have been unequivocally demonstrated to play a causal role in atherosclerotic cardiovascular disease. The last thirty years have witnessed ...a generation of clinical trials that have demonstrated a reduction in cardiovascular risk with the use of increasing intensive lipid lowering regimens involving statin therapy in combination with other agents. However, many patients fail to achieve treatment mandated LDL cholesterol goals. This highlights the need to develop additional approaches to lower LDL cholesterol levels.
(i) Contemporary data highlighting the atherogenicity of LDL cholesterol and cardiovascular benefits of current lipid lowering therapies. (ii) Importance of statin intolerance and inability to achieve LDL cholesterol goals in driving ongoing cardiovascular risk. (iii) Emergence of new therapeutic agents designed to achieve more effective lowering of LDL cholesterol.
Effective lowering of LDL cholesterol plays a critical role in approaches to the prevention of cardiovascular disease. A greater number of patients will require combinations of agents to achieve optimal lipid control. Accordingly, new agents will be required to provide sufficient choice for patients at high cardiovascular risk.
Numerous candidate EEG biomarkers have been put forward for use in clinical research on autism spectrum disorder (ASD), but biomarker development has been hindered by limited attention to the ...psychometric properties of derived variables, inconsistent results across small studies, and variable methodology. The authors evaluated the basic psychometric properties of a battery of EEG assays for their potential suitability as biomarkers in clinical trials.
This was a large, multisite, naturalistic study in 6- to 11-year-old children who either had an ASD diagnosis (N=280) or were typically developing (N=119). The authors evaluated an EEG battery composed of well-studied assays of resting-state activity, face perception (faces task), biological motion perception, and visual evoked potentials (VEPs). Biomarker psychometrics were evaluated in terms of acquisition rates, construct performance, and 6-week stability. Preliminary evaluation of use was explored through group discrimination and phenotypic correlations.
Three assays (resting state, faces task, and VEP) show promise in terms of acquisition rates and construct performance. Six-week stability values in the ASD group were moderate (intraclass correlations ≥0.66) for the faces task latency of the P1 and N170, the VEP amplitude of N1 and P1, and resting alpha power. Group discrimination and phenotype correlations were primarily observed for the faces task P1 and N170.
In the context of a large-scale, rigorous evaluation of candidate EEG biomarkers for use in ASD clinical trials, neural response to faces emerged as a promising biomarker for continued evaluation. Resting-state activity and VEP yielded mixed results. The study's biological motion perception assay failed to display construct performance. The results provide information about EEG biomarker performance that is relevant for the next stage of biomarker development efforts focused on context of use.
Microscale-based separations are increasingly being applied in the field of metabolomics for the analysis of small-molecule metabolites. These methods have the potential to provide improved ...sensitivity, less solvent waste, and reduced sample-size requirements. Ion-pair free microflow-based global metabolomics methods, which we recently reported, were further compared to analytical flow ion-pairing reagent containing methods using a sample set from a urea cycle disorder (UCD) mouse model. Mouse urine and brain homogenate samples representing healthy, diseased, and disease-treated animals were analyzed by both methods. Data processing was performed using univariate and multivariate techniques followed by analyte trend analysis. The microflow methods performed comparably to the analytical flow ion-pairing methods with the ability to separate the three sample groups when analyzed by partial least-squares analysis. The number of detected metabolic features present after each data processing step was similar between the microflow-based methods and the ion-pairing methods in the negative ionization mode. The observed analyte trend and coverage of known UCD biomarkers were the same for both evaluated approaches. The 12.5-fold reduction in sample injection volume required for the microflow-based separations highlights the potential of this method to support studies with sample-size limitations.
At a time when recurrent widespread scandals continue to put the ethics of businesspeople in question, this essay offers an open systems and experiential pedagogical approach designed to help a new ...generation of managers become more insightful and socially responsible. In joining the on-going conversation concerning curriculum development and learning outcomes in this journal and others, we believe that reintegrating the teaching of other disciplines, specifically developments in law and sustainability as part of strategy, may be a place to start.
Triglyceride (TG) levels encompass several lipoproteins that have been implicated in atherogenic pathways. Whether TG levels independently associate with cardiovascular disease both overall and, in ...particular among patients with established coronary artery disease (CAD) and type 2 diabetes (T2DM), remains controversial. Data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial was used to evaluate patients with T2DM and CAD. Cox proportional hazards models were used to determine the association between TG levels and outcomes. Stepwise adjustment was performed for demographics, clinical factors, lipid profile and statin treatment. The primary composite outcome was time to CV death, myocardial infarction (MI), or stroke and secondary outcome was CV death. Among 2,307 patients with T2DM and CAD, the mean (±SD) TG levels were 181 (±136) with a median (Q1–Q3) 148mg/dL (104–219). Overall, 51% of patients had TG <150 mg/dL, 18% 150–199 mg/dL, 28% 200–499 mg/dL and 3% ≥500 mg/dL. Participants with elevated TG levels (≥150 mg/dL) were younger (61 vs 63 years, p <0.001), had higher BMI (32 vs 30 kg/m2, p <0.001), more likely to have had prior MI (34.2 vs 30.1%, p = 0.033) and revascularization (25.8 vs 21.4%, p = 0.013), had lower HDL-C (34 vs 39 mg/dL, p <0.001) and higher HbA1c (8 vs 7%, p <0.001). In unadjusted analyses, baseline TG levels were linearly associated with both the primary composite and secondary outcomes. In fully adjusted analyses, every 50 mg/dL increase in TG level was associated with a 3.8% (HR 1.038, 95%CI 1.004–1.072, p <0.001) increase in the primary composite outcome and a 6.4% (HR 1.064 95%CI 1.018–1.113, p <0.001) increase in the secondary outcome. There was no interaction between TG and outcomes within key subgroups including female sex, additional non-coronary atherosclerotic disease, CKD or low LDL (<100 mg/dL). In conclusion, among patients with T2DM and CAD, elevated TG were independently associated with adverse cardiovascular outcomes, even after adjustment for clinical and simple biochemical covariates.
TRIM5α is an antiviral, cytoplasmic, E3 ubiquitin (Ub) ligase that assembles on incoming retroviral capsids and induces their premature dissociation. It inhibits reverse transcription of the viral ...genome and can also synthesize unanchored polyubiquitin (polyUb) chains to stimulate innate immune responses. Here, we show that TRIM5α employs the E2 Ub‐conjugating enzyme Ube2W to anchor the Lys63‐linked polyUb chains in a process of TRIM5α auto‐ubiquitination. Chain anchoring is initiated, in cells and in vitro, through Ube2W‐catalyzed monoubiquitination of TRIM5α. This modification serves as a substrate for the elongation of anchored Lys63‐linked polyUb chains, catalyzed by the heterodimeric E2 enzyme Ube2N/Ube2V2. Ube2W targets multiple TRIM5α internal lysines with Ub especially lysines 45 and 50, rather than modifying the N‐terminal amino group, which is instead αN‐acetylated in cells. E2 depletion or Ub mutation inhibits TRIM5α ubiquitination in cells and restores restricted viral reverse transcription, but not infection. Our data indicate that the stepwise formation of anchored Lys63‐linked polyUb is a critical early step in the TRIM5α restriction mechanism and identify the E2 Ub‐conjugating cofactors involved.
Synopsis
The anti‐retroviral factor TRIM5α restricts viral reverse transcription by recruiting two E2 Ub conjugation enzymes, leading to K63‐polyubiquitin chain anchoring to multiple internal TRIM5α lysine residues.
Ube2W, the heterodimer Ube2N/Ube2V2, and ubiquitin lysine 63 are each required for restriction of retroviral reverse transcription by TRIM5α.
The TRIM5α‐mediated blocks to retroviral reverse transcription and infection can be genetically uncoupled.
Ube2W serves to anchor Ube2N/V2‐synthesised K63‐linked polyubiquitin to several internal lysine residues in TRIM5α in vitro, principally RING lysines 45 and 50.
In cells, the N‐terminus of TRIM5α is quantitatively demethionylated and αN‐acetylated, preventing N‐terminal ubiquitin conjugation by Ube2W.
The anti‐retroviral factor TRIM5α restricts viral reverse transcription by recruiting two E2 Ub conjugation enzymes, leading to K63‐polyubiquitin chain anchoring to multiple internal TRIM5α lysine residues.
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