JCL roundtable: Lipid treatment targets

This Roundtable discussion concerns atherogenic risk markers and treatment targets used by clinical lipidologists in daily practice. Our purpose is to understand the risk marker framework that supports and enables the new ACC/AHA/Multisociety Cholesterol Guidelines. Some biomarkers are highly associated with atherogenic risk but fail to qualify as treatment targets. Prominent examples are high-density lipoprotein cholesterol, for which targeted treatment has failed to reduce cardiovascular risk, and lipoprotein(a), which currently lacks a highly effective mode of treatment. As a consequence, guidelines have focused consistently on low-density lipoprotein cholesterol (LDL-C) and more recently on non–high-density lipoprotein cholesterol. We discuss a new calculation for LDL-C that shows greater accuracy than the commonly performed Friedewald calculation. LDL-C treatment goals have renewed prominence in the 2018 Guidelines. Thresholds for treatment initiation or intensification inherently establish goals of reducing atherogenic cholesterol levels below the thresholds. Treatment goals may be absolute, such as less than 70 mg/dL for LDL-C in very high-risk secondary prevention or relative, such as 50% or greater reduction of LDL-C. The timeframe of treatment is another consideration because milder treatment started earlier may sometimes be preferred over stronger treatment given late in the course of atherosclerotic progression. Advanced lipid testing and vascular imaging, particularly coronary artery calcium, also have their place in risk assessment to guide clinical lipid practice.     

Validation: a critical step in bringing biomarkers to clinical fruition

Screening is vital to reducing morbidity and mortality due to cancer. A primary cause of poor survival is that many cancers are detected late and often after they have metastasized to distant sites. Therapies, therefore, become challenging for late-stage disease and are not successful for nearly all cancer types. The mortality rates from cancers where screening tools are available are lower than from cancers for which no viable screening tools exist. Even for cancers where screening tools currently exist, there is room for improvement, either in the accuracy of the tests or in increasing widespread use of screening by making the tests less invasive. For instance, despite widely available screening methods that can detect early-stage colon cancer or its precursors, only approximately 40% of newly diagnosed colon cancers are localized. It is a challenge to develop screening tests that are not only highly sensitive but also highly specific, to avoid putting patients through unnecessary biopsies and treatment. Biomarkers have great potential to improve the existing diagnostic accuracies of screening modalities and substitute invasive screening methods with noninvasive methodologies using bodily fluids such as plasma, serum, saliva, urine, etc. Biomarkers are defined by the National Institutes of Health as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” In this commentary, we discuss important measures that could be taken to increase the chances of bringing biomarkers to clinical fruition.     

Malondialdehyde as biomarker of oxidative damage to lipids caused by smoking

Thiobarbituric acid reactive substances (TBARS) and malondialdehyde (MDA) have been used as biomarkers of lipid oxidation for more than thirty years. The validity of these biomarkers has been rightfully criticized for a lack of specificity and problems with post sampling formation. Numerous assays have been published for their analysis giving rise to reference intervals for healthy non-smoking humans varying more than to orders of magnitude. In spite of these problems, these biomarkers remain among the most commonly reported indices of oxidative damage and the present review focuses on the problems associated with MDA/TBARS analysis, their potential as biomarkers of oxidative stress and the effect of smoking on MDA status.     

A personal history of markers of myocyte injury [myocardial infarction

Background

The measurement of proteins in blood to reflect damage to the heart is one of the most successful examples of easily measured biomarkers identifying a serious major health problem. The concept of using a blood test to reflect organ or cell injury requires a substance that is very abundant in the target cell, has a means of reaching blood, a reasonable half-life in blood, and ideally a specific form reflective only of the target cell in tissue. The myocyte's major role is contraction so proteins involved in contraction or the energy to support it should be good candidate markers.

Conclusions

All the various biomarkers that have been used to detect cardiac damage are involved in contraction or energy metabolism, but the markers evolved empirically starting with transaminases in the 1950s leading to troponins in the 1990s. This history is reviewed with reflections on my experiences with developing assays for CK-MB and Troponin I.     

Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics

Introduction: Diseases of the Central Nervous System (CNS) affect millions of people worldwide, with the number of people affected quickly growing. Unfortunately, the successful development of CNS-acting drugs is less than 10%, and this is attributed to the complexity of the CNS, unexpected side effects, difficulties in penetrating the blood-brain barrier and lack of biomarkers.

Areas covered: Herein, the authors first review how pharmacokinetic/pharmacodynamic (PK/PD) models are designed to predict the dose-dependent time course of effect, and how they are used to translate drug effects from animal to man. Then, the authors discuss how pharmacometabolomics gives insight into system-wide pharmacological effects and why it is a promising method to study interspecies differences. Finally, the authors advocate the application of PK/PD-metabolomics modeling to advance translational CNS drug development by discussing its opportunities and challenges.

Expert opinion: It is envisioned that PK/PD-metabolomics will increase our understanding of CNS drug effects and improve translational CNS drug development, thereby increasing success rates. The successful future development of this concept will require multi-level and longitudinal biomarker evaluation over a large dose range, multi-tissue biomarker evaluation, and the generation of a proof of principle by application to multiple CNS drugs in multiple species.     

The combined use of three widely available biochemical markers as predictor of organ failure in critically ill patients

Background: We hypothesized that lactate dehydrogenase, LDH/albumin ratio in combination with or without magnesium (Mg²⁺) could predict organ failure in critically ill adult patients. The aim of this study was to describe a new risk index for organ failure or mortality in critically ill patients based on a combination of these routinely available biochemical plasma biomarkers.

Methods: Patients?≥?18 years admitted to the intensive care unit (ICU) were screened. Albumin and LDH were analyzed at the time of admission to ICU (n?=?347). Organ failure assessed with ‘Sequential Organ Failure Assessment’ (SOFA) score was used, and 30-day mortality was recorded. The predictive value of the test was calculated using the areas under the receiving operating characteristic (ROC) curve.

Results: The LDH/albumin ratio was higher in patients who developed organ failure as compared to those who did not (p?n?=?183) admitted to ICU from the emergency department, the predictive values were 0.86 and 0.80, respectively.

Conclusion: The LDH/albumin ratio at ICU admission was associated with the development of multiple organ failure and 30-day mortality in this prospective study. The clinical value of this biomarker as a predictor of organ failure in critically ill patients is yet to be defined.     

Pre-analytical variables of circulating cell-free nucleosomes containing 5-methylcytosine DNA or histone modification H3K9Me3

Aim: To evaluate pre-analytical variables of circulating cell-free nucleosomes containing 5-methylcytosine DNA (5mC) or histone modification H3K9Me3 (H3K9Me3).

Materials and methods: Six studies were designed to assess the possible influence of pre-analytical variables. Study 1: influence of stasis and contamination with white-cells and platelets. Study 2: influence of within-day variations. Study 3: influence of day-to-day variation. Study 4: influence of temperature during handling and storage, and of neoplastic disease. Study 5: influence of colonoscopy. Study 6: influence of the surgical trauma. 5mC and H3K9Me3 measurements were performed using enzyme-linked immunosorbent assays.

Results: Stasis, white-cell and platelet contamination, within-day variations, varying storage time before centrifugation, colonoscopy, and surgical trauma had no significant influence on levels of 5mC or H3K9Me3. Day-to-day variations of 12.7% and 11.5% (intra-individual) and 98.1% and 60.8% (inter-individual) were shown for 5mC and H3K9Me3, respectively. Levels of 5mC or H3K9Me3 were significantly higher in samples stored at room temperature until centrifugation compared to samples stored on ice. Patients with cancer had significantly lower levels of 5mC or H3K9Me3 compared to levels in healthy individuals.

Conclusion: Levels of 5mC or H3K9Me3 appear stable in most pre-analytical settings if blood samples are stored at room temperature until centrifugation.     

尿毒症患者外周血单个核细胞超保守区域转录表达水平的分析

目的 尿毒症是由于肾衰竭致使代谢产物和其他有毒物质在体内蓄积而引起的一种自身中毒综合征,超保守区域转录子(transcribed ultra-conserved regions,T-UCRs)是lncRNA重要组成部分,转录自人类基因组中481个极度保守区域,希望分析尿毒症外周血单个核细胞的超保守区域转录表达水平,从而发现尿毒症潜在的诊断和预后的生物标志物.方法 本研究采用T-UCRs芯片技术分析了15例尿毒症患者和15例健康对照组的外周血单个核细胞的超保守区域转录表达水平,并且用实时荧光定量PCR技术验证了尿毒症患者与健康对照组表达差异最显著的基因的表达水平.结果 对比尿毒症患者与健康对照组,通过芯片筛选出T UCRs发现21个T-UCRs表达水平上调,49个T-UCRs表达水平下调,在表达上调和下调的T-UCRs中,对应的超保守区域uc.458-表达水平最显著(P-2.47524E-24;FC=3118.5361),其相关基因为RBFOX2.结论 通过GO分析以及验证后发现uc.458-可能是尿毒症潜在的生物标志物,RBFOX2可能是尿毒症潜在的关键基因.     

Cardiotoxicity of systemic agents used in breast cancer

Several breast cancer therapies can lead to cardiovascular toxicity: drugs such anthracyclines can cause permanent damage, anti-HER2 agents may cause transitory and reversible cardiac dysfunction and others, such as those used in endocrine therapy, primarily disturb lipid metabolism. Considering the seriousness of these complications, trials are now being conducted to address cardiotoxicity associated with new drugs; however, to fully understand their toxicity profiles, longer follow-up is needed. In this review, we compile the information available about cardiac toxicity related to well-established systemic breast cancer treatments, as well as newer drugs, including antiangiogenics, mTOR inhibitors and novel anti-HER2 agents. We also describe current and next generation cardiac biomarkers and functional tests that can optimize treatment and reduce and prevent the incidence of treatment-related cardiotoxicity