Emerging evidence supports that cancer incidence is increased in patients with cardiovascular (CV) disease and heart failure (HF), and patients with HF frequently die from cancer. Recently, data have ...been generated showing that circulating factors in relation to HF promote tumour growth and development in murine models, providing proof that a causal relationship exists between both diseases. Several common pathophysiological mechanisms linking HF to cancer exist, and include inflammation, neuro‐hormonal activation, oxidative stress and a dysfunctional immune system. These shared mechanisms, in combination with risk factors, in concert may explain why patients with HF are prone to develop cancer. Investigating the new insights linking HF with cancer is rapidly becoming an exciting new field of research, and we herein review the most recent data. Besides insights in mechanisms, we call for clinical awareness, that is essential to optimize treatment strategies of patients having developed cancer with a history of HF. Finally, ongoing and future trials should strive for comprehensive phenotyping of both CV and cancer end points, to allow optimal usefulness of data, and to better describe and understand common characteristics of these two lethal diseases.
Poor translation of efficacy data derived from animal models can lead to clinical trials unlikely to benefit patients-or even put them at risk-and is a potential contributor to costly and unnecessary ...attrition in drug development.
To develop a tool to assess, validate and compare the clinical translatability of animal models used for the preliminary assessment of efficacy.
We performed a scoping review to identify the key aspects used to validate animal models. Eight domains (Epidemiology, Symptomatology and Natural History-SNH, Genetic, Biochemistry, Aetiology, Histology, Pharmacology and Endpoints) were identified. We drafted questions to evaluate the different facets of human disease simulation. We designed the Framework to Identify Models of Disease (FIMD) to include standardised instructions, a weighting and scoring system to compare models as well as factors to help interpret model similarity and evidence uncertainty. We also added a reporting quality and risk of bias assessment of drug intervention studies in the Pharmacological Validation domain. A web-based survey was conducted with experts from different stakeholders to gather input on the framework. We conducted a pilot study of the validation in two models for Type 2 Diabetes (T2D)-the ZDF rat and db/db mouse. Finally, we present a full validation and comparison of two animal models for Duchenne Muscular Dystrophy (DMD): the mdx mouse and GRMD dog. We show that there are significant differences between the mdx mouse and the GRMD dog, the latter mimicking the human epidemiological, SNH, and histological aspects to a greater extent than the mouse despite the overall lack of published data.
FIMD facilitates drug development by serving as the basis to select the most relevant model that can provide meaningful data and is more likely to generate translatable results to progress drug candidates to the clinic.
This paper tries to explain why unemployment has such a severe effect on the subjective well-being of people. It is already known that unemployed have among the lowest levels of subjective well-being ...of all people. This paper explains and tests why this is so. The explanation is based on the social production function theory. This theory states that ultimately people strive for physical well-being and social approval. Because unemployment affect both physical well-being and social approval its effect is so large. We elaborate this explanation to account for the difference between men and women. Because men and women have different ways of achieveing social approval unemployment is more detremental for men than for women. We further analyze differences between single men and women and married men and women to test the explanation that is put forward. Using the European Social Survey held in 2004 the hypotheses are tested. We do find that having a job is one of the main factors affecting subjective well-being, that this effect is bigger for men than for women and that women profit from the jobs of their partners whereas men do not.
Does the negative effect of union membership on job satisfaction, as shown in Anglophone countries, also hold for Continental Western Europe? Given the differences in industrial relations, I ...hypothesize that the effect will be different. I also test hypotheses about the effect of empowerment on job satisfaction, which might explain the negative union effect, and broaden the analysis to include pay satisfaction. Analyses of European Social Survey data show that the negative union effect does not exist for Continental Western Europe and that this can be explained by empowerment of employees.
Aims
Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)‐α were largely unsuccessful. Interleukin (IL)‐6 is an important ...inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL‐6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations.
Methods and results
Interleukin‐6 was measured in 2329 patients 89.4% with a left ventricular ejection fraction (LVEF) ≤ 40% of the BIOSTAT‐CHF cohort. The primary outcome was all‐cause mortality and HF hospitalization during 2 years, with all‐cause, cardiovascular (CV), and non‐CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL‐6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N‐terminal pro‐brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF‐α/IL‐1‐related biomarkers, or having iron deficiency, atrial fibrillation and LVEF > 40% independently predicted elevated IL‐6 levels. IL‐6 independently predicted the primary outcome HR (95% confidence interval) per doubling: 1.16 (1.11–1.21), P < 0.001, all‐cause mortality 1.22 (1.16–1.29), P < 0.001 and CV as well as non‐CV mortality 1.16 (1.09–1.24), P < 0.001; 1.31 (1.18–1.45), P < 0.001, but did not improve discrimination in previously published risk models.
Conclusions
In a large, heterogeneous cohort of HF patients, elevated IL‐6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL‐6 as a potential therapeutic target in specific HF subpopulations.
The co‐occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing ...body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre‐clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.
We describe the co‐occurrence of cancer and heart failure (HF), their potential shared risk factors, and their pathophysiological mechanisms. We advocate intense interaction between cardiologists and oncologists to achieve unifying hypotheses and collaborative pre‐clinical and clinical studies.
Reports of a reproducibility crisis combined with a high attrition rate in the pharmaceutical industry have put animal research increasingly under scrutiny in the past decade. Many researchers and ...the general public now question whether there is still a justification for conducting animal studies. While criticism of the current modus operandi in preclinical research is certainly warranted, the data on which these discussions are based are often unreliable. Several initiatives to address the internal validity and reporting quality of animal studies (e.g., Animals in Research: Reporting In Vivo Experiments (ARRIVE) and Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE) guidelines) have been introduced but seldom implemented. As for external validity, progress has been virtually absent. Nonetheless, the selection of optimal animal models of disease may prevent the conducting of clinical trials, based on unreliable preclinical data. Here, we discuss three contributions to tackle the evaluation of the predictive value of animal models of disease themselves. First, we developed the Framework to Identify Models of Disease (FIMD), the first step to standardise the assessment, validation and comparison of disease models. FIMD allows the identification of which aspects of the human disease are replicated in the animals, facilitating the selection of disease models more likely to predict human response. Second, we show an example of how systematic reviews and meta-analyses can provide another strategy to discriminate between disease models quantitatively. Third, we explore whether external validity is a factor in animal model selection in the Investigator’s Brochure (IB), and we use the IB-derisk tool to integrate preclinical pharmacokinetic and pharmacodynamic data in early clinical development. Through these contributions, we show how we can address external validity to evaluate the translatability and scientific value of animal models in drug development. However, while these methods have potential, it is the extent of their adoption by the scientific community that will define their impact. By promoting and adopting high quality study design and reporting, as well as a thorough assessment of the translatability of drug efficacy of animal models of disease, we will have robust data to challenge and improve the current animal research paradigm.
Selenium and outcome in heart failure Bomer, Nils; Grote Beverborg, Niels; Hoes, Martijn F. ...
European journal of heart failure,
August 2020, Letnik:
22, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Aims
Severe deficiency of the essential trace element selenium can cause myocardial dysfunction although the mechanism at cellular level is uncertain. Whether, in clinical practice, moderate selenium ...deficiency is associated with worse symptoms and outcome in patients with heart failure is unknown.
Methods and results
BIOSTAT‐CHF is a multinational, prospective, observational cohort study that enrolled patients with worsening heart failure. Serum concentrations of selenium were measured by inductively coupled plasma mass spectrometry. Primary endpoint was a composite of all‐cause mortality and hospitalization for heart failure; secondary endpoint was all‐cause mortality. To investigate potential mechanisms by which selenium deficiency might affect prognosis, human cardiomyocytes were cultured in absence of selenium, and mitochondrial function and oxidative stress were assessed. Serum selenium concentration (deficiency) was <70 μg/L in 485 (20.4%) patients, who were older, more often women, had worse New York Heart Association class, more severe signs and symptoms of heart failure and poorer exercise capacity (6‐min walking test) and quality of life (Kansas City Cardiomyopathy Questionnaire). Selenium deficiency was associated with higher rates of the primary endpoint hazard ratio (HR) 1.23; 95% confidence interval (CI) 1.06–1.42 and all‐cause mortality (HR 1.52; 95% CI 1.26–1.86). In cultured human cardiomyocytes, selenium deprivation impaired mitochondrial function and oxidative phosphorylation, and increased intracellular reactive oxygen species levels.
Conclusions
Selenium deficiency in heart failure patients is independently associated with impaired exercise tolerance and a 50% higher mortality rate, and impaired mitochondrial function in vitro, in human cardiomyocytes. Clinical trials are needed to investigate the effect of selenium supplements in patients with heart failure, especially if they have low plasma concentrations of selenium.
Clinical trial failures (>99%) in Alzheimer's disease are in stark contrast to positive efficacy data in animals. We evaluated the correlation between animal and clinical efficacy outcomes ...(cognition) in Alzheimer's disease using data from registered drugs as well as interventions tested in phase II or III clinical trials for Alzheimer's disease.
We identified 20 interventions, which were tested in 208 animal studies in 63 different animal models. Clinical outcome was correlated with animal results in 58% of cases. But, individual animal models showed divergent results across interventions, individual interventions showed divergent results across animal models, and animal model outcomes were determined with 16 different methods.
This result is unsurprising due to poor external validity (what do we model) of the animal models. Although the animal models all share Alzheimer's disease symptoms, none represents the whole syndrome. Investigators did not motivate why one model was chosen over another, and did not consider the ways the disease phenomena were generated (spontaneous, (experimentally) induced or by genetic modification), or the species characteristics, which determine the outcomes. The explanation for the lack of correlation between animal and human outcomes can be manifold: the pathogenesis of Alzheimer's disease is not reflected in the animal model or the outcomes are not comparable.
Our conclusion is that currently no animal models exist which are predictive for the efficacy of interventions for Alzheimer's disease.
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