Personalised medicine is a medical model that aims to provide tailor-made prevention and treatment strategies for defined groups of individuals. The concept brings new challenges to the translational ...step, both in clinical relevance and validity of models. We have developed a set of recommendations aimed at improving the robustness of preclinical methods in translational research for personalised medicine.
These recommendations have been developed following four main steps: (1) a scoping review of the literature with a gap analysis, (2) working sessions with a wide range of experts in the field, (3) a consensus workshop, and (4) preparation of the final set of recommendations.
Despite the progress in developing innovative and complex preclinical model systems, to date there are fundamental deficits in translational methods that prevent the further development of personalised medicine. The literature review highlighted five main gaps, relating to the relevance of experimental models, quality assessment practices, reporting, regulation, and a gap between preclinical and clinical research. We identified five points of focus for the recommendations, based on the consensus reached during the consultation meetings: (1) clinically relevant translational research, (2) robust model development, (3) transparency and education, (4) revised regulation, and (5) interaction with clinical research and patient engagement. Here, we present a set of 15 recommendations aimed at improving the robustness of preclinical methods in translational research for personalised medicine.
Appropriate preclinical models should be an integral contributor to interventional clinical trial success rates, and predictive translational models are a fundamental requirement to realise the dream of personalised medicine. The implementation of these guidelines is ambitious, and it is only through the active involvement of all relevant stakeholders in this field that we will be able to make an impact and effectuate a change which will facilitate improved translation of personalised medicine in the future.
When a flame-retarded plastic material is selected for an application, the decision of the design engineer is based on the technical property profile and the price/performance ratio of the product. ...Looking at the large number of available flame retardant compounds on the market, it is important to understand differences in the performance of materials due to the chemical structure of the flame retardant, explains Elmar Schmitt of Clariant Produkte (Deutschland) GmbH.
Immune checkpoint inhibitors (ICI) have demonstrated meaningful patterns of clinical efficacy across various cancers. During their development, novel regulatory strategies and clinical design ...approaches were explored. This metrics‐based narrative review examines submission strategies and clinical evidence expectations of the US, European, and Japanese drug agencies, as well as their impact on approval and overall development times. Also discussed is the role of emerging clinical science and biomarker evaluation to get the first six ICI initially approved.
Products containing phytoestrogens are increasingly promoted as the “natural” alternative to estrogen replacement therapy. In the present study, we have used the in vitro micronucleus assay in L5178Y ...mouse lymphoma cells to investigate the genotoxic potential of the isoflavone daidzein, and of four daidzein metabolites known to be formed in humans. Whereas no induction of micronuclei was observed with daidzein up to the limit of solubility (100
μM), all four daidzein metabolites, i.e. equol (2.3-fold induction at 100
μM),
O-desmethylangolensin (6.2-fold induction at 10
μM), 4′,6,7-isoflavone (6.7-fold induction at 100
μM) and 3′,4′,7-isoflavone (8.2-fold induction at 100
μM) induced micronuclei in a concentration-dependent manner. Thus, both reductive and oxidative metabolites of the soy isoflavone daidzein exhibit genotoxic potential in vitro.
Anthocyanins, which are natural plant pigments from the flavonoid family, represent substantial constituents of the human diet. Because some other bioflavonoids are known to have estrogenic activity, ...the aim of this study was to determine the estrogenic activity of the anthocyanine aglycones. Binding affinity to the estrogen receptor-α was 10,000- to 20,000-fold lower than that of the endogenous estrogen estradiol. In the estrogen receptor-positive cell line MCF-7, the anthocyanidins induced expression of a reporter gene. The tested anthocyanidins showed estrogen-inducible cell proliferation in two cell lines (MCF-7 and BG-1), but not in the receptor-negative human breast cancer cell line MDA-MB-231. The phytoestrogen-induced cell proliferation could be blocked by addition of the receptor antagonist 4-hydroxytamoxifen. Combination treatments with the endogenous estrogen estradiol resulted in a reduction of estradiol-induced cell proliferation. Overall, the tested anthocyanidins exert estrogenic activity, which might play a role in altering the development of hormone-dependent adverse effects.
Estrogen-related cancers are often associated with the hormone’s tumor promoting activity. Recently, estradiol has also been demonstrated to induce gene mutations in the physiological concentration ...range. Mitotic disturbances are found at higher concentrations. In the present study we demonstrate data suggesting an additional mechanism for the induction of genetic damage, i.e. chromosomal breakage. Estrogen receptor-positive (BG-1) and -negative (UCI) human ovarian cancer cell lines were investigated for micronucleus formation after treatment with estradiol. BG-1 cells but not UCI cells showed an increase in micronucleus formation which correlated with the estradiol-induced cell proliferation. The specific estradiol receptor antagonist hydroxytamoxifen suppressed the formation of micronuclei in BG-1 cells. Increased micronucleus frequencies were also seen after normalization of the data to the number of cell divisions. Kinetochore analysis revealed a difference between micronuclei induced by picomolar concentrations of estradiol (kinetochore-negative) and micromolar concentrations (predominantly kinetochore-positive) leading to mitotic disturbances. In accordance with this finding, analysis of the cell cycle revealed decreased cell numbers in G2/M phase after treatment with picomolar concentrations, usually not found after mitotic disturbances. We hypothesize that hormone-specific forcing of responsive cells through the cell cycle leads to an override of checkpoints operating under homeostatic control of the cell cycle, resulting in genomic instability.
The carcinogenicity of sex hormones is considered to be the result of a combination of genotoxic and epigenetic modes of action. For estrogens, genotoxic activities include DNA damage by reactive ...metabolites and indirect genotoxicity by redox cycling and production of reactive oxygen species. Here, we present data on the induction of micronuclei in estrogen receptor-positive (MCF-7) and -negative (MDA) human breast cancer cell lines treated with estradiol to support an additional mechanism of chromosomal damage. MCF-7 cells, but not MDA cells, treated with estradiol in the picomolar concentration range showed an increase in micronucleus formation which correlated with the estradiol-induced cell proliferation. Addition of the specific estradiol-receptor antagonist hydroxytamoxifen suppressed the estradiol-induced formation of micronuclei in MCF-7 cells. Increased frequencies were also seen after normalization of the data to the number of cell divisions by additional treatment of the cells with cytochalasin B. Thus, formation of micronuclei was not due to the chromosomal damaging activity of estradiol. The induced genomic damage may be explained by a hormone-specific forcing of responsive cells through the cell cycle, thereby overriding checkpoints operating under homeostatic control of the cell cycle.
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