Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial.

BACKGROUND: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. METHODS: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. FINDINGS: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care. INTERPRETATION: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. FUNDING: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.

Regulation of macronutrient intake in termites: A dietary self-selection experiment.

Many animals have been shown to select among nutritionally complementary foods to reach a specific balance of nutrients that optimizes key life history traits. Nutritional ecology theory, however, predicts that an animal with a diet that is very stable in its composition, and with nutritional requirements that do not vary in their balance through time, would not need to display such mechanisms of regulation. Here we use the Australian termite Nasutitermes exitiosus as a model to test this prediction for the first time. We used the nutritional geometric framework to investigate the regulation of carbohydrate and protein, as well as the effects on foraging behaviour of protein type and group caste composition and size. Our results support the prediction of nutritional ecology, as termites failed to actively defend a well-defined macronutrient ratio. Termites maintained food collection relatively constant across protein type and group composition, and only appear to vary their collection by avoiding diets too rich in protein.

Datura innoxia plants hydroponically-inoculated with Agrobacterium rhizogenes display an enhanced growth and alkaloid metabolism.

BACKGROUND: The production of secondary metabolites through the culture of entire plants is of great interest. Soilless culture, such as hydroponics, enables the control of plant growth and metabolism. Specific environmental conditions must be developed to maximize the productivity of medicinal plants used as efficient natural bioreactors. METHODS: The nutrient solution of newly established hydroponic cultures ofDatura innoxia Mill. were inoculated with Agrobacterium rhizogenes (A.r.) wild strains (TR7, TR107, 11325 or 15834). Growth and the alkaloid contents of roots and aerial parts were analyzed. Axenic cultures were also performed with modified TR7 strains containing the egfp or gus reporter gene. In vitro isolated root cultures enabled the phenological and molecular demonstration of gene transfer. RESULTS: A.r.TR 7 led to a greater improvement in plant secondary metabolism and growth. Positive expression of the reporter genes occurred. Isolation and subculture of some of the roots of these plants showed a hairy root phenotype; molecular tests proved the transfer of bacterial genes into the roots isolated from the plants. CONCLUSIONS: Hyoscyamine and scopolamine productivity is enhanced after A.r. inoculation in the nutrient solution of hydroponic plants. Transformation events occur in the original roots of the plants. This leads to chimeric plants with a part of their roots harboring a hairy root phenotype. Such semi-composite plants could be used for successful specialized metabolite bioproduction in greenhouses.

A theoretical exploration of dietary collective medication in social insects.

Animals often alter their food choices following a pathogen infection in order to increase immune function and combat the infection. Whether social animals that collect food for their brood or nestmates adjust their nutrient intake to the infection states of their social partners is virtually unexplored. Here we develop an individual-based model of nutritional geometry to examine the impact of collective nutrient balancing on pathogen spread in a social insect colony. The model simulates a hypothetical social insect colony infected by a horizontally transmitted parasite. Simulation experiments suggest that collective nutrition, by which foragers adjust their nutrient intake to simultaneously address their own nutritional needs as well as those of their infected nestmates, is an efficient social immunity mechanism to limit contamination when immune responses are short. Impaired foraging in infected workers can favour colony resilience when pathogen transmission rate is low (by reducing contacts with the few infected foragers) or trigger colony collapse when transmission rate is fast (by depleting the entire pool of foragers). Our theoretical examination of dietary collective medication in social insects suggests a new possible mechanism by which colonies can defend themselves against pathogens and provides a conceptual framework for experimental investigations of the nutritional immunology of social animals.

Chemical diversity and antiviral potential in the pantropical Diospyros genus.

A screening using a dengue replicon virus-cell-based assay was performed on 3563 ethyl acetate (EtOAc) extracts from different parts of 1500 plants. The screening led to the selection of species from the genus Diospyros (Ebenaceae), among which 25 species distributed in tropical areas showed significant inhibitory activity on dengue virus replication. A metabolic analysis was conducted from the UPLC-HRMS profiles of 33 biologically active and inactive plant extracts, and their metabolic proximity is presented in the form of a dendrogram. The results of the study showed that chemical similarity is not related to plant species or organ. Overall, metabolomic profiling allowed us to define large groups of extracts, comprising both active and inactive ones. Closely related profiles from active extracts might indicate that the common major components of these extracts were responsible for the antiviral activity, while the comparison of chemically similar active and inactive extracts, will permit to find compounds of interest. Eventually, the phytochemical investigation of Diospyros glans bark EtOAc extract afforded usnic acid and 7 known ursane- and lupane-type triterpenoids, among which 5 were found significantly active against dengue virus replication. The inhibitory potency of these compounds was also evaluated on a DENV-NS5 RNA-dependant RNA polymerase assay.

Trastuzumab emtansine in advanced human epidermal growth factor receptor 2-positive breast cancer.

INTRODUCTION: Ado- trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate composed of trastuzumab, a stable linker (MCC), and the cytotoxic agent DM1 (derivative of maytansine; mertansine). T-DM1 retains the mechanisms of action of trastuzumab, but also acts as a, selectively delivered, tubulin inhibitor. Following antigen-mediated binding to the tumor cell, T-DM1 is endocytosed and intracellularly catabolized resulting in the release of its cytotoxic moiety. AREAS COVERED: T-DM1 has completed Phase III development and compared favorably with the lapatinib/capecitabine combination with a superior response rate (objective response rate [ORR]) and duration of response, longer duration of disease control (progression-free survival [PFS]), prolonged overall survival and improved tolerability and quality of life in patients with prior treatment with trastuzumab and a taxane. In a separate Phase III, T-DM1 was compared with any other chosen regimen in patients who had at least received two prior HER2-directed therapies. T-DM1 nearly doubled PFS. EXPERT OPINION: T-DM1 (Kadcyla) has become the treatment of choice in second-line and beyond for patients with advanced HER2-expressing breast cancer.

GPs' views concerning spirituality and the use of the FICA tool in palliative care in Flanders: a qualitative study.

BACKGROUND: According to recent recommendations, healthcare professionals in palliative care should be able to perform a spiritual history-taking. Previous findings suggest that the FICA tool is feasible for the clinical assessment of spirituality. However, little is known about the views of GPs on the use of this tool. AIM: To provide a solid overview of the views of Flemish GPs concerning spirituality and the use of the FICA tool for spiritual history-taking in palliative care. DESIGN AND SETTING: Qualitative interview study in Flanders, Belgium. METHOD: Twenty-three GPs participated in a semi-structured interview. The interviews were analysed by thematic analysis, which includes line-by-line coding and the generation of descriptive and analytical themes. RESULTS: The interviewees stated that they would keep in mind the questions of the FICA tool while having a spiritual conversation, but not use them as a checklist. The content of the tool was generally appreciated as relevant, however, many GPs found the tool too structured and prescribed, and that it limited their spontaneity. They suggested rephrasing the questions into spoken language. The perceived barriers during spiritual conversations included feelings of discomfort and fear, and the lack of time and specific training. Factors that facilitated spiritual conversations included the patients' acceptance of their diagnosis, a trusting relationship, and respect for the patients' beliefs. CONCLUSION: A palliative care process with attention focused on the patient's spirituality was generally perceived as a tough but rewarding experience. The study concludes that the FICA tool could be a feasible instrument for the clinical assessment of spirituality, provided that certain substantive and linguistic adjustments are made. Additional research is needed to find the most suitable model for spiritual history-taking, in response to the specific needs of GPs.