Engaging European society at the forefront of cancer research and care: How discussions at the 5th Gago Conference on European Science policy led to the Heidelberg Manifesto

European cancer research stakeholders met in October 2022 in Heidelberg, Germany, at the 5th Gago conference on European Cancer Policy, to discuss the current cancer research and cancer care policy landscape in Europe. Meeting participants highlighted gaps in the existing European programmes focusing on cancer research, including Europe's Beating Cancer Plan (EBCP), the Mission on Cancer (MoC), Understanding Cancer (UNCAN.eu), and the joint action CRANE, and put forward the next priorities, in the form of the Heidelberg Manifesto for cancer research. This meeting report presents all discussions that shed light on how infrastructures can be effectively shaped for translational, prevention, clinical and outcomes cancer research, with a focus on implementation and sustainability and while engaging patients and the public. In addition, we summarize recommendations on how to introduce frameworks for the digitalization of European cancer research. Finally, we discuss what structures, commitment, and resources are needed to establish a collaborative cancer research environment in Europe to achieve the scale required for innovation.

Strengthening Biorisk Management in Research Laboratories with Security-Sensitive Biological Agents Like SARS-CoV-2.

In this chapter, we discuss potential incidents associated with SARS-CoV-2 experimental work in high containment research laboratories. The risk landscape in high containment laboratories is changing due to the strong innovation drive of the life sciences research. Thus, the WHO has recommended life sciences organizations to incorporate good research practices and ethical principles into a risk-based approach of the biorisk management (BRM). Currently, BRM systems in high containment laboratories are predominantly steered by operational personnel and laboratory professional. It is well known that without having a systematic approach and leadership support from the organization, the BRM system in the high containment laboratory will not be sustainable. Even though the roles of organizations and their leadership in establishing the BRM system are spelt out in many international standards, guidance documents and national legislations, operational aspects of these roles are rarely discussed.It is therefore important for everyone to understand about their roles in organizational processes (communication, decision, and performance evaluation) involved in implementation of BRM related operational activities. In this chapter, discussion is based on operational activities of four main organizational behaviors that are considered to have strengthened BRM systems in high containment laboratories: (1) displaying a visible commitment and support to the BRM system from different levels of management, (2) developing a competent and responsible workforce with BRM technical skills and problem identification/solving skills, (3) integrating learning and improvement principles into the BRM system, and (4) enhancing the continuous motivation of laboratory personnel to avoid complacency. The categorization of these organizational behaviors is based on the International Atomic Energy Agency's principles and guidance for strengthening the safety and security culture in nuclear facilities. Furthermore, we encourage the laboratory management to identify gaps in processes and activities related to those organizational behaviors so that one could rapidly address biosafety and biosecurity vulnerabilities in high containment laboratories.

Synthesis of sugars embodying conjugated carbonyl systems and related triazole derivatives from carboxymethyl glycoside lactones. Evaluation of their antimicrobial activity and toxicity.

The synthesis of a series of pyranoid derivatives comprising a conjugated carbonyl function and related triazole derivatives, structurally suitable for bioactivity evaluation, was achieved in few steps starting from readily available carboxymethyl glycoside lactones (CMGL). 3-Enopyranosid-2-uloses were generated by oxidation/elimination of tri-O-acylated 2-hydroxy pyranosides. Subsequent Wittig olefination provided stereoselectively 2-C-branched-chain conjugated dienepyranosides with (E)-configuration around the exocyclic double bond. A heterogeneous CuI/Amberlyst-catalyzed 'click' chemistry protocol was used to convert glycosides bearing a propargyl moiety into the corresponding 1,2,3-triazoles. These new molecules were screened for their in vitro antibacterial and antifungal activities and those containing conjugated carbonyl systems demonstrated the best efficacy. (N-Dodecylcarbamoyl)methyl enone glycerosides were the most active ones among the enones tested. The α-anomer displayed very strong activities against Bacillus cereus and Bacillus subtilis and strong activity toward Enterococcus faecalis and the fungal pathogen Penicillium aurantiogriseum. The corresponding ß-anomer presented a very strong inhibitory effect against two fungal species (Aspergillus niger and P. aurantiogriseum). (N-Dodecyl-/N-propargyl/or N-benzylcarbamoyl)methyl dienepyranosides exhibited selectively a strong activity toward E. faecalis. Further acute toxicity evaluation indicated low toxic effect of the (N-dodecylcarbamoyl)methyl enone glyceroside α-anomer and of the carbamoylmethyl dienepyranosides N-protected with propargyl or benzyl groups.

Initial impacts of global risk mitigation measures taken during the combatting of the COVID-19 pandemic.

This paper presents an analysis of risk mitigation measures taken by countries around the world facing the current COVID-19 outbreak. In light of the current pandemic the authors collated and clustered (using harmonised terminology) the risk mitigation measures taken around the globe in the combat to contain, and since March 11, 2020, to limit the spread of the SARS-CoV-2 virus known to cause the Coronavirus disease 2019 (COVID-19). This overview gathers lessons learnt, providing an update on the current knowledge for authorities, sectors and first responders on the effectiveness of said measures, and may allow enhanced prevention, preparedness and response for future outbreaks. Various measures such as mobility restrictions, physical distancing, hygienic measures, socio-economic restrictions, communication and international support mechanisms have been clustered and are reviewed in terms of the nature of the actions taken and their qualitative early-perceived impact. At the time of writing, it is still too premature to express the quantitative effectiveness of each risk mitigation cluster, but it seems that the best mitigation results are reported when applying a combination of voluntary and enforceable measures.

Synthesis of novel purine nucleosides towards a selective inhibition of human butyrylcholinesterase.

The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown to treat the late symptoms of Alzheimer's disease as well as to act as neuroprotecting agents. In this work, we disclose the synthesis of novel 2-acetamidopurine nucleosides and, for the first time, regioselective N(7)-glycosylation with 2-acetamido-6-chloropurine, promoted by trimethylsilyl triflate, was accomplished by tuning the reaction conditions (acetonitrile as solvent, 65 degrees C, 5h) starting from 1-acetoxy bicyclic glycosyl donors, or by direct coupling of a methyl glucopyranoside with the nucleobase to obtain only N(7) nucleosides in reasonable yield (55-60%). The nucleosides as well as their sugar precursors were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. While none of the compounds tested inhibited AChE, remarkably, some of the N(7) nucleosides and sugar bicyclic derivatives showed potent inhibition towards BChE. Nanomolar inhibition was obtained for one compound competing well with rivastigmine, a drug currently in use for the treatment of Alzheimer's disease. Experimental results showed that the presence of benzyl groups on the carbohydrate scaffold and the N(7)-linked purine nucleobase were necessary for strong BChE inactivation. A preliminary evaluation of the acute cytotoxicity of the elongated bicyclic sugar precursors and nucleosides was performed indicating low values, in the same order of magnitude as those of rivastigmine.

Alkyl deoxy-arabino-hexopyranosides: synthesis, surface properties, and biological activities.

Octyl and dodecyl glycosides possessing 2-deoxy-arabino-hexopyranoside moieties belonging to the D- and L-series in their alpha- and beta-forms were synthesized by reaction of an acetyl protected glycal with octanol or dodecanol, catalyzed by triphenylphosphine hydrobromide, followed by deprotection. Their surface properties were studied and discussed in terms of the adsorption and aggregation parameters, pC(20), CMC, and gamma(CMC). The antimicrobial activities were assessed using the paper disk diffusion and broth dilution methods. Both the octyl and dodecyl 2-deoxy beta-D-glycosides inhibited significantly Enterococcus faecalis, a microbe also highly susceptible to dodecyl 2,6-dideoxy-alpha-L-arabino-hexopyranoside. This compound was particularly active against Bacillus cereus and Bacillus subtilis, presenting for both Bacillus species a minimal inhibitory concentration of the same order of magnitude and a minimal lethal concentration even smaller than that obtained for chloramphenicol, a bioactivity which remained unaltered after 1 year solution storage at 4 degrees C. In addition, activity over Listeria monocytogenes was also observed. Direct cytotoxicity and genotoxicity of the glycosides were determined by proliferative index (mitotic index) evaluation in peripheral human lymphocytes of healthy donors. All compounds induced acute toxicity effects, and the response was dose dependent for the alpha-anomer of both the alkyl 2-deoxy-arabino-hexopyranosides and for the corresponding dodecyl beta-anomer, what suggests that non-toxic but still bioactive concentrations may be found for these compounds.

New In Vitro Studies on the Bioprofile of Genista tenera Antihyperglycemic Extract.

The inhibition of α-glucosidase and glucose-6-phosphatase, two enzymes involved in the carbohydrate metabolism, is an important target to control glycaemia on individuals with type 2 diabetes. In this work we report for the first time the inhibition of both enzymes by the antihyperglycemic n-butanol extract from Genista tenera (Fabaceae). This extract decreased α-glucosidase and glucose-6-phosphatase activities to 0.97 and 80.25 %, respectively, being more effective than acarbose, and phlorizin, the positive controls, which reduced enzymes activities only to 17.39 and 96.06 %. Once inflammation and oxidative stress are related to diabetic impairments, the anti-inflammatory activity of the extract was also evaluated, through its inhibitory activity over COX-1 enzyme (47.5 % inhibition). Moreover, after induction of oxidative stress by UV radiation, the viability of irradiated rat liver hepatoma cells exposed to the extract was significantly higher (67.82 %) than that promoted by ascorbic acid, the positive control (45.05 %). In addition, the stability of the extract under gastrointestinal conditions was evaluated by HPLC-DAD-ESI-MS/MS. Flavonoid diglycosides were identified as the main constituents of the extract, and no alterations in the chemical composition nor in the antioxidant activity were observed after in vitro digestion with artificial gastric and pancreatic juices.

Bioactivity studies and chemical profile of the antidiabetic plant Genista tenera.

AIM OF THE STUDY: Genista tenera is a plant endemic to the island of Madeira and is used in folk medicine to control diabetes. In the present work we evaluate the antihyperglycaemic activity of its n-butanol extract and determine its chromatographic profile. In addition, this extract, the ethyl acetate and diethyl ether plant extracts were studied in order to assess the plant antioxidant and acetylcholinesterase inhibitory activities, as well as its cyto- and genotoxicities. MATERIALS AND METHODS: HPLC-DAD-ESI-MS was used to analyze the flavonoid profile of the n-butanol extract. The antihyperglycaemic activity of this extract was performed over streptozotocin induced diabetic Wistar rats (200 mg/kg, bw/day), for 15 days. Antioxidant activity (DPPH assay) and acetylcholinesterase inhibitory effect (Ellman method) were also performed. Acute cytotoxicity and genotoxicity were assessed by proliferative index quantification and the short-term chromosomal aberration technique, after exposure of lymphocytes to the extracts. RESULTS AND CONCLUSIONS: The n-butanol extract, where 21 monoglycosyl and 12 diglycosyl flavonoids were detected, significantly lowered blood glucose levels, bringing them to normal values after 15 days of treatment. The best radical scavenging activity was observed for the ethyl acetate extract (48.7% at 139.1 microg/mL), which was also the most effective one at the minimal concentration tested. The highest acetylcholinesterase inhibitory activity (77.0% at 70.0 microg/mL) was also obtained with the ethyl acetate extract. In vitro toxicity studies showed no evidence for acute cytotoxicity or genotoxicity. This is the first report on antidiabetic activity of genus Genista.