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The selective inhibition of enzymes that catalyze the conversion of arachidonic acid to inflammatory eicosanoids represents a promising approach for cancer therapy. We, therefore, focus on the incorporation of metabolically stable, sterically demanding and hydrophobic carboranes into existing dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids. Here, we present the first carborane-containing dual COX-2/5-LO inhibitors derived from RWJ-63556. The replacement of the fluorophenyl moiety by meta- or para-carborane resulted in five carborane-containing derivatives 3, 6, 9, 13 and 17 that show high inhibitory activities toward COX-2 and 5-LO in vitro. Cell viability studies on the A375 melanoma cell line revealed that meta-carborane derivative 3 shows higher anticancer activity compared to RWJ-63556 based on accumulation of lipid droplets in the cells due to blockage of the COX-2 and 5-LO pathways, indicating a promising approach for the design of potent dual COX-2/5-LO inhibitors.

Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivatives R-830, S-2474, KME-4, and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p-carborane and further substitution of the p-position resulted in four carborane-based di-tert-butylphenol analogs that show no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p-carborane analogs R-830-Cb, S-2474-Cb, KME-4-Cb, and E-5110-Cb exhibit lower anticancer activity compared to the related di-tert-butylphenols. Inter-estingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell pro-liferation more potently than its carbon-based R-830 counterpart. Considering all the ad-vantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies.

The presence of inflammatory mediators in the tumor microenvironment, such as cytokines, growth factors or eicosanoids, indicate cancer-related inflammatory processes. Targeting these inflammatory mediators and related signal pathways may offer a rational strategy for the treatment of cancer. This study focuses on the incorporation of metabolically stable, sterically demanding, and hydrophobic dicarba-closo-dodecaboranes (carboranes) into dual cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids. The di-tert-butylphenol derivative tebufelone represents a selective dual COX-2/5-LO inhibitor. The incorporation of meta- or para-carborane into the tebufelone scaffold resulted in eight carborane-based tebufelone analogs that show no COX inhibition but 5-LO inhibitory activities in vitro. Cell viability studies on HT29 colon adenocarcinoma cells revealed that the para-carborane analog 8 exhibits higher anticancer activity compared to tebufelone through the inhibition of cell proliferation. Hence, this strategy proved to be a promising approach to design potent 5-LO inhibitors with potential application as cytostatic agents.

"Evidence" is a key term in medicine and health services research, including Health Technology Assessment (HTA). Randomized clinical trials (RCTs) have undoubtedly dominated the scene of generating evidence for a long period of time, becoming the hallmark of evidence-based medicine (EBM). However, due to a number of misunderstandings, the lay audience and some researchers have sometimes placed too much trust in RCTs compared to other methods of investigation. One of the principal misunderstandings is to consider RCTs findings as isolated and self-apparent pieces of information. In other words, what has been essentially lacking was the awareness of the value-context of the evidence and, in particular, the value- and theory-ladenness (normativity) of scientific knowledge. This paper aims to emphasize the normativity that exists in the production of scientific knowledge, and in particular in the conduct of RCTs as well as in the performance of HTA. The work is based on some lessons learned from Philosophy of Science and the European project "VALIDATE" (VALues In Doing Assessments of healthcare TEchnologies"). VALIDATE was a three-year EU Erasmus+ strategic partnerships project (2018-2021), in which training in the field of HTA was further optimized by using insights from political science and ethics (in accordance with the recent definition of HTA). Our analysis may reveal useful insights for addressing some challenges that HTA is going to face in the future.

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Item does not contain fulltext, Health technology assessment (HTA) aims, through empirical analysis, to shed light on the value of health technologies (O'Rourke et al. [2020, International Journal of Technology Assessment in Health Care 36, 187-90]). HTA is, then, where facts and values meet. But how, where, and when do facts and values meet in HTA? Currently, HTA is usually portrayed as a sequential process, starting with empirical analysis (assessment), followed by a deliberation on the implications of the findings for a judgment of a health technology's value (appraisal). In this paper, we will argue that in HTA, empirical analysis and normative inquiry are much more closely entwined. In fact, as we hope to show, normative commitments act as an indispensable guide for the collection and interpretation of empirical evidence. Drawing on policy sciences, we will suggest a concrete methodology that can help HTA practitioners to integrate empirical analysis and normative inquiry in a transparent way. The proposed methodology can be conceived as a concrete means for conducting a scoping exercise in HTA. Moreover, it offers a distinct way of giving stakeholders a structural and constructive role in HTA. This paper outlines the approach developed by the values in doing assessments of health technologies project, a project funded by the Erasmus+ program (contract number 2018-1-NL01-KA203-038960), which is the European Union's program to support education, training, youth, and sport in Europe. The project has resulted in an E-learning course, an accompanying handbook, and a consensus statement, all freely available from the project's website www.validatehta.eu.

A2A adenosine receptors (A2A-AR) have a cardio-protective function upon ischemia and reperfusion, but on the other hand, their stimulation could lead to arrhythmias. Our aim was to investigate the potential use of the PET radiotracer [18F]FLUDA to determine the A2A-AR availability non-invasively for diagnosis of the A2AR status. Therefore, we compared mice with a cardiomyocyte-specific overexpressing of the human A2A-AR (A2A-AR TG) with the respective wild type (WT). We determined: (1) the functional impact of FLUDA on the contractile function of atrial mouse samples, (2) the binding parameters (Bmax and KD) of [18F]FLUDA on mouse and additionally on human atrial tissue samples by autoradiographic studies, and investigated (3) the in vivo uptake of the radiotracer by dynamic PET imaging in the two A2A-AR TG and WT. After A2A-AR stimulation by CGS 21680 in isolated atrial preparations antagonistic effects of FLUDA were found in A2A-AR-TG animals but not in WT mice. Radiolabeled [18F]FLUDA exhibited a KD of 5.9 ± 1.6 nM and a Bmax of 455 ± 78 fmol/mg protein in cardiac samples of A2A-AR TG, whereas in WT, as well as in human atrial preparations only low specific binding could was found. Dynamic PET studies revealed a significantly higher initial uptake of [18F]FLUDA into the myocardium of A2A-AR TG compared to WT. The hA2A-AR-specific binding of [18F]FLUDA in vivo was verified by pre-administration of the highly affine A2AAR-specific antagonist istradefylline. Conclusion: [18F]FLUDA is a promising PET probe for the non-invasive assessment of the A2A-AR as a marker for pathologies linked to an increased A2A-AR density in the heart, as shown in patients with heart failure.

PET data, mice; i.v. administration of [18F]FLUDA with and without pre-administration of istradefylline

Objectives: To conduct a formative evaluation of applying the VALIDATE approach in practice by 1) assessing how students appreciated the e-learning course, 2) exploring how, for what purposes and with what outcomes the acquired VALIDATE competences subsequently were used in internships in different institutional contexts, and how this was shaped by these contexts, and 3) what this shows on real-world use of VALIDATE. Methods: Comparative discussion of experiences of applying the VALIDATE approach via a semistructured survey and oral feedback from e-course students; final reports on internships in HTA practice, followed by semi-structured interviews with interns and supervisors to complement and interpret results. Results: All students considered the VALIDATE approach an enlightening and important addition to current HTA knowledge, especially regarding understanding the relation between empirical analysis and normative inquiry, identifying policy relevant questions and using the method of reconstructing interpretive frames for scoping. The latter appeared intellectually challenging and requiring some prior HTA knowledge. The use the VALIDATE approach in practice shows that interns productively re-defined the HTA problem, based on appreciation of different stakeholders definition of the issue; they experienced constraints from retrieving all relevant perspectives from existing literature as well as from institutional rules and routines. Conclusions: Some challenges in applying the VALIDATE approach deserve attention for its future use: currently used research approaches often assume a problem as given ; and the data needed on different perspectives is often not reported in scientific literature. Finally, data gathering on and evaluation of value dimensions was experienced as challenging.

Health technology assessment (HTA) aims, through empirical analysis, to shed light on the value of health technologies (O'Rourke et al. [2020, International Journal of Technology Assessment in Health Care 36, 187-90]). HTA is, then, where facts and values meet. But how, where, and when do facts and values meet in HTA? Currently, HTA is usually portrayed as a sequential process, starting with empirical analysis (assessment), followed by a deliberation on the implications of the findings for a judgment of a health technology's value (appraisal). In this paper, we will argue that in HTA, empirical analysis and normative inquiry are much more closely entwined. In fact, as we hope to show, normative commitments act as an indispensable guide for the collection and interpretation of empirical evidence. Drawing on policy sciences, we will suggest a concrete methodology that can help HTA practitioners to integrate empirical analysis and normative inquiry in a transparent way. The proposed methodology can be conceived as a concrete means for conducting a scoping exercise in HTA. Moreover, it offers a distinct way of giving stakeholders a structural and constructive role in HTA. This paper outlines the approach developed by the values in doing assessments of health technologies project, a project funded by the Erasmus+ program (contract number 2018-1-NL01-KA203-038960), which is the European Union's program to support education, training, youth, and sport in Europe. The project has resulted in an E-learning course, an accompanying handbook, and a consensus statement, all freely available from the project's website www.validatehta.eu.

Background Si afferma spesso che l’HTA debba molto del suo successo al legame con l’Evidence-based Medicine (EBM), un approccio alla medicina che pone enfasi su un particolare tipo di “evidenza”, ossia quella proveniente dagli studi randomizzati (RCTs) e le revisioni sistematiche. In tempi recenti, tuttavia, i processi di HTA sembrano sempre di più incorporare nelle valutazioni dati provenienti da studi non randomizzati e di Real World Evidence. È un fenomeno preoccupante? L’HTA sta forse abbassando la qualità delle sue indagini? I report di HTA hanno bisogno necessariamente di dati provenienti da RCTs e revisioni sistematiche per essere realizzati? Obiettivi del lavoro L’obiettivo del lavoro è quello di provare a fornire una risposta a tali quesiti. In particolare, l’obiettivo è quello di esplicitare, da un punto di vista epistemologico, il ruolo che gli studi non randomizzati e i RWD possono svolgere nei processi di HTA. Metodologia del lavoro L’analisi verrà condotta attraverso un processo di rivisitazione delle principali conclusioni a cui è pervenuta l’odierna epistemologia della scienza sul tema dell’evidenza e della loro applicazione al campo dell’HTA nell’ambito del progetto VALIDATE (VAlues in Doing Assessments of healthcare Technologies). Quest’ultima è una ricerca finanziata dall’Unione Europea nell’ambito del programma Erasmus+ per la formazione della prossima generazione di esperti nell’HTA. Per l’analisi autori di riferimento saranno coloro i quali hanno contribuito, a vario titolo, al superamento in ambito filosofico della c.d. dicotomia “fatti-valori” come Popper, Khun, Duhem, Quine, Gadamer, Habermas e Putman. Conclusioni Gli studi randomizzati e RWD non rappresentano una minaccia per l’HTA. Le questioni che accompagnano il loro uso non sono questioni di legittimità ma di rilevanza.

Prioritization of COVID-19 vaccines is one of the most relevant topics in the current pandemic emergency. Prioritization decisions are political decisions that are value-laden, and as such of ethical nature. Despite the clear political and ethical nature of this topic, prioritization decisions are often interpreted and presented as scientific decisions. The aim of this article is twofold. First, we aim to show critical points that characterize certain pandemic vaccination plans from the ethical viewpoint using four dimensions (problem definitions, incorporation of different perspectives, context, and specification). The four dimensions were drawn from findings of the European project “VALIDATE” (VALues In Doing Assessments of healthcare TEchnologies”, https://validatehta.eu). Second, we aim to reframe the issue about prioritization itself in the light of the four dimensions mentioned. Our conclusion is that policy-problem definitions, incorporation of different perspectives, contextual considerations and specification of moral principles seem to be common critical points of some vaccination plan documents. The European project “VALIDATE” seems to be able to provide a useful and profitable approach to address many of these critical points.