Some results of a radon survey in 207 Serbian schools

In this paper the results of radon concentration measurements performed in 207 schools in 7 communities of Southern Serbia are presented. The annual radon concentration varied from 17 Bqm-3 to 428 Bq m-3 with a median value of 96 Bq m-3. The arithmetic mean (AM) of the 207 annual averages was 118 Bq m-3 with a standard deviation (SD) of 78 Bq m-3. The best distribution fitting of radon concentration by log-normal function was obtained. The log-normal parameters are the following: geometric mean (GM) = Bq m-3, geometric standard deviation (GSD) = 1.9. In addition, a spatial distribution of the indoor radon concentration over the investigated areas is observed.JRC.E.8-Nuclear securit

A 10-year follow-up of yearly indoor radon measurements in homes, review of other studies and implications on lung cancer risk estimates

Uncertainty on long-term average radon concentration has a large impact on lung cancer risk assessment in epidemiological studies. The uncertainty can be estimated by year-to-year radon concentration variability, however few data are available. In Italy a study has been planned and conducted to evaluate year-to-year radon variability over several years in normally inhabited dwellings, mainly located in Rome. This is the longest study of this kind in Europe; repeat radon measurements are carried out for 10 years using LR-115 radon detectors in the same home in consecutive years. The study includes 84 dwellings with long-term average radon concentration ranging from 28 to 636 Bq/m3. The result shows that year-to-year variability of repeated measurements made in the same home in different years is low, with an overall coefficient of variation of 17%. This is smaller than most of those observed in studies from other European countries and USA, ranging from 15% to 62%. Influencing factors that may explain the differences between this study and other studies have been discussed. Due to the low yearly variability estimated in the present 10-year study, a negligible impact on lung cancer risk estimate for the Italian epidemiologica

Peptides-Coated Oncolytic Vaccines for Cancer Personalized Medicine

Publisher Copyright: Copyright © 2022 Feola, Russo, Martins, Lopes, Vandermeulen, Fluhler, De Giorgi, Fusciello, Pesonen, Ylösmäki, Antignani, Chiaro, Hamdan, Feodoroff, Grönholm and Cerullo.Oncolytic Viruses (OVs) work through two main mechanisms of action: the direct lysis of the virus-infected cancer cells and the release of tumor antigens as a result of the viral burst. In this sc.enario, the OVs act as in situ cancer vaccines, since the immunogenicity of the virus is combined with tumor antigens, that direct the specificity of the anti-tumor adaptive immune response. However, this mechanism in some cases fails in eliciting a strong specific T cell response. One way to overcome this problem and enhance the priming efficiency is the production of genetically modified oncolytic viruses encoding one or more tumor antigens. To avoid the long and expensive process related to the engineering of the OVs, we have exploited an approach based on coating OVs (adenovirus and vaccinia virus) with tumor antigens. In this work, oncolytic viruses encoding tumor antigens and tumor antigen decorated adenoviral platform (PeptiCRAd) have been used as cancer vaccines and evaluated both for their prophylactic and therapeutic efficacy. We have first tested the oncolytic vaccines by exploiting the OVA model, moving then to TRP2, a more clinically relevant tumor antigen. Finally, both approaches have been investigated in tumor neo-antigens settings. Interestingly, both genetically modified oncolytic adenovirus and PeptiCRAd elicited T cells-specific anti-tumor responses. However, in vitro cross-representation experiments, showed an advantage of PeptiCRAd as regards the fast presentation of the model epitope SIINFEKL from OVA in an immunogenic rather than tolerogenic fashion. Here two approaches used as cancer oncolytic vaccines have been explored and characterized for their efficacy. Although the generation of specific anti-tumor T cells was elicited in both approaches, PeptiCRAd retains the advantage of being rapidly adaptable by coating the adenovirus with a different set of tumor antigens, which is crucial in personalized cancer vaccines clinical setting.Peer reviewe

A novel immunopeptidomic-based pipeline for the generation of personalized oncolytic cancer vaccines

Besides the isolation and identification of major histocompatibility complex I-restricted peptides from the surface of cancer cells, one of the challenges is eliciting an effective antitumor CD8+ T-cell-mediated response as part of therapeutic cancer vaccine. Therefore, the establishment of a solid pipeline for the downstream selection of clinically relevant peptides and the subsequent creation of therapeutic cancer vaccines are of utmost importance. Indeed, the use of peptides for eliciting specific antitumor adaptive immunity is hindered by two main limitations: the efficient selection of the most optimal candidate peptides and the use of a highly immunogenic platform to combine with the peptides to induce effective tumor-specific adaptive immune responses. Here, we describe for the first time a streamlined pipeline for the generation of personalized cancer vaccines starting from the isolation and selection of the most immunogenic peptide candidates expressed on the tumor cells and ending in the generation of efficient therapeutic oncolytic cancer vaccines. This immunopeptidomics-based pipeline was carefully validated in a murine colon tumor model CT26. Specifically, we used state-of-the-art immunoprecipitation and mass spectrometric methodologies to isolate > 8000 peptide targets from the CT26 tumor cell line. The selection of the target candidates was then based on two separate approaches: RNAseq analysis and HEX software. The latter is a tool previously developed by Jacopo, 2020, able to identify tumor antigens similar to pathogen antigens in order to exploit molecular mimicry and tumor pathogen cross-reactive T cells in cancer vaccine development. The generated list of candidates (26 in total) was further tested in a functional characterization assay using interferon-gamma enzyme-linked immunospot (ELISpot), reducing the number of candidates to six. These peptides were then tested in our previously described oncolytic cancer vaccine platform PeptiCRAd, a vaccine platform that combines an immunogenic oncolytic adenovirus (OAd) coated with tumor antigen peptides. In our work, PeptiCRAd was successfully used for the treatment of mice bearing CT26, controlling the primary malignant lesion and most importantly a secondary, nontreated, cancer lesion. These results confirmed the feasibility of applying the described pipeline for the selection of peptide candidates and generation of therapeutic oncolytic cancer vaccine, filling a gap in the field of cancer immunotherapy, and paving the way to translate our pipeline into human therapeutic approach.Peer reviewe

Novel oncolytic adenovirus expressing enhanced cross-hybrid IgGA Fc PD-L1 inhibitor activates multiple immune effector populations leading to enhanced tumor killing in vitro, in vivo and with patient-derived tumor organoids

Background Despite the success of immune checkpoint inhibitors against PD-L1 in the clinic, only a fraction of patients benefit from such therapy. A theoretical strategy to increase efficacy would be to arm such antibodies with Fc-mediated effector mechanisms. However, these effector mechanisms are inhibited or reduced due to toxicity issues since PD-L1 is not confined to the tumor and also expressed on healthy cells. To increase efficacy while minimizing toxicity, we designed an oncolytic adenovirus that secretes a cross-hybrid Fc-fusion peptide against PD-L1 able to elicit effector mechanisms of an IgG1 and also IgA1 consequently activating neutrophils, a population neglected by IgG1, in order to combine multiple effector mechanisms. Methods The cross-hybrid Fc-fusion peptide comprises of an Fc with the constant domains of an IgA1 and IgG1 which is connected to a PD-1 ectodomain via a GGGS linker and was cloned into an oncolytic adenovirus. We demonstrated that the oncolytic adenovirus was able to secrete the cross-hybrid Fc-fusion peptide able to bind to PD-L1 and activate multiple immune components enhancing tumor cytotoxicity in various cancer cell lines, in vivo and ex vivo renal-cell carcinoma patient-derived organoids. Results Using various techniques to measure cytotoxicity, the cross-hybrid Fc-fusion peptide expressed by the oncolytic adenovirus was shown to activate Fc-effector mechanisms of an IgA1 (neutrophil activation) as well as of an IgG1 (natural killer and complement activation). The activation of multiple effector mechanism simultaneously led to significantly increased tumor killing compared with FDA-approved PD-L1 checkpoint inhibitor (Atezolizumab), IgG1-PDL1 and IgA-PDL1 in various in vitro cell lines, in vivo models and ex vivo renal cell carcinoma organoids. Moreover, in vivo data demonstrated that Ad-Cab did not require CD8+ T cells, unlike conventional checkpoint inhibitors, since it was able to activate other effector populations. Conclusion Arming PD-L1 checkpoint inhibitors with Fc-effector mechanisms of both an IgA1 and an IgG1 can increase efficacy while maintaining safety by limiting expression to the tumor using oncolytic adenovirus. The increase in tumor killing is mostly attributed to the activation of multiple effector populations rather than activating a single effector population leading to significantly higher tumor killing.Peer reviewe

A map of radon in primary schools of Southern Serbia.

Between 2008 and 2011 a survey of radon was performed in primary schools of several districts in Southern Serbia. The survey design and some of the results have been published previously (Zunic et al., 2010; Carpentieri et al., 2011). This article deals with the geographical distribution of the measured radon concentrations. Applying geostatistical methods we generate “school radon maps” of expected mean concentrations and estimated probabilities that a concentration threshold is exceeded. The resulting maps show a clearly structured spatial pattern which appears related to the geological background. In particular in areas with vulcanite and granitoid rocks, elevated Rn concentrations can be expected. The “school map” can therefore be considered as proxy to a map of the geogenic radon potential, and allows identification of radon-prone zones, e.g., areas in which higher Rn concentrations can be expected for natural reasons. It must be stressed that the “radon hazard”, or potential risk, estimated in this way, has to be distinguished from the actual radon risk, which is a function of exposure. This in turn may require (depending on the target variable which is supposed to measure risk) the number of persons affected, occupancy factors of buildings and anthropogenic factors, and a more general approach

Accesso precoce al mercato: dalle approvazioni condizionate di EMA agli accordi negoziali particolari di AIFA

The European Medicines Agency (EMA) has adopted assessment systems and drug registration procedures to respond to the needs for rapid patient access to therapies, such as Conditional Marketing Approval (CMA) and Under Exceptional Circumstances approval (UEC). The Italian Medicine Agency (AIFA) has introduced tools for governing prescriptive behaviour in order to promote appropriateness and correct use of drugs and to manage the uncertainty of financial impact, including Managed Entry Agreements (MEAs). The MEAs are conditional access agreements to the market for new drugs aimed at managing the uncertainty on the clinical and economic effects of the drugs themselves. The aim of this study is to analyse, through the use of the information systems of the AIFA and the institutional website of the EMA, how the drugs authorised by EMA with CMA or UEC have been managed on the access side to the Italian NHS. This in order to understand how the uncertainty deriving from the authorisation processes was subsequently reflected on the reimbursement processes to be borne by the NHS. From the analyses carried out, it emerges that 64% of the drugs approved with CMA were admitted to reimbursement and 68% of those approved with the UEC procedure. Furthermore, it can be noted that approval with CMA is predictive for the application of a financial-based or outcome-based MEA (61%), with the application of a monitoring register, unlike the drugs approved UEC for which no conditional reimbursement arrangements have been applied at the patient level. Furthermore, by carrying out a comparative analysis of the time of access to market following negotiation, from the positive opinion of the CHMP to the decision published in the Official Gazette of the Italian Republic, it emerged that the drugs approved by the UEC procedure take on average more time (897 days) to arrive at the price and reimbursement (P&R) compared to CMA drugs (636 days). Considering instead only the period from the request for P&R to the determination of P&R for the same group of drugs, the process seems to be on average faster for the drugs classified as UEC than for those with CMA (329 vs. 510 days)

Some results of a radon survey in 207 Serbian schools

In this paper the results of radon concentration measurements performed in 207 schools in 7 communities of Southern Serbia are presented. The annual radon concentration varied from 17 Bqm-3 to 428 Bq m-3 with a median value of 96 Bq m-3. The arithmetic mean (AM) of the 207 annual averages was 118 Bq m-3 with a standard deviation (SD)of 78 Bq m-3. The best distribution fitting of radon concentration by log-normal function was obtained. The log-normal parameters are the following: geometric mean (GM) = 97 Bq m-3, geometric standard deviation (GSD) = 1.9. In addition, a spatial distribution of the indoor radon concentration over the investigated areas is observed

Estimating the relation between radon concentrations in dwellings and schools; on the example of data from the Balkan region, South East Europe

Given its relevance as hazard to human health, today almost unanimously accepted, indoor Rn is increasingly subject to regulation with the purpose of reducing the risk. While so far, investigations were mostly focused on domestic indoor Rn, attention has been extended to working environments, as people spend good (or bad) part of their life in offices, schools, shops, factories and other workplaces. In the recently issued European Basic Safety Standards (BSS 2014) the same maximum reference levels for indoor Rn concentration, long-term mean 300 Bq/m³, were therefore set for dwellings and workplaces. Many national and regional indoor surveys exist for dwellings, but only a few for schools and kindergartens and little for other workplaces. In particular schools are given increasing attention because they are workplaces for students and teachers alike, and avoiding unnecessary risk to children is naturally seen as an especially important objective. It must be assumed that buildings on top of a ground with the same radon potential, but with different building characteristics and usage patterns, as is typically the case for dwellings and schools, have systematically different indoor Rn concentrations. Although this is well accepted, little is known about how these differences can be quantified, and what their extent is. We show on indoor Rn datasets of schools and dwellings from several regions in South-East Europe how such relations can be estimated and give results. These can be used for identifying regions in which one may decide to allocate resources preferentially for intensified surveys or mitigation or remediation activity, specifically targeted to a type of indoor environment

Quanto vale la negoziazione del prezzo di un nuovo farmaco in Italia?

Italy was used as a case study to investigate the determinants of the difference between the price proposal for medicines submitted by the industry and the final negotiated price (∆P). Data was gathered through the information system used by Italian Medicines Agency (AIFA) and the time-frame for this analysis is 2013-2017. Factors influencing the delta price were analyzed through a regression analysis. Forty four orphan drugs and 89 new other molecular entities obtained reimbursement in the period considered. Following the negotiation process, prices proposed by Marketing Authorization Holders (MAH) were lowered during the negotiation process by 25.1% and 28.6% on average for orphan drugs and other molecules respectively. The price reduction was higher for innovative drugs (-32.2%). Statistically significant determinants associated to higher price reduction were: i) the implementation of a product specific monitoring registry, ii) the negotiation of a financial-based (FB) Managed Entry Agreement, iii) a target population larger than 20,000 patients, iv) an expected National Health Service expenditure larger than € 200 million. The impact of some variables on the delta price was predictable (e.g. for drugs with an expected higher budget impact and a larger target population), others were more surprising (e.g. a significant price reduction for "innovative" drugs). The implementation of FB agreements, which often rely on confidential arrangements, was one of the determinants with higher impact on price reduction