The cross-talk among cells of the innate immunity can greatly affect both innate and adaptive responses. Here we analyzed the molecular interactions between human natural killer (NK) cells and autologous macrophages. Activated NK cells killed M0 and M2, whereas M1 macrophages were more resistant to lysis because of their higher expression of HLA class I molecules. Following exposure to LPS or bacillus Calmette-Guérin, M0 and M2, but not polarized (endotoxin tolerant) M1 macrophages, induced strong activation of resting NK cells. The expression of CD69 and CD25 activation markers and the acquisition of cytotoxicity against tumor cells and immature dendritic cells required soluble factors being mostly contact independent. On the contrary, IFN-γ production was contact dependent and required the interaction of DNAM-1 and 2B4 (on NK) with their ligands on macrophages as well as IL-18. IL-18 was involved also in the acquisition of CCR7 by NK cells. Interestingly, M0 and M2 cells expressed a membrane-bound form of IL-18, which was released in small amounts after LPS treatment. Our data indicate that, upon interaction with M0 macrophages exposed to microbial products, NK cells may amplify classical type 1 immune responses. In addition, M1-polarizing stimuli can rescue M2 macrophages from their immunomodulatory state and shape their functional behavior toward NK stimulatory capability.cytolityc activity | proinflammatory cytokines | lypopolissacaride | molecular interactions | nectins' family

Despite this was not a study performed on a cohort of patients followed up from birth to adolescence, the molecular patterns of allergen recognition resulted modified according to age. These findings may support, at molecular level, the clinical features of the allergic march.

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For the whole cohort significantly increased SMRs were detected for all causes, all cancers, liver, larynx, lung, pleural and bladder cancers, respiratory tract diseases, and cirrhosis of the liver. The analysis by job-title showed increased SMRs not only for pleural cancer, but also for lung, laryngeal cancers and respiratory tract diseases in occupations entailing heavy asbestos exposure. Bladder and liver cancers and liver cirrhosis mortality also appeared to be related to occupational exposure.

CAPOX and CAPIRI had similar efficacy in elderly patients, although CAPOX seemed to be better tolerated.

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Objectives: In this paper, we investigated the effects of the European Paediatric Regulation (EC) N° 1901/2006 with respect to satisfying the paediatric therapeutic needs, assessed in terms of the increased number of paediatric medicinal products, new therapeutic indications in specific high-need conditions (neonates, oncology, rare disease, etc.) and increased number of paediatric clinical studies supporting the marketing authorisation.Methods: We analysed the paediatric medicinal products approved by the European Medicines Agency in the period January 2007-December 2019, by collecting the following data: year of approval, active substance, legal basis for the marketing authorisation, type of medicinal product (i.e., chemical, biological, or ATMP), orphan drug status, paediatric indication, Anatomical Therapeutic Chemical code (first-level), number and type of paediatric studies. Data were compared with similar data collected in the period 1996–2006.Results: In the period January 1996–December 2019, in a total of 1,190 medicinal products and 843 active substances, 34 and 38%, respectively, were paediatric. In the two periods, before and after the Paediatric Regulation implementation, the paediatric/total medicinal products ratio was constant while the paediatric/total active substances ratio decreased. Moreover, excluding generics and biosimilars, a total of 106 and 175 paediatric medicines were granted a new paediatric indication, dosage or age group in the two periods; out of 175, 128 paediatric medicines had an approved Paediatric Investigational Plan. The remaining 47 were approved without an approved Paediatric Investigational Plan, following the provisions of Directive 2001/83/EC and repurposing an off-patent drug. The analysis of the clinical studies revealed that drugs with a Paediatric Investigational Plan were supported by 3.5 studies/drug while drugs without a Paediatric Investigational Plan were supported by only 1.6 studies/drug.Discussion: This report confirms that the expectations of the European Paediatric Regulation (EC) N° 1901/2006 have been mainly satisfied. However, the reasons for the limited development of paediatric medicines in Europe, should be further discussed, taking advantage of recent initiatives in the regulatory field, such as the Action Plan on Paediatrics, and the open consultation on EU Pharmaceutical Strategy.

URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-004507-20.