Publications by authors named "Alberto Mantovani"

784 Publications

Interleukin-1 in tumor progression, therapy, and prevention.

Cancer Cell 2021 Apr 27. Epub 2021 Apr 27.

Humanitas Research Hospital-IRCCS, Via Manzoni 56, 20089 Rozzano, Milan, Italy; Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy; The William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address:

Interleukin-1 (IL-1) is a key orchestrator of inflammation and plays an important role in tumor progression. Based on preclinical models and human genetic associations, we surmise that targeting IL-1 should be considered in treating selected human tumors as well as in a prevention and/or interception setting.
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http://dx.doi.org/10.1016/j.ccell.2021.04.011DOI Listing
April 2021

One dose of SARS-CoV-2 vaccine exponentially increases antibodies in recovered individuals with symptomatic COVID-19.

J Clin Invest 2021 May 6. Epub 2021 May 6.

Department of Biomedical Sciences, Humanitas University, Milan, Italy.

Background: Currently used COVID-19 vaccines require two doses to achieve optimal vaccination, and there is no indication as to whether individuals who have been exposed to SARS-CoV-2 should be vaccinated, or should receive one or two vaccine doses.

Methods: Here, we tested the antibody response developed after administration of the Pfizer/BioNTech vaccine in 124 healthcare professionals of which 57 had a previous history of SARS-CoV-2 exposure (SARS-CoV-2-Exp), with or without symptoms.

Results: Post-vaccine antibodies in SARS-CoV-2 exposed individuals increased exponentially within 5-18 days after the first dose compared to naïve subjects (P < 0.0001). In a multivariate Linear Regression (LR) model we showed that the antibody response depended on the IgG pre-vaccine titer and on the exposure to SARS-CoV-2. In symptomatic SARS-CoV-2 exposed individuals, IgG reached a plateau after the second dose, and those that voluntarily refrained from receiving the second dose (n = 7) retained their antibody response. Gastrointestinal symptoms, muscle pain and fever significantly positively correlated with increased IgG responses. By contrast, all a/paucisymptomatic and unexposed individuals showed an important increase after the second dose.

Conclusion: Thus, one vaccine dose is sufficient in symptomatic SARS-CoV-2 exposed subjects to reach a high titer of antibodies suggesting no need for a second dose, particularly in light of current vaccine shortage.

Trial Registration: ClincalTrials.gov NCT04387929FUNDING. This work was partially supported by a philantropic donation by Dolce & Gabbana and by the Italian Ministry of Health (Ricerca corrente).
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http://dx.doi.org/10.1172/JCI149154DOI Listing
May 2021

Human health risk-benefit assessment of fish and other seafood: a scoping review.

Crit Rev Food Sci Nutr 2021 May 6:1-22. Epub 2021 May 6.

Division of Diet, Disease Prevention and Toxicology, Technical University of Denmark, Copenhagen, Denmark.

Fish and other seafood are important sources of nutrients, but they are also sources of chemical contaminants that may cause adverse health effects. This article aimed to identify existing risk-benefit assessments (RBA) of fish, shellfish, and other seafood, compare methodologies, discuss differences and commonalities in findings, and identify limitations and ways forward for future studies. We conducted a scoping review of the scientific literature of studies in all languages published from 2000 through April 2019. We identified 106 RBA of fish and other seafood across Europe, Asia, North America, Africa, and at the global level. Studies were heterogeneous in terms of types of fish and other seafood considered, beneficial and adverse compounds assessed, and overall methodology. Collected data showed that a diet consisting of a variety of lean and fatty fish and other seafood is recommended for the overall population and that women of childbearing age and children should limit the consumption of fish and other seafood types that have a high likelihood of contamination. Our review emphasizes the need for evidence-based, up-to-date, and harmonized approaches in RBA in general.
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http://dx.doi.org/10.1080/10408398.2021.1915240DOI Listing
May 2021

Immuno-Hormonal, Genetic and Metabolic Profiling of Newborns as a Basis for the Life-Long OneHealth Medical Record: A Scoping Review.

Medicina (Kaunas) 2021 Apr 15;57(4). Epub 2021 Apr 15.

Department of Paediatrics and Neonatology, Dijklander Hospital, 1624 NP Hoorn, The Netherlands.

Holistic and life-long medical surveillance is the core of personalised medicine and supports an optimal implementation of both preventive and curative healthcare. Personal medical records are only partially unified by hospital or general practitioner informatics systems, but only for citizens with long-term permanent residence. Otherwise, insight into the medical history of patients greatly depends on their medical archive and memory. Additionally, occupational exposure records are not combined with clinical or general practitioner records. Environmental exposure starts preconceptionally and continues during pregnancy by transplacental exposure. Antenatal exposure is partially dependent on parental lifestyle, residence and occupation. Newborn screening (NBS) is currently being performed in developed countries and includes testing for rare genetic, hormone-related, and metabolic conditions. Transplacental exposure to substances such as endocrine disruptors, air pollutants and drugs may have life-long health consequences. However, despite the recognised impact of transplacental exposure on the increased risk of metabolic syndrome, neurobehavioral disorders as well as immunodisturbances including allergy and infertility, not a single test within NBS is geared toward detecting biomarkers of exposure (xenobiotics or their metabolites, nutrients) or effect such as oestradiol, testosterone and cytokines, known for being associated with various health risks and disturbed by transplacental xenobiotic exposures. The outcomes of ongoing exposome projects might be exploited to this purpose. Developing and using a OneHealth Medical Record (OneHealth) may allow the incorporated chip to harvest information from different sources, with high integration added value for health prevention and care: environmental exposures, occupational health records as well as diagnostics of chronic diseases, allergies and medication usages, from birth and throughout life. Such a concept may present legal and ethical issues pertaining to personal data protection, requiring no significant investments and exploits available technologies and algorithms, putting emphasis on the prevention and integration of environmental exposure and health data.
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http://dx.doi.org/10.3390/medicina57040382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071263PMC
April 2021

Assessing Environmental Factors within the One Health Approach.

Medicina (Kaunas) 2021 Mar 5;57(3). Epub 2021 Mar 5.

Department on Food Safety, Nutrition and Veterinary Public Health, Italian National Institute of Health (ISS), 00161 Roma, Italy.

One Health is a comprehensive and multisectoral approach to assess and examine the health of animals, humans and the environment. However, while the One Health approach gains increasing momentum, its practical application meets hindrances. This paper investigates the environmental pillar of the One Health approach, using two case studies to highlight the integration of environmental considerations. The first case study pertains to the Danish monitoring and surveillance programme for antimicrobial resistance, DANMAP. The second case illustrates the occurrence of aflatoxin M1 (AFM1) in milk in dairy-producing ruminants in Italian regions. A scientific literature search was conducted in PubMed and Web of Science to locate articles informing the two cases. Grey literature was gathered to describe the cases as well as their contexts. 19 articles and 10 reports were reviewed and informed the two cases. The cases show how the environmental component influences the apparent impacts for human and animal health. The DANMAP highlights the two approaches One Health and farm to fork. The literature provides information on the comprehensiveness of the DANMAP, but highlights some shortcomings in terms of environmental considerations. The AFM1 case, the milk metabolite of the carcinogenic mycotoxin aflatoxin B1, shows that dairy products are heavily impacted by changes of the climate as well as by economic drivers. The two cases show that environmental conditions directly influence the onset and diffusion of hazardous factors. Climate change, treatment of soils, water and standards in slaughterhouses as well as farms can have a great impact on the health of animals, humans and the environment. Hence, it is important to include environmental considerations, for example, via engaging environmental experts and sharing data. Further case studies will help to better define the roles of environment in One Health scenarios.
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http://dx.doi.org/10.3390/medicina57030240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999754PMC
March 2021

Monocyte-macrophage polarization and recruitment pathways in the tumour microenvironment of B-cell acute lymphoblastic leukaemia.

Br J Haematol 2021 Mar 13. Epub 2021 Mar 13.

Centro Ricerca Tettamanti, Pediatric Dep, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy.

B-cell acute lymphoblastic leukaemia (B-ALL) reprograms the surrounding bone marrow (BM) stroma to create a leukaemia-supportive niche. To elucidate the contribution of immune cells to the leukaemic microenvironment, we investigated the involvement of monocyte/macrophage compartments, as well as several recruitment pathways in B-ALL development. Immunohistochemistry analyses showed that CD68-expressing macrophages were increased in leukaemic BM biopsies, compared to controls and predominantly expressed the M2-like markers CD163 and CD206. Furthermore, the "non-classical" CD14 CD16 monocyte subset, expressing high CX3CR1 levels, was significantly increased in B-ALL patients' peripheral blood. CX3CL1 was shown to be significantly upregulated in leukaemic BM plasma, thus providing an altered migratory pathway possibly guiding NC monocyte recruitment into the BM. Additionally, the monocyte/macrophage chemoattractant chemokine ligand 2 (CCL2) strongly increased in leukaemic BM plasma, possibly because of the interaction of leukaemic cells with mesenchymal stromal cells and vascular cells and due to a stimulatory effect of leukaemia-related inflammatory mediators. C5a, a macrophage chemoattractant and M2-polarizing factor, further appeared to be upregulated in the leukaemic BM, possibly as an effect of PTX3 decrease, that could unleash complement cascade activation. Overall, deregulated monocyte/macrophage compartments are part of the extensive BM microenvironment remodelling at B-ALL diagnosis and could represent valuable targets for novel treatments to be coupled with classical chemotherapy.
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http://dx.doi.org/10.1111/bjh.17330DOI Listing
March 2021

Circulating pentraxin 3 in severe COVID-19 or other pulmonary sepsis.

Eur J Clin Invest 2021 May 13;51(5):e13530. Epub 2021 Mar 13.

Department of Anaesthesia and Critical Care, Azienda Ospedaliero-Universitaria S. Luigi Gonzaga, Orbassano, Italy.

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http://dx.doi.org/10.1111/eci.13530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995110PMC
May 2021

Check cystoscopy in the management of anterior urethral valves in a cohort of pediatric patients.

J Pediatr Urol 2021 04 27;17(2):231.e1-231.e7. Epub 2021 Feb 27.

Pediatric Urology Department Meyer Children Hospital, viale Pieraccini 24, Firenze, 50139, Italy.

Introduction: Anterior urethral valves (AUV) are a rare cause of lower urinary tract obstruction which could progress to renal damage, Clinical presentation varies according with patient's age and severity of obstruction, but, in most cases, diagnosis is based on voiding cysto-urethrogram (VCUG). To date, the treatment of choice is endoscopic ablation even if approved guidelines about the overall management of AUVs, including the recognition and treatment of residual valves, are not available.

Objective: We describe our protocol for AUV treatment based on primary endoscopic valve ablation followed by check cystoscopy 15 days later.

Study Design: Medical records of 5 patients with AUVs admitted from 2008 to 2018 to our Pediatric Urology Unit were retrospectively reviewed. Blood tests, urinalysis, renal US and VCUG were performed in all children, while urodynamic evaluation was performed in the 3/5 patients who could void spontaneously. All patients underwent endoscopic valves ablation and after 15 days after a second look cystoscopy was performed. Follow up was based on clinical and radiological evaluation with US, urinalysis and blood tests. Postoperative non-invasive urodynamic studies were performed in the 3/5 patient toilet-trained patients and VCUG was performed in 1/5 patient.

Results: and Discussion: At primary endoscopic ablation cystoscopy revealed AUVs in the penile urethra in three patients, in the penoscrotal urethra in one case, in the bulbar urethra in another case. In 3/5 patients check cystoscopy found residual valves and a second endoscopic ablation was performed. All patients achieved symptoms release and improved urodynamic parameters. No intra or post-operative complication were reported. The assessment of residual valves is variable in literature and it is usually described for posterior urethral valves (PUVs). Few series report the use of VCUG within the first week after valve ablation, our experience instead suggests that performing a second look cystoscopy, is very effective to evaluate the presence of residual AUVs and eventually proceed with further ablation.

Conclusion: Endoscopic ablation is the gold standard treatment for AUV, but residual valves management is not clearly defined. According to our experience, a check cystoscopy 15 days after primary ablation allows to identify and treat possible residual valves showing good results in terms of safety and efficacy.
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http://dx.doi.org/10.1016/j.jpurol.2020.11.028DOI Listing
April 2021

Risk-benefit in food safety and nutrition - Outcome of the 2019 Parma Summer School.

Food Res Int 2021 Mar 5;141:110073. Epub 2021 Jan 5.

University of Parma, Department of Food and Drug, Italy. Electronic address:

Risk-benefit assessment is the comparison of the risk of a situation to its related benefits, i.e. a comparison of scenarios estimating the overall health impact. The risk-benefit analysis paradigm mirrors the classical risk analysis one: risk-benefit assessment goes hand-in-hand with risk-benefit management and risk-benefit communication. The various health effects associated with food consumption, together with the increasing demand for advice on healthy and safe diets, have led to the development of different research disciplines in food safety and nutrition. In this sense, there is a clear need for a holistic approach, including and comparing all of the relevant health risks and benefits. The risk-benefit assessment of foods is a valuable approach to estimate the overall impact of food on health. It aims to assess together the negative and positive health effects associated with food intake by integrating chemical and microbiological risk assessment with risk and benefit assessment in food safety and nutrition. The 2019 Parma Summer School on risk-benefit in food safety and nutrition had the objective was to provide an opportunity to learn from experts in the field of risk-benefit approach in food safety and nutrition, including theory, case studies, and communication of risk-benefit assessments plus identify challenges for the future. It was evident that whereas tools and approaches have been developed, more and more case studies have been performed which can form an inherent validation of the risk-benefit approach. Executed risk-benefit assessment case studies apply the steps and characteristics developed: a problem formulation (with at least 2 scenarios), a tiered approach until a decision can be made, one common currency to describe both beneficial and adverse effects (DALYs in most instances). It was concluded that risk-benefit assessment in food safety and nutrition is gaining more and more momentum, while also many challenges remain for the future. Risk-benefit is on the verge of really enrolling into the risk assessment and risk analysis paradigm. The interaction between risk-benefit assessors and risk-benefit managers is pivotal in this, as is the interaction with risk-benefit communicators.
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http://dx.doi.org/10.1016/j.foodres.2020.110073DOI Listing
March 2021

Anticancer innovative therapy congress: Highlights from the 10th anniversary edition.

Cytokine Growth Factor Rev 2021 Feb 14. Epub 2021 Feb 14.

Immunotherapy and Innovative Therapeutics Unit, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address:

During the Tenth Edition of the Annual Congress on "Anticancer Innovative Therapy" [Milan, 23/24 January 2020], experts in the fields of immuno-oncology, epigenetics, tumor cell signaling, and cancer metabolism shared their latest knowledge on the roles of i] epigenetics, and in particular, chromatin modifiers, ii] cancer metabolism, iii] cancer stem cells [CSCs], iv] tumor cell signaling, and iv] the immune system. The novel therapeutic approaches presented included epigenetic drugs, cell cycle inhibitors combined with ICB, antibiotics and other off-label drugs, small-molecules active against CSCs, liposome-delivered miRNAs, tumor-specific CAR-T cells, and T-cell-based immunotherapy. Moreover, important evidence on possible mechanisms of resistance to these innovative therapies were also discussed, in particular with respect to resistance to ICB. Overall, this conference provided scientists and clinicians with a broad overview of future challenges and hopes to improve cancer treatment reasonably in the medium-short term.
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http://dx.doi.org/10.1016/j.cytogfr.2021.02.001DOI Listing
February 2021

Multifactorial Rare Diseases: Can Uncertainty Analysis Bring Added Value to the Search for Risk Factors and Etiopathogenesis?

Medicina (Kaunas) 2021 Jan 28;57(2). Epub 2021 Jan 28.

Department on Food Safety, Nutrition and Veterinary Public Health, Italian National Institute of Health (ISS), 00161 Roma, Italy.

Uncertainty analysis is the process of identifying limitations in knowledge and evaluating their implications for scientific conclusions. Uncertainty analysis is a stable component of risk assessment and is increasingly used in decision making on complex health issues. Uncertainties should be identified in a structured way and prioritized according to their likely impact on the outcome of scientific conclusions. Uncertainty is inherent to the rare diseases (RD) area, where research and healthcare have to cope with knowledge gaps due to the rarity of the conditions; yet a systematic approach toward uncertainties is not usually undertaken. The uncertainty issue is particularly relevant to multifactorial RD, whose etiopathogenesis involves environmental factors and genetic predisposition. Three case studies are presented: the newly recognized acute multisystem inflammatory syndrome in children and adolescents associated with SARS-CoV-2 infection; the assessment of risk factors for neural tube defects; and the genotype-phenotype correlation in familial Mediterranean fever. Each case study proposes the initial identification of the main epistemic and sampling uncertainties and their impacts. Uncertainty analysis in RD may present aspects similar to those encountered when conducting risk assessment in data-poor scenarios; therefore, approaches such as expert knowledge elicitation may be considered. The RD community has a main strength in managing uncertainty, as it proactively develops stakeholder involvement, data sharing and open science. The open science approaches can be profitably integrated by structured uncertainty analysis, especially when dealing with multifactorial RD involving environmental and genetic risk factors.
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http://dx.doi.org/10.3390/medicina57020119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911455PMC
January 2021

COVID-19 vaccines: where we stand and challenges ahead.

Cell Death Differ 2021 02 21;28(2):626-639. Epub 2021 Jan 21.

Istituto Clinico Humanitas IRCCS, Humanitas University, via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy.

In the eleven months elapsed since the identification of the SARS-CoV-2 virus and its genome, an exceptional effort by the scientific community has led to the development of over 300 vaccine projects. Over 40 are now undergoing clinical evaluation, ten of these are in Phase III clinical trials, three of them have ended Phase III with positive results. A few of these new vaccines are being approved for emergency use. Existing data suggest that new vaccine candidates may be instrumental in protecting individuals and reducing the spread of pandemic. The conceptual and technological platforms exploited are diverse, and it is likely that different vaccines will show to be better suited to distinct groups of the human population. Moreover, it remains to be elucidated whether and to what extent the capacity of vaccines under evaluation and of unrelated vaccines such as BCG can increase immunological fitness by training innate immunity to SARS-CoV-2 and pathogen-agnostic protection. Due to the short development time and the novelty of the technologies adopted, these vaccines will be deployed with several unresolved issues that only the passage of time will permit to clarify. Technical problems connected with the production of billions of doses and ethical ones connected with the availably of these vaccines also in the poorest countries, are imminent challenges facing us. It is our tenet that in the long run more than one vaccine will be needed to ensure equitable global access, protection of diverse subjects and immunity against viral variants.
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http://dx.doi.org/10.1038/s41418-020-00720-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818063PMC
February 2021

Tumor-associated myeloid cells: diversity and therapeutic targeting.

Cell Mol Immunol 2021 Mar 20;18(3):566-578. Epub 2021 Jan 20.

Department of Immunology and Inflammation, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy.

Myeloid cells in tumor tissues constitute a dynamic immune population characterized by a non-uniform phenotype and diverse functional activities. Both tumor-associated macrophages (TAMs), which are more abundantly represented, and tumor-associated neutrophils (TANs) are known to sustain tumor cell growth and invasion, support neoangiogenesis and suppress anticancer adaptive immune responses. In recent decades, several therapeutic approaches have been implemented in preclinical cancer models to neutralize the tumor-promoting roles of both TAMs and TANs. Some of the most successful strategies have now reached the clinic and are being investigated in clinical trials. In this review, we provide an overview of the recent literature on the ever-growing complexity of the biology of TAMs and TANs and the development of the most promising approaches to target these populations therapeutically in cancer patients.
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http://dx.doi.org/10.1038/s41423-020-00613-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027665PMC
March 2021

Potential harm caused by physicians' a-priori beliefs in the clinical effectiveness of hydroxychloroquine and its impact on clinical and economic outcome - A simulation approach.

J Crit Care 2021 Apr 9;62:138-144. Epub 2020 Dec 9.

Humanitas Univeristy, Department of Biomedical Science, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Mi) Italy; Department of Anesthesia and Intensive Care Medicine, Humanitas Clinical and Research Centre-IRCCS, Rozzano, Milan, Italy.

Background: Despite growing controversies around Hydroxychloroquine's effectiveness, the drug is still widely prescribed by clinicians to treat COVID19 patients. Therapeutic judgment under uncertainty and imperfect information may be influenced by personal preference, whereby individuals, to confirm a-priori beliefs, may propose drugs without knowing the clinical benefit. To estimate this disconnect between available evidence and prescribing behavior, we created a Bayesian model analyzing a-priori optimistic belief of physicians in Hydroxychloroquine's effectiveness.

Methodology: We created a Bayesian model to simulate the impact of different a-priori beliefs related to Hydroxychloroquine's effectiveness on clinical and economic outcome.

Results: Our hypothetical results indicate no significant difference in treatment effect (combined survival benefit and harm) up to a presumed drug's effectiveness level of 20%, with younger individuals being negatively affected by the treatment (RR 0.82, 0.55-1.2; (0.95 (1.1) % expected adverse events versus 0.05 (0.98) % expected death prevented). Simulated cost data indicate overall hospital cost (medicine, hospital stay, complication) of 18.361,41€ per hospitalized patient receiving Hydroxychloroquine treatment.

Conclusion: Off-label use of Hydroxychloroquine needs a rational, objective and datadriven evaluation, as personal preferences may be flawed and cause harm to patients and to society.
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http://dx.doi.org/10.1016/j.jcrc.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725088PMC
April 2021

Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration.

Front Pharmacol 2020 26;11:591908. Epub 2020 Nov 26.

Department of Biomedical Sciences, Humanitas University, Milan, Italy.

Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the () gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a "hot spot" for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD.
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http://dx.doi.org/10.3389/fphar.2020.591908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725797PMC
November 2020

25th anniversary of the Berlin workshop on developmental toxicology: DevTox database update, challenges in risk assessment of developmental neurotoxicity and alternative methodologies in bone development and growth.

Reprod Toxicol 2021 03 2;100:155-162. Epub 2020 Dec 2.

German Federal Institute for Risk Assessment, Berlin, Germany.

25 years after the first Berlin Workshop on Developmental Toxicity this 10th Berlin Workshop aimed to bring together international experts from authorities, academia and industry to consider scientific, methodologic and regulatory aspects in risk assessment of developmental toxicity and to debate alternative strategies in testing developmental effects in the future. Proposals for improvement of the categorization of developmental effects were discussed as well as the update of the DevTox database as valuable tool for harmonization. The development of adverse outcome pathways relevant to developmental neurotoxicity (DNT) was debated as a fundamental improvement to guide the screening and testing for DNT using alternatives to animal methods. A further focus was the implementation of an in vitro mechanism-based battery, which can support various regulatory applications associated with the assessment of chemicals and mixtures. More interdisciplinary and translation research should be initiated to accelerate the development of new technologies to test developmental toxicity. Technologies in the pipeline are (i) high throughput imaging techniques, (ii) models for DNT screening tests, (iii) use of computer tomography for assessment of thoracolumbar supernumerary ribs in animal models, and (iv) 3D biofabrication of bone development and regeneration tissue models. In addition, increased collaboration with the medical community was suggested to improve the relevance of test results to humans and identify more clinically relevant endpoints. Finally, the participants agreed that this conference facilitated better understanding innovative approaches that can be useful for the identification of developmental health risks due to exposure to chemical substances.
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http://dx.doi.org/10.1016/j.reprotox.2020.11.003DOI Listing
March 2021

Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade.

Immunity 2020 12 20;53(6):1215-1229.e8. Epub 2020 Nov 20.

Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, UK. Electronic address:

Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.
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http://dx.doi.org/10.1016/j.immuni.2020.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772804PMC
December 2020

Macrophage expression and prognostic significance of the long pentraxin PTX3 in COVID-19.

Nat Immunol 2021 01 18;22(1):19-24. Epub 2020 Nov 18.

Humanitas Clinical and Research Center-IRCCS, Milan, Italy.

Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19). RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
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http://dx.doi.org/10.1038/s41590-020-00832-xDOI Listing
January 2021

Dietary exposure of the Italian population to nickel: The national Total Diet Study.

Food Chem Toxicol 2020 Dec 15;146:111813. Epub 2020 Oct 15.

Istituto Superiore di Sanità- Italian National Institute of Health, Rome, Italy.

Dietary exposure of the Italian population to nickel has been assessed in the national Total Diet Study (TDS). Occurrence data were combined with national individual consumption data to estimate mean and high level dietary exposure of population subgroups according to age and gender, both at the national level and for the four main geographical areas of Italy. The mean chronic dietary exposure of infants and toddlers, children, adolescents, adults, and the elderly were 4.00, 4.57, 2.57, 1.55, and 1.47 μg/kg bw per day, respectively. These intakes lie in the intermediate range of exposure estimates from TDS carried out in other countries. Main contributors to the total nickel exposure for children and adolescents were 'sweet products' and 'cereals and cereal products'. In adults and the elderly nearly 30% of the exposure was associated to the consumption of 'cereals and cereal products'. Mean and 95th percentile chronic dietary exposure was below the TDI in all age groups. For the risk characterisation of acute oral exposure, exposure data for consumers only in the adult population were compared with the reference point for systemic contact dermatitis. Consumption of 'cocoa', 'chocolate', 'crustaceans and molluscs', 'pulses' had remarkable potential to elicit adverse effects in nickel-sensitised individuals.
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http://dx.doi.org/10.1016/j.fct.2020.111813DOI Listing
December 2020

Toxicological risk factors in the burden of malnutrition: The case of nutrition (and risk) transition in sub-Saharan Africa.

Food Chem Toxicol 2020 Dec 2;146:111789. Epub 2020 Oct 2.

Department of Food Safety, Nutrition, and Veterinary Public Health, Istituto Superiore di Sanita', Rome, Italy.

Toxicant exposures may worsen the micronutrient status, especially during the womb-to-childhood development, impairing organism programming and increasing the risk for health disorders in adulthood. Growing evidence calls for an integrated risk analysis of the interplay of environment, behavior and lifestyle, where a) imbalanced diet and micronutrient deficiencies may increase the vulnerability to toxicants and alter body defence systems and b) intake of antinutrients and contaminants may increase nutritional requirements. Such scenarios are especially evident in communities undergoing a fast nutrition transition, such as in many countries of sub-Saharan Africa. Specific challenges of toxicological risk analysis in sub-Saharan Africa still need a thorough assessment, including: rapid changes of lifestyle and consumers' preferences; dumping of foods and consumer' products; risk management under weak or non-existent awareness, legislation enforcement and infrastructures. The significant and growing literature from Africa-led scientific research should be used to build quality-controlled data repositories supporting regulatory top-down actions. Meanwhile, bottom-up actions (eg consumer's empowerment) could exploit social and economic drivers toward a qualified African presence in the global and local markets. A science-based combination of top-down and bottom-up actions on preventable toxicological risk factors will contribute fighting the new forms of malnutrition and prevent multi-factorial diseases. Exposures to toxicants should be included in the integrated approach proposed by WHO to address the urgent health challenge of simultaneously reduce the risk or burden of both malnutrition (ie deficiency of one or more essential nutrients) and overweight, obesity, and diet-related NCDs.
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http://dx.doi.org/10.1016/j.fct.2020.111789DOI Listing
December 2020

Risk assessment of dietary exposure to potentially toxic trace elements in emerging countries: A pilot study on intake via flour-based products in Yerevan, Armenia.

Food Chem Toxicol 2020 Dec 29;146:111768. Epub 2020 Sep 29.

National Institute of Health, Rome, Italy. Electronic address:

Flour-based products, one staple food items of Armenians' diet, can be major contributors to the total exposure to trace elements. Therefore, this pilot study estimated the exposure to potentially toxic trace elements (Pb, Cd, Hg, Ni, Mo, Cu), and the related health risks, through consumption of the main flour-based products (white bread, lavash, pasta, cookies) in the capital city Yerevan. The TE contents in market samples were analyzed using atomic absorption spectrometry. The product consumption data were obtained via a 24-h recall survey amongst Yerevan adults (1272 respondents). Following the K-mean clustering test, three clusters were determined for each type of the product intake. The daily intakes and margin of exposure of trace elements were calculated by the deterministic approach. Considering the health-based guidance values and the obtained daily intakes, concerns for consumer safety were identified in case of dietary exposure to Ni. Moreover, the estimated of all studied elements highlighted that a consumer health concern (identified by margin of exposure less than 10) cannot be excluded in the case of white bread (mainly) as well as lavash and cookies consumption. This pilot study provides important highlights towards future total diet studies in Armenia.
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http://dx.doi.org/10.1016/j.fct.2020.111768DOI Listing
December 2020

Prognostic significance of tumor-associated macrophages: past, present and future.

Semin Immunol 2020 04 14;48:101408. Epub 2020 Sep 14.

Department of Immunology and Inflammation, Humanitas Clinical and Research Center-IRCCS, Pieve Emanuele, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy. Electronic address:

Tumor tissues are populated by a multitude of macrophages, highly different in functional activity, localization and morphology. A clear contribution to disease progression has been shown in multiple cancer types, holding promise for the development of innovative macrophage-based prognostic tools. Current studies aimed at assessing the prognostic role of macrophages have documented the relevance of the macrophage population as a whole. However, dissecting the diversity of mononuclear phagocytes in tumor tissues has provided important information about the coexistence of distinct populations of macrophages with different prognostic significance. Here we summarize evidence of macrophage prognostic function in human cancer and focus on classical and modern strategies aimed at measuring macrophage features and deciphering their diversity. The wealth of new data generated will reshape our knowledge of macrophage complexity and hopefully foster the forthcoming development of these new metrics into prognostic tools as well as new therapeutic strategies.
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http://dx.doi.org/10.1016/j.smim.2020.101408DOI Listing
April 2020

Trained Innate Immunity, Epigenetics, and Covid-19.

N Engl J Med 2020 09;383(11):1078-1080

From the Humanitas Clinical and Research Center IRCCS and Humanitas University, Milan (A.M.); the William Harvey Research Institute, Queen Mary University of London, London (A.M.); the Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University, Nijmegen, the Netherlands (M.G.N.); and Immunology and Metabolism, Life, and Medical Sciences Institute, University of Bonn, Bonn, Germany (M.G.N.).

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http://dx.doi.org/10.1056/NEJMcibr2011679DOI Listing
September 2020

Safety and efficacy of DSP (NaEDTA, tannin-rich extract of , thyme oil and origanum oil) for pigs for fattening.

EFSA J 2020 Jun 10;18(6):e06163. Epub 2020 Jun 10.

Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety for the environment and efficacy of DSP (a mixture of disodium salt of ethylenediaminetetraacetic acid (Na EDTA), tannin-rich extract of , thyme oil and origanum oil) as a zootechnical feed additive for pigs for fattening. The European Commission request followed an inconclusive opinion of the FEEDAP Panel published in 2016. The applicant submitted additional information to allow the FEEDAP Panel to complete its assessment; these additional data, related to the safety for the environment and the efficacy of the additive, were the subject of this opinion. Concerning safety for the environment, the risk quotient (PEC/PNEC) value for aquatic organisms was < 1, indicating no concerns of DSP for the aquatic compartment; no toxicity data for terrestrial organisms were provided and consequently no conclusion on the safety of DSP for the terrestrial compartment could be reached, as well as on the risk for groundwater contamination. Based on the results from three studies in pigs for fattening in which final body weight and average daily weight gain were increased, and feed to gain ratio was improved, the FEEDAP Panel concluded that DSP has the potential to be efficacious as a zootechnical additive in pigs for fattening.
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http://dx.doi.org/10.2903/j.efsa.2020.6163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448043PMC
June 2020

Safety and efficacy of STABILFLOR as a zootechnical feed additive for pigs for fattening.

EFSA J 2020 Jun 8;18(6):e06145. Epub 2020 Jun 8.

Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of STABILFLOR (zinc ethylenediaminetetraacetic acid (Zn-EDTA) and copper diammonium EDTA (Cu-EDTA) dried on chicory pulp and supplemented with zinc oxide and copper oxide), as a zootechnical additive for pigs. STABILFLOR is intended to be used in feed for pigs for fattening at a minimum and maximum levels of 500 and 1,000 mg/kg complete feed, respectively. The Panel could not conclude on the safety of STABILFLOR for pigs for fattening owing to the lack of adequate data. At the proposed used levels in feed the additive may exert antimicrobial activity in the gut microbiota. The use of the additive resulted neither in residues of Zn-EDTA, Cu-EDTA or EDTA nor on an increase in total zinc and copper deposition in edible tissues; Zn-EDTA and Cu-EDTA had not a genotoxic potential; the Panel concluded that STABILFLOR at 1,000 mg/kg complete feed for pigs does not pose any concern to the safety of consumers. The handling of STABILFLOR will lead to a copper exposure of the users that poses a risk by inhalation; the additive is not a skin irritant or a skin sensitiser but is a severe eye irritant. Regarding environmental safety, no concern was expected for the terrestrial compartment. A risk for groundwater was highlighted for Zn-EDTA. Due to the absence of data, the risk for the aquatic compartment could not be assessed. Only one efficacy study showed positive effects of STABILFLOR in pigs for fattening at 1,000 mg/kg complete feed; a conclusion on the efficacy of STABILFLOR could not be drawn. The minimum use level of 500 mg STABILFLOR /kg complete feed was not tested.
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http://dx.doi.org/10.2903/j.efsa.2020.6145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448069PMC
June 2020

Assessment of the application for renewal of authorisation of l-histidine monohydrochloride monohydrate produced with NITE SD 00268 for salmonids and its extension of use to other fin fish.

EFSA J 2020 Apr 30;18(4):e06072. Epub 2020 Apr 30.

Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on l-histidine monohydrochloride (HCl) monohydrate produced by fermentation using NITE SD 00268 in the context of the renewal of the authorisation for salmonids when used as a nutritional additive. In addition, the applicant requested the extension of use of the additive for other fin fish. The applicant has provided evidence that the composition of the additive currently in the market complies with the conditions of authorisation. The production strain has been modified by conventional mutagenesis and it does not raise safety concerns. The use of l-histidine HCl monohydrate produced by fermentation using NITE SD 00268 is safe for salmonids and other fin fish when used as a nutritional additive to supplement the diet in appropriate amounts to cover the nutritional requirements, depending on the species, the physiological state of the animal, the performance level, the environmental conditions, the background amino acid composition of the unsupplemented diet and the status of some essential trace elements such as copper and zinc. The FEEDAP Panel considers the maximum total concentration of 1.7% histidine in feed for salmonids proposed by the applicant as safe. For other fin fish species, the level of 1.7% appears to cause adverse effects. Therefore, it is not possible to define a maximum concentration of histidine in fish other than salmonids as it depends on histidine nutritional requirements in the different fish species. The use of the authorised additive in salmonids production does not pose a risk for consumers, and the proposed maximum total concentration of 1.7% histidine in feed is considered safe for the consumer. l-Histidine HCl monohydrate produced using NITE SD 00268 supplemented at levels appropriate to cover the nutritional requirements of fish other than salmonids is considered safe for the consumer. The additive under assessment is not a skin irritant. In the absence of data, it is not possible to conclude on the potential of the additive to be toxic by inhalation, irritant to eyes or a skin sensitiser. The amino acid l-histidine is a natural component of plants and animals. The use of the additive under assessment in animal nutrition does not represent a risk to the environment. The additive is considered an efficacious source of the amino acid l-histidine for fish species.
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http://dx.doi.org/10.2903/j.efsa.2020.6072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447904PMC
April 2020

Safety and efficacy of l-tryptophan produced by fermentation with KCCM 10534 for all animal species.

EFSA J 2020 Apr 28;18(4):e06071. Epub 2020 Apr 28.

Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on l-tryptophan produced by fermentation with a non-genetically modified strain of KCCM 10534 when used as a nutritional additive in feed and water for drinking for all animal species and categories. The production strain KCCM 10534 is safe for the production of l-tryptophan and it was not detected in the final product. The use of l-tryptophan produced using KCCM 10534 in supplementing feed to compensate for tryptophan deficiency in feedingstuffs is safe for non-ruminant target species. There may be a risk for an increased production of toxic metabolites when unprotected tryptophan is used in ruminants. The FEEDAP Panel has concerns on the safety of the simultaneous oral administration of l-tryptophan via water for drinking and feed due to possible amino acid imbalances. The use of l-Tryptophan produced by KCCM 10534 in animal nutrition raises no safety concerns to consumers of animal products and to the environment. The additive under assessment is considered not toxic by inhalation, it is not a skin or eye irritant and is not a skin sensitiser. The endotoxin activity of the additive and its dusting potential indicate a risk by inhalation for the users. The product l-tryptophan is regarded as an effective source of the amino acid l-tryptophan for all non-ruminant species. In order to be as efficacious in ruminants as in non-ruminants, it should be protected from ruminal degradation.
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http://dx.doi.org/10.2903/j.efsa.2020.6071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448079PMC
April 2020

Safety and efficacy of Nimicoat (carvacrol) as a zootechnical additive for weaned piglets.

EFSA J 2020 Apr 21;18(4):e06070. Epub 2020 Apr 21.

Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy Nimicoat (carvacrol), as a zootechnical additive for weaned piglets. The additive is composed by carvacrol (≥  40 %) as an active substance encapsulated with high-melting lipids. Nimicoat is intended to be used in feed for weaned piglets at a minimum recommended dose of 250 mg/kg complete feed and at a maximum recommended dose of 1,000 mg/kg complete feed corresponding to a minimum and maximum of 100 and 400 mg carvacrol/kg complete feed, respectively. Based on a tolerance study, the FEEDAP Panel concluded that the use of Nimicoat in feed for weaned piglet at the maximum recommended dose of 1,000 mg/kg feed is safe for the target animal; however, a precise figure for the margin of safety cannot be defined. Nimicoat used in feed for weaned piglets at the maximum recommended concentration does not pose a safety concern for consumers. The additive is corrosive to eyes, skin and the respiratory mucosae. Concerning safety for the environment a Phase II was required; taking into consideration the data provided, the FEEDAP Panel concluded that the additive does not pose any risk to the terrestrial and aquatic compartments and that bioaccumulation potential for carvacrol is low and risk for secondary poisoning for worm/fish eating birds and mammals is not likely to occur. Only one study positively supporting efficacy of the additive was available; therefore, the FEEDAP Panel is not in a position to conclude on the efficacy of Nimicoat.
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http://dx.doi.org/10.2903/j.efsa.2020.6070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448059PMC
April 2020