Senescence-associated reprogramming induced by interleukin-1 impairs response to EGFR neutralization.

BACKGROUND: EGFR targeting is currently the main treatment strategy for metastatic colorectal cancer (mCRC). Results of different clinical trials show that patients with wild-type KRAS and BRAF benefit from anti-EGFR monoclonal antibodies (moAbs) cetuximab (CTX) or panitumumab. Unfortunately, despite initial response, patients soon became refractory. Tumor heterogeneity and multiple escaping routes have been addressed as the main culprit, and, behind genomic alterations already described, changes in signaling pathways induced by drug pressure are emerging as mechanisms of acquired resistance. We previously reported an association between reduced sensitivity to CTX and increased expression of IL-1. However, how IL-1 mediates CTX resistance in mCRC is still unclear. METHODS: Under CTX treatment, the upregulation of IL-1R1 expression and a senescence program in sensitive colorectal cancer (CRC) cell lines is examined over time using qPCR, immunoblotting, and immunofluorescence. RESULTS: In sensitive CRC cells, IL-1 appeared responsible for a CTX-mediated G0 phase arrest. On the contrary, CTX-resistant CRC cells (CXR) maintained high mRNA levels of IL-1R1 and a post-senescence reprogramming, as indicated by increased SNAIL expression. Interestingly, treatment of CXR cells with a recombinant decoy, able to sequester the soluble form of IL-1, pushed CTX-resistant CRC cells back into a stage of senescence, thus blocking their proliferation. Our model suggests a trans-regulatory mechanism mediated by IL-1 on EGFR signaling. By establishing senescence and regulating EGFR activity and expression, IL-1 exposure ultimately bestows resistance. CONCLUSIONS: To sum up, our findings point to the combined blockage of IL-1R and EGFR as a promising therapeutical approach to restore sensitivity to EGFR-targeting monoclonal antibodies.

Long-term benefits of exclusive human milk diet in small for gestational age neonates: a systematic review of the literature.

Evidence about feeding practices' consequences in small for gestational age newborns is not well established because they are less likely to initiate and continue breastfeeding than other newborns. Our aim was to study current knowledge about the benefits of exclusive human milk diet after 2 years of age in small for gestational age newborns. A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline criteria. Pubmed and Scopus were searched for studies published from databases inception until June 2, 2023. Included articles were analysed and synthesised. Risk of bias and level of evidence assessments were performed. They were enrolled small for gestational age newborns fed by breastfeeding, breast milk or donor milk. The systematic review included 9 articles which were related to 4 health domains: neurodevelopment, cardiovascular, somatic growth and bone mineralization and atopy. Extracted data support a beneficial effect of breastfeeding on these outcomes. Better quality of evidence and longer follow-up are needed.

Clinical Presentation and Severity of SARS-CoV-2 Infection Compared to Respiratory Syncytial Virus and Other Viral Respiratory Infections in Children Less than Two Years of Age.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the implementation of restrictive measures led to a dramatic reduction in respiratory syncytial virus (RSV) occurrence together with rare and mild bronchiolitis induced by SARS-CoV-2. We described the respiratory picture of SARS-CoV-2 infection and evaluated the frequency and the severity of SARS-CoV-2 bronchiolitis comparing it with other respiratory viral infections in children less than two years of age. The severity of respiratory involvement was evaluated based on the need for oxygen therapy, intravenous hydration, and the length of hospital stay. A total of 138 children hospitalized for respiratory symptoms were enrolled: 60 with SARS-CoV-2 and 78 with RSV. In the group of SARS-CoV-2-infected children, 13/60 (21%) received a diagnosis of co-infection. Among the enrolled children, 87/138 (63%) received a diagnosis of bronchiolitis. The comparative evaluation showed a higher risk of the need for oxygen therapy and intravenous hydration in children with RSV infection and co-infection compared to children with SARS-CoV-2 infection. In the children with a diagnosis of bronchiolitis, no differences in the main outcomes among the groups were observed. Although children with SARS-CoV-2 infection have less severe respiratory effects than adults, the pediatrician should pay attention to bronchiolitis due to SARS-CoV-2, which could have a severe clinical course in younger children.

Extracellular Vesicles and Epidermal Growth Factor Receptor Activation: Interplay of Drivers in Cancer Progression.

Extracellular vesicles (EVs) are of great interest to study the cellular mechanisms of cancer development and to diagnose and monitor cancer progression. EVs are a highly heterogeneous population of cell derived particles, which include microvesicles (MVs) and exosomes (EXOs). EVs deliver intercellular messages transferring proteins, lipids, nucleic acids, and metabolites with implications for tumour progression, invasiveness, and metastasis. Epidermal Growth Factor Receptor (EGFR) is a major driver of cancer. Tumour cells with activated EGFR could produce EVs disseminating EGFR itself or its ligands. This review provides an overview of EVs (mainly EXOs and MVs) and their cargo, with a subsequent focus on their production and effects related to EGFR activation. In particular, in vitro studies performed in EGFR-dependent solid tumours and/or cell cultures will be explored, thus shedding light on the interplay between EGFR and EVs production in promoting cancer progression, metastases, and resistance to therapies. Finally, an overview of liquid biopsy approaches involving EGFR and EVs in the blood/plasma of EGFR-dependent tumour patients will also be discussed to evaluate their possible application as candidate biomarkers.

IL-1 and senescence: Friends and foe of EGFR neutralization and immunotherapy.

Historically, senescence has been considered a safe program in response to multiple stresses in which cells undergo irreversible growth arrest. This process is characterized by morphological and metabolic changes, heterochromatin formation, and secretion of inflammatory components, known as senescence-associated secretory phenotype (SASP). However, recent reports demonstrated that anti-cancer therapy itself can stimulate a senescence response in tumor cells, the so-called therapy-induced senescence (TIS), which may represent a temporary bypass pathway that promotes drug resistance. In this context, several studies have shown that EGFR blockage, by TKIs or moAbs, promotes TIS by increasing IL-1 cytokine production, thus pushing cells into a "pseudo-senescent" state. Today, senotherapeutic agents are emerging as a potential strategy in cancer treatment thanks to their dual role in annihilating senescent cells and simultaneously preventing their awakening into a resistant and aggressive form. Here, we summarize classic and recent findings about the cellular processes driving senescence and SASP, and we provide a state-of-the-art of the anti-cancer strategies available so far that exploits the activation and/or blockade of senescence-based mechanisms.

Managing the introduction of genomic applications into the National Health Service: A special challenge for health technology assessment in Italy.

In recent years, the rapid proliferation of genomic tests for use in clinical practice has prompted healthcare systems to use a health technology assessment (HTA) approach to distinguish valuable from unwarranted applications. In this study, we narratively review the Italian HTA mechanisms for medical devices (MDs), both at the national and regional levels, and discuss the opportunity and benefits of extending them to genomic technologies, for which a dedicated assessment path was advocated by the National Plan for Public Health Genomics in 2017. We found that the National Health Technology Assessment Program for MDs, completed in 2019, had developed a structured pathway for the HTA of MDs; it established a hub-and-spoke structure, run by a governmental institution, and put in place transparent methodological procedures to cover all four HTA phases (i.e., proposal and prioritization, assessment, appraisal, and dissemination). However, several factors have hindered its adoption, and the regions are at different stages of its implementation. For these reasons, efforts should be made to ensure its effective deployment, both at national and regional levels. In addition, we argue that to harmonize the institutional roles and methodological procedures adopted, the time has come to concentrate resources on a single pathway for the assessment of all technologies that include both MDs and genomic applications.

Protection of Vaccine Preventable Diseases in a Population of HIV-Infected Children: A 3 Years Prospective Study.

Human Immunodeficiency Virus (HIV) infected children have a 30-70% chance of being incompletely immunized and may not respond serologically with the same magnitude or durability as uninfected children. The aim of the study was to describe the rate of protective antibodies titre and the persistence of the response against four recommended vaccinations in HIV infected children and adolescents. A two-phase observational study was performed in which protective IgG antibodies to measles, mumps, rubella and hepatitis B were determined and monitored for 12 and 24 months, in 26 perinatally HIV-infected children. The rate of protection for rubella and hepatitis B was significantly lower in the HIV group compared to the control group (92% vs. 65% for rubella and 78.4% vs. 45.4% for hepatitis B; p < 0.05). Children who received primary vaccination after initiating combination antiretroviral therapy (cART) had a higher rate of response. Seronegative patients who received a booster dose of vaccine had a good immunological response. HIV infection is associated with a lower response to vaccines against rubella and hepatitis. The beginning of cART before vaccination may be associated with a better response. The evaluation of the serological response is crucial in children with HIV infection in order to evaluate the protection of vaccine preventable diseases.

A Systematic Review and Bibliometric Analysis of the Scientific Literature on the Early Phase of COVID-19 in Italy.

Background: Studying the scientific literature about COVID-19 and Italy, one of the first countries to be hit by the pandemic, allows an investigation into how knowledge develops during a public health emergency. Methods: A systematic review of the literature was conducted to identify articles published on the topic between January and April 2020. Articles were classified according to type of study. Co-occurrence of terms, and geographic and temporal trends were analyzed. Results: Of the 238 articles included in the systematic review, the majority (37%) focused on hospital and clinical management of COVID-19, while 23.9% were commentaries. Epidemiological studies constituted 45.5% of the articles published by authors with non-Italian affiliations. Conclusion: The scientific articles on COVID-19 in Italy were varied in type of study, though with limited international impact. The lockdown and the pressure placed on hospitals during the first wave of the pandemic mainly resulted in publications on disease management and commentaries.

Atopic Manifestations in Children Born Preterm: A Long-Term Observational Study.

(1) Background: Preterm birth exposes the infant to the known risk factors for atopic diseases. We aimed to study the neonatal risk factors and to describe the clinical manifestations of atopy, including the march of symptoms, in a cohort of preschool children born preterm. (2) Methods: We enrolled neonates with gestational age < 32 weeks or birth weight < 1500 g. We classified patients in cases and controls according to the presence of at least one atopic manifestation. (3) Results: We observed 72 cases and 93 controls. Multivariate models showed that the administration of more than one cycle of antibiotics (B 0.902, p = 0.026) and gestational diabetes (B 1.207, p = 0.035) influence the risk of atopy in babies born preterm. In addition, risk of atopic dermatitis was influenced by gestational age < 29 weeks (B -1.710, p = 0.025) and gestational diabetes (B 1.275, p = 0.027). The risk of wheeze was associated with familiarity for asthma (B 1.392, p = 0.022) and the administration of more than one cycle of antibiotics (B 0.969, p = 0.025). We observed a significant reduction in the rate of atopic manifestation after 2 years of life (33.9% vs. 23.8%, p < 0.05). (4) Conclusions: Modifiable (gestational diabetes, antibiotics use) and unmodifiable (familiarity for asthma) conditions influence the risk of atopy in babies born preterm. Extreme prematurity reduces the risk of atopic dermatitis. Preterm babies showed a peculiar atopic march.

Liver Involvement in SARS-CoV-2 Vertically Infected Newborn: A Case Report.

Neonatal SARS-CoV-2 infection can occur antenatally, peripartum, or postnatally. In the newborn, clinical manifestations may vary including fever and respiratory, gastrointestinal and neurological symptoms. Most commonly, they are subclinical. We herein present a case of vertical transmission of SARS-CoV-2 presenting with liver injury, characterized by an increase in serum transaminases.

Complementary Feeding and Growth in Infants Born Preterm: A 12 Months Follow-Up Study.

Evidences demonstrated that timing of weaning influences long-term growth in full term infants. However, studies on preterm infants are still lacking, and the international guidelines are focused only on healthy full-term newborn, without consensus for preterms. We aimed at evaluating, in a cohort study, the consequences of different timing of weaning on auxological outcomes up to 12 months of corrected age in a population of neonates born with gestational age < 32 weeks or birth weight < 1500 g. We divided the enrolled neonates in two cohorts according to the timing of weaning: (i) Early Weaning: introduction of complementary food before 6 months of corrected age; (ii) Late Weaning: complementary food introduced after 6 months of corrected age. Growth parameters (weight, length, body mass index, and ponderal index) were measured at 12 months of life. The two groups were statistically comparable for baseline clinical characteristics, and differences on growth parameters were not reported between the two study groups. These results were confirmed in linear and binary logistic regression multivariate models. Timing of weaning is not related to growth of preterm newborns in the first 12 months of corrected age. Studies are needed to reach consensus for the appropriate nutritional approach for preterm babies after discharge.

ImmunizziAMO: A School-Based Field Trial to Teach New Generations the Importance of Vaccination through Games and to Fight Vaccine Hesitancy in Italy.

BACKGROUND: Vaccines simulate the first contact with infectious agents and evoke the immunological response without causing the disease and its complications. High rates of immunization among the population guarantee the interruption of the transmission chain of infectious diseases. Therefore, the population should be aware of the value of vaccination and motivated. In order to implement the spread of a correct culture about these issues, schools were recognized as a privileged operational setting. The aim of this project was to transmit knowledge and convey educational messages on the importance of vaccines, through the use of games, in elementary school children, their families and teachers. MATERIALS AND METHODS: A field trial study was implemented between April and October 2019. Sample size calculations highlighted the need to recruit at least 136 students in the schools. The intervention involved 10 classes (five first grade and five s grade classes) and was structured in frontal teaching sessions and gaming sessions. Knowledge was assessed comparing the results of a questionnaire administered before and after the intervention. The questionnaires referred to the following items: dangerousness of bacteria and viruses; capability of defending from microorganisms; the role of antibodies; functioning of the vaccine in a child; type of disease for which a vaccine is efficacious; duration of a vaccine; mother- child transmission of antibodies; herd immunity. RESULTS: 143 children participated in all the phases of the study. The comparison between the scores at the beginning and end of the intervention showed a significant increase in the knowledge about vaccines and immunity. The mean knowledge score arose from 3.52 (SD = 1.67) to 5.97 (SD = 1.81). CONCLUSIONS: This study suggests that the use of games in an elementary school effectively increase the knowledge related to the important topic of vaccination starting at childhood.