Preliminary Evidence of the Differential Expression of Human Endogenous Retroviruses in Kawasaki Disease and SARS-CoV-2-Associated Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some clinical features overlapping with Kawasaki disease (KD). Our research group and others have highlighted that the spike protein of SARS-CoV-2 can trigger the activation of human endogenous retroviruses (HERVs), which in turn induces inflammatory and immune reactions, suggesting HERVs as contributing factors in COVID-19 immunopathology. With the aim to identify new factors involved in the processes underlying KD and MIS-C, we analysed the transcriptional levels of HERVs, HERV-related genes, and immune mediators in children during the acute and subacute phases compared with COVID-19 paediatric patients and healthy controls. The results showed higher levels of HERV-W, HERV-K, Syn-1, and ASCT-1/2 in KD, MIS-C, and COV patients, while higher levels of Syn-2 and MFSD2A were found only in MIS-C patients. Moreover, KD and MIS-C shared the dysregulation of several inflammatory and regulatory cytokines. Interestingly, in MIS-C patients, negative correlations have been found between HERV-W and IL-10 and between Syn-2 and IL-10, while positive correlations have been found between HERV-K and IL-10. In addition, HERV-W expression positively correlated with the C-reactive protein. This pilot study supports the role of HERVs in inflammatory diseases, suggesting their interplay with the immune system in this setting. The elevated expression of Syn-2 and MFSD2A seems to be a distinctive trait of MIS-C patients, allowing to distinguish them from KD ones. The understanding of pathological mechanisms can lead to the best available treatment for these two diseases, limiting complications and serious outcomes.

Innovative strategies to predict and prevent the risk for malnutrition in child, adolescent, and young adult cancer survivors.

Children, adolescents, and young adult cancer survivors (CAYAs) constitute a growing population requiring a customized approach to mitigate the incidence of severe complications throughout their lifetimes. During cancer treatment, CAYAs cancer survivors undergo significant disruptions in their nutritional status, elevating the risks of mortality, morbidity, and cardiovascular events. The assessment of nutritional status during cancer treatment involves anthropometric and dietary evaluations, emphasizing the necessity for regular assessments and the timely identification of risk factors. Proactive nutritional interventions, addressing both undernutrition and overnutrition, should be tailored to specific age groups and incorporate a family-centered approach. Despite encouraging interventions, a notable evidence gap persists. The goal of this review is to comprehensively examine the existing evidence on potential nutritional interventions for CAYAs cancer survivors. We explore the evidence so far collected on the nutritional intervention strategies elaborated for CAYAs cancer survivors that should target both undernutrition and overnutrition, being age-specific and involving a family-based approach. Furthermore, we suggest harnessing artificial intelligence (AI) to anticipate and prevent malnutrition in CAYAs cancer survivors, contributing to the identification of novel risk factors and promoting proactive, personalized healthcare.

Case report: Histological findings of peri-appendicitis in three children with SARS-CoV-2 - related multisystem inflammatory syndrome: A mark for systemic inflammation?

Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition that can potentially develop after SARS-CoV-2 infection in children. Gastrointestinal manifestation in MIS-C can mimic acute abdomen, potentially leading to unnecessary surgical treatment. Immune-mediated mechanisms seem to be a determining factor in its pathogenesis, and histological studies can help to shed light on this aspect. We describe three cases of children diagnosed with MIS-C that underwent appendectomy. Methods: We retrospectively collected the clinical features and histological findings of three previously healthy children who underwent appendectomy for clinical suspicion of acute appendicitis but were later diagnosed with MIS-C. Findings: The three children presented with prominent abdominal manifestations and fever leading to the suspicion of acute abdomen. Histological findings showed transmural and perivascular inflammation. Notably, CD68+ macrophages were predominant in the child with milder abdominal symptoms without cardiac injury, while CD3+ lymphocytes in the patient presented with more severe abdominal pain and cardiovascular involvement at admission. Interpretation: Gastrointestinal symptoms of children with MIS-C improve after proper immunomodulatory therapy, conversely showing inadequate response to surgical appendectomy. Histological findings revealed different inflammatory cell infiltration that primarily involved perivisceral fat and vessels, and subsequently mucosal tissue, in contrast to other forms of acute appendicitis. Our findings suggest that this kind of peri-appendicitis in MIS-C could represent a focal sign of systemic inflammation, with different histological patterns compared to other forms of acute appendicitis.

The Role of Nutrition in Primary and Secondary Prevention of Cardiovascular Damage in Childhood Cancer Survivors.

Innovative therapeutic strategies in childhood cancer led to a significant reduction in cancer-related mortality. Cancer survivors are a growing fragile population, at risk of long-term side effects of cancer treatments, thus requiring customized clinical attention. Antineoplastic drugs have a wide toxicity profile that can limit their clinical usage and spoil patients' life, even years after the end of treatment. The cardiovascular system is a well-known target of antineoplastic treatments, including anthracyclines, chest radiotherapy and new molecules, such as tyrosine kinase inhibitors. We investigated nutritional changes in children with cancer from the diagnosis to the end of treatment and dietary habits in cancer survivors. At diagnosis, children with cancer may present variable degrees of malnutrition, potentially affecting drug tolerability and prognosis. During cancer treatment, the usage of corticosteroids can lead to rapid weight gain, exposing children to overweight and obesity. Moreover, dietary habits and lifestyle often dramatically change in cancer survivors, who acquire sedentary behavior and weak adherence to dietary guidelines. Furthermore, we speculated on the role of nutrition in the primary prevention of cardiac damage, investigating the potential cardioprotective role of diet-derived compounds with antioxidative properties. Finally, we summarized practical advice to improve the dietary habits of cancer survivors and their families.

The novel butyrate derivative phenylalanine-butyramide protects from doxorubicin-induced cardiotoxicity.

AIMS: Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine-butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function. METHODS AND RESULTS: In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co-administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase-2 mRNAs, which were not elevated on co-treatment with FBA. DOXO, but not FBA + DOXO mice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre-treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H2 O2 , which were blunted by FBA pre-treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour-killing action of DOXO. CONCLUSIONS: Phenylalanine-butyramide protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by reduction in oxidative stress and amelioration of mitochondrial function.