Search

Multiple endocrine neoplasia (MEN) syndromes are part of a spectrum of clinically well-defined tumor syndromes ultimately characterized by histologically similar tumors arising in patients and families with mutations in one of the following four genes: MEN1 , RET , CDKN1B , and MAX . The high level of genetic and phenotypic heterogeneity has been linked to phenocopies and modifying genes, as well as unknown mechanisms that might be investigated in the future based on preclinical and translational considerations. MEN1, also known as Wermer's syndrome (OMIM *131100), is an autosomal dominant syndrome codifying for the most frequent MEN syndrome showing high penetrance due to mutations in the MEN1 gene; nevertheless, clinical manifestations vary among patients in terms of tumor localization, age of onset, and clinical aggressiveness/severity, even within the same families. This has been linked to the effect of modifying genes, as described in the review. MEN 2-2b-4 and 5 also show remarkable clinical heterogeneity. The traditional view of genetically predisposing monogenic or multifactorial disorders is no longer valid, and mandates a change in scientific focus. Phenotypes are indeed rarely consistent across genetic backgrounds and environments. In the future, understanding factors and genetic variants that control cellular functions and the expression of disease genes should provide insights into fundamental disease processes, providing implications for counseling and therapeutic and prophylactic possibilities.

Background: Transient erythroblastopenia of childhood (TEC) is an acquired, self-limited pure red cell aplasia that usually occurs in children 4 years old and younger. This clinical condition has been priorly described to be linked to numerous viral and immunologic mechanisms. COVID-19, caused by the coronavirus SARS-CoV-2, was initially discovered in China in December 2019. The disease quickly spread worldwide, resulting in pandemic., Case Presentation: This manuscript reports a new clinically relevant condition associated to COVID-19, describing a child with clinical and biochemical signs of Pure Red Blood cells aplasia and complete absence of erythroblasts at the bone marrow needle aspiration with signs of erythrophagocytosis, resembling morphological signs such as in hemophagocytic lymphohistiocytosis (HLH), temporally associated to SARS-CoV-2 infection., Conclusion: This report highlights a newly described continuum laboratory and clinical spectrum of immune/hematological dysregulations secondary to SARS-CoV-2. SARS-CoV-2 infection-linked TEC has never been described in literature, but, according to our findings, should be considered in all the patients with transient erythroblastopenia without congenital red blood cell abnormalities and serology negative for major infections associated with TEC. This condition must be considered in the same spectrum of MIS-C and the inter-links among the two clinical manifestations, as well as a potential interdependence among them, should be considered in the future., (© 2024. The Author(s).)

Quality control testing of vaccines, including potency assessment, is critical to ensure equivalence of clinical lots. We developed a potency assay to support the clinical advancement of Nous-209, a cancer vaccine based on heterologous prime/boost administration of two multivalent viral vector products: GAd-209 and MVA-209. These consist of a mix of four Adeno (Great Ape Adenovirus; GAd) and four Modified Vaccinia Ankara (MVA) vectors respectively, each containing a different transgene encoding a synthetic polypeptide composed of antigenic peptide fragments joined one after the other. The potency assay employs quantitative Reverse Transcription PCR (RT-Q-PCR) to quantitatively measure the transcripts from the four transgenes encoded by each product in in vitro infected cells, enabling simultaneous detection. Results showcase the assay's robustness and biological relevance, as it effectively detects potency loss in one component of the mixture comparably to in vivo immunogenicity testing. This report details the assay's setup and validation, offering valuable insights for the clinical development of similar genetic vaccines, particularly those encoding synthetic polypeptides.

Diabetic nephropathy (DN) represents the most common microvascular complication in patients with diabetes. This progressive kidney disease has been recognized as the major cause of end-stage renal disease with higher morbidity and mortality. However, its tangled pathophysiology is still not fully known. Due to the serious health burden of DN, novel potential biomarkers have been proposed to improve early identification of the disease. In this complex landscape, several lines of evidence supported a critical role of microRNAs (miRNAs) in regulating posttranscriptional levels of protein-coding genes involved in DN pathophysiology. Indeed, intriguing data showed that deregulation of certain miRNAs (e.g., miRNAs 21, -25, -92, -210, -126, -216, and -377) were pathogenically linked to the onset and the progression of DN, suggesting not only a role as early biomarkers but also as potential therapeutic targets. To date, these regulatory biomolecules represent the most promising diagnostic and therapeutic options for DN in adult patients, while similar pediatric evidence is still limited. More, findings from these elegant studies, although promising, need to be deeper investigated in larger validation studies. In an attempt to provide a comprehensive pediatric overview in the field, we aimed to summarize the most recent evidence on the emerging role of miRNAs in pediatric DN pathophysiology.

Mechanisms underlying severe male infertility are still largely elusive. However, recently, a single-cell transcription study by our group identified several differentially expressed coding genes in all the somatic cell types in testes of patients with idiopathic germ cell aplasia (iGCA). Here, we leverage this work by extending the analysis also to the non-coding portion of the genome. As a result, we found that 43 LncRNAs were differentially expressed in the somatic cells of these patients. Interestingly, a significant portion of the overexpressed LncRNAs was found to be a target of TAF9B, a transcription factor known to be involved in germ cell survival. Moreover, several overexpressed LncRNAs were also found to be activated in a mouse model of Sertoli cells treated with bisphenol A, a widespread environmental contaminant, long suspected to impair male fertility. Finally, a literature search for MEG3, a maternally imprinted LncRNA overexpressed as well in our patients, found it to be involved, among other things, in obesity and inflammation, known comorbidities of iGCA, ultimately suggesting that our findings deepen the understanding of the molecular insights coupled not only to the pathogenesis, but also to the clinical course of this class of patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lavorgna, Tascini, Bertini, Lanzaro, Montorsi, Alfano and Salonia.)

In 2020, an international group of experts proposed to replace the term of nonalcoholic fatty liver disease with metabolic-associated fatty liver disease (MAFLD). This recent proposal reflects the close association of fatty liver with metabolic derangements, as demonstrated by previous robust data. Several factors [including genetics, inflammation, metabolic abnormalities, insulin resistance (IR), obesity, prenatal determinants, and gut-liver axis] have been found to be involved in MAFLD pathophysiology, but this tangled puzzle remains to be clearly understood. In particular, IR has been recognized as a key player in metabolic impairments development in children with fatty liver. On this ground, MAFLD definition focuses on the pathophysiological basis of the disease, by emphasizing the crucial role of metabolic impairments in this condition. Although primarily developed for adults, MAFLD diagnostic criteria have been recently updated with an age-appropriate definition for sex and age percentiles, because of the increasing attention to cardiometabolic risk in childhood. To date, accumulating evidence is available on the feasibility of MAFLD definition in clinical practice, but some data are still conflicting in highly selected populations. Considering the growing prevalence worldwide of fatty liver and its close relationship with metabolic dysfunction both in children and adults with subsequent increased cardiovascular risk, early strategies for MAFLD identification, treatment and prevention are needed. Novel therapeutic insights for MAFLD based on promising innovative biological techniques are also emerging. We aimed to summarize the most recent evidence in this intriguing research area both in children and adults., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Increased incidence of central precocious puberty (CPP) after coronavirus infectious disease-19 lockdown has been reported. Our study aims in investigating changes in CPP rates and in sleep patterns in CPP and healthy controls., Methods: CPP were retrospectively evaluated from April 2020 to April 2021. Parents of girls diagnosed with CPP during lockdown and of matched healthy controls filled out a questionnaire about sleep disturbances (SDSC questionnaire) and sleep schedules., Results: Thirty-five CPP and 37 controls completed the survey. Incidence of new CPP cases significantly increased in 2020-2021 compared to 2017-2020 (5:100 vs 2:100, p = 0.02). Sleep disturbance rates did not differ between CPP and healthy controls before lockdown. During lockdown, CPP reported higher rates of sleep disturbs for total score (p = 0.005), excessive somnolence (p = 0.049), sleep breathing disorders (p = 0.049), and sleep-wake transition disorders (p = 0.005). Moreover, CPP group more frequently shifted toward later bedtime (p = 0.03) during lockdown compared to controls. Hours of sleep and smartphone exposure around bedtime did not differ between groups., Conclusions: Our study confirms the observation of increased incidence of CPP after lockdown measures. Additionally, CPP showed higher rates of sleep disturbances and later bedtime compared to controls. The causality link between sleep disturbances and CPP should be further investigated to gain knowledge in this association., (© 2022. The Author(s).)

The rapid global spread of coronavirus disease 2019 (COVID-19) infection has become a major health issue with higher morbidity and mortality rates. Besides respiratory symptoms, a growing body of evidence indicates a variety of gastrointestinal manifestations including liver involvement. In this regard, several data supported an association between COVID-19 infection and liver injury in adults, while in children there is compelling but currently limited evidence. In particular, patients with COVID-19 have shown a higher risk of liver injury (mainly expressed as increased transaminase levels or hepatic steatosis). Conversely, a greater risk of more severe forms of COVID-19 infection has been observed in subjects with pre-existing chronic liver diseases. The dramatic interplay between COVID-19 and liver damage has been related to the inflammatory pathways chronically active in patients with nonalcoholic fatty liver disease and acutely in those affected by COVID-19, but other different pathogenic mechanisms have also been supposed. Of note, patients with previous metabolic comorbidities also had a higher risk of severe COVID-19 infection. This emphasizes the pathogenic interrelation of the inflammatory pathways with a dysregulated metabolic milieu in COVID-19 patients. Taking into account the prognostic role of fatty liver in COVID-19 patients and its intrinsic relationship with metabolic abnormalities even in childhood, a strict monitoring of this condition is recommended. We aimed to summarize the most recent evidence regarding the potential interplay between pediatric fatty liver and COVID-19., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interest to declare., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Rabies, caused by RNA viruses in the Genus Lyssavirus, is the most fatal of all infectious diseases. This neglected zoonosis remains a major public health problem in developing countries, causing the death of an estimated 25,000-159,000 people each year, with more than half of them in children. The high incidence of human rabies in spite of effective vaccines is mainly linked to the lack of compliance with the complicated administration schedule, inadequacies of the community public health system for local administration by the parenteral route and the overall costs of the vaccine. The goal of our work was the development of a simple, affordable and effective vaccine strategy to prevent human rabies virus infection. This next generation vaccine is based on a replication-defective chimpanzee adenovirus vector belonging to group C, ChAd155-RG, which encodes the rabies glycoprotein (G). We demonstrate here that a single dose of this vaccine induces protective efficacy in a murine model of rabies challenge and elicits strong and durable neutralizing antibody responses in vaccinated non-human primates. Importantly, we demonstrate that one dose of a commercial rabies vaccine effectively boosts the neutralizing antibody responses induced by ChAd155-RG in vaccinated monkeys, showing the compatibility of the novel vectored vaccine with the current post-exposure prophylaxis in the event of rabies virus exposure. Finally, we demonstrate that antibodies induced by ChAd155-RG can also neutralize European bat lyssaviruses 1 and 2 (EBLV-1 and EBLV-2) found in bat reservoirs., Competing Interests: Benjamin Wizel is an employee of the GSK group of companies.