Explore the vast range of titles available.

The benefits of schools’ closure, used as a containment strategy by many European countries, must be carefully considered against the adverse effects of child wellbeing. In this study, we assessed SARS-CoV-2 seroprevalence, which better estimates the real extent of the infection unraveling asymptomatic cases, among schoolchildren aged 3 to 18 in Milan, using dried blood spot, a safe and extremely viable methods for children, and then compared it between September 2020 and January 2021. Secondly, we evaluated the seroconversion rate and compared it between students attending schools in presence and those switched to distance-learning, using a logistic regression model, both as univariate and multivariate, adjusting for age and biological-sex. Among 1109 pupils, we found a seroprevalence of 2.8% in September before school reopening, while in January 2021, the seropositive rate was 12.5%, reflecting the general growth rate of infections during the second pandemic wave. The overall seroconversion rate was 10%, with no differences based on biological-sex and age groups; we observed no seroreversion. When considered age groups, the seroconversion rate was 10.5% (95%Confidence Interval, 2.9–24.8) among children attending preschools, 10.6% (95%Confidence Interval, 8.2–13.4) for primary schools, 9.9% (95%Confidence Interval, 6.8–13.8) for secondary schools, and 7.8% (95%Confidence Interval, 4–13.2) among high-school students. Interestingly, no differences in seroconversion rate were found between students who attended school compared to those who started remote learning in the first days of November. Furthermore, most patients (61%) reported that the contact occurred within the household. We reported a low seroconversion rate among school children in Milan, with no differences between those who attended from September 2020 to January 2021 compared to those who switched to remote learning in the first days of November. Our data suggest that schools do not amplify SARS-CoV-2 transmission, but rather reflect the level of the transmission in the community.

Background Cellular senescence is a biological process in which the cell cycle is arrested in response to DNA damage caused by different endogenous and exogenous stimuli. In senescent cells, activation of intracellular cascade induces epigenetic, morphological and metabolic changes. Among them, senescent status is characterized by an alteration of the epigenome and the establishment of a peculiar senescence-associated secretory phenotype (SASP), which contributes to the extracellular matrix remodeling and senescence spreading. Growing interest is directed towards senescence relevance both in physiological processes and in pathological ones, including rare progeroid syndromes. However, little is known about senescence contribution to the onset and development of rare diseases in which aging traits are not manifested. Main body Here, we review the current knowledge about senescence involvement in four rare mendelian disorders of the epigenetic machinery (i.e. chromatinopathies) and four rare lung diseases, that can be considered a paradigm for understanding how epigenome alteration and aberrant microenvironment modification in senescence process might drive disease onset and progression. First, we report the main characteristics of chromatinopathies and the relation between the chromatin-related epigenetic defects and the senescence features in Sotos syndrome, Cornelia de Lange syndrome, Rett syndrome, and Kleefstra syndromes. Thereafter, we describe the pathological alteration and senescence involvement in cystic fibrosis, idiopathic pulmonary fibrosis, pulmonary arterial hypertension and lymphangioleiomyomatosis, considering them as models of rare lung diseases in which accumulation of senescent cells and their proinflammatory SASP have a central role. Conclusion Exploring the role of senescence in different and less common diseases might promote the understanding of the senescent process as a novel player in rare disorders, for a more comprehensive vision of their complexity and the suggestion of novel possible therapeutical targets.

Modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine + nab-paclitaxel (GemNab) regimens represent a standard treatment in advanced pancreatic cancer (aPC). DPYD and UGT1A1 variants are relevant predictors of fluoropyrimidine and irinotecan-associated adverse events (AEs). Furthermore, data about the associations between polymorphisms in ABCB and CDA genes and GemNab-related toxicities are still controversial. The present study analyzes the association between DPYD, UGT, ABCB1, CDA variants, and AEs in aPC patients (pts) treated with mFOLFIRINOX or GemNab. Blood samples collected from 104 aPC pts treated with mFOLFIRINOX and 63 with GemNab were tested for DPYD c.1679T>G, IVS14+1G>A, c.2194G>A, c.2846A>T, UGT1A1*28, CDA c.79A>C, and ABCB1 c.1236C>T, c.2677G>T/A, c.3435C>T by real-time PCR and automatic sequencing. In mFOLFIRINOX cohort, DPYD IVS14+1GA genotype was associated with G4 hematological AEs, while the UGT1A1*28 significantly correlated with the risk of thrombocytopenia (p = 0.006). In the GemNab cohort, a significant association between CDA c.79CC and high-grade nausea was observed (p = 0.002). Moreover, the presence of at least a mutant allele in ABCB1 increased the risk of overall hematological AEs (p = 0.01), both further strengthened by the presence of CDA c.79CC (p = 0.0002). DPYD IVS14+1A allele is confirmed to be associated with fluoropyrimidine life-threatening toxicities, and UGT1A1*28 is related with a higher risk of hematologic AEs following irinotecan treatment. CDA c.79C and ABCB1 c.1236T, c.2677T/A, and c.3435T mutant alleles are predictive biomarkers of GemNab-related AEs. All these variants should be considered in aPC pts candidate to mFOLFIRINOX or GemNab treatments.

Adjuvant treatment for resectable non-small cell lung cancer (NSCLC) has seen significant advancements following the introduction of immune checkpoint inhibitors (ICIs). These therapies, which enhance the immune system’s ability to recognize and target cancer cells, have demonstrated substantial improvements in disease-free survival (DFS) following surgical resection. Recent studies have shown that ICIs can extend DFS, particularly for patients with high Programmed Death-Ligand 1 (PD-L1) expression but also for those with lower levels of PD-L1, suggesting a broader potential for their application. In the IMpower010 trial, atezolizumab improved DFS compared to best supportive care (BSC) in resected stage II–IIIA NSCLC, with a hazard ratio (HR) of 0.66 (95% CI 0.50–0.88) for patients with PD-L1 expression ≥1% and 0.79 (95% CI 0.64–0.96) for the overall stage II–IIIA population. In the PEARLS/KEYNOTE-091 trial, pembrolizumab also demonstrated a DFS benefit over a placebo for patients with stage IB–IIIA disease (HR 0.76; 95% CI 0.63–0.91), with a median DFS of 53.6 months versus 42.0 months. Despite these promising results, challenges remain regarding the optimal selection of patients, particularly in identifying the most effective biomarkers and determining the ideal duration of treatment. While ICIs are generally well-tolerated, immune-related adverse events, although manageable, require careful monitoring, especially when ICIs are used in combination with chemotherapy. Ongoing research is focused on optimizing treatment duration and exploring combination therapies, with the objective of further improving long-term survival outcomes. The integration of immunotherapy in the adjuvant setting represents a significant advancement in the management of resectable NSCLC. This review aims to provide an overview of the current evidence supporting the use of ICIs in the adjuvant treatment of NSCLC, focusing on treatment efficacy, safety profiles, and ongoing research into biomarkers and combination therapies.

The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. This multicentric study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS). A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (>31.3) and low (<31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age > 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI <31.3 versus >31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts. PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC.

Diaphanous related formins are regulatory cytoskeletal protein involved in actin elongation and microtubule stabilization. In humans, defects in two of the three diaphanous genes ( DIAPH1 and DIAPH3 ) have been associated with different types of hearing loss. Here, we investigate the role of the third member of the family, DIAPH2 , in nonsyndromic hearing loss, prompted by the identification, by exome sequencing, of a predicted pathogenic missense variant in DIAPH2 . This variant occurs at a conserved site and segregated with nonsyndromic X-linked hearing loss in an Italian family. Our immunohistochemical studies indicated that the mouse ortholog protein Diaph2 is expressed during development in the cochlea, specifically in the actin-rich stereocilia of the sensory outer hair cells. In-vitro studies showed a functional impairment of the mutant DIAPH2 protein upon RhoA-dependent activation. Finally, Diaph2 knock-out and knock-in mice were generated by CRISPR/Cas9 technology and auditory brainstem response measurements performed at 4, 8 and 14 weeks. However, no hearing impairment was detected. Our findings indicate that DIAPH2 may play a role in the inner ear; further studies are however needed to clarify the contribution of DIAPH2 to deafness.

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as “writer” of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann–Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein–Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.

Background the protein phosphatase 3 catalytic subunit alpha ( PPP3CA ) gene encodes for the alpha isoform of the calcineurin catalytic subunit, which controls the phosphorylation status of many targets. Currently, 23 pathogenic variants of PPP3CA are known, with clinical manifestations varying by mutation type and domain. Results through whole exome sequencing, we found two de novo variants in PPP3CA : a frameshift variant predicted leading to a truncated protein in Pt.1 and a splicing variant in Pt.2 associated with mild phenotype. PPP3CA is ubiquitously expressed with tissue-specificity of; namely, splicing isoform 1 prevailing over isoform 2 in the central nervous system. By analyzing isoform distribution in patient-derived cell lines, we highlight a skewed expression of both isoforms in Pt.1, whereas only isoform 2 shows a moderate reduction in Pt.2. In contrast, we did not observe significant abundance changes at the protein level. Cell lines derived from Pt.1 showed a reduced proliferation, associated with an increase in cell death and the upregulation of the unfolded protein response (UPR) pathway. Conclusion data suggest that an aberrant PPP3CA protein in Pt.1 could lead to UPR activation resulting in increased cell death. In Pt.2 an imbalance between the two main isoforms possibly explains the peculiar pathological manifestations, such as a moderate developmental delay.

Gonadotropin-releasing hormone (GnRH) deficiency (GD) is a disorder characterized by absent or delayed puberty, with largely unknown genetic causes. The purpose of this study was to obtain and exploit gene expression profiles of GnRH neurons during development to unveil novel biological mechanisms and genetic determinants underlying GD. Here, we combined bioinformatic analyses of immortalized and primary embryonic GnRH neuron transcriptomes with exome sequencing from GD patients to identify candidate genes implicated in the pathogenesis of GD. Among differentially expressed and filtered transcripts, we found loss-of-function (LoF) variants of the autism-linked neuroligin 3 (NLGN3) gene in two unrelated patients co-presenting with GD and neurodevelopmental traits. We demonstrated that NLGN3 is upregulated in maturing GnRH neurons and that NLGN3 wild-type, but not mutant, protein promotes neuritogenesis when overexpressed in developing GnRH cells. Our data represent proof of principle that this complementary approach can identify new candidate GD genes and demonstrate that LoF NLGN3 variants can contribute to GD. This novel genotype–phenotype correlation implies common genetic mechanisms underlying neurodevelopmental disorders, such as GD and autistic spectrum disorder.

Esophageal cancer remains a challenging disease due to limited treatment options and poor prognosis. In recent years, immune checkpoint inhibitors (ICI) have been proven to be safe and effective in the treatment of highly lethal malignancies, such as non-small cell lung cancer and melanoma. Recent clinical trials also showed promising activity in immune checkpoint inhibitors in pretreated advanced esophageal carcinoma and a potentially significant impact on the outcome of selected patients, independently of histology. Combination studies evaluating immunotherapy and chemotherapy and, in localized disease, radiotherapy are in progress and will hopefully confirm their promises in the near future. However, reliable predictive biomarkers are still lacking. Indeed, at present, the role of programmed cell death ligand 1 expression and other factors (such as microsatellite instability and tumor mutational burden) as predictive biomarkers of benefit to immune checkpoint inhibitors is still controversial. Our aim was to explore the rationale of ICIs in esophageal cancer, review the results already available in multiple settings, and investigate future perspectives with single-agent and combination strategies.