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Problem After Italy's first national restriction measures in 2020, a robust approach was needed to monitor the emerging epidemic of coronavirus disease 2019 (COVID-19) at subnational level and provide data to inform the strengthening or easing of epidemic control measures. Approach We adapted the European Centre for Disease Prevention and Control rapid risk assessment tool by including quantitative and qualitative indicators from existing national surveillance systems. We defined COVID-19 risk as a combination of the probability of uncontrolled transmission of severe acute respiratory syndrome coronavirus 2 and of an unsustainable impact of COVID-19 cases on hospital services, adjusted in relation to the health system's resilience. The monitoring system was implemented with no additional cost in May 2020. Local setting The infectious diseases surveillance system in Italy uses consistent data collection methods across the country's decentralized regions and autonomous provinces. Relevant changes Weekly risk assessments using this approach were sustainable in monitoring the epidemic at regional level from 4 May 2020 to 24 September 2021. The tool provided reliable assessments of when and where a rapid increase in demand for health-care services would occur if control or mitigation measures were not increased in the following 3 weeks. Lessons learnt Although the system worked well, framing the risk assessment tool in a legal decree hampered its flexibility, as indicators could not be changed without changing the law. The relative complexity of the tool, the impossibility of real-time validation and its use for the definition of restrictions posed communication challenges. Probleme Apres avoir pris ses premieres mesures de restriction nationales en 2020, l'Italie avait besoin d'une approche solide pour surveiller l'epidemie naissante de maladie a coronavirus 2019 (COVID-19) au niveau regional, et fournir les donnees permettant de renforcer ou d'alleger les mesures destinees a l'endiguer. Approche Nous avons adapte l'outil d'evaluation rapide des risques du Centre europeen de prevention et de controle des maladies en y integrant des indicateurs quantitatifs et qualitatifs issus des systemes de surveillance nationaux existants. Pour definir le risque lie a la COVID-19, nous avons associe la probabilite d'une transmission incontrolee du coronavirus 2 du syndrome respiratoire aigu severe, a l'impact immediat des cas de COVID-19 sur les services hospitaliers, en procedant a des ajustements selon la resilience du systeme de soins de sante. Le dispositif de surveillance a ete mis en reuvre en mai 2020 sans entrainer de couts supplementaires. Environnement local En Italie, le systeme de surveillance des maladies infectieuses repose sur des methodes uniformes de collecte de donnees dans les provinces autonomes et regions decentralisees a travers le pays. Changements significatifs Les evaluations des risques realisees toutes les semaines avec cette approche ont permis de surveiller l'epidemie a l'echelle regionale du 4 mai 2020 au 24 septembre 2021. L'outil a identifie les dates et lieux susceptibles de connaitre une augmentation rapide de la demande en services de soins de sante si aucune mesure supplementaire de controle et de lutte n'etait prise dans les trois semaines. Lecons tirees Bien que le systeme ait fonctionne, inscrire l'outil d'evaluation des risques dans un decret legislatif a reduit sa flexibilite, car les indicateurs ne pouvaient etre modifies sans reformer la loi. La relative complexite de l'outil, l'impossibilite de proceder a une validation en temps reel et son usage pour imposer des restrictions ont pose des problemes de communication. Situacion Tras las primeras medidas nacionales de restriccion en Italia en 2020, se necesitaba un enfoque solido para supervisar la epidemia emergente de la coronavirosis de 2019 (COVID-19) a nivel subnacional y proporcionar datos que informaran sobre el refuerzo o la flexibilizacion de las medidas de contencion de la epidemia. Enfoque Se adapto la herramienta de valoracion rapida de riesgos del Centro Europeo para la Prevencion y el Control de las Enfermedades, al incluir indicadores cuantitativos y cualitativos de los sistemas nacionales de vigilancia existentes. Se definio el riesgo de la COVID-19 como una combinacion de la probabilidad de transmision descontrolada del coronavirus del sindrome respiratorio agudo grave de tipo 2 y de un efecto no sostenible de los casos de la COVID-19 en los servicios hospitalarios, y se ajusto en relacion con la capacidad de recuperacion del sistema sanitario. El sistema de supervision se aplico sin costes adicionales en mayo de 2020. Marco regional El sistema de vigilancia de las enfermedades infecciosas en Italia aplica metodos de recopilacion de datos coherentes en todas las regiones y provincias autonomas descentralizadas del pais. Cambios importantes Las valoraciones semanales de los riesgos mediante este enfoque fueron sostenibles en la supervision de la epidemia a nivel regional entre el 4 de mayo de 2020 y el 24 de septiembre de 2021. La herramienta proporciono valoraciones fiables de cuando y donde se produciria un rapido aumento de la demanda de servicios sanitarios si no se incrementaban las medidas de contencion o mitigacion en las tres semanas siguientes. Lecciones aprendidas Aunque el sistema funciono bien, el hecho de enmarcar la herramienta de valoracion de los riesgos en un decreto legal dificulto su flexibilidad, ya que los indicadores no se podian modificar sin cambiar la ley. La relativa complejidad de la herramienta, la imposibilidad de validacion en tiempo real y su uso para la definicion de las restricciones plantearon problemas de comunicacion., Introduction In its first response to the emerging epidemic of coronavirus disease 2019 (COVID-19), the Italian government implemented national restriction measures with strict physical distancing and restrictions on public movements [...]

Molecular profiles of thymomas and recurrent thymomas are far from being defined. Herein, we report an analysis of a comprehensive genetic profile (CGP) in a highly selected cohort of recurrent thymomas. Among a cohort of 426 thymomas, the tissue was available in 23 recurrent tumors for matching the biomolecular results obtained from primary and relapse samples. A control group composed of non-recurrent thymoma patients was selected through a propensity score match analysis. CGP was performed using the NGS Tru-SightOncology assay to evaluate TMB, MSI, and molecular alterations in 523 genes. CGP does not differ when comparing initial tumor with tumor relapse. A significantly higher frequency of cell cycle control genes alterations (100.0% vs. 57.1%, p = 0.022) is detected in patients with early recurrence (<32 months) compared to late recurrent cases. The CGPs were similar in recurrent thymomas and non-recurrent thymomas. Finally, based on NGS results, an off-label treatment or clinical trial could be potentially proposed in >50% of cases (oncogenic Tier-IIC variants). In conclusion, CGPs do not substantially differ between initial tumor vs. tumor recurrence and recurrent thymomas vs. non-recurrent thymomas. Cell cycle control gene alterations are associated with an early recurrence after thymectomy. Multiple target therapies are potentially available by performing a comprehensive CGP, suggesting that a precision medicine approach on these patients could be further explored. [ABSTRACT FROM AUTHOR]

Background/Objectives: The relationship between sarcoidosis and the occurrence of neoplasia deserves to be investigated, but this relation has been observed in different and heterogeneous populations, leading to conflicting data. To clarify the causal relationship between these two diseases, different risk factors (e.g., smoking), concurrent comorbidities, corticosteroid therapy, and metastasis development—as an expression of cancer aggressiveness—were investigated. Methods: In a retrospective study on 287 sarcoidosis outpatients at the Pneumological Department of the Gemelli Foundation (Rome, Italy) between 2000 and 2024, the diagnosis of cancer was recorded in 36 subjects (12.5%). Results: The reciprocal timeline of the diseases showed three different scenarios: (1) cancer preceding sarcoidosis or sarcoid-like reactions (63.8%); (2) cancer arising after sarcoidosis diagnosis (8.3%); and (3) sarcoidosis accompanying the onset of malignancy (27.8%). Only two subjects with sarcoidosis and cancer showed metastasis, and one of them was affected by lymphoma. Conclusions: These data suggest that granulomatous inflammation due to sarcoidosis may assume an ambivalent role as a "double-edged sword", according to the M1/M2 macrophage polarization model: it represents a protective shield, preventing the formation of metastasis through the induction of immune surveillance against cancer while, on the other hand, it can be a risk factor for carcinogenesis due to the persistence of a chronic active inflammatory status. Low-dose steroid treatment was administered in only 31.6% of the cancer–sarcoidosis subjects for less than six months to control inflammation activity, with no promotive effect on carcinogenesis observed. [ABSTRACT FROM AUTHOR]

Tumor heterogeneity refers to the diversity observed among tumor cells: both between different tumors (inter-tumor heterogeneity) and within a single tumor (intra-tumor heterogeneity). These cells can display distinct morphological and phenotypic characteristics, including variations in cellular morphology, metastatic potential and variability treatment responses among patients. Therefore, a comprehensive understanding of such heterogeneity is necessary for deciphering tumor-specific mechanisms that may be diagnostically and therapeutically valuable. Innovative and multidisciplinary approaches are needed to understand this complex feature. In this context, proteogenomics has been emerging as a significant resource for integrating omics fields such as genomics and proteomics. By combining data obtained from both Next-Generation Sequencing (NGS) technologies and mass spectrometry (MS) analyses, proteogenomics aims to provide a comprehensive view of tumor heterogeneity. This approach reveals molecular alterations and phenotypic features related to tumor subtypes, potentially identifying therapeutic biomarkers. Many achievements have been made; however, despite continuous advances in proteogenomics-based methodologies, several challenges remain: in particular the limitations in sensitivity and specificity and the lack of optimal study models. This review highlights the impact of proteogenomics on characterizing tumor phenotypes, focusing on the critical challenges and current limitations of its use in different clinical and preclinical models for tumor phenotypic characterization. [ABSTRACT FROM AUTHOR]

Background: Pathogenic variants in the Polycystic Kidney Disease 2 (PKD2) gene are associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD) in approximately 30% of cases. In recent years, the high-throughput sequencing techniques have significantly increased the number of variants identified in affected patients. Here, we described the peculiar effect of a PKD2 splicing variant, the c.1717-2A>G, identified in an Italian male patient with ADPKD. This variant led to the unusual and rare skipping of two consecutive exons, causing a large in-frame deletion. Methods: The genetic evaluation of the patient was performed using the Next-Generation Sequencing (NGS) assay Clinical Exome Solution® (SOPHiA Genetics). Bioinformatics analysis was performed using the SOPHiA DDM platform (SOPHiA Genetics). Prediction of pathogenicity was carried out by integrating several in silico tools. RNA evaluation was performed to test the effect of the variant on the PKD2 splicing using a Reverse-Transcription PCR coupled with cDNA sequencing. Results: NGS revealed the presence of the PKD2 c.1717-2A>G variant that lies in the canonical splice site of intron 7. This rare variant was predicted to have a significant impact on the splicing, proved by the RNA-based analysis. We identified the presence of a transcript characterised by the simultaneous skipping of exons 8 and 9, with a retained reading frame and the merging of exons 7–10. Conclusions: We described for the first time a dual-exon skip event related to the presence of a single-base substitution in the PKD2 gene in an ADPKD-affected patient. We assumed that the molecular basis of such a rare mechanism lies in the specific order of intron removal. The finding represents novel evidence of an alternative and unusual splicing mechanism in the PKD2 gene, adding insights to the pathogenesis of the ADPKD. [ABSTRACT FROM AUTHOR]

Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the "redoxome" encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for this homeostasis. Due to their reactive thiol groups, cysteine (Cys) residues are particularly susceptible to oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, and sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what is referred to as "cysteinet" in the redox proteome, are essential for redox signaling in both physiological and pathological conditions, including neurodegeneration. Such modifications significantly influence protein misfolding and aggregation, key hallmarks of neurodegenerative diseases such as Alzheimer's, Parkinson's, and notably, amyotrophic lateral sclerosis (ALS). This review aims to explore the complex landscape of cysteine PTMs in the cellular redox environment, elucidating their impact on neurodegeneration at protein level. By investigating specific cysteine-sensitive proteins and the regulatory networks involved, particular emphasis is placed on the link between redox dysregulation and ALS, highlighting this pathology as a prime example of a neurodegenerative disease wherein such redox dysregulation is a distinct hallmark. [ABSTRACT FROM AUTHOR]

Background: CFTR-related disorder (CFTR-RD) is a clinical entity associated to complex diagnostic paths and newly upgraded standard of care. In CFTR-RD, CFTR genotyping represents a diagnostic surrogate marker. In case of novel haplotype, the diagnosis could represents an area of concern. We described the molecular evaluation of the rare CFTR variant E583G identified in trans with the F508del in a novel haplotype. Methods and results: An adult woman was referred to our pulmonary unit for persistent respiratory symptoms. CFTR Next Generation Sequencing was performed to evaluate full-gene mutational status. The variant identified was evaluated for its pathogenicity integrating clinical evidences with dedicated bioinformatics analyses. Clinical evaluation of patient matched with a mono-organ CFTR-RD diagnosis. Genotyping revealed the novel CFTR haplotype F508del/E583G. Multiple evidences of a deleterious effect of the CFTR E583G rare variant emerged from the bioinformatics analyses performed. Conclusions: Guidelines for CFTR-RD are available with the purpose of harmonizing clinical and molecular investigations. In such context, the identification of novel CFTR haplotype need to a deeper evaluation with a combination of skills. The novel E583G variant could be considered of clinical interest and overall a CFTR-RD Variants of Varying Clinical Consequences. [ABSTRACT FROM AUTHOR]