Biomedical subjects

Margherita Baldassarri

Publications and source records attributed to Margherita Baldassarri.

4 recordsLinked to original sources

PubMed2026

Trop-1/EpCAM Thr115 is a driver of hyperproliferative cell repair and of severe lung damage in COVID-19.

SARS-CoV-2 lung infection triggers an acute reaction that can severely impair oxygen exchange. However, the underlying molecular processes are poorly understood. The TROP1/EPCAM p.M115T polymorphism was found associated with COVID-19 severity. We discovered here that the T115 Trop-1/EpCAM is a driver of cell growth, whereas M115 Trop-1/EpCAM has little, if any, cell growth induction capacity. TROP1/EPCAM knockout mice showed altered proliferation of embryonic stem cells. The Trop-1/EpCAM T115 allele was then found to drive hyperproliferative capacity in murine fibrosarcoma cells. Corresponding growth stimulation was shown in human colon cancer cells, through CRISPR-Cas9 ablation of the endogenous TROP1/EPCAM and comparative transfection of TROP1/EPCAM p.T115 (T-mod) or p.M115 (M-mod) alleles. In COVID-19 patients, T115 Trop-1/EpCAM was shown to cause aberrant, hyperproliferative wound repair in SARS-CoV-2-damaged lung alveoli that led to critical oxygen-exchange impairment. Analysis of COVID-19 patient lungs at autopsy showed hyperproliferation of T115 Trop-1/EpCAM+ epithelial cells over the alveolar epithelium damaged by the infection. This correlated with T115 Trop-1/EpCAM+ inflammatory cells hyperproliferation and alveolar hyaline membrane formation. These multi-layered barriers were computed to reduce oxygen diffusion by up to 100-fold. Our findings indicate an unanticipated mechanism for lung damage by T115 Trop-1/EpCAM, and suggest a potential target for corresponding therapeutic approaches.

COVID-19↗

PubMed2025

The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS).

PURPOSE: Patients with PTEN Hamartoma Tumor Syndrome (PHTS) have high hereditary cancer risks for breast, endometrial, and thyroid cancer. Patients develop multiple primary cancers, but these risks remain uncertain. We aimed to provide the second primary cancer risk. METHODS: This European cohort study assessed second primary cancer risks with Kaplan-Meier analyses using data from medical files, registries and/or patient questionnaires. RESULTS: Overall, 279 adult PHTS patients with (a history of) cancer were included (80% female). Among females, 106 (54%) developed a PHTS-related second primary cancer after a PHTS-related first primary cancer, whereas 10 (29%) males developed a PHTS-related second primary cancer after a PHTS-related first primary cancer. The 5- and 10-year PHTS-related second primary cancer risks were 24.5% (95% CI = 18.1-32.5) and 45.7% (95% CI = 36.9-55.4) in females and 14.5% (95% CI = 5.7-34.1) and 19.8% (95% CI = 8.6-41.9) in males, respectively. Furthermore, 5- and 10-year risks for a second primary breast cancer after a first primary breast cancer were 23.3% (95% CI = 14.9-35.2) and 45.6% (95% CI = 33.0-60.2) in females, respectively. CONCLUSION: This study demonstrated that PHTS patients have high second primary cancer risks, which is driven by breast cancer in females. Hence, identifying patients with PHTS before or at first primary cancer diagnosis is essential to enable potential early detection or prevention of a second primary cancer through surveillance or risk-reducing surgery.

Humans↗

PubMed2025

AUTS2-related syndrome: Insights from a large European cohort.

PURPOSE: AUTS2-related syndrome is characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters, AUTS2 encodes 2 distinct long and short isoforms encoding a putative transcriptional activator. METHODS: Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2-related syndrome cohort of 58 patients harboring genomic rearrangements or single-nucleotide variants (SNVs). RESULTS: Pathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent of the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties, and speech delay are common features of AUTS2-related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both longer and shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, microretrognathia, broad nasal base, and anteverted nares. Behavioral disorders were more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only observed in patients with SNVs. CONCLUSION: This study provides a comprehensive clinical characterization of AUTS2-related syndrome, reveals few genotype-phenotype correlations, and suggests that the disruption of the 2 distinct AUTS2 transcripts has a different impact on the clinical phenotype.

Humans↗

PubMed2024

Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy.

PURPOSE: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype. METHODS: We collected patients with duplications encompassing ARID1A and ARID1B duplications. RESULTS: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 10.3 Mb (2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay, and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation reanalysis, resulting in the reclassification of 2 ARID1A and 2 ARID1B duplications as pathogenic. CONCLUSION: Our findings reveal that ARID1B duplications manifest a clinical phenotype, and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole-gene duplication rather than haploinsufficiency.

Humans↗