Non pathological sweat test, pancreatic insufficiency and Cystic Fibrosis: an unusual case in a child with F508del-duplication of exons 1-3 CFTR genotype.

While Cystic Fibrosis is characterized by a high phenotypic variability, a correlation is reported between the pancreatic status and the CFTR genotype. Here we report an unusual case of a child with Cystic Fibrosis (F508del-duplication of exons 1-3 genotype) diagnosed at 8 years old for pancreatic insufficiency and non-pathological sweat test, in absence of respiratory symptoms and acute episodes of pancreatitis. Nasal potential differences and intestinal current measurements were normal, while the short-circuit current measured on patient-derived colonoids grown on Transwell indicated the presence of a reduced CFTR-dependent current relative to non-CF colonoids with, a modest improvement of CFTR activity record following treatment with elexacaftor/tezacaftor/ivacaftor.

CFTR modulators response of S737F and T465N CFTR variants on patient-derived rectal organoids.

Background: Predictions based on patient-derived materials of CFTR modulators efficacy have been performed lately in patient-derived cells, extending FDA-approved drugs for CF patients harboring rare variants. Here we developed intestinal organoids from subjects carrying S737F- and T465N-CFTR in trans with null alleles to evaluate their functional impact on CFTR protein function and their restoration upon CFTR modulator treatment. The characterization of S737F-CFTR was performed in two subjects recently assessed in nasal epithelial cells but not in colonoids.

Elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and rare mutations.

Introduction: The triple combination of elexacaftor/tezacaftor/ivacaftor (ETI) has dramatically improved the outcome of people with Cystic Fibrosis (pwCF) with at least one F508del mutation. However, carriers of rare cystic fibrosis transmembrane conductance regulator (CFTR) variants are not candidates for this innovative treatment.

Methods: In this observational study, we report the results of the compassionate use of ETI in 10 pwCF carriers of rare mutations after 2 months of treatment.

First episode psychoses in people over-35 years old: uncovering potential actionable targets for early intervention services.

The traditional youth-oriented design of Early Intervention Services (EIS) may lead to the exclusion of patients who have their psychotic onset later in life. A retrospective study was conducted to compare first-episode psychosis (FEP) patients who accessed treatment when aged ≤ 35 years with those ≥36+. A total of 854 patients were identified among 46,222 individuals who had access to community psychiatric services from 1991 to 2021.

Loss of CFTR Reverses Senescence Hallmarks in SARS-CoV-2 Infected Bronchial Epithelial Cells.

SARS-CoV-2 infection has been recently shown to induce cellular senescence in vivo. A senescence-like phenotype has been reported in cystic fibrosis (CF) cellular models. Since the previously published data highlighted a low impact of SARS-CoV-2 on CFTR-defective cells, here we aimed to investigate the senescence hallmarks in SARS-CoV-2 infection in the context of a loss of CFTR expression/function.

Functional rescue of CFTR in rectal organoids from patients carrying R334W variant by CFTR modulators and PDE4 inhibitor Roflumilast.

Background: Many disease-causing variants in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene remain uncharacterized and untreated. Restoring the function of the impaired CFTR protein is the goal of personalized medicine, particularly in patients carrying rare CFTR variants. In this study, functional defects related to the rare R334W variant were evaluated after treatment with CFTR modulators or Roflumilast, a phosphodiesterase-4 inhibitor (PDE4i).

How the latent geometry of a biological network provides information on its dynamics: the case of the gene network of chronic myeloid leukaemia.

The concept of the latent geometry of a network that can be represented as a graph has emerged from the classrooms of mathematicians and theoretical physicists to become an indispensable tool for determining the structural and dynamic properties of the network in many application areas, including contact networks, social networks, and especially biological networks. It is precisely latent geometry that we discuss in this article to show how the geometry of the metric space of the graph representing the network can influence its dynamics. We considered the transcriptome network of the Chronic Myeloid Laeukemia K562 cells.

Sex differences in schizophrenia-spectrum diagnoses: results from a 30-year health record registry.

This study investigated sociodemographic and clinical differences between the sexes in individuals affected by schizophrenia-spectrum disorders (SSD) who accessed outpatient mental health services. Within a retrospective cohort of 45,361 outpatients receiving care in Ferrara (Italy) from 1991 to 2021, those with a SSD diagnosis were compared between the sexes for sociodemographic and clinical characteristics before and after the index date (when the ICD-9: 295.*diagnosis was first recorded) to assess early trajectory, age and type of diagnosis, and severity of illness indicated by medication use, hospitalization, and duration of psychiatric care.

Establishment of a Public Mental Health Database for Research Purposes in the Ferrara Province: Development and Preliminary Evaluation Study.

Background: The immediate use of data exported from electronic health records (EHRs) for research is often limited by the necessity to transform data elements into an actual data set.

Objective: This paper describes the methodology for establishing a data set that originated from an EHR registry that included clinical, health service, and sociodemographic information.

Methods: The Extract, Transform, Load process was applied to raw data collected at the Integrated Department of Mental Health and Pathological Addictions in Ferrara, Italy, from 1925 to February 18, 2021, to build the new, anonymized Ferrara-Psychiatry (FEPSY) database.

Crosslink between SARS-CoV-2 replication and cystic fibrosis hallmarks.

SARS-CoV-2, the etiological cause of the COVID-19 pandemic, can cause severe illness in certain at-risk populations, including people with cystic fibrosis (pwCF). Nevertheless, several studies indicated that pwCF do not have higher risks of SARS-CoV-2 infection nor do they demonstrate worse clinical outcomes than those of the general population. Recent studies indicate cellular and molecular processes to be significant drivers in pwCF lower infection rates and milder symptoms than expected in cases of SARS-CoV-2 infection.

Management of chronic myeloid leukaemia: current treatment options, challenges, and future strategies.

Small molecule therapy is a critical component of targeted anticancer treatment, with tyrosine kinase inhibitors (TKIs) being the first compounds to treat the clonal Chronic Myelogenous Leukaemia (CML) translocation t (9;22) (q34; q11) effectively since 2001. TKIs, such as imatinib, have improved the 10-year survival rate of CML patients to 80%. They bind the kinase and inhibit downstream signaling pathways.

CFTR Modulators Rescue the Activity of CFTR in Colonoids Expressing the Complex Allele p.[R74W;V201M;D1270N]/dele22_24.

An Italian, 46-year-old female patient carrying the complex allele p.[R74W;V201M;D1270N] in trans with CFTR dele22_24 was diagnosed at the Cystic Fibrosis (CF) Center of Verona as being affected by CF-pancreatic sufficient (CF-PS) in 2021. The variant V201M has unknown significance, while both of the other variants of this complex allele have variable clinical consequences, according to the CFTR2 database, with reported clinical benefits for treatment with ivacaftor + tezacaftor and ivacaftor + tezacaftor + elexacaftor in patients carrying the R74W-D1270N complex allele, which are currently approved (in USA, not yet in Italy).

CFTR Inhibitors Display In Vitro Antiviral Activity against SARS-CoV-2.

Several reports have indicated that SARS-CoV-2 infection displays unexpected mild clinical manifestations in people with cystic fibrosis (pwCF), suggesting that CFTR expression and function may be involved in the SARS-CoV-2 life cycle. To evaluate the possible association of CFTR activity with SARS-CoV-2 replication, we tested the antiviral activity of two well-known CFTR inhibitors (IOWH-032 and PPQ-102) in wild type (WT)-CFTR bronchial cells. SARS-CoV-2 replication was inhibited by IOWH-032 treatment, with an IC of 4.

Organoid Technology and Its Role for Theratyping Applications in Cystic Fibrosis.

Cystic fibrosis (CF) is a autosomal recessive, multisystemic disease caused by different mutations in the CFTR gene encoding CF transmembrane conductance regulator. Although symptom management is important to avoid complications, the approval of CFTR modulator drugs in the clinic has demonstrated significant improvements by targeting the primary molecular defect of CF and thereby preventing problems related to CFTR deficiency or dysfunction. CFTR modulator therapies have positively changed the patients' quality of life, especially for those who start their use at the onset of the disease.

Gene Expression Landscape of Chronic Myeloid Leukemia K562 Cells Overexpressing the Tumor Suppressor Gene PTPRG.

This study concerns the analysis of the modulation of Chronic Myeloid Leukemia (CML) cell model K562 transcriptome following transfection with the tumor suppressor gene encoding for Protein Tyrosine Phosphatase Receptor Type G (PTPRG) and treatment with the tyrosine kinase inhibitor (TKI) Imatinib. Specifically, we aimed at identifying genes whose level of expression is altered by PTPRG modulation and Imatinib concentration. Statistical tests as differential expression analysis (DEA) supported by gene set enrichment analysis (GSEA) and modern methods of ontological term analysis are presented along with some results of current interest for forthcoming experimental research in the field of the transcriptomic landscape of CML.

Ultrastructural Characterization of Human Bronchial Epithelial Cells during SARS-CoV-2 Infection: Morphological Comparison of Wild-Type and CFTR-Modified Cells.

SARS-CoV-2 replicates in host cell cytoplasm. People with cystic fibrosis, considered at risk of developing severe symptoms of COVID-19, instead, tend to show mild symptoms. We, thus, analyzed at the ultrastructural level the morphological effects of SARS-CoV-2 infection on wild-type (WT) and F508del (ΔF) CFTR-expressing CFBE41o- cells at early and late time points post infection.

spp. Adaptation in Cystic Fibrosis Infection and Candidate Biomarkers of Antimicrobial Resistance.

spp. can establish occasional or chronic lung infections in patients with cystic fibrosis (CF). Chronic colonization has been associated with worse prognosis highlighting the need to identify markers of bacterial persistence.

Successful Preservation of Native BCR::ABL1 in Chronic Myeloid Leukemia Primary Leukocytes Reveals a Reduced Kinase Activity.

Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the acquisition of t(9;22) generating the fusion tyrosine kinase BCR::ABL1. However, despite the crucial role of this protein in the dysregulation of numerous signal transduction pathways, a direct measure of BCR::ABL1 kinase activity in chronic phase (CP) CML was never accomplished due to intense degradative activity present in mature leukocytes. Therefore, we developed a procedure suitable to preserve BCR::ABL1 protein under non-denaturing, neutral pH conditions in primary, chronic phase (CP)-CML samples.

CFTR Modulation Reduces SARS-CoV-2 Infection in Human Bronchial Epithelial Cells.

People with cystic fibrosis should be considered at increased risk of developing severe symptoms of COVID-19. Strikingly, a broad array of evidence shows reduced spread of SARS-CoV-2 in these subjects, suggesting a potential role for CFTR in the regulation of SARS-CoV-2 infection/replication. Here, we analyzed SARS-CoV-2 replication in wild-type and CFTR-modified human bronchial epithelial cell lines and primary cells to investigate SARS-CoV-2 infection in people with cystic fibrosis.

Theratyping of the Rare CFTR Variants E193K and R334W in Rectal Organoid-Derived Epithelial Monolayers.

Background: The effect of presently available CFTR modulator combinations, such as elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA), on rare CFTR alleles is often unknown. Several assays have been developed, such as forskolin-induced swelling (FIS), to evaluate the rescue of such uncommon CFTR alleles both by established and novel modulators in patient-derived primary cell cultures (organoids). Presently, we assessed the CFTR-mediated electrical current across rectal organoid-derived epithelial monolayers.