Claudio Sorio | Università di Verona (original) (raw)

Papers by Claudio Sorio

Postdoc journal, Dec 10, 2017

postdoc journal, Dec 10, 2017

Journal of Cystic Fibrosis, Nov 1, 2021

BACKGROUND Glutathione S-transferase omega-1 (GSTO1-1) is a cytosolic enzyme that modulates the S... more BACKGROUND Glutathione S-transferase omega-1 (GSTO1-1) is a cytosolic enzyme that modulates the S-thiolation status of intracellular factors involved in cancer cell survival or in the inflammatory response. Studies focusing on chronic obstructive pulmonary disease (COPD) have demonstrated that GSTO1-1 is detectable in alveolar macrophages, airway epithelium and in the extracellular compartment, where its functions have not been completely understood. Moreover GSTO1-1 polymorphisms have been associated with an increased risk to develop COPD. Against this background, the aim of this study was to evaluate GSTO1-1 levels and its polymorphisms in cystic fibrosis (CF) patients. METHODS Clinical samples from a previous study published by our groups were analyzed for GSTO1-1 levels and polymorphisms. For comparison, a model of lung inflammation in CFTR-knock out mice was also used. RESULTS Our data document that soluble GSTO1-1 can be found in the airways of CF patients and correlates with inflammatory parameters such as neutrophilic elastase and the chemokine IL-8. A negative correlation was found between GSTO1-1 levels and the spirometric parameter FEV1 and the FEV1/FVC ratio. Additionally, the A140D polymorphism of GSTO1-1 was associated with lower levels of the antiinflammatory mediators PGE2 and 15(S)-HETE, and with lower values of the FEV1/FVC ratio in CF subjects with the homozygous CFTR ΔF508 mutation. CONCLUSIONS Our data suggest that extracellular GSTO1-1 and its polymorphysms could have a biological and clinical significance in CF. Pathophysiological functions of GSTOs are far from being completely understood, and more studies are required to understand the role(s) of extracellular GSTO1-1 in inflamed tissues.

Introduction: CFTR function measurement in vivo is an actual field of interest for detecting the ... more Introduction: CFTR function measurement in vivo is an actual field of interest for detecting the effects of CFTR genetic variants/rare mutations as well as of drugs targeting the basic defect. A quantitative assay for measur-ing CFTR function in murine and human primary intestinal crypt-based tis-sues was reported (Dekkers JF, et al. Nat Med. 2013;19:939-45); intestinal organoids can be developed after intestinal current measurements (ICM).CFTR functional assays in leukocytes have been previously shown to be capable of clearly discriminating CF and non-CF subjects (Sorio C, et al. PLoS One. 2011;6:e22212). JJ Wine, et al. (PLoS One. 2013;8:e77114) distinguished CF, non-CF and carriers by a ratiometric beta adrenergic/cholinergic sweat test.Methods and Results: European CF Society intestinal current mea-surements (ICM) and nasal potential difference (NPD) standardized oper-ating procedure (SOP) are applied at the CF Centre of Verona for research and diagnosis of atypical cases. We tested an individualized combination of standardized and new CFTR functional bioassays in a patient referred at our center for evaluation after several episodes of acute pancreatitis; CFTR genotype following sequencing analysis was G542X +/- IVS8 T7/T9, borderline sweat [Cl-]values of 41- 45 mEq/L were found by the Gibson and Cooke method. Lung function and sputum cultures were normal; azo-ospermia was excluded. Recent nasal surgery for deviated nasal septum and ensuing scars in both nostrils did not allow NPD measurements. ICM were measured in 4 biopsies with tracings resembling those obtained from non-CF subjects consistent with previously published normal range (Derichs N, et al. Thorax. 2010;65:594-9).CFTR activity by forskolin induced assay (Dekkers, et al.) was consis-tent with that of non-CF organoids; the pre-swollen lumen suggested a non-CF phenotype. CFTR function was tested by the membrane depolarization assay in monocytes. We defined the CF index as outcome of this assay, which was positive in all healthy subjects and negative in all CF patients: in this case the CF index was positive (CF index = +44). The above cited rati-ometric beta adrenergic/cholinergic sweat test provided results overlapping with those of carriers.Conclusions: This study combines relatively simple and robust assays in several tissues and proposes an example of possible individualized appli-cation as support for diagnosis. Missing the possibility to apply standard-ized NPD in this subject, all data were concordant in excluding CF diagno-sis. Such a combination of functional approaches can be valuable for testing drugs targeting the basic defect

Blood, Nov 5, 2021

Introduction The hallmark of CML is BCR-ABL1 (breakpoint cluster region gene-Abelson murine leuke... more Introduction The hallmark of CML is BCR-ABL1 (breakpoint cluster region gene-Abelson murine leukemia viral oncogene homolog 1) on Philadelphia chromosome, which is the result of a reciprocal translocation between the long arms of chromosomes 9 and 22 (t[9;22][q34;q11]) [1]. Chromosome 22 breakpoints influence the BCR portions preserved in the BCL-ABL1 fusion mRNA and protein and are mainly localized to one of three BCRs, namely major-BCR (M-BCR), minor BCR (m-BCR) and micro-BCR (µ-BCR). In comparison, breaks in chromosome 9 arise most frequently by alternative splicing of the two first ABL1 exons, and can also be generated in a large genetic region, upstream of exon Ib at the 5' end, or downstream of exon Ia at the 3' end. In the majority of CML cases, the breakpoint lies within the M-BCR and gives rise to e13a2 or e14a2 fusion mRNAs (previously denoted as b2a2 and b3a2) and a p210BCR-ABL fusion protein [2]. [3] Methodology We conducted a retrospective analysis of the files of 79 patients being treated in our center for CML with known BCR-ABL1 breakpoints; there were few more patients with known transcript type but excluded because either travelled immediately on diagnosis or had a failure due to confirmed compliance issues. Patients' management and response assessment was done based on ELN 2013 guidelines. The analysis is done based on two main groups, obese versus normal BMI, and then based on BCR-ABL1 transcripts: e13a2 versus e14a2. Ethical approval was obtained from Medical Research Center for Hamad Medical Corporation (MRC-01-18-337). Results Patients included 62 males (78.5%) and 17 females (21.5%) with the mean age at diagnosis 38.8±11.8 years (median, 38; range 21 to 69 years). The characteristics (demographics, anthropometric, hematological and clinico-pathological) of the patients and their association with transcript types and obesity are summarized in Table 1. Patient outcomes, cytogenetic and molecular responses The median follow-up was 30 months (range 6 to 196 months) and 38 months (range 3 to 192 months) in normal weight and obesity groups, respectively. The median follow-up was 28 months (range 3 to 196 months) and 39 months (range 10 to 192 months) in e14a2 and e13a2 patients, respectively. A total of 22 patients distributed among different groups ended up leaving the country (censored) after a variable duration of follow-up (6 - 196 months), 18 of them CML-CP, and 4 CML-AP. 3 patients died in our cohort, all of them had e14a2 transcript, one of them was in the normal weight/BMI group, two were in the obesity group. In e14a2 group, more patients were on imatinib at the time of analysis (15 (39.5%) vs 7 (17.1%) in e13a2 group, p = 0.026). The percentage of patients of had to switch TKI was similar in both groups (47.4% vs 53.7%, p = 0.576). However, less patients in e14a2 group had to switch TKI because of failure/progression (10 (55.6%) vs 17 (77.3%), p = 0.145); however, this didn't translate into a significant difference of achieving MMR at 1 year, where in e14a2 group, 10 patients achieved MMR at 1 year (31.3%), same as in e13a2 group (10 patients = 29.3%) p 0.331 (all shown in table 1). When comparing long-term outcomes, there was also no significant difference between groups based on transcript type with regards to MMR (44.7% vs 46.3% in e14a2 vs e13a2 respectively) or DMR (26.3% vs 22% respectively) as shown in figure. In the obesity group, there were 2 patients using ponatinib due to T315I mutation, compared to none in normal weight group. However, there were no significant differences in TKI used, switch of TKI, or reason for switch. Same applies for achieving MMR at 1 year, as 11 patients in the obesity group achieved MMR (28.2%) compared to 9 patients in normal weight group (33.3%), p = 0.778 (as shown in table 1). Regarding the long-term outcomes, more patients in the obesity group achieved MMR (53.2%) compared to normal weight group (34.3%), and this response was faster, but not statistically significant. This difference was less clear with regards to DMR (25.5% in the obesity group compared to 21.9% in normal weight group) as shown in figure. Conclusion In the patient-cohort studied there were no significant differences in molecular response based on transcript type or body weight/BMI. Figure 1 Figure 1. No relevant conflicts of interest to declare.

no available; Meeting Abstract: 18

Diagnostic pathology: open access, Jul 16, 2018

Protein tyrosine phosphatase receptor gamma (PTPRG) is a ubiquitously expressed member of the pro... more Protein tyrosine phosphatase receptor gamma (PTPRG) is a ubiquitously expressed member of the protein tyrosine phosphatasefamily known to act as a tumor suppressor gene in many different neoplasms with mechanisms of inactivation includingmutations and methylation of CpG islands in the promoter region. We identified a critical role in human hematopoiesis anddescribe a role as oncosuppressor in chronic myeloid leukemia (CML). We have described PTPRG expression in various tissuesand recently developed a monoclonal antibody capable of recognizing the native antigen of this phosphatase by flow cytometry: weconfirmed PTPRG protein downregulation in CML patients at diagnosis in the Philadelphia-positive myeloid lineage (includingCD34+/ CD38bright/dim cells). After effective tyrosine kinase inhibitor (TKI) treatment, its expression recovered in tandem withthe return of Philadelphia-negative hematopoiesis. Of note, PTPRG mRNA levels remain unchanged in tyrosine kinase inhibitors(TKI) non-responder patients, confirming that downregulation selectively occurs in primary CML cells. We have also identified anovel regulative loop involving CTNNB1 gene. The availability of this unique antibody permits its evaluation for clinical applicationincluding the support for diagnosis and follow-up of these disorders. Evaluation of the role of PTPRG in health and disease isfacilitated by the availability of a specific reagent capable to specifically detect its target in various experimental conditions.

Journal of Biological Chemistry, 1993

Virulence, Jul 27, 2018

Background: Cystic fibrosis (CF) lung infection is a complex condition where opportunistic pathog... more Background: Cystic fibrosis (CF) lung infection is a complex condition where opportunistic pathogens and defective immune system cooperate in developing a constant cycle of infection and inflammation. The major pathogen, Pseudomonas aeruginosa, secretes a multitude of virulence factors involved in host immune response and lung tissue damage. In this study, we examined the possible anti-inflammatory effects of molecules inhibiting P. aeruginosa virulence factors. Methods: Pyocyanin, pyoverdine and proteases were measured in bacterial culture supernatant from different P. aeruginosa strains. Inhibition of virulence factors by sub-inhibitory concentrations of clarithromycin and by protease inhibitors was evaluated. Lung inflammatory response was monitored by in vivo bioluminescence imaging in wild-type and CFTR-knockout mice expressing a luciferase gene under the control of a bovine IL-8 promoter. Results: The amount of proteases, pyocyanin and pyoverdine secreted by P. aeruginosa strains was reduced after growth in the presence of a sub-inhibitory dose of clarithromycin. Intratracheal challenge with culture supernatant containing bacteria-released products induced a strong IL-8mediated response in mouse lungs while lack of virulence factors corresponded to a reduction in bioluminescence emission. Particularly, sole inactivation of proteases by inhibitors Ilomastat and Marimastat also resulted in decreased lung inflammation. Conclusions: Our data support the assumption that virulence factors are involved in P. aeruginosa pro-inflammatory action in CF lungs; particularly, proteases seem to play an important role. Inhibition of virulence factors production and activity resulted in decreased lung inflammation; thus, clarithromycin and protease inhibitors potentially represent additional therapeutic therapies for P. aeruginosa-infected patients.

Blood, Feb 1, 1992

We recently showed that mRNA levels coding the highaffinity Fcy receptor for IgG (FcyR-I, CD64) a... more We recently showed that mRNA levels coding the highaffinity Fcy receptor for IgG (FcyR-I, CD64) and two of the components of the phagocytic superoxide anion-generating system-the heavy-chain subunit of cytochrome b , , , (gp91phox) and the 47-Kd cytosolic factor (p47-phox)-are modulated by interferon gamma (IFN-y). In this study, we examined whether dexamethasone (DEX) affects gp9l-phox and p47-phox mRNA expression of human polymorphonuclear leukocytes (PMN), treated or not with IFN-y. We also investigated whether staurosporine, a general inhibitor of protein kinases, influences gp9l-phox, p47-phox, and FcyR-l gene expression in PMN treated with or without IFN-y. We found that (1) gp9l-phox mRNA steady-state levels, expressed in control or IFN-ytreated PMN, were significantly inhibited, in a dose-dependent fashion, by both DEX and staurosporine; (2) p47-phox mRNA steady-state levels, expressed in control NTERFERON-GAMMA (IFN-y) is a cytokine that at-20°C. Actinomycin D (Calbiochem, San Diego, CA) was prepared fresh in RPMI-1640 medium (Flow Laboratories, Irvine, Scotland). All other chemicals (purchased from Sigma) were of

Lecture notes in networks and systems, 2023

Frontiers in Microbiology, May 11, 2023

SARS-CoV-2, the etiological cause of the COVID-19 pandemic, can cause severe illness in certain a... more 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 in vitro 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. These range from cytokine releases to biochemical alterations leading to morphological rearrangements inside the cells associated with CFTR impairment. Based on available data, the reported low incidence of SARS-CoV-2 infection among pwCF is likely a result of several variables linked to CFTR dysfunction, such as thick mucus, IL-6 reduction, altered ACE2 and TMPRSS2 processing and/or functioning, defective anions exchange, and autophagosome formation. An extensive analysis of the relation between SARS-CoV-2 infection and pwCF is essential to elucidate the mechanisms involved in this lower-than-expected infection impact and to possibly suggest potential new antiviral strategies.

Journal of Cystic Fibrosis, Jun 1, 2019

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The narrow chances of therapy and the poor prognosis of pancreatic cancer make basic research a c... more The narrow chances of therapy and the poor prognosis of pancreatic cancer make basic research a crucial way for both a better knowledge and a possible improvement in the treatment of this disease. The very limited availability of pancreatic specimen for genetic and biological studies forced the researchers to plan "in vitro" and "in vivo" models in order to overcome this handicap. Among the animal models, the one according to Fu et al. seemed to be the most helpful and effective approach. Nevertheless, being this model complex and failing in main perspective applications, an enlarged project perpetuating B-lymphocytes of the patients, successfully xenografting from vitally criopreserved specimen and developing cell lines from xenografts was planned. According to the aim of our project, a really perpetual and renewable bank of tumoral and normal tissue from patients suffering from pancreatic carcinoma was obtained. This model is also expected to be an effective approach for the evaluation of experimental chemotherapeutic schedules and new gene therapy assessment

Journal of Cystic Fibrosis, Jun 1, 2016

biodistribution to the lung showing a >4 fold increase in lung:plasma partitioning in rat biodist... more biodistribution to the lung showing a >4 fold increase in lung:plasma partitioning in rat biodistribution studies compared to lumacaftor. Conclusion: FDL169 is a novel F508del-CFTR corrector that increases the amount of F508del-CFTR at the cell surface, has low risk of reduced activity upon chronic treatment and distributes well into lung tissue.