Marco Cipolli - Academia.edu (original) (raw)

Papers by Marco Cipolli

Leukemia Research, 2006

St I been shown to modulate promoter activity in uitro. Our findings suggest that in a small perc... more St I been shown to modulate promoter activity in uitro. Our findings suggest that in a small percentage of children with RC the disorder is caused by constitutional mutations in TERC.

NeuroImage: Clinical, 2015

Shwachman-Diamond syndrome is a rare recessive genetic disease caused by mutations in SBDS gene, ... more Shwachman-Diamond syndrome is a rare recessive genetic disease caused by mutations in SBDS gene, at chromosome 7q11. Phenotypically, the syndrome is characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal dysplasia and variable cognitive impairments. Structural brain abnormalities (smaller head circumference and decreased brain volume) have also been reported. No correlation studies between brain abnormalities and neuropsychological features have yet been performed. In this study we investigate neuroanatomical findings, neurofunctional pathways and cognitive functioning of Shwachman-Diamond syndrome subjects compared with healthy controls. To be eligible for inclusion, participants were required to have known SBDS mutations on both alleles, no history of cranial trauma or any standard contraindication to magnetic resonance imaging. Appropriate tests were used to assess cognitive functions. The static images were acquired on a 3 × 0 T magnetic resonance scanner and blood oxygen level-dependent functional magnetic resonance imaging data were collected both during the execution of the Stroop task and at rest. Diffusion tensor imaging was used to assess brain white matter. The Tract-based Spatial Statistics package and probabilistic tractography were used to characterize white matter pathways. Nine participants (5 males), half of all the subjects aged 9-19 years included in the Italian Shwachman-Diamond Syndrome Registry, were evaluated and compared with nine healthy subjects, matched for sex and age. The patients performed less well than norms and controls on cognitive tasks (p = 0.0002). Overall, cortical thickness was greater in the patients, both in the left (+10%) and in the right (+15%) hemisphere, significantly differently increased in the temporal (left and right, p = 0.04), and right parietal (p = 0.03) lobes and in Brodmann area 44 (p = 0.04) of the right frontal lobe. The greatest increases were observed in the left limbic-anterior cingulate cortex (≥43%, p b 0.0004). Only in Broca3s area in the left hemisphere did the patients show a thinner cortical thickness than that of controls (p = 0.01). Diffusion tensor imaging showed large, significant difference increases in both fractional anisotropy (+37%, p b 0.0001) and mean diffusivity (+35%, p b 0.005); the Tract-based Spatial Statistics analysis identified six abnormal clusters of white matter fibres in the fronto-callosal, right fronto-external capsulae, left fronto-parietal, right pontine, temporo-mesial and left anterior-medial-temporal regions. Brain areas activated during the Stroop task and those active during the resting state, are different, fewer and smaller in patients and correlate with worse performance (p = 0.002). Cognitive impairment in Shwachman-Diamond syndrome subjects is associated with diffuse brain anomalies in the grey matter (verbal skills with BA44 and BA20 in the right hemisphere; perceptual skills with BA5, 37, 20, 21, 42 in the left hemisphere) and white matter connectivity (verbal skills with alterations in the fronto-occipital fasciculus and with the inferior-longitudinal fasciculus; perceptual skills with the arcuate fasciculus, limbic and

The Journal of Clinical Endocrinology & Metabolism

Objective We aimed to assess the order of severity of the defects of 3 direct determinants of glu... more Objective We aimed to assess the order of severity of the defects of 3 direct determinants of glucose regulation—beta-cell function, insulin clearance, and insulin sensitivity—in patients with cystic fibrosis (CF), categorized according their glucose tolerance status, including early elevation of mid-level oral glucose tolerance test (OGTT) glucose values (>140 and <200 mg/dL), referred to as AGT140. Methods A total of 232 CF patients aged 10 to 25 years underwent OGTT. Beta-cell function and insulin clearance were estimated by OGTT mathematical modeling and OGTT-derived biomarkers of insulin secretion and sensitivity were calculated. The association between glucometabolic variables and 5 glucose tolerance stages (normal glucose tolerance [NGT], AGT140, indeterminate glucose tolerance [INDET], impaired glucose tolerance [IGT], cystic fibrosis–related diabetes CFRD]) was assessed with a general linear model. Results Beta-cell function and insulin sensitivity progressively worse...

Italian Journal of Pediatrics

The Veneto region is one of the most affected Italian regions by COVID-19. Chronic lung diseases,... more The Veneto region is one of the most affected Italian regions by COVID-19. Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), may constitute a risk factor in COVID-19. Moreover, respiratory viruses were generally associated with severe pulmonary impairment in cystic fibrosis (CF). We would have therefore expected numerous cases of severe COVID-19 among the CF population. Surprisingly, we found that CF patients were significantly protected against infection by SARS-CoV-2. We discussed this aspect formulating some reasonable theories.

Nutrients

The effects of gluten free diet (GFD) on body mass index (BMI) and growth parameters in pediatric... more The effects of gluten free diet (GFD) on body mass index (BMI) and growth parameters in pediatric patients with celiac disease (CD) and their dependence on different socio-cultural environments are poorly known. We conducted an international retrospective study on celiac patients diagnosed at the University of Verona, Italy, and at the University of Chicago, Chicago, IL, USA, as underweight. A total of 140 celiac children and 140 controls (mean age 8.4 years) were enrolled in Chicago; 125 celiac children and 125 controls (mean age 7.3 years, NS) in Verona. At time of diagnosis, Italian celiac children had a weight slightly lower (p = 0.060) and a BMI z-score significantly (p < 0.001) lower than their American counterparts. On GFD, Italian celiac children showed an increased prevalence of both underweight (19%) as well as overweight (9%), while American children showed a decrease prevalence of overweight/obese. We concluded that while the GFD had a similar impact on growth of celi...

Blood

1336 Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder with an incidence of... more 1336 Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder with an incidence of 1 in 50.000 births. In 2001, the genetic defect of SDS was mapped to the centromeric region of chromosome 7 and in 2003 the defect was narrowed down to a single gene, which was named the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. The mutations in the SBDS gene were identified in 90% of patients. Pancreatic exocrine insufficiency, bone marrow dysfunction with peripheral blood cytopenias, skeletal abnormalities, short stature and immune dysfunction characterize the disorder. Neutropenia plays a crucial role in the occurrence of recurrent and severe infectious complications representing one of the major causes of death in SDS patients. The aim of our study is to better comprehend the marrow dysfunction occurring in SDS patients, by analysing the functional properties of bone marrow (BM)-derived mesenchymal stem cells (MSCs). BM cells obtained from patients and healthy donors (HDs) were...

BMJ Open

ObjectivesShwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder. Its predominan... more ObjectivesShwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder. Its predominant manifestations include exocrine pancreatic insufficiency, bone marrow failure and skeletal abnormalities. Patients frequently present failure to thrive and susceptibility to short stature. Average birth weight is at the 25th percentile; by the first birthday, >50% of patients drop below the third percentile for height and weight.The study aims at estimating the growth charts for patients affected by SDS in order to give a reference tool helpful for medical care and growth surveillance through the first 8 years of patient’s life.Setting and participantsThis retrospective observational study includes 106 patients (64 M) with available information from birth to 8 years, selected among the 122 patients included in the Italian National Registry of SDS and born between 1975 and 2016. Gender, birth date and auxological parameters at repeated assessment times were collected. The General Add...

Molecular Diagnosis & Therapy

Shwachman-Diamond syndrome (SDS) is a rare inherited disease mainly caused by mutations in the Sh... more Shwachman-Diamond syndrome (SDS) is a rare inherited disease mainly caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. However, it has recently been reported that other genes, including DnaJ heat shock protein family (Hsp40) member C21 (DNAJC21), elongation factor-like 1 (EFL1) and signal recognition particle 54 (SRP54) are also associated with an SDS-like phenotype. Interestingly, SBDS, DNAJC21, EFL1 and SRP54 are involved in ribosome biogenesis: SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21 stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking. These findings strengthen the postulate that SDS is a ribosomopathy. SDS is a multiple-organ disease mainly characterized by bone marrow failure, bone malformations, pancreatic insufficiency and cognitive disorders. Almost 15–20% of patients with SDS present myelodysplastic syndrome with a high risk of acute myeloid leukemia (AML) transformation. Unfortunately, besides bone marrow transplantation, no gene-based therapy for SDS has yet been developed. This review aims to recapitulate the recent findings on the molecular mechanisms of SDS underlying bone marrow failure, hematopoiesis and AML development and to draw a realistic picture of current perspectives.

American journal of hematology, Jan 29, 2017

Shwachman-Diamond syndrome (SDS) is a rare inherited recessive disease mainly caused by mutations... more Shwachman-Diamond syndrome (SDS) is a rare inherited recessive disease mainly caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, which encodes for the homonymous protein SBDS, whose function still remains to be fully established. SDS affects several organs causing bone marrow failure, exocrine pancreatic insufficiency, skeletal malformations, and cognitive disorders. About 15% of SDS patients develop myelodysplastic syndrome (MDS) and are at higher risk of developing acute myeloid leukemia (AML). Deficiency in SBDS expression has been associated with increased apoptosis and lack of myeloid differentiation in bone marrow hematopoietic progenitors. Importantly, most SDS patients carry nonsense mutations in SBDS. Since ataluren is a well-characterized small molecule inhibitor that can suppress nonsense mutations, here, we have assessed the efficacy of this drug in restoring SBDS expression in hematopoietic cells obtained from a cohort of SDS patients. Remarkably,...

New England Journal of Medicine, 2015

The Journal of Pediatrics, 2002

Journal of Allergy and Clinical Immunology, 2008

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an... more Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune genetic disorder caused by mutation of the forkhead box protein 3 gene (FOXP3), a key regulator of immune tolerance. Objective: We sought to provide clinical and molecular indicators that facilitate the understanding and diagnosis of IPEX syndrome. Methods: In 14 unrelated affected male subjects who were given diagnoses of IPEX syndrome based on FOXP3 gene sequencing, we determined whether particular FOXP3 mutations affected FOXP3 protein expression and correlated the molecular and clinical data.

Journal of Allergy and Clinical Immunology, 2011

Forkhead box protein 3 (FOXP3) mutations lead to increased T(H)17 cell numbers and regulatory T-c... more Forkhead box protein 3 (FOXP3) mutations lead to increased T(H)17 cell numbers and regulatory T-cell instability. ... Passerini L, Olek S, Di Nunzio S, Federica B, Hambleton S, Abinun M, Tommasini A, Vignola S, Cipolli M, Amendola M, Naldini L, Guidi L, Cecconi M, Roncarolo MG, ...

Gastroenterology, 2011

Different mutations in the cystic fibrosis gene (CFTR) are associated with different functional s... more Different mutations in the cystic fibrosis gene (CFTR) are associated with different functional status of the exocrine pancreas. We investigated whether CFTR genotypes determine the risk of pancreatitis in patients with cystic fibrosis (CF). METH-ODS: Patients with pancreatic-sufficient CF were identified from 2 CF population-based databases (N ϭ 277; 62 with pancreatitis and 215 without pancreatitis); patients' genotypes and clinical characteristics were analyzed. The loss of pancreatic function associated with each CFTR genotype was determined based on the pancreatic insufficiency prevalence (PIP) score. RESULTS: Patients with pancreatitis were more likely to have genotypes associated with mild (70%) than moderate-severe (30%) PIP scores (P ϭ .004). The cumulative proportion of patients who developed pancreatitis through to the age of 50 years was significantly greater for genotypes associated with mild (50%) than moderate-severe (27%) PIP scores (P ϭ .006). The genotype associated with mild PIP scores had a hazard ratio of 2.4 for pancreatitis (95% confidence interval, 1.3-4.5; P ϭ .006). Patients with pancreatitis were diagnosed with CF at an older median age than those without pancreatitis (14.9 years [interquartile range, 9.5-27.7] vs 9.3 years [interquartile range, 1.5-21.4]; P ϭ .003) and had lower mean levels of sweat chloride than patients without pancreatitis (74.5 Ϯ 26.2 mmol/L vs 82.8 Ϯ 25.2 mmol/L; P ϭ .03). CONCLU-SIONS: Specific CFTR genotypes are significantly associated with pancreatitis. Patients with genotypes associated with mild phenotypic effects have a greater risk of developing pancreatitis than patients with genotypes associated with moderate-severe phenotypes. This observation provides further insight into the complex pathogenesis of pancreatitis.

Archives of Disease in Childhood, 2014

To identify the incidence and outcomes of cholestasis and meconium ileus (MI) in infants with cys... more To identify the incidence and outcomes of cholestasis and meconium ileus (MI) in infants with cystic fibrosis (CF). Retrospective cohort study. Single-centre study. From January 1986 to December 2011, 401 infants with CF (69 with MI) presented to our centre. (1) incidence of cholestasis, (2) identification of risk factors for cholestasis, (3) association between the presence of cholestasis and MI and the development of clinically significant CF-associated liver disease (CFLD) defined as multilobular cirrhosis with portal hypertension. Cholestasis occurred in 23 of 401 infants (5.7%). There was a significantly higher incidence of cholestasis in infants with MI (27.1%) compared to those without MI (1.2%) (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Infants with MI had a 30.36-fold increased risk of developing cholestasis compared to those without MI (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Cholestasis resolved in all children, at a median (range) age of 9.2 (0.8-53.2) months in the MI group and 10.2 (2.0-19.4) months in the non-MI group. The majority of cholestatic infants (87.0%) and infants with MI (92.8%) did not develop clinically significant CFLD, not significantly different than either the 93.9% of non-cholestatic infants nor the 93.7% infants without MI. Cholestasis is an uncommon condition in CF affecting only 5.7% of the screened newborn CF population. The greatest risk factor for developing cholestasis is the presence of MI. However, the presence of MI appears not to be associated with the development of CFLD. An effect of neonatal cholestasis on the development of CFLD cannot be excluded by this study.

Archives of Disease in Childhood, 2007

Objective: To determine the pancreatic phenotype of infants with cystic fibrosis (CF) diagnosed i... more Objective: To determine the pancreatic phenotype of infants with cystic fibrosis (CF) diagnosed in the first week of life by a combined immunoreactive trypsin/mutation screening program. Design: A prospective evaluation of pancreatic function in infants with CF at the time of neonatal diagnosis and up to the age of 12. Setting: Two different centres (Verona, Italy and Westmead, Australia) to enable comparison of results between two regions where ,60% or >90% of patients, respectively, have at least one single DF508 a mutation. Patients: 315 children with CF including 149 at Verona and 166 at Westmead. Interventions: Fat balance studies over 3-5 days and pancreatic stimulation tests with main outcome measures being faecal fat or pancreatic colipase secretion. Patients with malabsorption are pancreatic insufficient (PI) or with normal absorption and pancreatic sufficient (PS). Results: 34 infants (23%) at Verona and 46 (28%) at Westmead were PS at diagnosis. 15% of those with two class I, II or III ''severe'' mutations and 26/28 (93%) of those with class IV or V mutations were PS at this early age. Of the 80 infants with PS, 20 became PI before the age of 12. All 20 had two severe mutations. Conclusion: Neonatal mutational screening programs for CF are less likely to detect PS patients with non-DF508 mutations. Of PS patients who are detected, those with two severe class I, II or III mutations are at particularly high risk of becoming PI during early childhood.

Annals of the New York Academy of Sciences, 2011

is an autosomal recessive disorder characterized by pancreatic exocrine insufficiency and bone ma... more is an autosomal recessive disorder characterized by pancreatic exocrine insufficiency and bone marrow failure, often associated with neurodevelopmental and skeletal abnormalities. Mutations in the SBDS gene have been shown to cause SDS. The purpose of this document is to provide draft guidelines for diagnosis, evaluation of organ and system abnormalities, and treatment of hematologic, pancreatic, dietary, dental, skeletal, and neurodevelopmental complications. New recommendations regarding diagnosis and management are presented, reflecting advances in understanding the genetic basis and clinical manifestations of the disease based on the consensus of experienced clinicians from Canada, Europe, and the United States. Whenever possible, evidencebased conclusions are made, but as with other rare diseases, the data on SDS are often anecdotal. The authors welcome comments from readers.

Clin Drug Invest, 2001

Objective: To measure azithromycin (AZM) concentrations in serum and bronchial secretions in pati... more Objective: To measure azithromycin (AZM) concentrations in serum and bronchial secretions in patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa pulmonary infection.

Pediatric Pulmonology

ABSTRACT