Publications by authors named "Francesco Raimondi"

142 Publications

RhoGAP19D inhibits Cdc42 laterally to control epithelial cell shape and prevent invasion.

J Cell Biol 2021 Apr;220(4)

Gurdon Institute, University of Cambridge, Cambridge, UK.

Cdc42-GTP is required for apical domain formation in epithelial cells, where it recruits and activates the Par-6-aPKC polarity complex, but how the activity of Cdc42 itself is restricted apically is unclear. We used sequence analysis and 3D structural modeling to determine which Drosophila GTPase-activating proteins (GAPs) are likely to interact with Cdc42 and identified RhoGAP19D as the only high-probability Cdc42GAP required for polarity in the follicular epithelium. RhoGAP19D is recruited by α-catenin to lateral E-cadherin adhesion complexes, resulting in exclusion of active Cdc42 from the lateral domain. rhogap19d mutants therefore lead to lateral Cdc42 activity, which expands the apical domain through increased Par-6/aPKC activity and stimulates lateral contractility through the myosin light chain kinase, Genghis khan (MRCK). This causes buckling of the epithelium and invasion into the adjacent tissue, a phenotype resembling that of precancerous breast lesions. Thus, RhoGAP19D couples lateral cadherin adhesion to the apical localization of active Cdc42, thereby suppressing epithelial invasion.
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http://dx.doi.org/10.1083/jcb.202009116DOI Listing
April 2021

Employing a systematic approach to biobanking and analyzing clinical and genetic data for advancing COVID-19 research.

Eur J Hum Genet 2021 Jan 17. Epub 2021 Jan 17.

Medical Genetics, University of Siena, Siena, Italy.

Within the GEN-COVID Multicenter Study, biospecimens from more than 1000 SARS-CoV-2 positive individuals have thus far been collected in the GEN-COVID Biobank (GCB). Sample types include whole blood, plasma, serum, leukocytes, and DNA. The GCB links samples to detailed clinical data available in the GEN-COVID Patient Registry (GCPR). It includes hospitalized patients (74.25%), broken down into intubated, treated by CPAP-biPAP, treated with O supplementation, and without respiratory support (9.5%, 18.4%, 31.55% and 14.8, respectively); and non-hospitalized subjects (25.75%), either pauci- or asymptomatic. More than 150 clinical patient-level data fields have been collected and binarized for further statistics according to the organs/systems primarily affected by COVID-19: heart, liver, pancreas, kidney, chemosensors, innate or adaptive immunity, and clotting system. Hierarchical clustering analysis identified five main clinical categories: (1) severe multisystemic failure with either thromboembolic or pancreatic variant; (2) cytokine storm type, either severe with liver involvement or moderate; (3) moderate heart type, either with or without liver damage; (4) moderate multisystemic involvement, either with or without liver damage; (5) mild, either with or without hyposmia. GCB and GCPR are further linked to the GCGDR, which includes data from whole-exome sequencing and high-density SNP genotyping. The data are available for sharing through the Network for Italian Genomes, found within the COVID-19 dedicated section. The study objective is to systematize this comprehensive data collection and begin identifying multi-organ involvement in COVID-19, defining genetic parameters for infection susceptibility within the population, and mapping genetically COVID-19 severity and clinical complexity among patients.
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http://dx.doi.org/10.1038/s41431-020-00793-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811682PMC
January 2021

Lung Ultrasound to Monitor Extremely Preterm Infants and Predict BPD: Multicenter Longitudinal Cohort Study.

Am J Respir Crit Care Med 2020 Dec 22. Epub 2020 Dec 22.

South Paris University Hospitals, "A.Beclere" Medical Center, NICU, Clamart (Paris), France;

Rationale: Lung ultrasound is useful in critically ill patients with acute respiratory failure. Given its characteristics, it could be also useful in extremely preterm infants with evolving chronic respiratory failure, as we lack accurate imaging tools to monitor them.

Objectives: To verify if lung ultrasound can monitor lung aeration and function, and has good reliability to predict bronchopulmonary dysplasia in extremely preterm neonates.

Methods: Multicenter, international, prospective, longitudinal, cohort, diagnostic accuracy study consecutively enrolling inborn neonates with gestational age ≤30+6 weeks. Lung ultrasound was performed on the first, seventh, fourteenth and twenty-eighth days of life and lung ultrasound scores were calculated and correlated with simultaneous blood gases and work of breathing score. Gestational age-adjusted lung ultrasound scores were created, verified in multivariate models and subjected to ROC analyses to predict bronchopulmonary dysplasia at 36 weeks post-menstrual age.

Main Results: Mean lung ultrasound scores are different between infants developing (n=72) or not developing (n=75) BPD (p<0.001,at any time-point). Lung ultrasound scores significantly correlate with oxygenation metrics and work of breathing at any time-point (p always<0.0001). Gestational age-adjusted lung ultrasound scores significantly predict bronchopulmonary dysplasia at 7 (area under ROC curve: 0.826-0.833;p<0.0001) and 14 (area under ROC curve: 0.834-0.858;p<0.0001) days of life. Bronchopulmonary dysplasia severity and gestational age-adjusted lung ultrasound scores are significantly correlated at 7 and 14 days (p always<0.0001).

Conclusions: Lung ultrasound scores allow to monitor lung aeration and function in extremely preterm infants. Gestational age-adjusted scores significantly predict the occurrence of BPD,starting from the seventh day of life.
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http://dx.doi.org/10.1164/rccm.202008-3131OCDOI Listing
December 2020

European Respiratory Society Statement on Thoracic Ultrasound.

Eur Respir J 2020 Oct 8. Epub 2020 Oct 8.

Academic Respiratory Unit, University of Bristol, Bristol, United Kingdom.

Thoracic ultrasound is increasingly considered to be an essential tool for the pulmonologist. It is used in diverse clinical scenarios, including as an adjunct to clinical decision making for diagnosis, a real-time guide to procedures, and a predictor or measurement of treatment response. The aim of this European Respiratory Society task force was to produce a statement on thoracic ultrasound for pulmonologists using thoracic ultrasound within the field of respiratory medicine. The multidisciplinary panel performed a review of the literature, addressing major areas of thoracic ultrasound practice and application. The selected major areas include equipment and technique, assessment of the chest wall, parietal pleura, pleural effusion, pneumothorax, interstitial syndrome, lung consolidation, diaphragm assessment, intervention guidance, training, and the patient perspective. Despite the growing evidence supporting the use of thoracic ultrasound, the published literature still contains a paucity of data in some important fields. Key research questions for each of the major areas were identified, which serve to facilitate future multi-centre collaborations and research to further consolidate an evidence-based use of thoracic ultrasound, for the benefit of the many patients being exposed to clinicians using thoracic ultrasound.
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http://dx.doi.org/10.1183/13993003.01519-2020DOI Listing
October 2020

Using LU score to predict extubation failure in preterm infants should consider gestational age at birth.

Pediatr Pulmonol 2020 12 6;55(12):3228. Epub 2020 Oct 6.

Division of Neonatology, Department of Translational Medical Sciences, Università "Federico II", Naples, Italy.

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http://dx.doi.org/10.1002/ppul.25093DOI Listing
December 2020

Neonatal lung ultrasound: From paradox to diagnosis … and beyond.

Early Hum Dev 2020 11 10;150:105184. Epub 2020 Sep 10.

Division of Neonatology, Section of Pediatrics, Department of Translational Medical Sciences, Università "Federico II", Naples, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.earlhumdev.2020.105184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481261PMC
November 2020

Neonatal Hyperbilirubinemia: An Updated Appraisal of National Guidelines.

Curr Pediatr Rev 2020 ;16(4):298-306

Division of Neonatology, Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.

Recent reports from several developed countries have documented a resurgence of bilirubin encephalopathy causing both healthcare and forensic issues. For these reasons, many national pediatric societies have issued recommendations on the diagnosis and the treatment of clinically significant neonatal hyperbilirubinemia. The differences among individual national documents may have an impact on neonatal healthcare. This paper shortly reviews the advantages and the shortcomings of the main international guidelines with a focus on the available evidence.
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http://dx.doi.org/10.2174/1573396316666200928101553DOI Listing
January 2020

Lung ultrasound features predict admission to the neonatal intensive care unit in infants with transient neonatal tachypnoea or respiratory distress syndrome born by caesarean section.

Eur J Pediatr 2021 Mar 19;180(3):869-876. Epub 2020 Sep 19.

Neonatal Intensive Care Unit, AOU Bologna, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

We aimed to evaluate the reliability of lung ultrasound (LU) to predict admission to the neonatal intensive care unit (NICU) for transient neonatal tachypnoea or respiratory distress syndrome in infants born by caesarean section (CS). A prospective, observational, single-centre study was performed in the delivery room and NICU of Sant'Orsola-Malpighi Hospital in Bologna, Italy. Term and late-preterm infants born by CS were included. LU was performed at 30' and 4 h after birth. LU appearance was graded according to a previously validated three-point scoring system (3P-LUS: type-1, white lung; type-2, black/white lung; type-3, normal lung). Full LUS was also calculated. One hundred infants were enrolled, and seven were admitted to the NICU. The 5 infants with bilateral type-1 lung at birth were all admitted to the NICU. Infants with type-2 and/or type-3 lung were unlikely to be admitted to the NICU. Mean full-LUS was 17 in infants admitted to the NICU, and 8 in infants not admitted. In two separate binary logistic regression models, both the 3P- and the full LUS proved to be independently associated with NICU admission (OR [95% CI] 0.001 [0.000-0.058], P = .001, and 2.890 [1.472-5.672], P = .002, respectively). The ROC analysis for the 3P-LUS yielded an AUC of 0.942 (95%CI, 0.876-0.979; P<.001), while ROC analysis for the full LUS yielded an AUC of 0.978 (95%CI, 0.926-0.997; P<.001). The AUCs for the two LU scores were not significantly different (p = .261).Conclusion: the 3P-LUS performed 30 min after birth proved to be a reliable tool to identify, among term and late preterm infants born to CS, those who will require NICU admission for transient neonatal tachypnoea or respiratory distress syndrome. What is known • Lung ultrasound (LU) has become an attractive diagnostic tool in neonatal settings, and guidelines on point-of-care LU in the neonatal intensive care unit (NICU) have been recently issued. • LU is currently used for diagnosing several neonatal respiratory morbidities and has been also proposed for predicting further intervention, such as NICU admission, need for surfactant treatment or mechanical ventilation in preterm infants. What is new • LU performed 30' after birth and evaluated through a simple three-point scoring system represents a reliable tool to identify, among term and late preterm infants born to caesarean section, those with transient neonatal tachypnoea or respiratory distress syndrome who will require NICU admission. • LU performed in the neonatal period confirms its potential role in ameliorating routine neonatal clinical management.
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http://dx.doi.org/10.1007/s00431-020-03789-zDOI Listing
March 2021

Do isolates from pharyngeal and rectal swabs match blood culture bacterial pathogens in septic VLBW infants? A pilot, cross-sectional study.

Eur J Pediatr 2021 Mar 28;180(3):799-806. Epub 2020 Aug 28.

Department of Translational Medical Sciences - Division of Neonatology, University of Naples Federico II, Naples, Italy.

Serial body site swabbing is used to monitor horizontal spread of aggressive bacterial species in the neonatal intensive care unit (NICU). Since colonization/carriage is thought to precede systemic infection, one might expect to retrieve colonizing pathogens from blood cultures. This hypothesis, however, has not been fully investigated in very low birth weight (VLBW) infants that are at high sepsis' risk. The primary outcome was, in a population of VLBW infants with late-onset sepsis, the matching between blood culture results and pathogens isolated from rectal and nose/pharyngeal surveillance swabs in the preceding 2 weeks. The secondary outcomes were the site of swabbing and time interval from colonization to blood culture positivity. Out of 333 VLBW neonates, 80 (24%) were diagnosed with bacterial sepsis. In 46 (57%) neonates, the blood culture showed the same pathogen species cultured from a swab. Of these, 30 were isolated from infants with both body sites colonized with an average time interval of 3.5 days; 2/16 were isolated from rectal swabs and 14 /16 from nose/pharyngeal samples.Conclusion: Our data show a fair correspondence between bacteria colonizing the nasopharynx and/or the rectum and pathogens later isolated from blood cultures. This association depends on the swabbing site, number of sites, and pathogen species. Although these data constitute valuable results, they are not sufficient for providing the sole base of a thoughtful clinical decision. What is Known: • Body site's colonization may precede systemic infection. • Little is known on this mechanism in VLBW infants that are at higher sepsis' risk. What is New: •Colonizing bacteria partially correspond to pathogens of blood cultures in VLBW infants with sepsis. • Correspondence depends on swabbing site, number of sites, and pathogen species.
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http://dx.doi.org/10.1007/s00431-020-03788-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886719PMC
March 2021

Lung ultrasound-guided surfactant administration: time for a personalized, physiology-driven therapy.

Eur J Pediatr 2020 12;179(12):1909-1911

Division of Pediatrics and Neonatal Critical Care, "A. Beclere" Medical Center, Paris Saclay University Hospitals APHP, Paris, France.

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http://dx.doi.org/10.1007/s00431-020-03745-xDOI Listing
December 2020

The Effect of Liraglutide on β-Blockade for Preventing Variceal Bleeding: A Case Series.

Ann Intern Med 2020 09 26;173(5):404-405. Epub 2020 May 26.

University of Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy (R.V., L.B., G.V., M.L.P., G.M., P.A.).

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http://dx.doi.org/10.7326/L20-0041DOI Listing
September 2020

The Natural History of Hearing Disorders in Asymptomatic Congenital Cytomegalovirus Infection.

Front Pediatr 2020 5;8:217. Epub 2020 May 5.

Division of Neonatology, Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy.

Cytomegalovirus (CMV) is the main cause of congenital infection in developed countries leading to deafness but the burden of sensorineural hearing loss (SNHL) in asymptomatic children remains incompletely characterized. Aim of this study was to evaluate the long-term audiological outcome in this group of patients. Consecutive neonates with congenital CMV infection were followed from 2002 to 2018. Patients were considered asymptomatic if free from any clinical and instrumental impairment at referral and underwent serial clinical exams, audiological evaluations and CMV-PCR determinations. A cohort of 258 children was analyzed and the disease onset was asymptomatic in 125 (48%) infants. Among these, we studied 102 patients with a follow-up longer than 1 year and a median observation period of 2.8 years (range: 1-10.3 years). No patient developed a stable delayed SNHL but only 14 (14%) presented a variable hearing impairment, seven of which bilateral. The unstable SNHL was mild in 12 infants and moderate in two. Patients with fluctuating SNHL had significantly higher urine viral load ( 0.002) and more often positive viremia ( 0.015) than babies with stable normal hearing. CMV infected, asymptomatic neonates have a low risk of transient SNHL later in infancy. Positive viremia and high urine viral load at onset are significant risk factors for delayed fluctuating SNHL. These data are relevant for an appropriate follow up plan of these patients.
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http://dx.doi.org/10.3389/fped.2020.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214611PMC
May 2020

Reducing post-extubation failure rates in very preterm infants: is BiPAP better than CPAP?

J Matern Fetal Neonatal Med 2020 Apr 7:1-6. Epub 2020 Apr 7.

Department of Translational Medical Sciences, Division of Neonatology, University "Federico II", Naples, Italy.

Continuous positive airway pressure (CPAP) is currently used in neonates after mechanical ventilation though it may occasionally be associated with air leaks syndromes or it may fail to support the baby. The pressure difference offered by bilevel continuous positive distending pressure (BiPAP) respect to CPAP may be an advantage to the spontaneously breathing patient. In this study, we compared the efficacy of CPAP and BiPAP in the firstweek post-extubation in a series of very preterm infants. Inborn neonates less than 30 weeks of gestational age who were intubated shortly after birth from January 2011 to December 2017 were enrolled in a retrospective study. The attending clinician assessed the patients for non-invasive respiratory support readiness and allocated them to CPAP (PEEP 4-6 cmHO) or BiPAP (PEEP 4-5 cmHO, rate 10-40; Thigh 0.7-1.2; upper-pressure level 8-10 cmHO). Both techniques were compared for preventing extubation failure within 7 days from extubation as defined per local protocol (primary outcome). Secondary outcomes were: definitive failure of extubation, pneumothorax during non-invasive respiratory support, periventricular leukomalacia, bronchopulmonary dysplasia, sepsis, patent ductus arteriosus and retinopathy of prematurity at discharge. We enrolled 134 neonates; the CPAP group included 89 babies while 45 received BiPAP. Patients did not differ for their general characteristics (EG, antenatal steroids, incidence of SGA, maternal hypertension, surfactant replacement therapy). Short term extubation failure was significantly higher in the former group (23/89 in CPAP vs 5/45 in BiPAP;  = .005). No infant developed air leak syndrome. Secondary outcomes were comparable between groups. Multivariate analysis showed that on the whole population the extubation failure was correlated to the insurgence of late-onset sepsis. BiPAP safely reduced early extubation failure compared to CPAP in our cohort of very preterm neonates within 7 days from extubation.
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http://dx.doi.org/10.1080/14767058.2020.1749256DOI Listing
April 2020

Why does the Aβ peptide of Alzheimer share structural similarity with antimicrobial peptides?

Commun Biol 2020 03 19;3(1):135. Epub 2020 Mar 19.

UK-Dementia Research Institute (UK-DRI) at King's College London, London, UK.

The Aβ peptides causally associated with Alzheimer disease have been seen as seemingly purposeless species produced by intramembrane cleavage under both physiological and pathological conditions. However, it has been increasingly suggested that they could instead constitute an ancient, highly conserved effector component of our innate immune system, dedicated to protecting the brain against microbial attacks. In this antimicrobial protection hypothesis, Aβ aggregation would switch from an abnormal stochastic event to a dysregulated innate immune response. In this perspective, we approach the problem from a different and complementary perspective by comparing the structure and sequence of Aβ(1-42) with those of bona fide antimicrobial peptides. We demonstrate that Aβ(1-42) bears convincing structural similarities with both viral fusion domains and antimicrobial peptides, as well as sequence similarities with a specific family of bacterial bacteriocins. We suggest a model of the mechanism by which Aβ peptides could elicit the immune response against microbes.
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http://dx.doi.org/10.1038/s42003-020-0865-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081199PMC
March 2020

Trends, risk factors and outcomes of healthcare-associated infections in a neonatal intensive care unit in Italy during 2013-2017.

Ital J Pediatr 2020 Mar 18;46(1):34. Epub 2020 Mar 18.

Department of Public Health, University of Naples "Federico II", Via S. Pansini n.5, 80131, Naples, Italy.

Background: Healthcare-associated infections (HAIs) occur frequently in intensive care units (NICUs). The aim of this study was to analyze the results of surveillance of HAIs in a III level NICU in Naples, Italy during 2013-2017 and to compare with those obtained during 2006-2010.

Methods: The surveillance included 1265 neonates of all birth weight (BW) classes with > 2 days NICU stay. Infections were defined using standard Centers for Disease Control and Prevention definitions adapted to neonatal pathology.

Results: A total of 125 HAIs were registered during 2013-2017 with a frequency of 9.9% and an incidence density of 3.2 per 1000 patient days. HAIs occurred in all BW classes with a decreasing trend from the lowest to the highest BW classes (p = < 0.001). Central line-associated blood stream infection (CLABSI) was the most frequent infection (69.6%), followed by ventilator associated pneumonia (VAP) (20%), urinary tract infection (UTI) (8.8%) and necrotizing enterocolitis (NEC) (1.6%). Also, CLABSI and VAP incidence density decreased from lower to highest BW classes showing a significant trend (p = 0.007). Most frequent pathogens responsible for CLABSI were: Coagulase-negative staphylococci (CONS) (25.3%), Candida parapsilosis (21.8%), Pseudomonas aeruginosa (5.7), Escherichia coli and Klebsiella pneumoniae (6.8%). No microbiological diagnosis was achieved for 20.7% of CLABSI. Pseudomonas aeruginosa (28%), Stenotrophomonas maltophilia (20%), and CONS (20%) were the most frequent pathogens responsible for VAP. CLABSI incidence density showed no differences between 2006 and 2010 and 2013-2017, while VAP incidence density for the 751-100 g BW class was higher during 2006-2010 than during 2013-2017 (p = 0.006). A higher incidence of the CLABSI caused by Gram positive bacteria (p = 0.002) or by undetermined etiology (p = 0.01) was observed during 2013-2017 than during 2006-2010, while a significant lower incidence of VAP caused by Gram-negative bacteria was found during 2013-2017 than during 2006-2010 (p = 0.007).

Conclusion: HAIs in the NICU developed in all BW classes with a decreasing trend from the lowest to the highest BW classes in both study periods. Differences in the aetiology of CLABSI and VAP were found between the two study periods. This reinforces the importance of HAIs surveillance protocol in the NICU, which monitors microbiological isolates and use of medical devices for all BW classes of neonates.
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http://dx.doi.org/10.1186/s13052-020-0799-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079437PMC
March 2020

May We Start Early Enteral Nutrition in Critically Ill Children?

JPEN J Parenter Enteral Nutr 2020 05 6;44(4):566. Epub 2020 Feb 6.

Neonatal Intensive Care Unit, Department of Translational Medical Science, University Federico II, Naples, Italy.

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http://dx.doi.org/10.1002/jpen.1780DOI Listing
May 2020

Molecular switch from MYC to MYCN expression in MYC protein negative Burkitt lymphoma cases.

Blood Cancer J 2019 11 20;9(12):91. Epub 2019 Nov 20.

Department of Medical Biotechnology, University of Siena, Siena, Italy.

MYC is the most altered oncogene in human cancer, and belongs to a large family of genes, including MYCN and MYCL. Recently, while assessing the degree of correlation between MYC gene rearrangement and MYC protein expression in aggressive B-cell lymphomas, we observed few Burkitt lymphoma (BL) cases lacking MYC protein expression despite the translocation involving the MYC gene. Therefore, in the present study we aimed to better characterize such cases. Our results identified two sub-groups of MYC protein negative BL: one lacking detectable MYC protein expression but presenting MYCN mRNA and protein expression; the second characterized by the lack of both MYC and MYCN proteins but showing MYC mRNA. Interestingly, the two sub-groups presented a different pattern of SNVs affecting MYC gene family members that may induce the switch from MYC to MYCN. Particulary, MYCN-expressing cases show MYCN SNVs at interaction interface that stabilize the protein associated with loss-of-function of MYC. This finding highlights MYCN as a reliable diagnostic marker in such cases. Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization.
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http://dx.doi.org/10.1038/s41408-019-0252-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868231PMC
November 2019

Histological chorioamnionitis and risk of pulmonary complications in preterm births: a systematic review and Meta-analysis.

J Matern Fetal Neonatal Med 2019 Nov 13:1-10. Epub 2019 Nov 13.

Department of Neurosciences, Reproductive and Dentistry Sciences, University of Naples "Federico II", Naples, Italy.

Histological chorioamnionitis is associated with significant adverse maternal, perinatal and long-term outcome. We performed a meta-analysis of 30 observational studies in order to clarify the association between Histological chorioamnionitis and pulmonary complications, like respiratory distress syndrome and Bronchopulmonary Dysplasia. Unadjusted data extracted from all studies showed that Histological chorioamnionitis has no effect on development of RDS (RR 0.93, 95% CI 1.08-1.67), while it increased the risk of Bronchopulmonary Dysplasia (RR 1.75, 95% CI 1.37-2.23). However, when we restricted the analysis to the studies that adjust for Gestational Age, in order to exclude the influence of prematurity, we found that HCA reduced the risk of respiratory distress syndrome (RR 0.57, CI 95% 0.35-0.93) and it did not affect the development of Bronchopulmonary Dysplasia (RR 0.99, CI 0.76-1.3). Our results confirmed a possible role of prenatal inflammation on lung maturation. However, further prospective studies with a selected population are needed, in order to clarify the role of Histological chorioamnionitis in neonatal pulmonary complications.
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http://dx.doi.org/10.1080/14767058.2019.1689945DOI Listing
November 2019

Auto-regulation of Rab5 GEF activity in Rabex5 by allosteric structural changes, catalytic core dynamics and ubiquitin binding.

Elife 2019 11 13;8. Epub 2019 Nov 13.

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.

Intracellular trafficking depends on the function of Rab GTPases, whose activation is regulated by guanine exchange factors (GEFs). The Rab5 GEF, Rabex5, was previously proposed to be auto-inhibited by its C-terminus. Here, we studied full-length Rabex5 and Rabaptin5 proteins as well as domain deletion Rabex5 mutants using hydrogen deuterium exchange mass spectrometry. We generated a structural model of Rabex5, using chemical cross-linking mass spectrometry and integrative modeling techniques. By correlating structural changes with nucleotide exchange activity for each construct, we uncovered new auto-regulatory roles for the ubiquitin binding domains and the Linker connecting those domains to the catalytic core of Rabex5. We further provide evidence that enhanced dynamics in the catalytic core are linked to catalysis. Our results suggest a more complex auto-regulation mechanism than previously thought and imply that ubiquitin binding serves not only to position Rabex5 but to also control its Rab5 GEF activity through allosteric structural alterations.
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http://dx.doi.org/10.7554/eLife.46302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855807PMC
November 2019

An Old Disease Comes Back: Reporting 2 Cases of Neonatal Measles.

J Pediatric Infect Dis Soc 2019 Oct 11. Epub 2019 Oct 11.

Neonatology, Department of Translational Medical Science, and, Napoli, Italy.

We report two cases of neonatal measles (one congenital and one post natal infection) admitted to our neonatal intensive care unit and discuss the management. This report intend to keep alert against measles and point out the risk for susceptible pregnant women and their offspring in countries with reduction of coverage from anti measles vaccine.
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http://dx.doi.org/10.1093/jpids/piz067DOI Listing
October 2019

Interconnecting Flexibility, Structural Communication, and Function in RhoGEF Oncoproteins.

J Chem Inf Model 2019 10 25;59(10):4300-4313. Epub 2019 Sep 25.

Department of Life Sciences , University of Modena and Reggio Emilia , via Campi 103 , 41125 Modena , Italy.

Dbl family Rho guanine nucleotide exchange factors (RhoGEFs) play a central role in cell biology by catalyzing the exchange of guanosine 5'-triphosphate for guanosine 5'-diphosphate (GDP) on RhoA. Insights into the oncogenic constitutive activity of the Lbc RhoGEF were gained by analyzing the structure and dynamics of the protein in different functional states and in comparison with a close homologue, leukemia-associated RhoGEF. Higher intrinsic flexibility, less dense and extended structure network, and less stable allosteric communication pathways in Lbc, compared to the nonconstitutively active homologue, emerged as major determinants of the constitutive activity. Independent of the state, the essential dynamics of the two RhoGEFs is contributed by the last 10 amino acids of Dbl homology (DH) and the whole pleckstrin homology (PH) domains and tends to be equalized by the presence of RhoA. The catalytic activity of the RhoGEF relies on the scaffolding action of the DH domain that primarily turns the switch I (SWI) of RhoA on itself through highly conserved amino acids participating in the stability core and essential for function. Changes in the conformation of SWI and disorganization of the RhoA regions deputed to nucleotide binding are among the major RhoGEF effects leading to GDP release. Binding of RhoA reorganizes the allosteric communication on RhoGEF, strengthening the communication among the canonical RhoA binding site on DH, a secondary RhoA binding site on PH, and the binding site for heterotrimeric G proteins, suggesting dual roles for RhoA as a catalysis substrate and as a regulatory protein. The structure network-based analysis tool employed in this study proved to be useful for predicting potentially druggable regulatory sites in protein structures.
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http://dx.doi.org/10.1021/acs.jcim.9b00271DOI Listing
October 2019

Rare, functional, somatic variants in gene families linked to cancer genes: GPCR signaling as a paradigm.

Oncogene 2019 09 23;38(38):6491-6506. Epub 2019 Jul 23.

BioQuant, Heidelberg University, Im Neuenheimer Feld 267, 69120, Heidelberg, Germany.

Oncodriver genes are usually identified when mutations recur in multiple tumours. Different drivers often converge in the activation or repression of key cancer-relevant pathways. However, as many pathways contain multiple members of the same gene family, individual mutations might be overlooked, as each family member would necessarily have a lower mutation frequency and thus not identified as significant in any one-gene-at-a-time analysis. Here, we looked for mutated, functional sequence positions in gene families that were mutually exclusive (in patients) with another gene in the same pathway, which identified both known and new candidate oncodrivers. For instance, many inactivating mutations in multiple G-protein (particularly G) coupled receptors, are mutually exclusive with Gα oncogenic activating mutations, both of which ultimately enhance cAMP signalling. By integrating transcriptomics and interaction data, we show that the G pathway is upregulated in multiple cancer types, even those lacking known GNAS activating mutations. This suggests that cancer cells may develop alternative strategies to activate adenylate cyclase signalling in multiple cancer types. Our study provides a mechanistic interpretation for several rare somatic mutations in multi-gene oncodrivers, and offers possible explanations for known and potential off-label cancer treatments, suggesting new therapeutic opportunities.
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http://dx.doi.org/10.1038/s41388-019-0895-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756116PMC
September 2019

and Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib.

Cancers (Basel) 2019 Jul 20;11(7). Epub 2019 Jul 20.

Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, 41121 Modena, Italy.

Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited efficacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 () and endothelial-derived nitric oxide synthase () genes in 135 patients with advanced HCC receiving sorafenib. Eight polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, rs55633437 and rs2070744 were associated with OS and PFS. In particular, patients with rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73-8.67, < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73-8.35, < 0.001) than those homozygous for the G allele. Moreover, patients with rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44-0.97; 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30-0.63; < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that rs55633437 and rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib.
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http://dx.doi.org/10.3390/cancers11071023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679015PMC
July 2019

Congenital Lung Malformations: Unresolved Issues and Unanswered Questions.

Front Pediatr 2019 13;7:239. Epub 2019 Jun 13.

Division of Paediatrics, Department of Translational Medical Sciences, Federico II University, Naples, Italy.

Advances in prenatal and postnatal diagnosis, perioperative management, and postoperative care have dramatically increased the number of scientific reports on congenital thoracic malformations (CTM). Nearly all CTM are detected prior to birth, generally by antenatal ultrasound. After delivery, most infants do well and remain asymptomatic for a long time. However, complications may occur beyond infancy, including in adolescence and adulthood. Prenatal diagnosis is sometimes missed and detection may occur later, either by chance or because of unexplained recurrent or persistent respiratory symptoms or signs, with difficult implications for family counseling and substantial delay in surgical planning. Although landmark studies have been published, postnatal management of asymptomatic children is still controversial and needs a resolution. Our aim is to provide a focused overview on a number of unresolved issues arising from the lack of an evidence-based consensus on the management of patients with CTM. We summarized findings from current literature, with a particular emphasis on the vigorous controversies on the type and timing of diagnostic procedures, treatments and the still obscure relationship between CTM and malignancies, a matter of great concern for both families and physicians. We also present an algorithm for the assessment and follow-up of CTM detected either in the antenatal or postnatal period. A standardized approach across Europe, based on a multidisciplinary team, is urgently needed for achieving an evidence-based management protocol for CTM.
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http://dx.doi.org/10.3389/fped.2019.00239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584787PMC
June 2019

Illuminating the Onco-GPCRome: Novel G protein-coupled receptor-driven oncocrine networks and targets for cancer immunotherapy.

J Biol Chem 2019 07 5;294(29):11062-11086. Epub 2019 Jun 5.

Department of Pharmacology, UCSD Moores Cancer Center, La Jolla, California 92093

G protein-coupled receptors (GPCRs) are the largest gene family of cell membrane-associated molecules mediating signal transmission, and their involvement in key physiological functions is well-established. The ability of GPCRs to regulate a vast array of fundamental biological processes, such as cardiovascular functions, immune responses, hormone and enzyme release from endocrine and exocrine glands, neurotransmission, and sensory perception ( vision, odor, and taste), is largely due to the diversity of these receptors and the layers of their downstream signaling circuits. Dysregulated expression and aberrant functions of GPCRs have been linked to some of the most prevalent human diseases, which renders GPCRs one of the top targets for pharmaceutical drug development. However, the study of the role of GPCRs in tumor biology has only just begun to make headway. Recent studies have shown that GPCRs can contribute to the many facets of tumorigenesis, including proliferation, survival, angiogenesis, invasion, metastasis, therapy resistance, and immune evasion. Indeed, GPCRs are widely dysregulated in cancer and yet are underexploited in oncology. We present here a comprehensive analysis of GPCR gene expression, copy number variation, and mutational signatures in 33 cancer types. We also highlight the emerging role of GPCRs as part of oncocrine networks promoting tumor growth, dissemination, and immune evasion, and we stress the potential benefits of targeting GPCRs and their signaling circuits in the new era of precision medicine and cancer immunotherapies.
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http://dx.doi.org/10.1074/jbc.REV119.005601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643028PMC
July 2019

Illuminating G-Protein-Coupling Selectivity of GPCRs.

Cell 2019 06 31;177(7):1933-1947.e25. Epub 2019 May 31.

CellNetworks, Bioquant, Heidelberg University, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany; Biochemie Zentrum Heidelberg (BZH), Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany. Electronic address:

Heterotrimetic G proteins consist of four subfamilies (G, G, G, and G) that mediate signaling via G-protein-coupled receptors (GPCRs), principally by receptors binding Gα C termini. G-protein-coupling profiles govern GPCR-induced cellular responses, yet receptor sequence selectivity determinants remain elusive. Here, we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique Gα subunit C termini. For each receptor, we probed chimeric Gα subunit activation via a transforming growth factor-α (TGF-α) shedding response in HEK293 cells lacking endogenous G and G proteins, and complemented G-protein-coupling profiles through a NanoBiT-G-protein dissociation assay. Interrogation of the dataset identified sequence-based coupling specificity features, inside and outside the transmembrane domain, which we used to develop a coupling predictor that outperforms previous methods. We used the predictor to engineer designer GPCRs selectively coupled to G. This dataset of fine-tuned signaling mechanisms for diverse GPCRs is a valuable resource for research in GPCR signaling.
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http://dx.doi.org/10.1016/j.cell.2019.04.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773469PMC
June 2019

PRECOG: PREdicting COupling probabilities of G-protein coupled receptors.

Nucleic Acids Res 2019 07;47(W1):W395-W401

CellNetworks, Bioquant, Heidelberg University, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.

G-protein coupled receptors (GPCRs) control multiple physiological states by transducing a multitude of extracellular stimuli into the cell via coupling to intra-cellular heterotrimeric G-proteins. Deciphering which G-proteins couple to each of the hundreds of GPCRs present in a typical eukaryotic organism is therefore critical to understand signalling. Here, we present PRECOG (precog.russelllab.org): a web-server for predicting GPCR coupling, which allows users to: (i) predict coupling probabilities for GPCRs to individual G-proteins instead of subfamilies; (ii) visually inspect the protein sequence and structural features that are responsible for a particular coupling; (iii) suggest mutations to rationally design artificial GPCRs with new coupling properties based on predetermined coupling features.
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http://dx.doi.org/10.1093/nar/gkz392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602504PMC
July 2019

Profiling of Epigenetic Features in Clinical Samples Reveals Novel Widespread Changes in Cancer.

Cancers (Basel) 2019 May 24;11(5). Epub 2019 May 24.

Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy.

Aberrations in histone post-translational modifications (PTMs), as well as in the histone modifying enzymes (HMEs) that catalyze their deposition and removal, have been reported in many tumors and many epigenetic inhibitors are currently under investigation for cancer treatment. Therefore, profiling epigenetic features in cancer could have important implications for the discovery of both biomarkers for patient stratification and novel epigenetic targets. In this study, we employed mass spectrometry-based approaches to comprehensively profile histone H3 PTMs in a panel of normal and tumoral tissues for different cancer types, identifying various changes, some of which appear to be a consequence of the increased proliferation rate of tumors, while others are cell-cycle independent. Histone PTM changes found in tumors partially correlate with alterations of the gene expression profiles of HMEs obtained from publicly available data and are generally lost in culture conditions. Through this analysis, we identified tumor- and subtype-specific histone PTM changes, but also widespread changes in the levels of histone H3 K9me3 and K14ac marks. In particular, H3K14ac showed a cell-cycle independent decrease in all the seven tumor/tumor subtype models tested and could represent a novel epigenetic hallmark of cancer. .
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http://dx.doi.org/10.3390/cancers11050723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562406PMC
May 2019

Familial intrahepatic cholestasis: New and wide perspectives.

Dig Liver Dis 2019 07 16;51(7):922-933. Epub 2019 May 16.

ITEC Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy; Research Centre for the Study of Hepatitis, University of Bologna, Italy. Electronic address:

Background: Progressive familial intrahepatic cholestasis (PFIC) includes autosomal recessive cholestatic rare diseases of childhood.

Aims: To update the panel of single genes mutations involved in familial cholestasis.

Methods: PubMed search for "familial intrahepatic cholestasis" alone as well as in combination with other key words was performed considering primarily original studies and meta-analyses.

Results: PFIC1 involves ATP8B1 gene encoding for aminophospholipid flippase FIC1. PFIC2 includes ABCB11 gene, encoding for protein functioning as bile salt export pump. PFIC3 is due to mutations of ABCB4 gene responsible for the synthesis of class III multidrug resistance P-glycoprotein flippase. PFIC4 and PFIC5 involve tight junction protein-2 gene and NR1H4 gene encoding for farnesoid X receptor. Benign Intrahepatic Cholestasis, Intrahepatic Cholestasis of Pregnancy and Low-phospholipid-associated cholelithiasis involve the same genes and are characterized by intermittent attacks of cholestasis, no progression to cirrhosis, reversible pregnancy-specific cholestasis and cholelithiasis in young people. Blood and liver tissue levels of bile-excreted drugs can be influenced by the presence of mutations in PFIC genes, causing drug-induced cholestasis. Mutations in PFIC genes might increase the risk of liver cancer.

Conclusion: There is a high proportion of unexplained cholestasis potentially caused by specific genetic pathophysiologic pathways. The use of next generation sequencing and whole-exome sequencing could improve the diagnostic process in this setting.
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http://dx.doi.org/10.1016/j.dld.2019.04.013DOI Listing
July 2019

Defective homologous recombination DNA repair as therapeutic target in advanced chordoma.

Nat Commun 2019 04 9;10(1):1635. Epub 2019 Apr 9.

German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.

Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
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http://dx.doi.org/10.1038/s41467-019-09633-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456501PMC
April 2019