Publications by authors named "Daniele Colombo"

38 Publications

A life-threatening small bowel obstruction as onset of an unknown sarcoidosis: A case report.

Respir Med Case Rep 2021 9;33:101379. Epub 2021 Mar 9.

Department of Public Health and Infectious Diseases, La Sapienza University of Rome, Rome, Italy.

Sarcoidosis is a systemic granulomatous disorder of unknown etiology characterized by non-caseating granulomas at the site of disease. A confident diagnosis should be established by the evidence of typical granulomas on biopsy and after exclusion of other conditions. Clinically recognizable Gastrointestinal involvement (GI) occurs in less than 1.6% of patients with sarcoidosis, with data revealing small intestine participation in 0.03% of the cases and few anecdotal reports describe a peritoneal presentation. Clinical manifestations of peritoneal sarcoidosis are abdominal discomfort, bloating, weight loss, epigastric and peri-umbilical pain with or without ascites, bowel obstruction. Treatment depends on symptoms and disease activity. Herein we describe the case of a 42-years-old male patient who developed an acute, life-threatening small bowel obstruction as first manifestation of sarcoidosis. To the best of our knowledge, this is the only report showing such extensive and acute onset of intra-abdominal sarcoidosis in the absence of a previous disease manifestation and without pulmonary involvement.
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http://dx.doi.org/10.1016/j.rmcr.2021.101379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994781PMC
March 2021

Evidences for lipid involvement in SARS-CoV-2 cytopathogenesis.

Cell Death Dis 2021 03 12;12(3):263. Epub 2021 Mar 12.

Laboratory of Electron Microscopy, National Institute for Infectious Diseases "Lazzaro Spallanzani", IRCCS, Rome, Italy.

The pathogenesis of SARS-CoV-2 remains to be completely understood, and detailed SARS-CoV-2 cellular cytopathic effects requires definition. We performed a comparative ultrastructural study of SARS-CoV-1 and SARS-CoV-2 infection in Vero E6 cells and in lungs from deceased COVID-19 patients. SARS-CoV-2 induces rapid death associated with profound ultrastructural changes in Vero cells. Type II pneumocytes in lung tissue showed prominent altered features with numerous vacuoles and swollen mitochondria with presence of abundant lipid droplets. The accumulation of lipids was the most striking finding we observed in SARS-CoV-2 infected cells, both in vitro and in the lungs of patients, suggesting that lipids can be involved in SARS-CoV-2 pathogenesis. Considering that in most cases, COVID-19 patients show alteration of blood cholesterol and lipoprotein homeostasis, our findings highlight a peculiar important topic that can suggest new approaches for pharmacological treatment to contrast the pathogenicity of SARS-CoV-2.
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http://dx.doi.org/10.1038/s41419-021-03527-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952828PMC
March 2021

Dermatological manifestations during COVID-19 and histological picture: Description of two clinical cases.

J Dermatol 2021 Feb 23. Epub 2021 Feb 23.

Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases "L. Spallanzani" IRCCS, Rome, Italy.

It is not yet entirely clear what is the relevance of skin symptoms and what clinical implications are related to their appearance in COVID-19 patients. We describe two cases of COVID-19-associated pneumonia, which presented skin manifestations in advanced stage of illness, when nasopharyngeal swabs became negative for SARS-CoV-2. The first case presented erythematous, maculopapular lesions; the second developed petechial, vesicular and blood-encrusted lesions on the limbs. Histopathology documented perivascular lymphocytic infiltrates, with prevalent CD4+ T-cells in both patients. The research of SARS-CoV-2 in tissues with real time RT-PCR was negative. Basal keratinocytes displayed C4d deposits in one case, who developed laboratory signs indicative of a procoagulative condition at the same time as the skin rash. Skin manifestations during SARS-CoV-2 infection seem to be clinically relevant and further studies are necessary to assess if they are linked to systemic complications, lack of viral clearance or cascades of immune responses induced by the virus, even in patients affected by mild pneumonia.
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http://dx.doi.org/10.1111/1346-8138.15714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013512PMC
February 2021

IL-1 Receptor Antagonist Anakinra in the Treatment of COVID-19 Acute Respiratory Distress Syndrome: A Retrospective, Observational Study.

J Immunol 2021 04 5;206(7):1569-1575. Epub 2021 Feb 5.

Infectious Diseases Unit, Alessandro Manzoni Hospital, 23900 Lecco, Italy.

The IL-1 receptor antagonist, anakinra, may represent a therapeutic option for acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 (COVID-19). In this study, COVID-19 ARDS patients admitted to the Azienda Socio Sanitaria Territoriale of Lecco, Italy, between March 5th to April 15th, 2020, and who had received anakinra off-label were retrospectively evaluated and compared with a cohort of matched controls who did not receive immunomodulatory treatment. The primary end point was survival at day 28. The population consisted of 112 patients (56 treated with anakinra and 56 controls). Survival at day 28 was obtained in 69 patients (61.6%) and was significantly higher in anakinra-treated patients than in the controls (75.0 versus 48.2%, = 0.007). When stratified by continuous positive airway pressure support at baseline, anakinra-treated patients' survival was also significant compared with the controls ( = 0.008). Univariate analysis identified anakinra usage (odds ratio, 3.2; 95% confidence interval, 1.47-7.17) as a significant survival predictor. This was not supported by multivariate modeling. The rate of infectious-related adverse events was similar between groups. In conclusion, anakinra improved overall survival and invasive ventilation-free survival and was well tolerated in patients with ARDS associated with COVID-19.
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http://dx.doi.org/10.4049/jimmunol.2001126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980530PMC
April 2021

Anti-IL6 treatment of serious COVID-19 disease: A monocentric retrospective experience.

Medicine (Baltimore) 2021 Jan;100(1):e23582

Department of Internal Medicine, ASST Ovest Milanese Ospedale di Legnano.

Abstract: COVID-19 is causing a high influx of patients suffering from serious respiratory complications leading the necessity to find effective therapies. These patients seem to present with cytokine perturbation and high levels of IL6. Tocilizumab and sarilumab could be effective in this condition.We retrospectively collected data about 112 consecutive hospitalized in a single center.Fifty (IL6 group) treated with tocilizumab (8 mg/kg intravenously [IV], 2 infusions 12 hours apart) or sarilumab 400 mg IV once and 62 treated with the standard of care but not anti-cytokine drugs (CONTROL group).To determine whether anti-IL6 drugs are effective in improving prognosis and reducing hospitalization times and mortality in COVID-19 pneumonia.To date 84% (42/50) of IL6 group patients have already been discharged and only 2/50 are still recovered and intubated in intensive care. Six/fifty patients (12%) died: 5/6 due to severe respiratory failure within a framework of severe acute respiratory distress syndrome (ARDS), 1 suffered an acute myocardial infarction, and 1 died of massive pulmonary thromboembolism. There were no adverse treatment events or infectious complications. Compared to the CONTROL group they showed a lower mortality rate (12% versus 43%), for the same number of complications and days of hospitalization.Anti-IL6 drugs seem to be effective in the treatment of medium to severe forms of COVID-19 pneumonia reducing the risk of mortality due to multi-organ failure, acting at the systemic level and reducing inflammation levels and therefore microvascular complications. However, it is essential to identify the best time for treatment, which, if delayed, is rendered useless as well as counterproductive. Further studies and ongoing clinical trials will help us to better define patients eligible as candidates for more aggressive intervention.
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http://dx.doi.org/10.1097/MD.0000000000023582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793456PMC
January 2021

Fatal pulmonary arterial thrombosis in a COVID-19 patient, with asymptomatic history, occurred after swab negativization.

Thromb J 2021 Jan 6;19(1). Epub 2021 Jan 6.

Laboratory of Electron Microscopy, National Institute for Infectious Diseases "L. Spallanzani", IRCCS, Rome, Italy.

Background: A considerable number of SARS-CoV-2 infected individuals could be asymptomatic and don't need medical treatment. The clinical spectrum of SARS-CoV-2 infection ranges from asymptomatic cases, medium-intensity forms with mild to moderate symptoms, to severe ones with bilateral pneumonia and respiratory distress. In cases with severe presentation of SARS-CoV-2 infection, the induction of hypercoagulability is one of the pathophysiological mechanism that can contribute to death.

Case Presentation: Here, we reported autoptic evidences of thrombotic pulmonary arterial fatal lesions in an asymptomatic COVID-19 patient, after swab negativization. Whole body complete post-mortem examination was performed, showing the presence of a large thrombus occluding the main pulmonary artery that was the cause of death. Histopathological analysis showed heterogeneous pattern of pathological changes in the lung tissue with numerous vascular thrombi, inflammatory cardiomyopathy and other histopathological modifications in kidneys, spleen and liver.

Conclusions: This study provides evidences that also asymptomatic patients may be at risk to develop thrombotic complications. An appropriate diagnostic screening for thrombotic complications and the early treatment recommendations of antithrombotic drugs could represent an important topic even in asymptomatic individuals.
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http://dx.doi.org/10.1186/s12959-020-00255-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785914PMC
January 2021

Fatal Takotsubo syndrome in critical COVID-19 related pneumonia.

Cardiovasc Pathol 2021 Mar-Apr;51:107314. Epub 2020 Nov 28.

Department of Anesthesia and Intensive Care Medicine, Sapienza University of Rome, Rome, Italy.

COVID-19 can involve several organs and systems, often with indirect and poorly clarified mechanisms. Different presentations of myocardial injury have been reported, with variable degrees of severity, often impacting on the prognosis of COVID-19 patients. The pathogenic mechanisms underlying cardiac damage in SARS-CoV-2 infection are under active investigation. We report the clinical and autopsy findings of a fatal case of Takotsubo Syndrome occurring in an 83-year-old patient with COVID-19 pneumonia. The patient was admitted to Emergency Department with dyspnea, fever and diarrhea. A naso-pharyngeal swab test for SARS-CoV-2 was positive. In the following week his conditions worsened, requiring intubation and deep sedation. While in the ICU, the patient suddenly showed ST segment elevation. Left ventricular angiography showed decreased with hypercontractile ventricular bases and mid-apical ballooning, consistent with diagnosis of Takotsubo syndrome. Shortly after the patient was pulseless. After extensive resuscitation maneuvers, the patient was declared dead. Autopsy revealed a subepicardial hematoma, in absence of myocardial rupture. On histology, the myocardium showed diffuse edema, multiple foci of contraction band necrosis in both ventricles and occasional coagulative necrosis of single cardiac myocytes. Abundant macrophages CD68+ were detected in the myocardial interstitium. The finding of diffuse contraction band necrosis supports the pathogenic role of increased catecholamine levels; the presence of a significant interstitial inflammatory infiltrate, made up by macrophages, remains of uncertain significance.
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http://dx.doi.org/10.1016/j.carpath.2020.107314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699026PMC
February 2021

Postmortem Findings in Italian Patients With COVID-19: A Descriptive Full Autopsy Study of Cases With and Without Comorbidities.

J Infect Dis 2020 11;222(11):1807-1815

National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy.

Background: Descriptions of the pathological features of coronavirus disease-2019 (COVID-19) caused by the novel zoonotic pathogen severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emanate from tissue biopsies, case reports, and small postmortem studies restricted to the lung and specific organs. Whole-body autopsy studies of COVID-19 patients have been sparse.

Methods: To further define the pathology caused by SARS-CoV-2 across all body organs, we performed autopsies on 22 patients with COVID-19 (18 with comorbidities and 4 without comorbidities) who died at the National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS Hospital, Rome, Italy. Tissues from the lung, heart, liver, kidney, spleen, and bone marrow (but not the brain) were examined. Only lung tissues were subject to transmission electron microscopy.

Results: COVID-19 caused multisystem pathology. Pulmonary and cardiovascular involvement were dominant pathological features. Extrapulmonary manifestations included hepatic, kidney, splenic, and bone marrow involvement, and microvascular injury and thrombosis were also detected. These findings were similar in patients with or without preexisting medical comorbidities.

Conclusions: SARS-CoV-2 infection causes multisystem disease and significant pathology in most organs in patients with and without comorbidities.
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http://dx.doi.org/10.1093/infdis/jiaa578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543426PMC
November 2020

Does trail making test predict long-term prognosis in older patients with COPD?

Aging Clin Exp Res 2020 Aug 17. Epub 2020 Aug 17.

Unit of Pneumology and Pulmonary Rehabilitation, Italian National Research Center on Aging (IRCCS INRCA), Casatenovo, Italy.

Executive abilities are frequently impaired in patients with chronic obstructive pulmonary disease (COPD). We aimed at investigating the association between trail making test (TMT) and survival. Our series consisted of 68 stable COPD outpatients followed-up every 6 months for 52.6 ± 27.6 months. Enrolled patients underwent a baseline comprehensive neuropsychological assessment, including mini-mental state exam, attentional matrices, digit span, Rey auditory verbal learning, Rey-Osterrieth complex figure, copy drawing, tokens test, verbal fluency, category fluency, frontal assessment battery, Raven's progressive matrices, TMT-A, -B and -B-A. The association between neuropsychological deficits and overall mortality was investigated by Cox regression. During follow-up period, 41 patients (60.3%) died. After adjusting for potential confounders, TMT-B was significantly associated with mortality (HR = 2.42, 95% CI = 1.10-5.31), along with age (HR = 1.06, 95% CI = 1.0-1.13), overall comorbidity (HR = 1.29, 95% CI = 1.02-1.62) and use of noninvasive ventilation (HR = 2.16, 95% CI = 1.05-4.45). Defective TMT-B may be associated with long-term mortality in patients with stable COPD.
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http://dx.doi.org/10.1007/s40520-020-01680-3DOI Listing
August 2020

Therapeutic innovation in Parkinson's disease: a 2020 update on disease-modifying approaches.

Expert Rev Neurother 2020 10 6;20(10):1047-1064. Epub 2020 Aug 6.

Open R&D Department, Zambon S.p.A ., Bresso, Italy.

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting more than 10 million patients worldwide. Despite increasing improvements in disease management, a huge medical need still exists as its relentless progression cannot be delayed by current treatments. Therefore, scientists, clinicians, and pharmaceutical companies are hunting new drugs with 'disease-modifying' properties.

Areas Covered: This review concentrates on new therapeutics - excluding cell and gene therapies - under investigation for PD with 'disease-modifying' potential. This is a global, comprehensive picture of the current innovative drug pipeline, where the main preclinical and clinical data available are provided. Drug candidates presented include α-synuclein modulating agents, neuroprotective agents and neuroinflammation modulators, kinase modulators, neurotrophic factors, and drugs acting on emerging targets.

Expert Opinion: There is excitement for agents with 'disease-modifying' properties and the authors found more than 130 assets, not including cell and gene therapies under investigation - most of them still in preclinical development - meaning that the science is progressing multiple, diverse new opportunities. Many limitations hamper the successful development of these drug candidates such as the translational accuracy of preclinical models, the current clinical development paradigm as well as the lack of biomarkers to be used in diagnosis and therapy management.
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http://dx.doi.org/10.1080/14737175.2020.1800454DOI Listing
October 2020

Pulmonary function in patients surviving to COVID-19 pneumonia.

Infection 2021 Feb 28;49(1):153-157. Epub 2020 Jul 28.

Respiratory Unit, IRCCS INRCA (Italian National Research Centre On Aging), 23880, Casatenovo, LC, Italy.

Purpose: The aim of our study was to assess respiratory function at the time of clinical recovery and 6 weeks after discharge in patients surviving to COVID-19 pneumonia.

Methods: Our case series consisted of 13 patients with COVID-19 pneumonia.

Results: At the time of clinical recovery, FEV1 (2.07 ± 0.72 L) and FVC (2.25 ± 0.86 L) were lower compared to lower limit of normality (LLN) values (2.56 ± 0.53 L, p = 0.004, and 3.31 ± 0.65 L, p < 0.001, respectively), while FEV1/FVC (0.94 ± 0.07) was higher compared to upper limit of normality (ULN) values (0.89 ± 0.01, p = 0.029). After 6 weeks pulmonary function improved but FVC was still lower than ULN (2.87 ± 0.81, p = 0.014).

Conclusion: These findings suggest that COVID-19 pneumonia may result in clinically relevant alterations in pulmonary function tests, with a mainly restrictive pattern.
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http://dx.doi.org/10.1007/s15010-020-01474-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386387PMC
February 2021

A single-centre experience of intravenous thrombolysis for stroke in COVID-19 patients.

Neurol Sci 2020 Sep 12;41(9):2325-2329. Epub 2020 Jul 12.

Unit of Neurology, "Alessandro Manzoni" Hospital - ASST Lecco, Via dell'Eremo 9/11, 23900, Lecco, Italy.

The sudden worldwide outbreak of Coronavirus Disease 2019 (COVID-19) has certainly provided new challenges in the management of acute ischaemic stroke, and the risk-benefit ratio of intravenous thrombolysis in COVID-19 positive patients is not well known. We describe four COVID-19 patients treated with intravenous thrombolysis for acute ischaemic stroke. Although rt-PA administration is the main therapeutic strategy, our patients experienced unpredictable complications and showed atypical features: the overall mortality was very high. In conclusion, in this article, we provide information about these cases and discuss the possible explanation behind this trend.
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http://dx.doi.org/10.1007/s10072-020-04591-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354364PMC
September 2020

Hand Grip Strength May Affect the Association Between Anticholinergic Burden and Mortality Among Older Patients Discharged from Hospital.

Drugs Aging 2020 06;37(6):447-455

Unit of Geriatric Pharmacoepidemiology and Biostatistics, Scientific Research Institute-Italian National Research Center on Aging (IRCCS INRCA), Ancona and Cosenza, Italy.

Background And Objective: The relationship between anticholinergic burden and mortality is unclear, and the impact of anticholinergic burden on prognosis may vary in the presence of other conditions common in old age. We aimed to investigate the role of hand grip strength as a potential effect modifier in the association between anticholinergic burden and 1-year mortality in older patients discharged from hospital.

Methods: Our series consisted of 620 older patients consecutively admitted to seven geriatric and internal medicine acute care wards in the context of a prospective multicenter observational study. Overall anticholinergic burden was assessed by Anticholinergic Cognitive Burden (ACB) score. Hand grip strength was assessed by the use of a North Coast medical hand dynamometer and categorized by using sex-specific cut-offs (women < 15 kg, men < 20 kg). The study outcome was 1-year mortality. Statistical analysis was performed by Cox regression analysis.

Results: After adjusting for potential confounders, the co-occurrence of an ACB score of 2 or more and low hand grip strength was significantly associated with mortality (hazard ratio [HR] = 2.30, 95% confidence interval [CI] 1.07-6.01). Stratified analysis confirmed that an ACB score of 2 or more was associated with mortality among patients with low (HR = 2.15, 95% CI 1.08-5.02), but not normal hand grip strength (HR = 0.88, 95% CI 0.13-3.52). The association was confirmed among patients with low hand grip strength after adjusting for the ACB score at the 3-month follow-up (HR = 2.20; 95% CI 1.09-4.87), as well as when considering the ACB score as a continuous variable (HR = 1.24, 95% CI 1.03-1.48).

Conclusions: The ACB score at discharge may predict mortality among older patients discharged from an acute care hospital with low hand grip strength. Hospital physicians should be aware that prescribing anticholinergic medications in such a vulnerable population may have negative prognostic implications.
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http://dx.doi.org/10.1007/s40266-020-00766-xDOI Listing
June 2020

Ferulic Acid Esters and Withanolides: In Search of Withania somnifera GABA Receptor Modulators.

J Nat Prod 2019 05 18;82(5):1250-1257. Epub 2019 Apr 18.

National Research Council (CNR) , Institute of Neuroscience , 09042 Monserrato , Italy.

Nine compounds, including two undescribed withanolides, withasomniferolides A and B (1 and 2), three known withanolides (3-5), a ferulic acid dimeric ester (6), and an inseparable mixture of three long alkyl chain ferulic acid esters (7-9), were isolated from a GABA receptor positive activator methanol extract of the roots of Withania somnifera. The structures of the isolated compounds were elucidated based on NMR, MS, and ECD data analysis. In order to bioassay the single ferulic acid derivatives, compounds 6-9 were also synthesized. The most active compound, docosanyl ferulate (9), was able to enhance the GABA receptor inhibitory postsynaptic currents with an IC value of 7.9 μM. These results, by showing an ability to modulate the GABA receptor function, cast fresh light on the biological activities of the secondary metabolites of W. somnifera roots.
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http://dx.doi.org/10.1021/acs.jnatprod.8b01023DOI Listing
May 2019

Dachshund Depletion Disrupts Mammary Gland Development and Diverts the Composition of the Mammary Gland Progenitor Pool.

Stem Cell Reports 2019 01 13;12(1):135-151. Epub 2018 Dec 13.

Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637551, Singapore. Electronic address:

DACH1 abundance is reduced in human malignancies, including breast cancer. Herein DACH1 was detected among multipotent fetal mammary stem cells in the embryo, among mixed lineage precursors, and in adult basal cells and (ERα) luminal progenitors. Dach1 gene deletion at 6 weeks in transgenic mice reduced ductal branching, reduced the proportion of mammary basal cells (Lin CD24 CD29) and reduced abundance of basal cytokeratin 5, whereas DACH1 overexpression induced ductal branching, increased Gata3 and Notch1, and expanded mammosphere formation in LA-7 breast cells. Mammary gland-transforming growth factor β (TGF-β) activity, known to reduce ductal branching and to reduce the basal cell population, increased upon Dach1 deletion, associated with increased SMAD phosphorylation. Association of the scaffold protein Smad anchor for receptor activation with Smad2/3, which facilitates TGF-β activation, was reduced by endogenous DACH1. DACH1 increases basal cells, enhances ductal formation and restrains TGF-β activity in vivo.
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http://dx.doi.org/10.1016/j.stemcr.2018.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335505PMC
January 2019

Correction to: Interstitial cells of Cajal increased in patients with rectal prolapse.

Int J Colorectal Dis 2018 09;33(9):1317

Department of Biomedicine and Prevention, Anatomic Pathology Section, University of Rome Tor Vergata, Rome, Italy.

The authors of the published version of this article missed to add the second affiliation of Mostafa Shalaby. The new affiliation is now added and presented correctly in this article. The remainder of the article remains unchanged.
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http://dx.doi.org/10.1007/s00384-018-3134-3DOI Listing
September 2018

Prevalence and variability of use of home mechanical ventilators, positive airway pressure and oxygen devices in the Lombardy region, Italy.

Monaldi Arch Chest Dis 2018 01 29;88(1):882. Epub 2018 Jan 29.

Istituti Clinici Scientifici Maugeri.

Few studies have analyzed the prevalence and accessibility of home mechanical ventilation (HMV) in Italy. We aimed to investigate the prevalence and prescription variability of HMV as well as of long-term oxygen therapy (LTOT) and continuous positive airway pressure (CPAP), in the Lombardy Region. Prescribing rates of HMV (both noninvasive and tracheostomies), CPAP (auto-CPAP, CPAP/other sleep machines) and LTOT (liquid-O2, O2-gas, concentrators) in the 15 Local Healthcare districts of Lombardy were gathered from billing data for 2012 and compared. Crude rates (per 100,000 population) and rates for the different healthcare districts were calculated. In 2012, 6325 patients were on HMV (crude prescription rate: 63/100,000) with a high variation across districts (8/100,000 in Milano 1 vs 150/100,000 in Pavia). There were 14,237 patients on CPAP (crude prescription rate: 142/100,000; CPAP/other sleep machines 95.3% vs auto-CPAP 4.7%) with also high intra-regional variation (56/100,000 in Mantova vs. 260/100,000 in Pavia). There were 21,826 patients on LTOT (prescription rate: 217/100,000 rate; liquid-O2 94%, O2-gas 2.08%, O2-concentrators 3.8%), with again high intra-regional variation (100/100,000 in Bergamo vs 410/100,000 in Valle Camonica). The crude rate of HMV prescriptions in Lombardy is very high, with a high intra-regional variability in prescribing HMV, LTOT and CPAP which is partly explainable by the accessibility to specialist centers with HMV/sleep-study facilities. Analysis of administrative data and variability mapping can help identify areas of reduced access for an improved standardization of services. An audit among Health Payer and prescribers to interpret the described huge variability could be welcomed.
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http://dx.doi.org/10.4081/monaldi.2018.882DOI Listing
January 2018

Binding of high mobility group A proteins to the mammalian genome occurs as a function of AT-content.

PLoS Genet 2017 12 21;13(12):e1007102. Epub 2017 Dec 21.

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

Genomic location can inform on potential function and recruitment signals for chromatin-associated proteins. High mobility group (Hmg) proteins are of similar size as histones with Hmga1 and Hmga2 being particularly abundant in replicating normal tissues and in cancerous cells. While several roles for Hmga proteins have been proposed we lack a comprehensive description of their genomic location as a function of chromatin, DNA sequence and functional domains. Here we report such a characterization in mouse embryonic stem cells in which we introduce biotin-tagged constructs of wild-type and DNA-binding domain mutants. Comparative analysis of the genome-wide distribution of Hmga proteins reveals pervasive binding, a feature that critically depends on a functional DNA-binding domain and which is shared by both Hmga proteins. Assessment of the underlying queues instructive for this binding modality identifies AT richness, defined as high frequency of A or T bases, as the major criterion for local binding. Additionally, we show that other chromatin states such as those linked to cis-regulatory regions have little impact on Hmga binding both in stem and differentiated cells. As a consequence, Hmga proteins are preferentially found at AT-rich regions such as constitutively heterochromatic regions but are absent from enhancers and promoters arguing for a limited role in regulating individual genes. In line with this model, we show that genetic deletion of Hmga proteins in stem cells causes limited transcriptional effects and that binding is conserved in neuronal progenitors. Overall our comparative study describing the in vivo binding modality of Hmga1 and Hmga2 identifies the proteins' preference for AT-rich DNA genome-wide and argues against a suggested function of Hmga at regulatory regions. Instead we discover pervasive binding with enrichment at regions of higher AT content irrespective of local variation in chromatin modifications.
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http://dx.doi.org/10.1371/journal.pgen.1007102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756049PMC
December 2017

Myopericytoma of the tongue base: A case report.

Acta Otorrinolaringol Esp 2018 Sep - Oct;69(5):304-305. Epub 2017 Oct 16.

Department of Otolaryngology and Head and Neck surgery, University of "Tor Vergata", Rome, Italy.

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http://dx.doi.org/10.1016/j.otorri.2017.06.010DOI Listing
April 2019

IL-13 and idiopathic pulmonary fibrosis: Possible links and new therapeutic strategies.

Pulm Pharmacol Ther 2017 08 10;45:95-100. Epub 2017 May 10.

Allergy and Respiratory Diseases, IRCCS San Martino-IST-University of Genoa, Italy.

The recent advances in the knowledge of immunological aspects of many pulmonary diseases, allowed to identify cells, biological functions, cytokines, and receptors that are preferentially involved in each disease. This is the case of asthma, where IL-13 (together with IL-4) is recognized as a central mediator. The role of IL-13 is strictly related, via complex signaling pathways, to eosinophil recruitment and activation, to mucus secretion, periostin generation and to fibrogenic processes (which are part of the remodeling process). These peculiar roles of IL-13 have suggested the hypothesis of its role in Idiopathic Pulmonary Fibrosis, and consequently of its antagonists in the treatment of such disease. We review herein the immunological roles of IL-13 in asthma and IPF, and the currently ongoing attempts to treat IPF by IL-13 antagonism strategies.
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http://dx.doi.org/10.1016/j.pupt.2017.05.007DOI Listing
August 2017

MCT1 in Invasive Ductal Carcinoma: Monocarboxylate Metabolism and Aggressive Breast Cancer.

Front Cell Dev Biol 2017 3;5:27. Epub 2017 Apr 3.

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson UniversityPhiladelphia, PA, USA.

Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lactate and pyruvate and a marker of mitochondrial metabolism. MCT1 is highly expressed in a subgroup of cancer cells to allow for catabolite uptake from the tumor microenvironment to support mitochondrial metabolism. We studied the protein expression of MCT1 in a broad group of breast invasive ductal carcinoma specimens to determine its association with breast cancer subtypes and outcomes. MCT1 expression was evaluated by immunohistochemistry on tissue micro-arrays (TMA) obtained through our tumor bank. Two hundred and fifty-seven cases were analyzed: 180 cases were estrogen receptor and/or progesterone receptor positive (ER+ and/or PR+), 62 cases were human epidermal growth factor receptor 2 positive (HER2+), and 56 cases were triple negative breast cancers (TNBC). MCT1 expression was quantified by digital pathology with Aperio software. The intensity of the staining was measured on a continuous scale (0-black to 255-bright white) using a co-localization algorithm. Statistical analysis was performed using a linear mixed model. High MCT1 expression was more commonly found in TNBC compared to ER+ and/or PR+ and compared to HER-2+ ( < 0.001). Tumors with an component were less likely to stain strongly for MCT1 ( < 0.05). High nuclear grade was associated with higher MCT1 staining ( < 0.01). Higher T stage tumors were noted to have a higher expression of MCT1 ( < 0.05). High MCT1 staining in cancer cells was associated with shorter progression free survival, increased risk of recurrence, and larger size independent of TNBC status ( < 0.05). MCT1 expression, which is a marker of high catabolite uptake and mitochondrial metabolism, is associated with recurrence in breast invasive ductal carcinoma. MCT1 expression as quantified with digital image analysis may be useful as a prognostic biomarker and to design clinical trials using MCT1 inhibitors.
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http://dx.doi.org/10.3389/fcell.2017.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376582PMC
April 2017

Emerging prognostic markers related to mesenchymal characteristics of poorly differentiated breast cancers.

Tumour Biol 2016 Apr 12;37(4):5427-35. Epub 2015 Nov 12.

Anatomic Pathology Section, Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.

Despite the screening program, breast cancer is the commonest cause of cancer death in women in the industrialized world. In this study, we investigate the correlation among poorly differentiated carcinoma, epithelial to mesenchymal transition (EMT) phenomenon, and expression of NF-kB, Sonic Hedgehog (SHH), K-RAS, and PTX3 in breast cancer in 100 breast biopsies. Samples were classified as follows: 30 benign lesions (BL), 30 ductal infiltrating carcinomas low grade (MLG1), and 40 ductal infiltrating carcinomas high grade (MLG3). Expression of vimentin, CD44, β-catenin, NF-kB, SHH, K-RAS, CD44, and PTX3 was studied by immunohistochemistry. The different rate of cells with vimentin, nuclear β-catenin, and CD44 expression in MLG3 as compared with MLG1 and BL suggested that the process of de-differentiation of breast cancer cells could be related to the EMT. Our results showed a significant increase in NF-kB signal in MLG3 (2.33 ± 0.77) with respect to MLG1 (1.26 ± 0.55) and BL (0.86 ± 0.52). SHH expression appeared low in BL (1.00 ± 0.41) and homogenously widespread in MLG1 (1.23 ± 0.63) and MLG3 (1.56 ± 0.54). An important increase in K-RAS signal was observed in MLG3 compared to that in BL (2.20 ± 0.69 vs 0.82 ± 0.59). As regards PTX3, we observed a strong expression in MLG3 (2.00 ± 0.78) with respect to BL (0.58 ± 0.55) and MLG1 (1.53 ± 0.76). The recurring expression of NF-kB, SHH, K-RAS, and PTX3 in vimentin- and CD44-positive breast cancer cells allows to speculate that breast cells acquire the ability to express these molecules in concomitance to EMT phenomenon.
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http://dx.doi.org/10.1007/s13277-015-4361-7DOI Listing
April 2016

Interstitial cells of Cajal increased in patients with rectal prolapse.

Int J Colorectal Dis 2016 May 2;31(5):1069-1070. Epub 2015 Oct 2.

Department of Biomedicine and Prevention, Anatomic Pathology Section, University of Rome Tor Vergata, Rome, Italy.

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http://dx.doi.org/10.1007/s00384-015-2386-4DOI Listing
May 2016

Idiopathic Ventricular Tachycardia: Transcatheter Ablation or Antiarrhythmic Drugs?

J Atr Fibrillation 2015 Feb-Mar;7(5):1164. Epub 2015 Feb 28.

Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino, IRCCS, Department of Cardiovascular Sciences, University of Milan, Milan, Italy.

Introduction: Ventricular tachycardia or frequent premature ventricular contractions (PVCs) can occur in the absence of any detectable structural heart disease. In this clinical setting, these arrhythmias are termed idiopathic. Usually, they carry a benign prognosis and any potential ablative intervention is carried out if patients are highly symptomatic or, more importantly, if frequent ventricular arrhythmias can lead to ventricular dysfunction.

Methods: In this paper, different forms of idiopathic ventricular tachycardia are reviewed. Outflow tract ventricular tachycardia from the right ventricle is the most frequent form of the so-called idiopathic ventricular tachycardia. Other forms of idiopathic ventricular arrhythmias include ventricular tachycardia/PVCs arising from tricuspid annulus, from the mitral annulus, inter-fascicular ventricular tachycardia and papillary muscle ventricular tachycardia. When interventional treatment is deemed necessary, detailed mapping ( earliest activation during VT/PVC, pace mapping ) is crucial as to identify the successful ablation site. Catheter ablation more than antiarrhythmic drug treatment is usually highly effective in eliminating idiopathic ventricular arrhythmias and providing prevention of recurrence.

Conclusions: Idiopathic VTs are not considered life-threatening arrhythmias and, prevention of recurrences is often achieved by means of catheter ablation that provides an improvement of quality of life. The overall acute success rate of catheter ablation is about 85-90% with a long-term prevention of arrhythmia recurrence of about 75-80%. It is advisable that the procedure is carried out by electrophysiologists with expertise in VT catheter ablation and extensive knowledge of cardiac anatomy as to ensure a high success rate and reduce the likelihood of major complications.
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http://dx.doi.org/10.4022/jafib.1164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135213PMC
February 2015

Prevention of respiratory infections in tracheostomized patients of a pediatric long-term rehabilitation setting.

Am J Infect Control 2015 Apr 8;43(4):394-6. Epub 2015 Feb 8.

Severe Acquired Brain Injury Unit, Scientific Institute IRCCS Eugenio Medea, Lecco, Italy.

Clinical practice protocols for the control and prevention of respiratory infections in rehabilitation settings, especially regarding pediatric tracheostomized patients, are currently lacking. To tackle this issue, we conducted a systematization of our clinical management protocols, aiming at defining a decisional algorithm and describing its key points in more detail. We focused on infection control, improvement of respiratory functions, and weaning from tracheostomy.
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http://dx.doi.org/10.1016/j.ajic.2014.12.015DOI Listing
April 2015

Electrophysiological efficacy of temperature-controlled bipolar radiofrequency.

Eur J Cardiothorac Surg 2015 May 1;47(5):e188-92; discussion e192. Epub 2015 Feb 1.

Department of Cardiothoracic Surgery, San Raffaele University Hospital, Milan, Italy.

Objective: Clinical success of atrial fibrillation (AF) ablation depends on persistent block of electrical conduction across the ablation lines. The fate of ablations performed with temperature-controlled bipolar radiofrequency (RF) is unknown. The purpose of this study was to validate the electrophysiological (EP) efficacy of these lesions, recording pulmonary vein isolation (PVI) after open chest ablation, in the human being.

Methods: Ten consecutive mitral patients (mean age: 53 ± 12 years) with concomitant AF were treated with the Cobra Revolution (Estech, San Ramon, CA, USA) bipolar RF device were enrolled for EP assessment. During surgery, pairs of additional temporary wires were positioned on the right PVs (RPV) and on the roof of the left atrium (RLA), before ablation. Pacing thresholds (PTs) were assessed before, after a single encircling ablation and at chest's closure. EP study was repeated before discharge and at 3 weeks. RLA wires served as control.

Results: Baseline PTs were 0.83 ± 0.81 mA (range 0.2-3 mA) from RPV and 1.13 ± 0.78 mA (range 0.3-3 mA) from RLA. PVI was reached in all patients acutely, and was maintained at 1 week. At 3 weeks, the PTs were 14.3 ± 4.3 mA from RPV (range 7-20 mA) and 3.1 ± 1.3 mA (range 1.5-7 mA) from RLA. All patients were discharged in sinus rhythm.

Conclusions: Cobra Revolution temperature-controlled bipolar RF provides complete PVI after a single ablation up to 1 week. This notwithstanding, only 30% of patients were completely isolated (exit block validation) at 3 weeks.
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http://dx.doi.org/10.1093/ejcts/ezv016DOI Listing
May 2015

Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation.

Nature 2015 Apr 21;520(7546):243-7. Epub 2015 Jan 21.

1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Faculty of Sciences, Petersplatz 1, CH-4001 Basel, Switzerland.

DNA methylation is an epigenetic modification associated with transcriptional repression of promoters and is essential for mammalian development. Establishment of DNA methylation is mediated by the de novo DNA methyltransferases DNMT3A and DNMT3B, whereas DNMT1 ensures maintenance of methylation through replication. Absence of these enzymes is lethal, and somatic mutations in these genes have been associated with several human diseases. How genomic DNA methylation patterns are regulated remains poorly understood, as the mechanisms that guide recruitment and activity of DNMTs in vivo are largely unknown. To gain insights into this matter we determined genomic binding and site-specific activity of the mammalian de novo DNA methyltransferases DNMT3A and DNMT3B. We show that both enzymes localize to methylated, CpG-dense regions in mouse stem cells, yet are excluded from active promoters and enhancers. By specifically measuring sites of de novo methylation, we observe that enzymatic activity reflects binding. De novo methylation increases with CpG density, yet is excluded from nucleosomes. Notably, we observed selective binding of DNMT3B to the bodies of transcribed genes, which leads to their preferential methylation. This targeting to transcribed sequences requires SETD2-mediated methylation of lysine 36 on histone H3 and a functional PWWP domain of DNMT3B. Together these findings reveal how sequence and chromatin cues guide de novo methyltransferase activity to ensure methylome integrity.
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http://dx.doi.org/10.1038/nature14176DOI Listing
April 2015

The Growing Culture Of A Minimally Fluoroscopic Approach In Electrophysiology Lab.

J Atr Fibrillation 2014 Aug-Sep;7(2):1104. Epub 2014 Aug 31.

CardiacArrhythmia Research Centre, Centro CardiologicoMonzino IRCCS, Milan, Italy.

Most of interventional procedures in cardiology are carried out under fluoroscopic imaging guidance. Besides other peri-interventional risks, radiation exposure should be considered for its stochastic (inducing malignancy) and deterministic effects on health (tissue reactions like erythema, hair loss and cataracts). In this article we analized the radiation risk from cardiovascular imaging to both patients and medical staff and discusses how customize the X-ray system and how to implement shielding measures in the cath lab. Finally, we reviewed the most recent developments and the latest findings in catheter navigation and 3D electronatomical mapping systems that may help to reduce patient and operator exposure.
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http://dx.doi.org/10.4022/jafib.1104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135258PMC
August 2014

Simultaneous assessment of contact pressure and local electrical coupling index using robotic navigation.

J Interv Card Electrophysiol 2014 Jun 16;40(1):23-31. Epub 2014 Mar 16.

Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino IRCCS, Via Parea 4, 20138, Milan, Italy.

Purpose: Contact with cardiac tissue is a determinant of lesion efficacy during atrial fibrillation (AF) ablation. The Sensei®X Robotic Catheter System (Hansen Medical, CA) has been validated for contact force sensing. The electrical coupling index (ECI) from the EnSite Contact™ system (St. Jude Medical, MN) has been validated as an indicator of tissue contact. We aimed at analyzing ECI behavior during radiofrequency (RF) pulses maintaining a stable contact through the robotic navigation contact system.

Methods: In 15 patients (age, 59 ± 12) undergoing AF ablation, pulmonary vein (PV) isolation was guided by the Sensei®X System, employing the Contact™ catheter.

Results: During the procedure, we assessed ECI changes associated with adequate contact based on the IntelliSense® force-sensing technology (Hansen Medical, CA. Baseline contact (27 ± 8 g/cm(2)) ECI value was 99 ± 13, whereas ECI values in a noncontact site (0 g/cm(2)) and in a light contact site (1-10 g/cm(2)) were respectively 66 ± 12 and 77 ± 10 (p < 0.0001). Baseline contact ECI values were not different depending on AF presentation (paroxysmal AF, 98 ± 9; persistent AF, 100 ± 9) or on cardiac rhythm (sinus rhythm, 97 ± 7; AF,101 ± 10). In all PVs, ECI was significantly reduced during and after ablation (ECI during RF, 56 ± 15; ECI after RF, 72 ± 16; p < 0.001). A mean reduction of 32.2% during RF delivery and 25.4% immediately after RF discontinuation compared with baseline ECI was observed.

Conclusions: Successful PV isolation is associated with a significant decrease in ECI of at least 20 %. This may be used as a surrogate marker of effective lesion in AF ablation.
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http://dx.doi.org/10.1007/s10840-014-9882-2DOI Listing
June 2014