Publications by authors named "Andrea Baiocchini"

33 Publications

Intraoperative Perfusion Assessment in Enhanced Reality Using Quantitative Optical Imaging: An Experimental Study in a Pancreatic Partial Ischemia Model.

Diagnostics (Basel) 2021 Jan 8;11(1). Epub 2021 Jan 8.

Research Institute against Digestive Cancer (IRCAD), 67000 Strasbourg, France.

To reduce the risk of pancreatic fistula after pancreatectomy, a satisfactory blood flow at the pancreatic stump is considered crucial. Our group has developed and validated a real-time computational imaging analysis of tissue perfusion, using fluorescence imaging, the fluorescence-based enhanced reality (FLER). Hyperspectral imaging (HSI) is another emerging technology, which provides tissue-specific spectral signatures, allowing for perfusion quantification. Both imaging modalities were employed to estimate perfusion in a porcine model of partial pancreatic ischemia. Perfusion quantification was assessed using the metrics of both imaging modalities (slope of the time to reach maximum fluorescence intensity and tissue oxygen saturation (StO2), for FLER and HSI, respectively). We found that the HSI-StO2 and the FLER slope were statistically correlated using the Spearman analysis (R = 0.697; = 0.013). Local capillary lactate values were statistically correlated to the HSI-StO2 and to the FLER slope (R = -0.88; < 0.001 and R = -0.608; = 0.0074). HSI-based and FLER-based lactate prediction models had statistically similar predictive abilities ( = 0.112). Both modalities are promising to assess real-time pancreatic perfusion. Clinical translation in human pancreatic surgery is currently underway.
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http://dx.doi.org/10.3390/diagnostics11010093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826658PMC
January 2021

A Novel Technique to Improve Anastomotic Perfusion Prior to Esophageal Surgery: Hybrid Ischemic Preconditioning of the Stomach. Preclinical Efficacy Proof in a Porcine Survival Model.

Cancers (Basel) 2020 Oct 14;12(10). Epub 2020 Oct 14.

Research Institute against Digestive Cancer (IRCAD), 67000 Strasbourg, France.

Esophagectomy often presents anastomotic leaks (AL), due to tenuous perfusion of gastric conduit fundus (GCF). Hybrid (endovascular/surgical) ischemic gastric preconditioning (IGP), might improve GCF perfusion. Sixteen pigs undergoing IGP were randomized: (1) Max-IGP ( = 6): embolization of left gastric artery (LGA), right gastric artery (RGA), left gastroepiploic artery (LGEA), and laparoscopic division (LapD) of short gastric arteries (SGA); (2) Min-IGP ( = 5): LGA-embolization, SGA-LapD; (3) Sham ( = 5): angiography, laparoscopy. At day 21 gastric tubulation occurred and GCF perfusion was assessed as: (A) Serosal-tissue-oxygenation (StO) by hyperspectral-imaging; (B) Serosal time-to-peak (TTP) by fluorescence-imaging; (C) Mucosal functional-capillary-density-area (FCD-A) index by confocal-laser-endomicroscopy. Local capillary lactates (LCL) were sampled. Neovascularization was assessed (histology/immunohistochemistry). Sham presented lower StO and FCD-A index (41 ± 10.6%; 0.03 ± 0.03 respectively) than min-IGP (66.2 ± 10.2%, -value = 0.004; 0.22 ± 0.02, -value < 0.0001 respectively) and max-IGP (63.8 ± 9.4%, -value = 0.006; 0.2 ± 0.02, -value < 0.0001 respectively). Sham had higher LCL (9.6 ± 4.8 mL/mol) than min-IGP (4 ± 3.1, -value = 0.04) and max-IGP (3.4 ± 1.5, -value = 0.02). For StO, FCD-A, LCL, max- and min-IGP did not differ. Sham had higher TTP (24.4 ± 4.9 s) than max-IGP (10 ± 1.5 s, -value = 0.0008) and min-IGP (14 ± 1.7 s, non-significant). Max- and min-IGP did not differ. Neovascularization was confirmed in both IGP groups. Hybrid IGP improves GCF perfusion, potentially reducing post-esophagectomy AL.
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http://dx.doi.org/10.3390/cancers12102977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602144PMC
October 2020

Hyperspectral evaluation of hepatic oxygenation in a model of total vs. arterial liver ischaemia.

Sci Rep 2020 09 22;10(1):15441. Epub 2020 Sep 22.

Institute of Physiology, EA3072 Mitochondria Respiration and Oxidative Stress, University of Strasbourg, Strasbourg, France.

Liver ischaemia reperfusion injury (IRI) is a dreaded pathophysiological complication which may lead to an impaired liver function. The level of oxygen hypoperfusion affects the level of cellular damage during the reperfusion phase. Consequently, intraoperative localisation and quantification of oxygen impairment would help in the early detection of liver ischaemia. To date, there is no real-time, non-invasive, and intraoperative tool which can compute an organ oxygenation map, quantify and discriminate different types of vascular occlusions intraoperatively. Hyperspectral imaging (HSI) is a non-invasive optical methodology which can quantify tissue oxygenation and which has recently been applied to the medical field. A hyperspectral camera detects the relative reflectance of a tissue in the range of 500 to 1000 nm, allowing the quantification of organic compounds such as oxygenated and deoxygenated haemoglobin at different depths. Here, we show the first comparative study of liver oxygenation by means of HSI quantification in a model of total vascular inflow occlusion (VIO) vs. hepatic artery occlusion (HAO), correlating optical properties with capillary lactate and histopathological evaluation. We found that liver HSI could discriminate between VIO and HAO. These results were confirmed via cross-validation of HSI which detected and quantified intestinal congestion in VIO. A significant correlation between the near-infrared spectra and capillary lactate was found (r = - 0.8645, p = 0.0003 VIO, r = - 0.7113, p = 0.0120 HAO). Finally, a statistically significant negative correlation was found between the histology score and the near-infrared parameter index (NIR) (r = - 0.88, p = 0.004). We infer that HSI, by predicting capillary lactates and the histopathological score, would be a suitable non-invasive tool for intraoperative liver perfusion assessment.
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http://dx.doi.org/10.1038/s41598-020-72915-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509803PMC
September 2020

Publisher Correction: Liver sinusoidal endothelial cells (LSECs) modifications in patients with chronic hepatitis C.

Sci Rep 2020 Jan 24;10(1):1420. Epub 2020 Jan 24.

Laboratory of Electron Microscopy, Department of Epidemiology and Preclinical Research National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-58227-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981110PMC
January 2020

Rescue of Replication-Competent ZIKV Hidden in Placenta-Derived Mesenchymal Cells Long After the Resolution of the Infection.

Open Forum Infect Dis 2019 Oct 9;6(10):ofz342. Epub 2019 Oct 9.

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

The Zika virus (ZIKV) genome, its negative-strand viral proteins, and virus-like particles were detected in placenta-derived mesenchymal cells (MSCs), indicating that ZIKV persists after virus clearance from maternal blood and can be rescued by in vitro cultivation. We report for the first time the presence of replication-competent ZIKV in MSCs from an asymptomatic woman who acquired infection during pregnancy.
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http://dx.doi.org/10.1093/ofid/ofz342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785694PMC
October 2019

Liver sinusoidal endothelial cells (LSECs) modifications in patients with chronic hepatitis C.

Sci Rep 2019 06 19;9(1):8760. Epub 2019 Jun 19.

Laboratory of Electron Microscopy, Department of Epidemiology and Preclinical Research National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy.

The sinusoidal endothelial cells present in the liver (LSECs) are tipically characterized by the presence of pores (fenestrae). During some pathological conditions LSECs undergo "capillarization", a process characterized by loss of fenestrations and acquisition of a vascular phenotype. In chronic liver disease capillarization has been reported to precede the development of fibrosis. LSECs modification in the setting of HCV infection is currently poorly investigated. Considering that HCV accounts for important changes in hepatocytes and in view of the intimate connection between hepatocytes and LSECs, here we set out to study in great detail the LSECs modifications in individuals with HCV-dependent chronic hepatitis. Electron microscopy analysis, and evaluation of CD32, CD31 and caveolin-1 expression showed that in HCV infection LSECs display major morphological changes but maintain their phenotypical identity. Capillarization was observed only in cases at initial stages of fibrosis. Our findings showed that the severity of LSECs modifications appears to be correlated with hepatocytes damage and fibrosis stage providing novel insight in the pathogenesis of HCV-chronic hepatitis.
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http://dx.doi.org/10.1038/s41598-019-45114-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584733PMC
June 2019

Alpha, Beta, gamma human PapillomaViruses (HPV) detection with a different sets of primers in oropharyngeal swabs, anal and cervical samples.

Virol J 2019 03 4;16(1):27. Epub 2019 Mar 4.

Laboratory of Virology, "Lazzaro Spallanzani" National Institute for Infectious Diseases, IRCCS, Via Portuense, 292, 00149, Rome, Italy.

Background: Recent studies have shown a 13-fold increase of oropharyngeal cancer in the presence of HPV, while α-HPV detection seems to be rare in oral cavity in comparison to anal or cervical district, many novel β and γ types have been isolated in this anatomical site suggesting a wide tropism range. Currently, there are no guidelines recommending HPV oral cavity screening as a mandatory test, and it remains unknown which HPV types should be included in HPV screening programs. Our goal was to assess HPV prevalence in oropharyngeal, anal, and cervical swabs using different sets of primers,which are able to amplify α, β, γ HPV types.

Methods: We analysed the presence of HPV DNA in oropharyngeal (n = 124), anal (n = 186), cervical specimens (n = 43) from HIV positive and negative patients using FAP59/64 and MY09/11 primers. All untyped strains were genetically characterized through PCR amplification and direct sequencing of partial L1 region, and the resulting sequences were classified through phylogenetic analysis.

Results: HPV prevalence was 20.9% in 124 oropharyngeal swab samples, including infections with multiple HPV types (5.6%). HPV prevalence in this anatomical site was significantly associated with serostatus: 63.3%in HIV positive and 36.3% in HIV negative patients (p < 0.05). Unclassified types were detected in 6 specimens. In our analysis, we did not observe any difference in HPV (α, β, γ) prevalence between men and women. Overall, β species were the most frequently detected 69.7%. When using anal swabs, for HIV positive patients, β genus prevalence was 1% and γ genus was 3.7% including 6 unclassified types. In cervical samples from 43 HIV positive women (18 HPV negative and 25 positive by MY09/11 PCR), only one sample was positivite for β species (2.4%) using FAP primers. Six of the untyped strains clustered with sequences from species 7, 9, 10, 8,12 of γ genus. Four sequences remained unclassified. Finally, β and γ HPV prevalence was significantly lower than their respective HPV prevalence as identified by the Luminex system in all anatomical sites that were analyzed in previous studies.

Conclusion: This study provides new information about viral isolates present in oropharyngeal site and it will contribute to improve the monitoring of HPV infection.
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http://dx.doi.org/10.1186/s12985-019-1132-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398256PMC
March 2019

Interplay of DDP4 and IP-10 as a Potential Mechanism for Cell Recruitment to Tuberculosis Lesions.

Front Immunol 2018 5;9:1456. Epub 2018 Jul 5.

Center for Vaccine Research, Statens Serum Institut, Copenhagen, Denmark.

Introduction: is one of the world's most successful pathogens equipped to establish itself within the human host as a subclinical infection without overt disease. Unable to eradicate the bacteria, the immune system contains the infection in a granuloma structure. Th1 cells that are essential for infection control are recruited to the site of infection directed by chemokines, predominantly CXCL10. It has previously been shown that CXCL10 in the plasma of patients chronically infected with hepatitis C virus is present primarily in an antagonist form. This is due to N-terminal truncation by the enzyme DPP4, which results in the antagonist form that is capable of binding its receptor CXCR3, but does not induce signaling. We aimed to explore whether such CXCL10 antagonism may have an impact on the pathogenesis of tuberculosis (TB).

Results: We measured plasma levels of agonist and antagonist CXCL10 by Simoa digital ELISA, as well as DPP4 enzyme activity in the plasma of 20 patients with active TB infection, 10 patients with pneumonia infection, and a group of 10 healthy controls. We found higher levels of total and antagonist CXCL10 and reduced DPP4 enzyme activity in the plasma of TB patients compared to controls. We traced the source of CXCL10 secretion using immunohistochemical and confocal analysis to multinucleated giant cells in the TB lesions, and variable expression by macrophages. Interestingly, these cells were associated with DPP4-positive T cells. Moreover, the analysis of lymphocytes at the site of TB infection (bronchoalveolar lavage) showed a reduced frequency of CXCR3 T cells.

Interpretation: Our data suggests that CXCL10 antagonism may be an important regulatory mechanism occurring at the site of TB pathology. CXCL10 can be inactivated shortly after secretion by membrane bound DPP4 (CD26), therefore, reducing its chemotactic potential. Given the importance of Th1 cell functions and IFN-γ-mediated effects in TB, our data suggest a possible unappreciated regulatory role of DPP4 in TB.

Perspectives: DPP4 is the target for a class of enzyme inhibitors used in the treatment of diabetes, and the results from this study suggest that these drugs could be repurposed as an adjunct immunotherapy of patients with TB and MDR-TB.
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http://dx.doi.org/10.3389/fimmu.2018.01456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041415PMC
July 2018

Combining Genetic Variants to Improve Risk Prediction for NAFLD and Its Progression to Cirrhosis: A Proof of Concept Study.

Can J Gastroenterol Hepatol 2018 14;2018:7564835. Epub 2018 Mar 14.

Internal Medicine, Geriatrics, and Hepatology Unit, University Campus Bio-Medico, Rome, Italy.

Background & Aims: Identifying NAFLD patients at risk of progression is crucial to orient medical care and resources. We aimed to verify if the effects determined by different single nucleotide polymorphisms (SNPs) could add up to multiply the risk of NAFLD and NASH-cirrhosis.

Methods: Three study populations, that is, patients diagnosed with NASH-cirrhosis or with noncirrhotic NAFLD and healthy controls, were enrolled. PNPLA3 rs738409, TM6SF2 rs58542926, KLF6 rs3750861, SOD2 rs4880, and LPIN1 rs13412852 were genotyped.

Results: One hundred and seven NASH-cirrhotics, 93 noncirrhotic NAFLD, and 90 controls were enrolled. At least one difference in allele frequency between groups was significant, or nearly significant, for the PNPLA3, TM6SF2, and KLF6 variants ( < 0.001, < 0.05, and = 0.06, resp.), and a risk score based on these SNPs was generated. No differences were observed for SOD2 and LPIN1 SNPs. When compared to a score of 0, a score of 1-2 quadrupled, and a score of 3-4 increased 20-fold the risk of noncirrhotic NAFLD; a score of 3-4 quadrupled the risk of NASH-cirrhosis.

Conclusions: The effects determined by disease-associated variants at different can add up to multiply the risk of NAFLD and NASH-cirrhosis. Combining different disease-associated variants may represent the way for genetics to keep strength in NAFLD diagnostics.
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http://dx.doi.org/10.1155/2018/7564835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872672PMC
March 2019

Non-alcoholic fatty liver disease severity is modulated by transglutaminase type 2.

Cell Death Dis 2018 02 15;9(3):257. Epub 2018 Feb 15.

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

Non-alcoholic fatty liver disease (NAFLD) is one of the most important liver diseases worldwide. Currently, no effective treatment is available, and NAFLD pathogenesis is incompletely understood. Transglutaminase type 2 (TG2) is a ubiquitous enzyme whose dysregulation is implicated in the pathogenesis of various human diseases. Here we examined the impact of TG2 on NAFLD progression using the high-fat-diet-induced model in both wild-type and TG2-deficient mice. Animals were fed with a standard chow diet or a high-fat diet (42% of the energy from fat) for 16 weeks. Results demonstrated that the absence of a functional enzyme, which causes the impairment of autophagy/mitophagy, leads to worsening of disease progression. Data were confirmed by pharmacological inhibition of TG2 in WT animals. In addition, the analysis of human liver samples from NAFLD patients validated the enzyme's involvement in the liver fat disease pathogenesis. Our findings strongly suggest that TG2 activation may offer protection in the context of NAFLD, thus representing a novel therapeutic target for tackling the NAFLD progression.
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http://dx.doi.org/10.1038/s41419-018-0292-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833377PMC
February 2018

Oral human Papillomavirus DNA detection in HIV-positive men: prevalence, predictors, and co-occurrence at anal site.

BMC Infect Dis 2018 01 8;18(1):25. Epub 2018 Jan 8.

HIV/AIDS Unit, INMI "L.Spallanzani", Rome, Italy.

Background: HIV-positive patients carry an increased risk of HPV infection and associated cancers. Therefore, prevalence and patterns of HPV infection at different anatomical sites, as well as theoretical protection of nonavalent vaccine should be investigated. Aim was to describe prevalence and predictors of oral HPV detection in HIV-positive men, with attention to nonavalent vaccine-targeted HPV types. Further, co-occurrence of HPV DNA at oral cavity and at anal site was assessed.

Methods: This cross-sectional, clinic-based study included 305 HIV-positive males (85.9% MSM; median age 44.7 years; IQR: 37.4-51.0), consecutively observed within an anal cancer screening program, after written informed consent. Indication for anal screening was given by the HIV physician during routine clinic visit. Paired oral rinse and anal samples were processed for the all HPV genotypes with QIASYMPHONY and a PCR with MY09/MY11 primers for the L1 region.

Results: At the oral cavity, HPV DNA was detected in 64 patients (20.9%), and in 28.1% of these cases multiple HPV infections were found. Prevalence of oral HPV was significantly lower than that observed at the anal site (p < 0.001), where HPV DNA was found in 199 cases (85.2%). Oral HPV tended to be more frequent in patients with detectable anal HPV than in those without (p = 0.08). Out of 265 HPV DNA-positive men regardless anatomic site, 59 cases (19.3%) had detectable HPV at both sites, and 51 of these showed completely different HPV types. At least one nonavalent vaccine-targeted HPV type was found in 17/64 (26.6%) of patients with oral and 199/260 (76.5%) with anal infection. At multivariable analysis, factors associated with positive oral HPV were: CD4 cells <200/μL (versus CD4 cells >200/μL, p = 0.005) and >5 sexual partners in the previous 12 months (versus 0-1 partner, p = 0.008).

Conclusions: In this study on Italian HIV-positive men (predominantly MSM), oral HPV DNA was detected in approximately one fifth of tested subjects, but prevalence was significantly lower than that observed at anal site. Low CD4 cell count and increasing number of recent sexual partners significantly increased the odds of positive oral HPV. The absence of co-occurrence at the two anatomical sites may suggest different routes or timing of infection.
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http://dx.doi.org/10.1186/s12879-017-2937-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759194PMC
January 2018

Postmortem diagnosis of sepsis: A preliminary immunohistochemical study with an anti-procalcitonin antibody.

Leg Med (Tokyo) 2017 09 13;28:1-5. Epub 2017 Jul 13.

Department of Anatomy, Histology Forensic Medicine and Orthopaedics, Sapienza University of Rome, Viale Regina Elena 336, Rome 00185, Italy.

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http://dx.doi.org/10.1016/j.legalmed.2017.07.002DOI Listing
September 2017

Case report: human papilloma virus type 120-related papillomatosis mimicking laryngeal carcinoma.

Infection 2017 Oct 22;45(5):709-713. Epub 2017 May 22.

Department of Surgical Biotechnologies and Sciences, ENT Section, "Sapienza" University of Rome, Latina, Italy.

Introduction: The relationship between human papilloma virus (HPV) and upper respiratory tract pathology was better understood in recent years and represents now an issue of particular interest in carcinogenesis and in immunocompromised host. We describe a case in which a rare genotype HPV-related papillomatosis mimics laryngeal carcinoma in an immunocompromised host.

Methods: A 54-year-old woman with a history of HIV-HCV coinfection and anal and laryngeal cancer successfully treated some years before was hospitalized for severe dyspnea, cough and dysphagia. Fiberoptic endoscopic evaluation raised the suspicion of tumor relapse showing the presence of a large glottic-supraglottic ulcerated mass. Several laryngeal biopsies demonstrated koilocytosis and p16 expression, according to a possible HPV infection, and focal figures of mild dysplasia of epithelium. 18 F-FDG PET/CT did not show high glycolytic activity at laryngeal level. An invasive upper respiratory tract papillomatosis in an immunocompromised host was suspected because of the patient's clinical improvement after antiretroviral therapy.

Conclusion: Pharyngeal swab and oral rinse harboured the same HPV120 genotype sequence, a betapapillomavirus of recent description and not yet related to any similar clinical presentations.
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http://dx.doi.org/10.1007/s15010-017-1028-xDOI Listing
October 2017

Simple and Reliable Method to Quantify the Hepatitis B Viral Load and Replicative Capacity in Liver Tissue and Blood Leukocytes.

Hepat Mon 2016 Oct 29;16(10):e28751. Epub 2016 Feb 29.

Laboratory of Virology, Marche Polytechnic University, Ancona, Italy.

Background: A functional cure of chronic hepatitis B (CHB) is feasible, but a clear view of the intrahepatic viral dynamics in each patient is needed. Intrahepatic covalently closed circular DNA (cccDNA) is the stable form of the viral genome in infected cells, and represents the ideal marker of parenchymal colonization. Its relationships with easily accessible peripheral parameters need to be elucidated in order to avoid invasive procedures in patients.

Objectives: The goal of this study was to design, set up, and validate a reliable and straightforward method for the quantification of the cccDNA and total DNA of the hepatitis B virus (HBV) in a variety of clinical samples.

Patients And Methods: Clinical samples from a cohort of CHB patients, including liver biopsies in some, were collected for the analysis of intracellular HBV molecular markers using novel molecular assays.

Results: A plasmid construct, including sequences from the HBV genome and from the human gene hTERT, was generated as an isomolar multi-standard for HBV quantitation and normalization to the cellular contents. The specificity of the real-time assay for the cccDNA was assessed using Dane particles isolated on a density gradient. A comparison of liver tissue from 6 untreated and 6 treated patients showed that the treatment deeply reduced the replicative capacity (total DNA/cccDNA), but had limited impact on the parenchymal colonization. The peripheral blood mononuclear cells (PBMCs) and granulocytes from the treated and untreated patients were also analyzed.

Conclusions: A straightforward method for the quantification of intracellular HBV molecular parameters in clinical samples was developed and validated. The widespread use of such versatile assays could better define the prognosis of CHB, and allow a more rational approach to time-limited tailored treatment strategies.
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http://dx.doi.org/10.5812/hepatmon.28751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111393PMC
October 2016

Patients with Tuberculosis Have a Dysfunctional Circulating B-Cell Compartment, Which Normalizes following Successful Treatment.

PLoS Pathog 2016 06 15;12(6):e1005687. Epub 2016 Jun 15.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

B-cells not only produce immunoglobulins and present antigens to T-cells, but also additional key roles in the immune system. Current knowledge on the role of B-cells in infections caused by intracellular bacteria is fragmentary and contradictory. We therefore analysed the phenotypical and functional properties of B-cells during infection and disease caused by Mycobacterium tuberculosis (Mtb), the bacillus causing tuberculosis (TB), and included individuals with latent TB infection (LTBI), active TB, individuals treated successfully for TB, and healthy controls. Patients with active or treated TB disease had an increased proportion of antibodies reactive with mycobacteria. Patients with active TB had reduced circulating B-cell frequencies, whereas only minor increases in B-cells were detected in the lungs of individuals deceased from TB. Both active TB patients and individuals with LTBI had increased relative fractions of B-cells with an atypical phenotype. Importantly, these B-cells displayed impaired proliferation, immunoglobulin- and cytokine- production. These defects disappeared upon successful treatment. Moreover, T-cell activity was strongest in individuals successfully treated for TB, compared to active TB patients and LTBI subjects, and was dependent on the presence of functionally competent B-cells as shown by cellular depletion experiments. Thus, our results reveal that general B-cell function is impaired during active TB and LTBI, and that this B-cell dysfunction compromises cellular host immunity during Mtb infection. These new insights may provide novel strategies for correcting Mtb infection-induced immune dysfunction towards restored protective immunity.
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http://dx.doi.org/10.1371/journal.ppat.1005687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909319PMC
June 2016

Extracellular Matrix Molecular Remodeling in Human Liver Fibrosis Evolution.

PLoS One 2016 21;11(3):e0151736. Epub 2016 Mar 21.

National Institute for Infectious Diseases L. Spallanzani, IRCCS, via Portuense 292, 00149 Rome, Italy.

Chronic liver damage leads to pathological accumulation of ECM proteins (liver fibrosis). Comprehensive characterization of the human ECM molecular composition is essential for gaining insights into the mechanisms of liver disease. To date, studies of ECM remodeling in human liver diseases have been hampered by the unavailability of purified ECM. Here, we developed a decellularization method to purify ECM scaffolds from human liver tissues. Histological and electron microscopy analyses demonstrated that the ECM scaffolds, devoid of plasma and cellular components, preserved the three-dimensional ECM structure and zonal distribution of ECM components. This method has been then applied on 57 liver biopsies of HCV-infected patients at different stages of liver fibrosis according to METAVIR classification. Label-free nLC-MS/MS proteomics and computation biology were performed to analyze the ECM molecular composition in liver fibrosis progression, thus unveiling protein expression signatures specific for the HCV-related liver fibrotic stages. In particular, the ECM molecular composition of liver fibrosis was found to involve dynamic changes in matrix stiffness, flexibility and density related to the dysregulation of predominant collagen, elastic fibers and minor components with both structural and signaling properties. This study contributes to the understanding of the molecular bases underlying ECM remodeling in liver fibrosis and suggests new molecular targets for fibrolytic strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151736PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801190PMC
August 2016

An anal cancer screening program for MSM in Italy: Prevalence of multiple HPV types and vaccine-targeted infections.

J Clin Virol 2015 Nov 11;72:49-54. Epub 2015 Sep 11.

Clinical Department, INMI "L. Spallanzani", Rome, Italy. Electronic address:

Background: Elevated HPV infection rates have been described in HIV-positive males, placing these subjects at high risk of anal neoplasia. Bivalent, quadrivalent, and nonavalent vaccines to prevent HPV infection have been developed, and recently proposed for gender-neutral immunization programs.

Objectives: In order to estimate the benefit that could be obtained by vaccination of HIV-positive men who have sex with men (MSM), we aimed at describing the frequency of multiple and vaccine-targeted HPV infections in MSM enrolled in an anal cancer screening program.

Study Design: The anal cancer screening program was conducted between July 2009 and October 2012. Mucosal anal samples were tested for HPV DNA using MY09/MY11 PCR primers and, if positive, genotyped using the CLART2HPV Clinical Array (35HPV types).

Results: A total of 220 MSM were screened and 88.6% were positive for HPV DNA: in 86.5% at least one high-risk (HR) type was found and in 13% only low-risk (LR) HPV were found. Multiple infections accounted for 84.5% of HPV DNA-positive cases and overall 160 different HPV genotype combinations were recognized (only three combinations were detected in more than one patient each). Based on strain coverage, at least one vaccine-targeted HPV type was found in 38.9%, 64%, and 78.4% of cases when considering bivalent, quadrivalent and nonavalent vaccines, respectively. At least one HR vaccine-targeted strain was found in 39% of MSM for bivalent and quadrivalent vaccines, and in 64% of cases for nonavalent prevention.

Conclusions: Anal HPV infections in unvaccinated mostly HIV-infected MSM are highly prevalent. The majority of this population has multiple infections with an extremely heterogeneous number of genotype combinations. The nonavalent vaccine could theoretically have prevented a minimum of one HR HPV type in two thirds of subjects.
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http://dx.doi.org/10.1016/j.jcv.2015.09.001DOI Listing
November 2015

Unusual case of B cell lymphoma after immunosuppressive treatment for psoriasis.

World J Hepatol 2015 Apr;7(5):814-8

Lorenzo Nosotti, Concetta Mirisola, Gastrointestinal and Liver Department, National Institute for Health, Migration and Poverty, 00153 Rome, Italy.

Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis, such as ciclosporin, methotrexate and tumour necrosis factor (TNF)-α blockers. The biologic agents currently used in psoriasis include alefacept, efalizumab, and the TNF-α antagonists etanercept, infliximab, and adalimumab. Infections and cancer are the main possible consequences of intended or unexpected immunosuppression. We report a 59-year-old man with a history of severe psoriasis vulgaris treated with traditional immunosuppressant drugs followed by anti-TNF-α therapy; the patient was firstly hospitalized for an acute cholestatic toxic hepatitis, which we supposed to be related to adalimumab. The first liver biopsy showed active disease with severe hepatocellular damage caused by heavy lymphocytes infiltrate in portal tracts at in the interface with a not conclusive diagnosis of lymphoproliferative disease. The correct diagnosis of T cell/histiocyte- rich large B cell lymphoma (T/HRBCL) was only reached through a gastric biopsy and a second liver biopsy. T/HRBCL is an uncommon morphologic variant of diffuse large B-cell lymphoma not described until now in psoriatic patients receiving immunosuppressive biologic agents. In psoriatic patients, treated with biologic immunosuppressive agents, the suspect of abdominal lymphoma should always be included as differential diagnosis. Abdominal ultrasound evaluation need therefore to be included in the pre-treatment screening as in the follow-up surveillance.
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http://dx.doi.org/10.4254/wjh.v7.i5.814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404387PMC
April 2015

The "delivery" of Adam: a medical interpretation of Michelangelo.

Mayo Clin Proc 2015 Apr;90(4):505-8

2nd Infectious Diseases Division, National Institute for Infectious Diseases, "Lazzaro Spallanzani," Rome, Italy.

This article describes what we believe to be the key to interpreting the concept represented by Michelangelo's painting the Creation of Adam. This fresco, one of his most famous masterpieces, is situated in the heart of the Sistine Chapel and is viewed by millions of people every year. A man of many talents, Michelangelo's proficiency in anatomical dissection is reflected in his artwork. As such, analyses of hidden meanings in this fresco have been ascribed, including the concept of the "Brain-God." However, we see a postpartum uterus and adjacent anatomy, justifying our interpretation that Michelangelo was depicting something far more fundamental: the birth of mankind.
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http://dx.doi.org/10.1016/j.mayocp.2015.02.007DOI Listing
April 2015

Communication between Human Dendritic Cell Subsets in Tuberculosis: Requirements for Naive CD4(+) T Cell Stimulation.

Front Immunol 2014 14;5:324. Epub 2014 Jul 14.

Department of Immunology, Max Planck Institute for Infection Biology , Berlin , Germany.

Human primary dendritic cells (DCs) are heterogeneous by phenotype, function, and tissue localization and distinct from inflammatory monocyte-derived DCs. Current information regarding the susceptibility and functional role of primary human DC subsets to Mycobacterium tuberculosis (Mtb) infection is limited. Here, we dissect the response of different primary DC subsets to Mtb infection. Myeloid CD11c(+) cells and pDCs (C-type lectin 4C(+) cells) were located in human lymph nodes (LNs) of tuberculosis (TB) patients by histochemistry. Rare CD141(hi) DCs (C-type lectin 9A(+) cells) were also identified. Infection with live Mtb revealed a higher responsiveness of myeloid CD1c(+) DCs compared to CD141(hi) DCs and pDCs. CD1c(+) DCs produced interleukin (IL)-6, tumor necrosis factor α, and IL-1β but not IL-12p70, a cytokine important for Th1 activation and host defenses against Mtb. Yet, CD1c(+) DCs were able to activate autologous naïve CD4(+) T cells. By combining cell purification with fluorescence-activated cell sorting and gene expression profiling on rare cell populations, we detected in responding CD4(+) T cells, genes related to effector-cytolytic functions and transcription factors associated with Th1, Th17, and Treg polarization, suggesting multifunctional properties in our experimental conditions. Finally, immunohistologic analyses revealed contact between CD11c(+) cells and pDCs in LNs of TB patients and in vitro data suggest that cooperation between Mtb-infected CD1c(+) DCs and pDCs favors stimulation of CD4(+) T cells.
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http://dx.doi.org/10.3389/fimmu.2014.00324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094910PMC
July 2014

Incomplete septal cirrhosis after high-dose methylprednisolone therapy and regression of liver injury.

Liver Int 2015 Feb 25;35(2):674-6. Epub 2014 Jun 25.

Second Infectious Diseases Division, INMI 'L.Spallanzani', Rome, 00149, Italy.

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http://dx.doi.org/10.1111/liv.12607DOI Listing
February 2015

Spike-in SILAC proteomic approach reveals the vitronectin as an early molecular signature of liver fibrosis in hepatitis C infections with hepatic iron overload.

Proteomics 2014 May;14(9):1107-15

Department of Cellular Biotechnologies and Haematology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy; "L. Spallanzani" National Institute for Infectious Diseases, IRCCS, Rome, Italy.

Hepatitis C virus (HCV)-induced iron overload has been shown to promote liver fibrosis, steatosis, and hepatocellular carcinoma. The zonal-restricted histological distribution of pathological iron deposits has hampered the attempt to perform large-scale in vivo molecular investigations on the comorbidity between iron and HCV. Diagnostic and prognostic markers are not yet available to assess iron overload-induced liver fibrogenesis and progression in HCV infections. Here, by means of Spike-in SILAC proteomic approach, we first unveiled a specific membrane protein expression signature of HCV cell cultures in the presence of iron overload. Computational analysis of proteomic dataset highlighted the hepatocytic vitronectin expression as the most promising specific biomarker for iron-associated fibrogenesis in HCV infections. Next, the robustness of our in vitro findings was challenged in human liver biopsies by immunohistochemistry and yielded two major results: (i) hepatocytic vitronectin expression is associated to liver fibrogenesis in HCV-infected patients with iron overload; (ii) hepatic vitronectin expression was found to discriminate also the transition between mild to moderate fibrosis in HCV-infected patients without iron overload.
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http://dx.doi.org/10.1002/pmic.201300422DOI Listing
May 2014

Brain localization of Kaposi's sarcoma in a patient treated by combination antiretroviral therapy.

BMC Infect Dis 2013 Dec 21;13:600. Epub 2013 Dec 21.

Clinical Department, National Institute for Infectious Diseases "L, Spallanzani" IRCCS, Via Portuense 292, 00149 Rome, Italy.

Background: Central nervous system is a very rare site of Kaposi's sarcoma in acquired immunodeficiency syndrome. Kaposi's sarcoma, a neoplasm of endothelial origin, occurs mainly in the skin, but can involve many tissues, especially in patients with a poor immunity. Combination antiretroviral therapy, highly active against human immunodeficiency virus type-1, has caused a dramatic reduction of cutaneous and visceral involvements. No report of central nervous system localization of Kaposi's sarcoma is described since the introduction of combination antiretroviral therapy in the late 90's.

Case Presentation: A 42 year-old Caucasian man affected by human immunodeficiency virus type-1 infection treated with combination antiretroviral therapy and showing relatively preserved immunity with low viral load presented gingival squamous cell carcinoma and visceral (lungs and lymph nodes) Kaposi's sarcoma. Chemotherapy and radiotherapy were performed with improvement of both neoplasms. Afterwards, a magnetic resonance imaging showed focal lesions of the brain. Despite new chemotherapy and radiotherapy the patient died. Histology after autopsy revealed brain lesions due to Kaposi's sarcoma with the detection of Human Herpesvirus 8 on tissue samples.

Conclusions: This is the first report in the combination antiretroviral therapy era of a very rare complication of Kaposi's sarcoma, such as that of brain localization, in a patient with a relatively good control of human immunodeficiency virus infection. Therefore, Kaposi's sarcoma should be considered in differential diagnosis with other intracranial mass lesions that can occur in human immunodeficiency virus infected-patients focusing the issue of appropriate treatment for central nervous system involvement.
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http://dx.doi.org/10.1186/1471-2334-13-600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878088PMC
December 2013

Acute hepatitis associated with clopidogrel: a case report and review of the literature.

Am J Ther 2015 Jan-Feb;22(1):e8-e13

1Hepatology Unit; and 2Anatomopathology Unit, National Institute for Infectious Diseases "L. Spallanzani," Rome, Italy.

Drug-induced hepatotoxicity is a common cause of acute hepatitis, and the recognition of the responsible drug may be difficult. We describe a case of clopidogrel-related acute hepatitis. The diagnosis is strongly suggested by an accurate medical history and liver biopsy. Reports about cases of hepatotoxicity due to clopidogrel are increasing in the last few years, after the increased use of this drug. In conclusion, we believe that physicians should carefully consider the risk of drug-induced hepatic injury when clopidogrel is prescribed.
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http://dx.doi.org/10.1097/MJT.0b013e318293b0d6DOI Listing
September 2015

Comparison of the Abbott RealTime High Risk HPV with Genomica HPV Clinical Array for the detection of human papillomavirus DNA.

APMIS 2013 Nov 11;121(11):1054-63. Epub 2013 Feb 11.

Laboratory of Virology.

Human papillomavirus (HPV) has been identified as the major cause of cervical cancer worldwide and HPV DNA testing is recommended in primary cervical cancer screening. Several molecular tests for detection/typing of HPV DNA with different sensitivity and specificity are commercially available. The present study compared the performance of the Abbott RealTime High Risk HPV assay and the Genomica HPV Clinical Array CLART2 in 78 specimens (63 cervical smears and 15 rectal/urethral swabs).The typing results of the Genomica assay were in absolute agreement with each of the four possible result categories of the Abbott assay (HPV16, HPV18, Other HR HPV, not detected) in 87.2% (68/78) of the samples, with a Cohen' kappa agreement coefficient for every HR type of 0.62 (95% CI: 0.39-0.85), higher in cervical swabs (k = 0.74, 95% CI: 0.50-0.99) than in rectal/urethral swabs (k = 0.36, 95% CI: 0.00-0.82). There was an excellent agreement of the Genomica results with those of Abbott in cervical samples harbored HPV single infection (100% agreement). Nonetheless, both methods may lose sensitivity for detecting HPV types in multiple infections, giving discordant results (10/78). This underlines the importance of establishing the analytical sensitivity in HPV type detection in single and multiple HPV infections. In rectal/urethral swabs, 5 of 15 (33%) discordant cases were observed, most of which became compatible when the Genomica assay was performed starting from nucleic acid extracted with the Abbott m2000sp system. These results suggest that nucleic extraction based on the magnetic beads technique is suitable for HPV DNA detection in urethral/rectal swabs.
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http://dx.doi.org/10.1111/apm.12054DOI Listing
November 2013

Pulmonary disease due to kayexalate aspiration.

Am J Med Sci 2013 Feb;345(2):149

Clinical Department, Hematology, National Institute for Infectious Diseases Lazzaro Spallanzani, Rome, Italy.

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http://dx.doi.org/10.1097/MAJ.0b013e31824d16bcDOI Listing
February 2013

Frequency and multiplicity of human papillomavirus infection in HIV-1 positive women in Italy.

J Clin Virol 2012 Jun 20;54(2):141-6. Epub 2012 Mar 20.

Laboratory of Virology, L. Spallanzani National Institute for Infectious Diseases, Rome, Italy.

Background: Natural history of HPV infection is altered in HIV positive women, with increased risk of cervical dysplasia. Limited data are available about the influence of HPV genotypes and HPV multiple infections on cervical disease in HIV positive women.

Objectives: We determined HPV genotype prevalence in cervical samples from 553 HIV-infected women attending the gynaecological service at "L. Spallanzani" Hospital. Association of HPV multiple infections with cervical abnormalities was investigated.

Study Design: MY09/MY11 consensus primers were used to detect HPV-DNA; HPV typing was performed by RFLP. A commercial array based kit was used to define unresolved RFLP patterns.

Results: HPV was detected in 244/553 (44.1%) patients, correlating with low CD4 counts (p<0.001) and age (p=0.001). Multiple HPV types were observed in 44.4% of cases, more frequently involving HR than LR HPV (OR=12.8, p<0.00001). Multiple HPV infections were associated with low CD4 counts (OR=3.8 in CD4<200 vs CD4≥500 cells/mm(3)). Dyskaryosis was associated with decreased CD4 counts (≥500 vs 200-499 vs <200 cells/mm(3), χ(2) for trend, p=0.001) and with HPV types multiplicity (1 vs 2-3 vs ≥4, χ(2) for trend, p<0.00001). Notably, in 3 H-SIL cases only LR types were detected (HPV62, n=2; HPV81, n=1).

Conclusions: Multiple HPV infections, often involving HR types, are frequent in HIV-infected women. Association between multiple HPV infection, low CD4 count and cytological abnormalities supports the interplay of virological and immunological factors in cervical cancer pathogenesis. Assessment of multiple HPV infections might gain importance in cervical cancer screening, particularly in patients with predisposing factors like immuno-suppression.
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http://dx.doi.org/10.1016/j.jcv.2012.02.013DOI Listing
June 2012

HIV-associated plasmablastic lymphoma diagnosed by fine-needle aspiration cytology.

Korean J Hematol 2011 Dec 27;46(4):214. Epub 2011 Dec 27.

Clinical Department, National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, Rome, Italy.

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http://dx.doi.org/10.5045/kjh.2011.46.4.214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259511PMC
December 2011