@article {10757, title = {Antibodies reacting to mimotopes of Simian virus 40 large T antigen, the viral oncoprotein, in sera from children.}, journal = {J Cell Physiol}, volume = {234}, year = {2019}, month = {2019 Apr}, pages = {3170-3179}, abstract = {

Recent data indicate that the Simian virus 40 (SV40) infection appears to be transmitted in humans independently from early SV40-contaminated antipolio vaccines. Serum antibodies against SV40 large T antigen (Tag) were analyzed in children/adolescents and young adults. To investigate antibodies reacting to SV40 Tag antigens, serum samples ( n = 812) from children and young adults were analyzed by indirect ELISAs using specific SV40 Tag mimotopes. Mimotopes were synthetic peptides corresponding to SV40 Tag epitopes. In sera ( n = 412) from healthy children up to 17 years old, IgG antibodies against SV40 Tag mimotopes reached an overall prevalence of 15\%. IgM antibodies against SV40 Tag were detected in sera of children 6-8 months old confirming and extending the knowledge that SV40 seroconversion occurs early in life. In children/adolescents affected by different diseases ( n = 180) SV40 Tag had a prevalence of 18\%, being the difference no significant compared to healthy subjects ( n = 220; 16\%) of the same age. Our immunological data indicate that SV40 circulates in children and young adults, both in healthy conditions and affected by distinct diseases. The IgM detection in sera from healthy children suggests that the SV40 infection/seroconversion occurs early in life (>6 months). Our immunological data support the hypothesis that SV40, or a closely related still unknown polyomavirus, infects humans. The SV40 seroprevalence is lower than common polyomaviruses, such as BKPyV and JCPyV, and other new human polyomaviruses. In addition, our immunological surveillance indicates a lack of association between different diseases, considered herein, and SV40.

}, issn = {1097-4652}, doi = {10.1002/jcp.27490}, author = {Mazzoni, Elisa and Frontini, Francesca and Rotondo, John Charles and Zanotta, Nunzia and Fioravanti, Arianna and Minelli, Francesca and Torreggiani, Elena and Campisciano, Giuseppina and Marcuzzi, Annalisa and Guerra, Giovanni and Tommasini, Alberto and Touz{\'e}, Antoine and Martini, Fernanda and Tognon, Mauro and Comar, Manola} } @article {10763, title = {Cervico-vaginal secretion cytokine profile: A non-invasive approach to study the endometrial receptivity in IVF cycles.}, journal = {Am J Reprod Immunol}, volume = {81}, year = {2019}, month = {2019 Jan}, pages = {e13064}, abstract = {

PROBLEM: Cytokines have a significant role in the process of embryo implantation, trophoblast growth, and differentiation by modulating the immune and endocrine system. The aim of this study was to investigate the profile of a large set of cytokines in the cervico-vaginal washing of women undergoing IVF, to explore the association of these proteins with a good receptive endometrium.

METHOD OF STUDY: A cohort of 155 women scheduled for IVF cycle was recruited. All patients were asymptomatic for genitourinary infections and had been screened for chlamydia, mycoplasma, and other bacterial infections. All IVF subjects were treated according to standard clinical and laboratory protocols. A panel of 48 immune factors was analyzed on cervico-vaginal washing, using magnetic bead-based multiplex immunoassays (Bio-Plex, BIO-RAD Laboratories, Milano, Italy).

RESULTS: A total of 99 patients reached embryo transfer, of which 31 had a clinical pregnancy. A pattern of four pro-inflammatory immune molecules, IL-12p40, IFN-a, MIF, and MCP3 (P~<~0.001), was found significantly up-regulated in the cervico-vaginal fluid of women with clinical pregnancy. A significantly increased expression of IL-9, Gro , and SDF-1 (P~<~0.05) was observed in the presence of endometriosis, while high levels of IL-13 and L-15 were associated with ovulatory infertility factor (P~<~0.05).

CONCLUSION: In this pilot study, we demonstrated that the expression of specific cytokines in the cervico-vaginal washing on the day of oocyte retrieval might have a positive correlation with the potential clinical pregnancy. Therefore, cervico-vaginal secretion cytokine profiling might be a new, non-invasive approach to study the endometrial receptivity in IVF management.

}, issn = {1600-0897}, doi = {10.1111/aji.13064}, author = {Zanotta, Nunzia and Monasta, Lorenzo and Skerk, Kristina and Luppi, Stefania and Martinelli, Monica and Ricci, Giuseppe and Comar, Manola} } @article {10781, title = {Four-miRNA Signature to Identify Asbestos-Related Lung Malignancies.}, journal = {Cancer Epidemiol Biomarkers Prev}, volume = {28}, year = {2019}, month = {2019 Jan}, pages = {119-126}, abstract = {

BACKGROUND: Altered miRNA expression is an early event upon exposure to occupational/environmental carcinogens; thus, identification of a novel asbestos-related profile of miRNAs able to distinguish asbestos-induced cancer from cancer with different etiology can be useful for diagnosis. We therefore performed a study to identify miRNAs associated with asbestos-induced malignancies.

METHODS: Four groups of patients were included in the study, including patients with asbestos-related (NSCLC) and asbestos-unrelated non-small cell lung cancer (NSCLC) or with malignant pleural mesothelioma (MPM), and disease-free subjects (CTRL). The selected miRNAs were evaluated in asbestos-exposed population.

RESULTS: Four serum miRNAs, that is miR-126, miR-205, miR-222, and miR-520g, were found to be implicated in asbestos-related malignant diseases. Notably, increased expression of miR-126 and miR-222 were found in asbestos-exposed subjects, and both miRNAs are involved in major pathways linked to cancer development. Epigenetic changes and cancer-stroma cross-talk could induce repression of miR-126 to facilitate tumor formation, angiogenesis, and invasion.

CONCLUSIONS: This study indicates that miRNAs are potentially involved in asbestos-related malignancies, and their expression outlines mechanism(s) whereby miRNAs may be involved in an asbestos-induced pathogenesis.

IMPACT: The discovery of a miRNA panel for asbestos-related malignancies would impact on occupational compensation and may be utilized for screening asbestos-exposed populations.

}, issn = {1538-7755}, doi = {10.1158/1055-9965.EPI-18-0453}, author = {Santarelli, Lory and Gaetani, Simona and Monaco, Federica and Bracci, Massimo and Valentino, Matteo and Amati, Monica and Rubini, Corrado and Sabbatini, Armando and Pasquini, Ernesto and Zanotta, Nunzia and Comar, Manola and Neuzil, Jiri and Tomasetti, Marco and Bovenzi, Massimo} } @article {10425, title = {Antibody response to polyomavirus primary infection: high seroprevalence of Merkel cell polyomavirus and lymphoid tissue involvement.}, journal = {J Neurovirol}, volume = {24}, year = {2018}, month = {2018 Jun}, pages = {314-322}, abstract = {

Human polyomaviruses (HPyVs) asymptomatically infect the human population establishing latency in the host, and their seroprevalence can reach 90\% in healthy adults. Few studies have focused on the pediatric population, and there are no reports regarding the seroprevalence of all the newly isolated HPyVs among Italian children. Therefore, we investigated the frequency of serum antibodies against 12 PyVs in 182 immunocompetent children from Northeast Italy, by means of a multiplex antibody detection system. Additionally, secondary lymphoid tissues were collected to analyze the presence of HPyV DNA sequences using a specific real-time PCRs or PCRs. Almost 100\% of subjects were seropositive for at least one PyV. Seropositivity ranged from 3\% for antibodies against simian virus 40 (SV40) in children from 0 to 3~years, to 91\% for antibodies against WU polyomavirus (WUPyV) and HPyV10 in children from 8 to 17~years. The mean number of PyV for which children were seropositive increased with the increasing of age: 4 standard deviations (SD) 1.8 in the 0-3-year group, 5 (SD 1.9) in the 4-7-year group, and 6 (SD 2.2) in the 8-17-year group. JC polyomavirus (JCPyV) DNA was detected in 1\% of the adenoids, WUPyV in 12\% of the tonsils, and 28\% of the adenoids, and Merkel cell polyomavirus (MCPyV) was present in 6 and 2\% of the tonsils and adenoids, respectively. Our study gives new insights on the serological evidence of exposure to PyVs during childhood, and on their possible respiratory route of transmission.

}, issn = {1538-2443}, doi = {10.1007/s13365-017-0612-2}, author = {Cason, Carolina and Monasta, Lorenzo and Zanotta, Nunzia and Campisciano, Giuseppina and Maestri, Iva and Tommasino, Massimo and Pawlita, Michael and Villani, Sonia and Comar, Manola and Delbue, Serena} } @article {10438, title = {Bariatric surgery drives major rearrangements of the intestinal microbiota including the biofilm composition.}, journal = {Front Biosci (Elite Ed)}, volume = {10}, year = {2018}, month = {2018 06 01}, pages = {495-505}, abstract = {

The intestinal microbiota disequilibrium has been associated with obesity, while the role of the gut mucosal biofilms in this pathology is still unknown. We analysed the changes in the intestinal microbiota of obese patients after bariatric surgery with the aim of disclosing the rearrangement of the biofilm configuration. Although the bariatric surgery drives major rearrangements of the gut microbiota, obese patients maintain the enterotype before and after surgery, as shown by normal weight patients, with an increase of and . The enterotype guarantees the strong ability to form a biofilm which allows a more efficient digestion of polysaccharides than planktonic communities and leads to the production of acetate which is a key player to inhibit enteropathogens. Additionally, the laparoscopic gastric bypass induces an increase of , a facultative anaerobic bacterium involved in intestinal and inflammatory disorders. Bariatric surgery influences the microbial composition of gut biofilm. Further studies are needed to elucidate the impact of this variation on recovery after surgery and on weight loss.

}, keywords = {Biofilms, Case-Control Studies, Gastric Bypass, Gastrointestinal Microbiome, Humans, Intestinal Mucosa, Obesity, Prospective Studies}, issn = {1945-0508}, author = {Campisciano, Giuseppina and Cason, Carolina and Palmisano, Silvia and Giuricin, Michela and Rizzardi, Alessia and Croce, Lory Saveria and De Manzini, Nicolo and Comar, Manola} } @article {10418, title = {Cerebrospinal Fluid Cytokine Expression Profile in Multiple Sclerosis and Chronic Inflammatory Demyelinating Polyneuropathy.}, journal = {Immunol Invest}, volume = {47}, year = {2018}, month = {2018 Feb}, pages = {135-145}, abstract = {

BACKGROUND: Cerebrospinal fluid (CSF) analysis in patients with particular neurologic disorders is a powerful tool to evaluate specific central nervous system inflammatory markers for diagnostic needs, because CSF represents the specific immune micro-environment to the central nervous system.

METHODS: CSF samples from 49 patients with multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), and non-inflammatory neurologic disorders (NIND) as controls were submitted to protein expression profiles of 47 inflammatory biomarkers by multiplex Luminex bead assay to investigate possible differences in the inflammatory process for MS and CIDP.

RESULTS: Our results showed differences in CSF cytokine levels in MS and CIDP; in particular, IL12 (p40) was significantly highly expressed in MS in comparison with CIDP and NIND, while SDF-1α and SCGF-β were significantly highly expressed in CIDP cohort when compared to MS and NIND. IL-9, IL-13, and IL-17 had higher expression levels in NIND if compared with the other groups.

CONCLUSIONS: Our study showed that, despite some common pathogenic mechanisms, central and peripheral nervous system demyelinating diseases, such as MS and CIDP, differ in some specific inflammatory soluble proteins in CSF, underlining differences in the immune response involved in those autoimmune diseases.

}, keywords = {Adult, Aged, Biomarkers, Central Nervous System, Diagnosis, Differential, Female, Hematopoietic Cell Growth Factors, Humans, Interleukin-12, Lectins, C-Type, Male, Middle Aged, Multiple Sclerosis, Peripheral Nervous System, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Proteins}, issn = {1532-4311}, doi = {10.1080/08820139.2017.1405978}, author = {Bonin, Serena and Zanotta, Nunzia and Sartori, Arianna and Bratina, Alessio and Manganotti, Paolo and Trevisan, Giusto and Comar, Manola} } @article {10445, title = {Cytokine profiles of women with vulvodynia: Identification of a panel of pro-inflammatory molecular targets.}, journal = {Eur J Obstet Gynecol Reprod Biol}, volume = {226}, year = {2018}, month = {2018 Jul}, pages = {66-70}, abstract = {

OBJECTIVE: The vulvar pain syndrome (VPS) is a multifactorial disease severely influencing the lifestyle of affected women. Among possible etiological factors, local injury, peripheral and/or central sensitization of the nervous system, and a chronic inflammatory status have been positively associated with the development of VPS. The identification of a constitutive altered local inflammatory profile in VPS women may represent an important point in the characterization of patients{\textquoteright} phenotype as a useful marker influencing the vulvar micro-environment. The aim of this study was to investigative the possible role of the local cytokines production in women with VPS in comparison to healthy women.

STUDY DESIGN: In this study were collected vaginal swabs from 57 healthy women (HC) who never suffered from VPS and from 30 patients diagnosed with vulvodynia (VPS) by at least 3 years and currently symptomatic. All patients included in this study showed the absence of Sexually Transmitted (STD) diseases and Reproductive Tract Infection. Real-time PCR was performed to assess the genomic sequences of ST pathogens. The Luminex Bio-Plex platform was used for the analysis of a panel of 48 immune factors.

RESULTS: Eleven molecules, specifically involved in the pro-inflammatory pathway were significantly modulated in VPS patients in comparison to healthy women, suggesting a persistent inflammatory process.

CONCLUSIONS: Therefore, these inflammatory factors could be possible biological markers involved in this disease. Nevertheless, other studies are needed to consider this specific immune profile as a valid marker of the vulvodynia.

}, keywords = {Adult, Aged, Cytokines, Female, Humans, Inflammation, Middle Aged, Vaginal Smears, Vulva, Vulvodynia, Women{\textquoteright}s Health}, issn = {1872-7654}, doi = {10.1016/j.ejogrb.2018.05.035}, author = {Zanotta, Nunzia and Campisciano, Giuseppina and Scrimin, Federica and Blendi, Ura and Marcuzzi, Annalisa and Vincenti, Ezio and Crovella, Sergio and Comar, Manola} } @article {10782, title = {Fractional CO laser for genitourinary syndrome of menopause in breast cancer survivors: clinical, immunological, and microbiological aspects.}, journal = {Lasers Med Sci}, volume = {33}, year = {2018}, month = {2018 Jul}, pages = {1047-1054}, abstract = {

The composition of vaginal microbiome in menopause and cancer survivor women changes dramatically leading to genitourinary syndrome of menopause (GSM) in up to 70\% of patients. Recent reports suggest that laser therapy may be valuable as a not hormonal therapeutic modality. The aim of the present study was to evaluate the effects of fractional CO laser treatment on the vaginal secretory pathway of a large panel of immune mediators, usually implicated in tissue remodeling and inflammation, and on microbiome composition in postmenopausal breast cancer survivors. The Ion Torrent PGM platform and the Luminex Bio-Plex platform were used for microbiome and immune factor analysis. The significant reduction of clinical symptoms and the non-significant changes in vaginal microbiome support the efficacy and safety of laser treatment. Moreover, the high remodeling status in vaginal epithelium is demonstrated by the significant changes in inflammatory and modulatory cytokine patterns. Laser therapy can be used for the treatment of GSM symptoms and does not show any adverse effects. However, further studies will be needed to clarify its long-term efficacy and other effects.

}, keywords = {Breast Neoplasms, Cancer Survivors, Cytokines, Dyspareunia, Female, Humans, Lasers, Gas, Menopause, Microbiota, Middle Aged, Prospective Studies, Syndrome, Vagina, Vaginal Diseases}, issn = {1435-604X}, doi = {10.1007/s10103-018-2471-3}, author = {Becorpi, Angelamaria and Campisciano, Giuseppina and Zanotta, Nunzia and Tredici, Zelinda and Guaschino, Secondo and Petraglia, Felice and Pieralli, Annalisa and Sisti, Giovanni and De Seta, Francesco and Comar, Manola} } @article {10799, title = {In vivo microbiome and associated immune markers: New insights into the pathogenesis of vaginal dysbiosis.}, journal = {Sci Rep}, volume = {8}, year = {2018}, month = {2018 02 02}, pages = {2307}, abstract = {

The microbiota fulfils a key role in the training and function of the immune system, which contributes to the symbiosis between the host and complex microbial communities. In this study, we characterized the interplay between vaginal bacteria and local immune mediators during dysbiosis in selected women of reproductive age who were grouped according to Nugent{\textquoteright}s criteria. The abundance of Gardnerella vaginalis and Bifidobacterium breve was increased in the intermediate dysbiotic status, while the presence of a plethora of non-resident bacteria characterized the group with overt vaginosis. In response to these increases, the anti-inflammatory IL1ra and pro-inflammatory IL2 increased, while the embryo trophic factors FGFβ and GMCSF decreased compared to the healthy milieu. A specific pattern, including IL1α, IL1β, IL8, MIG, MIP1α and RANTES, distinguished the intermediate group from the vaginosis group, while IL5 and IL13, which are secreted by Th2 cells, were significantly associated with the perturbation of the commensals Lactobacilli, Gardnerella and Ureaplasma. Summarizing, we postulate that although the dysbiotic condition triggers a pro-inflammatory process, the presence of a steady state level of Th2 may influence clinical manifestations. These results raise clinically relevant questions regarding the use of vaginal immunological markers as efficacious tools to monitor microbial alterations.

}, keywords = {Adult, Biomarkers, Cytokines, Dysbiosis, Female, Humans, Microbiota, Th2 Cells, Vagina}, issn = {2045-2322}, doi = {10.1038/s41598-018-20649-x}, author = {Campisciano, Giuseppina and Zanotta, Nunzia and Licastro, Danilo and De Seta, Francesco and Comar, Manola} } @article {10847, title = {Serum Stem Cell Growth Factor Beta for the Prediction of Therapy Response in Hepatocellular Carcinoma.}, journal = {Biomed Res Int}, volume = {2018}, year = {2018}, month = {2018}, pages = {6435482}, abstract = {

Introduction: Chronic inflammatory response is one of major contributors in the development of hepatocellular carcinoma (HCC). Inflammatory molecules, such as cytokines and growth factors in the circulation, can be useful in the diagnosis and prognosis of the patients. The stem cell growth factor beta (SCGF), a newly found protein, is a secreted sulfated glycoprotein and it functions as a growth factor for primitive hematopoietic progenitor cells. The level of SCGF had been reported to be elevated in several cancer types. However, there is very few or even no information on this protein in the study of HCC, even more in clinical studies.

Methods: A multiplex immunoassay panel of 48 cytokines and growth factors were utilized to screen 68 sera from 29 HCC patients at pretreatment (T0), 1 month (T1), and 6 months (T6) after treatment by either radiofrequency ablation (RF) or transarterial chemoembolization (TACE). Treatment response was evaluated according to mRECIST criteria.

Results: Immunoassay screening showed that the levels of IL-17, CTACK, TNF, IL-2R, IL-8, and SCGF were different in Complete Responders (CR) and Nonresponders (NR) groups. At T0 and T1, the SCGF level was significantly the highest in NR (23.8 and 40.7 ng/mL, respectively), followed by early recurrence (25.4 and 25.0 ng/mL), and CR (6.7 and 5.3 ng/mL), independently from HCV, stages, and treatment type. Low basal SCGF level was associated with longer disease-free survival compared to high SCGF.

Conclusion: In this study, for the first time, we demonstrate that the high level of serum SCGF at pre- and posttreatment is associated with HCC nonresponsiveness.

}, keywords = {Aged, Carcinoma, Hepatocellular, Chemoembolization, Therapeutic, Female, Hematopoietic Cell Growth Factors, Humans, Liver Neoplasms, Male, Middle Aged, Neoplasm Recurrence, Local, Retrospective Studies, Stem Cells, Treatment Outcome}, issn = {2314-6141}, doi = {10.1155/2018/6435482}, author = {Sukowati, Caecilia H C and Patti, Riccardo and Pascut, Devis and Ladju, Rusdina B and Tarchi, Paola and Zanotta, Nunzia and Comar, Manola and Tiribelli, Claudio and Croc{\`e}, Lory S} } @article {10439, title = {Vaginal microbiota dysmicrobism and role of biofilm-forming bacteria.}, journal = {Front Biosci (Elite Ed)}, volume = {10}, year = {2018}, month = {2018 06 01}, pages = {528-536}, abstract = {

Bacterial vaginosis involves the presence of a polymicrobial biofilm on the vaginal epithelium, guaranteeing immune escape and spread of antibiotic resistance. To spot known biofilm-forming bacteria, we profiled the vaginal microbiome of sixty-four symptomatic women suffering from a different grade of vaginal disorders and sixty asymptomatic healthy women. Specific microbial profiles distinguished symptomatic from asymptomatic women and characterized the grade of dysmicrobism within the symptomatic group. Lactobacillus crispatus and iners predominated on the healthy vaginal mucosa, while Lactobacillus gasseri predominated in the intermediate dysmicrobism. Furthermore, the intermediate grade of dysmicrobism was characterized by other lactic acid-producers species than Lactobacilli, able to rescue the microbial imbalance, and Ureaplasma parvum-serovar 3. The vaginosis group exhibited the overgrowth of Prevotella bivia, which is known to enhance the biofilm formation by Gardnerella vaginalis, and the presence of Streptococcus anginosus, which is emerging as a new cooperating player of the vaginal biofilm. Identifying specific microorganisms promoting or preventing the biofilm formation could increase the accuracy for a better definition of the vaginal dysmicrobism concept and therapeutic intervention.

}, keywords = {Adult, Biofilms, Female, Humans, Microbiota, Vagina, Vaginosis, Bacterial}, issn = {1945-0508}, author = {Campisciano, Giuseppina and Zanotta, Nunzia and Petix, Vincenzo and Corich, Lucia and De Seta, Francesco and Comar, Manola} } @article {10494, title = {Influence of vaginal lactoferrin administration on amniotic fluid cytokines and its role against inflammatory complications of pregnancy.}, journal = {J Inflamm (Lond)}, volume = {14}, year = {2017}, month = {2017}, pages = {5}, abstract = {

BACKGROUND: An altered amniotic cytokine profile has been reported in inflammatory pregnancy complications with a leading role for IL-6, a marker of the foetal systemic inflammatory response. Up to this date there is no exhaustive information neither on the foetal cytokine balance nor on the best method for its modulation. We aimed to evaluate the influence of vaginal lactoferrin administration on amniotic fluid concentration of 47 cytokines, chemokines and growth factors.

METHODS: Sixty women undergoing genetic amniocentesis were enrolled in an open-label clinical trial. 300~mg of vaginal lactoferrin (Florence, Italy) were randomly administered to obtain 3 groups: A, 20 untreated patients; B and C (20 patients in each) respectively treated 4 and 12~h before amniocentesis. Cytokines, chemokines and growth factors concentrations were quantified by a magnetic bead Luminex multiplex immunoassays panel technology. Data analysis was performed with the software Stata (v. 13.1) and GraphPad Prism (v. 5). Group comparisons were performed using Kruskal-Wallis followed by Mann-Whitney U tests, with Bonferroni correction for multiple comparisons. A < 0.05 was considered significant.

RESULTS: Among the 47 tested mediators, 24 (51.06\%) were influenced by lactoferrin. 11 (23.4\%), showed a highly significant difference (p <0.001); among these IL-9, IL-15, IFN-γ, IP-10, TNF-α, IL-1α and MCP-3 underwent a down-regulation, while IL-17 and FGF-basic, G-CSF, GM-CSF an up-regulation. Difference between group C and both B and A was small for IL-15, IP-10, IL-1α, MCP-3, while it was negligible for IL-9, IFN-γ and TNF-α. IL-17 and the 3 growth factors were strongly enhanced in B and C groups. IL-17, FGF-basic and GM-CSF showed increasing concentrations in both B and C groups, while G-CSF resulted up-regulated only in group C. Significance was intermediate ( < 0.01) for the down regulated IL-2RA, IL-12p40 and IFNα2 (6.38\%) while it was small for 10 mediators (21.27\%) 7 of which (IL-2, IL-4, eotaxin, PDGF-BB, RANTES, IL-18 and MIF) down-regulated and 3 (MCP-1, IL-3, and SDF-1α) up-regulated.

CONCLUSION: Lactoferrin down-regulates 17 pro-inflammatory amniotic mediators while up-regulating 7 anti-inflammatory amniotic mediators, 5 of which definitively belonging to an anti-inflammatory profile. These findings open to clinical investigation on its use against inflammatory complications of pregnancy.

}, issn = {1476-9255}, doi = {10.1186/s12950-017-0152-9}, author = {Maritati, Martina and Comar, Manola and Zanotta, Nunzia and Seraceni, Silva and Trentini, Alessandro and Corazza, Fabrizio and Vesce, Fortunato and Contini, Carlo} } @article {10576, title = {Natalizumab treatment of multiple sclerosis: new insights.}, journal = {Immunotherapy}, volume = {9}, year = {2017}, month = {2017 01}, pages = {157-171}, abstract = {

Natalizumab is a monoclonal antibody directed against the α4 chain of the very late activating antigen 4 and α4β7 integrins, present on the leukocytes surface, used as monotherapy for the treatment of relapsing-remitting multiple sclerosis. It substantially reduces relapse rate and the accumulation of disability, but its use is associated with a very adverse event, that is the development of progressive multifocal leukoencephalopathy, a fatal demyelinating disease of the CNS, due to the lytic replication of the human polyomavirus JC. The main focus of the review is to describe the newest insights on natalizumab, its current use in the clinical practice, the natalizumab-treated patients{\textquoteright} management and the risk stratification related to the progressive multifocal leukoencephalopathy development.

}, keywords = {Animals, Drug-Related Side Effects and Adverse Reactions, Humans, Immunotherapy, Integrin alpha Chains, Integrin alpha4, Integrin beta Chains, JC Virus, Leukoencephalopathy, Progressive Multifocal, Multiple Sclerosis, Relapsing-Remitting, Natalizumab, Risk, Virus Activation, Virus Replication}, issn = {1750-7448}, doi = {10.2217/imt-2016-0113}, author = {Delbue, Serena and Comar, Manola and Ferrante, Pasquale} } @article {10491, title = {Review on the role of the human Polyomavirus JC in the development of tumors.}, journal = {Infect Agent Cancer}, volume = {12}, year = {2017}, month = {2017}, pages = {10}, abstract = {

Almost one fifth of human cancers worldwide are associated with infectious agents, either bacteria or viruses, and this makes the possible association between infections and tumors a relevant research issue. We focused our attention on the human Polyomavirus JC (JCPyV), that is a small, naked DNA virus, belonging to the family. It is the recognized etiological agent of the Progressive Multifocal Leukoencephalopathy (PML), a fatal demyelinating disease, occurring in immunosuppressed individuals. JCPyV is able to induce cell transformation in vitro when infecting non-permissive cells, that do not support viral replication and JCPyV inoculation into small animal models and non human primates drives to tumor formation. The molecular mechanisms involved in JCPyV oncogenesis have been extensively studied: the main oncogenic viral protein is the large tumor antigen (T-Ag), that is able to bind, among other cellular factors, both Retinoblastoma protein (pRb) and p53 and to dysregulate the cell cycle, but also the early proteins small tumor antigen (t-Ag) and Agnoprotein appear to cooperate in the process of cell transformation. Consequently, it is not surprising that JCPyV genomic sequences and protein expression have been detected in Central Nervous System (CNS) tumors and colon cancer and an association between this virus and several brain and non CNS-tumors has been proposed. However, the significances of these findings are under debate because there is still insufficient evidence of a casual association between JCPyV and solid cancer development. In this paper we summarized and critically analyzed the published literature, in order to describe the current knowledge on the possible role of JCPyV in the development of human tumors.

}, issn = {1750-9378}, doi = {10.1186/s13027-017-0122-0}, author = {Delbue, Serena and Comar, Manola and Ferrante, Pasquale} } @article {10485, title = {Shifts of subgingival bacterial population after nonsurgical and pharmacological therapy of localized aggressive periodontitis, followed for 1 year by Ion Torrent PGM platform.}, journal = {Eur J Dent}, volume = {11}, year = {2017}, month = {2017 Jan-Mar}, pages = {126-129}, abstract = {

The possibility of targeting the hypervariable region V3 of the 16S rRNA gene using Ion Torrent Personal Genome Machine (PGM) could provide a complete analysis of subgingival plaque samples, potentially able to identify microbiological species missed by culture-based methods. A 16-year-old female smoker patient, affected by localized aggressive periodontitis, underwent a full-mouth disinfection protocol and was inserted in a 3-month recall program. Microbiological samples were collected at baseline and at 30, 100, 365 days follow-up and analyzed by Ion Torrent PGM. , , , and were the most represented pathogens at baseline. Nonsurgical treatment and systemic antibiotics drastically lowered the anaerobic species, and their presence remained limited after 100 days, while a consistent recolonization by anaerobic bacteria was detected at 365 days. The patient showed a general improvement of periodontal conditions. Differently from polymerase chain reaction and other microarray techniques, Ion Torrent performs a quantitative analysis of the microbiota, irrespective of the searched species. An accurate definition of the shifts of the bacterial community might help periodontal researchers for a better understanding of the impact of different treatment approaches or in intercepting nonresponsive conditions.

}, issn = {1305-7456}, doi = {10.4103/ejd.ejd_309_16}, author = {Campisciano, Giuseppina and Toschetti, Annamaria and Comar, Manola and Taranto, Rosanna Di and Berton, Federico and Stacchi, Claudio} } @article {10466, title = {Subclinical alteration of the cervical-vaginal microbiome in women with idiopathic infertility.}, journal = {J Cell Physiol}, volume = {232}, year = {2017}, month = {2017 Jul}, pages = {1681-1688}, abstract = {

Biomarkers have a wide application in research and clinic, they help to choose the correct treatment for diseases. Recent studies, addressing the vaginal microbiome using next generation sequencing (NGS), reported the involvement of bacterial species in infertility. We compared the vaginal microbiome of idiopathic infertile women with that of healthy, including bacterial vaginosis affected women and non-idiopathic infertile women, to identify bacterial species suitable as biomarkers. Information on microorganisms was obtained from the V3-16S rDNA sequencing of cervical-vaginal fluids of 96 women using the Ion Torrent platform. Data were processed with QIIME and classified against the Vaginal 16S rDNA Reference Database. The analysis revealed a significant beta-diversity variation (p < 0.001) between the four groups included in the study. L. iners, L. crispatus, and L. gasseri distinguished idiopathic infertile women from the other groups. In these women, a microbial profile similar to that observed in bacterial vaginosis women has been detected. Our results suggest that the quantitative assessment and identification of specific microorganisms of the cervical-vaginal microflora could increase the accuracy of available tools for the diagnosis of infertility and improve the adoption of therapeutic protocols.

}, keywords = {Adult, Biodiversity, Cervix Uteri, Cohort Studies, Demography, Female, Humans, Infertility, Female, Microbiota, Species Specificity, Vagina, Vaginosis, Bacterial}, issn = {1097-4652}, doi = {10.1002/jcp.25806}, author = {Campisciano, Giuseppina and Florian, Fiorella and D{\textquoteright}Eustacchio, Angela and Stankovi{\'c}, David and Ricci, Giuseppe and De Seta, Francesco and Comar, Manola} } @article {10571, title = {SV40 Infection of Mesenchymal Stromal Cells From Wharton{\textquoteright}s Jelly Drives the Production of Inflammatory and Tumoral Mediators.}, journal = {J Cell Physiol}, volume = {232}, year = {2017}, month = {2017 Nov}, pages = {3060-3066}, abstract = {

The Mesenchymal Stromal Cells from umbilical cord Wharton{\textquoteright}s jelly (WJSCs) are a source of cells with high potentiality for the treatment of human immunological disorders. Footprints of the oncogenic viruses Simian Virus 40 (SV40) and JC Virus (JCPyV) have been recently detected in human WJSCs specimens. The aim of this study is to evaluate if WJSCs can be efficiently infected by these Polyomaviruses and if they can potentially exert tumoral activity. Cell culture experiments indicated that WJSCs could sustain both SV40 and JCPyV infections. A transient and lytic replication was observed for JCPyV, while SV40 persistently infected WJSCs over a long period of time, releasing a viral progeny at low titer without evident cytopathic effect (CPE). Considering the association between SV40 and human tumors and the reported ability of the oncogenic viruses to drive the host innate immune response to cell transformation, the expression profile of a large panel of immune mediators was evaluated in supernatants by the Bioplex platform. RANTES, IL-3, MIG, and IL-12p40, involved in chronic inflammation, cells differentiation, and transformation, were constantly measured at high concentration comparing to control. These findings represent a new aspect of SV40 biological activity in the humans, highlighting its interaction with specific host cellular pathways. In view of these results, it seems to be increasingly urgent to consider Polyomaviruses in the management of WJSCs for their safely use as promising therapeutic source. J. Cell. Physiol. 232: 3060-3066, 2017. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Cell Line, Transformed, Cell Separation, Cell Transformation, Viral, Chemokine CCL5, Chemokine CXCL9, Cytopathogenic Effect, Viral, DNA, Viral, Host-Pathogen Interactions, Humans, Inflammation Mediators, Interleukin-12 Subunit p40, Interleukin-3, JC Virus, Mesenchymal Stem Cells, Real-Time Polymerase Chain Reaction, Simian virus 40, Time Factors, Up-Regulation, Viral Load, Virus Replication, Wharton Jelly}, issn = {1097-4652}, doi = {10.1002/jcp.25723}, author = {Cason, Carolina and Campisciano, Giuseppina and Zanotta, Nunzia and Valencic, Erica and Delbue, Serena and Bella, Ramona and Comar, Manola} } @article {8321, title = {Candidate Soluble Immune Mediators in Young Women with High-Risk Human Papillomavirus Infection: High Expression of Chemokines Promoting Angiogenesis and Cell Proliferation.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0151851}, abstract = {

BACKGROUND: The causal interpretation of cervical immune response to Human Papillomavirus (HPV) infection is complex and poorly characterized mainly due to the delicate balance that exists between viral infection, increase of inflammatory cytokines and host risk factors. This study aims to explore the significance of cervical immune mediators associated to cell survival, angiogenesis and interaction with immune response, in predicting the risk to develop HPV-related intraepithelial lesions.

METHODS: A panel of 48 cytokines and growth factors were explored in a selected cohort of 168 immunocompetent women including 88 diagnosed with low (LSIL) or high (HSIL) squamous intraepithelial lesions of the cervix and 80 with normal cervical cytology (NIL). HPV genotyping was performed by Linear Array HPV test and the soluble concentration of 48 immune molecules was analyzed using the Bio-Plex platform.

RESULTS: The prevalence of single HR-HPV infection was 30\% in NIL and 100\% in LSIL and HSIL women. The expression of 13 cytokines, including interleukins IL-6, IL-3, IL-12p40, IL-12p70, IL-16, IL-18, LIF, of chemokines CCL7 (MCP-3), CXCL9 (MIG), CXCL12 (SDF-1α) and of the tropic factors VEGF, G-CSF, M-CSF were significantly associated with the presence of infection, with levels being higher in women with precancerous lesions compared to NIL HPV negative women. Only the growth factor GM-CSF was positively associated with the cytological abnormalities.

CONCLUSIONS: The ability of HR-HPV to escape from innate immune recognition and to orchestrate the production of specific inflammatory and growth factors, involved in early inflammatory response and in the cell-proliferating phase of intraepithelial damage, was documented in women before the development of cervical lesions.

}, keywords = {Adult, Cell Survival, Cervix Uteri, Chemokines, Cohort Studies, Female, Humans, Neovascularization, Pathologic, Papillomaviridae, Papillomavirus Infections}, issn = {1932-6203}, doi = {10.1371/journal.pone.0151851}, author = {Zanotta, Nunzia and Tornesello, Maria Lina and Annunziata, Clorinda and Stellato, Giovanni and Buonaguro, Franco Maria and Comar, Manola} } @article {8314, title = {HPV genotypes distribution in Chlamydia trachomatis co-infection in a large cohort of women from north-east Italy.}, journal = {J Med Microbiol}, volume = {65}, year = {2016}, month = {2016 May}, pages = {406-13}, abstract = {

Human papillomavirus (HPV) and Chlamydia trachomatis are pathogens with oncogenic potential associated with persistent infections. Epidemiological data on C. trachomatis infection status, C. trachomatis/HPV co-infection and the relationship between HPV genotypes in Italian women are only preliminary. The aim of the present study was to characterize the relationship between HPV genotypes and C. trachomatis in an extending cohort of asymptomatic immunocompetent women from an area of north-east Italy. A retrospective study was conducted using Luminex technology on cervical swabs from asymptomatic immunocompetent women, comprising 921 attending the prevention centre for the Cervical Cancer Program and 6214 who had been referred to the Sexually Transmitted Infections Center, with clinical indications of HPV and C. trachomatis infections. A quantitative real-time PCR was performed to assess chronic C. trachomatis infection by heat-shock protein 60 (Hsp60) gene expression. The overall prevalence of the investigated pathogens was 39 \% (359/921) for HPV and 4 \% (251/6214) for C. trachomatis. The Hsp60 gene was detected in 57 \% of the women infected with C. trachomatis. HPV co-infection was present in 58 \% of C. trachomatis-infected women. A high prevalence of co-infection was found in women with chronic C. trachomatis infection (68 \%, P = 0.0002), especially in women <= 25 years (72 \%) where HPV multiple infections were found in 78 \% (P = 0.022). HPV genotype distribution showed that uncommon low-risk genotypes were associated with C. trachomatis. These results indicate a high frequency of co-detection of multiple HPV genotypes in chronically infected young women and suggest that the expression of the C. trachomatis Hsp60 gene may favour HPV infection.

}, issn = {1473-5644}, doi = {10.1099/jmm.0.000245}, author = {Seraceni, Silva and Campisciano, Giuseppina and Contini, Carlo and Comar, Manola} } @article {7713, title = {Association Study between Cervical Lesions and Single or Multiple Vaccine-Target and Non-Vaccine Target Human Papillomavirus (HPV) Types in Women from Northeastern Brazil.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0132570}, abstract = {

We performed an association between high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL) and single or multiple vaccine-target as well as non-vaccine target Human papillomavirus (HPV) types. Using bead-based HPV genotyping, 594 gynecological samples were genotyped. An association between squamous intraepithelial lesion (SIL) and presence of HPV16, 18, 31, 58 and 56 types were calculated. The risk was estimated by using odds ratio (OR) and 95\% of confidence intervals (CI). A total of 370 (62.3\%) women were HPV positive. Among these, 157 (42.7\%) presented a single HPV infection, and 212 (57.3\%) were infected by more than one HPV type. HPV31 was the most prevalent genotype, regardless single and multiple HPV infections. Single infection with HPV31 was associated with LSIL (OR=2.32; 95\%CI: 1.01 to 5.32; p=0.04); HPV31 was also associated with LSIL (OR=3.28; 95\%CI: 1.74 to 6.19; p= 0.0002) and HSIL (OR=3.82; 95\%CI: 2.10 to 6.97; p<0.001) in multiple HPV infections. Risk to harbor cervical lesions was observed in multiple HPV infections with regard to the HPV56 (OR=5.39; 95\%CI: 2.44 to 11.90; p<0.001for LSIL; OR=5.37; 95\%CI: 2.71 to 10.69; p<0.001) and HPV58 (OR=3.29; 95\%CI: 1.34 to 8.09; p=0.0091 for LSIL; OR=3.55; 95\%CI: 1.56 to 8.11; p=0.0026) genotypes. In addition, women coinfected with HPV16/31/56 types had 6 and 5-fold increased risk of HSIL (OR=6.46; 95\%CI: 1.89 to 22.09; p=0.002) and LSIL (OR=5.22; 95\%CI: 1.10 to 24.70; p=0.03), respectively. Multiple HPV infections without HPV16/18 has 2-fold increased risk of HSIL (OR=2.57; 95\%CI: 1.41 to 4.70; p=0.002) and LSIL OR=2.03; 95\%CI: 1.08 to 3.79; p=0.02). The results of this study suggest that single and multiple vaccine target as well as non-vaccine target HPV types are associated with LSIL and HSIL. These finding should be taken into consideration in the design of HPV vaccination strategies.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0132570}, author = {Chagas, B{\'a}rbara Simas and Comar, Manola and Gurgel, Ana Pavla Almeida Diniz and Paiva, S{\'e}rgio and Seraceni, Silva and de Freitas, Antonio Carlos and Crovella, Sergio} } @article {8062, title = {Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma.}, journal = {Lung Cancer}, year = {2015}, month = {2015 Sep 25}, abstract = {

OBJECTIVES: Malignant mesothelioma (MM) is a highly aggressive tumor with poor prognosis. A major challenge is the development and application of early and highly reliable diagnostic marker(s). Serum biomarkers, such as {\textquoteright}soluble mesothelin-related proteins{\textquoteright} (SMRPs), is the most studied and frequently used in MM. However, the low sensitivity of SMRPs for early MM limits its value; therefore, additional biomarkers are required. In this study, two epigenetically regulated markers in MM (microRNA-126, miR-126, and methylated thrombomodulin promoter, Met-TM) were combined with SMRPs and evaluated as a potential strategy to detect MM at an early stage.

MATERIALS AND METHODS: A total of 188 subjects, including 45 MM patients, 99 asbestos-exposed subjects, and 44 healthy controls were prospectively enrolled, serum samples collected, and serum levels of SMRPs, miR-126 and Met-TM evaluated. Logistic regression analysis was performed to evaluate the diagnostic value of the three biomarkers. Using this approach, the performance of the {\textquoteright}3-biomarker classifier{\textquoteright} was tested by calculating the overall probability score of the MM and control samples, respectively, and the ROC curve was generated.

RESULTS AND CONCLUSION: The combination of the three biomarkers was the best predictor to differentiate MM patients from asbestos-exposed subjects and healthy controls. The accuracy and cancer specificity was confirmed in a second validation cohort and lung cancer population. We propose that the combination of the two epigenetic biomarkers with SMRPs as a diagnosis for early MM overcomes the limitations of using SMRPs alone.

}, issn = {1872-8332}, doi = {10.1016/j.lungcan.2015.09.021}, author = {Santarelli, Lory and Staffolani, Sara and Strafella, Elisabetta and Nocchi, Linda and Manzella, Nicola and Grossi, Paola and Bracci, Massimo and Pignotti, Elettra and Alleva, Renata and Borghi, Battista and Pompili, Cecilia and Sabbatini, Armando and Rubini, Corrado and Zuccatosta, Lina and Bichisecchi, Elisabetta and Valentino, Matteo and Horwood, Keith and Comar, Manola and Bovenzi, Massimo and Dong, Lan-Feng and Neuzil, Jiri and Amati, Monica and Tomasetti, Marco} } @article {7772, title = {Immunologic evidence of a strong association between non-Hodgkin lymphoma and simian virus 40.}, journal = {Cancer}, volume = {121}, year = {2015}, month = {2015 Aug 1}, pages = {2618-26}, abstract = {

BACKGROUND: Non-Hodgkin lymphoma (NHL), the most common cancer of the lymphatic system, is of unknown etiology. The identification of etiologic factors in the onset of NHL is a key event that could facilitate the prevention and cure of this malignancy. Simian virus 40 (SV40) has been considered an oncogenic agent in the onset/progression of NHL.

METHODS: In this study, an indirect enzyme-linked immunosorbent assay with 2 synthetic peptides that mimic SV40 antigens of viral capsid proteins 1 to 3 was employed to detect specific antibodies against SV40. Serum samples were taken from 2 distinct cohorts of NHL-affected patients (NHL1 [n = 89] and NHL2 [n = 61]) along with controls represented by oncologic patients affected by breast cancer (BC; n = 78) and undifferentiated nasopharyngeal carcinoma (UNPC; n = 64) and 3 different cohorts of healthy subjects (HSs; HS1 [n = 130], HS2 [n = 83], and HS3 [n = 87]).

RESULTS: Immunologic data indicated that in serum samples from NHL patients, antibodies against SV40 mimotopes were detectable with a prevalence of 40\% in NHL1 patients and with a prevalence of 43\% in NHL2 patients. In HSs of the same median age as NHL patients, the prevalence was 16\% for the HS1 group (57 years) and 14\% for the HS2 group (65 years). The difference was statistically significant (P < .0001 and P < .001). Interestingly, the difference between NHL1/NHL2 patients and BC patients (40\%/43\% vs 15\%, P < .001) and between NHL1/NHL2 patients and UNPC patients (40\%/43\% vs 25\%, P < .05) was significant.

CONCLUSIONS: Our data indicate a strong association between NHL and SV40 and thus a need for innovative therapeutic approaches for this hematologic malignancy.

}, keywords = {Adult, Aged, Antibodies, Viral, Capsid Proteins, Enzyme-Linked Immunosorbent Assay, Female, Humans, Lymphoma, Non-Hodgkin, Male, Middle Aged, Polyomavirus Infections, Seroepidemiologic Studies, Simian virus 40, Tumor Virus Infections}, issn = {1097-0142}, doi = {10.1002/cncr.29404}, author = {Tognon, Mauro and Luppi, Mario and Corallini, Alfredo and Taronna, Angelo and Barozzi, Patrizia and Rotondo, John Charles and Comar, Manola and Casali, Maria Vittoria and Bovenzi, Massimo and D{\textquoteright}Agostino, Antonio and Vinante, Fabrizio and Rigo, Antonella and Ferrarini, Isacco and Barbanti-Brodano, Giuseppe and Martini, Fernanda and Mazzoni, Elisa} } @article {7758, title = {MBL2 polymorphisms in women with atypical squamous cells of undetermined significance.}, journal = {J Med Virol}, volume = {87}, year = {2015}, month = {2015 May}, pages = {851-9}, abstract = {

Infection with high risk Human papillomavirus (HPV) is the main known cause of cervical cancer. HPV induces different grades of lesions: among them, Atypical squamous cells of undetermined significance are abnormal lesions that could evolve in pre-cancer lesions or spontaneously regress. The mannose binding lectin (MBL) is an innate immunity serum protein also found in cervico-vaginal mucosa, whose expression is known to be affected by polymorphisms in exon 1 and promoter of the MBL2 gene. In the present study the possible association between MBL2 functional polymorphisms and susceptibility to develop atypical squamous cells of undetermined significance was investigated in a group of women from North-East of Italy, stratified for HPV infection status. The MBL2 D and O alleles and the deficient producer combined genotypes, responsible for low MBL production, were more represented among atypical squamous cells of undetermined significance positive women than healthy controls and the results were confirmed when only HPV negative samples were considered. These results suggest a possible involvement of MBL2 functional polymorphisms in atypical squamous cells of undetermined significance susceptibility.

}, keywords = {Adolescent, Adult, Atypical Squamous Cells of the Cervix, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Italy, Mannose-Binding Lectin, Polymorphism, Single Nucleotide, Young Adult}, issn = {1096-9071}, doi = {10.1002/jmv.24080}, author = {Zupin, Luisa and Polesello, Vania and Casalicchio, Giorgia and Freato, Nadia and Maestri, Iva and Comar, Manola and Crovella, Sergio and Segat, Ludovica} } @article {7712, title = {The mediating role of interpersonal conflict at work in the relationship between negative affectivity and biomarkers of stress.}, journal = {J Behav Med}, volume = {38}, year = {2015}, month = {2015 Dec}, pages = {922-31}, abstract = {

This study examined the association between interpersonal conflict at work (ICW) and serum levels of three possible biomarkers of stress, namely the pro-inflammatory cytokines Interleukin 1 beta (IL-1β), Interleukin 12 (IL-12), and Interleukin 17 (IL-17). Additionally, this study investigated the role of negative affectivity (NA) in the relationship between ICW and the pro-inflammatory cytokines. Data from 121 employees in an Italian healthcare organization were analyzed using structural equation modeling. Results showed that ICW was positively associated with IL-1β, IL-12, and IL-17, after controlling for the effect of gender. Moreover, ICW completely mediated the relationship between NA and the pro-inflammatory cytokines IL-1β, IL-12, and IL-17. This mediating effect was significant after controlling for the effect of gender. Overall, this study suggests that work-related stress may be associated with biomarkers of inflammation, and that negative affectivity may influence the stress process affecting the exposure to psychosocial stressors.

}, issn = {1573-3521}, doi = {10.1007/s10865-015-9658-x}, author = {Girardi, Damiano and Falco, Alessandra and De Carlo, Alessandro and Benevene, Paula and Comar, Manola and Tongiorgi, Enrico and Bartolucci, Giovanni Battista} } @article {3490, title = {Beta defensin-1 gene polymorphisms and susceptibility to atypical squamous cells of undetermined significance lesions in Italian gynecological patients.}, journal = {J Med Virol}, volume = {86}, year = {2014}, month = {2014 Dec}, pages = {1999-2004}, abstract = {

The role of the human beta-defensin 1 (hBD-1) in the susceptibility to the onset of the Atypical Squamous Cells of Undetermined Significance (ASCUS) lesion, in the presence or not of HPV infection, is still unknown. In the current study, the three functional single nucleotide polymorphisms (SNPs) -52G > A, -44C > G, and -20G > A at the 5{\textquoteright} un-translated region (UTR) of DEFB1 gene, encoding hBD-1, were analyzed in ASCUS lesion gynecological patients and healthy women from the north-east of Italy (Trieste). Cervical samples from 249 European-Caucasian women were collected, screened for HPV and cytologically evaluated; DEFB1 genotyping has been performed by direct sequencing. No significant differences were found for -52G > A, -44C > G, and -20G > A SNPs allele and genotype frequencies between women with and without ASCUS lesions. DEFB1 minor haplotypes were significantly more frequent in ASCUS lesion positive than negative women, associating with an increased risk of this type of lesion. When women were stratified according to HPV infection status, significant differences in the distribution of -52G > A SNP genotype frequencies were found: the presence of the A allele in the homozygous genotype A/A associated with a lower risk of developing ASCUS lesions in HPV negative women. DEFB1 minor haplotypes were also associated with an increased risk of developing ASCUS lesions, being significantly more frequent in HPV negative women with lesions, than without lesions. Although these results highlight the possible involvement of DEFB1, further studies are needed to support the role of DEFB1 in the modulation of the susceptibility to ASCUS lesions.

}, keywords = {5{\textquoteright} Untranslated Regions, Adolescent, Adult, Atypical Squamous Cells of the Cervix, beta-Defensins, Female, Genotype, Humans, Italy, Papillomavirus Infections, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Uterine Cervical Neoplasms, Young Adult}, issn = {1096-9071}, doi = {10.1002/jmv.23878}, author = {Casalicchio, Giorgia and Freato, Nadia and Maestri, Iva and Comar, Manola and Crovella, Sergio and Segat, Ludovica} } @article {3587, title = {HPV and Chlamydia trachomatis co-detection in young asymptomatic women from high incidence area for cervical cancer.}, journal = {J Med Virol}, volume = {86}, year = {2014}, month = {2014 Nov}, pages = {1920-5}, abstract = {

Chlamydia trachomatis causing chronic inflammatory diseases has investigated as possible human papillomavirus (HPV) cofactor in cervical cancer. The aim of this study is to evaluate the prevalence of Chlamydia trachomatis and HPV co-infection in different cohorts of asymptomatic women from a Northern Italy area at high incidence for cervical cancer. Cervical samples from 441 females were collected from Cervical Cancer Screening Program, Sexually Transmitted Infectious and Assisted Reproductive Technology centres. HPV and Chlamydia trachomatis were detected simultaneously and genotyped using a highly sensitive bead based assay. The overall prevalence of Chlamydia trachomatis was estimated 9.7\%, in contrast with the reported national data of 2.3\%, and co-infection with HPV was diagnosed in the 17\% of the samples. In females <= 25 years of age, the infection reached a peak of 22\% and co-infection with HPV of 45.8\% (P < 0.001). Of note, in young females diagnosed with low grade cervical lesions, no significant difference between Chlamydia trachomatis and HPV distribution was observed, while differently, HPV co-infection was found significantly associated to the presence of intraepithelial lesions when compared to older females (20\% vs. 1\%; P < 0.001). In this study, the use of a high sensitive molecular technique exhibited higher analytical sensitivity than the referred assays for the diagnosis of Chlamydia trachomatis and HPV co-infection in asymptomatic females, leading to reduction of the potential to identify incorrectly the infection status. An active screening for timely treatment of Chlamydia trachomatis infection is suggested in young females to evaluate a possible decrease in incidence of pre-cancer intraepithelial lesions.

}, keywords = {Adolescent, Adult, Age Factors, Cervix Uteri, Chlamydia Infections, Chlamydia trachomatis, Coinfection, Female, Genotype, Humans, Incidence, Italy, Middle Aged, Papillomaviridae, Papillomavirus Infections, Prevalence, Young Adult}, issn = {1096-9071}, doi = {10.1002/jmv.24041}, author = {Bellaminutti, Serena and Seraceni, Silva and De Seta, Francesco and Gheit, Tarik and Tommasino, Massimo and Comar, Manola} } @article {3503, title = {In vivo detection of polyomaviruses JCV and SV40 in mesenchymal stem cells from human umbilical cords.}, journal = {Pediatr Blood Cancer}, volume = {61}, year = {2014}, month = {2014 Aug}, pages = {1347-9}, abstract = {

BACKGROUND: Multipotent stromal cells are present in the Wharton{\textquoteright}s jelly matrix (WJSC) of the umbilical cord and can be used as an allogeneic source of cells to treat immunological disorders. Recently it was demonstrated that adult bone marrow (BM)-derived mesenchimal stromal cells (MSC) are susceptible to infection with viruses showing potential oncogenic properties, such as the polyomavirus JC (JCV). The aim of this study was to investigate the presence of human polyomaviruses (JCV, BK Virus-BKV, SV40, and Merkel cell polyomavirus-MCPyV) in WJSC, and explore the risk of infection.

PROCEDURE: MSC samples from 35 umbilical cords were investigated by quantitative Real Time PCRs for the presence of DNA sequences of JCV, BKV, SV40, and MCPyV.

RESULTS: JCV DNA was detected in 1/35 (2.8\%) of MSC samples, while SV40 DNA was found in 3/35 (8.6\%) of the examined samples. None of the samples showed sequences of BKV and MCPyV.

CONCLUSIONS: The present study demonstrates the in vivo ability of polyomaviruses to infect WJSC. Since the therapeutic approach with the WJSC has high potentiality and a more intensive use can be easily hypothesized, the need to develop consensus guidelines to detect rare viral infections in MSC is pressing.

}, keywords = {DNA, Viral, Female, Fetal Blood, Humans, JC Virus, Male, Mesenchymal Stromal Cells, Polyomavirus Infections, Simian virus 40, Tumor Virus Infections}, issn = {1545-5017}, doi = {10.1002/pbc.24943}, author = {Comar, Manola and Delbue, Serena and Zanotta, Nunzia and Valencic, Erica and Piscianz, Elisa and Del Savio, Rossella and Tesser, Alessandra and Tommasini, Alberto and Ferrante, Pasquale} } @article {3589, title = {Increased levels of C-C chemokine RANTES in asbestos exposed workers and in malignant mesothelioma patients from an hyperendemic area.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e104848}, abstract = {

BACKGROUND: Asbestos-induced mesothelial inflammatory processes are thought to be the basic mechanisms underlying Malignant Mesothelioma (MM) development. Detection of MM often occurs at late stage due to the long and unpredictable latent period and the low incidence in asbestos exposed individuals. The aim of this study was to investigate early immunological biomarkers to characterize the prognostic profile of a possible asbestos-induced disease, in subjects from a MM hyperendemic area.

METHODS: The Luminex Multiplex Panel Technology was used for the simultaneous measurement of serum levels of a large panel of 47 analytes, including cytokines and growth factors, from workers previously exposed to asbestos (Asb-workers), asbestos-induced MM patients and healthy subjects. In addition, to explore the influence on serum cytokines profile exerted by SV40 infection, a cofactor in MM development, a quantitative real time PCR was performed for sequences detection in the N-terminal and intronic regions of the SV40 Tag gene. Statistical analysis was done by means of the Mann-Whitney test and the Kruskall-Wallis test for variance analysis.

RESULTS: A variety of 25 cytokines linked to pulmonary inflammation and tumor development were found significantly associated with Asb-workers and MM patients compared with healthy controls. A specific pattern of cytokines were found highly expressed in Asb-workers: IFN-alpha (p<0.05), EOTAXIN (p<0.01), RANTES (p<0.001), and in MM patients: IL-12(p40), IL-3, IL-1 alpha, MCP-3, beta-NGF, TNF-beta, RANTES (p<0.001). Notably, the chemokine RANTES measured the highest serum level showing an increased gradient of concentration from healthy subjects to Asb-workers and MM patients (p<0.001), independently of SV40 infection.

CONCLUSION: This study shows that, in subjects from an hyperendemic area for MM, the C-C chemokine RANTES is associated with the exposure to asbestos fibres. If validated in larger samples, this factor could have the potential to be a critical biomarker for MM prognosis as recently reported for breast tumor.

}, keywords = {Aged, Aged, 80 and over, Asbestos, Biomarkers, Tumor, Case-Control Studies, Chemokine CCL5, Cytokines, Endemic Diseases, Gene Expression, Gene Expression Profiling, Humans, Lung Neoplasms, Mesothelioma, Middle Aged, Occupational Exposure, Simian virus 40, Viral Proteins}, issn = {1932-6203}, doi = {10.1371/journal.pone.0104848}, author = {Comar, Manola and Zanotta, Nunzia and Bonotti, Alessandra and Tognon, Mauro and Negro, Corrado and Cristaudo, Alfonso and Bovenzi, Massimo} } @article {3609, title = {Neutralizing and IgG antibodies against simian virus 40 in healthy pregnant women in Italy.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e110700}, abstract = {

OBJECTIVE: Polyomavirus simian virus 40 (SV40) sequences have been detected in various human specimens and SV40 antibodies have been found in human sera from both healthy individuals and cancer patients. This study analyzed serum samples from healthy pregnant women as well as cord blood samples to determine the prevalence of SV40 antibodies in pregnancy.

METHODS: Serum samples were collected at the time of delivery from two groups of pregnant women as well as cord bloods from one group. The women were born between 1967 and 1993. Samples were assayed by two different serological methods, one group by neutralization of viral infectivity and the other by indirect ELISA employing specific SV40 mimotopes as antigens. Viral DNA assays by real-time polymerase chain reaction were carried out on blood samples.

RESULTS: Neutralization and ELISA tests indicated that the pregnant women were SV40 antibody-positive with overall prevalences of 10.6\% (13/123) and 12.7\% (14/110), respectively. SV40 neutralizing antibodies were detected in a low number of cord blood samples. Antibody titers were generally low. No viral DNA was detected in either maternal or cord bloods.

CONCLUSIONS: SV40-specific serum antibodies were detected in pregnant women at the time of delivery and in cord bloods. There was no evidence of transplacental transmission of SV40. These data indicate that SV40 is circulating at a low prevalence in the northern Italian population long after the use of contaminated vaccines.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0110700}, author = {Comar, Manola and Wong, Connie and Tognon, Mauro and Butel, Janet S} } @article {3483, title = {No evidence of Polyomavirus and EBV infections in Italian patients with mixed cryoglobulinemia infected chronically with HCV.}, journal = {J Med Virol}, volume = {86}, year = {2014}, month = {2014 Apr}, pages = {666-71}, abstract = {

Mixed cryoglobulinemia is a lymphoproliferative disorder associated with hepatitis C virus (HCV). In patients chronically affected by HCV the prevalence of mixed cryoglobulinemia is variable ranging from 0\% to 56\%. To verify whether polyomaviruses (PyV) play a role in this disorder a total of 222 blood samples from 63 HCV chronic patients, 43 with mixed cryoglobulinemia, 59 chronic lymphocytic leukemia, 50 polytransfused patients, and 50 blood donors were evaluated for Merkel (MCPyV), BKV, JCV, and SV40. EBV was additionally included in the analysis since association with this disorder has been reported. Mixed cryoglobulinemia patients infected chronically with HCV resulted negative for both PyV and EBV. MCPyV was found in 1 subject with Merkel Cell Carcinoma, in 10\% of polytransfused and in 10\% of blood donors while EBV was detected in 22\% of polytransfused, 10\% of B-cell lymphatic leukemia patients and 4\% of blood donors (P < 0.01). Taken together, the absence of PyV and EBV in HCV-mixed cryoglobulinemia patients seems to exclude a direct involvement of these viruses in the pathogenesis of this disease while the presence of MCPyV in healthy individuals, at the same rate as in polytransfused patients, may reinforce data on a minimal role of this virus in other human pathologies.

}, keywords = {Adult, Base Sequence, Cryoglobulinemia, DNA, Viral, Epstein-Barr Virus Infections, Female, Hepacivirus, Hepatitis C, Chronic, Herpesvirus 4, Human, Humans, Italy, Leukemia, B-Cell, Male, Middle Aged, Polyomavirus, Polyomavirus Infections, Sequence Analysis, DNA, Vaginal Smears, Young Adult}, issn = {1096-9071}, doi = {10.1002/jmv.23867}, author = {Comar, Manola and Zanotta, Nunzia and Del Savio, Rossella and Vascotto, Fulvia and Calabrese, Nadia and Zorat, Francesca and Pozzato, Gabriele} } @article {1916, title = {Asbestos and SV40 in malignant pleural mesothelioma from a hyperendemic area of north-eastern Italy.}, journal = {Tumori}, volume = {98}, year = {2012}, month = {2012 Mar-Apr}, pages = {210-4}, abstract = {

AIMS AND BACKGROUND: Malignant mesothelioma is a fatal cancer of increasing incidence in north-eastern Italy. Together with asbestos, the polyomavirus SV40 was hypothesized to contribute to the onset of malignant mesothelioma. To investigate the putative role of SV40 in the individual susceptibility to asbestos-induced malignant mesothelioma, we conducted a molecular epidemiological study on a series of malignant mesothelioma patients from an area in north-eastern Italy hyperendemic for malignant pleural mesothelioma.

METHODS AND STUDY DESIGN: We collected 63 mesothelioma samples from incidence cases of patients diagnosed with malignant pleural mesothelioma in the period 2009-2010. DNA was extracted from patients{\textquoteright} tissue biopsies using the BioRobot EZ1 Qiagen workstation. SV40 sequence detection and quantification was performed by specific real time PCR. The 74.6\% of the 63 enrolled patients had a history of asbestos exposure. The epithelioid histotype was more prevalent in males (64.0\%) and the mixed in females (61.5\%) who showed significantly higher cancer co-morbidity (46.1\% vs 12\%, P = 0.005). SV40 was detected in 22\% of MM tumors, with a low viral load. In SV40-positive patients, a threefold increased risk of asbestos exposure was observed, more evident in females (OR 4.32) than in males (OR 1.20).

CONCLUSIONS: Our findings indicate that a high prevalence of SV40 was present in malignant mesothelioma incident cases from an area hyperendemic for malignant mesothelioma in north-eastern Italy. Although asbestos is considered the main risk factor in malignant mesothelioma onset, a role for SV40 could be hypothesized.

}, keywords = {Adult, Aged, Asbestos, Carcinogens, Disease Susceptibility, DNA, Viral, Endemic Diseases, Female, Humans, Italy, Male, Mesothelioma, Middle Aged, Pleural Neoplasms, Polyomavirus Infections, Real-Time Polymerase Chain Reaction, Risk Factors, Simian virus 40, Tumor Virus Infections, Viral Load}, issn = {2038-2529}, doi = {10.1700/1088.11931}, author = {Comar, Manola and Zanotta, Nunzia and Pesel, Giuliano and Visconti, Patrizia and Maestri, Iva and Rinaldi, Rosa and Crovella, Sergio and Cortale, Maurizio and De Zotti, Renata and Bovenzi, Massimo} } @article {1965, title = {Association between the JC polyomavirus infection and male infertility.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e42880}, abstract = {

In recent years the incidence of male infertility has increased. Many risk factors have been taken into consideration, including viral infections. Investigations into viral agents and male infertility have mainly been focused on human papillomaviruses, while no reports have been published on polyomaviruses and male infertility. The aim of this study was to verify whether JC virus and BK virus are associated with male infertility. Matched semen and urine samples from 106 infertile males and 100 fertile males, as controls, were analyzed. Specific PCR analyses were carried out to detect and quantify large T (Tag) coding sequences of JCV and BKV. DNA sequencing, carried out in Tag JCV-positive samples, was addressed to viral protein 1 (VP1) coding sequences. The prevalence of JCV Tag sequences in semen and urine samples from infertile males was 34\% (72/212), whereas the BKV prevalence was 0.94\% (2/212). Specifically, JCV Tag sequences were detected in 24.5\% (26/106) of semen and 43.4\% (46/106) of urine samples from infertile men. In semen and urine samples from controls the prevalence was 11\% and 28\%, respectively. A statistically significant difference (p<0.05) in JCV prevalence was disclosed in semen and urine samples of cases vs. controls. A higher JC viral DNA load was detected in samples from infertile males than in controls. In samples from infertile males the JC virus type 2 strain, subtype 2b, was more prevalent than ubiquitous type 1. JCV type 2 strain infection has been found to be associated with male infertility. These data suggest that the JC virus should be taken into consideration as an infectious agent which is responsible for male infertility.

}, keywords = {Adult, Amino Acid Sequence, Amino Acid Substitution, Base Sequence, BK Virus, Capsid Proteins, DNA, Viral, Humans, Infertility, Male, JC Virus, Male, Molecular Sequence Data, Polyomavirus Infections, Semen, Sequence Analysis, DNA, Tumor Virus Infections}, issn = {1932-6203}, doi = {10.1371/journal.pone.0042880}, author = {Comar, Manola and Zanotta, Nunzia and Croci, Eleonora and Murru, Immacolata and Marci, Roberto and Pancaldi, Cecilia and Dolcet, Ornella and Luppi, Stefania and Martinelli, Monica and Giolo, Elena and Ricci, Giuseppe and Tognon, Mauro} } @article {1972, title = {Comparison of hybrid capture II, linear array, and a bead-based multiplex genotyping assay for detection of human papillomavirus in women with negative pap test results and atypical squamous cells of undetermined significance.}, journal = {J Clin Microbiol}, volume = {50}, year = {2012}, month = {2012 Dec}, pages = {4041-6}, abstract = {

Many methods with different levels of analytical sensitivity and clinical specificity have been developed to detect the presence of high-risk (HR) types of the human papillomavirus (HPV) in cervical samples. The Hybrid Capture II (HC-II) assay is broadly used for primary screening. In addition, several HPV genotyping assays, based on PCR methods, display higher sensitivity than the HC-II and are also used in screening programs. We evaluated the performance of three HPV DNA tests, namely, the HC-II, the Linear Array (LA) HPV genotyping assay, and an HPV type-specific E7 PCR bead-based multiplex genotyping assay (TS-MPG) that is a laboratory-developed method for the detection of HPV, in 94 women with atypical squamous cells of undetermined significance (ASC-US) and in cytological samples from 86 women with a negative Pap test. The HPV prevalence with the TS-MPG assay was increased compared to the prevalence with the LA and HC-II assays. The HPV DNA prevalence in women with ASC-US was greater with the TS-MPG assay (46.2\%) than with the LA (36.3\%) and HC-II (29.7\%) assays. The HPV DNA prevalence in the control group was greater with the TS-MPG assay (32.1\%) than with the LA assay (10.7\%). Two women with ASC-US who were HPV DNA negative by the HC-II and positive by the TS-MPG or/and LA assays had lesions that progressed to low-grade squamous intraepithelial and high-grade squamous intraepithelial lesions. This study shows that the TS-MPG assay exhibited higher analytical sensitivity than the LA and HC-II assays for the detection of HPV DNA, which reduces the potential to incorrectly identify a woman{\textquoteright}s HPV infection status.

}, keywords = {Adult, DNA, Viral, Female, Humans, Molecular Diagnostic Techniques, Papillomavirus Infections, Sensitivity and Specificity, Uterine Cervical Neoplasms, Virology}, issn = {1098-660X}, doi = {10.1128/JCM.02105-12}, author = {Comar, Manola and Iannacone, Michelle R and Casalicchio, Giorgia and McKay-Chopin, Sandrine and Tommasino, Massimo and Gheit, Tarik} } @article {1986, title = {High prevalence of serum antibodies reacting with simian virus 40 capsid protein mimotopes in patients affected by malignant pleural mesothelioma.}, journal = {Proc Natl Acad Sci U S A}, volume = {109}, year = {2012}, month = {2012 Oct 30}, pages = {18066-71}, abstract = {

Human malignant pleural mesothelioma (MPM) is considered a rare tumor, but recent estimations indicate that one-quarter million people will die of this neoplasm in Europe in the next three decades. The mineral asbestos is considered the main causative agent of this neoplasm. MPM is largely unresponsive to conventional chemotherapy/radiotherapy. In addition to asbestos exposure, genetic predisposition to asbestos carcinogenesis and to simian virus (SV)40 infection has also been suggested. SV40 is a DNA tumor virus found in some studies to be associated at high prevalence with MPM. SV40 sequences have also been detected, although at a lower prevalence than in MPM, in blood specimens from healthy donors. However, some studies have failed to reveal SV40 footprints in MPM and its association with this neoplasm. These conflicting results indicate the need for further investigations with new approaches. We report on the presence of antibodies in serum samples from patients affected by MPM that specifically react with two different SV40 mimotopes. The two SV40 peptides used in indirect ELISAs correspond to viral capsid proteins. ELISA with the two SV40 mimotopes gave overlapping results. Our data indicate that in serum samples from MPM-affected patients (n = 97), the prevalence of antibodies against SV40 viral capsid protein antigens is significantly higher (26\%, P = 0.043) than in the control group (15\%) represented by healthy subjects (n = 168) with the same median age (66 y) and sex. Our results suggest that SV40 is associated with a subset of MPM and circulates in humans.

}, keywords = {Amino Acid Sequence, Antibodies, Viral, Capsid Proteins, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Mesothelioma, Molecular Sequence Data, Pleural Neoplasms, Pregnancy, Simian virus 40}, issn = {1091-6490}, doi = {10.1073/pnas.1213238109}, author = {Mazzoni, Elisa and Corallini, Alfredo and Cristaudo, Alfonso and Taronna, Angelo and Tassi, Gianfranco and Manfrini, Marco and Comar, Manola and Bovenzi, Massimo and Guaschino, Roberto and Vaniglia, Francesca and Magnani, Corrado and Casali, Ferruccio and Rezza, Giovanni and Barbanti-Brodano, Giuseppe and Martini, Fernanda and Tognon, Mauro G} } @article {1883, title = {JCV+ Patients with Inflammatory bowel disease show elevated plasma levels of MIG and SCF.}, journal = {Inflamm Bowel Dis}, volume = {18}, year = {2012}, month = {2012 Jun}, pages = {1194-6}, keywords = {Adolescent, Adult, Chemokine CXCL9, Child, DNA, Viral, Female, Humans, Inflammatory Bowel Diseases, JC Virus, Leukoencephalopathy, Progressive Multifocal, Male, Stem Cell Factor, Young Adult}, issn = {1536-4844}, doi = {10.1002/ibd.22953}, author = {Comar, Manola and Secchiero, Paola and De Lorenzo, Elisa and Martelossi, Stefano and Tommasini, Alberto and Zauli, Giorgio} } @article {1975, title = {Merkel-cell polyomavirus (MCPyV) is rarely associated to B-chronic lymphocytic leukemia (1 out of 50) samples and occurs late in the natural history of the disease.}, journal = {J Clin Virol}, volume = {55}, year = {2012}, month = {2012 Dec}, pages = {367-9}, abstract = {

BACKGROUND: Previous studies have reported conflicting results on the frequency and potential pathogenetic role of Merkel-cell polyomavirus (MCPyV) in B-chronic lymphocytic leukemia (B-CLL).

OBJECTIVES: To evaluate the association of MCPyV to B-CLL and to investigate the occurrence of MCPyV infection in relationship to the natural history of B-CLL.

STUDY DESIGN: Samples of primary B-CLL peripheral blood mononuclear cells were obtained from two distinct University Hospitals of Italy from January 2010. For one B-CLL patient, it was possible to retrospectively examine the blood sample at diagnosis of B-CLL (March 2004) and several pathological tissues of cutaneous tumors occurring during the course of the disease.

RESULTS: Only one out of 50 B-CLL blood samples examined was positive for MCPyV DNA. Retrospective analysis revealed that MCPyV DNA was absent in peripheral blood sample at diagnosis, becoming present only in advanced disease stages also in tonsil tissue as well as in a biopsy of differentiated squamous cell carcinoma.

CONCLUSIONS: The association with MCPyV seems to represent a rare and late event during the natural history of B-CLL.

}, keywords = {Aged, Aged, 80 and over, Blood, Female, Humans, Italy, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Merkel cell polyomavirus, Middle Aged, Palatine Tonsil, Polyomavirus Infections, Prevalence, Skin, Tumor Virus Infections}, issn = {1873-5967}, doi = {10.1016/j.jcv.2012.08.011}, author = {Comar, Manola and Cuneo, Antonio and Maestri, Iva and Melloni, Elisabetta and Pozzato, Gabriele and Soffritti, Olga and Secchiero, Paola and Zauli, Giorgio} } @article {1971, title = {NLRP1 polymorphisms in patients with asbestos-associated mesothelioma.}, journal = {Infect Agent Cancer}, volume = {7}, year = {2012}, month = {2012}, pages = {25}, abstract = {

UNLABELLED:

BACKGROUND: An increasing incidence of malignant mesothelioma (MM) cases in patients with low levels of asbestos exposure suggests the interference of alternative cofactors. SV40 infection was detected, as co-morbidity factor, only in 22\% of asbestos-MM patients from a North-Eastern Italy area. An additional mechanism of injury related to asbestos exposure in MM development has been recently associated to inflammatory responses, principally driven by interleukin (IL)-1 beta ({\ss}) activated within the inflammasome complex.NLRP3 inflammosome has been described as the intracellular sensor for asbestos able to induce inflammasome activation and IL-1{\ss} secretion while NLRP1 is expressed in lung epithelial cells and alveolar macrophages and contributes to the immune response and to survival/apoptosis balance. This study proposes to evaluate the impact of known NLRP3 and NLRP1 polymorphisms in the individual susceptibility to asbestos-induced mesothelioma in subjects from a hyperendemic area for MM.

METHODS: 134 Italian patients with diagnosis of mesothelioma due (MMAE, n=69) or not (MMAF, n=65) to asbestos, 256 healthy Italian blood donors and 101 Italian healthy subjects exposed to asbestos (HCAE) were genotyped for NLRP1 (rs2670660 and rs12150220) and NLRP3 (rs35829419 and rs10754558) polymorphisms.

RESULTS: While NLRP3 SNPs were not associated to mesothelioma, the NLRP1 rs12150220 allele T was significantly more frequent in MMAE (0.55) than in HCAE (0.41) (p=0.011; OR=1.79) suggesting a predisponent effect of this allele on the development of mesothelioma. This effect was amplified when the NLRP1 rs2670660 allele was combined with the NLRP1 rs12150220 allele (p=0.004; OR=0.52).

CONCLUSION: Although NLRP3 SNPs was not involved in mesothelioma predisposition, these data proposed NLRP1 as a novel factor possibly involved in the development of mesothelioma.

}, issn = {1750-9378}, doi = {10.1186/1750-9378-7-25}, author = {Girardelli, Martina and Maestri, Iva and Rinaldi, Rosa R and Tognon, Mauro and Boldorini, Renzo and Bovenzi, Massimo and Crovella, Sergio and Comar, Manola} } @article {1923, title = {Simian virus 40 efficiently infects human T lymphocytes and extends their lifespan.}, journal = {Exp Hematol}, volume = {40}, year = {2012}, month = {2012 Jun}, pages = {466-76}, abstract = {

The relevance of viral infections to the onset and progression of human hematologic malignancies and other blood diseases is still a matter of active investigation. Purified human T lymphocytes isolated from the peripheral blood mononuclear cells of healthy blood donors were experimentally infected with simian virus 40 (SV40), a small DNA tumor virus. SV40-positive T lymphocytes extended their lifespan up to day 80 postinfection (PI). Expression of viral antigens, such as the large T antigen and the viral capsid protein VP1 from the early and late regions, respectively, was detected up to day 40 PI. SV40 viral progeny were continuously produced from day 10 to 40 PI. SV40 DNA sequences were detected in infected T cells for up to 80 days. Our data indicate that human T lymphocytes can be efficiently infected with SV40. Although T cells infected by SV40 were not immortalized, 30\% of these lymphocytes appeared to be morphologically transformed with an enlarged T-cell shape. Our investigation provides a simple model for studying the interactions of human T lymphocytes with this small DNA tumor virus and it might represent an experimental tool for investigating new biomarkers and targets for innovative therapeutic approaches.

}, keywords = {Antigens, Polyomavirus Transforming, Cell Line, Transformed, Cell Survival, Humans, Microscopy, Electron, Transmission, Simian virus 40, T-Lymphocytes}, issn = {1873-2399}, doi = {10.1016/j.exphem.2012.02.008}, author = {Mazzoni, Elisa and Rigolin, Gian Matteo and Alaribe, Franca Nneka and Pancaldi, Cecilia and Maniero, Stefania and Comar, Manola and Martini, Fernanda and Tognon, Mauro} } @article {1909, title = {Specific protein profile in cerebrospinal fluid from HIV-1-positive cART-treated patients affected by neurological disorders.}, journal = {J Neurovirol}, volume = {18}, year = {2012}, month = {2012 Oct}, pages = {416-22}, abstract = {

Cytokines/chemokines are involved in the immune response of infections, including HIV-1. We defined the profile of 48 cytokines/chemokines in cerebrospinal fluid from 18 cART patients with chronic HIV-1 infection by Luminex technology. Nine patients were affected with leukoencephalopathies: five with John Cunningham virus (JCV) + progressive multifocal leukoencephalopathy (PML) and four with JCV-not determined leukoencephalopathy (NDLE). In addition, nine HIV-1-positive patients with no neurological signs (NND) and five HIV-1-negative patients affected with acute disseminated encephalomyelitis (ADEM) were enrolled. Ten cytokines (IL-15, IL-3, IL-16, IL-18, CTACK, GRO1, SCF, MCP-1, MIF, SDF) were highly expressed in HIV-1-positive patients while IL-1Ra and IL-17 were present at a lower level. In addition, the levels of IL-17, IL-9, FGF-basic, MIP-1β, and MCP-1 were significantly higher (p < 0.05) in patients with neurological diseases (PML, NDLE, ADEM) with respect to NND. Focusing the attention to the cytokine profile in JCV + PML patients with respect to JCV-NDLE patients, only TNF-β was significantly downregulated (p < 0.05) in JCV + PML patients. This pilot study emphasized the role of immunoregulation in HIV-1-related neurological disorders during cART treatment.

}, keywords = {Adult, Aged, Anti-HIV Agents, Cytokines, Encephalomyelitis, Acute Disseminated, Female, HIV Infections, HIV-1, Humans, Leukoencephalopathy, Progressive Multifocal, Male, Middle Aged, Pilot Projects}, issn = {1538-2443}, doi = {10.1007/s13365-012-0109-y}, author = {Zanin, Valentina and Delbue, Serena and Marcuzzi, Annalisa and Tavazzi, Eleonora and Del Savio, Rossella and Crovella, Sergio and Marchioni, Enrico and Ferrante, Pasquale and Comar, Manola} } @article {1778, title = {High prevalence of BK polyomavirus sequences in human papillomavirus-16-positive precancerous cervical lesions.}, journal = {J Med Virol}, volume = {83}, year = {2011}, month = {2011 Oct}, pages = {1770-6}, abstract = {

High- and low-grade cervical lesions were analyzed for the presence of polyomavirus (PYV) and human papillomavirus (HPV) sequences. In precancerous cervical lesions, the overall prevalence of PYV sequences was 44\% (41/93). Specifically, among the PYV-positive samples, 83\% (34/41) tested positive for BK polyomavirus (BKV) sequences, whereas 17\% (7/41) were positive for JC-virus. None of the samples were positive for simian virus 40. The presence of BKV DNA in high-grade squamous intraepithelial lesions was confirmed by in situ PCR. BKV sequences were detected more frequently in high-grade squamous intraepithelial lesions, together with the genotype HPV-16. The association of BKV with precancerous cervical lesions suggests that this polyomavirus participates with HPV-16 in the cell transformation process. Alternatively, BKV might multiply better in HPV-16-positive cells from precancerous cervical lesions than in HPV-16-negative cells.

}, keywords = {Adult, BK Virus, Cervical Intraepithelial Neoplasia, Cervix Uteri, DNA, Viral, Female, Human papillomavirus 16, Human papillomavirus 18, Human papillomavirus 31, Humans, JC Virus, Middle Aged, Oncogene Proteins, Viral, Papillomavirus Infections, Precancerous Conditions, Simian virus 40, Uterine Cervical Diseases}, issn = {1096-9071}, doi = {10.1002/jmv.22184}, author = {Comar, Manola and Bonifacio, Daniela and Zanconati, Fabrizio and Di Napoli, Michela and Isidoro, Erica and Martini, Fernanda and Torelli, Lucio and Tognon, Mauro} } @article {1743, title = {Merkel cell polyomavirus DNA sequences in the buffy coats of healthy blood donors.}, journal = {Blood}, volume = {117}, year = {2011}, month = {2011 Jun 30}, pages = {7099-101}, abstract = {

Merkel cell polyomavirus (MCPyV), a DNA tumor virus, has been found to be associated with Merkel cell carcinoma and chronic lymphocytic leukemia. MCPyV sequences have also been detected in various normal tissues in tumor-affected patients. Immunologic studies have detected MCPyV antibodies in as many as 80\% of healthy blood donors. This high seroprevalence suggests that MCPyV infection is widespread in humans. In our study, buffy coats, which were examined for MCPyV DNA Tag sequences, showed a prevalence of 22\%. Viral DNA load was revealed in blood samples from 10 to 100 molecules/100 000 cells. DNA sequencing confirmed that polymerase chain reaction amplicons belong to the MCPyV strain, MKL-1. To interpret the putative role of MCPyV in chronic lymphocytic leukemia, we may infer that, during a long period of viral persistence in blood cells, this DNA tumor virus may generate mutants, which are able to participate as cofactors in the multistep process of cell transformation.

}, keywords = {Adult, Aged, Base Sequence, Blood Buffy Coat, Carcinoma, Merkel Cell, Databases, Nucleic Acid, DNA, Viral, Expressed Sequence Tags, Humans, Italy, Middle Aged, Molecular Sequence Data, Polymerase Chain Reaction, Polyomavirus, Polyomavirus Infections, Prevalence, Reverse Transcriptase Polymerase Chain Reaction, Sequence Alignment, Sequence Analysis, DNA, Tumor Virus Infections, Viral Load, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2010-09-310557}, author = {Pancaldi, Cecilia and Corazzari, Valentina and Maniero, Stefania and Mazzoni, Elisa and Comar, Manola and Martini, Fernanda and Tognon, Mauro} } @article {1606, title = {A molecular case-control study of the Merkel cell polyomavirus in colon cancer.}, journal = {J Med Virol}, volume = {83}, year = {2011}, month = {2011 Apr}, pages = {721-4}, abstract = {

To explore the putative role of the Merkel cell polyomavirus in human colon cancer, a prospective molecular case-control study was undertaken in patients and their relatives enrolled during a screening program. Fresh tissue samples from 64 cases of colon cancer (mean age 69.9 {\textpm} 11.0 years; 40 males) and fresh biopsies from 80 relatives (mean age 53.7 {\textpm} 8.6 years; 43 male; 55 son/daughter, 23 brother/sister, 2 parents) were analyzed by PCR and sequencing. Pre-cancerous lesions, namely adenomas and polyps, were detected in 15 (18.8\%) and 9 (11.2\%) of the controls, respectively. In addition, 144 blood samples were examined. Merkel cell polyomavirus DNA was detected in 6.3\% of cases and 8.8\% of controls. This difference was not statistically significant in the logistic regression analysis, after adjustment for age. Whereas blood samples from both cases and controls tested negative, the DNA Merkel cell polyomavirus was identified in 12.5\% of adenoma/polyp tissues. No statistically significant difference was found when prevalence rates of Merkel cell polyomavirus in normal, pre-cancerous and cancer tissues were compared. Sequence analysis of the viral LT3 and VP1 regions showed high homology (>99\%) with those of strains circulating worldwide, especially with genotypes detected in France. The findings of this survey are consistent with the hypothesis that the Merkel cell polyomavirus, in addition to other human polyomaviruses, can be recovered frequently from the gastrointestinal tract, because it is transmitted throughout the fecal-oral route. Moreover, the study does not indicate a role for Merkel cell polyomavirus in the genesis of colon cancer.

}, keywords = {Aged, Aged, 80 and over, Case-Control Studies, Cluster Analysis, Colonic Neoplasms, DNA, Viral, Female, Genotype, Humans, Italy, Male, Merkel Cells, Middle Aged, Molecular Sequence Data, Polymerase Chain Reaction, Polyomavirus, Polyomavirus Infections, Prevalence, Sequence Analysis, DNA, Tumor Virus Infections}, issn = {1096-9071}, doi = {10.1002/jmv.22004}, author = {Campello, Cesare and Comar, Manola and D{\textquoteright}Agaro, Pierlanfranco and Minicozzi, Anna and Rodella, Luca and Poli, Albino} } @article {1607, title = {Secondary lymphoid tissue as an important site for WU polyomavirus infection in immunocompetent children.}, journal = {J Med Virol}, volume = {83}, year = {2011}, month = {2011 Aug}, pages = {1446-50}, abstract = {

The polyomaviruses KI and WU (KIPyV and WUPyV) have been identified in respiratory specimens from children with acute respiratory infections, which suggests the respiratory tract as a possible site of infection. However, the persistence of infection in the lymphoid system is unknown. Fresh samples (n = 211) of tonsils, adenoids, and peripheral blood mononuclear cells (PBMCs) from 83 immunocompetent children (mean age 4.8 years) were tested for amplification of the KIPyV VP1 and WUPyV VP2 genes. The known BK and JC polyomaviruses and the lymphotropic human herpesvirus (HHV)-6 were also investigated by quantitative real-time PCR and direct sequencing. In addition, 98 nasopharyngeal swabs collected from children (mean age 6.2 years) affected by seasonal influenza-like illness were tested. Of the lymphoid tissues, 34.9\% were positive for WUPyV, 4.8\% for BK virus, and 33.8\% for HHV-6. KIPyV and JC virus were not detected in these specimens. None of the polyomaviruses were detected in PBMCs. Among the nasopharyngeal samples, the prevalence of WUPyV was 27.5\%, although 70\% of the positive samples were co-infected with at least one of the following respiratory viruses: influenza virus, adenovirus, and respiratory syncytial virus. Phylogenetic analysis revealed high sequence homology (99\%) between lymphoid- and nasopharynx-derived WUPyV strains. These results suggest that the tonsils and adenoids of immunocompetent children are a reservoir for WUPyV infection; probably due to the respiratory route of transmission. In addition, the prevalence of WUPyV was high among the children, and the virus was identified more frequently in older children than during the first years of life.

}, keywords = {Adenoids, Child, Child, Preschool, DNA, Viral, Female, Humans, Infant, Leukocytes, Mononuclear, Male, Nasopharynx, Palatine Tonsil, Phylogeny, Polymerase Chain Reaction, Polyomavirus, Polyomavirus Infections, Prevalence, Sequence Analysis, DNA, Sequence Homology}, issn = {1096-9071}, doi = {10.1002/jmv.22124}, author = {Comar, Manola and Zanotta, Nunzia and Rossi, Tatiana and Pelos, Giorgio and D{\textquoteright}Agaro, Pierlanfranco} } @article {1721, title = {The significance of mannose-binding lectin gene polymorphisms on the risk of BK virus coinfection in women with human papillomavirus-positive cervical lesions.}, journal = {Hum Immunol}, volume = {72}, year = {2011}, month = {2011 Aug}, pages = {663-6}, abstract = {

The simultaneous detection of oncogenic human papillomavirus (HPV) and BK virus (BKV) has been recently reported in cervical cancers, suggesting that these viruses may act together in the process of cell transformation; host genetic polymorphisms may also influence virus persistence/reactivation. To disclose a possible role of the gene encoding for the mannose-binding lectin, MBL2, in susceptibility to BKV infection, we analyzed functional polymorphisms in the first exon of MBL2 in women stratified for the presence/absence of BKV and affected by different grades of HPV-induced cervical precancerous lesions. All BKV-positive samples were also HPV positive (HPV 16), and all presented with high-grade squamous intraepithelial lesions. The MBL2 A allele was significantly more frequent in BKV-negative patients than in BKV-positive patients. These data indicate a possible role for the A allele in conferring protection to BKV infection in high-risk HPV-positive women (odds ratio 0.40, 95\% confidence interval 0.20-0.85, p = 0.01).

}, keywords = {Adult, Aged, Alleles, BK Virus, Cervical Intraepithelial Neoplasia, Cervix Uteri, DNA Fingerprinting, DNA, Viral, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Human papillomavirus 16, Humans, Italy, Mannose-Binding Lectin, Odds Ratio, Papillomavirus Infections, Polymorphism, Genetic, Polyomavirus Infections, Risk, Viral Load}, issn = {1879-1166}, doi = {10.1016/j.humimm.2011.04.002}, author = {Comar, Manola and Segat, Ludovica and Crovella, Sergio and Bovenzi, Massimo and Cortini, Enzo and Tognon, Mauro} } @article {1632, title = {Detection of SV40 in colon cancer: a molecular case-control study from northeast Italy.}, journal = {J Med Virol}, volume = {82}, year = {2010}, month = {2010 Jul}, pages = {1197-200}, abstract = {

To explore the involvement of the simian polyomavirus SV40 in human colon cancer, a molecular case-control study was undertaken in patients and in their relatives living in an area where the spread of SV40 has already been documented. From 2006 to 2008, 94 colon cancer patients (age: 37-90 years) and 91 subjects (age: 32-70 years) relatives of each index case were enrolled. A blood sample and a specimen of cancer tissue or biopsy were collected, from each patient or control, respectively. Samples were analyzed twice for Polyomavirus (i.e., SV40, JCV, and BKV) by PCR and by quantitative real-time PCR (RT-qPCR) with reproducible results. No BKV/JCV was detected either in normal or pathological tissues. SV40 was not present in control subjects, either normal tissue or in biopsies from adenomas or polyps. All blood samples were negative. Conversely, six adenocarcinoma specimens were positive for SV40 sequences (overall prevalence 6.4\%, P = 0.03 in comparison with controls). Nevertheless, the SV40-associated colon cancer risk proved statistically not significant (OR = 3.91; P = 0.115) when adjusted for age. Quantitation of SV40 DNA performed by RT-qPCR showed a low viral load ranging from 6.2 x 10(1) to 9 x 10(3) copies per reaction. This molecular case-control survey showed, for the first time in fresh samples and by RT-qPCR, that SV40 can be detected in colon cancer tissue. However, the finding was not statistically significant when compared with a well-structured community control group. Thus, the role of SV40 and other polyomavirus in colon cancer genesis deserves further investigation.

}, keywords = {Adenocarcinoma, Adult, Aged, Aged, 80 and over, BK Virus, Case-Control Studies, Colonic Neoplasms, DNA, Viral, Female, Humans, Italy, JC Virus, Male, Middle Aged, Polymerase Chain Reaction, Polyomavirus Infections, Simian virus 40, Tumor Virus Infections}, issn = {1096-9071}, doi = {10.1002/jmv.21798}, author = {Campello, Cesare and Comar, Manola and Zanotta, Nunzia and Minicozzi, Anna and Rodella, Luca and Poli, Albino} } @article {1640, title = {JCV/BKV and SV40 viral load in lymphoid tissues of young immunocompetent children from an area of north-east Italy.}, journal = {J Med Virol}, volume = {82}, year = {2010}, month = {2010 Jul}, pages = {1236-40}, abstract = {

Polyomavirus infection occurring during childhood is followed by a lifelong latency in immunocompetent subjects. The major site of polyomavirus persistence are the uroepithelial cells which leads to oral transmission. It has recently been hypothesized that tonsils could be a possible reservoir. The role of tonsil, adenoid, and peripheral blood mononuclear cells (PBMCs) as possible sites of JCV, BKV, and SV40 latency in young healthy children was assessed. Two hundred fifteen fresh specimens, including 57 tonsil, 80 adenoid, and 78 PBMC samples from 80 immunocompetent children (mean age 4.8 years) were analyzed to determine the viral load by quantitative real-time PCR. The human herpes virus 6 (HHV-6) was tested as a lymphotropic reference virus. Polyomavirus was detected in 5/80 (6.2\%) children while HHV-6 infection affected 27/80 children (33.7\%) (P < 0.001). SV40 was detected in one adenoid sample, while footprints of BKV were found in one adenoid and three tonsil samples. JCV was never found in all samples. Polyomavirus sequences were not detected in the 78 blood samples. One adenoid and two tonsils from three children (1.4\%) were positive for both polyomavirus and HHV-6. Infections were characterized by low replication rates ranging typically from 1 x 10e(2)/5.5 x 10e(4) to 6.8 x 10e(3)/8.5 x 10e(4) viral copies/number of cells. In conclusion, tonsils and adenoids of children could effectively harbor BKV and SV40, although only very few cells proved to be infected. Nevertheless, the low prevalence of polyomavirus, in comparison with the lymphotropic HHV-6, suggests that these tissues are unlikely to be the preferred site of polyomavirus latency, at least in younger children.

}, keywords = {Adenoids, BK Virus, Carrier State, Child, Child, Preschool, Female, Herpesvirus 6, Human, Humans, Immunocompetence, Italy, JC Virus, Male, Neutrophils, Palatine Tonsil, Polyomavirus Infections, Simian virus 40, Viral Load, Virus Latency}, issn = {1096-9071}, doi = {10.1002/jmv.21786}, author = {Comar, Manola and Zanotta, Nunzia and Bovenzi, Massimo and Campello, Cesare} }