@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 {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 {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 {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 {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 {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 {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 {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} }