Serum IgG antibodies from pregnant women reacting to mimotopes of simian virus 40 large T antigen, the viral oncoprotein

Simian virus 40 (SV40) large T antigen (LT) coding sequences were revealed in different human samples, whereas SV40 antibodies (Ab) were detected in human sera of cancer patients and healthy individuals, although with a lower prevalence. Previous studies carried out by the neutralization assay gave a SV40 seroprevalence, in the general population, up to 8%, although higher rates, 12%, were detected in kidney transplant children, in a group of HIV-positive patients, and in healthy females. In this study, serum samples from pregnant women, together with those from non-pregnant women, were analyzed to check the prevalence of IgG Ab reacting to SV40 LT antigens. Serum samples were collected from pregnant and non-pregnant women, with the same mean age. Women were in the range of 15-48 years old. Samples were assayed by an indirect ELISA employing specific SV40 LT mimotopes as antigens, whereas functional analysis was performed by neutralization of the viral infectivity in cell cultures. As a control, sera were analyzed for Ab against BK polyomavirus (BKPyV), which is a human polyomavirus homologous to SV40. Statistical analyses employed chi-square with Yates' correction, and Student's t tests. Indirect ELISAs indicated that pregnant women tested SV40 LT-positive with a prevalence of 17% (23/134), whereas non-pregnant women had a prevalence of 20% (36/180) (P > 0.05). Ab against BKPyV were detected with a prevalence of 80% in pregnant women and with a prevalence of 78% in non-pregnant women. These data indicate that SV40 infects at a low prevalence pregnant women. We may speculate that SV40, or a close human polyomavirus still undetected, could be transmitted from mother to fetus

Hydroxylapatite-collagen hybrid scaffold induces human adipose-derived mesenchymal stem cells to osteogenic differentiation in vitro and bone regrowth in patients

Tissue engineering-based bone graft is an emerging viable treatment modality to repair and regenerate tissues damaged as a result of diseases or injuries. The structure and composition of scaffolds should modulate the classical osteogenic pathways in human stem cells. The osteoinductivity properties of the hydroxylapatite-collagen hybrid scaffold named Coll/Pro Osteon 200 were investigated in an in vitro model of human adipose mesenchymal stem cells (hASCs), whereas the clinical evaluation was carried out in maxillofacial patients. Differentially expressed genes (DEGs) induced by the scaffold were analyzed using the Osteogenesis RT2 PCR Array. The osteoinductivity potential of the scaffold was also investigated by studying the alkaline phosphatase (ALP) activity, matrix mineralization, osteocalcin (OCN), and CLEC3B expression protein. Fifty patients who underwent zygomatic augmentation and bimaxillary osteotomy were evaluated clinically, radiologically, and histologically during a 3-year follow-up. Among DEGs, osteogenesis-related genes, including BMP1/2, ALP, BGLAP, SP7, RUNX2, SPP1, and EGFR, which play important roles in osteogenesis, were found to be upregulated. The genes to cartilage condensation SOX9, BMPR1B, and osteoclast cells TNFSF11 were detected upregulated at every time point of the investigation. This scaffold has a high osteoinductivity revealed by the matrix mineralization, ALP activity, OCN, and CLEC3B expression proteins. Clinical evaluation evidences that the biomaterial promotes bone regrowth. Histological results of biopsy specimens from patients showed prominent ossification. Experimental data using the Coll/Pro Osteon 200 indicate that clinical evaluation of bone regrowth in patients, after scaffold implantation, was supported by DEGs implicated in skeletal development as shown in "in vitro" experiments with hASCs

Serum IgG against Simian Virus 40 antigens are hampered by high levels of sHLA-G in patients affected by inflammatory neurological diseases, as multiple sclerosis

Background: Many investigators detected the simian polyomavirus SV40 footprints in human brain tumors and neurologic diseases and recently it has been indicated that SV40 seems to be associated with multiple sclerosis (MS) disease. Interestingly, SV40 interacts with human leukocyte antigen (HLA) class I molecules for cell entry. HLA class I antigens, in particular non-classical HLA-G molecules, characterized by an immune-regulatory function, are involved in MS disease, and the levels of these molecules are modified according with the disease status. Objective: We investigated in serum samples, from Italian patients affected by MS, other inflammatory diseases (OIND), non-inflammatory neurological diseases (NIND) and healthy subjects (HS), SV40-antibody and soluble sHLA-G and the association between SV40-prevalence and sHLA-G levels. Methods: ELISA tests were used for SV40-antibodies detection and sHLA-G quantitation in serum samples. Results: The presence of SV40 antibodies was observed in 6 % of patients affected by MS (N = 4/63), 10 % of OIND (N = 8/77) and 15 % of NIND (N = 9/59), which is suggestive of a lower prevalence in respect to HS (22 %, N = 18/83). MS patients are characterized by higher sHLA-G serum levels (13.9 \ub1 0.9 ng/ml; mean \ub1 St. Error) in comparison with OIND (6.7 \ub1 0.8 ng/ml), NIND (2.9 \ub1 0.4 ng/ml) and HS (2.6 \ub1 0.7 ng/ml) subjects. Interestingly, we observed an inverse correlation between SV40 antibody prevalence and sHLA-G serum levels in MS patients. Conclusion: The data obtained showed a low prevalence of SV40 antibodies in MS patients. These results seems to be due to a generalized status of inability to counteract SV40 infection via antibody production. In particular, we hypothesize that SV40 immune-inhibitory direct effect and the presence of high levels of the immune-inhibitory HLA-G molecules could co-operate in impairing B lymphocyte activation towards SV40 specific peptides

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Roles of dysregulated Notch pathway and small DNA tumor viruses in cancer initiation and progression

Notch pathway is a major determinant of cell fate, and research within the last 30 years has shown dysfunctions within this pathway in the majority of solid tumors and leukemias. The molecular mechanisms causing aberrant expression of Notch in cancer are still partially known. Mesotheliomas, breast, and cervical cancers are among the cancer types for which the dysregulation of Notch has been reported together with the association of simian virus 40 (SV40) or human papillomavirus (HPV) infections. In mesotheliomas and cervical cancer, there is clear evidence that these viruses cause and rely on dysregulation of the Notch pathway to promote and sustain cell transformation. The existence of a relationship in tumors between DNA viruses and Notch could have an impact on cancer therapy by implementing Notch inhibition to interfere with the growth of SV40- and HPV-positive cancers. In addition, since Notch links innate and acquired immunity and plays a key role in the regulation of the anti-viral response, targeting Notch in the presence of oncogenic viruses infections may help prevent the onset and progression of cancers associated with the exposure to these viruses

Premi Natta e Copernico www.preminattacopernico.it

Nel 2003, in occasione della ricorrenza del centenario della nascita di Giulio Natta (26.02.1903), Nobel per la Chimica (1963) per la scoperta del Polipropilene e del 500° anniversario del conferimento della laurea a Nicolò Copernico avvenuta presso l’Ateneo Ferrarese il 31.05.1503, vengono istituiti i premi "Giulio Natta e Nicolò Copernico" per la Ricerca scientifica e l'innovazione tecnologica. I premi “Giulio Natta e Nicolò Copernico”, sono stati promossi dall’omonimo Comitato Fondatore e nascono da un’idea del Prof. Mauro Tognon, condivisa dal Lion Club Portomaggiore-San Giorgio, dal Prof. Pietro Dalpiaz e dal Prof. Paolo Galli. Lo scopo principale dell’istituzione dei premi in oggetto è la divulgazione della Scienza e della Tecnica. I premi “Giulio Natta e Nicolò Copernico” vengono attribuiti ogni anna dal 2003, rispettivamente a un Ricercatore affermato e ad un giovane Ricercatore

Premi Natta e Copernico www.preminattacopernico.it

Nel 2003, in occasione della ricorrenza del centenario della nascita di Giulio Natta (26.02.1903), Nobel per la Chimica (1963) per la scoperta del Polipropilene e del 500° anniversario del conferimento della laurea a Nicolò Copernico avvenuta presso l’Ateneo Ferrarese il 31.05.1503, vengono istituiti i premi "Giulio Natta e Nicolò Copernico" per la Ricerca scientifica e l'innovazione tecnologica. I premi “Giulio Natta e Nicolò Copernico”, sono stati promossi dall’omonimo Comitato Fondatore e nascono da un’idea del Prof. Mauro Tognon, condivisa dal Lion Club Portomaggiore-San Giorgio, dal Prof. Pietro Dalpiaz e dal Prof. Paolo Galli. Lo scopo principale dell’istituzione dei premi in oggetto è la divulgazione della Scienza e della Tecnica. I premi “Giulio Natta e Nicolò Copernico” vengono attribuiti ogni anna dal 2003, rispettivamente a un Ricercatore affermato e ad un giovane Ricercatore

Premi Natta e Copernico www.preminattacopernico.it

.Nel 2003, in occasione della ricorrenza del centenario della nascita di Giulio Natta (26.02.1903), Nobel per la Chimica (1963) per la scoperta del Polipropilene e del 500° anniversario del conferimento della laurea a Nicolò Copernico avvenuta presso l’Ateneo Ferrarese il 31.05.1503, vengono istituiti i premi "Giulio Natta e Nicolò Copernico" per la Ricerca scientifica e l'innovazione tecnologica. I premi “Giulio Natta e Nicolò Copernico”, sono stati promossi dall’omonimo Comitato Fondatore e nascono da un’idea del Prof. Mauro Tognon, condivisa dal Lion Club Portomaggiore-San Giorgio, dal Prof. Pietro Dalpiaz e dal Prof. Paolo Galli. Lo scopo principale dell’istituzione dei premi in oggetto è la divulgazione della Scienza e della Tecnica. I premi “Giulio Natta e Nicolò Copernico” vengono attribuiti ogni anna dal 2003, rispettivamente a un Ricercatore affermato e ad un giovane Ricercatore