The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Michele Carbone - One of the best experts on this subject based on the ideXlab platform.
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molecular pathways targeting mechanisms of asbestos and erionite carcinogenesis in Mesothelioma
Clinical Cancer Research, 2012Co-Authors: Michele Carbone, Haining YangAbstract:Malignant Mesothelioma is an aggressive malignancy related to asbestos and erionite exposure. AP-1 transcriptional activity and the NF-κB signaling pathway have been linked to mesothelial cell transformation and tumor progression. HGF and c-Met are highly expressed in Mesotheliomas. Phosphoinositide 3-kinase, AKT, and the downstream mTOR are involved in cell growth and survival, and they are often found to be activated in Mesothelioma. p16(INK4a) and p14(ARF) are frequently inactivated in human Mesothelioma, and ∼50% of Mesotheliomas contain the NF2 mutation. Molecular therapies aimed at interfering with these pathways have not improved the dismal prognosis of Mesothelioma, except possibly for a small subset of patients who benefit from certain therapies. Recent studies have shown the importance of asbestos-induced inflammation in the initiation and growth of Mesothelioma, and HMGB1 and Nalp3 inflammasome have been identified as key initiators of this process. Asbestos induces cell necrosis, causing the release of HMGB1, which in turn may activate Nalp3 inflammasome, a process that is enhanced by asbestos-induced production of reactive oxygen species. HMGB1 and Nalp3 induce proinflammatory responses and lead to interleukin-1β and TNF-α secretion and NF-κB activity, thereby promoting cell survival and tumor growth. Novel strategies that interfere with asbestos- and erionite-mediated inflammation might prevent or delay the onset of Mesothelioma in high-risk cohorts, including genetically predisposed individuals, and/or inhibit tumor growth. The very recent discovery that germline BAP1 mutations cause a new cancer syndrome characterized by Mesothelioma, uveal melanoma, and melanocytic tumors provides researchers with a novel target for prevention and early detection.
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A cytokeratin- and calretinin-negative staining sarcomatoid malignant Mesothelioma.
Anticancer Research, 2004Co-Authors: Michael G. Hurtuk, Michele CarboneAbstract:Malignant Mesothelioma, or Mesothelioma, is a mesothelial-based malignancy that may occur in the pleura, pericardium and peritoneum. Mesothelioma is a very aggressive cancer with limited treatment, and a median survival of about 1 year. At times, the diagnosis of Mesothelioma may be problematic. The final diagnosis of Mesothelioma relies on histology and often is dependent upon immunohistochemistry. It is generally assumed that Mesotheliomas must stain positive for cytokeratin and calretinin and negative staining for these markers would rule out the diagnosis. We encountered a patient with a pleural-based, cytokeratin- and calretinin-negative sarcomatoid malignancy. These negative stainings would rule out the diagnosis of Mesothelioma but, after careful consideration of the patient's clinical records, and additional histological and immunohistochemical studies, we conclude that this patient suffered from Mesothelioma of the sarcomatoid type.
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The pathogenesis of Mesothelioma
Seminars in oncology, 2002Co-Authors: Michele Carbone, Robert A. Kratzke, Joseph R. TestaAbstract:Abstract About 80% of malignant Mesotheliomas (MM) in the Western World develop in individuals with higher than background exposure to asbestos. Only a fraction of those exposed to asbestos develop Mesothelioma, indicating that additional factors play a role. Simian virus 40 (SV40), a DNA tumor virus that preferentially causes Mesothelioma in hamsters, has been detected in several human Mesotheliomas. The expression of the SV40 large tumor antigen in Mesothelioma cells, and not in nearby stromal cells, and the capacity of antisense T-antigen treatment to arrest Mesothelioma cell growth in vitro suggest that SV40 contributes to tumor development. The capacity of T-antigen to bind and inhibit cellular p53 and retinoblastoma (Rb)-family proteins in Mesothelioma, together with the very high susceptibility of human mesothelial cells to SV40-mediated transformation in vitro, supports a causative role of SV40 in the pathogenesis of Mesothelioma. Asbestos appears to increase SV40-mediated transformation of human mesothelial cells in vitro, suggesting that asbestos and SV40 may be cocarcinogens. p53 mutations are rarely found in Mesothelioma; p16, p14ARF, and NF2 mutations/losses are frequent. Recent studies revealed the existence of a genetic factor that predisposes affected individuals to Mesothelioma in the villages of Karain and Tuzkoy, in Anatolia, Turkey. Erionite, a type of zeolite, may be a cofactor in these same villages, where 50% of deaths are caused by Mesothelioma. Mesothelioma appears to have a complex etiology in which environmental carcinogens (asbestos and erionite), ionizing radiation, viruses, and genetic factors act alone or in concert to cause malignancy. Semin Oncol 29:2-17. Copyright © 2002 by W.B. Saunders Company.
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human Mesotheliomas contain the simian virus 40 regulatory region and large tumor antigen dna sequences
The Journal of Thoracic and Cardiovascular Surgery, 1998Co-Authors: Jessica S Donington, Paola Rizzo, Harvey I. Pass, Michael Nishimura, Ronald C Kennedy, Michele CarboneAbstract:Abstract Background: A cohort (20%) of patients with Mesothelioma will not have an exposure to asbestos. Recently, a DNA tumor virus (simian virus 40) has been shown to cause hamster Mesotheliomas; we previously described simian virus 40–like DNA amino terminus sequences in 29 of 48 Mesotheliomas. We analyzed an additional 42 Mesotheliomas to determine (1) whether our initial observations were durable and (2) the extent to which the simian virus 40 genome is present in Mesotheliomas. Methods: Genomic DNA was extracted from snap frozen Mesothelioma tumor samples and from the simian virus 40–induced hamster Mesothelioma tumor H9A. Polymerase chain reaction primers were used to amplify various simian virus 40 large T-antigen regions including a 105–base pair amino terminus fragment, a 281–base pair carboxyl terminus fragment, and a 310–base pair fragment of the enhancer promoter region. Endonuclease digestions and Southern blotting were used to verify the expected product. Results: Thirty of the 42 (71%) samples amplified T-antigen amino sequences, and specificity was verified by Southern hybridization. Sixteen of 42 samples (38%) amplified the appropriate size fragment for the carboxyl terminus, and digestion with BsaB1 matched that of H9A. Twenty-two of 42 samples (52%) amplified simian virus 40 regulatory sequences and Fok 1 digestion matched that of the hamster control tumor. Sequence analysis (4 patients) revealed 100% homology with the regulatory region of simian virus 40 strain 776. Conclusions: These data suggest an association between the simian virus 40 virus and human Mesothelioma that could be exploited for diagnostic/therapeutic options including early detection and potential vaccination strategies. (J Thorac Cardiovasc Surg 1998;116:854-9)
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a multi institutional study confirms the presence and expression of simian virus 40 in human malignant Mesotheliomas
Cancer Research, 1998Co-Authors: Joseph R. Testa, Michele Carbone, Paola Rizzo, Ari Hirvonen, Kamel Khalili, Barbara Krynska, Kaija Linnainmaa, Frederick D Pooley, Valerie W Rusch, Guanghui XiaoAbstract:Abstract Exposure to the carcinogen asbestos is a major factor in the development of malignant Mesothelioma. However, not all Mesotheliomas are associated with asbestos exposure, and only a small minority of people exposed to asbestos develop Mesothelioma. Therefore, the identification of the cofactors that render certain individuals more susceptible to asbestos or that cause Mesothelioma in people not exposed to asbestos has been a major priority of the International Mesothelioma Interest Group. The possible association of SV40 with Mesothelioma was recently discussed in a special session at the Fourth International Mesothelioma Interest Group Conference, and it was decided to conduct a multi-institutional study to independently verify the presence of this tumor virus in Mesotheliomas. We report the results of this investigation: (a) DNA and protein analyses revealed SV40 sequences and SV40 large T antigen expression in 10 of 12 Mesotheliomas tested (83%); and (b) electron microscopy demonstrated variable amounts of asbestos fibers in 5 (71%) of 7 corresponding lung tissues available for analysis. Our results demonstrate that SV40 DNA is frequently present and expressed in Mesotheliomas in the United States. Because our data demonstrate that some patients test positive for both SV40 and asbestos, the possibility that these two carcinogens interact should be investigated in future studies.
Paola Rizzo - One of the best experts on this subject based on the ideXlab platform.
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human Mesotheliomas contain the simian virus 40 regulatory region and large tumor antigen dna sequences
The Journal of Thoracic and Cardiovascular Surgery, 1998Co-Authors: Jessica S Donington, Paola Rizzo, Harvey I. Pass, Michael Nishimura, Ronald C Kennedy, Michele CarboneAbstract:Abstract Background: A cohort (20%) of patients with Mesothelioma will not have an exposure to asbestos. Recently, a DNA tumor virus (simian virus 40) has been shown to cause hamster Mesotheliomas; we previously described simian virus 40–like DNA amino terminus sequences in 29 of 48 Mesotheliomas. We analyzed an additional 42 Mesotheliomas to determine (1) whether our initial observations were durable and (2) the extent to which the simian virus 40 genome is present in Mesotheliomas. Methods: Genomic DNA was extracted from snap frozen Mesothelioma tumor samples and from the simian virus 40–induced hamster Mesothelioma tumor H9A. Polymerase chain reaction primers were used to amplify various simian virus 40 large T-antigen regions including a 105–base pair amino terminus fragment, a 281–base pair carboxyl terminus fragment, and a 310–base pair fragment of the enhancer promoter region. Endonuclease digestions and Southern blotting were used to verify the expected product. Results: Thirty of the 42 (71%) samples amplified T-antigen amino sequences, and specificity was verified by Southern hybridization. Sixteen of 42 samples (38%) amplified the appropriate size fragment for the carboxyl terminus, and digestion with BsaB1 matched that of H9A. Twenty-two of 42 samples (52%) amplified simian virus 40 regulatory sequences and Fok 1 digestion matched that of the hamster control tumor. Sequence analysis (4 patients) revealed 100% homology with the regulatory region of simian virus 40 strain 776. Conclusions: These data suggest an association between the simian virus 40 virus and human Mesothelioma that could be exploited for diagnostic/therapeutic options including early detection and potential vaccination strategies. (J Thorac Cardiovasc Surg 1998;116:854-9)
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a multi institutional study confirms the presence and expression of simian virus 40 in human malignant Mesotheliomas
Cancer Research, 1998Co-Authors: Joseph R. Testa, Michele Carbone, Paola Rizzo, Ari Hirvonen, Kamel Khalili, Barbara Krynska, Kaija Linnainmaa, Frederick D Pooley, Valerie W Rusch, Guanghui XiaoAbstract:Abstract Exposure to the carcinogen asbestos is a major factor in the development of malignant Mesothelioma. However, not all Mesotheliomas are associated with asbestos exposure, and only a small minority of people exposed to asbestos develop Mesothelioma. Therefore, the identification of the cofactors that render certain individuals more susceptible to asbestos or that cause Mesothelioma in people not exposed to asbestos has been a major priority of the International Mesothelioma Interest Group. The possible association of SV40 with Mesothelioma was recently discussed in a special session at the Fourth International Mesothelioma Interest Group Conference, and it was decided to conduct a multi-institutional study to independently verify the presence of this tumor virus in Mesotheliomas. We report the results of this investigation: (a) DNA and protein analyses revealed SV40 sequences and SV40 large T antigen expression in 10 of 12 Mesotheliomas tested (83%); and (b) electron microscopy demonstrated variable amounts of asbestos fibers in 5 (71%) of 7 corresponding lung tissues available for analysis. Our results demonstrate that SV40 DNA is frequently present and expressed in Mesotheliomas in the United States. Because our data demonstrate that some patients test positive for both SV40 and asbestos, the possibility that these two carcinogens interact should be investigated in future studies.
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simian virus 40 large t antigen binds p53 in human Mesotheliomas
Nature Medicine, 1997Co-Authors: Michele Carbone, Paola Rizzo, Daphne J Y Mew, Antonio Procopio, V Esposito, Philip M Grimley, Viji Shridhar, Andrea De Bartolomeis, Maria Teresa Giuliano, Seth M SteinbergAbstract:We found that simian virus 40 (SV40) induces Mesotheliomas in hamsters and that 60% of human Mesotheliomas contain and express SV40 sequences, results now confirmed by others [ref. 3-5, and presentations by D. Griffiths & R. Weiss, F. Galateau-SallE, and H.I.P. at "Simian virus 40: A possible human polyoma virus," NIH workshop, 27-28 January 1997, Bethesda, MD (transcript available through SAG Corp., Washington, DC 20008)]. Mesothelioma, an aggressive malignancy resistant to therapy, originates from the serosal lining of the pleural, pericardial and peritoneal cavities. The incidence of Mesothelioma continues to increase worldwide because of exposure to crocidolite asbestos. However, at least 20% of Mesotheliomas in the United States are not associated with asbestos exposure, and only a minority of people exposed to high concentrations of asbestos develop Mesothelioma. Thus, other carcinogens may induce Mesothelioma in individuals not exposed to asbestos, and/or may render particular individuals more susceptible to the carcinogenic effect of asbestos. We investigated whether the expression of the SV40 large T-antigen (Tag) interferes with the normal expression of the tumor suppressor gene p53 in human Mesotheliomas. We found that SV40 Tag retains its ability to bind and to inactivate p53, a cellular protein that when normally expressed plays an important role in suppressing tumor growth and in inducing sensitivity to therapy. Our findings do not establish a cause-and-effect relation, but indicate that the possibility that SV40 contributes to the development of human Mesotheliomas should be carefully investigated.
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the retinoblastoma gene family prb p105 p107 prb2 p130 and simian virus 40 large t antigen in human Mesotheliomas
Nature Medicine, 1997Co-Authors: A De Luca, Paola Rizzo, Harvey I. Pass, V Esposito, Alfonso Baldi, G Giordano, M Caputi, Candace M Howard, Luigi Bagella, Feliciano BaldiAbstract:The oncoprotein of simian virus-40, SV40 large T-antigen (Tag), is reported to target and to inactivate growth suppressive proteins such as the retinoblastoma family and p53 (ref. 4, 5), leading to transformation of human cell lines in vitro, tumor production in rodents, and detection of Tag in several human cancers including Mesotheliomas. The retinoblastoma family contains three members, pRb, p107 and pRb2/p130 (ref. 9), that are phosphorylated in a cell cycle-dependent manner, have cell growth suppressive properties and bind to specific members of the E2F family and various cyclins. Even though Mesotheliomas are among the most aggressive human cancers, alterations of important cell-cycle "controllers," such as the Rb family genes, have never been reported in these tumors. We found the presence of SV40-like sequences in 86% of 35 archival specimens of Mesothelioma. We also demonstrated that SV40 Tag, isolated from frozen biopsies of human Mesothelioma, binds each of the retinoblastoma family proteins, pRb, p107 and pRb2/p130, in four of four specimens. We propose that the tumorigenic potential of SV40 Tag in some human Mesotheliomas may arise from its ability to interact with and thereby inactivate several tumor and/or growth suppressive proteins.
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simian virus 40 like dna sequences in human pleural Mesothelioma
Oncogene, 1994Co-Authors: Harvey I. Pass, Michele Carbone, Paola Rizzo, M Marinetti, M Di Muzio, Daphne J Y Mew, Arthur S Levine, Antonio ProcopioAbstract:Mesotheliomas are pleural, pericardial, or peritoneal neoplasms frequently associated with asbestos exposure, and it is estimated that over the next twenty years up to 80,000 new cases are expected in the USA alone. We found simian virus 40-like DNA sequences in 29 of 48 Mesotheliomas studied (60%) and demonstrated simian virus large-T antigen expression in 13 of 16 specimens. The matching lung samples did not contain simian virus 40-like sequences; however, they contained asbestos. These findings are to our knowledge the first demonstration of a physical link between DNA virus-like sequences and human Mesothelioma. We suggest that a simian virus 40-like virus may act independently or as a co-carcinogen with asbestos. Moreover, the selective large T antigen expression by Mesothelioma and not by the surrounding pulmonary parenchyma may have both diagnostic and therapeutic implications.
Harvey I. Pass - One of the best experts on this subject based on the ideXlab platform.
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human Mesotheliomas contain the simian virus 40 regulatory region and large tumor antigen dna sequences
The Journal of Thoracic and Cardiovascular Surgery, 1998Co-Authors: Jessica S Donington, Paola Rizzo, Harvey I. Pass, Michael Nishimura, Ronald C Kennedy, Michele CarboneAbstract:Abstract Background: A cohort (20%) of patients with Mesothelioma will not have an exposure to asbestos. Recently, a DNA tumor virus (simian virus 40) has been shown to cause hamster Mesotheliomas; we previously described simian virus 40–like DNA amino terminus sequences in 29 of 48 Mesotheliomas. We analyzed an additional 42 Mesotheliomas to determine (1) whether our initial observations were durable and (2) the extent to which the simian virus 40 genome is present in Mesotheliomas. Methods: Genomic DNA was extracted from snap frozen Mesothelioma tumor samples and from the simian virus 40–induced hamster Mesothelioma tumor H9A. Polymerase chain reaction primers were used to amplify various simian virus 40 large T-antigen regions including a 105–base pair amino terminus fragment, a 281–base pair carboxyl terminus fragment, and a 310–base pair fragment of the enhancer promoter region. Endonuclease digestions and Southern blotting were used to verify the expected product. Results: Thirty of the 42 (71%) samples amplified T-antigen amino sequences, and specificity was verified by Southern hybridization. Sixteen of 42 samples (38%) amplified the appropriate size fragment for the carboxyl terminus, and digestion with BsaB1 matched that of H9A. Twenty-two of 42 samples (52%) amplified simian virus 40 regulatory sequences and Fok 1 digestion matched that of the hamster control tumor. Sequence analysis (4 patients) revealed 100% homology with the regulatory region of simian virus 40 strain 776. Conclusions: These data suggest an association between the simian virus 40 virus and human Mesothelioma that could be exploited for diagnostic/therapeutic options including early detection and potential vaccination strategies. (J Thorac Cardiovasc Surg 1998;116:854-9)
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the retinoblastoma gene family prb p105 p107 prb2 p130 and simian virus 40 large t antigen in human Mesotheliomas
Nature Medicine, 1997Co-Authors: A De Luca, Paola Rizzo, Harvey I. Pass, V Esposito, Alfonso Baldi, G Giordano, M Caputi, Candace M Howard, Luigi Bagella, Feliciano BaldiAbstract:The oncoprotein of simian virus-40, SV40 large T-antigen (Tag), is reported to target and to inactivate growth suppressive proteins such as the retinoblastoma family and p53 (ref. 4, 5), leading to transformation of human cell lines in vitro, tumor production in rodents, and detection of Tag in several human cancers including Mesotheliomas. The retinoblastoma family contains three members, pRb, p107 and pRb2/p130 (ref. 9), that are phosphorylated in a cell cycle-dependent manner, have cell growth suppressive properties and bind to specific members of the E2F family and various cyclins. Even though Mesotheliomas are among the most aggressive human cancers, alterations of important cell-cycle "controllers," such as the Rb family genes, have never been reported in these tumors. We found the presence of SV40-like sequences in 86% of 35 archival specimens of Mesothelioma. We also demonstrated that SV40 Tag, isolated from frozen biopsies of human Mesothelioma, binds each of the retinoblastoma family proteins, pRb, p107 and pRb2/p130, in four of four specimens. We propose that the tumorigenic potential of SV40 Tag in some human Mesotheliomas may arise from its ability to interact with and thereby inactivate several tumor and/or growth suppressive proteins.
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neurofibromatosis type 2 nf2 gene is somatically mutated in Mesothelioma but not in lung cancer
Cancer Research, 1995Co-Authors: Yoshitaka Sekido, Harvey I. Pass, Daphne J Y Mew, Scott Bader, Michael F Christman, Adi F Gazdar, John D MinnaAbstract:We have found 16 of 28 small cell lung cancers, 17 of 31 non-small cell lung cancers, 2 of 3 carcinoids, and 12 of 14 Mesotheliomas that had chromosome 22 cytogenetic abnormalities. To determine whether the neurofibromatosis type 2 (NF2) gene located on chromosome 22 participates in the oncogenesis of these malignancies, we studied DNAs from lung cancer cell lines and Mesotheliomas using Southern blot analysis and the single-strand conformation polymorphism (SSCP) technique for mutations covering 8 of the 16 known NF2 exons. We detected 7 mutations in 17 Mesotheliomas (41%) within the coding region of NF2 but none in 75 lung cancer cell lines (38 small cell lung cancers, 34 non-small cell lung cancers, and 3 carcinoids). These mutations were found to be somatic when normal tissue was available for testing. Four Mesothelioma cell lines had relatively large deletions (approximately 10-50 kilobases) in the NF2 gene detectable by Southern blot analysis. Two Mesothelioma cell lines had nonsense mutations at codons 57 and 341, respectively. Another Mesothelioma obtained as a specimen directly from a patient, had a 10-base pair microdeletion from nucleotide 1004 to nucleotide 1013 causing a frameshift mutation. These results suggest that the NF2 gene participates in the oncogenesis in a subset of Mesotheliomas but not in lung cancers.
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simian virus 40 like dna sequences in human pleural Mesothelioma
Oncogene, 1994Co-Authors: Harvey I. Pass, Michele Carbone, Paola Rizzo, M Marinetti, M Di Muzio, Daphne J Y Mew, Arthur S Levine, Antonio ProcopioAbstract:Mesotheliomas are pleural, pericardial, or peritoneal neoplasms frequently associated with asbestos exposure, and it is estimated that over the next twenty years up to 80,000 new cases are expected in the USA alone. We found simian virus 40-like DNA sequences in 29 of 48 Mesotheliomas studied (60%) and demonstrated simian virus large-T antigen expression in 13 of 16 specimens. The matching lung samples did not contain simian virus 40-like sequences; however, they contained asbestos. These findings are to our knowledge the first demonstration of a physical link between DNA virus-like sequences and human Mesothelioma. We suggest that a simian virus 40-like virus may act independently or as a co-carcinogen with asbestos. Moreover, the selective large T antigen expression by Mesothelioma and not by the surrounding pulmonary parenchyma may have both diagnostic and therapeutic implications.
Antonio Procopio - One of the best experts on this subject based on the ideXlab platform.
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simian virus 40 large t antigen binds p53 in human Mesotheliomas
Nature Medicine, 1997Co-Authors: Michele Carbone, Paola Rizzo, Daphne J Y Mew, Antonio Procopio, V Esposito, Philip M Grimley, Viji Shridhar, Andrea De Bartolomeis, Maria Teresa Giuliano, Seth M SteinbergAbstract:We found that simian virus 40 (SV40) induces Mesotheliomas in hamsters and that 60% of human Mesotheliomas contain and express SV40 sequences, results now confirmed by others [ref. 3-5, and presentations by D. Griffiths & R. Weiss, F. Galateau-SallE, and H.I.P. at "Simian virus 40: A possible human polyoma virus," NIH workshop, 27-28 January 1997, Bethesda, MD (transcript available through SAG Corp., Washington, DC 20008)]. Mesothelioma, an aggressive malignancy resistant to therapy, originates from the serosal lining of the pleural, pericardial and peritoneal cavities. The incidence of Mesothelioma continues to increase worldwide because of exposure to crocidolite asbestos. However, at least 20% of Mesotheliomas in the United States are not associated with asbestos exposure, and only a minority of people exposed to high concentrations of asbestos develop Mesothelioma. Thus, other carcinogens may induce Mesothelioma in individuals not exposed to asbestos, and/or may render particular individuals more susceptible to the carcinogenic effect of asbestos. We investigated whether the expression of the SV40 large T-antigen (Tag) interferes with the normal expression of the tumor suppressor gene p53 in human Mesotheliomas. We found that SV40 Tag retains its ability to bind and to inactivate p53, a cellular protein that when normally expressed plays an important role in suppressing tumor growth and in inducing sensitivity to therapy. Our findings do not establish a cause-and-effect relation, but indicate that the possibility that SV40 contributes to the development of human Mesotheliomas should be carefully investigated.
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simian virus 40 like dna sequences in human pleural Mesothelioma
Oncogene, 1994Co-Authors: Harvey I. Pass, Michele Carbone, Paola Rizzo, M Marinetti, M Di Muzio, Daphne J Y Mew, Arthur S Levine, Antonio ProcopioAbstract:Mesotheliomas are pleural, pericardial, or peritoneal neoplasms frequently associated with asbestos exposure, and it is estimated that over the next twenty years up to 80,000 new cases are expected in the USA alone. We found simian virus 40-like DNA sequences in 29 of 48 Mesotheliomas studied (60%) and demonstrated simian virus large-T antigen expression in 13 of 16 specimens. The matching lung samples did not contain simian virus 40-like sequences; however, they contained asbestos. These findings are to our knowledge the first demonstration of a physical link between DNA virus-like sequences and human Mesothelioma. We suggest that a simian virus 40-like virus may act independently or as a co-carcinogen with asbestos. Moreover, the selective large T antigen expression by Mesothelioma and not by the surrounding pulmonary parenchyma may have both diagnostic and therapeutic implications.
Daphne J Y Mew - One of the best experts on this subject based on the ideXlab platform.
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simian virus 40 large t antigen binds p53 in human Mesotheliomas
Nature Medicine, 1997Co-Authors: Michele Carbone, Paola Rizzo, Daphne J Y Mew, Antonio Procopio, V Esposito, Philip M Grimley, Viji Shridhar, Andrea De Bartolomeis, Maria Teresa Giuliano, Seth M SteinbergAbstract:We found that simian virus 40 (SV40) induces Mesotheliomas in hamsters and that 60% of human Mesotheliomas contain and express SV40 sequences, results now confirmed by others [ref. 3-5, and presentations by D. Griffiths & R. Weiss, F. Galateau-SallE, and H.I.P. at "Simian virus 40: A possible human polyoma virus," NIH workshop, 27-28 January 1997, Bethesda, MD (transcript available through SAG Corp., Washington, DC 20008)]. Mesothelioma, an aggressive malignancy resistant to therapy, originates from the serosal lining of the pleural, pericardial and peritoneal cavities. The incidence of Mesothelioma continues to increase worldwide because of exposure to crocidolite asbestos. However, at least 20% of Mesotheliomas in the United States are not associated with asbestos exposure, and only a minority of people exposed to high concentrations of asbestos develop Mesothelioma. Thus, other carcinogens may induce Mesothelioma in individuals not exposed to asbestos, and/or may render particular individuals more susceptible to the carcinogenic effect of asbestos. We investigated whether the expression of the SV40 large T-antigen (Tag) interferes with the normal expression of the tumor suppressor gene p53 in human Mesotheliomas. We found that SV40 Tag retains its ability to bind and to inactivate p53, a cellular protein that when normally expressed plays an important role in suppressing tumor growth and in inducing sensitivity to therapy. Our findings do not establish a cause-and-effect relation, but indicate that the possibility that SV40 contributes to the development of human Mesotheliomas should be carefully investigated.
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neurofibromatosis type 2 nf2 gene is somatically mutated in Mesothelioma but not in lung cancer
Cancer Research, 1995Co-Authors: Yoshitaka Sekido, Harvey I. Pass, Daphne J Y Mew, Scott Bader, Michael F Christman, Adi F Gazdar, John D MinnaAbstract:We have found 16 of 28 small cell lung cancers, 17 of 31 non-small cell lung cancers, 2 of 3 carcinoids, and 12 of 14 Mesotheliomas that had chromosome 22 cytogenetic abnormalities. To determine whether the neurofibromatosis type 2 (NF2) gene located on chromosome 22 participates in the oncogenesis of these malignancies, we studied DNAs from lung cancer cell lines and Mesotheliomas using Southern blot analysis and the single-strand conformation polymorphism (SSCP) technique for mutations covering 8 of the 16 known NF2 exons. We detected 7 mutations in 17 Mesotheliomas (41%) within the coding region of NF2 but none in 75 lung cancer cell lines (38 small cell lung cancers, 34 non-small cell lung cancers, and 3 carcinoids). These mutations were found to be somatic when normal tissue was available for testing. Four Mesothelioma cell lines had relatively large deletions (approximately 10-50 kilobases) in the NF2 gene detectable by Southern blot analysis. Two Mesothelioma cell lines had nonsense mutations at codons 57 and 341, respectively. Another Mesothelioma obtained as a specimen directly from a patient, had a 10-base pair microdeletion from nucleotide 1004 to nucleotide 1013 causing a frameshift mutation. These results suggest that the NF2 gene participates in the oncogenesis in a subset of Mesotheliomas but not in lung cancers.
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simian virus 40 like dna sequences in human pleural Mesothelioma
Oncogene, 1994Co-Authors: Harvey I. Pass, Michele Carbone, Paola Rizzo, M Marinetti, M Di Muzio, Daphne J Y Mew, Arthur S Levine, Antonio ProcopioAbstract:Mesotheliomas are pleural, pericardial, or peritoneal neoplasms frequently associated with asbestos exposure, and it is estimated that over the next twenty years up to 80,000 new cases are expected in the USA alone. We found simian virus 40-like DNA sequences in 29 of 48 Mesotheliomas studied (60%) and demonstrated simian virus large-T antigen expression in 13 of 16 specimens. The matching lung samples did not contain simian virus 40-like sequences; however, they contained asbestos. These findings are to our knowledge the first demonstration of a physical link between DNA virus-like sequences and human Mesothelioma. We suggest that a simian virus 40-like virus may act independently or as a co-carcinogen with asbestos. Moreover, the selective large T antigen expression by Mesothelioma and not by the surrounding pulmonary parenchyma may have both diagnostic and therapeutic implications.
