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1. Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy.

Author

Pérez-Guijarro, Eva, Yang, Howard, Araya, Romina, El Meskini, Rajaa, Michael, Helen, Vodnala, Suman, Marie, Kerrie, Smith, Cari, Chin, Sung, Lam, Khiem, Thorkelsson, Andres, Iacovelli, Anthony, Kulaga, Alan, Fon, Anyen, Michalowski, Aleksandra, Hugo, Willy, Lo, Roger, Restifo, Nicholas, Sharan, Shyam, Van Dyke, Terry, Goldszmid, Romina, Weaver Ohler, Zoe, Lee, Maxwell, Day, Chi-Ping, and Merlino, Glenn

Subjects
Animals, Antineoplastic Agents, Immunological, CTLA-4 Antigen, Cells, Cultured, Disease Models, Animal, Drug Screening Assays, Antitumor, Female, Gene Expression Regulation, Neoplastic, Genetic Heterogeneity, Humans, Immunotherapy, Ipilimumab, Melanoma, Mice, Mice, Inbred C57BL, Mice, Transgenic, Prognosis, Programmed Cell Death 1 Receptor, RNA-Seq, Treatment Outcome, Whole Genome Sequencing
Abstract

Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.

Published
2020

2. Loss of Brca1 and Trp53 in adult mouse mammary ductal epithelium results in development of hormone receptor-positive or hormone receptor-negative tumors, depending on inactivation of Rb family proteins

Author

Szabova, Ludmila, Gordon, Melanie B., Lu, Lucy, Pate, Nathan, Bassel, Laura, Iacovelli, Anthony J., Karim, Baktiar, Homan, Philip J., Householder, Deborah B., Guerin, Theresa M., Burkett, Sandra, Day, Amanda M., Custer, Wendi, and Weaver Ohler, Zoe

Published
2022
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3. Supplementary Table 2 from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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4. Data from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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5. Supplementary Figure 2 from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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6. Supplementary Methods from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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7. Supplementary Table 3 from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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8. Supplementary Figure 6 from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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9. Supplementary Table 1 from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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10. Supplementary Figure 1 from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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11. Supplementary Figure 5 from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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12. Supplementary Figure 7 from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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13. Supplementary Figure 3 from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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14. Supplementary Figure 4 from Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, primary, Carretero, Julian, primary, Martin, Philip L., primary, El Meskini, Rajaa, primary, Iacovelli, Anthony J., primary, Gumprecht, Michelle, primary, Kulaga, Alan, primary, Guerin, Theresa, primary, Schlomer, Jerome, primary, Baran, Maureen, primary, Kozlov, Serguei, primary, McCann, Thomas, primary, Mena, Salvador, primary, Al-Shahrour, Fatima, primary, Alexander, Danny, primary, Wong, Kwok-Kin, primary, and Van Dyke, Terry, primary

Published
2023
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15. Author Correction: Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy

Author

Pérez-Guijarro, Eva, Yang, Howard H., Araya, Romina E., El Meskini, Rajaa, Michael, Helen T., Vodnala, Suman Kumar, Marie, Kerrie L., Smith, Cari, Chin, Sung, Lam, Khiem C., Thorkelsson, Andres, Iacovelli, Anthony J., Kulaga, Alan, Fon, Anyen, Michalowski, Aleksandra M., Hugo, Willy, Lo, Roger S., Restifo, Nicholas P., Sharan, Shyam K., Van Dyke, Terry, Goldszmid, Romina S., Weaver Ohler, Zoe, Lee, Maxwell P., Day, Chi-Ping, and Merlino, Glenn

Published
2021
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16. Additional file 16 of Loss of Brca1 and Trp53 in adult mouse mammary ductal epithelium results in development of hormone receptor-positive or hormone receptor-negative tumors, depending on inactivation of Rb family proteins

Author

Szabova, Ludmila, Gordon, Melanie B., Lu, Lucy, Pate, Nathan, Bassel, Laura, Iacovelli, Anthony J., Karim, Baktiar, Homan, Philip J., Householder, Deborah B., Guerin, Theresa M., Burkett, Sandra, Day, Amanda M., Custer, Wendi, and Weaver Ohler, Zoe

Abstract

Additional file 16. Original uncropped Western blots.

Published
2022
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17. Internet addiction's effect on likeability and rapport

Author

Iacovelli, Anthony and Valenti, Stavros

Subjects
Internet, Internet, Computers, Psychology and mental health, Sociology and social work
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.chb.2008.10.006 Byline: Anthony Iacovelli, Stavros Valenti Keywords: Internet addiction; Excessive Internet use Abstract: The Internet Paradox refers to findings that demonstrated that the increase in communications brought about by Internet usage actually had negative effects on user's psychological well-being and social involvement. This study proposes that face-to-face contact promotes the development of rapport and thereby individuals that use the internet excessively will lack these necessary social skills. Specifically, we investigate whether, through use of telephone communications, average users ratings of likeability and rapport would differ when speaking to excessive internet users. This experiment utilized previously unacquainted individuals who conversed by telephone while discussing both, a cooperative and an adversarial task. Results indicate that excessive users were more likely to be depressed and socially inhibited, and also were rated as having a lower level of rapport and likeability. Further research is required in order to explain the role of personality in excessive internet usage. Author Affiliation: Hofstra University, Department of Psychology, 135 Hauser Hall, Hempstead, NY 11549, USA

Published
2009

18. OTX2 mutations contribute to the otocephaly-dysgnathia complex

Author

Chassaing, Nicolas, Sorrentino, Susanna, Davis, Erica E, Martin-Coignard, Dominique, Iacovelli, Anthony, Paznekas, William, Webb, Bryn D, Faye-Petersen, Ona, Encha-Razavi, Férechté, Lequeux, Leopoldine, Vigouroux, Adeline, Yesilyurt, Ahmet, Boyadjiev, Simeon A, Kayserili, Hülya, Loget, Philippe, Carles, Dominique, Sergi, Consolato, Puvabanditsin, Surasak, Chen, Chih-Ping, Etchevers, Heather C, Katsanis, Nicholas, Mercer, Catherine L, Calvas, Patrick, and Jabs, Ethylin Wang

Published
2012
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20. Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy

Author

National Institutes of Health (US), National Cancer Institute (US), Ressler Family Foundation, Bristol-Myers Squibb, Melanoma Research Alliance (US), Pérez-Guijarro, Eva, Yang, Howard H., Araya, Romina E., El Meskini, Rajaa, Michael, Helen T., Vodnala, Suman Kumar, Marie, Kerrie L., Smith, Cari, Chin, Sung, Lam, Khiem C., Thorkelsson, Andres, Iacovelli, Anthony J., Kulaga, Alan, Fon, Anyen, Michalowski, Aleksandra M., Hugo, Willy, Lo, Roger S., Restifo, Nicholas P., Sharan, Shyam K., Van Dyke, Terry, Goldszmid, Romina S., Weaver Ohler, Zoe, Lee, Maxwell P., Day, Chi-Ping, Merlino, Glenn, National Institutes of Health (US), National Cancer Institute (US), Ressler Family Foundation, Bristol-Myers Squibb, Melanoma Research Alliance (US), Pérez-Guijarro, Eva, Yang, Howard H., Araya, Romina E., El Meskini, Rajaa, Michael, Helen T., Vodnala, Suman Kumar, Marie, Kerrie L., Smith, Cari, Chin, Sung, Lam, Khiem C., Thorkelsson, Andres, Iacovelli, Anthony J., Kulaga, Alan, Fon, Anyen, Michalowski, Aleksandra M., Hugo, Willy, Lo, Roger S., Restifo, Nicholas P., Sharan, Shyam K., Van Dyke, Terry, Goldszmid, Romina S., Weaver Ohler, Zoe, Lee, Maxwell P., Day, Chi-Ping, and Merlino, Glenn

Abstract

Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.

Published
2020

21. Multi-model preclinical platform predicts clinical response of melanoma to immunotherapy

Author

Pérez-Guijarro, Eva, primary, Yang, Howard H., additional, Araya, Romina E., additional, El Meskini, Rajaa, additional, Michael, Helen T., additional, Vodnala, Suman Kumar, additional, Marie, Kerrie L., additional, Graff-Cherry, Cari, additional, Chin, Sung, additional, Iacovelli, Anthony J., additional, Kulaga, Alan, additional, Fon, Anyen, additional, Michalowski, Aleksandra M., additional, Hugo, Willy, additional, Lo, Roger S., additional, Restifo, Nicholas P., additional, Van Dyke, Terry, additional, Sharan, Shyam K., additional, Goldszmid, Romina S., additional, Ohler, Zoe Weaver, additional, Lee, Maxwell P., additional, Day, Chi-Ping, additional, and Merlino, Glenn, additional

Published
2019
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25. HOXB1 Founder Mutation in Humans Recapitulates the Phenotype of Hoxb1[superscript −/−] Mice

Author

Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology. Research Laboratory of Electronics, Schubert, Christian R., Webb, Bryn D., Shaaban, Sherin, Gaspar, Harald, Cunha, Luis F., Hao, Ke, Robson, Caroline D., Chan, Wai-Man, Andrews, Caroline, MacKinnon, Sarah, Oystreck, Darren T., Hunter, David G., Iacovelli, Anthony J., Ye, Xiaoqian, Camminady, Anne, Engle, Elizabeth C., Jabs, Ethylin Wang, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology. Research Laboratory of Electronics, Schubert, Christian R., Webb, Bryn D., Shaaban, Sherin, Gaspar, Harald, Cunha, Luis F., Hao, Ke, Robson, Caroline D., Chan, Wai-Man, Andrews, Caroline, MacKinnon, Sarah, Oystreck, Darren T., Hunter, David G., Iacovelli, Anthony J., Ye, Xiaoqian, Camminady, Anne, Engle, Elizabeth C., and Jabs, Ethylin Wang

Abstract

Members of the highly conserved homeobox (HOX) gene family encode transcription factors that confer cellular and tissue identities along the antero-posterior axis of mice and humans. We have identified a founder homozygous missense mutation in HOXB1 in two families from a conservative German American population. The resulting phenotype includes bilateral facial palsy, hearing loss, and strabismus and correlates extensively with the previously reported Hoxb1[superscript −/−] mouse phenotype. The missense variant is predicted to result in the substitution of a cysteine for an arginine at amino acid residue 207 (Arg207Cys), which corresponds to the highly conserved Arg5 of the homeodomain. Arg5 interacts with thymine in the minor groove of DNA through hydrogen bonding and electrostatic attraction. Molecular modeling and an in vitro DNA-protein binding assay predict that the mutation would disrupt these interactions, destabilize the HOXB1:PBX1:DNA complex, and alter HOXB1 transcriptional activity., National Human Genome Research Institute (U.S.) (Grant U54 HG003067), Swiss National Science Foundation, National Institutes of Health (U.S.) (Grant R01 EY15298), National Institutes of Health (U.S.) (Grant R01 HD018655), National Institutes of Health (U.S.) (Grant U54 HG003067)

Published
2014

28. A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors

Author

El Meskini, Rajaa, primary, Iacovelli, Anthony J., additional, Kulaga, Alan, additional, Gumprecht, Michelle, additional, Martin, Philip, additional, Baran, Maureen, additional, Householder, Deborah B., additional, Van Dyke, Terry, additional, and Weaver Ohler, Zoë, additional

Published
2014
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30. Temporal Molecular and Biological Assessment of an Erlotinib-Resistant Lung Adenocarcinoma Model Reveals Markers of Tumor Progression and Treatment Response

Author

Weaver, Zoë, primary, Difilippantonio, Simone, additional, Carretero, Julian, additional, Martin, Philip L., additional, El Meskini, Rajaa, additional, Iacovelli, Anthony J., additional, Gumprecht, Michelle, additional, Kulaga, Alan, additional, Guerin, Theresa, additional, Schlomer, Jerome, additional, Baran, Maureen, additional, Kozlov, Serguei, additional, McCann, Thomas, additional, Mena, Salvador, additional, Al-Shahrour, Fatima, additional, Alexander, Danny, additional, Wong, Kwok-Kin, additional, and Van Dyke, Terry, additional

Published
2012
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32. OTX2mutations contribute to the otocephaly-dysgnathia complex

Author

Chassaing, Nicolas, primary, Sorrentino, Susanna, additional, Davis, Erica E, additional, Martin-Coignard, Dominique, additional, Iacovelli, Anthony, additional, Paznekas, William, additional, Webb, Bryn D, additional, Faye-Petersen, Ona, additional, Encha-Razavi, Férechté, additional, Lequeux, Leopoldine, additional, Vigouroux, Adeline, additional, Yesilyurt, Ahmet, additional, Boyadjiev, Simeon A, additional, Kayserili, Hülya, additional, Loget, Philippe, additional, Carles, Dominique, additional, Sergi, Consolato, additional, Puvabanditsin, Surasak, additional, Chen, Chih-Ping, additional, Etchevers, Heather C, additional, Katsanis, Nicholas, additional, Mercer, Catherine L, additional, Calvas, Patrick, additional, and Jabs, Ethylin Wang, additional

Published
2012
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36. Abnormalities in cartilage and bone development in the Apert syndrome FGFR2+/S252W mouse

Author

Wang, Yingli, primary, Xiao, Ran, additional, Yang, Fan, additional, Karim, Baktiar O., additional, Iacovelli, Anthony J., additional, Cai, Juanliang, additional, Lerner, Charles P., additional, Richtsmeier, Joan T., additional, Leszl, Jen M., additional, Hill, Cheryl A., additional, Yu, Kai, additional, Ornitz, David M., additional, Elisseeff, Jennifer, additional, Huso, David L., additional, and Jabs, Ethylin Wang, additional

Published
2005
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37. Abnormalities in cartilage and bone development in the Apert syndrome FGFR2+/S252W mouse.

Author

Yingli Wang, Ran Xiao, Fan Yang, Karim, Baktiar O., Iacovelli, Anthony J., Juanliang Cai, Lerner, Charles P., Richtsmeier, Joan T., Leszl, Jen M., Hill, Cheryl A., Kai Yu, Ornitz, David M., Elisseeff, Jennifer, Huso, David L., and Jabs, Ethylin Wang

Subjects
FIBROBLAST growth factors, GROWTH factors, MITOGENS, TRANSGENIC mice, SKULL, LUNGS, HEART
Abstract

Apert syndrome is an autosomal dominant disorder characterized by malformations of the skull, limbs and viscera. Two-thirds of affected individuals have a S252W mutation in fibroblast growth factor receptor 2 (FGFR2). To study the pathogenesis of this condition, we generated a knock-in mouse model with this mutation. The Fgfr2+/S252W mutant mice have abnormalities of the skeleton, as well as of other organs including the brain, thymus, lungs, heart and intestines. In the mutant neurocranium, we found a midline sutural defect and craniosynostosis with abnormal osteoblastic proliferation and differentiation. We noted ectopic cartilage at the midline sagittal suture, and cartilage abnormalities in the basicranium, nasal turbinates and trachea. In addition, from the mutant long bones, in vitro cell cultures grown in osteogenic medium revealed chondrocytes, which were absent in the controls. Our results suggest that altered cartilage and bone development play a significant role in the pathogenesis of the Apert syndrome phenotype. [ABSTRACT FROM AUTHOR]

Published
2005
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38. A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors

Author

El Meskini, Rajaa, Iacovelli, Anthony J., Kulaga, Alan, Gumprecht, Michelle, Martin, Philip L., Baran, Maureen, Householder, Deborah B., Van Dyke, Terry, and Weaver Ohler, Zoë

Abstract

Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment.

Published
2015
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