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1. A concerted increase in readthrough and intron retention drives transposon expression during aging and senescence

Author

Kamil Pabis, Diogo Barardo, Olga Sirbu, Kumar Selvarajoo, Jan Gruber, and Brian K Kennedy

Subjects
aging, transposon expression, senescense, intron retention, transcriptional readthrough, Medicine, Science, Biology (General), QH301-705.5
Abstract

Aging and senescence are characterized by pervasive transcriptional dysfunction, including increased expression of transposons and introns. Our aim was to elucidate mechanisms behind this increased expression. Most transposons are found within genes and introns, with a large minority being close to genes. This raises the possibility that transcriptional readthrough and intron retention are responsible for age-related changes in transposon expression rather than expression of autonomous transposons. To test this, we compiled public RNA-seq datasets from aged human fibroblasts, replicative and drug-induced senescence in human cells, and RNA-seq from aging mice and senescent mouse cells. Indeed, our reanalysis revealed a correlation between transposons expression, intron retention, and transcriptional readthrough across samples and within samples. Both intron retention and readthrough increased with aging or cellular senescence and these transcriptional defects were more pronounced in human samples as compared to those of mice. In support of a causal connection between readthrough and transposon expression, analysis of models showing induced transcriptional readthrough confirmed that they also show elevated transposon expression. Taken together, our data suggest that elevated transposon reads during aging seen in various RNA-seq dataset are concomitant with multiple transcriptional defects. Intron retention and transcriptional readthrough are the most likely explanation for the expression of transposable elements that lack a functional promoter.

Published
2024
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2. Globally invariant behavior of oncogenes and random genes at population but not at single cell level

Author

Olga Sirbu, Mohamed Helmy, Alessandro Giuliani, and Kumar Selvarajoo

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Cancer is widely considered a genetic disease. Notably, recent works have highlighted that every human gene may possibly be associated with cancer. Thus, the distinction between genes that drive oncogenesis and those that are associated to the disease, but do not play a role, requires attention. Here we investigated single cells and bulk (cell-population) datasets of several cancer transcriptomes and proteomes in relation to their healthy counterparts. When analyzed by machine learning and statistical approaches in bulk datasets, both general and cancer-specific oncogenes, as defined by the Cancer Genes Census, show invariant behavior to randomly selected gene sets of the same size for all cancers. However, when protein–protein interaction analyses were performed, the oncogenes-derived networks show higher connectivity than those relative to random genes. Moreover, at single-cell scale, we observe variant behavior in a subset of oncogenes for each considered cancer type. Moving forward, we concur that the role of oncogenes needs to be further scrutinized by adopting protein causality and higher-resolution single-cell analyses.

Published
2023
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3. Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author

Liam D. Hendrikse, Parthiv Haldipur, Olivier Saulnier, Jake Millman, Alexandria H. Sjoboen, Anders W. Erickson, Winnie Ong, Victor Gordon, Ludivine Coudière-Morrison, Audrey L. Mercier, Mohammad Shokouhian, Raúl A. Suárez, Michelle Ly, Stephanie Borlase, David S. Scott, Maria C. Vladoiu, Hamza Farooq, Olga Sirbu, Takuma Nakashima, Shohei Nambu, Yusuke Funakoshi, Alec Bahcheli, J. Javier Diaz-Mejia, Joseph Golser, Kathleen Bach, Tram Phuong-Bao, Patryk Skowron, Evan Y. Wang, Sachin A. Kumar, Polina Balin, Abhirami Visvanathan, John J. Y. Lee, Ramy Ayoub, Xin Chen, Xiaodi Chen, Karen L. Mungall, Betty Luu, Pierre Bérubé, Yu C. Wang, Stefan M. Pfister, Seung-Ki Kim, Olivier Delattre, Franck Bourdeaut, François Doz, Julien Masliah-Planchon, Wieslawa A. Grajkowska, James Loukides, Peter Dirks, Michelle Fèvre-Montange, Anne Jouvet, Pim J. French, Johan M. Kros, Karel Zitterbart, Swneke D. Bailey, Charles G. Eberhart, Amulya A. N. Rao, Caterina Giannini, James M. Olson, Miklós Garami, Peter Hauser, Joanna J. Phillips, Young S. Ra, Carmen de Torres, Jaume Mora, Kay K. W. Li, Ho-Keung Ng, Wai S. Poon, Ian F. Pollack, Enrique López-Aguilar, G. Yancey Gillespie, Timothy E. Van Meter, Tomoko Shofuda, Rajeev Vibhakar, Reid C. Thompson, Michael K. Cooper, Joshua B. Rubin, Toshihiro Kumabe, Shin Jung, Boleslaw Lach, Achille Iolascon, Veronica Ferrucci, Pasqualino de Antonellis, Massimo Zollo, Giuseppe Cinalli, Shenandoah Robinson, Duncan S. Stearns, Erwin G. Van Meir, Paola Porrati, Gaetano Finocchiaro, Maura Massimino, Carlos G. Carlotti, Claudia C. Faria, Martine F. Roussel, Frederick Boop, Jennifer A. Chan, Kimberly A. Aldinger, Ferechte Razavi, Evelina Silvestri, Roger E. McLendon, Eric M. Thompson, Marc Ansari, Maria L. Garre, Fernando Chico, Pilar Eguía, Mario Pérezpeña, A. Sorana Morrissy, Florence M. G. Cavalli, Xiaochong Wu, Craig Daniels, Jeremy N. Rich, Steven J. M. Jones, Richard A. Moore, Marco A. Marra, Xi Huang, Jüri Reimand, Poul H. Sorensen, Robert J. Wechsler-Reya, William A. Weiss, Trevor J. Pugh, Livia Garzia, Claudia L. Kleinman, Lincoln D. Stein, Nada Jabado, David Malkin, Olivier Ayrault, Jeffrey A. Golden, David W. Ellison, Brad Doble, Vijay Ramaswamy, Tamra E. Werbowetski-Ogilvie, Hiromichi Suzuki, Kathleen J. Millen, Michael D. Taylor, Neurology, and Pathology

Subjects
Histone Demethylases, Otx Transcription Factors, Multidisciplinary, Core Binding Factor alpha Subunits, Muscle Proteins, Cell Differentiation, Article, Metencephalon, Repressor Proteins, Ki-67 Antigen, Cerebellum, Mutation, Humans, Cell Lineage, Hedgehog Proteins, Cerebellar Neoplasms, T-Box Domain Proteins, Medulloblastoma, Transcription Factors
Abstract

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Published
2022

4. Author Correction: Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Author

Kevin Bielamowicz, David Przelicki, Avesta Rastan, Alex Manno, Kaitlin Kharas, Nabil Ahmed, Joonas Haapasalo, Alyssa C. M. Joynt, Claudia M. Kuzan-Fischer, Randy Van Ommeren, Meenakshi Hegde, Craig Daniels, Mads Daugaard, Cory Richman, Poul H. Sorensen, Kenneth Aldape, Raul Suarez, Alberto Delaidelli, Polina Balin, A. Sorana Morrissy, Stephen Yip, Pasqualino De Antonellis, Lei Qin, Carolina Nor, Stephen C. Mack, Betty Luu, Ahmed Z. Gad, Cynthia Hawkins, Antony Michealraj, Sujith K. Joseph, Zied Abdullaev, Borja L. Holgado, Ning Huang, Ana Guerreiro Stucklin, Kristen Fousek, Xiaochong Wu, John M. Maris, Livia Garzia, Vijay Ramaswamy, Jonelle G. Pallota, Uri Tabori, Michelle Ly, Matthew L. Baker, Michael D. Taylor, Tajana Douglas, Dilakshan Srikanthan, Florence M.G. Cavalli, Juliette Hukin, Srinidhi Varadharajan, Martin Komosa, Sachin Kumar, Maria C. Vladoiu, Olga Sirbu, Claudia C. Faria, Laura K. Donovan, and Liam D. Hendrikse

Subjects
Medulloblastoma, Oncology, Ependymoma, medicine.medical_specialty, business.industry, medicine.medical_treatment, General Medicine, Immunotherapy, medicine.disease, CNS cancer, General Biochemistry, Genetics and Molecular Biology, Text mining, Cerebrospinal fluid, Cancer immunotherapy, Internal medicine, medicine, Car t cells, business
Published
2021

5. Author Correction: Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author

Liam D. Hendrikse, Parthiv Haldipur, Olivier Saulnier, Jake Millman, Alexandria H. Sjoboen, Anders W. Erickson, Winnie Ong, Victor Gordon, Ludivine Coudière-Morrison, Audrey L. Mercier, Mohammad Shokouhian, Raúl A. Suárez, Michelle Ly, Stephanie Borlase, David S. Scott, Maria C. Vladoiu, Hamza Farooq, Olga Sirbu, Takuma Nakashima, Shohei Nambu, Yusuke Funakoshi, Alec Bahcheli, J. Javier Diaz-Mejia, Joseph Golser, Kathleen Bach, Tram Phuong-Bao, Patryk Skowron, Evan Y. Wang, Sachin A. Kumar, Polina Balin, Abhirami Visvanathan, John J. Y. Lee, Ramy Ayoub, Xin Chen, Xiaodi Chen, Karen L. Mungall, Betty Luu, Pierre Bérubé, Yu C. Wang, Stefan M. Pfister, Seung-Ki Kim, Olivier Delattre, Franck Bourdeaut, François Doz, Julien Masliah-Planchon, Wieslawa A. Grajkowska, James Loukides, Peter Dirks, Michelle Fèvre-Montange, Anne Jouvet, Pim J. French, Johan M. Kros, Karel Zitterbart, Swneke D. Bailey, Charles G. Eberhart, Amulya A. N. Rao, Caterina Giannini, James M. Olson, Miklós Garami, Peter Hauser, Joanna J. Phillips, Young S. Ra, Carmen de Torres, Jaume Mora, Kay K. W. Li, Ho-Keung Ng, Wai S. Poon, Ian F. Pollack, Enrique López-Aguilar, G. Yancey Gillespie, Timothy E. Van Meter, Tomoko Shofuda, Rajeev Vibhakar, Reid C. Thompson, Michael K. Cooper, Joshua B. Rubin, Toshihiro Kumabe, Shin Jung, Boleslaw Lach, Achille Iolascon, Veronica Ferrucci, Pasqualino de Antonellis, Massimo Zollo, Giuseppe Cinalli, Shenandoah Robinson, Duncan S. Stearns, Erwin G. Van Meir, Paola Porrati, Gaetano Finocchiaro, Maura Massimino, Carlos G. Carlotti, Claudia C. Faria, Martine F. Roussel, Frederick Boop, Jennifer A. Chan, Kimberly A. Aldinger, Ferechte Razavi, Evelina Silvestri, Roger E. McLendon, Eric M. Thompson, Marc Ansari, Maria L. Garre, Fernando Chico, Pilar Eguía, Mario Pérezpeña, A. Sorana Morrissy, Florence M. G. Cavalli, Xiaochong Wu, Craig Daniels, Jeremy N. Rich, Steven J. M. Jones, Richard A. Moore, Marco A. Marra, Xi Huang, Jüri Reimand, Poul H. Sorensen, Robert J. Wechsler-Reya, William A. Weiss, Trevor J. Pugh, Livia Garzia, Claudia L. Kleinman, Lincoln D. Stein, Nada Jabado, David Malkin, Olivier Ayrault, Jeffrey A. Golden, David W. Ellison, Brad Doble, Vijay Ramaswamy, Tamra E. Werbowetski-Ogilvie, Hiromichi Suzuki, Kathleen J. Millen, and Michael D. Taylor

Subjects
Multidisciplinary
Published
2022

6. Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

Author

Samuel Weiss, Leo J.Y. Kim, Xiaochong Wu, Randy Van Ommeren, Yanqing Jiang, Kaitlin Kharas, Evgeny Kanshin, Moloud Ahmadi, Alberto Delaidelli, Geneviève Deblois, David Przelicki, Stephane Angers, Hiromichi Suzuki, Sameer Agnihotri, Bradly G. Wouters, Graham MacLeod, Ricky Tsai, Pasqualino De Antonellis, Michelle Ly, Stacey L. Krumholtz, Paul Guilhamon, James Loukides, Ravi N. Vellanki, Alex Rasnitsyn, Hamza Farooq, Daniel Schramek, Nada Jabado, María Sánchez-Osuna, Laura K. Donovan, Vijay Ramaswamy, Ibrahim El-Hamamy, Joonas Haapasalo, Jeremy N. Rich, Michael D. Taylor, Benjamin A. Garcia, Mike Tyers, Kyle Juraschka, Winnie Ong, Olivier Saulnier, Panagiotis Prinos, John J.Y. Lee, Borja L. Holgado, Olga Sirbu, Craig Daniels, Cheryl H. Arrowsmith, Cory Richman, Poul H. Sorensen, Kulandaimanuvel Antony Michealraj, Sheila K. Singh, Andrea Bajic, Polina Balin, Stephen C. Mack, Betty Luu, Fiona J. Coutinho, Dilakshan Srikanthan, Florence M.G. Cavalli, Sachin Kumar, Evan Y. Wang, Mathieu Lupien, Peter B. Dirks, Maria C. Vladoiu, Lincoln Stein, Livia Garzia, Ahmad Malik, John Wojcik, Avesta Rastan, Michealraj, K. A., Kumar, S. A., Kim, L. J. Y., Cavalli, F. M. G., Przelicki, D., Wojcik, J. B., Delaidelli, A., Bajic, A., Saulnier, O., Macleod, G., Vellanki, R. N., Vladoiu, M. C., Guilhamon, P., Ong, W., Lee, J. J. Y., Jiang, Y., Holgado, B. L., Rasnitsyn, A., Malik, A. A., Tsai, R., Richman, C. M., Juraschka, K., Haapasalo, J., Wang, E. Y., De Antonellis, P., Suzuki, H., Farooq, H., Balin, P., Kharas, K., Van Ommeren, R., Sirbu, O., Rastan, A., Krumholtz, S. L., Ly, M., Ahmadi, M., Deblois, G., Srikanthan, D., Luu, B., Loukides, J., Wu, X., Garzia, L., Ramaswamy, V., Kanshin, E., Sanchez-Osuna, M., El-Hamamy, I., Coutinho, F. J., Prinos, P., Singh, S., Donovan, L. K., Daniels, C., Schramek, D., Tyers, M., Weiss, S., Stein, L. D., Lupien, M., Wouters, B. G., Garcia, B. A., Arrowsmith, C. H., Sorensen, P. H., Angers, S., Jabado, N., Dirks, P. B., Mack, S. C., Agnihotri, S., Rich, J. N., and Taylor, M. D.

Subjects
Epigenomics, Ependymoma, Male, ependymoma, Epigenomic, Somatic cell, cancer metabolism, Infratentorial Neoplasms, Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, Histones, Brain Neoplasm, 03 medical and health sciences, Epigenome, 0302 clinical medicine, Histone demethylation, Histone methylation, medicine, Animals, Humans, Epigenetics, 030304 developmental biology, hindbrain development, Cell Proliferation, Infratentorial Neoplasm, 0303 health sciences, Brain Neoplasms, Animal, Lysine, Infant, DNA Methylation, medicine.disease, microenvironment, Mice, Inbred C57BL, Histone, Acetylation, paediatric cancer, Mutation, biology.protein, Cancer research, 030217 neurology & neurosurgery, epigenetic, Human
Abstract

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma. Hypoxia reprograms the cellular metabolome and epigenome to promote growth of the most lethal ependymomas.

Published
2020

7. The predicted collagen-binding domains of Drosophila SPARC are essential for survival and for collagen IV distribution and assembly into basement membranes

Author

Sebastian Duncan, Olga Sirbu, Samuel Delage, Maurice J. Ringuette, Alexa Chioran, and Theodore J. Brown

Subjects
Collagen Type IV, Hemocytes, Mutant, Fat Body, Biology, Basement Membrane, Animals, Genetically Modified, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, medicine, Adipocytes, Animals, Drosophila Proteins, Wings, Animal, Osteonectin, Molecular Biology, 030304 developmental biology, Cell Size, Basement membrane, chemistry.chemical_classification, 0303 health sciences, Binding Sites, EF hand, Colocalization, Cell Biology, Phenotype, Cell biology, medicine.anatomical_structure, Drosophila melanogaster, chemistry, Cell culture, Larva, Cystine, Genes, Lethal, COP-Coated Vesicles, CRISPR-Cas Systems, Glycoprotein, 030217 neurology & neurosurgery, Intracellular, Developmental Biology, Molecular Chaperones
Abstract

The assembly of basement membranes (BMs) into tissue-specific morphoregulatory structures requires non-core BM components. Work in Drosophila indicates a principal role of collagen-binding matricellular glycoprotein SPARC (Secreted Protein, Acidic, Rich in Cysteine) in larval fat body BM assembly. We report that SPARC and collagen IV (Col(IV)) first colocalize in the trans-Golgi of hemocyte-like cell lines. Mutating the collagen-binding domains of Drosophila SPARC led to the loss of colocalization with Col(IV), a fibrotic-like BM, and 2nd instar larval lethality, indicating that SPARC binding to Col(IV) is essential for survival. Analysis of this mutant at 2nd instar reveals increased Col(IV) puncta within adipocytes, reflecting a disruption in the intracellular chaperone-like activity of SPARC. Removal of the disulfide bridge in the C-terminal EF-hand2 of SPARC, which is known to enhance Col(IV) binding, did not lead to larval lethality; however, a less intense fat body phenotype was observed. Additionally, both SPARC mutants exhibited altered fat body BM pore topography. Wing imaginal disc-derived SPARC did not localize within Col(IV)-rich matrices. This raises the possibility that SPARC interaction with Col(IV) requires initial intracellular interaction to colocalize at the BM or that wing-derived SPARC undergoes differential post-translational modifications that impacts its function. Collectively, these data provide evidence that the chaperone-like activity of SPARC on Col(IV) begins just prior to their co-secretion and demonstrate for the first time that the Col(IV) chaperone-like activity of SPARC is necessary for Drosophila development beyond the 2nd instar.

Published
2019

8. Collagen-binding byDrosophilaSPARC is essential for survival and for collagen IV distribution and assembly into basement membranes

Author

Olga Sirbu, Sebastian Duncan, Alexa Chioran, Theodore J. Brown, S. Delage, and Maurice J. Ringuette

Subjects
chemistry.chemical_classification, 0303 health sciences, Chemistry, Mutant, Colocalization, Phenotype, Epitope, Cell biology, Staining, 03 medical and health sciences, Imaginal disc, 0302 clinical medicine, Glycoprotein, 030217 neurology & neurosurgery, 030304 developmental biology, Cysteine
Abstract

The assembly of basement membranes (BMs) into tissue-specific morphoregulatory structures requires non-core BM components. Work inDrosophilaindicates a principal role of collagen-binding matricellular glycoprotein SPARC (Secreted Protein, Acidic, Rich in Cysteine) in larval fat body BM assembly. We report that SPARC and collagen IV (Col(IV)) first colocalize in the trans-Golgi of hemocytes. Mutating the collagen-binding epitopes of SPARC leads to 2ndinstar larval lethality, indicating that SPARC binding to Col(IV) is essential for survival. Analysis of this mutant reveals increased Col(IV) puncta within adipocytes and intense perimeter Col(IV) staining surrounding the fat body as compared to wild-type larvae, reflecting a disruption in chaperone-like activity. In addition, Col(IV) in the wing imaginal disc was absent. Removal of the disulfide bridge in EF-hand2, which is known to enhance Col(IV) binding by SPARC, did not lead to larval lethality; however, a similar but less intense fat body phenotype was observed. Additionally, both SPARC mutants have altered fat body BM pore topography. Wing imaginal disc-derived SPARC did not localize within Col(IV)-rich matrices, indicating a distinct variant. Collectively, these data demonstrate the essential role of Col(IV) chaperone-like activity of SPARC toDrosophiladevelopment and indicate tissue-specific variants with differential functions.

Published
2019

9. Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Author

Carolina Nor, Martin Komosa, Olga Sirbu, Nabil Ahmed, Joonas Haapasalo, Kristen Fousek, Jonelle G. Pallota, Betty Luu, Cynthia Hawkins, Kenneth Aldape, Uri Tabori, David Przelicki, Srinidhi Varadharajan, Liam D. Hendrikse, Meenakshi Hegde, Claudia M. Kuzan-Fischer, Ana Guerreiro Stucklin, Tajana Douglas, Ahmed Z. Gad, Xiaochong Wu, Randy Van Ommeren, Polina Balin, Alex Manno, Sachin Kumar, Raul Suarez, Avesta Rastan, Craig Daniels, Mads Daugaard, Maria C. Vladoiu, Stephen Yip, Cory Richman, Michelle Ly, Matthew L. Baker, Kaitlin Kharas, Laura K. Donovan, Stephen C. Mack, Claudia C. Faria, Pasqualino De Antonellis, Ning Huang, Poul H. Sorensen, Zied Abdullaev, Lei Qin, Livia Garzia, Alyssa C. M. Joynt, A. Sorana Morrissy, Michael D. Taylor, Sujith K. Joseph, Antony Michealraj, Dilakshan Srikanthan, Florence M.G. Cavalli, Borja L. Holgado, John M. Maris, Alberto Delaidelli, Vijay Ramaswamy, Kevin Bielamowicz, Juliette Hukin, Donovan, L. K., Delaidelli, A., Joseph, S. K., Bielamowicz, K., Fousek, K., Holgado, B. L., Manno, A., Srikanthan, D., Gad, A. Z., Van Ommeren, R., Przelicki, D., Richman, C., Ramaswamy, V., Daniels, C., Pallota, J. G., Douglas, T., Joynt, A. C. M., Haapasalo, J., Nor, C., Vladoiu, M. C., Kuzan-Fischer, C. M., Garzia, L., Mack, S. C., Varadharajan, S., Baker, M. L., Hendrikse, L., Ly, M., Kharas, K., Balin, P., Wu, X., Qin, L., Huang, N., Stucklin, A. G., Morrissy, A. S., Cavalli, F. M. G., Luu, B., Suarez, R., De Antonellis, P., Michealraj, A., Rastan, A., Hegde, M., Komosa, M., Sirbu, O., Kumar, S. A., Abdullaev, Z., Faria, C. C., Yip, S., Hukin, J., Tabori, U., Hawkins, C., Aldape, K., Daugaard, M., Maris, J. M., Sorensen, P. H., Ahmed, N., and Taylor, M. D.

Subjects
0301 basic medicine, Ependymoma, Male, medicine.medical_treatment, T-Lymphocytes, Immunotherapy, Adoptive, Mice, 0302 clinical medicine, Cerebrospinal fluid, Drug Delivery Systems, HEK293 Cell, Cancer immunotherapy, Tumor Cells, Cultured, Neoplasm Metastasis, Child, Cerebrospinal Fluid, Receptors, Chimeric Antigen, Brain Neoplasms, General Medicine, Neoplasm Metastasi, Treatment Outcome, 030220 oncology & carcinogenesis, Child, Preschool, Female, Cancer Vaccine, Human, Cancer Vaccines, General Biochemistry, Genetics and Molecular Biology, Brain Neoplasm, 03 medical and health sciences, medicine, Animals, Humans, Cerebellar Neoplasms, neoplasms, Injections, Intraventricular, Medulloblastoma, Animal, business.industry, Cerebellar Neoplasm, Infant, Immunotherapy, Recurrent Medulloblastoma, medicine.disease, Interleukin-13 receptor, Xenograft Model Antitumor Assays, Chimeric antigen receptor, 030104 developmental biology, HEK293 Cells, T-Lymphocyte, Cancer research, business, Drug Delivery System
Abstract

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood–brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.

Published
2019

10. Methodological Aspects of Calculation of Financial Intermediation Services Indirectly Measured according to SNA-2008

Author

Olga Sirbu and Elena Cara

Subjects
intermediate consumption, gross value added, the financial corporations, Process management, interest, the nonfinancial corporations, Research methodology, Financial intermediary, General Engineering, government sector, Energy Engineering and Power Technology, Analogy, Gross value added, Datasource, System of National Accounts represents production, financial intermediation services indirectly measured, Economics, Intermediate consumption, Government sector, credit, Industrial organization, institutional units
Abstract

In this article is specified the role of SNA in the economy, there are described new adjustments of the SNA 2008, focusing on FISIM calculation according to SNA 1993 and SNA 2008 methodologies. Thus being mentioned the specific allocation of FISIM both by economic activities and institutional sectors, which are the advantages of switching to a new method of calculation of FISIM and which are the informational datasource of performing these calculations. The research methodology was based on traditional research methods and techniques – scientific abstraction, analogy, analysis and synthesis of data.

Published
2014
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11. The Methodology of Elaboration of the Production Account for Financial Activities in Accordance With SNA – 2008

Author

Olga SIRBU

Subjects
System of National Accounts, production account, intermediate consumption Gross Value Added, Classification of economic activities in the Republic of Moldova (CAEM), profit or loss account
Abstract

In this article are described the new System of National Accounts 2008 adjustments, focusing on production account development for the financial activities, more detailed for National Bank, Commercial Banks, other financial intermediation, insurance companies, activities auxiliary to financial institutions in Republic of Moldova. Which are the advantages of switching to a new method of calculation of financial activities and which are sources of information to perform these calculations. The research methodology was based on traditional research methods and techniques – scientific abstraction, analogy, analysis and synthesis of data.

Published
2013

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