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22 results on '"Batrakou, Dzmitry G."'

1. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial

Author

Hong, David S., Van Tine, Brian A., Biswas, Swethajit, McAlpine, Cheryl, Johnson, Melissa L., Olszanski, Anthony J., Clarke, Jeffrey M., Araujo, Dejka, Blumenschein, Jr, George R., Kebriaei, Partow, Lin, Quan, Tipping, Alex J., Sanderson, Joseph P., Wang, Ruoxi, Trivedi, Trupti, Annareddy, Thejo, Bai, Jane, Rafail, Stavros, Sun, Amy, Fernandes, Lilliam, Navenot, Jean-Marc, Bushman, Frederic D., Everett, John K., Karadeniz, Derin, Broad, Robyn, Isabelle, Martin, Naidoo, Revashnee, Bath, Natalie, Betts, Gareth, Wolchinsky, Zohar, Batrakou, Dzmitry G., Van Winkle, Erin, Elefant, Erica, Ghobadi, Armin, Cashen, Amanda, Grand’Maison, Anne, McCarthy, Philip, Fracasso, Paula M., Norry, Elliot, Williams, Dennis, Druta, Mihaela, Liebner, David A., Odunsi, Kunle, and Butler, Marcus O.

Published
2023
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3. Nuclear envelope transmembrane proteins in differentiation systems

Author

Batrakou, Dzmitry G., Schirmer, Eric, and Sawyer, Lindsay

Subjects
571.6, nuclear envelope, adipogenesis
Abstract

Historically, our perception of the nuclear envelope has evolved from a simple barrier isolating the genome from the rest of a cell to a complex system that regulates functions including transcription, splicing, DNA replication and repair and development. Several recent proteomic studies uncovered a great variety of nuclear envelope transmembrane proteins (NETs). Diseases associated with several nuclear envelope proteins, mostly NETs, affect many tissues e.g. muscle, adipose tissue, skin, bones. Many NETs of the inner nuclear membrane have been shown to interact with chromatin, suggesting that their influencing gene expression might explain NET roles in disease. This work is focused on finding novel interactions of NETs with chromatin. First, SUN2 post-translational modifications were analysed and the effect of phosphomimetic and phospho-null mutants on heterochromatin and the cytoskeleton was tested by overexpression. However, no obvious changes were found. Second, several tissue-preferential NETs were tested in an adipocyte differentiation system. NET29 changed chromosome 6 position in pre-adipocytes. This matched changes in chromosome positioning that occur during adipocyte differentiation when NET29 is normally induced. Post-translational modifications of NET29 are likely to play a vital role in this process because a phospho-null mutant dominantly blocked chromosome repositioning. The effect of over-expression and down-regulation of NET29 on transcription was tested and results suggest that NET29 negatively regulates expression of myogenic genes during adipogenesis. This thesis is split into six chapters. Chapter I is an overview of the nuclear envelope, adipogenesis and chromatin remodelling, Chapter II is a detailed description of methods used in this study. Chapter III focuses on post-translational modifications of SUN2, as well as trials to identify novel partners of SUN2. Chapter IV and V deal with a novel nuclear envelope transmembrane protein and its role in adipogenesis. Finally, the last chapter includes a discussion and recommended future directions.

Published
2012

4. Phase 1 Clinical Trial Evaluating the Safety and Anti-Tumor Activity of ADP-A2M10 SPEAR T-Cells in Patients With MAGE-A10+ Head and Neck, Melanoma, or Urothelial Tumors

Author

Hong, David S., primary, Butler, Marcus O., additional, Pachynski, Russell K., additional, Sullivan, Ryan, additional, Kebriaei, Partow, additional, Boross-Harmer, Sarah, additional, Ghobadi, Armin, additional, Frigault, Matthew J., additional, Dumbrava, Ecaterina E., additional, Sauer, Amy, additional, Brophy, Francine, additional, Navenot, Jean-Marc, additional, Fayngerts, Svetlana, additional, Wolchinsky, Zohar, additional, Broad, Robyn, additional, Batrakou, Dzmitry G., additional, Wang, Ruoxi, additional, Solis, Luisa M., additional, Duose, Dzifa Yawa, additional, Sanderson, Joseph P., additional, Gerry, Andrew B., additional, Marks, Diane, additional, Bai, Jane, additional, Norry, Elliot, additional, and Fracasso, Paula M., additional

Published
2022
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7. Autologous T cell therapy for MAGE-A4+solid cancers in HLA-A*02+patients: a phase 1 trial

Author

Hong, David S., Van Tine, Brian A., Biswas, Swethajit, McAlpine, Cheryl, Johnson, Melissa L., Olszanski, Anthony J., Clarke, Jeffrey M., Araujo, Dejka, Blumenschein, George R., Kebriaei, Partow, Lin, Quan, Tipping, Alex J., Sanderson, Joseph P., Wang, Ruoxi, Trivedi, Trupti, Annareddy, Thejo, Bai, Jane, Rafail, Stavros, Sun, Amy, Fernandes, Lilliam, Navenot, Jean-Marc, Bushman, Frederic D., Everett, John K., Karadeniz, Derin, Broad, Robyn, Isabelle, Martin, Naidoo, Revashnee, Bath, Natalie, Betts, Gareth, Wolchinsky, Zohar, Batrakou, Dzmitry G., Van Winkle, Erin, Elefant, Erica, Ghobadi, Armin, Cashen, Amanda, Grand’Maison, Anne, McCarthy, Philip, Fracasso, Paula M., Norry, Elliot, Williams, Dennis, Druta, Mihaela, Liebner, David A., Odunsi, Kunle, and Butler, Marcus O.

Abstract

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer (NCT03132922). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N= 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit–risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.

Published
2023
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10. Tissue-specific NETs alter genome organization and regulation even in a heterologous system

Author

de las Heras, Jose I., Zuleger, Nikolaj, Batrakou, Dzmitry G., Czapiewski, Rafal, Kerr, Alastair R W, and Schirmer, Eric C.

Subjects
gene position, NET, spatial genome organization, DamID, nuclear envelope, tissue specificity, gene regulation
Abstract

Different cell types exhibit distinct patterns of 3D genome organization that correlate with changes in gene expression in tissue and differentiation systems. Several tissue-specific nuclear envelope transmembrane proteins (NETs) have been found to influence the spatial positioning of genes and chromosomes that normally occurs during tissue differentiation. Here we study 3 such NETs: NET29, NET39, and NET47, which are expressed preferentially in fat, muscle and liver, respectively. We found that even when exogenously expressed in a heterologous system they can specify particular genome organization patterns and alter gene expression. Each NET affected largely different subsets of genes. Notably, the liver-specific NET47 upregulated many genes in HT1080 fibroblast cells that are normally upregulated in hepatogenesis, showing that tissue-specific NETs can favor expression patterns associated with the tissue where the NET is normally expressed. Similarly, global profiling of peripheral chromatin after exogenous expression of these NETs using lamin B1 DamID revealed that each NET affected the nuclear positioning of distinct sets of genomic regions with a significant tissue-specific component. Thus NET influences on genome organization can contribute to gene expression changes associated with differentiation even in the absence of other factors and overt cellular differentiation changes.

Published
2017

14. Tissue specificity in the nuclear envelope supports its functional complexity

Author

de Las Heras, Jose I, Meinke, Peter, Batrakou, Dzmitry G, Srsen, Vlastimil, Zuleger, Nikolaj, Kerr, Alastair Rw, and Schirmer, Eric C

Abstract

Nuclear envelope links to inherited disease gave the conundrum of how mutations in near-ubiquitous proteins can yield many distinct pathologies, each focused in different tissues. One conundrum-resolving hypothesis is that tissue-specific partner proteins mediate these pathologies. Such partner proteins may have now been identified with recent proteome studies determining nuclear envelope composition in different tissues. These studies revealed that the majority of the total nuclear envelope proteins are tissue restricted in their expression. Moreover, functions have been found for a number these tissue-restricted nuclear envelope proteins that fit with mechanisms proposed to explain how the nuclear envelope could mediate disease, including defects in mechanical stability, cell cycle regulation, signaling, genome organization, gene expression, nucleocytoplasmic transport, and differentiation. The wide range of functions to which these proteins contribute is consistent with not only their involvement in tissue-specific nuclear envelope disease pathologies, but also tissue evolution.

Published
2013

18. Specific nuclear envelope transmembrane proteins can promote the location of chromosomes to and from the nuclear periphery

Author

Zuleger, Nikolaj, primary, Boyle, Shelagh, additional, Kelly, David A, additional, de las Heras, Jose I, additional, Lazou, Vassiliki, additional, Korfali, Nadia, additional, Batrakou, Dzmitry G, additional, Randles, K Natalie, additional, Morris, Glenn E, additional, Harrison, David J, additional, Bickmore, Wendy A, additional, and Schirmer, Eric C, additional

Published
2013
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19. The nuclear envelope proteome differs notably between tissues

Author

Korfali, Nadia, primary, Wilkie, Gavin S., additional, Swanson, Selene K., additional, Srsen, Vlastimil, additional, de las Heras, Jose, additional, Batrakou, Dzmitry G., additional, Malik, Poonam, additional, Zuleger, Nikolaj, additional, Kerr, Alastair R.W., additional, Florens, Laurence, additional, and Schirmer, Eric C., additional

Published
2012
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21. Several Novel Nuclear Envelope Transmembrane Proteins Identified in Skeletal Muscle Have Cytoskeletal Associations

Author

Wilkie, Gavin S., primary, Korfali, Nadia, additional, Swanson, Selene K., additional, Malik, Poonam, additional, Srsen, Vlastimil, additional, Batrakou, Dzmitry G., additional, de las Heras, Jose, additional, Zuleger, Nikolaj, additional, Kerr, Alastair R.W., additional, Florens, Laurence, additional, and Schirmer, Eric C., additional

Published
2011
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22. The Leukocyte Nuclear Envelope Proteome Varies with Cell Activation and Contains Novel Transmembrane Proteins That Affect Genome Architecture

Author

Korfali, Nadia, primary, Wilkie, Gavin S., additional, Swanson, Selene K., additional, Srsen, Vlastimil, additional, Batrakou, Dzmitry G., additional, Fairley, Elizabeth A.L., additional, Malik, Poonam, additional, Zuleger, Nikolaj, additional, Goncharevich, Alexander, additional, de las Heras, Jose, additional, Kelly, David A., additional, Kerr, Alastair R.W., additional, Florens, Laurence, additional, and Schirmer, Eric C., additional

Published
2010
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