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1. Cambios organizacionales que se producen al obtener una certificación ISO 9000

Author

Javier Maya Mendoza, Luis Felipe Llanos, and César Vela Beltrán del Río

Subjects
cambio organizacional, cultura organizacional, sistema de gestión de calidad, normas iso 9000, Commerce, HF1-6182, Business, HF5001-6182
Abstract

La certificación del sistema de gestión de calidad de una empresa ante las normas ISO 9000 puede originar cambios organizacionales en la operación de los procesos, en la forma de analizar y solucionar problemas de índole administrativa y operativa, en la toma de decisiones, entre otros. En este contexto, el objetivo de la presente investigación es identificar los principales cambios que se presentan en las organizaciones que se certifican ante esta norma internacional. El método de investigación consistió en el diseño y la aplicación de un cuestionario a través de entrevistas estructuradas a 85 personas de diferentes posiciones organizacionales que han participado en el proceso de certificación de un sistema de gestión de calidad ante las normas ISO 9000. La tipología de investigación es del tipo cualitativo, descriptivo, analítico y propositivo. Los resultados demostraron que los cambios que se presentan con mayor frecuencia en las organizaciones certificadas son: la formalización organizacional, el establecimiento de objetivos y la mejora en el flujo de información, por lo que se concluye que en las empresas que obtienen la certificación ISO 9000 se producen cambios positivos para la óptima gestión de las mismas.

Published
2024
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3. The nexus of nuclear envelope dynamics, circular economy and cancer cell pathophysiology

Author

Kristina Keuper, Jiri Bartek, and Apolinar Maya-Mendoza

Subjects
Nuclear mechanics, Nuclear envelope dynamics, Nuclear lamina, Lamina-associated proteins, Circular economy of the nuclear envelope, Cytology, QH573-671
Abstract

The nuclear envelope (NE) is a critical component in maintaining the function and structure of the eukaryotic nucleus. The NE and lamina are disassembled during each cell cycle to enable an open mitosis. Nuclear architecture construction and deconstruction is a prime example of a circular economy, as it fulfills a highly efficient recycling program bound to continuous assessment of the quality and functionality of the building blocks. Alterations in the nuclear dynamics and lamina structure have emerged as important contributors to both oncogenic transformation and cancer progression. However, the knowledge of the NE breakdown and reassembly is still limited to a fraction of participating proteins and complexes. As cancer cells contain highly diverse nuclei in terms of DNA content, but also in terms of nuclear number, size, and shape, it is of great interest to understand the intricate relationship between these nuclear features in cancer cell pathophysiology. In this review, we provide insights into how those NE dynamics are regulated, and how lamina destabilization processes may alter the NE circular economy. Moreover, we expand the knowledge of the lamina-associated domain region by using strategic algorithms, including Artificial Intelligence, to infer protein associations, assess their function and location, and predict cancer-type specificity with implications for the future of cancer diagnosis, prognosis and treatment. Using this approach we identified NUP98 and MECP2 as potential proteins that exhibit upregulation in Acute Myeloid Leukemia (LAML) patients with implications for early diagnosis.

Published
2024
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4. Promoting Post-Restraint Patient Debriefing in an Acute Psychiatric Inpatient setting

Author

Harry Jackson, Munzir Quraishy, Maya Mendoza, and Alex Berry

Subjects
Psychiatry, RC435-571
Abstract

Aims Controlled physical restraint is a commonly used, but controversial practice in inpatient psychiatric settings, at times bringing psychiatric practice into potential conflict with accepted medical ethical standards for preserving autonomy and bodily-integrity. However, physical restraint can produce high levels of patient distress, re-traumatise those who have experienced physical or sexual abuse, and may lead to inadvertent bodily injury, and even death on rare occasions. There is an international consensus to attempt to reduce restrictive practices, including physical restraint, as demonstrated in the World Health Organization's Quality Rights Initiative. Post-restraint patient debriefing can promote recovery, prevent future restraint, and promote a more ethical and humanising care environment. We aimed to audit the frequency of restraint events, and post-restraint debriefs offered to patients in a single, London-based, male acute psychiatric ward. Methods In the pre-intervention sample, data was extracted from the records of patients admitted over a six-month period (n = 75), to identify the number of patients who had undergone restraint and the number who had been debriefed. The search terms “restrain”, “PMVA”, “response team” and “debrief” were used. After each restraint event, the notes for the following two weeks were reviewed to see if a debrief was delivered. The intervention consisted of a single description and dissemination of the results in a ward business meeting, with instruction that all staff members within the ward multidisciplinary team can help provide debrief if appropriate to do so. Where a patient was known to have been restrained, debriefs were offered during subsequent ward round reviews as appropriate. In the post-intervention sample, we collected data from patients admitted over a 10-month period (n = 89). We used Chi-Squared testing to compare categorical variables pre- and post-intervention. Results Pre-intervention, 15 patients underwent restraint and of these, 8 patients (53.33%) were debriefed. Post-intervention, 21 patients underwent restraint and of these, 10 patients (47.62%) were debriefed. There was no statistical difference in the proportion of patients offered a psychological debrief (p = 0.735). Conclusion Following a single intervention there was not a sustained difference in the proportion of post-restraint debriefs offered. It is likely more sustained interventions would bring about more substantive practice change. Incorporating the need for post-restraint debriefs in daily ward safety-huddles, or in structured “ward round proformas”, may increase the proportion of patients offered post-restraint debriefing. It is possible that the note review strategy did not capture all debriefs delivered.

Published
2024
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5. MDC1 maintains active elongation complexes of RNA polymerase II

Author

Pappas, George, Munk, Sebastian Howen Nesgaard, Watanabe, Kenji, Thomas, Quentin, Gál, Zita, Gram, Helena Hagner, Lee, MyungHee, Gómez-Cabello, Daniel, Kanellis, Dimitris Christos, Olivares-Chauvet, Pedro, Larsen, Dorthe Helena, Gregersen, Lea Haarup, Maya-Mendoza, Apolinar, Galanos, Panagiotis, and Bartek, Jiri

Published
2023
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8. A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization

Author

Zampetidis, Christos P., Galanos, Panagiotis, Angelopoulou, Andriani, Zhu, Yajie, Polyzou, Aikaterini, Karamitros, Timokratis, Kotsinas, Athanassios, Lagopati, Nefeli, Mourkioti, Ioanna, Mirzazadeh, Reza, Polyzos, Alexandros, Garnerone, Silvano, Mizi, Athanasia, Gusmao, Eduardo G., Sofiadis, Konstantinos, Gál, Zita, Larsen, Dorthe H., Pefani, Dafni-Eleftheria, Demaria, Marco, Tsirigos, Aristotelis, Crosetto, Nicola, Maya-Mendoza, Apolinar, Papaspyropoulos, Angelos, Evangelou, Konstantinos, Bartek, Jiri, Papantonis, Argyris, and Gorgoulis, Vassilis G.

Published
2021
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9. Selección y evaluación de las herramientas de mejora de procesos

Author

Javier Maya Mendoza and Luis Felipe Llanos

Subjects
sistemas de calidad, iso 9000, eficacia, viabilidad, Commerce, HF1-6182, Business, HF5001-6182
Abstract

La falta o mal uso de herramientas de mejora en la mediana empresa del sector industrial sumado a la sobrevaloración y elección errónea de las mismas originan una mala implementación y poca eficacia en la mejora de procesos. El objetivo de la investigación es evaluar y proponer las herramientas de mejora que logren procesos eficaces en empresas medianas del sector industrial capaces de producir productos y servicios de calidad. La metodología consistió en el diseño, validación y la aplicación de un cuestionario a través de entrevistas estructuradas con expertos en el área de productividad y calidad para identificar y evaluar, mediante una escala de Likert, las herramientas propuestas y en donde se usó el software SPSS-23 para el procesamiento de los datos. La tipología de investigación de este trabajo es del tipo documental-descriptivo, analítico y propositivo. A partir de los resultados se concluye que las herramientas que pertenecen a la ingeniería de calidad son las mejor evaluadas, además de ser utilizadas regularmente en la industria.

Published
2022
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10. The human nucleoporin Tpr protects cells from RNA-mediated replication stress

Author

Martin Kosar, Michele Giannattasio, Daniele Piccini, Apolinar Maya-Mendoza, Francisco García-Benítez, Jirina Bartkova, Sonia I. Barroso, Hélène Gaillard, Emanuele Martini, Umberto Restuccia, Miguel Angel Ramirez-Otero, Massimiliano Garre, Eleonora Verga, Miguel Andújar-Sánchez, Scott Maynard, Zdenek Hodny, Vincenzo Costanzo, Amit Kumar, Angela Bachi, Andrés Aguilera, Jiri Bartek, and Marco Foiani

Subjects
Science
Abstract

Tpr nucleoporin is known to be essential for nuclear transport and mitosis processes. Here the authors explore the link between Tpr and genome instability providing insights into the role of Tpr in safeguarding cells from RNA-mediated replication stress.

Published
2021
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11. AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity

Author

Maiani, Emiliano, Milletti, Giacomo, Nazio, Francesca, Holdgaard, Søs Grønbæk, Bartkova, Jirina, Rizza, Salvatore, Cianfanelli, Valentina, Lorente, Mar, Simoneschi, Daniele, Di Marco, Miriam, D’Acunzo, Pasquale, Di Leo, Luca, Rasmussen, Rikke, Montagna, Costanza, Raciti, Marilena, De Stefanis, Cristiano, Gabicagogeascoa, Estibaliz, Rona, Gergely, Salvador, Nélida, Pupo, Emanuela, Merchut-Maya, Joanna Maria, Daniel, Colin J., Carinci, Marianna, Cesarini, Valeriana, O’sullivan, Alfie, Jeong, Yeon-Tae, Bordi, Matteo, Russo, Francesco, Campello, Silvia, Gallo, Angela, Filomeni, Giuseppe, Lanzetti, Letizia, Sears, Rosalie C., Hamerlik, Petra, Bartolazzi, Armando, Hynds, Robert E., Pearce, David R., Swanton, Charles, Pagano, Michele, Velasco, Guillermo, Papaleo, Elena, De Zio, Daniela, Maya-Mendoza, Apolinar, Locatelli, Franco, Bartek, Jiri, and Cecconi, Francesco

Published
2021
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12. Real-world evaluation of rapid and laboratory-free COVID-19 triage for emergency care: external validation and pilot deployment of artificial intelligence driven screening

Author

Andrew A S Soltan, MB BChir, Jenny Yang, MSc, Ravi Pattanshetty, FRCEM, Alex Novak, FRCEM, Yang Yang, DPhil, Omid Rohanian, PhD, Sally Beer, PGCert, Marina A Soltan, MRCP, David R Thickett, ProfFRCP, Rory Fairhead, BA, Tingting Zhu, DPhil, David W Eyre, ProfDPhil, David A Clifton, ProfDPhil, Adam Watson, Akshay Bhargav, Alex Tough, Alice Rogers, Ayisha Shaikh, Carolina Valensise, Charlotte Lee, Claire Otasowie, David Metcalfe, Ekta Agarwal, Elham Zareh, Evelyn Thangaraj, Florence Pickles, Gabriella Kelly, Gayatri Tadikamalla, George Shaw, Heather Tong, Hettie Davies, Jasdeep Bahra, Jessica Morgan, Joe Wilson, Joseph Cutteridge, Katherine O'Byrne, Luiza Farache Trajano, Madeleine Oliver, Maria Pikoula, Maya Mendoza, Melissa Keevil, Muhammad Faisal, Natasha Dole, Oscar Deal, Rebecca Conway-Jones, Shajeel Sattar, Sneha Kundoor, Sumaiyah Shah, and Vani Muthusami

Subjects
Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Summary: Background: Uncertainty in patients' COVID-19 status contributes to treatment delays, nosocomial transmission, and operational pressures in hospitals. However, the typical turnaround time for laboratory PCR remains 12–24 h and lateral flow devices (LFDs) have limited sensitivity. Previously, we have shown that artificial intelligence-driven triage (CURIAL-1.0) can provide rapid COVID-19 screening using clinical data routinely available within 1 h of arrival to hospital. Here, we aimed to improve the time from arrival to the emergency department to the availability of a result, do external and prospective validation, and deploy a novel laboratory-free screening tool in a UK emergency department. Methods: We optimised our previous model, removing less informative predictors to improve generalisability and speed, developing the CURIAL-Lab model with vital signs and readily available blood tests (full blood count [FBC]; urea, creatinine, and electrolytes; liver function tests; and C-reactive protein) and the CURIAL-Rapide model with vital signs and FBC alone. Models were validated externally for emergency admissions to University Hospitals Birmingham, Bedfordshire Hospitals, and Portsmouth Hospitals University National Health Service (NHS) trusts, and prospectively at Oxford University Hospitals, by comparison with PCR testing. Next, we compared model performance directly against LFDs and evaluated a combined pathway that triaged patients who had either a positive CURIAL model result or a positive LFD to a COVID-19-suspected clinical area. Lastly, we deployed CURIAL-Rapide alongside an approved point-of-care FBC analyser to provide laboratory-free COVID-19 screening at the John Radcliffe Hospital (Oxford, UK). Our primary improvement outcome was time-to-result, and our performance measures were sensitivity, specificity, positive and negative predictive values, and area under receiver operating characteristic curve (AUROC). Findings: 72 223 patients met eligibility criteria across the four validating hospital groups, in a total validation period spanning Dec 1, 2019, to March 31, 2021. CURIAL-Lab and CURIAL-Rapide performed consistently across trusts (AUROC range 0·858–0·881, 95% CI 0·838–0·912, for CURIAL-Lab and 0·836–0·854, 0·814–0·889, for CURIAL-Rapide), achieving highest sensitivity at Portsmouth Hospitals (84·1%, Wilson's 95% CI 82·5–85·7, for CURIAL-Lab and 83·5%, 81·8–85·1, for CURIAL-Rapide) at specificities of 71·3% (70·9–71·8) for CURIAL-Lab and 63·6% (63·1–64·1) for CURIAL-Rapide. When combined with LFDs, model predictions improved triage sensitivity from 56·9% (51·7–62·0) for LFDs alone to 85·6% with CURIAL-Lab (81·6–88·9; AUROC 0·925) and 88·2% with CURIAL-Rapide (84·4–91·1; AUROC 0·919), thereby reducing missed COVID-19 cases by 65% with CURIAL-Lab and 72% with CURIAL-Rapide. For the prospective deployment of CURIAL-Rapide, 520 patients were enrolled for point-of-care FBC analysis between Feb 18 and May 10, 2021, of whom 436 received confirmatory PCR testing and ten (2·3%) tested positive. Median time from arrival to a CURIAL-Rapide result was 45 min (IQR 32–64), 16 min (26·3%) sooner than with LFDs (61 min, 37–99; log-rank p

Published
2022
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16. Globalización y neoconstitucionalismo en un Estado constitucional democrático de Derecho

Author

José Luis Maya Mendoza

Subjects
neoconstitucionalismo, nuevo constitucionalismo latinoamericano, estado constitucional democrático de derecho, globalización, neoliberalismo, Jurisprudence. Philosophy and theory of law, K201-487
Abstract

El neoconstitucionalismo, también identificado como Nuevo Constitucionalismo Latinoamericano, representa una doctrina que comenzó a desarrollarse desde la segunda mitad del siglo XX, tomando como base una constitución larga, rígida y garantizada, sustentada en el concepto de Estado constitucional de derecho y reformulada a partir de la tripartición bobbiana del positivismo jurídico. Por su tendencia a promover la protección de los derechos humanos y desarrollar un sólido modelo de gobernanza en donde se establezca una mejor relación entre gobernantes y gobernados, plasmada en la reforma constitucional de México de 2011, en materia de derechos humanos y amparo, el neoconstitucionalismo, aporta los elementos necesarios para promover un Estado democrático que fomente el bienestar social en un entorno de desigualdad social a nivel internacional generado por el modelo neoliberal capitalista.

Published
2018

18. Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1α and the NAMPT-NAD+ pathway

Author

Scott Maynard, Arnaldur Hall, Panagiotis Galanos, Salvatore Rizza, Tatsuro Yamamoto, Helena Hagner Gram, Sebastian H N Munk, Muhammad Shoaib, Claus Storgaard Sørensen, Vilhelm A Bohr, Mads Lerdrup, Apolinar Maya-Mendoza, and Jiri Bartek

Subjects
Mice, Progeria, Sirtuin 1, Genetics, Animals, Humans, Fibroblasts, Lamin Type A, NAD, DNA, Mitochondrial, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Chromatin, Mitochondria
Abstract

Mutations in the lamin A/C gene (LMNA) cause laminopathies such as the premature aging Hutchinson Gilford progeria syndrome (HGPS) and altered lamin A/C levels are found in diverse malignancies. The underlying lamin-associated mechanisms remain poorly understood. Here we report that lamin A/C-null mouse embryo fibroblasts (Lmna−/− MEFs) and human progerin-expressing HGPS fibroblasts both display reduced NAD+ levels, unstable mitochondrial DNA and attenuated bioenergetics. This mitochondrial dysfunction is associated with reduced chromatin recruitment (Lmna−/− MEFs) or low levels (HGPS) of PGC1, the key transcription factor for mitochondrial homeostasis. Lmna−/− MEFs showed reduced expression of the NAD+biosynthesis enzyme NAMPT and attenuated activity of the NAD+-dependent deacetylase SIRT1. We find high PARylation in lamin A/C-aberrant cells, further decreasing the NAD+ pool and consistent with impaired DNA base excision repair in both cell models, a condition that fuels DNA damage-induced PARylation under oxidative stress. Further, ATACsequencing revealed a substantially altered chromatin landscape in Lmna−/− MEFs, including aberrantly reduced accessibility at the Nampt gene promoter. Thus, we identified a new role of lamin A/C as a key modulator of mitochondrial function through impairments of PGC1 and the NAMPT-NAD+ pathway, with broader implications for the aging process.

Published
2022
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19. The Contribution of Lysosomes to DNA Replication

Author

Joanna Maria Merchut-Maya and Apolinar Maya-Mendoza

Subjects
lysosomes, autophagy, mTORC1, DNA synthesis, cancer, Cytology, QH573-671
Abstract

Lysosomes, acidic, membrane-bound organelles, are not only the core of the cellular recycling machinery, but they also serve as signaling hubs regulating various metabolic pathways. Lysosomes maintain energy homeostasis and provide pivotal substrates for anabolic processes, such as DNA replication. Every time the cell divides, its genome needs to be correctly duplicated; therefore, DNA replication requires rigorous regulation. Challenges that negatively affect DNA synthesis, such as nucleotide imbalance, result in replication stress with severe consequences for genome integrity. The lysosomal complex mTORC1 is directly involved in the synthesis of purines and pyrimidines to support DNA replication. Numerous drugs have been shown to target lysosomal function, opening an attractive avenue for new treatment strategies against various pathologies, including cancer. In this review, we focus on the interplay between lysosomal function and DNA replication through nucleic acid degradation and nucleotide biosynthesis and how these could be exploited for therapeutic purposes.

Published
2021
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20. Formaldehyde-induced DNA histone crosslinks cause replication stress and replication fork breakage in mitosis

Author

Duxin, Julien Philippe Carlos, Benedict, Bente, Lisbye, Michael, Maya-Mendoza, Apolinar, Kristensen, Stella Munkholm, Duxin, Julien Philippe Carlos, Benedict, Bente, Lisbye, Michael, Maya-Mendoza, Apolinar, and Kristensen, Stella Munkholm

Abstract

Formaldehyde is a genotoxic compound that threatens human health from both exogenous and endogenous sources. Formaldehyde is classified as a human carcinogen and is found at high concentration in the blood (around 100 µM). The deficiency in formaldehyde clearance give rise to bone marrow failure and cancer predisposition, and an increase in genome instability. The primary DNA lesion induced by formaldehyde in vivo is thought to be a DNA-protein crosslink, and recently it has been suggested that histones are the major proteins that are crosslinked to DNA by formaldehyde. Based on cellular sensitivity of cells to formaldehyde, multiple DNA repair pathways have been suggested to participate in the resolution of formaldehyde induced lesions, for example the Fanconi anemia proteins. However, how these pathways collaborate, and which lesion underpins the pathology of endogenous formaldehyde remains unknown. Here, we show that formaldehyde treatment of an in vitro nucleosome reconstituted plasmid generates DNA histone crosslinks. Using Xenopus egg extracts, we find that these lesions cause replication inhibition and replication stress. Interestingly, these results resemble those of a formaldehyde treated chromatinized plasmid that our lab has studied previously, suggesting that histones could be the primary protein crosslinked upon formaldehyde treatment. Moreover, when the formaldehyde treated nucleosome reconstituted plasmid was replicated in mitotic-like extracts, the replication forks are breaking . This suggests mitotic repair of formaldehyde-induced DNA protein lesions, a discovery that might shed light on the current proposed repair pathways counteracting formaldehyde-induced DNA damage.

Published
2023

21. MDC1 maintains active elongation complexes of RNA polymerase II

Author

European Commission, Danish Cancer Society Research Center, Danish Council for Independent Research, Lundbeck Foundation, Novo Nordisk Foundation, Swedish Research Council, Danish National Research Foundation, Japan Society for the Promotion of Science, Independent Research Fund Denmark, Pappas, George, Munk, Sebastian Howen Nesgaard, Watanabe, Kenji, Thomas, Quentin, Gál, Zita, Gram, Helena Hagner, Lee, MyungHee, Gómez-Cabello, Daniel, Kanellis, Dimitris C., Olivares-Chauvet, Pedro, Larsen, Dorthe Helena, Gregersen, Lea Haarup, Maya-Mendoza, Apolinar, Galanos, Panagiotis, Bartek, Jiri, European Commission, Danish Cancer Society Research Center, Danish Council for Independent Research, Lundbeck Foundation, Novo Nordisk Foundation, Swedish Research Council, Danish National Research Foundation, Japan Society for the Promotion of Science, Independent Research Fund Denmark, Pappas, George, Munk, Sebastian Howen Nesgaard, Watanabe, Kenji, Thomas, Quentin, Gál, Zita, Gram, Helena Hagner, Lee, MyungHee, Gómez-Cabello, Daniel, Kanellis, Dimitris C., Olivares-Chauvet, Pedro, Larsen, Dorthe Helena, Gregersen, Lea Haarup, Maya-Mendoza, Apolinar, Galanos, Panagiotis, and Bartek, Jiri

Abstract

The role of MDC1 in the DNA damage response has been extensively studied; however, its impact on other cellular processes is not well understood. Here, we describe the role of MDC1 in transcription as a regulator of RNA polymerase II (RNAPII). Depletion of MDC1 causes a genome-wide reduction in the abundance of actively engaged RNAPII elongation complexes throughout the gene body of protein-encoding genes under unperturbed conditions. Decreased engaged RNAPII subsequently alters the assembly of the spliceosome complex on chromatin, leading to changes in pre-mRNA splicing. Mechanistically, the S/TQ domain of MDC1 modulates RNAPII-mediated transcription. Upon genotoxic stress, MDC1 promotes the abundance of engaged RNAPII complexes at DNA breaks, thereby stimulating nascent transcription at the damaged sites. Of clinical relevance, cancer cells lacking MDC1 display hypersensitivity to RNAPII inhibitors. Overall, we unveil a role of MDC1 in RNAPII-mediated transcription with potential implications for cancer treatment.

Published
2023

22. Data from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Venkatesan, Subramanian, primary, Angelova, Mihaela, primary, Puttick, Clare, primary, Zhai, Haoran, primary, Caswell, Deborah R., primary, Lu, Wei-Ting, primary, Dietzen, Michelle, primary, Galanos, Panagiotis, primary, Evangelou, Konstantinos, primary, Bellelli, Roberto, primary, Lim, Emilia L., primary, Watkins, Thomas B.K., primary, Rowan, Andrew, primary, Teixeira, Vitor H., primary, Zhao, Yue, primary, Chen, Haiquan, primary, Ngo, Bryan, primary, Zalmas, Lykourgos-Panagiotis, primary, Al Bakir, Maise, primary, Hobor, Sebastijan, primary, Grönroos, Eva, primary, Pennycuick, Adam, primary, Nigro, Ersilia, primary, Campbell, Brittany B., primary, Brown, William L., primary, Akarca, Ayse U., primary, Marafioti, Teresa, primary, Wu, Mary Y., primary, Howell, Michael, primary, Boulton, Simon J., primary, Bertoli, Cosetta, primary, Fenton, Tim R., primary, de Bruin, Robertus A.M., primary, Maya-Mendoza, Apolinar, primary, Santoni-Rugiu, Eric, primary, Hynds, Robert E., primary, Gorgoulis, Vassilis G., primary, Jamal-Hanjani, Mariam, primary, McGranahan, Nicholas, primary, Harris, Reuben S., primary, Janes, Sam M., primary, Bartkova, Jirina, primary, Bakhoum, Samuel F., primary, Bartek, Jiri, primary, Kanu, Nnennaya, primary, and Swanton, Charles, primary

Published
2023
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23. Supplementary Figure 4 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Venkatesan, Subramanian, primary, Angelova, Mihaela, primary, Puttick, Clare, primary, Zhai, Haoran, primary, Caswell, Deborah R., primary, Lu, Wei-Ting, primary, Dietzen, Michelle, primary, Galanos, Panagiotis, primary, Evangelou, Konstantinos, primary, Bellelli, Roberto, primary, Lim, Emilia L., primary, Watkins, Thomas B.K., primary, Rowan, Andrew, primary, Teixeira, Vitor H., primary, Zhao, Yue, primary, Chen, Haiquan, primary, Ngo, Bryan, primary, Zalmas, Lykourgos-Panagiotis, primary, Al Bakir, Maise, primary, Hobor, Sebastijan, primary, Grönroos, Eva, primary, Pennycuick, Adam, primary, Nigro, Ersilia, primary, Campbell, Brittany B., primary, Brown, William L., primary, Akarca, Ayse U., primary, Marafioti, Teresa, primary, Wu, Mary Y., primary, Howell, Michael, primary, Boulton, Simon J., primary, Bertoli, Cosetta, primary, Fenton, Tim R., primary, de Bruin, Robertus A.M., primary, Maya-Mendoza, Apolinar, primary, Santoni-Rugiu, Eric, primary, Hynds, Robert E., primary, Gorgoulis, Vassilis G., primary, Jamal-Hanjani, Mariam, primary, McGranahan, Nicholas, primary, Harris, Reuben S., primary, Janes, Sam M., primary, Bartkova, Jirina, primary, Bakhoum, Samuel F., primary, Bartek, Jiri, primary, Kanu, Nnennaya, primary, and Swanton, Charles, primary

Published
2023
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24. TRACERx Consortium Members from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Venkatesan, Subramanian, primary, Angelova, Mihaela, primary, Puttick, Clare, primary, Zhai, Haoran, primary, Caswell, Deborah R., primary, Lu, Wei-Ting, primary, Dietzen, Michelle, primary, Galanos, Panagiotis, primary, Evangelou, Konstantinos, primary, Bellelli, Roberto, primary, Lim, Emilia L., primary, Watkins, Thomas B.K., primary, Rowan, Andrew, primary, Teixeira, Vitor H., primary, Zhao, Yue, primary, Chen, Haiquan, primary, Ngo, Bryan, primary, Zalmas, Lykourgos-Panagiotis, primary, Al Bakir, Maise, primary, Hobor, Sebastijan, primary, Grönroos, Eva, primary, Pennycuick, Adam, primary, Nigro, Ersilia, primary, Campbell, Brittany B., primary, Brown, William L., primary, Akarca, Ayse U., primary, Marafioti, Teresa, primary, Wu, Mary Y., primary, Howell, Michael, primary, Boulton, Simon J., primary, Bertoli, Cosetta, primary, Fenton, Tim R., primary, de Bruin, Robertus A.M., primary, Maya-Mendoza, Apolinar, primary, Santoni-Rugiu, Eric, primary, Hynds, Robert E., primary, Gorgoulis, Vassilis G., primary, Jamal-Hanjani, Mariam, primary, McGranahan, Nicholas, primary, Harris, Reuben S., primary, Janes, Sam M., primary, Bartkova, Jirina, primary, Bakhoum, Samuel F., primary, Bartek, Jiri, primary, Kanu, Nnennaya, primary, and Swanton, Charles, primary

Published
2023
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25. Supplementary Figure 2 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Venkatesan, Subramanian, primary, Angelova, Mihaela, primary, Puttick, Clare, primary, Zhai, Haoran, primary, Caswell, Deborah R., primary, Lu, Wei-Ting, primary, Dietzen, Michelle, primary, Galanos, Panagiotis, primary, Evangelou, Konstantinos, primary, Bellelli, Roberto, primary, Lim, Emilia L., primary, Watkins, Thomas B.K., primary, Rowan, Andrew, primary, Teixeira, Vitor H., primary, Zhao, Yue, primary, Chen, Haiquan, primary, Ngo, Bryan, primary, Zalmas, Lykourgos-Panagiotis, primary, Al Bakir, Maise, primary, Hobor, Sebastijan, primary, Grönroos, Eva, primary, Pennycuick, Adam, primary, Nigro, Ersilia, primary, Campbell, Brittany B., primary, Brown, William L., primary, Akarca, Ayse U., primary, Marafioti, Teresa, primary, Wu, Mary Y., primary, Howell, Michael, primary, Boulton, Simon J., primary, Bertoli, Cosetta, primary, Fenton, Tim R., primary, de Bruin, Robertus A.M., primary, Maya-Mendoza, Apolinar, primary, Santoni-Rugiu, Eric, primary, Hynds, Robert E., primary, Gorgoulis, Vassilis G., primary, Jamal-Hanjani, Mariam, primary, McGranahan, Nicholas, primary, Harris, Reuben S., primary, Janes, Sam M., primary, Bartkova, Jirina, primary, Bakhoum, Samuel F., primary, Bartek, Jiri, primary, Kanu, Nnennaya, primary, and Swanton, Charles, primary

Published
2023
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26. Supplementary Tables S1-S4 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Venkatesan, Subramanian, primary, Angelova, Mihaela, primary, Puttick, Clare, primary, Zhai, Haoran, primary, Caswell, Deborah R., primary, Lu, Wei-Ting, primary, Dietzen, Michelle, primary, Galanos, Panagiotis, primary, Evangelou, Konstantinos, primary, Bellelli, Roberto, primary, Lim, Emilia L., primary, Watkins, Thomas B.K., primary, Rowan, Andrew, primary, Teixeira, Vitor H., primary, Zhao, Yue, primary, Chen, Haiquan, primary, Ngo, Bryan, primary, Zalmas, Lykourgos-Panagiotis, primary, Al Bakir, Maise, primary, Hobor, Sebastijan, primary, Grönroos, Eva, primary, Pennycuick, Adam, primary, Nigro, Ersilia, primary, Campbell, Brittany B., primary, Brown, William L., primary, Akarca, Ayse U., primary, Marafioti, Teresa, primary, Wu, Mary Y., primary, Howell, Michael, primary, Boulton, Simon J., primary, Bertoli, Cosetta, primary, Fenton, Tim R., primary, de Bruin, Robertus A.M., primary, Maya-Mendoza, Apolinar, primary, Santoni-Rugiu, Eric, primary, Hynds, Robert E., primary, Gorgoulis, Vassilis G., primary, Jamal-Hanjani, Mariam, primary, McGranahan, Nicholas, primary, Harris, Reuben S., primary, Janes, Sam M., primary, Bartkova, Jirina, primary, Bakhoum, Samuel F., primary, Bartek, Jiri, primary, Kanu, Nnennaya, primary, and Swanton, Charles, primary

Published
2023
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27. Supplementary Figure 3 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Venkatesan, Subramanian, primary, Angelova, Mihaela, primary, Puttick, Clare, primary, Zhai, Haoran, primary, Caswell, Deborah R., primary, Lu, Wei-Ting, primary, Dietzen, Michelle, primary, Galanos, Panagiotis, primary, Evangelou, Konstantinos, primary, Bellelli, Roberto, primary, Lim, Emilia L., primary, Watkins, Thomas B.K., primary, Rowan, Andrew, primary, Teixeira, Vitor H., primary, Zhao, Yue, primary, Chen, Haiquan, primary, Ngo, Bryan, primary, Zalmas, Lykourgos-Panagiotis, primary, Al Bakir, Maise, primary, Hobor, Sebastijan, primary, Grönroos, Eva, primary, Pennycuick, Adam, primary, Nigro, Ersilia, primary, Campbell, Brittany B., primary, Brown, William L., primary, Akarca, Ayse U., primary, Marafioti, Teresa, primary, Wu, Mary Y., primary, Howell, Michael, primary, Boulton, Simon J., primary, Bertoli, Cosetta, primary, Fenton, Tim R., primary, de Bruin, Robertus A.M., primary, Maya-Mendoza, Apolinar, primary, Santoni-Rugiu, Eric, primary, Hynds, Robert E., primary, Gorgoulis, Vassilis G., primary, Jamal-Hanjani, Mariam, primary, McGranahan, Nicholas, primary, Harris, Reuben S., primary, Janes, Sam M., primary, Bartkova, Jirina, primary, Bakhoum, Samuel F., primary, Bartek, Jiri, primary, Kanu, Nnennaya, primary, and Swanton, Charles, primary

Published
2023
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28. Supplementary Figure 1 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Venkatesan, Subramanian, primary, Angelova, Mihaela, primary, Puttick, Clare, primary, Zhai, Haoran, primary, Caswell, Deborah R., primary, Lu, Wei-Ting, primary, Dietzen, Michelle, primary, Galanos, Panagiotis, primary, Evangelou, Konstantinos, primary, Bellelli, Roberto, primary, Lim, Emilia L., primary, Watkins, Thomas B.K., primary, Rowan, Andrew, primary, Teixeira, Vitor H., primary, Zhao, Yue, primary, Chen, Haiquan, primary, Ngo, Bryan, primary, Zalmas, Lykourgos-Panagiotis, primary, Al Bakir, Maise, primary, Hobor, Sebastijan, primary, Grönroos, Eva, primary, Pennycuick, Adam, primary, Nigro, Ersilia, primary, Campbell, Brittany B., primary, Brown, William L., primary, Akarca, Ayse U., primary, Marafioti, Teresa, primary, Wu, Mary Y., primary, Howell, Michael, primary, Boulton, Simon J., primary, Bertoli, Cosetta, primary, Fenton, Tim R., primary, de Bruin, Robertus A.M., primary, Maya-Mendoza, Apolinar, primary, Santoni-Rugiu, Eric, primary, Hynds, Robert E., primary, Gorgoulis, Vassilis G., primary, Jamal-Hanjani, Mariam, primary, McGranahan, Nicholas, primary, Harris, Reuben S., primary, Janes, Sam M., primary, Bartkova, Jirina, primary, Bakhoum, Samuel F., primary, Bartek, Jiri, primary, Kanu, Nnennaya, primary, and Swanton, Charles, primary

Published
2023
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29. Supplementary Data Figures 1-8 from Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress

Author

Young, Lucy A., primary, O'Connor, Lenka Oplustil, primary, de Renty, Christelle, primary, Veldman-Jones, Margaret H., primary, Dorval, Thierry, primary, Wilson, Zena, primary, Jones, David R., primary, Lawson, Deborah, primary, Odedra, Rajesh, primary, Maya-Mendoza, Apolinar, primary, Reimer, Corinne, primary, Bartek, Jiri, primary, Lau, Alan, primary, and O'Connor, Mark J., primary

Published
2023
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30. Supplementary Tables from Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress

Author

Young, Lucy A., primary, O'Connor, Lenka Oplustil, primary, de Renty, Christelle, primary, Veldman-Jones, Margaret H., primary, Dorval, Thierry, primary, Wilson, Zena, primary, Jones, David R., primary, Lawson, Deborah, primary, Odedra, Rajesh, primary, Maya-Mendoza, Apolinar, primary, Reimer, Corinne, primary, Bartek, Jiri, primary, Lau, Alan, primary, and O'Connor, Mark J., primary

Published
2023
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31. Supplementary Methods Table from Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress

Author

Young, Lucy A., primary, O'Connor, Lenka Oplustil, primary, de Renty, Christelle, primary, Veldman-Jones, Margaret H., primary, Dorval, Thierry, primary, Wilson, Zena, primary, Jones, David R., primary, Lawson, Deborah, primary, Odedra, Rajesh, primary, Maya-Mendoza, Apolinar, primary, Reimer, Corinne, primary, Bartek, Jiri, primary, Lau, Alan, primary, and O'Connor, Mark J., primary

Published
2023
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32. BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

Author

Rikke D. Rasmussen, Madhavsai K. Gajjar, Lucie Tuckova, Kamilla E. Jensen, Apolinar Maya-Mendoza, Camilla B. Holst, Kjeld Møllgaard, Jane S. Rasmussen, Jannick Brennum, Jiri Bartek, Martin Syrucek, Eva Sedlakova, Klaus K. Andersen, Marie H. Frederiksen, and Petra Hamerlik

Subjects
Science
Abstract

BRCA1 loss can result in collapse of replication forks into DNA double strand breaks that can contribute to malignant transformation. Here, the authors find that BRCA1 promotes the expression of RRM2 protecting glioblastoma cells from replication stress, DNA damage and apoptosis.

Published
2016
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33. Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states

Author

Antony Adamson, Christopher Boddington, Polly Downton, William Rowe, James Bagnall, Connie Lam, Apolinar Maya-Mendoza, Lorraine Schmidt, Claire V. Harper, David G. Spiller, David A. Rand, Dean A. Jackson, Michael R. H. White, and Pawel Paszek

Subjects
Science
Abstract

In biological systems, timing is often critical to the interpretation of signals that determine cell fate. Here the authors demonstrate how single cells and cellular populations respond dynamically to pulsatile stimulation by TNFα and IL-1β, and suggest a mechanism by which the two cytokines can synergistically modulate inflammation.

Published
2016
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35. Supplementary Figure 1 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Charles Swanton, Nnennaya Kanu, Jiri Bartek, Samuel F. Bakhoum, Jirina Bartkova, Sam M. Janes, Reuben S. Harris, Nicholas McGranahan, Mariam Jamal-Hanjani, Vassilis G. Gorgoulis, Robert E. Hynds, Eric Santoni-Rugiu, Apolinar Maya-Mendoza, Robertus A.M. de Bruin, Tim R. Fenton, Cosetta Bertoli, Simon J. Boulton, Michael Howell, Mary Y. Wu, Teresa Marafioti, Ayse U. Akarca, William L. Brown, Brittany B. Campbell, Ersilia Nigro, Adam Pennycuick, Eva Grönroos, Sebastijan Hobor, Maise Al Bakir, Lykourgos-Panagiotis Zalmas, Bryan Ngo, Haiquan Chen, Yue Zhao, Vitor H. Teixeira, Andrew Rowan, Thomas B.K. Watkins, Emilia L. Lim, Roberto Bellelli, Konstantinos Evangelou, Panagiotis Galanos, Michelle Dietzen, Wei-Ting Lu, Deborah R. Caswell, Haoran Zhai, Clare Puttick, Mihaela Angelova, and Subramanian Venkatesan

Abstract

Assessing APOBEC3 gene expression using immunohistochemical and bioinformatic approaches.

Published
2023
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36. Supplementary Figure 2 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Charles Swanton, Nnennaya Kanu, Jiri Bartek, Samuel F. Bakhoum, Jirina Bartkova, Sam M. Janes, Reuben S. Harris, Nicholas McGranahan, Mariam Jamal-Hanjani, Vassilis G. Gorgoulis, Robert E. Hynds, Eric Santoni-Rugiu, Apolinar Maya-Mendoza, Robertus A.M. de Bruin, Tim R. Fenton, Cosetta Bertoli, Simon J. Boulton, Michael Howell, Mary Y. Wu, Teresa Marafioti, Ayse U. Akarca, William L. Brown, Brittany B. Campbell, Ersilia Nigro, Adam Pennycuick, Eva Grönroos, Sebastijan Hobor, Maise Al Bakir, Lykourgos-Panagiotis Zalmas, Bryan Ngo, Haiquan Chen, Yue Zhao, Vitor H. Teixeira, Andrew Rowan, Thomas B.K. Watkins, Emilia L. Lim, Roberto Bellelli, Konstantinos Evangelou, Panagiotis Galanos, Michelle Dietzen, Wei-Ting Lu, Deborah R. Caswell, Haoran Zhai, Clare Puttick, Mihaela Angelova, and Subramanian Venkatesan

Abstract

APOBEC3 gene expression during senescence and cell cycle progression.

Published
2023
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37. Supplementary Tables S1-S4 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Charles Swanton, Nnennaya Kanu, Jiri Bartek, Samuel F. Bakhoum, Jirina Bartkova, Sam M. Janes, Reuben S. Harris, Nicholas McGranahan, Mariam Jamal-Hanjani, Vassilis G. Gorgoulis, Robert E. Hynds, Eric Santoni-Rugiu, Apolinar Maya-Mendoza, Robertus A.M. de Bruin, Tim R. Fenton, Cosetta Bertoli, Simon J. Boulton, Michael Howell, Mary Y. Wu, Teresa Marafioti, Ayse U. Akarca, William L. Brown, Brittany B. Campbell, Ersilia Nigro, Adam Pennycuick, Eva Grönroos, Sebastijan Hobor, Maise Al Bakir, Lykourgos-Panagiotis Zalmas, Bryan Ngo, Haiquan Chen, Yue Zhao, Vitor H. Teixeira, Andrew Rowan, Thomas B.K. Watkins, Emilia L. Lim, Roberto Bellelli, Konstantinos Evangelou, Panagiotis Galanos, Michelle Dietzen, Wei-Ting Lu, Deborah R. Caswell, Haoran Zhai, Clare Puttick, Mihaela Angelova, and Subramanian Venkatesan

Abstract

Supplementary Table 1: Overview of data resource. Supplementary Table 2: List of antibodies used for immunofluorescence. Supplementary Table 3: List of antibodies used for western blotting. Supplementary Table 4. List of primers used for PCR.

Published
2023
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38. Supplementary Figure 3 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Charles Swanton, Nnennaya Kanu, Jiri Bartek, Samuel F. Bakhoum, Jirina Bartkova, Sam M. Janes, Reuben S. Harris, Nicholas McGranahan, Mariam Jamal-Hanjani, Vassilis G. Gorgoulis, Robert E. Hynds, Eric Santoni-Rugiu, Apolinar Maya-Mendoza, Robertus A.M. de Bruin, Tim R. Fenton, Cosetta Bertoli, Simon J. Boulton, Michael Howell, Mary Y. Wu, Teresa Marafioti, Ayse U. Akarca, William L. Brown, Brittany B. Campbell, Ersilia Nigro, Adam Pennycuick, Eva Grönroos, Sebastijan Hobor, Maise Al Bakir, Lykourgos-Panagiotis Zalmas, Bryan Ngo, Haiquan Chen, Yue Zhao, Vitor H. Teixeira, Andrew Rowan, Thomas B.K. Watkins, Emilia L. Lim, Roberto Bellelli, Konstantinos Evangelou, Panagiotis Galanos, Michelle Dietzen, Wei-Ting Lu, Deborah R. Caswell, Haoran Zhai, Clare Puttick, Mihaela Angelova, and Subramanian Venkatesan

Abstract

Generation and characterization of A3A and A3B knockouts in TIIP cells.

Published
2023
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39. TRACERx Consortium Members from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Charles Swanton, Nnennaya Kanu, Jiri Bartek, Samuel F. Bakhoum, Jirina Bartkova, Sam M. Janes, Reuben S. Harris, Nicholas McGranahan, Mariam Jamal-Hanjani, Vassilis G. Gorgoulis, Robert E. Hynds, Eric Santoni-Rugiu, Apolinar Maya-Mendoza, Robertus A.M. de Bruin, Tim R. Fenton, Cosetta Bertoli, Simon J. Boulton, Michael Howell, Mary Y. Wu, Teresa Marafioti, Ayse U. Akarca, William L. Brown, Brittany B. Campbell, Ersilia Nigro, Adam Pennycuick, Eva Grönroos, Sebastijan Hobor, Maise Al Bakir, Lykourgos-Panagiotis Zalmas, Bryan Ngo, Haiquan Chen, Yue Zhao, Vitor H. Teixeira, Andrew Rowan, Thomas B.K. Watkins, Emilia L. Lim, Roberto Bellelli, Konstantinos Evangelou, Panagiotis Galanos, Michelle Dietzen, Wei-Ting Lu, Deborah R. Caswell, Haoran Zhai, Clare Puttick, Mihaela Angelova, and Subramanian Venkatesan

Abstract

A complete list of investigators in the Tracking Non-Small Cell Lung Cancer Evolution through Therapy (TRACERx) Consortium

Published
2023
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40. Supplementary Figure 4 from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Charles Swanton, Nnennaya Kanu, Jiri Bartek, Samuel F. Bakhoum, Jirina Bartkova, Sam M. Janes, Reuben S. Harris, Nicholas McGranahan, Mariam Jamal-Hanjani, Vassilis G. Gorgoulis, Robert E. Hynds, Eric Santoni-Rugiu, Apolinar Maya-Mendoza, Robertus A.M. de Bruin, Tim R. Fenton, Cosetta Bertoli, Simon J. Boulton, Michael Howell, Mary Y. Wu, Teresa Marafioti, Ayse U. Akarca, William L. Brown, Brittany B. Campbell, Ersilia Nigro, Adam Pennycuick, Eva Grönroos, Sebastijan Hobor, Maise Al Bakir, Lykourgos-Panagiotis Zalmas, Bryan Ngo, Haiquan Chen, Yue Zhao, Vitor H. Teixeira, Andrew Rowan, Thomas B.K. Watkins, Emilia L. Lim, Roberto Bellelli, Konstantinos Evangelou, Panagiotis Galanos, Michelle Dietzen, Wei-Ting Lu, Deborah R. Caswell, Haoran Zhai, Clare Puttick, Mihaela Angelova, and Subramanian Venkatesan

Abstract

Correlation between APOBEC3 expression and different measures of CIN.

Published
2023
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41. Data from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution

Author

Charles Swanton, Nnennaya Kanu, Jiri Bartek, Samuel F. Bakhoum, Jirina Bartkova, Sam M. Janes, Reuben S. Harris, Nicholas McGranahan, Mariam Jamal-Hanjani, Vassilis G. Gorgoulis, Robert E. Hynds, Eric Santoni-Rugiu, Apolinar Maya-Mendoza, Robertus A.M. de Bruin, Tim R. Fenton, Cosetta Bertoli, Simon J. Boulton, Michael Howell, Mary Y. Wu, Teresa Marafioti, Ayse U. Akarca, William L. Brown, Brittany B. Campbell, Ersilia Nigro, Adam Pennycuick, Eva Grönroos, Sebastijan Hobor, Maise Al Bakir, Lykourgos-Panagiotis Zalmas, Bryan Ngo, Haiquan Chen, Yue Zhao, Vitor H. Teixeira, Andrew Rowan, Thomas B.K. Watkins, Emilia L. Lim, Roberto Bellelli, Konstantinos Evangelou, Panagiotis Galanos, Michelle Dietzen, Wei-Ting Lu, Deborah R. Caswell, Haoran Zhai, Clare Puttick, Mihaela Angelova, and Subramanian Venkatesan

Abstract

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast ductal carcinoma in situ, and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non–small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution.Significance:This study reveals the dynamics and drivers of APOBEC3 gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution.This article is highlighted in the In This Issue feature, p. 2355

Published
2023
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43. Data from Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress

Author

Mark J. O'Connor, Alan Lau, Jiri Bartek, Corinne Reimer, Apolinar Maya-Mendoza, Rajesh Odedra, Deborah Lawson, David R. Jones, Zena Wilson, Thierry Dorval, Margaret H. Veldman-Jones, Christelle de Renty, Lenka Oplustil O'Connor, and Lucy A. Young

Abstract

DNA damage checkpoint kinases ATR and WEE1 are among key regulators of DNA damage response pathways protecting cells from replication stress, a hallmark of cancer that has potential to be exploited for therapeutic use. ATR and WEE1 inhibitors are in early clinical trials and success will require greater understanding of both their mechanism of action and biomarkers for patient selection. Here, we report selective antitumor activity of ATR and WEE1 inhibitors in a subset of non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL) cell lines, characterized by high MYC protein expression and CDKN2A/B deletion. Activity correlated with the induction of replication stress, indicated by increased origin firing and retardation of replication fork progression. However, ATR and WEE1 inhibitors caused different amounts of DNA damage and cell death in distinct phases of the cell cycle, underlying the increased potency observed with WEE1 inhibition. ATR inhibition caused DNA damage to manifest as 53BP1 nuclear bodies in daughter G1 cells leading to G1 arrest, whereas WEE1 inhibition caused DNA damage and arrest in S phase, leading to earlier onset apoptosis. In vivo xenograft DLBCL models confirmed differences in single-agent antitumor activity, but also showed potential for effective ATR inhibitor combinations. Importantly, insights into the different inhibitor mechanisms may guide differentiated clinical development strategies aimed at exploiting specific vulnerabilities of tumor cells while maximizing therapeutic index. Our data therefore highlight clinical development opportunities for both ATR and WEE1 inhibitors in non-GCB DLBCL subtypes that represent an area of unmet clinical need.Significance:ATR and WEE1 inhibitors demonstrate effective antitumor activity in preclinical models of DLBCL associated with replication stress, but new mechanistic insights and biomarkers of response support a differentiated clinical development strategy.

Published
2023
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44. Supplementary Data Figures 1-8 from Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress

Author

Mark J. O'Connor, Alan Lau, Jiri Bartek, Corinne Reimer, Apolinar Maya-Mendoza, Rajesh Odedra, Deborah Lawson, David R. Jones, Zena Wilson, Thierry Dorval, Margaret H. Veldman-Jones, Christelle de Renty, Lenka Oplustil O'Connor, and Lucy A. Young

Abstract

This file contains all supplementary figures. Figure 1-7 provide additional analysis of genetic and cell features associated with AZD6738 and AZD1775 activity in DLBCL cell lines, including immunochemistry, immunoblots, immunofluorescence and flow cytometry data to further support the conclusions made from data presented in the main manuscript. Fig 8 provides tumour volume and body weight measurements for individual animals used in the in vivo studies.

Published
2023
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45. Supplementary Tables from Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress

Author

Mark J. O'Connor, Alan Lau, Jiri Bartek, Corinne Reimer, Apolinar Maya-Mendoza, Rajesh Odedra, Deborah Lawson, David R. Jones, Zena Wilson, Thierry Dorval, Margaret H. Veldman-Jones, Christelle de Renty, Lenka Oplustil O'Connor, and Lucy A. Young

Abstract

This file contains Supplementary Tables 1-6. Table S1 lists the growth inhibitory values of AZD6738 and cell doubling rates in DLBCL cell lines used in the study. Table S2 details the median replication fork velocities of DLBCL cell lines treated with DMSO and AZD6738 in Figure 3. Table S3 lists the statistical significance for DNA fibre analysis in Figure 3. Tables S4-S6 summarise the in vivo experiment groups used in the manuscript, including animal numbers in study, efficacy and body weight loss.

Published
2023
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46. Author Correction: BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

Author

Rasmussen, Rikke D., Gajjar, Madhavsai K., Tuckova, Lucie, Jensen, Kamilla E., Maya-Mendoza, Apolinar, Holst, Camilla B., Møllgård, Kjeld, Rasmussen, Jane S., Brennum, Jannick, Bartek, Jr, Jiri, Syrucek, Martin, Sedlakova, Eva, Andersen, Klaus K., Frederiksen, Marie H., Bartek, Jiri, and Hamerlik, Petra

Published
2018
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47. Selección y evaluación de las herramientas de mejora de procesos

Author

Maya Mendoza, J. and Llanos, L. F.

Abstract

La falta o mal uso de herramientas de mejora en la mediana empresa del sector industrial sumado a la sobrevaloración y elección errónea de las mismas originan una mala implementación y poca eficacia en la mejora de procesos. El objetivo de la investigación es evaluar y proponer las herramientas de mejora que logren procesos eficaces en empresas medianas del sector industrial capaces de producir productos y servicios de calidad. La metodología consistió en el diseño, validación y la aplicación de un cuestionario a través de entrevistas estructuradas con expertos en el área de productividad y calidad para identificar y evaluar, mediante una escala de Likert, las herramientas propuestas y en donde se usó el software SPSS-23 para el procesamiento de los datos. La tipología de investigación de este trabajo es del tipo documental-descriptivo, analítico y propositivo. A partir de los resultados se concluye que las herramientas que pertenecen a la ingeniería de calidad son las mejor evaluadas, además de ser utilizadas regularmente en la industria.

Published
2022

49. Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1α and the NAMPT-NAD+ pathway

Author

Maynard, Scott, primary, Hall, Arnaldur, additional, Galanos, Panagiotis, additional, Rizza, Salvatore, additional, Yamamoto, Tatsuro, additional, Gram, Helena Hagner, additional, Munk, Sebastian H N, additional, Shoaib, Muhammad, additional, Sørensen, Claus Storgaard, additional, Bohr, Vilhelm A, additional, Lerdrup, Mads, additional, Maya-Mendoza, Apolinar, additional, and Bartek, Jiri, additional

Published
2022
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