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2,983 results on '"Wright, Timothy"'

5. Investigating combinations of radium-223 and androgen deprivation therapies in advanced prostate cancer

Author

Wright, Timothy, Cole, Aidan, and Prise, Kevin

Subjects
Prostate cancer, abiraterone, enzalutamide, radiation, radium-223, DNA damage repair
Abstract

Abiraterone and Enzalutamide are anti-androgens shown to be among the treatments to improve overall and progression-free survival in mCRPC. However, although commonly used in clinical settings, many questions exist regarding drug selection, scheduling with radiation, potential synergy with radiation and the underlying mechanisms governing any potential synergy. Another key unexplored area of interest is if the combination of AR inhibitors with the α-emitter radium-223, which targets bone metastases, can be utilised to improve patient response over radium223 alone. This thesis addressed these issues by conducting the first detailed analysis of the effects of Abiraterone and Enzalutamide alone or in combination with X-rays, radium-223 or Olaparib across a range of biological endpoints, including, survival, DNA damage, cell cycle, DNA repair and cell death across a panel of AR-insensitive (PC3) and AR-sensitive (LNCaP) prostate models and osteosarcoma bone (SJSA-1) models. The results of this study report that in AR-sensitive settings, Abiraterone and Enzalutamide radiosensitise in both low and high LET settings through the downregulation of essential DNA repair proteins involved in homologous recombination (HR) and nonhomologous end joining (NHEJ), with reductions in HR at least in part due to cell cycle distribution changes, resulting in increased levels of DNA damage and cell death. Furthermore, synthetic lethality approaches using Olaparib in combination with Abiraterone or Enzalutamide showed combinations resulted in increased radiosensitisation, DNA damage and cell death over single agent use. In conclusion, this thesis provides the first in vitro comparison of Abiraterone and Enzalutamide with and without radium-223, demonstrating that while both Abiraterone and Enzalutamide could be used to enhance tumour response, Abiraterone proved superior across all endpoints measured and synthetic lethality approaches could be used to enhance this efficacy even further. Overall this thesis supports that combinations of Abiraterone and Enzalutamide can be utilised with radium-223 to improve tumour response.

Published
2023

7. Rotating Hinge Revision Total Knee Arthroplasty Provides Greater Arc of Motion Gains for Patients Who Have Severe Arthrofibrosis

Author

Bauer, Thomas W., Blevins, Jason L., Bogner, Eric A., Bostrom, Mathias P., Carli, Alberto, Chalmers, Brian P., Figgie, Mark P., Della Valle, Alejandro Gonzalez, Haas, Steven B., Jerabek, Seth A., Jules-Elysee, Kethy M., Kirksey, Meghan A., Koff, Matthew F., Lessard, Samantha, Mayman, David J., McLawhorn, Alexander S., Pannellini, Tania, Parks, Michael L., Potter, Hollis G., Rodeo, Scott A., Schiller, Nicholas, Sculco, Thomas P., Tam, Kathleen, Verwiel, Chloe, Westrich, Geoffrey H., Wright, Timothy M., Youssef, Mark, Liow, Ming Han Lincoln, Flevas, Dimitrios A., Braun, Sebastian, Nocon, Allina, Lee, Gwo-Chin, and Sculco, Peter K.

Published
2025
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26. The environmental consequences of climate-driven agricultural frontiers

Author

Hannah, Lee, Roehrdanz, Patrick R, C., Krishna Bahadur K, Fraser, Evan DG, Donatti, Camila I, Saenz, Leonardo, Wright, Timothy Max, Hijmans, Robert J, Mulligan, Mark, Berg, Aaron, and van Soesbergen, Arnout

Subjects
Climate Change Impacts and Adaptation, Agricultural, Veterinary and Food Sciences, Environmental Sciences, Horticultural Production, Climate Action, Life on Land, Biodiversity, Carbon, Climate Change, Crops, Agricultural, Soil, Water Quality, General Science & Technology
Abstract

Growing conditions for crops such as coffee and wine grapes are shifting to track climate change. Research on these crop responses has focused principally on impacts to food production impacts, but evidence is emerging that they may have serious environmental consequences as well. Recent research has documented potential environmental impacts of shifting cropping patterns, including impacts on water, wildlife, pollinator interaction, carbon storage and nature conservation, on national to global scales. Multiple crops will be moving in response to shifting climatic suitability, and the cumulative environmental effects of these multi-crop shifts at global scales is not known. Here we model for the first time multiple major global commodity crop suitability changes due to climate change, to estimate the impacts of new crop suitability on water, biodiversity and carbon storage. Areas that become newly suitable for one or more crops are Climate-driven Agricultural Frontiers. These frontiers cover an area equivalent to over 30% of the current agricultural land on the planet and have major potential impacts on biodiversity in tropical mountains, on water resources downstream and on carbon storage in high latitude lands. Frontier soils contain up to 177 Gt of C, which might be subject to release, which is the equivalent of over a century of current United States CO2 emissions. Watersheds serving over 1.8 billion people would be impacted by the cultivation of the climate-driven frontiers. Frontiers intersect 19 global biodiversity hotspots and the habitat of 20% of all global restricted range birds. Sound planning and management of climate-driven agricultural frontiers can therefore help reduce globally significant impacts on people, ecosystems and the climate system.

Published
2020

35. Clinical and Microbial Determinants of Upper Respiratory Colonization With Streptococcus pneumoniae and Native Microbiota in People With Human Immunodeficiency Virus Type 1 and Control Adults.

Author

Nicholson, Lindsay K, Kofonow, Jennifer M, Robertson, Charles E, Wright, Timothy, Li, Qing, Gardner, Edward M, Frank, Daniel N, and Janoff, Edward N

Subjects
HIV, STREPTOCOCCUS pneumoniae, COLONIZATION (Ecology), STREPTOCOCCAL diseases, HUMAN microbiota
Abstract

Background The substantial risk for respiratory and invasive infections with Streptococcus pneumoniae (Spn) among people with HIV-1 (PWH) begins with asymptomatic colonization. The frequency of Spn colonization among US adults with and without HIV-1 infection is not well characterized in the conjugate vaccine era. Methods We determined Spn colonization frequency by culture and specific lytA gene quantitative polymerase chain reaction (PCR) and microbiota profile by 16S ribosomal RNA gene sequencing in nasopharyngeal (NP) and oropharyngeal (OP) DNA from 138 PWH and 93 control adults and associated clinical characteristics. Results The frequencies of Spn colonization among PWH and controls did not differ (11.6% vs 8.6%, respectively; P =.46) using combined results of culture and PCR, independent of vaccination or behavioral risks. PWH showed altered microbiota composition (ie, β-diversity; NP: P =.0028, OP: P =.0098), decreased α-diversity (NP: P =.024, OP: P =.0045), and differences in the relative abundance of multiple bacterial taxa. Spn colonization was associated with altered β-diversity in the nasopharynx (P =.011) but not oropharynx (P =.21). Conclusions Despite widespread conjugate vaccine and antiretroviral use, frequencies of Spn colonization among PWH and controls are currently consistent with those reported in the preconjugate era. The persistently increased risk of pneumococcal disease despite antiretroviral therapy may relate to behavioral and immunologic variables other than colonization. [ABSTRACT FROM AUTHOR]

Published
2024
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