ORCID Profile
0000-0002-6276-815X
Current Organisations
University of Helsinki
,
Just Skin Treatment Clinic
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Publisher: Springer Science and Business Media LLC
Date: 11-05-2023
DOI: 10.1038/S41589-023-01326-1
Abstract: Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been h ered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.
Publisher: Cold Spring Harbor Laboratory
Date: 05-07-2022
DOI: 10.1101/2022.07.03.498529
Abstract: Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been h ered by excessive toxicity. Here, we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of proinflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryo-EM structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.
Publisher: Wiley
Date: 26-09-2020
DOI: 10.1002/JMRS.434
Publisher: Wiley
Date: 08-05-2023
DOI: 10.1002/JMRS.688
Publisher: Wiley
Date: 26-01-2023
DOI: 10.1002/JMRS.652
Abstract: Radiation therapy (RT) offers a less invasive management option for bariatric cancer patients. As the proportion of Australians categorised overweight or obese approaches 70%, it is not well understood how this growth will impact RT departments. The aim of this study was to evaluate the current and potential future body mass index (BMI) of RT patients at one centre, with the purpose of identifying variables that may impact resource planning decisions. De‐identified demographic data including gender, age, diagnosis code, activity code and BMI were obtained from MOSAIQ® oncology information system for 5548 courses of RT commenced between 2017 and 2020, and retrospectively analysed. Descriptive statistics were used to summarise the data. Simple and multiple linear regression was used to analyse for statistically significant relationships between variables. Of all patient courses, 64% were overweight or obese. Average BMI increased over time by 0.3 kg/m 2 per year. Courses related to the young and elderly had a lower average BMI. Breast, brain/skull, and pelvis rostate treatment sites had a significant association with a higher average BMI. Thorax treatment sites had a lower average BMI, but this average is increasing at the fastest rate of all treatment sites. Prone breast courses had an average BMI 5.58 kg/m 2 higher than IMRT/VMAT courses. Results demonstrate that patient BMI is increasing. Resources related to breast courses (breast board, prone board) and thorax courses (lung board) may experience increased strain in the future. Modifications to department workflow and scheduling are likely required. Further research into staffing implications is recommended.
Publisher: Elsevier BV
Date: 12-2021
Publisher: Elsevier BV
Date: 06-2020
Publisher: Wiley
Date: 03-2019
DOI: 10.1002/JMRS.2_324
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JMIR.2017.11.002
Abstract: The use of three-dimensional virtual reality technologies in education has been widely reported in the literature. The goal of this article is to review how the virtual environment for radiotherapy training (VERT) can be utilised to support the teaching of intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy, and dynamic conformal arc therapy techniques. Utilising Pinnacle v14 (Philips Radiation Oncology Systems, Madison, WI) and Monaco v 5.10 (Elekta CMS, Maryland Heights, MO), we exported IMRT, volumetric-modulated arc therapy, and dynamic conformal arc therapy treatment plans to VERT. Quality assurance (QA) plans were also exported from the Monaco planning software to demonstrate theoretical concepts and virtual plan delivery using the ArcCHECK phantom (Sun Nuclear Corp, Melbourne, FL) and solid water IMRT phantom. Several VERT features were utilised to critically evaluate dose coverage and organ at risk sparing on inverse treatment plans. The display of gantry and multileaf collimator motion and fluence maps could be a useful feature in the education of treatment planning concepts. QA could be delivered on VERT to demonstrate patient-specific QA concepts in a virtual environment. Anecdotal evidence shows that the use of VERT for collaborative plan evaluation sessions is likely to engage the students and improve their ability to evaluate treatment plans. VERT can be utilised to reinforce understanding of treatment plan evaluation skills, QA, and treatment delivery of inverse plans in educational environments.
Publisher: Cambridge University Press (CUP)
Date: 18-01-2017
DOI: 10.1017/S1460396916000546
Abstract: Radiation oncology information systems (OIS) play a crucial role in radiation therapy by ensuring accurate and safe delivery of treatment. A MOSAIQ OIS system is currently used to support undergraduate radiation therapist training at Queensland University of Technology. This review addresses the rationale for implementation and integration in teaching environments and explores the pedagogical benefits supported by educational theory. A review of MOSAIQ functionality shows potential to transform learning through the development of authentic and engaging learning tasks. It provides students with an opportunity to learn two-dimensional image matching through the use of digitally reconstructed radiographs and electronic portal images as well as three-dimensional image matching using computed tomography (CBCT) data in a safe learning environment without clinical time pressures. In addition, this provides the students with knowledge of quality assurance (QA) checks through the verification of treatment parameters and the transfer of information from the planning system to the treatment units. However, there are several potential challenges and practical considerations that need to be overcome. The application of MOSAIQ OIS could potentially transform teaching and learning strategies for student radiation therapists. Increased knowledge and hands-on skills at undergraduate levels in areas such as image matching and QA can be powerful tools to drive the standards of practice a step further.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 09-2018
Publisher: Elsevier BV
Date: 09-2018
Publisher: Elsevier BV
Date: 03-2016
Publisher: Elsevier BV
Date: 06-2020
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Peter J Caldwell.