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The life of Leonardo da Vinci
A long-awaited new translation of Giorgio Vasari's \"Life of Leonardo da Vinci,\" illustrated for the first time, that preserves Vasari's compelling narrative and respects his meaning with a new precision. Giorgio Vasari's Lives of the Most Excellent Painters, Sculptors, and Architects (1550 and 1568) is a classic of cultural history. In his monumental assembly of artists' lives, no life is more vivid than that of Leonardo da Vinci, a near-contemporary of Vasari. Illustrated with the works of art discussed by Vasari, and including a selection of Da Vinci's studies of science and technology, The Life of Leonardo da Vinci paints an intriguing picture of the progress of art in the hands of the master. Succinct notes also provide new insights in light of modern knowledge of Da Vinci's career. This beautiful gift edition offers a literary translation by eminent scholar Martin Kemp that respects the sixteenth-century Italian, transposing Vasari's vocabulary into its modern equivalent. Translated in partnership with Lucy Russell, the text will be the first to integrate the 1550 edition and the expanded version of 1568. This fascinating and accessible read coincides with the five hundredth anniversary of Da Vinci's death.
Book
When patients’ voices aren’t heard: estimands and statistical methods for handling missing patient-reported outcomes in oncology studies
Introduction
Patient-reported outcomes (PROs) are integral to oncology clinical trials, yet missing data - especially due to intercurrent events (ICEs) of disease progression pose challenges for robust and interpretable analysis. While regulatory and best practice guidelines now emphasize the explicit definition of estimands, including strategies for handling ICEs, and supplementary analyses to examine their robustness, practical recommendations for their implementation in PRO analyses remain limited.
Methods
We present a methodological framework for defining estimands and statistical analysis for a longitudinal change in a PRO confirmatory endpoint, including strategies for handling the main ICE of disease progression using a simulated clinical trial. We propose for the ICE of disease progression using either a hypothetical or treatment policy strategy for the main and supplementary analysis, and present implementation of two methods targeting a hypothetical approach and one method for treatment policy approach (implicit multiple imputation in a longitudinal model, a joint modelling of longitudinal PROs and time-to-progression, and multiple imputation using control-based imputation post progression).
Results
We present the occurrence of ICEs and missing data and provide a tutorial for conducting analysis in the presence of disease progression using hypothetical and treatment policy strategies respectively. Despite the occurrence of disease progression events and other missing data, conducting supplementary analysis provided confidence in our overall interpretation for the simulated trial.
Conclusions
Our recommendations provide practical guidance for specifying estimands, selecting statistical analysis methods, and interpreting PRO analyses in oncology trials with missing data. Accurately estimating the treatment effect on quality-of-life, in a way which is interpretable, is crucial to aid patients and other stakeholders when making treatment decisions.
Journal Article
Feminist art activisms and artivisms
The first volume in the new Plural series, this publication seeks to critically dissect the term 'activism,' which today seems to have become a catchword for any woman's empowerment through the arts, and reveal the diversity of practices and realities that it comprises. Presenting a range of critical insights, perspectives, and practices from artists, activists, and academics, it reflects on the role of feminist interventions in the field of contemporary art, the public sphere, and politics. In the process, it touches upon broader questions of cultural difference, history, class, economic standing, ecological issues, and sexual orientation, as well as the ways in which these intersect.
Book
Cerebrovascular amyloid Angiopathy in bioengineered vessels is reduced by high-density lipoprotein particles enriched in Apolipoprotein E
Background
Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer’s disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood.
Methods
Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding.
Results
We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen-I protein levels produced by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE.
Conclusion
The findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally-acting apoE in AD.
Journal Article
Knaves over queens
As the alien Xenovirus reaches Britain, Prime Minister Sir Winston Churchill, now gifted with extraordinary longevity, joins with Alan Turing to set up a special organization, the Order of the Silver Helix, to outmaneuver the terrifying mutations of the virus in Britain.
BOOK
An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases
Introduction
The neurovascular unit (NVU) – the interaction between the neurons and the cerebrovasculature – is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU.
Method
We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries.
Results
This system, composed of primary human vascular cells (endothelial cells, smooth muscle cells and astrocytes) and induced pluripotent stem cell (iPSC) derived neurons, demonstrates a physiological multilayer organization of the involved cell types. It reproduces key characteristics of cortical neurons and astrocytes and enables formation of a selective and functional endothelial barrier. We provide proof-of-principle data showing that this in vitro human arterial NVU may be suitable to study neurovascular components of neurodegenerative diseases such as Alzheimer’s disease (AD), as endogenously produced phosphorylated tau and beta-amyloid accumulate in the model over time. Finally, neuronal and glial fluid biomarkers relevant to neurodegenerative diseases are measurable in our arterial NVU model.
Conclusion
This model is a suitable research tool to investigate arterial NVU functions in healthy and disease states. Further, the design of the platform allows culture under native-like flow conditions for extended periods of time and yields sufficient tissue and media for downstream immunohistochemistry and biochemistry analyses.
Journal Article
Pharmacodynamic modelling of resistance to epidermal growth factor receptor inhibition in brain metastasis mouse models
PurposeEpidermal growth factor receptor (EGFR) is thought to play a role in the regulation of cell proliferation; with its activation stimulating tumour growth. EGFR inhibitors have shown promise in the treatment of cancer, particularly in non-small cell lung cancer, however, resistance is observed in the majority of patients. A tumour growth model was developed aiming to explain this resistance.MethodsThe model incorporating populations of both sensitive and resistant cells were fitted to data from a study of EGFR inhibitor AZD3759 in brain metastasis mouse models. The observed regrowth of tumours in higher dose groups suggested the development of resistance to treatment. The bioluminescence observations were highly variable, covering many orders of magnitude, so to assess how reliable the model was, the parameter estimates were compared to those found in less noisy subcutaneous mouse models.ResultsThe fitted model suggested that resistance was mainly due to a proportion of cells being resistant at baseline, and the contribution of mutations occurring during the study leading to resistance was negligible. Estimated growth rate and dose–response was found to be comparable between brain metastasis and subcutaneous mouse models.ConclusionsThe developed model to describe resistance suggests that the resistance to EGFR-inhibition seen in these xenografts is best described by assuming a small percentage of cells are resistant to treatment at baseline. This model suggests changes to dosing and dosing schedule may not prevent resistance to treatment developing, and that additional treatments would need to be used in combination to overcome resistance.
Journal Article