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"FISHER, David"
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The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology
Certain transcription factors have vital roles in lineage development, including specification of cell types and control of differentiation. Microphthalmia-associated transcription factor (MITF) is a key transcription factor for melanocyte development and differentiation. MITF regulates expression of numerous pigmentation genes to promote melanocyte differentiation, as well as fundamental genes for maintaining cell homeostasis, including genes encoding proteins involved in apoptosis (eg, BCL2) and the cell cycle (eg, CDK2). Loss-of-function mutations of MITF cause Waardenburg syndrome type IIA, whose phenotypes include depigmentation due to melanocyte loss, whereas amplification or specific mutation of MITF can be an oncogenic event that is seen in a subset of familial or sporadic melanomas. In this article, we review basic features of MITF biological function and highlight key unresolved questions regarding this remarkable transcription factor.
Journal Article
The melanoma revolution: From UV carcinogenesis to a new era in therapeutics
Melanoma, the deadliest form of skin cancer, is an aggressive disease that is rising in incidence. Although melanoma is a historically treatment-resistant malignancy, in recent years unprecedented breakthroughs in targeted therapies and immunotherapies have revolutionized the standard of care for patients with advanced disease. Here, we provide an overview of recent developments in our understanding of melanoma risk factors, genomics, and molecular pathogenesis and how these insights have driven advances in melanoma treatment. In addition, we review benefits and limitations of current therapies and look ahead to continued progress in melanoma prevention and therapy. Remarkable achievements in the field have already produced a paradigm shift in melanoma treatment: Metastatic melanoma, once considered incurable, can now be treated with potentially curative rather than palliative intent.
Journal Article
Precision medicine for cancer with next-generation functional diagnostics
Genome-based cancer therapeutic matching is limited by incomplete biological understanding of the relationship between phenotype and cancer genotype. This Opinion article proposes that this limitation can be addressed by functional testing of live patient tumour cells exposed to potential therapies.
Precision medicine is about matching the right drugs to the right patients. Although this approach is technology agnostic, in cancer there is a tendency to make precision medicine synonymous with genomics. However, genome-based cancer therapeutic matching is limited by incomplete biological understanding of the relationship between phenotype and cancer genotype. This limitation can be addressed by functional testing of live patient tumour cells exposed to potential therapies. Recently, several 'next-generation' functional diagnostic technologies have been reported, including novel methods for tumour manipulation, molecularly precise assays of tumour responses and device-based
in situ
approaches; these address the limitations of the older generation of chemosensitivity tests. The promise of these new technologies suggests a future diagnostic strategy that integrates functional testing with next-generation sequencing and immunoprofiling to precisely match combination therapies to individual cancer patients.
Journal Article
Bill O'Reilly's Legends & lies : the real West
\"How did Davy Crockett save President Jackson's life--only to end up dying at the Alamo? Was the Lone Ranger based on a real lawman--and was he an African American? What amazing detective work led to the capture of Black Bart, the 'gentleman bandit' and one of the West's most famous stagecoach robbers? Did Butch Cassidy and the Sundance Kid really die in a hail of bullets in South America? Generations of Americans have grown up on TV shows, movies, and books about these Western icons. But what really happened in the Wild West?\"-- Provided by publisher.
Book
B-cell-specific checkpoint molecules that regulate anti-tumour immunity
The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth
1
,
2
. Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by
Havcr1
) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of
Havcr1
in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.
Manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.
Journal Article
Explore/create : my life in pursuit of new frontiers, hidden worlds, and the creative spark
The legendary entrepreneur and online gaming pioneer, creator of the Ultima series and the forthcoming Shroud of Avatar, and private space travel advocate examines the importance of adventure and curiosity in his life in this inspiring memoir, complete with interactive tie-ins, puzzles, tricks, and secret codes.
Book
A brief introduction to mixed effects modelling and multi-model inference in ecology
The use of linear mixed effects models (LMMs) is increasingly common in the analysis of biological data. Whilst LMMs offer a flexible approach to modelling a broad range of data types, ecological data are often complex and require complex model structures, and the fitting and interpretation of such models is not always straightforward. The ability to achieve robust biological inference requires that practitioners know how and when to apply these tools. Here, we provide a general overview of current methods for the application of LMMs to biological data, and highlight the typical pitfalls that can be encountered in the statistical modelling process. We tackle several issues regarding methods of model selection, with particular reference to the use of information theory and multi-model inference in ecology. We offer practical solutions and direct the reader to key references that provide further technical detail for those seeking a deeper understanding. This overview should serve as a widely accessible code of best practice for applying LMMs to complex biological problems and model structures, and in doing so improve the robustness of conclusions drawn from studies investigating ecological and evolutionary questions.
Journal Article