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Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche
The sub-population of tumor cells termed ‘cancer stem cells’ (CSCs) possess the capability to generate tumors, undergo epithelial–mesenchymal transition (EMT) and are implicated in metastasis, making treatments to specifically target CSCs an attractive therapeutic strategy. Tumor hypoxia plays a key role in regulating EMT and cancer stem cell function. Carbonic anhydrase IX (CAIX) is a hypoxia-inducible protein that regulates cellular pH to promote cancer cell survival and invasion in hypoxic microenvironments and is a biomarker of poor prognosis for breast cancer metastasis and survival. Here, we demonstrate that inhibition of CAIX expression or activity with novel small-molecule inhibitors in breast cancer cell lines, or in primary metastatic breast cancer cells, results in the inhibition of breast CSC expansion in hypoxia. We identify the mTORC1 axis as a critical pathway downstream of CAIX in the regulation of cancer stem cell function. CAIX is also required for expression of EMT markers and regulators, as well as drivers of ‘stemness’, such as Notch1 and Jagged1 in isolated CSCs. In addition, treatment of mice bearing orthotopic breast tumors with CAIX-specific small-molecule inhibitors results in significant depletion of CSCs within these tumors. Furthermore, combination treatment with paclitaxel results in enhanced tumor growth delay and eradication of lung metastases. These data demonstrate that CAIX is a critical mediator of the expansion of breast CSCs in hypoxic niches by sustaining the mesenchymal and ‘stemness’ phenotypes of these cells, making CAIX an important therapeutic target for selectively depleting breast CSCs.
Journal Article
Recovering the Body
The Anthropocene has been officially declared as a new geological epoch owing to the lasting impact made by humans on environments, negatively affecting the health and even survival of human populations. Furthermore, over the past decade, molecular science has shown that the human genome is reactive to environments that are external and internal to the body. Hence, environments impact directly on individual bodies by bringing about epigenetic changes in the genome. Following a discussion of human exceptionalism and its limitations, I argue that an anthropology of embodiment should be situated in time and space, and recognition given to local biologies as a subcategory of situated biologies evident globally. Examples are then given of the intergenerational transmission of epigenetic effects due to environmental toxic exposures with a concluding call for anthropologists to engage with the worldwide challenge.
Journal Article
Comprehending the Body in the Era of the Epigenome
This paper suggests that it is urgent for anthropologists to respond to a current move in epigenetics in which nature and nurture are no longer understood as dichotomous elements. It is argued that a neobiological reductionism is currently taking shape due to molecularization of the environment by epigeneticists. Anthropological concepts of embodiment should be retheorized in light of this development. The formation of epigenetics as a discipline is discussed, then the habitual black-boxing of the post-Enlightenment material body is noted. Five illustrative examples are given of recent epigenetic findings: the impact of maternal stress on fetal dysfunction, social deprivation and epigenetic changes, food as molecularized epigenetics, aging and epigenetics, and toxins as epigenetic triggers. \"Embedded bodies,\" \"local biologies,\" and \"biosocial becomings\" are introduced as concepts that enable the insertion of an anthropological perspective into this emerging debate. A brief account of historical trauma and its ongoing effects as experienced by First Nations and Inuit of Canada are given in conclusion. It is argued that historical and ethnographic accounts are indispensable if epigenetic findings are to avoid neoreductionism and contribute to policy changes to improve human well-being.
Journal Article
The great migration
\"Follow the huge herds of wildebeest on their year-round journey. Watch out for hungry lions and crocodiles!\"--Cover.
Book
Tensor-on-Tensor Regression
I propose a framework for the linear prediction of a multiway array (i.e., a tensor) from another multiway array of arbitrary dimension, using the contracted tensor product. This framework generalizes several existing approaches, including methods to predict a scalar outcome from a tensor, a matrix from a matrix, or a tensor from a scalar. I describe an approach that exploits the multiway structure of both the predictors and the outcomes by restricting the coefficients to have reduced PARAFAC/CANDECOMP rank. I propose a general and efficient algorithm for penalized least-squares estimation, which allows for a ridge (L
2
) penalty on the coefficients. The objective is shown to give the mode of a Bayesian posterior, which motivates a Gibbs sampling algorithm for inference. I illustrate the approach with an application to facial image data. An R package is available at
https://github.com/lockEF/MultiwayRegression
.
Journal Article
Emperor penguins
\"Spend a year in the life of the emperor penguins, including their journey across frozen Antarctica\"-- Publisher's description.
Book
Autonomous Temporal Probability Concentration: Clockworks and the Second Law of Thermodynamics
According to thermodynamics, the inevitable increase of entropy allows the past to be distinguished from the future. From this perspective, any clock must incorporate an irreversible process that allows this flow of entropy to be tracked. In addition, an integral part of a clock is a clockwork, that is, a system whose purpose is to temporally concentrate the irreversible events that drive this entropic flow, thereby increasing the accuracy of the resulting clock ticks compared to counting purely random equilibration events. In this article, we formalize the task of autonomous temporal probability concentration as the inherent goal of any clockwork based on thermal gradients. Within this framework, we show that a perfect clockwork can be approximated arbitrarily well by increasing its complexity. Furthermore, we combine such an idealized clockwork model, comprised of many qubits, with an irreversible decay mechanism to showcase the ultimate thermodynamic limits to the measurement of time.
Journal Article