Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer

A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.     

Graphical Choices and Geometrical Thought in the Transmission of Theodosius’ Spherics from Antiquity to the Renaissance

Spherical geometry studies the sphere not simply as a solid object in itself, but chiefly as the spatial context of the elements which interact on it in a complex three-dimensional arrangement. This compels to establish graphical conventions appropriate for rendering on the same plane—the plane of the diagram itself—the spatial arrangement of the objects under consideration. We will investigate such “graphical choices” made in the Theodosius’ Spherics from antiquity to the Renaissance. Rather than undertaking a minute analysis of every particular element or single variant, we will try to uncover the more general message each author attempted to convey through his particular graphical choices. From this analysis, it emerges that the different kinds of representation are not the result of merely formal requirements but mirror substantial geometrical requirements expressing different ways of interpreting the sphere and testify to different ways of reasoning about the elements that interact on it.     

Cartesian echoes in Kant’s philosophy of nature

In this paper, we take the cue from a recent observation of Dan Warren about pre-Newtonian elements in Kant’s philosophy of nature to argue that there are two puzzles concerning Kant’s claim that mechanical laws presuppose dynamical laws in Chapter Three of Metaphysical Foundations of Natural Science. We offer responses on Kant’s behalf to these puzzles. These responses take us through a journey via Kant’s first pre-Critical work, True Estimation of Living Forces, and the then lively debate between Cartesians and Leibnizians. We show how some important Cartesian echoes, clearly evident in True Estimation, have played a role in shaping some seminal ideas of Kant on dynamical forces.     

‘Working in a new world’: Kuhn,constructivism, and mind-dependence

In The Structure of Scientific Revolutions, Kuhn famously advanced the claim that scientists work in a different world after a scientific revolution. Kuhn's view has been at the center of a philosophical literature that has tried to make sense of his bold claim, by listing Kuhn's view in good company with other seemingly constructivist proposals. The purpose of this paper is to take some steps towards clarifying what sort of constructivism (if any) is in fact at stake in Kuhn's view. To this end, I distinguish between two main (albeit not exclusive) notions of mind-dependence: a semantic notion and an ontological one. I point out that Kuhn's view should be understood as subscribing to a form of semantic mind-dependence, and conclude that semantic mind-dependence does not land us into any worrisome ontological mind-dependence, pace any constructivist reading of Kuhn.     

Optical nano-imaging of gate-tunable graphene plasmons

The ability to manipulate optical fields and the energy flow of light is central to modern information and communication technologies, as well as quantum information processing schemes. However, because photons do not possess charge, a way of controlling them efficiently by electrical means has so far proved elusive. A promising way to achieve electric control of light could be through plasmon polaritons—coupled excitations of photons and charge carriers—in graphene. In this two-dimensional sheet of carbon atoms, it is expected that plasmon polaritons and their associated optical fields can readily be tuned electrically by varying the graphene carrier density. Although evidence of optical graphene plasmon resonances has recently been obtained spectroscopically, no experiments so far have directly resolved propagating plasmons in real space. Here we launch and detect propagating optical plasmons in tapered graphene nanostructures using near-field scattering microscopy with infrared excitation light. We provide real-space images of plasmon fields, and find that the extracted plasmon wavelength is very short—more than 40 times smaller than the wavelength of illumination. We exploit this strong optical field confinement to turn a graphene nanostructure into a tunable resonant plasmonic cavity with extremely small mode volume. The cavity resonance is controlled in situ by gating the graphene, and in particular, complete switching on and off of the plasmon modes is demonstrated, thus paving the way towards graphene-based optical transistors. This successful alliance between nanoelectronics and nano-optics enables the development of active subwavelength-scale optics and a plethora of nano-optoelectronic devices and functionalities, such as tunable metamaterials, nanoscale optical processing, and strongly enhanced light–matter interactions for quantum devices and biosensing applications.     

A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size

Autosomal recessive primary microcephaly is a potential model in which to research genes involved in human brain growth. We show that two forms of the disorder result from homozygous mutations in the genes CDK5RAP2 and CENPJ. We found neuroepithelial expression of the genes during prenatal neurogenesis and protein localization to the spindle poles of mitotic cells, suggesting that a centrosomal mechanism controls neuron number in the developing mammalian brain.