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.     

The endocannabinoid system in rat gliosomes and its role in the modulation of glutamate release

The endocannabinoid system and endocannabinoid receptor-driven modulation of glutamate release were studied in rat brain cortex astroglial gliosomes. These preparations contained the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, as well their major biosynthetic (N-acyl-phosphatidylethanolamines-hydrolyzing-phospholipase D and diacylglycerol-lipase) and catabolic (fatty acid amide-hydrolase and monoacylglycerol-lipase) enzymes. Gliosomes expressed type-1 (CB1R), type-2 (CB2R) cannabinoid, and type-1 vanilloid (TRPV1) receptors, as ascertained by Western blotting and confocal microscopy. Methanandamide, a stable analogue of anandamide acting as CB1R, CB2R, and TRPV1 agonist, stimulated or inhibited the depolarization-evoked gliosomal [³H]d-aspartate release, at lower and higher concentrations, respectively. Experiments with ACEA (arachidonyl-2′-chloroethylamide), JWH133 ((6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]-pyran) and capsaicin, selective agonists at CB1R, CB2R and TRPV1, respectively, demonstrated that potentiation of [³H]d-aspartate release was due to CB1R while inhibition to CB2R and TRPV1 engagement. These findings were confirmed by using selective receptor antagonists. Furthermore, CB1R activation caused increase of intracellular IP3 and Ca²⁺ concentration, suggesting an involvement of phospholipase C.     

Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome

The overgrowth- and tumor-associated Beckwith-Wiedemann syndrome results from dysregulation of imprinted genes on chromosome 11p15.5. Here we show that inherited microdeletions in the H19 differentially methylated region (DMR) that abolish two CTCF target sites cause this disease. Maternal transmission of the deletions results in hypermethylation of the H19 DMR, biallelic IGF2 expression, H19 silencing and Beckwith-Wiedemann syndrome, indicative of loss of function of the IGF2-H19 imprinting control element.     

Mapping of central monoamine neurons in the monkey

Zusammenfassung Verteilung und Morphologie von Katecholamin-(KA) 5-Hydroxytryptamin-Neuronen im Affengehirn stimmt mit früheren Befunden über das Rattengehirn gut überein. Die Zahl der KA-Zellkörper in Area Subceorulea ist jedoch bedeutend grösser bei Affen, und eine neue Art terminaler KA-Nervenfasern von starker Fluoreszenzintensität und im Durchmesser variierender Varikosität wurde aufgefunden.     

‘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.