Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer

Conceptual models of carcinogenesis typically consist of an evolutionary sequence of heritable changes in genes controlling proliferation, apoptosis, and senescence. We propose that these steps are necessary but not sufficient to produce invasive breast cancer because intraductal tumour growth is also constrained by hypoxia and acidosis that develop as cells proliferate into the lumen and away from the underlying vessels. This requires evolution of glycolytic and acid-resistant phenotypes that, we hypothesise, is critical for emergence of invasive cancer. Mathematical models demonstrate severe hypoxia and acidosis in regions of intraductal tumours more than 100 m from the basement membrane. Subsequent evolution of glycolytic and acid-resistant phenotypes leads to invasive proliferation. Multicellular spheroids recapitulating ductal carcinoma in situ (DCIS) microenvironmental conditions demonstrate upregulated glucose transporter 1 (GLUT1) as adaptation to hypoxia followed by growth into normoxic regions in qualitative agreement with model predictions. Clinical specimens of DCIS exhibit periluminal distribution of GLUT-1 and Na+/H+ exchanger (NHE) indicating transcriptional activation by hypoxia and clusters of the same phenotype in the peripheral, presumably normoxic regions similar to the pattern predicted by the models and observed in spheroids. Upregulated GLUT-1 and NHE-1 were observed in microinvasive foci and adjacent intraductal cells. Adaptation to hypoxia and acidosis may represent key events in transition from in situ to invasive cancer

Evidence of strong stabilizing effects on the evolution of boreoeutherian (Mammalia) dental proportions.

The dentition is an extremely important organ in mammals with variation in timing and sequence of eruption, crown morphology, and tooth size enabling a range of behavioral, dietary, and functional adaptations across the class. Within this suite of variable mammalian dental phenotypes, relative sizes of teeth reflect variation in the underlying genetic and developmental mechanisms. Two ratios of postcanine tooth lengths capture the relative size of premolars to molars (premolar-molar module, PMM), and among the three molars (molar module component, MMC), and are known to be heritable, independent of body size, and to vary significantly across primates. Here, we explore how these dental traits vary across mammals more broadly, focusing on terrestrial taxa in the clade of Boreoeutheria (Euarchontoglires and Laurasiatheria). We measured the postcanine teeth of N = 1,523 boreoeutherian mammals spanning six orders, 14 families, 36 genera, and 49 species to test hypotheses about associations between dental proportions and phylogenetic relatedness, diet, and life history in mammals. Boreoeutherian postcanine dental proportions sampled in this study carry conserved phylogenetic signal and are not associated with variation in diet. The incorporation of paleontological data provides further evidence that dental proportions may be slower to change than is dietary specialization. These results have implications for our understanding of dental variation and dietary adaptation in mammals

Mechanistic insights on ultra-tough polylactide-based ionic nanocomposites

peer reviewe

A metodologia de Lamarck

Neste artigo, o método científico de Jean-Baptiste Lamarck é estudado sob o ponto de vista de seu discurso metodológico, bem como sob o ponto de vista de sua prática científica. Essa metodologia é comparada à preconizada por Condillac, assim como à dos "ideólogos" (idéologues) grupo no qual se costuma incluir o próprio Lamarck. Mostra-se que o discurso metodológico de Lamarck assemelha-se ao dos ideólogos; no entanto, sua prática científica não se coaduna com esse enfoque. Em vez de seguir uma abordagem empirista, a obra de Lamarck se fundamenta em princípios metafísicos gerais sobre a natureza. Sob o ponto de vista dos ideólogos, seu trabalho deveria ser rejeitado - o que de fato ocorreu - como um mero sistema (système) metafísico - no sentido pejorativo utilizado pelos seguidores de Condillac. No entanto, o presente artigo argumenta que esse é justamente um importante e inovador aspecto da obra de Lamarck, que permitiu a eclosão do evolucionismo moderno

Abrupt global events in the Earth's history: a physics perspective

The timeline of the Earth's history reveals quasi-periodicity of the geological record over the last 542 Myr, on timescales close, in the order of magnitude, to 1 Myr. What is the origin of this quasi-periodicity? What is the nature of the global events that define the boundaries of the geological time scale? I propose that a single mechanism is responsible for all three types of such events: mass extinctions, geomagnetic polarity reversals, and sea-level fluctuations. The mechanism is fast, and involves a significant energy release. The mechanism is unlikely to have astronomical causes, both because of the energies involved, and because it acts quasi-periodically. It must then be sought within the Earth itself. And it must be capable of reversing the Earth's magnetic field. The last requirement makes it incompatible with the consensus model of the origin of the geomagnetic field - the hydromagnetic dynamo operating in the Earth's fluid core. In the second part of the paper, I show that a vast amount of seemingly unconnected geophysical and geological data can be understood in a unified way if the source of the Earth's main magnetic field is a ~200-km-thick lithosphere, repeatedly magnetized as a result of methane-driven oceanic eruptions, which produce ocean flow capable of dynamo action. The eruptions are driven by the interplay of buoyancy forces and exsolution of dissolved gas, which accumulates in the oceanic water masses prone to stagnation and anoxia. Polarity reversals, mass extinctions, and sequence boundaries are consequences of these eruptions. Unlike the consensus model of geomagnetism, this scenario is consistent with the paleomagnetic data showing that "directional changes during a [geomagnetic polarity] reversal can be astonishingly fast, possibly occurring as a nearly instantaneous jump from one inclined dipolar state to another in the opposite hemisphere".Comment: Final journal version. New title, significant changes. Supersedes v.

Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker

BackgroundHistone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA.MethodsThis phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin.ResultsIn total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(-1) on days 1-3, followed by doxorubicin (20 mg m(-2)) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day(-1) of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day(-1). Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for > or =8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression.ConclusionThese findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day(-1). The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting