EMT Inducers Catalyze Malignant Transformation of Mammary Epithelial Cells and Drive Tumorigenesis towards Claudin-Low Tumors in Transgenic Mice

The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT–inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell–like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation

Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis:Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors

Objective: To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (SpA) and prior inadequate response to or intolerance of 1 or 2 tumor necrosis factor inhibitors (TNFi). Methods: In this phase III randomized, double-blind, placebo-controlled trial, adult patients with an inadequate response to or intolerance of 1 or 2 TNFi and an established diagnosis of axial SpA (according to the Assessment of SpondyloArthritis international Society [ASAS] criteria for radiographic axial SpA, with radiographic sacroiliitis defined according to the modified New York criteria and ≥1 feature of SpA) were recruited and randomized 1:1:1 to receive placebo or 80-mg subcutaneous ixekizumab every 2 weeks (IXEQ2W) or 4 weeks (IXEQ4W), with an 80-mg or 160-mg starting dose. The primary end point was 40% improvement in disease activity according to the ASAS criteria (ASAS40) at week 16. Secondary outcomes and safety were also assessed. Results: A total of 316 patients were randomized to receive placebo (n = 104), IXEQ2W (n = 98), or IXEQ4W (n = 114). At week 16, significantly higher proportions of IXEQ2W patients (n = 30 [30.6%]; P = 0.003) or IXEQ4W patients (n = 29 [25.4%]; P = 0.017) had achieved an ASAS40 response versus the placebo group (n = 13 [12.5%]), with statistically significant differences reported as early as week 1 with ixekizumab treatment. Statistically significant improvements in disease activity, function, quality of life, and spinal magnetic resonance imaging–evident inflammation were observed after 16 weeks of ixekizumab treatment versus placebo. Treatment-emergent adverse events (AEs) with ixekizumab treatment were more frequent than with placebo. Serious AEs were similar across treatment arms. One death was reported (IXEQ2W group). Conclusion: Ixekizumab treatment for 16 weeks in patients with active radiographic axial SpA and previous inadequate response to or intolerance of 1 or 2 TNFi yields rapid and significant improvements in the signs and symptoms of radiographic axial SpA versus placebo

Key signalling nodes in mammary gland development and cancer. The Snail1-Twist1 conspiracy in malignant breast cancer progression

Breast cancer is the most common cancer among women, and despite significant advances in diagnosing and treating it, metastatic spread of cancer cells results in a high mortality rate. Epithelial-to-mesenchymal transition (EMT) is an embryonic program in which epithelial cells lose their characteristics and gain mesenchymal features. Therefore, EMT might play a very important role during malignant tumour progression. In this review we summarise recent advances in breast cancer research with a particular focus on the transcription factors Snail1 and Twist1. Besides discussing the role of EMT in normal mammary gland development, we describe regulatory mechanisms involving newly discovered upstream regulators and microRNAs, the association of EMT with breast cancer stem cells, and the involvement of the tumour microenvironment in breast cancer progression

Palaeohydrological evolution and implications for palaeoclimate since the Late Glacial at Laguna de Fuente de Piedra, southern Spain

Here, we present a terrestrial multi-proxy record of Late Quaternary environmental changes in the southern Iberian Peninsula covering approximately 30 ka. This sedimentary record originates from a saline playa lake (Laguna de Fuente de Piedra) hosted within a complex geological setting dominated by Triassic claystones and evaporites, Jurassic carbonates and Miocene deposits leading to a complex hydrogeological setting. Dissolution of evaporites in the catchment and intense evaporation are responsible for saline waters fluctuating in the basin. Thus, salinity as palaeohydrological proxy, requires a decoupling of internal and external hydrogeochemical processes. The greatest accumulation of evaporites in the LFP late Pleistocene–Holocene record coincides with a more humid or, at least, less evaporative, period. Based on multi-proxy data we describe five lacustrine lithofacies (2–5), and fluvial deposits (1) from sediment cores. The proposed conceptual lake margin model contains three main lake water stages repeated within the sedimentary succession and building up the characteristic lithofacies. Lake water stages refer to a flooding stage (influx > outflux), high water stage (influx = outflux), and low water stage (influx < outflux). The lithostratigraphy reveals a palaeohydrological record suggesting climate changes and associated lake level fluctuations. Lake level oscillations of different amplitudes have been identified. Low amplitude changes have been revealed for the periods from 28 ka cal BP to 17.5 ka cal BP and from 8.2 ka cal BP to present, whereas in between (17.5 ka cal BP to 8.2 ka cal BP) the Late Pleistocene/Holocene transition shows high amplitude lake level changes. The latter coincides with an increased influence of saline subsurface waters, due to groundwater level rising (sulfate signature). In contrast, the Holocene, records the low amplitude oscillations and a drop of the groundwater levels, which creates a less saline or fresher footprint in the sediments (carbonate signature). Thus, the periods of low amplitude lake level oscillations, low inputs of clastics and low groundwater levels (drier) coincide with periods of minimal seasonal insolation difference. In contrast, the period of higher amplitude lake level oscillations, higher input of clastics and higher groundwater table (wetter) is correlative to periods of maximum difference between summer and winter insolation. © 2016, Elsevier Ltd and INQUA

Late holocene environments in Las Tablas de Daimiel (south central Iberian peninsula, Spain)

The use of a high resolution pollen record in combination with geochemical data from sediments composed mainly of layers of charophytes alternating with layers of vegetal remains plus some detrital beds permits the reconstruction of the environmental evolution of the last 3000 years in an inland wetland of the Mediterranean domain, thus introducing a new climatic dataset for the Late Holocene. Hydrological fluctuations, reflected in the relationship between emerged and aquatic vegetation and inorganic and organic C and N changes, can be related to aridity or humid phases, while relations among arboreal taxa (Quercus and Pinus) and Artemisia are used as temperature indicators. Five climatic periods have been identified: a Subatlantic Cold Period (<150 b.c.), cold and arid; the RomanWarm Period (150 b.c.–a.d. 270), warmer and wetter; the Dark Ages (a.d. 270–a.d. 950), colder and drier; the Medieval Warm Period (a.d. 950–a.d. 1400), warmer and wetter; and the Little Ice Age (>a.d. 1400) indicated by a cooling and drying trend. Despite the lack of any direct evidence of human action, there are some episodes related to deforestation during the Reconquista (Middle Ages) that mask the real climatic signal

Drosophila histone H2A variant (H2Av) controls poly(ADP-ribose) polymerase 1 (PARP1) activation in chromatin

According to the histone code hypothesis, histone variants and modified histones provide binding sites for proteins that change the chromatin state to either active or repressed. Here, we identify histone variants that regulate the targeting and enzymatic activity of poly(ADP-ribose) polymerase 1 (PARP1), a chromatin regulator in higher eukaryotes. We demonstrate that PARP1 is targeted to chromatin by association with the histone H2A variant (H2Av)—the Drosophila homolog of the mammalian histone H2A variants H2Az/H2Ax—and that subsequent phosphorylation of H2Av leads to PARP1 activation. This two-step mechanism of PARP1 activation controls transcription at specific loci in a signal-dependent manner. Our study establishes the mechanism through which histone variants and changes in the histone modification code control chromatin-directed PARP1 activity and the transcriptional activation of target genes

Neutron and X-Ray diffraction study of internal stress in thermomechanically fatigued single-crystal superalloy

The relationship between internal stress and thermomechanical fatigue (TMF) in a Ni-based single-crystal superalloy is studied by neutron and X-ray diffraction. The extents of internal stress, deformation, lattice mismatch, and distortion during TMF are characterized by the determined deviatoric stress invariants and lattice parameters and compared with relevant microstructural information from scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The results show that, in general, the macroscopic stress, plastic deformation, lattice mismatch, and distortion have all increased during TMF. The lattice mismatches of the TMF samples are at a high level, where the values along [100]/[010] are negative, but those along [001] are positive. The tetragonal lattice distortion of the γ matrix is slightly greater than that of the γ′ precipitates, where the c/a values of the γ matrix are smaller than 1, but that of the γ′ precipitate larger than 1. The γ matrix yields and becomes hardened at the initial TMF cycle and gradually loses most of its strength during the earlier TMF cycles, associated with stress relaxation and homogenous deformation. However, the γ′ precipitates yield and become hardened later, bearing the most stress up to the necking of the superalloy. This process is associated with a buildup of stress and significant concentrated and inhomogeneous distribution of deformation in the γ′ precipitate. The residual deformation states of the superalloy and its component phases at the earlier TMF are basically shearing, and only become stretched at a later stage of TMF. The microstructure of the TMF samples shows an initial stage of rafting, where the dislocations are accumulated at the γ/γ\ifmmode′\else$′$\fi interfaces of the γ matrix channels, but both dislocation networks and stacking faults are inhomogeneously distributed in the γ′ precipitates