po 178 wdr5 promotes metastasis dissemination in breast cancer

Introduction The core subunit of the COMPASS-like complex, WD Repeat Domain 5 (WDR5) has a prominent role in cell self-renewal, reprogramming and Epithelial-to-Mesenchymal transition (EMT) in different tumour types. We have identified WDR5 as an epigenetic target in in vivo and in vitro shRNA screenings performed in MCF10DCIS.com (from now MCF10DCIS) breast cancer (BC) cells. Here, we show that WDR5 can regulate metastasis dissemination in BC by stimulating TGFB-induced EMT. Material and methods MCF10DCIS and MDAMB231 cells and six metastatic PDXs were used for in vivo and in vitro studies. Cells were transduced to silence WDR5 (shWDR5) or a neutral control (shLuc). Transcriptomic profiles were evaluated by RNA-seq in shLuc and shWDR5 PDXs and MCF10DCIS cells. Differentially expressed genes (DEGs) were identified using Log2FC>|0.6| and FDR t test for in vivo and in vitro experiments. Results and discussions WDR5 interference significantly inhibited tumour growth and in vitro migration of PDXs and MCF10DCIS cells and reduced metastatic burden of MDAMB231 cells in vivo . These data suggested that WDR5 may be involved in cell motility, promoting invasiveness and metastasis. Gene Ontology performed on DEGs highlighted an enrichment of functions related to EMT and TGFB signalling. Indeed, protein and mRNA levels of a series of gene implicated in EMT (e.g. SNAI1, TWIST1, CDH2, SNAI2, ZEB1) were strongly reduced in shWDR5 PDXs and MCF10DCIS cells, thus suggesting a regulatory role of WDR5 in EMT. H3K4me3 levels were globally affected and concordantly reduced at TSS level of SNAI1 and TWIST1 genes in shWDR5 MCF10DCIS cells, confirming that WDR5 can transcriptionally regulate EMT in BC. Moreover, the induction of EMT by TGFB treatment can be abrogated in WDR5-deficient cells, suggesting that the EMT induced by TGFB is WDR5-dependent. Conclusion Our evidences support a model in which WDR5 is responsible for mediating the epithelial-to-mesenchymal transition and metastasis dissemination in BC. WDR5 is essential for TGFB response and its inhibition may be a successful approach to prevent progression of metastatic BC

Microvesicles Derived from Mesenchymal Stem Cells Enhance Survival in a Lethal Model of Acute Kidney Injury

Several studies demonstrated that treatment with mesenchymal stem cells (MSCs) reduces cisplatin mortality in mice. Microvesicles (MVs) released from MSCs were previously shown to favor renal repair in non lethal toxic and ischemic acute renal injury (AKI). In the present study we investigated the effects of MSC-derived MVs in SCID mice survival in lethal cisplatin-induced AKI. Moreover, we evaluated in vitro the effect of MVs on cisplatin-induced apoptosis of human renal tubular epithelial cells and the molecular mechanisms involved. Two different regimens of MV injection were used. The single administration of MVs ameliorated renal function and morphology, and improved survival but did not prevent chronic tubular injury and persistent increase in BUN and creatinine. Multiple injections of MVs further decreased mortality and at day 21 surviving mice showed normal histology and renal function. The mechanism of protection was mainly ascribed to an anti-apoptotic effect of MVs. In vitro studies demonstrated that MVs up-regulated in cisplatin-treated human tubular epithelial cells anti-apoptotic genes, such as Bcl-xL, Bcl2 and BIRC8 and down-regulated genes that have a central role in the execution-phase of cell apoptosis such as Casp1, Casp8 and LTA. In conclusion, MVs released from MSCs were found to exert a pro-survival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection conferred by MSCs

Ecological phytochemistry of Cerrado (Brazilian savanna) plants

The Cerrado (the Brazilian savanna) is one of the vegetation formations of great biodiversity in Brazil and it has experienced strong deforestation and fragmentation. The Cerrado must contain at least 12,000 higher plant species.We discuss the ecological relevance of phytochemical studies carried out on plants from the Cerrado, including examples of phytotoxicity, antifungal, insecticidal and antibacterial activities. The results have been classified according to activity and plant family. The most active compounds have been highlighted and other activities are discussed. A large number of complex biochemical interactions occur in this system. However, only a small fraction of the species has been studied from the phytochemical viewpoint to identify the metabolites responsible for these interactions

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Nociceptive Afferents to the Premotor Neurons That Send Axons Simultaneously to the Facial and Hypoglossal Motoneurons by Means of Axon Collaterals

It is well known that the brainstem premotor neurons of the facial nucleus and hypoglossal nucleus coordinate orofacial nociceptive reflex (ONR) responses. However, whether the brainstem PNs receive the nociceptive projection directly from the caudal spinal trigeminal nucleus is still kept unclear. Our present study focuses on the distribution of premotor neurons in the ONR pathways of rats and the collateral projection of the premotor neurons which are involved in the brainstem local pathways of the orofacial nociceptive reflexes of rat. Retrograde tracer Fluoro-gold (FG) or FG/tetramethylrhodamine-dextran amine (TMR-DA) were injected into the VII or/and XII, and anterograde tracer biotinylated dextran amine (BDA) was injected into the caudal spinal trigeminal nucleus (Vc). The tracing studies indicated that FG-labeled neurons receiving BDA-labeled fibers from the Vc were mainly distributed bilaterally in the parvicellular reticular formation (PCRt), dorsal and ventral medullary reticular formation (MdD, MdV), supratrigeminal nucleus (Vsup) and parabrachial nucleus (PBN) with an ipsilateral dominance. Some FG/TMR-DA double-labeled premotor neurons, which were observed bilaterally in the PCRt, MdD, dorsal part of the MdV, peri-motor nucleus regions, contacted with BDA-labeled axonal terminals and expressed c-fos protein-like immunoreactivity which induced by subcutaneous injection of formalin into the lip. After retrograde tracer wheat germ agglutinated horseradish peroxidase (WGA-HRP) was injected into VII or XII and BDA into Vc, electron microscopic study revealed that some BDA-labeled axonal terminals made mainly asymmetric synapses on the dendritic and somatic profiles of WGA-HRP-labeled premotor neurons. These data indicate that some premotor neurons could integrate the orofacial nociceptive input from the Vc and transfer these signals simultaneously to different brainstem motonuclei by axonal collaterals

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV

Search for pair-produced long-lived neutral particles decaying to jets in the ATLAS hadronic calorimeter in ppcollisions at √s=8TeV

The ATLAS detector at the Large Hadron Collider at CERN is used to search for the decay of a scalar boson to a pair of long-lived particles, neutral under the Standard Model gauge group, in 20.3fb−1of data collected in proton–proton collisions at √s=8TeV. This search is sensitive to long-lived particles that decay to Standard Model particles producing jets at the outer edge of the ATLAS electromagnetic calorimeter or inside the hadronic calorimeter. No significant excess of events is observed. Limits are reported on the product of the scalar boson production cross section times branching ratio into long-lived neutral particles as a function of the proper lifetime of the particles. Limits are reported for boson masses from 100 GeVto 900 GeV, and a long-lived neutral particle mass from 10 GeVto 150 GeV

Acquired immunologic tolerance: with particular reference to transplantation

The first unequivocally successful bone marrow cell transplantation in humans was recorded in 1968 by the University of Minnesota team of Robert A. Good (Gatti et al. Lancet 2: 1366–1369, 1968). This achievement was a direct extension of mouse models of acquired immunologic tolerance that were established 15 years earlier. In contrast, organ (i.e. kidney) transplantation was accomplished precociously in humans (in 1959) before demonstrating its feasibility in any experimental model and in the absence of a defensible immunologic rationale. Due to the striking differences between the outcomes with the two kinds of procedure, the mechanisms of organ engraftment were long thought to differ from the leukocyte chimerism-associated ones of bone marrow transplantation. This and other concepts of alloengraftment and acquired tolerance have changed over time. Current concepts and their clinical implications can be understood and discussed best from the perspective provided by the life and times of Bob Good