RUNX-mediated growth arrest and senescence are attenuated by diverse mechanisms in cells expressing RUNX1 fusion oncoproteins

RUNX gene over-expression inhibits growth of primary cells but transforms cells with tumor suppressor defects, consistent with reported associations with tumor progression. In contrast, chromosomal translocations involving RUNX1 are detectable in utero, suggesting an initiating role in leukemias. How do cells expressing RUNX1 fusion oncoproteins evade RUNX-mediated growth suppression? Previous studies showed that the TEL-RUNX1 fusion from t(12;21) B-ALLs is unable to induce senescence-like growth arrest (SLGA) in primary fibroblasts while potent activity is displayed by the RUNX1-ETO fusion found in t(8;21) AMLs. We now show that SLGA potential is suppressed in TEL-RUNX1 but reactivated by deletion of the TEL HLH domain or mutation of a key residue (K99R). Attenuation of SLGA activity is also a feature of RUNX1-ETO9a, a minor product of t(8;21) translocations with increased leukemogenicity. Finally, while RUNX1-ETO induces SLGA it also drives a potent senescence-associated secretory phenotype (SASP), and promotes the immortalisation of rare cells that escape SLGA. Moreover, the RUNX1-ETO SASP is not strictly linked to growth arrest as it is largely suppressed by RUNX1 and partially activated by RUNX1-ETO9a. These findings underline the heterogeneous nature of premature senescence and the multiple mechanisms by which this failsafe process is subverted in cells expressing RUNX1 oncoproteins

Collaboration of MYC and RUNX2 in lymphoma simulates T‐cell receptor signaling and attenuates p53 pathway activity

MYC and RUNX oncogenes each trigger p53‐mediated failsafe responses when overexpressed in vitro and collaborate with p53 deficiency in vivo. However, together they drive rapid onset lymphoma without mutational loss of p53. This phenomenon was investigated further by transcriptomic analysis of premalignant thymus from RUNX2/MYC transgenic mice. The distinctive contributions of MYC and RUNX to transcriptional control were illustrated by differential enrichment of canonical binding sites and gene ontology analyses. Pathway analysis revealed signatures of MYC, CD3, and CD28 regulation indicative of activation and proliferation, but also strong inhibition of cell death pathways. In silico analysis of discordantly expressed genes revealed Tnfsrf8/CD30, Cish, and Il13 among relevant targets for sustained proliferation and survival. Although TP53 mRNA and protein levels were upregulated, its downstream targets in growth suppression and apoptosis were largely unperturbed. Analysis of genes encoding p53 posttranslational modifiers showed significant upregulation of three genes, Smyd2, Set, and Prmt5. Overexpression of SMYD2 was validated in vivo but the functional analysis was constrained by in vitro loss of p53 in RUNX2/MYC lymphoma cell lines. However, an early role is suggested by the ability of SMYD2 to block senescence‐like growth arrest induced by RUNX overexpression in primary fibroblasts

Addiction to Runx1 is partially attenuated by loss of p53 in the Eμ-Myc lymphoma model

The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt’s lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ- Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status

"Driven to distraction?" Children's experiences of car travel

This is an Author's Accepted Manuscript of an article published in volume, 4, issue 1, pages 59-76 in Mobilities 2009. Copyright @ 2009 Taylor & Francis, available online at: http://www.tandfonline.com/doi/abs/10.1080/17450100802657962.Cars have become increasingly significant features in the lives of many children and adults in the UK and elsewhere. Whilst there is a growing body of research considering how adults experience automobility, that is the increasingly central role of cars within societies, there has been little equivalent research exploring children's perspectives. Drawing upon a variety of methods including personal diaries, photographs, in‐depth interviews and surveys amongst schools within Buckinghamshire and North London, the paper contributes to filling this gap in existing research through exploring how cars are not only journey spaces for children, but are also sites for play, relaxation, homework, companionship, technology and the consumption of commodities. Using a Foucauldian analysis of power, insights into wider familial processes relating to mobility are provided by exploring how cars are sites of conflicting power relations between parents and children. The paper also explores how children's everyday experiences of cars were framed by wider sets of power relations, including car corporations which design and manufacture these spaces, and the role of capital which commodifies everyday activities in cars. In doing so, the paper challenges existing research on automobility for only focusing upon adults' experiences of cars and begins to theorise a more inclusive account of automobility which incorporates children and young people

HGF Mediates the Anti-inflammatory Effects of PRP on Injured Tendons

Platelet-rich plasma (PRP) containing hepatocyte growth factor (HGF) and other growth factors are widely used in orthopaedic/sports medicine to repair injured tendons. While PRP treatment is reported to decrease pain in patients with tendon injury, the mechanism of this effect is not clear. Tendon pain is often associated with tendon inflammation, and HGF is known to protect tissues from inflammatory damages. Therefore, we hypothesized that HGF in PRP causes the anti-inflammatory effects. To test this hypothesis, we performed in vitro experiments on rabbit tendon cells and in vivo experiments on a mouse Achilles tendon injury model. We found that addition of PRP or HGF decreased gene expression of COX-1, COX-2, and mPGES-1, induced by the treatment of tendon cells in vitro with IL-1β. Further, the treatment of tendon cell cultures with HGF antibodies reduced the suppressive effects of PRP or HGF on IL-1β-induced COX-1, COX-2, and mPGES-1 gene expressions. Treatment with PRP or HGF almost completely blocked the cellular production of PGE2 and the expression of COX proteins. Finally, injection of PRP or HGF into wounded mouse Achilles tendons in vivo decreased PGE2 production in the tendinous tissues. Injection of platelet-poor plasma (PPP) however, did not reduce PGE2 levels in the wounded tendons, but the injection of HGF antibody inhibited the effects of PRP and HGF. Further, injection of PRP or HGF also decreased COX-1 and COX-2 proteins. These results indicate that PRP exerts anti-inflammatory effects on injured tendons through HGF. This study provides basic scientific evidence to support the use of PRP to treat injured tendons because PRP can reduce inflammation and thereby reduce the associated pain caused by high levels of PGE2. © 2013 Zhang et al

Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging

We have previously shown that healthy older adults exhibit reduced cutaneous immune responses during a varicella zoster virus (VZV) antigen challenge that correlated with a nonspecific inflammatory response to the injection itself. Here we found that needle damage during intradermal injections in older adults led to an increase in the number of cutaneous senescent fibroblasts expressing CCL2, resulting in the local recruitment of inflammatory monocytes. These infiltrating monocytes secreted prostaglandin E2, which inhibited resident memory T cell activation and proliferation. Pretreatment of older participants with a p38 mitogen-activated protein kinase inhibitor in vivo decreased CCL2 expression and inhibited monocyte recruitment and secretion of prostaglandin E2. This coincided with an increased response to VZV antigen challenge in the skin. Our results point to a series of molecular and cellular mechanisms that link cellular senescence, tissue damage, excessive inflammation and reduced immune responsiveness in human skin and demonstrate that tissue-specific immunity can be restored in older adults by short-term inhibition of inflammatory responses

First Stars VIII -- Enrichment of the neutron-capture elements in the early Galaxy

Our aim is to measure accurate, homogeneous neutron-capture element abundances for the sample of 32 EMP giant stars studied earlier in this series, including 22 stars with [Fe/H] $< -$3.0. Based on high-resolution, high S/N spectra from the ESO VLT/UVES, 1D, LTE model atmospheres, and synthetic spectrum fits, we determine abundances or upper limits for the 16 elements Sr, Y, Zr, Ba, La, Ce, Pr, Nd, Sm, Eu, Gd, Dy, Ho, Er, Tm, and Yb in all stars. As found earlier, [Sr/Fe], [Y/Fe], [Zr/Fe] and [Ba/Fe] are below Solar in the EMP stars, with very large scatter. However, we find a tight anti-correlation of [Sr/Ba], [Y/Ba], and [Zr/Ba] with [Ba/H] for $-4.5 <$ [Ba/H] $< -2.5$, also when subtracting the contribution of the main $r$-process as measured by [Ba/H]. The huge, well-characterised scatter of the [n-capture/Fe] ratios in our EMP stars is in stark contrast to the negligible dispersion in the [$\alpha$/Fe] and [Fe-peak/Fe] ratios for the same stars found in Paper V. These results demonstrate that a second (``weak'' or LEPP) $r$-process dominates the production of the lighter neutron-capture elements for [Ba/H] $< -2.5$. The combination of very consistent [$\alpha$/Fe] and erratic [n-capture/Fe] ratios indicates that inhomogeneous models for the early evolution of the halo are needed. Our accurate data provide strong constraints on future models of the production and mixing of the heavy elements in the early Galaxy.Comment: 19 pages, 16 figures, A&A accepte

Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia

Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injur

Revisiting histories of anti-racist thought and activism

This piece reconsiders histories of anti-racist thought and practice, including the linkages between anti-racisms and other traditions of liberatory thought. We argue that anti-racism should be understood as a strand in radical thought linking internationalism, institutional critique and street activism, in the process interfeeding with other social movements. The traditions of anti-racist thought discussed in this special issue exemplify these cross-cutting influences