In the present study, we sought to elucidate the effect of miR-145 on glioma cell progression and its mechanisms of action. We examined the effects of miR-145 on proliferation and invasion of U87 glioma cells and on capillary tube formation. Our data show that restoration of miR-145 in U87 glioma cells significantly reduced their in vitro proliferation, invasion and angiogenesis. However, decreased miR-145 expression promoted U87 glioma cell proliferation, invasion and angiogenesis, and reduced-expression of miR-145 increased ADAM17 and EGFR expression in U87 cells. Overexpression of miR-145 reduced ADAM17 and EGFR expression. VEGF secretion and VEGF expression were decreased by increased miR-145 expression in U87 cells and were reversed by miR-145 down-regulation in vitro. Nude mice with intracerebral implantation of U87 overexpressing miR-145 cells exhibited significantly reduced tumor growth and promoted survival compared with control groups. Taken together, these results suggest a role for miR-145 as a tumor suppressor which inhibits glioma cell proliferation, invasion and angiogenesis in vitro and reduces glioma growth in vivo.

The Bronze Age barrows on the downs of southern England have been investigated and discussed for nearly 200 years, but much less attention has been paid to similar structures in the areas of heathland beyond the chalk and river gravels. They were built in a phase of expansion towards the end of the Early Bronze Age, and more were constructed during the Middle Bronze Age. They have a number of distinctive characteristics. This paper considers the interpretation of these monuments and their wider significance in relation to the pattern of settlement. It also discusses the origins of field systems in lowland England. crichel down, launceston down and beaulieu heathA large number of prehistoric burial mounds were excavated during the Second World War as their sites were taken over for use by the armed forces. Among them were the barrows on Crichel Down and Launceston Down on the Wessex chalk, and those on Beaulieu Heath in the New Forest. Both excavations were conducted by the same people. Stuart Piggott and Margaret Piggott worked together at Crichel Down, where the sites of a series of barrows were to be used as a bombing range (Piggott and Piggott 1944). Margaret Piggott also worked at Beaulieu Heath where the mounds were removed to make way for a military airfield (Piggott 1943). Again Stuart Piggott contributed to the excavation report.These projects were important as it was rare for so many barrows to be excavated in a single location, or for them to be explored by the same techniques. Of course the circumstances of the excavations imposed some constraints. At Crichel and Launceston Downs the work focused on 16 of the smaller Bronze Age barrows so that more monuments could be explored in the time available. When the site reverted to farmland in 1958, two larger mounds (Long Crichel Barrows 5 and 7) were completely excavated (Green, Lynch and White 1982). At Beaulieu Heath there were fewer limitations, but parts of the ten barrows were only sampled (Fig. 1).Work at Long Crichel Barrows 5 and 7 was more extensive than the earlier research, and when it was published the authors of the report were able to draw on the results of a number of projects that had taken place during the intervening years. As a result they paid more attention to the stages by which the structures were built. They also discussed the reuse of older graves. In doing so, they rejected the traditional view that the barrows were intended to house 'individual' burials. Instead each could be considered as a cemetery in its own right.

Among the molecular signals underlying cutaneous inflammation is the transcription complex NF-kB, its upstream modulators, and cytokines and chemokines that are the downstream proinflammatory effectors. Central to NF-kB activation is IkB kinase (IKK), which phosphorylates IkBa, releasing NF-kB to the nucleus. In a screening of a kinase inhibitor library, we identified two IKK inhibitors that were high-affinity substrates for p-glycoprotein (ABCB1), the multidrug resistance protein known to facilitate transdermal drug delivery. ACHP (2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridinecarbonitrile) and IKK 16 prevented both nuclear translocation of NF-kB and activation of a NF-kB reporter and reduced the induction of cytokine and chemokine transcripts in human or mouse keratinocytes by IL-1a, tumor necrosis factor-a, and phorbol myristate acetate. ACHP, but not IKK 16, was nontoxic to mouse or human keratinocytes at any dose tested. In mice, topical ACHP prevented the cutaneous inflammation induced by topical phorbol myristate acetate or imiquimod, reduced the inflammation from erythema doses of artificial sunlight, and lowered the tumor incidence of mice treated with 7,12-dimethyl benzanthracene when applied before phorbol myristate acetate. Topical ACHP also reduced the NF-kB and IL-17 inflammatory signature after multiple doses of imiquimod. Thus, ACHP and IKK 16 hit their NF-kB target in mouse and human keratinocytes, and ACHP is an effective topical nonsteroidal anti-inflammatory in mice.

Cholangiocarcinoma is a rare, aggressive malignancy with limited treatment options, due to a paucity of actionable mutations and low response to immune checkpoint inhibitors. Furthermore, its extreme heterogeneity prevents identification of actionable dependencies from bulk-tissue profiles. To address these challenges, we introduce a highly generalizable, single-cell framework for the mechanism-based prioritization of drugs to treat rare, highly heterogeneous tumors. Analysis of transformed cells, accounting for only 10% of a cholangiocarcinoma patient biopsy revealed three molecularly-distinct subpopulations, predicted to be sensitive to four drugs by regulatory network-based analysis. Validation in a low-passage, patient-derived xenograft (PDX) from the same patient confirmed tumor growth rate control by two of these drugs (plicamycin and dacinostat) and further validated predicted subpopulation-specific effects, suggesting they may represent promising candidates for follow-up clinical trials, either alone or in combination with current standard-of-care chemotherapies. The proposed approach can be generalized to elucidate complementary dependencies of rare, heterogeneous tumors, at the single cell level.