Topotecan Decreases the Expression of Programmed Death-Ligand 1 in Glioblastoma Cell Lines; Implications for Immunotherapy

Glioblastoma (GBM) is the most aggressive primary brain tumor and thrives in a microenvironment of relative immunosuppression. The poor clinical outcome of these malignant tumors requires the development of novel treatment options/therapeutic regimens. Accordingly, numerous immunotherapies for GBM are currently being tested in ongoing clinical trials. Herein we have examined the ability of the FDA approved drug topotecan to suppress programmed death-ligand 1 (PD-L1) expression. Our results suggest a role for topotecan as an adjuvant therapy in treatment regimens targeting certain GBM patient subpopulations in whom the expression of PD-L1 has been confirmed.This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke/National Institutes of Health (NINDS/NIH)

Identification of ALDH1A3 as a Viable Therapeutic Target in Breast Cancer Metastasis-Initiating Cells

The development of efficacious therapies targeting metastatic spread of breast cancer to the brain represents an unmet clinical need. Accordingly, an improved understanding of the molecular underpinnings of central nervous system spread and progression of breast cancer brain metastases (BCBM) is required. In this study, the clinical burden of disease in BCBM was investigated, as well as the role of aldehyde dehydrogenase 1A3 (ALDH1A3) in the metastatic cascade leading to BCBM development. Initial analysis of clinical survival trends for breast cancer and BCBM determined improvement of breast cancer survival rates; however, this has failed to positively affect the prognostic milestones of triple-negative breast cancer (TNBC) brain metastases (BM). ALDH1A3 and a representative epithelial-mesenchymal transition (EMT) gene signature (mesenchymal markers, CD44 or Vimentin) were compared in tumors derived from BM, lung metastases (LM), or bone metastases (BoM) of patients as well as mice after injection of TNBC cells. Selective elevation of the EMT signature and ALDH1A3 were observed in BM, unlike LM and BoM, especially in the tumor edge. Furthermore, ALDH1A3 was determined to play a role in BCBM establishment via regulation of circulating tumor cell adhesion and migration phases in the BCBM cascade. Validation through genetic and pharmacologic inhibition of ALDH1A3 via lentiviral shRNA knockdown and a novel small-molecule inhibitor demonstrated selective inhibition of BCBM formation with prolonged survival of tumor-bearing mice. Given the survival benefits via targeting ALDH1A3, it may prove an effective therapeutic strategy for BCBM prevention and/or treatment

Austerity urbanism and Olympic counter-legacies: gendering, defending and expanding the urban commons in East London

This article reflects on an occupation led by single mothers to contest the destruction of social housing in post-Olympics East London. In the process, it argues for a more gendered theorisation of the urban commons. Drawing on auto-ethnography, participant observation and qualitative interviews, the article argues three central points: First, that the occupation demonstrates the gendered nature of the urban commons and the leadership of women in defending them from enclosure; second that the defence of an existing urban commons enabled the creation of a new temporary commons characterised by the collectivisation of gendered socially reproductive activities; and third that this commoning has had a lasting impact on housing activism at the city scale and beyond. This impact is conceptualised as an ‘Olympic counter-legacy’ that is characterised by the forging of new relationships and affinities, the strengthening of networked activism and circulation of tactics between campaign groups

A novel quantitative high-throughput screen identifies drugs that both activate SUMO conjugation via the inhibition of microRNAs 182 and 183 and facilitate neuroprotection in a model of oxygen and glucose deprivation

The conjugation/de-conjugation of Small Ubiquitin-like Modifier (SUMO) has been shown to be associated with a diverse set of physiologic/pathologic conditions. The clinical significance and ostensible therapeutic utility offered via the selective control of the global SUMOylation process has become readily apparent in ischemic pathophysiology. Herein, we describe the development of a novel quantitative high-throughput screening (qHTS) system designed to identify small molecules capable of increasing SUMOylation via the regulation/inhibition of members of the microRNA (miRNA)-182 family. This assay employs a SHSY5Y human neuroblastoma cell line stably transfected with a dual firefly-Renilla luciferase reporter system for identification of specific inhibitors of either miR-182 or miR-183. In this study, we have identified small molecules capable of inducing increased global conjugation of SUMO in both SHSY5Y cells and rat E18-derived primary cortical neurons. The protective effects of a number of the identified compounds were confirmed via an in vitro ischemic model (oxygen/glucose deprivation). Of note, this assay can be easily repurposed to allow high-throughput analyses of the potential drugability of other relevant miRNA(s) in ischemic pathobiology.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Intramural Research Program of the NINDS/NIH, an IRTA-OxCam Fellowship and by the Wellcome Trust [RRZA/057 and RG79423]

Clobetasol promotes neuromuscular plasticity in mice after motoneuronal loss via sonic hedgehog signaling, immunomodulation and metabolic rebalancing

Motoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders

Extracellular vesicles are independent metabolic units with asparaginase activity.

Extracellular vesicles (EVs) are membrane particles involved in the exchange of a broad range of bioactive molecules between cells and the microenvironment. Although it has been shown that cells can traffic metabolic enzymes via EVs, much remains to be elucidated with regard to their intrinsic metabolic activity. Accordingly, herein we assessed the ability of neural stem/progenitor cell (NSC)-derived EVs to consume and produce metabolites. Our metabolomics and functional analyses both revealed that EVs harbor L-asparaginase activity, catalyzed by the enzyme asparaginase-like protein 1 (Asrgl1). Critically, we show that Asrgl1 activity is selective for asparagine and is devoid of glutaminase activity. We found that mouse and human NSC EVs traffic Asrgl1. Our results demonstrate, for the first time, that NSC EVs function as independent metabolic units that are able to modify the concentrations of critical nutrients, with the potential to affect the physiology of their microenvironment.This work has received support from the Italian Multiple Sclerosis Association (AISM, grant 2010/R/31 and grant 2014/PMS/4 to SP), the Italian Ministry of Health (GR08-7 to SP), the European Research Council (ERC) under the ERC-2010-StG Grant agreement n° 260511-SEM_SEM, the Medical Research Council, the Engineering and Physical Sciences Research Council, and the Biotechnology and Biological Sciences Research Council UK Regenerative Medicine Platform Hub “Acellular Approaches for Therapeutic Delivery” (MR/K026682/1 to SP), The Evelyn Trust (RG 69865 to SP), The Bascule Charitable Trust (RG 75149 to SP) and core support grant from the Wellcome Trust and Medical Research Council to the Wellcome Trust – MRC Cambridge Stem Cell Institute. N.I. was supported by a FEBS long-term fellowship. C.F., A.S.H., and E.G. were funded by the Medical Research Council, Core Fund SKAG006