Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma.

Schwannoma tumours typically arise on the 8th cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the 8th or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required. Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a pre-clinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth

Assessment of digital image correlation measurement errors: methodology and results

Optical full-field measurement methods such as Digital Image Correlation (DIC) are increasingly used in the field of experimental mechanics, but they still suffer from a lack of information about their metrological performances. To assess the performance of DIC techniques and give some practical rules for users, a collaborative work has been carried out by the Workgroup “Metrology” of the French CNRS research network 2519 “MCIMS (Mesures de Champs et Identification en Mécanique des Solides / Full-field measurement and identification in solid mechanics, http://www.ifma.fr/lami/gdr2519)”. A methodology is proposed to assess the metrological performances of the image processing algorithms that constitute their main component, the knowledge of which being required for a global assessment of the whole measurement system. The study is based on displacement error assessment from synthetic speckle images. Series of synthetic reference and deformed images with random patterns have been generated, assuming a sinusoidal displacement field with various frequencies and amplitudes. Displacements are evaluated by several DIC packages based on various formulations and used in the French community. Evaluated displacements are compared with the exact imposed values and errors are statistically analyzed. Results show general trends rather independent of the implementations but strongly correlated with the assumptions of the underlying algorithms. Various error regimes are identified, for which the dependence of the uncertainty with the parameters of the algorithms, such as subset size, gray level interpolation or shape functions, is discussed

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment

Phylogenomic analysis of a 55.1 kb 19-gene dataset resolves a monophyletic Fusarium that includes the Fusarium solani Species Complex

Scientific communication is facilitated by a data-driven, scientifically sound taxonomy that considers the end-user¿s needs and established successful practice. In 2013, the Fusarium community voiced near unanimous support for a concept of Fusarium that represented a clade comprising all agriculturally and clinically important Fusarium species, including the F. solani species complex (FSSC). Subsequently, this concept was challenged in 2015 by one research group who proposed dividing the genus Fusarium into seven genera, including the FSSC described as members of the genus Neocosmospora, with subsequent justification in 2018 based on claims that the 2013 concept of Fusarium is polyphyletic. Here, we test this claim and provide a phylogeny based on exonic nucleotide sequences of 19 orthologous protein-coding genes that strongly support the monophyly of Fusarium including the FSSC. We reassert the practical and scientific argument in support of a genus Fusarium that includes the FSSC and several other basal lineages, consistent with the longstanding use of this name among plant pathologists, medical mycologists, quarantine officials, regulatory agencies, students, and researchers with a stake in its taxonomy. In recognition of this monophyly, 40 species described as genus Neocosmospora were recombined in genus Fusarium, and nine others were renamed Fusarium. Here the global Fusarium community voices strong support for the inclusion of the FSSC in Fusarium, as it remains the best scientific, nomenclatural, and practical taxonomic option availabl

Incidence and severity of scorpion stings in Algeria

Scorpion stings are a public health problem in the Maghreb region. In Algeria, epidemiological data were collected over the past twenty years by the Algerian health authorities. This study is an analysis of morbidity and mortality data collected from 2001 to 2010. Annual incidence and mortality due to scorpion envenoming were 152 ± 3.6 stings and 0.236 ± 0.041 deaths per 100,000 people (95% CI), respectively. The risk of being stung by a scorpion was dramatically higher in southern areas and central highlands due to environmental conditions. Incidence of envenoming was especially higher in the adult population, and among young males. In contrast, mortality was significantly higher among children under 15 years, particularly ages 1-4. Upper limbs were more often affected than lower limbs. Most stings occurred at night, indoors and during the summer. Data collected since 2001 showed a reduction of mortality by nearly 50%, suggesting that the medical care defined by the national anti-scorpion project is bearing fruit

Isolation and characterization of a myotoxin from the venom of Macrovipera lebetina transmediterranea

The Macrovipera lebetina venom consists of a complex mixture of proteins belonging to a few main families according to their enzymatic and pharmacological activity. Given the serious pathophysiological effects caused by M. lebetina bites mainly induced by muscle degeneration, we decided to investigate the myotoxic activity of some venom fractions. In the present study we describe the purification and characterization of a 22.600 kDa protein, named in the following Mlp4.2, that shares myotoxic but not haemorrhagic activity in vivo. Herein we report that Mlp4.2 is a metalloproteinase belonging to the PI-SVMPS family able, in vitro, to proteolyse extracellular matrix proteins as laminin and fibronectin. Histological observations of mouse anterior tibialis Mlp4.2-treated muscle, demonstrate that this protein induces a massive degeneration of myofibers but not haemorrhage. The immunofluorescence analysis of protein-treated anterior tibialis, demonstrates that Mlp4.2 is able to disarray the laminin network surrounding muscle fibers. Finally Mlp4.2 did not show any direct cytolytic activity towards the myogenic cell line C2C12 in culture. The data reported herein suggest that the myotoxicity of Mlp4.2 is primarily linked to the disruption of the muscle fibers interaction with extracellular matrix proteins