Using the wax moth larva Galleria mellonella infection model to detect emerging bacterial pathogens

This is the final version. Available from PeerJ via the DOI in this recordData Availability: The following information was supplied regarding data availability: Using the wax moth larva Galleria mellonella infection model to detect emerging bacterial pathogens. Dryad Digital Repository DOI 10.5061/dryad.130q4qb.Climate change, changing farming practices, social and demographic changes and rising levels of antibiotic resistance are likely to lead to future increases in opportunistic bacterial infections that are more difficult to treat. Uncovering the prevalence and identity of pathogenic bacteria in the environment is key to assessing transmission risks. We describe the first use of the Wax moth larva Galleria mellonella, a well-established model for the mammalian innate immune system, to selectively enrich and characterize pathogens from coastal environments in the South West of the UK. Whole-genome sequencing of highly virulent isolates revealed amongst others a Proteus mirabilis strain carrying the Salmonella SGI1 genomic island not reported from the UK before and the recently described species Vibrio injenensis hitherto only reported from human patients in Korea. Our novel method has the power to detect bacterial pathogens in the environment that potentially pose a serious risk to public health.Natural Environment Research Council (NERC

A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma

The phosphatidylinositol 3-kinase signal transduction pathway members are often activated in tumor samples from patients with non-Hodgkin's lymphoma (NHL). Everolimus is an oral agent that targets the raptor mammalian target of rapamycin (mTORC1). The goal of this trial was to learn the antitumor activity and toxicity of single-agent everolimus in patients with relapsed/refractory aggressive NHL. Patients received everolimus 10 mg PO daily. Response was assessed after two and six cycles, and then every three cycles until progression. A total of 77 patients with a median age of 70 years were enrolled. Patients had received a median of three previous therapies and 32% had undergone previous transplant. The overall response rate (ORR) was 30% (95% confidence interval: 20–41%), with 20 patients achieving a partial remission and 3 a complete remission unconfirmed. The ORR in diffuse large B cell was 30% (14/47), 32% (6/19) in mantle cell and 38% (3/8) in follicular grade 3. The median duration of response was 5.7 months. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 14, 18 and 38% of patients, respectively. Everolimus has single-agent activity in relapsed/refractory aggressive NHL and provides proof-of-concept that targeting the mTOR pathway is clinically relevant

Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

Understanding the benefit of metformin use in cancer treatment

Biguanides have been developed for the treatment of hyperglycemia and type 2 diabetes. Recently, metformin, the most widely prescribed biguanide, has emerged as a potential anticancer agent. Epidemiological, preclinical and clinical evidence supports the use of metformin as a cancer therapeutic. The ability of metformin to lower circulating insulin may be particularly important for the treatment of cancers known to be associated with hyperinsulinemia, such as those of the breast and colon. Moreover, metformin may exhibit direct inhibitory effects on cancer cells by inhibiting mammalian target of rapamycin (mTOR) signaling and protein synthesis. The evidence supporting a role for metformin in cancer therapy and its potential molecular mechanisms of action are discussed

Introgressive Hybridization of Schistosoma haematobium Group Species in Senegal: Species Barrier Break Down between Ruminant and Human Schistosomes

The file attached is the Published/publisher’s pdf version of the article.Copyright: © 2013 Webster et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Suppression of Cellular Transformation by Poly (A) Binding Protein Interacting Protein 2 (Paip2)

Controlling translation is crucial for the homeostasis of a cell. Its deregulation can facilitate the development and progression of many diseases including cancer. Poly (A) binding protein interacting protein 2 (Paip2) inhibits efficient initiation of translation by impairing formation of the necessary closed loop of mRNA. The over production of Paip2 in the presence of a constitutively active form of hRasV12 can reduce colony formation in a semi-solid matrix and focus formation on a cell monolayer. The ability of Paip2 to bind to Pabp is required to suppress the transformed phenotype mediated by hRasV12. These observations indicate that Paip2 is able to function as a tumor suppressor

Simultaneous Inhibition of mTOR-Containing Complex 1 (mTORC1) and MNK Induces Apoptosis of Cutaneous T-Cell Lymphoma (CTCL) Cells

BACKGROUND: mTOR kinase forms the mTORC1 complex by associating with raptor and other proteins and affects a number of key cell functions. mTORC1 activates p70S6kinase 1 (p70S6K1) and inhibits 4E-binding protein 1 (4E-BP1). In turn, p70S6K1 phosphorylates a S6 protein of the 40S ribosomal subunit (S6rp) and 4E-BP1, with the latter negatively regulating eukaryotic initiation factor 4E (eIF-4E). MNK1 and MNK2 kinases phosphorylate and augment activity of eIF4E. Rapamycin and its analogs are highly specific, potent, and relatively non-toxic inhibitors of mTORC1. Although mTORC1 activation is present in many types of malignancies, rapamycin-type inhibitors shows relatively limited clinical efficacy as single agents. Initially usually indolent, CTCL displays a tendency to progress to the aggressive forms with limited response to therapy and poor prognosis. Our previous study (M. Marzec et al. 2008) has demonstrated that CTCL cells display mTORC1 activation and short-term treatment of CTCL-derived cells with rapamycin suppressed their proliferation and had little effect on the cell survival. METHODS: Cells derived from CTCL were treated with mTORC1 inhibitor rapamycin and MNK inhibitor and evaluated for inhibition of the mTORC1 signaling pathway and cell growth and survival. RESULTS: Whereas the treatment with rapamycin persistently inhibited mTORC1 signaling, it suppressed only partially the cell growth. MNK kinase mediated the eIF4E phosphorylation and inhibition or depletion of MNK markedly suppressed proliferation of the CTCL cells when combined with the rapamycin-mediated inhibition of mTORC1. While MNK inhibition alone mildly suppressed the CTCL cell growth, the combined MNK and mTORC1 inhibition totally abrogated the growth. Similarly, MNK inhibitor alone displayed a minimal pro-apoptotic effect; in combination with rapamycin it triggered profound cell apoptosis. CONCLUSIONS: These findings indicate that the combined inhibition of mTORC1 and MNK may prove beneficial in the treatment of CTCL and other malignancies