Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells.

AbstractContext: Proton Pump Inhibitors (PPIs) reduce tumor acidity and therefore resistance of tumors to drugs. Carbonic Anhydrase IX (CA IX) inhibitors have proven to be effective against tumors, while tumor acidity might impair their full effectiveness.Objective: To analyze the effect of PPI/CA IX inhibitors combined treatment against human melanoma cells.Methods: The combination of Lansoprazole (LAN) and CA IX inhibitors (FC9-399A and S4) has been investigated in terms of cell proliferation inhibition and cell death in human melanoma cells.Results: The combination of these inhibitors was more effective than the single treatments in both inhibiting cell proliferation and in inducing cell death in human melanoma cells.Discussion: These results represent the first successful attempt in combining two different proton exchanger inhibitors.Conclusion: This is the first evidence on the effectiveness of a new approach against tumors based on the combination of PPI and CA IX inhibitors, thus providing an alter..

TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations associated with drug resistance and invasiveness of colon cancer cells

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"Is social inclusion through PE, sport and PA still a rhetoric?" evaluating the relationship between physical education, sport and social inclusion

This Special Issue is part of Educational Review’s Hall of Fame, comprising the journal’s most read and highly cited papers. As part of this I will be critiquing a milestone paper within the field(s) of Sport, PE and (I will extend to) PA by Professor Richard Bailey. The paper has been amongst the most-cited in the journal and I have personally cited the paper numerous times in my own work thus far. Upon its original publication (nearly 13 years ago), the article (managed to provide a very useful distinction between PE and sport (and PA), which is important given the constant slippage between the terms in many articles since. In this response article, I will try to provide a brief summary of the paper from Bailey, but at the same time examine closely the notion of social inclusion through sport and PE by summarising work that has subsequently been conducted. I will conclude by summarising that some 13 years later spurious claims about effective inclusive practices through sport abound, and we still lack clear evidence to support the rhetoric about the ways in which sport and PE can contribute to social inclusion

The challenges of intersectionality: Researching difference in physical education

Researching the intersection of class, race, gender, sexuality and disability raises many issues for educational research. Indeed, Maynard (2002, 33) has recently argued that ‘difference is one of the most significant, yet unresolved, issues for feminist and social thinking at the beginning of the twentieth century’. This paper reviews some of the key imperatives of working with ‘intersectional theory’ and explores the extent to these debates are informing research around difference in education and Physical Education (PE). The first part of the paper highlights some key issues in theorising and researching intersectionality before moving on to consider how difference has been addressed within PE. The paper then considers three ongoing challenges of intersectionality – bodies and embodiment, politics and practice and empirical research. The paper argues for a continued focus on the specific context of PE within education for its contribution to these questions

Asymmetric triplex metallohelices with high and selective activity against cancer cells

Small cationic amphiphilic α-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defence peptides and ​p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 ​p53++, causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli. At a glanc

Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery

Linear peptides can mimic and disrupt protein-protein interactions involved in critical cell signaling pathways. Such peptides however are usually protease sensitive and unable to engage with intracellular targets due to lack of membrane permeability. Peptide stapling has been proposed to circumvent these limitations but recent data has suggested that this method does not universally solve the problem of cell entry and can lead to molecules with off target cell lytic properties. To address these issues a library of stapled peptides was synthesized and screened to identify compounds that bound Mdm2 and activated cellular p53. A lead peptide was identified that activated intracellular p53 with negligible nonspecific cytotoxicity, however it still bound serum avidly and only showed a marginal improvement in cellular potency. These hurdles were overcome by successfully identifying a pyridinium-based cationic lipid formulation, which significantly improved the activity of the stapled peptide in a p53 reporter cell line, principally through increased vesicular escape. These studies under score that stapled peptides, which are cell permeable and target specific, can be identified with rigorous experimental design and that these properties can be improved through use with lipid based formulations. This work should facilitate the clinical translation of stapled peptides

The health determinants in young children: Testing a new surveillance system in Italy

In recent years, the scientific community has stressed the need to invest in the first 1,000 days of life - the time spanning between conception and the 2nd birthday - because it is during this period that the foundations of health are laid and whose effects will be present throughout the life and may influence the next generation. Taking this into account, in 2013 the National Centre for Disease Prevention and Control (CCM) of the Italian Ministry of Health promoted and financed a project to test a surveillance system of the main determinants of health concerning the child between the conception period and the 2nd years of life which are included in the National Programme “GenitoriPiù”: folic acid before and during pregnancy, abstention from tobacco and alcohol during pregnancy and lactation, breastfeeding, infant sleep position, vaccination attitude, and early reading. The Project, started in January 2014 and ended in August 2016, has piloted the design, testing, and evaluation of the surveillance system with the view to national extension and the repeatability over time. The surveillance system has been designed to collect data through a questionnaire compiled by mothers in vaccination centres, in order to produce indicators which will enable territorial and intertempo-ral comparisons to be made. The project has shown the feasibility of this system, identifying favourable conditions and possible difficulties, and its ability to collect important information on children's health