Circulating microRNAs: The Future of Biomarkers in Anti-doping Field.

microRNAs (miRNAs) are small non-coding RNAs that regulate various biological processes. Cell-free miRNAs have been proposed as biomarkers of disease, including diagnosis, prognosis, and monitoring of treatment responses. These circulating miRNAs are highly stable in several body fluids, including plasma and serum; hence, in view of their potential use as novel, non-invasive biomarkers, the profiles of circulating miRNAs have been explored in the field of anti-doping. This chapter describes the enormous potential of circulating miRNAs as a new class of biomarkers for the detection of doping substances, and highlights the advantages of measuring these stable species over other methods that have already been implemented in anti-doping regimes. Incorporating longitudinal measurements of circulating miRNAs into the Athlete Biological Passport is proposed as an efficient strategy for the implementation of these new biomarkers. Furthermore, potential challenges related to the transition of measurements of circulating miRNAs from research settings to practical anti-doping applications are presented.

Conclusions and future directions for sports events management scholarship

The book adopts a unique stakeholder perspective, structured around the groups and individuals who have an interest in and co-create sports events, including organising committees, promoters, sport organisations, spectators, community groups, sponsors, host governments, the media and NGOs. Each chapter addresses a specific stakeholder, defines that stakeholder and its relationships with sports events, describes the managerial requirements for a successful event, assesses current research and directions for future research, and outlines the normative dimensions of stakeholder engagement (such as sustainability and legacy)

Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014.

The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma.

Trimodal therapy for invasive bladder cancer: is it really equal to radical cystectomy?

PURPOSE OF REVIEW: Trimodal therapy (TMT) is considered the most effective bladder-sparing approach for muscle-invasive urothelial carcinoma of the bladder (MIBC) and an alternative to radical cystectomy. The purpose of this article was to review and summarize the current knowledge on the equivalence of TMT and radical cystectomy based on the recent literature. RECENT FINDINGS: TMT consists of a maximal transuretral resection of the bladder, followed by a concurrent radiotherapy and chemotherapy, limiting salvage radical cystectomy to nonresponder tumors or muscle-invasive recurrence. In large population studies, less than 6% of the patients with nonmetastatic MIBC receive a chemoradiation therapy and this rate is stable. A growing body of evidence exists that TMT provides good oncologic outcomes with low morbidity when compared with radical cystectomy. TMT requires, however, a close follow-up because of the high risk of local recurrence and salvage radical cystectomy in up to 30% of the patients. Salvage radical cystectomy can be performed with adequate results but does not offer the same opportunity of reconstruction and functional outcomes than primary radical cystectomy. SUMMARY: Although radical cystectomy is still the treatment of reference for most of the patients with localized MIBC, TMT represents a reasonable alternative in highly selected patients. Any firm conclusion on the equivalence or superiority of one treatment to the other is still limited by the lack of randomized controlled trials and the heterogeneity of the available literature. Future studies and multidisciplinary approach are mandatory to optimize the patient selection and regimen of TMT.

Robert Jütte (Ed.), Medical Pluralism. Past - Present - Future (Stuttgart, F. Steiner Verlag, 2013)

Initiée en anthropologie à la fin des années 1970, la notion de pluralisme médical se voit réappropriée par diverses disciplines des sciences humaines, à l'instar des treize contributions de cet ouvrage collectif édité par Robert Jütte. Historiens, sociologues et anthropologues y interviennent à la suite d'un colloque organisé en 2001 en Italie par l'Institut d'histoire de la médecine de la Fondation Robert Bosch et le Centre Italo-Tedesco pour l'Excellence européenne, en collaboration avec le Forum de dialogue Pluralismus in der Medizin. Encore très questionnée et souvent nuancée selon les contextes, la définition du pluralisme médical se situe quelque part entre le fait que différentes formes de soins existent simultanément et s'influencent les unes les autres, et le constat d'une popularité grandissante des médecines alternatives et complémentaires défiant l'hégémonie de la biomédecine - cette situation s'observant plus particulièrement dans les pays occidentaux. C'est dans ce dernier contexte que s'inscrit le volume, dont chacune des contributions examine le phénomène du pluralisme médical soit en Allemagne, en Italie, en France ou en Grande-Bretagne - avec une exception pour l'Inde. La profondeur diachronique adoptée par l'ouvrage, couvrant l'époque pré-moderne à nos jours, offre une exploration élargie des expériences thérapeutiques. Ainsi sont évoqués, d'une part, les tenants de la médecine dite orthodoxe ou conventionnelle, regroupant les praticiens officiels que sont les médecins académiques en première ligne, suivis des chirurgiens, barbiers, apothicaires et sages-femmes; d'autre part sont pris en compte les représentants des médecines complémentaires, alternatives, naturelles ou encore populaires - des homéopathes aux acupuncteurs en passant par les magnétiseurs et les magiciennes guérisseuses. La réflexion sur les concurrences et les complémentarités entre ces acteurs variés, qui fait consensus au sein des contributions, est développée sous divers aspects.

Predicting the future effectiveness of protected areas for bird conservation in Mediterranean ecosystems under climate change and novel fire regime scenarios

AimGlobal environmental changes challenge traditional conservation approaches based on the selection of static protected areas due to their limited ability to deal with the dynamic nature of driving forces relevant to biodiversity. The Natura 2000 network (N2000) constitutes a major milestone in biodiversity conservation in Europe, but the degree to which this static network will be able to reach its long-term conservation objectives raises concern. We assessed the changes in the effectiveness of N2000 in a Mediterranean ecosystem between 2000 and 2050 under different combinations of climate and land cover change scenarios. LocationCatalonia, Spain. MethodsPotential distribution changes of several terrestrial bird species of conservation interest included in the European Union's Birds Directive were predicted within an ensemble-forecasting framework that hierarchically integrated climate change and land cover change scenarios. Land cover changes were simulated using a spatially explicit fire-succession model that integrates fire management strategies and vegetation encroachment after the abandonment of cultivated areas as the main drivers of landscape dynamics in Mediterranean ecosystems. ResultsOur results suggest that the amount of suitable habitats for the target species will strongly decrease both inside and outside N2000. However, the effectiveness of N2000 is expected to increase in the next decades because the amount of suitable habitats is predicted to decrease less inside than outside this network. Main conclusionsSuch predictions shed light on the key role that the current N2000may play in the near future and emphasize the need for an integrative conservation perspective wherein agricultural, forest and fire management policies should be considered to effectively preserve key habitats for threatened birds in fire-prone, highly dynamic Mediterranean ecosystems. Results also show the importance of considering landscape dynamics and the synergies between different driving forces when assessing the long-term effectiveness of protected areas for biodiversity conservation.

Areas of high conservation value in Georgia: present and future threats by invasive alien plants

Georgia is known for its extraordinary rich biodiversity of plants, which may now be threatened due to the spread of invasive alien plants (IAP). We aimed to identify (i) the most prominent IAP out of 9 selected potentially invasive and harmful IAP IAP by predicting thetheir distribution of 9 selected IAP under current and future climate conditions in Georgia as well as in its 43 Protected Areas, as a proxy for areas of high conservation value and (ii) the Protected Areas most at risk due to these IAP. We used species distribution models based on 6 climate variables and then filtered the obtained distributions based on maps of soil and vegetation types, and on recorded occurrences, resulting into the predicted ecological distribution of the 9 IAP's at a resolution of 1km2. We foundOur habitat suitability analysis showed that Ambrosia artemisiifolia, (24% and 40%) Robinia pseudoacaia (14% and 19%) and Ailanthus altissima (9% and 11%) have the largest potential distribution are the most abundant (predicted % area covered)d) IAP, with Ailanthus altissima the potentially most increasing one over the next fifty years (from 9% to 13% and from 11% to 25%), for Georgia and the Protected Areas, respectively. Furthermore, our results show indicate two areas in Georgia that are under specifically high threat, i.e. the area around Tbilisi and an area in the western part of Georgia (Adjara), both at lower altitudes. Our procedure to identify areas of high conservation value most at risk by IAP has been applied for the first time. It will help national authorities in prioritizing their measures to protect Georgia's outstanding biodiversity from the negative impact of IAP.

Olympic social responsibility : a challenge for the future

Social responsibility, especially in the fields of education, society and peace, is one of the cornerstones of the olympic ideal and strategic vision (contribute to building a better world through sport). The article reviews the literature on organizational social responsibility (OSR) and the relationship between sport/olympism and OSR in order to examine the conditions governing the implementation and success of the International Olympic Committee's strategic vision. Several ways in which the IOC could promote a more ambitious and better-integrated social strategy: revise its performance model, notably evaluate and present in a social responsibility report; promote the adoption of OSR initiatives and strategies within the Olympic System from the bottom-up, rather than from the top-down; share best practices in the different countries for promoting and developing "sport for all"; create a World Agency for Development through Sport, or partnering and funding the international platform on sport and development; creating a World Agency for the International Governance of Sport. Two possible scenarios for the future of Olympic responsibility are finally discussed: strategy of "small steps" and a more ambitious local and global social strategy through sport and olympism.

Future development of gastrointestinal cancer incidence and mortality rates in Switzerland: a tumour registry- and population-based projection up to 2030.

QUESTIONS UNDER STUDY: Since tumour burden consumes substantial healthcare resources, precise cancer incidence estimations are pivotal to define future needs of national healthcare. This study aimed to estimate incidence and mortality rates of oesophageal, gastric, pancreatic, hepatic and colorectal cancers up to 2030 in Switzerland. METHODS: Swiss Statistics provides national incidences and mortality rates of various cancers, and models of future developments of the Swiss population. Cancer incidences and mortality rates from 1985 to 2009 were analysed to estimate trends and to predict incidence and mortality rates up to 2029. Linear regressions and Joinpoint analyses were performed to estimate the future trends of incidences and mortality rates. RESULTS: Crude incidences of oesophageal, pancreas, liver and colorectal cancers have steadily increased since 1985, and will continue to increase. Gastric cancer incidence and mortality rates reveal an ongoing decrease. Pancreatic and liver cancer crude mortality rates will keep increasing, whereas colorectal cancer mortality on the contrary will fall. Mortality from oesophageal cancer will plateau or minimally increase. If we consider European population-standardised incidence rates, oesophageal, pancreatic and colorectal cancer incidences are steady. Gastric cancers are diminishing and liver cancers will follow an increasing trend. Standardised mortality rates show a diminution for all but liver cancer. CONCLUSIONS: The oncological burden of gastrointestinal cancer will significantly increase in Switzerland during the next two decades. The crude mortality rates globally show an ongoing increase except for gastric and colorectal cancers. Enlarged healthcare resources to take care of these complex patient groups properly will be needed.

Immunogenicity of dimorphic and C-terminal fragments of Plasmodium falciparum MSP2 formulated with different adjuvants in mice.

BACKGROUND: Plasmodium falciparum MSP2 is a blood stage protein that is associated with protection against malaria. It was shown that the MSP2 dimorphic (D) and constant (C) regions were well recognized by immune human antibodies, and were characterized by major conserved epitopes in different endemic areas and age groups. These Abs recognized merozoite-derived proteins in WB and IFA. Here, the goal was to determine in mice the immunogenicity of the two allelic MSP2 D and C domains formulated with different adjuvants, for their possible use in future clinical studies. METHOD: Female A/J, C3H, and ICR mice were immunized subcutaneously 3 times at 3-week interval with a mixture of allelic and conserved MSP2 long synthetic peptides formulated with different adjuvants. One week after the third injection, sera from each group were obtained and stored at -20°C for subsequent testing. RESULTS: Both domains of the two MSP2 families are immunogenic and the fine specificity and intensity of the Ab responses are dependent on mouse strains and adjuvants. The major epitopes were restricted to the 20-mer peptide sequences comprising the last 8aa of D and first 12aa of C of the two allelic families and the first 20aa of the C region, this for most strains and adjuvants. Strong immune responses were associated with GLA-SE adjuvant and its combination with other TLR agonists (CpG or GDQ) compared to alhydrogel and Montanide. Further, the elicited Abs were also capable of recognizing Plasmodium-derived MSP2 and inhibiting parasite growth in ADCI. CONCLUSION: The data provide a valuable opportunity to evaluate in mice different adjuvant and antigen formulations of a candidate vaccine containing both MSP2 D and C fragments. The formulations with GLA-SE seem to be a promising option to be compared with the alhydrogel one in human clinical trials.

Ownership Effects on Unrelated Diversification: An Institutions' Perspective

Purpose To show that differences in the extent to which firms engage in unrelated diversification can be attributed to differences in ownership structure. Methodology/approach We draw on longitudinal data and use a panel analysis specification to test our hypotheses. Findings We find that unrelated diversification destroys value; pressure-sensitive Anglo-American owners in a firm’s equity reduce unrelated diversification, whereas pressure-resistant domestic owners increase unrelated diversification; the greater the firm’s free cash flow, the greater the negative effect of pressure-sensitive Anglo-American owners on unrelated diversification. Research limitations/implications We contribute to corporate governance and strategy research by bringing in owners’ institutional origin as a shaper of owner preferences in particular with regards to unrelated diversification. Future research may expand our investigation to more than one home institutional context, and theorize on institutional origin effects beyond the dichotomy between Anglo-American and non-Anglo-American (not oriented toward shareholder value maximization) owners. Practical implications Policy makers, financial analysts, owners, and managers may want to reflect about the implications of ownership structure, as well as promoting or joining corporations with particular ownership configurations. Social implications A shareholder value-destroying strategy, such as unrelated diversification has adverse consequences for society at large, in terms of opportunity costs, that is, resources could be allocated to value-creating activities instead. Promoting an ownership configuration that creates value should contribute to social welfare. Originality/value Owners may not be exclusively driven by shareholder value maximization, but can be influenced by normative beliefs (biases) stemming from the institutional context they originate from.