Pretargeted radioimmunotherapy using genetically engineered antibody-streptavidin fusion proteins for treatment of non-hodgkin lymphoma.

Purpose: Pretargeted radioimmunotherapy (PRIT) using streptavidin (SAv)-biotin technology can deliver higher therapeutic doses of radioactivity to tumors than conventional RIT. However, "endogenous" biotin can interfere with the effectiveness of this approach by blocking binding of radiolabeled biotin to SAv. We engineered a series of SAv FPs that downmodulate the affinity of SAv for biotin, while retaining high avidity for divalent DOTA-bis-biotin to circumvent this problem.Experimental Design: The single-chain variable region gene of the murine 1F5 anti-CD20 antibody was fused to the wild-type (WT) SAv gene and to mutant SAv genes, Y43A-SAv and S45A-SAv. FPs were expressed, purified, and compared in studies using athymic mice bearing Ramos lymphoma xenografts.Results: Biodistribution studies showed delivery of more radioactivity to tumors of mice pretargeted with mutant SAv FPs followed by (111)In-DOTA-bis-biotin [6.2 +/- 1.7% of the injected dose per gram (%ID/gm) of tumor 24 hours after Y43A-SAv FP and 5.6 +/- 2.2%ID/g with S45A-SAv FP] than in mice on normal diets pretargeted with WT-SAv FP (2.5 +/- 1.6%ID/g; P = 0.01). These superior biodistributions translated into superior antitumor efficacy in mice treated with mutant FPs and (90)Y-DOTA-bis-biotin [tumor volumes after 11 days: 237 +/- 66 mm(3) with Y43A-SAv, 543 +/- 320 mm(3) with S45A-SAv, 1129 +/- 322 mm(3) with WT-SAv, and 1435 +/- 212 mm(3) with control FP (P < 0.0001)].Conclusions: Genetically engineered mutant-SAv FPs and bis-biotin reagents provide an attractive alternative to current SAv-biotin PRIT methods in settings where endogenous biotin levels are high. Clin Cancer Res; 17(23); 7373-82. (C)2011 AACR.

Alcohol-attributable mortality in Switzerland in 2011--age-specific causes of death and impact of heavy versus non-heavy drinking.

BACKGROUND: Alcohol use causes high burden of disease and injury globally. Switzerland has a high consumption of alcohol, almost twice the global average. Alcohol-attributable deaths and years of life lost in Switzerland were estimated by age and sex for the year 2011. Additionally, the impact of heavy drinking (40+grams/day for women and 60+g/day for men) was estimated. METHODS: Alcohol consumption estimates were based on the Addiction Monitoring in Switzerland study and were adjusted to per capita consumption based on sales data. Mortality data were taken from the Swiss mortality register. Methodology of the Comparative Risk Assessment for alcohol was used to estimate alcohol-attributable fractions. RESULTS: Alcohol use caused 1,600 (95% CI: 1,472 - 1,728) net deaths (1,768 deaths caused, 168 deaths prevented) among 15 to 74 year olds, corresponding to 8.7% of all deaths (men: 1,181 deaths; women: 419 deaths). Overall, 42,627 years of life (9.7%, 95% CI: 40,245 - 45,008) were lost due to alcohol. Main causes of alcohol-attributable mortality were injuries at younger ages (15-34 years), with increasing age digestive diseases (mainly liver cirrhosis) and cancers (particularly breast cancers among women). The majority (62%) of all alcohol-attributable deaths was caused by chronic heavy drinking (men: 67%; women: 48 %). CONCLUSION: Alcohol is a major cause of premature mortality in Switzerland. Its impact, among young people mainly via injuries, among men mainly through heavy drinking, calls for a mix of preventive actions targeting chronic heavy drinking, binge drinking and mean consumption.

Cis interactions of immunoreceptors with MHC and non-MHC ligands

The conventional wisdom is that cell-surface receptors interact with ligands expressed on other cells to mediate cell-to-cell communication (trans interactions). Unexpectedly, it has recently been found that two classes of receptors specific for MHC class I molecules not only interact with MHC class I molecules expressed on opposing cells, but also with those on the same cell. These cis interactions are a feature of immunoreceptors that inhibit, rather than activate, cellular functions. Here, we review situations in which cis interactions have been observed, the characteristics of receptors that bind in trans and cis, and the biological roles of cis recognition.

Strategic alliances between companies and non-governmental organizations pursuing the creation of shared value: an exploratory study at the base of the pyramid in Brazil

Na última década, uma crescente atenção tem sido dedicada ao desenvolvimento de estratégias que permitem uma empresa de atender os mercados de baixa renda de uma forma rentável e ao mesmo tempo enfrentar os desafios sociais. Uma das ferramentas estratégicas identificados para operar com sucesso na base da pirâmide ( BoP ), consiste no estabelecimento de alianças com organizações não governamentais (ONGs). Isso, no entanto, é um desafio, especialmente porque os atores do setor empresarial e da sociedade civil são movidos por um propósito diferente e adotam uma abordagem diferente na condução das suas atividades. O objetivo desta pesquisa é, portanto, investigar precisamente como ONGs e empresas podem alavancar os seus respectivos recursos e capacidades para criar valor econômico e social , servindo este segmento. Um estudo de casos múltiplos, com foco na base da pirâmide brasileira é utilizado, a fim de entender as dificuldades e fatores de sucesso para a criação e gestão de tais alianças e identificar os recursos e capacidades que são mobilizados por cada parceiro. Os resultados sugerem que as principais dificuldades estão em encontrar um parceiro adequado; superar percepções estereotipadas negativos e falta de confiança e, finalmente, na diferente estrutura, cultura e processos. Por sua vez, os fatores mais importantes que levam ao sucesso incluem a escolha do parceiro certo; compatibilidade em termos de missão, estratégia e valores; estabelecimento de confiança e comprometimento; comunicação eficaz e, finalmente, a capacidade da aliança de gerar valor para ambos os parceiros. Além disso, os resultados demostram que o papel das ONGs é na maior parte limitado a agir como uma ponte entre a empresa e as comunidades de baixa renda, enquanto as capacidades operacionais e os recursos financeiros são fornecidos pelas empresas.

Social entrepreneurship practices and social change In Brazil: a qualitative study in three non-governmental organizations

Social Entrepreneurship (SE) has attracted growing interest from a wide variety of actors over the last 30 years, especially due to a general agreement that it could be an important tool for tackling many of the world’s social ills. In the academic sphere, this growing interest did not translate into a matured field of study. Quite the opposite, a quick look at this literature makes it evident that: SE has been consistently subjected to numerous theoretical discussions and disagreements, especially over the definition of the concept of SE which is often based on a taken-for-granted notion of social change; it has been more systematically investigated in restricted contexts, often leaving aside so called developing/emerging countries like Brazil and especially lacking in-depth qualitative studies; SE literature lags behind SE practices and few studies focus on how SE actually occurs in a daily and bottom-up manner. In order to address such gaps, this thesis examines how social entrepreneurship practices accomplish social change in the context of Brazil. In this investigation I conducted an inductive practice-based, qualitative/ethnographic study in three Non-Governmental Organizations (NGOs) located in different cities in the Brazilian state of São Paulo. Data collection lasted from February 2014 until March 2015 and was mainly done through participant observations and through in-depth unstructured conversations with research participants. Secondary data and documents were also collected whenever available. The participants of this study included a variety of the studied organizations’ stakeholders: two founders, volunteers, employees, donors and beneficiaries. Observation data was kept in fieldnotes, conversations were recorded whenever possible and were later transcribed. Data was analyzed through an iterative thematic analysis. Through this I identified eight recurrent themes in the data: (1) structure; (2) relationship with other organizational actors (sub-themes: relationship with state, relationship with businesses and relationship with other NGOs); (3) beliefs, spirituality and moral authority; (4) social position of participants, (5) stakeholders’ mobilization and participation; (6) feelings; (7) social purpose; and (8) social change. These findings were later discussed under the lens of practice theory, and in this discussion I argue and show that, in the context studied: (a) even though SE embraces a wide variety of different social purposes, they are intertwined with a common notion of social change based on a general understanding and aspiration for social equality; (b) this social change is accomplished in a processual and ongoing manner as stakeholders from antagonistic social groups felt compelled to and participated in SE practices. In answering the proposed research question the contributions of this thesis are: (i) the elaboration a working definition for SE based on its relationship with social change; (ii) providing in-depth empirical evidence which accounts for and explains this relationship; (iii) characterizing SE in the Brazilian context and reflecting upon its transferability to other contexts. This thesis also makes a methodological contribution, for it demonstrates how thematic analysis can be used in practice-based studies.