Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer. Poly-chemotherapy with cytotoxic and genotoxic drugs causes substantial toxicity and more specific therapies targeting the underlying molecular lesions are highly desired. Perturbed Ras signaling is prevalent in T-ALL and occurs via oncogenic RAS mutations or through overexpression of the Ras activator RasGRP1 in ~65% of T-ALL patients. Effective small molecule inhibitors for either target do not currently exist. Genetic and biochemical evidence link phosphoinositide 3-kinase (PI3K) signals to T-ALL, PI3Ks are activated by Ras-dependent and Ras-independent mechanisms, and potent PI3K inhibitors exist. Here we performed comprehensive analyses of PI3K-Akt signaling in T-ALL with a focus on class I PI3K. We developed a multiplex, multiparameter flow cytometry platform with pan- and isoform-specific PI3K inhibitors. We find that pan-PI3K and PI3K γ-specific inhibitors effectively block basal and cytokine-induced PI3K-Akt signals. Despite such inhibition, GDC0941 (pan-PI3K) or AS-605240 (PI3Kγ-specific) as single agents did not efficiently induce death in T-ALL cell lines. Combination of GDC0941 with AS-605240, maximally targeting all p110 isoforms, exhibited potent synergistic activity for clonal T-ALL lines in vitro, which motivated us to perform preclinical trials in mice. In contrast to clonal T-ALL lines, we used a T-ALL cancer model that recapitulates the multi-step pathogenesis and inter- and intra-tumoral genetic heterogeneity, a hallmark of advanced human cancers. We found that the combination of GDC0941 with AS-605240 fails in such trials. Our results reveal that PI3K inhibitors are a promising avenue for molecular therapy in T-ALL, but predict the requirement for methods that can resolve biochemical signals in heterogeneous cell populations so that combination therapy can be designed in a rational manner

Heated tobacco products: another tobacco industry global strategy to slow progress in tobacco control.

There has been a global decline in tobacco consumption that, if continued, will negatively impact the tobacco industry's profits. This decline led the industry to invent and market new products, including heated tobacco products (HTP). HTP are an extension of the industry's strategies to undermine government's tobacco regulatory efforts as they are being promoted as part of the solution for the tobacco epidemic. Under the moniker of 'harm reduction', the tobacco companies are attempting to rehabilitate their reputation so they can more effectively influence governments to roll back existing tobacco control policies or create exemptions for their HTP. Rolling back tobacco control policies will make it easier for the companies to renormalise tobacco use to increase social acceptability for all their products. When regulations are absent or when loopholes exist in classifying HTP as a tobacco product (thus subject to all tobacco control regulations), the industry's marketing of HTP is making these products more visible to the public and more accessible. Governments need to ensure that HTP are regulated as tobacco products or drugs and reject partnerships with the tobacco companies to promote 'harm reduction'. The tobacco companies remain the vector of the tobacco-caused epidemic and cannot be part of the global tobacco control solution

Crossing the Line: Selection and Evolution of Virulence Traits

The evolution of pathogens presents a paradox. Pathogenic species are often absolutely dependent on their host species for their propagation through evolutionary time, yet the pathogenic lifestyle requires that the host be damaged during this dependence. It is clear that pathogenic strategies are successful in evolutionary terms because a diverse array of pathogens exists in nature. Pathogens also evolve using a broad range of molecular mechanisms to acquire and modulate existing virulence traits in order to achieve this success. Detailing the benefit of enhanced selection derived through virulence and understanding the mechanisms through which virulence evolves are important to understanding the natural world and both have implications for human health

Private Social Investment Trends in Latin America

This publication, coordinated by Institute for Development of Social Investment (IDIS) in Brazil, brings to the public the debates of the International Seminar on Social Investment in Latin America, in 2007. IDIS experience can contribute to the debate on the issue of social investment. Since its founding in 1999, more than 100 clients in Brazil and Latin America were guided by our Institute