NFKB1 regulates human NK cell maturation and effector functions

12siopenopenLougaris, Vassilios; Patrizi, Ornella; Baronio, Manuela; Tabellini, Giovanna; Tampella, Giacomo; Damiati, Eufemia; Frede, Natalie; van der Meer, Jos W.M.; Fliegauf, Manfred; Grimbacher, Bodo; Parolini, Silvia; Plebani, AlessandroLougaris, Vassilios; Patrizi, Ornella; Baronio, Manuela; Tabellini, Giovanna; Tampella, Giacomo; Damiati, Eufemia; Frede, Natalie; van der Meer, Jos W. M.; Fliegauf, Manfred; Grimbacher, Bodo; Parolini, Silvia; Plebani, Alessandr

Political institutions and debt crises

This paper shows that political institutions matter in explaining defaults on external and domestic debt obligations. We explore a large number of political and macroeconomic variables using a non-parametric technique to predict safety from default. The advantage of this technique is that it is able to identify patterns in the data that are not captured in standard probit analysis. We find that political factors matter, and do so in different ways for democratic and non-democratic regimes, and for domestic and external debt. In democracies, a parliamentary system or sufficient checks and balances almost guarantee the absence of default on external debt when economic fundamentals or liquidity are sufficiently strong. In dictatorships, high stability and tenure play a similar role for default on domestic debt

Intrinsic honesty and the prevalence of rule violations across societies

Deception is common in nature and humans are no exception. Modern societies have created institutions to control cheating, but many situations remain where only intrinsic honesty keeps people from cheating and violating rules. Psychological, sociological and economic theories suggest causal pathways to explain how the prevalence of rule violations in people’s social environment, such as corruption, tax evasion or political fraud, can compromise individual intrinsic honesty. Here we present cross-societal experiments from 23 countries around the world that demonstrate a robust link between the prevalence of rule violations and intrinsic honesty. We developed an index of the ‘prevalence of rule violations’ (PRV) based on country-level data from the year 2003 of corruption, tax evasion and fraudulent politics. We measured intrinsic honesty in an anonymous die-rolling experiment. We conducted the experiments with 2,568 young participants (students) who, due to their young age in 2003, could not have influenced PRV in 2003. We find individual intrinsic honesty is stronger in the subject pools of low PRV countries than those of high PRV countries. The details of lying patterns support psychological theories of honesty. The results are consistent with theories of the cultural co-evolution of institutions and values, and show that weak institutions and cultural legacies that generate rule violations not only have direct adverse economic consequences, but might also impair individual intrinsic honesty that is crucial for the smooth functioning of society

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications.

The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic subunit of two multi-protein complexes, referred to as mTORC1 and mTORC2. Signaling downstream of mTORC1 has a critical role in leukemic cell biology by controlling mRNA translation of genes involved in both cell survival and proliferation. mTORC1 activity can be downmodulated by upregulating the liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway. Here, we have explored the therapeutic potential of the anti-diabetic drug, metformin (an LKB1/AMPK activator), against both T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples from T-ALL patients displaying mTORC1 activation. Metformin affected T-ALL cell viability by inducing autophagy and apoptosis. However, it was much less toxic against proliferating CD4þ T-lymphocytes from healthy donors. Western blot analysis demonstrated dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cells treated with metformin. Remarkably, metformin targeted the side population of T-ALL cell lines as well as a putative leukemia-initiating cell subpopulation (CD34þ/CD7/CD4) in patient samples. In conclusion, metformin displayed a remarkable anti-leukemic activity, which emphasizes future development of LKB1/AMPK activators as clinical candidates for therapy in T-ALL. Leukemia (2012) 26, 91–100; doi:10.1038/leu.2011.269; published online 4 October 201

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder arising from T-cell progenitors. T-ALL accounts for 15% of newly diagnosed ALL cases in children and 25% in adults. Although the prognosis of T-ALL has improved, due to the use of polychemotherapy schemes, the outcome of relapsed/chemoresistant T-ALL cases is still poor. A signaling pathway that is frequently upregulated in T-ALL, is the phosphatidylinositol 3-kinase/Akt/mTOR network. To explore whether Akt could represent a target for therapeutic intervention in T-ALL, we evaluated the effects of the novel allosteric Akt inhibitor, MK-2206, on a panel of human T-ALL cell lines and primary cells from T-ALL patients. MK-2206 decreased T-ALL cell line viability by blocking leukemic cells in the G0/G1 phase of the cell cycle and inducing apoptosis. MK-2206 also induced autophagy, as demonstrated by an increase in the 14-kDa form of LC3A/B. Western blotting analysis documented a concentration-dependent dephosphorylation of Akt and its downstream targets, GSK-3a/b and FOXO3A, in response to MK-2206. MK-2206 was cytotoxic to primary T-ALL cells and induced apoptosis in a T-ALL patient cell subset (CD34þ/CD4/CD7), which is enriched in leukemia-initiating cells. Taken together, our findings indicate that Akt inhibition may represent a potential therapeutic strategy in T-ALL