The newborn innate immune system is characterized as functionally distinct, resulting in impaired proinflammatory responses to many stimuli and a bias toward Th2 development. Although the magnitude of impairment can be partially overcome, for instance through activation of TLR7/8 in newborn dendritic cells, the newborn innate response remains distinct from that of adults. Using human in vitro modeling of newborn and adult dendritic cells, we investigated the role of extracellular and intracellular regulators in driving age-specific responses to TLR7/8 stimulation. MicroRNA expression profiling and plasma switch experiments identified Let-7g as a novel regulator of newborn innate immunity. Activation-induced expression of Let-7g in monocyte-derived dendritic cells (MoDCs) is driven by newborn plasma and reduces expression of costimulatory receptors CD86, MHC class I, and CCR7 and secretion of IFN-α and sCD40L. Conversely, an increase in secretion of the Th2-polarizing cytokine IL-12p40 is observed. Overexpression of Let-7g in adult MoDCs resulted in the same observations. Small interfering RNA-mediated ablation of Let-7g levels in newborn MoDCs resulted in an adult-like phenotype. In conclusion, this study reveals for the first time (to our knowledge) that age-specific differences in human plasma induce the microRNA Let-7g as a key mediator of the newborn innate immune phenotype. These observations shed new light on the mechanisms of immune ontogeny and may inform approaches to discover age-specific immunomodulators, such as adjuvants.The recent trend toward an industrialization of brain exploration and the technological prowess of artificial intelligence algorithms and high-performance computing has caught the imagination of the public. These impressive advances are fueling an uncontrolled societal hype, the more amplified, the more "Blue Sky" the claim is. Will we ever be able to simulate a brain in silico? Will "it" (the digital avatar) be conscious? The Blue Brain Project (BBP) and the European flagship the Human Brain Project (HBP) have surfed on this wave for the past 10 years. https://www.selleckchem.com/products/d34-919.html Their already significant lifetimes now offer new case studies for neuroscience sociology and epistemology, as the projects mature. Their distinctive "Blue Sky" flavor has been a key feature in securing unprecedented funding (more than one billion Euros) mostly through supranational institutions. The longitudinal analysis of these ventures provides clues to how the neuromyth they propagate sells science, in a scientific world based on an economy of promises.This commentary puts the In Silico movie in perspective of the Human Brain Project (HBP) and clarifies major differences between this project and the Blue Brain Project, emphasizing that the two projects are very different in scope.The phosphoinositol-3 kinase (PI3K)-AKT pathway is one of the most mutated in human cancers, predominantly associated with the loss of the signaling antagonist, PTEN, and to lesser extents, with gain-of-function mutations in PIK3CA (encoding PI3K-p110α) and AKT1. In addition, most oncogenic driver pathways activate PI3K/AKT signaling. Nonetheless, drugs targeting PI3K or AKT have fared poorly against solid tumors in clinical trials as monotherapies, yet some have shown efficacy when combined with inhibitors of other oncogenic drivers, such as receptor tyrosine kinases or nuclear hormone receptors. There is growing evidence that AKT isoforms, AKT1, AKT2, and AKT3, have different, often distinct roles in either promoting or suppressing specific parameters of oncogenic progression, yet few if any isoform-preferred substrates have been characterized. This review will describe recent data showing that the differential activation of AKT isoforms is mediated by complex interplays between PTEN, PI3K isoforms and upstream tyrosine kinases, and that the efficacy of PI3K/AKT inhibitors will likely depend on the successful targeting of specific AKT isoforms and their preferred pathways.Pancreatic cancer is characterized by aberrant activity of oncogenic KRAS, which is mutated in 90% of pancreatic adenocarcinomas. Because KRAS itself is a challenging therapeutic target, we focused on understanding key signaling pathways driven by KRAS as a way to reveal dependencies that are amenable to therapeutic intervention. Analyses in primary human pancreatic cancers and model systems revealed that the receptor for the cytokine leukemia inhibitory factor (LIF) is downregulated by mutant KRAS. Furthermore, downregulation of the LIF receptor (LIFR) is necessary for KRAS-mediated neoplastic transformation. We found LIFR exerts inhibitory effects on KRAS-mediated transformation by inhibiting expression of the glucose transporter GLUT1, a key mediator of the enhanced glycolysis found in KRAS-driven malignancies. Decreased LIFR expression leads to increased GLUT1 as well as increases in glycolysis and mitochondrial respiration. The repression of GLUT1 by LIFR is mediated by the transcription factor STAT3, indicating a tumor-suppressive role for STAT3 within cancer cells with mutated KRAS. Finally, reflecting a clinically important tumor-suppressive role of LIFR, decreased LIFR expression correlates with shorter survival in pancreatic cancer patients with mutated KRAS. Similar findings were found in non-small cell lung cancers driven by mutated KRAS, suggesting that silencing LIFR is a generalized mechanism of KRAS-mediated cellular transformation. These results indicate that the LIFR/STAT3 pathway may mediate either tumor-promoting or tumor-suppressive signaling pathways depending on the genetic background of tumor cells, and may play diverse roles within other cells in the tumor microenvironment. IMPLICATIONS Mutant KRAS drives downregulation of the receptor for LIF, thereby allowing an increase in expression of the glucose transporter GLUT1 and increases in glycolysis and mitochondrial respiration.NK cells are cytotoxic lymphocytes displaying strong antimetastatic activity. Mouse models and in vitro studies suggest a prominent role of the mechanistic target of rapamycin (mTOR) kinase in the control of NK cell homeostasis and antitumor functions. However, mTOR inhibitors are used as chemotherapies in several cancer settings. The impact of such treatments on patients' NK cells is unknown. We thus performed immunophenotyping of circulating NK cells from metastatic breast cancer patients treated with the mTOR inhibitor everolimus over a three-month period. Everolimus treatment resulted in inhibition of mTORC1 activity in peripheral NK cells, whereas mTORC2 activity was preserved. NK cell homeostasis was profoundly altered with a contraction of the NK cell pool and an overall decrease in their maturation. Phenotype and function of the remaining NK cell population was less affected. This is, to our knowledge, the first in vivo characterization of the role of mTOR in human NK cells.