SYK Regulates mTOR Signaling in AML

Spleen Tyrosine Kinase (SYK) was recently identified as a new target in acute myeloid leukemia (AML); however, its mechanistic role in this disease is poorly understood. Based on the known interaction between SYK and mTOR signaling in lymphoma, we hypothesized that SYK may regulate mTOR signaling in AML. Both small-molecule inhibition of SYK and SYK-directed shRNA suppressed mTOR and its downstream signaling effectors, as well as its upstream activator, AKT. Moreover, the inhibition of multiple nodes of the PI3K signaling pathway enhanced the effects of SYK suppression on AML cell viability and differentiation. Evaluation of the collateral MAPK pathway revealed a heterogeneous response to SYK inhibition in AML with down-regulation of MEK and ERK phosphorylation in some AML cell lines but a paradoxical increase in MEK/ERK phosphorylation in RAS-mutated AML. These studies reveal SYK as a regulator of mTOR and MAPK signaling in AML and demonstrate that inhibition of PI3K pathway activity enhances the effects of SYK inhibition on AML cell viability and differentiation

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells

Time and Origin of Cichlid Colonization of the Lower Congo Rapids

Most freshwater diversity is arguably located in networks of rivers and streams, but, in contrast to lacustrine systems riverine radiations, are largely understudied. The extensive rapids of the lower Congo River is one of the few river stretches inhabited by a locally endemic cichlid species flock as well as several species pairs, for which we provide evidence that they have radiated in situ. We use more that 2,000 AFLP markers as well as multilocus sequence datasets to reconstruct their origin, phylogenetic history, as well as the timing of colonization and speciation of two Lower Congo cichlid genera, Steatocranus and Nanochromis. Based on a representative taxon sampling and well resolved phylogenetic hypotheses we demonstrate that a high level of riverine diversity originated in the lower Congo within about 5 mya, which is concordant with age estimates for the hydrological origin of the modern lower Congo River. A spatial genetic structure is present in all widely distributed lineages corresponding to a trisection of the lower Congo River into major biogeographic areas, each with locally endemic species assemblages. With the present study, we provide a phylogenetic framework for a complex system that may serve as a link between African riverine cichlid diversity and the megadiverse cichlid radiations of the East African lakes. Beyond this we give for the first time a biologically estimated age for the origin of the lower Congo River rapids, one of the most extreme freshwater habitats on earth

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

The Challenge of Primary Central Nervous System Lymphoma

Primary central nervous system (CNS) lymphoma is a challenging subtypes of aggressive non-Hodgkin lymphoma. Emerging clinical data suggest that optimized outcomes are achieved with dose-intensive CNS-penetrant chemotherapy and avoiding whole brain radiotherapy. Anti-CD20 antibody-based immunotherapy as a component of high-dose methotrexate-based induction programs may contribute to improved outcomes. An accumulation of insights into the molecular and cellular basis of disease pathogenesis is providing a foundation for the generation of molecular tools to facilitate diagnosis as well as a roadmap for integration of targeted therapy within the developing therapeutic armamentarium for this challenging brain tumor

Executive Functions, Physical Abilities, and Their Relationship with Tactical Performance in Young Soccer Players

While tactical performance in soccer is associated with the players’ and teams’ collective actions in the context of game stimuli, how tactical performance relates to players’ executive functions (EFs) and physical abilities should be examined. In this study, we examined these relationships among 81 Under-15 male soccer players who underwent tactical evaluation (FUT-SAT), EF tests (i.e.,(Stop-Signal Test and Design Fluency Test)), and physical tests (i.e.,(Maturity Offset, Yoyo Endurance Test II, Sargent Jump Test, and Sprint Test)). Multiple linear regression modeling with the stepwise method showed that approximately 48% of overall game tactical performance variance was explained by inhibitory control, biological maturation, and sprint capacity (p =.004; d =.54; r2 =.479), whereas 35% of offensive tactical performance variance was explained by the same dimensions (p =.001; d =.91; r2 =.353). In addition, approximately 28% of defensive tactical performance variance was explained by cognitive flexibility and aerobic resistance (p =.007; d =.39; r2 =.280). These results reflect the combined importance of EFs and physical abilities for tactical performance in young soccer players, suggesting that these abilities may be targets for training when trying to improve young players’ performance

Hypoxia Is a Dominant Remodeler of the Effector T Cell Surface Proteome Relative to Activation and Regulatory T Cell Suppression.

Immunosuppressive factors in the tumor microenvironment (TME) impair T cell function and limit the antitumor immune response. T cell surface receptors and surface proteins that influence interactions and function in the TME are proven targets for cancer immunotherapy. However, how the entire surface proteome remodels in primary human T cells in response to specific suppressive factors in the TME remains to be broadly and systematically characterized. Here, using a reductionist cell culture approach with primary human T cells and stable isotopic labeling with amino acids in cell culture-based quantitative cell surface capture glycoproteomics, we examined how two immunosuppressive TME factors, regulatory T cells (Tregs) and hypoxia, globally affect the activated CD8+ surface proteome (surfaceome). Surprisingly, coculturing primary CD8+ T cells with Tregs only modestly affected the CD8+ surfaceome but did partially reverse activation-induced surfaceomic changes. In contrast, hypoxia drastically altered the CD8+ surfaceome in a manner consistent with both metabolic reprogramming and induction of an immunosuppressed state. The CD4+ T cell surfaceome similarly responded to hypoxia, revealing a common hypoxia-induced surface receptor program. Our surfaceomics findings suggest that hypoxic environments create a challenge for T cell activation. These studies provide global insight into how Tregs and hypoxia remodel the T cell surfaceome and we believe represent a valuable resource to inform future therapeutic efforts to enhance T cell function