CARMA1 is a novel regulator of T-ALL disease and leukemic cell migration to the CNS

No abstract available

Clinical expression and antigenic profiles of a Plasmodium vivax vaccine candidate: Merozoite Surface Protein 7 (PvMSP-7)

Background: Vivax malaria is the predominant form of malaria outside Africa, affecting about 14 million people worldwide, with about 2.5 billion people exposed. Development of a Plasmodium vivax vaccine is a priority, and merozoite surface protein 7 (MSP-7) has been proposed as a plausible candidate. The P. vivax genome contains 12 MSP-7 genes, which contribute to erythrocyte invasion during blood-stage infection. Previous analysis of MSP-7 sequence diversity suggested that not all paralogs are functionally equivalent. To explore MSP-7 functional diversity, and to identify the best vaccine candidate within the family, MSP-7 expression and antigenicity during bloodstream infections were examined directly from clinical isolates. Methods: Merozoite surface protein 7 gene expression was profiled using RNA-seq data from blood samples isolated from ten human patients with vivax malaria. Differential expression analysis and co-expression cluster analysis were used to relate PvMSP-7 expression to genetic markers of life cycle stage. Plasma from vivax malaria patients was also assayed using a custom peptide microarray to measure antibody responses against the coding regions of 12 MSP-7 paralogs. Results: Ten patients presented diverse transcriptional profiles that comprised four patient groups. Two MSP-7 paralogs, 7A and 7F, were expressed abundantly in all patients, while other MSP-7 genes were uniformly rare (e.g. 7J). MSP-7H and 7I were significantly more abundant in patient group 4 only, (two patients having experienced longer patency), and were co-expressed with a schizont-stage marker, while negatively associated with liver-stage and gametocyte-stage markers. Screening infections with a PvMSP-7 peptide array identified 13 linear B-cell epitopes in five MSP-7 paralogs that were recognized by plasma from all patients. Conclusions: These results show that MSP-7 family members vary in expression profile during blood infections; MSP-7A and 7F are expressed throughout the intraerythrocytic development cycle, while expression of other paralogs is focused on the schizont. This may reflect developmental regulation, and potentially functional differentiation, within the gene family. The frequency of B-cell epitopes among paralogs also varies, with MSP-7A and 7L consistently the most immunogenic. Thus, MSP-7 paralogs cannot be assumed to have equal potential as vaccines. This analysis of clinical infections indicates that the most abundant and immunogenic paralog is MSP-7A

AutoSNAP: Automatically Learning Neural Architectures for Instrument Pose Estimation

Despite recent successes, the advances in Deep Learning have not yet been fully translated to Computer Assisted Intervention (CAI) problems such as pose estimation of surgical instruments. Currently, neural architectures for classification and segmentation tasks are adopted ignoring significant discrepancies between CAI and these tasks. We propose an automatic framework (AutoSNAP) for instrument pose estimation problems, which discovers and learns the architectures for neural networks. We introduce 1)~an efficient testing environment for pose estimation, 2)~a powerful architecture representation based on novel Symbolic Neural Architecture Patterns (SNAPs), and 3)~an optimization of the architecture using an efficient search scheme. Using AutoSNAP, we discover an improved architecture (SNAPNet) which outperforms both the hand-engineered i3PosNet and the state-of-the-art architecture search method DARTS.Comment: Accepted at MICCAI 2020 Preparing code for release at https://github.com/MECLabTUDA/AutoSNA

The persistent dynamic secrets of senescence

While the beneficial versus detrimental implications of the senescence-associated secretome remain an issue of debate, time-resolved analyses of its composition, regulatory mechanisms and functional consequences have been largely missing. The dynamic activity of NOTCH is now shown to direct two distinct senescence phenotypes, by first promoting a pro-senescent TGF-{beta}1-dependent secretome, followed by a second wave of pro-inflammatory, senescence-clearing cytokines

Notch Ankyrin Repeat Domain Variation Influences Leukemogenesis and Myc Transactivation

, cell-based and structural analyses to compare the abilities of activated Notch1-4 to support T cell development, induce T cell acute lymphoblastic leukemia/lymphoma (T-ALL), and maintain T-ALL cell growth and survival., a direct Notch target that has an important role in Notch-associated T-ALL.We conclude that the leukemogenic potentials of Notch receptors vary, and that this functional difference stems in part from divergence among the highly conserved ankyrin repeats, which influence the transactivation of specific target genes involved in leukemogenesis

Notch signaling during human T cell development

Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse

Aberrant signaling in T-cell acute lymphoblastic leukemia: biological and therapeutic implications

T-cell acute lymphoblastic leukemia (T-ALL) is a biologically heterogeneous disease with respect to phenotype, gene expression profile and activation of particular intracellular signaling pathways. Despite very significant improvements, current therapeutic regimens still fail to cure a portion of the patients and frequently implicate the use of aggressive protocols with long-term side effects. In this review, we focused on how deregulation of critical signaling pathways, in particular Notch, PI3K/Akt, MAPK, Jak/STAT and TGF-beta, may contribute to T-ALL. Identifying the alterations that affect intracellular pathways that regulate cell cycle and apoptosis is essential to understanding the biology of this malignancy, to define more effective markers for the correct stratification of patients into appropriate therapeutic regimens and to identify novel targets for the development of specific, less detrimental therapies for T-ALL

Enhanced Notch Activation Is Advantageous but Not Essential for T Cell Lymphomagenesis in Id1 Transgenic Mice

T cell lymphoblastic leukemia (T-ALL) is known to be associated with chromosomal abnormalities that lead to aberrant expression of a number of transcription factors such as TAL1, which dimerizes with basic helix-loop-helix (bHLH) E proteins and inhibits their function. Activated Notch receptors also efficiently induce T cell leukemogenesis in mouse models. Interestingly, gain-of-function mutations or cryptic transcription initiation of the Notch1 gene have been frequently found in both human and mouse T-ALL. However, the correlations between these alterations and overall Notch activities or leukemogenesis have not been thoroughly evaluated. Therefore, we made use of our collection of T cell lymphomas developed in transgenic mice expressing Id1, which like TAL1, inhibits E protein function. By comparing expression levels of Notch target genes in Id1-expressing tumors to those in tumors induced by a constitutively active form of Notch1, N1C, we were able to assess the overall activities of Notch pathways and conclude that the majority of Id1-expressing tumors had elevated Notch function to a varying degree. However, 26% of the Id1-expressing tumors had no evidence of enhanced Notch activation, but that did not delay the onset of tumorigenesis. Furthermore, we examined the genetic or epigenetic alterations thought to contribute to ligand-independent activation or protein stabilization of Notch1 and found that some of the Id1-expressing tumors acquired these changes, but they are not uniformly associated with elevated Notch activities in Id1 tumor samples. In contrast, N1C-expressing tumors do not harbor any PEST domain mutations nor exhibit intragenic transcription initiation. Taken together, it appears that Notch activation provides Id1-expressing tumor cells with selective advantages in growth and survival. However, this may not be absolutely essential for lymphomagenesis in Id1 transgenic mice and additional factors could also cooperate with Id1 to induce T cell lymphoma. Therefore, a broad approach is necessary in designing T-ALL therapy