Precursor B-ALL cell lines differentially respond to syk inhibition by entospletinib

Background: Impaired B-cell receptor (BCR) function has been associated with the pro-gress of several B-cell malignancies. The spleen tyrosine kinase (SYK) represents a potential therapeutic target in a subset of B-cell neoplasias. In precursor B-acute lymphoblastic leukemia (B-ALL), the pathogenic role and therapeutic potential of SYK is still controversially discussed. We evaluate the application of the SYK inhibitor entospletinib (Ento) in pre-and pro-B-ALL cell lines, character-izing the biologic and molecular effects. Methods: SYK expression was characterized in pre-B-ALL (NALM-6) and pro-B-ALL cell lines (SEM and RS4;11). The cell lines were exposed to different Ento concentrations and the cell biological response analyzed by proliferation, metabolic activity, apop-tosis induction, cell-cycle distribution and morphology. BCR pathway gene expression and protein modulations were further characterized. Results: Ento significantly induced anti-proliferative and pro-apoptotic effects in NALM-6 and SEM, while barely affecting RS4;11. Targeted RNAseq revealed pronounced gene expression modulation only in NALM-6, while Western Blot analyses demonstrated that vital downstream effector proteins, such as pAKT, pERK, pGSK3β, p53 and BCL-6, were affected by Ento exposure in the inhibitor-sensitive cell lines. Conclusion: Different acting modes of Ento, independent of pre-BCR dependency, were characterized, unexpected in SEM. Ac-cordingly, SYK classifies as a potential target structure in a subset of pro-B-ALLs. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Fairtrade and Labour Markets in Ethiopia and Uganda

Drawing on four years of fieldwork in Ethiopia and Uganda, this paper addresses gaps in knowledge about the mechanisms linking agricultural exports with poverty reduction, the functioning of rural labour markets, and the relevance to the lives of the poorest people of Fairtrade. Statistical analysis of survey evidence, complemented by qualitative research, highlights the relatively poor payment and non-pay working conditions of those employed in research sites dominated by Fairtrade producer organizations. We conclude that Fairtrade is not an effective way to improve the welfare of the poorest rural people

Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes

A series of 73 bisphosphonium salts and 10 monophosphonium salt derivatives were synthesized and tested in vitro against several wild type and resistant lines of Trypanosoma brucei (T. b. rhodesiense STIB900, T. b. brucei strain 427, TbAT1-KO, and TbB48). More than half of the compounds tested showed a submicromolar EC 50 against these parasites. The compounds did not display any cross-resistance to existing diamidine therapies, such as pentamidine. In most cases, the compounds displayed a good selectivity index versus human cell lines. None of the known T. b. brucei drug transporters were required for trypanocidal activity, although some of the bisphosphonium compounds inhibited the low affinity pentamidine transporter. It was found that phosphonium drugs act slowly to clear a trypanosome population but that only a short exposure time is needed for irreversible damage to the cells. A comparative molecular field analysis model (CoMFA) was generated to gain insights into the SAR of this class of compounds, identifying key features for trypanocidal activity. © 2012 American Chemical Society.Peer Reviewe

Probing R-parity violating models of neutrino mass at the Tevatron via top Squark decays

We have estimated the limiting branching ratio of the R-parity violating (RPV) decay of the lighter top squark, \tilde t_1 \ar l^+ d ($l=e$ or $\mu$ and d is a down type quark of any flavor), as a function of top squark mass(\MST) for an observable signal in the di-lepton plus di-jet channel at the Tevatron RUN-II experiment with 2 fb$^{-1}$ luminosity. Our simulations indicate that the lepton number violating nature of the underlying decay dynamics can be confirmed via the reconstruction of \MST. The above decay is interesting in the context of RPV models of neutrino mass where the RPV couplings ($\lambda'_{i3j}$) driving the above decay are constrained to be small (\lsim 10^{-3} - 10^{-4} ). If $\tilde t_1$ is the next lightest super particle - a theoretically well motivated scenario - then the RPV decay can naturally compete with the R-parity conserving (RPC) modes which also have suppressed widths. The model independent limiting BR can delineate the parameter space in specific supersymmetric models, where the dominating RPV decay is observable and predict the minimum magnitude of the RPV coupling that will be sensitive to Run-II data. We have found it to be in the same ballpark value required by models of neutrino mass, for a wide range of \MST. A comprehensive future strategy for linking top squark decays with models of neutrino mass is sketched.Comment: 28 pages, 14 Figure

Stop and Sbottom Searches in Run II of the Fermilab Tevatron

We estimate the Tevatron Run II potential for top and bottom squark searches. We find an impressive reach in several of the possible discovery channels. We also study some new channels which may arise in non-conventional supersymmetry models. In each case we rely on a detailed Monte Carlo simulation of the collider events and the CDF detector performance in Run I.Comment: 30 pages, LaTeX, 10 figure

Search for the Supersymmetric Partner of the Top-Quark in ppˉp \bar{p} Collisions at s=1.8TeV\sqrt{s} = 1.8 {\rm TeV}

We report on a search for the supersymmetric partner of the top quark (stop) produced in $t \bar{t}$ events using $110 {\rm pb}^{-1}$ of $p \bar{p}$ collisions at $\sqrt{s} = 1.8 {\rm TeV}$ recorded with the Collider Detector at Fermilab. In the case of a light stop squark, the decay of the top quark into stop plus the lightest supersymmetric particle (LSP) could have a significant branching ratio. The observed events are consistent with Standard Model $t \bar{t}$ production and decay. Hence, we set limits on the branching ratio of the top quark decaying into stop plus LSP, excluding branching ratios above 45% for a LSP mass up to 40 {\rm GeV/c}$^{2}$.Comment: 11 pages, 4 figure

Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies

Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4+ T cells but not in cynomolgus T lymphocytes. The sustained Ca++-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-γ and TNF-α. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-γ and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells

Current understanding of the human microbiome

Author Posting. © The Author(s), 2018. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Medicine 24 (2018): 392–400, doi:10.1038/nm.4517.Our understanding of the link between the human microbiome and disease, including obesity, inflammatory bowel disease, arthritis and autism, is rapidly expanding. Improvements in the throughput and accuracy of DNA sequencing of the genomes of microbial communities associated with human samples, complemented by analysis of transcriptomes, proteomes, metabolomes and immunomes, and mechanistic experiments in model systems, have vastly improved our ability to understand the structure and function of the microbiome in both diseased and healthy states. However, many challenges remain. In this Review, we focus on studies in humans to describe these challenges, and propose strategies that leverage existing knowledge to move rapidly from correlation to causation, and ultimately to translation.Many of the studies described here in our laboratories were supported by the NIH, NSF, DOE, and the Alfred P. Sloan Foundation.2018-10-1