Search Results (3)

Pegmatitic deposits of critical metals (e.g., Li, Ta, Be) are becoming increasingly significant, with growing interest in understanding metal enrichment processes and potential vectors to aid the discovery of new resources. In southeast Ireland, the Leinster pegmatite belt comprises several largely concealed Li-Cs-Ta albite-spodumene-type pegmatites. We carried out detailed mineralogical characterization and whole-rock geochemical analyses of six drill cores intersecting pegmatite bodies and their country rocks. Exomorphic halos 2–6 m thick, enriched in Li, Rb, Be, B, Cs, Sn and Ta, are identified in both mica schists and granitic rocks adjacent to spodumene pegmatites. Metasomatism in wall rocks visible to the naked eye is restricted to a few tens of centimeters, suggesting country rock permeability plays a key role in the dispersion of these fluids. We propose that halos result from the discharge of rare element-rich residual fluids exsolved near the end of pegmatite crystallization. Halo geochemistry reflects the internal evolution of the crystallizing pegmatite system, with residual fluid rich in incompatible elements accumulated by geochemical fractionation (Be, B, Cs, Sn, Ta) and by auto-metasomatic resorption of spodumene and K-feldspar (Li, Rb). The possibility of identifying rare-element enrichment trends by analysis of bedrock, stream sediments and soils brings opportunities for mineral exploration strategies in Ireland and for similar albite-spodumene pegmatites worldwide. Full article

The retention and re-migration of Chronic Lymphocytic Leukemia cells into cytoprotective and proliferative lymphoid niches is thought to contribute to the development of resistance, leading to subsequent disease relapse. The aim of this study was to elucidate the molecular processes that govern CLL cell migration to elicit a more complete inhibition of tumor cell migration. We compared the phenotypic and transcriptional changes induced in CLL cells using two distinct models designed to recapitulate the peripheral circulation, CLL cell migration across an endothelial barrier, and the lymph node interaction between CLL cells and activated T cells. Initially, CLL cells were co-cultured with CD40L-expressing fibroblasts and exhibited an activated B-cell phenotype, and their transcriptional signatures demonstrated the upregulation of pro-survival and anti-apoptotic genes and overrepresentation of the NF-κB signaling pathway. Using our dynamic circulating model, we were able to study the transcriptomics and miRNomics associated with CLL migration. More than 3000 genes were altered when CLL cells underwent transendothelial migration, with an overrepresentation of adhesion and cell migration gene sets. From this analysis, an upregulation of the FAK signaling pathway was observed. Importantly, PTK2 (FAK) gene expression was significantly upregulated in migrating CLL cells (PTK2 Fold-change = 4.9). Here we demonstrate that TLR9 agonism increased levels of p-FAK (p ≤ 0.05), which could be prevented by pharmacological inhibition of FAK with defactinib (p ≤ 0.01). Furthermore, a reduction in CLL cell migration and invasion was observed when FAK was inhibited (p ≤ 0.0001), supporting a role for FAK in both CLL migration and tissue invasion. When taken together, our data highlights the potential for combining FAK inhibition with current targeted therapies as a more effective treatment regime for CLL. Full article

In this study, we evaluated an NF-κB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B- and T-lymphocytes. Basal NF-κB subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then assessed in terms of cytotoxicity and the expression of nuclear NF-κB subunits following monoculture and co-culture with CD40L-expressing fibroblasts, as a model of the lymphoid niche. CW15337 induced a dose-dependent increase in apoptosis, and nuclear expression of the non-canonical NF-κB subunit, p52, was correlated with sensitivity to CW15337 (p = 0.01; r² = 0.39). Co-culture on CD40L-expressing cells induced both canonical and non-canonical subunit expression in nuclear extracts, which promoted in vitro resistance against fludarabine and ABT-199 (venetoclax) but not CW15337. Furthermore, the combination of CW15337 with fludarabine or ABT-199 showed cytotoxic synergy. Mechanistically, CW15337 caused the selective inhibition of non-canonical NF-κB subunits and the transcriptional repression of BCL2L1, BCL2A1 and MCL1 gene transcription. Taken together, these data suggest that the NIK inhibitor, CW15337, exerts its effects via suppression of the non-canonical NF-κB signaling pathway, which reverses BCL2 family-mediated resistance in the context of CD40L stimulation. Full article