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- Chiodin, G, et al.
(författare)
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High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL
- 2022
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Ingår i: Blood advances. - : American Society of Hematology. - 2473-9537 .- 2473-9529. ; 6:18, s. 5494-5504
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Tidskriftsartikel (refereegranskat)abstract
- Chronic lymphocytic leukemia (CLL) cells have variably low surface IgM (sIgM) levels/signaling capacity, influenced by chronic antigen engagement at tissue sites. Within these low levels, CLL with relatively high sIgM (CLLhigh) progresses more rapidly than CLL with low sIgM (CLLlow). During ibrutinib therapy, surviving CLL cells redistribute into the peripheral blood and can recover sIgM expression. Return of CLL cells to tissue may eventually recur, where cells with high sIgM could promote tumor growth. We analyzed time to new treatment (TTNT) following ibrutinib in 70 patients with CLL (median follow-up of 66 months) and correlated it with pretreatment sIgM levels and signaling characteristics. Pretreatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca2+ mobilization (iCa2+), in vitro (r = 0.70; P < .0001). High sIgM levels/signaling strongly correlated with short TTNT (P < .05), and 36% of patients with CLLhigh vs 8% of patients with CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pretherapy sIgM levels (r = −0.68; P = .01) or iCa2+ (r = −0.71; P = .009). In patients, sIgM-mediated iCa2+ and ERK phosphorylation levels were reduced by ibrutinib therapy but not abolished. The residual signaling capacity downstream of BTK was associated with high expression of sIgM, whereas it was minimal when sIgM expression was low (P < .05). These results suggested that high sIgM levels facilitated CLL cell resistance to ibrutinib in patients. The CLL cells, surviving in the periphery with high sIgM expression, include a dangerous fraction that is able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches.
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| 2. |
- Greczynski, Grzegorz, et al.
(författare)
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Metal-ion subplantation: A game changer for controlling nanostructure and phase formation during film growth by physical vapor deposition
- 2020
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Ingår i: Journal of Applied Physics. - : AMER INST PHYSICS. - 0021-8979 .- 1089-7550. ; 127:18
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Tidskriftsartikel (refereegranskat)abstract
- Up until recently, thin film growth by magnetron sputtering relied on enhancing adatom mobility in the surface region by gas-ion irradiation to obtain dense layers at low deposition temperatures. However, an inherently low degree of ionization in the sputtered material flux during direct-current magnetron sputtering (DCMS), owing to relatively low plasma densities involved, prevented systematic exploration of the effects of metal-ion irradiation on the film nanostructure, phase content, and physical properties. Employing only gas-ion bombardment results in an inefficient energy and momentum transfer to the growing film surface. Also, for enhanced substrate biasing, the higher concentration of implanted noble gas atoms at interstitial lattice positions causes elevated compressive stress levels. High-power impulse magnetron sputtering (HiPIMS), however, provides controllable metal-ion ionization and, more importantly, enables the minimization of adverse gas-ion irradiation effects. The latter can be realized by the use of pulsed substrate bias applied synchronously with the metal-ion-rich portion of each HiPIMS pulse (metal-ion-synchronized HiPIMS), based on the results of time-resolved ion mass spectrometry analyses performed at the substrate position. In this way, both the metal-ion energy and the momentum can be precisely controlled for one to exploit the benefits of irradiation by metal-ions, which are also the film-forming species. Systematic studies performed in recent years using binary and ternary transition metal-based nitrides as model systems revealed new phenomena with accompanying unique and attractive film growth pathways. This Perspective paper focuses on the effects of low-mass metal-ion irradiation and their role for the nanostructure and phase control. We review basic findings and present original results from ion mass spectrometry studies and materials characterization for the effect of metal-ion subplantation. Key correlations are highlighted, which, if properly engaged, enable unprecedented control over film nanostructure and phase formation and, hence, the resulting properties. We show generalization from the findings to present a new concept for thin film growth in a hybrid HiPIMS/DCMS configuration with metal-ion-synchronized bias. Based on the results obtained for TM-based nitrides, there are no evident physical limitations preventing the extension of this deposition process concept for other materials systems or other metal-ion-based thin film growth techniques. Further exciting findings could, thus, be anticipated for the future.
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