Microglial activation can exacerbate the neuronal damage seen in various neurodegenerative diseases. K+ channels control the membrane potential in most cells, which may regulate activation; thus, I ...hypothesize that the activity of specific K+ channels is required for microglial activation. In activated microglia, both Kv1.3 mRNA and protein level increased concomitantly with the upregulation Kv1.3-like current. Similarly, mRNA and protein levels increased for Kv1.2. In contrast, Kv1.5 mRNA and protein levels remained unchanged. In activated microglia, 4-aminopyridine, a Kv1.x channel blocker, eliminated the stimulation-induced increases in respiratory burst and phagocytosis, but not NO production or proliferation. Dendrotoxin treatment, which blocks Kv1.2 and Kv1.6, blocked phagocytosis while agitoxin treatment, which blocks Kv1.3, blocked the respiratory burst. These results imply that alterations in Kv channel expression modulate changes in some of the activation processes in microglia. Taken together, these results suggest that Kv channel blockers are potential targets for inhibiting microglia activation.
Nilotinib is a highly selective Bcr-Abl inhibitor approved for imatinib-resistant chronic myeloid leukemia (CML). Nilotinib and dasatinib, a multi-targeted kinase inhibitor also approved for ...second-line therapy in CML, have different patterns of kinase selectivity, pharmacokinetics, and cell uptake and efflux properties, and thus patients may respond to one following failure of the other. An international phase II study of nilotinib was conducted in CML patients (39 chronic phase (CP), 21 accelerated phase (AP)) after failure of both imatinib and dasatinib. Median times from diagnosis of CP or AP to nilotinib therapy were 89 and 83 months, respectively. Complete hematological response and major cytogenetic response (MCyR) rates in CP were 79% and 43%, respectively. Of 17 evaluable patients with CML-AP, 5 (29%) had a confirmed hematological response and 2 (12%) a MCyR. The median time to progression has not yet been reached in CP patients. At 18 months 59% of patients were progression-free. Median overall survival for both populations has not been reached, and the estimated 18-month survival rate in CML-CP was 86% and that at 12 months for CML-AP was 80%. Nilotinib is an effective therapy in CML-CP and -AP following failure of both imatinib and dasatinib therapy.
•In haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide, conditioning intensity and graft source impact graft-versus-host disease (GVHD).•In reduced-intensity ...conditioning, peripheral blood compared to bone marrow is significantly associated with chronic GVHD.•Older donor age is associated with higher risk of acute GVHD and nonrelapse mortality.
Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio HR, 1.53; 95% confidence interval CI, 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
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