Arsenic trioxide (ATO) and MEK1 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells

Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras-mitogen-activated protein kinase ( MAPK) can confer an aggressive, apoptosis-resistant phenotype to leukemia cells. In this study, we report that acute promyelocytic leukemia (APL) cells exploit the Ras-MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad, delaying arsenic trioxide (ATO)-induced apoptosis. Both in APL cell line NB4 and in APL primary blasts, the inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) and Bad phosphorylation by MEK1 inhibitors enhanced apoptosis in ATO-treated cells. We isolated an arsenic-resistant NB4 subline (NB4-As-R), which showed stronger ERK1/2 activity (2.7-fold increase) and Bad phosphorylation (2.4-fold increase) compared to parental NB4 cells in response to ATO treatment. Upon ATO exposure, both NB4 and NB4-As-R cell lines doubled protein levels of the death antagonist Bcl-xL, but the amount of free Bcl-xL that did not heterodimerize with Bad was 1.8-fold greater in NB4-As-R than in the parental line. MEK1 inhibitors dephosphorylated Bad and inhibited the ATO-induced increase of Bcl-xL, overcoming ATO resistance in NB4-As-R. These results may provide a rationale to develop combined or sequential MEK1 inhibitors plus ATO therapy in this clinical setting

Fatal herpesvirus-6 encephalitis in a recipient of a T-cell-depleted peripheral blood stem cell transplant from a 3-loci mismatched related donor

Human herpesvirus-6 (HHV-6), like all the other herpes viruses, remains latent in host cells after primary infection but can be reactivated In immuno-compromised patients causing fever, skin rash, bone marrow (BM) suppression, pneumonitis, Sinusitis and meningoencephalitis. We describe the case of a man with chronic myelogenous leukemia who developed encephalitis associated with acute graft-versus-host disease two months after a T-cell-depleted mismatched peripheral blood stem cell transplant. Magnetic resonance images of the brain revealed multiple bilateral foci of signal abnormality. HHV-6 was the only pathogen detected in cerebrospinal fluid by PCR. treatment with both ganciclovir and foscarnet was unsuccessful and the patient gradually deteriorated and died. Other cases of HHV-6 encephalitis after bone marrow transplantation are reviewed

Engineering donor mesenchymal cells with IL-7 hastens naive T cell recruitment in vitro and supports immunologic reconstitution after HSCT in NOD/SCID mice

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117: Naive and memory T regulatory cells respond to mesenchymal cells regulation

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Modeling Stygofauna Resilience to the Impact of the Climate Change in the Karstic Groundwaters of South Italy

We predicted the global warming effects on the stygofauna of Murgia–Salento karstic groundwaters in Italy for 2050, which contribute to a biodiversity loss assessment in the climate change context. For quantitative impact estimations, we defined a local resilience score (LRS) for sampled species between 2018 and 2021. A resilience model equation of the stygobiont species conservation was obtained from a surface best-fit of the assigned LRS and the corresponding values of independent variables describing the environmental quality of monitored habitats and LRS. The principal components of the correlation between the monitored variables and LRS were obtained via factor analysis. Three-dimensional surface maps of stygofauna species resilience (SSR) were constructed to visualize and quantitatively compare the biodiversity loss of species assemblages owing to environmental and habitat quality modifications. The proposed SSR model was applied to the sampled stygofauna, and the decrease in local species resilience for 2050 was predicted. Independent variable factors were updated for 2050 to consider increases of up to 2 °C and 0.04 mS/cm in groundwater temperature and electric conductance observed for 2021. The SSR model results predicted a high impact on the resilience of Parastenocaris cf. orcina (80%), newly retrieved Crustacea Copepod Cyclopidae gen 1 sp 1, and three other stygobites (~50%). The resilience of Metacyclops stammeri had minor impacts

Allogeneic transplantation across the HLA barriers.

In high-risk acute leukemia patients, a 10-fold increase in the dose of extensively T-cell-depleted hematopoietic stem cells ensures sustained full-donor engraftment of one-haplotype-mismatched transplants without graft-vs.-host disease. Since our first successful pilot study, which exploited the principle of a megadose stem cell transplant, our efforts have concentrated on developing new conditioning regimens, optimizing graft processing and improving the post-transplant immunologic recovery. The results so far achieved in more than 100 high-risk acute leukemia patients show that haploidentical transplantation is now a clinical reality. Because virtually all patients in need of a hematopoietic stem cell transplant have a full-haplotype-mismatched family donor, a T-cell-depleted mismatched transplant can be offered with curative intent, thus extending allogeneic transplantation procedures to virtually all candidates