CD34-derived dendritic cells transfected ex vivo with HIV-Gag mRNA induce polyfunctional T-cell responses in nonhuman primates

The pivotal role of DCs in initiating immune responses led to their use as vaccine vectors. However, the relationship between DC subsets involved in antigen presentation and the type of elicited immune responses underlined the need for the characterization of the DCs generated in vitro. The phenotypes of tissue-derived APCs from a cynomolgus macaque model for human vaccine development were compared with ex vivo-derived DCs. Monocyte/macrophages predominated in bone marrow (BM) and blood. Myeloid DCs (mDCs) were present in all tested tissues and were more highly represented than plasmacytoid DCs (pDCs). As in human skin, Langerhans cells (LCs) resided exclusively in the macaque epidermis, expressing CD11c, high levels of CD1a and langerin (CD207). Most DC subsets were endowed with tissue-specific combinations of PRRs. DCs generated from CD34(+) BM cells (CD34-DCs) were heterogeneous in phenotype. CD34-DCs shared properties (differentiation and PRR) of dermal and epidermal DCs. After injection into macaques, CD34-DCs expressing HIV-Gag induced Gag-specific CD4(+) and CD8(+) T cells producing IFN-γ, TNF-α, MIP-1β, or IL-2. In high responding animals, the numbers of polyfunctional CD8(+) T cells increased with the number of booster injections. This DC-based vaccine strategy elicited immune responses relevant to the DC subsets generated in vitro.     

A comparison of survival with and without extracorporeal life support treatment for severe poisoning due to drug intoxication

Background

The use of extracorporeal life support (ECLS) as a treatment for severe cardiovascular impairment due to poisoning is unclear. Therefore, we conducted a retrospective cohort analysis to compare survival among critically ill poisoned patients treated with or without ECLS.

Methods

All consecutive patients admitted into 2 university hospitals in northwestern France over the past decade for persistent cardiac arrest or severe shock following poisoning due to drug intoxication were included. ECLS was preferentially performed in 1 of the 2 centers.

Results

Sixty-two patients (39 women, 23 men; mean age 48 ± 17 years) fulfilled inclusion criteria: 10 with persistent cardiac arrest and 42 with severe shock. Fourteen patients were treated with ECLS and 48 patients with conventional therapies. All subjects received vasopressor and fluid loading. Patients treated with or without ECLS at ICU admission had comparable drug ingestion histories, Simplified Acute Physiology Score (SAPS II score) (66 ± 18), Sequential Organ Failure Assessment (SOFA) score (median: 11 [IQR, 9–13]), Glasgow Coma Scale score (median: 3 [IQR, 3–11]), need for ventilator support (n = 56) and extra renal support (n = 23). Thirty-five (56%) patients survived: 12/14 (86%) ECLS patients and 23/48 (48%) non-ECLS patients (p = 0.02, by Fisher exact test). None of the patients with persistent cardiac arrest survived without ECLS support. Based on admission data, beta-blocker intoxication (p = 0.02) was also associated with lower mortality. In multivariate analysis, adjusting for SAPS II and beta-blocker intoxication, ECLS support remained associated with lower mortality [Adjusted Odds Ratio, 0.18; 95% CI, 0.03–0.96; p = 0.04].

Conclusion

In the absence of response to conventional therapies, we consider that ECLS may improve survival in critically ill poisoned patients experiencing cardiac arrest and severe shock.     

Cerebral ageing-the role of insulin and insulin-like growth factor signalling:A review

Cerebral ageing is a complex biological process associated with progressing cerebrovascular disease and neuronal death. It does not always, however, associate with a functional decline, as the ageing mammalian brain retains considerable functional plasticity which supports successful cerebral ageing where age-related cognitive decline is modest. On the contrary, pathological cerebral ageing results in memory impairment and cognitive deterioration, with Alzheimer's disease(AD) being a florid example. Trophic/growth factors promote brain plasticity; among them are peptides which belong tothe insulin family. Preclinical research suggests that the evolutionarily conserved brain insulin/insulin-like growth factor-1(IGF-1) signalling system controls lifespan and protects against some features of AD such as neurodegeneration-related accumulation of toxic proteins and cognitive deficiencies, as observed in animal models. Insulin and IGF-1 activate cell signalling mechanisms which play protective and regenerative roles; abnormalities in the insulin/IGF-1 system may trigger a cascade of neurodegeneration in AD. AD patients show cerebral resistance to insulin which associates with IGF-I resistance and dysregulation of insulin/IGF-1 receptors as well as cognitive deterioration. This review is focused on the roles of the insulin/IGF-1 signalling system in cerebral ageing and its potential involvement in neurodegeneration in the human brain as seen against the background of preclinical evidence.     

Population pharmacokinetics and pharmacogenetics of vincristine in paediatric patients treated for solid tumour diseases

Purpose  

The interindividual variability of vincristine pharmacokinetics is quite large, but the origins of this variability are not properly understood. The aim of this study was to develop a population pharmacokinetic model of vincristine in a paediatric population treated for solid tumour disease and evaluate the impact of different ABCB1, CYP3A4 and CYP3A5 polymorphisms on the different pharmacokinetic parameters.     

Histone deacetylase inhibitors in the treatment of hematological malignancies

Histone deacetylases inhibitors (HDACi) represent a new epigenetic targeting therapy class, which is widely investigated in fundamental research and clinical trials. They are able to restore and increase tumor suppressor genes expression and to play an anti-tumoral activity through numerous targets, which are distributed all over the main differentiation, proliferation and survival cellular pathways. Their use in hematology led to vorinostat (SAHA) and romidepsin approval by FDA for the treatment of refractory cutaneous T-cell lymphomas. Preclinical and preliminary clinical results show a promising antineoplasic activity in most hematologic malignancies. This review will focus on the HDACi recent developments and current investigations, highlighted by recent communications.     

Therapy-related acute myeloid leukemia: role of DNA repair

The survival improvement of patients treated with chemotherapy or radiotherapy for malignancies are increasing therapy-related acute myeloid leukemia (t-AML). It was thought to be the direct consequence of genetic events induced by such treatments. We here review the mechanisms of specific chemotherapy-related DNA damage inducing the chromosomal or genomic abnormalities characteristic of t-AML. We also focus on how such aberrations could initiate or participate to leukemogenesis. However, only a part of patients exposed to cytotoxic therapy is developing t-AML, suggesting that some genetic predisposition may be involved such as polymorphisms in genes related to DNA repair.