The allogeneic graft-versus-cancer effect

Allogeneic haematological stem cell transplantation (HSCT) has developed into immunotherapy. Donor CD4⁺, CD8⁺ and natural killer (NK) cells have been reported to mediate graft- versus -leukaemia (GVL) effects, using Fas-dependent killing and perforin degranulation to eradicate malignant cells. Cytokines, such as interleukin-2, interferon-γ and tumour necrosis factor-α potentiate the GVL effect. Post-transplant adoptive therapy of cytotoxic T-cells (CTL) against leukaemia-specific antigens, minor histocompatibility antigens, or T-cell receptor genes may constitute successful approaches to induce anti-tumour effects. Clinically, a significant GVL effect is induced by chronic rather than acute graft- versus -host disease (GVHD). An anti-tumour effect has also been reported for myeloma, lymphoma and solid tumours. Reduced intensity conditioning enables HSCT in older and disabled patients and relies on the graft- versus -tumour effect. Donor lymphocyte infusions promote the GVL effect and can be given as escalating doses with response monitored by minimal residual disease. A high CD34⁺ cell dose of peripheral blood stem cells increases GVL. There is a balance between effective immunosuppression, low incidence of GVHD and relapse. For instance, T-cell depletion of the graft increases the risk of relapse. This paper reviews the current knowledge in graft- versus -cancer effects. Future directions, such as immunotherapy using leukaemia-specific CTLs, allo-depleted T-cells and suicide gene manipulated T-cells, are presented.     

No influence of brain-derived neurotrophic factor (BDNF) polymorphisms on treatment response in a naturalistic sample of patients with major depression

The role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of major depressive disorder (MDD) remains to be elucidated. Recent post hoc analyses indicated a potential association of three polymorphisms in the BDNF gene with worse treatment outcome in patients with the subtype of melancholic depression. We aimed at replicating these findings in a German naturalistic multicenter follow-up. Three polymorphisms in the BDNF gene (rs7103411, rs6265 (Val66Met) and rs7124442) were genotyped in 324 patients with MDD and 470 healthy controls. We applied univariate tests and logistic regression models stratifying for depression subtype and gender. The three polymorphisms were not associated with MDD as diagnosis. Further, no associations were found in univariate tests. With logistic regression, we only found a tendency towards an association of the rs6265 (Val66Met) polymorphism with overall response to treatment (response rates: GG (val/val) < GA (val/met) < AA (met/met); p = 0.0129) and some gender differences for the rs6265 (Val66Met) and rs7103411 polymorphisms. Treatment outcome stratified for subtypes of depression did not differ significantly between the investigated polymorphisms or using haplotype analyses. However, results showed a tendency towards significance. At this stage, we cannot support an influence of these three polymorphisms. Further studies in larger patient samples to increase sample sizes of subgroups are warranted.     

Impact of Modified Frozen Elephant Trunk Procedure on Downstream Aorta Remodeling in Acute Aortic Dissection: CT Scan Follow-Up

World Journal of Surgery - The aim was to evaluate the impact of a modified frozen elephant trunk procedure (mFET) on remodeling of the downstream aorta following acute aortic dissections. Over a...     

Malaria-specific transgenic CD4(+) T cells protect immunodeficient mice from lethal infection and demonstrate requirement for a protective threshold of antibody production for parasite clearance

T cells are important in the immune response to malaria, both for their cytokines and their help for antibody production. To look at the relative importance of these roles, a T-cell receptor (TCR) transgenic mouse has been generated carrying a TCR specific for an epitope of the merozoite surface protein 1 (MSP-1) of the malaria parasite, Plasmodium chabaudi. In adoptive transfer experiments, malaria-specific CD4(+) T cells expand and produce interferon gamma (IFN-gamma) early in infection, but the population contracts quickly despite prolonged persistence of the parasite. MSP-1-specific CD4(+) cells can protect immunodeficient mice from lethal infection; however, the parasite is only completely cleared in the presence of B cells showing that T helper cells are critical. Levels of malaria-specific antibody and the speed of their production clearly correlate with the time of resolution of infection, indicating that a critical threshold of antibody production is required for parasite clearance. Furthermore, T cells specific for a shed portion of MSP-1 are able to provide help for antibody to the protective region, which remains bound to the infected erythrocyte, suggesting that MSP-1 has all of the components necessary for a good vaccine.     

EEG network connectivity changes in mild cognitive impairment — Preliminary results

Resting state EEGs were compared between patients with amnestic subtype of mild cognitive impairment (aMCI) and matched elderly controls at two times over a one year period. The study aimed at investigating the role of functional connectivity between and within different brain regions in relation to the progression of cognitive deficit in MCI. The EEG was recorded in two sessions during eyes closed and eyes open resting conditions. Functional brain connectivity was investigated based on the measurement of phase synchronization in different frequency bands. Delta and theta synchronization characteristics indicated decreased level of local and large-scale connectivity in the patients within the frontal, between the frontal and temporal, and frontal and parietal brain areas which was more pronounced 1 year later. As a consequence of opening the eyes connectivity in the alpha1 band within the parietal lobe decreased compared to the eyes closed condition but only in the control group. The lack of alpha1 band reactivity following eye opening could reliably differentiate patients from controls. Our preliminary results support the notion that the functional disconnection between distant brain areas is a characteristic feature of MCI, and may prove to be predictive in terms of the progression of this condition.