HLA-B8 association with late-stage melanoma – an immunological lesson?

<p>Abstract</p> <p>Background</p> <p>Differences in HLA allele frequencies between the diseased and healthy populations may signify efficient immune responses, a notion that has been successfully tested for infectious diseases or for association with genetic elements involved in a distinct type of immunity. This retrospective study is intended to detect differences in MHC class I carrier frequencies of advanced melanoma patients compared to healthy bone marrow donors.</p> <p>Methods</p> <p>The HLA-A and -B carrier frequencies of 748 stage IV melanoma patients retrieved from serotyping at 6 different centers in Germany were compared using a chi-square test to 13,386 fully HLA typed bone marrow donors registered in the German national bone marrow donor registry.</p> <p>Results</p> <p>The comparison of HLA carrier frequencies in advanced cancer patients with healthy bone marrow donors revealed a significant decrease in HLA-B8 carrier frequencies, which was also apparent in patients with advanced disease compared to patients with loco-regional disease.</p> <p>Conclusion</p> <p>The data suggest that protective immune responses restricted to distinct MHC class I molecules may be operational in a subset of melanoma patients, which is the prerequisite for a large scale screen for the corresponding epitopes. Alternatively, the known association of the ancestral haplotype HLA-A1, -B8 and -DR3 with genetic elements such as distinct TNF-α alleles might have a protective effect on disease progression. In any case, identification of the cause of protection within this patient subset might lead to a significant improvement in the efficacy of current immunotherapeutic approaches.</p

A novel attenuated replication-competent adenovirus for melanoma therapy.

To generate a replication-competent adenovirus (Ad) with specificity for melanoma, we constructed a tissue-specific promoter restricting E1A expression to melanoma cells. The combination of four copies of a mouse tyrosinase enhancer element (TE) fused to the human tyrosinase promoter (TP) yielded up to 2000-fold higher luciferase reporter activity in tyrosinase-expressing melanoma cells than in nonmelanoma cells. Insertion of the composite TETP construct upstream of the E1A gene was combined with deleting as far as possible the intertwined endogenous Ad enhancer/promoter (EP). The resulting AdDeltaEP-TETP vector, also deleted for the E3 region, was found to replicate in tyrosinase-positive melanoma cells, such as SK-Mel23 as efficiently as wild-type Ad5, but at a more than 50-fold reduced level in nonmelanoma tumour cells and primary human cells. Injection of AdDeltaEP-TETP into xenotransplanted melanomas, but not into HeLa-derived tumours led to long-lasting tumour regression in nude mice. This AdDeltaEP-TETP virus might be useful for the treatment of accessible lesions in advanced melanoma patients

The alpha v beta 5 integrin of hematopoietic and nonhematopoietic cells is a transduction receptor of RGD-4C fiber-modified adenoviruses

Epithelial and endothelial cells expressing the primary Coxsackie virus B adenovirus (Ad) receptor (CAR) and integrin coreceptors are natural targets of human Ad infections. The fiber knob of species A, C, D, E and F Ad serotypes binds CAR by mimicking the CAR-homodimer interface, and the penton base containing arginine-glycine aspartate (RGD) motifs binds with low affinity to alphav integrins inducing cell activation. Here, we generated seven different genetically modified Ad vectors with RGD sequences inserted into the HI loop of fiber knob. All mutants bound and infected CAR and alphav integrin-positive epithelial cells with equal efficiencies. However, the Ads containing two additional cysteines, both N and C terminals of the RGD sequence (RGD-4C), were uniquely capable of transducing CAR-less hematopoietic and nonhematopoietic human tumor cell lines and primary melanoma cells. Both binding and transduction of RGD-4C Ad were blocked by soluble RGD peptides. Flow cytometry of cell surface integrins and virus binding to CAR-less cells in the presence of function-blocking anti-integrin antibodies indicated that the alphavbeta5 integrin, but not alphavbeta3, alphaIIbbeta3 or beta1, alpha5 or alpha6-containing integrins served as a functional transduction receptor of the RGD-4C Ads. However, in cells with low levels of alphavbeta5 integrin, the function-blocking anti-alphavbeta5 antibodies were not effective, unlike soluble RGD peptides. Collectively, our data demonstrate that the alphavbeta5 integrin is a functional transduction receptor of RGD-4C Ads in the absence of CAR, and that additional RGD receptors are targets of these viruses. The RGD-4C vectors further extend the tropism of Ads towards potential human therapie

Acute Exercise and Motor Memory Consolidation: The Role of Exercise Intensity

A single bout of high intensity aerobic exercise (~90% VO2peak) was previously demonstrated to amplify off-line gains in skill level during the consolidation phase of procedural memory. High intensity exercise is not always a viable option for many patient groups or in a rehabilitation setting where low to moderate intensities may be more suitable. The aim of this study was to investigate the role of intensity in mediating the effects of acute cardiovascular exercise on motor skill learning. We investigated the effects of different exercise intensities on the retention (performance score) of a visuomotor accuracy tracking task. Thirty six healthy male subjects were randomly assigned to one of three groups that performed either a single bout of aerobic exercise at 20 min post motor skill learning at 45% (EX45), 90% (EX90) maximal power output (Wmax) or rested (CON). Randomization was stratified to ensure that the groups were matched for relative peak oxygen consumption (ml O2/min/kg) and baseline score in the tracking task. Retention tests were carried out at 1 (R1) and 7 days (R7) post motor skill learning. At R1, changes in performance scores were greater for EX90 compared to CON (p<0.001) and EX45 (p = 0.011). The EX45 and EX90 groups demonstrated a greater change in performance score at R7 compared to the CON group (p = 0.003 and p<0.001, respectively). The change in performance score for EX90 at R7 was also greater than EX45 (p = 0.049). We suggest that exercise intensity plays an important role in modulating the effects that a single bout of cardiovascular exercise has on the consolidation phase following motor skill learning. There appears to be a dose-response relationship in favour of higher intensity exercise in order to augment off-line effects and strengthen procedural memory