Putative association between the -1415 T/C polymorphism of spermidine/spermine N1-acetyltransferase (SSAT1) gene and alcohol use disorders in women and men

Background: The activity of N-methyl-D-aspartate (NMDA) glutamate receptor, which responds to the levels of polyamines, modifies the neurotoxicity caused by ethanol. We aimed to investigate if the functionality of the spermidine/spermine N1-acetyltransferase (SSAT1) gene could be associated with a differential risk for alcoholism. Methods: We studied a sample of 586 subjects: 104 alcohol-dependent patients, 273 patients with psychiatric disorders but without substance dependence, and 209 healthy controls. After gender stratification, the allele frequency distribution of the SSAT1 gene was compared between these three groups. Results: In females, the TC genotype was significantly more frequent in alcohol-dependent patients than in non-alcohol-dependent psychiatric controls (χ^2?=?7.509 df?=?2, p?=?0.023). A trend was found when alcohol-dependent females were compared with the healthy control group (χ^2?=?4.897 df?=?2, p?=?0.086). No statistical differences were found among the males. Discussion and conclusion: Gender differences in the regulation of SSAT1 gene expression may possibly be due to gender-specific effects of stress, ethanol toxicity, and/or polyamines levels. Further studies are needed to confirm our findings.     

The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

Background We have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reduce-graft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting. DESIGN AND METHODS: We evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease. RESULTS: The combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN γ, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft-versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. Conclusions The current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft-versus-host disease while maintaining the graft-versus-leukemia effect.     

The combination of bortezomib and dexamethasone is an efficient therapy for relapsed/refractory scleromyxedema: a rare disease with new clinical insights

Scleromyxedema (SM) is a rare primary cutaneous inflammatory mucinosis characterised by papular mucinosis, monoclonal gammopathy and extracutaneous involvement. Most therapeutic options have failed in SM but high-dose therapy followed by autologous peripheral blood stem cell transplantation (APBSCT) appears to be highly effective, although SM normally relapses. We report the case of a 29-yr-old patient with severe SM who achieved stringent complete response with Bortezomib plus Dexamethasone after an early relapse subsequent to a high-dose melphalan regimen followed APBSCT. It is of particular note that dermatological lesions responded to both therapies before M-component modifications, suggesting that SM is independent of M-component characteristics. However, treatment should be directed towards the underlying plasma cell malignancy with typical anti-myeloma agents.