Malignant progression in cancer requires populations of tumor-initiating cells (TICs

Summary Background Nonsteroidal anti‐inflammatory drugs (NSAIDs) act as cofactors worsening the allergic reactions induced by food allergens. Aim The aim of this study was to evaluate the effect of both lysine acetylsalicylate (L‐ASA) (non‐selective cyclooxygenase (COX) inhibitor) and valdecoxib (selective COX‐2 inhibitor) in basophils activated by peach lipid transfer protein (Pru p 3) in patients with food‐dependent NSAID‐induced anaphylaxis (FDNIA). Methods Twenty Pru p 3‐allergic patients with FDNIA group, eleven peach anaphylaxis not exacerbated by NSAIDs (no‐NSAID group) and 5 healthy volunteers were recruited. Basophil activation (BA) was measured as expression of CD63 (Flow2CAST™; Bühlmann®), after stimulation with Pru p 3, both alone and in combination with L‐ASA (1.13, 3.38 and 6.78 mm) or valdecoxib (0.87, 7.8 and 31.25 μm). Results Basophils from no‐NSAID group were significantly more reactive and sensitive to Pru p 3 than those from the FDNIA group. In both groups, an increase in BA was observed when basophils were exposed to Pru p 3 and L‐ASA. In the FDNIA group, valdecoxib partially terminates the BA induced by Pru p 3, whereas in the no‐NSAID group, a dual effect was observed depending on the concentration tested. Conclusions This study indicates that subjects with food‐induced anaphylaxis differ from FDNIA subjects in the higher reactivity and sensitivity of their basophils to allergen challenge. We have shown a direct effect of NSAIDs on basophils using a human model of FDNIA. Our results also suggest that selective COX2 inhibitors might be a safe alternative. BA test may be a useful tool in the study of the pathogenic mechanism of the cofactor phenomenon.

The CDw50 differentiation antigen is defined by 101-1D2 and 140-11 monoclonal antibodies (mAb), both produced and characterized in our laboratory. This molecule is broadly expressed on hematopoetic cells but not on other cells. In this report we show that these 2 mAb recognize different epitopes of the same molecule, which are resistant to neuraminidase and proteases. We also demonstrate that the CDw50 antigen is expressed on thymocytes and T lymphocytes as an N-glycosylated glycoprotein monomer with a relative molecular weight (Mr) of 130,000 daltons with intrachain disulfide bonds, and that this molecule is resistant to treatment with phosphatidylinositol (PI) phospholipase C and therefore probably not PI-anchored to the membrane. CDw50 is a poorly or non-constitutively phosphorylated molecule that becomes phosphorylated by treatment with phorbol 12-myristate 13-acetate (PMA) of peripheral blood mononuclear cells (PBMC). The addition of affinity-purified CDw50 mAb inhibits primary mixed lymphocyte culture (MLC) but not secondary MLC, cytotoxicity or proliferation induced by mitogens. The inhibition of alloreactivity is mediated at the level of both responding and stimulator cells.

Eleven AJCC stage IV melanoma patients with progressive disease after treatment with biochemotherapy were treated with autologous dendritic cells pulsed with heterologous tumor cell lysates. The vaccine used mature DCs (CD1a+++, CD40++, CD80++, CD83+, and CD86+++) generated from peripheral blood monocytes in the presence of GM-CSF and IL-4. After 7 days, DCs were matured with a defined cocktail of cytokines (IL-1+IL-6+TNF-alpha+PGE2) and simultaneously pulsed with lysates of heterologous melanoma cell lines, for 2 days. A total of 4 x 10(6) DCs was injected monthly under ultrasound control in an inguinal lymph node of normal appearance. The study was closed when all patients died as a consequence of tumor progression. No sign of toxicity was observed during the study. One patient experienced a partial response lasting 5 months, and two patients showed a mixed response which lasted 3 months. The median survival of the whole group was 7.3 months (range 3-14 months). This vaccination program had specific antitumoral activity in highly pretreated and large tumor burden stage IV melanoma patients and was well tolerated. The clinical responses and the median survival of the group of patients, together with the low toxicity of our DC vaccine, suggest that this approach could be applied to earlier AJCC stage IV melanoma patients.