Targeting 11q23 positive acute leukemia cells with high molecular weight-melanoma associated antigen-specific monoclonal antibodies

Background  Acute leukemia with 11q23 aberrations is associated with a poor outcome with therapy. The lack of efficacy of conventional therapy has stimulated interest in developing novel strategies. Recent studies have shown that 11q23-positive acute leukemia cells express the high molecular weight-melanoma associated antigen (HMW-MAA). This tumor antigen represents a useful target to control growth of human melanoma tumors in patients and in severe combined immunodeficient (SCID) mice, utilizing antibody-based immunotherapy. This effect appears to be mediated by inhibition of the HMW-MAA function such as triggering of the focal adhesion kinase/proline-rich tyrosine kinase 2 (Pyk2) pathways. Therefore, in this study we tested whether HMW-MAA-specific monoclonal antibodies (mAb) could inhibit growth of 11q23-positive leukemia cells in SCID mice. Methods  HMW-MAA-specific mAb were tested for their ability to inhibit the in vitro proliferation of an 11q23-positive acute myeloid leukemia (AML) cell line and blasts from four patients with 11q23 aberrations and their in vivo growth in subcutaneous and disseminated xenograft models. Results  The HMW-MAA-specific mAb did not affect in vitro proliferation although they down-regulated phosphorylated (P) Pyk2 expression. Furthermore, the mAb enhanced the in vitro anti-proliferative effect of cytarabine. In vivo the mAb inhibited the growth of leukemic cells in a dose-dependent fashion. However, the difference did not reach statistical significance. No effect was detected on P-Pyk2 expression. Furthermore, HMW-MAA-specific mAb in combination with cytarabine did not improve tumor inhibition. Lastly, the combination of two mAb which recognize distinct HMW-MAA determinants had no detectable effect on survival in a disseminated xenograft model. Conclusions  HMW-MAA-specific mAb down-regulated P-Pyk2 expression and enhanced the anti-proliferative effect of cytarabine in vitro, but had no detectable effect on survival or growth of leukemia cells in vivo. Whether the HMW-MAA-specific mAb can be used as carriers of toxins or chemotherapeutic agents against 11q23-acute leukemia remains to be determined.     

Relationship between HLA class I antigen processing machinery component expression and the clinicopathologic characteristics of bladder carcinomas

Purpose  

The goal of this study was to analyze protein expression of antigen processing machinery (APM) components in bladder carcinoma (BC), and to assess the clinical significance of defects in their expression.     

Sensibilisation des larves deMelolontha melolontha L. a la mycose aBeauveria tenella par une infection préalable aBacillus popilliae

Résumé Les effets sur les vers blancs de l'infection successive par la maladie laiteuse àBacillus popilliae ?Melolontha? puis par la mycose àBeauveria tenella ont été étudiés en élevage, à 20°C, chez des larves du troisième stade. Un effet stimulateur réciproque des deux affections a été mis en évidence d'après les taux de morbidité et de mortalité ainsi que d'après les délais d'évolution de chaque maladie. Ce synergisme met en relief l'importance de l'état physiologique de l'insecte dans le succès de l'intervention d'un pathogène.

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Summary The effects on white grubs of successive infections by the milky disease (Bacillus popilliae ?Melolontha?) and then with the mycosis byBeauveria tenella have been studied in the laboratory at 20°C on third instar larvae. A mutual stimulative effect of these diseases is obvious from the morbidity and mortality rates as also from the development time of each disease. This synergism shows the importance of the physiological state of the insect to the success of the pathogen.

     

Selective in vitro toxicity of purothionin conjugated to the monoclonal antibody 225.28S to a human high-molecular-weight melanoma-associated antigen

The toxic agent purothionin was conjugated to the monoclonal antibody 225.28S to a human high-molecular-weight melanoma-accociated antigen. The toxic conjugate displayed in vitro toxicity to cultured human Colo 38 melanoma cells as indicated by reduced uptake of 3H-thymidine following a 24-h incubation and loss of cell viability following a 7-day incubation. The effect is dose-dependent and is specific since addition of the toxic conjugate to a cultured Raji B lymphoid cells did not affect their 3H-thymidine uptake or their viability.     

Finding flexible patterns in a text: an application to three-dimensional molecular matching

Finding certain regularities in a text is an important problemin many areas, e.g. in the analysis of biological moleculessuch as nucleic acids or proteins. In the latter case, the textmay be sequences of amino acids or a linear coding of three-dimensionalstructures, and the regularities then correspond to lexicalor structural motifs common to two, or more, proteins. We firstrecall an earlier algorithm that found these regularities ina flexible way. Then we introduce a generalized version of thisalgorithm designed for the particular case of protein three-dimensionalstructures, since these structures present a few peculiaritiesthat make them computationally harder to process. Finally, wegive some applications of our new algorithm on concrete examples     

Effects ofp-chlorophenylalanine on cortical monoamines and on the activity of noradrenergic neurons

The catecholamines noradrenaline, dopamine, adrenaline, the indoleamine 5-hydroxy-tryptamine (5-HT; serotonin), and some of their major metabolites were assayed, using high performance liquid chromatography (HPLC), in the neocortex of normal rats as well as in animals in which 5-HT synthesis had been inhibited withp-chlorophenylalanine. Besides important depletions in serotonin and in 5-hydroxyindole-3-acetic acid, noradrenaline levels were significantly reduced, but the content in 3-methoxy-4-hydroxyphenylglycol was increased, indicating an augmented utilization of this amine. The levels of dopamine and 3-methoxytyramine were also reduced, although homovanillic acid and 3,4-dihydroxyphenylacetic acid levels remained constant. The spontaneous unitary activity of identified noradrenergic neurons in the Locus coeruleus was increased, indicating an hyperactivity of this system. These results can be interpreted in relation to functional interactions between the catecholamines and serotonin; i.e.: a decrease in endogenous serotonin results in the loss of a negative feedback control of noradrenaline release.Special Issue dedicated to Prof. Eduardo De Robertis.     

Susceptibility of Oryctes rhinoceros adults to Metarrhizium anisopliae

The susceptibility of Oryctes rhinoceros adults to infections due to entomopathogenic fungi (Beauveria bassiana, Beauveria tenella, Metarrhizium anisopliae, Paecilomyces fumoso-roseus, and Spicaria rileyi) was studied by spraying titrated spores suspensions on the insect integument. The results show a definite susceptibility of the adults to Metarrhizium anisopliae strains of the major type only.