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All-trans retinoic acid (ATRA) has only limited single agent activity in AML without the PML-RARα fusion (non-M3 AML). In search of a sensitizing strategy to overcome this relative ATRA resistance, we investigated the potency of the HDAC class-I selective inhibitor entinostat in AML cell lines Kasumi-1 and HL-60 and primary AML blasts. Entinostat alone induced robust differentiation of both cell lines, which was enhanced by the combination with ATRA. This “priming” effect on ATRA-induced differentiation was at least equivalent to that achieved with the DNA hypomethylating agent decitabine, and could overall be recapitulated in primary AML blasts treated ex vivo. Moreover, entinostat treatment established the activating chromatin marks acH3, acH3K9, acH4 and H3K4me3 at the promoter of the RARβ2 gene, an essential mediator of retinoic acid (RA) signaling in different solid tumor models. Similarly, RARβ2 promoter hypermethylation (which in primary blasts from 90 AML/MDS patients was surprisingly infrequent) could be partially reversed by decitabine in the two cell lines. Re-induction of the epigenetically silenced RARβ2 gene was achieved only when entinostat or decitabine were given prior to ATRA treatment. Thus in this model, reactivation of RARβ2 was not necessarily required for the differentiation effect, and pharmacological RARβ2 promoter demethylation may be a bystander phenomenon rather than an essential prerequisite for the cellular effects of decitabine when combined with ATRA. In conclusion, as a “priming” agent for non-M3 AML blasts to the differentiation-inducing effects of ATRA, entinostat is at least as active as decitabine, and both act in part independently from RARβ2. Further investigation of this treatment combination in non-M3 AML patients is therefore warranted, independently of RARβ2 gene silencing by DNA methylation. [ABSTRACT FROM AUTHOR]

Background : Dermatophytes are common in both developed and developing countries, the species involved and the resulting clinical entities vary geographically. Aim of study: To determine public health importance of dermatophytes with special regard to the distribution of the zoophilic species among the examined human cases. Methods: Patient specimens (dermatophytosis-like lesions) were mycologi-cally examined using direct microscopic and cultural examinations. Results: The overall dermatophyte infection rates among the examined patients (260) were 81.5% and 61.9% by direct microscopic and cultural examinations, respectively. A total of 161 dermatophyte isolates were obtained from culturally positive human specimens. The most common isolated species were Trichophyton violaceum (60, 37.3 %) and Microsporum canis (46, 28.6%), followed by Trichophyton rubrum (20, 12.4%), Trichophyton tonsurans (16, 9.9%) and Trichophyton mentagrophytes (11, 6.8%). The less frequently isolated species were Trichophyton verrucosum (3, 1.9%), Epidermophyton floccosum (3, 1.9%), Microsporum gypseum (1, 0.6%) and Microsporum audouinii (1, 0.6%). The current study further revealed that out of 161 culturally positive patients, 61 (37.9%) had contact with pet animals, 6 (3.7%) had contact with farm animals, 7 (4.3%) had a history of rodent presence in or around their home and 87 (54%) had no contact with animals. Conclusions and recommendations: Although the anthropophilic species dominated the aetiology of human dermatophytosis in present study, the zoophilic species represented nearly one third of the totally obtained isolates, with the most important organisms being M. canis, T. mentagrophytes var. mentagrophytes and T verrucosum. These findings indicate the necessity of human beings taking appropriate control measures when they are in contact with animals. [ABSTRACT FROM AUTHOR]