Bacteria preparations of HDAC4 have weak but measurable deacetylase activity, the low efficiency can be restored either by mutation of an active site histidine to tyrosine, or by the use of a ...non-acetylated lysine substrate.
It has been widely debated whether class IIa HDACs have catalytic deacetylase activity, and whether this plays any part in controlling gene expression. Herein, it has been demonstrated that class IIa HDACs isolated from mammalian cells are contaminated with other deacetylases, but can be prepared cleanly in
Escherichia coli. These bacteria preparations have weak but measurable deacetylase activity. The low efficiency can be restored either by: mutation of an active site histidine to tyrosine, or by the use of a non-acetylated lysine substrate, allowing the development of assays to identify class IIa HDAC inhibitors.
Skin cancer is the most common malignancy and can be treated in various ways. One treatment modality is Mohs micrographic surgery. Due to the increasing incidence of skin cancer in the last decades, ...there is a need for improvement of the Mohs technique to optimize its effectiveness.
The aim of this study was to evaluate the use of dermoscopy to guide demarcation of Mohs micrographic surgery margins and ascertain whether this method can reduce operative time and, therefore, reduce surgical morbidity and cost.
The sample comprised 44 patients who underwent Mohs micrographic surgery, allocated into two groups: the control group and the intervention group. In the latter, surgical margins were guided by dermoscopy.
There were no statistically significant differences between the two groups by chi-square analysis (p = 0.399).
Although outcomes were similar in the two groups, demonstrating that dermoscopy does not help in the demarcation of surgical margins for Mohs micrographic surgery, the study provides a practical proposal for improvement of the Mohs technique.
High-throughput screening assays with multiple readouts enable one to monitor multiple assay parameters. By capturing as much information about the underlying biology as possible, the detection of ...true actives can be improved. This report describes an extension to standard luciferase reporter gene assays that enables multiple parameters to be monitored from each sample. The report describes multiplexing luciferase assays with an orthogonal readout monitoring cell viability using reduction of resazurin. In addition, this technical note shows that by using the luciferin substrate in live cells, an assay time course can be recorded. This enables the identification of nonactive or unspecific compounds that act by inhibiting luciferase, as well as compounds altering gene expression or cell growth.
Dyschromatosis symmetrica hereditaria (DSH), also known as reticulated acropigmentation of Dohi, is an autosomal dominant disease with high penetrance, characterized by hypo- and hyperpigmented ...macules of varying sizes on the dorsal of the extremities with reticulated pattern. This paper presents a female patient with typical dermatological lesions, but only diagnosed in adulthood. It is necessary to perform differential diagnosis with other pigmentary disorders. This entity is not very common in South America, and the vast majority of cases were described in Japanese population. Since it is a benign disease, it is important to be aware of this diagnosis in order to establish the correct conduct for these patients.
5-Aryl-2-(trifluoroacetyl)thiophenes were identified as a new series of class II HDAC inhibitors (HDACi). Further development of this new series led to compounds such as 6h, a potent inhibitor of ...HDAC4 and HDAC6 (HDAC4 WT IC50 = 310 nM, HDAC6 IC50 = 70 nM) that displays 40-fold selectivity over HDAC1 and improved stability in HCT116 cancer cells (t 1/2 = 11 h). Compounds 6h and 2 show inhibition of α-tubulin deacetylation in HCT116 cells at 1 μM concentration and antiproliferation effects only at concentrations where inhibition of histone H3 deacetylation is observed.
The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel ...agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway.
Introdução: Nas últimas quatro décadas a dermatologia transformou-se, de especialidade puramente clínica, em especialidade clinicocirúrgica. O dermatologista passou a realizar, além da diagnose e do ...tratamento clínico,o tratamento cirúrgico das afecções e neoplasias cutâneas,a correção de cicatrizes e procedimentos cutâneos necessários para melhora da aparência individual. Objetivo: Demonstrar a mudança do perfil das atividades do Serviço de Dermatologia do HC-UFPR no período estudado. Material e métodos: Foi realizada a revisão sistemática dos registros próprios do Ambulatório de Dermatologia, além dos dados fornecidos pelo Sistema de Estatística e Planejamento do HC-UFPR entre 2002 e 2007. Resultados: Houve aumento relativo de 16% no número de procedimentos cirúrgicos no período estudado, com aumento também de sua complexidade, passando o índice de exerese de lesões benignas em relação ao da exerese de tumores malignos de 2,25:1 em 2002 para 1,04:1 em 2007. Quanto aos procedimentos cosmiátricos, a realização de peelings ampliou-se 74% no período estudado. O preenchimento e aaplicação de toxina botulínica passaram de procedimentos esporádicos em 2002 para procedimentos de rotina, com 3,33 preenchimentos/mês e três aplicações toxina/mês. Conclusões: Os dados obtidos demonstram objetivamente a transformação das atividades do Serviço de Dermatologia do HC-UFPR, de principalmente clínicas, para clinicocirúrgicas, com aumento da complexidade dos procedimentos realizados no treinamento do residente de dermatologia, em concordância com a evolução da especialidade no Brasil e no mundo.
The evolution of a novel series of HDAC inhibitors containing an unusual ketone zinc binding group is described. SAR studies resulted in optimization to potent, low molecular weight, selective, ...non-hydroxamic acid HDAC inhibitors.
Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in clinical trials. A structurally novel series of HDAC inhibitors based on the natural cyclic tetrapeptide Apicidin is described. Selected screening of the sample collection looking for
L-2-amino-8-oxodecanoic acid (
L-Aoda) derivatives identified a small acyclic lead molecule
1 with the unusual ketone zinc binding group. SAR studies around this lead resulted in optimization to potent, low molecular weight, selective, non-hydroxamic acid HDAC inhibitors, equipotent to current clinical candidates.
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