Impact of Variants in the ATIC and ARID5B Genes on Therapeutic Failure with Imatinib in Patients with Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm derived from the balanced reciprocal translocation of chromosomes 9 and 22 t (9q34 and 22q11), which leads to the formation of the Philadelphia chromosome and fusion of the BCR-ABL genes. The first-line treatment for CML is imatinib, a tyrosine kinase inhibitor that acts on the BCR-ABL protein. However, even though it is a target-specific drug, about 25% of patients do not respond to this treatment. The resistance mechanisms involved in this process have been investigated and studies have shown that germinal alterations can influence this mechanism. The aim of this work was to investigate 32 polymorphisms in 24 genes of carcinogenic pathway to verify the influence of these genetic variants on the response to treatment with imatinib. Our results demonstrated that individuals with the recessive GG genotype for the rs2372536 variant in the ATIC gene are approximately three times more likely to experience treatment failure with imatinib (p = 0.045, HR = 2.726, 95% CI = 0.9986-7.441), as well as individuals with the TT genotype for the rs10821936 variant in the ARID5B gene, who also have a higher risk for treatment failure with imatinib over time (p = 0.02, HR = 0.4053, IC 95% = 0.1802-0.911). In conclusion, we show that variants in the ATIC and ARIDB5 gene, never screened in previous studies, could potentially influence the therapeutic response to imatinib in patients treated for CML.

Decrease of serum adenine nucleotide hydrolysis in an irritant contact dermatitis mice model: potential P2X7R involvement.

Extracellular adenosine 5'-triphosphate (ATP) has significant effects on a variety of pathological conditions and it is the main physiological agonist of P2X7 purinergic receptor (P2X7R). It is known that ATP acting via purinergic receptors plays a relevant role on skin inflammation, and P2X7R is required to neutrophil recruitment in a mice model of irritant contact dermatitis (ICD).The present study investigated the effects of chemical irritant croton oil (CrO) upon ATP, ADP, and AMP hydrolysis in mice blood serum, and the potential involvement of P2X7R. The topical application CrO induced a decrease on soluble ATP/ADPase activities (~50 %), and the treatment with the selective P2X7R antagonist, A438079, reversed these effects to control level. Furthermore, we showed that CrO decreased cellular viability (52.6 % ± 3.9) in relation to the control and caused necrosis in keratinocytes (PI positive cells). The necrosis induced by CrO was prevented by the pre-treatment with the selective P2X7R antagonist A438079. The results presented herein suggest that CrO exerts an inhibitory effect on the activity of ATPDase in mouse serum, reinforcing the idea that ICD has a pathogenic mechanism dependent of CD39. Furthermore, it is tempting to suggest that P2X7R may act as a controller of the extracellular levels of ATP.

Desaminases de DNA e a infecção por HPV: da restrição viral à progressão ao câncer cervical

As proteínas APOBEC3 (A3) pertencem a uma família de citidinas desaminases e apresentam a capacidade de inserir mutações em sequências de DNA e/ou RNA. Estas enzimas apresentam um importante papel na resposta imune inata antiviral. Recentemente, um dos membros desta família, A3B, foi identificado como uma importante fonte de mutagênese em diversos tipos de câncer. De forma interessante, o câncer cervical e o câncer de cabeça e pescoço, ambos associados à infecção por HPV, estão entre os tipos de câncer que apresentam os níveis mais altos de expressão de A3B e as maiores proporções de mutações em citidinas no contexto preferencial desta enzima. Assim, o objetivo deste estudo é o de investigar a relação entre a infecção pelo HPV e a super expressão de A3B, bem como seus possíveis papéis no desenvolvimento do câncer cervical e na restrição viral. Neste trabalho, demonstramos que os níveis de RNAm e a atividade enzimática de A3B são incrementados em linhagens de queratinócitos após a transfecção do genoma viral, e que este efeito é anulado na ausência da expressão da oncoproteína viral E6. Experimentos de transdução demonstraram que a expressão de E6 é suficiente para induzir a super expressão de A3B e queE6´s de HPVs de alto risco são capazes de induzir níveis mais altos de A3B quando comparado com E6´s de baixo risco ou de tipos não-carcinogênicos. Experimentos de nocaute em linhagens celulares HPV-positivas mostraram que E6 endógeno é necessário para a super expressão de A3B. Em concordância com os dados encontrados em cultura células, análises realizadas utilizando informações de amostras de câncer de cabeça e pescoço disponíveis em bancos de dados públicos demonstram que níveis de A3B são mais altos em...

The APOBEC3 (A3) proteins belong to a family of cytidine deaminases and have the capacity of editing DNA and/or RNA sequences. These enzymes have an important role in antiviral innate immune responses. Recently one member of this family, A3B, was identified as an important source of mutagenesis in a variety of human cancers. Interestingly, cervical and head/neck cancers, both known to be HPV-associated, are among the tumor types displaying the highest A3B expression levels and cytosine mutational loads in A3B-preferredtrinucleotide contexts. Thus, the aim of this study is to investigate the correlation of HPV infection and A3B overexpression, as well as its possible role on the development of cervicalcancer and on viral restriction. Here we demonstrate that the mRNA levels and the enzymatic activity of A3B are increased in keratinocytes transfected with a viral genome, and that thiseffect is abrogated in the absence of the E6 viral oncoprotein. Transduction experiments showed that the E6 oncoprotein alone was sufficient to cause A3B upregulation, and a panel of high-risk E6 proteins triggered higher A3B levels than did a panel of low-risk or noncancer E6 proteins. Knockdown experiments in HPV-positive cell lines showed that endogenous E6 is required for A3B upregulation. Analyses of publicly available head/neck cancer data further support this relationship, as A3B levels are higher in HPV-positive cancers than in HPV negative cancers. Considering the antiviral role of the APOBEC proteins, we also investigatedtheir role on restriction of HPV infection. In order to do this, a panel of 293T cellsoverexpressing different APOBEC proteins was challenged with HPV particles carrying a plasmid expressing GFP...

Pyrimidine salvage pathway in Mycobacterium tuberculosis.

The causative agent of tuberculosis (TB), Mycobacterium tuberculosis, infects one-third of the world population. TB remains the leading cause of mortality due to a single bacterial pathogen. The worldwide increase in incidence of M. tuberculosis has been attributed to the high proliferation rates of multi and extensively drug-resistant strains, and to co-infection with the human immunodeficiency virus. There is thus a continuous requirement for studies on mycobacterial metabolism to identify promising targets for the development of new agents to combat TB. Singular characteristics of this pathogen, such as functional and structural features of enzymes involved in fundamental metabolic pathways, can be evaluated to identify possible targets for drug development. Enzymes involved in the pyrimidine salvage pathway might be attractive targets for rational drug design against TB, since this pathway is vital for all bacterial cells, and is composed of enzymes considerably different from those present in humans. Moreover, the enzymes of the pyrimidine salvage pathway might have an important role in the mycobacterial latent state, since M. tuberculosis has to recycle bases and/or nucleosides to survive in the hostile environment imposed by the host. The present review describes the enzymes of M. tuberculosis pyrimidine salvage pathway as attractive targets for the development of new antimycobacterial agents. Enzyme functional and structural data have been included to provide a broader knowledge on which to base the search for compounds with selective biological activity.