Exploiting epigenetic targets to overcome taxane resistance in prostate cancer.

The development of taxane resistance remains a major challenge for castration resistant prostate cancer (CR-PCa), despite the effectiveness of taxanes in prolonging patient survival. To uncover novel targets, we performed an epigenetic drug screen on taxane (docetaxel and cabazitaxel) resistant CR-PCa cells. We identified BRPF reader proteins, along with several epigenetic groups (CBP/p300, Menin-MLL, PRMT5 and SIRT1) that act as targets effectively reversing the resistance mediated by ABCB1. Targeting BRPFs specifically resulted in the resensitization of resistant cells, while no such effect was observed on the sensitive compartment. These cells were successfully arrested at the G2/M phase of cell cycle and underwent apoptosis upon BRPF inhibition, confirming the restoration of taxane susceptibility. Pharmacological inhibition of BRPFs reduced ABCB1 activity, indicating that BRPFs may be involved in an efflux-related mechanism. Indeed, ChIP-qPCR analysis confirmed binding of BRPF1 to the ABCB1 promoter suggesting direct regulation of the ABCB1 gene at the transcriptional level. RNA-seq analysis revealed that BRPF1 knockdown affects the genes enriched in mTORC1 and UPR signaling pathways, revealing potential mechanisms underlying its functional impact, which is further supported by the enhancement of taxane response through the combined inhibition of ABCB1 and mTOR pathways, providing evidence for the involvement of multiple BRPF1-regulated pathways. Beyond clinical attributes (Gleason score, tumor stage, therapy outcome, recurrence), metastatic PCa databases further supported the significance of BRPF1 in taxane resistance, as evidenced by its upregulation in taxane-exposed PCa patients.

Aspergillus fumigatus mitogen-activated protein kinase MpkA is involved in gliotoxin production and self-protection.

Aspergillus fumigatus is a saprophytic fungus that can cause a variety of human diseases known as aspergillosis. Mycotoxin gliotoxin (GT) production is important for its virulence and must be tightly regulated to avoid excess production and toxicity to the fungus. GT self-protection by GliT oxidoreductase and GtmA methyltransferase activities is related to the subcellular localization of these enzymes and how GT can be sequestered from the cytoplasm to avoid increased cell damage. Here, we show that GliT:GFP and GtmA:GFP are localized in the cytoplasm and in vacuoles during GT production. The Mitogen-Activated Protein kinase MpkA is essential for GT production and self-protection, interacts physically with GliT and GtmA and it is necessary for their regulation and subsequent presence in the vacuoles. The sensor histidine kinase SlnASln1 is important for modulation of MpkA phosphorylation. Our work emphasizes the importance of MpkA and compartmentalization of cellular events for GT production and self-defense.

Is there a relationship between middle concha bullosa and ethmoid roof asymmetry? / Existe uma relação entre a concha média bolhosa e a assimetria do teto etmoidal?

Abstract Introduction The middle turbinate and ethmoid roof are intranasal structures and may have many anatomical variations. These structures, which serve as anatomical markers during functional sinus surgery, are important for preventing complications and performing a proper surgery. Knowledge of anatomical variations will increase surgical success and reduce complications. Objective We aimed to investigate the presence of asymmetry in the ethmoidal roof and anatomical variation in patients with and without concha bullosa. Methods In this study, the files of patients who underwent paranasal computed tomography between 2012 and 2018 were analyzed retrospectively. The patients were divided into two groups, as patients with and without concha bullosa. Differences between the two groups in terms of age, gender, septum deviation, ethmoid artery dehiscence, ethmoid roof asymmetry were examined. Results The 369 patients included in our study were divided into two groups; those with concha bullosa and those without concha bullosa. The mean age of the patients with concha bullosa was 36.1 ± 13.4 (min-max: 12-74) and the mean age of patients without concha bullosa was 37.5 ± 14.3 (min-max: 10-81). The ethmoid roof depths were compared between the two groups and a significant difference was observed (p < 0.001). The ethmoid roof depth was higher in the group with concha bullosa (p < 0.001). Conclusion The results of our study indicate that the ethmoidal roof tends to be higher in patients with middle concha bullosa.

Resumo Introdução A concha média e o teto etmoidal são estruturas intranasais e podem apresentar muitas variações anatômicas. Essas estruturas, usadas como marcadores anatômicos durante a cirurgia sinusal funcional, são importantes para evitar complicações e para a feitura adequada da cirurgia. O conhecimento das variações anatômicas aumenta o sucesso cirúrgico e reduz as complicações. Objetivo Investigar a presença de assimetria no teto etmoidal e variações anatômicas em pacientes com e sem concha bolhosa. Método Os prontuários dos pacientes submetidos à tomografia computadorizada de seios paranasais entre 2012 e 2018 foram analisados retrospectivamente. Os pacientes foram divididos em dois grupos, pacientes com e sem concha bolhosa. As diferenças entre os dois grupos em termos de idade, sexo, desvio do septo, deiscência da artéria etmoidal e assimetria do teto etmoidal foram avaliadas. Resultados Os 369 pacientes incluídos em nosso estudo foram divididos em dois grupos: com concha bolhosa e sem concha bolhosa. A média de idade dos pacientes com concha bolhosa foi de 36,1 ± 13,4 (mín-máx: 12-74 anos) e a média de idade dos pacientes sem concha bolhosa foi de 37,5 ± 14,3 (mín-máx: 10-81 anos). As profundidades do teto etmoidal foram comparadas entre os dois grupos, observou-se diferença significante (p < 0,001). Observou-se que a profundidade do teto etmoidal foi maior no grupo com concha bolhosa (p < 0,001). Conclusão O resultado do nosso estudo indica que pacientes com concha média bolhosa tendem a apresentar uma maior profundidade do teto etmoidal.