RESUMO
BACKGROUND: Early diagnosis and continuous monitoring are necessary for an efficient management of cervical cancers (CC). Liquid biopsy, such as detecting circulating tumor DNA (ctDNA) from blood, is a simple, non-invasive method for testing and monitoring cancer markers. However, tumor-specific alterations in ctDNA have not been extensively investigated or compared to other circulating biomarkers in the diagnosis and monitoring of the CC. Therfore, Next-generation sequencing (NGS) analysis with blood samples can be a new approach for highly accurate diagnosis and monitoring of the CC. METHOD: Using a bioinformatics approach, we designed a panel of 24 genes associated with CC to detect and characterize patterns of somatic single-nucleotide variations, indels, and copy number variations. Our NGS CC panel covers most of the genes in The Cancer Genome Atlas (TCGA) as well as additional cancer driver and tumor suppressor genes. We profiled the variants in ctDNA from 24 CC patients who were being treated with systemic chemotherapy and local radiotherapy at the Jeonbuk National University Hospital, Korea. RESULT: Eighteen out of 24 genes in our NGS CC panel had mutations across the 24 CC patients, including somatic alterations of mutated genes (ZFHX3-83%, KMT2C-79%, KMT2D-79%, NSD1-67%, ATM-38% and RNF213-27%). We demonstrated that the RNF213 mutation could be used potentially used as a monitoring marker for response to chemo- and radiotherapy. CONCLUSION: We developed our NGS CC panel and demostrated that our NGS panel can be useful for the diagnosis and monitoring of the CC, since the panel detected the common somatic variations in CC patients and we observed how these genetic variations change according to the treatment pattern of the patient.
Assuntos
DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Neoplasias do Colo do Útero/genética , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adenosina Trifosfatases/genética , Idoso , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , DNA Tumoral Circulante/sangue , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Feminino , Marcadores Genéticos , Proteínas de Homeodomínio/genética , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética , Sensibilidade e Especificidade , Ubiquitina-Proteína Ligases/genética , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapiaRESUMO
Global warming poses a considerable threat to human health, necessitating a proper understanding of mechanisms underlying cell death in the pathogenesis of heat-related diseases. Although mechanisms governing cytoplasmic response to heat are well understood, processes regulating cellular response to disruption of proteostasis in the endoplasmic reticulum (ER) due to heat stress remain unclear. The current study reveals that hyperthermic conditions may lead to a disturbance of ER homeostasis, also known as ER stress. Subsequent activation of the unfolded protein response (UPR) resulted in concomitant induction of cell death. Among the three UPR signaling pathways, the eIF2α phosphorylation pathway, and not the IRE1α/ATF6α pathways, is likely the main contributor to cell death under heat stress. Considering the role of eIF2α in translational control, we investigated the protective effect of translation rate on heat stress-mediated cell death. When protein synthesis was attenuated using cycloheximide or homoharringtonine, cell death due to heat stress was significantly reduced. In summation, we propose that transient modulation of protein synthesis by eIF2α phosphorylation has a pivotal role in protecting cells from heat stress-induced apoptosis. Therefore, pharmacological agents that promote eIF2α phosphorylation or reduce ER stress may contribute to the development of promising therapeutic approaches against heat-related diseases.
RESUMO
Auditory function takes a major part in human life. While sensorineural hearing loss is related with many factors including genetic disorders, age and noise, the clear causes are not well understood. Even more, the currently available treatments with drugs cause side effects, which thus are considered suboptimal. Here, we communicate the delivery systems with biomaterials that can be possible therapeutic options to restore hearing and vestibular functions. We introduce briefly the various pathological factors related with hearing loss and the limitation of current therapies, detail the recent studies on delivery systems including nanoparticles and hydrogels and discuss future clinical availability.