One of the major limitations associated with platinum use is the resistance that almost invariably develops in different tumor types. In the current study, we sought to identify epigenetically regulated microRNAs as novel biomarkers of platinum resistance in lung and ovarian cancers, the ones with highest ratios of associated chemo-resistance.Methods: We combined transcriptomic data from microRNA and mRNA under the influence of an epigenetic reactivation treatment in a panel of four paired cisplatin -sensitive and -resistant cell lines, followed by real-time expression and epigenetic validations for accurate candidate selection in 19 human cancer cell lines. To identify specific candidate genes under miRNA regulation, we assembled “in silico” miRNAs and mRNAs sequences by using ten different algorithms followed by qRT-PCR validation. Functional assays of site-directed mutagenesis and luciferase activity, miRNAs precursor overexpression, silencing by antago-miR and cell viability were performed to confirm their specificity in gene regulation. Results were further explored in 187 primary samples obtained from ovarian tumors and controls.Results: We identified 4 candidates, miR-7, miR-132, miR-335 and miR-148a, which deregulation seems to be a common event in the development of resistance to cisplatin in both tumor types. miR-7 presented specific methylation in resistant cell lines, and was associated with poorer prognosis in ovarian cancer patients. Our experimental results strongly support the direct regulation of MAFG through miR-7 and their involvement in the development of CDDP resistance in human tumor cells.Conclusion: The basal methylation status of miR-7 before treatment may be a potential clinical epigenetic biomarker, predictor of the chemotherapy outcome to CDDP in ovarian cancer patients. To the best of our knowledge, this is the first report linking the regulation of MAFG by miRNA-7 and its role in chemotherapy response to CDDP. Furthermore, this data highlights the possible role of MAFG as a novel therapeutic target for platinum resistant tumors.
Objective We aimed to assess the relationship between major air pollutants and the natural history and mortality of idiopathic pulmonary fibrosis (IPF). Methods We conducted a retrospective cohort study from 2013 to 2019 among 52 patients with IPF from the pneumology department of a tertiary hospital. According to their geocoded residential address, each patient was assigned a mean concentration of carbon monoxide (CO), nitrogen dioxide, particulate matter 2.5 and 10, ozone, and sulfur dioxide, as measured at a single surveillance station in central Madrid, Spain. We analyzed forced vital capacity (FVC), CO diffusing capacity, 6-minute walking test, degree of dyspnea, radiologic pattern, and signs of pulmonary hypertension in all patients. Results Patients’ mean age was 66 ± 10 years, and 79% were men. The mean predicted FVC was 78.9 ± 0.5%. Forty-two patients met the criteria for severe disease, and 18 patients died. Mortality was significantly associated with increased CO exposure (for each 0.1 mg/m2 increase: odds ratio 2.45, 95% confidence interval 1.39–4.56). We observed no association between any of the other investigated contaminants and IPF mortality or severity. Conclusions Air pollution, specifically that caused by carbon monoxide, can increase mortality in patients with IPF.
BackgroundNeoadjuvant radio- or chemoradiation (nIRT) therapy is the standard treatment for loco-regional advanced rectal cancer patients of the lower or middle third. Currently, intensity modulated radiation therapy (IMRT) is not the recommended radiation technique even though IMRT has advantages compared to 3D-radiation regarding dose sparing to organs at risk like small bowel and urinary bladder. So far, the benefit of IMRT concerning the anal sphincter complex is not examined. With this study we intended to evaluate the dose distribution on the anal sphincters of rectal cancer patients treated with IMRT in comparison with 3D-techniques.MethodsWe selected 16 patients for the IMRT-group and 16 patients for the 3D-group with rectal cancer of the middle third who were treated in our institute. All patients received 45 Gy in a chemoradiation protocol. Patients in both groups were matched regarding stage, primary tumor distance to the anal verge and size of the tumor. We delineated the internal and external anal sphincters, the addition of both sphincters and the levator ani muscle in all patients. Subsequently, we evaluated and compared dose parameters of the different sphincters in both groups and analysed the configuration of the isodoses in the area of the caudal radiation field, respectively.ResultsMost of the relevant dose parameters of the caudal sphincters (Dmean, Dmedian, V10–V40) were significantly reduced in the IMRT-group compared to the 3D-group. Accordingly, the isodoses at the caudal edge of the target volume in the IMRT group demonstrated a steep dose fall. The levator ani muscle always was included into the planned target volumes and received the full dose in both groups.ConclusionsThe modern VMAT-IMRT can significantly reduce the dose to the anal sphincters for rectal cancer patients of the middle third who were treated with conventional chemoradiation therapy.
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