Mouse p53-deficient cancer models as platforms for obtaining genomic predictors of human cancer clinical outcomes

Mutations in the TP53 gene are very common in human cancers, and are associated with poor clinical outcome. Transgenic mouse models lacking the Trp53 gene or that express mutant Trp53 transgenes produce tumours with malignant features in many organs. We previously showed the transcriptome of a p53-deficient mouse skin carcinoma model to be similar to those of human cancers with TP53 mutations and associated with poor clinical outcomes. This report shows that much of the 682-gene signature of this murine skin carcinoma transcriptome is also present in breast and lung cancer mouse models in which p53 is inhibited. Further, we report validated gene-expression-based tests for predicting the clinical outcome of human breast and lung adenocarcinoma. It was found that human patients with cancer could be stratified based on the similarity of their transcriptome with the mouse skin carcinoma 682-gene signature. The results also provide new targets for the treatment of p53-defective tumours

Tumor BRCA1, RRM1 and RRM2 mRNA Expression Levels and Clinical Response to First-Line Gemcitabine plus Docetaxel in Non-Small-Cell Lung Cancer Patients

Overexpression of RRM1 and RRM2 has been associated with gemcitabine resistance. BRCA1 overexpression increases sensitivity to paclitaxel and docetaxel. We have retrospectively examined the effect of RRM1, RRM2 and BRCA1 expression on outcome to gemcitabine plus docetaxel in advanced non-small-cell lung cancer (NSCLC) patients. = 0.001). Low BRCA1 expression was the only factor significantly associated with longer time to progression in 31 patients receiving cisplatin-based second-line therapy.The mRNA expression of BRCA1, RRM1 and RRM2 is potentially a useful tool for selecting NSCLC patients for individualized chemotherapy and warrants further investigation in prospective studies

Paleoseismic evidence of the 1715 C.E earthquake on the Purgatorio Fault in Southern Peru: implications for seismic hazard in subduction zones

Active faults in the forearc of southern Peru pose a poorly understood hazard to the region. The Purgatorio Fault is a 60 km-long fault that extends between Moquegua and Tacna that has hosted several scarp-forming earthquakes over the last 6 ka. We present new measurements of the fault scarp geomorphology along the Purgatorio Fault and use dating of the stratigraphy within a new paleoseismic trench excavated across the fault to establish the chronology of scarp formation. We find that the most recent surface-rupturing earthquake on the Purgatorio Fault occurred sometime between 1630C.E and 1790C.E and had a moment magnitude (Mw) of ~7. We propose that this most recent surface-rupturing earthquake on the Purgatorio Fault was the 1715C.E earthquake recorded in the historical catalogue of the region, which was previously attributed to the megathrust offshore. Our results highlight the importance of establishing a paleoseismic record of onshore faults to differentiate between major megathrust and forearc earthquakes. Given the proximity of these shallow, onshore faults to coastal communities in Peru, the shallow earthquakes they generate may pose a severe, yet often overlooked, seismic hazard

Effects of dose modifications on the safety and efficacy of dacomitinib for EGFR mutation-positive non-small-cell lung cancer

Aim: We evaluated reasons for dacomitinib dose reduction (DR) and examined adverse event (AE) incidence, key efficacy end points (progression-free survival [PFS]/overall survival [OS]), and pharmacokinetics in dose-reducing patients in the ARCHER 1050 trial. Patients & methods: Newly diagnosed patients with EGFR mutation-positive, advanced non-small-cell lung cancer received oral dacomitinib (45 mg once-daily [QD]), with stepwise toxicity-managing DR (30 and 15 mg QD) permitted. Results: Skin toxicities (62.7%) were the most common DR-leading AEs. The AE incidence and severity decreased following DRs. Initial plasma dacomitinib exposure (45 mg QD) was generally lower in patients remaining at 45 mg QD compared with dose-reducing patients. Median PFS and OS were similar in all dacomitinib-treated patients and dose-reducing patients. Conclusion: Tolerability-guided dose modifications enabled patients to continue with dacomitinib and benefit from PFS/OS improvement

Hazardous base surges of Taal’s 2020 eruption

After 43 years of repose, Taal Volcano erupted on 12 January 2020 forming hazardous base surges. Using field, remote sensing (i.e. UAV and LiDAR), and numerical methods, we gathered primary data to generate well-constrained observed information on dune bedform characteristics, impact dynamic pressures and velocities of base surges. This is to advance our knowledge on this type of hazard to understand and evaluate its consequences and risks. The dilute and wet surges traveled at 50-60 ms−1 near the crater rim and decelerated before making impact on coastal communities with dynamic pressures of at least 1.7 kPa. The base surges killed more than a thousand livestock in the southeast of Taal Volcano Island, and then traveled another ~ 600 m offshore. This work is a rare document of a complete, fresh, and practically undisturbed base surge deposit, important in the study of dune deposits formed by volcanic and other processes on Earth and other planets

Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer

EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo

BRCA1: A Novel Prognostic Factor in Resected Non-Small-Cell Lung Cancer

BACKGROUND: Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). METHODOLOGY AND PRINCIPAL FINDINGS: We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). CONCLUSIONS: Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy, especially in stage IB, where the role of adjuvant chemotherapy has not been clearly demonstrated

Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression

BACKGROUND: Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels. METHODOLOGY/PRINCIPAL FINDINGS: We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1-1.7]; P = 0.05). CONCLUSIONS/SIGNIFICANCE: Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy. TRIAL REGISTRATION: (ClinicalTrials.gov) NCT00883480

Prospective study of asbestos-related diseases incidence cases in primary health care in an area of Barcelona province

<p>Abstract</p> <p>Background</p> <p>Asbestos related diseases include a number of conditions due to inhalation of asbestos fibres at work, at home or in the environment, such as pleural mesothelioma, asbestosis and calcified pleural plaques. Few epidemiological studies have established the incidence of asbestos related diseases in our area. The present proposal is based on a retrospective study externally funded in 2005 that is currently taking place in the same area and largely carried out by the same research team.</p> <p>The aim of the study is to achieve a comprehensive and coordinated detection of all new cases of Asbestos Related Diseases presenting to primary care practitioners.</p> <p>Methods/design</p> <p>This is a multicentre, multidisciplinary and pluri-institutional prospective study.</p> <p><b>Setting</b></p> <p>12 municipalities in the Barcelona province within the catchment area of the health facilities that participate in the study.</p> <p><b>Sample</b></p> <p>This is a population based study, of all patients presenting with diseases caused by asbestos in the study area.</p> <p><b>Measurements</b></p> <p>A clinical and epidemiological questionnaire will be filled in by the trained researchers after interviewing the patients and examining their clinical reports.</p> <p>Discussion</p> <p>Data on the incidence of the different Asbestos Related Diseases in this area will be obtained and the most plausible exposure source and space-time-patient profile will be described. The study will also improve the standardization of patient management, the coordination between health care institutions and the development of preventive activities related with asbestos exposure and disease.</p