Basin-scale land use impacts on world deltas: Human vs natural forcings

A new global database of 86 deltas and river basins was analyzed to investigate the relative importance of deforestation and land use changes versus natural forcings in determining long-term total delta size. Results show that mean river flow and shelf slope were the most important variables, whereas population density and sediment load had a much lower importance. Deforestation and other variables related to land-use generally had a very small effect, but were more influential in a subset comprising Mediterranean and Black Sea deltas. As most deltas have developed over thousands of years, the much shorter-lived anthropogenic signals from deforestation and other landscape perturbations have had only secondary impact on the total area of deltas. Also, delta progradation is strongly influenced on sand deposition, whereas anthropogenic impacts on sediment load have more often impacted mostly the finer sediment being deposited offshore (prodelta deposits) or in the deltaic plain. These data disproves the hypothesis that delta size and growth is strongly influenced by human forcings, particularly for larger deltas, since Holocene delta building is mainly determined by natural forces. However, humans are influencing the geomorphology of deltas, particularly over the last century when the Anthropocene nature of deltas has become manifest. A more precise terminology is proposed to clarify concepts such as “human-made”, “human-engineered” or “human-influenced” deltas.info:eu-repo/semantics/acceptedVersio

On defining rules for cancer data fabrication

Funding: This research is partially funded by the Data Lab, and the EU H2020 project Serums: Securing Medical Data in Smart Patient-Centric Healthcare Systems (grant 826278).Data is essential for machine learning projects, and data accuracy is crucial for being able to trust the results obtained from the associated machine learning models. Previously, we have developed machine learning models for predicting the treatment outcome for breast cancer patients that have undergone chemotherapy, and developed a monitoring system for their treatment timeline showing interactively the options and associated predictions. Available cancer datasets, such as the one used earlier, are often too small to obtain significant results, and make it difficult to explore ways to improve the predictive capability of the models further. In this paper, we explore an alternative to enhance our datasets through synthetic data generation. From our original dataset, we extract rules to generate fabricated data that capture the different characteristics inherent in the dataset. Additional rules can be used to capture general medical knowledge. We show how to formulate rules for our cancer treatment data, and use the IBM solver to obtain a corresponding synthetic dataset. We discuss challenges for future work.Postprin

Single-arm, open label prospective trial to assess prediction of the role of ERCC1/XPF complex in the response of advanced NSCLC patients to platinum-based chemotherapy

Background: Platinum-based therapy, combined or not with immune checkpoint inhibitors, represents a front-line choice for patients with non-small-cell lung cancer (NSCLC). Despite the improved outcomes in the last years for this malignancy, only a sub-group of patients have long-term benefit. Excision repair cross-complementation group 1 (ERCC1) has been considered a potential biomarker to predict the outcome of platinum-based chemotherapy in NSCLC. However, the ERCC1 gene is transcribed in four splice variants where the isoform 202 was described as the only one active and able to complex Xeroderma pigmentosum group F-complementing protein (XPF). Here, we prospectively investigated if the active form of ERCC1, as assessed by the ERCC1/XPF complex (ERCC1/XPF), could predict the sensitivity to platinum compounds.Patients and methods: Prospectively enrolled, patients with advanced NSCLC treated with a first-line regimen containing platinum were centrally evaluated for ERCC1/XPF by a proximity ligation assay. Overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were analyzed.Results: The absence of the ERCC1/XPF in the tumor suggested a trend of worst outcomes in terms of both OS [hazard ratio (HR) 1.41, 95% confidence interval (CI) 0.67-2.94, P 0.373] and PFS (HR 1.61, 95% CI 0.88-3.03, P = 0.123). ORR was marginally influenced in ERCC1/XPF-negative and -positive groups [odds ratio (stable disease progressive disease versus complete response partial response) 0.87, 95% a 0.25-3.07, P = 0.832].Conclusion: The lack of ERCC1/XPF complex in NSCLC tumor cells might delineate a group of patients with poor outcomes when treated with platinum compounds. ERCC1/XPF absence might well identify patients for whom a different therapeutic approach could be necessary

A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men

Background Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). Methods We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan® PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. Results The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32–4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50–6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. Conclusions To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD

Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC

Introduction: We hypothesized that activating KRAS mutations and inactivation of the liver kinase B1 (LKB1) oncosuppressor can cooperate to sustain NSCLC aggressiveness. We also hypothesized that the growth advantage of KRAS/LKB1 co-mutated tumors could be balanced by higher sensitivity to metabolic stress conditions, such as metformin treatment, thus revealing new strategies to target this aggressive NSCLC subtype. Methods: We retrospectively determined the frequency and prognostic value of KRAS/LKB1 co-mutations in tissue specimens from NSCLC patients enrolled in the TAILOR trial. We generated stable LKB1 knockdown and LKB1-overexpressing isogenic H1299 and A549 cell variants, respectively, to test the in vitro efficacy of metformin. We also investigated the effect of metformin on cisplatin-resistant CD133+cells in NSCLC patient-derived xenografts. Results: We found a trend towards worse overall survival in patients with KRAS/LKB1 co-mutated tumors as compared to KRAS-mutated ones (hazard ratio: 2.02, 95% confidence interval: 0.94\u20134.35, p = 0.072). In preclinical experiments, metformin produced pro-apoptotic effects and enhanced cisplatin anticancer activity specifically in KRAS/LKB1 co-mutated patient-derived xenografts. Moreover, metformin prevented the development of acquired tumor resistance to 5 consecutive cycles of cisplatin treatment (75% response rate with metformin-cisplatin as compared to 0% response rate with cisplatin), while reducing CD133+cells. Conclusions: LKB1 mutations, especially when combined with KRAS mutations, may define a specific and more aggressive NSCLC subtype. Metformin synergizes with cisplatin against KRAS/LKB1 co-mutated tumors, and may prevent or delay the onset of resistance to cisplatin by targeting CD133+cancer stem cells. This study lays the foundations for combining metformin with standard platinum-based chemotherapy in the treatment of KRAS/LKB1 co-mutated NSCLC

[Molecular analysis of the gene of steroidogenic acute regulatory protein (StAR) in adrenal incidentaloma].

The steroidogenic acute regulatory protein (StAR) plays an essential role in steroidogenesis, facilitating cholesterol entry into the inner compartment of mitochondria. Mutations (either transitions or transversions) of StAR gene have been described as a cause of lethal forms of congenital lipoid adrenal hyperplasia. Adrenal incidentalomas are frequently discovered during radiologic examinations performed in patients with diagnosis for other diagnostic problems. Enzymatic defects along the steroidogenetic cascade are observed with high frequency in these patients. Aim of the present study was to asses the involvement of alteration of the StAR gene in incidentally discovered adrenal masses (incidentalomas). The mutational analysis of 32 incidentalomas demonstrated a "missense" mutation in exon five of the gene in one of the tumors analysed. This is the first evidence of an alteration of the StAR gene in adrenal incidentalomas