The value of cell-free circulating tumour DNA profiling in advanced non-small cell lung cancer (NSCLC) management

Liquid biopsy (LB) has boosted a remarkable change in the management of cancer patients by contributing to tumour genomic profiling. Plasma circulating cell-free tumour DNA (ctDNA) is the most widely searched tumour-related element for clinical application. Specifically, for patients with lung cancer, LB has revealed valuable to detect the diversity of targetable genomic alterations and to detect and monitor the emergence of resistance mechanisms. Furthermore, its non-invasive nature helps to overcome the difficulty in obtaining tissue samples, offering a comprehensive view about tumour diversity. However, the use of the LB to support diagnostic and therapeutic decisions still needs further clarification. In this sense, this review aims to provide a critical view of the clinical importance of plasma ctDNA analysis, the most widely applied LB, and its limitations while anticipating concepts that will intersect the present and future of LB in non-small cell lung cancer patients

Northern areas as refugia for temperate species under current climate warming: Atlantic salmon (Salmo salar L.) as a model in Northern Europe

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordIn this work, patterns of geographical genetic diversity in Atlantic salmon Salmo salar were studied across the whole Atlantic arc, as well as whether patterns (and thus genetic population structure) were affected by water temperatures. Salmo salar populations were here characterized using microsatellite loci and then analysed in the light of ocean surface temperature data from across the region. Analysis showed the presence of a latitudinal cline of genetic variability (higher in northern areas) and water temperatures (sea surface temperatures) determining genetic population structure (the latter in combination with genetic drift in southern populations). Under the current global change scenario, northern areas of Europe would constitute refuges for diversity in the future. This is effectively the inverse of what appears to have happened in glacial refugia during the last glacial maximum. From this perspective, the still abundant and large northern populations should be considered as precious as the small almost relict southern ones and perhaps protected. Careful management of the species, coordinated across countries and latitudes, is needed in order to avoid its extinction in Europe.J. L. Horreo was supported by a MINECO Spanish postdoctoral grant (“Juan de la CiervaIncorporación” (ref. IJCI-2015-23618). This work was funded by the European Union INTERREG IIIB programme (Atlantic Salmon Arc Project [ASAP], Project No. 040 and ASAP-2, Project No. 203). This study received additional funding from the Principality of Asturias Grants for Excellent Research (GRUPIN-2014-093) and the Contract CN-14-076

Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota

Objective Gastric carcinoma development is triggered by Helicobacter pylori. Chronic H. pylori infection leads to reduced acid secretion, which may allow the growth of a different gastric bacterial community. This change in the microbiome may increase aggression to the gastric mucosa and contribute to malignancy. Our aim was to evaluate the composition of the gastric microbiota in chronic gastritis and in gastric carcinoma. Design The gastric microbiota was retrospectively investigated in 54 patients with gastric carcinoma and 81 patients with chronic gastritis by 16S rRNA gene profiling, using next-generation sequencing. Differences in microbial composition of the two patient groups were assessed using linear discriminant analysis effect size. Associations between the most relevant taxa and clinical diagnosis were validated by real-time quantitative PCR. Predictive functional profiling of microbial communities was obtained with PICRUSt. Results The gastric carcinoma microbiota was characterised by reduced microbial diversity, by decreased abundance of Helicobacter and by the enrichment of other bacterial genera, mostly represented by intestinal commensals. The combination of these taxa into a microbial dysbiosis index revealed that dysbiosis has excellent capacity to discriminate between gastritis and gastric carcinoma. Analysis of the functional features of the microbiota was compatible with the presence of a nitrosating microbial community in carcinoma. The major observations were confirmed in validation cohorts from different geographic origins. Conclusions Detailed analysis of the gastric microbiota revealed for the first time that patients with gastric carcinoma exhibit a dysbiotic microbial community with genotoxic potential, which is distinct from that of patients with chronic gastritis.This research was supported by a Worldwide Cancer Research grant to CF and JCM (Reference 16-1352). RMF, JPM and IPR have fellowships from Fundacao para a Ciencia e a Tecnologia (FCT; SFRH/BPD/84084/2012, PD/BD/114014/2015 and SFRH/BD/110803/2015, respectively) through Programa Operacional Capital Humano (POCH) and the European Union. JPM's fellowship is in the framework of FCT's PhD Programme BiotechHealth (Ref PD/0016/2012). i3S-Instituto de Investigacao e Inovacao em Saude is funded by Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020-Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through Fundacao para a Ciencia e a Tecnologia (FCT)/Ministerio da Ciencia, Tecnologia e Inovacao (POCI-01-0145-FEDER-007274)

An efficient collocation method for a Caputo two-point boundary value problem

peer-reviewedA two-point boundary value problem is considered on the interval , where the leading term in the differential operator is a Caputo fractional-order derivative of order with . The problem is reformulated as a Volterra integral equation of the second kind in terms of the quantity , where is the solution of the original problem. A collocation method that uses piecewise polynomials of arbitrary order is developed and analysed for this Volterra problem; then by postprocessing an approximate solution of is computed. Error bounds in the maximum norm are proved for and . Numerical results are presented to demonstrate the sharpness of these bounds.ACCEPTEDpeer-reviewe

Extracting the Distribution Amplitudes of the rho meson from the Color Glass Condensate

We extract the leading twist-2 and subleading twist-3 Distribution Amplitudes (DAs) of the rho meson using the HERA data on diffractive rho photoproduction. We do so using several Colour Glass Condensate (CGC) inspired and a Regge inspired dipole models. We find that our extracted twist-2 DA is not much model dependent and is consistent with QCD Sum Rules and lattice predictions. The extracted twist-3 DA is more model dependent but is still consistent with the Sum Rules prediction.Comment: 21 pages, 10 figures, 3 tables. Section 6 revised, figures 8 and 9 and table 3 updated. Conclusions essentially unchange

Sentinel Node Total Tumour Load As a Predictive Factor for Non-Sentinel Node Status in Early Breast Cancer Patients – The porttle study

OSNA is a molecular assay for the detection of sentinel node metastasis. TTL emerged as a concept that seems to accurately predict the status of the NSN. Authors tried to confirm this motion. This is a retrospective and multicentric study that analyzed 2164 patients, 579 of whom had positive SN and completion AD. Logistic regression models were performed in order to identify a suitable cutoff to identify patients who benefit from AD. Univariate and multivariate regression analysis showed a relationship between TTL>30000 and the presence of NSN metastasis (OR 2.84, CI 1.99-4.08, p < 0.001). Logistic regression indicated that the cutoff of 30000 copies/μL better discriminates patients with NSN positivity and allows wide use of these criteria. This cutoff value may safely assist clinicians and patients to decide to proceed or not with an AD.info:eu-repo/semantics/publishedVersio

The Role of Liquid Biopsy in Early Diagnosis of Lung Cancer

Liquid biopsy is an emerging technology with a potential role in the screening and early detection of lung cancer. Several liquid biopsy-derived biomarkers have been identified and are currently under ongoing investigation. In this article, we review the available data on the use of circulating biomarkers for the early detection of lung cancer, focusing on the circulating tumor cells, circulating cell-free DNA, circulating micro-RNAs, tumor-derived exosomes, and tumor-educated platelets, providing an overview of future potential applicability in the clinical practice. While several biomarkers have shown exciting results, diagnostic performance and clinical applicability is still limited. The combination of different biomarkers, as well as their combination with other diagnostic tools show great promise, although further research is still required to define and validate the role of liquid biopsies in clinical practice.This work is financed by the ERDF—European Regional Development Fund through the Operational Programme for Competitiveness and Internationalization—COMPETE 2020 Programme and by National Funds through the Portuguese funding agency, FCT—Fundação para a Ciência e a Tecnologia within project POCI-01-0145-FEDER-030263. Authors thank Abílio Cunha and Francisco Correia for the illustration work. NC-M acknowledges the Portuguese Foundation for Science and Technology under Horizon 2020 Program (PTDC/PSI-GER/28076/2017)

Liquid biopsy for disease monitoring in non-small cell lung cancer: The link between biology and the clinic

Introduction: Cell-free DNA (cfDNA) analysis offers a non-invasive method to identify sensitising and resistance mutations in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Next-generation sequencing (NGS) of circulating free DNA (cfDNA) is a valuable tool for mutations detection and disease' s clonal monitoring. Material and methods: An amplicon-based targeted gene NGS panel was used to analyse 101 plasma samples of advanced non-small cell lung cancer (NSCLC) patients with known oncogenic mutations, mostly EGFR mutations, serially collected at different clinically relevant time points of the disease. Results: The variant allelic frequency (VAF) monitoring in consecutive plasma samples demonstrated different molecular response and progression patterns. The decrease in or the clearance of the mutant alleles was associated with response and the increase in or the emergence of novel alterations with progression. At the best response, the median VAF was 0% (0.0% to 3.62%), lower than that at baseline, with a median of 0.53% (0.0% to 9.9%) (p = 0.004). At progression, the VAF was significantly higher (median 4.67; range: 0.0–36.9%) than that observed at the best response (p = 0.001) and baseline (p = 0.006). These variations anticipated radiographic changes in most cases, with a median time of 0.86 months. Overall, the VAF evolution of different oncogenic mutations predicts clinical outcomes. Conclusion: The targeted NGS of circulating tumour DNA (ctDNA) has clinical utility to monitor treatment response in patients with advanced lung adenocarcinoma.This work was supported by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020; and by FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the projects “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274), and “Transferencia horizontal de resistencia à terapia: mudança de paradigma na monitorização de pacientes com cancro” (PTDC/DTPPIC/2500/2014); and by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), in the framework of the project NORTE-01-0145-FEDER-000029

Using an in-vitro biofilm model to assess the virulence potential of Bacterial Vaginosis or non-Bacterial Vaginosis Gardnerella vaginalis isolates

Gardnerella vaginalis is the most common species found in bacterial vaginosis (BV). However, it is also present in a significant proportion of healthy women and G. vaginalis vaginal colonization does not always lead to BV. In an effort to better understand the differences between G. vaginalis isolated from women with a positive (BV) versus a negative (non-BV) diagnosis of BV, we compared the virulence potential of 7 BV and 7 non-BV G. vaginalis isolates and assessed the virulence factors related to biofilm formation, namely: initial adhesion and cytotoxic effect, biofilm accumulation, susceptibility to antibiotics, and transcript levels of the known vaginolysin, and sialidase genes. Furthermore, we also determined the ability of G. vaginalis to displace lactobacilli previously adhered to HeLa cells. Our results showed that non-BV strains were less virulent than BV strains, as suggested by the lower cytotoxicity and initial adhesion to Hela cells. Significant differences in expression of known virulence genes were also detected, further suggesting a higher virulence potential of the BV associated G. vaginalis. Importantly, we demonstrated that BV associated G. vaginalis were able to displace pre-coated vaginal protective lactobacilli and we hypothesize this to be a trigger for BV development.European Union funds (FEDER/COMPETE) and by national funds (FCT) under the project with reference FCOMP-01-0124-FEDER-008991 (PTDC/BIA-MIC/098228/2008). FCT Strategic Project of UID/BIO/04469/2013 unit the project NORTE-07-0124-FEDER-000027, co-funded by the Programa Operacional Regional do Norte(ON.2 – O Novo Norte), QREN, FEDER, and the project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462). FCT individual fellowship SFRH/BD/93963/2013