Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumour aggressiveness

Monocarboxylate transporters (MCTs) are vital for intracellular pH homeostasis by extruding lactate from highly glycolytic cells. These molecules are key players of the metabolic reprogramming of cancer cells, and evidence indicates a potential contribution in urothelial bladder cancer (UBC) aggressiveness and chemoresistance. However, the specific role of MCTs in the metabolic compartmentalization within bladder tumors, namely their preponderance on the tumor stroma, remains to be elucidated. Thus, we evaluated the immunoexpression of MCTs in the different compartments of UBC tissue samples (n = 111), assessing the correlations among them and with the clinical and prognostic parameters. A significant decrease in positivity for MCT1 and MCT4 occurred from normoxic toward hypoxic regions. Significant associations were found between the expression of MCT4 in hypoxic tumor cells and in the tumor stroma. MCT1 staining in normoxic tumor areas, and MCT4 staining in hypoxic regions, in the tumor stroma and in the blood vessels were significantly associated with UBC aggressiveness. MCT4 concomitant positivity in hypoxic tumor cells and in the tumor stroma, as well as positivity in each of these regions concomitant with MCT1 positivity in normoxic tumor cells, was significantly associated with an unfavourable clinicopathological profile, and predicted lower overall survival rates among patients receiving platinum-based chemotherapy. Our results point to the existence of a multi-compartment metabolic model in UBC, providing evidence of a metabolic coupling between catabolic stromal and cancer cells' compartments, and the anabolic cancer cells. It is urgent to further explore the involvement of this metabolic coupling in UBC progression and chemoresistance.This study was supported by the Life and Health Sciences Research Institute (ICVS) from the School of Health Sciences of the University of Minho. JA received a postdoctoral fellowship from ICVS (reference ICVS-SSRL: ON.2 SR&TD Integrated Program, NORTE-07-0124-FEDER-000017).info:eu-repo/semantics/publishedVersio

Combining 1,3-Ditriazolylbenzene and Quinoline to Discover a New G-Quadruplex-Interactive Small Molecule Active against Cancer Stem-Like Cells

Quadruplex nucleic acids are promising targets for cancer therapy. In this study we used a fragment‐based approach to create new flexible G‐quadruplex (G4) DNA‐interactive small molecules with good calculated oral drug‐like properties, based on quinoline and triazole heterocycles. G4 melting temperature and polymerase chain reaction (PCR)‐stop assays showed that two of these compounds are selective G4 ligands, as they were able to induce and stabilize G4s in a dose‐ and DNA sequence‐dependent manner. Molecular docking studies have suggested plausible quadruplex binding to both the G‐quartet and groove, with the quinoline module playing the major role. Compounds were screened for cytotoxicity against four cancer cell lines, where 4,4′‐(4,4′‐(1,3‐phenylene)bis(1H‐1,2,3‐triazole‐4,1‐diyl))bis(1‐methylquinolin‐1‐ium) (1 d) showed the greater activity. Importantly, dose–response curves show that 1 d is cytotoxic in the human colon cancer HT‐29 cell line enriched in cancer stem‐like cells, a subpopulation of cells implicated in chemoresistance. Overall, this study identified a new small molecule as a promising lead for the development of drugs targeting G4 in cancer stem cells

Strength training to prevent falls in older adults: A systematic review with meta-analysis of randomized controlled trials

We performed a systematic review with meta-analysis of randomized controlled trials (RCTs) to assess the effects of strength training (ST), as compared to alternative multimodal or unimodal exercise programs, on the number of falls in older adults (=60 years). Ten databases were consulted (CINAHL, Cochrane Library, EBSCO, EMBASE, PEDro, PubMed, Scielo, Scopus, SPORTDiscus and Web of Science), without limitations on language or publication date. Eligibility criteria were as follows: RCTs with humans =60 years of age of any gender with one group performing supervised ST and a group performing another type of exercise training, reporting data pertaining falls. Certainty of evidence was assessed with Grading of Recommendations, Assessment, Development and Evaluation (GRADE). Meta-analysis used a random effects model to calculate the risk ratio (RR) for number of falls. Five RCTs with six trials were included (n = 543, 76% women). There was no difference between ST and alternative exercise interventions for falls (RR = 1.00, 95% CI 0.77–1.30, p = 0.99). The certainty of evidence was very low. No dose–response relationship could be established. In sum, ST showed comparable RR based on number of falls in older adults when compared to other multimodal or unimodal exercise modalities, but evidence is scarce and heteroge-neous, and additional research is required for more robust conclusions. Registration: PROSPERO CRD42020222908

A review of acoustic telemetry in Europe and the need for a regional aquatic telemetry network

Background Globally, there are a large and growing number of researchers using biotelemetry as a tool to study aquatic animals. In Europe, this community lacks a formal network structure. The aim of this study is to review the use of acoustic telemetry in Europe and document the contribution of cross-boundary studies and inter-research group collaborations. Based on this, we explore the potential benefits and challenges of a network approach to identify future priorities and best practices for aquatic biotelemetry research in Europe. Results Over the past decade, there was an approximately sevenfold increase in the number of acoustic telemetry studies published on marine and diadromous species in Europe compared to a sixfold increase globally. Over 90% of these studies were conducted on fishes and undertaken in coastal areas, estuaries, or rivers. 75% of these studies were conducted by researchers based in one of five nations (Norway, UK, France, Portugal, and Spain) and, even though 34% were based on collaborations between scientists from several countries, there was only one study with an acoustic receiver array that extended beyond the borders of a single country. In recent years, acoustic telemetry in European waters has evolved from studying behavioural aspects of animals (82.2%), into more holistic approaches addressing management-related issues (10%), tagging methods and effects (5%), and technology and data analysis development (2.8%). Conclusions Despite the increasing number of publications and species tracked, there is a prominent lack of planned and structured acoustic telemetry collaborations in Europe. A formal pan-European network structure would promote the development of (1) a research platform that could benefit the acoustic telemetry community through capacity building, (2) a centralized database, and (3) key deployment sites and studies on priority species requiring research in Europe. A network may increase efficiency, expand the scope of research that can be undertaken, promote European science integration, enhance the opportunities and success of acquiring research funding and, ultimately, foster regional and transatlantic collaborations. It may also help address research priorities such as the large-scale societal challenges arising from climate change impacts and assist the EU’s Marine Strategy Framework Directive via identification of good environmental status of endangered or commercially important species.info:eu-repo/semantics/publishedVersio

f(R) theories

Over the past decade, f(R) theories have been extensively studied as one of the simplest modifications to General Relativity. In this article we review various applications of f(R) theories to cosmology and gravity - such as inflation, dark energy, local gravity constraints, cosmological perturbations, and spherically symmetric solutions in weak and strong gravitational backgrounds. We present a number of ways to distinguish those theories from General Relativity observationally and experimentally. We also discuss the extension to other modified gravity theories such as Brans-Dicke theory and Gauss-Bonnet gravity, and address models that can satisfy both cosmological and local gravity constraints.Comment: 156 pages, 14 figures, Invited review article in Living Reviews in Relativity, Published version, Comments are welcom

Surveillance of active human cytomegalovirus infection in hematopoietic stem cell transplantation (HLA sibling identical donor): search for optimal cutoff value by real-time PCR

<p>Abstract</p> <p>Background</p> <p>Human cytomegalovirus (CMV) infection still causes significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, it is extremely important to diagnosis and monitor active CMV infection in HSCT patients, defining the CMV DNA levels of virus replication that warrant intervention with antiviral agents in order to accurately prevent CMV disease and further related complications.</p> <p>Methods</p> <p>During the first 150 days after allogeneic HSTC, thirty patients were monitored weekly for active CMV infection by <it>pp65 </it>antigenemia, nested-PCR and real-time PCR assays. Receiver operating characteristic (ROC) plot analysis was performed to determine a threshold value of the CMV DNA load by real-time PCR.</p> <p>Results</p> <p>Using ROC curves, the optimal cutoff value by real-time PCR was 418.4 copies/10⁴PBL (sensitivity, 71.4%; specificity, 89.7%). Twenty seven (90%) of the 30 analyzed patients had active CMV infection and two (6.7%) developed CMV disease. Eleven (40.7%) of these 27 patients had acute GVHD, 18 (66.7%) had opportunistic infection, 5 (18.5%) had chronic rejection and 11 (40.7%) died - one died of CMV disease associated with GVHD and bacterial infection.</p> <p>Conclusions</p> <p>The low incidence of CMV disease in HSCT recipients in our study attests to the efficacy of CMV surveillance based on clinical routine assay. The quantification of CMV DNA load using real-time PCR appears to be applicable to the clinical practice and an optimal cutoff value for guiding timely preemptive therapy should be clinically validated in future studies.</p