First insights into circulating XDR and pre-XDR Mycobacterium tuberculosis in Southern Brazil.

Drug-resistant tuberculosis (DR-TB) is major problem in the fight against TB. Multidrug resistant (MDR) TB patients have a reduced treatment success rates and for, extensively drug-resistant (XDR) TB the cure rate does not exceed 25% in many countries. To evaluate the pre-XDR-TB and XDR-TB prevalence and transmission in Rio Grande do Sul State, in southern Brazil, we performed a retrospective WGS-based analysis of 87 MDR-TB cases, aiming to identify resistance-conferring mutations and its phylogenetic distinctiveness.

In Vitro Assessment of Antimicrobial, Antioxidant, and Cytotoxic Properties of Saccharin-Tetrazolyl and -Thiadiazolyl Derivatives: The Simple Dependence of the pH Value on Antimicrobial Activity.

The antimicrobial, antioxidant, and cytotoxic activities of a series of saccharin-tetrazolyl and -thiadiazolyl analogs were examined. The assessment of the antimicrobial properties of the referred-to molecules was completed through an evaluation of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values against Gram-positive and Gram-negative bacteria and yeasts. Scrutiny of the MIC and MBC values of the compounds at pH 4.

Analysis of Immunogenicity Data in the Product Information of Biological Drugs: A Need to Report Immunogenicity Data Systematically.

Objective: The aim of this analysis was to evaluate whether the current unsystematic assessment leads to sufficient reporting of immunogenicity-related information in the Summary of Product Characteristics (SmPCs) of biological products approved in the European market.

Methods: Immunogenicity-related information was identified and extracted from a group of 72 biological drugs that complied with drug-selection criteria. Afterwards, 12 dichotomous questions were proposed to evaluate whether any issues are being commonly neglected.

Ceramide Domains in Health and Disease: A Biophysical Perspective.

Ceramides are the central molecules in sphingolipid metabolism. In addition, they are recognized as important modulators of cell function, playing key roles in several cellular processes that range from cell proliferation to cell death. Moreover, ceramides were implicated in multiple diseases, including cancer, neurodegenerative and metabolic diseases, and also in infection by different pathogens.

Mammalian sphingoid bases: Biophysical, physiological and pathological properties.

Sphingoid bases encompass a group of long chain amino alcohols which form the essential structure of sphingolipids. Over the last years, these amphiphilic molecules were moving more and more into the focus of biomedical research due to their role as bioactive molecules. In fact, free sphingoid bases interact with specific receptors and target molecules and have been associated with numerous biological and physiological processes.

Meeting Report - The 2019 FEBS special meeting on sphingolipid biology: sphingolipids in physiology and pathology.

Sphingolipids are a fundamental class of molecules that are involved in structural, organizational and signaling properties of eukaryotic membranes. Defects in their production or disposal lead to acquired and inherited human diseases. A growing community of scientists has embraced the challenge to dissect different aspects of sphingolipid biology using a variety of approaches, and a substantial part of this community met last May in the beautiful town of Cascais in Portugal.

Nucleolin-based targeting strategies for cancer therapy: from targeted drug delivery to cytotoxic ligands.

Cancer is currently the second leading cause of death worldwide and current therapeutic approaches remain ineffective in several cases. Therefore, there is a need to develop more efficacious therapeutic agents, especially for subtypes of cancer lacking targeted therapies. Limited drug penetration into tumors impairs the efficacy of therapies targeting cancer cells.

Mammalian sphingoid bases: Biophysical, physiological and pathological properties.

Sphingoid bases encompass a group of long chain amino alcohols which form the essential structure of sphingolipids. Over the last years, these amphiphilic molecules were moving more and more into the focus of biomedical research due to their role as bioactive molecules. In fact, free sphingoid bases interact with specific receptors and target molecules, and have been associated with numerous biological and physiological processes.

Evaluation of a gene-by-gene approach for prospective whole-genome sequencing-based surveillance of multidrug resistant Mycobacterium tuberculosis.

Whole-genome sequencing (WGS) offers unprecedented resolution for tracking Mycobacterium tuberculosis transmission and antibiotic-resistance spread. Still, the establishment of standardized WGS-based pipelines and the definition of epidemiological clusters based on genetic relatedness are under discussion. We aimed to implement a dynamic gene-by-gene approach, fully relying on freely available software, for prospective WGS-based tuberculosis surveillance, demonstrating its application for detecting transmission chains by retrospectively analysing all M/XDR strains isolated in 2013-2017 in Portugal.

Genome-wide analysis of Mycobacterium tuberculosis polymorphisms reveals lineage-specific associations with drug resistance.

Background: Continuing evolution of the Mycobacterium tuberculosis (Mtb) complex genomes associated with resistance to anti-tuberculosis drugs is threatening tuberculosis disease control efforts. Both multi- and extensively drug resistant Mtb (MDR and XDR, respectively) are increasing in prevalence, but the full set of Mtb genes involved are not known. There is a need for increased sensitivity of genome-wide approaches in order to elucidate the genetic basis of anti-microbial drug resistance and gain a more detailed understanding of Mtb genome evolution in a context of widespread antimicrobial therapy.

Therapeutic Strategies Targeting Amyloid-β in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-β (Aβ) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD.

Cisplatin-Membrane Interactions and Their Influence on Platinum Complexes Activity and Toxicity.

Cisplatin and other platinum(II) analogs are widely used in clinical practice as anti-cancer drugs for a wide range of tumors. The primary mechanism by which they exert their action is through the formation of adducts with genomic DNA. However, multiple cellular targets by platinum(II) complexes have been described.

Cytotoxicity and Chemotherapeutic Potential of Natural Rosin Abietane Diterpenoids and their Synthetic Derivatives.

Cancer is a major cause of morbidity and mortality worldwide. Chemotherapeutic agents currently used in cancer treatment are associated with severe side effects and development of resistance. Thus, there is a pressing need for novel and more potent anticancer drugs with high selectivity for tumor cells and reduced toxicity to normal tissue.

Anticancer Hybrid Combinations: Mechanisms of Action, Implications and Future Perspectives.

The exponential growth of cancer cases worldwide together with recent advances concerning the pathophysiological mechanisms of the disease at the molecular level led to a paradigm shift in chemotherapy, from monotherapy to targeted drug combination regimens. However, adverse effects and the emergence of multidrug resistance (MDR) limit the effectiveness of these therapies. In this context, hybrid combinations mixing anticancer drugs and bioactive phytochemical components from medicinal plants, or even plant extracts, that can act synergistically on multiple targets and signaling pathways represent a promising approach with the potential to expand the current therapeutic arsenal.

1-Deoxysphingolipids.

Sphingolipids (SLs) are fundamental components of eukaryotic cells. 1-Deoxysphingolipids differ structurally from canonical SLs as they lack the essential C1-OH group. Consequently, 1-deoxysphingolipids cannot be converted to complex sphingolipids and are not degraded over the canonical catabolic pathways.

Nitrogen isotope signature evidences ammonium deprotonation as a common transport mechanism for the AMT-Mep-Rh protein superfamily.

Ammonium is an important nitrogen (N) source for living organisms, a key metabolite for pH control, and a potent cytotoxic compound. Ammonium is transported by the widespread AMT-Mep-Rh membrane proteins, and despite their significance in physiological processes, the nature of substrate translocation (NH/NH) by the distinct members of this family is still a matter of controversy. Using cells expressing representative AMT-Mep-Rh ammonium carriers and taking advantage of the natural chemical-physical property of the N isotopic signature linked to NH/NH conversion, this study shows that only cells expressing AMT-Mep-Rh proteins were depleted in N relative to N when compared to the external ammonium source.

Terpenoids from Euphorbia pedroi as Multidrug-Resistance Reversers.

The phytochemical study of Euphorbia pedroi led to the isolation of a new tetracyclic triterpenoid with an unusual spiro scaffold, spiropedroxodiol (1), along with seven known terpenoids (2-8). Aiming at obtaining compounds with improved multidrug-resistance (MDR) reversal activity, compound 8, an ent-abietane diterpene, was derivatized by introducing nitrogen-containing and aromatic moieties, yielding compounds 9-14. The structures of compounds were characterized by detailed spectroscopic analysis, including 2D NMR experiments (COSY, HMQC/HSQC, HMBC, and NOESY).

Using a cancer registry to capture signals of adverse events following immune and targeted therapy for melanoma.

Background Toxicity of oncology treatments in real-life patients is frequently disregarded and hence underreported. Objective To characterize adverse events (AEs) of immunotherapy and targeted therapy reported in patients with locally advanced or metastatic melanoma. Setting District Hospital for Cancer treatment (Instituto Português de Oncologia de Lisboa Francisco Gentil).

Dissecting whole-genome sequencing-based online tools for predicting resistance in Mycobacterium tuberculosis: can we use them for clinical decision guidance?

Whole-genome sequencing (WGS)-based bioinformatics platforms for the rapid prediction of resistance will soon be implemented in the Tuberculosis (TB) laboratory, but their accuracy assessment still needs to be strengthened. Here, we fully-sequenced a total of 54 multidrug-resistant (MDR) and five susceptible TB strains and performed, for the first time, a simultaneous evaluation of the major four free online platforms (TB Profiler, PhyResSE, Mykrobe Predictor and TGS-TB). Overall, the sensitivity of resistance prediction ranged from 84.

Anticancer activity and antibody-dependent cell-mediated cytotoxicity of novel anti-nucleolin antibodies.

Nucleolin arises as a relevant target for cancer therapy, as it is overexpressed at the surface of cancer and angiogenic endothelial cells thus enabling a dual cellular targeting strategy. Immunotherapeutic strategies, albeit of proven therapeutic relevance, have been scarcely explored against this target. Therefore, this work aimed at engineering an anti-nucleolin VHH-based antibody capable of triggering anticancer immune responses.

L.: an update review of its phytochemistry and biological activity.

The worldwide interest in the use of medicinal plants has been growing, and its beneficial effects being rediscovered for the development of new drugs. Based on their vast ethnopharmacological applications, which inspired current research in drug discovery, natural products can provide new and important leads against various pharmacological targets. This work pioneers an extensive and an updated literature review on the current state of research on L.