How Genomics Is Changing What We Know About the Evolution and Genome of Bordetella pertussis

The evolution of Bordetella pertussis from a common ancestor similar to Bordetella bronchiseptica has occurred through large-scale gene loss, inactivation and rearrangements, largely driven by the spread of insertion sequence element repeats throughout the genome. B. pertussis is widely considered to be monomorphic, and recent evolution of the B. pertussis genome appears to, at least in part, be driven by vaccine-based selection. Given the recent global resurgence of whooping cough despite the wide-spread use of vaccination, a more thorough understanding of B. pertussis genomics could be highly informative. In this chapter we discuss the evolution of B. pertussis, including how vaccination is changing the circulating B. pertussis population at the gene-level, and how new sequencing technologies are revealing previously unknown levels of inter- and intra-strain variation at the genome-level

Cabozantinib as a second-line treatment option in hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) is one of the most frequent tumors affecting the gastrointestinal tract and a universal cause of morbidity and mortality. Cabozantinib is a strong multi-inhibitor of receptor tyrosine kinases approved for renal cell carcinoma that could be useful also for the treatment of HCC. Areas covered: This review describes the chemical structure, the pharmacologic properties and current knowledge of the efficacy of cabozantinib in the treatment of HCC based on data available from first phase and later phase clinical trials. The ongoing studies testing cabozantinib, either alone or in combination with other drugs, are also described. Expert opinion: Despite the recent achievements in the use of cabozantinib for patients diagnosed with hepatocellular carcinoma, data are still needed to allow clinicians to make better decisions on how to treat specific patient subgroups.</p

Cabozantinib as a second-line treatment option in hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) is one of the most frequent tumors affecting the gastrointestinal tract and a universal cause of morbidity and mortality. Cabozantinib is a strong multi-inhibitor of receptor tyrosine kinases approved for renal cell carcinoma that could be useful also for the treatment of HCC. Areas covered: This review describes the chemical structure, the pharmacologic properties and current knowledge of the efficacy of cabozantinib in the treatment of HCC based on data available from first phase and later phase clinical trials. The ongoing studies testing cabozantinib, either alone or in combination with other drugs, are also described. Expert opinion: Despite the recent achievements in the use of cabozantinib for patients diagnosed with hepatocellular carcinoma, data are still needed to allow clinicians to make better decisions on how to treat specific patient subgroups.</p

Nanopore-Based Metagenomic Sequencing in Respiratory Tract Infection:A Developing Diagnostic Platform

Respiratory tract infection (RTI) remains a significant cause of morbidity and mortality across the globe. The optimal management of RTI relies upon timely pathogen identification via evaluation of respiratory samples, a process which utilises traditional culture-based methods to identify offending microorganisms. This process can be slow and often prolongs the use of broad-spectrum antimicrobial therapy, whilst also delaying the introduction of targeted therapy as a result. Nanopore sequencing (NPS) of respiratory samples has recently emerged as a potential diagnostic tool in RTI. NPS can identify pathogens and antimicrobial resistance profiles with greater speed and efficiency than traditional sputum culture-based methods. Increased speed to pathogen identification can improve antimicrobial stewardship by reducing the use of broad-spectrum antibiotic therapy, as well as improving overall clinical outcomes. This new technology is becoming more affordable and accessible, with some NPS platforms requiring minimal sample preparation and laboratory infrastructure. However, questions regarding clinical utility and how best to implement NPS technology within RTI diagnostic pathways remain unanswered. In this review, we introduce NPS as a technology and as a diagnostic tool in RTI in various settings, before discussing the advantages and limitations of NPS, and finally what the future might hold for NPS platforms in RTI diagnostics.</p

Nanopore-Based Metagenomic Sequencing in Respiratory Tract Infection:A Developing Diagnostic Platform

Respiratory tract infection (RTI) remains a significant cause of morbidity and mortality across the globe. The optimal management of RTI relies upon timely pathogen identification via evaluation of respiratory samples, a process which utilises traditional culture-based methods to identify offending microorganisms. This process can be slow and often prolongs the use of broad-spectrum antimicrobial therapy, whilst also delaying the introduction of targeted therapy as a result. Nanopore sequencing (NPS) of respiratory samples has recently emerged as a potential diagnostic tool in RTI. NPS can identify pathogens and antimicrobial resistance profiles with greater speed and efficiency than traditional sputum culture-based methods. Increased speed to pathogen identification can improve antimicrobial stewardship by reducing the use of broad-spectrum antibiotic therapy, as well as improving overall clinical outcomes. This new technology is becoming more affordable and accessible, with some NPS platforms requiring minimal sample preparation and laboratory infrastructure. However, questions regarding clinical utility and how best to implement NPS technology within RTI diagnostic pathways remain unanswered. In this review, we introduce NPS as a technology and as a diagnostic tool in RTI in various settings, before discussing the advantages and limitations of NPS, and finally what the future might hold for NPS platforms in RTI diagnostics.</p

Comparative genomics of Bordetella pertussis isolates from New Zealand, a country with an uncommonly high incidence of whooping cough

Whooping cough, the respiratory disease caused by Bordetella pertussis , has undergone a wide-spread resurgence over the last several decades. Previously, we developed a pipeline to assemble the repetitive B. pertussis genome into closed sequences using hybrid nanopore and Illumina sequencing. Here, this sequencing pipeline was used to conduct a more high-throughput, longitudinal screen of 66 strains isolated between 1982 and 2018 in New Zealand. New Zealand has a higher incidence of whooping cough than many other countries; usually at least twice as many cases per 100000 people as the USA and UK and often even higher, despite similar rates of vaccine uptake. To the best of our knowledge, these strains are the first New Zealand B. pertussis isolates to be sequenced. The analyses here show that, on the whole, genomic trends in New Zealand B. pertussis isolates, such as changing allelic profile in vaccine-related genes and increasing pertactin deficiency, have paralleled those seen elsewhere in the world. At the same time, phylogenetic comparisons of the New Zealand isolates with global isolates suggest that a number of strains are circulating in New Zealand, which cluster separately from other global strains, but which are closely related to each other. The results of this study add to a growing body of knowledge regarding recent changes to the B. pertussis genome, and are the first genetic investigation into B. pertussis isolates from New Zealand

The Hippo pathwaya:Key interaction and catalytic domains in organ growth control, stem cell self-renewal and tissue regeneration

The Hippo pathway is a conserved pathway that interconnects with several other pathways to regulate organ growth, tissue homoeostasis and regeneration, and stem cell self-renewal. This pathway is unique in its capacity to orchestrate multiple processes, from sensing to execution, necessary for organ expansion. Activation of the Hippo pathway core kinase cassette leads to cytoplasmic sequestration of the nuclear effectors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), consequently disabling their transcriptional co-activation function. Components upstream of the core kinase cassette have not been well understood, especially in vertebrates, but are gradually being elucidated and include cell polarity and cell adhesion proteins.</jats:p

An overview of the clinical use of cabozantinib in the treatment of advanced non-clear-cell renal cell carcinoma (NCCRCC)

Patients diagnosed with non-clear renal cell carcinoma have often been excluded from clinical trials due to the shortage of treatments available, the low incidence of tumours with non-clear histology, and the corresponding diversity of intrinsic molecular features. This approach led to a knowledge gap in finding the optimal treatment for patients diagnosed with non-clear cell renal carcinoma. Cabozantinib, a potent multiple tyrosine kinase receptor inhibitor, has been recently investigated in patients with non-clear cell histologies of renal cell cancer. In this review, we have summarized available data on the use of cabozantinib in non-clear renal cell carcinoma.</p

A peptide from the staphylococcal protein Efb binds P-selectin and inhibits the interaction of platelets with leukocytes

Aims: P-selectin is a key surface adhesion molecule for the interaction of platelets with leukocytes. We have shown previously that the N-terminal domain of Staphylococcus aureus extracellular fibrinogen-binding protein (Efb) binds to P-selectin and interferes with platelet-leukocyte aggregate formation. Here, we aimed to identify the minimal Efb motif required for binding platelets and to characterize its ability to interfering with the formation of platelet-leukocyte aggregates. Methods and Results: Using a library of synthetic peptides, we mapped the platelet-binding site to a continuous 20 amino acid stretch. The peptide Efb68-87 was able to bind to resting and, to a greater extent, thrombin-stimulated platelets in the absence of fibrinogen. Dot blots, pull-down assays and P-selectin glycoprotein ligand-1 (PSGL-1) competitive binding experiments identified P-selectin as the cellular docking site mediating Efb68-87 platelet binding. Accordingly, Efb68-87 did not bind to other blood cells and captured platelets from human whole blood under low shear stress conditions. Efb68-87 did not affect platelet activation as tested by aggregometry, flow cytometry and immunoblotting, but inhibited the formation of platelet-leukocyte aggregates (PLAs). Efb68-87 also interfered with the platelet-dependent stimulation of neutrophil extracellular traps (NETs) formation in vitro. Conclusions: We have identified Efb68-87 as a novel selective platelet-binding peptide. Efb68-87 binds directly to P-selectin and inhibits interactions of platelets with leukocytes that lead to PLA and NET formation. As PLAs and NETs play a key role in thromboinflammation, Efb68-87 is an exciting candidate for the development of novel selective inhibitors of the proinflammatory activity of platelets