4 research outputs found
MOESM1 of Extraordinary clinical benefit to sequential treatment with targeted therapy and immunotherapy of a BRAF V600E and PD-L1 positive metastatic lung adenocarcinoma
Additional file 1. Full report of comprehensive genomic profiling (CGP) based on FoundationOneÂŽ panel
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Microbial diversity and antimicrobial resistance in faecalsamples from acute medical patients assessed through metagenomic sequencing
Antimicrobial resistance (AMR) is a threat to global public health. However, unsatisfactory approaches to directly measuring the AMR burden carried by individuals has hampered efforts to assess interventions aimed at reducing selection for AMR. Metagenomics can provide accurate detection and quantification of AMR genes within an individual person’s faecal flora (their gut “resistome”). Using this approach, we aimed to test the hypothesis that differences in antimicrobial use across different hospitals in the United Kingdom will result in observable differences in the resistome of individual patients. Three National Health Service acute Hospital Trusts with markedly different antibiotic use and Clostridioides difficile infection rates collected faecal samples from anonymous patients which were discarded after C. difficile testing over a period of 9 to 15 months. Metagenomic DNA was extracted from these samples and sequenced using an Illumina NovaSeq 6000 platform. The resulting sequencing reads were analysed for taxonomic composition and for the presence of AMR genes. Among 683 faecal metagenomes we found huge variation between individuals in terms of taxonomic diversity (Shannon Index range 0.10–3.99) and carriage of AMR genes (Median 1.50 genes/cell/sample overall). We found no statistically significant differences in diversity (median Shannon index 2.16 (IQR 1.71–2.56), 2.15 (IQR 1.62–2.50) and 2.26 (IQR 1.55–2.51)) or carriage of AMR genes (median 1.37 genes/cell/sample (IQR 0.70–3.24), 1.70 (IQR 0.70–4.52) and 1.43 (IQR 0.55–3.71)) at the three trusts respectively. This was also the case across the sample collection period within the trusts. While we have not demonstrated differences over place or time using metagenomic sequencing of faecal discards, other sampling frameworks may be more suitable to determine whether organisational level differences in antibiotic use are associated with individual-level differences in burden of AMR carriage
Selective Reaction Monitoring of Negative Electrospray Ionization Acetate Adduct Ions for the Bioanalysis of Dapagliflozin in Clinical Studies
Dapagliflozin
(Farxiga), alone, or in the fixed dose combination
with metformin (Xigduo), is an orally active, highly selective, reversible
inhibitor of sodium-glucose cotransporter type 2 (SGLT2) that is marketed
in United States, Europe, and many other countries for the treatment
of type 2 diabetes mellitus. Here we report a liquid chromatography–tandem
mass spectrometry (LC–MS/MS) bioanalytical assay of dapagliflozin
in human plasma. A lower limit of quantitation (LLOQ) at 0.2 ng/mL
with 50 ÎĽL of plasma was obtained, which reflects a 5-fold improvement
of the overall assay sensitivity in comparison to the previous most
sensitive assay using the same mass spectrometry instrumentation.
In this new assay, acetate adduct ions in negative electrospray ionization
mode were used as the precursor ions for selective reaction monitoring
(SRM) detection. Sample preparation procedures and LC conditions were
further developed to enhance the column life span and achieve the
separation of dapagliflozin from potential interferences, especially
its epimers. The assay also quantifies dapagliflozin’s major
systemic circulating glucuronide metabolite, BMS-801576, concentrations
in human plasma. The assay was successfully transferred to contract
research organizations (CROs), validated, and implemented for the
sample analysis of pediatric and other critical clinical studies.
This assay can be widely used for bioanalytical support of future
clinical studies for the newly approved drug Farxiga or any combination
therapy containing dapagliflozin