Serum Flt3 ligand is biomarker of progenitor cell mass and prognosis in acute myeloid leukemia, bioRxiv, 2019-03-25

AbstractFms-like tyrosine kinase 3 (Flt3) is a hematopoietic growth factor receptor expressed on lymphomyeloid progenitors and frequently, by AML blasts. Its ligand, Flt3L, has non-hematopoietic and lymphoid origins, is detectable during homeostasis and increases to high levels in states of hypoplasia due to genetic defects or treatment with cytoreductive agents. Measurement of Flt3L by ELISA reveals that Flt3+AML, is associated with depletion of Flt3L to undetectable levels. After induction chemotherapy, Flt3L is restored in patients entering CR, but remains depressed in those with refractory disease. Weekly sampling reveals marked differences in the kinetics of Flt3L response during the first 6 weeks of treatment, proportionate to the clearance of blasts and cellularity of the BM. In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 135 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib. In these patients, attainment of CR was associated with higher Flt3L at day 26 (Mann-Whitney p &lt; 0.0001). Day 26 Flt3L was also associated with survival Flt3L ≤ 291pgml was associated with inferior event-free survival; and, Flt3L &gt;1185pgml was associated with higher overall survival (p = 0.0119). Serial measurement of Flt3L in patients who had received a hematopoietic stem cell transplant for AML further illustrated the potential value of declining Flt3L to identify relapse. Together these observations suggest that measurement of Flt3L provides a non-invasive estimate of progenitor cell mass in most patients with AML, with the potential to inform clinical decisions.Graphical abstract<jatsfig id=ufig1 position=float fig-type=figure orientation=portrait><jatsgraphic xmlnsxlink=httpwww.w3.org1999xlink xlinkhref=588319_ufig1 position=float orientation=portrait >

biorxiv cancer-biology 100-200-users 2019

The ability of single genes vs full genomes to resolve time and space in outbreak analysis, bioRxiv, 2019-03-24

AbstractInexpensive pathogen genome sequencing has had a transformative effect on the field of phylodynamics, where ever increasing volumes of data have promised real-time insight into outbreaks of infectious disease. As well as the sheer volume of pathogen isolates being sequenced, the sequencing of whole pathogen genomes, rather than select loci, has allowed phylogenetic analyses to be carried out at finer time scales, often approaching serial intervals for infections caused by rapidly evolving RNA viruses. Despite its utility, whole genome sequencing of pathogens has not been adopted universally and targeted sequencing of loci is common in some pathogen-specific fields. In this study we aim to highlight the utility of sequencing whole genomes of pathogens by re-analysing a well-characterised collection of Ebola virus sequences in the form of complete viral genomes (~19kb long) or the rapidly evolving glycoprotein (GP, ~2kb long) gene. We quantify changes in phylogenetic, temporal, and spatial inference resolution as a result of this reduction in data and compare these to theoretical expectations. We propose a simple intuitive metric for quantifying temporal resolution, i.e. the time scale over which sequence data might be informative of various processes as a quick back-of-the-envelope calculation of statistical power available to molecular clock analyses.

biorxiv epidemiology 0-100-users 2019

 

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