28 research outputs found
Estimating a Representative Value and Proportion of True Zeros for Censored Analytical Data with Applications to Contaminated Site Assessment
This paper demonstrates a maximum
likelihood (ML)-based approach
to derive representative (âbest guessâ) contaminant
concentrations from data with censored values (e.g., less than the
detection limit). The method represents an advancement over existing
techniques because it is capable of estimating the proportion of measurements
that are true zeros and incorporating varying levels of censorship
(e.g., sample specific detection limits, changes through time in method
detection). The ability of the method to estimate the proportion of
true zeros is validated using precipitation data. The stability and
flexibility of the method are demonstrated with stochastic simulation,
a sensitivity analysis, and unbiasedness analysis including varying
numbers of significant digits. A key aspect of this paper is the application
of the statistical analysis to real site rock core contaminant concentration
data collected within a plume at two locations using high resolution
depth-discrete sampling. Comparison of the representative values for
concentrations at each location along the plume center-line shows
a larger number of true zeros and generally lower concentrations at
the downgradient location according to the conceptual site model,
leading to improved estimates of attenuation with distance and/or
time and associated confidence; this is not achievable using deterministic
methods. The practical relevance of the proposed method is that it
provides an improved basis for evaluating change (spatial, temporal,
or both) in environmental systems
CD44 engagement enhances acute myeloid leukemia cell adhesion to the bone marrow microenvironment by increasing VLA-4 avidity.
Adhesive properties of leukemia cells shape the degree of organ infiltration and the extent of leukocytosis. CD44 and the integrin VLA-4, a CD49d/CD29 heterodimer, are important factors of progenitor cell adhesion in bone marrow (BM). Here, we report their cooperation in acute myeloid leukemia (AML) by a novel non-classical CD44-mediated way of inside-out VLA-4 activation. In primary AML BM samples from patients and the OCI-AML3 cell line, CD44 engagement by hyaluronan induced inside-out activation of VLA-4 resulting in enhanced leukemia cell adhesion on VCAM-1. This was independent from VLA-4 affinity regulation but based on ligand-induced integrin clustering on the cell surface. CD44-induced VLA-4 activation could be inhibited by the Src family kinase inhibitor PP2 and the multikinase inhibitor midostaurin. In further consequence, the increased adhesion on VCAM-1 allowed AML cells to strongly bind stromal cells. Thereby VLA-4/VCAM-1 interaction promoted activation of Akt, MAPK, NF-kB and mTOR signaling and decreased AML cell apoptosis. Collectively, our investigations provide a mechanistic description of an unusual CD44 function in regulating VLA-4 avidity in AML, supporting AML cell retention in the supportive BM microenvironment