Association of differential expression of immunoregulatory molecules and presence of targetable mutations may inform rational design of clinical trials.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and genomic biomarker-driven targeted therapies have revolutionized the modern oncologic treatment arsenal. The next step has been to combine targeted agents and ICIs. In doing so, some combination regimens may be more logical than others. PATIENTS AND METHODS: Whole-exome and whole-transcriptome sequencing were performed on 2739 unselected later-stage clinical cases from 24 solid tumor subtypes in the NantHealth database, and data were also curated from 5746 similarly sequenced patients across 28 solid tumor subtypes in The Cancer Genome Atlas (TCGA). Significant differential expression of 10 immunoregulatory molecules [IRMs (genes)] was analyzed for association with mutant versus wild-type genes. RESULTS: Twenty-three significant associations between currently actionable variants and RNA-expressed checkpoint genes were identified in the TCGA cases; 10 were validated in the external cohort of 2739 clinical cases from NantHealth (P values were adjusted using Benjamini-Hochberg multiple hypothesis correction to reduce false-discovery rate). Within the same 5746 TCGA profiles, 2740 TCGA patients were identified as having one or more potentially oncogenic single-nucleotide variant (SNV) mutation within an established 50-gene hotspot panel. Of the 50 genes, SNVs within 15 were found to be significantly associated with differential expression of at least one IRM after adjusting for tissue enrichment; six were confirmed significant associations in an independent set of 2739 clinical cases from NantHealth. CONCLUSIONS: Logically combining ICIs with targeted therapies may offer unique treatment strategies for patients with cancer. The presence of specific mutations impacts the expression of IRMs, an observation of potential importance for selecting combinations of gene- and immune-targeted therapeutics.

Determination of Structure of Aggregates by Confocal Scanning Laser Microscopy.

The fractal dimension of a particle aggregate can provide fundamental information on the structure and origin of the aggregate. The analysis of large chemically homogeneous fractal objects has been achieved, but reliable methods of estimating the fractal dimensions of large and chemically heterogeneous aggregates are needed. To this end, we used confocal scanning laser microscopy in which thin optical sections of aggregates were obtained in order to calculate their 2D and ultimately 3D fractal dimensions according to the Mandelbrot theory. Fractal dimensions of 2.08 +/- 0.11 for a Brownian aggregation of latex particles and 2.25 +/- 0.12 for shear aggregation were determined using the confocal technique. These values are within the ranges for universality classes predicted for such aggregates and observed by previous investigators. Thus, this method appears to provide reliable estimates of the fractal dimension with particular utility in the characterization of aggregates composed of larger particles or complex materials where the fractal dimension may not be accessible by light-scattering measurements. The confocal method is used to analyze flocs of activated sludge material as one example of the application of this method to more complex, large (up to 500 µm), and chemically heterogeneous flocs. Copyright 1998 Academic Press.

Hydrodynamics of Fractal Aggregates with Radially Varying Permeability.

Hydrodynamic properties of fractal aggregates with radially varying permeability are investigated in terms of two parameters: radius of equivalent solid sphere experiencing the same drag as the aggregate (Omega*radius of aggregate) and fluid collection efficiency (eta) of the aggregate. Resistance to the fluid flow through the aggregate is predicted to increase with increasing fractal dimension, while the fluid collection efficiency is expected to decrease. It is shown that a reasonable estimate of the fluid drag force on a fractal aggregate may be obtained by assigning a constant volume-averaged porosity to the aggregate and using any of the expressions available in the literature for aggregates with uniform permeability. The two hydrodynamic parameters, Omega and eta, are used to modify the existing expressions for interactions between solid spheres to account for the porous nature of aggregates and thus calculate the collision rate kernels for interacting aggregates. The ratio of hydrodynamic radius of an aggregate to its radius of gyration predicted by the proposed model was in reasonable agreement with an experimental value reported in the literature.