John P. Miller

The relative importance in geomorphic processes of extreme or catastrophic events and more frequent events of smaller magnitude can be measured in terms of (1) the relative amounts of "work" done on the landscape and (2) in terms of the formation of specific features of the landscape. For many processes, above the level of competence, the rate of movement of material can be expressed as a power function of some stress, as for example, shear stress. Because the frequency distributions of the magnitudes of many natural events, such as floods, rainfall, and wind speeds, approximate log-normal distributions, the product of frequency and rate, a measure of the work performed by events having different frequencies and magnitudes will attain a maximum. The frequency at which this maximum occurs provides a measure of the level at which the largest portion of the total work is accomplished. Analysis of records of sediment transported by rivers indicates that the largest portion of the total load is carried by flows which occur on the average once or twice each year. As the variability of the flow increases and hence as the size of the drainage basin decreases, a larger percentage of the total load is carried by less frequent flows. In many basins 90 per cent of the sediment is removed by storm discharges which recur at least once every five years. Transport of sand and dust by wind in general follows the same laws. The extreme velocities associated with infrequent events are compensated for by their rarity, and it is found that the greatest bulk of sediment is transported by more moderate events. Many rivers are competent to erode both bed and banks during moderate flows. Observations of natural channels suggest that the channel shape as well as the dimensions of meandering rivers appear to be associated with flows at or near the bankfull stage. The fact that the bankfull stage recurs on the average once every year or two years indicates that these features of many alluvial rivers are controlled by these more frequent flows rather than by the rarer events of catastrophic magnitude. Because the equilibrium form of wind-blown dunes and of wave-formed beaches is quite unstable, the frequency of the events responsible for their form is less clearly definable. However, dune form and orientation are determined by both wind velocity and frequency. Similarly, a hypothetical example suggests that beach slope oscillates about a mean value related in part to wave characteristics generated by winds of moderate speed. Where stresses generated by frequent events are incompetent to transport available materials, less frequent ones of greater magnitude are obviously required. Closer observation of many geomorphic processes is required before the relative importance of different processes and of events of differing magnitude and frequency in the formation of given features of the landscape can be adequately evaluated.

UNLABELLED: Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features in pretreatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of patients with metastatic melanoma initially treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) blockade (n = 53) followed by programmed death-1 (PD-1) blockade at progression (n = 46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In this study, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified. SIGNIFICANCE: These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types. Cancer Discov; 6(8); 827-37. ©2016 AACR.See related commentary by Teng et al., p. 818This article is highlighted in the In This Issue feature, p. 803.

Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.

The hydraulic factors of width, depth, velocity, and suspendedsediment load of ephemeral streams near Santa Fe, N. Mex., were measured during flood flow. Later, channel slope was measured. These flood-flow data, in conjunction with an analysis of drainage-basin configuration by the methods proposed by Horton, are used to determine the generalized interrelation of stream order and hydraulic variables. The method developed for determining this interrelation allows an integration of the geographic and physiographic characteristics of a drainage basin with the channel characteristics; specifically, the interrelation of the length, number, and drainage area of streams of various sizes with their respective discharge, width, depth, velocity, slope, channel roughness, and suspended-sediment load.