Formation, Deformation, and Incision of Colorado River Terraces Upstream of Moab, Utah

Fluvial terraces contain information about incision, deformation, and climate change. In this study, a chronostratigraphic record of Colorado River terraces is constructed from optically stimulated luminescence (OSL) dating of Pleistocene alluvium and real-time kinematic (RTK) GPS surveys of terrace form. This record is analyzed to relate terrace formation to late Pleistocene climate fluctuations, and terrain analyses and longitudinal profile patterns reveal recent salt-related activity in the northern Paradox Basin as well as patterns in Colorado Plateau incision. A well-preserved, correlative suite of mainstem (M) fluvial deposits exists along the Colorado River upstream of Moab, Utah. Absolute dates indicate sedimentation \u3e70 ka (M7, M6/M5), 70-50 ka (M4), 50-40 ka (M3), and 35-25 ka (M2). The M4 and M2 formed during the crescendo to glacial maxima, but the M7, M6/M5, and M3 were deposited during variable climate of marine isotope stages (MIS) 5 and 3. Deposits include thin (\u3c7 \u3em) strath terraces and thick (10-20 m) fill terraces. Our results suggest that terrace sedimentation is linked to enhanced sediment flux during glaciations in Rocky Mountain headwaters (M4 and M2), but major deposits also formed during dryland tributary sediment loading with markedly different timing (M6/M5 and M3). Conversely, incision may be driven by higher deglacial flows. Clast provenance data demonstrate greater percentages of locally-sourced sediment in M6/M5 and M3 deposits. Valley-bottom geometry and neotectonics control terrace form, with strath terraces found in bedrock-restricted reaches and fill terraces in wider valleys. Previously speculated salt deformation in this area is confirmed by localized collapse preserved in M4 stratigraphy in the Cache Valley graben and ~15 m of broader subsidence upstream. Concavity and knickzone distributions in tributary profiles are discordant and represent subtle expressions of salt-tectonic activity. Finally, a surprisingly rapid incision rate of ~900 m/Ma over the past ~70 ka suggests that the Colorado River may be responding to flexural rebound in the central plateau, but is faster than that predicted by the debated bull\u27s-eye pattern of regional incision. This locally high rate may also reflect a transient wave of incision, as suggested by increased Pleistocene rates interpreted by studies in Glen and Grand canyons

Linkages of fluvial terrace formation and geometry to Milankovitch-scale climate change revealed by the chronostratigraphy of the Colorado River above Moab, UT, and regional correlations

The Colorado River flows from its Rocky Mountain headwaters to the Gulf of California, draining most of the Colorado Plateau. Although the river’s hydrology is set in the Rockies, its sediment load is largely supplied by the plateau drylands of the lower drainage. Terrace genesis at Milankovitch timescales • Reflects changing dynamics between fluctuating hydrology and local sediment supply? • Relations to major late Pleistocene climate shifts? • Do study terraces correlate regionally? (i.e. are pulses of sedimentation transient or synchronous?) • What controls the formation of fill vs. strath terraces? Deformation of terraces • Is there a detectable influence of salt tectonism on terrace form and type? Our goal is to address these questions through detailed chronostratigraphy, correlation, surveying, and long-profile analysis

Active salt deformation and rapid, transient incision along the Colorado River near Moab, Utah

In certain settings, erosion is driven by and balanced with tectonic uplift, but the evolution of many landscapes is dominated by other factors such as geologic substrate, drainage history, and transient incision. The Colorado Plateau is an example where these controls are debated and where salt deformation is hypothesized to be locally active and driven by differential unloading, although this is unconfirmed and unquantified in most places. We use luminescence-dated Colorado River terraces upstream of Moab, Utah, to quantify rates of salt-driven subsidence and uplift at the local scale. Active deformation in the study area is also supported by patterns of concavity along tributary drainages crossing salt structures. Subsidence in Professor Valley at a time-averaged rate of _500 m/Myr (meters/million years) is superimposed upon rapid bedrock incision rates that increase from _600 to _900 m/Myr upstream through the study area. Such high rates are unexpected given the absence of sources of regional tectonic uplift here. Instead, the incision rate pattern across the greater area is consistent with a transient signal, perhaps still from ancient drainage integration through Grand Canyon far downstream, and then amplified by unloading at both the broad regional scale and at the local canyon scale. ©2015. American Geophysical Union. All Rights Reserved

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa.MethodsIn these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety.ResultsAs of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred.ConclusionBintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.Multiple funders. See acknowledgments within article for details.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.semcancer.2015.09.00