Influence of bilberry-derived anthocyanidins on key regulators of colorectal cancer development.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths within the United States. A variety of factors including exposure to environmental carcinogens, such as benzo[a]pyrene (B[a]P), dysbiosis of the gut microbiome and hereditary influences, including APC mutations, have been shown to lead to an increased risk of developing colorectal cancer. Given the recent alarming rise in cases of colorectal cancer diagnosed in individuals under the age of 40, further insight into developing novel and effective prevention and treatment strategies are warranted. The family of plant pigments known as the anthocyanins has been identified with a variety of health benefits including chemopreventive and therapeutic effects. However, a limitation to current clinical applications of anthocyanins is the high doses that are required. In order to overcome this barrier we tested the active moiety, anthocyanidins, native bilberry mixture of anthocyanidins (Anthos), at various doses for chemopreventive and therapeutic effects against colorectal cancer both in vitro and in vivo. Anthos treatment led to favorable modulation of several key contributors to the development of CRC including Src/EGFR pathway, Phase I/II enzyme expression and the inflammatory microenvironment, with special emphasis on the expression of PD-L1, a key immune checkpoint protein both in vitro and in vivo using an ApcMin/+ ETBF mouse tumor model. These results provide a promising outlook on the impact of berry Anthos for treatment and prevention of bacteria and B[a]P-driven colorectal cancer. Results from this study also provide novel mechanistic insight into the chemopreventive and therapeutic activities of Anthos

Prevention and treatment of familial adenomatous polyposis and colorectal cancer by bilberry-derived anthocyanidins.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths within the United States. Familial adenomatous polyposis (FAP) is an inherited disorder which if left untreated will develop into colon cancer. The family of plant-derived compounds, anthocyanins, show significant therapeutic potential against a variety of diseases, however, they are limited by their instability and poor bioavailability. The goal of my Master’s research project was to determine whether anthocyanidins (non-glycosylated anthocyanins) are more effective than the native anthocyanins, and whether exosomal formulation of anthocyanidins (ExoAnthos) can enhance therapeutic potency compared with free Anthos against both FAP and CRC. The antiproliferative effects of the native mixture of Anthos isolated from bilberry, with and without exosomal formulation, as well as individual Anthos against APC mutant (HT-29, Caco2), APC wild-type (HCT116) colon cancer cells and CCD-18Co normal colon cells were assessed using an MTT assay. To assess chemopreventive effects, the impact of the Anthos on polyp number was investigated in the APCMin/+ mouse model for FAP. While therapeutic efficacy of the Anthos treatment on colorectal tumor number was assessed in vivo using an APCMin/+ ETBF mouse tumor model. Early mechanistic work was undertaken to assess the impact of Anthos treatment on EGFR and Src phosphorylation using western blot analysis. Antiproliferation studies showed that ExoAnthos significantly lowered the IC50 compared to free Anthos against colon cancer cells. Anthos treatment led to significant reductions in polyp and tumor counts in vivo. Reduced Src and EGFR phosphorylation was also observed. These results provide a promising outlook on the future of the berry Anthos for treatment and prevention for both FAP and CRC

How long is a hillslope?

Hillslope length is a fundamental attribute of landscapes, intrinsically linked to drainage density, landslide hazard, biogeochemical cycling and hillslope sediment transport. Existing methods to estimate catchment average hillslope lengths include inversion of drainage density or identification of a break in slope–area scaling, where the hillslope domain transitions into the fluvial domain. Here we implement a technique which models flow from point sources on hilltops across pixels in a digital elevation model (DEM), based on flow directions calculated using pixel aspect, until reaching the channel network, defined using recently developed channel extraction algorithms. Through comparisons between these measurement techniques, we show that estimating hillslope length from plots of topographic slope versus drainage area, or by inverting measures of drainage density, systematically underestimates hillslope length. In addition, hillslope lengths estimated by slope–area scaling breaks show large variations between catchments of similar morphology and area. We then use hillslope length–relief structure of landscapes to explore nature of sediment flux operating on a landscape. Distinct topographic forms are predicted for end-member sediment flux laws which constrain sediment transport on hillslopes as being linearly or nonlinearly dependent on hillslope gradient. Because our method extracts hillslope profiles originating from every ridgetop pixel in a DEM, we show that the resulting population of hillslope length–relief measurements can be used to differentiate between linear and nonlinear sediment transport laws in soil mantled landscapes. We find that across a broad range of sites across the continental United States, topography is consistent with a sediment flux law in which transport is nonlinearly proportional to topographic gradient

Quantifying Geomorphic Controls on Time in Weathering Systems

AbstractThe time minerals spend in the weathering zone is crucial in determining soil biogeochemical cycles, solid state chemistry and soil texture. This length of time is closely related to erosion rates and can be modulated by sediment transport, mixing rates within the soil and the temporal evolution of erosion. Here we describe how time length can be approximated using geomorphic metrics and how topography reveals changing residence times of minerals within soils. We also show model simulations from a field site in California that can reproduce observed solid state geochemistry in the eroding portion of the landscape

Hillslopes record the growth and decay of landscapes

Earth's surface archives the combined history of tectonics and erosion, which tend to roughen landscapes, and sediment transport and deposition, which smooth them. We analyzed hillslope morphology in the tectonically active Dragon’s Back Pressure Ridge in California, United States, to assess whether tectonic uplift history can be reconstructed using measurable attributes of hillslope features within landscapes. Hilltop curvature and hillslope relief mirror measured rates of vertical displacement caused by tectonic forcing, and their relationships are consistent with those expected when idealizing hillslope transport as a nonlinear diffusion process. Hilltop curvature lags behind relief in its response to changing erosion rates, allowing growing landscapes to be distinguished from decaying landscapes. Numerical modeling demonstrates that hillslope morphology may be used to infer changes in tectonic rates