Inhibition of focal adhesion kinase (FAK), a non-receptor tyrosine kinase linked to tumour cell survival, causes cell rounding, loss of adhesion and apoptosis in human cancer cell lines. In this study, we tested antisense oligonucleotide inhibitors of FAK, in combination with 5-fluorouracil (5-FU), to increase its sensitivity in human melanoma cell lines. Antisense oligonucleotides directed to the 5' mRNA sequence of FAK and missense control oligonucleotides were used. In BL melanoma cells, treatment with FAK antisense oligonucleotide was associated with a 2.5-fold increase in cell death compared with treatment with control oligonucleotide (33+/-2% vs. 13+/-3%, P<0.0001). 5-FU alone had no effect on BL cells (4.4% cell death, P=0.15). The addition of 5-FU after antisense oligonucleotide resulted in a significant synergistic increase in cell death equal to 69+/-2% compared with treatments with antisense oligonucleotide alone, 5-FU alone and control oligonucleotide (P<0.0001). Similar results were found in the C8161 melanoma cell line. In both cell lines, reduction in cell viability was accompanied by an increased loss of adhesion and increased apoptosis that was proportional to the decrease in viability. Treatment with antisense oligonucleotide plus 5-FU resulted in significantly decreased p125FAK expression in both C8161 and BL melanoma cell lines, demonstrated by Western blot analyses. These data show that the downregulation of FAK by antisense oligonucleotide combined with 5-FU chemotherapy results in a greater loss of adhesion and greater apoptosis in melanoma cells than treatment with either agent alone, suggesting that the combination may be a potential therapeutic agent for human melanoma in vivo.

The compounding effects of anthropogenic legacies for environmental pollution are significant, but not well understood. Here, we show that centennial‐scale legacies of milldams and decadal‐scale legacies of road salt salinization interact in unexpected ways to produce hot spots of nitrogen (N) in riparian zones. Riparian groundwater and stream water concentrations upstream of two mid‐Atlantic (Pennsylvania and Delaware) milldams, 2.4 and 4 m tall, were sampled over a 2 year period. Clay and silt‐rich legacy sediments with low hydraulic conductivity, stagnant and poorly mixed hydrologic conditions, and persistent hypoxia in riparian sediments upstream of milldams produced a unique biogeochemical gradient with nitrate removal via denitrification at the upland riparian edge and ammonium‐N accumulation in near‐stream sediments and groundwaters. Riparian groundwater ammonium‐N concentrations upstream of the milldams ranged from 0.006 to 30.6 mgN L−1 while soil‐bound values were 0.11–456 mg kg−1. We attribute the elevated ammonium concentrations to ammonification with suppression of nitrification and/or dissimilatory nitrate reduction to ammonium (DNRA). Sodium inputs to riparian groundwater (25–1,504 mg L−1) from road salts may further enhance DNRA and ammonium production and displace sorbed soil ammonium‐N into groundwaters. This study suggests that legacies of milldams and road salts may undercut the N buffering capacity of riparian zones and need to be considered in riparian buffer assessments, watershed management plans, and dam removal decisions. Given the widespread existence of dams and other barriers and the ubiquitous use of road salt, the potential for this synergistic N pollution is significant.

Watershed export of excessive reactive nitrogen (N) is a major environmental concern globally, as eutrophication of coastal waters causes hypoxia, habitat degradation, and loss of biodiversity (Howarth, 2008;Schaefer et al., 2009). Functioning riparian zones that are hydrologically connected to streams and rivers help mitigate downstream N transport through N removal by numerous biogeochemical pathways (Vidon et al., 2010;Zhao et al., 2021). Complete denitrification is a particularly important removal pathway by which facultative anaerobic bacteria reduce nitrate and nitrite to N 2 gas, permanently removing N from reactive pools (Groffman et al., 1992;Hill, 2019;Lutz et al., 2020). Denitrification occurs in areas with available organic carbon (C), high concentrations of nitrate, and wet, low oxygen sediments (Zhao et al., 2021). These conditions are often present in riparian

Oregon estuaries provide important opportunities to assess controls on tidal saline wetland carbon burial and sediment accretion as both rates of relative sea level rise (RSLR; −1.4 ± 0.9 to 2.8 ± 0.8 mm yr−1) and fluvial suspended sediment load relative to estuary area (0.23 to 17 × 103 t km−2 yr−1) vary along the coast. We hypothesized that vertical accretion, measured using excess 210Pb in least‐disturbed wetlands within seven Oregon estuaries, would vary with either RSLR or sediment load relative to estuary area, and carbon burial would correlate strongly to sediment accretion. Mean rates of high marsh accretion (0.8 ± 0.2 to 4.1 ± 0.2 mm yr−1) indicate that Oregon tidal wetlands have mainly kept pace with twentieth‐century RSLR with the exception that the accretionary balance in the central coast is negative, suggesting drowning. Experiencing the fastest rates of RSLR, central‐coast estuaries may foreshadow the fates of other Oregon estuaries under future accelerated sea level rise. Comparison of mass accumulation rates with sediment loads, however, indicates low trapping efficiency and therefore no fluvial sediment limitation. Thus, nonlinear feedback between RSLR and sediment accretion may enhance wetland resistance to drowning. Among wetlands keeping pace with or exceeding RSLR, sediment accretion displays no significant relationship with elevation but rather appears controlled by both the rate of RSLR and relative sediment load, highlighting the importance of incorporating both factors into future studies of tidal saline wetlands. Carbon burial rates, controlled by sediment accretion, will likely increase with future accelerated sea level rise.

Dams are increasingly being removed across the United States (US) (Bellmore et al., 2017;Foley et al., 2017). Since 1912, more than 1,490 dams have been removed across the US and Pennsylvania leads the nation in the number of milldams and their removals (American Rivers, 2020). Most (>90%) of these milldams are classified as low-head dams (height < 7 m) and are typically a relic of colonial and post-colonial era milling activities (Merritts et al., 2011;Walter & Merritts, 2008). Dam removal numbers could be higher since not all dam removals are recorded. This could particularly be true for the Mid-Atlantic Piedmont region, where thousands of small mill dams existed since the late 1600s (Walter & Merritts, 2008).Low-head dam removals are primarily being driven by needs for public safety, reduction in financial liability, recreational access, aesthetics, and/or improvement in fish habitat (