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The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical effi cacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identifi cation and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF , NRAS , or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors. SIGNIFICANCE: BRAF and MEK inhibitors have activity in MAPK-dependent cancers with BRAF or RAS mutations. However, resistance is associated with pathway alterations resulting in phospho-ERK reactivation. Here, we describe a novel ERK1/2 kinase inhibitor that has antitumor activity in MAPK inhibitor-naïve and MAPK inhibitor-resistant cells containing BRAF or RAS mutations. Cancer Discov; 3(7); 742-50.

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SUMMARYFestuca rubra, Jfuncus gerardii, Armeria maritima, Plantago maritima. Aster tripolium, Triglochin maritima, Puccinellia maritima and Salicornia europaea from a salt marsh near Portaferry, County Down, were grown on drained and waterlogged salt marsh soils under saline and non-saline conditions. Shoot and root yields and the concentrations of sodium, potassium, calcium, magnesium, manganese and iron in the shoots were determined after a 2-month growing period. The tolerance of the plants to waterlogging and salinity differed in a way which was correlated with their position on the salt marsh ecotone.The growth of upper marsh species, but not that of lower marsh species, was strongly limited by hoth salinity and waterlogging. Only Salicornia europaea gave its maximum yield on the saline treatments and only Puccinellia maritima showed a preference for waterlogged soils. Reduced yields on the saline treatments were associated with large increases in shoot sodium concentrations but in general, salinity and waterlogging had little effect on shoot cation concentrations. It is suggested that factors other than the greater availibility of iron and manganese on araerobic salt marsh soils are involved in determining species distribution along the salt marsh ecotone.

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).

The effects of shade on periphyton and invertebrates were investigated by comparisons in 12 replicate channels beside a pasture stream where shade cloth reduced the photosynthetically available radiation (PAR) by 0, 60, 90, and 98%. Periphytic productivity decreased with increasing shade. Periphyton chlorophyll a was consistently low (< 30 mg m -2 ) under 98 and 90% shade and usually low at 60% shade, whereas blooms were common during summer in the unshaded channels. More periphytic taxa occurred in the open than shaded channels and the relative concentration of the photoprotective pigment beta-carotene decreased with increasing shade. Nitrate uptake rates by periphyton, measured in separate chamber studies, decreased progressively as shade increased from 60% through 90% to 98%, and were more strongly correlated with gross primary productivity than periphyton chlorophyll a and particulate carbon levels. Total invertebrate and chironomid densities declined significantly as shade increased from 60 to 90% and invertebrate taxa richness declined markedly between 90 and 98% shade. Most collector-browsing invertebrates (other than chironomids) had similar densities under 0-90% shade and only declined at 98%. This suggests a weak coupling of these invertebrates with local M96078