Everglades Ridge, Slough, and Tree Island Mosaics: Year 2 Annual Report

Status and history of the Ridge-Slough Mosaic The Florida Everglades is a large subtropical wetland with diverse hydrologic, edaphic, and vegetative characteristics. Historically, a significant portion of this system was a slow moving river originating from the Kissimmee River floodplain, flowing into the vast but shallow Lake Okeechobee, and draining south-southwest over extensive peatlands into Florida Bay (McVoy 2011). Human-induced alterations to the hydrologic regime, including reduction, stabilization, and impoundment of water flow through diversion and compartmentalization of water via canals and levees have degraded pre-drainage vegetation patterns and microtopographic structure (Davis and Ogden 1994, Ogden 2005, McVoy 2011). The Everglades peatland emerged 5,000 years ago with the stabilization of sea level at approximately current elevations (Loveless 1959, Gleason and Stone 1994). This, combined with subtropical rainfalls, allowed a vast mass of water to slowly flow over a limestone bedrock platform 160 km long and 50 km wide at a near uniform descent totaling about 6 m, ultimately reaching Florida Bay (Stephens 1956, Gleason and Stone 1994, McVoy 2011). Vegetation quickly colonized the area, and peat, in the absence of adequate respiration, accumulated on the limestone bedrock to a depth of 3-3.7 m (Gleason and Stone 1994, McVoy et al. 2011). The “River of Grass” referenced by Douglas (1947) alludes to the dually intertwined processes of the historic riverine nature of the Everglades and the vast sawgrass (Cladium jamaicense) communities that have dominated the landscape for about the last 1,000 years (Bernhardt and Willard 2009)

The Monitoring and Assessment Plan (MAP) Greater Everglades Wetlands Module- Landscape Pattern- Ridge, Slough, and Tree Island Mosaics: Year 1 Annual Report

In the current managed Everglades system, the pre-drainage, patterned mosaic of sawgrass ridges, sloughs and tree islands has been substantially altered or reduced largely as a result of human alterations to historic ecological and hydrological processes that sustained landscape patterns. The pre-compartmentalization ridge and slough landscape was a mosaic of sloughs, elongated sawgrass ridges (50-200m wide), and tree islands. The ridges and sloughs and tree islands were elongated in the direction of the water flow, with roughly equal area of ridge and slough. Over the past decades, the ridge-slough topographic relief and spatial patterning have degraded in many areas of the Everglades. Nutrient enriched areas have become dominated by Typha with little topographic relief; areas of reduced flow have lost the elongated ridge-slough topography; and ponded areas with excessively long hydroperiods have experienced a decline in ridge prevalence and shape, and in the number of tree islands (Sklar et al. 2004, Ogden 2005)

Preliminary results of Galileo direct imaging of S-L 9 impacts

Direct Galileo imaging data were obtained of the Jupiter impact sites for Comet Shoemaker-Levy 9 fragments K, N, and W during their early, high-energy phases. Initial ∼5s-long flashes for all 3 impacts result from radiant bolides; analogous, abrupt onsets of luminosity observed by the Galileo photopolarimeter for other impacts must also be the bolide phase. The 3 bolides were dim at 0.56 or 0.89µm (few percent of total Jupiter) and had similar amplitudes, despite huge late-stage differences observed from Earth. Subsequent, continuous luminosity lasting ∼40s for K and ∼10s for N is optical radiation as the initial bolide train erupts into a “fireball”. The K light curve may show (a) two impacts 10s apart or (b) delayed evolution of the fireball

PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development. Statement of significance PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors

Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse

Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma

Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (\u3e4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten−/−). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies

Light and flow regimes regulate the metabolism of rivers

Mean annual temperature and mean annual precipitation drive much of the variation in productivity across Earth's terrestrial ecosystems but do not explain variation in gross primary productivity (GPP) or ecosystem respiration (ER) in flowing waters. We document substantial variation in the magnitude and seasonality of GPP and ER across 222 US rivers. In contrast to their terrestrial counterparts, most river ecosystems respire far more carbon than they fix and have less pronounced and consistent seasonality in their metabolic rates. We find that variation in annual solar energy inputs and stability of flows are the primary drivers of GPP and ER across rivers. A classification schema based on these drivers advances river science and informs management.We thank Ted Stets, Jordan Read, Tom Battin, Sophia Bonjour, Marina Palta, and members of the Duke River Center for their help in developing these ideas. This work was supported by grants from the NSF 1442439 (to E.S.B. and J.W.H.), 1834679 (to R.O.H.), 1442451 (to R.O.H.), 2019528 (to R.O.H. and J.R.B.), 1442140 (to M.C.), 1442451 (to A.M.H.), 1442467 (to E.H.S.), 1442522 (to N.B.G.), 1624807 (to N.B.G.), and US Geological Survey funding for the working group was supported by the John Wesley Power Center for Analysis and Synthesis. Phil Savoy contributed as a postdoc- toral associate at Duke University and as a postdoctoral associate (contractor) at the US Geological Survey

BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc

SummaryMYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.PaperFlic

SMARCB1 regulates the hypoxic stress response in sickle cell trait during the pathogenesis of renal medullary carcinoma.

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