U.S. Army Corps of Engineers Freshwater Harmful Algal Bloom Research & Development Initiative

Freshwater Harmful Algal Blooms (HABs) are particularly impactful to the U.S. Army Corps of Engineers (USACE), which manages vast freshwater resources and waterways that provide a variety of services including navigation, flood risk reduction, recreation, fish and wildlife management, as well as potable water supply. The Water Resources Development Act of 2018 (WRDA 2018) authorized the U.S. Army Engineer Research Development Center (USACE-ERDC) to implement a 5-year technology demonstration program to deliver scalable technologies for HAB prevention, detection and management that will reduce HAB frequency and effects to our nation’s freshwater resources across scales (e.g. small waterbodies to river reaches), ecoregions (e.g. subtropical Florida to temperate Ohio and New York), and system types (e.g. reservoirs, riverine, lakes). The USACE-ERDC HAB Research & Development (R&D) portfolio features a range of HAB-combatting methods, models, and technologies that may be used alone or in combination to effectively reduce HAB frequency and impacts to water resource development projects across the nation. An overview of USACE-ERDC sponsored HAB R&D projects will highlight the range of HAB methods, models, and technologies in development, and will provide an opportunity to engage with federal, state, local, and university partners

Building geochemically based quantitative analogies from soil classification systems using different compositional datasets.

Soil heterogeneity is a major contributor to the uncertainty in near-surface biogeochemical modeling. We sought to overcome this limitation by exploring the development of a new classification analogy concept for transcribing the largely qualitative criteria in the pedomorphologically based, soil taxonomic classification systems to quantitative physicochemical descriptions. We collected soil horizons classified under the Alfisols taxonomic Order in the U.S. National Resource Conservation Service (NRCS) soil classification system and quantified their properties via physical and chemical characterizations. Using multivariate statistical modeling modified for compositional data analysis (CoDA), we developed quantitative analogies by partitioning the characterization data up into three different compositions: Water-extracted (WE), Mehlich-III extracted (ME), and particle-size distribution (PSD) compositions. Afterwards, statistical tests were performed to determine the level of discrimination at different taxonomic and location-specific designations. The analogies showed different abilities to discriminate among the samples. Overall, analogies made up from the WE composition more accurately classified the samples than the other compositions, particularly at the Great Group and thermal regime designations. This work points to the potential to quantitatively discriminate taxonomically different soil types characterized by varying compositional datasets

Tungsten Toxicity, Bioaccumulation, and Compartmentalization into Organisms Representing Two Trophic Levels

Metallic tungsten has civil and military applications and was considered a green alternative to lead. Recent reports of contamination in drinking water and soil have raised scrutiny and suspended some applications. This investigation employed the cabbage Brassica oleracae and snail Otala lactea as models to determine the toxicological implications of sodium tungstate and an aged tungsten powder-spiked soil containing monomeric and polymeric tungstates. Aged soil bioassays indicated cabbage growth was impaired at 436 mg of W/kg, while snail survival was not impacted up to 3793 mg of W/kg. In a dermal exposure, sodium tungstate was more toxic to the snail, with a lethal median concentration of 859 mg of W/kg. While the snail significantly bioaccumulated tungsten, predominately in the hepatopancreas, cabbage leaves bioaccumulated much higher concentrations. Synchrotron-based mapping indicated the highest levels of W were in the veins of cabbage leaves. Our results suggest snails consuming contaminated cabbage accumulated higher tungsten concentrations relative to the concentrations directly bioaccumulated from soil, indicating the importance of robust trophic transfer investigations. Finally, synchrotron mapping provided evidence of tungsten in the inner layer of the snail shell, suggesting potential use of snail shells as a biomonitoring tool for metal contamination

Stability of solid-phase selenium species in fly ash after prolonged submersion in a natural river system

Selenium (Se) chemistry can be very complex in the natural environment, exhibiting different valence states (-2, 0, +4, +6) representing multiple inorganic, methylated, or complexed forms. Since redox associated shifts among most of known Se species can occur at environmentally relevant conditions, it is important to identify these species in order to assess their potential toxicity to organisms. In June of 2009, researchers from the US Army Engineer Research & Development Center (ERDC) conducted investigations of the fly ash spilled 6. months previously into the Emory River at the TVA Kingston Fossil Plant, TN. Ash samples were collected on site from both the original ash pile (that did not move during the levee failure), from the spill zone (including the Emory River), and from the ash recovery ditch (ARD) containing ash removed during dredging cleanup operations. The purpose of this work was to determine the state of Se in the spilled fly ash and to assess its potential for transformation and resultant chemical stability from its prolonged submersion in the river and subsequent dredging. Sequential chemical extractions suggested that the river environment shifted Se distribution toward organic/sulfide species. Speciation studies by bulk XANES analysis on fly ash samples showed that a substantial portion of the Se in the original ash pile had transformed from inorganic selenite to a mixture of Se sulfide and reduced (organo)selenium (Se(-II)) species over the 6-month period. μ-XRF mapping data showed that significant trends in the co-location of Se domains with sulfur and ash heavy metals. Ten-d extended elutriate tests (EETs) that were bubbled continuously with atmospheric air to simulate worst-case oxidizing conditions during dredging showed no discernible change in the speciation of fly ash selenium. The enhanced stability of the organo- and sulfide-selenium species coincided with the mixture of the ash material with humic materials in the river, corresponding with notable shifts in the ash carbon- and nitrogen-functionality. © 2013

Phase 1 Study of the IDH1m Inhibitor FT-2102 As a Single Agent in Patients with IDH1m Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Abstract Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients and 3% of MDS patients and produce 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation. FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation. Herein, we present preclinical and clinical data from an ongoing Phase 1/2 study of single-agent (SA) FT-2102 in patients with IDH1m AML and MDS (CT.gov: NCT02719574). Methods: Extensive pre-clinical evaluations were performed on FT-2102, including CYP interactions in-vivo in rat and in-vitro in human tissue and in-vivo QTc toxicology in monkeys. The clinical Phase 1 study was initiated to evaluate the safety, PK/PD, and antileukemic activity of FT-2102 in patients with IDH1m AML or MDS and included both dose escalation and expansion phases. FT-2102 was administered daily until disease progression or unacceptable toxicity. Eligibility criteria included: IDH1m AML/MDS [relapsed/refractory (R/R) or treatment naïve (TN) for whom standard therapy was contraindicated], adequate liver and renal function, no prior IDH1 inhibitors, and no restrictions for concomitant non-anticancer medications. Investigator-assessed responses were per modified IWG 2003/2006 criteria. Efficacy was assessed at Cycle 2 Day 1 and as clinically indicated thereafter. Adverse events (AEs) were assessed throughout the study per NCI CTCAE version 4.03. Results: Evaluation of FT-2102 in in-vivo rat and in-vitro human tissue indicated hepatic metabolism by CYP enzymes (CPY3A4, 2C9, 1A1) as the major route of excretion. Animal toxicology studies predicted the threshold for QTc risk occurred at exposures >5.5 fold higher than the murine exposure at which 90% 2-HG reduction was observed. In the clinical study, at the time of the data cutoff, 31 patients (pts) had been treated with SA FT-2102, with a median of 3 mo. on treatment (range: 0.2 to 20 mo.). Of the 31pts treated, 25 had AML (22 R/R; 3 TN) and 6 had MDS (4 R/R; 2 TN). The median number of prior anti-leukemia therapies was 2 (range: 0-9) for AML pts and 1 (range: 0-4) for MDS pts. FT-2102 doses were: 150 mg QD (n=8), 300 mg QD (n=4), 150 mg BID (n=16), and 100 mg QD with food (n=3). Eighteen pts discontinued treatment, most commonly due to death (n=5), progressive disease (n=5), HSCT (n=3), or lack of response (n=3). Severe (≥Grade 3) AEs occurring in >5% of pts included thrombocytopenia (26%), febrile neutropenia (23%), anemia (19%), pneumonia (13%), neutropenia (7%), hypokalemia (7%), pyrexia (7%) and leukocytosis (6%). Three pts had differentiation syndrome (IDH-DS), which resolved with temporary interruption of FT-2102, treatment with dexamethasone, hydroxyurea, and supportive care in all three. One pt had transient QTcF prolongation (Grade 3) which resolved with temporary interruption of FT-2102 and cessation of suspected concomitant medications. Eight pts died on treatment or within 28 days of the last dose, with no deaths considered related to FT-2102. No DLTs were observed during dose escalation. Selection of FT-2102 150 mg BID as the RP2D was supported by PK and PD data. Durable steady-state (Css) achieved by Week 2 was well below the threshold for QTc risk predicted by preclinical studies. The predicted IC90 was confirmed with prompt and durable 2-HG reduction to normal levels by C2D1 at the RP2D. Table 1 shows the Investigator-assessed ORR per IWG. Responses have been observed from 1 to 6 months on treatment, with stable disease observed beyond 6 months; 42% of the patients remain on treatment. Conclusions: FT-2102 preclinical evaluations suggest a low risk of clinically significant CYP-mediated drug-drug interaction and QTc prolongation. SA FT-2102 is well tolerated in AML and MDS, with 150 mg BID selected as the RP2D based on safety, PK and PD (2-HG) response. Significant clinical activity has been observed in heavily pre-treated and in TN patients, both in AML and MDS. FT-2102 continues being investigated at a dose of 150 mg BID in a Phase 2 study. Three SA Phase 2 cohorts are currently open for enrollment in R/R AML, AML/MDS with CR/CRi (i.e., with MRD), and in pts with R/R MDS/AML with prior exposure to an IDH1m inhibitor. Data updates will be available at the time of presentation. Disclosures Lee: LAM Therapeutics: Research Funding; Karyopharm Therapeutics Inc: Consultancy; AstraZeneca: Consultancy; Clinipace: Consultancy; Amgen: Consultancy. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Ferrell:Incyte: Research Funding. Kelly:Forma Therapeutics Inc.: Employment. Li:Forma Therapeutics Inc.: Employment. Sweeney:Forma Therapeutics Inc.: Employment. Watson:Forma Therapeutics Inc.: Employment. Mohamed:Forma Therapeutics Inc.: Employment. Cortes:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding