Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia

Pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) exhibit favorable survival rates. However, for AML and ALL patients carrying KMT2A gene translocations clinical outcome remains unsatisfactory. Key players in KMT2A-fusion-driven leukemogenesis include menin and DOT1L. Recently, menin inhibitors like revumenib have garnered attention for their potential therapeutic efficacy in treating KMT2A-rearranged acute leukemias. However, resistance to menin inhibition poses challenges, and identifying which patients would benefit from revumenib treatment is crucial. Here, we investigated the in vitro response to revumenib in KMT2A-rearranged ALL and AML. While ALL samples show rapid, dose-dependent induction of leukemic cell death, AML responses are much slower and promote myeloid differentiation. Furthermore, we reveal that acquired resistance to revumenib in KMT2A-rearranged ALL cells can occur either through the acquisition of MEN1 mutations or independently of mutations in MEN1. Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in KMT2A-rearranged acute leukemia.</p

The effect of the runoff size on the pesticide concentration in runoff water and in FOCUS streams simulated by PRZM and TOXSWA

Within the European Union the exposure of aquatic organisms to pesticides is assessed by simulations with the so-called FOCUS Surface Water Scenarios. Runoff plays an important role in these scenarios. As little is known about the effect of runoff size on the exposure, we investigated the effect of runoff size on the concentration in the runoff water and in streams simulated with the PRZM and TOXSWA models for two FOCUS runoff scenarios.For weakly sorbing pesticides (K F,oc -1) the pesticide concentration in the runoff water decreased exponentially with increasing daily runoff size. The runoff size hardly affected the pesticide concentration in the runoff water of strongly sorbing pesticides (K F,oc ≥1000Lkg-1).For weakly sorbing pesticides the concentration in the FOCUS stream reached a maximum at runoff sizes of about 0.3 to 1. mm. The concentration increased rapidly when the runoff size increased from 0 to 0.1. mm and gradually decreased when runoff exceeded 1. mm. For strongly sorbing pesticides the occurrence of the maximum concentration in the stream is clearly less pronounced and lies approximately between 1 and 20. mm runoff. So, this work indicates that preventing small runoff events (e.g. by vegetated buffer strips) reduces exposure concentrations strongly for weakly sorbing pesticides.A simple metamodel was developed for the ratio between the concentrations in the stream and in the runoff water. This model predicted the ratios simulated by TOXSWA very well and it demonstrated that (in addition to runoff size and concentration in runoff) the size of the pesticide-free base flow and pesticide treatment ratio of the catchment determine the stream concentration to a large extent

Monitoring and risk assessment of pesticides in irrigation systems in Debra Zeit, Ethiopia.

Since Ethiopia is going through a rapid transformation of its agricultural sector, we assessed the human health and environmental risks due to the past use of organochlorine pesticides (OCPs) as well as the risks of the current pesticide use by farmers. A monitoring programme and risk assessment was carried out for the Wedecha-Belbela irrigation system in the Debra Zeit area. The Wedecha and Belbela rivers and adjacent temporary ponds were sampled and examined for the presence of OCPs between August and October 2014, while data on the current pesticide use by small- and large-scale farmers was collected by interviews. The usage patterns were evaluated for risks of using the river or temporary ponds as source of drinking water and for risks for the aquatic ecosystems in the river and ponds with the aid of the PRIMET_Registration_Ethiopa_1.1 model. The samples were collected in five sampling periods, and results indicate that most of the 18 target OCPs were not detected above the detection limit, while g-chlordane may pose chronic risks when surface water is used as drinking water. Endosulfan and heptachlor pose risks to aquatic organisms at second-tier level, while for heptachlor-epoxide B, g-chlordane and b-BHC only risks could be determined at the first tier due to a lack of data. For all nine pesticides used by small-scale farmers the calculated acute risks to humans were low. Second tier risk assessment for the aquatic ecosystem indicated that lambda-cyhalothrin, endosulfan, profenofos, and diazinon may pose high risks

Monitoring and risk assessment of pesticides in irrigation systems in Debra Zeit, Ethiopia.

<p>Since Ethiopia is going through a rapid transformation of its agricultural sector, we assessed the human health and environmental risks due to the past use of organochlorine pesticides (OCPs) as well as the risks of the current pesticide use by farmers. A monitoring programme and risk assessment was carried out for the Wedecha-Belbela irrigation system in the Debra Zeit area. The Wedecha and Belbela rivers and adjacent temporary ponds were sampled and examined for the presence of OCPs between August and October 2014, while data on the current pesticide use by small- and large-scale farmers was collected by interviews. The usage patterns were evaluated for risks of using the river or temporary ponds as source of drinking water and for risks for the aquatic ecosystems in the river and ponds with the aid of the PRIMET_Registration_Ethiopa_1.1 model. The samples were collected in five sampling periods, and results indicate that most of the 18 target OCPs were not detected above the detection limit, while g-chlordane may pose chronic risks when surface water is used as drinking water. Endosulfan and heptachlor pose risks to aquatic organisms at second-tier level, while for heptachlor-epoxide B, g-chlordane and b-BHC only risks could be determined at the first tier due to a lack of data. For all nine pesticides used by small-scale farmers the calculated acute risks to humans were low. Second tier risk assessment for the aquatic ecosystem indicated that lambda-cyhalothrin, endosulfan, profenofos, and diazinon may pose high risks.</p

Revised guidance on the risk assessment of plant protection products on bees (Apis mellifera, Bombus spp. and solitary bees)

The European Commission asked EFSA to revise the risk assessment for honey bees, bumble bees and solitary bees. This guidance document describes how to perform risk assessment for bees from plant protection products, in accordance with Regulation (EU) 1107/2009. It is a review of EFSA’s existing guidance document, which was published in 2013. The guidance document outlines a tiered approach for exposure estimation in different scenarios and tiers. It includes hazard characterisation and provides risk assessment methodology covering dietary and contact exposure. The document also provides recommendations for higher tier studies, risk from metabolites and plant protection products as mixture

Revised guidance on the risk assessment of plant protection products on bees (Apis mellifera, Bombus spp. and solitary bees)

Abstract The European Commission asked EFSA to revise the risk assessment for honey bees, bumble bees and solitary bees. This guidance document describes how to perform risk assessment for bees from plant protection products, in accordance with Regulation (EU) 1107/2009. It is a review of EFSA's existing guidance document, which was published in 2013. The guidance document outlines a tiered approach for exposure estimation in different scenarios and tiers. It includes hazard characterisation and provides risk assessment methodology covering dietary and contact exposure. The document also provides recommendations for higher tier studies, risk from metabolites and plant protection products as mixture

Additional file 1 of Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia

Supplementary Material

Supplementary information to the revised guidance on the risk assessment of plant protection products on bees (Apis mellifera, Bombus spp. and solitary bees)

The European Commission asked EFSA to revise the guidance on the risk assessment for honey bees, bumble bees and solitary bees for Regulation (EU) 1107/2009. The guidance document is a review ofEFSA’s existing guidance document, which was published in 2013. The guidance document outlines the approach for exposure estimation in different scenarios and tiers. It includes hazard characterisation and provides risk assessment methodology covering dietary and contact exposure. The guidance documental so provides recommendations for higher tier studies, risk from metabolites and mixture. This document includes supplementary information for the guidance