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Abstract The impact of pesticides on health is a major public health concern. A higher risk to develop chronic lymphoid malignancies has been demonstrated to be associated with occupational pesticide exposure (OPE). By contrast, little is known of the impact of OPE on the occurrence of myeloid malignancies especially acute myeloid leukemia (AML). The purpose of this meta-analysis is to summarize data on the association between OPE and AML. A relevant dataset of case–control studies was extracted. Among 6784 references extracted, 14 were selected, representing 3,955 AML patients and 9,948 control subjects diagnosed between 1976 and 2010. An adverse association was found between OPE and AML (OR = 1.51; 95%CI: 1.10–2.08), not affected by sensitivity analyses. Funnel plot asymmetry suggested a publication bias underestimating OR. Stratified analysis showed the association to be driven by studies with: (1) monocentric AML patients and hospital-based control population, (2) Newcastle–Ottawa scale > 6 and the group of studies identified as with the lowest risk, (3) exposure assessment through peer-to-peer interview, (4) diagnosis in North America and Asia and after 1995, (5) restriction to de novo AML. Moreover, the association between OPE and AML was significant with insecticides. These findings broaden the spectrum of pesticide toxicity to myeloid malignancies.

Abstract: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for transformation in secondary acute myeloid leukemia. This study focused on the redox metabolism of bone marrow (BM) cells from 97 patients compared with 25 healthy controls. The level of reactive oxygen species (ROS) was quantified by flow cytometry in BM cell subsets as well as the expression level of 28 transcripts encoding for major enzymes involved in the antioxidant cellular response. Our results highlight increased ROS levels in BM nonlymphoid cells and especially in primitive CD34posCD38low progenitor cells. Moreover, we identified a specific antioxidant signature, dubbed “antioxidogram,” for the different MDS subgroups or secondary acute myeloblastic leukemia (sAML). Our results suggest that progression from MDS toward sAML could be characterized by 3 successive molecular steps: (1) overexpression of enzymes reducing proteic disulfide bonds (MDS with

Abstract Background In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload. Case presentation An 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15. Conclusions This case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.

The bone marrow (BM) microenvironment plays a crucial role in the development and progression of leukemia (AML). Intracellular reactive oxygen species (ROS) are involved in the regulation of the biology of leukemia-initiating cells, where the antioxidant enzyme GPx-3 could be involved as a determinant of cellular self-renewal. Little is known however about the role of the microenvironment in the control of the oxidative metabolism of AML cells. In the present study, a coculture model of BM mesenchymal stromal cells (MSCs) and AML cells (KG1a cell-line and primary BM blasts) was used to explore this metabolic pathway. MSC-contact, rather than culture with MSC-conditioned medium, decreases ROS levels and inhibits the Nrf-2 pathway through overexpression of GPx3 in AML cells. The decrease of ROS levels also inactivates p38MAPK and reduces the proliferation of AML cells. Conversely, contact with AML cells modifies MSCs in that they display an increased oxidative stress and Nrf-2 activation, together with a concomitant lowered expression of GPx-3. Altogether, these experiments suggest that a reciprocal control of oxidative metabolism is initiated by direct cell–cell contact between MSCs and AML cells. GPx-3 expression appears to play a crucial role in this cross-talk and could be involved in the regulation of leukemogenesis.

Background: A current challenge in medical education is the steep exposure to the complexity and uncertainty of clinical practice in early clerkship. The gap between pre-clinical courses and the reality of clinical decision-making can be overwhelming for undergraduate students. The Learning-by-Concordance (LbC) approach aims to bridge this gap by embedding complexity and uncertainty by relying on real-life situations and exposure to expert reasoning processes to support learning. LbC provides three forms of support: 1) expert responses that students compare with their own, 2) expert explanations and 3) recognized scholars’ key-messages. Method: Three different LbC inspired learning tools were used by 900 undergraduate medical students in three courses: Concordance-of-Reasoning in a 1st-year hematology course; Concordance-of-Perception in a 2nd-year pulmonary physio-pathology course, and; Concordance-of-Professional-Judgment with 3rd-year clerkship students. Thematic analysis was conducted on freely volunteered qualitative comments provided by 404 students. Results: Absence of a right answer was challenging for 1st year concordance-of-reasoning group; the 2nd year visual concordance group found radiology images initially difficult and unnerving and the 3rd year concordance-of-judgment group recognized the importance of divergent expert opinion. Conclusions: Expert panel answers and explanations constitute an example of “cognitive apprenticeship” that could contribute to the development of appropriate professional reasoning processes.