The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation.

Midwifery learning and forecasting: Predicting content demand with user-generated logs.

Every day, 800 women and 6700 newborns die from complications related to pregnancy or childbirth. A well-trained midwife can prevent most of these maternal and newborn deaths. Data science models together with logs generated by users of online learning applications for midwives can help improve their learning competencies.

Some pleural effusions labeled as idiopathic could be produced by the inhalation of silica.

Objectives: Exposure to silica nanoparticles has been associated with pleural effusions (PEs) in animal models and case series. We hypothesized that some PEs labelled as "idiopathic" could, in fact, be secondary to inhalation of silica.

Methods: A retrospective case control study was designed utilizing a prospectively maintained pleural database.

Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells.

Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis.

Lack of p62 Impairs Glycogen Aggregation and Exacerbates Pathology in a Mouse Model of Myoclonic Epilepsy of Lafora.

Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates-the so-called Lafora Bodies (LBs)-in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins.

CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation.

Hematopoietic stem cells (HSCs) reside at the apex of the hematopoietic differentiation hierarchy and sustain multilineage hematopoiesis. Here, we show that the transcriptional regulator CITED2 is essential for life-long HSC maintenance. While hematopoietic-specific Cited2 deletion has a minor impact on steady-state hematopoiesis, Cited2-deficient HSCs are severely depleted in young mice and fail to expand upon aging.

Dual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in -ITD Acute Myeloid Leukemia.

Purpose: AXL has been shown to play a pivotal role in the selective response of -ITD acute myeloid leukemia (AML) cells to FLT3 tyrosine kinase inhibitors (TKI), particularly within the bone marrow microenvironment.

Experimental Design: Herein, we compared the effect of dual FLT3/AXL-TKI gilteritinib with quizartinib through models mimicking hematopoietic niche conditions, in primary AML blasts, and with dosing regimens allowing plasma concentration close to those used in clinical trials.

Results: We observed that gilteritinib maintained a stronger proapoptotic effect in hypoxia and coculture with bone marrow stromal cells compared with quizartinib, linked to a dose-dependent inhibition of AXL phosphorylation.

α-Tocopherol Attenuates Oxidative Phosphorylation of CD34 Cells, Enhances Their G0 Phase Fraction and Promotes Hematopoietic Stem and Primitive Progenitor Cell Maintenance.

Alpha tocopherol acetate (αTOA) is an analogue of alpha tocopherol (αTOC) that exists in the form of an injectable drug. In the context of the metabolic hypothesis of stem cells, we studied the impact of αTOA on the metabolic energetic profile and functional properties of hematopoietic stem and progenitor cells. In ex vivo experiments performed on cord blood CD34 cells, we found that αTOA effectively attenuates oxidative phosphorylation without affecting the glycolysis rate.

JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells.

Lifelong multilineage hematopoiesis critically depends on rare hematopoietic stem cells (HSCs) that reside in the hypoxic bone marrow microenvironment. Although the role of the canonical oxygen sensor hypoxia-inducible factor prolyl hydroxylase has been investigated extensively in hematopoiesis, the functional significance of other members of the 2-oxoglutarate (2-OG)-dependent protein hydroxylase family of enzymes remains poorly defined in HSC biology and multilineage hematopoiesis. Here, by using hematopoietic-specific conditional gene deletion, we reveal that the 2-OG-dependent protein hydroxylase JMJD6 is essential for short- and long-term maintenance of the HSC pool and multilineage hematopoiesis.

Description of a knock-in mouse model of JAK2V617F MPN emerging from a minority of mutated hematopoietic stem cells.

The major weakness of most knock-in JAK2V617F mouse models is the presence of the JAK2 mutation in all rather than in a few hematopoietic stem cells (HSC), such as in human "early-stage" myeloproliferative neoplasms (MPN). Understanding the mechanisms of disease initiation is critical as underscored by the incidence of clonal hematopoiesis of indeterminate potential associated with JAK2V617F. Currently, such studies require competitive transplantation.

Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical "3 + 7" treatment (cytarabine and daunorubicin) is currently challenged by new therapeutic strategies, including drugs depending on the molecular landscape of AML. This panel of mutations makes it possible to combine some of these new treatments with conventional chemotherapy.

Targeting the RNA mA Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation, generating self-renewing leukemic stem cells (LSCs). Here, we show that the mRNA mA reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse mA transcripts that contribute to the overall integrity of LSC function, including the tumor necrosis factor receptor Tnfrsf2, whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis.

Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib STAT5-and hypoxia-dependent upregulation of AXL.

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche.

Catapulting HSCs into action.

In this issue of , Umemoto et al. (https://doi.org/10.

Chronic myeloid leukemia progenitor cells require autophagy when leaving hypoxia-induced quiescence.

Albeit tyrosine kinase inhibitors anti-Abl used in Chronic Myeloid Leukemia (CML) block the deregulated activity of the Bcr-Abl tyrosine kinase and induce remission in 90% of patients, they do not eradicate immature hematopoietic compartments of leukemic stem cells. To elucidate if autophagy is important for stem cell survival and/or proliferation, we used culture in low oxygen concentration (0.1% O for 7 days) followed back by non-restricted O supply (normoxic culture) to mimic stem cell proliferation and commitment.

Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.

Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specific deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure.

Assessing gender disparities in excess mortality of heroin or cocaine users compared to the general population.

Background: Previous analyses of excess mortality in drug users compared with the general population have almost always been based on mortality ratios, reporting much higher figures in women than men. This study tests the hypothesis that being a heroin or cocaine user adds more death risk in women than men in Spain.

Methods: A retrospective cohort of 15,305 heroin users (HUs) and 11,905 cocaine users (CUs) aged 15-49 starting drug treatment in 1997-2007 was recruited in Spain and followed until December 2008 to determine vital status and cause of death.

CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells.

The regulation of hematopoietic stem cell (HSC) survival and self-renewal within the bone marrow (BM) niche is not well understood. We therefore investigated global transcriptomic profiling of normal human HSC/hematopoietic progenitor cells [HPCs], revealing that several chemokine ligands (CXCL1-4, CXCL6, CXCL10, CXCL11, and CXCL13) were upregulated in human quiescent CD34(+)Hoescht(-)Pyronin Y(-) and primitive CD34(+)38(-), as compared with proliferating CD34(+)Hoechst(+)Pyronin Y(+) and CD34(+)38(+) stem/progenitor cells. This suggested that chemokines might play an important role in the homeostasis of HSCs.

Adult hematopoietic stem cells lacking Hif-1α self-renew normally.

The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension.

Enforcing regulations on alcohol sales and use as universal environmental prevention.

The informal social control over alcohol consumption that was traditional in Southern European countries has weakened. At the same time there is an increase in binge drinking and drunkenness among young people in Spain. To mitigate this problem, regulations on alcohol and driving and restrictions on the sale and consumption of alcohol have been adopted.

Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance.

Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development.

Job Loss, Unemployment and the Incidence of Hazardous Drinking during the Late 2000s Recession in Europe among Adults Aged 50-64 Years.

Background: To estimate the incidence of hazardous drinking in middle-aged people during an economic recession and ascertain whether individual job loss and contextual changes in unemployment influence the incidence rate in that period.

Methods: Longitudinal study based on two waves of the SHARE project (Survey of Health, Ageing and Retirement in Europe). Individuals aged 50-64 years from 11 European countries, who were not hazardous drinkers at baseline (n = 7,615), were selected for this study.

Effect of immigration background and country-of-origin contextual factors on adolescent substance use in Spain.

Purpose: The effects of adolescent- and parental-birthplace and country-of-origin contextual factors on substance use among adolescents with recent immigrant background (ARIBs) are poorly understood. We aimed to assess these effects and identify the main mediating factors in Spain.

Methods: Participants were 12,432 ARIBs (≥1 foreign-born parent) and 75,511 autochthonous adolescents from pooled 2006-2010 school surveys.

Injury-Related Mortality Over 12 Years in a Cohort of Patients with Alcohol Use Disorders: Higher Mortality Among Young People and Women.

Background: The goal of this study was to estimate excess death due to external causes among 18- to 64-year-olds with alcohol use disorder (AUD) who were treated at public outpatient treatment centers, and the time elapsed from treatment initiation to death.

Methods: We conducted a retrospective longitudinal study among 7,012 outpatients aged 18 to 64 years who began treatment for AUD between 1997 and 2007. Deaths due to external causes (intentional and unintentional injuries) were monitored until the end of 2008.

Gender differences in hazardous drinking among middle-aged in Europe: the role of social context and women's empowerment.

Background: The aim of this study was to estimate the magnitude of gender differences in hazardous drinking among middle-aged people and to analyse whether these differences are associated with contextual factors, such as public policies or socioeconomic factors.

Methods: Cross-sectional design. The study population included 50- to 64-year-old residents of 16 European countries who participated in the Survey of Health, Ageing and Retirement in Europe project conducted in 2010-12 (n = 26 017).