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The Healthy, Hunger Free Kids Act (HHFKA) of 2010, a reauthorization of the Child Nutrition Act sets new nutrition standards for meal patterns, food sold and served in schools, and ...requires training and professional standards development for all school nutrition personnel. Major improvements are being made across the country and in Louisiana to incorporate these standards, increase access to healthy food and promote student wellness. The National School Lunch and National School Breakfast Programs improve diet, reduce food insecurity and improve overall health. In April 2015, LSU's Pennington Biomedical Research Center partnered with the Louisiana Department of Education's Division of Nutrition Support to launch the Louisiana Fit Kids project, which aims to strengthen child nutrition programs through a variety of key initiatives. An interactive website was launched to include meal planning, assist with implementation of professional standards requirements for child nutrition personnel, house the approved Smart Snacks listing for Louisiana, and other child nutrition topics. High on the priority list is the completion of a statewide needs assessment to determine training needs, technical assistance requirements, and other priorities which will help allocate resources for future action plans. The needs assessment survey was launched in September 2015 with plans to publish results by January 2016. The data collected will be analyzed to categorize the five regions of the state in terms of trainings needed, technology available and other aspects of their child nutrition program. Portions of the survey include questions about barriers to successful implementation of the child nutrition program, along with training needs related to meal planning and meal pattern requirements. Preliminary data suggest barriers to meal participation vary between 33–83%, trainings related to meal planning vary between 29–63% or meal pattern requirements vary between 40–57%. Complete survey results will point to differences in the five regions of the state and will allow comparisons to other states and national child nutrition data. Louisiana has set some standards differently from USDA, primarily restricting calorie content in the Smart Snacks listing and with several products excluded that have been exempted by USDA. Results of the needs assessment survey and differences between Louisiana and USDA will be the focus of this presentation, along with a discussion of future directions for this project which has Louisiana on the forefront of high achievements in the realm of child nutrition within the school system.
Support or Funding Information
Supported by the Louisiana Department of Education, Division of Nutrition Support
Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger ...E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model.
Introduction: Regulation of the epithelial to mesenchymal transition (EMT) is an emerging theme in acute leukemia biology (1, 2). EMT is required for many aspects of development, including ...gastrulation and mesoderm formation. It has also been associated with malignant processes such as epithelial tumor cell invasion and metastasis, and the development, function and chemo-resistance of cancer stem cells. Master regulators of EMT belong to the Snail (Snai1/Snai2/Snai3) and Zeb (Zeb1/Zeb2) families of transcription factors. While they have primarily been studied in relation to solid organ development and embryogenesis, recent work has begun to uncover novel roles for these proteins in both normal and malignant hematopoiesis.
A mounting body of evidence implicates the founding member of the Snail family, SNAI1, in Acute Myeloid Leukaemia (AML) development. Transgenic Snai1 expression induces myeloid leukaemia in mice (3), and human AML cells show increased SNAI1 expression compared to haematopoietic stem and progenitor cells (HSPCs). We have also found that shRNA knockdown of SNAI1 in AML cells induces differentiation, as measured by increased CD11b expression. In this paper we elucidate the mechanisms by which elevated levels of Snai1 impair normal hematopoiesis and promote leukemogenesis.
Results: We employed murine retroviral and transgenic models to drive high levels of Snai1 in hematopoietic cells in vivo. Homozygous expression of a Snai1 transgene, using the endothelial and hematopoietic restricted Tie2-Cre, resulted in embryonic lethality at E15.5-17.5. Embryos were highly anemic, exhibiting normal primitive erythropoiesis, but severely impaired definitive erythropoiesis. Retroviral mediated overexpression of Snai1 during adult hematopoiesis resulted in a significant expansion of the Granulocyte-Macrophage progenitor (GMP) compartment, with a concomitant reduction in Megakaryocyte-Erythroid progenitor (MEP) numbers. Downstream myeloid development was also perturbed, with a strong differentiation bias towards macrophage production, at the expense of granulocyte development. Mice (n=4) have also begun to develop an aggressive AML beginning at 12 months of age, consistent with the previously published transgenic model (3).
The effects of Snai1 expression on myeloid development are reminiscent of those observed in mice lacking Gfi1 or Gfi1b, suggesting possible competition for, or altered function of, their common co-repressor: the chromatin modulator Lsd1. To test this hypothesis, we generated a mutant form of Snai1 that does not bind Lsd1 and retrovirally expressed it in HSPCs. Unlike wild-type Snai1, the mutant form was unable to induce hematopoietic defects or AML development in mice.
We next conducted gene expression profiling on the HPC7 hematopoietic progenitor cell line, with or without ectopic Snai1 expression. We observed a significant up-regulation of GMP-associated genes and more mature monocyte/macrophage related genes. These data, along with morphological analysis, suggested that Snai1 expressing HPC7 cells take on a macrophage-biased GMP-like phenotype, but do not fully differentiate into mature myeloid cells. Moreover, there was a significant correlation to gene expression programs from Gfi1/1b knockout HSCs, further implicating loss of Gfi1/1b activity in driving these myeloid phenotypes.
Strikingly, we also observed evidence of inflammatory cytokine production and activation of key downstream signaling pathways that contribute to AML cell survival and proliferation. Whether this effect is due to altered regulation of Lsd1 targets, or instead represents a distinct Lsd1-independent mechanism, remains to be determined.
Conclusion: We have shown that Snai1 expression perturbs myeloid cell development and induces AML in an Lsd1-dependent manner. Snai1 expression likely contributes to increased survival and proliferation of leukemic cells via induction of key inflammatory signaling pathways that support tumor cell growth. These data confirm the importance of Snai1 in AML development and pathogenesis.
References:
1. Goossens S, et al. (2015).Nature communications 6:5794.
2. Stavropoulou V, et al. (2016). Cancer cell 30(1):43-58.
3. Perez-Mancera PA, et al. (2005). Human molecular genetics 14(22):3449-3461.
No relevant conflicts of interest to declare.
This article describes a highly successful bilingual education program at Davis Bilingual Magnet School in Tucson, Arizona. After two decades of bilingual schooling in which children of all language ...backgrounds study content via both Spanish and English, Davis has developed strong community support through special attention to additive bilingualism/biliteracy and by creating a challenging and nurturing learning environment. By examining the school's long-term success from the perspectives of teachers, families, and dual language immersion students themselves, the study highlights successful bilingual schooling in a manner that acknowledges but goes beyond performance on standardized tests.
Elevated expression of the Zinc finger E-box binding homeobox transcription factor-2 (ZEB2) is correlated with poor prognosis and patient outcome in a variety of human cancer subtypes. Using a ...conditional gain-of-function mouse model, we recently demonstrated that ZEB2 is an oncogenic driver of immature T-cell acute lymphoblastic leukemia (T-ALL), a heterogenic subgroup of human leukemia characterized by a high incidence of remission failure or hematological relapse after conventional chemotherapy. Here, we identified the lysine-specific demethylase KDM1A as a novel interaction partner of ZEB2 and demonstrated that mouse and human T-ALLs with increased ZEB2 levels critically depend on KDM1A activity for survival. Therefore, targeting the ZEB2 protein complex through direct disruption of the ZEB2-KDM1A interaction or pharmacological inhibition of the KDM1A demethylase activity itself could serve as a novel therapeutic strategy for this aggressive subtype of human leukemia and possibly other ZEB2-driven malignancies.
•ZEB2, a novel driver of immature T-ALL, interacts with the lysine-specific demethylase KDM1A.•KDM1A function is critical for leukemic survival of T-ALL cells with high ZEB2 levels.
Aberrant expression of the SNAIL & ZEB families of Epithelial to Mesenchymal Transition (EMT) modulators is an emerging theme in acute leukemia biology. EMT regulation has long been implicated in ...epithelial tumor pathogenesis, however a role in hematopoietic malignancy has only recently been explored. In this study, we describe a novel mechanism of AML pathogenesis involving SNAI1 induced epigenetic dysregulation via corruption of the histone demethylase LSD1.
SNAI1 is expressed ∼10-fold higher in AML blasts compared to normal hematopoietic cells, suggesting a functional role for SNAI1 in AML. Indeed, SNAI1 knockdown induces differentiation in human AML cells, while Snai1 deletion delays tumour onset in mouse AML models. Furthermore, transgenic Snai1 expression perturbs myeloid development, resulting in accumulation of immature myeloid cells with enhanced self-renewal capacity - ultimately predisposing mice to AML. Intriguingly, impaired myeloid development by Snai1 absolutely requires its interaction with Lsd1, a H3K4 histone demethylase that has emerged as a novel therapeutic target in AML. Mechanistically, this interaction results in corruption of Lsd1 function via aberrant recruitment to Snai1 gene targets, and sequestration away from its own targets. Ultimately, this leads to changes in H3K4me1/2 methylation at specific promoters and enhancers, and subsequently altered gene expression.
This model provides insight into the mechanisms by which LSD1 can be perturbed in AML, and offers a possible explanation for why LSD1 inhibition/loss has somewhat dichotomous effects on normal and malignant hematopoietic stem cells. Furthermore, as other members of the SNAIL and ZEB families are known to interact with LSD1, it is likely that this model will be more broadly applicable to other EMT modulators in AML, representing a possible new focus for future therapeutic studies.
Ethnic Cleansing in the Balkans looks at the phenomenon of ethnic cleansing in the Balkans over the last two hundred years. It argues that the events that occurred during this time can be ...demystified, that the South East of Europe was not destined to become violent and that constructions of the Balkans as endemically violent misses a important political point and historical point.Carmichael provides an account of ethnic cleansing in the Balkans as a single historical phenomenon and brings together a vast array of primary and secondary sources to produce a concise and accessible argument. This book will be of interest to students and researchers of European studies, history and comparative politics.
To assess the role of distal nephron apical Na channel (ENaC) gene expression in Na wasting by the immature kidney, ENaC alpha-, beta-, and gamma-subunit mRNA levels were examined in the rat by ...RT-PCR. In microdissected nephron segments, all three ENaC subunit mRNAs were detected in the distal convoluted tubule, connecting tubule, cortical collecting duct, and outer medullary collecting duct. The inner medullary collecting duct and all other nephron segments were consistently negative. The mRNA levels were quantified in kidneys at different developmental stages by multiplex RT-PCR with "primer dropping," with endoplasmic reticulum-specific cyclophilin mRNA as an internal standard. All three ENaC mRNA levels were low or undetectable on gestational day 16 and only slightly higher 3 days before birth. A sharp rise was observed between 3 days before and 1-3 days after birth; the levels at postnatal days 1-3 were already similar to those of adult kidneys. The results suggest that ENaC subunit gene expression is not a limiting factor in the full-term newborn rat kidney, but low levels of expression may limit distal Na absorption in more immature kidneys, such as those of very premature human infants.
Deregulated gene expression due to genetic alterations, such as gene fusions affecting transcription and/or epigenetic factors is the hallmark of acute myeloid leukemia and the basis for the ...differentiation block of hematopoietic progenitors. Acute megakaryoblastic leukemia (AMKL) is a subtype of poor prognosis acute myeloid leukemia (AML) affecting primarily young children. Recently, the ETO2-GLIS2 fusion has been identified in 20-30% of de novo AMKL and associated with the worst prognosis in this subtype of AML. To characterize the transformation induced by ETO2-GLIS2, we first defined the consequences of ETO2-GLIS2 expression on hematopoietic progenitors and the contribution of ETO2 and GLIS2 on differentiation and self-renewal. Using methylcellulose replating assays and phenotype characterization, we show that the GLIS2 moiety drives the megakaryocytic phenotype whereas both the ETO2 and GLIS2 moieties are required for maintaining self-renewal. Global expression profiling and comparison to patients' signature consistently identify ETO2-GLIS2-mediated deregulation of major transcriptional regulators of hematopoiesis and leukemogenesis, including overexpression of the ERG oncogene. ChIP-seq analysis reveals that ETO2-GLIS2 is recruited at normal ETO2 complexes sites and also at GLIS2-specific targets through binding via GLIS2 DNA-binding domain.
We demonstrate that ETO2-GLIS2 fusion localize at half of H3K27Ac-dense enhancers, so called super-enhancers, to control transcription of associated genes. We show that interaction of ETO2-GLIS2 with ETO2 complexes is an essential node for the transcriptional control by the fusion at enhancer elements. Indeed, ETO2-GLIS2 dimerizes and interacts with endogenous ETO2 via its NHR2 domains. An NHR2 peptide-interference strategy inhibits oligomerization, reverses the transcriptional activation at enhancers, promotes megakaryocytic differentiation and abrogates human AMKL cells maintenance in vivo. Finally, upregulation of ERG by ETO2-GLIS2 further strengthen enhancers formation as ERG is co-recruited generating a feed forward loop at these elements and its knockdown or genetic inactivation downregulates expression of ETO2-GLIS2 targets required for leukemic cells survival. We propose that the megakaryocytic differentiation arrest and self-renewal controlled by ETO2-GLIS2 results from an imbalance in the expression of master transcription factors imposed by aberrant chromatin structures at enhancers that may be disrupted by targeting the NHR2 interface.
No relevant conflicts of interest to declare.
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