bluuebunny/crossref_metadata_2025_split huggingface dataset:
LDL Discordance in Pediatric Survivors of Acute Lymphoblastic Leukemia
Authors: Rosen Galit , Shaibi Gabriel Q 
Published: October 2019

Abstract
Background: Survivors of childhood acute lymphoblastic leukemia (ALL) have a four-fold excess risk of mortality secondary to cardiovascular events compared to the general population. While it is well-known that LDL has a role in atherogenesis and subsequent cardiac events, recent studies consistently show that LDL particle number (LDLp) is a stronger, independent predictor of coronary heart disease in adults compared to LDL-cholesterol (LDLc), especially when the values are discordant. There is emerging evidence that LDL discordance also occurs in children. We studied this phenomenon in pediatric ALL survivors and identify associated risk factors.
Methods: Complete data were available from 64 patients enrolled in the Phoenix Children’s Hospital pediatric cancer survivorship registry. Patients were 12.9±3.5 years of age (range: 7.7-22.7 years) with a mean time off therapy of 5.5±2.6 years (range 2.3-11.4 years). LDLc and LDLp were assessed by NMR spectroscopy. Patients were assessed by a registered dietician for calcium, fat, and fruit intake as well as physical activity. Ideal LDLc and LDLp were defined as <160 mg/dL and <1600 nmol/L, respectively, based on American Heart Association guidelines for people with standard cardiac risk. Discordance was classified based on ideal vs. not-ideal status for each parameter.
Results: Mean BMI was 22.7±5.7 kg/m2 (range 14-38 kg/m2); mean BMI percentile was 73.1±26.1% (0.9-99.5%) with 42% of patients considered overweight or obese at the time of evaluation. Mean LDLc and LDLp were 79±25.5 mg/dL (29-164 nmol/L) and 1124±517 nmol/L (411-2837 nmol/L), respectively, with 89% (n=56) of survivors exhibiting ideal LDLc and 47% (n=30) of survivors exhibiting ideal LDLp. In a subgroup of patients with ideal LDLc, 40.6% (n=26) exhibited not-ideal LDLp and were classified as discordant. Regression analysis showed that after adjusting for age and gender, BMI (p<0.00001) and LDLc (p<0.00001) were significant independent predictors of LDLp while lifestyle factors and time off therapy were not significant predictors of LDLp. When patients were grouped as concordant (ideal LDLc and LDLp, n=30) or discordant (ideal LDLc and elevated LDLp, n=25), BMI was 17.6% higher in the discordant group (25.0±5.4 kg/m2 vs. 20.6±5.0 kg/m2, p=0.003).
Conclusion: In this population of pediatric ALL survivors, LDLc measurements may not provide a complete assessment of cardiovascular disease risk. Given that LDLp is an early predictor of cardiovascular outcomes, conventional lipid testing may underestimate the true cardiovascular disease risk in ALL survivors. Survivors may benefit from early, expanded screening and targeted intervention. Further studies should focus on the broader pathophysiology of cardiovascular disease in pediatric ALL survivors.

Disclosures
No relevant conflicts of interest to declare.
Periodic Monitoring of Components of the Metabolic Syndrome in Adolescent Survivors of Childhood Cancer
Authors: Lee Young-Ho , Shin HyeKyung , Kang Hye-Roung , Yang Seung 
Published: October 2019

Abstract
Purpose: The components of metabolic syndrome (MS) have been tended to increase and associated with cardiovascular risks in long-term survivors of childhood cancer. We investigated the prevalence of components of MS in adolescent survivors of childhood cancer and tried to monitor them periodically.
Materials and methods: We investigated 44 adolescent survivors of childhood cancer, median age 14.9 years (range 10–19.8 years) and median follow-up time elapsed after off-therapy 7.4 years (range 5–16.5 years). We measured body mass index (BMI), systolic and diastolic blood pressure, triglycerides (TG), high-density lipoprotein (HDL)–cholesterol, and fasting glucose. Fatty liver was evaluated by ultrasound examinations during follow-up period.
Results: No survivors demonstrated MS with 3 components, however, 18% of survivors (8/44) have 2 abnormal components and 43% (19/44) have 1 abnormal components, respectively. The frequency of each component was: increased BMI, 11%; elevated blood pressure, 0%; elevated TG level, 41%, low HDL cholesterol, 27%; and elevated fasting glucose, 0%. Among these components, the increased TG levels were highly prevalent in survivors than in general population (p=0.000). Fatty liver was identified in 8 survivors (18.2%). Sixteen of 44 survivors (36.4%) received at least 3 repeated examinations annually. Twelve out of 16 survivors have 1 or 2 abnormal components at initial examination. Their number of metabolic components have been shown to decrease in 4, persisted in 3, and increased in 5 survivors. Three of 4 survivors who have no components of MS at initial examination showed at least 1 abnormal component during follow-up.
Conclusions: We observed the high incidence of increased TG level in adolescent survivors of childhood cancer, and detected abnormal components of MS during periodic follow-up. Lifestyle interventions and periodic long-term follow-up monitoring would be needed to reduce the metabolic risks in childhood cancer survivors.

Disclosures
No relevant conflicts of interest to declare.
Bilateral Involvement Is an Independent Risk Factor in Testicular Relapse of Childhood ALL: Results of the Trials ALL-REZ BFM 83 - 2002
Authors: Chen-Santel Christiane , Tabien Ulrike , van Schewick Claudia , Schrappe Martin , Escherich Gabriele , Eggert Angelika , Henze Günter , Stackelberg Arend , Hundsdörfer Patrick 
Published: October 2019

Abstract

Introduction:
In childhood acute lymphoblastic leukemia (ALL) about 15-20% of patients suffer from relapse after frontline therapy. The testes are the second most frequent site of extramedullary relapse. Up to now there are no data on the impact of the extent of testicular relapse on prognosis.
Patients and Methods:
We retrospectively analyzed outcome of children with testis relapse of ALL who were treated according to ALL-REZ BFM trials from March 1983 until December 2013. Only patients with first relapse were included in the analysis. From a total of 1603 boys registered within the ALL-REZ trials since 1983, testicular involvement was identified in 302 patients. Local therapy consisted of orchiectomy (or irradiation at 24 Gray) of clinically involved testes. Clinically not involved testes were irradiated at 15 or 18 Gray in case of histologically proven leukemic infiltration. Most patients received intensive multi-drug chemotherapy followed by conventional maintenance therapy.
Results:
Extent and time point of relapse did not significantly differ between isolated testicular (n=135) and combined BM and testicular relapse (n=167). Isolated testicular relapse was associated with improved 5 year-event free survival (pEFS) compared with combined relapse (0.70±0.04 vs. 0.54±0.04, p=0.005). Bilateral testicular involvement accounted for a worse pEFS than unilateral involvement (0.48±0.05 vs. 0.71±0.04, p<0.0001). This was particularly evident in patients with isolated testicular relapse (bilateral (0.53±0.08) vs. unilateral relapse (0.79±0.05), p<0.0001), but not in combined relapse (bilateral (0.45±0.06) vs. unilateral relapse (0.62±0.06), p=0.11). Only in patients with very early/early isolated testicular relapse bilateral testicular involvement was associated with poor outcome (0.40±0.09 vs. 0.68±0.08, p=0.015), whereas no significant differences were detected in the late relapse group (0.79±0.11 vs 0.86±0.05, p=0.11). Multivariate analysis identified time point of relapse, extent of testicular relapse and combined relapse as independent risk factors in testicular ALL relapse. Subsequent local relapse was rare, ninty-eight patients (32.5%) suffered a subsequent, mostly BM relapse.
Conclusion:
Isolated testicular relapse is associated with improved outcome compared to combined BM/testicular relapse. Bilateral testicular involvement is an independent risk factor for relapse, particularly prognosis of patients with (very) early isolated bilateral testicular relapse was poor. As local in contrast to systemic subsequent relapse was rare, this group of patients might benefit from intensification of chemotherapy including allogeneic stem cell transplantation.

Disclosures
No relevant conflicts of interest to declare.
Ex vivo Fucosylation Enhances Regulatory T Cell Anti-Graft Versus Host Disease Potency in Mice
Authors: Parmar Simrit , Liu Xiaoying , Eric Yvon , zweidler-mcCay Patrick , Shah Nina , Rezvani Katayoun , McNiece Ian K. , Shpall Elizabeth J. 
Published: October 2019

Abstract
Emerging preclinical data indicate a potential therapeutic use of regulatory T cells (Tregs) to suppress or eliminate graft versus host disease (GVHD). Adoptive therapy with Tregs has been examined as a prophylactic strategy for GVHD. Thus far, 1:1 ratio of Tregs to conventional T cells (Tcons) has been required to prevent GVHD, and such high targeted cell doses are hard to achieve in a clinical setting due to variability in Treg frequency and expansion potential. As a result, novel strategies are needed to generate clinically-effective Treg products. Additionally, since the ability of Tregs to enter inflamed tissues has been shown to be critically dependent on their ability to bind E- and P-selectins, we sought to exploit this pathway to improve Treg homing. Incubation of culture expanded Cord Blood (CB) Tregswith fucosyltransferase-VI (FTVI) increased the degree of fucosylation from 8% to 64%. Importantly, fucosylated Tregs are able to suppress T cell proliferation in an in vitro allogeneic mixed lymphocyte assay and show preferential increase in the E-selectin binding ability when compared to untreated Tregs. We injected 10e6 Tregs vs. 10e6 fucosylated Tregs followed by 10e7 peripheral blood mononuclear cells in the sublethally irradiated NOD/SCID gamma null (NSG) xenogenic GVHD mouse model, and recipients of untreated Tregs showed weight loss as early as day 6 whereas fucosylated Treg recipients retained weight until day 12 (Fig 1). Fucosylated Tregs were detected in the peripheral blood of mice until day 31 as opposed to day 12 for untreated Tregs. As compared to recipients of untreated Tregs, lower numbers of GVH-inducing allogeneic T-cells were detected in the secondary lymphoid organs in the fucosylated Treg recipients (Table 1). The overall survival of fucosylated Treg recipients was significantly superior to that of untreated Treg recipients (Fig 2). We conclude that prophylactic treatment with fucosylated Tregs prevents GVHD and improves survival in a xenogenic mouse model at doses that are i) at less than 1:1 ratio with conventional T-cells (Tcon) and ii) are lower as compared to untreated Tregs. We believe that by overcoming the 1:1 dose requirement of Tregs: Tcons, we will be able to effectively translate Treg based adoptive therapy into the clinic for the prevention of GVHD. Establishing fucosylated Tregs as a preventive strategy for GVHD will result in a major breakthrough in the field of stem cell transplantation eliminating a major life threatening outcome of the therapy.
Figure 1 Figure 1.
Figure 2 Figure 2.
Figure 3 Figure 3.

Disclosures
No relevant conflicts of interest to declare.
PIM2 Pro-Survival Functions Are Mediated By RSK2 in AML
Authors: Hospital Marie-Anne , Jacquel Arnaud , Green Alexa , Lambert Mireille , Auberger Patrick , Lacombe Catherine , Hermine Olivier , Moura Ivan C , Mayeux Patrick , Bouscary Didier , Tamburini Jerome 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) is a poor prognosis hematologic malignancy accounting for 30% of AML cases. Constitutive FLT3-ITD activation drives STAT5 signaling resulting in enhanced PIM kinases expression. PIM serine/threonine kinases (including PIM1,-2,-3) are involved in cell cycle and apoptosis regulation and thus represent emerging therapeutic targets. We previously reported an increased PIM2 protein expression in primary AML cells compared to normal CD34+ immature hematopoietic cells. Here, we aimed to study PIM kinases as potential therapeutic target in FLT3-ITD AML.
In two distinct FLT3-ITD+ human AML cell lines (MV4-11 and MOLM-14) doxycycline (Dox)-induced shRNA-mediated PIM2 knockdown enhanced apoptosis, attested by an increase in early apoptotic (annexin V positive, DAPI negative) and late apoptotic (both annexin V, DAPI positive) cells. Cell death upon PIM2 knockdown was confirmed by an inhibition of colony formation in methylcellulose. Mechanisms of apoptosis induction involved release of second mitochondria-derived activator of caspases (SMAC) as well as increased p53 and Bax expression and Bax nuclear translocation, leading to loss of mitochondrial membrane potential.
To gain further mechanistic insights, we performed global gene expression profiling in the MOLM-14 cell line lentivirally transduced with Dox-inducible PIM2 shRNA. Consistent with our functional analysis, cell-cycle regulatory genes (including c-MYC, CHK1 or PLK1) and pro-survival genes (including RSK2 or BCL2) were down-regulated, while pro-apoptotic genes (most notably TP53 and BAX) were up-regulated. Here we focused on RSK2, a member of the mitogen-activated protein kinase (MAPK) signaling pathway that has not been previously reported to be a target of PIM2. In the MOLM-14 cell line, PIM2 knockdown reduced RSK2 mRNA and protein levels. RSK2 knockdown using a Dox-inducible RSK2 shRNA induced apoptosis similarly to that observed following PIM2 knockdown in this cell line. In parallel with PIM2 knockdown, RSK2 down-regulation enhanced p53 expression and activity, as measured by increased expression of its transcriptional target p21, as well as Bax expression.
In summary, our results suggest that RSK2 is a PIM2 transcriptional target that contributes to PIM-2-dependent cell survival mediated by a novel RSK2-p53-Bax signaling pathway. RSK2 therefore warrants further study as a potential pharmacologic target in AML (particularly in cases resistant to PIM inhibition) as well as other PIM-addicted malignancies.

Disclosures
No relevant conflicts of interest to declare.
APP Gene Is Correlated with C-KIT Mutations and Indicates Poor Disease Outcome in AML1-ETO-Positive Acute Myeloid Leukemia
Authors: Yu Guopan , Jiang Ling , Meng Fan Yi , Yin Changxin , Wang Zhixiang , Zhou Hongsheng , Jiang Xuejie , Zhong Qingxiu , Cao Rui , Liao Libin 
Published: October 2019

Abstract
Amyloid precursor protein (APP) has been reported to be highly expressed in AML1-ETO-positive acute myeloid leukemia (AML1-ETO-positive AML), and we found it correlate with extramedullary infiltration regulated of by APP/ERK/MMP-2 signal pathway in our previous study. It is also known that C-KIT mutations highly expressed in AML1-ETO-positive AML and cooperates with full-length AML1-ETO to induce AML in mice. In this study we further described a close correlation of APP gene with C-KIT mutations, as well as APP related clinical and prognostic significance in 65 patients with AML1-ETO-positive AML.
65 cases of AML1-ETO-positive AML patients with median age of 30 years old, who were admitted to our hospital from February, 2006 to June, 2013 and made the diagnosis according to WHO2008 diagnosis standard, were enrolled into this study. APP expression in bone marrow cells before the first chemotherapy was assessed by quantitative reverse transcriptase (QRT)-PCR method. These cases were accordingly divided into APP-H group (n=33, with high level of APP by QRT-PCR) and APP-L group (n=32, with lower level of APP by QRT-PCR) according to median APP expression. Incidence of C-KIT mutations, clinical characteristics and prognosis including complete response (CR), overall survival (OS), and recurrence free survival (RFS) with median 35 (6-96) months followed-up was differentiated between the two groups. Furthermore, expression of APP and AML1/ETO fusion gene were simultaneously monitored at the time of 3, 6, 12 and 24 months or relapse after CR by QRT-PCR method.
The incidence of C-KIT mutations was significantly increased in the APP-H group, as compared with the APP-L group (39.4% versus 12.5%) and it was positively correlative with APP expression (rp=0.435, P=0.004). Of the 17 patients harboring C-KIT mutations, 13 patients overexpressed APP gene (P=0.014) (Figure 1). Clinically, APP-H patients exhibited significantly elevated white blood cells count, increased extramedullary infiltration (P=0.039 and P=0.019, respectively). Moreover, APP overexpression was related to low rate of two-cycle CR, RFS and OS (P=0.020, P=0.001 and P=0.029, respectively) (Table 1). In addition, the change of APP expression was consistent with that of AML1-ETO fusion gene monitored by QRT-PCR method at different status of leukemia, though APP expressed differently in different patients with the same AML1-ETO expression.
Taken together, these data suggest that APP gene is correlated with C-KIT mutations and indicates poor disease outcome and dynamic monitoring APP expression could be another choice of minimal residual disease monitoring in AML1-ETO-positive AML.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Genome Editing Toolbox
Authors: Scharenberg Andrew M. 
Published: October 2019

Abstract
Nucleases capable of making targeted breaks in genomic DNA are a core technology required for genome engineering, an emerging field of technology for making precise alterations in cellular genomes. Over the past ten years, four major platforms have emerged for generation of nucleases able to make targeted DNA breaks with a high degree of efficiency and specificity: homing endonucleases, zinc finger nucleases, transcription activator-like (TAL) effector nucleases, and RNA-guided nucleases. This talk will cover the biochemistry and platform-specific attributes of each type of nuclease, along with evolution/improvements in nucleases and related technologies and aspects of the practical implementation of nuclease technology for gene knockout and gene repair in primary hematopoietic cells.

Disclosures
Scharenberg: Pregenen Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cellectis therapeutics: Consultancy.
Taking it to the Clinic: Genome Editing for Blood Disorders
Authors: Urnov Fyodor D. 
Published: October 2019

Abstract
The ability to engineer precise genetic modification of human stem cells offers the promise to extend the range of their potential therapeutic application. This possibility is now being realized via the use of zinc finger nucleases (ZFNs). ZFNs are customizable, sequence-specific endonucleases that can be designed to introduce a discrete cleavage event at any user-chosen location within the stem cell genome. This presentation will describe our progress in translating ZFN-modified hematopoietic stem/progenitor cells (HSPCs) from concept to clinic, focusing on preclinical proof-of-concept studies supporting the development of autologous, genome-edited CD34+ HSPCs as potential treatments for both HIV/AIDS as well as certain monogenic diseases of the blood, such as β-thalassemia.

Disclosures
Urnov: Sangamo BioSciences: Employment.
Hepcidin at the Nexus of Infection and Anemia
Authors: Drakesmith Hal 
Published: October 2019

Abstract
Humans have two main reasons for needing to control the amount and distribution of iron in the body. First, iron is used in fundamental physiological processes, including carrying oxygen, generating energy from oxygen, and in utilizing the energy for activities such as macromolecular synthesis and DNA repair. However, iron requirements are not stable over time; blood loss, growth, pregnancy, changes in diet and even altitude all have powerful and sometimes acute effects on our need for iron and how we route it to tissues that need it – for example, in the case of blood loss, iron is released for erythropoiesis to help replace lost red blood cells. The second reason to regulate iron is in response to infection; evidence for a critical influence of iron on the outcome of infections is broad. Sequencing of microbial genomes reveals significant investment into iron acquisition, allowing pathogenic organisms to obtain iron from multiple host sources. Iron is required for pathogen proliferation and increased availability of host iron, either through experimental administration in animal models or, in humans, due to genetic causes or because of nutritive or therapeutic iron supplementation, exacerbates infection or increases its incidence. Part of the innate immune response to infection is to deny iron to the pathogen, slowing its growth and giving more time for other arms of immunity to mobilize. The hypoferremia of infection helps to inhibit growth of microbes in the bloodstream, and may be a critical response to prevent potentially fatal septicemia. Hepcidin is the liver-encoded peptide hormone that allows the body to maintain iron homeostasis, to rapidly release iron for erythropoiesis, and to lock iron away from microorganisms in response to infection. The ability to integrate these activities lies in the unique sensitivity of hepcidin expression to diverse physiological inputs. Transcription of hepcidin is enhanced by signals deriving from iron accumulation (through BMP/SMAD signaling) and from immune mediators (IL-6, IL-22, IFN-a), and is suppressed by expanded erythropoiesis via erythroferrone. In animal models the relative strengths of these signals determine hepcidin synthesis, and thus determine iron absorption, release, and storage. Our lab has been focusing on understanding hepcidin regulation in human populations where infectious disease, anemia, iron deficiency and inherited red cell disorders are all prevalent, for example sub-Saharan Africa and the Indian subcontinent. This lecture will describe how hepcidin analysis has helped us to understand the complex etiology of childhood anemia in malarious regions, suggested methods to improve iron therapeutic strategies, and indicated ways to use hepcidin diagnostically. The latter applications are now beginning to be tested clinically at the University of Oxford.

Disclosures
No relevant conflicts of interest to declare.
Regulation of Hematopoiesis by Cholesterol
Authors: Tall Alan R. 
Published: October 2019

Abstract
Leukocytosis is a risk factor for athero-thrombotic disease in humans, and develops in animal models of atherosclerosis in response to feeding high-fat, high-cholesterol diets. The ATP binding cassette transporters ABCA1 and ABCG1 promote cholesterol efflux to apoA-1 and high density lipoprotein (HDL), respectively and are targets of liver X receptor (LXR) transcription factors. Mice lacking ABCA1/G1 develop a dramatic myeloproliferative phenotype with monocytosis and neutrophilia, associated with expansion and proliferation of hematopoietic stem and myeloid progenitor populations (HSPCs). The transporters are highly expressed in HSPCs where they act to control proliferative responses to growth factors (IL-3, GM-CSF) by regulating plasma membrane lipid rafts and cell surface expression of the common β subunit of the IL-3/GM-CSF receptor. ABCG4 is closely related to ABCG1 but is expressed primarily in the megakaryocyte progenitor (MkP) population of the bone marrow. ABCG4-deficient mice have MkP proliferation and expansion, thrombocytosis, increased platelet/leukocyte aggregates and accelerated atherosclerosis. ABCG4 promotes cholesterol efflux onto HDL, and thereby reduces the cell surface expression of the thrombopoietin (TPO) receptor. This appears to involve membrane cholesterol enrichment and interruption of a negative feedback loop involving the TPO receptor and mediated by Lyn Kinase and c-CBL which mediate ubiquitination and internalization/degradation of the receptor. Overall results suggest that ATP binding cassette transporters promote cholesterol efflux, decrease membrane lipid raft formation and enhance the feedback downregulation of growth factor receptors in response to growth factor binding, with anti-proliferative responses that may be beneficial in atherosclerosis and myeloproliferative neoplasms.

Disclosures
No relevant conflicts of interest to declare.