bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pediatric Patients with Extramedullary Leukemia Involving the Central Nervous System Have a Superior Outcome.
Authors: Johnston Donna , Alonzo Todd , Gerbing Robert , Lange Beverly , Woods William G. 
Published: October 2019

Abstract
Purpose: Extramedullary leukemia (EML), formally known as chloroma, is discrete collections of leukemia cells outside of the bone marrow. EML is often seen within the central nervous system (CNS) and these are often treated in a similar fashion as leukemia cells within the cerebral spinal fluid (CSF). We previously demonstrated that the presence of leukemia cells within the CSF (CNS leukemia) does not affect overall survival. We sought to determine the outcome of patients with central nervous system EML and compare these patients with those with CNS disease and non CNS EML.
Methods: Patients enrolled on Children’s Cancer Group protocols 2861, 2891, 2941 and 2961 being treated for de novo acute myeloid leukemia (AML) with intensive timing chemotherapy were classified for the presence of CNS disease as CNS1 (<5 wbc in the CSF without blasts), CNS2 (<5 wbc in the CSF with blasts), or CNS3 (≥ 5 wbc in the CSF with blasts), as well as EML in the CNS (eg orbit, brain, etc) or non-CNS EML (eg skin, lung, etc). These patient’s outcomes were then analyzed.
Results: A total of 1459 patients treated with intensive timing chemotherapy were analyzed in this study. At diagnosis, 1113 (76%) were CNS1, 143 (13%) CNS2, 154 (11%) CNS3, 48 (3%) had CNS EML, 57 (4%) had a non-CNS EML, and only 6 patients (0.4%) with CNS EML had CNS3 status. Patients with CNS EML had a significantly higher overall survival from study entry compared to patients with non-CNS EML (83% vs 38%, p<0.001), and compared to CNS3 patients (83% vs 50%, p<0.001). The patients with CNS EML also had a significantly higher event free survival compared to patients with non-CNS EML (65% vs 34%, p<0.001), and compared to CNS3 patients (65% vs 34%, p<0.001). There was no significant difference in relapse risk, bone marrow relapse, isolated CNS relapse, or EML relapse comparing patients with CNS EML and non-CNS EML. CNS EML patients had a significantly lower relapse risk compared to CNS3 patients (29% vs 49%, p=0.025). There was not a significant difference in bone marrow relapse, isolated CNS relapse, or EML relapse comparing these 2 groups of patients.
Conclusion: Patients with extramedullary leukemia involving the CNS had a significantly better survival than patients with non-CNS EML or patients with CNS leukemia at diagnosis. This should reassure clinicians caring for these often challenging patients.
A Protease-Resistant PML-RARα Has Increased Leukemogenic Potential in a Murine Model of Acute Promyelocytic Leukemia (APL).
Authors: Uy Geoffrey L. , Welch John S. , Lane Andrew A. , Ley Timothy J. 
Published: October 2019

Abstract
Previous work from our group has demonstrated that the azurophil granule protease, neutrophil elastase (NE) can cleave PML-RARα (PR), the fusion protein that initiates acute promyelocytic leukemia; we identified valines 420 and 432 within the PML domain as the initial sites of NE cleavage. Furthermore, neutrophil elastase deficiency reduces the penetrance of leukemia in a knock-in model of APL in which the human PR cDNA is knocked into the 5′ untranslated region of the murine cathepsin G gene (Lane and Ley, Cell 2003) In this study, we demonstrate that mutation of residues V420 and V432 to arginine (2VR) confers resistance to proteolytic cleavage by NE. V420 and V432 are also cleaved using marrow extracts derived from NE deficient mice, indicating that other marrow-derived proteases can cleave PR at these two valines; the 2VR mutation confers resistance to these proteases as well. To determine the role that cleavage of PR plays in leukemogenesis, we generated protease-resistant PR mice by inserting the PR(2VR) allele into the murine cathepsin G locus via homologous recombination. Analysis of marrow from 6–8 week old preleukemic mice indicates that myeloid progenitors from PR(WT) and PR(2VR) mice both have increased replating efficiency in methocellulose cultures with a trend towards increased efficiency with PR(2VR)mice (WT=0%, PR(WT)=0.45%, PR(2VR)=1.65% at 4th replating, p=NS). Both PR(WT) and PR(2VR) mice develop a phenotypically identical, fatal myeloid leukemia characterized by splenic infiltration with blasts that co-express CD117 (c-kit) and Gr-1, and that are morphologically promyelocytes. A tumor watch revealed that PR(2VR) mice (n=89) demonstrated a shortened latency of leukemia development (274 days) compared to PR(WT) mice (n=41, 473 days, p=0.0003). These results indicate that resistance to proteolysis confers an increased leukemogenic potential to the PR fusion protein, which may be due to increased levels of full length PR in the myeloid progenitors of these mice. Based on these observations, we suggest NE-mediated cleavage of PR is not required for its activity. Therefore, the mechanism by which NE deficiency affects APL penetrance may be indirect.
Synergistic Cytarabine:Daunorubicin Ratios Delivered by CPX-351 to Human Leukemia Xenografts Is Associated with Liposome-Mediated Bone Marrow Drug Accumulation, Intracellular Delivery of Encapsulated Agents to Leukemia Cells, and Increased Efficacy.
Authors: Mayer Lawrence , Lim Wahseng , Santos Nancy Dos , Xie Sherwin , Hopkins Andrea , Huang Ruby , Wilkins Lindsey , Kelly Sarah , Bermudes David , Harasym Troy , Tardi Paul 
Published: October 2019

Abstract
CPX-351, a liposomal formulation of cytarabine:daunorubicin co-encapsulated at a synergistic 5:1 molar drug ratio, has been previously shown to be highly active in various preclinical leukemia models. In the present investigations, we utilized a bone marrow engrafted human lymphocytic leukemia xenograft model in order to elucidate the pharmacodynamic basis for its superior efficacy compared to un-encapsulated cytarabine:daunorubicin combinations. In normal bone marrow, the un-encapsulated cytarabine:daunorubicin saline-based cocktail and CPX-351 provided comparable cell suppression after intravenous treatment at maximum tolerated dose. In contrast, when these formulations were administered to tumor bearing mice, CPX-351 completely ablated leukemia cells from the bone marrow for multiple weeks whereas the saline-based drug cocktail induced only transient leukemia suppression. Examination of drug levels in the bone marrow compartment revealed that cytarabine:daunorubicin concentrations were significantly elevated for CPX-351. More striking was the observation that whereas bone marrow drug concentrations over time appeared comparable after each dose of the saline-based drug cocktail, the first dose of CPX-351 promoted elevated bone marrow drug accumulation for subsequent doses. Under these conditions, the cytarabine:daunorubicin ratio in bone marrow was maintained near the administered 5:1 molar ratio for CPX- 351 while the drug ratio changed more than 100-fold within 4 hours after administration of the saline-based drug cocktail. Confocal fluorescence microscopy of leukemia cells exposed to CPX-351 in vitro revealed that CPX-351 liposomes were taken up into cytoplasmic vacuoles and subsequently released their drug contents intracellularly. Taken together, these results indicate that the improved efficacy observed following CPX-351 administration in vivo is related to liposome-mediated prolonged and direct exposure of leukemia cells to synergistic drug ratios.
Flavopiridol Down-Regulates Genes Involved in Cell Cycle Regulation and Tumor Progression in Adults with Refractory or Poor-Risk Acute Leukemia.
Authors: Resar Linda , Hillion Joelle , Alino Katrina , Rudek Michelle , Karp Judith 
Published: October 2019

Abstract
Acute leukemia in adults continues to be a formidable clinical challenge that demands further investigation to identify more rational therapies. To optimize anti-leukemia therapy, we are investigating the prototypical cyclin dependent kinase (cdk) inhibitor, flavopiridol, in refractory or poor-risk disease. Flavopiridol is a cytotoxic molecule that is thought to induce cell cycle arrest by blocking cyclin-dependent kinase (cdk) function, thereby interfering with RNA Polymerase II activity and globally down-regulating gene expression. In the setting of pan-cdk inhibition, E2F1 is released and appears to drive apoptosis in transformed cells. Consistent with these proposed mechanisms of action, a previous study from our group showed that flavopiridol induces apoptosis in vitro in leukemic blasts from patients with refractory leukemia. Administration of flavopiridol was associated with a decrease in one or more of the following proteins in the leukemic blasts: RNA Polymerase II, STAT3, cyclin D1, Bcl-2, and Mcl-1. Serum VEGF levels also decreased in most patients. We are now investigating mRNA levels of the genes encoding these proteins by quantitative, RT-PCR in leukemic blasts from adult patients with refractory or poor-risk leukemia before and after flavopiridol therapy. We have treated 26 patients with flavopiridol at an escalating, hybrid dose followed by ara-c and mitxantrone. Adequate RNA from leukemic blasts before and after flavopiridol administration was available from 8 of 11 patients studied thus far. All cases (8/8) exhibit a marked decrease in mRNA for VEGF following flavopiridol. mRNA levels for other putative flavopiridol target genes is also decreased in a subset of leukemic blast samples after therapy, as follows: E2F1 (6/8), STAT3 (6/8), Mcl-1 (6/8), RNA Polymerase subunit 2a (3/3), and cyclin D1 (2/3). In contrast, bcl-2 mRNA levels increased after flavopiridol in most cases (7/8), which could represent a compensatory mechanism of leukemic blasts to avoid apoptotic cell death. Our preliminary studies indicate that flavopiridol is cytotoxic in poor-risk and refractory acute leukemia. Studies are underway to determine if down-regulation of any putative target genes correlates with pharmacologic data or clinical responses.
CYP2C19*2 and *3 Polymorphisms Are Associated with High Post- Treatment Platelet Reactivity in Korean Patients with Acute Coronary Syndrome Undergoing Percutanous Coronary Intervention.
Authors: Kim In-Suk , Jeong Young-Hoon , Lee Gyeong-Won 
Published: October 2019

Abstract
Background: Cytochrome P450 (CYP) 2C19 is an enzyme showing genetic polymorphism that may cause marked interindividual and interethnic variation in the metabolism and disposition of its substrates. CYP2C19*2 and CYP2C19*3 are the most common of CYP2C19 polymorphisms, and show phenotypic poor metabolism. Recent data have shown that the CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet response to clopidogrel in healthy controls and Caucasian patients with acute coronary syndrome. However, It is unknown whether CYP2C19 *3, which is frequently noted in Asian, is also associated with platelet response to clopidogrel. Therefore, this study was conducted to analyze the effect of CYP2C19 *2 and *3 polymorphisms on high post-treatment platelet reactivity (HPPR) on clopidogrel in Korean patients with acute coronary syndrome, as a representative of Asian populations.
Methods: The study included 136 consecutive patients undergoing percutanous coronary intervention (PCI). Adenosine diphosphate (ADP)-induced platelet aggregation by light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay (Ultegra rapid platelet function assay; Accumetrics Inc., USA) were assessed after a loading dose and after the maintenance dose of clopidogrel before discharge. CYP2C19 genotype was analyzed by Snapshot method.
Results: The genotypic distributions of CYP2C19*1/*1, *1/*2, *1/*3, *2/*2, and *2/*3 were 57 (41.9%), 47 (34.6%), 12 (8.8%), 14 (10.3%), 6 (4.4%), and 6(4.4%), respectively. The frequencies of CYP2C19 mutant alleles in Korean were higher than Caucasians. The CYP2C19*2 and CYP2C19*3 polymorphisms were significantly associated with persistent higher platelet aggregation by LTA, and lower inhibition of platelet reactivity by VerifyNow P2Y12 assay after clopidogrel than CYP2C19*1 genotype. The CYP2C19*2 and *3 alleles were more frequent in clopidogrel hyporesponsiveness, defined by persistent HPPR (5 uM ADP-induced platelet aggregation >50%; p = 0.01).
Conclusions: This study suggests that the CYPC19*2 and *3 alleles influence clopidogrel hyporesponsiveness after clopidogrel in Asian patients with acute coronary syndromes undergoing PCI. These findings can have a significant impact on the future design of pharmacognetic antiaggregant strategies for acute coronary syndrome on antiplatelet treatment.
Runx1 Interactions in Stem Cell Biology.
Authors: Speck Nancy A. , Chen Michael , Yokomizo Tomomasa , Zeigler Brandon , Dzierzak Elaine 
Published: October 2019

AbstractThe study of developmental hematopoiesis has provided important insights into the molecules that establish and sustain this process throughout adult life. At the base of the hematopoietic hierarchy is the hematopoietic stem cell (HSC), which emerges in the mouse conceptus starting at 10.5 days post coitus (≥ 34 somite pair stages).1 HSCs have been found in several distinct sites: the yolk sac, umbilical and vitelline arteries, the dorsal aorta in the aorta/gonad/mesonephros (AGM) region, fetal liver, and, more recently, the placenta.1–4 HSCs emerge from these sites (yolk sac, umbilical and vitelline arteries, and AGM region) through the formation of intra-aortic hematopoietic clusters that develop from endothelium.5–7 Studies in mouse, zebrafish, chick, and frog embryos established that Runx1 (AML1) is the earliest specific marker of all definitive hematopoietic sites in the conceptus. Runx1 is expressed in endothelial and mesenchymal cells and in intraaortic hematopoietic clusters, and marks all committed HPs and HSCs in both the embryo and the adult.6,8–10 It has been proposed that Runx1 functions during the transition from a “hemogenic endothelium” to intra-aortic clusters and HSCs.8 Here, we show that deletion of Runx1 in vascular endothelial cadherin (VEC) positive cells blocks the emergence of intra-aortic hematopoietic clusters, HPs, and HSCs. Greater than 95% of adult bone marrow cells are marked when VEC-Cre is used to delete a Rosa26 reporter allele, demonstrating that almost all blood cells have transited through a VEC+ intermediate at some point in their life. On the other hand, Runx1 deletion with Vav-Cre, which occurs in fetal liver HPs and HSCs, does not block hematopoiesis. Collectively, these data demonstrate that Runx1 is absolutely required in endothelial cells for hematopoietic cluster, HP, and HSC formation, but after HSCs are born from endothelium, Runx1 is no longer required to maintain them.
Age-Related Changes in Tissue-Specific Stem Cells.
Authors: Wagers Amy J. , Cerletti Massimiliano , Mayack Shane R. , Kim Francis S. , Shadrach Jennifer L. 
Published: October 2019

Abstract
Aging of multicellular organisms typically involves progressive decline in the body’s ability to maintain homeostatic cell replacement and to regenerate tissues and organs after injury. In both the blood and the skeletal muscle, aging significantly impairs regenerative activity and can dysregulate normal homeostatic production of mature cells. These age-acquired defects in tissue function profoundly impact the health of older individuals, as evidenced by the high incidence of age-related muscle deterioration (sarcopenia), bone marrow failure, immune dysfunction, and blood cancers in the elderly. How aging causes deterioration of tissue function is poorly understood, but several lines of evidence suggest that loss or functional impairment of tissue-specific stem cells directly contributes to age-dependent failures in tissue repair. Interestingly, the effects of aging on tissue stem cell function appear to arise at least in part from alterations in the aged tissue environment, which can inhibit stem cell activity in older animals and may be regulated by factors that circulate naturally in the bloodstream. By making use of sensitive in vivo and in vitro approaches, including direct cell isolation by FACS, we are investigating the extrinsic factors and interactions that control stem cell function in aged animals. Our current studies have pointed us toward a discrete set of metabolic regulators and inflammatory cytokines, which may alter the signals that stem cells receive from their environment in aged animals. The knowledge we gain from these ongoing studies will help to define novel strategies to delay or reverse the onset of age-related disease, extending the healthful life of aging individuals.
The JunB Transcriptional Network: from Hematopoietic Stem Cells to Myeloid Function.
Authors: Passegué Emmanuelle 
Published: October 2019

Abstract
Hematopoietic development is organized hierarchically, starting with a rare population of hematopoietic stem cells (HSCs) that gives rise to a series of committed myeloid progenitors and mature cells with particular functional and immunophenotypic properties. HSCs are operationally defined by their ability to provide long-term multilineage reconstitution when transplanted into hematopoietically compromised recipient, and are the only cells within the myeloid series that self-renew throughout life. Under steady-state conditions, HSCs are largely quiescent, slowly cycling cells. However, in response to environmental stresses, HSCs can undergo dramatic expansion and contraction to ensure proper homeostatic replacement of blood cells. HSCs are found predominantly in the bone marrow (BM) associated with several recently described vascular and endosteal niches. A complex balance of cell extrinsic factors present in these niches maintains HSCs in relatively dormant states and regulate their trafficking to and from these BM microenvironments. Recent studies have highlighted the roles of specific signal transducer (Pten), polycomb group protein (Bmi1), transcription factors (JunB, Gfi-1, Hox genes), and extrinsic regulatory pathways (Notch, TGF-beta, Wnt) in controlling HSC selfrenewal, proliferation, and differentiation. Here, we will review the various experimental approaches used to identify and functionally assess HSC and myeloid progenitor activity in the mouse. We will discuss how HSCs are molecularly equipped to integrate signals from the microenvironment, and how such regulations control the balance between proliferation and early myeloid differentiation. The case of the JunB/AP-1 transcription factor will be used as an example of pathological situation. Inactivation of JunB leads to the development of a myloproliferative disease (MPD) arising from the HSC compartment. JunB normally controls HSC proliferation by regulating the expression levels of key cell cycle regulators, including Bmi1, and limits the rate at which HSCs produce early myeloid progenitors by maintaining appropriate responsiveness to both Notch and TGF-beta signaling pathways. The transforming effect of JunB loss is, therefore, due to a broad deregulation of the regulatory mechanisms controlling HSC differentiation, leading to overproduction of myeloid progenitors and MPD development in vivo. These results provide insights into fundamental issues in hematopoiesis and leukemogenesis.
Mild Pro-Inflammatory State and Anemia in Older Persons.
Authors: Longo Dan L. , Ferrucci Luigi , Ershler William 
Published: October 2019

Abstract
Aging is characterized by a progressive dysregulation of homeostatic equilibrium. Inflammation is perhaps the most studied aspect of such homeostatic dysregulation, particularly in the context of anemia. Older persons and even “extremely healthy” older individuals are often affected by a mild pro-inflammatory state marked by high levels of pro-inflammatory markers, such as IL-6 and C-reactive protein (CRP). Patients with overt inflammatory diseases tend to develop anemia, usually of mild severity. Four mechanisms by which inflammation may affect anemia have been hypothesized:
inhibition of proliferation and differentiation of erythroid precursors by inflammatory cytokines and/or downregulation of the EPO biological response; blunted EPO production; upregulation of hepcidin synthesis and consequent impairment of intestinal absorption and iron recycling; and reduced erythrocyte survival, not fully compensated by increased erythropoiesis.
Studies have shown that the pro-inflammatory state of aging inflammation is associated with EPO levels higher than expected in non-anemic individuals and lower than expected in anemic individuals, suggesting the existence of a pre-anemic state where EPO resistance is compensated by increased EPO levels. Only when this compensatory mechanism fails does anemia become clinically evident. Consistent with this hypothesis, individuals with high EPO and high levels of inflammatory markers are at high risk of developing anemia. The mediating role of hepcidin in the pathogenesis of anemia of inflammation is suggested by an extensive literature. By interacting with the unique iron transporter, ferroportin, hepcidin controls iron intestinal absorption and mobilization from hepatocytes and macrophages, thereby causing low serum iron and ineffective erythropoiesis. Patients affected by disease characterized by overt inflammation, such as rheumatoid arthritis, abscess, and sepsis, show increased hepcidin urinary excretion. There is some evidence that the mild-pro-inflammatory state of aging does not cause hepcidin upregulation, although it is associated with low serum iron, lower transferrin saturation, and higher ferritin concentration. Thus, the iron lowering effect of moderate inflammation may be mediated by some still-unknown mechanism other than hepcidin. Studies are needed to test the hypothesis that the mild inflammation affects erythrocyte lifespan.
Platelet Death.
Authors: Josefsson Emma C. , Schoenwaelder Simone , White Michael , Goschnick Matthew , Roberts Andrew W. , Mason Kylie D. , Jackson Shaun , Huang David C. , Kile Benjamin T. 
Published: October 2019

Abstract
Human platelets exhibit a circulating lifespan of ~10 days, mouse platelets ~5 days. This finite existence is circumscribed by members of the Bcl-2 family of proteins, which control the intrinsic apoptosis pathway. Pro-survival Bcl-xL is the critical regulator of platelet lifespan, functioning to keep pro-death Bak and Bax in check, thereby maintaining platelet viability. After 5–10 days in the circulation, platelets not consumed in hemostatic processes initiate a Bak and Bax-dependent cell death program and clearance from the bloodstream. Mutations in Bcl-xL reduce platelet lifespan in a dose-dependent fashion, while deletion of Bak and Bax extend it. Studies with the BH3 mimetic compound ABT-737, which inhibits pro-survival Bcl-xL, have shown that platelets induced to undergo cell death in vitro exhibit many of the hallmarks of apoptosis in nucleated cells, including mitochondrial damage, caspase activation and externalization of membrane phosphatidylserine (PS). Whether any of these features occur during physiological platelet clearance remains unclear. Certainly, mitochondrial damage can reduce the recovery of transfused platelets, but whether PS – which is known to promote the pro-coagulant activity of agonist-activated platelets – also acts as a clearance signal for dying platelets in vivo is yet to be established. Conversely, Bak and Bax may play a role in mediating PS exposure triggered by activation. Supporting the idea that there may be crosstalk between classical platelet signaling pathways and the intrinsic apoptosis pathway is recent evidence that platelet agonists can also activate caspases. Intriguingly, elements of the intrinsic pathway may also contribute to the generation of platelets by megakaryocytes. Several groups have demonstrated that megakaryocytes contain activated caspases and that their inhibition can block platelet shedding by cultured cells. Preliminary evidence we have generated suggests that Bcl-2 family proteins may be required for platelet production in vivo. Thus, it appears that there is much to be understood about the role of the intrinsic apoptosis pathway in the regulation of platelet biogenesis, function, and death.