bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B28: Co-occupancy of AML1-ETO and N-CoR defines a dominant phenotypic signature in leukemic cells.
Authors: Trombly Daniel J. , Whitfield Troy W. , Padmanabhan Srivatsan , Gordon Jonathan A. , Lian Jane B. , Wijnen Andre J. van , Zaidi Sayyed K. , Stein Janet L. , Stein Gary S. 
Published: August 2015

Abstract
The t(8;21) chromosomal translocation produces AML1-ETO, an oncogenic fusion protein that compromises the function of AML1, a transcription factor critical for the myeloid cell differentiation. The differentiation arrest and self-renewal phenotypes of cells expressing AML1-ETO have been chiefly studied at the single gene level. In order to understand how the genome-wide occupancy of AML1-ETO and associated co-regulators contributes to the leukemic properties of Kasumi-1 cells, a model system for human t(8;21) leukemia, chromatin immunoprecipitation-sequencing (ChIP-seq) experiments were employed. Genome-wide DNA binding profiles for AML1 and AML1-ETO in Kasumi-1 cells showed that both proteins were enriched at introns and distal upstream regulatory regions, the latter implying that distal elements are likely important for target gene regulation. Importantly, A substantial fraction of AML1/AML1-ETO-p300 co-localization occurs near transcriptional start sites (TSSs) in promoter regions associated with transcriptionally active loci, as indicated by an observed enrichment of the H3K4me3 histone modification. A significant discovery of the current study is the co-localization of AML1/AML1-ETO with N-CoR on regions that are primarily distal to TSSs. Analyses of both gene expression data and gene ontology suggest that the AML1/AML1-ETO co-localization with N-CoR, more so than with p300, is associated with the leukemic phenotype of Kasumi-1 cells. De novo motif discovery reveals that PU.1 motifs are over-represented in regions co-occupied by AML1-ETO and N-CoR compared to other AML1-ETO bound regions. Our findings establish a novel and predominant AML leukemia signature characterized by occupancy of the AML1-ETO/N-CoR complex at genomic regions enriched in motifs for myeloid differentiation factors. We propose that this property is critical for maintenance of the leukemic phenotype.
Citation Format: Daniel J. Trombly, Troy W. Whitfield, Srivatsan Padmanabhan, Jonathan A. Gordon, Jane B. Lian, Andre J. van Wijnen, Sayyed K. Zaidi, Janet L. Stein, Gary S. Stein. Co-occupancy of AML1-ETO and N-CoR defines a dominant phenotypic signature in leukemic cells. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B28.
Abstract B38: F317i mutation-associated nilotinib resistance in a child with CML: A first report.
Authors: Tucker Heidi , Kent Paul 
Published: August 2015

Abstract
Background: Philadelphia chromosome, t(9;22), positive (Ph+) chronic myelogenous leukemia (CML) accounts for only 2-2.5% of childhood leukemia cases or about 60 cases per year in the US. Tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis and treatment of CML in adults and children. Failure of TKIs is often due to mutations. In adult CML, the F317i mutation has been implicated in resistance to first and second line TKIs (imatinib/dasatinib) without affecting sensitivity to the third line TKI, nilotinib. The F317i mutation has been documented a handful of times in adult CML and in childhood Ph+ALL cases. We describe what we believe to be a first report of F317i mutation in a child with Ph+ CML who, after initial major molecular responses, rapidly developed resistance to first, second and third line TKIs.
The current Childrens Oncology Group trial of oral nilotinib (COG AAML1321) does not recognize F317i as a mutation associated with nilotinib resistance.
Case: An 11-year old female with classic chronic phase (CP) CML was found to have the F317i mutation after initially achieving an MMR during the first 3 months of treatment while on dasatinib. After results of the F317i mutation were received, the patient was switched to nilotinib and again achieved an MMR in the first 2 months before rapidly decompensating with a pre B cell ALL blast crisis. The child was then treated with ALL induction and consolidation and allogeneic stem cell transplant and again achieved an MMR which has been sustained for 5 months.
Methods: Cases of the F317i mutation have been documented in adults, however, we did an extensive literature search of PubMed, Ovid, and Google Scholar using keywords “F317” as well as F317i, ” and we were unable to find another report of this mutation in a child.
Discussion: CML in children is rare and to our knowledge the F317i mutation in children has not been previously reported. In contrast to how the F317i mutation is expected to behave in adult Ph+ CML, our patient developed resistance to nilotinib.
Conclusion: Our CML patient failed nilotinib. The F317i mutation in a child may warrant closer molecular monitoring and the consideration of early stem cell transplantation.
Citation Format: Heidi Tucker, Paul Kent. F317i mutation-associated nilotinib resistance in a child with CML: A first report. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B38.
Abstract IA13: Preclinical development of a humanized anti-CD47 antibody targeting AML stem cells.
Authors: Majeti Ravi 
Published: August 2015

Abstract
Human acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by rare self-renewing leukemia stem cells (LSC), which must be eliminated in order to cure the patient. We originally identified increased expression of CD47 on human AML LSC compared to their normal counterparts. CD47 is a widely expressed cell surface protein that functions as a regulator of phagocytosis mediated by cells of the innate immune system, such as macrophages and dendritic cells. CD47 serves as the ligand for a receptor on these innate immune cells, SIRP-alpha, which in turn delivers an inhibitory signal for phagocytosis. In this way, CD47 essentially functions as a “don't eat me” signal. We previously found increased expression of CD47 on primary human acute myeloid leukemia (AML) stem cells, and demonstrated that blocking monoclonal antibodies directed against CD47 enabled the phagocytosis and elimination of AML, non-Hodgkin's lymphoma (NHL), and many solid tumors in xenograft models. These results established CD47 as a promising clinical therapeutic antibody target for human AML and other cancers. Towards this goal, we have now developed a novel humanized anti-CD47 antibody with potent efficacy and favorable toxicokinetic properties as a candidate human therapeutic. A novel monoclonal anti-human CD47 antibody, 5F9, was generated, and antibody humanization was carried out by grafting its complementarity determining regions (CDRs) onto a human IgG4 format. The resulting humanized 5F9 antibody (Hu5F9-G4) bound monomeric human CD47 with an 8 nM affinity. Hu5F9-G4 induced potent macrophage-mediated phagocytosis of primary human AML cells in vitro and completely eradicated human AML in vivo, leading to long-term disease-free survival of patient-derived xenografts. Moreover, Hu5F9-G4 synergized with rituximab to eliminate NHL engraftment and cure xenografted mice. Finally, toxicokinetic studies in non-human primates showed that Hu5F9-G4 could be safely administered intravenously at doses able to achieve potentially therapeutic serum levels. Thus, Hu5F9-G4 is actively being developed for clinical trials in human cancers including AML.
Citation Format: Ravi Majeti. Preclinical development of a humanized anti-CD47 antibody targeting AML stem cells. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA13.
Abstract IA30: How cells survive: Single cell analysis reveals properties of non-genetic apoptosis resistance.
Authors: Green Douglas R. 
Published: August 2015

Abstract
The mechanism of non-genetic resistance to TRAIL-induced apoptosis remains unresolved as the regulatory pathways involved are interconnected and complex. Single-cell mass cytometry was used to profile functional changes in regulatory factors while simultaneously monitoring apoptotic progression in TRAIL-treated cells. Cells resistant to TRAIL possessed diverse signaling states, however only cells within a subset of these states, termed “essential persisters” (EPs), were able to survive long-term and replicate. Constriction of the EP signaling states with kinase perturbagens decreased cell survival, however, the EPs occupied unique signaling states for each cell line tested. In order to overcome cell-type specific resistance, single peturbogen data was used to predict the effects of perturbagen combinations on survival. The level of EP signaling state constriction by a single perturbagen was a more robust predictor of combinatorial effects than extrapolating from single perturbogen cell survival data directly. These findings provide a population-level understanding of non-genetic resistance and explain the shortcoming of previous ‘bulk’ methods for identifying mechanisms of TRAIL-resistance. The use of signaling space constriction in persisters may guide design of therapies against non-genetic resistance in the future.
Citation Format: Douglas R. Green. How cells survive: Single cell analysis reveals properties of non-genetic apoptosis resistance. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA30.
Abstract IA32: BCL-2 inhibition–An example of translational medicine–Update.
Authors: Gordon Gary B. 
Published: August 2015

Abstract
Apoptosis, a conserved and carefully regulated cell suicide event, is the principal mechanism used by the organism to remove senescent, damaged, and redundant cells in order to maintain cellular homeostasis. Tumors dysregulate this pathway by perturbing the dynamic balance between pro-apoptotic and pro-survival members of the BCL-2 family proteins and as such, these proteins are compelling targets for the development of cancer therapeutics. Synthesizing small molecules capable of disrupting protein-protein interactions, however, has posed a major challenge for the field. Early BCL-2 antagonists, while active in the pre-clinical models, had failed to demonstrate efficacy in the clinic. Structure-activity based drug design has led to development of several new selective inhibitors of the BCL-2 and BCL-XL including navitoclax, ABT-199, and S-55746 with all three exhibiting activity in pre-clinical testing. Navitoclax has demonstrated tumor growth inhibition in select hematological malignancies but its utility was limited by accompanying thrombocytopenia. The next generation molecule, ABT-199, is an oral BCL-2-selective inhibitor that has shown activity in the clinic. This presentation will review the journey of drug discovery and development from the mechanism-based postulate and preclinical work to the translational studies and ultimately to the bedside.
Citation Format: Gary B. Gordon. BCL-2 inhibition–An example of translational medicine–Update. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA32.
Inhibitor development in non-severe haemophilia across Europe
Authors: Iorio Alfonso , Lassila Riitta , Peyvandi Flora , Calizzani Gabriele , Gatt Alex , Lambert Thierry , Windyga Jerzy , Gilman Estelle , Makris Michael , Fischer Kathelijn ,   the EUHASS participants
Published: August 2015

SummaryEvidence about inhibitor formation in non-severe haemophilia and the potential role for clotting factor concentrate type is scant. It was the aim of this study to report inhibitor development in non-severe haemophilia patients enrolled in the European Haemophilia Safety Surveillance (EUHASS) study. Inhibitors are reported quarterly and total treated patients annually. Incidence rates and 95 % confidence intervals (95 % CI) were calculated according to diagnosis and concentrate used. Between 1–10–2008 and 31–12–2012, 68 centres reported on 7,969 patients with non-severe haemophilia A and 1,863 patients with non-severe haemophilia B. For haemophilia A, 37 inhibitors occurred in 8,622 treatment years, resulting in an inhibitor rate of 0.43/100 treatment years (95 % CI 0.30–0.59). Inhibitors occurred at a median age of 35 years, after a median of 38 exposure days (EDs; P25-P75: 20-80); with 72 % occurring within the first 50 EDs. In haemophilia B, one inhibitor was detected in 2,149 treatment years, resulting in an inhibitor rate of 0.05/100 years (95% CI 0.001–0.26). This inhibitor developed at the age of six years, after six EDs. The rate of inhibitors appeared similar across recombinant and plasma derived factor VIII (FVIII) concentrates. Rates for individual concentrates could not be calculated at this stage due to low number of events. In conclusion, inhibitors in non-severe haemophilia occur three times more frequently than in previously treated patients with severe haemophilia at a rate of 0.43/100 patient years (haemophilia A) and 0.05/100 years (haemophilia B). Although the majority of inhibitors developed in the first 50 EDs, inhibitor development continued with increasing exposure to FVIII.
The role of platelets in inflammation
Authors: Storey Robert , Thomas Mark 
Published: August 2015

SummaryThere is growing recognition of the critical role of platelets in inflammation and immune responses. Recent studies have indicated that antiplatelet medications may reduce mortality from infections and sepsis, which suggests possible clinical relevance of modifying platelet responses to inflammation. Platelets release numerous inflammatory mediators that have no known role in haemostasis. Many of these mediators modify leukocyte and endothelial responses to a range of different inflammatory stimuli. Additionally, platelets form aggregates with leukocytes and form bridges between leukocytes and endothelium, largely mediated by platelet P-selectin. Through their interactions with monocytes, neutrophils, lymphocytes and the endothelium, platelets are therefore important coordinators of inflammation and both innate and adaptive immune responses.
Cardiac Resynchronization Therapy Reduces Subcellular Heterogeneity of Ryanodine Receptors, T-Tubules, and Ca
2+
Sparks Produced by Dyssynchronous Heart Failure
Authors: Li Hui , Lichter Justin G. , Seidel Thomas , Tomaselli Gordon F. , Bridge John H.B. , Sachse Frank B. 
Published: August 2015

Background—
Cardiac resynchronization therapy (CRT) is a major advance for treatment of patients with dyssynchronous heart failure (DHF). However, our understanding of DHF-associated remodeling of subcellular structure and function and their restoration after CRT remains incomplete.

Methods and Results—

We investigated subcellular heterogeneity of remodeling of structures and proteins associated with excitation–contraction coupling in cardiomyocytes in DHF and after CRT. Three-dimensional confocal microscopy revealed subcellular heterogeneity of ryanodine receptor (RyR) density and the transverse tubular system (t-system) in a canine model of DHF. RyR density at the ends of lateral left ventricular cardiomyocytes was higher than that in cell centers, whereas the t-system was depleted at cell ends. In anterior left ventricular cardiomyocytes, however, we found a similar degree of heterogeneous RyR remodeling, despite preserved t-system. Synchronous heart failure was associated with marginal heterogeneity of RyR density. We used rapid scanning confocal microscopy to investigate effects of heterogeneous structural remodeling on calcium signaling. In DHF, diastolic Ca
2+
spark density was smaller at cell ends versus centers. After CRT, subcellular heterogeneity of structures and function was reduced.

Conclusions—
RyR density exhibits remarkable subcellular heterogeneity in DHF. RyR remodeling occurred in lateral and anterior cardiomyocytes, but remodeling of t-system was confined to lateral myocytes. These findings indicate that different mechanisms underlie remodeling of RyRs and t-system. Furthermore, we suggest that ventricular dyssynchrony exacerbates subcellular remodeling in heart failure. CRT efficiently reduced subcellular heterogeneity. These results will help to explain remodeling of excitation–contraction coupling in disease and restoration after CRT.
Association Between Visceral and Subcutaneous Adipose Depots and Incident Cardiovascular Disease Risk Factors
Authors: Abraham Tobin M. , Pedley Alison , Massaro Joseph M. , Hoffmann Udo , Fox Caroline S. 
Published: August 2015

Background—
Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) vary in volume and quality. We evaluated whether fat volume or attenuation (indirect measure of quality) predicts metabolic risk factor changes.

Methods and Results—

Framingham Heart Study Multi-detector Computed Tomography Substudy participants (n=1730, 45% women) were followed up over a mean of 6.2 years. Baseline VAT and SAT volume (in cm
3
) and attenuation (in Hounsfield units) were assessed. Outcomes included blood pressure, lipids, and glucose. We constructed multivariable regression models predicting change from baseline to follow-up. Baseline VAT was associated with metabolic risk factors at follow-up. Per 500-cm
3
increase in baseline VAT, glucose was 2.34 mg/dL higher (95% confidence interval, 1.71–2.97) and high-density lipoprotein was 1.62 mg/dL lower (95% confidence interval, 0.97–2.28) in women (
P
<0.0001 for both). These findings remained significant after adjustment for body mass index. Results for SAT were similar although less striking. Lower (more negative) fat attenuation was associated with more adverse metabolic profiles at follow-up. For example, per 5-unit decrease in baseline VAT Hounsfield units, log triglycerides increased by 0.08 mg/dL (95% confidence interval, 0.05–0.12;
P
=0.005), which remained significant after adjustment for baseline VAT. Among men, VAT and SAT Hounsfield units were associated with changes in cardiovascular disease risk factors but were mostly attenuated after baseline volume adjustment.

Conclusions—
VAT volume and SAT volume are associated with incident metabolic risk factors beyond overall adiposity. Decreases in fat attenuation are also associated with incident risk factors. These findings suggest that both volume and quality of VAT and SAT contribute to metabolic risk.
Spouses of Stroke Survivors Report Reduced Health-Related Quality of Life Even in Long-Term Follow-Up
Authors: Persson Josefine , Holmegaard Lukas , Karlberg Ingvar , Redfors Petra , Jood Katarina , Jern Christina , Blomstrand Christian , Forsberg-Wärleby Gunilla 
Published: August 2015

Background and Purpose—
The consequences for the family of stroke survivor are generally studied in a short-term perspective. The aim of this study was to assess long-term aspects of health-related quality of life among spouses of stroke survivors.

Methods—
Data on stroke survivors, controls, and spouses were collected from the 7-year follow-up of the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The health-related quality of life of spouses was assessed by the Short Form-36, and the characteristics of stroke survivors were assessed using the National Institutes of Health Stroke Scale, the Mini-Mental State Examination, the Hospital Anxiety and Depression Scale, the Barthel Index, and the modified Rankin Scale.

Results—

Dyads of 248 stroke survivors aged <70 at stroke onset and 245 dyads of matched controls were included. Spouses of stroke survivors and spouses of controls had a median age of 64 and 65, respectively; proportion of men was 35% and 34%, respectively. The spouses of stroke survivors reported lower scores in all the mental domains (
P
=0.045;
P
<0.001), as well as in the domains of general health (
P
=0.013) and physical role (
P
=0.006), compared with the spouses of controls. Predictors of poor physical health of the spouses were their own age and the level of global disability of the stroke survivor. Predictors of poor mental health of the spouses were depressive symptoms, cognitive impairment, and global disability among the stroke survivors.

Conclusions—
The health-related quality of life of spouses of stroke survivors is reduced not only during the first years but also in the long-term perspective.
Maximal Admission Core Lesion Compatible With Favorable Outcome in Acute Stroke Patients Undergoing Endovascular Procedures
Authors: Ribo Marc , Tomasello Alejandro , Lemus Miguel , Rubiera Marta , Vert Carla , Flores Alan , Coscojuela Pilar , Pagola Jorge , Rodriguez-Luna David , Bonet Sandra , Muchada Marian , Rovira Alex , Molina Carlos A. 
Published: August 2015

Background and Purpose—
Multiparametric imaging is meant to identify nonreversible lesions and predict on admission the minimum final infarct volume, a strong predictor of outcome. We aimed to confirm this hypothesis and define the maximal admission lesion volume compatible with favorable outcome (MALCOM).

Methods—
We studied patients with internal carotid artery/middle cerebral artery occlusion selected with multiparametric computed tomography/magnetic resonance imaging, who underwent endovascular procedures. Admission infarct core was measured on initial cerebral blood volume–computed tomography perfusion or diffusion weighted imaging–magnetic resonance imaging. We defined percentage of lesion growth (final lesion admission core/admission core) and MALCOM: cutoff admission core volume above which probability of modified Rankin Scale 0 to 2 is <10%.

Results—

Fifty-seven patients were studied (29 magnetic resonance imaging and 28 computed tomography perfusion). Mean core volume was 28±22 mL, and recanalization thrombolysis in cerebral ischemia 2b-3 was 77%. At 24 hours, mean infarct volume was 64±97 mL, and at 3 months modified Rankin Scale 0 to 2 was 45%. Median lesion growth was smaller in recanalizers (16.7% versus 198.3%;
P
<0.01). MALCOM was 39 mL. When recanalization was achieved, 64% of patients within MALCOM (<39 mL) achieved favorable outcome, whereas despite recanalization only 12% of patients beyond MALCOM (>39 mL) achieved modified Rankin Scale 0 to 2 (
P
=0.01). A regression model adjusted for age and recanalization showed that the only predictor of favorable outcome was having admission core lesion below MALCOM (OR: 9.3, 95% CI: 1.9–46.4;
P
<0.01). Analysis according to imaging modality showed that computed tomography–cerebral blood volume allowed larger MALCOM (42 mL) than magnetic resonance–diffusion weighted imaging (29 mL). In octogenarians, MALCOM (15 mL) was lower in younger patients (40 mL).

Conclusions—
Admission lesion core is associated with final infarct volume and is a strong predictor of favorable outcome. MALCOM according to imaging modality and patient age could be set and used on admission to select candidates for endovascular procedures.