bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natural Killer (NK) or NK/T Cell Lineage Large Granular Lymphocytosis Associated with Dasatinib Therapy for Philadelphia Chromosome Positive Leukemia.
Authors: Kim Dong Hwan , Kamel-Reid Suzanne , Chang Hong , Sutherland Robert , Jung Chul Won , Kim Hyeoung Joon , Lee Je-Jung , Lipton Jeffrey H. 
Published: October 2019

Abstract
Dasatinib, a dual tyrosine kinase inhibitor, is known to modulate or suppress T-cell activation and proliferation. We report a series of patients of chronic peripheral lymphocytosis development, identified as natural killer (NK) cells or NK/T-cells based on their large granular lymphocyte (LGL) morphologies and CD16+CD56+CD3− or CD3+ immunophenotypic profiles during dasatinib therapy. All cases that developed LGL lymphocytosis achieved optimal molecular response (8/8 in LGL+ patients vs 3/10 in LGL− patients, p=0.002). A 51Cr release assay demonstrated that NK cell cytotoxicity has been enhanced in a case of LGL lymphocytosis compared to normal healthy donors (Figure 1), and that NK cell cytotoxicity in dasatinib-responders was superior to that in non-responders (Figure 2). In summary, the present study suggests that NK or NK/T cell lineage LGL lymphocytosis develops associated with dasatinib therapy and that LGL might have a therapeutic effect on Ph+ leukemic cells.
Figure 1. Cytotoxicity of NK cells isolated from the patients developing large granular lymphocytosis following dasatinib therapy as assessed by 51Cr release assays using target cells as K562 (A) and T2 cell line (B) as target cells. Figure 1. Cytotoxicity of NK cells isolated from the patients developing large granular lymphocytosis following dasatinib therapy as assessed by 51Cr release assays using target cells as K562 (A) and T2 cell line (B) as target cells. Figure 2. The result of 51Cr release assays comparing cytotoxicity of NK cells isolated from patients responding to dasatinib therapy (responder) and not responding (non-responder) following dasatinib therapy using K562 cell line as target cells. Figure 2. The result of 51Cr release assays comparing cytotoxicity of NK cells isolated from patients responding to dasatinib therapy (responder) and not responding (non-responder) following dasatinib therapy using K562 cell line as target cells.
Disruption of the NHR4 Domain Structure in AML1-ETO Abrogates Its Interaction with SON and Promotes AML1-ETO-Associated Leukemogenesis.
Authors: Ahn Eun-Young , Yan Ming , Malakhova Oxana A , Boyapati Anita , Ommen Hans Beier , Hines Robert , Hokland Peter , Zhang Dong-Er 
Published: October 2019

Abstract
AML1-ETO is generated from t(8;21)(q22;q22), which is commonly associated with acute myeloid leukemia (AML), especially FAB M2 AML. While full length AML1-ETO fails to promote leukemia due to its detrimental effects on cell proliferation, an alternatively spliced isoform without its C-terminal NHR3 and NHR4 domains strongly induces leukemia. The NHR4 domain has a zinc-chelating topology and has been implicated in transcriptional repression through recruitment of the NCoR/SMRT complexes. Here, we report that disruption of the zinc-chelating structure in the NHR4 domain of AML1-ETO by replacing only one critical amino acid leads to rapid onset of leukemia, suggesting that the NHR4 domain is responsible for generating inhibitory effects on leukemia development. To identify the molecular mechanism of this leukemogenic effect, we searched for NHR4-interacting factors with yeast two hybrid screening, and identified a novel NHR4-interacting protein, SON, a potential DNA/RNA-binding protein. The N-terminal fragment of SON with 81 amino acids, which is encoded by exons 1 and 2, was sufficient to interact with the NHR4 domain of ETO. Interaction of endogenous SON and AML1-ETO was also detected in t(8;21) AML cell lines. A serine substitution of cysteine 663 which disrupts the zinc-chelating topology of the NHR4 domain completely abolished its interaction with SON, while retaining the interaction with another ETO-binding protein, N-CoR. Knockdown of SON by siRNA resulted in significant growth arrest. Disruption of the interaction between AML1-ETO and endogenous SON by overexpressing the SON N-terminal fragment rescued cells from AML1-ETO-induced growth arrest. These results suggest that SON is an indispensable factor for cell growth and the interaction between endogenous SON and AML1-ETO generates negative effects on cell growth. In t(8;21) AML patient-derived primary leukemic cells and cell lines, abnormal cytoplasmic localization of SON was detected, which may keep cells proliferating in the presence of full length AML1-ETO. Taken together, these results uncovered the crucial role of the NHR4 domain in determination of cellular fate during AML1-ETO-associated leukemogenesis and revealed the interaction of the NHR4 domain with SON, an essential protein for normal cell growth.
Autocrine IGF-1/IGF-1R Signaling Is Responsible for PI3K/Akt Constitutive Activation in Acute Myeloid Leukemia.
Authors: Chapuis Nicolas , Tamburini Jerome , Cornillet-Lefebvre Pascale , Gillot Lucile , Bardet Valérie , Willems Lise , Park Sophie , Green Alexa Samantha , Ifrah Norbert , Dreyfus Francois , Mayeux Patrick , Lacombe Catherine , Bouscary Didier 
Published: October 2019

Abstract
The PI3K/Akt axis is implicated in cell proliferation and survival and appears promising for target inhibition. The constitutive activation of PI3K (PI3K+) that reflects intrinsic cytokine-independent signaling properties of blast cells is detected in 50% of AML samples at diagnosis. Several cytokines and growth factors are known to stimulate the PI3K/Akt pathway, such as FLT-3, SCF or IGF-1 but the mechanisms leading to the constitutive PI3K activation are unknown. The IGF-1/IGF-1R signaling is thought to have a crucial role in the development and progression of cancers. In AML, IGF-1 promotes cell growth and survival via PI3K signaling. As we previously reported an IGF-1 autocrine production in AML leukemic cells, we investigated whether IGF-1/IGF-1R signaling could be responsible for the constitutive activity of PI3K in AML. We show here in primary AML blast cells that IGF-1R is constantly expressed and constitutively phosphorylated in PI3K+ samples. The constitutive phosphorylation of Akt is fully inhibited in 70% of PI3K+ samples by aIR3, a neutralizing anti-IGF-1R monoclonal antibody but neither ERK nor P70S6K phosphorylation are modified by aIR3. Moreover, siRNA-mediated decrease of the IGF-1 autocrine production markedly reduces Akt phosphorylation in leukemic cells. Finally, no mutation is detected within the complete sequence of IGF-1R cDNA from PI3K+ AML samples. In conclusion, the constitutive activity of PI3K/Akt proceed from the activation of IGF-1R due to an IGF-1 autocriny in 70% of PI3K+ primary AML samples. Our current data strengthen the rational of targeted therapy against IGF-1R in AML.
Intensified Induction Chemotherapy with Regimen Containing Intermediate Dose Cytarabine for De Novo Acute Myeloid Leukemia.
Authors: Wang Jianxiang , Mi Yingchang , Liu Jiazhuo , Fu Mingwei , Wang Ying , Lin Dong , Bian Shougeng 
Published: October 2019

Abstract
Abstract□F
Objective To analyze the complete remission (CR) rate, disease free survival (DFS) and overall survival (OS) of de novo acute myeloid leukemia (AML) patients induced with HAD (Homoharringtonine-HHT, cytosine arabinoside-AraC, daunorubicin-DNR) regimen containing intermediate dose AraC (ID-AraC) and to explore the impact of cytogenetic abnormalities on the prognosis.
Methods 87 AML patients were treated with HAD regimen containing ID-AraC as induction therapy. HAD regimen was as follow: HHT 2mg/m2.d, Day 1–7; Ara-C 100mg/m2, Day 1–4, 1–1.5g/m2/q12h, Day 5–7; DNR 40 mg/m2.d, Day 1–3. CR rate, DFS and OS were calculated.83 patients who had karyotype results were divided into 3 groups according to SWOG criteria respectively. Differences in CR rate, DFS and OS among different groups were evaluated.
Results The CR rate of the 87 cases was 80/87 (92%). Median DFS of the 80 CR patients was NR (not reach). DFS rates at 1 and 3 years were 76.3% and 63.4% respectively. The median OS of the 87 patients was 16 (range from 2 to 67) months. OS rates at 1 and 3 years were 86.0% and 58.7% respectively. According to SWOG criteria, CR rate, median DFS and OS were 100%, NR for the favorable group„dG88.9%, NR and 16 months for the intermediate group„dG83.3%, 4.5 months and 7.5 months for the adverse group. The differences among the three groups were statistically significant excepting for CR rate between adverse and intermediate groups.
Conclusions HAD regimen containing ID-AraC as induction chemotherapy regimen is very effective in de novo AML of adult patients, can achieve higher CR rate and longer survival time than standard dose HAD regimen. Most of the patients were able to endure therapy. Cytogenetics is the important prognostic factor for AML patients. The differences among the three groups were statistically significant.
A Phase I/II Study with CP-4055 in Patients with Haematologic Malignancies.
Authors: O’Brien Susan , Rizzieri David A. , Vey Norbert , Kantarjian Hagop M , Jacobsen Tove Flem , Nilsson Bo I , Staudacher Karin , Giles Francis 
Published: October 2019

Abstract
Background: CP-4055 (ELACYT™, cytarabine 5′-elaidic acid ester) is a novel cytotoxic nucleoside analogue. While CP-4055 has similar mechanisms of action to cytarabine, it is, unlike cytarabine, independent of nucleoside transporters for cellular uptake.
Aims: Determination of efficacy and safety of CP-4055 in patients (pts) with haematologic malignancies receiving CP-4055 either as monotherapy or in combination with idarubicin.
Methods: The first patient was enrolled in May 2006. Pts received IV CP-4055 over 2 hours (2 hr IV) or 24 hours (CIV, Arm B) in a day 1–5 q3w schedule.
Results: Seventy-seven pts (46 male and 31 female) with a median age of 61 years (range 21– 92) were enrolled in the first phase I part. The majority of the pts presented with refractory/ relapsed AML and most pts had received two or more previous chemotherapeutic regimens. The recommended dose for CP-4055 monotherapy was determined to be 2000 mg/m2/d. Four pts had CR/CRp among 29 relapsed/refractory AML pts treated with this regimen The starting dose for CP-4055 in combination with idarubicin was 1150 mg/ m2/d CIV. Four pts (2 male, 2 female) have been enrolled. MTD has been determined at 1150 mg/m2/d and accrual is ongoing at 1000 mg/m2/d. DLTs were typhilitis and hand-foot-syndrome. In the phase II monotherapy part, accrual of patients with AML who have failed two prior lines of therapy is ongoing. The first evaluation for safety and futility will be prepared after 20 pts.
Summary/Conclusion: CP-4055 was well tolerated when administered both as 2–4 h IV and as CIV d1–5 q3w. The recommended dose for CP-4055 monotherapy was determined to be 2000 mg/m2/d in a d1–5 q3w schedule. The starting dose for CP-4055 in combination with idarubicin was 1150 mg/m2/d. MTD has been reached and accrual is ongoing at 1000 mg/m2/d.. The study continues.
QLT0267, a Small Molecule Inhibitor of ILK and FLT3 Is Cytotoxic to Acute Myeloid Leukemia (AML) ‘Stem Cells’ Detected in Immunodeficient Mice.
Authors: Muranyi Andrew L , Dedhar Shoukat , Hogge Donna E. 
Published: October 2019

Abstract
The phosphatidylinositol-3-kinase (PI-3K) and FMS-like tyrosine kinase 3 (FLT3) receptor signaling pathways are constitutively active in many AML blast samples suggesting these as therapeutic targets. Integrin linked kinase (ILK) is involved in Akt and GSK3 activation, key downstream effectors of the PI-3K pathway, and participates in the regulation of apoptosis, cell cycle progression, and tumour angiogenesis in many solid tumours. ILK is also expressed ubiquitously in AML blasts. In previous experiments to explore the effect of targeting ILK in AML, QLT0267, a small molecule inhibitor of ILK, was shown to be cytotoxic to AML blasts and colony forming cells (CFC) from some patient samples. Since AML samples containing the FLT3 internal-tandem duplication (ITD) were more susceptible to QLT0267-induced cell kill than FLT3 wildtype (WT) cells we tested the possibility that QLT0267 could inhibit FLT3 as well as ILK. In vitro kinase assays from 4 AML samples showed that QLT0267 produces equivalent inhibition of ILK and FLT3 (both WT and ITD) while Western blotting of 2 AML samples cultured with QLT0267 showed a dose and time dependant decrease in both FLT3 and Akt phosphorylation. 5 AML samples (4 FLT3-ITD, 1 FLT3 WT), were cultured for 24 h ± QLT0267, and assayed for AML CFC or 6-week suspension culture initiating cells (SC-IC). The mean percents kill for 20 and 50 μM QLT0267, respectively, were 92%, and 100% for AML-CFC and 71% and 92% for SC-IC. CD34+CD38− blasts (enriched for AML cells which engraft in immunodeficient mice) from these same samples were analyzed for expression of ILK, pGSK3, and FLT3. Intracellular staining detected ILK and pGSK3 protein in CD34+CD38− cells at levels similar to those present in other AML cell populations. QRT-PCR showed FLT-3 expression in CD34+CD38− cells from all 5 AML samples with 2 of these showing higher expression in this population than in the remainder of AML blasts. To determine if simultaneous targeting of ILK and FLT3 would kill AML progenitors that engraft in mice 4 AML samples (FLT3-ITD +) were cultured for 24 h ± QLT0267, and then injected IV into sublethally irradiated NOD/SCID or NOD/SCID IL2γRnull mice. As shown in the Table, treatment with 20 μM QLT0267 significantly reduced AML engraftment for 3 of 4 samples while the 50 μM dose was effective for 2 of the 3 samples tested (p<0.05, student t-test). Thus, combined targeting of ILK and FLT3 will kill AML cells, including candidate leukemic stem cells that sustain long-term engraftment in mice. Further preclinical evaluation of the potential therapeutic usefulness of this strategy is ongoing.
QLT0267 (μM) 0 20 50 AML Sample % engraftment ± SD AML cells in mouse bone marrow  Week 16 (n=) 1 86 ± 11  (4) 53 ± 30  (6) 2 ± 3  (4) 2 46 ± 45  (5) 3 ± 5  (6) 0  (2) 3 47 ± 40  (5) 1 ± 2  (4) 0  (6) 4 90 ± 14  (3) 1 ± 1  (3) ND
From Venus and Mars: Gender Specific Analysis of Blood Platelets
Authors: Schubert Peter , Coupland Danielle , Walsh Geraldine M. , Chen Cindy , Devine Dana V. 
Published: October 2019

Abstract
Cardiovascular disease epidemiological studies reveal compelling evidence that this disease is strongly influenced by gender. Other laboratory based studies have suggested that gender disparities can also be detected in platelet physiological measurements. These observations have led us to ask whether gender differences may play a role in platelet quality and integrity during storage. We have applied proteomic approaches to gain an understanding of the molecular mechanisms of gender-specific platelet signal transduction and its potential significance to transfusion medicine. Buffy coat platelet concentrates (N=4) pooled from four male or female donors, respectively, were analyzed by 2D gel electrophoresis and revealed 15 reproducible protein differences between their individual platelet proteomes. Validation by western blot analysis confirmed the proteomic data demonstrating differences in the expression profiling of proteins including 14-3-3, myosin, platelet factor 4 and SH3-domain binding protein glutamic acid-rich like protein as well as in posttranslational modification of proteins including pleckstrin and 14-3-3. These findings spurred a more detailed gender-specific analysis of single donors. In vitro measures (N=28 of each gender) for platelet function revealed that female platelets showed an averaged 15% higher level of activation as well as GPIIb/IIIa activation monitored by CD62P or Pac-1 binding, respectively. This point towards differences in signal transduction and western blot analyses of the platelet proteome of these individuals showed an averaged two to three-fold higher expression of signaling proteins including 14-3-3, Rap1, RhoA and RhoGDI. Furthermore, female platelets contain a two-fold higher level of activated Rap1 supporting the gender-influenced signaling hypothesis. To test whether these gender-specific results might have an impact on transfusion medicine, biochemical analyses of buffy coat platelet concentrates during storage were carried out. Preliminary data indicate that female platelets maintain the higher level of platelet activation during a 7-day storage period paralleled with elevated metabolic activity as monitored by glucose and lactate levels, respectively. These data can be used to assess other potential molecular mechanisms underlying the differences in the gender-specific signaling platelet proteome. Thus far, the clinical significance of these findings in transfusion medicine is unknown.
Gfi1 as a Regulator of Hematopoietic Differentiation.
Authors: Grimes H. Leighton , Velu Chinavenmeni S. , Horman Shane , Chaubey Aditya , Bourdeau Tristan , Xu Haiming , Zhu Jinfang , Paul William , Colmenares Clemencia , Williams David A. , Gebelein Brian 
Published: October 2019

Abstract
Growth Factor Independent-1 (Gfi1) is a transcriptional repressor originally identified as a target of Moloney leukemia virus insertion mutagenesis. Gfi1 potently collaborates with Myc and Pim oncogenes to mediate T cell transformation. Retroviral insertions which activate Gfi1 are among the most frequent events in MoMLV-induced T cell, but not myeloid, leukemias. Orthologous proteins in Drosophila (Senseless) and C.elegans (Pag-3) are key regulators of developmental decisions. Gfi1−/− mice display lymphopenia, neutropenia, and abnormally proliferative HSC and progenitors which eventually lead to bone marrow failure. Humans with bone marrow failure syndromes, such as Severe Congenital Neutropenia or Non-Immune Chronic Idiopathic Neutropenia of Adults, display mutations in GFI1, which produce dominant negative acting GFI1 proteins. The SCN-associated GFI1N382S mutant proteins derepress a subset of GFI1 target genes, including CSF1 and CSF1R, to block granulopoeisis. Normally, Gfi1 antagonizes monopoiesis mediated by Pu.1, Egr1, Egr2, and Nab2. Thus, Gfi1 loss of function may impair granulopoiesis by failing to successfully repress monopoeitic differentiation. GFI1 dysfunction may also underlie Specific Granule Deficiency. GFI1 is able to synergize with C/EBP transcription factors to activate genes, such as neutrophil collagenase. Gfi1 may, therefore, enhance granulopoietic differentiation through C/EBP factors. Though great progress has been made in understanding Gfi1 biological and biochemical functions, we are only beginning to understand the role of Gfi1 in integrating hematopoietic transcriptional programming. We find that Gfi1 signaling controls both the differentiation and transformation of myeloid progenitors through an evolutionarily conserved transcriptional and post-transcriptional network.
Immunological Memory: Remembering Our Pathogens.
Authors: Ahmed Rafi 
Published: October 2019

Abstract
Acute viral infections induce long-term humoral and cellular immunity. However, the nature of T- and B-cell memory is different. Antiviral B-cell memory is usually manifested by continuous antibody production that lasts for many years after infection or vaccination. In contrast, the effector phase of the T cell response is short-lived (a few weeks), and “memory” in the T-cell compartment results from the presence of memory T cells, which are found at higher frequencies and can respond faster and develop into effector cells (i.e., CTL or cytokine producers) more efficiently than can naïve T cells. In this talk, I will discuss the following aspects of immunological memory:
Functional differences between naïve and memory T cells; Memory T cell differentiation and memory cell subsets; and Protective immunity by memory CD8 T cells.
Homeostasis of Mature T Cells.
Authors: Surh Charles D. 
Published: October 2019

Abstract
The overall size and composition of the mature T cell pool is regulated by homeostatic mechanisms. A hallmark of homeostatic regulation is the ability of the T cells to undergo spontaneous “homeostatic” proliferation in response to severe lymphopenia. By defining the factors that drive such homeostatic proliferation, we have determined that homeostasis of naïve and memory T cells is controlled by signals from contact with self-MHC/peptide ligands and/or two cytokines, namely IL-7 and IL-15. In addition, we have recently described a simple and highly effective way to administer IL-2, IL-7, IL-15, and other cytokines to strongly expand selective populations of T cell under normal physiological conditions. This new approach overcomes the current limitations that prevent therapeutic use of these essential T cell regulators in their native form. Identification of these homeostatic factors has already proven to be highly clinically relevant in devising novel therapeutic modalities for treatment of cancer and restoration of the immune deficiency from lympho-depleting regiments and advanced aging. The new method of delivering exogenous cytokines should further expand the clinical applicability of homeostatic cytokines.
Genome-Wide Epigenetics in Myeloid Leukemias.
Authors: Figueroa Maria Eugenia , Greally John , Delwel Ruud , Melnick Ari M. 
Published: October 2019

Abstract
While the role of genetic alterations in cancer is well-recognized, epigenetic deregulation has only recently been identified as a hallmark of malignant transformation. The term “epigenetic” refers to a heritable regulation of gene expression that is not dependent on changes in the DNA sequence. These epigenetic modifications – including but not limited to DNA methylation and covalent modifications of histone tails – play a crucial role in determining chromatin structure and gene expression. Abnormal epigenetic regulation can lead to aberrant chromatin structure and deregulation of transcriptional activity. Epigenetic lesions can affect cancer-related genes, such as CDKN2B, CDKN2A, RB, and BRCA1, and it is not rare for epigenetic lesions to accompany genetic mutations of these and other genes, suggesting that epigenetic deregulation can form a part of the multi-step process of oncogenesis. An alteration in the distribution of DNA methylation has been demonstrated in AML as well as in other malignancies. Generally, intergenic DNA methylation is reported to decrease and promoter methylation to increase. Hypomethylation of DNA can lead to genomic instability and further increase the number of genetic lesions, while promoter hypermethylation has been associated with aberrant silencing of tumor suppressor genes. Altered levels of acetylation at specific histone residues were also shown to be associated with aberrant chromatin structure and gene deregulation in AML. Several oncogenic transcription factors and fusion proteins, such as PML-RARalpha, and AML1-ETO, can introduce aberrant epigenetic programming in myeloid cells through recruitment of epigenetic modifying enzymes to their target genes. However, the emerging field of epigenomic profiling has yielded evidence that epigenetic deregulation in AML is more profound and cannot always be linked to the presence of a given fusion protein. The mechanisms leading to genome-wide epigenetic deregulation still remain largely unidentified, although environmental factors and aging can contribute to this process. Current epigenetic profiling studies have revealed that DNA methylation or histone modification patterns can identify biologically distinct forms of AML that may not be readily identified through other methods. New data suggest that specific DNA methylation profiles may be associated with response to therapeutic agents, including epigenetic-targeted drugs. Numerous epigenetic candidate biomarkers have been recently described in both myeloid and lymphoid malignancies. Integrative analysis of DNA methylation, histone modifications, and gene expression may synergize to identify in far greater depth than single platform studies differences in gene regulation among leukemias. Overall, the emerging field of epigenomics provide a new opportunity to more accurately identify biological variation and therapeutically target acute myeloid leukemias.