bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Combination Of Arsenic, Interferon-Alpha, and Zidovudine Restores An “Immunocompetent-like” Micro-Environment In Patients With Adult T-Cell Leukemia/Lymphoma
Authors: Kchour Ghada , Rezaee S. A. Rahim , Farid Reza , Ghantous Akram , Rafatpana Houshang , Tarhini Mahdi , Kooshyar Mohamad-Mehdi , El Hajj Hiba , Berry Fadwa , Nasser Roudaina , Shirdel Abbas , Dassouki Zeina , Ezzedine Mohamad , Rahimi Hossein , Ghavamzadeh Ardeshir , de Thé Hugues , Hermine Olivier , Mahmoudi Mahmoud , Bazarbachi Ali 
Published: October 2019

Abstract

Background
HTLV-I associated adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis due to chemo-resistance and immuno-compromised micro-environment. The combination of zidovudine and interferon-alpha (IFN) significantly improved survival in ATL. Promising results were reported by adding arsenic trioxide to zidovudine and IFN.

Methods
Here we assessed Th1/Th2/Treg cytokine gene expression profiles in 16 ATL patients before and 30 days after treatment with arsenic/IFN/zidovudine, in comparison with HTLV-I healthy carriers and sero-negative blood donors.

Results
ATL patients at diagnosis displayed a Treg/Th2 cytokine profile with significantly elevated transcript levels of Foxp3, interleukin-10 (IL-10), and IL-4 and had a reduced Th1 profile evidenced by decreased transcript levels of interferon-γ (IFN-γ) and IL-2. Most patients (15/16) responded, with CD4+CD25+ cells significantly decreasing after therapy, paralleled by decreases in Foxp3 transcript. Importantly, arsenic/IFN/zidovudine therapy sharply diminished IL-10 transcript and serum levels concomittant with decrease in IL-4 and increases in IFN-γ and IL-2 mRNA, whether or not values were adjusted to the percentage of CD4+CD25+ cells.

Conclusions
The observed shift from a Treg/Th2 phenotype before treatment toward a Th1 phenotype after treatment with arsenic/IFN/zidovudine may play an important role in restoring an immuno-competent micro-environment, which enhances the eradication of ATL cells and the prevention of opportunistic infections.

Disclosures:
Off Label Use: Off label use of arsenic trioxide, zidovudine and interferon-alpha for the treatment of adult T cell leukemia/lymphoma.
Birinapant Enhances Bendamustine-Induced Apoptosis In Activated B Cell-Diffuse Large Cell Lymphoma Cells
Authors: Joshi Indira D , Smith Mitchell R 
Published: October 2019

Abstract
Birinapant (TL32711), a Smac mimetic in clinical testing, potently targets Inhibitor of Apoptosis Proteins (IAPs, including cIAPs and XIAP) to unblock intrinsic and extrinsic pathways, enabling caspase-dependent apoptosis via multiple signals. Birinapant also inactivates canonical NF-kB signaling through cIAPs. We investigated the pro-apoptotic effects of birinapant, alone and in combination with bendamustine (BDM), an active lymphoma therapeutic agent, in a panel of B cell lymphoma cell lines representing germinal center/follicular (GC) vs. activated B cell (ABC) subtypes. We hypothesized that the efficacy of this potential combination therapeutic strategy might differ between GC and ABC lymphoma types, as ABC are reported to be NF-kB-dependent. We used the following EBV negative cell lines: WSU-FSCCL t(14:18)+ follicular lymphoma (FL), FC-TxFL2 t(14:18)+ transformed FL, and SU-DHL4 GC-type diffuse large B cell lymphoma (DLBCL) as examples of GC origin lymphomas. U2932 and TMD8 cell lines represent ABC-type DLBCL. Apoptosis was determined by annexin V staining and confirmed by caspase-3 activation, each assessed by flow cytometric methods following 48 h incubation. Birinapant had little effect (<5% annexin V+ cells) as a single agent on any of these B cell lymphoma cell lines at ≤ 100 nM, though a low level of apoptosis (7-12% annexin V+ cells) was detectable at 10-20 µM in GC types. Addition of birinapant 30-60 minutes prior to BDM did not further enhance the already high level (>50% annexin V+) of apoptosis induced by 10 uM BDM in WSU-FSCCL and FC-TxFL2, and only slightly enhanced the low level of BDM-induced apoptosis in the GC DLBCL cell line DHL-4 (to 10-15%). In the ABC DLBCL cell lines, however, whereas 10uM BDM induced <5% annexin V+ cells for U2932 and 10-15% for TMD8, addition of 100 nM birinapant 30-60 minutes prior to 10 uM BDM induced 35-40% annexin V+ cells in each of these ABC-DLBCL cell lines. This enhancement was schedule-dependent, not observed when birinapant was added after BDM. Thus, the cell lines representing FL and transformed FL are sensitive to BDM at clinically-achievable concentrations, without further enhancement by birinapant. The 3 DLBCL lines were relatively insensitive to BDM compared with FL cells, but BDM-induced apoptosis was markedly enhanced when birinapant was added before (but not after) BDM in the 2 ABC type DLBCL lines. Further explorations into the mechanism of birinapant sensitization of ABC-DLBCL to BDM, issues of dose and schedule, and role of NF-kB-dependency are ongoing. These data suggest that therapeutic trials of BDM plus birinapant would be of interest in ABC type DLBCL.

Disclosures:
No relevant conflicts of interest to declare.
Long Term Outcomes Of Imatinib In Chronic Myeloid Leukemia In Saudi Population, Single Center Study
Authors: Alsobhi Enaam Mohammed , Abrar Mohammed m , Abdelaal Mohammed A , Alsaeed Ahmad S. , Al-Absi Ahmed , Zahrani Zaid A , Warsi Ashraf A , Al-Amri Abdulfattah , El-Hemaidi Ihab 
Published: October 2019

Abstract

Background
The introduction of Imatinib therapy has significantly changed the treatment of patients with newly diagnosed chronic myeloid leukemia (CML) and improved survival. Since the International Randomized Study of Interferon (IRIS), a number of studies were conducted involving diverse populations and showed significant variations in the treatment outcome. To date, there has been no published study on the effectiveness of imatinib in adult CML patients in Saudi Arabia. The aim of the present study was to present a single-institution experience in the treatment with imatinib of newly diagnosed patients with CML and compare it with results from international studies.

Methods
A total of 101 medical records of consecutive adult CML patients treated with imatinib as first line therapy at King Abdulaziz Medical City, Jeddah, Saudi Arabia between 2001 and 2012 were retrospectively reviewed. Survival and response rates were evaluated.

Results
The estimated overall survival (OS) rates at 5 and 10 years were 95%±2.3% when patients were stratified by cytogenetic type (stander vs.variant Ph positive chromosome) at presentations, significant difference in OS, EFS, and PFS were noted (P=0.001). Complete haematological response was achieved in 94 (93.1%) of our patients, cytogenetic response (CR) in 84 (83.2%) while complete and major cytogenetic response (MCR) were observed in 70 (69.3%) and 6 (5.9%) of the patients respectively. (MR), 62 patients (61.4%) achieved major molecular response (MMR) and 34 (33.7%) complete molecular response.

Conclusion
compared to other studies among different population, our results confirm the previously noted variation in the response to imatinib. Our study has shown that Ph variant has an impact on the outcome. Further study may be indicated. However second TKI generations as first line in treatment CML with Ph variants should be consider!

Disclosures:
No relevant conflicts of interest to declare.
Chromosomal Instability: A Probable Unfavorable Prognostic Factor For Patients Of Myeloidysplastic Syndromes
Authors: Xiao Yajuan , Huang Yuanlu , Xu Na , Lin Rong , Zhou Xuan , Xiao Xiaozhen , Gao Guanlun , Xiaoli, MD Liu 
Published: October 2019

Abstract

Objective
Myelodysplastic syndromes (MDS) are a group of heterogeneous hematopoetic stem cell clonal disorders with a high frequency of karyotypic abnormalities (40-60%). Among karyotypic abnormalities, abnormal chromosome numbers (aneuploidy) occurs frequently. In aneuploidy, chromosomal instability (CIN) is defined as persistent mis-segregation of whole chromosomes and is caused by defects during mitosis with an odd number of chromosomes. CIN is associated with tumor heterogenesis, multidrug resistance and aggressiveness in solid tumor. Hence, we performed a one-center study on MDS patients to uncover the role of CIN in MDS clinical development.

Method
A total of 104 cases , 62 male and 42 female, aged from 15 years to 89 years, were tested by fluorescent in situ hybridization (FISH) and karyotypic analysis before any therapeutic intervention. According to the cytogenetic analysis of those two technology they were separated into 5 groups including: CIN, normal karyotype, complex karyotype excluding CIN, deletion chromosome 7 abnormality and other chromosomal abnormalities. All cases were followed up for a median of 19.5 months.

Results
Karyotyping and FISH identified 70 (67.3%) patients with abnormal karyotypes containing 32 cases of CIN, 9 cases of deletion chromosome 7 abnormality and 5 cases of complex karyotype excluding CIN. The median survival for CIN group was 13 months (incredible interval:6-20 months) compared with 23 months (incredible interval :20-27 months) in all cases, 44months in normal karyotype, 23 months in deletion chromosome 7 abnormality and 13 months in complex karyotype excluding CIN group (P=0.001 for log rank method). In CIN group, 11 cases transformed into acute leukemia with a incidence of 34% with no significant difference with total cases. And the length of time for leukemia transformation shows no significant difference between CIN group and total cases.

Conclusion
Chromosomal instability in MDS patients of the study revealed worst prognosis compared with other groups. This may suggest that chromosomal instability in MDS chromosomal abnormality confer a significant independent adverse impact on patients survival. However this effect might have no relation to leukemia transformation.

Disclosures:
No relevant conflicts of interest to declare.
Evaluation Of The JAK2-V617F Gene Mutation In Egyptian Patients With Essential Thrombocythemia and Polycythemia Vera
Authors: El Zaafarany Maha Ibrahim , Abdel-Ghaffar A. Hasan , Elkhodary Tawfik R. , Salem Dalia A. , Soliman Eman A. , Shamaa Sameh S. 
Published: October 2019

Abstract
An activating mutation of Janus kinase 2 (JAK2-V617F) was previously described in chronic myeloproliferative disorders (MPD). In previously published studies, the frequency of the JAK2-V617F mutation was determined to be 80–90 % for patients with polycythemia vera (PV) and 40–70 % for essential thrombocythemia (ET). In this study, we analyzed the relationship between the JAK2-V617F mutation and clinical-hematological parameters in Egyptian patients with MPD and compared these findings with published studies from other geographic regions and previous studies in EGYPT. A total of 56 patients were studied; of which, 32 were diagnosed with PV and 24 with ET. The mutation status of JAK2 was determined using allele-specific oligonucleotide (ASO) PCR assay. We found that 53% of the PV group and 79% of the ET group were positive for the JAK2-V617F mutation. When all patients were analyzed; patient age, levels of WBCs, levels of hemoglobin, levels of platelets and splenomegaly were significantly different in patients with the JAK2-V617F mutation (p < 0.05). The JAK2-V617F mutation is frequently detected in the Egyptian patients with MPD, and especially in patients with ET. Hence, it would be useful to include JAK2 mutation screening in the initial evaluation of patients suspected to have MPD especially ET.

Disclosures:
No relevant conflicts of interest to declare.
ADAR1 Is Essential For Erythroid Development
Authors: Liddicoat Brian , Hartner Jochen , Chalk Alistair , Lu Jun , Orkin Stuart H. , Walkley Carl R 
Published: October 2019

Abstract
Understanding the mechanisms controlling erythroid differentiation may allow therapeutic regulation of erythropoiesis. Focus so far has concentrated on the roles of transcription factors in determining erythroid fate, however one mechanism of gene regulation that has been poorly explored is that of direct modification of RNA. It is now becoming apparent that RNA sequences can be widely modified by RNA editing. Adenosine-to-Inosine (A-to-I) RNA editing is a posttranscriptional process resulting in sequence alterations to RNA transcripts, which is catalyzed by members of the adenosine deaminase acting on RNA (ADAR) family of enzymes. We have previously reported that targeted disruption of ADAR1 in hematopoietic stem cells (HSC) resulted in a global upregulation of type I and II interferon-inducible transcripts and rapid apoptosis (Hartner et al., Nature Immunology 2009). This study identified that ADAR1 is essential for maintenance of both the fetal and adult HSC compartment in a cell-autonomous fashion. Although ADAR1 is dispensable for myeloid development and B-lymphopoiesis, investigation of its role in erythropoiesis is granted owing to the severe loss erythrocytes in ADAR1 null mice. To determine the role of ADAR1 in erythropoiesis, we generated mice with an erythroid-restricted deletion of ADAR1 (EpoR-Cre Adar1fl/-). These animals were found to die in utero at ∼E14.5. The fetal liver (FL) was small and had significantly lower cellularity than in control littermates. Analysis of FL erythropoiesis demonstrated increased apoptosis and a loss of cells after the phenotypic polychromatic erythroblast stage of erythroid differentiation. When transplantation studies were done with EpoR-Cre Adar1fl/- FL and control EpoR-Cre Adar1fl/+ FL, recipients of EpoR-Cre Adar1fl/- FL could not restore erythropoiesis and were anemic in contrast to the controls. They also developed splenomegaly suggestive of extramedullary hemopoiesis occurring as a compensatory mechanism. To understand the mechanism through which ADAR1 regulates erythroid development, gene expression arrays and miRNA profiling were performed. As with HSCs, loss of ADAR1 caused a significant upregulation of IFN signatures in EpoR-Cre Adar1fl/- FL. Interestingly, despite evidence related to regulation of miRNA function by ADARs, there were only subtle changes to the expression pattern and levels of miRNAs in Adar1-deficient erythroid cells. These results demonstrate that ADAR1 is an essential in vivo mediator of erythroid cell fate and a critical negative regulator of the IFN response in cells specifically committed to erythropoiesis.

Disclosures:
Hartner: TaconicArtemis: Employment.
Iron Chelation Therapy Could Rapidly Reduce Oxidative DNA Damage In CD34+ Hematopoietic Cells Before Decrease Of Serum Ferritin Level
Authors: Kobune Masayoshi , Kikuchi Shohei , Iyama Satoshi , Takada Kohichi , Murase Kazuyuki , Ono Kaoru , Horiguchi Hiroto , Kamihara Yusuke , Hashimoto Akari , Tatekoshi Ayumi , Hayashi Tsuyoshi , Sato Tsutomu , Miyanishi Koji , Sato Yasushi , Takimoto Rishu , Kato Junji 
Published: October 2019

Abstract

Introduction
Myelodysplastic syndrome (MDS) is characterized by dysplastic and ineffective hematopoiesis, peripheral blood cytopenias and a risk of leukemic transformation. Most MDS patients eventually require red blood cell (RBC) transfusions for anemia and consequently develop iron overload. Excess free iron in cells catalyzes generation of reactive oxygen species (ROS) especially hydroxyl radical that cause oxidative DNA damage including formation of mutagenic 8-hydroxy-2'-deoxyguanosine (8-OHdG) and DNA double strand breaks. However, it is unclear whether iron-mediated oxidative stress affects the pathophysiology of MDS.

Methods
This study included MDS patients who visited our university hospital and affiliated hospitals (n=43). Among them, 13 patients received iron chelation therapy when their serum ferritin (SF) level was greater than 1000 ng/mL or they required more than 20 RBC transfusions (or 100 mL/kg of RBC). We analyzed hemoglobin, SF level and chromosomal abnormality and 8-OHdG levels in peripheral blood mononuclear cells (PBMC) obtained from MDS patients before and after iron chelator, deferasirox administration.

Results
We showed that reactive oxygen species (ROS) in hematopoietic cells was higher in MDS patients with high SF level. Furthermore, the 8-OHdG levels in MDS patients were significantly higher than those in healthy volunteers and the 8-OHdG levels were positively correlated with SF (p=0.003, r=0.495) and chromosomal abnormalities (p=0.019). Importantly, the 8-OHdG levels in PBMC and CD34+ cells of MDS patients dramatically decreased 3 month after deferasirox administration (the 8-OHdG levels in PBMC, 3.374±78, p<0.05) although SF level were not reduced within 3 month (Figure). However, SF level decreased to 500-600 ng/mL after 36 months of iron chelation therapy, 8-OHdG is a sensitive marker of cellular iron chelation therapy by deferasirox which readily passes through the plasma membrane. When patients were divided into the no Iron chelation group (n=10) and high Iron chelation group (n=13), the survival time was significantly longer in the latter group than the former group (P=0.046) although International prognostic scoring system (IPSS) was not significantly difference between both groups. Further, 50% of patients without iron chelation group developed into leukemia, while no patients did progress into leukemia during 36 month.

Conclusion
These results indicated that cellular excess iron could contribute to the pathophysiology of MDS and iron chelation therapy could improve the oxidative DNA damage in MDS patients.

Disclosures:
No relevant conflicts of interest to declare.
The Mutational Profile of Plasma Cell Disorders
Authors: Futreal Andy 
Published: October 2019

Abstract
Multiple myeloma is a plasma cell malignancy that is the second most common hematologic cancer. The genetics of the disease have been previously characterized by two major subtypes involving recurrent translocations of the immunoglobulin heavy chain, c-MAF, cyclin D (CCND1) and FGFR3/MMSET oncogenes, and the hyperdiploid group with multiple recurrent trisomies. Further, there are characterized cytogenetic/ploidy subsets that appear to carry prognostic significance. Specifically, gains of chromosomes 5, 9, 11, 15, and 19 confer a good prognosis whilst gain of 1q plus deletions of 1p, 12p, 14q, 16q, and 22q confer a poor prognosis. More recently the application of massively parallel sequencing has revealed further insights into the genetic architecture of multiple myeloma. Work from several groups has identified the contribution of mutations in genes involved in non-canonical NF-kB signaling, MAPK signaling and histone methylation, as well as infrequent mutation of cancer genes implicated in other tumor types and novel genes. These data will be presented to give an overall update on the current state of multiple myeloma genetics and our current level of insight in the genomic complexity that characterizes this disease.

Disclosures:
No relevant conflicts of interest to declare.
Hematology from the Ground Up: Lessons from C. elegans
Authors: Hamza Iqbal 
Published: October 2019

Abstract
Heme is a vital cofactor responsible for diverse biological functions such as gas synthesis and sensing, circadian clock control, microRNA processing, and xenobiotic detoxification. Heme synthesis occurs in the mitochondria in eukaryotes. Free heme is a hydrophobic and cytotoxic macrocycle. How then is heme transported through cellular membranes and organelles? What are the mechanisms for incorporating heme into specific hemoproteins that reside in the cytoplasm, peroxisomes, mitochondria, secretory pathway, and nucleus? Our work with the invertebrate animal model Caenorhabditis elegans has demonstrated that this roundworm is exceptional because it does not synthesize heme but rather utilizes environmental heme to manufacture heme-containing proteins that have human homologs. Genomic screens in C. elegans identified several novel genes which we termed Heme Responsive Genes (HRGs). HRG-1, the first metazoan heme importer/transporter, is a permease with four transmembrane domains, and is conserved in vertebrates. Depletion of hrg-1 paralogs in worms causes disruption of organismal heme sensing. Zebrafish with lower levels of hrg1 reveals hydrocephalus, yolk tube malformations, and profound defects in erythropoiesis. Hrg1 is strongly expressed in macrophages of the reticuloendothelial system in human and mouse tissues and is upregulated in a time- and dose-dependent manner by either erythrophagocytosis (EP) or induction of hemolytic anemia in mice. Hrg1 traffics to the phagolysosomal membranes during EP and depletion of Hrg1 in mouse macrophages causes attenuation of heme transport from the phagolysosomal compartment, concomitant with suppression of heme degradation and iron export. Importantly, studies using yeast, zebrafish, and mouse macrophages reveal that specific missense polymorphisms in Hrg1 are defective in heme transport. To uncover additional molecules in organismal heme homeostasis, we conducted a genome-wide RNAi screen in live, transgenic heme-sensor worms. The screen identified several hundred new candidates that integrate signals from different tissues to regulate systemic heme homeostasis. Our findings represent major discoveries in heme trafficking and establish a paradigm for heme transport in animals.

Disclosures:
Hamza: Rakta Therapeutics: CEO Other, Consultancy.