bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Hyperactive Transcriptional State Marks Genome Reactivation during Mitotic Exit
Authors: Blobel Gerd A. , Hsiung Chris C.S. , Huang Peng , Keller Cheryl , Ginart Paul , Jahn Kristen , Bartman Caroline , Stonestrom Aaron James , Evans Perry , Giardine Belinda , Hardison Ross C. , Raj Arjun 
Published: October 2019

Abstract
The tremendous proliferative capacity of erythroid precursor cells underlies the production of over a million red blood cells per second in adult humans. During every mitosis the mammalian nucleus is disassembled and transcriptionally silent. Genome reactivation after mitosis is a key step in the propagation of transcriptional programs through cell generations, yet how this occurs remains largely unexplored. We carried out the first genome wide survey of transcription in cells emerging from mitosis using RNA polymerase II ChIP seq in purified populations at various post-mitotic time points. Using unsupervised approaches, we discover and classify genome reactivation patterns among genes. A surprisingly large fraction of genes (~25%) displays a post-mitotic spike in transcription. This spike represents the first complete round of transcription and accounts for the greatest gene-to-gene variance in temporal patterns of transcription in G1 phase. Another notable and contrasting pattern is gene activation late in the G1 phase.
Single-molecule RNA FISH imaging demonstrates that the post-mitotic transcriptional spike represents the highest activity throughout the cell cycle and results in an increase in mature mRNAs, indicating that the phenomenon has the capacity to alter gene expression. Surprisingly, the post-mitotic transcriptional spike occurs independent of enhancer action and can be recapitulated with promoter sequences ectopically integrated into the genome. In contrast, late-G1 gene reactivation is distinct and requires enhancer function.
Our findings uncover novel modes of transcriptional control during exit from mitosis with implications for our understanding of transitions in gene expression states in dividing cells.

Disclosures
No relevant conflicts of interest to declare.
CREB Controls C/Ebpd to Impair Myeloid Differentiation Process in Acute Myeloid Leukemia
Authors: Tregnago Claudia , Manara Elena , Bisio Valeria , Borga Chiara , Bresolin Silvia , Aveic Sanja , Germano Giuseppe , Basso Giuseppe , Martina Pigazzi 
Published: October 2019

Abstract
Purpose. The cAMP response element binding protein (CREB) is a transcription factor documented to be crucial for normal and neoplastic hematopoiesis. Its overexpression has already been demonstrated to impair myelopoiesis and to aberrantly control cell proliferation, apoptosis and cell cycle progression, both in vitro and in vivo. Its protein overexpression has been found in patients with acute myeloid leukemia (AML) contributing to decrease survival. CREB guides the expression of more than 5000 different targets in a tissue/cell-type specific fashion, and to date its main network towards leukemogenesis remains unknown. Here we aim to identify through which genes CREB triggers AML by using a CREB overexpressing transgenic zebrafish which developed AML in adulthood.
Patients and methods. We performed gene expression profile of RNA from the kidney marrow of 14-months old CREB-zebrafish (n=5) and control zebrafish (n=5). Principal component analysis was performed using Partek Genomic Suite software to integrate zebrafish AML signature with human signature found in pediatric AML to find common CREB target genes. AML cell lines were used to validate CREB targets in vitro.
Results. By GEP analysis and integration data we found 20 differentially expressed genes in both the zebrafish and human leukemia. Several of them were involved in the myeloid differentiation process, such as JUN, FOS and C/EBPδ. We confirmed that C/EBPδ protein levels highy correlated with phosphoCREB levels in zebrafish tumor as well as in a cohort of 66 pediatric patients with AML (r=0.79). We silenced and overexpressed CREB in AML or healthy bone marrow primary cultures respectively, and found that C/EBPδ was controlled by CREB transcriptional activity. We took advantages of a previously created HL60(CREB-) cell line, where CREB protein levels was absent compared to the control cell line called HL60(CREB+), where CREB was overexpressed. HL60(CREB-) cell line expressed lowered C/EBPδ levels compared to HL60(CREB+). To investigate CREB's role on differentiation program, cell lines were treated with all-trans-retinoic acid (ATRA). The evaluation of CD11b expression revealed that HL60(CREB-) differentiated to a higher extent compared to HL60(CREB+).Enhanced myeloid differentiation was also confirmed by cell morphology examination. Then we silenced C/EBPδ gene in HL60(CREB+) cell line and treated with ATRA, confirming that C/EBPδ lowered expression increased CD11b expression, phenocopying the HL60(CREB-) behavior.
Conclusion. These results indicated that C/EBPδ is a CREB target crucial for myeloid differentiation. The new role discovered for CREB proto-oncogene in blocking myeloid differentiation process opens for further opportunities with differentiation agents to cure AML.

Disclosures
No relevant conflicts of interest to declare.
In silico Tissue-Based Expression Analysis of YY1 and Cancer Stem Cell (CSC) Transcription Factors in Hematological Malignancies: Unraveling New Therapeutic Targets
Authors: Kaufhold Samantha , Garban Hermes , Bonavida Benjamin 
Published: October 2019

Abstract
Introduction: Yin Yang 1 (YY1) is a transcription factor, (a 44 kDa protein), ubiquitously expressed in many tissues and cancers. YY1 exerts multiple functions, including transcriptional regulation of many genes involved in cell proliferation, chromatin remodeling, drug and immune resistance, and metastasis [1].Cancer stem cells (CSCs) are a small subset of cancer cells that drive tumorigenesis and metastasis and are considered to be resistant to cytotoxic therapies; they are pluripotent and capable of self-renewal.
Objective: To determine if YY1 is a transcription factor that regulates CSCs.
Hypothesis: We hypothesized that YY1 may be overexpressed in CSCs, and its expression may be coordinated with the expression of CSC transcription factors. The overexpressions and activities of SOX2, OCT4 (POU5F1), BMI1 and NANOG are characteristics of the CSC phenotype in many cancers.
Methods: The above hypothesis was tested by comparing the expression patterns of the four CSC markers and YY1 in hematological malignancies. The data were collected from the Human Protein Atlas proteomics database, and only high and medium expressions were considered positive.
Results: From the data that were collected, the overall percentage of positively stained cells was determined. Our preliminary findings demonstrated that there was a strong correlation between the expression patterns of YY1 and BMI1, some correlation between YY1, OCT4 and SOX2, and no correlation between YY1 and NANOG, which was usually underexpressed. The interactomes of OCT4 and SOX2 are important parts of the regulatory network of hESCs. Further, multiple DNA binding proteins, including YY1, are enriched in both interactomes [2].
Conclusion: The findings suggest strongly that CSCs may overexpress YY1 in coordination with the overexpressions of SOX2, BMI1, and OCT4. They further suggest that YY1 may constitute a CSC biomarker, and they revealed potential therapeutic targets.
[1] Critical Reviews™ in Oncogenesis Volume 16, 2011 [2] Gao F et al., Sci Report 3:1588,2013.

Disclosures
No relevant conflicts of interest to declare.
Downregulation of SATB1 Increase the Invasiveness of Jurkat Cell Via Activation of the WNT/Beta-Catenin Signaling Pathway in Vitro
Authors: Luo Xiaodan , Xu Lihua , Liu Dan , Wang Yaya , Wu Xiaohong , Tan Huo 
Published: October 2019

Abstract
Backgroud: Special AT-rich sequence-binding protein-1 (SATB1) is critical for genome organizer that reprograms chromatin organization and transcription profiles, and associated with tumor growth and metastasis in several cancer types. Many studies suggest that SATB1 overexpression is an indicator of poor prognosis in various cancers, such as breast cancer, malignant cutaneous melanoma, liver cancer, etc. However, their expression patterns and function values for adult T-cell leukemia (ATL) are still largely unknown. Objective: The aim of this study is to examine the levels of SATB1 in ATL and to explore its function and mechanisms in ATL.
METHODS: 20 ATL peripheral blood samples and 20 normal controls were collected. Expressions of SATB1 in both groups were evaluated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Cellular proliferation and invasion of SATB1-knockdown Jurkat cells and cells in control group were evaluated by manually count and transwell matrigel invasion assay, respectively.
RESULTS: SATB1 expressions were decreased in ATL peripheral blood mononuclear cells (p<0.001) compared with normal controls. Knockdown of SATB1 gene might increase Jurkat cell invasiveness through the activation of Wnt/β-Catenin signaling pathway.
CONCLUSIONS: SATB1 expression is down-regulated in ATL and decreased expression of SATB1 increase the invasiveness of Jurkat cell through the activation of Wnt/β-Catenin signaling pathway in vitro.
Acknowledgments This study was supported by grants from the National Natural Science Foundation of China (81200399) and Key Clinical Disciplines of Guangdong Province (20111219)

Disclosures
No relevant conflicts of interest to declare.
Identification of Novel Mir-34a Targets in a c-Myc Murine Model
Authors: Contreras Jorge R. , Tran Tiffany M , Palanichamy Jayanth Kumar , Casero David , Rao Dinesh S. 
Published: October 2019

Abstract
MicroRNAs (miRNAs) serve a fundamental function in the post-transcriptional regulation of gene expression. MiRNA-mediated repression is mediated by the RNA-induced silencing complex (RISC) and is generally thought to be predicted by base-pairing in the seed region of the microRNA. In predicting the effects of miRNAs on gene expression, it is important to consider that the transcriptional context will result in differential targeting of transcripts, and necessitates the study of miRNA function in the cell type of interest. Here, to study tumor suppressive functions of two miRNAs, miR-146a and miR-34a, we utilized the Eμ-Myc transgenic mouse bred to targeted knockouts for these two miRNAs. We found that miR-146a deficiency led to more aggressive B-cell neoplasms that showed a more differentiated B-cell phenotype. Transcriptional changes were fairly limited and were not enriched for miR-146a targets as a class. However, the changes included differences that were consistent with regulation of the transcription factor Egr1, which was demonstrated to be a direct target in human cells. In miR-34a deficient mice with the Eμ-Myc transgene, we did not observe changes in survival or in the phenotype of the neoplasms that developed. However, transcriptional profiling revealed changes in many predicted miR-34a targets, as determined by gene set enrichment analyses (GSEA). Novel predicted targets are being analyzed by luciferase assays. These analyses reveal the importance of assessing cell-type and disease-specific miRNA targeting, which can reveal novel and previously unknown miRNA targets and facilitate our understanding of leukemia and lymphoma pathogenesis.

Disclosures
No relevant conflicts of interest to declare.
Potential Crosstalk of Interleukin-6-Heme Oxygenase-1 Dependent Mechanism Involved in Resistance to Lenalidomide in Multiple Myeloma Cells
Authors: Wang Jishi , Wu Weibing , Ma Dan , Wang Ping , Cao Lu , Fang Qin , Zhao Jiangyuan , Lu Tangsheng 
Published: October 2019

Abstract
Interleukin-6 (IL-6), as one of the most important multiple myeloma (MM) survival factors, has been verified to determine poor prognosis of MM. IL-6 mainly originates from paracrine of bone marrow stromal cells and autocrine of MM cells. As an enzyme having cytoprotective effects, heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors. The HO-1 expression levels in bone marrow CD138+ cells of MM patients, which were significantly higher than those of healthy donors, were positively correlated with serum IL-6 levels and intracellular IL-6 mRNA expression levels. Cultivating U266 and CD138+ cells with exogenous IL-6 in vitro induced high HO-1 expressions and allowed them to resist lenalidomide, probably because IL-6 activated the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. Without IL-6 co-culture, on the other hand, up-regulating HO-1 expressions in U266 cells and bone marrow CD138+ cells from MM patients significantly up-regulated the mRNA expression level of IL-6 and facilitated autocrine IL-6 production. The findings were associated with high HO-1 expression-enhanced of p38 MAPK phosphorylation. Down-regulating HO-1 expression sensitized U266 and CD138+ cells toward lenalidomide. Therefore, we postulated that HO-1 predominantly controlled IL-6 paracrine and autocrine, and that IL-6 in bone marrow microenvironment of MM patients stimulated MM cells to highly express HO-1 and to resist lenalidomide. High HO-1 expression also stimulated autocrine IL-6 production, thus further augmenting the drug resistance and exacerbating the disease. This study provides valuable experimental evidence for using HO-1 as a possible marker for MM prognosis and drug resistance and as a potential treatment target.

Disclosures
No relevant conflicts of interest to declare.
Histone Deacetylation Inhibitor Sensitizes T-ALLs to Topoisomerase II Inhibitor By Attenuating G2 Cell Cycle Arrest and Blocking Nuclear Entry of Ctip during DNA Repair
Authors: Liu Jin-Hwang , Lin Yu-Hern , Liu Hon-Wen , Gau Jyh-Pyng 
Published: October 2019

Abstract
Double strand DNA repair can be epigenetically modulated to sensitize the malignant cells to chemotherapy. CTV-1 and Molt-3 were segregated as T-acute lymphoblastic cells (T-ALL) according to their expression profiles. We found in these cells doxorubicin, a topoisomerase II (TOP2) inhibitor, induced expression and phosphorylation of cell cycle checkpoint kinase 1(CHK1) associated with G2 cell cycle arrest before achieving apoptosis; while a histone deacetylation inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA), synergistically enhanced cell death by attenuation of expression and phosphorylation of CHK1, and by attenuated expression and phosphorylation of a double strand DNA repair protein, C-terminal binding protein (CtBP)-interacting protein [CtIP], and was associated with shortened G2 cell cycle arrest. Very often is Doxorubicin as a topoisomerase II inhibitor enrolled in the treatment of T-ALL. We evidenced with isobologram synergistic cell-killing by doxorubicin and SAHA in CTV-1 and Molt-3 T-ALL cell lines of which expression and phosphorylation of CHK1 were negatively affected by SAHA. In the SAHA-treated T-ALL cells, the repair of doxorubicin-induced double strand DNA break (DSB) was associated with increased γH2AX. However, although SAHA increased expression of γH2AX and acetyl H2AX, apoptosis was enhanced with shortened G2/M arrest and the hampered nuclear entry of CtIP revealed by immunofluorescent confocal microscopy. HDACi thus synergistically impaired the topoisomerase II-induced DSB repair and enhanced apoptosis by eliciting DNA repair with γH2AX expression; however, aborted the DNA repair and induced apoptosis by hampering the nuclear entry of CtIP. Attenuation of activated CHK1 may be potentially a biomarkers of synergistic cytotoxicities of HDACi and DSB-inducing chemotherapeutics.

Disclosures
Off Label Use: in vitro study only. suberoylanilide hydroxamic acid in combination with topoisomerase II inhibitor may have synergistic effects. .
Coagulation Disorder after Treatment of Pegaspargase and L-Asparaginase
Authors: Xu Linwei , Wei Xiaolei , Wei Yongqiang , Huang Fen , Hao Xiaoxiao , Zhou Qinjun , Feng Ru 
Published: October 2019

Abstract
Introduction:
Pegaspargase(PEG-ASP) and L-asparaginase(L-ASP) has been widely used in the treatment of acute lymphatic leukemia, changes of coagulation function after treatment are not actually the same. So we performed the present study to analyze coagulation disorder after PEG-ASP and L-ASP treatment of adults with acute lymphatic leukemia.
Methods and materials:
Totally 153 hospitalized patients with acute lymphatic leukemia treated with L-ASP or PEG-ASP were studied from January, 2010 to January, 2015. Of all 153 patients analyzed, they received L-ASP treatment 158 dose times and PEG-ASP treatment 60 dose times respectively.
Results:
There is no difference of the distribution of age, sex, white blood cell count at diagnosis and risk factors of the disease. Agranulocytosis combining with intestinal infection, bleeding or thrombosis and the inducing remission rate between the two groups has no significant difference (p=0.11,0.61,0.33). The total infusion of fresh frozen plasma or cryoprecipitate or fibrinogen after treatment shows no significant difference between the two groups (p=0.11,0.75,0.21).Fibrinogen level decreases slower in the treatment of PEG-ASP(9.37 day vs 7.40 day, p=0.02) than that of L-ASP. What's more, fibrinogen decreases slower when L-ASP used at interval compared with continuous use, however, the incidence rate of bleeding and related complications is higher when used at interval early (p =0.028).
Conslusion:
Because of the preponderance to monitor the changes of fibrinogen and the equal rate of complications and inducing remission rate, it is recommended to use PEG-ASP. L-ASP used at interval can monitor the coagulation function easily than continuous use, but the early use of L-ASP may overlay the drug side effects and related hematology toxicity caused by chemotherapy, then cause an increased incidence of complications.

Disclosures
No relevant conflicts of interest to declare.
High-Dose Cytarabine Alone Versus Cytarabine Plus Anthracycline for Consolidation Therapy in Non-Promyelocytic Acute Myeloid Leukemia
Authors: Kim Sung-Hyun , Kim So Yeon , Lee Ji Hyun , Lee Suee , Oh Sung Yong , Kim Hyo-Jin , Kim Dae Sik , Kang Ka-Won , Lee Se Ryeon , Park Yong , Sung Hwa Jung , Choi Chul Won , Kim Byung Soo 
Published: October 2019

Abstract
Standard consolidation therapy of acute myeloid leukemia (AML) contains high-dose cytarabine (HiDC). However, optimal dose of cytarabine and benefit of additional chemotherapeutic agents remain unresolved problems. One hundred and forty-two patients among 173 newly diagnosed AML patients, who achieved complete remission following induction chemotherapy and subsequently received different consolidation therapies in 4 independent institutes, were retrospectively analyzed. Patients were divided into 3 groups by consolidation regimens: HiDC (1.5-3g/m2, bid, Days 1,3,5) alone in 44 patients (Group A), HiDC plus anthracycline in 46 patients (Group B), and intermediate-dose cytarabine (1g/m2, bid, Days 1,3,5) plus anthracycline in 52 patients (Group C). Overall survival (OS), relapse-free survival (RFS), disease-free survival (DFS), and event-free survival (EFS), were not significantly different in Group A vs. Group B. However, Group B showed longer RFS, DFS, and EFS, as compared with Group C. Treatment-related mortality was significantly higher in Group B, as compared with Group A (P=0.040) and Group C (P=0.013). Cytogenetic risk was the only significant prognostic factor in OS, RFS, DFS and EFS.
In this study, the addition of anthracycline to HiDC as consolidation chemotherapy in AML patients did not improve treatment outcomes, and had more toxicity. HiDC enhanced RFS, DFS, and EFS, as compared with intermediate-dose cytarabine. Therefore, HiDC single therapy could be considered as standard consolidation therapy for non-promyelocytic AML

Disclosures
Choi: Alexion Pharmaceuticals: Research Funding.
Effect of Early Removal of Central Catheterization in Febrile Neutropenic Patients with Acute Leukemia
Authors: Hwang Su Hyun , Choi Yong Won , Jeong Seong Hyun , Park Joon Seong 
Published: October 2019

Abstract
Background: A guideline of central line-related blood stream infection (CRBSI) is only for immune-competent patients with end-stage renal disease on hemodialysis. We need widely acceptable guideline whether remove or maintain a central catheter in febrile neutropenic patients.
Method: Medical records from 293 cases (95 patients) of febrile neutropenia with Central Catheterization were obtained retrospectively, and clinical characteristics, particularly duration of fever, were analyzed according to the early removal of central catheterization under anti-cancer chemotherapy for acute leukemia.
Results: Forty-eight cases (16.4%) have already baseline fever and 25 cases (8.5%) showed baseline pneumonic infiltration prior to chemotherapy. The insertion sites of catheterization were subclavian (85.3%), internal jugular (12.6%), and others (2.0%). Early removal of central catheter was done at 93 cases (31.7%) and the cause of early removal was fever (63.4%), malfunction (11.8%), and others (24.7%). The duration of fever was significantly shortened by early removal of central catheterization (5.4 vs 7.5 days, p=0.003, Figure 1A). In addition, the duration of fever was related with age, diagnosis, type of chemotherapy, presence of baseline fever or pneumonic consolidation in univariate analysis. The site of central access or body mass index as well as existence of CRBSI did not affect duration of fever. In multivariate analysis, early removal of central catheter was independently associated with short duration of fever (OR=0.619, 95% CI=0.46-0.83, p=0.001, Table 1). The effect of early removal of central catheter was highlighted when micro-organisms were documented (Figure 1B).
Summary: In patients with febrile neutropenia, early removal of central catheter can shorten the duration of fever particularly when BSI was documented.

Disclosures
No relevant conflicts of interest to declare.