bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telomere Length Changes of Lymphocytes in Aplastic Anemia
Authors: Fu Rong , Zhang Jiangbo , Shao Zonghong 
Published: October 2019

Abstract
Aplastic anemia (AA) is a primary disorder of severe bone marrow failure characterized by pancytopenia. The pathogenesis of AA is closely related to T cell hyperfunction. Abnormal telomere shortening of bone marrow mononuclear cells which has been reported in AA not only lead to genomic instability and apoptosis but also regulate T cells immunity to antigen. Interestingly,lymphocytes with shorter telomere length have undergone apoptosis escape in autoimmune disease. In our study, the relative telomere length (RTLs) of CD3+, CD3+CD4+, CD3+CD8+, CD19+ and CD34+ cells were investigated in 14 untreated AA patients and 32 controls. The RTLs of CD3+,CD3+CD4+ and CD3+CD8+T lymphocytes were shorter than those of the controls. Meanwhile, no differences in CD19+B and CD34+ cells were found between AA and controls. A change in telomere length may be involved in the pathogenesis of AA and could be considered as a predictive biomarker for the diagnose of AA.

Disclosures
No relevant conflicts of interest to declare.
Disproportionate Sex Chromosome Loss in Abnormal Karyotypes of Male and Female Patients with Diagnoses of Myeloid or Lymphoid Neoplasms
Authors: Cantu Eduardo S. , Nemana Lakshmi , Pierre Robert V. , Moses Mike 
Published: October 2019

Abstract
Sex chromosome loss (SCL) occurs in different types of human cells and is likely related to aging, but could also be related to other factors. We reviewed cytogenetic studies of bone marrow samples from patients (males and females) with clinical diagnoses of either myeloid or lymphoid delineation in order to establish if SCL is associated with abnormal karyotypes found in these malignancies. Prevalence of clonal SCL (POC-SCL = % cases having ≥ 3 cells with SCL/study) was evaluated retrospectively in a total of 9,593 bone marrow cytogenetic studies performed in our laboratory during a recent calendar year. Results from this database were identified as normal or abnormal karyotypes, as male or female patients, and as having a myeloid or a lymphoid diagnosis. POC-SCL values were determined for each of these designations. Student-t tests were then applied to ascertain if POC-SCL values were significantly different with respect to these three variables. Our statistical analyses showed that: 1) POC-SCL was higher in abnormal than in normal karyotypes. This was true for abnormal male and female karyotypes in both myeloid and lymphoid disorders, compared to cases with normal karyotypes. 2) POC-SCL values were higher in male karyotypes for normal and abnormal myeloid cases, than in females. This was also true in normal karyotypes of lymphoid cases, but had similarly high values for both genders in abnormal karyotypes of lymphoid cases. 3) POC-SCL was about the same in total myeloid versus total lymphoid cases. However, closer examination indicated a higher POC-SCL value was seen in lymphoid patients with normal male and female karyotypes than for myeloid patients with normal male and female karyotypes. Interestingly, POC-SCL was higher in the abnormal myeloid male karyotypes than in the normal male karyotypes, while it was higher in abnormal lymphoid female karyotypes than in the normal female karyotypes. Although clonal-SCL may not reflect a primary biological marker associated with these cancers, our results clearly show that clonal-SCL segregates selectively with abnormal karyotypes associated with myeloid and lymphoid malignancies. Moreover, not only is there a disproportionate over-representation of -Y in abnormal karyotypes, but –X is also a significantly frequent finding in abnormal karyotypes of these diseases.

Disclosures
Cantu: Integrated Oncology: Employment. Nemana:Integrated Oncology: Employment. Pierre:Integrated Oncology: Consultancy. Moses:Integrated Oncology: Employment.
OCT1 gene Expression Is an Independent Prognostic Factor in Diffuse Large B Cell Lymphoma
Authors: Gouveia Gisele Rodrigues , Ferreira Suzete Cleusa , Siqueira Sheila , Pereira Juliana 
Published: October 2019

Abstract
Background: Transcription factors associated with the POU domain modulate the expression of several genes of B lymphoid differentiation, including the IgH. The study of these factors allowed to better understand the pathogenesis of lymphomas and to establish the lineage and the differentiation stage of the malignant cell. The silencing of OCT1 in tumor cell lines reduced its malignant transformation, but its ectopic expression enhanced the tumorigenesis ability. However, few studies has been evaluated the role of the OCT1 gene expression in lymphoma. In this study we assessed the impact of the OCT1 gene expression in the survival of patients with Diffuse Large B Cell Lymphoma (DLBCL).
Methods: From January 2006 to January 2011 were evaluated 77 patients with DLBCL treated with R-CHOP at Clinical Hospital and Cancer Institute of Sao Paulo University. The RNA was extracted from the paraffin block at lymphoma diagnosis and gene expression analysis was performed by relative quantification method by Real-Time PCR (qRT-PCR). After the data normalization using two different reference genes, the median expression of OCT1 was obtained. The overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. The relative risks were obtained by Cox regression bivariate intervals with 95% of confidence. The significance level of 5% was accepted and the IBM SPSS Statistics software version 20.0 was used.
Results: Patients showing OCT1 expression < the median presented higher OS (p = 0.010) and PFS (p = 0.016) than patients with OCT1 expression ≥ median with a hazard rate (HR) for OS and PFS of 2.45 and 1.14, respectively. In multivariate analysis the PFS was also higher in patients with OCT1 expression < the median (p = 0.035). The stratification by the international prognostic index (IPI) and age showed that the expression of OCT1 < median showed a statistically significant difference in the OS (p = 0.048) in IPI intermediate-high (HI) and high (HR) patients (p = 0.048), with a HR of 2.32 in HI plus HR group. The PFS (p = 0.025) and OS (p = 0.025) were lower in patients ≥ 60 years and OCT1 expression ≥ the median.
Conclusion: Our data suggest that the expression of OCT1 showed a predictive prognostic impact in DLBCL independently of IPI. Patients with lower expression of OCT1 presented a better OS and PFS.
Figure 1 SG curve for the OCT1 gene expression. Figure 1. SG curve for the OCT1 gene expression.
Figure 2 SLP curve for the OCT1 gene expression. Figure 2. SLP curve for the OCT1 gene expression.
Figure 3 SG curve for to expression of OCT1 gene for subgroup IPI intermediate-high and high. Figure 3. SG curve for to expression of OCT1 gene for subgroup IPI intermediate-high and high.

Disclosures
No relevant conflicts of interest to declare.
Gambogic Acid Suppresses Hypoxia-Induced HIF-1α/VEGF Expression Via Inhibiting PI3K/Akt/mTOR Pathway in Multiple Myeloma Cells
Authors: Wang Fei , Zhang Wei , Guo Liting , Cheng Jian , Liu Ping , Chen Baoan 
Published: October 2019

Abstract
In multiple myeloma (MM), the hypoxic environment is an important factor causing tumor angiogenesis which is strongly correlated to disease progression and unfavorable outcome by activating the key transcription factor, hypoxia-inducible factor-1α (HIF-1α). Gambogic acid (GA) is the major active ingredient of gamboge, which has been shown to possess antitumor effect by in vitro and in vivo study. However, the underlying molecular mechanism that whether GA inhibits tumor angiogenesis remains not well understood. In this study, we investigated the effects of GA on expression of HIF-1α, and its downstream target gene vascular endothelial growth factor (VEGF) in human MM U266 cells. We found that hypoxia induced increase in the level of HIF-1α subunit protein and activated the PI3K/Akt/mTOR pathway. Moreover, the treatment with GA markedly decreased HIF-1α and VEGF expression under hypoxic condition. Mechanistic studies exhibited that GA inhibited the production of HIF-1α by reducing phosphorylation of Akt and mTOR in U266 cells. Furthermore, in vivo study revealed that intravenous injection of GA once every other day for two weeks could suppress tumor volumes by antiangiogenesis activity. Taken together, our results identify GA suppress hypoxia-activated pathways that linked to MM progression, at least partly, by the inhibition of PI3K/Akt/mTOR signaling pathway. Therefore, GA may be a new potent therapeutic agent against human MM cells.

Disclosures
No relevant conflicts of interest to declare.
Effect of DMSA Modified Fe3O4 and Multidrug Resistance Modulator HZ08 on the Reversal of Multidrug Resistance in K562/A02 Cell Line
Authors: Shen Fei , Zhou Mingfei , Lu Xuzhang , Chen Yanping , Chen Baoan 
Published: October 2019

Abstract
The objective of the present study was to investigate the reversible effect of HZ08 and daunorubicin(DNR) combined with dimercaptosuccinic acid modified iron oxide (DMSA-Fe3O4) magnetic nanoparticles (MNPs) in human chronic leukemia cell line K562/A02, and the mechanism potentially involved. The growth inhibition rate of K562/A02 cells was determined by Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis and intracellular concentration of DNR were detected by flow cytometry (FCM). DAPI staining was used to view apoptotic cellular morphology. Subsequently, transcription levels of MDR1 mRNA and expression levels of P-glycoprotein (P-gp) and caspase-3 were determined by real time polymerase chain reaction (real-time PCR) and Western blotting analysis, respectively. group clearly exhibited more morphological changes (severe structural alterations) than other groups. In addition, transcription of MDR1 gene and protein expression of P-gp and caspase-3 of K562/A02 cells were regulated at the most remarkable extent in DNR-HZ08-MNPs group when compared with other groups. These findings suggest that the remarkable effects of the novel DNR-HZ08-MNPs on multidrug resistant K562/A02 leukemia cells would be a promising strategy for overcoming multidrug resistance.

Disclosures
No relevant conflicts of interest to declare.
Small Molecule ONC201/TIC10 Induces Caspase-Dependent Apoptosis in Acute Lymphoblastic Leukemia Cells Via Modulation of Bcl-2 and IAP Family Proteins
Authors: Prabhu Varun Vijay , Lulla Amriti R. , Wagner Jessica M , Hernandez-Borrero Liz J. , Talekar Mala K. , Kline Christina L. , Dicker David T. , Barth Brian M , Pu Jeffrey J. , Claxton David F. , Allen Joshua E. , El-Deiry Wafik S. 
Published: October 2019

Abstract
ONC201/TIC10 is a potent small molecule anti-tumor agent in several types of solid tumors and lymphomas. ONC201/TIC10 is on track to enter clinical trials for patients with advanced cancer in 2014, with IND issued by the FDA in March, 2014. Early trials will evaluate the safety and efficacy of ONC201/TIC10 as a monoagent in hematological malignancies. In the current study, we evaluated the anti-cancer effects of the small molecule in Acute Lymphoblastic Leukemia (ALL). Analysis of cell viability by the CellTiter-Glo method revealed that ONC201/TIC10 treatment reduces the viability of three ALL cell lines (Reh, Jurkat, MOLT-4) in a dose- (2.5/5/10 μM) and time-dependent manner (24/48/72 h). We have previously reported that ONC201/TIC10-mediated reduction in cell viability and apoptosis in various types of solid tumors occurs at 60/72 h. Interestingly, ONC201/TIC10 reduces the viability of ALL cell lines within 24/48 h at the indicated doses. An inactive TIC10 isomer compound synthesized by Medkoo Biosciences with a structure related to the active ONC201/TIC10 compound does not reduce the viability of ALL cells. Sub-G1 analysis indicated that ONC201/TIC10 induces apoptosis in ALL cells and a pan-caspase inhibitor reduces ONC201/TIC10-mediated apoptosis. Western blot analysis was used to further investigate the mechanism of ONC201/TIC10-mediated apoptosis. ONC201/TIC10-mediated apoptosis involves PARP cleavage and caspase-9 activation. Anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-xl are downregulated while the pro-apoptotic Bcl-2 family member Bim is upregulated in response to ONC201/TIC10 treatment. ONC201/TIC10 also downregulates the inhibitor of apoptosis (IAP) family proteins cIAP1 and cIAP2. We have previously shown that the anti-tumor effect of ONC201/TIC10 involves inhibition Akt and ERK phosphorylation resulting in Foxo3a activation and TRAIL-gene transcription. We observed inhibition of Akt phosphorylation upon ONC201/TIC10 treatment of ALL cells. Thus, ONC201/TIC10 holds promise as a novel agent for the treatment of ALL based on its robust activity in preclinical models of the disease. Our ongoing studies are evaluating the impact of this novel therapy on ALL cells with different translocations, and are introducing combination therapy with ONC201/TIC10 for ALL.
Figure 1 Figure 1.

Disclosures
Allen: Oncoceutics: Employment, Equity Ownership, Patents & Royalties. El-Deiry:Oncoceutics, Inc.: Equity Ownership, Patents & Royalties.
The Outcome of Childhood Acute Lymphoblastic Leukemia with MLL Gene Rearrangement Treated with the Protocol (CCLG-ALL2008)
Authors: SUN Yina , Chai Yi-huan , He Hai-long , LU Jun , WANG Yi , Zhao Wen-li , Xiao Pei-fang , Fan Jun-jie , Hu Shaoyan 
Published: October 2019

Abstract
Objective: MLL gene rearrangement in pediatric acute lymphoblastic leukemia (ALL) was regarded as high risk factor because of the poorer outcome of overall survival(OS). Some reports further proved that patients with MLL/AF4 had the worse outcome than MLL rearranged with other partners. CCLG-ALL2008 protocol has been carried out in China for more than 5 years. However, there was no reports to evaluate its efficiency on pediatric ALL patients with MLL rearrangement. In this study, we analyzed the data of ALL patients to compare the outcome of patients with MLL rearrangement positive and negative treated by CCLG-2008 protocol.
Methods During the period from 2009 to 2013, 379 patients were enrolled in this protocol, of which 19 cases were MLL rearrangement positive and treated with CCLG-ALL2008 protocol for high-risk (HR) group. The treatment efficiency was evaluated on the time points of day 7, day15, day 33 and 12th week after treatment, respectively. OS and treatment-related mortality (TRD) was calculated within high risk groups of MLL positive and negative.
Results Patients with MLL rearrangement positive accounted for 5.01% of all patients. The characteristics and response to the treatment were illustrated in Table 1. Cases younger than 2 years old, with initial white blood cell (WBC) 50*109/L , or MRD more than 10-2 on day 33 had a lower OS (P<0.05). Compared with high risk group with MLL negative, MLL rearrangement positive group didn't show any statistic difference in the recurrence rate, TRD, and 5 years event-free survival (EFS)(P>0.05). Compared with the male, female patients had a better 5 year EFS (100% versus 50%±17%, P<0.05) (Figure 1). Age did matter in MLL rearrangement positive group, older than 2 years cases had a better 5 years EFS than those younger than 2 years old (86%±11% versus 27%±11%, P<0.05) (Figure 2). Multivariate COX regression analysis found that prednisone response on day 7 has impacted a role on OS (P<0.05). Other factors such as gender, age (older than 2 years), WBC count, MLL fusion partners, and MRD on day 15 and day 33 and week 12th didn't show statistic influence on OS in ALL patients with MLL gene rearrangement treated by the protocol of CCLG-ALL2008.
Conclusion Factors including female, older than 2 years of age, sensitivity to prednisone, are good prognostic index in predicting the outcome of 5 years of OS and EFS in childhood ALL with MLL gene rearrangement.
Table 1 Clinical and laboratory characteristics of ALL patients with MLL positive Table 1. Clinical and laboratory characteristics of ALL patients with MLL positive
Figure 1 Gender exerts influence on 5 years EFS in MLL rearrangement group Figure 1. Gender exerts influence on 5 years EFS in MLL rearrangement group
Figure 2 Figure 2. Age influenced 5 years EFS in MLL rearrangement group

Disclosures
No relevant conflicts of interest to declare.
Low-Dose Arsenic Trioxide Combined with Aclacinomycin a Synergistically Enhance the Cytotoxic Effect on Human Acute Myelogenous Leukemia KG-1a Cell Line By the Induction of Apoptosis
Authors: Ye Yongbin , Xu Xiaojun , Zhang Mingwan , Qiu Dafa , Bai Xiaochun , Wang Jing , Weng Guangyang , Ruiqing Zhou , Guo Ziwen , He Huiqing , Yi Wenfang , He Xin , Kunyuan Guo 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is a kind of common disorder in the elderly. Although remarkable progress has been made in the treatment of this deadly disease over the past few decades, the outcome remains poor. While conventional chemotherapy may be effective for some elderly patients, the vast majority do not tolerate intensive conventional treatment well, thus the development of a more effective method to overcome this problem is necessary. Aclacinomycin A (ACM), an antitumor antibiotic, was used to treat various tumors including AML. However, its high toxicity limits its clinical application. Previous studies reported that arsenic trioxide (As2O3) has shown substantial efficacy in treating patients suffering from AML. However, the molecular mechanisms of As2O3-induced cytotoxic effect of AML cells are not yet fully known. The aim of this study was to investigate the synergistic cytotoxic effect of low-dose As2O3 combined with ACM on human KG-1a cells and to clarify the possible mechanism underlying this combination treatment. Our results showed that As2O3 or ACM inhibited proliferation of KG-1a cells in a time- and dose-independent manner. In the flow cytometric analysis, the low-dose of the matched combination treatment induced a more prominent apoptosis than the single agent-treated groups. Furthermore, western blot analysis showed that the combination treatment decreased Bcl-2 expression and increased caspase-3 expression more significantly than the single drug treatments. More importantly, we showed that the combination index (CI) values were < 1 in all matched combination groups analyzed by compusyn software. In conclusion, our data showed that low-dose As2O3 combined with ACM showed a more prominent cytotoxic effect than single agent treatment on KG-1a cells. These results may provide a high efficiency but low-toxicity therapeutic benefits for AML.

Disclosures
No relevant conflicts of interest to declare.
High Expression of Mir-15a Predicts Shorter Survival and Worse Response to Chemotherapy in Patients with Acute Myeloid Leukemia (AML)
Authors: Butrym Aleksandra , Baczynska Dagmara , Tukiendorf Andrzej , Rybka Justyna , Dobosz Tadeusz , Jurczak Wojciech , Kuliczkowski Kazimierz , Mazur Grzegorz 
Published: October 2019

Abstract
Background: MicroRNAs (miRNAs) are small non-coding RNA molecules, that control gene expression by targeting messenger RNA (mRNA), via degradation or suppression of translation. Aberrant expression of microRNAs (miRs) has been proved to have a role in acute myeloid leukemias (AML)
The aim of the study was to determine expression of miR-15a in acute myeloid leukemia patients before and after chemotherapy and its influence on patient clinical outcome.
Methods: miRNAs from isolated leukemic cells were extracted using mirVanaTM miRNA Isolation kit (Ambion Inc., Carlsbad, CA, USA) following the manufacturer's protocol. Reverse transcriptase (RT) reactions were performed for mature miRNA cDNA synthesis in separate tubes using specific stem-loop RT primers and TaqMan® MicroRNATM Reverse Transcription kit (Applied Biosystems, Foster City, CA, USA). After microRNA isolation, reverse transcriptase reactions were performed, followed by cDNA amplification. The relative amount of microRNA-15a was normalized according to the reference RNU48 level. Results were considered statistically significant with p-value < 0.05.
Results: 95 patients (aged 60.2 ± 15.0, 22–90, Male = 61%) with newly diagnosed AML were included into the study. Samples of the bone marrow for miR-15a expression analysis were collected before start of chemotherapy and repeated after completed induction chemotherapy (40 patients). A control group of 20 matched patients was also taken into account. The analyzed group consisted of: 7 patients with AML M0, 34 had M1, 29 had M2, 14 had M4 and 11 had M5.
AML patients has higher miR-15a expression than control group (p=0.005633). The risk of death in AML patients was higher in patients with higher miR-15a expression on diagnosis (p=0.0430), Fig.1. Patients with lower miR-15a expression were more likely to achieve complete remission after induction chemotherapy (p=0.0130). After successful chemotherapy we observed significant drop in miR-15a expression.
Conclusions: We proved that miR-15a was upregulated in AML patients and its expression influenced remission achieving and death risk.
Figure 1. Survival of AML patients depending on miR-15a expression. Figure 1. Survival of AML patients depending on miR-15a expression.

Disclosures
No relevant conflicts of interest to declare.
Hodgkin’s Disease (1975-2012): Long-Term Results of a Single Center
Authors: Celkan Tiraje , Özdemir Gül Nihal , Akı Hilal , Apak Hilmi , Özkan Alp , Hallaç Metin , Adaletli İbrahim , Özcan Rahşan , Ergen Şefika Arzu , Yıldız İnci 
Published: October 2019

Abstract
Aim: To investigate the clinical features, diagnostic and treatment results and long-survival of children with HL at a single center in Turkey.
Methods: Retrospective data were extracted from medical records of children (<18 years old) diagnosed and treated for HL between 1975 and 2012 at Istanbul University, Cerrahpasa Medical Faculty.
Results: Twohundred-fortyeight patients (M/F: 1.8) were identified for analysis. Mean age at diagnosis was 10 years. Four-percent were stage 1, 43% were stage 2, 34% were stage 3 and 17% were stage 4 at diagnosis. B symptoms were present in 105 children (42%). Mixed cellular was the most common subtype (50%) followed by nodular sclerosis. MOPP regimen was primarily used until 1989 along with extended field radiotherapy (30-40 Gy) after 1989 ABVD with involved field RT (20-25 Gy) was the treatment of choice. Onehundred-fortyseven patients (42%) had radiotherapy. Median follow-up time was 14.3 years (range: 5 months-38 years). PET was used for assessment in 45 cases. Ten year overall survival rate was 99%. Ten year event free survival rate (EFS) was 90%. Univariate analysis showed that stage, histological subtype, presence of B symptoms and hematological parameters were not related to OS while treatment regimen correlated. Twenty-six patients relapsed and 17 patients expired on follow-up. Ten patients who relapsed were treated with autologous stem cell transplantation, 3 of them relapsed again and were treated with brentixumab. Secondary tumours developed in 4 patients (1.6%). One had AML, 1 osteosarcoma, 1 thyroid papillary cancer and 1 had craniopharyngioma.
Conclusion: Ethnic and regional differences in the epidemiology and pathological aspects of HL may be associated with differences in clinical features and prognosis however we found that clinical features and treatment outcomes are similiar in Turkish patients. Our results showed that hematological parameters and B symptoms were not significant prognostic parameters.

Disclosures
No relevant conflicts of interest to declare.