bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Herbicide Isoproturon Induces Activation-Induced Cytidine Deaminase Expression in Germinal Center B Cells
Authors: Leeman-Neill Rebecca J , Johnson Daniel E , Swerdlow Steven H 
Published: October 2019

Abstract
Several epidemiologic studies have demonstrated an increased risk of non-Hodgkin B cell lymphoma with exposure to pesticides, including herbicides, fungicides and insecticides. Few studies have specifically demonstrated an increased risk for follicular lymphoma in individuals exposed to pesticides. The molecular mechanisms of these associations have not been fully investigated. Activation-induced cytidine deaminase (AID), which physiologically mediates somatic hypermutation in germinal center B cells, has been found to have off-target effects that play an important role in oncogenic mutagenesis driving germinal center type B cell lymphomas. Elevated levels of AID among peripheral blood mononuclear cells has been found to be associated with higher numbers of circulating follicular lymphoma-like cells in individuals exposed to pesticides. Increased AID expression and/or activity represents a possible mechanistic link between pesticide exposure and lymphomagenesis.
In order to test the hypothesis that pesticides might lead to an increased risk of germinal center neoplasia by increasing AID levels, four pesticides including isoproturon (a phenylurea herbicide), chlorpyrifos (an organophosphate insecticide), DDT (an organochlorine insecticide), and lindane (an organochlorine insecticide), were screened for their ability to increase AID expression in germinal center type B cells (Ramos and Raji, Burkitt lymphoma cell lines). After 48 hours of treatment with concentrations ranging from 50-200 μM, RNA was extracted, reverse transcribed and cDNA subject to SYBR green Realtime PCR amplification of AID.
AID was found to be expressed, at low levels, in untreated Ramos and Raji cells, compared to acute myeloid leukemia cell lines HL60 and U937, which served as negative controls showing no AID expression. Isoproturon treatment resulted in a dose dependent, up to 6-fold, increase in AID in Ramos cells. A smaller, up to 1.9 fold increase was seen in Raji cells. None of the other pesticide treatments resulted in increased expression of AID (Fig. 1).
The findings demonstrate that AID expression is induced by isoproturon, a member of the class of phenylurea herbicides which is among the most commonly used herbicides worldwide and generally considered to be relatively safe for humans. These results support a possible role for off-target AID activity in pesticide-exposure related lymphomagenesis. Future studies will investigate the mechanism by which AID is upregulated andwhether or not there is induction of oncogenic mutagenesis in germinal center B cells exposed to phenylurea herbicides.

Disclosures
No relevant conflicts of interest to declare.
Mir-155 Enhances B-Cell Lymphoma Growth By Targeting TBRG1
Authors: Kluiver Joost , Slezak-Prochazka Izabella , Winkle Melanie , Visser Lydia , Diepstra Arjan , Kroesen Bart-Jan , Van den Berg Anke 
Published: October 2019

Abstract
Several studies have indicated an important role for miR-155 in the pathogenesis of B-cell lymphoma. Highly elevated levels of miR-155 were indeed observed in most B-cell lymphomas with the exception of Burkitt lymphoma (BL). However, the molecular mechanisms that underlie the oncogenic role of miR-155 in B-cell lymphoma are not well understood. To identify the miR-155 targets relevant for B-cell lymphoma, we performed RNA immunoprecipitation of Argonaute 2 in Hodgkin lymphoma (HL) cells upon miR-155 inhibition and in BL cells upon ectopic expression of miR-155. We identified 54 miR-155-specific target genes in BL cells and confirmed miR-155 targeting of DET1, TBRG1 (NIAM1), TRIM32, HOMEZ, PSIP1 and JARID2. Five of these targets are also regulated by endogenous miR-155 in HL cells. Both overexpression of miR-155 and inhibition of expression of the miR-155 target gene TBRG1 increased proliferation of BL cells. In primary B-cell lymphoma TBRG1-positive cases have significant lower levels of miR-155 as compared to TBRG1-negative cases, suggesting that TBRG1 is also regulated by miR-155 in primary B-cell lymphoma. Thus, our data indicate that miR-155 plays an oncogenic role in B-cell lymphoma by targeting the tumor suppressor TBRG1.

Disclosures
No relevant conflicts of interest to declare.
Targeting Reptin Function in Acute Myeloid Leukaemia
Authors: Armenteros-Monterroso Elena , Zhao Lu , de Boer Jasper , Williams Owen 
Published: October 2019

Abstract
Acute myeloid leukaemia (AML) is characterized by the rapid growth of immature white blood cells, which accumulate in the bone marrow and are not able to differentiate into normal functioning cells. Despite recent advances in AML therapy, cytogenetically defined subgroups with poor prognosis are still prevalent. Chromosomal translocations, which encode abnormal fusion proteins, are common in patients with AML, and the MLL (Mixed Lineage Leukaemia) locus is the most frequently rearranged in paediatric AML. Previous studies in our laboratory used global gene expression analysis in conditionally immortalized MLL-rearranged mouse myeloid cells to demonstrate that the Reptin gene was positively regulated by MLL-fusion genes. Reptin (also known as RUVBL2), together with its related family member Pontin (also known as RUVBL1), functions as part of multi-protein complexes involved in chromatin remodelling, DNA repair, regulation of transcription and ribonucleoprotein assembly. Further work in our laboratory found Reptin to be essential for sustaining the hyperproliferative state and clonogenic potential, as well as suppressing apoptosis, of human AML cells, both MLL-rearranged and non-MLL rearranged. Here, we present our recent data, investigating the transcriptional pathways regulated by Reptin in order to identify clinically approved drugs that can modulate these pathways, and using xenotransplantation assays to establish the efficacy of targeting Reptin in vivo. Our preliminary results indicate that Reptin regulates the function of the oncoprotein c-MYC in human AML cell lines and represents an exciting novel candidate target for the therapy of human AML.

Disclosures
No relevant conflicts of interest to declare.
Clinical Significance of Soluble Interleukin-2 Receptor in Patients with Acute Leukemia
Authors: Wang Dongjiao , Wang Jujuan , Qiu Hongxia , Duan Limin , Tian Tian 
Published: October 2019

Abstract
Objective: Investigate the expression level and clinical significance of serum soluble interleukin-2 receptor (sIL-2R, sCD25) in patients with acute leukemia.
Methods: Serum sCD25 level were measured using enzyme linked immunosorbent assays (ELISA) in 97 acute leukemia patients and 10 healthy contrlols. Clinical and laboratory features, including bone marrow cellularity, white blood cell count (WBC), platelets (PLT), lactate dehydrogenase (LDH), serum ferritin (SF), erythrocyte sedimentation rate (ESR), as well as overall survival (OS) data were collected.
Results: (1) Serum sCD25 level of the newly diagnosed leukemia group was significantly higher than that of the control group (P<0.0001). (2) Among the newly diagnosed AML patients, serum sCD25 level of the M3 group was significantly lower than that of the M2 or non-M2/M3 group (P<0.05). In addition, serum sCD25 level of the low/intermediate risk (AML) or standard risk (ALL) group was lower than that of the high risk group (P<0.05). (3) Serum sCD25 level of the complete remission (CR) group was significantly lower than that of the newly diagnosed group (P<0.002). However, no significant decrease was found in serum sCD25 level of the relapsed/refractory group compared to that of the newly diagnosed group. (4) Serum sCD25 level in newly diagnosed patients was positively correlated with peripheral WBC, LDH and SF. (5) Furthermore, although OS of the low sCD25 level group (sCD25<2000pg/ml) was not significantly different compared to the intermediate sCD25 level group (2000≤sCD25≤4000pg/ml) (P=0.532), both that of the low or intermediate sCD25 level group were significantly superior to that of the high sCD25 level group (sCD25>4000pg/ml) (P<0.05).
Conclusion: Serum sCD25 levels have important clinical significance in evaluating disease activity, treatment outcomes and prognosis in patients with acute leukemia.

Disclosures
No relevant conflicts of interest to declare.
Secondary Central Nervous System (CNS) Involvement in Patients Diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) during the First Line R-CHOP Treatment and after the End of Treatment
Authors: Romejko-Jarosinska Joanna , Osowiecki Michal , Ostrowska Beata , Kotarska Martyna , Domanska-Czyz Katarzyna , Szymanski Marcin , Targonski Lukasz , Borawska Anna , Druzd-Sitek Agnieszka , Paszkiewicz-Kozik Ewa , Poplawska Lidia , Rymkiewicz Grzegorz , Walewski Jan 
Published: October 2019

Abstract
Background: Secondary central nervous system (CNS) involvement is an unfavorable risk factor with an impact on overall survival (OS) in malignant lymphoma.
Methods: We conducted a retrospective analysis of secondary CNS involvement in patients diagnosed with Diffuse Large B-Cell lymphoma (DLBCL) on the first line treatment and after the end of treatment. We collected data on 361 patients diagnosed with DLBCL.
Results: The median age (range) was 66 (17-91) years. All patients received first-line R-CHOP21 (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone) between 2006-2011. Patients with primary involvement of testis, nasopharynx, orbit and CNS received CNS prophylaxis with 15 mg methotrexate intrathecally (IT). Secondary CNS involvement was confirmed in 18 (4.9%) patients which stands for 24.6% (18/73) patients with relapsed lymphoma. Median time from first R-CHOP to lymphoma relapse was 10 months (range 3-33). CNS involvement in first 12 months of treatment was 3.9% (95% CI: 1.8%, 5.8%). Median (range) OS from diagnosis of CNS involvement was 3 (3-79) months. Clinical stage III/IV, IPI 4, breast, 2 or more extranodal sites and NCCN-IPI unfavorable site involvement increased the risk of CNS involvement. Three patients who had received methotrexate IT prophylaxis had CNS involvement at relapse. No patient with primary testis involvement had CNS relapse.
Conclusion: Less than 5% of patients had secondary CNS involvement on first line treatment and after end of treatment. Advanced stage, high-risk IPI, 2 or more extranodal sites of involvement increased the risk of CNS involvement after first-line treatment for DLBCL. CNS prophylaxis appears effective in patients with primary testicular lymphoma

Disclosures
Walewski: Karyopharm: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodation, Research Funding; Celgene: Honoraria, Other: travel, accommodation, Research Funding; Gilead: Consultancy, Honoraria, Other: travel, accommodation; Takeda: Consultancy, Honoraria, Other; Ariad: Consultancy; Janssen-Cilag: Consultancy; Mundipharma: Consultancy, Honoraria, Research Funding; Genetics: Other: travel, accommodation; Teva: Consultancy, Honoraria; Seattle: Other: travel, accommodation; GSK/Novartis: Research Funding; Boehringer Ingelheim: Consultancy; Sanofi: Honoraria, Other: travel, accommodation; Servier: Consultancy.
Characteristics of the TCR Vbeta Repertoire and Identical Clonally Expanded T Cells in Chronic Myeloid Leukemia Patients in Advanced Phase with ABL Mutations
Authors: Xu Ling , Lu Yuhong , Lai Jing , Yu Wei , Jin Zhenyi , Xu Yan , Chen Jie , Zha Xianfeng , Chen Shaohua , Yang Lijian , Li Yangqiu 
Published: October 2019

Abstract
Abstract
Tumor specific or related antigen cytotoxic lymphocyte (CTL) have been identified in chronic myeloid leukemia patients, however, whether they are constituted by specific type of T cell receptor chains has not been illustrated so far. Previous studies have reported abnormal TCR repertoires and clonally expanded TCR Vβ T cells in chronic myeloid leukemia in chronic phase (CP-CML). In this study, we investigated the distribution and clonality of the TCR Vβ repertoire in 5 CML patients in blast crisis (BC-CML) and one in acceleration phase (AP-CML) with ABL kinase domain mutations (KDMs) including T315I, E255K, F317L+S417Y, Y-253F and L387M+T-315A. Examination of TCR Vβ expression and clonality was performed by reverse transcription-polymerase chain reaction (RT-PCR) combined with GeneScan analysis. Significantly skewed TCR Vβ repertoires were observed in those patients, and 4 to 8 oligoclonally expanded TCR Vβ subfamilies could be identified in each sample, which distributed in 15/24 different subfamilies (TCR Vβ4, Vβ5, Vβ6, β8, Vβ9, Vβ10, Vβ15, Vβ16, Vβ17, Vβ18, Vβ19, Vβ21, Vβ22, Vβ23, Vβ24). Intriguingly, a relatively highly expanded Vβ9 clone with the same length as CDR3 (139 bp) was found in all three CML patients in lymphoid blast crisis (LBC-CML) who had different KDMs, but the clone was not detected in the other two CML patient in myeloid blast crisis (MBC-CML) or the one CML patients in accelerated phase. In conclusion, restricted TCR Vβ repertoire expression and decreased clone complexity was a general phenomenon in the BC-CML patients with different KDMs, indicating the T-cell immunodeficiency status of these patients, and clonally expanded Vβ9 T cell clones may represent a specific immune response to leukemia-associated antigens in LBC-CML patients.

Disclosures
Li: The Foundation for High-level Talents in Higher Education of Guangdong, China ([2013]246-54),and the Guangzhou Science and Technology Project Foundation (201510010211): Research Funding; National Natural Science Foundation of China (81270604, U1301226, and 81400109), the Guangdong Natural Science Foundation (S2013040016151 and S2013020012863): Research Funding.
A Phase II, Open-Label Pilot Study to Evaluate the Hematopoietic Stem Cell Mobilization of TG-0054 Combined with G-CSF in 12 Patients with Multiple Myeloma, Non-Hodgkin Lymphoma or Hodgkin Lymphoma - an Interim Analysis
Authors: Setia Gayatri , Hagog Nabil , Jalilizeinali Bita , Funkhouser Sharon , Pierzchanowski Loretta , Lan Fengshuo , Gabig Theodore G. , Kiner-Strachan Bonnie , Kelleher Karen , Hsu Ming-Chu , Chang Li-Wen , Schuster Michael W. 
Published: October 2019

Abstract
Background: TG-0054 (burixafor) is a potent and selective antagonist of human chemokine receptor CXCR4 that inhibits the binding of stromal-derived factor 1 (SDF-1). Interruption of the CXCR4/SDF-1 interaction prevents sequestration of CD34+ stem cells to the bone marrow and subsequently mobilizes these cells into the peripheral blood within 1 to 3 hours of drug administration.
Materials and Methods: An open-label, phase II pilot trial was conducted in patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), or Hodgkin's lymphoma (HL) to evaluate the safety and stem cell mobilization of TG-0054 in combination with G-CSF. We planned to treat twelve patients with subcutaneous injections of 10 µg/kg/day G-CSF in the afternoon for 4 days. On the morning of Day 5, patients received 3.14 mg/kg TG-0054 and underwent large volume (18-24L) leukapheresis approximately 2 hours post-drug infusion. Patients were allowed by protocol to undergo leukapheresis for 1-5 days to obtain the predetermined target of ≥5.0 x 106 CD34+ cells/kg. 9 of 12 patients have been treated thus far with a plan to treat 3 additional patients.
Results: A planned interim analysis revealed that6 of the 9 patients treated thus far collected more than 10 x 106 CD34+ cells/kg in 1 leukapheresis session. 2 patients required 2 days to achieve the study endpoint, and 1 outlier patient who had received Revlimid only 1 week prior to peripheral blood CD34 analysis failed to mobilize stem cells until he was allowed 2 more weeks to recover from his Revlimid treatment. Burixafor was well tolerated, and there were no adverse events that were attributed to the drug. All of the patients engrafted promptly after melphalan (7 patients) or BEAM (2 patients) conditioning regimens.
Conclusion: Burixafor in combination with G-CSF is a potent and well-tolerated mobilizer of stem cells into the peripheral blood, and with the exception of 1 outlier, was able to mobilize >5.0 x 106 CD34+ cells/kg in 1-2 leukapheresis sessions in all patients treated thus far (median 1 day). This contrasts with our historical controls that required a median of 2-3 days to achieve a collection of ≥5.0 x 106 CD34+ cells/kg. A total of 12 patients will be treated on this pilot study. These encouraging results warrant the further testing of this drug in a larger randomized clinical trial.

Disclosures
Hsu: Taigen Biotechnology: Employment. Chang:Taigen Biotechnology: Employment. Schuster:Taigen Biotechnology: Research Funding.
Prognostic Implications of Abdominal Computed Tomography at Diagnosis in Patients with Polycythemia Vera or Essential Thrombocythemia
Authors: Song Ik Chan , Lee Jeong Eun , Choi Yoon Seok , Moon Ji Young , Lee Hyo Jin , Yun Hwan Jung , Kim Samyong , Baek Seung Woo , Shin Kyung Sook , Jo Deog-Yeon 
Published: October 2019

Abstract
Background: To our knowledge, no reports have examined the clinical significance of splenomegaly measured using computed tomography (CT) in patients with polycythemia vera (PV) or essential thrombocythemia (ET). This study retrospectively analyzed abdominal CT in PV and ET patients to determine the prognostic role of splenomegaly on CT at diagnosis.
Methods: This study enrolled patients who were newly diagnosed with PV or ET between 2005 and 2014 at Chungnam National University Hospital. Spleen volume was estimated by measuring the caudocranial dimension and maximum size and thickness in the axial plane on cross-sectional images (Prassopoulos et al. Eur Radiol 1997;7(2):246-8).
Results: In total, 46 patients were diagnosed with PV and 73 with ET; abdominal CT was performed at diagnosis in 38 (82.6%) PV patients and 45 (61.6%) ET patients. The International Working Group for Myeloproliferative Neorplams Research and Treament (IWG-MRT) risk score and International Prognostic Score for ET (IPSET) were well applied to these patients group. In the PV group, there were no significant differences in clinical features or laboratory findings between patients who did or did not undergo CT. In the ET group, patients who underwent abdominal CT had lower hemoglobin and hematocrit levels, and were less likely to have a history of thrombosis than those who did not. Splenomegaly was observed in 29 (73.7%) patients with PV and 18 (40.0%) patients with ET. Splenomegaly greater than twice the normal value was observed in 11 (28.9%) PV patients and 4 (8.9%) ET patients. In the PV group, patients with splenomegaly on CT had significantly higher leukocyte and lactate dehydrogenase (LDH) levels than patients without splenomegaly. Splenomegaly more than twice the normal value were not observed in PV patients over 67 years old; in younger patients, PV patients with splenomegaly greater than twice the normal value had lower overall survival than those with smaller spleens (p = 0.02). In the ET group, patients with splenomegaly on CT had higher hemoglobin, hematocrit, leukocyte, and LDH levels than did patients without splenomegaly, but there was no difference in their overall survival (p = 0.643).
Conclusion: These results indicate that splenomegaly measured by abdominal CT might be useful for predicting prognosis in patients with PV.

Disclosures
Jo: Alexion Pharmaceuticals: Research Funding.
LOXL2 Highly-Expressed Induce the Transition of Stromal Cells into Cancer-Associated Fibroblasts Which Maybe Involve in Myeloproliferative Neoplasms Progession
Authors: Xu Na , Li Yuling , Zhou Xuan , Li Lin , Lu Qisi , Liu Qifa , Xiaoli Liu 
Published: October 2019

Abstract
Backgroud and objective: Myeloproliferative neoplasms (MPNs) are malignant disorders by proliferation of one of the myeloid lineages and characteristically show an increase in bone marrow reticulin reticulin-fibrosis.Lysyl oxidases like-2(LOXL2) is copper-dependent amine oxidases that play a critical role in the biogenesis of connective tissue by crosslinking extracellular matrix proteins, collagen and elastin,and Cancer associated-fibroblasts (CAFs) are major mediators in tumor microenvironment. Studies found that loxl2 stimulate CAFs grouth solid tumor,and the expression of LOXL2 is increased in MPN patients,espessionly in PMF patients.Here, we want to evaluate whether the expression of higher LOXL2 associated to CAFs during various MPN progression.
Patients and methods: We compared normal bone marrows and those from patients with chronic myeloid leukemia(CML)(include CML-CP n=20,CML-BC n=13),polycythemia vera(PV)(n=18), essential thrombocythemia(ET) (n=23), and primary myelofibrosis (PMF) (n=8). We detected α-smooth actin and reticulin protein by immunohistochemical staining, examined LOXL2 expression by western blot in bone marrow and ELIZA kit in serum.
Results: LOXL2 was not detected in normal bone marrows and serum.The level of LOXL2 gene is over expressed in PMF (p<0.01) and CML-BC (p=0.02). In other MPNs a differential pattern of expression were statistically significant (P< 0.010).The level of LOXL2 expression associated with reticulin protein expression in bone marrow, especially if reticulin protein expressed higher than 2+(p=0.01).
We detected α-smooth actin positive stromal cells in CML-BC and PMF patients,and the level of LOXL2 expression is related to α-smooth actin positive stromal cells(p<0.05).we also detected α-smooth actin after co-cultured mesenchymal stem cell(MSCs) with sLOXL2 for 96 hour.
Conclusion: Higher level of LOXL2 could be promote MPN progression by modulating several functions of surrounding stromal cells which acquire features of cancer-associated fibroblasts involved in the pathogenesis of MPN. These findings maybe used as the basis for future targeted therapy directed against MPN progression.

Disclosures
No relevant conflicts of interest to declare.
Epidemiology Data of Patients with Chronic Lymphocytic Leukemia in West Central Mexico
Authors: Campos-Cabrera Virgina , Campos-Cabrera Gregorio , Campos-Cabrera Salvador , Rivera-Trujillo Alicia , Hernandez-Rodriguez Sonia , Gomez-Guijosa Miguel-Angel , Mora-Torres Maria , Pedraza-Colin Maria-Luisa , Cuin-Macedo Sergio , Pita-Ramirez Luis , Campos-Villagomez Jose-Luis 
Published: October 2019

Abstract
Background: chronic lymphocytic leukemia (CLL) is a rare disease in Mexican mestizos (Br J Haematol 2015;169:909-911 and Int J Hematol 1999;69:253-255). No significant data on epidemiology is available.
Methods: epidemiological data from samples referred to Laboratorios Fatima de Michoacan for flow cytometry immunophenotyping for neoplastic hematological disease.
Results: 229 samples were received, 52 were diagnosed as CLL (22.7 %). Male 32 and female 20, ratio 1.6 a 1. Age from 33 to 89 years, average 66; 31 to 40 one, 41 to 50 two, 51 to 60 eleven, 61 to 70 twenty four, 71 to 80 ten, more than 81 four. Expression of CD 38 and ZAP-70 in three; only CD38 in 2, only ZAP-70 in three.
Conclusions: similar results in male female ratio and age of presentation are noted as compared with international data. Low frequency of expression in CD38 and ZAP-70 may be due pre-analytic phase in the management of the sample. As a regional group we are trying to have epidemiology data in non-malignant and malignant hematological diseases to form specific protocol treatments.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.