bluuebunny/crossref_metadata_2025_split huggingface dataset:
PS982 THE ROLE OF STAT3 ISOFORMS IN ACUTE MYELOID LEUKEMIA
Authors: Aigner P. , Mizutani T. , Horvath J. , Just V. , Sill H. , Grebien F. , Moriggl R. , Casanova E. , Stoiber D. 
Published: June 2019

Background:Signal transducer and activator of transcription 3 (STAT3) plays a central role in proliferation, differentiation and oncogenic transformation. It is expressed in two alternatively spliced isoforms, STAT3α and truncated STAT3β, which lacks the C‐terminal transactivation domain and instead carries seven unique amino acids. Interestingly, STAT3β recently gained attention as a powerful anti‐tumorigenic molecule and protective prognostic marker. This has been shown in patients with esophageal squamous cell carcinoma as well as in mouse models for breast, skin and colon cancer. Deregulated STAT3 signaling is frequently observed in leukemogenesis and generally associated with a poor clinical outcome in patients with acute myeloid leukemia (AML). In addition, it has been shown that the expression ratios of STAT3α and STAT3β change upon myeloid differentiation. However, the exact role of STAT3β in AML patients and during disease progression remains unknown.Aims:The goal of our study is to analyze the contribution of the two STAT3 isoforms to leukemogenesis with a particular focus on STAT3β in AML development.Methods:We analyzed more than 50 AML patient samples for STAT3β/STAT3α mRNA expression levels and its correlation with clinical prognosis and overall survival. Furthermore, we generated an inducible Stat3β transgenic mouse model and crossed it with Pten‐deficient mice, a previously described model for AML. In addition, we used fetal liver‐derived stem cells from Stat3β transgenic mice, transduced with a retrovirus encoding for the MLL‐AF9 translocation, in a transplant model for AML.Results:We observed a correlation between clinical prognosis and STAT3β/STAT3α expression ratio. A higher STAT3β/STAT3α ratio was further associated with a favorable clinical prognosis and a significantly increased overall survival. In both in vivo mouse models we could demonstrate that the expression of STAT3β impairs leukemogenesis and leukemic cell infiltration into hematopoietic organs. The STAT3β‐dependent delay in disease progression and leukemic infiltration resulted in a significant increase of overall survival.Summary/Conclusion:In summary, the results of our study demonstrate STAT3β as an anti‐tumorigenic molecule in AML mouse models and the STAT3β/STAT3α ratio in AML patient derived blasts positively correlates with survival.
PS1103 NOVEL COMPOUND HETEROZYGOUS MUTATIONS CAUSING FACTOR XI DEFICIENCY IN UNRELATED TWO CHINESE PATIENTS
Authors: Li Q. , Zhou R. 
Published: June 2019

Background:Coagulation factor XI deficiency is a rare bleeding disorder, whose molecular mechanism is not well understood.Aims:To investigate the molecular pathogenesis of coagulation factor XI (FXI) deficiency in two unrelated Chinese patientsMethods:The diagnosis was validated by coagulant assays: APTT and correct test, PT and coagulation factors activities. The patients’ DNA were extracted and all exons and flanking sequences of FXI gene were amplified using PCR. After purified, the products were sequenced directly, the mutations were detected by comparing with wild sequences and analysed using some bioinformatics software.Results:The two patients were diagnosed as coagulation factor XI deficiency due to prolonged APTT, corrected APTT and low activities of coagulation factor FXI. The results of APTT, corrected APTT and FXI:C were 88.1 s, 32.9 s,1.1% and 107.1 s, 31.5 s, 3.8% for patient1 and patient2, respectively. Genetic analysis showed compound heterozygous mutations g.1251–1G>A and g.1271delT in patient1 and the sequencing results of TA plasmid clones found that the two mutations were located on different single strands of chromosomes. Double heterozygous mutations g.1070A>G and g.1446C>G were detected in patient2 resulting in Lys357Arg and Cys482Stop. Software analysis suggested the mutations probably brought amino acid sequence changed, protein features affected and splice site changed.Summary/Conclusion:Double heterozygous mutations g.1251–1G>A, g.1271delT and g.1070A>G, g.1446C>G had been identified in unrelated two coagulation factor XI deficiency Chinese patients, which might be the reasons for their prolonged APTT and low FXI:C. To the best of our knowledge, the four mutations are reported firstly in literature.
PS1126 JNK1: AN EMERGING THERAPEUTIC TARGET IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) DOWNSTREAM OF THE B‐CELL RECEPTOR, WHICH OVERCOMES IBRUTINIB RESISTANCE
Authors: Decker S. , Saleem S. Khaja , Kissel S. , Duyster J. , Dierks C. 
Published: June 2019

Background:B‐cell receptor (BCR) inhibitors like ibrutinib are highly effective in the treatment of CLL, but frequent occurrence of resistance mutations limits treatment duration and causes relapses in many patients. The C‐Jun NH2‐terminal protein kinases 1 (JNK 1) belongs to the family of serine/threonine kinases, is involved in cell proliferation, survival and differentiation, and is located downstream of the BCR in CLL.Aims:Therefore, we aimed to validate JNK1 as crucial mediator of BCR signaling in CLL. Further, we wanted to validate JNK1 as a therapeutic target in ibrutinib‐resistant CLL.Methods:Patient derived xenograft mice from CLL patients and ibrutinib‐resistant CLL patients, and Eμ‐TCL1 tg mice were daily treated with the JNK1 inhibitor SP600125 using oral gavage. After 2 and 3 weeks of treatment, mice were sacrificed, and spleen and bone marrow cells were harvested and stained for CLL cells (BD).Results:In this study, we found that JNK1 is overexpressed and highly activated especially in IgVH unmutated B‐CLL lymphocytes with adverse prognosis, and overactive BCR signaling. JNK inhibition with the kinase inhibitors SP600125 and CC‐930, the substrate binding inhibitor protein L‐JNKi or siRNA mediated silencing all lead to apoptosis induction in IgVH unmutated primary human CLL samples. JNK1 inhibition was effective even in the presence of protective stroma cells, and resulted in down‐regulation of the anti‐apoptotic proteins BCL2 and MCL1, and the oncogenic transcription factor c‐JUN. By performing knockdown experiments and kinase inhibition of essential upstream BCR‐signaling mediators in CLL like SYK, BTK and PI3K, we identified JNK1 as a crucial downstream kinase in the BCR signaling pathway. In vivo treatment studies in patient derived xenograft mouse models and the Eμ‐TCL1 tg mouse model with the JNK1 inhibitor SP600125 confirmed our results and strongly reduced CLL cell numbers in the peripheral blood and spleen of both mouse models. JNK1 inhibition was even effective in a CLL xenograft model of a patient being resistant to ibrutinib treatment. In addition to direct effects on CLL cells, we found that JNK1 inhibitors in vivo also improve T‐cell responses, and reduce the frequency of immunosuppressive Tregs, while increasing the activity of CD4+ and CD8+ T‐cells.Summary/Conclusion:In conclusion, our studies revealed JNK1 as a promising novel therapeutic target in CLL downstream of the BCR, which can overcome ibrutinib resistance, and additionally improve immune responses against CLL cells.
PS1144 TARGETING IRAK4 DISRUPTS INFLAMMATORY PATHWAYS AND DELAYS TUMOR DEVELOPMENT IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Moya L. Rosich , Gimenez N. , Schulz R. , Higashi M. , Aymerich M. , Villamor N. , Delgado J. , Juan M. , Lopez‐Guerra M. , campo E. , Seiffert M. , Colomer D. 
Published: June 2019

Background:Interleukin‐1 receptor‐associated kinase 4 (IRAK4) plays a critical role in Toll‐like receptor (TLR) signal transduction and innate immune responses. Recruitment and subsequent activation of IRAK4 upon TLR stimulation is mediated by the myeloid differentiation primary response 88 (MYD88) adaptor protein. Around 3% of chronic lymphocytic leukemia (CLL) patients have activating mutations of MYD88, a driver mutation in this disease.Aims:Here, we studied the effects of TLR activation and the pharmacological inhibition of IRAK4 with ND2158, an IRAK4 competitive inhibitor, as a therapeutic approach in CLL.Methods:TLR stimulation was performed with an agonist mix of Pam3CSK4, HKLM, FSL1 and ODN2006. Cytokine secretion and CLL proliferation were assessed by Luminex system and carboxyfluorescein succinimidyl ester staining, respectively. For in vivo studies, the Eμ‐TCL1 adoptive transfer mouse model was used.Results:Our in vitro studies demonstrated that ND2158 preferentially killed CLL cells in a dose‐dependent manner. We further observed a decrease in NF‐κB and STAT3 signaling, cytokine secretion, proliferation and migration of primary CLL cells from MYD88‐mutated and –unmutated cases. In the Eμ‐TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells.Summary/Conclusion:Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease.
PS1191 PROGNOSTIC SIGNIFICANCE OF REGULATORY T CELLS (TREGS) IN CHRONIC MYELOID LEUKEMIA PATIENTS TREATED WITH GENERIC IMATINIB
Authors: Saj F. 
Published: June 2019

Background:It has been observed that the proportion of regulatory T cells (Tregs) is elevated in untreated Chronic Myeloid Leukemia (CML) patients that curtail tumor‐specific immune response. The degree of imatinib‐related Treg inhibition correlates with CML prognosis. There is limited information on the dynamics of Tregs in CML patients treated with generic imatinib. We studied Treg proportions in newly‐diagnosed CML patients (at baseline and 3 months of treatment with generic imatinib).Aims:To evaluate Tregs in periperal blood of newly diagnosed patients of CML‐Chronic phase and their association with disease progression.Methods:Newly‐diagnosed adult CML patients in chronic phase were prospectively studied from July 2017 to March 2018. At baseline, a peripheral blood sample for Treg analysis was collected from CML patients before starting imatinib and from healthy controls. At 3 months, in addition to quantitative RQPCR for BCR‐ABL, a repeat peripheral blood sample was collected for Treg analysis. Treg percentage in peripheral blood was assessed by flowcytometry (triple laser BD FACS Canto II flow cytometer). Following sample acquisition on flow cytometer, the data was analysed using BD FACSDIVA software (Becton Dickinson, USA). Tregs were calculated as percentage of CD4+ T lymphocytes.Results:Fifty‐seven newly‐diagnosed CML patients and 30 age‐ and sex‐matched healthy controls were prospectively enrolled. The median age of the CML patients was 39 years (range 16 – 64years); 47.3% were males. The BCR‐ABL (IS) % at 3months was <1%, 1–10% and >10% in 15 (26.3%), 26 (45.6%) and 16 (28.1%) patients, respectively. The mean baseline Treg% of CML patients (3.61 ± 0.32%) was significantly higher than the mean Treg % of controls (1.58 ± 0.21%) (p < 0.001). The mean Treg% at 3 months in CML patients (1.73 ± 0.35%) was significantly lower than baseline Treg% (3.61 ± 0.32%) (p < 0.001). Baseline Treg% in CML patients showed significant positive correlation with Sokal score (r = 0.29), Hasford score (r = 0.33) and EUTOS score (r = 0.28) (p < 0.05). The baseline Treg% correlated significantly with the BCR‐ABL% at 3months (p = 0.03).Summary/Conclusion:We found a significantly higher proportion of Tregs in CML patients in chronic phase vis‐a‐vis healthy controls which significantly decreased with generic imatinib treatment at 3 months. The study results add evidence to the hypothesis that imatinib‐related Treg suppression is another novel mechanism through which it targets CML. Our findings lend support to the fact that generic imatinib is reasonably efficacious in restoring immunological milieu in CML patients.
PS1279 A PRACTICAL UPDATE ON THE EPIDEMIOLOGY AND RISK FACTORS FOR THE EMERGENCE AND MORTALITY OF BLOODSTREAM INFECTIONS IN 3014 PATIENTS WITH HEMATOLOGICAL MALIGNANCY RECEIVING CHEMOTHERAPY
Authors: Hu J. , Chen S. , Yang T. 
Published: June 2019

Background:The pathogenic epidemiology, antibiotic resistance, and risk factors of bloodstream infections (BSIs) in patients with hematologic malignancies (HMs) receiving chemotherapy is importment for clinican.Aims:To investigate the pathogenic epidemiology and antibiotic resistance of bloodstream infections (BSIs) in patients with hematologic malignancies (HMs) receiving chemotherapy, and to determine the risk factors for BSIs.Methods:Retrospective chart review of patients diagnosed with HMs (n = 3014) was performed (1/2013–12/2016), and patients classified as having BSIs (n = 725) or not (n = 2289). Clinical characteristics and pathogens were evaluated, and risk factors for BSIs identified by univariate and multivariate Logtistic and COX regression analyses.Results:BSI frequency was 24.1%, with 744 different isolated strains in 725 cases. Gram‐negative (G‐) represented 64.7% of the 744 isolated strains, while Gram‐positive (G+) and fungi were 27.7% and 7.7%, respectively. The most common isolates were Klebsiella pneumoniae (19.2%), and 90% of extended‐spectrum beta‐lactamases (ESBL)‐producing enterobacteria were multidrug‐resistant. Methicillin‐resistant Coagulase‐negative Staphylococci and Methicillin‐resistant Staphylococcus aureus accounted for 87.16% and 37.93% of the cases, respectively. Multivariate analysis revealed that male, age ≥ 45 and <65 yr, hospital length of stay (LOS) ≥ 9d, neutropenia ≥ 7d before BSIs, ≥ 2 antibiotics, gastrointestinal, perirectal and urinary tract infections independently predicted BSIs emergence. Furthermore, age ≥ 65, neutropenia ≥ 7d before BSIs, no HM remission, lower white blood cell count, ≥ 3 antibiotics, respiratory infections, and Acinetobacter baumannii and Stenotrophomonas maltophilia BSIs were independent predictors of 30‐day mortality.Summary/Conclusion:Antibiotic resistance was high, outcome was poor, and mortality due to BSIs was high in this patient cohort. Therefore, close attention should be paid to the risk factors identified here during management of these patients with BSIs.image
PS1510 FLUPENTIXOL MELITRACEN COMBINED WITH ONDANSETRON IN PREVENTION OF NAUSEA AND VOMITING INDUCED BY CONDITIONING IN PATIENT TO UNDERGO HSCT
Authors: Lu Y. , Fan R. , Kuang L. , Feng B. , Shan Y. 
Published: June 2019

Background:Nausea and vomiting are the most common complaints for patients with haematological neoplasia during conditioning. The risk of hematopoiesis stem cell transplantation (HSCT) always cause people in anxiety and depression, which add patients’ discomforts.Aims:The aim of this study is to observe the effect of lupentixol melitracen combined with ondansetron on nausea and vomiting.Methods:160 patients with hematological neoplasia in the state of complete remission were included in this study. The patients were randomly divided into control group and lupentixol melitracen group. For patients in control group, they received recommended‐dose of ondansetron during conditioning each day. For patients in lupentixol melitracen group, they received lupentixol melitracen 10.5 mg combined with ondansetron each day. The incidence of nausea and vomiting was evaluated before, during and after chemotherapeutics infusion in the first day of conditioning.Results:Totally 158 patients, 78 in control group and 80 in lupentixol melitracen group could be evaluated. The difference of chemotherapy drug intensity in the two groups has no statistical significance (P > 0.05). The incidence of nausea before, during and immediately after chemotherapeutics infusion was respectively 5.2%, 72.5%, 60.6% in the control group and 1.6%, 53.3%, 45.5% in the lupentixol melitracen group, and the difference was significant between the two groups (P < 0.05). While the incidence of vomiting in the two groups has no significant difference (P > 0.05).Summary/Conclusion:Flupentixol melitracen combined with ondansetron is more effective to prevent nausea than single ondansetron in patients during the first day of conditioning but no more effect on vomiting in our study.
PS1559 EFFICACY AND TOXICITY OF SEAM (SEMUSTINE, ETOPOSIDE, CYTARABINE, AND MELPHALAN) CONDITIONING REGIMEN FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION IN LYMPHOMA
Authors: Zhang L. , Chen X. , Liu S. , Zhu Q. , Wu D. , Huang H. 
Published: June 2019

Background:BEAM (carmustine, etoposide, cytarabine, and melphalan) is considered the gold standard conditioning regimen for autologous stem cell transplantation (auto‐SCT) in lymphoma. However, a shortage of old drugs is a worldwide problem, and carmustine (BCNU) is on this list. Alternative regimens are therefore being developed and used by many institutions. Semustine (Me‐CCNU), an alternative oral nitrosourea agent, has been chosen as a potential substitute. In China, we substituted BCNU by Me‐CCNU to provide the modified conditioning regimen SEAM (semustine, etoposide, cytarabine, and melphalan).Aims:The aim of this study was to evaluate the safety and efficacy of the SEAM regimen followed by auto‐SCT for malignant lymphoma patients.Methods:We retrospectively reviewed the records of patients with lymphoma who underwent auto‐SCT with SEAM regimen (n = 97) from January 2010 to June 2018 in our center. We evaluated the safety and efficacy of the SEAM regimen by comparing with previous studies using BEAM as conditioning regimen.Results:The median age of patients (n = 97) was 42 years (range, 15–65). The median time to neutrophil engraftment was 9.5 days (range, 7–15 days), and the median time to platelet engraftment was 12 days (range, 7–25 days). Grade 3–4 nausea/vomiting, mucositis and diarrhea were observed in 21.6%, 36.1%, and 11.3% of patients, respectively. Veno‐occlusive disease (VOD) and idiopathic pulmonary syndrome (IPS) were not observed. Treatment‐related mortality (TRM) at 100 days occurred in 2 patients (2.1%). After a median follow‐up time of 53.9 months, 31 patients (32.0%) showed progression over a median duration of 4.87 months (range, 1.1–40.53) after transplantation. In addition, the 3‐year incidence of disease relapse or progression (CIR) was 34%. The estimated progression‐free survival (PFS) and overall survival (OS) at 3 years were 62% and 75%, respectively. Compared with previous studies using BEAM as the conditioning regimen, this study shows that the SEAM conditioning regimen has a comparable efficacy and safety profile.Summary/Conclusion:The incidence and severity of non‐hematological regimen‐related toxicities of the SEAM conditioning regimen in this study were almost identical to that of BEAM conditioning regimen as reported in the previous studies. The SEAM conditioning regimen followed by auto‐SCT was well tolerated and had an efficacy and safety profile comparable to BEAM. Therefore, SEAM conditioning regimen is feasible whether in efficacy, safety or sources of drugs and might be an ideal alternative to BEAM conditioning regimen for auto‐SCT in lymphoma.image
PS1576 ADENOSINE DIPHOSPHATE RECEPTOR GENE (P2Y12) SEQUENCE VARIANTS AMONG SWEDISH, PALESTINIAN AND CONGOLESE INDIVIDUALS
Authors: Asees M. , Seir R. Abu , Hesse C. , Reza A. 
Published: June 2019

Background:The P2Y12 receptor plays a central role in platelet aggregation and thrombus formation. Recently, inter‐individual variations in platelet response of healthy untreated individuals were established which was explained by genetic variations in the P2Y12 receptor gene. Several single nucleotide polymorphisms (SNPs) in the P2Y12 receptor have been associated with increased platelet reactivity and risk of cardiovascular diseases.Aims:This study aimed to evaluate the pathological H2 haplotype (using G52T as a tag‐SNP) and 18C>T polymorphisms in three different ethnic groups; Palestinians, Swedish and Congolese. in addition to that, to investigate the effect of H2 haplotype pn palatelt aggregation induced by ADP/TRAP agonists.Methods:The H2 haplotype and 18C>T SNPs were determined in conveniently selected healthy individuals from different ethnic groups (n = 254). The whole exon‐3 of P2Y12 was sequenced and analyzed by using ABI PRISM 310 Genetic Analyzer. The major and the minor allele frequencies of the P2Y12 SNPs were determined in the study population and the genetic differences between ethnic groups in P2Y12 were elucidated. In addition, the frequency of the genotypes were calculated among the different ethnic groups.Results:In this study, five benign single nucleotide polymorphisms (SNPs) were genotyped and identified; 18C>T, 36G>T, 162G>T, 546C>T and 989A>G. The overall frequencies of each SNP in the study population (n = 254) was 21.9, 10, 0.4, 0.6 and 0.4%, respectively. The frequency of H2 haplotype was among Swedish 23.6% (n = 55), Congolese 12.0% (n = 54) and Palestinian 4.1% (n = 145). There were significant differences in frequency of H2 haplotype and 18C>T among the ethnic groups (P < 0.001). In regard to the pathological SNPs (767G>A [p. Arg256Gln] and (793C>T [Arg265Trp]) all of the study participants were negative.Summary/Conclusion:There are significant differences in the frequencies of the genetic variants of the P2Y12 exon‐3 between the studied ethnic groups. Application of these findings may explain the variable platelet response in healthy individuals and in patient under thienopyridine compounds. Further studies should be performed to study the effect of the genetic variations effect on ADP or TRAP‐ induced platelet aggregation.
PS1585 ELDERLY WITH ANTIPHOSPHOLIPID SYNDROME PRESENT WITH DISTINCT CLINICAL PROFILE: A RETROSPECTIVE SINGLE CENTER STUDY
Authors: Bountola S. , Perifanis V. , Kazantzi A. , Keramidioti C. , Hassapopoulou‐Matami E. , Hatzitolios A. , Girtovitis F. 
Published: June 2019

Background:Antiphospholipid syndrome (APS) is an acquired autoimmune disorder. It is characterized by venous and/or arterial thrombosis and/or pregnancy related morbidity in the presence of persistent antiphospholipid antibodies (aPL). It can occur as primary or as secondary APS in association with an autoimmune disorder (usually SLE). APS mainly affects women who are of child‐bearing age and less often elderly patients.Aims:We aimed to describe the clinical and immunological features of APS in patients diagnosed after the age of 55.Methods:The PSA (Phospholipid Syndrome Aged) study is a retrospective study of patients with suspected APS, who were referred to the Thrombosis and Haemostasis Clinic during the last decade (2009–2018). Clinical and serological data of patients with late onset APS (occurred after the age of 55) were analyzed and compared with patients presenting with early onset APS. The aPL (anticardiolipin (ACA) and anti‐b2GP‐I antibodies, IgG and IgM) were measured by ELISA (Euroimmun, Germany).Results:We evaluated 149 patients diagnosed with APS (56,4% males, median age 43,74 ± 13,4 years). Patients with late onset APS were 32 (21,5%) and consisted Group A. The other 117 patients were Group B. Median follow‐up was 62,5 months (13–147). The most common clinical manifestation was stroke (20,5%), followed by deep vein thrombosis of the lower extremities (15,4%) and pulmonary embolism (12,7%). Clinical characteristics of patients are shown in table 1. x2 test was used to assess statistical significance.All triple positive patients were in group B (10 women and one man). All patients were treated with antithrombotic treatment including antiplatelet agents (26,5%) and/or oral anticoagulants (69%). 14% of the patients received only LMWH (younger women). Male gender, LA positivity and a higher frequency of secondary APS were statistically significant in the older group.Summary/Conclusion:Elderly APS patients should not be disregarded because they represent 21,4% of an APS population. Patients aged >55 who are diagnosed with APS share a distinct disease profile. Clinicians must be aware of this situation in order to identify specific causes, to evaluate the risk of recurrence and to establish a therapeutic approach.image