bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of a Mouse Model of Hypereosinophilic Syndrome
Authors: Zimmermann Nives , Gibbons William J , Homan Shelli M , Klingler Andrea , Prows Daniel R 
Published: October 2019

Abstract
Introduction: Hypereosinophilic syndrome is characterized by sustained blood and/or tissue hypereosinophilia leading to tissue damage and organ dysfunction. Nearly half the cases are classified as idiopathic, since no known cause is identified and there is no evidence of a clonal disorder. In such cases, nonspecific treatment approaches, including corticosteroids, hydroxyurea and interferon-alpha, are used aimed at mitigating eosinophil-mediated organ damage. However, mortality occurs primarily due to cardiac and thromboembolic complications. Understanding the cause and mechanism of disease would aid in the development of targeted therapies with greater efficacy and fewer side effects. For instance, while the traditional view is that eosinophils are detrimental via toxicity of their granule proteins, recent studies suggest other mechanisms including non-canonical cell death subroutines, such as regulated necrosis, release of pro-thrombotic DNA "traps" and others. Lack of a mouse model hinders testing such hypotheses in vivo. We have developed a mouse model of eosinophil-associated hypereosinophilic syndrome characterized by multi-organ involvement including lethal prothrombotic myocardial damage.
Results: We discovered a spontaneous mouse mutant in our colony with a hypereosinophilic phenotype. Mice develop peripheral blood eosinophilia, infiltration of lungs, spleen and heart by eosinophils, and extensive myocardial damage and remodeling. This ultimately leads to heart failure and premature death, often by 14 weeks of age. Histopathologic assessment of the hearts from affected mice (Fig. 1) revealed a robust inflammatory infiltrate of the ventricular myocardium. Immunohistochemistry demonstrated that this infiltrate is composed primarily of eosinophils (MBP) and B lymphocytes (B220), leading to myocardial damage and replacement fibrosis. In some cases, hearts showed dilatation and thinning of the right ventricular wall, suggestive of an inflammatory dilated cardiomyopathy. An exam of most mice revealed primarily atrial thrombi, which often filled the entire/majority of the chamber. Expression analysis by protein multiplex assay in heart homogenates revealed overexpression of Th1 and Th2 cytokines and chemokines, including IL-4, IL-6, LIF, IL-16, IP-10/Cxcl10, MIG/Cxcl9, Eotaxin-1/Ccl11, RANTES/Ccl5, MIP-1β/Ccl4, MIP-3β/Ccl19, MCP-1/Ccl2, MCP-3/Ccl7, MDC/Ccl22 and TARC/Ccl17.
Conclusion: The pathologies observed in the mutant line are reminiscent of those seen in patients with hypereosinophilia, where cardiac-related morbidities, like congestive heart failure and thrombi, are the most common causes of death. As such, our model provides an opportunity to test mechanistic hypotheses and develop targeted therapies.

Disclosures
No relevant conflicts of interest to declare.
Low-Dose Decitabine Could Improve the Imbalance of M1/M2 Ratio in Immune Thrombocytopenia
Authors: Shao Xia , Li Feng , Cheng Luya , Chen Pu , Min Zhihui , Ji Lili , Wu Boting , Cheng Yunfeng 
Published: October 2019

Abstract
Background
Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease characterized by increased immune-mediated platelet destruction and insufficient platelet production. As the impaired balance of M1 macrophage and M2 macrophage subsets increases platelet destruction, the M1/M2 ratio has become the focus of attention. The demethylating agent, decitabine (DAC) has been successfully used in the treatment of myelodysplastic syndrome with a moderate response in thrombocytopenia. Interestingly, at low doses, DAC induces megakaryocyte differentiation and maturation in vitro via inducing hypomethylation, thus having the potential to promote platelet release in ITP patients. In addition, several reports suggest that DAC can promote the polarization of macrophages to M2 macrophages. Therefore, we hypothesized that low dose of DAC treatment could lead to shrinkage of platelet destruction in murine model of ITP via promoting the M2 macrophage polarization.
Methods
Platelets isolated from Wistar rats were transferred into CBA/Ht mice via intraperitoneal injection weekly to induce a marine model of primary ITP. Starting on day 8, ITP mice were treated with low-dose DAC (0.25 mg/kg/d, n = 8) or PBS (n = 8) for two consecutive weeks intraperitoneally. Platelet counts were recorded every three days. The spleens were removed at day 10, from which M1 macrophages (F4/80+ CD11c+) and M2 macrophages (F4/80+ CD206+) were identified by flow cytometry analysis and immunofluorescence.
Results
The platelet levels in ITP group began to descend sharply at the second week after transferring platelets when compared with the control group (735.0 ± 25.2 × 109vs. 390.3 ± 70.0 × 109, p < 0.05). Mice in DAC-treated group recovered from thrombocytopenia by day 10 (713.8 ± 29.1 × 109vs. 311.0 ± 4.5 × 109, p < 0.001). In the following days, it still showed significantly higher level of platelet in DAC-treated group than ITP group despite the trend to decline. Comparing with the ITP group, immunofluorescence revealed that spleen samples showed stronger M2 expression pattern in DAC group, and the ratio of M1/M2 declined regardless of the fact that both the percentage of M1 macrophage and M2 macrophage was increased when DAC was applied.
Conclusions
Low dose DAC can promote the polarization of both M1 and M2 macrophage, especially M2 macrophage, thus reversing the unbalanced M1/M2 ratio in ITP group. Further studies are required to investigate the mechanism underlies the specialized polarization of macrophages.

Disclosures
No relevant conflicts of interest to declare.
Corticosteroids Combined with Cyclosporine a Is Superior to Corticosteroids As First-Line Treatment for Autoimmune Hemolytic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Lv Weiran , Qu Hong , Wu Meiqing , Fan Zhiping , Huang Fen , Xu Na , Xuan Li , Lin Ren , Zhao Ke , Sun Jing , Lai Yongrong , Xu Yajing , Liu Qifa 
Published: October 2019

Abstract
We retrospectively investigated the incidence and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients with autoimmune hemolytic anemia (AIHA). A total of 1,377 patients enrolled in this study, and the 3-year cumulative incidence of AIHA was 2.2±0.4%. Twenty-five patients with AIHA received treatment, including 15 patients who received corticosteroids combined with Cyclosporine A(CsA )and 10 who received corticosteroids monotherapy. After four weeks of treatment, the patients treated with corticosteroids combined with CsA had a higher complete response rate than those with corticosteroids monotherapy (66.7% vs. 11.1%; P=0.013). One patient (6.7%) experienced AIHA relapse in the combined group, and 5 (50.0%) relapsed in the monotherapy group (P=0.023). The 5-year cumulative incidence of malignant disease relapse was 5.5±5.1% and 27.4±1.4% (P=0.032), the OS was 86.3 ± 7.4% and 65.2 ± 1.6% (P=0.046), and the transplant-related mortality (TRM) post-transplantation was 9.3±6.4% and 22.8±1.6% (P=0.140), respectively, for patients with AIHA and those without AIHA. Our results indicate that corticosteroids combined with CsA is superior to corticosteroids as first-line treatment for AIHA, and AIHA does not contribute to increased primary disease relapse and TRM.

Disclosures
No relevant conflicts of interest to declare.
A Potential Mechanism for the Antioxidant Compound Kushen Injection Targeting the ROS Signaling Pathway in Acute Myeloid Leukemia
Authors: Jin Yanxia , Yang Qian , Liang Li , Ding Lu , Liang Yuxing , Zhang Dongdong , Yang Tian , Zhao Mingfeng , Zhou Fuling 
Published: October 2019

Abstract
Abstract
It is a challenge for treatment of acute myeloid leukemia (AML) in clinic. The increase in the levels of reactive oxygen species (ROS) in AML patients has been previously described; thus, it is important to regulate ROS levels in AML.
In this study, we found that intracellular ROS levels in AML cells were decreased, the total antioxidant capacity (T-AOC) and glutathione (GSH) contents were increased and xanthine oxidase (XOD) vitality was decreased when treated with the compound kushen injection (CKI). This shows that CKI inhibited the proliferation of AML cell lines and patient cells and enhanced the cytotoxicity of AML cells, which has few toxic effects on haematopoietic stem cells (HSCs) and T cells. At the single-cell level, individual AML cells died gradually by CKI treatment on optofluidic chips. CKI could promote apoptosis and arrest cell cycle at G1/G0 phase in U937 cells.
Furthermore, higher peroxiredoxin-3 (Prdx3) expression levels were found in CKI-treated U937 cells through quantitative proteomics detection. Mechanically, the expression of Prdx3 and peroxiredoxin-2 (Prdx2) was up-regulated in CKI-treated AML cells, while thioredoxin 1 (Trx1) was reduced. Laser confocal microscopy showed that the Prdx2 and Trx1 proteins could be co-localized by CKI treatment.
In vivo, in the CKI-treated group, survival was longer in an AML patient-derived xenograft model in B-NSG mice. The disease was partially alleviated by decreased CD45+ immunophenotyping in peripheral blood and bone marrow smear analysis. After CKI injection, the T-AOC vitality, GSH content and CAT activity increased and the concentration of H2O2decreased in mouse plasma. A bone marrow biopsy and immunohistochemistry analysis showed that Prdx3 and Prdx2 expression was increased, while Trx1 expression was decreased.
In a conclusion, we provided a model for the anti-leukaemic effects of CKI. CKI decreased intracellular ROS levels by up-regulating the expression of Prdx2 in the cytoplasm and Prdx3 in the mitochondria and down-regulating Trx1 expression, which maintained the intracellular REDOX and further inhibited AML cell proliferation.
Therefore, antioxidant CKI is a promising drug for the treatment of AML in the clinic. We aimed to explore the therapeutic efficacy of low toxicity natural antioxidants against AML by targeting ROS pathways and providing new strategies to improve survival in AML patients.

Disclosures
No relevant conflicts of interest to declare.
Trends in Multiple Myeloma Incidence in the United States (US): Demographic and Geographic Considerations and Focus on Young Adults
Authors: Ruan Gordon , Goyal Gaurav , Hashmi Shahrukh K. , Kapoor Prashant , Go Ronald S. 
Published: October 2019

Abstract
Background: The incidence of multiple myeloma (MM) in the US is increasing among non-Hispanic (NH) White males and females as well as NH Black males (Costa LJ, Blood Advances 2017). However, more specific incidence studies accounting for geographic and age subgroups are limited. There is also a growing concern that incidence of many cancers is increasing in the younger population. Utilizing the Surveillance, Epidemiology, and End Results Program (SEER), we investigated the trends in MM incidence in the US according to demographic and geographic subgroups with a focus on the young adults.
Methods: Incidence rates (case/100,0000) were calculated using SEER*Stat and 2000-2015 data from SEER-18 registries age-adjusted to the U.S. 2000 standard population. We calculated the annual percentage change (APC) of incidence rates according to age groups and stratified by sex, race, and registry. Age at diagnosis was analyzed in 10-year intervals starting at 20 years. All analyses used ICD-O-3 codes 9732/3 with microscopically confirmed MM.
Results: There were 69,613 MM patients included in the analysis. The mean age at diagnosis was 68 years and decreased over time from 68.5 years in 2000 to 67.6 years in 2015. Men comprised 55.5% of the population. Patients <50 years constituted 7.9% of the population with 6.6% between 40-49 years. The incidence significantly (all p values <0.01) increased from 2000-2015 for the entire cohort (incidence 6.9-9.5; APC 1.1) and for males (8.6-9.5; 1.1) and females (5.7-6.3; 0.8). The highest increase in incidence among the age groups (Figure) was in 40-49 years (1.9-2.7; 2.1). When analyzing the trends for age groups stratified by sex, women ages 40-49 years had the highest increase in incidence (1.6-2.6; 2.4). The APCs of SEER-18 registries stratified by age and sex are reported in the Table. The highest APCs (>3.0) were observed in the registries of Atlanta, Greater Georgia, Hawaii, and New Jersey. When the SEER-18 registries were further stratified by race, white men ages 40-49 years in Seattle and New Jersey had APCs of 5.5 and 2.9 respectively, while Black women ages 40-49 years in Greater Georgia had an APC of 3.3. Only 3 groups of individuals had a significant decline in the incidence: Asian women ≥70 years in Los Angeles (APC -6.4), White women ≥70 years in Los Angeles (APC -1.9), and men 50-59 years in San Jose (APC -1.5).
Conclusions: The overall incidence of MM is increasing in the US with the highest increment among young adults between the age groups 40-49 years. We observed geographic and demographic differences in the incidence rates, which may reflect genetic and environmental influences. Interestingly, a few geo-demographic subgroups had a decline in the incidence. Further research is needed to determine the reasons behind the observed trends.

Disclosures
Kapoor: Celgene: Research Funding; Takeda: Research Funding.
Efficacy of Early Convert to Dasatinib in Chronic Myeloid Leukemia Patients Who Inresponse or Intolerance to Imatinib
Authors: Liang Liu , Xu Na , Zhou Xuan , JiXian Huang , Chen Chen , Tong Lin , wan-Er Wu , Yin Changxin , Liu Qifa , Xiaoli Liu 
Published: October 2019

Abstract
Blackground:Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm hallmarked by the presence of fusion protein kinase derived from reciprocal translocation between chromosome 9 and 22, breakpoint cluster region (BCR)-Abelsonleukemia virus (ABL). Since the discovery of a tyrosine kinase inhibitor (TKI), CML has become a chronic illness if managed appropriately. The use of the first generation of TKI such as imatinib, benefit for most CML patients, but there are still a significant number of patients resistance to imatinib , need switched to second generation TKIs, such as dasatinib or nilotinib. however the efficiency and safety of CML patients who inresponse or intolerance to imatinib early convert to dasatinib should clinical studies.
Objective: To evaluate the efficiency and safety of CML patients who inresponse or intolerance to imatinib early convert to dasatinib.
Methods:We retrospectively analyzed 70 CML patients who inresponse or intolerance to imatinib in Southern Hospital from March 2014 to April 2016;real-time quantitative PCR method was used to detect BCR-ABL1 fusion gene Sanger sequencer.
Results: 37 CML patients BCR/ABL (IS)>10% treated by imatinib for 3 to 6 months,
had early conversion to dasatinib. Among them, 31 cases had low response to imatinib (sokal score was middle and high risk) and 6 cases intolerance to imatinib. 24 cases (64.9%) reached BCR/ABL (IS) < 10% after convert to dasatinib for 3 months, and 6 cases (40.5%) reached MMR after convert to dasatinib for 6 months.15 cases (40.5%) reached MMR in 12 months after conversion to dasatinib.33 patients (treated with imatinib for 3 to 6 months) did not undergo early transformation. Among them, 31 patients had poor response to imatinib and 2 patients intolerance to imatinib ,these patients continued imatinib or add imatinib dose to 600mg or 800mg qd. 13 patients (51%) did not reach the BCR/ABL (IS) < 10% for next 3 months, only 12 cases (36.3%) achieved MMR after 12 months follow-up, and 4 patients changed to dasatinib or nilatinib becase detected mutation during follow-up.The most common hematological adverse effects during dasatinib treatment were thrombocytopenia, neutropenia, anemia, and non-hematological adverse effects such as edema, pleural effusion, alopecia, gastrointestinal reactions and rare pulmonary hypertension. AEs can be alleviated by reducing or suspending dasatinib use.
Conclusion: The cml patients who inresponse or intolerance to imatinib early convert to dasatinib will gain an earlier and greater benefit, and adverse effects of dasatinib are controllable.
Key words:Chronic myeloid leukemia, Imatinib, Dasatinib, Early conversion

Disclosures
No relevant conflicts of interest to declare.
AYA ALL: Real World Experience from a Tertiary Care Center in North India
Authors: Das Satyaranjan , Yanamandra Uday , Moslem Mir , Kapoor Rajan , Pramanik Suman , Kumar Rajiv , Khurana Harshit , Sharma Sanjeevan , Verma Tarun , Jasjit Singh , Sharma Ajay , Nair Velu 
Published: October 2019

Abstract
Introduction: The outcomes of Adolescent and young adult (AYA) have been studied in various hemato-oncology subsets. Patients of AYA-ALL have improved outcomes by paediatric-inspired or fully paediatric protocols. The outcomes published from trials are different from the actual practise, that too in the real-world settings with resource constraints.
Objective: To study the characteristics and outcomes of AYA-ALL from real world settings.
Methodology: It is a retrospective observational study wherein the data of all patients of AYA-ALL managed at a tertiary care center in North India over the last 14 years (2004-2018) were analyzed. All case records of the AYA-ALL were perused, digitalized and their survival statistics derived.
Results:Amongst a total of 611ALL case records, 116 (18.98%) were AYA-ALL. AYA-ALL cases with complete data (n-116) were analysed for overall survival. The mean age of the patients was 26.65 ± 6.61 years (range 16-39) (Fig. A). Males constituted 32.7% (n-78) and females, 67.2% (n-38) of AYA-ALL. On risk stratification, 67 (57.7%), 26 (22.4%), and 23 (19.8%) patients were classified as standard, intermediate and high risk. Phenotypically, 78 patients were B-ALL, 23 were T-ALL and rest were MPAL.
Of these 61 patients (52.5%) received adult ALL (GMALL protocol), 26 patients (22.3%) received paediatric BFM protocol, 19 patients (16.3%) received Hyper-CVAD, 8 patients (6.8%) MCP841 protocol and 2 received modified drugs not adhering to any fixed protocol. Week 4 Bone marrow evaluation was in CR in 91.4% of patients. L-Asparaginase was given in only 74.5% of the patients. An interruption in the therapy of more than 2 weeks for various reasons was present in 35% of the patients. Prophylactic cranial irradiation was given in 42.4% of the patients and high dose methotrexate was given in 25.2% of the patients. Relapse was seen in 27.7% of the patients. CNS disease was present in 9.4% of the patients. Only 8% of the patients were subjected to transplant.
The cumulative overall survival at 1y (1y-OS) was 86.98% with 3y and 5y OS being 67.9% and 55.6% (Fig. B). The survivalsbased on the type of protocol was statistically different with the best survival with GMALL protocol and the least survival with Hyper-CVAD therapy (log rank p-0.0011) (Fig.C). The survival was also significantly different between different risk groups (p-0.003) (Fig.D). The survival was not statistically different between males and females (p-0.5), B-ALL vs T-ALL (p-0.6) (Fig. E, F).
Conclusion: We have demonstrated in this study the improved outcomes of AYA-ALL who usually present in late chronic phase in resource constraint settings. Contrary to the belief, adult GMALL protocol had better survival vis-à-vis pediatric BFM protocol in this cohort of AYA-ALL.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Zinc Finger Protein X-Linked Exhibits Pro-Leukemia Activity Via WNT3 in Chronic Myeloid Leukemia Stem/Progenitor Cells
Authors: Zhang Xiuyan , Wang Yu , Xiao Lun , Zhou Haixia , Zhu Li , Zhao Yun 
Published: October 2019

Abstract
Zinc Finger protein, X-linked (ZFX) is a transcriptional regulator, which controls the self-renewal of both embryonic and hematopoietic stem cells and participates in pathogenesis of various cancers. Zfx deficiency impairs Notch intracellular domain (NotchIC) induced acute T-cell leukemia (T-ALL) or MLL-AF9 induced acute myeloid leukemia (AML) in mice models. However, the function of ZFX in chronic myeloid leukemia (CML) stem/progenitor cells has not been elucidated yet.
In the present study, qRT-PCR analysis showed that ZFX expression was significantly higher in CD34+ cells from CML patients in chronic phase (CP) (n=8, 3.1-fold, P=0.0052) and patients in blast crisis (BC) (n=8, 18.6-fold, P=0.0050) compared with that in healthy donors (n=4). Two independent shRNA sequences against ZFX were delivered in CD34+ cells with lentiviral vector. The silence of ZFX had a stronger inhibitory effect on colony-forming cell (CFC) ability of CML CD34+ cells (75±5%) than that of healthy donor CD34+ cells (44±5%). Furthermore, ZFX silencing augmented Imatinib Mesylate (IM) sensitivity of CML CD34+ cells, especially in IM-resistant samples; due to the fact that ZFX silencing increased apoptosis induced by IM. To obtain the molecular insights of how ZFX acts, we generated transcriptome data comparing ZFX silenced CML CD34+ cells with control cells. qRT-PCR data validated that ZFX silencing caused a significantly declined expression of WNT3 in K562, MEG-01 and CML CD34+ cells (n=5). In addition, ZFX silencing decreased WNT3 protein expression as well. Interestingly, WNT3 had significantly higher expression in CD34+ cells from patients in CP (n=10, 5-fold, P=0.0006) compared with that in healthy donors (n=8). Silence of WNT3 inhibited the growth of K562 cells and enhanced IM sensitivity of these cells as well. Overexpression of WNT3 restored the growth inhibition and IM hypersensitivity upon ZFX silencing. Chromatin immunoprecipitation (ChIP) analysis revealed that ZFX was able to bind with WNT3 promoter, and luciferase assay showed that ZFX silencing significantly decreased the activity of WNT3 promoter. Finally, we also found that the expressions of c-Myc and cyclin D1 were reduced by ZFX silencing or WNT3 silencing, suggesting decreased WNT/Catenin signaling.
Taken together, we have demonstrated that ZFX is aberrantly expressed in CML stem/progenitor cells, and it modulates the growth and IM response of CML stem/progenitor cells via wnt/Catenin pathway indicating ZFX is a new regulator of CML stem/progenitor cells, which deepens the understanding of CML pathology and potentially provides clues for novel therapies against this disease.

Disclosures
No relevant conflicts of interest to declare.