bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Pain Control on Invasive Clinical Procedure on Children with Leukemia
Authors: WANG Jiayi , He Yingyi , Liang Zhimin , Ye Tiezhen , Zhang Hui 
Published: October 2019

Abstract
Background: Palliative care is becoming more and more important for systemic cancer treatment in developed countries, while this remains infamous topic in developing countries, such as in China. Contemporary treatment strategies have greatly contributed to the improved outcome in childhood cancer patients, survivorship comes at the cost of developing some treatment-related health condition, such as pain-related depression, chronic pain etc. Thus, developing a well-tolerated pain control methods is of great importance within the cancer treatment. Objective: To evaluate the impact and outcome of different pain control applications on invasive procedure in children with leukemia, and record the adverse reactions. Methods: The enrollment of childhood leukemia patients in our hospital from November 2011 to November 2016 were divided into four groups, that is successively midazolam + local anesthesia (group A), midazolam + ketamine +local anesthesia (group B), midazolam + fentanyl + local anesthesia (group C), and fentanyl + propofol + local anesthesia (group D). The efficacy and adverse reactions were systemically recorded. The inter-group diffferences were calculated using x2 test. Results: No significancewas observed in age, gender, and disease distribution in these four groups by ANOVA ONEWAY analysis. The sedation outcome is more pronunced in group D than others. Also, the quality of procedural pain control in group D was the best (P<0.01). In terms of the analgesic effect, group B and D were better than that group A and C. There was significant difference in Hallucination was more easily detected in group B and C. Systemic recovery was delayed in group B other than group A, C, and D. Basing on the survey, we did found that the family members were more willing to accept pain control treatment for their sick kids under the safety assurance. The compliance was significantly improved in group D. Conclusion: Upon adequate auxiliary breathing preparation and rigorous monitor, propofol combined with low-dose fentanyl was the best sedative/analgesic option for pain control within leukemia patients receiving invasive procedure.The outcome of propofol combined with low-dose fentanyl wasvery safe, satisfactory and compliable. Up to now, this study is the first pain control study for invasive procedure in China mainland, it deserves being paid attention.

Disclosures
No relevant conflicts of interest to declare.
Hairy Cell Leukemia Variant
Authors: Ashangari Chandralekha , Cheruku Divya , Tumula Praveen K. 
Published: October 2019

Abstract
Introduction: Hairy cell leukemia-variant (HCL-V) is an uncommon disorder, accounting for approximately 0.4% of chronic lymphoid malignancies and 10% of all HCL cases, without sexual predominance. Here is an attempt to submit a rare case presentation of HCL-V.
Case:A 66 year old female presented to the clinic after she was referred from her primary care for further evaluation of pancytopenia. Past medical history was significant for diabetes mellitus and hypertension. Splenomegaly was noted on examination. Initial bloodwork showed a leukocyte count of 4.9, hemoglobin level of 11.8, platelet count of 78. LDH was 166. CT scan showed significant splenomegaly along with retroperitoneal adenopathy. Peripheral blood flow cytometry demonstrated a CD11c positive monoclonal B cell population suggestive of Hairy Cell Leukemia variant, positive for CD19, CD20, CD22, CD45, CD52, and kappa (moderate-bright), negative for CD5, CD10, CD23, CD38, CD103, CD123, BRAF V600. Left shift myeloid elements were noted but no significant myeloid blasts were noticed. She was diagnosed HCL-V with 17p deletion and 90% marrow involvement. She was treated with 8 doses Rituximab. After 1 year, she relapsed and was started on Cladribine and Rituximab weekly for 8 doses. She relapsed 1 year after Cladribine and Rituximab with splenomegaly and cytopenias, and she was started on Ibrutinib. 4 months after treatment with Ibrutinib, her cytopenias improved with normalization of spleen size. She is tolerating off label medication Ibrutinib well and currently asymptomatic.
Discussion: This case represents an extremely rare hematological malignancy a distinct case of HCL-v due to 17p deletion and refractory to multiple therapies. Patients with multiply relapsed HCL-v are also appropriate candidates for moxetumomab pasudotox because HCL-v retains a high level of expression of CD22. Hairy cell leukemia variant is a chronic lymphoproliferative disorder whose characteristics resemble the classic form and splenic marginal zone lymphoma, making differential diagnosis essential for therapeutic follow-up, as hairy cell leukemia variant has a decreased response to drugs prescribed for the classic form. Immunophenotyping is a key tool for diagnosis, as some markers are different between these neoplasms. Therefore, immunophenotyping, clinical, morphological, and immunohistochemical manifestations must be considered in the differential diagnosis.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Performance of Diagnostic Tests for Plasma Cell Myeloma
Authors: Zagoya Gilda , Ruiz-Argüelles Alejandro , Ruiz-Arguelles Guillermo J. 
Published: October 2019

Abstract
Introduction. In vitro laboratory tests to diagnose of plasma cell myeloma vary considerably in sensitivity, specificity and positive and negative predictive values. We compared the performance of quantification of free immunoglobulin light chains with other methods used to detect a monoclonal protein in serum and/or urine.
Objective. Compare sensitivity, specificity and positive and negative predictive values of several in vitro laboratory tests to detect monoclonal proteins in serum and urine in persons with plasma cell myeloma.
Methods. 70 subjects with plasma cell myeloma and 50 controls were studied. Diagnostic tests included: (1) quantification of free and total immunoglobulin light-chains by immune assays; (2) immune fixation of heavy-and light-chains in serum and urine after gel electrophoresis; and (3) serum protein capillary electrophoresis. Diagnosis of plasma cell myeloma was based on clinical and radiological criteria, bone marrow examination and flow cytometric immune phenotyping with monoclonal antibodies to CD56, CD19, CD138 (CD38) and CD45. Sensitivity, specificity and positive and negative predictive values for each tests were estimated from contingency tables.
Results. Quantification of free immmunoglobulin light-chains had the highest sensitivity and specificity and best positive and negative predictive values. Immune fixation of serum immunoglobulins was next best. Quantification of total immunoglobulin light-chains was the least sensitive and specific with the worst positive and negative predictive values. Quantitation of free light-chains had the additional advantage of objectivity (independence from observer bias). The immune fixation test was the most subject to observer bias.
Conclusion. Quantification of free immunoglobulin light-chains had the best sensitivity, specificity and positive and negative predictive values for diagnosing plasma cell myeloma. (Table 1)

Disclosures
No relevant conflicts of interest to declare.
Vascular Proteomics Reveals Critical Roles of ADAMTS18 in Stroke Associated with Imbalanced Level of Von Willebrand Factor Versus ADAMTS13
Authors: Zhu Rui , Pan Yi-Hsuan , Lu Tiantian , Dang Suying , Liao Chen-Chung , Zhang Wei 
Published: October 2019

Abstract
Background and Purpose -Stroke is the second leading cause of death worldwide. Acute ischemic stroke (AIS) is frequently induced by internal carotid artery thrombosis. Clinically, most arterial thrombus formation is initiated by platelets adhering to the damaged vessel wall. The adherent platelets become activated and bind with fibrinogen and von Willebrand factor (vWF), allowing formation of a platelet aggregate or mural thrombus. Identifying new mechanism involved in this pathogenesis is critical for understanding the molecular basis of thrombus formation and ultimately developing new therapeutic interventions for stroke. The ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs) family comprises 19 secreted metalloproteinases that cleave extracellular matrix components and have diverse functions in numerous disease and physiological contexts. Several ADAMTS genes (ADAMTS -7,-8, 12, and 13) have been shown to be involved in cardiovascular disease and pediatric stroke. ADAMTS18 remains "orphan" protease. We have previously shown that ADAMTS18 deficiency causes abnormal remodeling of the common carotid artery (CCA) and an increase in carotid thrombosis and size of cerebral infarct in mice. Thus, the stroke-prone Adamts18 KO mice could be valuable for identification of molecular signatures of accelerated carotid thrombosis related to stroke. One of the major steps yet to be taken by the field is the widespread use of proteomics to uncover the critical molecular events and signaling pathway involved in ADAMTS gene-related stroke.
Methods and Results -Here, we carried out the first proteomics comparison of protein expression patterns in CCA and abdominal artery (AA) between Adamts18 knockout (KO) mice and their wild-type (WT) littermates. A total of 1654 proteins were identified in four separate CCA samples (0.4-1 mg/wet weight each), and 1810 proteins were detected in four separate AA samples (2.3-3.6 mg/wet weight each). The abundances of 154 proteins in CCA and 55 proteins in AA were significantly different between KO and WT mice. Ingenuity® Pathway Analysis revealed that ADAMTS18 deficiency predisposes mice to stroke by altering the abundance of many proteins related to cytoskeleton, prothrombotic activity, coagulation, angiogenesis, oxidative homeostasis, and energy metabolism. Western blotting and qRT-PCR analyses further revealed the imbalanced level of von Willebrand factor and ADAMTS13, the pivotal pathogenic factors of ischemic stroke, in CCA of KO mice.
Conclusion and Significance -Results of this first vascular proteomic study of Adamts18 KO mice establish a substantial new resource for investigation of how ADAMTS gene affects cellular phenotypes of stroke. These new findings contribute to inform novel prevention strategies and direct therapeutic development for stroke.

Disclosures
No relevant conflicts of interest to declare.
A Small Nucleolar RNA Linked to Diamond-Blackfan Anemia
Authors: Mayeux Adeline , Montel-Lehry Nathalie , Saby Manon , Anton Aurore , Karboul Narjesse , Galimand Julie , Bourdeau Helene , Levy Jonathan , Tabet Anne-claude , Narla Mohandas , MacInnes Alyson W. , Dufourcq Pascale , Blader Patrick , Leblanc Thierry , O' Donohue Marie-francoise , Gleizes Pierre-Emmanuel , Da Costa Lydie 
Published: October 2019

Abstract
Diamond-Blackfan anemia (DBA) is a rare congenital erythroblastopenia associated with haploinsufficiency of more than 15 ribosomal protein genes. We identified in the French registry a DBA patient exhibiting a large heterozygous deletion in ribosomal protein gene RPSA, making it a new candidate as a DBA-associated gene. The deletion was confirmed by qPCR using specific intron/exon primers that could discriminate the RPSA gene from pseudo-genes. Consistent loss of function of this allele, RPSA mRNAs were underrepresented in erythroid cultures and in lymphoblastoid cells (LCLs) derived from the patient. Additionally, an important decrease in erythroid proliferation was observed in erythroid progenitor and precursor cells derived from the patient's bone marrow CD34+ cells, together with a delay in erythroid differentiation, the activation of the p53 pathway, and a G0/G1 cell cycle arrest, which are regular features of DBA patient cells. Similar to other RP genes linked to DBA, interruption of RPSA expression in zebrafish embryos strongly affected development of the head and erythroid cell differentiation, supporting its relevance as a candidate DBA gene. Northern blot analysis also revealed impaired pre-ribosomal RNA (pre-rRNA) processing in patient LCLs compared to controls. But unexpectedly, the observed pre-rRNA profile was clearly different from that observed in HeLa cells upon RPSA knockdown and suggested a dysfunction of pre-rRNA processing upstream of that produced by a shortage of RPSA. We noticed that the RPSA gene hosts the intron-encoded H/ACA snoRNAs snoRA6 and snoRA62, the latter being included in the deletion. Q-RT-PCR analysis of patient cells showed decreased levels of snoRA62 when compared to controls and to other RP-mutated DBA patients. Strikingly, knocking out the snoRNA62 coding sequence in human haploid HAP1 cells with Crispr/Cas9 resulted in a pre-rRNA maturation defect similar to that observed in the RPSA+/mut DBA patient, thereby revealing a role for snoRA62 in human pre-rRNA processing. These data strongly suggest that, in addition to RPSA haploinsufficiency, the primum movens of DBA in this particular patient includes the deletion of the intronic snoRA62 hosted in the RPSA gene. To our knowledge, this is the first time that a snoRNA is linked to DBA. We will discuss this ongoing work in light of our most recent results in cells and zebrafish models.

Disclosures
No relevant conflicts of interest to declare.
Occurrence and Severity of DLI Associated Chronic Gvhd Influence the Clinical Outcomes in Relapsed Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Yu Wenjing , Mo Xiao-Dong , Zhang Xiaohui , Xu Lan-Ping , Wang Yu , Yan Chen-Hua , Chen Huan , Chen Yu-Hong , Han Wei , Wang Feng-Rong , Wang Jing-Zhi , Liu Kaiyan , Huang Xiaojun 
Published: October 2019

Abstract
The aim of this study was to investigate the occurrence and severity of chemotherapy plus donor lymphocyte infusion (Chemo-DLI) associated chronic graft-versus-host disease (cGVHD) in a consecutive cohort of patients with acute leukemia who experienced relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT; n = 104). The 5-year cumulative incidence of complete remission (CR) after Chemo-DLI was 81.0% (95% CI, 73.3-88.7%) and 84.6% (95% CI, 74.5-94.7%) in the moderate and severe cGVHD groups, respectively, which was significantly higher than that of the mild cGVHD 40.9% (95% CI, 29.3-52.5%) and non-cGVHD groups 29.2% (95% CI 23.1-35.3%) (Figure 1). The cumulative incidence of non-relapse mortality was comparable between patients with and without cGVHD . The 5-year probabilities of progression-free survival after Chemo-DLI were 42.9% (95% CI, 26.2-70.2%) and 34.6% (95% CI, 15.3-78.2%) in moderate and severe cGVHD groups, respectively, which were both significantly higher than those of mild cGVHD 9.1% (95% CI, 2.4-34.1%) and non-cGVHD groups 8.3% (95% CI 3.3-21.3%) (Figure 2). The 5-year probabilities of overall survival after Chemo-DLI were 56.7% (95% CI, 38.9-82.7%) and 43.1% (95% CI, 22.1-84.0%), in moderate and severe cGVHD groups, respectively, which were both significantly higher than those of the mild cGVHD 9.1% (95% CI 1.8-47.1%) and non-cGVHD groups 14.9% (95% CI, 7.3-30.2%) (Figure 3). Our observations highlight the close relation between cGVHD and immune-mediated graft-versus-leukemia (GVL) effect in patients with relapse receiving Chemo-DLI; however, mild cGVHD may not be associated with a sufficiently strong GVL effect to induce remission and improve survival.

Disclosures
No relevant conflicts of interest to declare.
Syndecan-2 Surface Expression Identifies Hematopoietic Stem Cells with Increased Repopulating Capacity
Authors: Termini Christina , Li Michelle , Kim Joyce , Zhao Liman , Chute John P 
Published: October 2019

Abstract
Syndecans are transmembrane glycoproteins, which can regulate cell proliferation, growth, and adhesion through interactions with neighboring proteins within the plasma membrane or at the cytoplasmic interface. Although syndecans have been described to regulate aberrant signaling in hematological malignances, the role of syndecans in regulating normal hematopoietic stem cell (HSC) proliferation, differentiation, and self-renewal is largely unknown. We demonstrate that syndecan-1 and syndecan-3 are expressed on the surface of < 10% of murine hematopoietic stem and progenitor cells, whereas, syndecan-4 is expressed on 50% of lineage negative (Lin-) progenitor cells and 98% of c-Kit+Sca-1+Lin- (KSL) hematopoietic stem/progenitor cells, KSL CD34-CD48-CD150+/- short-term HSCs, and 100% of CD34-CD48-CD150+ long-term HSCs. Interestingly, we find that syndecan-2 is expressed by 11% of KSL CD34-CD48-CD150+/- short-term HSCs and 36% of CD34-CD48-CD150+ long-term HSCs. More specifically, our data demonstrate a 15-fold increase in syndecan-2 surface expression on KSL CD34-CD48-CD150+ HSCs compared to Lin- progenitor cells (p<.0001, ****). Collectively, these data suggest that syndecan-2 may be a marker for long-term HSCs. In keeping with this hypothesis, we found that syndecan-2+ CD34- KSL cells produce two-fold more granulocyte, erythrocyte, monocyte, megakaryocyte (GEMM) colonies compared to syndecan-2- CD34- KSL cells (p=.0017, **). Cell cycle analyses revealed a significant increase in BrdU incorporation in syndecan-2+ KSL cells compared to syndecan-2- KSL cells (90% versus 40%, p<.0001, ****). Competitive repopulation assays comparing syndecan-2+ or syndecan-2- CD34- KSL bone marrow cells demonstrated that mice transplanted with syndecan-2+ CD34- KSL cells displayed threefold increased donor multilineage hematopoietic cell repopulation compared to mice transplanted with syndecan-2- CD34- KSL cells. These data suggest that syndecan-2 expression marks a highly proliferative population of HSCs with increased multilineage repopulating capacity and that syndecan-2+ HSCs can be readily isolated to enhance the efficacy of hematopoietic cell transplantation.

Disclosures
No relevant conflicts of interest to declare.
Identification of High Serum Apolipoprotein A1 As a Favorable Prognostic Indicator in Patients with Multiple Myeloma
Authors: Liu Peng , Liang Lifan , Li Jing 
Published: October 2019

Abstract
Purpose
To explore the prognostic significance of serum lipid profiles in patients with multiple myeloma (MM).
Patients and methods
The study retrospectively enrolled 307 MM patients in Zhongshan Hospital, Shanghai, China, from 2007 to 2016. We evaluated the prognostic significance of the prediagnostic serum lipid profile [cholesterol, triglyceride, low-density lipoprotein (LDL), high-density lipoprotein (HDL), Apolipoprotein A1 (Apo A1) and Apolipoprotein B (Apo B)]. Prognostic factors identified through univariate and multivariate analysis were used to construct a new model based on Lasso Cox regression.
Results
In our cohort, lipid levels showed significant difference between ISS stages (P<0.001 in cholesterol, P<0.001 in LDL, P=0.002 in HDL, P<0.001 in Apo A1, P<0.001 in Apo B). However, only Apo A1 showed statistically significance in overall survival (OS), progression free survival (PFS) and cause specific survival (CSS) (P=0.038, P=0.028, P=0.011) in univariate Cox regression. Patients with higher Apo A1 displayed longer OS (median OS, 67 months vs. 30 months; P<0.001). Also, Apo A1 was revealed to be independent prognostic parameters through multivariate analysis. Combining the Apo A1 level, a Zhongshan Score model was constructed with Lasso regression for prognosis prediction. This model exhibited higher accuracy than International Staging System (ISS) and Durie and Salmon (DS) system.
Conclusion
Among all the serum lipid profiles, serum Apo A1 is a powerful prognostic indicator for patients with MM.

Disclosures
No relevant conflicts of interest to declare.
ZEB2 and LMO2 Drive Immature T-Cell Lymphoblastic Leukemia Via Distinct Oncogenic Mechanisms
Authors: Goossens Steven , Wang Jueqiong , Tremblay Cedric , Van Vlierberghe Pieter , Berx Geert , Taghon Tom , Haigh Jody J 
Published: October 2019

Abstract
ZEB2, a E-box binding homeobox transcription factor, is able to induce epithelial-to-mesenchymal transition in the context of solid tumors. As such, its expression is correlated with cancer cell invasion, dissemination and metastasis, but also with the acquisition of cancer stem cell properties and therapy resistance.
Using conditional knockout mice, we previously have shown that ZEB2 is an essential hematopoietic transcription factors, indispensable for normal embryonic(1) and adult(2) hematopoiesis. In addition, using conditional overexpressing mice we have demonstrated that ZEB2 is a bona fide driver of an immature subtype of T-ALL with increased leukemia-initiating potential(3).
Here, we investigated the effects of ZEB2 overexpression on normal T-cell differentiation. Already from young age, ZEB2-overexpressing mice have a smaller thymus, with increased percentages of early T-cell precursors. Detailed flow cytometric analysis indicate a T-cell differentiation delay at the beta-selection checkpoint, with accumulation of DN3 (CD4- CD8- CD44- CD25+) cells. Using in vitro differentiation assays on OP9-DL1 stromal cells, we demonstrate that the perturbed T-cell differentiation is independent of the thymic micro-environment. Lowering the dose of exogenous interleukin-7 levels in the culture media can partially rescue this phenotype, which suggests that ZEB2-overexpressing thymocytes are delayed in T-cell differentiation due to their inability to downregulate the interleukin-7 receptor (IL7R) levels.
Both the perturbed T-cell differentiation, and the latency/penetrance of immature subtype of the T-ALL formed in ZEB2-overexpressing mice is similar to what has been described for LMO2-overexpressing mice. Based on this phenocopy, we hypothesized that ZEB2 and LMO2 induce immature T-ALL via converging oncogenic pathway and/or via regulating similar crucial genes for the T-cell differentiation program. However, in contrast to LMO2, ZEB2-overexpresssing pre-leukemic thymocytes do not display aberrant self-renewal potential as demonstrated by transplantation experiments in sublethal irradiated syngeneic hosts. In addition, by using multiple Cre-transgenic lines, allowing the expression of ZEB2 at different stages of T-cell differentiation, we demonstrate that the oncogenic potential of ZEB2 is independent of the perturbed T-cell differentiation observed during the early stage of the disease.
Based on these results we conclude that ZEB2 and LMO2 both drive the development of an immature subtype of T-ALL, but via distinct oncogenic mechanisms.
(1) Goossens S. et al., Blood 2011 May 26; 117(21):5620-30.
(2) Li J. et al., Blood 2017 Jan 26; 129(4):460-472.
(3) Goossens S. et al., Nat Commun. 2015 Jan 7;6:5794.

Disclosures
No relevant conflicts of interest to declare.