bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final Analysis of a Phase II Study of Intrapatient Dose-Escalation of Eltrombopag in Patients Receiving Azacitidine for Myelodysplasia/AML
Authors: Dickinson Michael J. , Herbert Kirsten , Sardjono Caroline , Le Thao , Zannino Diana , Wood Colin , Seymour John F , Kenealy Melita , Prince Miles 
Published: October 2019

Abstract
Background: Pre-existing thrombocytopenia in MDS/AML is worsened during the initial cycles of azacitidine (AZA) therapy, resulting in bleeding risk and possible platelet transfusion. Eltrombopag (EPG) is an oral TPO-receptor agonist. In vitro, it has anti-proliferative effects on AML blasts.
Aim:  To assess the safety of escalated doses of EPG in patients undergoing AZA for MDS/AML
Method An investigator-initiated phase-II, single arm, study of EPG with AZA. Inclusion: relapsed or de-novo MDS/CMML/AML (blasts 5-30%); or symptomatic cytopenia; or blasts 31-50% if >/=65 years or previously-treated disease; and platelets
Result Of 25 patients, 10 had prior therapy, which was chemo in 7; of these 6 had blasts >/=10%, 2 with blasts 20% or above. Of the 15 de-novo patients, 7 had blasts >/=20% (AML) and a further 2 had blasts between 10 and 19%. The median platelet count was 38x10^9/L (range 8-127). A median 11(2-24) cycles AZA and 6 cycles of EPG were delivered. One patient developed GrII EPG-related LFT abnormalities (resolved). Grade 3 fatigue was attributed to the combination in one patient. Thrombocytosis (>450 x109/L) resulting in EPG cessation occurred in 6 (at 50, 50, 150 and three at 200mg), without complications. 10 patients experienced reversible skin yellowing. Response/improvement was seen in 18 (72%): 7CR, 3CRm, 5HI-P,1 HI-N,2 with >50% blast reduction from >20% (8%). 5 patients had progression at first response. There were 19 events in total (17 progressions, 2 with worsening haematology). Median PFS was 12.0 months (95% CI 5.6 to 24.3 months). Median OS was 15.3 months (95% CI 11.9 to 31.7 months).
Platelet improvement was seen in 54% (13/24) of patients with baseline platelets <100 at median (range) at 46d (7-107) following commencement of AZA. Only one patient (4%) had an improvement in platelets following the monotherapy phase.
Conclusion Eltrombopag could be safely delivered at these doses. A phase III international study has commenced to better define the role of this combination as supportive care for patients undergoing treatment with azacitidine. Table:Characteristics and best responses observed.MDS/AML CharacteristicsBest ResponseMDS <20% Blasts, De Novo (N=7)5CR, 1SD, 1 HI-NAML >/=20%, De Novo (N=8)1CR, 1PR, 3 Hi-P, 1SD, 2 PDPrior therapy for MDS/AMLBlasts <20% (N=7)1CR, 3CRm, 1SD, 1PD, 1Hi-PPrior therapy for MDS/AMLBlasts >/=20% (N=3)2PD, 1 Hi-P
Figure: Overall survival of the trial population. Figure:. Overall survival of the trial population.

Disclosures
Dickinson: GSK: Consultancy; Celgene: Honoraria. Off Label Use: Eltrombopag for MDS. Sardjono:GSK: Employment. Seymour:Celgene: Consultancy, Honoraria, Speakers Bureau. Kenealy:Celgene: Honoraria, Research Funding. Prince:Celgene: Consultancy, Honoraria, Research Funding.
Clinical Presentation and Treatment Responses in IgM AL Amyloidosis, a Series of 106 Patients
Authors: Sloan John Mark , Sissoko Moussa , Seldin David C , Sworder Brian , Angelino Kennneth , Broce Mike , Berk John L , Sanchorawala Vaishali 
Published: October 2019

Abstract
Objective: AL amyloidosis is a multiorgan disease due to deposition of misfolded monoclonal immunoglobulin light chains. AL amyloidosis with IgM paraproteinemia is a rare variant of this disease; accounting for approximately 6% of AL amyloidosis cases. The clonal cell of origin may be a plasma cell or lymphoplasmacytic cell, and treatments targeting each have been employed. This study describes clinical and laboratory features of IgM AL amyloidosis patients and their response to different therapeutic regimens.
Methods: 106 patients with IgM-related AL amyloidosis were evaluated at the BUMC Amyloidosis Center during 1996-2012. Treatment and response information was available on 46 treated after 2003, during the era of new agents for plasma cell diseases. In this cohort, there were 5 treatment groups: high-dose melphalan/stem cell transplant (HDM/SCT); bortezomib-based regimens; standard doses of the alkylating agents melphalan or cyclophosphamide; immunomodulatory agents (IMiDs); and rituximab-based regimens. Treatment regimens were assigned by bone marrow pathology and patient-specific factors.
Results: For the 106 patients, the median age at diagnosis was 67 years (range: 38-89 years) with 52 (56%) males. The kidney was the most commonly involved organ (51%) followed by heart (41%) and GI tract (23%). Median IgM was 590 g/dL (range: 29-9130). The clonal population had lambda light chain restriction in 69% of patients. For the 46 patients treated after 2003, overall response rates and rates of very good partial or complete responses were were 100% and 80% respectively, with HDM/SCT; 82% and 30% with bortezomib-containing regimens; 80% and 25% with regimens that included rituximab; 75% and 0% with regimens in which an IMiD was included; and 63% and 20% with other alkylator regimens. There was no association between treatment response and organ involvement, sex, or age.

Disclosures
Sloan: Millenium: Consultancy.
Lovastatin Induces Platelet Apoptosis
Authors: Zhao Qing , Chen Mengxing , Zhou Ling , Zhao Lili , Yan Rong , Dai Kesheng 
Published: October 2019

Abstract
Introduction
Lovastatin, the inhibitors of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, is widely used in treatments of coronary artery diseases. Lovastatin induces apoptosis in nucleate cells, such as macrophages, cancer cells, and skeletal muscle cells. Lovastatin has side effects of thrombocytopenia and hemorrhage, however, the possible pathogenesis of the side effects have still remained unknown.
Methods and Results
In this study, we found that collagen and thrombin-induced platelet aggregation was obviously reduced in platelets treated by lovastatin, while platelet activation (expression of P-selectin or PAC-1 binding on platelet surface) was not detected. The apoptosis markers in both intrinsic mitochondrial pathway (ΔΨm changes, PS exposure, Bax/Bak and Bcl-XL expression, and caspase9/3 activation) and extrinsic pathway (caspase 8) were detected in platelets treated with lovastatin. Apoptosis decreased in platelets after being pretreated by tetrapeptide arginine-glycine-aspartic acid-serine (RGDS) peptide (the GPIIb/IIIa antagonist). Lovastatin was
intraperitoneally injected into C57 mice at a dose of 5 mg/kg for four hours. The circulating platelets were significantly decreased by lovastatin compared with that of vehicle control.
Conclusion
Lovastatin induced platelet apoptosis by both intrinsic mitochondrial and extrinsic pathways, which might be the possible pathogenesis of thrombocytopenia or hemorrhage in patients treated with lovastatin.

Disclosures
No relevant conflicts of interest to declare.
Do Sexual Hormones Influence the Coagulation Parameters during the Normal Menstrual Cycle
Authors: Halimeh Susan , Rott Hannelore , Osseiran Ihsan , Kappert Guenther , Siebert Manuela 
Published: October 2019

Abstract
Introduction:
The blood coagulation can be influenced by different variables like mental stress, physical activity or oral anticoagulants. During the normal menstrual cycle changes have been observed on different time points. A study of Chaireti et al (1) found an association of progesterone and factor II, factor VII and factor X.
We investigated the possible influence of the sexual hormones on the coagulation parameters.
Samples and methods:
We conducted a laboratory work group in 35 women sent to our lab. The following tests were conducted: Blood count, VWF:RCo, VWF:Ag, VWF:CB, Fibrinogen (Clauss), activities of FII, FV, FVII, FVIII (clotting and chromogenic), FIX, FX, FXI, FXII, FXIII, FSH, LH, Progesterone and Oestradiole during the menstrual cycle on predefined time points (day 1-6, day 7-11, day 12-18, day 19-23, day 24-28).
Results:
We found slight variations in nearly all coagulation parameters but without significance. The box-plots of the Von Willebrand activity shows that the means are relative close together. Clear variations could not be found. The Friedman-Test showed no significance. As expected the changes of the sexual hormones during the menstrual cycle showed highest significance.
Conclusion:
The influence of sexual hormones on coagulation parameters was not significant. The slight fluctuations may be caused by imprecision of the measurement and intra individual changes from day to day. Changes during the menstrual cycle could not be verified.
Nevertheless it is advisable to investigate unclear negative results, when a conspicuous medical history or a corresponding clinic occurs. It is not necessary to regard the time point in the menstrual cycle for the blood collection.
Literature: Chaireti R, Gustafsson KM, Byström B, Bremme K, Lindahl TL, Endogenous thromboin potential is higher during the luteal phase than during the follicular phase of a normal menstrual cycle, Hum Repro, 2013 Jul, 28 (7) 1846-52

Disclosures
No relevant conflicts of interest to declare.
Since the Process of Transfusion-Induced Alloimmunization Is Not Harmless, Can We Mitigate It?
Authors: Szymanski Irma O. , Orton Sharyn L 
Published: October 2019

Abstract
Transfusion protocols have remained unchanged for decades. Accordingly, it is necessary to avoid transfusion reactions by giving patients ABO- and irregular antibody-compatible red blood cells (RBC). Prevention of immunization to the Rh antigen D is also required since anti-D may cause a serious hemolytic disease of fetus and newborn. Prevention of transfusion-induced immunization to other blood group antigens is neither required nor feasible for the general transfused population.
We consider the process of alloimmunization to be harmful due to the following untoward effects: 1) Destruction of transfused RBC negates transfusion's intended therapeutic benefits and may cause transfusion reactions. 2) Some alloantibodies become undetectable after a relatively short period (e.g., anti-Jka) so that in the future such seemingly compatible transfusions cause severe, sometimes fatal delayed transfusion reactions. 3) RBC autoimmunity may follow alloimmunization and cause hemolytic anemia in the recipient.
To take the first step toward preventing transfusion-induced alloimmunization we calculated, using our antibody database, the immunogenicity of RBC antigens in a predominantly white female and male populations according to the methods of *Giblett (Transfusion 1961;1(4): 233) and **Tormey and Stack. (Blood 2009;114: 4279). The latter method corrects immunogenicities for antibody evanescence. The Table below shows that the three highly immunogenic antigens against which clinically significant antibodies were frequently formed were E, Jka and K, both in females and males. Immunogenicity of Rh C antigen was not calculated, since anti-C occurs most often with anti-D.
Figure 1 Figure 1.
In summary, we suggest a first step toward improving immunological safety of RBC transfusions by preventing immunization to E, Jka and K antigens. Automated typing or DNA analysis would facilitate mass typing of both donors' and recipients' RBC antigens.

Disclosures
No relevant conflicts of interest to declare.
miRNA Expression Profiling in Mesenchymal Stromal/Stem Cells Derived from G-CSF Primed Bone Marrows
Authors: Gunel-Ozcan Aysen , Cagnan Ilgin , Kansu Emin , Uckan Duygu 
Published: October 2019

Abstract
Regulatory microRNAs (miRNAs) are involved in the molecular control of hematopoiesis and diseases that result from aberrations during this process. Bone marrow (BM) transplantation is a commonly used therapy for patients with certain hematopoietic diseases. Prior to BM transplantation, donors are occasionally treated with granulocyte colony-stimulating factor (G-CSF) to increase the number of hematopoietic stem or progenitor cells in the collected stem cell product. Here we aimed to assess the effects of G-CSF priming on miRNA expression of BM derived mesenchymal stromal/stem cells (BM-MSCs) from healthy donors.
Previously isolated and characterized BM-MSCs from 3 days G-CSF (10 μg/kg/d) treated (n=5) and untreated (n=8) healthy donors were used for miRNA expression profiling with Affymetrix GeneChip 2.0 Array. Following Robust Multi-array Average (RMA) normalization, data analysis was carried out in Partek Genomics Suite software package (Partek Incorporated). Differentially expressed miRNAs between G-CSF primed and unprimed groups were determined (p<0.05, fold change ±1.5).
A total of 2156 miRNAs were upregulated whereas 2436 miRNAs were downregulated after in-vivo G-CSF priming. The expression of hp_hsa-mir-1238 and has-miR-3180-3p non-coding RNAs was significantly increased in G-CSF primed BM-MSCs (p<0.001). Modular enrichment analysis of hsa-miR-3180-3p predicted target genes by GeneCodis 3 software revealed that some may play a role in different types of cancer such as small cell lung cancer (Adjusted p-value: 8.47338e-7, 0.000382029). Our data indicate that G-CSF treatment changes miRNA expression of bone marrow stromal cells (MSCs) and this change might be important to evaluate for long-term biosafety.

Disclosures
No relevant conflicts of interest to declare.
Bone Marrow Contains High Levels of Microparticles
Authors: Rank Andreas , Nieuwland Rienk , Koehler Anton , Kolb Hans Jochem , Toth Bettina 
Published: October 2019

Abstract
Background: Microparticles (MP) are shed in humans from a broad variety of cells and play an important role in activation of coagulation, cell to cell interaction and transport of membrane components. Alternations in plasma levels have been found in a variety of diseases, mostly associated with thrombosis and inflammation. However, little is known about tissue levels of MP. The aim of this pilot study was to investigate the bone marrow compartment as a possible source of circulating MP.
Material and Methods: MP were analysed in bone marrow blood and peripheral blood in 12 healthy stem cell donors. MPs were isolated and measured by flow-cytometric double-staining (FACScalibur, BD) with Anexin V and cell-specific antibodies for hematopoietic cells, platelets, white blood cells, red blood cells and endothelial cells. Statistical analysis was performed with SPSS for Windows 20.0.
Results: Total MP levels differed between bone marrow and peripheral blood: 14.8 x109/l [8.5–19.3] vs. 9.2 x109/l [3.8–14.8] (median value [25-75 percentile]), p=0.060. Pattern of MP´s origin varied likewise: in bone marrow blood (bmb), main cell source of MP were CD235a positive red blood cells/erythropoetic cells (6.4x109/l [3.7–13.7], 43.2% of total bmb MP), CD61 positive platelets/megacaryocytes (4.1x109/l [1.7–10.1], 27.7% of total bmb MP), CD45 positive leucocytes/myeloic and lymphatic progenitor cells (3.8x109/l [2.7-4.9], 25.7% of total bmb MP) and CD62e positive endothelial cells (0.3x109/l [0.1-1.0], 2.0% of total bmb MP). In contrast, MP in peripheral blood (pb) mainly derived from CD61 positive platelets/megacaryocytes (8.5x109/l [2.4–14.4], 92.0% of total pb MP), CD45 positive leucocytes/myeloic and lymphatic progenitor cells (0.5x109/l [0.2–1.1], 4.5% of total pb MP), CD235a positive red blood cells/erythropoetic cells (0.2x109/l [0.1–0.6], 1.8% of total pb MP), and CD62e positive endothelial cells (0.1x109/l [0.0–0.1], 0.9% of total pb MP). Mean levels of tissue factor bearing MP were low in bone marrow blood as well as in peripheral blood (0.19 x109/l [0.16 – 0.29] and 0.08 x109/l [0.05 – 0.12], respectively, p=0.004).
Conclusion: Within our study we were able to detect MP in bone marrow blood. When comparing MP from bone marrow and peripheral blood, major differences with regard to cell source and concentration was present. Our data suggest that the blood – bone marrow barrier is not only existentant for cells, but also for circulating MP.

Disclosures
No relevant conflicts of interest to declare.
A New Approach of PNH Clone Detection
Authors: Galtseva Irina V. , Fidarova Zalina T. , Mikhailova Elena A. , Borisov Vyacheslav I. , Troitskaia Vera V. , Parovichnikova Elena N. , Savchenko Valeri G. 
Published: October 2019

Abstract
Introduction
The presence of the CD157 GPI-protein on both monocytes and granulocytes only gives opportunity to use it as a target for paroxysmal nocturnal hemoglobinuria (PNH) phenotype cells detection instead of CD24 and CD14, thus improving the technique of PNH-cells evaluation. In present study we used standard technique (International Clinical Cytometry Society (ICCS) guideline proposal) together with 5 color combination of mAbs for detection of PNH-clone on the monocytes and granulocytes simultaneously in one test-tube.
Objectives: improvement of PNH cells detection technique.
Materials and methods: Blood samples were collected from 37 patients (pts) with bone marrow failure syndrome (aplastic anemia – 34 pts., PNH - 2 pts., myelodysplastic syndrome – 1 pt.; 23 female and 14 men; median age 24 (15 to 66). PNH clone was detected by flow cytometry in all 37 pts. Three healthy donors were in control group.
The comparison of the standard 4-color technique of PNH clone size detection on monocytes (FLAER, CD14, CD64, CD45 reagents) and on granulocytes (FLAER, CD24, CD15, CD45 reagents) with the 5-color technique using CD157 GPI-protein antibodies for the both cells populations in one test-tube (FLAER, CD157, CD15, CD64, CD45) were performed.
Results: Both methods showed the same high sensitivity for determining of PNH clone. The correlation coefficient was 0,9994 for granulocytes and 0,9924 for monocytes (Figure 1).
Figure 1 Figure 1.
In group of patients with minor PNH-clone (range from 0,01% to 0,99%) the clone size was twice times bigger on monocytes compared to granulocytes using the standard method, whereas with antibodies against CD157 this difference disappeared. In patients with PNH-clone between 1% and 10% the clone was nearly three times less on granulocytes than monocytes using both methods; in the group with clone more than 10% there was no differences between cells populations.
Table 1. Average value of PNH clone on leukocytes in groups of patients both techniques PNH clone Gr, % (mean) Mon, % (mean) CD24-/FLAER- CD157-/FLAER- CD14-/FLAER- CD157-/FLAER- 0%-0,99% 0,178 0,349 0,323 0,378 1%-9,99% 3,98 3,76 9,54 9,98 >10% 71,52 71,52 71,85 71,34
Conclusion: The results of the PNH clone detection obtained with CD157 mAbs are comparable with the standard technique proposed by ISSC. However, the use of CD157 antibodies has important advantage: the PNH clone size detection in one test-tube with 5-color combination reduces time and expenses. Additionally, using of 5-color CD157 antibodies kit would be preferable for the monitoring and detection of minor PNH clone.

Disclosures
No relevant conflicts of interest to declare.
IgG Subclasses Abnormal in Immune-Related Pancytopenia
Authors: Shao Zonghong , Shao Yuanyuan , Fu Rong 
Published: October 2019

Abstract
In recent years, we found some patients with idiopathic cytopenia of undetermined significance (ICUS)responded well to corticosteroid and/or high-dose intravenous immunoglobulin treatment. We had detected both IgG and IgM antibodies by bone marrow mononuclear-cell-Coombs test, flow cytometric and immunofluorescence analysis on the various bone marrow cell membrane. We also detected IgG in the BM supernatant of these ICUS patients, which can target several antigens on hematopoietic cells membranes by western blot. Then We termed this group of ICUS cases with autoantibodies as immuno-related hemocytopenia(IRP). IgG include IgGl, IgG2, IgG3, IgG4. IgG subclass defects, increased or imbalance in autoimmune diseases, infectious diseases, cancer and other diseases is an indication of the immune response, and IgG subclass in the development of the disease process also plays a different effect. Analysis of IgG subclass is beneficial for the disease etiology, pathogenesis and prognosis. 46 IRP patients and 20 normal controls were enrolled in this study. 58.69% patients’ hematopoietic cell antibody IgG were positive tested by flow cytometric. Hematopoietic cell antibody IgG-positive patients’ bone marrow supernatant were detected and analyzed, IgG1 and IgG3 were increased in the bone marrow supernatant of the patients with IRP, positively related to CD5+ B lymphocytes, and negative correlated with hematopoietic function. Further studies are needed to confirm which IgG subclass plays an important role in the pathogenesis of IRP.

Disclosures
No relevant conflicts of interest to declare.
Proteomics Profiles of CD34+ Cells in Bone Marrow of Patients with Severe Aplastic Anemia
Authors: Shao Zonghong , Qi Weiwei , Fu Rong 
Published: October 2019

Abstract
Objective
Application of isobaric tags for relative and absolute quantification (iTRAQ) technology, the proteins of CD34+ cells in bone marrow for patients with severe aplastic anemia (SAA) and normal controls were analyzed. To obtain differential proteomics profiles of CD34+ cells in bone marrow for SAA specificity. To preliminary screen the autoantigen which may cause immune system hyperfunction in SAA, providing a theoretical basis for further elucidating the immune pathogenesis of SAA.
Methods
Untreated SAA patients, remission SAA patients, as well as normal controls in Tianjin Medical University General Hospital from 2013.1 to 2014.2 were enrolled in this study. CD34+ cells in bone marrow for 29 cases of recovery SAA patients and 10 normal human were purified by immunomagnetic cell sorting, total protein were extracted and were processed enzymolysis, labeled sample by iTRAQ reagent, then analyzed the protein of sample by multidimensional liquid chromatography tandem mass spectrometry of Q Exactive, identified proteins by application of database, compared the different expression of proteins between SAA patients and normal controls, to preliminary screen the autoantigen which may cause immune system hyperfunction in SAA.
Results
Expression of differential proteomic profiles for CD34+ cells in SAA bone marrow were obtained. The protein confidence > 95% and identification of peptide protein false positive rate < 1% were limited, 15120 peptides and 3208 protein were identified. The Ratio of different proteins (SAA group/ normal group) greater than 2.794 and less than 0.323 and the confidence limit greater than 95% were limited , 157 different proteins with high confidence were identified, of which 54 up-regulated proteins, 103 down regulated proteins. The physiological function of proteins involved cell apoptosis, cell cycle, RNA splicing and metabolism, protein modification and transfer, the ubiquitin proteasome mediated protein degradation.
Conclusions
The proteome profiles of CD34+ cells in SAA bone marrow were obtained successfully, and it was proved that iTRAQ marker tandem mass spectrometry for proteome of bone marrow cells for patients with SAA was an effective method. It was found that 157 abnormal expression proteins of CD34+ cells in SAA bone marrow, the function of proteins mainly involved apoptosis, cell cycle, protein modification and transport, RNA processing and splicing, the ubiquitin proteasome system. We preliminary predicted autoantigen which may cause SAA immune "waterfall" activation.

Disclosures
No relevant conflicts of interest to declare.