bluuebunny/crossref_metadata_2025_split huggingface dataset:
Donor Versus No Donor Analysis of Newly Diagnosed Myeloma Patients Included in the HOVON 50/54 Study
Authors: Lokhorst Henk , Sonneveld Pieter , van der Holt Bronno , van Oers Marinus , Raymakers Reinier , Zweegman Sonja , Minnema Monique C. , Zijlmans Mark 
Published: April 2020

Abstract
The value of allo-SCT in myeloma is disputed. Prospective randomized trials are the gold standard for the evaluation of treatment efficacy; however such a design is difficult to perform in an allo-setting. As the availability of a matched sibling donor is a random process, the presence or absence of a donor can be used as a surrogate for randomization. Patients with an HLA–identical sibling donor, included in the phase-III HOVON50 study, that was designed to assess the effect of thalidomide in induction treatment and as maintenance after high-dose therapy (HDM 200 mg/m2) and auto-SCT could proceed to the Hovon 54 study in which an Allo-SCT after conditioning with low dose TBI only was performed between 2–6 months after HDM. In the first survey performed in a subset of patients that had received at least 1 course of HDM and for whom tissue typing data were already available, 124 could be classified as having a sibling donor and 124 as having no sibling donor. Tissue typing data of another 81 patients are still waited for. Both groups were comparable with regard to age, myeloma stage, and prognostic factors including cytogenetics and ISS stage. 94% of the patients in the no donor group achieved at least a PR (35% CR, 32% VGPR and 26% PR), versus 96% of the patients in the donor group (40% CR, 34% VGPR and 22% PR). After a median follow-up of 38 months after HDM, PFS and OS were also comparable between the two groups. Median PFS was 32 versus 28 months for the donor group and no donor group respectively (P=0.44), while median OS was 61 and 54 months (P=0.14). Among the 98 patients in the donor group who received an allo-SCT non relapse mortality was 10% at 1 year and 13% at 3 years after allo-SCT. This first preliminary analysis showed no improvement of tandem Auto Allo-RIC as part of first line therapy in myeloma as compared Auto-SCT followed by maintenance therapy. A longer follow-up may be needed for definite conclusions. An update of the results including those patients with yet unknown tissue typing status and longer follow up will be presented
Lentivirus-Mediated RNA Interference Targeting Vascular Endothelial Growth Factor Gene Enhances the Sensitivity of K562 Cells to Imatinib
Authors: Li Li , Zhang Ri , Cen Jiannong , Zhu Ziling 
Published: April 2020

Abstract
Background: Vascular endothelial growth factor (VEGF), one of the most potent mediators of angiogenesis, plays an important role in tumor cell proliferation and migration. Elevated VEGF levels are found in both the plasma and the bone marrow of patients with chronic myelogeneous leukemia(CML). Moreover, the CML-associated oncogene Bcr-Abl induces endogenous secretion of VEGF. The aim of this study was to construct a lentiviral vector-mediated RNA interference (RNAi) of vascular endothelial growth factor (VEGF) gene and to investigate the effects of RNAi inhibiting VEGF gene alone or in combination with imatinib on the proliferation and apoptosis of K562 leukemic cell line.
Methods: A lentiviral expression vector containing short hairpin RNA (shRNA ) targeting VEGF was constructed and cotransfected with the pPACKH1 packaging plasmids mixture into 293T cells by Lipofectamine 2000. K562 cells were infected with the packaged lentivirus. The levels of VEGF mRNA and protein were detected by real-time quantitative RT- PCR, Western blot and ELISA. Cellular proliferation was determined by trypan blue exclusion and MTT assay. imatinib -induced apoptosis was analyzed by flow cytometry.
Results: The lentiviral shRNA vector targeting VEGF has been constructed and transfected into K562 cells successfully. The expression of VEGF mRNA and protein in K562-shVEGF cells transfected with pRNAT-shRNA were significantly inhibited when compared with those of K562 and K562–con cells (mock transfection). The proliferation rate of K562-shVEGF cells slowed down. After imatinib treatment, the percentages of apoptotic cells in K562-shVEGF cells increased more significantly than those of K562 and K562–con cells.
Conclusion: Suppression of VEGF by lentivirus-mediated RNAi could effectively inhibit proliferation and increase the sensitivity of K562 cells to imatinib. These results indicate that Bcr/Abl-targeting compound in combination with anti-angiogenic therapies may provide a potent therapeutic strategy to CML.
Small-Molecule Screen Identifies ROS as Key Regulators of Actin Dynamics in Neutrophils
Authors: Hattori Hidenori , Subramanian Kulandayan K , Luo Hongbo R. 
Published: April 2020

Abstract
Precise spatial and temporal control of actin polymerization and depolymerization is essential for mediating various cellular processes such as migration, phagocytosis, vesicle trafficking and adhesion. In this study, we used a small-molecule functional screening approach to identify novel regulators of actin dynamics during neutrophil migration. Here we show that NADPH-oxidase dependent Reactive Oxygen Species act as negative regulators of actin polymerization. Neutrophils with pharmacologically inhibited oxidase or isolated from Chronic Granulomatous Disease (CGD) patient and mice displayed enhanced F-actin polymerization, multiple pseudopods formation and impaired chemotaxis. ROS localized to pseudopodia and inhibited actin polymerization by driving actin glutathionylation at the leading edge of migrating cells. Consistent with these in vitro results, adoptively transferred CGD murine neutrophils also showed impaired in vivo recruitment to sites of inflammation. Together, these results present a novel physiological role for ROS in regulation of action polymerization and shed new light on the pathogenesis of CGD.
Clinical Characteristics in Neonates with Alloimmune Neutropenia: Significance of the Detection of Antineutrophil Antibodies
Authors: Mizoguchi Yoko , Nakamura Kazuhiro , Karakawa Shuhei , Sato Takashi , Onodera Rie , Kurita Emi , Hiraoka Asako , Taniguchi Kikuyo , Kobayashi Masao 
Published: April 2020

Abstract
Neonate alloimmune neutropenia (NAIN) is caused by the transplacental transfer of maternal alloantibodies directed against antigens on the infant’s neutrophils. To date, there are scant studies about its clinical characteristics and characterization of antineutrophil antibodies though some case reports are found. In this study we analyzed 11 cases with NAIN from January 2005 to December 2007. The diagnosis of NAIN was confirmed by the transient neutropenia less than 500/μl of absolute neutrophil count (ANC), the detection of maternal antineutrophil antibody, the incompatibility of neutrophil antigens between parents, and their mothers without autoimmune diseases. Antineutrophil antibodies were detected by granulocyte indirect immunofluorescence test using flow cytometry. To quantify the strength of the antibodies, the ratio of the mean fluorescence channel of each sample to that of control serum was expressed as relative fluorescence intensity according to the method reported previously (Blood99: 3468, 2002). The median age at diagnosis in NAIN patients was 8 days after birth ranged from 0 to 30 days. The average of ANC at the presentation was 170/μl ranged from 0 to 500/μl. All antineutrophil antibodies detected in sera of both neonates and their mothers were against HNA-1 antigens. The alloantibody against HNA-1a was found in 2 cases, that against HNA-1b was in 6 cases, and that against FcγR IIIb was found in 3 cases. The fact that the frequencies of homozygote of HNA-1a and HNA-1b in Japanese population were approximately 50% and 12%, respectively may reflect the frequency of alloantibody specificity in NAIN. During the neutropenic period, 7 cases with NAIN showed mild to moderate infections associated with neutropenia, such as pyrexia and pyodermia. In contrast, 4 of 11 cases with NAIN did not have any infectious episodes in their clinical course. In all patients, the spontaneous recovery of neutropenia with the disappearance of alloantibody was observed within 6 months (median 85 days ranged from 3 weeks to 6 months). The duration until spontaneous resolution of neutropenia was dependent on the strength of alloantibody found in sera of the mothers and neonates. Two patients with significantly high strength of alloantibodies had the relatively long duration to restore the neutropenia(4 months and 6 months). In conclusion, the specificity of antineutrophil antibodies in patients with alloimmune neutropenia is dependent on the frequencies of neutrophil antigens in Japanese population. The quantification of alloantibodies in neonates and their mothers may be useful in considering the clinical course of neutropenia in neonates.
Folate Receptor Saturation, Recycling, and Release Kinetics in Activated Macrophages
Authors: Varghese Bindu , Vlashi Erina , Low Philip S. 
Published: April 2020

Abstract
Activated macrophages over-express a receptor for the vitamin, folic acid. Conjugation of folic acid to low molecular weight drugs, genes, liposomes, nanoparticles, and imaging agents does not significantly compromise the vitamin’s affinity for its receptor, thus facilitating both therapeutic and imaging agents to be targeted as folate conjugates to activated macrophages. In these studies the in vivo kinetics and binding characteristics of the folate receptor on macrophages has been characterized with the objective of optimizing targeted drug delivery. Our results show that saturation of the receptor in inflamed tissues can be reached at a dose of 100 nmol/kg. Furthermore, the rapid recycling characteristics of the receptor (every 10–20 minutes) suggests that frequent dosing will allow for maximal uptake of folate conjugates by activated macrophages accumulated in inflamed tissues. Finally, the short circulation half-life (30 minutes) of the water-soluble folate conjugate used in this study minimizes the possibility of nonspecific uptake by receptor-negative tissues. The kinetic observations made in this study can be utilized to optimize the therapeutic efficacy and imaging agent delivery of folate conjugates to activated macrophages in vivo.
Single Use of Rasburicase (rasb) Leads to Insufficient Tumor Lysis Syndrome (TLS) Control in Adults: Outcome and Resource Utilization in a One Year Real-Life Observational Study
Authors: Krych Matthaeus , Ostermann Julia , Hiddemann Wolfgang , Ostermann Helmut 
Published: April 2020

Abstract
TLS due to the rapid lysis of tumor cells following initiation of chemotherapy can lead to the release of intracellular components into the extracellular space. Among these hyperuricemia might exceed the excretory capacity of the kidneys and lead to renal failure. Rasb is a recombinant urate oxidase given during the first 3–5 days of chemotherapy to effectively lower uric acid serum levels. Limited data suggest that a single prechemotherapy dose of rasb might be sufficiently efficacious and this single dose regimen is widely used to reduce treatment costs.
We analyzed the clinical and economical data of all adults who received rasb for prophylaxis or treatment of TLS at a university hospital during a one year period. The goal was to describe treatment patterns and outcome outside of clinical trials and to verify whether patients with TLS can be treated cost-effectively. 38 patients (pts) received rasb, however 1/3 of the pts were treated off-label for other reasons then TLS. 24 pts (median age 66 yrs, 21 male) received rasb for malignancy-associated hyperuricemia and were eligible for further clinical and economical evaluation. 2/3 of these pts were treated for hematological malignancies (acute leukemia 6pts, lymphoma 8 pts) and 8 pts for solid tumors. Apart from hydration (mean volume 2 l per day; all pts), furosemide (mean dose 80 mg/day; all pts) and urinary alkalinization with sodium bicarbonate (pH &gt; 7; 7 pts), 20 patients received a single 7,5 mg dose of rasb and 4 pts received multi dose. In 14 pts a tumor lysis was observed. 6 pts died, three fatalities were directly associated with TLS. Mortality was higher among pts with single dose rasb vs. multi dose rasb (30% vs. 0 %) and higher among patients with urinary alkalinization (71% vs. 5%). No anaphylaxis, hemolysis or methemoglobinemia was observed in this cohort.
The mean duration of hospitalisation was 23 days, the mean treatment costs were 16.200 €. The costs exceeded the revenues based on diagnosis related groups for Germany (G-DRG) in 18 pts and resulted in a 7% funding gap. 107.000 € were spent for drugs for these patients, 10% of these for rasb.
We conclude from this observational study that
TLS is a menacing disease, resulted in a 12,5 % mortality and should therefore be cautiously monitored and treated, single dose rasb was associated with a higher mortality rate then multi dose, urinary alkalinization cannot be recommended when rasb is used, TLS leads to a 7 % underfunding in the respective G-DRGs, for TLS pts. the usage of rasb elevates the total drug expenses by 10%.
Differential Regulations and Roles of Mcl-1 and Bcl-Xl during Megakaryopoiesis
Authors: Oh Doyeun , Yoon Seongmin , Park Seonyang , Bae Jeehyeon 
Published: April 2020

Abstract
Backgrounds: Platelet plays an essential role in thrombosis and hemostasis and is produced from hematopoietic stem cells through a serious of differentiation and maturation processes called megakaryopoiesis. The major factor known to control platelet formation is thrombopoietin (TPO), but recently more proteins including apoptosis regulators have been reported to involve in megakaryopoiesis. Evolutionally conserved Bcl-2 family proteins are central regulators of apoptosis. Antiapoptotic Bcl-2 subfamily comprised of Bcl-xL, Mcl-1, Bcl-2, Bcl-w, and Bfl-1 plays a pivotal role in controlling cell death and survival under various conditions. According a recent study, Bcl-xL is a key molecular clock that determines the life span of platelets, but the role and regulation of Bcl-2 members in megakaryopoiesis are largely unknown.
Methods and Results: We have established an in vitro system of megakaryopoiesis and performed the profiling of Bcl-2 family genes during megakaryocytosis. We found that Bcl-xL and Mcl-1 were predominant molecules among other members of the pro-survival proteins as determined by quantitative RT-PCR. TPO differentially regulates Bcl-xL and Mcl-1 in Meg-01 cells, in which Bcl-xL protein was significantly up-regulated while the level of Mcl-1 was attenuated. Furthermore, the roles of Bcl-xL and Mcl-1 during megakaryopoiesis were determined by modulating the expression levels of two proteins. Overexpression of Mcl-1 prominently enhanced the viability of the cells, whereas the knockdown of Mcl-1 promoted apoptosis of the cells. In contrast, forced expression of Bcl-xL did not affect the cell survival but rather significantly stimulated differentiation of megakarycytes.
Conclusion: Bcl-xL and Mcl-1 are likely essential molecules during megakaryopoiesis. Moreover, the present study implies that although both Bcl-xL and Mcl-1 are members of antiapoptotic Bcl-2 family that promote the survival of different cells, these two proteins have distinctive and non-redundant functions in megakaryocytes.
Mobilization of Hematopoietic Progenitors Following Myocardial Ischemic Injury Underpins the Physiological and Therapeutic Benefits of G-CSF on Myocardial Repair
Authors: Curtis Davi D J. , Kanellakis Peter , Bobik Alex 
Published: April 2020

Abstract
Despite promising pre-clinical results, administration of granulocyte-colony stimulating factor (G-CSF) for improving heart function in humans after acute myocardial infarction has been disappointing. Therefore, a better understanding of the mechanism(s) of heart repair by G-CSF is urgently required. To address the potential mechanism of G-CSF, we have generated chimeric mice using G-CSF receptor knockout mice to distinguish the hematopoietic benefits of G-CSF from the direct effects of G-CSF on cardiomyocytes and blood vessels. Lethally irradiated wild-type mice were reconstituted with G-CSFR −/− bone marrow (BM) cells to generate G-CSFR BM −/− chimeras. Alternatively, lethally irradiated G-CSFR −/− mice were reconstituted with wild-type BM cells to generate G-CSFR cardiac −/− chimeras. Myocardial ischemic injury was induced by transient (60 minutes) occlusion of the left coronary artery. Mice were treated daily with saline or G-CSF for 5 days beginning 4 hours after ischemic injury. Mice were sacrificed 28 days post-injury for assessment of cardiac function and cellular repair. As previously reported in wild-type mice, G-CSFR −/− cardiac chimeras had 30–50% improved cardiac function compared with saline-treated G-CSFR −/− cardiac chimeras (ANOVA; P&lt;0.05). This suggests that the benefits of G-CSF are NOT due to direct effects on cardiomyocytes or blood vessels, as previously proposed by Harada et al. (Nature Medicine2005; 11: 305–311). In contrast, G-CSF BM −/− chimeras had dramatically impaired cardiac repair following ischaemic injury. The most striking finding was that saline-treated G-CSFR BM −/− mice had 20% worse cardiac function and cellular repair than saline-treated control G-CSFR BM +/+ mice (ANOVA; P&lt;0.05). Furthermore, G-CSF treatment in G-CSFR BM −/− mice produced no significant benefit on cardiac function or cellular repair. The lack of benefit of G-CSF in these mice was due to an inability of G-CSF to mobilise hematopoietic progenitors because treatment of G-CSFR BM −/− mice with the CXCR4 antagonist, AMD3100 improved cardiac function and cellular repair as well as G-CSF in control G-CSFR BM +/+ mice. Together, these results suggest that mobilization of hematopoietic progenitors is a critical component of not only the therapeutic but also physiologic effects of G-CSF for repair after acute myocardial ischemic injury.
Multiple Site Gfi1b Self-Regulation and GATA1/SCL Pentameric Complex: Shifting the Equilibrium towards Repression
Authors: Hernández Aurora , Villegas Ana , Iborra Francisco , Wood William G. , Anguita Eduardo 
Published: April 2020

Abstract
Transcription factor Gfi1b is required for erythroid and megakaryocytic differentiation. Gfi1b is over-expressed in patients and cell lines of erythroid and megakaryocytic leukemias. This indicates that this gene must be tightly regulated to achieve normal erythropoiesis and megakaryopoiesis. The mechanism of it is largely unknown. We have searched for conserved noncoding sequences from multiple evolutionary diverse species (multispecies conserved sequences, MCSs) between Gfi1b neighboring genes and localized several elements containing multiple highly conserved erythroid specific transcription factor binding sites. These MCSs localize with erythroid specific DNasa1 hypersensitive sites. Chromatin immunoprecipitation (ChIP) assays demonstrated GATA1/SCL/E2A/Ldb1/LMO2 pentameric complex and NF-E2, together with Gfi1b, binding in human and mouse cell lines and primary cells representing different stages of erythropoiesis and megakaryopoiesis. Analysis of histone modifications and cofactors binding in relation with Gfi1b expression and protein level gives clues about how activating and repressive complexes attach to Gfi1b promoter and potential long distance regulatory elements maintaining an equilibrium that changes with gene downregulation.
Absence of Association Between TNF α Polymorphysm and Cerebral Large Vessel Abnormalities in Adults with Sickle Cell Anemia
Authors: Vicari Perla , Silva Gisele Sampaio , Noguti Maria A E , Neto Faustino Moreira , Santos Normelia Jesus , Massaro Ayrton Roberto , Figueiredo Maria Stella 
Published: April 2020

Abstract
Purpose: Stroke is a common and serious complication of sickle cell disease (SCD) affecting children as well as adults. Recent reports suggested that promoter region polymorphism in the tumour necrosis factor alpha (TNF-α) gene at position −308 is an important risk factor for large vessel stroke in children with SCD. The role of TNF-α polymorphism in the frequency of magnetic resonance angiography (MRA) abnormalities in adults with SCD is still uncertain. Our objective was to evaluate TNF-α polymorphism in adults with SCD from a tertiary University-based hospital in Sao Paulo, Brazil and correlate them to brain magnetic resonance imaging (MRI) and MRA findings.
Casuistic and Methods: The determination of the G-308A polymorphism of the TNF-α gene was performed in forty-nine adult patients with SCD followed in our outpatient clinic. All subjects were evaluated with brain MRI and MRA to determine the presence of previous stroke, arterial tortuosity and intracranial stenosis
Results: Thirty-three patients (67.3%) had abnormal brain MRA scans (intracranial stenosis or arterial tortuosity). Eight patients (16.3%) had intracranial stenosis on MRA and 29 (59.2%) showed arterial tortuosity. Forty one patients (83.7%) had the GG TNF-α (−308) genotype and eight had the GA genotype. There were no cases of AA genotype. There was no correlation between homozygosis for the TNF-α (−308) G allele and MRA abnormalities.
Conclusion: Although TNF-α (−308) polymorphism has been considered a potential predictor of genetic risk for stroke in children with SCA, we found no association between the polymorphism and large vessel abnormalities in adults with sickle cell disease. (FAPESP: 04/04498-4)