bluuebunny/crossref_metadata_2025 huggingface dataset:
Disaster Militarism? Military Humanitarian Assistance and Disaster Relief
Authors: Simm Gabrielle
Published: October 2019

Military assets, which include personnel, make an important contribution to disaster relief. However, military deployments can be politically sensitive, and the relevant international law is contested and not binding. This article compares two sets of UN Office for the Coordination of Humanitarian Affairs (UN OCHA) Guidelines on this issue. The 2007 Oslo Guidelines1 state that military assets should be used in disaster relief only as a last resort, while the 2014 Asia-Pacific Regional Guidelines2 acknowledge that military assets are often the first to respond to disasters in the region. Drawing on examples primarily from Asia, this article explores the apparent conflict between these two UN Guidelines and asks two questions about the deployment of foreign military assets in disaster relief. First, to what extent does international law authorize or limit the deployment of foreign military assets in disaster relief? Second, what are the politics of deploying military assets in disaster relief? This article argues that, rather than representing a global standard, the Oslo Guidelines better reflect European practice within Europe, while the Asia-Pacific Regional Guidelines are more representative of practice worldwide. It concludes that the type of military aid provided is key to its compliance with international law and its political acceptance.
Intelligence, Diplomacy, Entertainment: Catherine II’s Son Tours Europe Incognito
Authors: Ananieva Anna
Published: October 2019

From September 1781 to November 1782 Grand Duke Paul Petrovich, in the company of his wife, Grand Duchess Mariia Feodorovna, visited the major royal courts of Europe under the pseudonym “Comte & Comtesse du Nord.” By emphasizing the ceremonial meanings of high-status incognito tour, this article addresses the seemingly paradoxical relationship between the private status public visibility of the traveling Russian court analyzes the narratives about it in the European press in other documentary accounts related to the tour.
Fragile Treasures and Their “Russianness”
Authors: Karg Josephine
Published: October 2019

This article examines the role of the revival of majolica in the search for a national art. It argues that the reinvention of majolica and the reform of the kustar art industry were intimately linked with the rise of ethnographic research and the revitalization of vernacular culture. The Abramtsevo circle became a nucleus for both. The endeavor to revive national heritage and to encourage the handicraft industry was spearheaded by private patronage, which had largely originated from the new urban elite in Moscow. The works made in the ceramics workshop in Abramtsevo were a significant manifestation of the Neo-Russian style and emblematized the typical “Russian” handicraft objects. This article posits that the revival of majolica pursued two main goals: the manufacture of high-quality products to stimulate the art market and the creation of national “Russian” art through the use of vernacular forms. The invention of a national style was publicized at international exhibitions and through reproduction in art magazines. The painter Mikhail Vrubel, who worked in the Abramtsevo ceramics workshop from 1890 until around 1900, became a key figure in the revival of majolica.
Reforms in the Field of Pensions, Education and Housing, as Portrayed in the Russian Mass Media
Authors: Prisiazhniuk Daria , Holm-Hansen Jørn
Published: October 2019

Welfare reforms in contemporary Russia are based on partial redistribution of responsibilities and resources from the state to other actors, including private business and civil society. Reforms in old age pensions, housing and utilities, primary and secondary education have affected wide social groups and have triggered public debates and protests, reflected in the mass media. This article analyses how these reforms are portrayed in three Russian media outlets representing different political positions—Rossiiskaia gazeta (official government media outlet), Novaia gazeta (independent media outlet belonging to the liberal opposition), and Zavtra (patriotic media outlet belonging to the nationalist opposition). The two independent papers have divergent critical perspectives on reforms. These three Federation-wide newspapers represent the range of political positions that are articulated publicly on non-securitized issues in contemporary Russia.
Comparisons of QPFs Derived from Single- and Multicore Convection-Allowing Ensembles
Authors: Clark Adam J.
Published: October 2019

This study compares ensemble precipitation forecasts from 10-member, 3-km grid-spacing, CONUS domain single- and multicore ensembles that were a part of the 2016 Community Leveraged Unified Ensemble (CLUE) that was run for the 2016 NOAA Hazardous Weather Testbed Spring Forecasting Experiment. The main results are that a 10-member ARW ensemble was significantly more skillful than a 10-member NMMB ensemble, and a 10-member MIX ensemble (5 ARW and 5 NMMB members) performed about the same as the 10-member ARW ensemble. Skill was measured by area under the relative operating characteristic curve (AUC) and fractions skill score (FSS). Rank histograms in the ARW ensemble were flatter than the NMMB ensemble indicating that the envelope of ensemble members better encompassed observations (i.e., better reliability) in the ARW. Rank histograms in the MIX ensemble were similar to the ARW ensemble. In the context of NOAA’s plans for a Unified Forecast System featuring a CAM ensemble with a single core, the results are positive and indicate that it should be possible to develop a single-core system that performs as well as or better than the current operational CAM ensemble, which is known as the High-Resolution Ensemble Forecast System (HREF). However, as new modeling applications are developed and incremental changes that move HREF toward a single-core system are made possible, more thorough testing and evaluation should be conducted.
Have drug combinations supplanted stem cell transplantation in myeloma?
Authors: Palumbo Antonio , Cavallo Federica
Published: October 2019

The introduction of proteasome inhibitor and immunomodulatory drugs has considerably changed the treatment paradigm of multiple myeloma. Autologous stem cell transplantation (ASCT) is superior to conventional chemotherapy and is considered the standard of care for patients younger than 65 years. Nevertheless, the favorable results shown by multidrug inductions, consolidations, and long-term maintenance approaches have challenged the role of ASCT. This article provides an overview of recent and ongoing clinical trials and aims to define the role of ASCT in the era of novel agents.
Case vignettes and other brain teasers of monoclonal gammopathies
Authors: Gertz Morie , Buadi Francis K.
Published: October 2019

There are a number of rare monoclonal gammopathies that do not have a characteristic laboratory, imaging, or pathologic study. Recognition requires keeping the specific syndrome in mind. This article reviews 6 rare syndromes associated with monoclonal proteins and gives specific “pearls” so a clinician can be certain not to overlook these important disorders that easily can be misdiagnosed as MGUS, Waldenstrom, and multiple myeloma.
Optimizing hydroxyurea therapy for sickle cell anemia
Authors: Ware Russell E.
Published: October 2019

Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA.
Mutations in MPNs: prognostic implications, window to biology, and impact on treatment decisions
Authors: Shammo Jamile M. , Stein Brady L.
Published: October 2019

The last decade has witnessed tremendous scientific advances, ushered in by the JAK2 V617F discovery, contributing to enhanced diagnostic capability and understanding of the biology of myeloproliferative neoplasms (MPNs). Discovery of the calreticulin mutations filled a diagnostic gap; more recent work sheds light on its contribution to disease pathogenesis, and prognosis. Recent studies have also identified novel JAK2 and MPL mutations in patients with essential thrombocythemia and myelofibrosis (MF). Especially in MF, the driver mutational profile has prognostic implications, with additive contributions from the acquisition of additional somatic mutations. The hope is that sophisticated molecular profiling will not only aid in prognostication, but also guide selection of therapy for patients with MPNs.
Down syndrome and AML: where do we go from here?
Authors: Tomizawa Daisuke , Kolb E. Anders
Published: October 2019

It is well documented that young children with Down syndrome (DS) have both a 500-fold increased incidence of acute myeloid leukemia (ML-DS) and a decreased tolerance of intensive chemotherapy. In this issue of Blood, Uffmann et al present the results of a large, multicentered, international, nonrandomized trial reducing the etoposide exposure while preserving the excellent outcomes reported in previous trials.1 This trial builds on international experience demonstrating that most young children with ML-DS may be cured with less intensive therapy, and confirms that there remains a significant subset of patients for whom we have limited therapeutic options.
Off-the-shelf TCR for graft-versus-leukemia without GVHD
Authors: Locke Frederick L. , Anasetti Claudio
Published: October 2019

In this issue of Blood, Dossa et al report the engineering of T-cell receptor (TCR) transgenic T cells against the human minor histocompatibility antigen HA-1 for the prevention or treatment of leukemia relapse after allogeneic stem cell transplantation.1
ACUTE HEMOLYTIC ANEMIA AND HEMOGLOBINURIA FOLLOWING SULFADIAZINE MEDICATION
Authors: ROSS JOSEPH F. , PAEGEL BERTHA L.
Published: October 2019

1. A case of acute hemolytic anemia with hemoglobinuria precipitated by sulfadiazine is described.

2. Spherocytosis and increased hypotonic saline fragility were demonstrated during the acute phase of the disease.

3. Abnormal hemagglutinins and hemolysins were not present in the patient's serum.

4. The significance of these findings as related to the etiology of the disease is discussed.
INDIVIDUAL BLOOD DIFFERENCES IN RELATION TO PREGNANCY, WITH SPECIAL REFERENCE TO THE PATHOGENESIS OF PREECLAMPTIC TOXEMIA
Authors: HURST JANE G. , TAYLOR HOWARD C. , WIENER ALEXANDER S.
Published: October 2019

1. The titers of the isoagglutinins anti-A and anti-B in pregnant women at term do not differ significantly from the isoagglutinin titers in normal male adult blood donors. This indicates that pregnancy itself does not ordinarily stimulate a rise in isoagglutinin titer.

2. The frequency of incompatible blood groups in the infants of 31 mothers with toxemia of pregnancy was slightly higher (29 per cent) than that in a series of 166 infants of mothers without toxemia (22.3 per cent), but the difference was not statistically significant.

3. Of 37 normal mothers whose infants had blood groups incompatible with theirs, 9 were found to have a significant rise in isoagglutinin titer one week post partum. An appreciable rise in isoagglutinin titer occurred under similar circumstances in 6 of 9 mothers with toxemia. The series are too small to permit definite conclusions regarding the significance of this in relation to toxemia. However, there appears to be no doubt that under certain circumstances parturition can stimulate a rise in the maternal isoagglutinin titer.

4. No correlation was found between the occurrence of Rh incompatibility and toxemia of pregnancy.

5. The data obtained furnish additional evidence to support the theory of multiple allelic genes of heredity of the Rh blood types and also Race and Taylor’s theory of inheritance of the Hr factor.
EXPERIMENTAL LEUKOCYTOSIS. THE INEFFICACY OF P-CHLOROXYLENOL AND METHYL ACETAMIDE AS BONE MARROW STIMULANTS
Authors: MEYER LEO M.
Published: October 2019

1. Single and multiple injections of CXM (methyl acetamide and p-chloroxylenol) have a similar action in increasing the total number of polymorphonuclear leukocytes in the peripheral blood of a group of 32 rats. No "shift to the left" takes place.

2. There is no stimulation of the myeloid elements of the bone marrow to suggest that this leukocytosis is due to hyperplasia.

3. The evidence suggests that the mechanism for the leukocytosis produced by the CXM consists of releasing blood cells from depots in the body. This action is selective for the granulocytes as the red cells and platelets are not affected.

4. There is progressive degeneration of the parenchymal cells of the liver after single and multiple injections of these substances.

5. If less toxic combinations of methyl acetamide and para-chloro-xylenol could be obtained, they might be of value in the treatment of certain patients with leukopenia or agranulocytosis more particularly when the bone marrow is hyperplastic but the granulocytes are not released.
A Study of the Morphology of the Living Cells of Blood and Bone Marrow in Vital Films with the Phase Contrast Microscope
Authors: ACKERMAN G. ADOLPH , BELLIOS NICHOLAS C.
Published: October 2019

The cells of normal human blood and bone marrow have been examined in the living condition by means of the phase contrast microscope employing both supravital and unstained most films. The morphologic characteristics of the cells studied in this manner have been carefully described and illustrated.
Serum Electrophoretic Pattern and Morphology of Myeloma Cells
Authors: CHADBOURN WAYNE A. , ZINNEMAN HORACE H.
Published: October 2019

The electrophoretic pattern of the serum proteins of 27 patients with multiple myeloma have been compared to the morphologic characteristics of the abnormal cells in the smear of the bone marrow. The cases were classified into four types of serum globulin abnormalities: Normal pattern or minimal protein alteration, "beta" pattern, "M" pattern, and "gamma" pattern. The following morphologic characteristics of the myeloma cells were evaluated: Diameter of the nucleus, diameter of the cell, eccentricity of the nucleus, clumping of nuclear chromatin, presence and number of nucleoli, mitoses, color of the cytoplasm, multiplicity of nuclei, presence of detached masses of cytoplasm in the smear, vacuoles in the cytoplasm, granularity of the cytoplasm, peripheral rim of darkly stained cytoplasm, Russell bodies, Mott cells, presence of a "Hof" and rouleaux formation of the red blood cells.

The relative area of the cytoplasm, derived from the diameter of the myeloma cell, was found to be the most valid among all morphologic characteristics in predicting the type of serum protein pattern. Small size and a small amount of cytoplasm of myeloma cells were related to the beta globulin pattern while large size and abundant cytoplasm were related to the gamma and "M" globulin patterns.
In Vitro Studies of Erythropoiesis
Authors: THOMAS E. D.
Published: October 2019

A method has been described whereby erythropoiesis may be studied in vitro by measuring simultaneously oxygen consumption and the rate of incorporation of radioactive glycine into hemin by rabbit bone marrow. This rate shows only a very slight decrease in the first 20 hours. The optimal pH is about 8.0. The effect of normal serum on this process has been studied. Duplicate determinations show good agreement, but various normal sera show considerable variation in the ability to promote hemin synthesis. Normal serum has been shown to have a marked stimulating effect on hemin synthesis even after considerable dilution. Human serum halts completely the synthesis of hemin by rabbit bone marrow. An interesting dissociations between hemin synthesis and oxygen consumption has been pointed out. This effect is most apparent in experiments on heat-deproteinized serum. This material retains its ability to stimulate oxygen consumption but does not stimulate hemin synthesis at all. The relation of the stimulating effect of normal serum to the hypothetical erythropoietic hormone is discussed.
Hemolytic Property of Some Carbohydrases; Their Possible Role in Red Cell Destruction
Authors: LEROY ELIE P. , SPURRIER WILMA
Published: October 2019

β-glucuronidase, in concentration above the normal level in the blood, hemolyzed human red blood cells after a latent period of 10 to 12 hours. Erythrocytes sensitized by specific antibodies are lysed in the presence of β-glucuronidase in physiologic concentrations (approximately 200 Fishman units per 100 ml. of serum). Other enzymes, such as hyaluronidase and lysozyme, are hemolytic also. Similarity between these enzymes and the lysins found in pre-incubated tissue extracts is pointed out. It is suggested that β-glucuronidase and hyaluronidase play some role in the destruction of red blood cells under certain pathologic conditions. The inhibition of the lytic action of β-glucuronidase by D-glucosaccharic acid and by small concentration of silver nitrate is shown. Inhibitors of β-glucuronidase lysis could be of some value in the treatment of some hemolytic disorders.
V H mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia
Authors: Kröber Alexander , Seiler Till , Benner Axel , Bullinger Lars , Brückle Elsbeth , Lichter Peter , Döhner Hartmut , Stilgenbauer Stephan
Published: October 2019

In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (VH) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed VH mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q−, +8q, 11q−, +12q, 13q−, t(14q), 17p−) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of VH mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (Pcor) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% VH homology (95% confidence interval [CI], 96%-98% homology,Pcor <.001) and at 7% CD38 expression (95% CI, 20%-71% expression, Pcor = .02). In univariate analyses, unmutated VH genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in theVH unmutated and VHmutated subgroups. High-risk genomic aberrations such as 17p− and 11q− occurred almost exclusively in the VHunmutated subgroup, whereas favorable aberrations such as 13q− and 13q− as single abnormalities were overrepresented in theVH mutated subgroup. In multivariate analysis, unmutated VH, 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of VH mutation status and genomic aberrations to predict outcome in CLL.
The small proteoglycan decorin supports adhesion and activation of human platelets
Authors: Guidetti Gianni , Bertoni Alessandra , Viola Manuela , Tira Enrica , Balduini Cesare , Torti Mauro
Published: October 2019

Decorin is a small leucine-rich proteoglycan able to interact with several molecules of the subendothelial matrix, such as collagen and fibronectin. In this work, we investigated the ability of purified decorin to support adhesion of human platelets. We found that gel-filtered platelets were actually able to interact with immobilized decorin. Platelet adhesion to decorin was time dependent, required the presence of Mg2+ ions, and was totally mediated by the protein core of the proteoglycan. Platelet stimulation with either adenosine diphosphate (ADP) or a thrombin receptor–activating peptide significantly increased interaction of these cells with the proteoglycan. Upon adhesion to immobilized decorin a number of platelet proteins were found to become tyrosine-phosphorylated. By immunoprecipitation experiments with specific antibodies, the tyrosine phosphorylation of the tyrosine kinase Syk and the phospholipase Cγ2 (PLCγ2) isozyme was demonstrated in decorin-adherent platelets. Interaction of platelets with decorin was selectively prevented by 2 different antibodies against membrane integrin α2β1, but not by a number of antibodies against other membrane receptors. In addition, integrin α2β1, purified from platelet membranes, was able to specifically interact with immobilized decorin. Finally, purified decorin bound to Sepharose beads could precipitate integrin α2β1 from a platelet membrane glycoprotein preparation. Therefore, these results demonstrate that human platelets can bind to immobilized decorin through integrin α2β1, and that this interaction results in the tyrosine phosphorylation of intracellular proteins.
Rapamycin Has Biological Activity in a Subset of Patients with Myelodysplastic Syndrome - Results of a Phase I/II Trial.
Authors: Platzbecker Uwe , Haase Michael , Herbst Regina , Hanel Anette , Voigtmann Karsten , Thiede Christian , Mohr Brigitte , Schleyer Eberhard , Leopold Traugott , Hanel Mathias , Ehninger Gerhard , Bornhauser Martin
Published: October 2019

The pathophysiology of myelodysplastic syndrome (MDS) involves disturbed regulation of angiogenesis, apoptosis, proliferation and differentiation as well as immune surveillance. There is increasing evidence that rapamycin (sirolimus) might affect these pathways positively thus possibly being of therapeutic benefit in patients with this disease. These data prompted us to perform a phase I/II study to evaluate the safety and efficacy of rapamycin in the treatment of patients with MDS. Nineteen patients (median age 72 years) diagnosed with MDS according to the WHO classification received rapamycin orally with a target blood concentration of 3–12 ng/ml. Rapamycin was administered for a median of 3.7 months (range 0.3–11). Three patients (1 x RAEB-2, 1 x RAEB-1, 1 x RCMD) showed either a major (1 x platelet, 1 x neutrophil) or a minor (1 x erythroid, 2 x platelet) hematological response according to the IWG criteria. There was no statistically significant difference in the rapamycin plasma levels between the three responders (median plasma level 3.62, range 1.63–4.39) and non-responders (median plasma level 4.22, range 2.81–7.4). Major side effects were hyperlipidemia (n=4), stomatitis (n=3), thrombocytopenia (n=2) and urinary tract infection (n=1). Study medication had to be stopped due to side effects in five patients (26 %), one of them being a responder to rapamycin. Plasma levels of rapamycin were not elevated in patients experiencing toxicity.

Taken together these data demonstrate that rapamycin might have biological activity in patients with rather advanced MDS. New and possibly less toxic analogues of rapamycin are currently developed. They could be candidates for future trials in patients with MDS.
Cytogenetic Abnormalities Predict Disease Progression in Primary Myelodysplastic Syndrome: A Multicentric Study in 508 Chinese Patients.
Authors: Chen Bing , Zhao Wei-Li , Jin Jie , Xue Yong-Quan , Cheng Xin , Chen Xiao-Ting , Cui Jing , Chen Zhi-Mei , Cao Qi , Yang Guang , Yao Ying , Tong Jian-Hua , Li Jun-Min , Chen Jue , Xiong Shu-Min , Shen Zhi-Xiang , Chen Zhu , Chen Sai-Juan
Published: October 2019

Myelodysplastic syndrome (MDS) is a clonal stem cell disorder characterized by ineffective hematopoiesis and frequent leukemia progression. Cytogenetic abnormalities are presented in MDS patients and predict poor prognosis. To better define their relevance to clinical outcome in Chinese patients with primary MDS, cytogenetic analysis was performed in 508 cases and retrospectively compared with clinical data. The median age was 49 years which was 10 years younger than that of western patients. The median overall survival was 34 (range 1–161) months, with the 2-year and 5-year survival rate of 50.0% and 15.0%, respectively. Among 367 cases with evaluable karyotype in bone marrow mononuclear cells, cytogenetic abnormalities were found in 136 of them (37.1%), including 56 cases (15.3%) of numeric abnormality and 80 cases (21.8%) of structural abnormality. Higher incidence of cytogenetic abnormality was found in RAEB-T (43/86, 50.0%) and RAEB (44/106, 41.5%) patients than that of RA patients (38/143, 26.6%). RAEB and RAEB-T had more cases of non-hypodipoidy, double aberrations with translocation, and complex aberrations. In RA, the most frequent aberrations were duplication and numeric changes. This study also showed RAEB appears to be the course of MDS that genome turbulence was under the evolution pressure. In RAEB-T, the genome abnormalities tend to be uniform and behaved as special translocation, which is in accordance with the clinical behavior of AL. Poor prognosis and early leukemia transformation were observed in the patients with cytogenetic abnormalities, especially with complex cytogenetic aberrations and chromosome translocations. In conclusion, cytogenetic abnormalities possess strong predictive value on disease outcome in primary MDS patients.
Notch Signaling-Dependant Expulsion of Parasites through Mast Cell-Mediated Immunity.
Authors: Sakata-Yanagimoto Mamiko , Yamaguchi-Nakagami Etsuko , Sakai Toru , Kumano Keiki , Kunisato Atsushi , Crcareva Aleksandra , Kurokawa Mineo , Ogawa Seishi , Yasutomo Koji , Hirai Hisamaru , Chiba Shigeru
Published: October 2019

[Background] Notch signaling is known to be important in hematopoiesis, but very little information is available about its significance in mast cells. Here we provide direct evidence that notch signaling is critical for both development and function of mast cells in vitro and in vivo.

[Methods] A Lin− fraction of mouse bone marrow cells was cultured on immobilized Delta1 in the presence of SCF and IL-3, and emerging Lin−FcεRI+c-Kit+ mast cells were characterized. Next, production of mouse mast cell protease-1 (mMCP-1), which is specific for nematode infection through locally expressed TGF-β1 in vivo, by bone marrow-derived mast cells (BMMC) was analyzed after the stimulation with Delta1 in the presence of TGF-β1. Finally, mice were infected with Strongyloides venezuelensis after pre-treatment with Delta1, and expulsion of the worms was examined.

[Results] Lin−FcεRI+c-Kit+ mast cells developed remarkably earlier if stimulated with Delta1 (at one week, 15% vs. 3%). DAPT, a γ-secretase inhibitor, blocked the Delta1 effect, while it did not affect the regular time-course mast cell generation by SCF and IL-3. SB431542, a selective inhibitor of TGF-β1 signaling, also blocked early mast cell generation by Delta1. Delta1 augmented mMCP-1 expression and secretion from BMMC by 50 fold. Both DAPT and SB431542 showed a dose-dependent inhibition of Delta1 effect on mMCP-1 expression and secretion. Pre-treatment of the hosts with Delta1 promoted the expulsion of S. venezuelensis, (left/inoculated ratios of worms, 3% vs. 40%) while Delta1 had no effect in the mast cell-deficient W/Wv mice.

[Discussion] Our observations reveal that notch signaling regulates both development and function of mast cells in vitro in conjunction with TGF-β1 signaling. In vivo, it is also likely that Delta1 facilitates the functional maturation of intestinal mast cells to eradicate parasites. More precise mechanism of Delta1 action on mast cells in vivo is under a study.
Autologous Non-Myeloablative Hematopoietic Stem Cell Transplantation (NST) for Severe Systemic Lupus Erythematosus.
Authors: Burt Richard K. , Oyama Yu , Statkute Laisvyde , Krosnjar Nela , Verda Larissa , Kowalska Barbara , Traynor Ann E.
Published: October 2019

Unlike leukemia in which the goal of hematopoietic stem cell transplantation (HSCT) is myeloablation and immune suppression is an unwanted side effect, for autoimmune diseases the goal of autologous HSCT is immune ablation and myeloablation is an unwanted side effect. We, therefore, have performed autologous non-myeloablative hematopoietic stem cell transplantation (NST) in treatment refractory systemic lupus erythematosus (SLE) using an intense immune suppressive (“ablative”) regimen followed by autologous stem cell support to shorten the post NST cytopenic interval. Autologous NST has been performed in 45 patients with severe SLE treated over the last 7 years at Northwestern University (Chicago). Candidates were less than 60 years old with either renal (WHO class III or IV nephritis), CNS (cerebritis, transverse myelitis), or pulmonary (alveolar hemorrhage, interstitial pneumonitis, shrinking lung syndrome) involvement or vasculitis despite pulse cyclophosphamide, autoimmune transfusion dependent cytopenias despite steroids, danazol, and alkylating agents, or anti-phospholipid syndrome defined by Sapporo criteria with recurrent thrombi despite anti-coagulation. Peripheral blood stem cells were mobilized with 2.0 g.m2 cyclophosphamide and granulocyte colony-stimulating factor and CD34+ enriched (Isolex, Baxter). The immune ablative conditioning regimen consisted of 200mg/kg cyclophosphamide, and 90mg/kg equine antithymocyte globulin. One patient died from mucormycosis after HSC mobilization (treatment-related mortality-TRM). Four patients died of causes unrelated to NST at 11, 15, 18, and 30 months after NST. Three died of relapsed SLE, one patient with a history of Libman-Sacks died of MRSA endocarditis at 18 months after NST while in remission. Complete remission defined as a prednisone ≤ 10 mg/day with no evidence of active disease and no other immune suppressive drugs except hydroxychloroquine was achieved in 66% of patients. In these 45 patients, autologous NST for SLE had a 2% TRM and 66% long term disease free remission. If patients maintain remission for 2 years, relapse is unlikely.

Figure Figure
Polymorphism of the α2A-Adrenergic Receptor Gene and Epinephrine-Induced Platelet Aggregation.
Authors: Afshar-Kharghan Vahid , Sun Carrol , Zhang Hui , Wood Jennifer , Leal Suzanne , Dong Jing-Fei , Bray Paul F.
Published: October 2019

The α2A-adrenergic receptor mediates important physiologic responses, such as regulation of blood pressure, control of sympathetic autonomic responses, as well as the platelet response to epinephrine. The gene encoding the α2A-adrenergic receptor is polymorphic. One of the polymorphisms, known as the Dra I polymorphism, is located in the 3′ untranslated region of this gene. The Dra I polymorphism of the α2A-adrenergic receptor is associated with a higher incidence of systemic arterial hypertension among African-Americans. Although the presence of this polymorphism was known by Southern-blot analysis of the human genomic DNA for more than a decade, the exact location and nature of this polymorphism was unknown. We have located the Dra I polymorphism in the 3′ untranslated region of the α2A-adrenergic receptor gene (G1838A) and developed a PCR-based detection method. The allele and haplotype frequencies for polymorphisms of the α2A-adrenergic receptor gene in different ethnic groups were identified. After studying the correlation between epinephrine-induced platelet aggregation and the genotypes for the G1838A polymorphism among 235 human subjects, it was found that the 1838G allele is associated with an increase in the level of platelet aggregation in response to epinephrine among African-Americans, but not among Caucasians or Hispanics. This polymorphism may be responsible for the variability in the epinephrine-induced platelet aggregation among individuals and acts as a risk factor for thrombotic vascular event.
Transcriptional Regulation of the SCL Locus: Identification of an Enhancer That Targets Primitive Erythroid Cells.
Authors: Delabesse* Eric , Ogilvy* Sarah , Chapman Michael A. , Göttgens Berthold , Green Anthony R.
Published: October 2019

The stem cell leukaemia (SCL) gene encodes a bHLH protein that is essential for the formation of all haematopoietic lineages. In addition, maintenance of SCL expression is required for normal differentiation along the erythroid and megakaryocytic lineages, whereas failure to downregulate SCL transcription during T-cell differentiation is associated with T-cell ALL. Current evidence therefore demonstrates that appropriate transcriptional regulation is essential for the biological functions of SCL and this focuses attention on the mechanisms whereby transcription of SCL itself is initiated and maintained.

We have previously used biochemical, comparative genomic and transgenic assays to identify 5 distinct enhancers which target different subdomains of the normal SCL expression pattern. However these enhancers do not explain how erythroid expression of SCL is achieved and we have postulated the existence of an additional erythroid enhancer. It is also unclear whether the known SCL enhancers regulate neighbouring genes within the SCL locus. We have therefore quantitated the transcripts from SCL and its neighbouring genes in a large panel of human and murine haematopoietic cell types. Our results reveal a striking and unexpected co-expression of SCL and its downstream neighbour MAP17 (r=0.8; n=31). We demonstrate the existence of appropriately spliced low abundance SCL-MAP17 fusion transcripts suggesting that co-expression reflects transcriptional read-through rather than a shared enhancer. A systematic survey of histone H3 and H4 acetylation throughout the SCL locus was also performed in both cell lines and primary haematopoietic cells. A peak of acetylation downstream of MAP17 (and 40 kb downstream of SCL exon 1a) was found to correlate with expression of SCL but not other neighbouring genes. This region contains peaks of homology in 4-way genomic sequence comparisons (human/dog/mouse/rat) and functions as an erythroid-restricted enhancer in vitro. Morever, in transgenic mice this enhancer directs b-galactosidase expression to the vast majority of circulating primitive erythroblasts but not to fetal liver definitive erythroblasts.
Recruitment of mSin3A and Histone Deacetylase 2 (HDAC2) by the Chromatin Remodeling Protein BRG1 Mediates Transcriptional Repression in Erythroid Progenitors.
Authors: Xu Zhixiong , Meng Xianzhang , Cai Ying , Brandt Stephen J.
Published: October 2019

The Swi/Snf chromatin remodeling complexes are critical for activating or repressing transcription of specific genes and require one of two homologous ATPases, Brg1 and Brm. Although Brg1 is also known to be involved in ß-globin gene transcription and a recent report showed that Brg1-containing complexes could be recruited to the ß-globin promoter and its locus control region (LCR), the exact roles of Brg1 in erythroid gene expression and differentiation have not been directly investigated. We previously showed that Brg1, but not Brm, is recruited to the Protein 4.2 (P4.2) promoter by a multi-protein DNA-binding complex containing TAL1/SCL, E47, GATA-1, LMO2, and Ldb1. This complex transactivates P4.2 gene expression through tandem E box-GATA elements in its proximal promoter. We report here that overexpression of Brg1 in murine erythroleukemia (MEL) cells significantly reduced the proportion of benzidine-stained cells and dramatically inhibited expression of mRNA for P4.2 and ß-globin but not glycophorin A and erythroid Kruppel-like factor in MEL cells induced to differentiate with dimethyl sulfoxide (DMSO). Further, overexpression of Brg1 repressed P4.2 promoter activity in a dose-dependent manner in DMSO-treated MEL cells, while treatment of cells with trichostatin A, a specific HDAC inhibitor, attenuated Brg1-directed inhibition of reporter activity in transient transfection analysis. In addition, coimmunoprecipitation analysis showed that Brg1 interacted stably with the corepressor mSin3A and HDAC2 in erythroid cells, suggesting that HDAC activity is involved in Brg1-mediated transcriptional repression. Quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated that Brg1 occupancy of the P4.2 and ß-globin promoters and hypersensitive site 2 (HS2) of the ß-globin LCR decreased upon erythroid differentiation. Importantly, the selective transcriptional repression of P4.2 and ß-globin gene expression by Brg1 correlated with increased loading of mSin3A and HDAC2 on the P4.2 promoter and ß-globin HS2, respectively. Together, these results suggest that Brg1-mediated transcriptional repression of select erythroid genes is characterized by the localized recruitment of a corepressor complex containing mSin3A and HDAC2 in a process of active repression.
Synergistic Interaction between Notch ligand Delta-1 and IL-6/Soluble IL-6 Receptor Fusion Protein in the Generation of BFU-E from Primitive Hematopoietic Progenitors.
Authors: Yamamura Kentaro , Ohishi Kohshi , Katayama Naoyuki , Shiku Hiroshi , Masuya Masahiro , Heike Yuji , Nishikawa Mitsuo , Nakahata Tatsutoshi
Published: October 2019

We have previously reported that Notch ligand Delta-1 may enhance the generation of NOD/SCID-repopulating hematopoietic stem cells and thymus-repopulating T cell precursors from cord blood [CB] CD34+CD38- cells. A complex of IL-6/soluble IL-6 receptor is shown to induce the expansion and proliferation of primitive hematopoietic progenitors that express gp130 but not the IL-6 receptor α chain, in mobilized peripheral blood (MPB) as well as in CB. In this study, we explored the interaction between Delta-1 and IL-6/soluble IL-6 receptor fusion protein [FP] in the generation of hematopoietic progenitors from MPB- and CB-derived primitive hematopoietic progenitors. MPB CD34+ Thy-1+ cells were cultured in serum-free medium with SCF, flt-3 ligand, TPO, and IL-3 [4GF], 4GF plus Delta-1, 4GF plus FP, and 4GF plus FP plus Delta-1. Delta-1 was used after immobilized to the culture plates. Freshly isolated cells and cultured cells were assessed for colony-forming ability by replating cells into semisolid medium containing SCF, flt-3 ligand, TPO, IL-3, IL-6, G-CSF, GM-CSF, and EPO. Colonies were counted at day 14. The numbers of BFU-E, CFU-Mix, and CFU-GM were 37-fold, 18-fold, and 135-fold increased, respectively, in cultures with 4GF plus FP, as compared with those in freshly isolated cells. The addition of both Delta-1 and FP to cultures resulted in 216-fold, 22-fold, and 132-fold increases in the numbers of BFU-E, CFU-Mix, and CFU-GM, respectively, relative to freshly isolated cells. Delta-1 did not affect the generation of colony-forming cells in cultures without FP. Thus, Delta-1 and FP synergistically enhanced the generation of BFU-E from primitive hematopoietic progenitors in MPB. In the cultures of CB CD34+CD38- cells with SCF, flt-3 ligand, TPO [3GF], 3GF plus Delta-1, 3GF plus FP, and 3GF plus FP plus Delta-1, the synergistic enhancement by Delta-1 and FP was observed in the generation of BFU-E and CFU-Mix. These data suggest a novel role for interaction between Notch and gp130 signalings in the generation of erythroid progenitors from primitive hematopoietic progenitors.
Low Dose Thalidomide and Donor Lymphocyte Infusion as Adoptive Immunotherapy after Allogeneic Stem Cell Transplantation in Patients with Multiple Myeloma.
Authors: Kroeger Nicolaus , Shimoni Avichai , Zagrivnaja Maria , Ayuk Francis , Lioznov Michael , Schieder Heike , Fehse Boris , Zabelina Tatjana , Nagler Arnon , Zander Axel
Published: October 2019

To improve anti-myeloma effect of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation in multiple myeloma, we investigated in a phase I/II study the effect of low dose thalidomide (100 mg) followed by DLI in 18 patients with progressive disease or residual disease and prior ineffective DLI after allografting. The median age was 53 years (range 31–64). Twelve patients received prior DLI and either relapsed again (n=1), or showed no response (PD: n=3; SD: n=8). The overall response rate was 67% including 22% complete remission. Major toxicity of thalidomide was weakness grade I/II (68%) and peripheral neuropathy grade I/II (28%). Only 2 patients experienced mild grade I acute graft versus host disease (aGvHD) of the skin, while no grade II-IV aGvHD was seen. De novo limited chronic GvHD (cGvHD) was seen in two patients (11%). The median time to response was 108 days (range, 36–266 days). In 5 patients not responding to 100 mg, the dose of thalidomide was increased (200 mg n=4; 300 mg n=1) and subsequently two of them responded with partial remission. In three patients dose escalation of DLI was performed, resulting in one minor and one partial remission. No difference regarding response was observed between unrelated and related donors (66% each). Five out of 6 patients with deletion 13 responded, while 5 out of 9 patients without deletion 13 responded to thalidomide plus DLI. In patients who failed to respond to prior DLI, the disease status could be converted in 6 patients with SD after first DLI into CR (n=2), PR (n=3), MR (n=1) while two with SD remainded SD after thalidomide plus DLI. In three patients with progressive disease after DLI the combination of thalidomide and DLI resulted in one CR, one PR and one minor remission.

The two-years estimated overall and progression-free survival was 100 % and 84%, respectively. Adoptive immunotherapy with low dose Thalidomide and DLI induces strong anti-myeloma effect with low incidence of graft versus host disease.
Thrombopoietin Regulates Proliferation and Maturation of Murine Mast Cells.
Authors: Migliaccio Giovanni , Ghinassi Barbara , Centurione Lucia , Zingariello Maria , Bianchi Lucia , Pancrazi Alessandro , Paoletti Francesco , Vannucchi Alessandro M. , Rana Rosa Alba , Nishikawa Mitsuo , Migliaccio Anna Rita
Published: October 2019

Megakaryocytopoiesis is regulated by extrinsic (interaction of the growth factor thrombopoietin, TPO with its receptor Mpl) and intrinsic (interaction between the trascription factors GATA-1 and Fog-1) factors. The observation that mice impaired for GATA-1 expression (i.e. harbouring the GATA-1low mutation) are defective not only in megakaryocyte maturation but also in mast cell differentiation (Migliaccio et al. J Exp Med197:281, 2003), led us to investigate whether TPO might control mast cell differentiation as well. We first observed that mice genetically unable to responde to TPO (Mplnull mice) express in the connective tissues 5 times more mast cells than their normal littermates. Then, we analysed the effects on mast cell differentiation of in vivo treatment with TPO. Normal mice, and their GATA-1low littermates, were injected i.p. with TPO (100 μg/kg/day per 5 days, kindly provided by Kirin Brewery, Japan) and the number of immature (Toluidinepos) and mature (AlcianBlue/Saphraninepos) mast cells present in the connective tissues of the animals, as well as the frequency of GATA-1pos and TUNELpos mast cells, was evaluated 14 days after treatment. In wild-type animals, TPO reduced the presence of GATA-1 in mast cells (by immuno-histochemistry) and increased the number of immature cells (from 320±28 to 852±60) and of those undergoing apoptosis (from 16±1 to 600±43). In contrast, in GATA-1low animals, TPO-treatment induced the expression of GATA-1 in mast cells while decreased the number of immature cells (from 1100±72 to 427±29) as well as that of apoptotic cells (from 600±45 to 60±2). The role of TPO on mast cell differentiation were further confirmed by the analysis of the effects exerted by the growth factor on in vitro differentiation of bone marrow derived mast cells (BMMC). In these experiments, wild type bone marrow and spleen cells were cultured for 21 days with SCF and IL-3 with or without TPO and BMMC differentiation measured on the basis of the number of cells expressing the phenotype c-kithigh/CD34high and FcεRIpos. In cultures stimulated with SCF and IL-3, all the cells expressed the phenotype c-kithigh/CD34high and FcεRIpos. In contrast, in cultures supplemented also with SCF, IL-3 and TPO, only 25% of the cells were c-kithigh/CD34high and none of them was FcεRIpos. These results establish a role for TPO in the control of mast cell differentiation (possibly by modulating the GATA-1 content of the cells) and unveil further similarities between the mechanism(s) controlling megakaryocyte and mast cell differentiation.
The Low-Molecular-Weight-Heparin, Tinzaparin, Is Effective and Safe in the Treatment and Prophylaxis of Venous Thromboembolic Disease during Pregnancy.
Authors: Jorgensen Maja , Nielsen Jorn D.
Published: October 2019

During pregnancy the incidence of venous thromboembolism (VTE) is approximately 6 times higher than in age-matched, non-pregnant women and venous thromboembolism remains the most common cause of maternal morbidity and mortality. Low-molecular-weight-heparins are recommended for treatment of VTE during pregnancy and for prophylaxis of VTE in pregnant women with major thromboembolic risk factors. We used tinzaparin for prophylaxis and treatment of VTE in 305 consecutive pregnant women referred to the Thrombosis Centre, Gentofte University Hospital, from 1997 to 2004. In 268 pregnancies the mothers had thrombophilia, 52 women were admitted with acute VTE and 184 had previous VTE. Other clinical risk factors included previous bad obstetric outcome, recurrent miscarriages, cardiac disorders or previous thromboembolic stroke. An individual risk assessment of each pregnant woman was performed. Very high risk females were treated with tinzaparin 90 – 100 IU/kg bid, high risk females were treated with tinzaparin 100 – 125 IU/kg daily and women with moderate risk were treated with 50 – 75 IU/kg daily.

302 of 305 pregnancies (99 %) in 263 females resulted in 310 healthy babies. 306 of 310 babies had appropriate birth weight for gestational week and all babies had normal Apgar score. Two females had miscarriages (week 10 and 20) and 1 female had an elective abortion. No females had pulmonary embolism. Deep venous thrombosis occurred in 4 of 305 pregnancies = 1,3 % (week 6, 11, 27 and one day postpartum). Wound hematoma was observed after cesarean section in two women and postpartum bleeding episodes (700 – 1500 ml) were observed in 7 women (4 had severe vaginal or cervical tearings, 2 had retained placenta and 1 had placental abruption). We found no incidence of thrombocytopenia or symptomatic osteoporosis.

We find that individually dosed tinzaparin is safe and seems effective in the prevention of thromboembolic complications during pregnancy. Individual risk stratification is recommended.