bluuebunny/crossref_metadata_2025_split huggingface dataset:
Action of Disodium Ethylenediamine Tetracetate on Blood Coagulation
Authors: TRIANTAPHYLLOPOULOS DEMETRIOS C. , QUICK ARMAND J. , GREENWALT TIBOR J. 
Published: October 2019

Abstract
A. The action of EDTA on the coagulation mechanism was studied. EDTA was found:
1. To exert no direct effect on prothrombin or thrombin.
2. To have an inhibitory action on labile factor.
3. To increase the speed of conversion of prothrombinogen to prothrombin.
B. The effect of incubation or aeration of plasma on thrombin time was studied. It was found that aeration or incubation increases the thrombin time of plasma. The following observations lead one to attribute this prolongation to a heparinoid activity:
1. The property of incubated plasma to prolong the thrombin time of fresh plasma when added to it.
2. The ability of protamine to shorten the thrombin time of incubated or aerated plasma.
3. The sensitivity of the thrombin time of incubated or aerated plasma to pH changes and calcium concentration.
C. The incidental observation was made that cooling reverses the prolonged thrombin time produced by incubation.
Autoerythrocyte Sensitization A Form of Purpura Producing Painful Bruising Following Autosensitization to Red Blood Cells in Certain Women
Authors: GARDNER FRANK H. , DIAMOND LOUIS K. 
Published: October 2019

Abstract
Four patients with purpura who manifested an unusual response to bruising were studied. This response was characterized by the development of an area of painful ecchymosis at the site of trauma followed by progressive erythema and edema. This unusual tissue response was seen only in women. The various features of the cases suggested an autosensitization by the patients to their own blood.
Special studies utilizing skin testing procedures indicated an abnormal tissue response of sensitivity to red blood cells. The factor responsible was present in the red cell stroma and was not associated with the hemoglobin.
The clinical manifestations and possible therapy are discussed.
This syndrome may represent another example of autosensitization such as has been speculated for lupus erythematosus, some forms of acquired hemolytic anemia and of thrombocytopenic purpura, and for an increasing number of disease states.
The Effect of Various Metabolites on the Growth of Marrow Cells in Vitro
Authors: SWAN HAROLD T. , REISNER EDWARD H. , SILVERMAN MORRIS 
Published: October 2019

Abstract
Marrow was cultured on chick plasma clots, glass surfaces and in suspension and the influence of various metabolites and antimetabolites on the growth and differentiation of red cell precursors was studied.
Vitamin B12 appeared to stimulate cell growth in cultures grown on clots and to convert megaloblastic hematopoiesis to normoblastic in cultures grown on glass.
In suspension cultures of megaloblastic marrows in pernicious anemia serum significant cell increases were obtained with the addition of folinic acid, but not with vitamin B12. Both vitamin B12 and folinic acid appeared to accelerate the conversion of megaloblasts to normoblasts in differential counts of stained smears of such cultures. No enhancing effect of intrinsic factor upon the activity of B12 in suspension cultures of megaloblasts was observed. The effect of folinic acid could be blocked by colchicine and folinic acid could reverse the inhibitory effects of Amethopterin. These facts indicated that folinic acid acted in suspension cultures by stimulating mitosis.
Megaloblasts could be produced from normoblastic marrows by culturing them in pernicious anemia serum, or in normal serum in the presence of Amethopterin.
Susceptibility to Thrombosis in Normal Young, Aging, Cortisone-treated, Heparinized and X-irradiated Hamsters as Tested by Topical Application of Thrombin
Authors: BERMAN HERBERT J. , FULTON GEORGE P. , LUTZ BRENTON H. , PIERCE DAVID L. 
Published: October 2019

Abstract
1. Thrombin applied topically to the everted cheek pouch of the hamster produced platelet and not red thrombi in exposed, uninjured blood vessels with circulating blood. Red thrombi were produced in stagnant blood. Thrombus formation occurred in the venules for the most part and seldom in arterioles or capillaries.
2. An in vivo test for platelet thrombus susceptibility, based on the thrombin reaction and the resistance of the hamster to thrombosis, has been described.
3. Thrombus susceptibility, measured by the thrombin test, increased with age and during cortisone treatment, and decreased after heparin injection and following large doses of whole body x-irradiation.
4. The thrombin susceptibility test could be correlated with the platelet count in x-irradiated hamsters, showing a relatively critical minimum concentration of blood platelets (100,000/cu.mm.) required for platelet thrombosis.
5. The relationship of platelet concentration to platelet thrombus formation and predisposition to hemorrhage has been discussed.
Multilineage Dysplasia Is Associated with Worse Clinical Outcome Independent of the Diagnosis of Acute Myeloid Leukemia or Myelodysplastic Syndrome.
Authors: Amin Hesham M. , Pierce Sherry A. , Estey Elihu H. , Kantarjian Hagop M. , O’Brien Susan M. , Giles Francis J. , Albitar Maher 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematopoietic neoplasms. The World Health Organization (WHO) classification includes the two new categories: AML with dysplasia in more than one lineage (multilineage dysplasia; MLD) and refractory cytopenia with MLD. However, the relevance of dysplasia in one lineage versus more than one lineage and the importance of separating MDS with MLD from AML with MLD are not known. We studied 1110 patients with AML and 171 patients with MDS classified according to the WHO criteria and treated at MD Anderson Cancer Center from 1995 to 2003. All MDS patients had advanced disease requiring treatment and included 19 patients with refractory anemia (RA), 7 with RA with ringed sideroblasts (RARS), and 145 with RA with excess blasts (RAEB). Survival analysis showed no statistical significance in overall survival between MDS patients and AML patients when classified according to the WHO classification (P=0.196). When AML and MDS patients were considered as one group, but divided based on the presence or absence of MLD, patients with MLD had significantly shorter survival (P=.004; Figure 1). More importantly, multivariate Cox proportional hazard model showed that the shorter survival in the combined AML and MDS patients with MLD was independent of cytogenetic abnormalities, antecedent hematologic disease, performance status, and the original diagnosis of AML or MDS. As expected, shorter survival was found in AML patients with MLD as compared with those with no dysplasia or dysplasia of one lineage (P=.003). The presence of dysplasia in one lineage was irrelevant for the clinical course. Apoptosis detection using annexin V staining or mitochondrial membrane potential analysis showed significantly higher apoptosis in AML patients with MLD as compared with those patients without MLD and the presence of increased apoptosis correlated with shorter survival (P=.04). The present study demonstrates that the criteria established by the WHO classification for the diagnosis of AML and MDS can be significantly enhanced if the presence or absence of MLD is considered irrespective of the percentage of blasts. Furthermore, apoptosis can be detected in AML and MDS patients using annexin V staining or mitochondrial membrane potential analysis and it can be utilized to indirectly reflect the level of dysplasia in these patients. With the progress in targeted therapy, the classification of leukemia and myelodysplasia based on biological abnormalities may provide more helpful clues for therapy and clinical management.
Figure Figure
The Severe Chronic Neutropenia International Registry - 10 Years of Follow-Up.
Authors: Dale David C. , Bolyard Audrey Anna , Schwinzer Beate , Pracht Gusal , Bonilla Mary Ann , Boxer Laurence , Freedman Melvin , Donadieu Jean , Kannourakis George , Alter Blanche P. , Cham Bonnie , Winkelstein Jerry , Kinsey Sally E. , Fier Carol , Zeidler Connie , Welte Karl 
Published: October 2019

Abstract
2004 marks the 10th anniversary of the Severe Chronic Neutropenia International Registry (SCNIR), a registry organized to improve understanding and treatment of the hematological disorders causing severe chronic neutropenia. The SCNIR enrolls patients with blood neutrophil counts intermittently or continuously less than 0.5x109/L whose neutropenia is not attributed to cancer, cancer chemotherapy, or systemic autoimmune diseases. Longitudinal data has now been collected on 1163 patients with a range of follow-up of 0.01 to 15.66 years. By diagnostic category the patients include severe congenital neutropenia (422), cyclic neutropenia (205), idiopathic neutropenia (349), autoimmune neutropenia (68), glycogen storage disease (42), Barth syndrome (10), myelokathexis (8), Shwachman-Diamond syndrome (37), immune deficiency syndromes (7), and others (15). Overall, 1053 (90.5%) of these patients have been treated longitudinally with G-CSF (dose range 0.02 to 300 mcg/kg/day, median 3.33 mcg/kg/day) or received G-CSF transiently. Among other treatments, 76 patients were treated with allogeneic bone marrow or stem cell transplants (SCT). The reasons for SCT were myelodysplasia (MDS) or acute myeloid leukemia (AML) (43), chromosomal aberrations or G-CSF receptor mutation (9), partial or non-response to G-CSF (21), or other reasons (3). G-CSF has dramatically changed the natural history of these disorders reducing the occurrence of infection, hospitalization, and antibiotics, and improving patients’ quality of life. A small percentage of patients, 14% (163/1163), show evidence of osteoporosis/osteopenia; the predisposing factors for this complication remain unclear. MDS and AML has occurred in 63 patients: severe congenital neutropenia (13.7%, 58/422), Shwachman-Diamond syndrome (8.1%, 3/37) and 2 others with the clinical diagnoses of cyclic neutropenia (1) and idiopathic neutropenia (1). The SCNIR has also provided a rich resource for studies on the genetic and molecular basis for these disorders. These include the finding of mutations in the gene for neutrophil elastase (ELA2) in causing cyclic and congenital neutropenia, the role of mutations in the gene for the G-CSF receptor in the evolution of severe congenital neutropenia to AML and the importance of apoptosis as the cellular mechanism for several diseases causing severe chronic neutropenia. The SCNIR illustrates the value of a patient registry to improve our understanding of rare hematological diseases.
Idiopathic Hypereosinophilic Syndrome (HES) with FIP1L1-PDGFRA Rearrangement Can Be Effectively Treated with Imatinib.
Authors: Martinelli Giovanni , Cilloni Daniela , Ottaviani Emanuela , Malagola Michele , Messa Francesca , Rondoni Michela , Bosi Costanza , Gottardi Enrico , Rosti Gianantonio , Ricci Paolo , Gaitani Stavroula , Pane Fabrizio , Testoni Nicoletta , Mecucci Cristina , Soverini Simona , Piccaluga Pier Paolo , Amabile Marilina , Tiribelli Mario , Zaccaria Alfonso , Grafone Tiziana , De Vivo Antonello , Pileri Stefano , Fattori Pierpaolo , Bocchia Monica , Serra Anna , Maurillo Luca , Fanin Renato , Cross Nicholas C.P. , Merante Serena , Cazzola Mario , Alimena Giuliana , Frassoni Francesco , Galieni Piero , Russo Domenico , Gobbi Marco , Gugliotta Luigi , Lauria Francesco , Mazza Patrizio , Ferrara Felicetto , Gherlinzoni Filippo , Leoni Pietro , Musto Pellegrino , Baccarani Michele , Saglio Giuseppe 
Published: October 2019

Abstract
We studied 141 patients with HES, of which 55 primary HES (39%) defined as a peripheral blood eosinophilia greater than 1,500 cells/μL for longer than 6 months, absence of other apparent aetiologies for eosinophilia and symptoms of organ involvement. All patients were studied by molecular analysis for PDGFRB-TEL, FGFR1-BCR and BCR-ABL transcripts, frequently associated with HES/CMML/MDS syndrome: all these transcripts were absent in our series. We also sought for the recently reported involvement of PDGFRα, cryptically translocated with FIP1L1 in some HES pts responsive to Imatinib therapy: 13 pts (23%) were positive for the FIP1L1-PDGFRA rearrangement and all of them showed previously unreported, abnormal-sized fusion transcripts. Curiously, all FIP1L1-PDGFRA positive pts were male. We enrolled in a national clinical trial 31 (55%) primary HES pts, including all 13 (23%) FIP1L1-PDGFRA positive, with imatinib mesylate (100 to 400 mg/day). Median follow up of treatment was 4,5 moths (range 2–28). Rapid and complete haematological responses to imatinib therapy were recorded only in all FIP1L1-PDGFRA positive pts (100%) after one months of therapy and partial response in only one cases with HES without FIP1L1-PDGFRA fusion transcript. Complete molecular response without evidence of FIP1L1-PDGFRA transcript by qualitative RT-PCR was also recorded in all responding pts after median 2 months of therapy. We conclude that FIP1L1-PDGFRA rearrangement may be useful molecular marker of myeloproliferative HES, a predictor of imatinib-responsiveness and as a means to follow therapy in this subgroup of pts.
European Multicenter Experience on Idiopathic Hypereosinophilic Syndrome (HES) with FIP1L1-PDGFRA Rearrangement treated with Imatinib.
Authors: Martinelli Giovanni , Apperley Jane , Reiter Andreas , Cross Nicholas P. , Cilloni Daniela , Grimwade David , Hochhaus Andreas , Ottaviani Emanuela , Cools Jan , Prin Lionel , Malagola Michele , Walz C , Preudhomme Claude , Messa Francesca , Rondoni Michela , Gottardi Enrico , Rosti Gianantonio , Mecucci Cristina , Pane Fabrizio , Testoni Nicoletta , Soverini Simona , Merante Serena , Alimena Giuliana , Baccarani Michele , Hehlmann Rudiger , Aventin Anna , Sureda Anna , Gomez Jose-Roman , Duyster Justus , Verhoef Gregor , Saglio Giuseppe 
Published: October 2019

Abstract
Idiopathic hypereosinophilic syndrome (HES) is an infrequent hematological disorder characterized by persistent eosinophilia with organ involvement, often presenting to other medical specialists. We studied 89 primary HES defined as a peripheral blood eosinophilia greater than 1,500 cells/μL for longer than 6 months, absence of other apparent aetiologies for eosinophilia and symptoms of organ involvement. All patients were negative by molecular analysis for TEL-PDGFRB, and/or BCR-ABL transcripts, frequently associated with HES/CMML/MDS syndromes. We also sought for the recently reported involvement of PDGFRalpha, cryptically fused with FIP1L1 in some HES patients responsive to Imatinib therapy: 34 patients were positive for the FIP1L1-PDGFRA rearrangement and all of them showed previously unreported, abnormal-sized fusion transcripts. A specific RT-PCR assay has been set up for this analysis and a quantitative Q-RT-PCR Taqman assay is in development. Of note, all FIP1L1-PDGFRA positive patients were male. 56 out of 89 (62%) primary HES patients, including 31/34 FIP1L1-PDGFRA positive, were sensitive to imatinib mesylate (100 to 400 mg/daily). Median follow up of treatment was 10 months (range 2–28). Rapid and complete haematological responses (CHR) to imatinib therapy were recorded in all FIP1L1-PDGFRA positive patients (91%) after one month of therapy and partial response in nine cases with HES but without FIP1L1-PDGFRA fusion transcript. Complete molecular response without evidence of FIP1L1-PDGFRA transcript by qualitative RT-PCR was also recorded in the majority of responding patients after median 2 months of therapy, however in few cases the complete molecular response could be recognised only after more than 18 months of imatinib therapy. We conclude that FIP1L1-PDGFRA rearrangement is a useful molecular marker of myeloproliferative HES, a predictor of imatinib-responsiveness and as a means to follow therapy in this subgroup of patients.
DLEU2, Located within the CLL 13q14 Deletion Locus, Encodes an Antisense RNA for the Putative Bicistronic RFP2/LEU5 Gene in Humans and Mouse.
Authors: Corcoran Martin M. , Hammarsund Marianne , Zhu Chaoyong , Lerner Mikael , Kapanadze Bagrat , Larsson Catharina , Forsberg Lars , Ibbotson Rachel E. , Einhorn Stefan , Oscier David G. , Grander Dan , Sangfelt Olle 
Published: October 2019

Abstract
Our group previously identified two novel genes, RFP2/LEU5 and DLEU2, within a 13q14.3 genomic region of loss seen in various malignancies, including chronic lymphocytic leukemia and mantle cell lymphoma. However, no specific inactivating mutations were found in these or other genes in the vicinity of the deletion, strongly suggesting that a nonclassical tumor-suppressor mechanism may be involved. Our recent analysis demonstrates that the DLEU2 gene encodes a putative noncoding antisense RNA, with one exon directly overlapping the first exon of the RFP2/LEU5 gene in the opposite orientation. In addition, the RFP2/LEU5 transcript can be alternatively spliced to produce either several monocistronic transcripts or a putative bicistronic transcript encoding two separate open-reading frames, adding to the complexity of the locus. The finding that these gene structures are conserved in mouse, including the putative bicistronic RFP2/LEU5 transcript as well as the antisense relationship with DLEU2, further underlines the significance of this unusual organization and suggests a biological function for DLEU2 in the regulation of RFP2/LEU5. Further characterisation of the 13q14 deletion locus distal to the RFP2/DLEU2 region has resulted in the identification of two novel evolutionary conserved genes DLEU7 and DLEU8, the latter of which may function as both a protein encoding and an cis-antisense gene. The combined data indicates that the CLL 13q14 deletion locus encompasses a highly complex gene regulatory system, the partial deletion of which may affect the post-transcriptional regulation of non-deleted genes in the vicinity.
Glycoprotein (GP) VI Is Associated with GPIb-IX-V on the Membrane of Resting and Activated Platelets.
Authors: Berndt Michael C. , Arthur Jane F. , Gardiner Elizabeth E. , Ozaki Yukio , Kahn Mark L. , Andrews Robert K. 
Published: October 2019

Abstract
The platelet collagen receptor, glycoprotein (GP)VI, initiates platelet aggregation at low shear stress while GPIb-IX-V, which binds von Willebrand factor, elicits platelet aggregation under high shear conditions. To investigate the possibility that GPIb-IX-V and GPVI are associated on the platelet surface, we first ascertained that aggregation induced by a GPVI-specific agonist, collagen-related peptide, like collagen, is markedly cross-blocked by a GPIbα-specific monoclonal antibody, SZ2. Immunoprecipitation of GPIb-IX with anti-GPIbα from the 1% (v/v) Triton-soluble fraction of unstimulated platelets and immunoblotting with anti-GPVI demonstrated association between GPIb-IX and GPVI. This association was maintained when platelets were activated by thrombin. Pre-treatment of platelets with methyl-β-cyclodextrin to disrupt lipid rafts did not affect association in resting or activated platelets under these conditions of detergent lysis. The association is also independent of cytoskeletal attachment, since it was unaffected by treatment with N-ethylmaleimide or DNaseI, which dissociate GPIb-IX from filamin and the actin-containing cytoskeleton, respectively. Finally, the association involves an interaction between the ectodomains of GPIbα and GPVI, since soluble fragments of GPIbα (glycocalicin) and GPVI are co-precipitated from the platelet supernatant under conditions where GPVI is shed. A contribution of GPIb-IX-V to GPVI-induced platelet responses, and vice versa, therefore warrants further investigation.
CD63 Modulates Spreading and Tyrosine Phosphorylation of Platelets on Immobilized Fibrinogen.
Authors: Israels Sara J. , McMillan-Ward Eileen 
Published: October 2019

Abstract
CD63 is a member of the tetraspanin superfamily of integral membrane proteins. Present on a variety of cells, tetraspanins form lateral associations with integrins and may act as ‘organizers’ of multimolecular networks that modulate integrin-mediated signaling, cell morphology, motility and migration. In resting platelets CD63 is present on the membranes of dense granules and lysosomes. Following platelet activation and exocytosis, CD63 relocates to the plasma membrane where it associates with the platelet integrin αIIbβ3-CD9 complex, and with the actin cytoskeleton in an αIIbβ3-dependent manner. In the current study, D545, a monoclonal antibody directed at the second extracellular loop of CD63, was used to investigate the role of CD63 in platelet adhesion, spreading and tyrosine phosphorylation, as determined by immunofluorescence microscopy, confocal imaging and immunoblotting. As previously demonstrated, D545 did not alter adhesion of platelets to fibrinogen, but did affect platelet spreading. Thrombin-activated platelets showed marked spreading, F-actin reorganization, redistribution of vinculin and extensive tyrosine phosphorylation, all of which were inhibited by D545. Similarly D545 inhibited the phosphorylation of focal adhesion kinase in thrombin-activated adherent platelets. These results suggest that CD63 may modulate αIIbβ3-dependent cytoskeletal reorganization.
In some malignant cell lines CD63 has been shown to associate with phosphatidylinositol (PI) kinase. To address a similar association in platelets, lipid kinase assays were performed on D545 immunoprecipitates, using PI as substrate. CD63 co-immunoprecipitated with a lipid kinase that was stimulated by non-ionic detergents, inhibited by adenosine, but unaffected by wortmannin. These enzymatic properties are consistent with a PI 4-kinase type II. The CD63-PI 4-kinase complex was co-purified from both resting and activated platelets and therefore was not activation-dependent. The linkage of CD63 with PI 4-kinase may result in the recruitment of the signaling enzyme to specific membrane locations and influence phosphoinositide-dependent signaling.