bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE COINCIDENCE OF MEDITERRANEAN ANEMIA AND PERNICIOUS ANEMIA IN A YOUNG SICILIAN
Authors: CROSBY WILLIAM H. , SACKS HARRY J. 
Published: October 2019

Abstract
1. Coincidental Mediterranean anemia and pernicious anemia were found in a 26 year old soldier of Sicilian parentage.
2. The diagnosis of pernicious anemia was made on the finding of achlorhydria after histamine, glossitis, megaloblastic bone marrow and macrocytic anemia which responded to liver extract on two occasions.
3. The diagnosis of mild Mediterranean anemia was made by finding the target-oval-cell trait in the patient and in five members of his family.
4. It is of interest that target cells were not found in the peripheral blood until treatment with liver was begun. While pernicious anemia dominated, the character of the peripheral blood picture was macrocytic. Liver therapy corrected this, whereupon "hypochromic polycythemia" characteristic of mild Mediterranean anemia was found.
IRON METABOLISM
Authors: FINCH CLEMENT A. , GIBSON JOHN G. , PEACOCK WENDELL C. , FLUHARTY REX G. 
Published: October 2019

Abstract
By determining the percentage utilization of intravenously administered radioiron for hemoglobin production over a period of two to three weeks, certain measurements of internal iron metabolism can be made.
With a normal rate of blood production, changes in per cent utilization reflect alteration in iron stores. Iron depletion is characterized by more rapid and more complete utilization of radioiron. States of iron excess in hemochromatosis can be identified by their profound depression of radioiron utilization.
If, on the other hand, storage iron is not greatly altered, the percentage utilization is determined by the function of the erythropoietic tissue. In myelophthisic anemias, in uremia, and in infection, a similar depression of the curve is found.
The rate of erythropoiesis may further be estimated by the slope of the utilization curve, and evidence of abnormal red cell destruction is found in early and abrupt plateau of the utilization curve.
A correlation has been made in a variety of hematologic disorders between the radioiron utilization for hemoglobin production and the clinical factors which might be expected to affect iron metabolism in these patients.
Significance of detection of occult non-Hodgkin's lymphoma in histologically uninvolved bone marrow by a culture technique
Authors: Sharp JG , Joshi SS , Armitage JO , Bierman P , Coccia PF , Harrington DS , Kessinger A , Crouse DA , Mann SL , Weisenburger DD 
Published: October 2019

Abstract
Prolonged disease-free survival of patients with recurrent or resistant non-Hodgkin's lymphoma (NHL) has been achieved with high-dose therapy followed by autologous bone marrow transplantation (ABMT). A concern with the use of ABMT is that the marrow that is reinfused may contain undetected NHL cells with the potential to reestablish metastatic disease in the recipient. Using a culture technique that is sensitive for detecting occult lymphoma cells in BM, we analyzed histologically normal marrow harvests from 59 consecutive patients with intermediate- or high-grade NHL who were candidates for high-dose therapy and ABMT. The culture results indicated that 22 of the patients had occult lymphoma in their marrow. Forty-three patients underwent high-dose therapy followed by ABMT. Twenty-four achieved a complete clinical remission. Those with occult lymphoma in their harvests (11 patients) continued to relapse for up to 3 years, whereas no relapses were observed beyond 8 months in 13 patients receiving marrow that did not contain detectable lymphoma cells using the culture technique. The relapses in the patients who achieved a complete remission occurred at sites of prior bulky disease rather than at new sites, suggesting that the ability to detect occult lymphoma cells in marrow is a marker of biologic aggressiveness and/or resistance to therapy, or that the reinfused cells could only grow in previously involved sites. The detection of lymphoma cells in marrow used for ABMT is an important adverse prognostic factor, and appears to be independent of other clinical predictors of outcome such as sensitivity or resistance of disease to prior chemotherapy.
Nucleolar proteins B23 and C23 as target antigens in chronic graft- versus-host disease
Authors: Wesierska-Gadek J , Penner E , Hitchman E , Kier P , Sauermann G 
Published: October 2019

Abstract
Previously we observed that sera from recipients of allogeneic bone marrow transplants who developed extensive chronic graft-versus-host disease (GVHD) intensively stained the nucleolar region of target cells in indirect immunofluorescence microscopy. To identify the target antigens, immunoblotting experiments were performed using isolated nuclei, isolated nucleoli, and purified nuclear and nucleolar proteins as the antigen source. The nucleolar phosphoproteins B23 and C23 were identified as the main target antigens. Eleven of 19 extensive chronic GVHD sera reacted with these nucleolar phosphoproteins. In addition, four sera recognized histone H1, and two sera recognized the nuclear lamins A and C. Our patients reacting with the nucleolar proteins had symptoms resembling that of scleroderma or Sjogren's syndrome.
Transplantation of bone marrow cells from transgenic mice expressing the human MDR1 gene results in long-term protection against the myelosuppressive effect of chemotherapy in mice
Authors: Mickisch GH , Aksentijevich I , Schoenlein PV , Goldstein LJ , Galski H , Stahle C , Sachs DH , Pastan I , Gottesman MM 
Published: October 2019

Abstract
Many human cancers that are initially responsive to chemotherapy eventually fail to respond to treatment. For some drugs, dose escalation that may be required for a cure cannot be achieved because sensitive tissues such as bone marrow (BM) limit cytotoxic therapy. Approaches to prevent or circumvent BM toxicity are therefore a high priority of research on dose escalation protocols. In this study, we have transplanted BM cells from transgenic mice that constitutively express physiologic amounts of a functional human multidrug resistance (MDR1) cDNA to lethally irradiated C57BL/6 x SJL F1 mice (n = 36). From 6 weeks to 10 months after the transplant, all animals contained MDR1 DNA in spleen and BM specimens as indicated by Southern blot analysis, and expressed MDR1 messenger RNA in BM samples as detected by slot blot analysis. In addition, these animals were resistant to the myelosuppressive effect of doxorubicin, daunomycin, taxol, vinblastine, vincristine, etoposide, and actinomycin D, whereas control animals that were reconstituted with normal BM were drug sensitive. Finally, the chemoprotection afforded by the MDR1 gene could readily be reversed by adding chemosensitizers such as cyclosporin A and R-verapamil to chemotherapy. Hence, it appears that BM cells expressing the human MDR1 gene maintain this function after transplantation to host animals for a minimum of 10 months, and confer multidrug resistance to these BM recipients. This selective advantage conferred by expression of the MDR1 cDNA suggests a strategy for the use of MDR1 gene therapy in cancer chemotherapy and for the introduction of otherwise nonselectable genes into BM.
Intensive chemotherapy with mitoxantrone and high-dose cytosine arabinoside followed by granulocyte-macrophage colony-stimulating factor in the treatment of patients with acute lymphocytic leukemia
Authors: Kantarjian HM , Estey EH , O'Brien S , Anaissie E , Beran M , Rios MB , Keating MJ , Gutterman J 
Published: October 2019

Abstract
Thirty-four adults with refractory acute lymphocytic leukemia received salvage therapy with mitoxantrone 5 mg/m2 intravenously over 1 hour daily for 5 days and cytosine arabinoside (ara-C) 3 g/m2 intravenously over 2 hours every 12 hours for six doses, followed by granulocyte- macrophage colony-stimulating factor (GM-CSF) 125 microgram/m2 intravenously over 4 hours daily until recovery of granulocytes above 2.0 x 10(3)/microL. Their outcome was compared with 29 prognostically similar historical control patients treated with the identical chemotherapy without GM-CSF. Overall, the complete response rates were similar in the treatment and control groups (13 of 34 [38%] v 11 of 29 [38%]). There was a trend for less remission induction mortality in the GM-CSF-treated patients (2 of 34 [6%] v 6 of 29 [21%]; P = .08), but, conversely, a higher rate of resistant disease (19 of 34 [56%] v 10 of 29 [34%]; P = .09). Recovery of granulocyte counts above 500/microL was significantly faster in the GM-CSF-treated group (25 days v 33 days; P less than .01), but there was no reduction in the incidence of febrile episodes (91% v 93%) or of documented infections (59% v 59%). Survival was prolonged in the GM-CSF-treated patients but was not of clinical relevance (31 v 20 weeks; P = .05). In summary, the addition of GM-CSF to intensive chemotherapy in refractory adult ALL was associated with a reduction in the remission induction mortality, probably secondary to a shorter duration of granulocytopenia, but not with an improvement in complete response rates.
Heterogeneity in filamentous actin content among individual human blood platelets
Authors: Oda A , Daley JF , Cabral C , Kang JH , Smith M , Salzman EW 
Published: October 2019

Abstract
The content of filamentous actin in individual platelets was measured by flow cytometry, using a fluorescent probe specific for filamentous actin (F-actin), 7-nitrobenz-2-oxa-1,3-phallacidin (NBD-phallacidin). NBD-phallacidin binding to fixed platelets was specific in that either pretreatment of platelets with unlabeled phallacidin or absorption of NBD-phallacidin by rabbit skeletal F-actin, but not globular actin (G- actin), resulted in a significant loss in the bound fluorescent probe. Mean NBD-phallacidin binding to fixed platelets varied with the agonist and paralleled the changes in F-actin reported with the DNAse I inhibition assay. (1) NBD-phallacidin binding increased with stimulation by ADP, U46619 (a prostaglandin H2 analogue), or collagen and paralleled shape change. (2) Epinephrine did not increase NBD- phallacidin binding. (3) Platelets treated at 4 degrees C contained more F-actin than did platelets kept at 37 degrees C. (4) Cytochalasin D (10 mumol/L) inhibited the increase of phallacidin binding to individual platelets stimulated by either ADP or U46619. In measurements of cytosolic free calcium concentration ([Ca2+]i) by flow cytometry in Indo-1-loaded platelets, ADP's dose-response for actin polymerization was similar to that for calcium mobilization. As shown by flow cytometry, a tail population that had a minimal increase in F- actin upon stimulation with ADP or U46619 also contained the platelets with the least forward and right angle light scattering, which are functions of platelet size and shape. When platelets treated with NBD- phallacidin were incubated with S12-murine monoclonal antibody (a marker of alpha-granule secretion detected by phycoerythrin-conjugated antimouse IgG second antibody), phallacidin fluorescence paralleled S12 binding. Thus, human blood platelets are heterogeneous in regard to actin polymerization at rest and in association with platelet activation; different degrees of phallacidin binding may identify functionally different platelet populations.
Human Plasminogen Activator Inhibitor-1 (PAI-1) Deficiency: Characterization of a Large Kindred With a Null Mutation in the PAI-1 Gene
Authors: Fay William P. , Parker Andrew C. , Condrey Lorraine R. , Shapiro Amy D. 
Published: October 2019

AbstractPlasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue- and urokinase-type plasminogen activators, is considered a critical regulator of the fibrinolytic system. We previously reported a child with abnormal bleeding and complete PAI-1 deficiency caused by a frame-shift mutation in exon 4 of the PAI-1 gene. The purpose of this study was to provide genetic and clinical data on the extended pedigree of the original proband to better define the phenotype associated with PAI-1 deficiency. Allele-specific oligonucleotide hybridization was used to genotype individuals, and serum PAI-1 antigen was measured by enzyme-linked immunosorbent assay. By this approach we have identified 19 individuals who are heterozygous for the PAI-1 null allele and 7 homozygous individuals with complete PAI-1 deficiency. Clinical manifestations of PAI-1 deficiency were restricted to abnormal bleeding, which was observed only after trauma or surgery in homozygous affected individuals. A spectrum of bleeding patterns was observed, including intracranial and joint bleeding after mild trauma, delayed surgical bleeding, severe menstrual bleeding, and frequent bruising. Fibrinolysis inhibitors, including ε-aminocaproic acid and tranexamic acid, were effective in treating and preventing bleeding episodes. Other than abnormal bleeding, no significant developmental or other abnormalities were observed in homozygous PAI-1–deficient individuals. Heterozygous PAI-1 deficiency was not associated with abnormal bleeding, even after trauma or surgery. These observations define the clinical spectrum of PAI-1 deficiency and provide additional evidence to support the hypothesis that the primary function of plasminogen activator inhibitor-1 in vivo is to regulate vascular fibrinolysis.
Recombinant Human Thrombopoietin in Combination With Granulocyte Colony-Stimulating Factor Enhances Mobilization of Peripheral Blood Progenitor Cells, Increases Peripheral Blood Platelet Concentration, and Accelerates Hematopoietic Recovery Following High-Dose Chemotherapy
Authors: Somlo George , Sniecinski Irena , ter Veer Anna , Longmate Jeffrey , Knutson Gaylord , Vuk-Pavlovic Stanimir , Bhatia Ravi , Chow Warren , Leong Lucille , Morgan Robert , Margolin Kim , Raschko James , Shibata Stephen , Tetef Merry , Yen Yun , Forman Stephen , Jones Dennie , Ashby Mark , Fyfe Gwen , Hellmann Susan , Doroshow James H. 
Published: October 2019

Abstract
Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 μg/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 μg/kg on days −3, −1, and 1, or 0.6 μg/kg on days −1 and 1. G-CSF, 5 μg/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34+ cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 × 106/kg (range, 1.3 to 17.6) versus 0.8 × 106/ kg (range, 0.3 to 4.2), P = .0003. The targeted minimum yield of 3 × 106CD34+ cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF–mobilized group versus 10% of G-CSF–mobilized patients (P = .001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P= .0001) and platelet recovery (day 9 v 10, P= .07) were accelerated, and fewer erythrocyte (3 v 4,P = .02) and platelet (4 v 5, P = .02) transfusions were needed compared with G-CSF–mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P &lt; .0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 μg/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF–mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.
Prognostic Importance of 6-Mercaptopurine Dose Intensity in Acute Lymphoblastic Leukemia
Authors: Relling Mary V. , Hancock Michael L. , Boyett James M. , Pui Ching-Hon , Evans William E. 
Published: October 2019

Abstract6-Mercaptopurine (6MP) and methotrexate are the backbone of continuation therapy for childhood acute lymphoblastic leukemia (ALL). In studies of oral 6MP and methotrexate, indices of chronic systemic exposure to active metabolites of these agents, namely, red blood cell (RBC) concentrations of methotrexate polyglutamates (MTXPGs) and thioguanine nucleotides (TGNs) have positively correlated with event-free survival (EFS). Our objective was to evaluate whether MTXPGs, TGNs, and the dose intensity of administered methotrexate and 6MP were prognostic in the setting of a treatment protocol in which all treatment was coordinated through a single center, and the weekly doses of methotrexate were given parenterally. On protocol Total XII, 182 children achieved remission and received weekly methotrexate 40 mg/m2 parenterally and daily oral 6MP, interrupted every 6 weeks during the first year by pulse chemotherapy. A total of 709 TGN, 418 MTX-PG, and 267 thiopurine methyltransferase (TPMT) measurements, along with complete dose intensity information (dose received divided by protocol dose per week) for 19,046 weeks of 6MP and methotrexate, were analyzed. In univariate analyses, only higher dose intensity of 6MP and of weekly methotrexate were significant predictors of overall EFS (P = .006 and .039, respectively). The occurrence of neutropenia was associated with worse outcome (P = .040). In a multivariate analysis, only higher dose intensity of 6MP (P = .020) was a significant predictor of EFS, with lower TPMT activity (P = .096) tending to associate with better outcome. 6MP dose intensity was also associated (P = .007) with EFS among patients with homozygous wild-type TPMT phenotype. Lower 6MP dose intensity was primarily due to missed weeks of therapy and not to reductions in daily dose. We conclude that increased dose-intensity of oral 6MP is an important determinant of EFS in ALL, particularly among those children with a homozygous wild-type TPMT phenotype. However, increasing intensity of therapy such that neutropenia precludes chemotherapy administration may be counterproductive.
Hematopoietic stem cells with controllable tEpoR transgenes have a competitive advantage in bone marrow transplantation
Authors: Kirby Suzanne , Walton William , Smithies Oliver 
Published: October 2019

Abstract
In a previous study, it was found that a truncated erythropoietin receptor transgene (tEpoR tg) enables multilineage hematopoietic progenitor amplification after treatment with erythropoietin (epo) in vitro and in vivo. This study used competitive bone marrow (BM) repopulation to show that tEpoR tg facilitates transplantation by hematopoietic stem cells (HSC). Individual multilineage colonies, committed myeloid progenitor colonies, and lymphoid colonies (pre-B colony-forming units) were grown from the marrow of animals 6 months after they received a 50/50 mixture of transgene and wild-type BM cells. In epo-treated recipients, the transgene-bearing cells significantly outcompeted the wild-type cells (84%-100% versus 16%-0%, respectively). In recipients treated with phosphate-buffered saline, the repopulation was minimally different from the donor mixture (49%-64% transgene versus 51%-36% wild-type). The epo-induced repopulation advantage is maintained in secondary transplants. In addition, neither accelerated HSC depletion nor uncontrollable proliferation occurred during epo-stimulated serial transplants of transgene-containing BM. Thus, the tEpoR tg functions in a benign fashion in HSC and allows for a significant and controllable repopulation advantage in vivo without excessive HSC depletion relative to wild-type BM.
A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations
Authors: Hromas Robert , Shopnick Rinah , Jumean Hani George , Bowers Charles , Varella-Garcia Marileila , Richkind Kathleen 
Published: October 2019

Abstract
AML1 is a transcriptional activator that is essential for normal hematopoietic development. It is the most frequent target for translocations in acute leukemia. We recently identified 3 patients in whom pancytopenia developed almost 50 years after high-level radiation exposure from nuclear explosions during or after World War II. In all 3 patients, acute myeloid leukemia (AML) eventually developed that had similar characteristics and clinical courses. Cytogenetics from the 3 patients revealed a t(1;21)(p36;q22), a t(18;21)(q21;q22), and a t(19;21)(q13.4;q22). By fluorescent in situ hybridization (FISH), all 3 translocations disrupted the AML1 gene. Two of theseAML1 translocations, the t(18;21) and the t(19;21), have not been reported previously. It is possible that the AML1 gene is a target for radiation-induced AML.
Misdiagnosis of primary immune thrombocytopenia and frequency of bleeding: lessons from the McMaster ITP Registry
Authors: Arnold Donald M. , Nazy Ishac , Clare Rumi , Jaffer Anushka M. , Aubie Brandon , Li Na , Kelton John G. 
Published: October 2019

Key PointsOne in 7 patients suspected of having primary ITP was misdiagnosed at some point during their disease course; 56.1% had grade 2 bleeding. The McMaster ITP Registry is a useful tool to improve the diagnosis of ITP and identify unique subgroups of patients.
A cross-sectional analysis of cardiovascular disease in the hemophilia population
Authors: Sood Suman L. , Cheng Dunlei , Ragni Margaret , Kessler Craig M. , Quon Doris , Shapiro Amy D. , Key Nigel S. , Manco-Johnson Marilyn J. , Cuker Adam , Kempton Christine , Wang Tzu-Fei , Eyster M. Elaine , Kuriakose Philip , von Drygalski Annette , Gill Joan Cox , Wheeler Allison , Kouides Peter , Escobar Miguel A. , Leissinger Cindy , Galdzicka Sarah , Corson Marshall , Watson Crystal , Konkle Barbara A. 
Published: October 2019

Key PointsCV risk factors are common in older men with hemophilia. Although older men with hemophilia have less CV disease than comparable unaffected men, CV events do occur and require treatment.