bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjuvant immunotoxin therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with B-cell non- Hodgkin's lymphoma
Authors: Grossbard ML , Gribben JG , Freedman AS , Lambert JM , Kinsella J , Rabinowe SN , Eliseo L , Taylor JA , Blattler WA , Epstein CL 
Published: October 2019

Abstract
Anti-B-blocked ricin (anti-B4-bR) combines the specificity of the anti- B4 (CD19) monoclonal antibody with the protein toxin “blocked ricin.” In blocked ricin, affinity ligands are attached to the ricin B-chain to attenuate its lectin binding capacity. In a phase I trial, Anti-B4-bR was administered by 7-day continuous infusion to 12 patients in complete remission after autologous bone marrow transplantation (ABMT) for relapsed B-cell non-Hodgkin's lymphoma (NHL). Patients were treated at 20, 40, and 50 micrograms/kg/d for 7 days. Potentially therapeutic serum levels could be sustained for 3 to 4 days. The maximum tolerated dose was 40 micrograms/kg/d for 7 days (total 280 micrograms/kg). The dose-limiting toxicities were reversible grade IV thrombocytopenia and elevation of hepatic transaminases. Mild capillary leak syndrome was manifested by hypoalbuminemia, peripheral edema (4 patients), and dyspnea (1 patient). Anti-immunotoxin antibodies developed in 7 patients. Eleven patients remain in complete remission between 13 and 26 months post-ABMT (median 17 months). These results show that Anti-B4- bR can be administered with tolerable, reversible toxicities to patients with B-cell NHL in complete remission following ABMT.
Double heterozygosity for mutations in the platelet glycoprotein IX gene in three siblings with Bernard-Soulier syndrome
Authors: Wright SD , Michaelides K , Johnson DJ , West NC , Tuddenham EG 
Published: October 2019

Abstract
Bernard-Soulier syndrome (BSS) giant platelets have defective and/or deficient glycoprotein (GP) Ib/IX complexes, causing absent ristocetin- induced aggregation, defective interaction with von Willebrand factor, morphologic abnormality, and a clinical bleeding tendency. Recently several mutations have been described in the platelet GPIb alpha gene in individuals exhibiting the BSS phenotype. We have studied a family with classical BSS, and have excluded lesions at the GPIb alpha locus by restriction fragment length polymorphism linkage analysis. Analysis of the genes for two other components of the platelet GPIb:IX complex, namely GPIb beta and GPIX, showed two different missense mutations in the coding region of the GPIX gene: an A-->G transition in codon 21 results in conversion of an aspartic acid to glycine and an A-->G change in codon 45 converts an asparagine residue to serine. Three affected individuals are doubly heterozygous for these mutations, which alter conserved residues in or flanking the GPIX leucine-rich glycoprotein motif. Both mutations create new recognition sites for the enzyme Fnu 4H1; therefore, this enzyme was used to screen 60 normal subjects (120 alleles). Neither mutation was detected in any subject other than direct relatives of the affected individuals. Although low levels of GPIb were demonstrable by both flow cytometry and immunoblot analysis in an affected individual's platelets, there was no evidence of GPIX immunoreactivity. We propose that expression of abnormal GPIX prevents stable assembly of the GPIb/IX complex, causing BSS in the doubly heterozygous individuals in this family.
Spreading of platelets on fibrin is mediated by the amino terminus of the beta chain including peptide beta 15-42
Authors: Hamaguchi M , Bunce LA , Sporn LA , Francis CW 
Published: October 2019

Abstract
We have investigated the adhesion and spreading of platelets on polymerized fibrin of varying structure to identify sites that mediate these interactions. Fibrin was prepared with thrombin to remove both fibrinopeptide A (FPA) and fibrinopeptide B (FPB) and with reptilase or Agkistrodon contortrix thrombin-like enzyme (ACTE) to selectively remove FPA or FPB, respectively. Residual fibrin-bound enzymes were inhibited with D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone (PPACK). Platelet adhesion was independent of fibrinopeptide cleavage and was equal on fibrin prepared with each of the three enzymes. In contrast, FPB cleavage increased spreading as quantitated by fluorescence microscopy of platelets stained for glycoprotein IIb-IIIa. The 24% +/- 4% spreading on reptilase-fibrin was significantly less than the 70% +/- 8% on thrombin-fibrin or 65% +/- 9% on ACTE-fibrin (P < .0005 for both). Protease III from Crotalus atrox venom was used to specifically cleave residues B beta 1–42 from fibrinogen to further investigate the role of the beta chain N-terminus in promoting platelet spreading. After clotting with thrombin, this fibrin derivative lacked beta 15–42 and supported significantly less spreading. A monoclonal antibody (MoAb) reactive with beta 15–21 inhibited spreading on thrombin-fibrin as did peptide beta 15–42, while control MoAbs and peptides had no significant effect. These results indicate that adhesion and spreading of platelets on fibrin are mediated by different interactions, and that spreading can be mediated by FPB cleavage and the amino terminus of the beta chain including residues beta 15–42.
Clinical importance of CD7 expression in acute myelocytic leukemia. The Japan Cooperative Group of Leukemia/Lymphoma [see comments]
Authors: Kita K , Miwa H , Nakase K , Kawakami K , Kobayashi T , Shirakawa S , Tanaka I , Ohta C , Tsutani H , Oguma S 
Published: October 2019

Abstract
Forty patients (9 females and 31 males; mean age 41.9 years) with CD7+ acute myelocytic leukemia (AML) were investigated; they were classified into the following subgroups according to French-American-British classification: 15 M1, 18 M2, 3 M4, and 4 M5. Leukemic cells from all the patients were negative for T-cell-specific antigens, surface CD3, and T-cell-receptor molecules. The sex and age distributions were different from those of CD7- AML patients (P < .01). Hepatomegaly and central nervous system involvement were also frequent in the CD7+ AML patients. The phenotype of and responsiveness to hematopoietic growth factors by the leukemic cells showed their immaturity, as evidenced by frequent expression of CD34, HLA-DR, and TdT, and the greatest growth response to interleukin-3. No particular karyotypic abnormality was shown. One hundred eighty AML patients were treated with a therapeutic regimen routinely used for AML. The CD7+ AML patients showed a significantly lower response than CD7- AML patients (P < .01), and had a poorer prognosis (P < .01). CD7+ AML patients with M1 or M5b had unfavorable responses to the therapeutic regimen in comparison with patients with M2, M4, or M5a. In addition, 3 of 4 CD7+ CD2+ AML patients, who did not respond to the therapy, were induced into complete remission with an acute lymphoblastic leukemia therapy. The results presented here indicate the diagnostic importance of CD7 positivity in AML, suggesting that the cellular and clinical characteristics of CD7+ AML are sufficient for it to be recognized as a distinct category of AML.
E-selectin-dependent neutrophil adhesion to Rickettsia rickettsii- infected endothelial cells
Authors: Sporn LA , Lawrence SO , Silverman DJ , Marder VJ 
Published: October 2019

Abstract
Increased neutrophil or HL60 cell adhesion to Rickettsia rickettsii- infected endothelial cells (ECs) was observed at 6 to 8 hours after the initiation of infection, diminishing by 24 hours. Similar increases were observed using formaldehyde-fixed neutrophils. Cellular association and likely the intracellular presence of rickettsiae was required for enhanced neutrophil adhesion, because culture medium conditioned by infected cells or rickettsiae rendered noninfective by pretreatment with tetracycline were ineffective at inducing neutrophil adhesion. Increases in neutrophil adhesion caused by infection were blocked by pretreatment of ECs with cycloheximide, suggesting the involvement of new protein synthesis in the cells' response. Flow cytometric analysis of infected cells showed increases in cell surface expression of E-selectin compared with uninfected control cells. Furthermore, incubation of 6- to 8-hour infected cells with a blocking monoclonal antibody against E-selectin (BB11) inhibited neutrophil adhesion an average of 61%. These results suggest the involvement of E- selectin in neutrophil adhesion to infected ECs occurring early in the course of the infection process. EC-initiated recruitment of neutrophil adhesion during rickettsiae infection could contribute to the pathologic changes associated with Rocky Mountain Spotted Fever.
Detection of ALL-1/AF4 fusion transcript by reverse transcription- polymerase chain reaction for diagnosis and monitoring of acute leukemias with the t(4;11) translocation
Authors: Biondi A , Rambaldi A , Rossi V , Elia L , Caslini C , Basso G , Battista R , Barbui T , Mandelli F , Masera G 
Published: October 2019

Abstract
The chromosomal breakpoints of t(4;11) translocation of acute lymphoblastic leukemia (ALL) have been recently identified at molecular level and shown to involve the AF4 (FEL) gene on chromosome 4 and the ALL-1 (MLL, Hrx) gene on chromosome 11. The ALL-1/AF4 fusion gene is transcribed into a chimeric mRNA. Using primer sets derived from ALL-1 and AF4 cDNAs by reverse transcription-polymerase chain reaction (RT- PCR), we were able to amplify the breakpoint sites of the fusion transcript of all 15 ALL cases with karyotypic or molecular evidence of the t(4;11). DNA fragments of different size were obtained as the consequence of different breakpoints on chromosome 11 and the presence of alternative splicing of ALL-1 exon 8. The feasibility of monitoring the residual cells carrying the t(4;11) in 2 ALL patients with different clinical outcome was evaluated. Overall, the presented results provide evidence that RT-PCR can be used as a rapid method for detecting this chromosomal abnormality and following the patient's response to therapy.
Insulin-like growth factor-1 potentiates expansion of interleukin-7- dependent pro-B cells
Authors: Gibson LF , Piktel D , Landreth KS 
Published: October 2019

Abstract
Commitment to B-lymphocyte differentiation is characterized by expression of the B220 form of the common leukocyte antigen (Ly-5) and D-JH rearrangement of the Ig heavy chain gene complex. B-lineage progenitor cells, or pro-B cells, that have initiated Ig gene rearrangement, but do not express detectable Ig heavy or light chain protein, have recently been shown to retain substantial capacity for expansion in vitro in the presence of bone marrow (BM) stromal cells and interleukin-7 (IL-7). Although the potentiating effect of stromal cells on pro-B-cell proliferation can be partially attributed to the ligand for the proto-oncogene receptor c-kit (c-kit ligand [KL] or stem cell factor), several lines of evidence suggest that c-kit-mediated cell signalling is not required for pro-B-cell expansion. Previous studies from this laboratory demonstrated that insulin-like growth factor-1 (IGF-1) potentiated the proliferative effect of IL-7 on nonadherent cells from lymphoid long-term BM cultures in a manner similar to that shown for KL. To further delineate specific cell stages that respond to lymphopoietic cytokines, we derived continuously proliferating pro-B-cell lines from day-14 murine fetal liver in the presence of IL-7 and BM stromal cell clone S10. Initial expansion and continued proliferation of these pro-B-cell lines was absolutely dependent on the presence of both IL-7 and stromal cells. In the absence of KL, IL-7-stimulated proliferation of these cells in short- term cultures and addition of either recombinant IGF-1 or KL significantly potentiated this proliferative response. Although IGF-2 and insulin also potentiated the effect of IL-7, our data suggest that neither IGF-2 nor insulin represent normal regulators of intramyeloid lymphocyte development. IGF-1 and KL activate unique cascades of intracellular signalling events and inclusion of both cytokines in cultures of IL-7-stimulated pro-B cells resulted in additive potentiation of the proliferative response. Taken together, these results suggest that expansion of pro-B cells in vivo is maintained by at least three stromal cell-derived cytokines. IL-7 appears to be unique in delivering the primary proliferative signal for pro-B-cell expansion; however, both KL and IGF-1 potentiate the proliferative effect of IL-7 on these cells. The functional redundancy and additive effects of IGF-1 and KL as amplification signals for developing B- lineage cells underscore the essential nature of clonal expansion and diversification in development of immunocompetent lymphoid cells.
Mechanisms of tumor necrosis factor-granulocyte-macrophage colony- stimulating factor-induced dendritic cell development
Authors: Santiago-Schwarz F , Divaris N , Kay C , Carsons SE 
Published: October 2019

Abstract
In a previous report, we described that tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) synergistically enhanced the development of dendritic cell (DC) progeny from early stem cells and that there is a common monocyte-DC progenitor cell. Low levels of DC were obtained with GM-CSF alone, and TNF by itself failed to induce stem cell development. Here, we investigate mechanisms by which TNF and GM-CSF institute increases in DC, and how these same molecules support later stages of DC differentiation. We show that TNF is required as the first signal, that there is upregulation of GM-CSF receptors (GM-CSFRs), and that TNF inhibits the differentiation of colony-forming units-granulocyte. High levels of GM- CSFR were always associated with conditions yielding a large number of DC, and a kinetic analysis showed a close ontogenic relationship between DC and GM-CSFR levels. The addition of anti-GM-CSF or anti-TNF antibodies blocked synergistic responses related to DC development, including high levels of GM-CSFRs. Anti-GM-CSF was the most potent inhibitor of proliferation (80%) and macrophage, DC, and polymorphonuclear (PMN) cell development. With polyclonal anti-TNF, inhibition was less (35%), and there was a shift from myelomonocytic and DC to PMN progeny. Our results support the concept that receptor upregulation is an important mechanism for growth factor synergy. Our data also indicate that the opposing effects of TNF on hematopoiesis contribute to the selection of the DC pathway and emphasize the importance of GM-CSFRs not only in initiated DC development, but also in controlling DC viability and function.
Activation of human platelets by immune complexes prepared with cationized human IgG
Authors: Schattner M , Lazzari M , Trevani AS , Malchiodi E , Kempfer AC , Isturiz MA , Geffner JR 
Published: October 2019

Abstract
The present study shows that the ability of soluble immune complexes (IC), prepared with human IgG and rabbit IgG antibodies against human IgG, to trigger platelet activation was markedly higher for IC prepared with cationized human IgG (catIC) compared with those prepared with untreated human IgG (cIC). CatIC induced platelet aggregation and adenosine triphosphate release in washed platelets (WP), gel-filtered platelets (GFP), or platelet-rich plasma (PRP) at physiologic concentrations of platelets (3 x 10(8)/mL) and at low concentrations of catIC (1 to 30 micrograms/mL). On the contrary, under similar experimental conditions, cIC did not induce aggregation in PRP, WP, or GFP. Low aggregation responses were only observed using high concentrations of both WP (9 x 10(8)/mL) and cIC (500 micrograms/mL). Interestingly, catIC were also able to induce platelet activation under nonaggregating conditions, as evidenced by P-selectin expression. Cationized human IgG alone did not induce platelet aggregation in PRP but triggered either WP or GFP aggregation. However, the concentration needed to induce these responses, was about eightfold higher than those required for catIC. The responses induced either by catIC or cationized human IgG were completely inhibited by treatment with heparin, dextran sulphate, EDTA, prostaglandin E1, or IV3, a monoclonal antibody against the receptor II for the Fc portion of IgG (Fc gamma RII). The data presented in this study suggest that IgG charge constitutes a critical property that conditions the ability of IC to trigger platelet activation.
Southern blot patterns, frequencies, and junctional diversity of T-cell receptor-delta gene rearrangements in acute lymphoblastic leukemia
Authors: Breit TM , Wolvers-Tettero IL , Beishuizen A , Verhoeven MA , van Wering ER , van Dongen JJ 
Published: October 2019

Abstract
Southern blot analysis of T-cell receptor (TCR)-delta gene rearrangements is useful for diagnostic studies on the clonality of lymphoproliferative diseases. We have developed 18 new TCR-delta gene probes by use of the polymerase chain reaction (PCR) techniques. Application of these probes for detailed analysis of the TCR-delta genes in normal control samples, 138 T-cell acute lymphoblastic leukemias (T-ALL), and 91 precursor B-ALL allowed us to determine the TCR-delta gene restriction map for five restriction enzymes, as well as the Southern blot restriction enzyme patterns of all theoretically possible TCR-delta gene rearrangements. Based on this information, it appeared that 97% of all 213 detected TCR-delta gene rearrangements in our series of ALL could be detected by use of the TCRDJ1 probe and that the majority (76%) of the 213 rearrangements could be identified precisely. In T-ALL, we found a strong preference for the complete rearrangements V delta 1-J delta 1 (33%), V delta 2-J delta 1 (10%), and V delta 3-J delta 1 (7%) and the incomplete rearrangement D delta 2- J delta 1 (11%). In precursor B-ALL, the majority of rearrangements consisted of V delta 2-D delta 3 (72%) and D delta 2-D delta 3 (10%). The junctional diversity of these 6 preferential TCR-delta rearrangements was analyzed and showed an extensive junctional insertion (approximately 30 nucleotides) for complete V delta-J delta rearrangements, whereas incomplete rearrangements had correspondingly smaller junctional regions. The detailed TCR-delta gene restriction map and probes presented here, in combination with the Southern blot patterns of TCR-delta gene rearrangements, are important for TCR-delta gene studies in ALL; all TCR-delta gene rearrangements can be detected and the majority can be identified precisely. Identification of rearrangements is a prerequisite for subsequent PCR analysis of TCR- delta gene junctional regions, eg, for detection of minimal residual disease during follow-up of ALL patients.
Prevention and induction of occlusive coronary vascular disease in autoimmune (W/B)F1 mice by haploidentical bone marrow transplantation: possible role for anticardiolipin autoantibodies
Authors: Mizutani H , Engelman RW , Kinjoh K , Kurata Y , Ikehara S , Good RA 
Published: October 2019

Abstract
Male (NZW x BXSB)F1 (W/BF1) mice develop systemic autoimmunity involving autoantibodies, thrombocytopenia, lupus nephritis, and coronary vascular disease with myocardial infarction (CVD). To determine whether this murine lupus-associated CVD could be transferred to otherwise autoimmune-resistant (C57BL/6 x C3H/He)F1 (B6C3F1) mice via W/BF1 T-cell-depleted marrow (TCDM) transplants, or conversely whether the CVD of W/BF1 mice could be prevented by the reciprocal transplant, reciprocal haploidentical transplants of TCDM were performed. CVD developed only in mice with systemic autoimmunity. Mice that developed lupus had glomerulonephritis and thrombocytopenia and also had elevated titres of autoantibodies to double-strand DNA, cardiolipin, and platelets and elevated levels of circulating immune complexes. Of control W/BF1 mice, 80% developed lupus, and of these, 81% developed CVD with a mean grade of 2.5 +/- 0.8. Engraftment of W/BF1 mice with B6C3F1 marrow protected 90% of the recipients from the development of lupus, and none developed CVD. Engraftment of B6C3F1 mice with W/BF1 marrow induced lupus in 60% of the recipients, and of those, 33% developed CVD with a mean grade of 1.3 +/- 0.3. The B6C3F1 recipients of W/BF1 marrow which developed CVD had significantly higher titres of autoantibodies to cardiolipin (aCL; P < .01). These findings show that genetic abnormalities present in the W/BF1 hematopoietic stem cells contribute to autoantibody development, including aCL, and suggest that thrombogenic mechanisms induced by aCL may contribute to the development of CVD in this form of murine lupus erythematosus.
Selective targeting of human lymphokine-activated killer cells by CD3 monoclonal antibody against the interferon-inducible high-affinity Fc gamma RI receptor (CD64) on autologous acute myeloid leukemic blast cells
Authors: Notter M , Ludwig WD , Bremer S , Thiel E 
Published: October 2019

Abstract
The potential of the CD3 monoclonal antibody (MoAb) OKT3 to selectively target lymphokine-activated killer (LAK) cells and T-cell clones in vitro against autologous tumor cells was studied using material from patients with acute leukemias (19 acute myeloid leukemias [AML], and 3 acute lymphoblastic leukemias [ALL]). Cytotoxicity mediated by patient LAK cells against AML blasts, but not against ALL cells and autologous Epstein-Barr virus-transformed B cells, was enhanced 1.5-fold to 9.3- fold by OKT3 in all AML patients studied. The following findings suggest that the major target molecule on AML cells for OKT3-coated LAK cells is the high-affinity Fc receptor for IgG (Fc gamma RI; CD64): (1) susceptibility to killing by OKT3-coated effector LAK cells segregated with target cell expression of CD64; (2) preincubation of AML blasts with monomeric OKT3 (murine IgG2a), the Fc portion of which is known to have preferential binding affinity to CD64, resulted in lysis by autologous T cells that were not spontaneously cytotoxic; (3) OKT3- dependent increase in lysis of primary and relapsed AML cells by autologous T-cell clones correlated with the amount of target cell expression of CD64; (4) anti-leukemic cytotoxicity of OKT3-coated T cells could partially be inhibited by monomeric human Ig, the natural ligand of CD64; and (5) expression of CD64 (Fc gamma RI) on fresh AML cells could be increased by interferon-gamma (IFN-gamma) and IFN-alpha translating into further enhancement of lysis by autologous OKT3-coated LAK cells. Nonmalignant CD34+ cells sorted from peripheral blood were found to lack expression of CD64 and hence were not affected by OKT3- triggered T-cell targeting, as detected by colony formation assays. In conclusion, the in vitro data presented provide a rationale for the combined clinical use of recombinant interleukin-2, IFN-gamma, and low doses of CD3 MoAb to eliminate AML cells while sparing nonmalignant hematopoietic progenitor cells, for example, in the setting of purging procedures for autologous bone marrow transplantation.