bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms accounting for the defective natural killer activity in patients with hairy cell leukemia
Authors: Trentin L , Zambello R , Agostini C , Ambrosetti A , Chisesi T , Raimondi R , Bulian P , Pizzolo G , Semenzato G 
Published: October 2019

Abstract
Natural killer (NK) cell activity is severely impaired in untreated patients with hairy cell leukemia (HCL). In an attempt to investigate whether this impairment is related to a defect at the target cell binding and/or at the post target cell binding level, we evaluated the peripheral blood mononuclear cells (PBMC) of HCL patients for their ability to: (1) bind and kill K-562 NK-sensitive targets at the single cell binding level; (2) release the NK cytotoxic factor (NKCF) under different in vitro stimuli, including K-562 and phytohemoagglutinin; and (3) kill K-562 targets in a lectin-dependent cellular cytoxicity (LDCC) assay. This study demonstrates that untreated HCL patients' PBMC show a low ability to form conjugates with K-562 targets at the single cell binding level (5.7% +/- 1.0%) with respect to patients studied after treatment (9.3% +/- 1.3%) and controls (15.0% +/- 4.0%); P less than .05 and P less than .001, respectively. A decreased ability to kill the bound target was demonstrated in untreated cases (1.2% +/- 1.1%) versus patients studied after treatment and controls (12.3% +/- 1.6%, 17.0% +/- 3.1% respectively); P less than .001 in both conditions. After activation of effector cells with interleukin-2 (IL- 2) in vitro, an increase in the ability of PBMC to form conjugates with K-562 targets and kill the bound target was demonstrated in each group of patients. Moreover, IL-2 was able to increase the cytotoxicity against NK-sensitive targets in all patients tested. Evaluation of NKCF production showed that untreated patients release low levels of NKCF when PBMC were incubated in the presence of K-562 stimulators (1.8% +/- 0.7%) with respect to patients after interferon-alpha (IFN-alpha) therapy (7.6% +/- 2.1%) and controls (12.9% +/- 2.2%); P less than .02 and P less than .001, respectively. When the recognition mechanisms were bypassed by triggering the cells with lectins in an LDCC assay, we demonstrated an increase of the lytic activity in both groups of patients with respect to the baseline values. However, the cytotoxic capacity observed in untreated patients was significantly lower than that observed in subjects after IFN-alpha therapy and controls (P less than .001). These findings suggest that the impaired NK activity observed in patients with HCL is related to defects both at the target and posttarget cell binding levels.
CD28 ligation in T-cell activation: evidence for two signal transduction pathways
Authors: Ledbetter JA , Imboden JB , Schieven GL , Grosmaire LS , Rabinovitch PS , Lindsten T , Thompson CB , June CH 
Published: October 2019

Abstract
The CD28 homodimer is thought to function as a signal transducing receptor during activation of T cells. Evidence is presented that the degree of aggregation of CD28 on the cell surface regulates two distinct CD28-associated signals. Binding of bivalent CD28 monoclonal antibody (MoAb) 9.3 upregulates lymphokine production by messenger RNA (mRNA) stabilization, without direct initiation of lymphokine mRNA transcription. This signal was not dependent on inositol phospholipid production or activation of a protein tyrosine kinase (PTK). In contrast, further crosslinking of CD28 on the cell surface rapidly induced formation of large amounts of inositol trisphosphate (InsP3) and increased cytoplasmic calcium concentration [( Ca2+]i), but did not stimulate PTK. CD28 crosslinking directly activated a subset of resting T cells, since CD25 (interleukin [IL]-2 receptor alpha chain) mRNA was rapidly induced in purified T cells, and proliferation, even without addition of exogenous IL-2, was sometimes observed. CD25 expression was detected on the cell surface of approximately 20% of CD4+ T cells. The degree of CD28 aggregation required for activation was investigated by preparing soluble 9.3 x 9.3 conjugates ranging in size from approximately 300 Kd to greater than 1,000 Kd, and comparing their function in T-cell proliferation assays with phorbol-12-myristate-13- acetate (PMA), anti-CD3, or IL-2. There was a correlation between conjugate size and proliferation with IL-2, whereas costimulation with PMA or CD3 was optimized at a lower degree of CD28 aggregation. The inositol phospholipid (InsP) generation and increase in [Ca2+]i after CD28 receptor aggregation appeared to proceed through a pathway different from the CD3/T-cell receptor (TCR) pathway since it was enhanced by pretreatment with PMA, while the InsP and [Ca2+]i signal from crosslinking CD3 was suppressed by PMA. Furthermore, the proliferation response to CD28 aggregation was resistant to inhibition by CD3 modulation. Thus, CD28 aggregation appears to trigger a phospholipase C activation pathway that differs from the CD3/TCR-linked pathway.
Prognostic value of lymphocyte homing receptor and S phase fraction in non-Hodgkin's lymphoma
Authors: Jalkanen S , Joensuu H , Klemi P 
Published: October 2019

Abstract
Lymphocyte homing receptors (HRs) mediate lymphocyte binding to high endothelial venules, and control their circulation between the blood and the lymphoid organs. The role of HRs and nuclear DNA content in the spread and prognosis of non-Hodgkin's lymphoma was studied from paraffin-embedded tumor sections of 104 patients followed-up for the minimum of 5 years after the diagnosis. HR expression was analyzed by staining with a monoclonal antibody, Hermes-3, and DNA content by flow cytometry. Ten (10%) lymphomas were HR negative (HR-), 14 (13%) weakly (HR+/-), and 80 (77%) strongly positive (HR+). HR- lymphomas disseminated less often than HR+/- or HR+ lymphomas (P = .03), and their prognosis was more favorable (P = .03), although they often had a large S phase fraction (SPF), indicating a rapid proliferation rate. A large SPF (greater than 12%) was strongly associated with an unfavorable histologic type in Working Formulation (P = .0001) and poor survival (P = .006), whereas DNA aneuploidy was not. The 5-year survival rate corrected for intercurrent deaths was 61% in lymphomas with SPF less than 12% or with HR-, but only 15% if SPF was greater than 12% and HR+ (P less than .0001). In multivariate analysis stage (P less than .001), SPF (P = .002) and HR (P = .003) were the only independent prognostic factors.
Actions of human interleukin-4/B-cell stimulatory factor-1 on proliferation and differentiation of enriched hematopoietic progenitor cells in culture
Authors: Sonoda Y , Okuda T , Yokota S , Maekawa T , Shizumi Y , Nishigaki H , Misawa S , Fujii H , Abe T 
Published: October 2019

Abstract
We studied the effects of recombinant human interleukin-4 (IL-4) on colony formation by enriched hematopoietic progenitors. IL-4 alone did not support colony formation at all. When IL-4 was combined with granulocyte colony-stimulating factor (G-CSF), the number of pure neutrophil colonies increased three times over that supported by G-CSF alone. IL-4 added 5 days after the addition of G-CSF failed to exert this synergistic effect, indicating that IL-4 acts on the early stage of proliferation. The mapping experiments (sequential observation of colony formation) have clearly shown that IL-4 did not initiate progenitor cell proliferation. Based on these data, IL-4 may possess a direct action on progenitor cells; however, it can only act as a costimulant with G-CSF. In contrast, IL-4 had possible inhibitory effects on macrophage colony formation supported by interleukin-3 (IL- 3) and macrophage colony-stimulating factor (M-CSF). In other words, IL- 4 may induce progenitor cells to become sensitive to G-CSF and thereby induce neutrophil differentiation. Delayed addition experiments demonstrated that human IL-4, unlike murine IL-4, could support neither proliferation nor survival of erythroid burst or mixed colony forming cells. Neutrophil colony forming cells only survived and recovered after addition of G-CSF and erythropoietin on day 5 of incubation. On the other hand, IL-3 supported neutrophil, erythroid burst, and mixed colony forming cells as reported previously (Sonoda et al, Proc Natl Acad Sci USA, 85:4360, 1988). These results led us to propose that IL-4 possibly acts with more mature progenitor cells than those of IL-3 or granulocyte-macrophage (GM)-CSF.
Recombinant tumor necrosis factor enhances the proliferative responsiveness of murine peripheral macrophages to macrophage colony- stimulating factor but inhibits their proliferative responsiveness to granulocyte-macrophage colony-stimulating factor
Authors: Chen BD , Mueller M 
Published: October 2019

Abstract
Tumor necrosis factor (TNF) is a protein produced by activated macrophages in response to endotoxin. The effect of recombinant murine TNF (rMuTNF) on the growth of murine tissue-derived macrophage colony- forming units (CFU-M) which are responsive to both macrophage and granulocyte-macrophage colony-stimulating factors (M-CSF and GM-CSF), was studied. TNF alone did not stimulate macrophage proliferation but did prolong their survival in vitro. The proliferative response of CFU- M to M-CSF, however, was greatly enhanced by the presence of TNF. The enhancement effect of TNF is dose-dependent, reaching a maximum at approximately 50 U/mL. In contrast, the proliferative responsiveness of CFU-M to GM-CSF was inhibited by the concurrent addition of rMuTNF. Both effects appear to be caused directly by rMuTNF, rather than by the secondary factor(s) produced by TNF-treated macrophages. TNF treatment also induced a transient downmodulation of M-CSF receptors in cultured macrophages and accelerated their uptake and use of exogenous M-CSF, which may account for, at least in part, the enhanced proliferative activity in response to M-CSF. Short-term treatment (24 hours) was not sufficient to induce either an enhancing or an inhibitory effect upon CFU-M. This study suggests an autoregulatory role for TNF in the production of mature tissue macrophages by selectively enhancing their proliferative response to lineage specific growth factor, M-CSF.
Purification and characterization of factor VIII 372-Cys: a hypofunctional cofactor from a patient with moderately severe hemophilia A
Authors: O'Brien DP , Pattinson JK , Tuddenham EG 
Published: October 2019

Abstract
We have purified factor VIII from a patient with moderately severe hemophilia A (FVIII, 4 U/dL; FVIII:Ag, 110 U/dL) and subjected the protein to Western blot analysis after time course activation with thrombin. The cross reacting material-positive (CRM+) FVIII has the normal distribution of heavy and light chains before thrombin activation, and, after incubation with the enzyme, appropriate cleavages are made at positions 740 and 1689. However, the normal thrombin cleavage at position 372 in the heavy chain of this molecule does not occur. This result is consistent with the demonstration in the patient's leukocyte DNA of a C to T transition in codon 372, leading to the substitution of a cysteine for an arginine residue at the heavy chain internal cleavage site. The severely impaired functional activity of this molecule confirms that the heavy chain of FVIII must be proteolysed in order to effect full cofactor activation in vivo. However, a threefold activation was detected when this protein was incubated with thrombin. No evidence of thrombin-mediated cleavage at position 336 in the heavy chain was detected, in contrast to the variant recombinant B domainless-molecule, FVIII 372-Ile, described by Pittman and Kaufman (Proc Natl Acad Sci USA 85:2429, 1988). Using gel permeation studies of the FVIII/von Willebrand factor (vWF) complex before and after thrombin activation, we have demonstrated that the 40 Kd A2 domain of wild type FVIII dissociates from vWF after cleavage by the enzyme. In contrast, incomplete dissociation was detected in the case of FVIII 372-Cys. We conclude that the functional defect in FVIII 372-Cys is a consequence of the resistance to proteolysis of the internal scissile bond in the heavy chain.
Reticulocytes II: Reexamination of the in vivo survival of stress reticulocytes
Authors: Noble NA , Xu QP , Hoge LL 
Published: October 2019

Abstract
Very young reticulocytes are released into the circulation in response to the stress of anemia. These stress reticulocytes have shortened in vivo survival when transfused into normal recipients, and are generally considered to be abnormal because they have skipped a terminal cell division. We reevaluated one aspect of their abnormality: that of in vivo survival. Using methodology that accounted for all cells transfused, in vivo survival of both normal and stress reticulocytes was investigated in both normal and anemic recipients. The experiments demonstrate that: (1) survival of reticulocytes is normal only when normal reticulocytes are injected into nonanemic animals; (2) intrinsic properties of stress reticulocytes lead to their immediate removal from the circulation by normal recipients to a significantly greater extent than by anemic recipients; and (3) both stress and normal reticulocytes are removed at an accelerated rate over time by anemic recipients. Taken together, the data indicate that in the course of becoming anemic, an adaptation occurs that allows cells produced during anemia to circulate considerably longer in anemic animals than they could in normal nonanemic animals. Other studies disclosed that increased reticulocyte survival in anemic animals could not be attributed to reticuloendothelial overload, but is induced by adaptation of the spleen, decreasing its removal of stress reticulocytes.
Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19)(q23;p13): a Pediatric Oncology Group study
Authors: Crist WM , Carroll AJ , Shuster JJ , Behm FG , Whitehead M , Vietti TJ , Look AT , Mahoney D , Ragab A , Pullen DJ 
Published: October 2019

Abstract
The prognostic significance of chromosomal translocations, particularly t(1;19) (q23;p13), was evaluated in children with pre-B and early pre-B acute lymphoblastic leukemia (ALL). Patients were treated on a risk- based protocol of the Pediatric Oncology Group (POG) between February 1986 and May 1989. An abnormal clone was detected in 46% (130 of 285) of pre-B cases and 56% (380 of 679) of early pre-B cases. Translocation of any type was associated with a worse treatment outcome than other karyotypic abnormalities: 15 of 66 versus 3 of 64 failed therapy in the pre-B group (P = .001), and 37 of 141 versus 23 of 239 failed in the early pre-B group (P less than .001). The t(1;19) (q23;p13) occurred significantly more often in cases of pre-B ALL with a clonal abnormality than in early pre-B ALL cases (29 of 130 v 5 of 380, P less than .001). Among the 285 pre-B cases in which bone marrow was studied cytogenetically, those with t(1;19) had a significantly worse treatment outcome than all others (11 of 29 v 27 of 256 have failed therapy, P less than .001). This difference is significant (P less than .001) after adjustment for leukocyte count, age, and other relevant features. Cases with the t(1;19) also had a worse prognosis than pre-B patients with other translocations (4 of 37 have failed, P less than .01) or with any other karyotypic abnormality (7 of 101 have failed, P less than .001). We conclude that chromosomal translocations confer a worse prognosis for non-T, non-B-cell childhood ALL, and that the t(1;19) is largely responsible for the poor prognosis of the pre-B subgroup.
Direct sequence analysis of the 14q+ and 18q- chromosome junctions in follicular lymphoma
Authors: Cotter F , Price C , Zucca E , Young BD 
Published: October 2019

Abstract
Although the t(14;18) chromosome translocation has been demonstrated to be a highly consistent feature of follicular lymphomas, the underlying mechanism generating this fusion has remained uncertain. To examine this question further, a polymerase chain reaction strategy has been devised to permit the amplification and direct sequencing of the resultant 14q+ and 18q- reciprocal junctions. Direct sequence analysis of amplified 14q+ junctions established that 7 of 11 tumors contained a bcl-2 (mbr) sequence fused to an immunoglobulin JH region (five were J6 and two were J5). One of these junctions had an unusual configuration with the bcl-2 and JH sequences separated by a recognizable DH region. This finding suggests that at least some of the junctional sequences, previously thought of as N insertions, may be fragments of unrecognized DH regions. It was also possible to amplify and sequence 18q- junctions using a primer based on the DH recombination signal sequences. Several 18q- junctions were shown to consist of DH/bcl-2 (either mbr or mcr) fusions. In two tumors the 14q+ and 18q- junctions were fully sequenced, and it was demonstrated that the bcl-2 sequence was conserved during mbr and mcr translocations. This contrasts with previous analyses that demonstrated either loss or duplication of several bases at the breakpoints in the bcl-2 gene.
Association between clonogenic cell growth and clinical risk group in B- cell chronic lymphocytic leukemia
Authors: Dadmarz R , Rabinowe SN , Cannistra SA , Andersen JW , Freedman AS , Nadler LM 
Published: October 2019

Abstract
Chronic lymphocytic leukemia of B-cell origin (B-CLL) is a disease with a variable clinical course, despite the fact that the neoplastic cells in this disorder are homogeneous with respect to morphology, immunophenotype, and cell cycle stage. To further investigate the heterogeneity observed in the clinical behavior of B-CLL, we determined the phenotype and growth requirements of clonogenic cells from 28 patients with B-CLL from low-, intermediate-, and high-risk groups as defined by the Rai staging system. Using methyl-cellulose as a semi- solid media with feeder cells and/or growth factors, colonies were observed with one or more of the culture conditions tested in 25 of 28 CLLs. Phenotypic analysis of colonies demonstrated that the clonogenic cells uniformly expressed la, CD19, CD20, CD5, and the identical light chain as the original CLL cell cultured. However, heterogeneity was observed in clonogenic B-CLL cell growth among the three different CLL risk groups. Clonogenic cells from patients with low-risk CLL required either irradiated unstimulated T cells, with or without conditioned media (CM) or irradiated activated T cells alone for colony formation. Both the number of colonies (227 +/- 15) as well as the number of cells per colony (220 +/- 82) were large, with a mean cloning efficiency of 0.39%. In contrast, clonogenic cells from patients with intermediate- and high-risk CLL required the combination of both irradiated activated T cells and CM. As compared with the low-risk CLLs, both the number and size of the colonies formed by the intermediate- (74 +/- 17, 70 +/- 39) and high- (83 +/- 28, 40 +/- 14) risk groups were significantly lower (P less than .0001). Similarly, the mean cloning efficiency was significantly reduced to 0.15% and 0.14%, respectively. None of the recombinant cytokines (interleukin 1 [IL-1] to IL-7, tumor necrosis factor, alpha and gamma-interferon, B-cell growth factor, and granulocyte macrophage colony-stimulating factor) alone or in combination with each other could entirely replace the stimulatory effect of the activated T cells. These data suggest that clinical progression of B-CLL is associated with a loss of clonogenic potential in the circulating pool of neoplastic cells, which require as yet undefined factors provided by activated T cells and CM.
Detection of Epstein-Barr virus genome in benign polyclonal proliferative T cells of a young male patient
Authors: Yoneda N , Tatsumi E , Kawanishi M , Teshigawara K , Masuda S , Yamamura Y , Inui A , Yoshino G , Oimomi M , Baba S 
Published: October 2019

Abstract
Epstein-Barr virus (EBV) DNA was detected in polyclonal T cells that proliferated transiently in a 21-year-old male (referred to as H.J.) who underwent an apparently benign lymphocytosis (white blood cells, 31 x 10(6)/microL; lymphocyte, 79%) with fever, tonsillar swelling, lymphadenopathy, and hepatosplenomegaly. The symptoms and signs subsided mostly within a month of hospitalization. The major population of the lymphocytes at admission was positive for CD3, CD8 (4/8 ratio, 0.16), WT31, and DR antigen. Eight percent of the leukocytes were too blastoid to be classified as atypical lymphocytes of infectious mononucleosis (IM). The blastoid lymphocytes and the duration and degree of the lymphocytosis and hypergammaglobulinemia appeared inconsistent with IM, whereas the EBV serology indicated either EBV primary infection or a secondary alteration of normal seropositive EBV immunity. The genomic analysis of T-cell receptor beta chain in the peripheral blood mononuclear cells (PBMC) at admission with a C beta probe did not show a monoclonal rearrangement. EBV genome was detected in these cells, using the BamHI W and K probe, but not in the cells after discharge. Analysis of the EBV terminal repeat junctional sequence, using Xho I fragment of the latent membrane protein (LMP) probe binding with the terminus, did not show monoclonal or oligoclonal populations. EBV-associated nuclear antigen (EBNA) was detected in 36% of the PBMC at admission, but not in the later cells. These EBNA- positive cells were found to form rosette with sheep erythrocytes. The PBMC of six acute IM patients contained neither EBV DNA nor EBNA- positive cells. The observations in this case show a unique type of EBV infection in T cells that has not been previously reported.
Altered expression of neutrophil peripheral benzodiazepine receptor in X-linked chronic granulomatous disease
Authors: Zavala F , Veber F , Descamps-Latscha B 
Published: October 2019

Abstract
This study was aimed at determining whether the peripheral benzodiazepine receptor (PBZDR), which is abundantly expressed on mononuclear phagocytes, is involved in host defense mechanisms depending on phagocyte membrane-associated NADPH-oxidase complex. Analysis by reversible and covalent binding of PBZDR expression on human neutrophils shows that it is modulated during NADPH-oxidase activation with phorbol 12-myristate 13-acetate. Based on a series of 17 patients with chronic granulomatous disease (CGD), results show that PBZDR expression is dramatically impaired in X-linked CGD, an inherited disorder due to a mutation on the gene coding for cytochrome b558 NADPH- oxidase component, whereas it is unaffected in autosomal recessive CGD where cytochrome b558 is normally expressed, suggesting a link between PBZDR and cytochrome b558 expressions. PBZDR can be assigned by covalent binding to an 18-Kd membrane protein. These results suggest that the neutrophil PBZDR, which can accommodate the widely prescribed anxiolytic drug Valium (diazepam), is involved in host defense against pathogens, a function that could be affected by neuroimmune interactions.