bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential expression of bcl-2 and susceptibility to anti-Fas- mediated cell death in peripheral blood lymphocytes, monocytes, and neutrophils
Authors: Iwai K , Miyawaki T , Takizawa T , Konno A , Ohta K , Yachie A , Seki H , Taniguchi N 
Published: October 2019

Abstract
The recently identified Fas antigen (Ag) is a cell surface molecule that can mediate apoptosis. The cytoplasmic product of proto-oncogene bcl-2 has been shown to prolong the cellular survival by inhibiting apoptosis. To elucidate the physiologic significance of expression of both molecules, we examined the expression of Fas Ag and bcl-2 on blood leukocyte populations and evaluated their sensitivity to the cytolytic action of anti-Fas antibody. Although Fas Ag was expressed on a fraction of lymphocytes, both neutrophils and monocytes expressed Fas Ag constitutively. In contrast, there was marked difference among these leukocytes regarding bcl-2 expression. Lymphocytes expressed bcl-2 intensely, but monocytes showed weaker bcl-2 expression, and neutrophils were essentially absent for bcl-2 expression. Seemingly reflecting this lack of bcl-2-expression, neutrophils more easily underwent apoptotic cell death in vitro as compared with monocytes and lymphocytes. We showed that anti-Fas antibody affectively accelerated apoptotic cell death in neutrophils. However, the apoptosis-inducing effect of anti-Fas antibody was minimal on monocytes, and lymphocytes were resistant to this antibody. These results suggest that anti-Fas- mediated cell death may, in part, be determined by bcl-2 expression status in Fas+ lymphoid and hematopoietic cells.
High levels of the shed form of L-selectin are present in patients with acute leukemia and inhibit blast cell adhesion to activated endothelium
Authors: Spertini O , Callegari P , Cordey AS , Hauert J , Joggi J , von Fliedner V , Schapira M 
Published: October 2019

Abstract
L-selectin is expressed by most leukocytes and mediates the initial step of adhesion to vascular endothelium. A feature of this adhesion receptor is to be shed from the cell surface. We report here the presence of high levels of the shed form of L-selectin (sL-selectin) in plasma from patients with acute leukemia. We also show that sL-selectin purified from acute leukemia plasma exhibits functional activity. The mean (+/- 1 SD) plasma level of sL-selectin among 100 healthy individuals was 2.1 +/- 0.7 micrograms/mL. This value was increased (> 2 SD above the mean) in 63% of 58 patients with acute lymphoblastic leukemia (ALL) and 59% of 93 patients with acute myelogenous leukemia ([AML] P < .001). Repeated measurements in 24 patients showed normal- range levels in 16 of 16 patients in complete remission and high levels in eight of eight patients with therapy-resistant acute leukemia or leukemia relapse. Furthermore, elevated sL-selectin levels were detected in cerebrospinal fluid of three patients with ALL suffering from a relapse limited to the central nervous system. Epitope mapping with monoclonal antibodies demonstrated that L-selectin shedding from leukemic blasts was accompanied by conformational changes of its epidermal growth factor-like domain. A functional role for sL-selectin purified from leukemic plasma was supported by its ability to completely inhibit L-selectin-dependent adhesion of blast cells to tumor necrosis factor-alpha (TNF-alpha)-activated endothelium in vitro. These results suggest that sL-selectin may have an important role in the regulation of leukemic cell adhesion to endothelium. In addition, monitoring of the sL-selectin level may be useful for evaluating leukemia activity, in particular for the detection of leukemia relapse.
Ganciclovir treatment of herpes simplex thymidine kinase-transduced primary T lymphocytes: an approach for specific in vivo donor T-cell depletion after bone marrow transplantation?
Authors: Tiberghien P , Reynolds CW , Keller J , Spence S , Deschaseaux M , Certoux JM , Contassot E , Murphy WJ , Lyons R , Chiang Y 
Published: October 2019

Abstract
Allogeneic bone marrow transplantation (BMT) is associated with a severe complication--graft-versus-host disease (GVHD). Although effectively preventing GVHD, ex vivo T-lymphocyte marrow depletion unfortunately increases graft rejection and reduces the graft-versus- leukemia (GVL) effect. The ex vivo transfer of the herpes simplex thymidine kinase (HS-tk) suicide gene into T cells before their infusion with hematopoietic stem cells could allow for selective in vivo depletion of these T cells with ganciclovir (GCV) if subsequent GVHD was to occur. Thus, one could preserve the beneficial effects of the T cells on engraftment and tumor control in patients not experiencing severe GVHD. To obtain T cells specifically depleted by GCV, we transduced primary T cells with a retroviral vector containing the HS-tk and neomycin resistance (NeoR) genes. Gene transfer was performed by coculturing PHA +/- CD3- or alloantigen-stimulated purified T cells on an irradiated retroviral vector producer cell line or by incubating the T cells in supernatant from the producer. Subsequent culture in G418 for 1 week allowed for the selection of transduced cells. GCV treatment of interleukin-2-responding transduced and selected cells resulted in greater than 80% growth inhibition, whereas GCV treatment of control cells had no effect. Similarly, the allogeneic reactivity of HS-tk-transduced cells was specifically inhibited by GCV. Combining transduced and nontransduced T cells did not show a bystander effect, thus implying that all of the cells inhibited by GCV were indeed transduced. Lastly, studies involving the transduction of the HUT-78 (T-lymphoma) cell line suggest that stable expression of HS-tk can be maintained over 3 months in vitro in the absence of G418. In summary, we have established the feasibility of generating HS-tk-transduced T cells for subsequent in vivo transfer with hematopoietic stem cells and, if GVHD occurs, specific in vivo GCV- induced T-cell depletion in allogeneic BMT recipients.
A randomized, placebo-controlled trial of recombinant human granulocyte colony-stimulating factor administration in newborn infants with presumed sepsis: significant induction of peripheral and bone marrow neutrophilia
Authors: Gillan ER , Christensen RD , Suen Y , Ellis R , van de Ven C , Cairo MS 
Published: October 2019

Abstract
Host defenses in the human neonate are limited by immaturity in phagocytic immunity. Such limitations seem to predispose infected newborns to neutropenia from an exhaustion of the neutrophil reserve. Among the critical defects thus far identified in neonatal phagocytic immunity is a specific reduction in the capacity of mononuclear cells to express granulocyte colony-stimulating factor (G-CSF) after stimulation. However, the safety, pharmacokinetics, and biological efficacy of administration of recombinant human (rh)G-CSF to infected human newborns to compensate for this deficiency is unknown. Forty-two newborn infants (26 to 40 weeks of age) with presumed bacterial sepsis within the first 3 days of life were randomized to receive either placebo or varying doses of rhG-CSF (1.0, 5.0 or 10.0 micrograms/kg every 24 hours [36 patients] or 5.0 or 10.0 micrograms/kg every 12 hours [6 patients]) on days 1, 2, and 3. Complete blood counts with differential and platelet counts were obtained at hours 0, 2, 6, 24, 48, 72, and 96. Circulating G-CSF concentrations were determined at hours 0, 2, 6, 12, 14, 16, 18, 24, and 36. Tibial bone marrow aspirates were obtained after 72 hours for quantification of the bone marrow neutrophil storage pool (NSP), neutrophil proliferative pool, granulocyte progenitors, and pluripotent progenitors. Functional activation of neutrophils (C3bi expression) was determined 24 hours after rhG-CSF or placebo administration. Intravenous rhG-CSF was not associated with any recognized acute toxicity. RhG-CSF induced a significant increase in the blood neutrophil concentration 24 hours after the 5 and 10 micrograms/kg doses every 12 and 24 hours and it was sustained as long as 96 hours. A dose-dependent increase in the NSP was seen following rhG-CSF. Neutrophil C3bi expression was significantly increased at 24 hours after 10 micrograms/kg every 24-hour dose of rhG- CSF. The half-life of rhG-CSF was 4.4 +/- 0.4 hours. The rhG-CSF was well tolerated at all gestational ages treated. The rhG-CSF induced a significant increase in the peripheral blood and bone marrow absolute neutrophil concentration and in C3bi expression. Future clinical trials aimed at improving the outcome of overwhelming bacterial sepsis and neutropenia in newborn infants might include the use of rhG-CSF.
The tetrapeptide AcSDKP specifically blocks the cycling of primitive normal but not leukemic progenitors in long-term culture: evidence for an indirect mechanism
Authors: Cashman JD , Eaves AC , Eaves CJ 
Published: October 2019

Abstract
In the present study, we investigated the ability of the tetrapeptide NAc-Ser-Asp-Lys-Pro-OH (AcSDKP), a reported inhibitor of primitive hematopoietic cells, to influence the proliferative behavior of primitive normal and chronic myeloid leukemia (CML) progenitor cells in the adherent layer of long-term cultures (LTCs). Addition of > or = 50 ng/mL of AcSDKP to LTCs of normal cells at the time of the regular weekly half-medium change selectively and reversibly decreased the proportion of high proliferative potential erythroid and granulopoietic progenitors in the adherent layer that were in S-phase without changing their numbers, but had no effect on either the cycling activity or number of analogous (neoplastic) cells in the adherent layer of CML LTCs. Specificity of the effect of AcSDKP on primitive normal progenitors was demonstrated by the finding that a similar addition of either the control peptide, AcSDKE, or 100 ng/mL of tumor necrosis factor-alpha (TNF-alpha, which contains the SDKP sequence), or SDKP itself (at 300 ng/mL) did not inhibit the proliferation of primitive normal progenitors in LTC adherent layers. Incorporation of > or = 30 ng/mL of AcSDKP (but not the related control peptide, AcSDKE) directly into methylcellulose cultures of normal marrow cells resulted in a dose- dependent suppression of colony formation, which was not seen in similar studies with CML marrow or after removal of adherent cells from normal marrow. Additional experiments showed that the inhibitory effect of AcSDKP on primitive normal progenitor cycling in the LTC system could be overcome by the simultaneous addition of macrophage inflammatory protein-1 beta (MIP-1 beta); an antagonist of MIP-1 alpha. The apparent differential effect of AcSDKP on primitive normal and CML progenitors may thus be a secondary consequence of the differential responsiveness of these cells to MIP-1 alpha for another molecule antagonized by MIP-1 beta), whose production or release by adherent marrow cells is inducible by AcSDKP. Such a mechanism may offer a method for obtaining localized increases in vivo of cytokines like MIP- 1 alpha, suggesting novel and perhaps less toxic strategies for protecting primitive normal progenitors during repeated treatments with cycle-active chemotherapeutic agents where escalating the dose of drug given would be desirable.
The immunosuppressant rapamycin blocks in vitro responses to hematopoietic cytokines and inhibits recovering but not steady-state hematopoiesis in vivo
Authors: Quesniaux VF , Wehrli S , Steiner C , Joergensen J , Schuurman HJ , Herrman P , Schreier MH , Schuler W 
Published: October 2019

Abstract
The immunosuppressive drug rapamycin suppresses T-cell activation by impairing the T-cell response to lymphokines such as interleukin-2 (IL- 2) and interleukin-4 (IL-4). In addition, rapamycin blocks the proliferative response of cell lines to a variety of hematopoietic growth factors, including interleukin-3 (IL-3), interleukin-6 (IL-6), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage- colony stimulating factor (GM-CSF), and kit ligand (KL), suggesting that it should be a strong inhibitor of hematopoiesis. In this report, we studied the effects of rapamycin on different hematopoietic cell populations in vitro and in vivo. In vitro, rapamycin inhibited the proliferation of primary bone marrow cells induced by IL-3, GM-CSF, KL, or a complex mixture of factors present in cell-conditioned media. Rapamycin also inhibited the multiplication of colony-forming cells in suspension cultures containing IL-3 plus interleukin-1 (IL-1) or interleukin-11 (IL-11) plus KL. In vivo, treatment for 10 to 28 days with high doses of rapamycin (50 mg/kg/d, orally) had no effect on myelopoiesis in normal mice, as measured by bone marrow cellularity, proliferative capacity, and number of colony-forming progenitors. In contrast, the same treatment strongly suppressed the hematopoietic recovery normally seen 10 days after an injection of 5-fluorouracil (5- FU; 150 mg/kg, intravenously [i.v.]). Thus, rapamycin may be detrimental in myelocompromised individuals. In addition, the results suggest that the rapamycin-sensitive cytokine-driven pathways are essential for hematopoietic recovery after myelodepression, but not for steady-state hematopoiesis.
Immunophenotype of adult acute lymphoblastic leukemia, clinical parameters, and outcome: an analysis of a prospective trial including 562 tested patients (LALA87). French Group on Therapy for Adult Acute Lymphoblastic Leukemia
Authors: Boucheix C , David B , Sebban C , Racadot E , Bene MC , Bernard A , Campos L , Jouault H , Sigaux F , Lepage E 
Published: October 2019

Abstract
The aim of the multicentric trial LALA87 was to test the efficacy of different postremission therapies in adults (15 to 60 year olds) with acute lymphoblastic leukemia (ALL). An immunologic subclassification based on surface marker expression was proposed. Among the 562 tested patients, 511 were assigned either to the B lineage (361 cases, 63%) or to the T lineage (150 cases, 26%). T-ALL were significantly associated with male sex, age less than 35 years, mediastinal mass, central nervous system involvement, high white blood cell count, and low anemia. In a univariate and multivariate analysis, T-cell leukemia had a more favorable outcome than B-cell leukemia with respective median disease-free survivals (DFSs) of 28 and 14 months (P &lt; .005). However, the type of postremission therapy modifies the value of the immunophenotype prognostic factor. In the chemotherapy arm, T-ALL patients (26 patients) had a more favorable outcome than B-ALL patients (57 patients) (P &lt; .003). In the autologous bone marrow transplantation (ABMT) arm, the apparent better outcome of T-ALL patients (35 T/50 B) did not reach statistical significance (P = .2) and there was no difference in the allogeneic bone marrow transplantation (alloBMT) arm (37 T/71 B: P = .9). In the B-cell-lineage leukemias, subclassification by stages and myeloid antigen coexpression (10%) were not associated with different prognosis. CD10+ T-ALL (31 patients) were associated with a better DFS compared with the CD10- T-ALL (73 patients) with respective median DFS, not reached and 18.5 months (P = .04).
Human HL-60 myeloid leukemia cells transport dehydroascorbic acid via the glucose transporters and accumulate reduced ascorbic acid
Authors: Vera JC , Rivas CI , Zhang RH , Farber CM , Golde DW 
Published: October 2019

Abstract
The cellular accumulation of vitamin C, a substance critical to human physiology, is mediated by transporters located at the cell membrane, and is regulated in a cell-specific manner. Neoplastic cells may have special needs for vitamin C. Therefore, we investigated the transport of vitamin C in a human myeloid leukemia cell line (HL-60). The HL-60 cells lacked the capacity to transport the reduced form of vitamin C, ascorbic acid, but they showed a remarkable ability to transport the oxidized form of vitamin C, dehydroascorbic acid (DHA). Uptake- accumulation studies indicated that the HL-60 cells accumulated ascorbic acid when provided with DHA. Kinetic analysis showed the presence of two functional activities involved in the uptake of DHA, one with low affinity and one with high affinity. Cytochalasin B and phloretin, which inhibit the passage of glucose through the facilitative glucose transporters, also inhibited the transport of DHA by HL-60 cells. Transport of DHA was completed by D- but not L-hexoses, and was sensitive to D-hexose-dependent counter transport acceleration. These data support the concept that HL-60 myeloid leukemic cells transport DHA through the facilitative hexose transporters (glucose transporters) and accumulate the reduced form of ascorbic acid.
Developmental regulation of human gamma- and beta-globin genes in the absence of the locus control region
Authors: Starck J , Sarkar R , Romana M , Bhargava A , Scarpa AL , Tanaka M , Chamberlain JW , Weissman SM , Forget BG 
Published: October 2019

Abstract
Two lines of transgenic mice carrying a normal 40-kb Kpn I beta-globin cluster transgene lacking the locus control region (LCR) were analyzed for the expression of human gamma- and beta-globin genes during mouse development. After RNase protection assays, the ratios of human G gamma- , A gamma-, or beta-mRNAs relative to endogenous mouse zeta + alpha mRNAs were obtained for each stage of development. The two gamma transgenes were expressed in day-11.5 blood (embryonic stage) and day- 13.5 blood (early fetal stage), but their expression was markedly decreased by day 16.5 of fetal life. Expression of the beta transgene was essentially absent at day 13.5, appeared at a low level by day 16.5, and was maximal by day 18.5, reaching a level similar to that observed in adult mice. Therefore, developmentally regulated expression of the human gamma- and beta-globin transgenes was obtained in the absence of the LCR. The relative expression of human gamma- and beta- globin genes was also examined in mice carrying 40-kb Kpn I beta- cluster transgenes with two different base substitutions associated with nondeletion forms of hereditary persistence of fetal hemoglobin (HPFH), -202 C-->G G gamma HPFH and -117 G-->A A gamma HPFH. The ratio of G gamma- to beta-globin transcripts was markedly increased in red blood cells of adult mice from three different lines carrying the transgene with the -202 G gamma HPFH mutation. This result confirms our previous preliminary results (Tanaka et al: Ann NY Acad Sci, 612:167, 1990) indicating that the -202 G gamma HPFH phenotype was reproduced in transgenic mice. The relatively low levels of G gamma-mRNA expression in adult mice carrying the non-HPFH transgene excludes a major influence of the 3′ beta-globin enhancer, present upstream of the G gamma gene because of the tandem repeat insertion, as a factor in the persistent G gamma gene expression observed in blood of adult mice carrying the -202 G gamma HPFH transgene. This conclusion is also supported by the fact that, in mice carrying the -117 A gamma HPFH transgene, G gamma-globin mRNA was detected in blood of adult animals only at low levels similar to that observed in the non-HPFH lines. However, the A gamma-HPFH phenotype was not reproduced in the transgenic lines carrying the -117A gamma HPFH mice.
Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia
Authors: ten Hoeve J , Arlinghaus RB , Guo JQ , Heisterkamp N , Groffen J 
Published: October 2019

Abstract
The chimeric BCR/ABL protein is characteristic of Philadelphia (Ph)+ leukemia because it is the direct product of the Ph translocation and it has been shown to play a causal role in the genesis of leukemia. The BCR/ABL protein exhibits a deregulated tyrosine-kinase activity capable of phosphorylating different cellular substrates in vivo and in vitro. CRKL, an adaptor protein consisting of SH2 and SH3 domains in the absence of a catalytic domain, is one potential in vivo substrate of BCR/ABL. Previous experiments have shown that CRKL is phosphorylated on tyrosine in the chronic myelogenous leukemia (CML) cell line K562 and that CRKL is a substrate for ABL and for BCR/ABL in COS-1 cells. In the current study, we show that in peripheral blood cells a direct correlation exists between the presence of BCR/ABL and the phosphorylation status of CRKL. In Ph- peripheral blood cells, CRKL is present only in the nonphosphorylated form. In contrast, all BCR/ABL+ CML and acute lymphoblastic leukemia patient samples examined showed clear tyrosine-phosphorylation of CRKL. This result strongly suggests that CRKL is a biologically significant substrate for BCR/ABL and is likely to play a major role in the development of Ph+ leukemia.
Primary leukemia cells resistant to alpha-interferon in vitro are defective in the activation of the DNA-binding factor interferon- stimulated gene factor 3
Authors: Xu B , Grander D , Sangfelt O , Einhorn S 
Published: October 2019

Abstract
Cells from one-third of chronic lymphocytic leukemia (CLL) patients are resistant to alpha-interferon (alpha-IFN) as measured by induction of blast transformation. We have previously shown that all CLL clones express alpha/beta-IFN receptors, but that the resistant cells are defective in the induction of the enzyme 2′,5′-oligoadenylate synthetase (2′,5-A synthetase). Thus, the deficiency in IFN sensitivity is localized somewhere between the interaction of the IFN molecule with its receptor and induction of 2′,5′-A synthetase. We have now further characterized the resistance of CLL clones to IFN by investigating whether it is associated with a defect in the activation of IFN- stimulated gene factor 3 (ISGF3), which is involved in the activation of alpha-IFN-stimulated genes (ISGs). A defect induction of ISGF3 after alpha-IFN treatment was found in 4 of 12 CLL patients. There was a close correlation between defective induction of ISGF3 and a lack of enhancement of 2′,5′-A synthetase as well as induction of blast transformation. Pretreatment with gamma-IFN and mixing experiments with extracts from IFN-sensitive cells indicate that a lack of the gamma- component of ISGF3 was the reason for defect in activation in 2 of the patients. We conclude that a defect in activation of ISGF3 is a possible cause for resistance in CLL cells to IFN-induced blast transformation in vitro.
Bone marrow transplantation in Fanconi anemia using matched sibling donors
Authors: Kohli-Kumar M , Morris C , DeLaat C , Sambrano J , Masterson M , Mueller R , Shahidi NT , Yanik G , Desantes K , Friedman DJ 
Published: October 2019

Abstract
Eighteen patients with Fanconi anemia (FA) with evidence of bone marrow (BM) aplasia underwent allogenic BM transplants (BMT) from matched sibling donors (MSD). Median age at BMT was 7.6 years. Conditioning consisted of low-dose cyclophosphamide (CY; 5 mg/kg x 4 days) and thoracoabdominal irradiation (TAI; 400 cGy). Graft-versus-host disease (GVHD) prophylaxis included cyclosporin A and prednisone. In addition antithymocyte globulin (ATG) was administered in the pretransplant period to promote engraftment and in the posttransplant period for additional GVHD prophylaxis. Engraftment occurred rapidly (median, 12 days for an absolute neutrophil count > or = 0.5 x 10(9)/L; median, 22 days for platelet count > or = 50 x 10(9)/L). Seventeen patients have sustained engraftment and are transfusion-independent, with Lansky scores of 100% at median follow-up of 27 months. One patient developed graft failure 4 months after initial engraftment and required a second BM infusion. None of the patients developed acute GVHD; 3 patients (16%) developed chronic GVHD. BMT is a feasible option for FA patients having an MSD and should be performed at a young age and early in the course of the disease, before the development of complications. We believe the addition of ATG to the transplant regimen of low-dose CY, TAI, and cyclosporin was responsible for improvement in the survival of FA patients undergoing BMT. The regimen was well tolerated and was associated with a low incidence of complications including GVHD.