bluuebunny/crossref_metadata_2025_split huggingface dataset:
Marrow transplantation from hepatitis C virus seropositive donors: transmission rate and clinical course
Authors: Shuhart MC , Myerson D , Childs BH , Fingeroth JD , Perry JJ , Snyder DS , Spurgeon CL , Bevan CA , McDonald GB 
Published: October 2019

Abstract
Bone marrow transplant recipients are at risk for acquiring hepatitis C infection from the donated marrow. Twelve patients who were hepatitis C virus (HCV) RNA-negative pretransplant received marrow from anti-HCV seropositive donors. HCV RNA was present in the sera of seven of these donors. After transplant, serial serum specimens were obtained from all marrow recipients for determination of HCV RNA and aminotransferase levels. All seven recipients of marrow from HCV RNA-positive donors were HCV RNA-positive after marrow infusion; none cleared virus from the serum. All five recipients of marrow from anti-HCV seropositive, HCV RNA-negative donors remained free of HCV RNA in serum up to day 100. Abnormal serum aminotransferases were common in both HCV RNA- negative and HCV RNA-positive marrow recipients. One HCV-infected recipient developed marked elevation in aminotransferases after immunosuppressive drugs were stopped. We conclude that the presence of HCV RNA in the serum of marrow donors is an accurate predictor of HCV infection in marrow recipients. The acute infection was subclinical in all patients. The long-term risk of chronic hepatitis C virus infection in these patients remains to be determined.
Advances in the biology and treatment of B-cell chronic lymphocytic leukemia
Authors: O'Brien S , del Giglio A , Keating M 
Published: October 2019

Abstract
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the western hemisphere. Diagnosis and staging of CLL are usually straightforward, but predicting an individual patient's prognosis is still a challenge. Cytogenetic abnormalities provide important prognostic information in CLL and may show its molecular heterogeneity. A search for oncogene abnormalities continues, although no consistent defects have been identified. New agents such as fludarabine produce high complete remission rates and have generated interest in earlier treatment as a first step in a potential cure. Fludarabine also makes autologous bone marrow transplant feasible as a consolidation therapy. Immunologic abnormalities and minimal residual disease persist in most patients in remission. Combining fludarabine with other active agents and devising effective postremission strategies may change the natural history of CLL.
Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2
Authors: Delia D , Aiello A , Formelli F , Fontanella E , Costa A , Miyashita T , Reed JC , Pierotti MA 
Published: October 2019

Abstract
The cancer chemopreventive retinoid N-(4-hydroxyphenyl)-all-trans retinamide (HPR) was recently shown by us to have antiproliferative and apoptotic effects on human leukemic cell lines, including those unresponsive to all-trans retinoic acid (ATRA). We have now characterized further the process of HPR-induced cell death. We report that inhibitors of RNA transcription and of protein synthesis, activators of protein kinase C (PKC), inhibitors of tyrosine kinases, Zn++, and the antioxidants acetylcysteine, ascorbic acid, alpha- tocopherol, and deferoxamine suppressed HPR-induced apoptosis. HL60 cells induced toward monocytic differentiation by 1,25 dihydroxyvitamin- D3 [1,25(OH)2D3], but not those induced toward the granulocytic differentiation by ATRA, showed reduced responses to HPR. The transport of HPR by cells with different sensitivity to the retinoid, however, was similar, even after treatment with the phorbol ester 12-O- tetradecanoylphorbol-13-acetate (TPA), which induces unresponsiveness to HPR. The expression of the apoptosis-related genes bcl-2, p53, and c- myc was examined to determine their role in HPR-triggered cell death. The levels of bcl-2 mRNA were markedly diminished by 24 hours of HPR treatment in all cell lines except in the relatively HPR-insensitive line K422. However, probably because of its long half-life, bcl-2 protein levels were either unchanged or only slightly decreased. Downregulation of p53 mRNA was also observed within 24 hours of HPR exposure in NB4 but not K422 cells, but no changes in the amount of p53 protein were found. Suppression of c-myc transcription was observed in all cells except K422. The protective role of bcl-2 on cell death by HPR was investigated in HL60 as well as 697 pre-B leukemia and Jurkat T- acute lymphocytic leukemia (T-ALL) cells constitutively expressing high levels of bcl-2 proteins due to gene transfer manipulation. Compared with control cells, the onset of apoptosis in these cells with deregulated bcl-2 production was delayed by at least 24 hours. These findings establish that cell death by HPR requires RNA transcription and protein synthesis and is regulated by the activation of PKC. Although changes in bcl-2, p53, and c-myc expression are found in cells treated with HPR, the time-course of these events suggests that HPR- triggered apoptosis is not directly controlled by these genes. Finally, while ectopic overexpression of bcl-2 does not protect cells from death by HPR, it markedly delays its onset.(ABSTRACT TRUNCATED AT 400 WORDS)
The Mpl receptor is expressed in the megakaryocytic lineage from late progenitors to platelets
Authors: Debili N , Wendling F , Cosman D , Titeux M , Florindo C , Dusanter-Fourt I , Schooley K , Methia N , Charon M , Nador R 
Published: October 2019

Abstract
The Mpl receptor (Mpl-R) is a cytokine receptor belonging to the hematopoietin receptor superfamily for which a ligand has been recently characterized. To study the lineage distribution of Mpl-R in normal hematopoietic cells, we developed a monoclonal antibody (designated M1 MoAb) by immunizing mice with a soluble form of the human Mpl-R protein. With few exceptions, Mpl-R was detected by indirect immunofluorescent analysis on all human leukemic hematopoietic cell lines with pluripotential and megakaryocytic phenotypes, but not on other cell lines. By immunoprecipitation and immunoblotting, M1 MoAb recognized a band at 82 to 84 kD corresponding to the expected size of the glycosylated receptor. Among normal hematopoietic cells, M1 MoAb strongly stained megakaryocytes (MK) and Mpl-R was detected on platelets by indirect immunofluorescence staining or immunoblotting. On purified CD34+ cells, less than 2% of the population was stained, but the labeling was weak and just above the threshold of detection. However, dual-labeling with the M1 and antiplatelet glycoprotein MoAbs showed that most Mpl-R+/CD34+ cells coexpressed CD41a, CD61, or CD42a, suggesting that cell surface appearance of Mpl-R and platelet glycoproteins could be coordinated. M1-positive and M1-negative subsets were sorted from purified CD34+ cell populations. Colony assays showed that the absolute number of hematopoietic progenitors was extremely low and no primitive progenitors were present in the CD34+/Mpl-R+ fraction. However, this cell fraction was significantly enriched in low proliferative colony-forming units-MK. When the CD34+/Mpl-R+ fraction was grown in liquid culture containing human aplastic serum and a combination of growth factors, mature MK were seen as early as day 4, whereas the predominant cell population was erythroblasts on day 8. Similar data were also obtained with the CD34+/Mpl-R- fraction with, however, a delay in the time of appearance of both MK and erythroblasts. In conclusion, Mpl-R is a cytokine receptor restricted to the MK cell lineage. Its expression is low on CD34+ cells and these cells mainly correspond to late MK progenitors and transitional cells. These data indicate that the action of the Mpl-R ligand might predominate during the late stages of human MK differentiation.
Glanzmann's thrombasthenia associated with deletion-insertion and alternative splicing in the glycoprotein IIb gene
Authors: Peretz H , Rosenberg N , Usher S , Graff E , Newman PJ , Coller BS , Seligsohn U 
Published: October 2019

Abstract
Glanzmann's thrombasthenia is a bleeding disorder characterized by a decrease or absence of the functional platelet membrane glycoprotein (GP) complex, GPIIb/IIIa (alpha IIb beta 3). We describe a new deletion- insertion mutation in the GPIIb gene causing type I Glanzmann's thrombasthenia in two siblings of a consanguineous Iranian-Jewish family. The proband's platelets bound more antibodies against the vitronectin receptor-alpha V beta 3 than normal platelets, suggesting a normal GPIIIa (beta 3) gene and a defect in the GPIIb gene. Sequencing of amplified cDNA and genomic DNA fragments showed a 6-bp deletion and 31-bp insertion in exon 25 of the GPIIb gene. The predominant platelet GPIIb mRNA of the proband was a product of the splicing of exon 24 to a cryptic AG acceptor site in the insertion and encoded for deletion of amino acids Leu817-Asn826 and insertion of eight different amino acids. Cotransfection of COS-7 cells with expression vectors containing wild- type GPIIIa cDNA and the mutated GPIIb cDNA failed to produce detectable amounts of GPIIb/IIIa on the surface of the cells. Allele- specific restriction analysis of genomic DNA of family members showed homozygosity for the mutation in the affected siblings, heterozygosity in the parents, and homozygosity for the normal allele in an unaffected sibling. The observed mutation is in a region that is conserved from rodents to humans and has been suggested to be involved in the interaction between GPIIb and GPIIIa when these GPs are complexed in solution.
One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews [see comments]
Authors: Shpilberg O , Peretz H , Zivelin A , Yatuv R , Chetrit A , Kulka T , Stern C , Weiss E , Seligsohn U 
Published: October 2019

Abstract
In recent years four mutations causing factor XI deficiency have been identified in Jews of Ashkenazi (European) origin. Two of them, type II (a nonsense mutation) and type III (a missense mutation), were found to prevail among 125 unrelated Ashkenazi Jews with severe factor XI deficiency. A finding of type II mutation in four unrelated Iraqi- Jewish families raised the possibility that this mutation is also common in Iraqi Jews, who represent the ancient gene pool of the Jews. A molecular-based analysis performed in 1,040 consecutively hospitalized patients disclosed the following results: Among 531 Ashkenazi-Jewish patients, the type II allele frequency was 0.0217 and among 509 Iraqi-Jewish patients, 0.0167 (P = .50). The type III allele frequency in the Ashkenazi-Jewish patients was 0.0254, whereas none of 502 Iraqi-Jewish patients examined had this mutation. These data suggest that the type II mutation was present in Jews already 2.5 millenia ago. The data also indicate that the estimated risk for severe factor XI deficiency in Ashkenazi Jews (due to either genotype) is 0.22% and in Iraqi Jews, 0.03%, and that the estimated risk of heterozygosity in Ashkenazi Jews is 9.0% and in Iraqi Jews, 3.3%. As patients with severe factor XI deficiency are prone to bleeding after injury and patients with partial deficiency may have similar bleeding complications when an additional hemostatic derangement is present, the observed high frequencies should be borne in mind when surgery is planned for individuals belonging to these populations.
Interferon-alpha induces circulating tumor necrosis factor receptor p55 in humans
Authors: Tilg H , Vogel W , Dinarello CA 
Published: October 2019

Abstract
In the present studies we investigated the effect of interferon-alpha (IFN alpha) on the release of the soluble (extracellular) form of the tumor necrosis factor p55 receptor (TNFsRp55), because TNFsRp55 is a natural antagonist of tumor necrosis factor (TNF)-induced inflammation and also might be part of the antiinflammatory properties of IFN alpha. Plasma levels of TNFsRp55 were measured by a specific radioimmunoassay in five healthy volunteers and in five patients with chronic hepatitis C treated with IFN alpha. Levels showed a significant increase after a single injection of 5.0 million U IFN alpha in both healthy and hepatitis patient groups. Peak values (3.5 to 4.5 ng/mL) were observed within 12 hours of beginning treatment. Thereafter, levels promptly declined, reaching baseline values within 24 hours. TNF alpha and C- reactive protein (CRP) levels were below the detection limit in the same plasma samples. In addition, IFN alpha suppressed significantly interleukin (IL)-1 alpha-induced TNF alpha protein synthesis by human peripheral blood mononuclear cells. These results suggest that the antiinflammatory properties of IFN alpha may be, in part, also due to the induction and/or release of TNF soluble receptors and the suppression of TNF alpha synthesis.
Suppression of the delayed rectifier type of voltage gated K+ outward current in megakaryocytes from patients with myelogenous leukemias
Authors: Kapural L , Feinstein MB , O'Rourke F , Fein A 
Published: October 2019

Abstract
In normal human megakaryocytes, we identified a delayed rectifier type of voltage-gated outward K+ current (DRK). In two human megakaryoblastic tumor cell lines (DAMI, CHRF-288–11) and the human erythroleukemia cell line (HEL) the DRK current was not detected. To determine if the absence of the DRK current in the tumor cells is the result of the underlying malignant state, we examined megakaryocytes from myelogenous leukemia patients. In 24 of 29 megakaryocytes from the myelogenous leukemia patients, the DRK current was greatly suppressed, whereas in the remaining 5 megakaryocytes a normal large amplitude DRK current was present. We had the opportunity to reexamine megakaryocytes from a patient with acute promyelocytic leukemia (M3), after chemotherapy. Whereas the DRK current was suppressed before treatment, the current reappeared after chemotherapy. Exposure to the adenylate cyclase activator, forskolin, caused the appearance of a voltage-gated outward current in the megakaryocytes of patients with acute myelogenous leukemia. This finding suggests either that the channels underlying the DRK current are present but somehow suppressed in megakaryocytes from these patients or that forskolin induces a different voltage-gated outward current. We suggest that the megakaryocytes from the myelogenous leukemia patients with suppressed DRK current are abnormal, whereas the others may be normal megakaryocytes. The suppression of the DRK current may be a contributory factor to the dysregulation of thrombopoiesis (Zittoun et al: Semin Hop Paris 44:183, 1968 and Rabellino et al: Blood 63:615, 1984) in myelogenous leukemias.
Role of accessory cells in cytokine production by T cells in chronic B- cell lymphocytic leukemia
Authors: Decker T , Flohr T , Trautmann P , Aman MJ , Holter W , Majdic O , Huber C , Peschel C 
Published: October 2019

Abstract
We investigated the production of cytokines by highly purified T helper cells from B-cell chronic lymphocytic leukemia (B-CLL) patients stimulated by different activation pathways, and we studied the influence of various accessory cell populations on the pattern of the secretion of cytokines, including interleukin (IL)-2, IL-4, interferon- gamma (IFN-gamma), and IL-10. Neither a qualitative nor a quantitative difference in cytokine production and proliferative capacity was observed in CLL-derived purified T cells compared with normal individuals, when T cells were stimulated by different pathways, including CD3, CD2, and costimulation with CD28. Addition of autologous accessory cells (aAC), however, dramatically influenced the cytokine pattern of normal versus B-CLL-derived T cells. CLL cells as aAC caused a marked increase of IL-2, whereas IFN-gamma was only slightly induced and IL-4 was not influenced. In contrast, in normal individuals addition of aAC, which predominantly consisted of monocytes, resulted in a significant increase of IFN-gamma and a reduction of IL-4 secretion. IL-2 production was inhibited by higher concentrations of aAC. The increased stimulation of IL-2 production by CLL cells was not specific to the leukemic cell population, as purified B cells from normal individuals had the same effect. On the other hand, purified monocytes from CLL patients and controls both induced IFN-gamma production and inhibited IL-4 secretion. After antigen-specific stimulation with tetanus toxoid, cytokine secretion was influenced by the type of aAC in a similar pattern. We conclude that T helper cells derived from patients with B-CLL are intrinsically normal and that the predominance of B cells as accessory cells in CLL significantly alters the immune function of T helper cells in vitro.
BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents
Authors: Bedi A , Barber JP , Bedi GC , el-Deiry WS , Sidransky D , Vala MS , Akhtar AJ , Hilton J , Jones RJ 
Published: October 2019

Abstract
A critical determinant of the efficacy of antineoplastic therapy is the response of malignant cells to DNA damage induced by anticancer agents. The p53 tumor-suppressor gene is a critical component of two distinct cellular responses to DNA damage, the induction of a reversible arrest at the G1/S cell cycle checkpoint, and the activation of apoptosis, a genetic program of autonomous cell death. Expression of the BCR-ABL chimeric gene produced by a balanced translocation in chronic myeloid leukemia, confers resistance to multiple genotoxic anticancer agents. BCR-ABL expression inhibits the apoptotic response to DNA damage without altering either the p53-dependent WAF1/CIP1-mediated G1 arrest or DNA repair. BCR-ABL-mediated inhibition of DNA damage-induced apoptosis is associated with a prolongation of cell cycle arrest at the G2/M restriction point; the delay of G2/M transition may allow time to repair and complete DNA replication and chromosomal segregation, thereby preventing a mitotic catastrophe. The inherent resistance of human cancers to genotoxic agents may result not only by the loss or inactivation of the wild-type p53 gene, but also by genetic alterations such as BCR-ABL that can delay G2/M transition after DNA damage.
Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages
Authors: Weinberg JB , Misukonis MA , Shami PJ , Mason SN , Sauls DL , Dittman WA , Wood ER , Smith GK , McDonald B , Bachus KE 
Published: October 2019

Abstract
Nitric oxide (NO) is produced by numerous different cell types, and it is an important regulator and mediator of many processes including smooth muscle relaxation, neurotransmission, and murine macrophage- mediated cytotoxicity for microbes and tumor cells. Although murine macrophages produce NO readily after activation, human monocytes and tissue macrophages have been reported to produce only low levels of NO in vitro. The purpose of this study was to determine if stimulated human mononuclear phagocytes produce inducible nitric oxide synthase (iNOS) mRNA, protein, and enzymatic activity. By reverse transcriptase- polymerase chain reaction (RT-PCR) analysis, we show that human monocytes can be induced to express iNOS mRNA after treatment with lipopolysaccharide (LPS) and/or interferon-gamma (IFN-gamma). By immunofluorescence and immunoblot analyses, we show monocytes and peritoneal macrophages contain detectable levels of iNOS antigen after stimulations with cytokines in vitro. Control monocytes or those cultured with LPS and/or various cytokines have low levels of NOS functional activity as measured by the ability of cell extracts to convert L-arginine to L-citrulline, and they produce low levels of the NO catabolites nitrite and nitrate. Peritoneal macrophages have significantly enhanced nitrite/nitrate production and NOS activity after treatment with LPS and/or IFN-gamma, whereas monocyte nitrite/nitrate production and NOS activity are not altered by the treatments. Monocytes cultured with various live or heat-killed bacteria, fungi, or human immunodeficiency virus (HIV)-1 do not produce high levels of nitrite/nitrate. Antibodies against transforming growth factor-beta (TGF-beta), a factor known to inhibit iNOS expression and NO production in mouse macrophages, do not enhance NO production in human monocytes or macrophages. Biopterin, an obligate cofactor of iNOS enzymatic activity, is undetectable in freshly isolated or cultured human monocytes and peritoneal macrophages. However, replenishment of intracellular levels of tetrahydrobiopterin by culture with the cell- permeable, nontoxic precursor sepiapterin does not enhance the abilities of the human mononuclear phagocytes to produce NO in vitro. Mixing experiments show no evidence of a functional NOS inhibitor in human mononuclear phagocytes. Thus, we demonstrate that human mononuclear phagocytes can produce iNOS mRNA and protein, and (despite this) their abilities to generate NO are very low.
Functional expression of Fas antigen (CD95) on hematopoietic progenitor cells
Authors: Nagafuji K , Shibuya T , Harada M , Mizuno S , Takenaka K , Miyamoto T , Okamura T , Gondo H , Niho Y 
Published: October 2019

Abstract
We investigated the expression of an apoptosis-associated antigen (Fas) (CD95) on hematopoietic progenitor cells in the presence or absence of interferon-gamma (IFN-gamma) and/or tumor necrosis factor-alpha (TNF- alpha). CD34+ cells freshly isolated from bone marrow did not express Fas. However, IFN-gamma and/or TNF-alpha induced the expression of both the mRNA of Fas and Fas itself in a dose-dependent fashion on the surface of CD34+ cells after 48 hours of serum-free culture. IFN-gamma and TNF-alpha had a synergistic effect on the induction of Fas, when both cytokines were added to the culture. The TNF-alpha-induced Fas expression is mediated by p55 TNF-alpha receptor. CD34+ cells cultured in medium alone or with stem cell factor (SCF) showed some slight expression of Fas. When anti-Fas antibody (IgM) was added to CD34+ cells after the induction of Fas expression, CD34+ cells underwent apoptosis, as shown by a decrease in the number of viable cells, morphologic changes, the induction of DNA fragmentation, and a decrease in the number of colony-forming cells (CFC) including colony-forming unit granulocytes/macrophages (CFU-GM) and burst-forming unit erythroids (BFU-E). These observations indicate that IFN-gamma and/or TNF-alpha, well known as negative hematopoietic regulators, induce functional Fas on hematopoietic progenitor cells. The suppression of hematopoiesis by negative hematopoietic regulators may be mediated in part by Fas induction.