bluuebunny/crossref_metadata_2025_split huggingface dataset:
B7-2–positive myeloma: incidence, clinical characteristics, prognostic significance, and implications for tumor immunotherapy
Authors: Pope Belinda , Brown Ross D. , Gibson John , Yuen Edna , Joshua Doug 
Published: October 2019

AbstractDeficiencies in B7:CD28 costimulation are considered to be one of the major causes of the failure to generate a tumor-specific immune response. Up-regulating the expression of the B7 molecules on malignant B cells has been shown to stimulate cytotoxic T cells. Plasma cells from patients with myeloma express a tumor-specific idiotype but lack CD80 (B7-1) and have a variable expression of CD86 (B7-2). This study has identified the incidence and clinical significance of high CD86 expression on plasma cells at diagnosis and studied the ability of trimeric human CD40 ligand (huCD40LT) to up-regulate the expression of the B7 family on malignant plasma cells. CD86 expression on plasma cells was increased in 54% of the patients studied at diagnosis (n = 35) and was associated with a significantly shorter survival (median, 28 versus 57 months; χ2 = 4.6;P = .03) and a higher tumor load (patients with more than 50% bone marrow plasma cells, 47% versus 6%; χ2 = 7.2; P = .005). CD86 expression was highest on immature and primitive plasma cells (CD38++, CD45+) of both patients and controls and was associated with a CD40+, CD20+, CD19−, CD138+ phenotype. The shortened survival was associated with high CD86 only on mature (CD38++, CD45−) plasma cells (χ2 = 7.6; P = .006). There was no significant correlation between high CD86 and other known prognostic markers, including serum β2-microglobulin, serum thymidine kinase, and labeling index. The addition of huCD40LT to short-term cultures up-regulated both CD80 and CD86 expression on B cells (CD19+) and CD80 on plasma cells (CD38++), but did not up-regulate CD86 expression on plasma cells. Thus, B7-2–positive myeloma consists of a subgroup of patients with a relatively poor prognosis, and CD40LT may be useful in immunotherapy protocols because it up-regulates CD80 expression on malignant plasma cells without inducing B7-2–positive myeloma.
Myeloid differentiation of FdCP1 cells is dependent on Stat5 processing
Authors: Piazza Flavia , Valens Jason , Lagasse Eric , Schindler Christian 
Published: October 2019

AbstractThe IL-3 family of cytokines transduces signals through Stat5 and regulates myeloid development. Previous studies have determined that a carboxy terminally truncated isoform of Stat5 is activated in immature myeloid cells. This isoform, which lacks a transcriptional activation domain, is generated by a protein-processing event. To determine whether Stat5 cleavage plays an important role in the growth and maturation of myeloid progenitors, the FdCP1 model of myeloid maturation was evaluated. FdCP1 cells are IL-3–dependent myeloid progenitors that differentiate into monocytes when cultured in granulocyte macrophage–colony-stimulating factor (GM-CSF). Consistent with their immature phenotype, when FdCP1 cells are cultured in IL-3 they exhibit robust protease activity and signal through truncated Stat5 isoforms. In contrast, maturation leads to a loss of protease activity and a switch to the expression to full-length Stat5 isoforms. Introduction of a noncleavable, full-length Stat5 mutant into undifferentiated FdCP1 cells leads to a partially differentiated phenotype and prevents further differentiation in response to GM-CSF. These results support our hypothesis that Stat5 processing is important for myeloid maturation.
Antileukemic efficacy of 2′-deoxycoformycin in monocytic leukemia cells
Authors: Niitsu Nozomi , Yamamoto-Yamaguchi Yuri , Kasukabe Takashi , Okabe-Kado Junko , Umeda Masanori , Honma Yoshio 
Published: October 2019

Abstract2′-Deoxycoformycin (dCF) as a single agent has been reported to be less effective against myeloid than against lymphoid malignancies in clinical trials. However, previous studies have shown that in the presence of 2′-deoxyadenosine (dAd), human monocytoid leukemia cell lines are much more sensitive to dCF with regard to the inhibition of cell proliferation. Thus, dCF might be useful for treating monocytoid leukemia with the aid of dAd analogs. The antiproliferative effects of dCF in combination with dAd or its derivatives were examined on normal and malignant blood and bone marrow cells. In the presence of 10 μmol/L dAd, the concentration of dCF required to inhibit the viability of primary monocytoid leukemia cells was much lower than that required to inhibit normal or non-monocytoid leukemic cells. Among the dAd analogs, 9-β-d-arabinofuranosyladenine (AraA) was also effective in combination with dCF. Athymic nude mice were inoculated with human monocytoid leukemia U937 cells and treated with dCF or a dAd analog or both. Although dCF alone slightly but significantly prolonged the survival of mice inoculated with U937 cells, combined treatment with dCF and AraA markedly prolonged their survival. These data suggest that the combination of dCF and AraA may be useful for the clinical treatment of acute monocytic leukemia.
Peyer's patch eosinophils: identification, characterization, and regulation by mucosal allergen exposure, interleukin-5, and eotaxin
Authors: Mishra Anil , Hogan Simon P. , Brandt Eric B. , Rothenberg Marc E. 
Published: October 2019

AbstractThe gastrointestinal immune system is traditionally thought to be composed of lymphocytes located within Peyer's patches and the lamina propria. We have recently reported that eosinophils also reside in the gastrointestinal tract during healthy states, in particular, within the lamina propria, and that these cells substantially increase after oral allergen exposure. We now demonstrate the presence of eosinophils in Peyer's patches and characterize the signals that regulate the accumulation of eosinophils in Peyer's patches. In contrast to the lamina propria, intestinal Peyer's patches have very low levels of eosinophils under healthy states. However, elevated levels of interleukin-5 (IL-5), generated by transgenic or pharmacologic approaches, result in a dramatic increase in eosinophil levels in Peyer's patches. Most eosinophils are located in the outer cortex and interfollicular regions of the Peyer's patches. To dissect the mechanism of eosinophil trafficking to Peyer's patches, the role of eotaxin was examined. Mice transgenic for IL-5 and genetically deficient in eotaxin were found to have reduced levels of eosinophils in Peyer's patches compared with IL-5-transgenic mice. To prove that eosinophils also traffic to Peyer's patches in wild-type mice, allergic hypersensitivity was induced and Peyer's patches were examined. Exposure to mucosal allergen promoted marked accumulation of eosinophils in Peyer's patches and this process was attenuated in eotaxin-deficient mice. In summary, these data demonstrate that elevated levels of IL-5 and mucosal allergen exposure promote eotaxin-dependent eosinophil trafficking to Peyer's patches. These studies suggest that eosinophils may cooperate with lymphocytes in the development of mucosal immune responses in the gastrointestinal tract.
Human erythrocyte pyrimidine 5′-nucleotidase, PN-I, is identical to p36, a protein associated to lupus inclusion formation in response to α-interferon
Authors: Amici Adolfo , Emanuelli Monica , Raffaelli Nadia , Ruggieri Silverio , Saccucci Franca , Magni Giulio 
Published: October 2019

AbstractErythrocyte maturation is accompanied by RNA degradation and release of mononucleotides. We have previously purified PN-I, a pyrimidine nucleotidase whose deficiency is associated with hemolytic anemia. Computer-aided analysis of PN-I tryptic and CNBr peptide sequences revealed substantial identity with tryptic peptide sequences reported for p36, an α-interferon-induced protein. PN-I partial sequences were matched through the expressed sequence tag database with different human complementary DNA (cDNA) clones, whose sequences were exploited to screen a human placenta cDNA library. PN-I cDNA, coding for a 286-residue protein, was expressed in Escherichia coli, yielding a fully active recombinant enzyme. The recombinant protein sequence comprised the peptide sequences determined for PN-I and p36. Rabbit antisera raised against two peptides deriving from p36 and PN-I tryptic digestions, respectively, recognized both wild-type and recombinant PN-I. Molecular properties of the two proteins were essentially the same. We conclude that p36 and PN-I are identical proteins.
Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a pediatric oncology group study
Authors: Abshire Thomas C. , Pollock Brad H. , Billett Amy L. , Bradley Patricia , Buchanan George R. 
Published: October 2019

Abstract
The relapse rate in childhood acute lymphoblastic leukemia (ALL) is approximately 30% but few reinduction regimens have investigated the intensive use of polyethylene glycol Escherichia coliasparaginase (PEG-Asp). Therefore, we assessed the pharmocokinetics and efficacy of PEG-Asp in this setting. Children with B-precursor ALL, in first marrow and/or extramedullary relapse were eligible. Reinduction included doxorubicin on day 1, prednisone for 28 days, vincristine weekly for 4 weeks, and PEG-Asp either weekly or biweekly by randomization. Asparaginase levels and antibody to both E coli asparaginase and PEG-asp were measured weekly just before each PEG-asp dose. Overall, 129 of 144 patients (pts) (90%) achieved a complete remission (CR). There was a highly significant difference in CR rates between weekly (69 of 71; 97%) and biweekly (60 of 73; 82%) PEG-Asp dosing (P = .003). Grade 3 or 4 infectious toxicity was common (50%), but only 4 pts died of sepsis during induction. Other toxicities were infrequent and hypersensitivity was rare (6 of 144; 4%). Low asparaginase levels were associated with high antibody titers to either native (P = .024) or PEG asp (P = .0013). The CR rate was significantly associated with higher levels of asparaginase (P = .012). Patients with ALL in first relapse receiving weekly PEG-Asp had a higher rate of second remission compared with biweekly dosing. Low levels of asparaginase were associated with high antibody titers. Increased asparaginase levels may correlate with an improved CR rate. The use of intensive PEG-Asp should be explored further in the treatment of ALL.
Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment
Authors: Taube Janis , Halsall David , Baglin Trevor 
Published: October 2019

Abstract
Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin. Genetic polymorphisms inCYP2C9 producing variants with altered catalytic properties have been identified. Patients (n = 561) with a target international normalized ratio (INR) of 2.5 who had been treated with warfarin for more than 2 months were anonymously genotyped for the wild-typeCYP2C9*1 allele and the 2C9*2 and2C9*3 variants. The mean maintenance dose of warfarin in patients who were wild-type for both alleles was 5.01 mg. The maintenance dose of warfarin was significantly related to genotype (Kruskall-Wallis, χ2 = 17.985, P = .001) with mean maintenance doses in patients with variant alleles between 61% and 86% of that in wild-type patients. The odds ratio for the2C9*2 allele in patients with a maintenance dose of 1.5 mg or less was 5.42 (95% CI 1.68-17.4). The odds ratio for one or more variant alleles in patients developing an INR of 8.0 or greater was 1.52 (95% CI 0.64-3.58). The SD of the mean INR, percentage of high INRs, and person-time spent in range were determined as parameters of stability. There was no difference between patients grouped according to genotype for any parameter of stability. This study confirmed an association between CYP2C9 genotype and warfarin sensitivity. However, the possession of a variant allele does not increase the likelihood of severe over-anticoagulation or stability of anticoagulation during long-term therapy.
Effective targeting of tumor vasculature by the angiogenesis inhibitors vasostatin and interleukin-12
Authors: Yao Lei , Pike Sandra E. , Setsuda Joyce , Parekh Justin , Gupta Ghanshyam , Raffeld Mark , Jaffe Elaine S. , Tosato Giovanna 
Published: October 2019

AbstractSolid tumors are dependent on preexisting vasculature and neovascularization for their growth. Successful cancer therapies targeting the tumor vasculature would be expected to block the existing tumor blood supply and to prevent tumor neovascularization. We tested the antitumor activity of experimental therapy with 2 distinct antiangiogenic drugs. Vasostatin inhibits endothelial cell growth and neovascularization, and interleukin-12 (IL-12) targets the tumor vasculature acting through interferon-γ (IFN-γ) and the downstream chemokines interferon-inducible protein-10 (IP-10) and monokine induced by IFN-γ. Individually, vasostatin and IL-12 produced distinct efficacy profiles in trials aimed at reducing tumor growth in athymic mice. In combination, these inhibitors halted the growth of human Burkitt lymphoma, colon carcinoma, and ovarian carcinoma. Thus, cancer therapy that combines distinct inhibitors of angiogenesis is a novel, effective strategy for the experimental treatment of cancer.
Acute myeloblastic leukemic cells acquire cellular cytotoxicity under genotoxic stress: implication of granzyme B and perforin
Authors: Bruno Alain Pierre , Lautier Dominique , d'Orgeix Aurélie de Thonel , Laurent Guy , Quillet-Mary Anne 
Published: October 2019

AbstractGranzyme B (GrB) and perforin (PFN) are the major components of cytoplasmic granules contained in immune cellular effectors. The granule secretory pathway is one of the mechanisms by which these cells exert their cellular cytotoxicity. Recently, it has been reported that GrB and PFN are also present in circulating hemopoietic CD34+ progenitor cells mobilized by chemotherapy and granulocyte-colony stimulating factor, whereas these proteins are undetected in steady-state peripheral CD34+ cells. In this study, we hypothesized that anticancer agents may increase GrB and PFN expression in immature myeloid leukemic cells and that these treated leukemic cells become cellular effectors through a granule-dependent mechanism. Our results show that KG1a, HEL, and TF-1 CD34+acute myeloblastic leukemia cells expressed both GrB and PFN. Moreover, ionizing radiation, aracytine, and etoposide not only increase GrB and PFN expression but also conferred potent cellular cytotoxicity to these cells toward various cellular targets. Cellular cytotoxicity required cell-cell contact, was not influenced by anti-tumor necrosis factor α or anti-Fas blocking antibodies, and was abrogated by GrB inhibitors or antisense. These results suggest that, when exposed to genotoxic agents, immature leukemic cells acquire potent GrB- and PFN-dependent cellular cytotoxicity that can be potentially directed against normal residual myeloid progenitors or immune effectors.
Bcr-Abl kinase down-regulates cyclin-dependent kinase inhibitor p27 in human and murine cell lines
Authors: Jonuleit Tarja , van der Kuip Heiko , Miething Cornelius , Michels Heike , Hallek Michael , Duyster Justus , Aulitzky Walter E. 
Published: October 2019

Abstract
Chronic myeloid leukemia (CML) is a malignant stem cell disease characterized by an expansion of myeloid progenitor cells expressing the constitutively activated Bcr-Abl kinase. This oncogenic event causes a deregulation of apoptosis and cell cycle progression. Although the molecular mechanisms protecting from apoptosis in CML cells are well characterized, the cell cycle regulatory event is poorly understood. An inhibitor of the cyclin-dependent kinases, p27, plays a central role in the regulation of growth factor dependent proliferation of hematopoietic cells. Therefore, we have analyzed the influence of Bcr-Abl in the regulation of p27 expression in various hematopoietic cell systems. An active Bcr-Abl kinase causes down-regulation of p27 expression in murine Ba/F3 cells and human M07 cells. Bcr-Abl blocks up-regulation of p27 after growth factor withdrawal and serum reduction. In addition, p27 induction by transforming growth factor-beta (TGF-β) is completely blocked in Bcr-Abl positive M07/p210 cells. This deregulation is directly mediated by the activity of the Bcr-Abl kinase. A Bcr-Abl kinase inhibitor completely abolishes p27 down-regulation by Bcr-Abl in both Ba/F3 cells transfected either with a constitutively active Bcr-Abl or with a temperature sensitive mutant. The down-regulation of p27 by Bcr-Abl depends on proteasomal degradation and can be blocked by lactacystin. Overexpression of wild-type p27 partially antagonizes Bcr-Abl–induced proliferation in Ba/F3 cells. We conclude that Bcr-Abl promotes cell cycle progression and activation of cyclin-dependent kinases by interfering with the regulation of the cell cycle inhibitory protein p27.
ADP induces partial platelet aggregation without shape change and potentiates collagen-induced aggregation in the absence of Gαq
Authors: Ohlmann Philippe , Eckly Anita , Freund Monique , Cazenave Jean-Pierre , Offermanns Stefan , Gachet Christian 
Published: October 2019

Abstract
Platelets from Gαq knockout mice are unable to aggregate in response to physiological agonists like adenosine 5′-diphosphate (ADP), thromboxane A2, thrombin, or collagen, although shape change still occurs in response to all of these agonists except ADP. ADP-induced platelet aggregation results from simultaneous activation of the purinergic P2Y1receptor coupled to calcium mobilization and shape change and of a distinct P2 receptor, P2cyc, coupled through Gi to adenylyl cyclase inhibition, which is responsible for completion and amplification of the response. P2cyc could be the molecular target of the antithrombotic drug clopidogrel and the adenosine triphosphate (ATP) analogs AR-C69931MX, AR-C67085, and AR-C66096. The aim of the present study was to determine whether externally added ADP could still act through the Gi pathway in Gαq-deficient mouse platelets and thereby amplify the residual responses to agonists such as thrombin or collagen. It was found that (1) ADP and adrenaline still inhibited cyclic AMP accumulation in Gαq-deficient platelets; (2) both agonists restored collagen- but not thrombin-induced aggregation in these platelets; (3) the effects of ADP were selectively inhibited in vitro by the ATP analog AR-C69931MX and ex vivo by clopidogrel and hence were apparently mediated by the P2cyc receptor; and (4) high concentrations of ADP (100 μmol/L) induced aggregation without shape change in Gαq-deficient platelets through activation of P2cyc. Since adrenaline was not able to induce platelet aggregation even at high concentrations, we conclude that the effects of ADP mediated by P2cyc are not restricted to the inhibition of adenylyl cyclase through Gi2.
Homocysteine-responsive ATF3 gene expression in human vascular endothelial cells: activation of c-Jun NH2-terminal kinase and promoter response element
Authors: Cai Yong , Zhang Chun , Nawa Tigre , Aso Teijiro , Tanaka Makiko , Oshiro Satoru , Ichijo Hidenori , Kitajima Shigetaka 
Published: October 2019

AbstractActivating transcription factor (ATF) 3 is a member of ATF/cyclic adenosine monophosphate (cAMP)–responsive element binding protein (ATF/CREB) family of transcription factors and functions as a stress-inducible transcriptional repressor. To understand the stress-induced gene regulation by homocysteine, we investigated activation of the ATF3 gene in human endothelial cells. Homocysteine caused a rapid induction of ATF3 at the transcriptional level. This induction was preceded by a rapid and sustained activation of c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK), and dominant negative mitogen-activated protein kinase kinase 4 and 7 abolished these effects. The effect of homocysteine appeared to be specific, because cysteine or homocystine had no appreciable effect, but it was mimicked by dithiothreitol and β-mercaptoethanol as well as tunicamycin. The homocysteine effect was not inhibited by an active oxygen scavenger. Deletion analysis of the 5′ flanking sequence of the ATF3 gene promoter revealed that one of the major elements responsible for the induction by homocysteine is an ATF/cAMP responsive element (CRE) located at −92 to −85 relative to the transcriptional start site. Gel shift, immunoprecipitation, and cotransfection assays demonstrated that a complex (or complexes) containing ATF2, c-Jun, and ATF3 increased binding to the ATF/CRE site in the homocysteine-treated cells and activated the ATF3 gene expression, while ATF3 appeared to repress its own promoter. These data together suggested a novel pathway by which homocysteine causes the activation of JNK/SAPK and subsequent ATF3 expression through its reductive stress. Activation of JNK/SAPK and ATF3 expression in response to homocysteine may have a functional role in homocysteinemia-associated endothelial dysfunction.
Reduced oncogenicity of p190 Bcr/Abl F-actin–binding domain mutants
Authors: Heisterkamp Nora , Voncken Jan Willem , Senadheera Dinithi , Gonzalez-Gomez Ignacio , Reichert Anja , Haataja Leena , Reinikainen Arja , Pattengale Paul K. , Groffen John 
Published: October 2019

AbstractThe deregulated Bcr/Abl tyrosine kinase is responsible for the development of Philadelphia (Ph)-positive leukemia in humans. To investigate the significance of the C-terminal Abl actin-binding domain within Bcr/Abl p190 in the development of leukemia/lymphoma in vivo, mutant p190 DNA constructs were used to generate transgenic mice. Eight founder and progeny mice of 5 different lines were monitored for leukemogenesis. Latency was markedly increased and occurrence decreased in the p190 del C lines as compared with nonmutated p190BCR/ABL transgenics. Western blot analysis of involved hematologic tissues of the p190 del C transgenics with end-stage disease showed high-level expression of the transgene and tyrosine phosphorylation of Cbl and Hef1/Cas, proteins previously shown to be affected by Bcr/Abl. These results show that the actin-binding domain of Abl enhances leukemia development but does not appear to be an absolute requirement for leukemogenesis.
Nonmalignant disease associated with human herpesvirus 8 reactivation in patients who have undergone autologous peripheral blood stem cell transplantation
Authors: Luppi Mario , Barozzi Patrizia , Schulz Thomas F. , Trovato Raffaella , Donelli Amedea , Narni Franco , Sheldon Julie , Marasca Roberto , Torelli Giuseppe 
Published: October 2019

Abstract
Fever, cutaneous rash, and hepatitis—for which an infectious cause was suspected—developed in an Italian patient with non-Hodgkin lymphoma after autologous peripheral blood stem cell (PBSC) transplantation. Polymerase chain reaction (PCR) with degenerate primers for the highly conserved DNA polymerase gene of herpesviruses detected herpesvirus sequences 100% identical to human herpesvirus-8 (HHV-8) in serial cell-free serum samples, collected immediately before or concomitant with the occurrence of clinical symptoms; no other common infections were documented. The presence of the HHV-8 genome (clade C) was confirmed by PCR with HHV-8–specific primers for orf 26 and orf-K1. HHV-8 viremia was undetectable either before transplantation or when the patient was clinically asymptomatic. Semiquantitative PCR analysis showed variations of the viral load correlating with the clinical status. Anti–HHV-8 antibodies were detected before and after transplantation by an immunofluorescence assay for lytic antigens. Active HHV-8 infection may be associated with nonmalignant illness after PBSC/bone marrow transplantation.