bluuebunny/crossref_metadata_2025_split huggingface dataset:
γ-Interferon Production in Peripheral Blood Mononuclear Cells and Tumor Infiltrating Lymphocytes From Kaposi's Sarcoma Patients: Correlation With the Presence of Human Herpesvirus-8 in Peripheral Blood Mononuclear Cells and Lesional Macrophages
Authors: Sirianni Maria Caterina , Vincenzi Laura , Fiorelli Valeria , Topino Simone , Scala Enrico , Uccini Stefania , Angeloni Antonio , Faggioni Alberto , Cerimele Decio , Cottoni Francesca , Aiuti Fernando , Ensoli Barbara 
Published: October 2019

AbstractEvidence indicates that, at least in the early stage, Kaposi's sarcoma (KS) is a cytokine-mediated disease and that it is consistently associated with a novel herpesvirus termed human herpesvirus-8 (HHV-8). To gain insights into the mechanisms by which cytokines and HHV-8 may cooperate in disease pathogenesis, we examined the phenotype, the Th1 (γ-interferon [γIFN]) and Th2 (interleukin-4 [IL-4]) cytokine profile and the presence of HHV-8 in peripheral blood mononuclear cells (PBMC), tumor-infiltrating lymphocytes (TIL), and spindle cell cultures derived from skin lesions of patients affected by classical KS (C-KS) and acquired immunodeficiency syndrome (AIDS)-associated KS (AIDS-KS). TIL and spindle cell cultures were examined at day 0 or after culture in conditioned media from activated T cells (TCM) that contain the same cytokines increased in KS tissues. No differences were found in the immunophenotype of PBMC from C-KS patients versus controls, except for AIDS-KS patients who showed a T-CD8+ expansion. However, a preferential infiltration of T-CD8+ cells was found in all KS lesions examined, which was maintained after culture of TIL in TCM. γIFN production was found in both PBMC and cultures derived from all KS examined; some IL-4 positive supernatants were found only in three AIDS-KS cases. Uninvolved skin did not show appreciable lymphocyte infiltration or cytokine production. The culture conditions of the lesional skin allowed also the appearance of adherent, spindle-like cells bearing markers of tissue macrophages. Finally, most or all of the PBMC, lesions, and macrophagic cell cultures from the skin lesions were found to be positive for HHV-8 infection by nested polymerase chain reaction (PCR). These findings indicate that patients with KS express a Th1 phenotype with a prevalent γIFN production, likely accounted for by the local T-CD8+ infiltration. By analogy with other viral infections (ie, Epstein-Barr virus), this suggests that in loco recruitment of lymphoid cells and the subsequent γIFN production may be in response to or elicited by HHV-8 that was found in both PBMC and macrophagic cell cultures from the lesions of the same patients.
Application of Interphase Fluorescence In Situ Hybridization for the Detection of the Burkitt Translocation t(8;14)(q24;q32) in B-Cell Lymphomas
Authors: Siebert Reiner , Matthiesen Peter , Harder Svetlana , Zhang Yanming , Borowski Annekathrin , Zühlke-Jenisch Reina , Metzke Simone , Joos Stefan , Weber-Matthiesen Klaus , Grote Werner , Schlegelberger Brigitte 
Published: October 2019

Abstract
The translocation t(8;14)(q24;q32) is the characteristic chromosomal aberration of Burkitt's-type lymphomas and leukemias (BLs). On the molecular level, the t(8;14) juxtaposes the c-myc gene in 8q24 next to the IgH locus in 14q32, resulting in overexpression of the transcription factor c-Myc. The detection of a t(8;14) is a major aim in the diagnostic process of all patients with high-grade B-cell lymphomas because treatment strategies differ between BL and other high-grade lymphomas. As chromosome analyses are sometimes hampered by the low yield or poor quality of metaphase spreads and as the application of molecular genetic techniques is limited by the distribution of the 8q24 breakpoints over a region of about some hundred kilobases, we set out to establish an interphase fluorescence in situ hybridization (FISH) assay for the detection of the t(8;14). A cosmid probe hybridizing to the IgH constant region in 14q32 was combined with a differently labeled probe of pooled cosmid clones spanning the c-myc locus in 8q24. Interphase nuclei lacking a t(8;14) show two separated signals corresponding to each probe, whereas interphase nuclei carrying a t(8;14) display a split of the c-myc probe and a colocalization of at least one of the splitted signals with the IgH probe. Based on the results of extensive control studies, the cutoff level for this stringent (type I) criteria was set at 2%. Additionally, colocalization of at least one c-myc signal with one IgH signal alone (without signal split for the c-myc probe) was used as a less stringent (type II) criteria with a cutoff limit of 11%. Nine BLs and one Burkitt-like lymphoma were investigated by this approach. Cytogenetically, all tumors contained a translocation t(8;14)(q24;q32) except for one BL, in which cytogenetic analysis had failed. In interphase FISH, all lymphomas and leukemias met the less stringent criteria for the diagnosis of the t(8;14). Additionally, in all tumors but the Burkitt-like lymphoma, a t(8;14) could be diagnosed according to the stringent criteria. The percentage of cells found to harbor the t(8;14) by FISH ranged from 4.3% to 100%. Comparison of cytogenetic and FISH results revealed a significantly lower percentage of t(8;14)+ interphase nuclei than metaphase cells (P =  .004). In conclusion, the described FISH assay provides a feasible and sensitive tool for the routine detection of the translocation t(8;14) in interphase cells which might also offer new insights into the biology of high-grade B-cell lymphomas.
Shortened Telomeres Involved in a Case With a Jumping Translocation at 1q21
Authors: Hatakeyama Shinji , Fujita Kazuhiro , Mori Hiraku , Omine Mitsuhiro , Ishikawa Fuyuki 
Published: October 2019

Abstract
The jumping translocation (JT) is a rare chromosomal abnormality in which a specific chromosomal segment translocates onto the ends of various chromosomes (jumps). In most cases, the region distal to 1q21 jumps onto numerous different telomeres. Here we report a molecular study of the JT involving 1q21 found in a patient with acute myelomonocytic leukemia that had transformed from myelodysplastic syndrome (MDS). This is the first report describing the analysis of the molecular structure of the JT. We demonstrated the presence of a stretch of telomeric repeats at the breakpoint by means of a fluorescence in situ hybridization experiment, molecular cloning, and nucleotide sequencing of the fused region. A significant amount of variant telomeric repeats (a telomeric sequence having one-base mismatch within the authentic telomeric repeat TTAGGG) was found in this region. The variant telomeric repeat has been shown to be present in the proximal region of telomeres and does not perform telomeric functions by itself. Therefore, these results indicated that the telomeres had already been critically shortened when the jumps occurred. We suggest that the extended proliferation of cancer cells during the premalignant stage, such as MDS, results in chromosomal instability due to the loss of telomeric functions.
Both Stroma and Stem Cell Factor Maintain Long-Term Growth of ELM Erythroleukemia Cells, but Only Stroma Prevents Erythroid Differentiation in Response to Erythropoietin and Interleukin-3
Authors: O'Prey Jim , Leslie Nick , Itoh Katsukiko , Ostertag Wolfram , Bartholomew Chris , Harrison Paul R. 
Published: October 2019

AbstractDefining how the stromal requirements of hematopoietic progenitors change during leukemia progression is an important topic that is not well understood at present. The murine ELM erythroleukemia is an interesting model because the erythroid progenitors retain dependence on bone marrow-derived stromal cells for long-term growth in vitro, and they also undergo erythroid differentiation in the presence of erythropoietin (EPO) and interleukin-3 (IL-3). In this report, we have shown using neutralizing antibodies that stem cell factor (SCF), insulin-like growth factor (IGF)-1, and integrin signaling pathways are all involved. We then determined whether ELM cells can be maintained long-term without stroma in various combinations of growth factors produced by stroma cells or growth factors for which ELM cells have receptors. This showed that ELM cells could be maintained with high efficiency in SCF alone; furthermore, the cells remained absolutely SCF-dependent and did not become more tumorigenic than cells maintained on stroma. In contrast, ELM cells underwent clonal extinction when serially cloned in IGF1; any cells that survived long-term growth in IGF-1 were found to be IGF1-independent. One important difference between maintaining ELM cells on stroma and growth in SCF is that stroma reversibly inhibits their differentiation in response to EPO and IL-3, whereas SCF does not.
Prion Protein Expression in Human Leukocyte Differentiation
Authors: Dodelet Vincent C. , Cashman Neil R. 
Published: October 2019

AbstractThe cellular isoform of the prion protein (PrPC) is a small glycoprotein attached to the outer leaflet of the plasma membrane by a glycosylphosphatidylinositol anchor. This molecule is involved in the pathogenesis of prion diseases in both humans and animals. We have characterized the expression patterns of PrPC during human leukocyte maturation by flow cytometry with monoclonal antibodies to PrPC, the glycan moiety CD15, and the stem cell marker CD34. We observe that prion protein is present on CD34+bone marrow (BM) stem cells. Although lymphocytes and monocytes maintain PrPC expression throughout their differentiation, PrPC is downregulated upon differentiation along the granulocyte lineage. In vitro retinoic acid–induced differentiation of the premyeloid line HL-60 into granulocyte-like cells mimics the suppression of PrPC in granulocyte differentiation, as both PrPC mRNA and protein are downregulated. These data suggest that selected BM cells and peripheral mononuclear cells may support prion agent replication, because this process is dependent on availability of PrPC. Additionally, retinoic acid–induced extinction of PrPC expression in HL-60 cells provides a potential model to study PrP gene regulation and protein function. Finally, these data suggest the existence of cell-specific glycoforms of PrPC that may determine cellular susceptibility to infection by the prion agent.
TEL-AML1 Fusion Transcript in Relapsed Childhood Acute Lymphoblastic Leukemia
Authors: Seeger Karlheinz , Adams Hans-Peter , Buchwald Dirk , Beyermann Birgit , Kremens Bernhard , Niemeyer Charlotte , Ritter Jörg , Schwabe Dirk , Harms Dörte , Schrappe Martin , Henze Günter 
Published: October 2019

Abstract
The cryptic translocation t(12;21)(p13;q22) has been recently recognized as the most common genetic rearrangement in B-lineage childhood acute lymphoblastic leukemia (ALL). The resulting fusion transcript, termed TEL-AML1, has been associated with an excellent prognosis at initial ALL diagnosis. Hence, we postulated that the incidence of TEL-AML1 fusion should be lower in patients with ALL relapse. To address this assumption and to investigate the prognostic significance of TEL-AML1 expression in relapsed childhood ALL, bone marrow samples of 146 children were analyzed by reverse-transcriptase (RT)-polymerase chain reaction (PCR). All children were treated according to Berlin-Frankfurt-Münster (BFM) ALL relapse trial protocols (ALL-REZ BFM 90-96). Their clinical features and outcome were compared with those of 262 patients who could not be tested due to lack of bone marrow samples. Thirty-two of 146 children with relapsed ALL were TEL-AML1–positive. Four of the negative patients had T-lineage and nine Philadelphia chromosome (Ph1)-positive leukemia. Thus, the incidence ofTEL-AML1 in relapsed Ph1-negative, B-cell precursor ALL is 32 of 133 (24%). The 32 TEL-AML1–positive and 101 negative patients differed significantly with respect to duration of last remission (42.5 v 27 months; P = .0001) and age at initial diagnosis (53.5 v 74 months;P = .0269). At a median follow-up time of 21.5 months, children positive for TEL-AML1 had a significantly (P = .0011) higher probability of event-free survival (EFS; 0.79 v 0.33). The predominant majority of patients had been treated for initial ALL according to German multicenter BFM (108 of 133) or Cooperative ALL study group (CoALL) (19 of 133) frontline protocols. The comparison of tested and not-tested (N = 262) patients showed no significant difference.TEL-AML1 positivity predicted a favorable short-term outcome; long-term results are unknown. Screening for TEL-AML1 should become routine at relapse diagnosis and might be used for therapy stratification in future trials.
Monosodium Urate Microcrystals Induce Cyclooxygenase-2 in Human Monocytes
Authors: Pouliot Marc , James Michael J. , McColl Shaun R. , Naccache Paul H. , Cleland Leslie G. 
Published: October 2019

AbstractThe formation and deposition of monosodium urate (MSU) microcrystals in articular and periarticular tissues is the causative agent of acute or chronic inflammatory responses known as gouty arthritis. Mononuclear phagocyte activation is involved in early triggering events of gout attacks. Because stimulated mononuclear phagocytes can constitute an important source of the inducible isoform of cyclooxygenase (COX-2), we evaluated the effects that proinflammatory microcrystals might have on COX-2 protein expression in crystal-stimulated monocytes. We found that MSU crystals, but not calcium pyrophosphate dihydrate (CPPD) crystals, induced COX-2, which correlated with the synthesis of prostaglandin E2 (PGE2) and thromboxane A2(TXA2). Crystal-induced de novo synthesis of COX-2 was dependent on transcriptional and translational events. Inhibition of tyrosine phosphorylation, by herbimycin A, blocked crystal-induced COX-2. Similarly, an inhibitor of the p38 mitogen-activated protein kinase, SB 203580, inhibited the stimulation of COX-2. Colchicine inhibited crystal-induced COX-2. In all cases, prostanoid synthesis was concomitantly inhibited. Taken together, these results implicate COX-2 in the development of MSU-induced inflammation.
ALK-Positive Lymphoma: A Single Disease With a Broad Spectrum of Morphology
Authors: Benharroch Daniel , Meguerian-Bedoyan Zarouhie , Lamant Laurence , Amin Chauki , Brugières Laurence , Terrier-Lacombe Marie-Jose , Haralambieva Eugenia , Pulford Karen , Pileri Stefano , Morris Stephan W. , Mason David Y. , Delsol Georges 
Published: October 2019

Abstract
The t(2;5)(p23;q35) translocation, associated with anaplastic large-cell lymphoma (ALCL), results in the expression of a chimeric NPM-ALK protein that can be detected by the ALK1 monoclonal antibody. This report describes the morphologic and phenotypic spectrum of 123 cases of lymphoma that all express ALK protein. The results provide strong evidence that the morphologic patterns of ALCL described in previous reports as representing possible subtypes of ALCL, eg, common type, lymphohistiocytic, or small cell patterns, are morphologic variants of the same disease entity. All of these morphologic patterns could be found within this series, and in some patients different subtypes coexisted in a single biopsy or were found in successive biopsies from a single patient. The link between these morphologic subtypes is further reinforced by the presence in all cases of a highly characteristic large cell, with an eccentric nucleus and an eosinophilic paranuclear region. We suggest that this cell can be considered as a major distinguishing feature of ALK-positive lymphomas. Another characteristic of these tumors was the perivascular pattern of neoplastic cell infiltration seen in a significant number of cases. In addition to ALK protein, all tumors expressed epithelial membrane antigen and lacked CD15, features that may be of value in differentiating ALCL from Hodgkin's disease. In the majority of cases (84%), malignant cells showed both a cytoplasmic and nuclear staining for ALK1 and thus presumably carried the 2;5 translocation, but staining was restricted to the cytoplasm in a few cases, suggesting that translocations other than t(2;5) may induce expression of ALK protein. We conclude from this study that ALK-positive neoplasms represent a distinct entity. Because their morphology is often neither anaplastic nor large cell, we suggest that they should henceforward be referred to as ALK lymphomas.
Anti–VLA4/VCAM-1—Induced Mobilization Requires Cooperative Signaling Through the kit/mkit Ligand Pathway
Authors: Papayannopoulou Thalia , Priestley Gregory V. , Nakamoto Betty 
Published: October 2019

Abstract
Although a large body of data on mobilization have yielded valuable clues, the mechanism(s) dictating egress of stem/progenitor cells during baseline hematopoiesis and after their mobilization are poorly understood. We have previously provided functional in vivo evidence that cytoadhesion molecules, specifically the β1integrins, are involved in mobilization; however, the mechanism by which this was achieved was unclear. To provide further insights into the anti–very late antigen 4 (VLA4)/anti–vascular cell adhesion molecule 1 (VCAM-1)—induced mobilization, we used these antibodies to treat mutant mice with compromised growth factor receptor function. We found that mobilization by anti-VLA4 does not depend on a functional granulocyte colony-stimulating factor, interleukin-7 (IL-7), or IL-3α receptor. By contrast, the functional kit receptor is required, because W/Wv mice responded minimally, whereas Steel-Dickie (Sl/Sld) responded normally. Both Wv and Sl/Sld mice did not respond to anti–VCAM-1 treatment, in contrast to their +/+ littermates and despite normal levels of VCAM-1 expression in bone marrow cells. The defective response to anti–VCAM-1 in W/Wv mice was corrected after their transplantation with +/+ cells. mev/mev mice showed increased numbers of circulating progenitors before treatment and a heightened response after anti-VLA4 or anti–VCAM-1 treatment. Downmodulation of kit expression was detected in normal bone marrow cells after anti-VLA4 treatment. On the strength of the above findings we conclude that (1) anti–VLA4/VCAM-1—induced mobilization likely requires signaling for stimulation of cell migration; (2) this cooperative signaling involves the kit/kit ligand pathway, and provides a novel example of integrin/cytokine crosstalk; and (3) migration mediated through the kit/kit ligand pathway may be a common contributor to different mobilization stimuli. Dissection of the exact molecular pathways that lead to mobilization remains a future challenge.
JAK2 and JAK1 Constitutively Associate With an Interleukin-5 (IL-5) Receptor α and βc Subunit, Respectively, and Are Activated Upon IL-5 Stimulation
Authors: Ogata Norihisa , Kouro Taku , Yamada Atsuko , Koike Masamichi , Hanai Nobuo , Ishikawa Takeru , Takatsu Kiyoshi 
Published: October 2019

AbstractThe human interleukin-5 receptor (hIL-5R) consists of a unique α subunit (hIL-5Rα) and a common β subunit (βc) that activate two Janus kinases (JAK1 and JAK2) and a signal transducer and activator of transcription (STAT5). The precise stoichiometry of the hIL-5R subunits and the role of JAK kinases used in IL-5 signaling were investigated. We analyzed the interaction between hIL-5Rα and βc by immunoprecipitation using anti–hIL-5Rα and anti-βc monoclonal antibodies. The binding of JAK1 and JAK2 to each hIL-5R subunit was also evaluated in the hIL-5–responsive cell line, TF-h5Rα. It was observed that IL-5 stimulation induced the recruitment of βc to hIL-5Rα, although in the absence of IL-5 the subunits remain independent. In the absence of IL-5, JAK2 and JAK1 were associated with hIL-5Rα and βc, respectively. IL-5 stimulation resulted in tyrosine phosphorylation of JAK2, JAK1, βc, and STAT5. Moreover, IL-5–induced dimerization of IL-5R subunits caused JAK2 activation and βc phosphorylation even in the absence of JAK1 activation. Furthermore, tyrosine phosphorylation of JAK1 was dependent on the activation of JAK2. Detailed study of the C-terminal truncated cytoplasmic domain of hIL-5Rα revealed that the cytoplasmic stretch at position 346-387, containing the proline-rich region, is necessary for JAK2 binding. These observations suggest that activation of hIL-5Rα–associated JAK2 is indispensable for the IL-5 signaling event.
Evidence for the Involvement of Both Retinoic Acid Receptor- and Retinoic X Receptor-Dependent Signaling Pathways in the Induction of Tissue Transglutaminase and Apoptosis in the Human Myeloma Cell Line RPMI 8226
Authors: Joseph Bertrand , Lefebvre Olga , Méreau-Richard Claude , Danzé Pierre-Marie , Belin-Plancot Marie-Thérèse , Formstecher Pierre 
Published: October 2019

AbstractIn this study, we show that both all-trans-retinoic acid (atRA) and 9-cis-retinoic acid (9-cis-RA) are potent inducers of tissue transglutaminase (TGase II), an enzyme involved in apoptosis, at the level of both enzyme activity and mRNA in the human myeloma cell line RPMI 8226. RPMI 8226 cells were shown to express mRNAs for all the retinoid receptors subtypes, ie, RARα, RARβ, RARγ, RXRα, RXRβ, and RXRγ. To identify which of these receptors are involved in regulating TGase II expression, several receptor-selective synthetic retinoids were used. Neither CD367, a very potent retinoid that selectively binds and activates receptors of the RAR family, nor CD2425, an RXR-selective agonist, induced TGase II when used alone. However, combination of CD367 and CD2425 resulted in nearly full induction of the enzyme. Moreover, when used in combination with atRA, CD367 partially inhibited the atRA-dependent induction of TGase II, whereas CD2425 enhanced it. The effects of Am 580, CD417, and CD437, three synthetic retinoids selective for the RARs subtypes RARα, RARβ, and RARγ, respectively, were also investigated. None of these compounds was able to induce TGase II when used alone; however, the combination of each of them with CD2425 resulted in strong induction of the enzyme activity, reaching 30% to 50% of the values obtained in the presence of retinoic acid and suggesting functional redundancy between the RAR subtypes. Finally, treatment with atRA or the combination of CD367 and CD2425, but not with CD367 or CD2425 alone, was also shown to trigger apoptosis in RPMI 8226 cells, with prominent accumulation of TGase II immunoreactivity in apoptotic cells. Taken together these data suggest that the induction of TGase II expression and apoptosis in the RPMI 8226 myeloma cell line required ligand-dependent activation of both the RAR and RXR receptors.
Enhanced MDR1 Gene Expression in Human T-Cell Leukemia Virus-I–Infected Patients Offers New Prospects for Therapy
Authors: Lau Alan , Nightingale Simon , Taylor Graham P. , Gant Timothy W. , Cann Alan J. 
Published: October 2019

AbstractOverexpression of P-glycoprotein (P-gp), the protein product of the multidrug resistance gene (MDR1), confers a drug resistant phenotype on cells. This phenotype is reminiscent of human T-cell leukemia virus (HTLV)-transformed leukemic cells, for which no consistently effective chemotherapeutic regime has been found. The presence of an active multiple drug resistance (MDR) phenotype in freshly isolated peripheral blood mononuclear cells (PBMC) from HTLV-I–infected subjects was investigated. Significant P-gp–mediated efflux activity and enhanced MDR1 mRNA expression was observed in nine of 10 HTLV-infected subjects. The development of MDR phenotypes was found to be independent of disease type or status with significant MDR activities being observed in adult T-cell leukemia (ATL), HTLV-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), and asymptomatic HTLV-infected individuals. P-gp–mediated drug efflux was also found to be restricted to CD3+ T-cell populations. Furthermore, we show the novel finding that theMDR1 gene promoter is transcriptionally activated by the HTLV-I tax protein, suggesting a molecular basis for the development of drug resistance in HTLV-I infections. These observations open up the possibility of new chemotherapeutic approaches to HTLV-associated diseases through the use of P-gp inhibitors.