bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular Expression of Antiapoptotic BCL-2 Oncoprotein in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia: A Children's Cancer Group Study
Authors: Uckun Fatih M. , Yang Zhiwen , Sather Harland , Steinherz Peter , Nachman James , Bostrom Bruce , Crotty Lisa , Sarquis Mireille , Ek Onur , Zeren Tamer , Tubergen David , Reaman Gregory , Gaynon Paul 
Published: October 2019

Abstract
We found a marked variation in BCL-2 oncoprotein expression levels of primary leukemic cells from 338 children with newly diagnosed acute lymphoblastic leukemia (ALL). None of the high-risk features predictive of poor treatment outcome in childhood ALL, such as older age, high white blood cell (WBC) count, organomegaly, T-lineage immunophenotype, ability of leukemic cells to cause overt leukemia in severe combined immunodeficient (SCID) mice, presence of MLL-AF4, and BCR-ABL fusion transcripts were associated with high levels of BCL-2 expression. Overall, high BCL-2 levels were not associated with slow early response, failure to achieve complete remission, or poor event-free survival. High BCL-2 levels in primary leukemic cells predicted slow early response only in T-lineage ALL patients, which comprised approximately 15% of the total patient population. Even for this small subset of patients, the level of BCL-2 expression did not have a significant impact on the short-term event-free survival.
Is Kaposi's Sarcoma–Associated Herpesvirus Ubiquitous in Urogenital and Prostate Tissues?
Authors: Tasaka Taizo , Said Jonathan W. , Morosetti Roberta , Park Dorothy , Verbeek Walter , Nagai Masami , Takahara Jiro , Koeffler H. Phillip 
Published: October 2019

AbstractControversy exists as to whether Kaposi's sarcoma–associated herpesvirus (KSHV) is more widespread than originally reported. Recently, Monini et al reported that KSHV is ubiquitous in urogenital and prostate tissues and sperm of healthy Italian adults using nested polymerase chain reaction (PCR). We have examined for the presence of KSHV in 10 normal prostates from Italian men and 10 from men from the United States, as well as 32 prostatic, 30 vulvar, 24 ovarian, 20 cervical, and 30 testicular cancer specimens from patients from the United States. None of the patients had a history of human immunodeficiency virus infection. The samples were tested by nested PCR. The sensitivity of this assay was determined by a dilution study performed by diluting KSHV DNA from the KS-1 cells (a primary effusion lymphoma cell line which is estimated to have 16 copies of KSHV per cell) in DNA from a K562 myeloid cell line. The nested PCR that we used can detect 2.4 copies of KSHV sequences on a background of K562 DNA. All the samples were negative for KSHV sequences. Therefore, we cannot confirm the finding that KSHV sequences are ubiquitous in urogenital and prostate tissues. Furthermore, because our samples were from both the United States and Italy, the discrepancy between results is unlikely to be explained by either ethnic or environmental factors. False-positive results easily occur using nested primer PCR because of contamination. Our data argue that KSHV is not widely disseminated in urogenital tissues from nonimmunosuppressed individuals.
Molecular Analysis of Rh Transcripts and Polypeptides From Individuals Expressing the DVI Variant Phenotype: An RHD Gene Deletion Event Does Not Generate All DVIccEe Phenotypes
Authors: Avent Neil D. , Liu Wendy , Jones Jeff W. , Scott Marion L. , Voak Douglas , Pisacka Martin , Watt Julie , Fletcher Anne 
Published: October 2019

AbstractThe D antigen is a mosaic comprising at least 30 epitopes. Partial Rh D phenotypes occur when there is absence of one or more of these epitopes, with the remainder expressed. The DVI phenotype is the most common of the partial D phenotypes, lacking most D antigen epitopes (ep D) (epD1, 2, 5-8 using the 9-epitope model or epD 1-4,7-22, 26-29 using the 30-epitope model). DVI mothers may become immunized by transfusion with D-positive blood (if typed as D-positive using polyclonal typing reagents) or by fetuses which have all of the D antigen. This situation can give rise to severe hemolytic disease of the newborn (HDN). The molecular basis of the DVI phenotype has previously been proposed to occur by two different genetic mechanisms, one (in individuals of DVICcee phenotype) where a gene conversion event generates a hybrid RHD-RHCE-RHD gene; the second (in individuals of DVIccEe phenotype) was proposed to be caused by a partial RHD gene deletion. We present evidence that in four DVICcee phenotypes studied, this phenotype is not generated by a partial RHD gene deletion, but occurs by a similar mechanism to the DVICcee phenotypes. In two individuals we have found hybrid RHD-RHCE-RHD transcripts in both DVICe and DVIcE haplotypes. These differ in that the DVICe transcripts are derived from an RHD gene where exons 4-6 have been replaced with RHCE equivalents (encoding Ala226 ); the DVIcE transcripts are derived from an RHD gene where exons 4 and 5 are replaced by RHCE equivalents (encoding Pro226 ). We provide direct evidence that Rh DVI polypeptides are expressed at the erythrocyte surface as full-length polypeptide products. We have used immunoprecipitation experiments using anti-D reactive with DVI erythrocytes followed by immunoblotting the immune complexes with rabbit sera immunoreactive to the fourth external and C-terminal domains of all Rh polypeptides. Our results illustrate that these domains are present on all Rh DVI proteins studied, and suggest that Rh DVI polypeptide species studied here exist as full-length Rh proteins.
Acute Chest Syndrome in Sickle Cell Disease: Clinical Presentation and Course
Authors: Vichinsky Elliott P. , Styles Lori A. , Colangelo Linda H. , Wright Elizabeth C. , Castro Oswaldo , Nickerson Bruce ,   the Cooperative Study of Sickle Cell Disease
Published: October 2019

AbstractAcute chest syndrome (ACS) is an important cause of morbidity and mortality in sickle cell disease (SCD). Previous studies reported conflicting pictures of ACS making therapeutic interventions difficult. The Cooperative Study of Sickle Cell Disease prospectively followed 3,751 patients enrolled from birth to 66 years of age for ACS. Data on presenting signs and symptoms, laboratory findings, and hospital course were collected. There were 1,722 ACS episodes in 939 patients. Young children (age 2 to 4 years) presented with fever and cough, a negative physical exam, and rarely had pain. Adults were often afebrile and complained of shortness of breath, chills, and severe pain. Upper lobe disease was more common in children; multilobe and lower lobe disease affected adults more often. Severe hypoxia occurred in 18% of adults tested and could not be predicted by examination or laboratory findings. Bacteremia was documented in 3.5% of episodes, but was strongly influenced by age (14% of infants and 1.8% of patients <10 years). ACS was most common in winter with children having the most striking increase. Transfusion was used less frequently, but earlier in children. Young children were hospitalized for 5.4 days versus 9 days for adults. Fifty percent of adults had a pain event in the 2 weeks preceding ACS and children were more likely to have febrile events. The death rate was four times higher in adults than in children. Fatal cases generally developed rapid pulmonary failure and one third were associated with bacteremia. Age has a striking effect on the clinical picture of ACS. In children, ACS was milder and more likely due to infection, whereas in adults ACS was severe, associated with pain and had a higher mortality rate.
Association of HLA-C Disparity With Graft Failure After Marrow Transplantation From Unrelated Donors
Authors: Petersdorf Effie W. , Longton Gary M. , Anasetti Claudio , Mickelson Eric M. , McKinney Susan K. , Smith Anajane G. , Martin Paul J. , Hansen John A. 
Published: October 2019

AbstractDisparity for HLA-A or HLA-B antigens increases the risk of marrow graft rejection, but the relevance of HLA-C is unknown because typing methods have not been sufficiently accurate for clinical use. We designed a matched case-control study and employed DNA sequencing methods to evaluate the role of HLA-C disparity in 21 patients who experienced graft failure (cases) following transplantation with unmanipulated marrow from either HLA-A, B serologically matched, DRB1 matched (n = 14) or single locus mismatched (n = 7) unrelated donors. For each case, two patients who successfully engrafted were selected as controls based on similarity for factors known or suspected to influence engraftment. The estimated odds ratio (OR) of graft failure for an HLA-C mismatch relative to match (univariable model) was 5.2 (95% CI, 1.4, 19; P = .01). Serologically undetectable HLA-A or HLA-B allele disparity was also associated with graft failure. The association between HLA-C disparity and graft failure remained significant even after accounting for the contribution of HLA-A and/or HLA-B allele disparity (OR 4.0; 95% CI, 1.1, 15; likelihood ratio test P = .03). These results show that HLA-C functions as a transplantation antigen and that HLA-A and HLA-B allele mismatches are biologically important. Molecular-based methods for pretransplant assessment of class I compatibility should be implemented for the selection of unrelated marrow donors.
Fusion of the Platelet-Derived Growth Factor Receptor β to a Novel Gene CEV14 in Acute Myelogenous Leukemia After Clonal Evolution
Authors: Abe Akihiro , Emi Nobuhiko , Tanimoto Mitsune , Terasaki Hiroshi , Marunouchi Toru , Saito Hidehiko 
Published: October 2019

AbstractChromosomal translocations involving band 5q31-35 occur in several hematologic disorders. A clone with a t(5; 14)(q33; q32) translocation appeared at the relapse phase in a patient with acute myelogenous leukemia who exhibited a sole chromosomal translocation, t(7; 11), at initial diagnosis. After the appearance of this clone, the leukemia progressed with marked eosinophilia, and combination chemotherapy was ineffective. Southern blot analysis showed a rearrangement of the platelet-derived growth factor receptor β (PDGFRβ) gene at 5q33 which was not observed at initial diagnosis. This translocation resulted in a chimeric transcript fusing the PDGFRβ gene on 5q33 with a novel gene, CEV14, located at 14q32. Expression of the 5′ region of the PDGFRβ cDNA, upstream of the breakpoint, was not detected. However, the 3′ region of PDGFRβ, which was transcribed as part of the CEV14-PDGFRβ fusion gene, was detected. A partial cDNA for a novel gene, CEV14, includes a leucine zipper motif and putative thyroid hormone receptor interacting domain and is expressed in a wide range of tissues. The expression of a CEV14-PDGFRβ fusion gene in association with aggressive leukemia progression suggests that this protein has oncogenic potential.
Bidirectional Effect of Interleukin-10 on Early Murine B-Cell Development: Stimulation of flt3-Ligand Plus Interleukin-7–Dependent Generation of CD19− ProB Cells From Uncommitted Bone Marrow Progenitor Cells and Growth Inhibition of CD19+ ProB Cells
Authors: Veiby Ole P. , Borge Ole J. , Mårtensson Annica , Beck Eric X. , Schade Andrew E. , Grzegorzewski Krzysztof , Lyman Stewart D. , Mårtensson Inga-Lill , Jacobsen Sten E.W. 
Published: October 2019

AbstractB-cell commitment and early development from multipotent hematopoietic progenitor cells has until recently been considered to be dependent on direct interaction with stromal cells. We recently showed that the flt3 ligand (FL) has a unique ability to interact with interleukin-7 (IL-7) to directly and selectively promote B-cell development from murine bone marrow progenitor cells with a combined myeloid and lymphoid potential. Here we report that whereas IL-10 alone has no ability to stimulate growth of primitive (Lin−Sca-1+c-kit+) bone marrow progenitor cells, it potently enhances FL + IL-7–induced proliferation (sevenfold). This enhanced proliferation results from recruitment of progenitors unresponsive to FL + IL-7 alone, as well as from increased growth of individual clones, resulting in a 7,000-fold cellular expansion over 12 days. Single cell cultures and delayed addition studies suggested that the stimulatory effect of IL-10 was directly mediated on the progenitor cells. The cells generated in response to FL + IL-7 + IL-10 appeared to be almost exclusively proB cells, as shown by their expression of B220, CD24, CD43, and lack of expression of cμ, myeloid, erythroid, and T-cell surface antigens. Although IL-10 also enhanced kit ligand (KL) + IL-7–induced proliferation of Lin−Sca-1+c-kit+ progenitor cells, the resulting cells were predominantly myeloid progeny. Accordingly, FL + IL-7 + IL-10 was 100-fold more efficient in stimulating production of proB cells than KL + IL-7 + IL-10. In contrast to its ability to stimulate the earliest phase of proB cell formation and proliferation, IL-10 inhibited growth of proB cells generated in response to FL + IL-7. Analysis of CD19 expression on cells generated in FL + IL-7 + IL-10 showed that almost all cells generated under these conditions lacked expression of CD19, in contrast to cells generated in the absence of IL-10, which were predominantly CD19+. Replating of sorted CD19+ and CD19− proB cells in FL + IL-7 or FL + IL-7 + IL-10 showed that IL-10 efficiently blocked growth of CD19+, but not CD19− cells. Both CD19− and CD19+ cells expressed λ5 and VpreB , shown to be specific for B-cell progenitors. In addition, sorted CD19− cells generated CD19+ cells in response to FL + IL-7. Thus, IL-10 has a dual regulatory effect on early B-cell development from primitive murine bone marrow progenitor cells in that it enhances FL + IL-7–induced proB-cell formation and growth before acquisition of CD19 expression, whereas growth of CD19+ proB cells is inhibited.
Functional Heterogeneity of Human CD34+ Cells Isolated in Subcompartments of the G0 /G1 Phase of the Cell Cycle
Authors: Gothot André , Pyatt Robert , McMahel Jon , Rice Susan , Srour Edward F. 
Published: October 2019

AbstractUsing simultaneous Hoechst 33342 (Hst) and Pyronin Y (PY) staining for determination of DNA and RNA content, respectively, human CD34+ cells were isolated in subcompartments of the G0 /G1 phase of the cell cycle by flow cytometric cell sorting. In both bone marrow (BM) and mobilized peripheral blood (MPB) CD34+ cells, primitive long-term hematopoietic culture-initiating cell (LTHC-IC) activity was higher in CD34+ cells isolated in G0 (G0CD34+ cells) than in those residing in G1 (G1CD34+ cells). However, as MPB CD34+ cells displayed a more homogeneous cell-cycle status within the G0 /G1 phase and a relative absence of cells in late G1 , DNA/RNA fractionation was less effective in segregating LTHC-IC in MPB than in BM. BM CD34+ cells belonging to four subcompartments of increasing RNA content within the G0 /G1 phase were evaluated in functional assays. The persistence of CD34 expression in suspension culture was inversely correlated with the initial RNA content of test cells. Multipotential progenitors were present in G0 or early G1 subcompartments, while lineage-restricted granulomonocytic progenitors were more abundant in late G1 . In vitro hematopoiesis was maintained for up to 6 weeks with G0CD34+ cells, whereas production of clonogenic progenitors was more limited in cultures initiated with G1CD34+ cells. To test the hypothesis that primitive LTHC-ICs would reenter a state of relative quiescence after in vitro division, BM CD34+ cells proliferating in ex vivo cultures were identified from their quiescent counterparts by a relative loss of membrane intercalating dye PKH2, and were further fractionated with Hst and PY. The same functional hierarchy was documented within the PKH2dim population whereby LTHC-IC frequency was higher for CD34+ cells reselected in G0 after in vitro division than for CD34+ cells reisolated in G1 or in S/G2 + M. However, the highest LTHC-IC frequency was found in quiescent PKH2bright CD34+ cells. Together, these results support the concept that cells with distinct hematopoietic capabilities follow different pathways during the G0 /G1 phase of the cell cycle both in vivo and during ex vivo culture.
Thrombopoietin Upregulates the Promoter Conformation of p53 in a Proliferation-Independent Manner Coincident With a Decreased Expression of Bax: Potential Mechanisms for Survival Enhancing Effects
Authors: Ritchie Alec , Gotoh Akihiko , Gaddy Jay , Braun Stephen E. , Broxmeyer Hal E. 
Published: October 2019

AbstractThrombopoietin (Tpo) has proliferative and maturational effects on immature and more committed cells, respectively. We previously reported a role for Tpo as a survival factor in the factor-dependent human cell line M07e by demonstrating that Tpo suppresses apoptosis in the absence of induced proliferation. Wild-type p53 is a tumor suppressor gene that can play a vital role in mediating growth factor withdrawal-induced apoptosis in factor-dependent hematopoietic cells. Wild-type p53 can switch from a suppressor conformation, with an antiproliferative, pro-apoptotic phenotype, to a promoter conformation that has a diminished ability to mediate cell cycle arrest and apoptosis. In an effort to elucidate the mechanisms through which Tpo suppresses apoptosis, we investigated the effects of Tpo treatment on p53-mediated apoptosis in M07e cells. Tpo upregulated the expression of the promoter conformation of p53 in M07e cells coincident with a downregulation of Bax and Mdm2 protein levels. Protein levels of Bcl-2 and Bcl-xL did not significantly vary as a function of growth-factor stimulation. Conversely, the levels of suppressor conformation p53 were maximal when M07e was in a growth arrested state and decreased during factor stimulation. Furthermore, Tpo treatment induced an extranuclear buildup and greatly weakened the DNA binding capacity of p53. p53-specific antisense oligonucleotide treatment recapitulated the effects of Tpo treatment on the levels of Bax, Mdm-2, and Bcl-2. These results suggest that Tpo is suppressing growth factor withdrawal induced-apoptosis, at least in part, by downregulating the expression of pro-apoptotic Bax protein levels, through modulating the conformation of p53, which results in a functional inactivation of its pro-apoptotic abilities.
Protective Effect of a Single Interleukin-12 (IL-12) Predose Against the Toxicity of Subsequent Chronic IL-12 in Mice: Role of Cytokines and Glucocorticoids
Authors: Sacco Silvano , Heremans Hubertine , Echtenacher Berndt , Buurman Wim A. , Amraoui Zoulikha , Goldman Michel , Ghezzi Pietro 
Published: October 2019

AbstractThe mechanisms of interleukin-12 (IL-12) toxicity were studied in mice using a schedule (murine rIL-12, 400 ng/mouse, intraperitoneally [IP] once daily for 5 days) that markedly reduced body weight and food intake. On day 5, IL-12–treated mice had elevated serum and spleen IFN-γ and tumor necrosis factor (TNF). Serum sTNFR-P75 and corticosterone (CS) were also elevated. IL-12 toxicity was partially prevented by anti–IFN-γ antibodies or dexamethasone (DEX). A pre-dose of IL-12 (200 ng/mouse on day −14) completely prevented the toxicity of subsequent IL-12. The IL-12 predose also inhibited IL-12–induced IFN-γ levels, but did not modify IL-12–induced CS, TNF or sTNFR-P75. A protective effect was observed with a predose of lipopolysaccharide (LPS) or murine recombinant (r)IL-10. The protective effect of the IL-12 predose was reduced by coadministration of anti–IFN-γ, but a predose of murine rIFN-γ was not protective, suggesting that IFN-γ is necessary but not sufficient for the protective effect of IL-12. The IL-12 predose specifically protected against IL-12 toxicity and did not modify LPS toxicity. These data indicate that IL-12 can induce tolerance to its own toxicity, probably through a downregulation of IL-12–induced IFN-γ but independently of endogenous glucocorticoids. IFN-γ, and possibly IL-10, might be important in this tolerance.
Growth and Dissemination of Lewis Lung Carcinoma in Plasminogen-Deficient Mice
Authors: Bugge Thomas H. , Kombrinck Keith W. , Xiao Qing , Holmbäck Kenn , Daugherty Cynthia C. , Witte Dave P. , Degen Jay L. 
Published: October 2019

AbstractPlasminogen activation has been proposed to play a critical role in cancer invasion and metastasis. The effects of complete ablation of plasminogen activation in cancer was studied by inoculation of a metastatic Lewis lung carcinoma expressing high levels of plasminogen activator into plasminogen-deficient (Plg−/−) mice and matched control mice. Primary tumors developed in all mice with no difference in the rate of appearance between Plg−/− and control mice. However, the primary tumors in Plg−/− mice were smaller and less hemorrhagic and displayed reduced skin ulceration. In addition, dissemination of the tumor to regional lymph nodes was delayed in Plg−/− mice. Surprisingly, no quantitative differences were observed in lung metastasis between Plg−/− and control mice. In addition, Plg deficiency was compatible with metastasis of the primary tumor to a variety of other organs. Nevertheless, Plg−/− mice displayed a moderately increased survival after primary tumor resection. These findings suggest that plasmin-mediated proteolysis contributes to the morbidity and mortality of Lewis lung carcinoma in mice, but sufficient proteolytic activity is generated in Plg−/− mice for efficient tumor development and metastasis.
Mitochondrial Antisense RNA for Cytochrome C Oxidase (MARCO) Can Induce Morphologic Changes and Cell Death in Human Hematopoietic Cell Lines
Authors: Shirafuji Naoki , Takahashi Satoshi , Matsuda Satoru , Asano Shigetaka 
Published: October 2019

AbstractTo identify essential molecules capable of inducing terminal morphologic maturation and cell death of myeloid progenitor cells, we isolated cDNA clones by functional expression cloning using a library constructed from all-trans retinoic acid (ATRA)-treated human promyelocytic HL-60 cells. Clones which induced morphologic changes in HL-60 cells from blastic cells to mature neutrophilic granulocytes were selected. The isolated positive cDNA clone was demonstrated to encode an antisense RNA for cytochrome c oxidase/serine tRNA derived from a mitochondrial gene (MARCO). When MARCO was expressed in HL-60 cells with the lac switch system, blastic cell morphology became neutrophilic after 48-hour incubation with IPTG, and cell death was observed after 3 days. Also, high molecular weight DNA fragmentation was observed after 36 hours in culture. Similar results were observed using transformants from human K562 cells and CMK cells. RT-PCR analysis revealed that MARCO was transcribed in both ATRA and TNF-α systems, and also in human blood neutrophilic granulocytes. Following transfection with cytochrome c oxidase expression plasmids, TNF-α–induced high molecular weight DNA fragmentation in U937 cells and HL-60 cells was inhibited in these transformants. These results indicate that maturational changes in hematopoietic cells and the process of cell death may be induced by mitochondrial respiratory insufficiency, and also that the mitochondrial gene MARCO may be used as one of the candidates for gene supplementation therapy for the acute leukemias.