bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Diagnostic and Relapse Flow Cytometry Phenotypes in Childhood ALL: Implications for Residual Disease (MRD) Detection.
Authors: Borowitz Michael J. , Pullen D. Jeanette , Winick Naomi , Martin P. L. , Bowman W. Paul , Camitta Bruce 
Published: October 2019

Abstract
Flow cytometric analysis of MRD depends on detecting phenotypically abnormal populations. Phenotypic shifts are known to occur but there is little information to indicate how these shifts affect detection of MRD. We compared diagnostic and relapse bone marrow specimens in 36 children with precursor B-ALL studied with the two-tube panel CD19-APC/CD45-PerCP/CD10-PE/CD20-FITC and CD19/45/9/34 (Leukemia 13:558,1999). Small phenotypic shifts of either intensity or coefficient of variation of the distribution of at least one marker were seen in 34 cases, while 7 cases had shifts of 4 or more markers. Phenotypic shifts were complex and could not be explained simply by a change in maturation stage. CD19 was the most stable marker, changing in only 8 cases, CD45 changed in 10; CD10 in 13; CD9 in 14; CD20 in 16 and CD34 in 18. CD10 and CD20 generally lost intensity while CD45 mostly increased. CD34 changed from positive to negative (5 cases) or relapsed as the CD34-negative component when the diagnostic sample was partially positive (9 cases). In 26 cases there was a sufficient change in phenotype from diagnosis to relapse to determine if day 28 MRD more closely resembled the initial diagnostic or the subsequent relapse sample. In 13/19 MRD+ cases the day 28 phenotype resembled the diagnostic specimen and in 6 it resembled relapse. Surprisingly, time to relapse was similar in both groups. In 6 of the 7 MRD negative cases, retrospective review of the data did not identify an abnormal population that resembled either diagnosis or relapse. In the remaining case, in which both CD34 and CD10 were lost from diagnosis to relapse, it is possible that a MRD population resembling relapse might have been missed. We conclude that phenotypic shifts between diagnostic and relapse specimens in childhood ALL are relatively common, but that in general they do not interfere with the ability to recognize MRD. However, MRD analysis that adheres to rigid gating looking only for the precise abnormal phenotype seen at diagnosis might miss some positive cases.
Cyp33-MLL Interaction Modulates Human HOX Gene Expression and Chromatin Structure.
Authors: Diaz Manuel O. , Koonce Mark A. 
Published: October 2019

Abstract
The MLL gene is involved in translocations and fusion genes associated with human leukemia. We have identified a protein, Cyp33, which interacts with the PHD fingers of MLL, and modulates the expression of HOX genes regulated by MLL. In order to define possible mechanisms for this modulation, we set up an experimental system in which the Cyp33 protein is conditionally expressed from a transgene under the control of a tetracycline inducible promoter. Two different cell lines with such inducible gene were established, based on the human kidney epithelial cells HEK293, and the human lymphoblastic leukemia cell line Jurkat, respectively. In these systems we have shown that induction of Cyp33 expression over endogenous levels, leads to downregulation of the HOXC8 gene, but this downregulation is reversible, the HOXC8 being re-expressed when Cyp33 is de-induced and its levels go back to normal. This indicates that Cyp33 overexpression does not erase an epigenetic mark for HOXC8 gene expression. Concordantly, no change in methylation of histone H3 at lysines 4 or 9 is observed upon Cyp33 overexpression. We also showed that both MLL and Cyp33 bind to the promoter of HOXC8, and that histones H3 and H4 at this promoter are de-acetylated upon Cyp33 overexpression. This deacetylation, as well as the downregulation of HOXC8 expression, are prevented by cyclosporin A and by trichostatin A, suggesting that the prolyl-isomerase activity of Cyp33 is necessary for these effects, and that histone deacetylation mediates these effects. We have previously shown that overexpression of Cyp33 enhances the recruitment of HDAC1 to the repression domain of MLL. We now show that this enhanced recruitment is inhibited by cyclosporin A. These results suggest a model in which Cyp33 is recruited to MLL and targets the MLL repression domain to promote the recruitment of histone deacetylases, thus allowing or promoting the silencing of the MLL regulated genes. In this model Cyp33 functions downstream of the gene activation or silencing epigenetic marks.
A Conserved Regulatory Element in the Mammalian β-Globin Promoters.
Authors: Wada-Kiyama Yuko , Kato Megumi , Onishi Yoshiaki , Kiyama Ryoiti 
Published: October 2019

Abstract
Recent progresses in the study of histone modifications in gene networks and signaling revived the importance of chromatin for controlling gene functions. However, the difficulty of chromatin study lies first in the number of necleosomes in a cell: roughly 107 nucleosomes, each containing a different DNA sequence, are continuously tied as ”beads and strings”, interacting each other, between the neighboring ones as well as the distant ones. Chromatin organization and nucleosome stability is crucial in massive changes of chromatin enviroment such as in DNA replication and formation of chromosomes at cell division as well as in the local changes as observed in transcription of genes, changes of active/inactive chromatin regions and their boundary formation. One of the best ways to study this complex state is first to classify these nucleosomes based on some definitive criteria. Realization that all nucleosomes are not behaving identically is not new. However, explanation at the molecular level of such differences needs a comprehensive analysis of the genome structure by molecular biological experiments and by computational extractions which became available only in recent years. We provide here evidence for a conserved regulatory element for transcription of the β-like globin gene as a summary of our recent studies of a total of over 30 genes using experimental and/or computational approaches (Onishi & Kiyama. Nucl. Acids Res.29, 3448–3457, 2001; Onishi & Kiyama J. Biol. Chem.278, 8163–8171, 2003; Kato et al. J. Mol. Biol.332, 111–125, 2003; Wanapirak et al. J. Mol. Evol.56, 649–657, 2003; Onishi & Kiyama. Recent Res. Devel. Nucl. Acids in press). The element is characterized by the appearance of AA- or TT-dinucleotides in the A+T-rich region located 200 to 400 bp upstream of cap sites. G tracts 3 to 5 nucleotides long exist between the A+T-rich region and the conserved transcription factor binding sites (GATA-1 site and the CACCC, CCAAT, and ATA boxes). An average periodicity of AA- or TT- dinucleotides in the region from a total of eighteen β-family globin genes from four species was approximately 13 bp, suggesting DNA in these regions to show right-handed superhelicity. A proposed biological meaning of this element is to adjust the spatial positions for the first interaction of the transcription factors which should recognize specific DNA sequences in the presence of packed chromatin.
P21 Induces Apoptosis in 32d Cells Undergoing G-Csf-Stimulated Differentiation--This Effect Requires Threonine 57 in Its Cdk2-Inhibitory Domain.
Authors: Ghanem Louis , Steinman Richard A. 
Published: October 2019

Abstract
p21waf1 has been reported to promote hematopoietic stem cell quiescence and to be overexpressed in a subset of leukemias. p21 has been shown to function both as an agonist and antagonist of apoptosis, cell cycling and differentiation in vitro. Functions of p21 and of phosphorylated forms of p21 in granulopoiesis have not been examined hitherto. We hypothesized that p21 would antagonize granulocytic differentiation based on oberved downmodulation of p21 during normal granulopoiesis and the reported antagonism of kerotinocyte differentiation by exogenous p21. The murine myeloblast cell line 32Dcl3, which proliferates in IL-3 and differentiates in G-CSF, was used to model the effects of exogenous wild type and mutant p21 on granulocytic differentiation. Our results demonstrate that the level of p21 protein decreased upon initiation of differentiation. The decrease in p21 protein was secondary to a decrease in p21 message stability as well as proteosomal degradation. Conceivably, the observed decrease in p21 protein was necessary for proper differentiation. In order to determine this, we established stable retroviral transfectants of 32Dcl3 cells to express exogenous wild-type p21, or p21 mutated at threonine-57, threonine-145, serine-146 or both threonine 145 and serine 146 (other studies have shown that mutation of T57 within the cdk2-binding domain of p21 makes p21 resistant to GSK3beta-mediated degradation; the T145 and S146 residues are substrates of Akt which is activated downstream of IL-3 in 32Dcl3 cells). Overexpression of wild-type, T145 or S146 mutants caused growth arrest and triggered apoptosis within 48 hours of stimulation with G-CSF when compared to controls. In contrast, the T57A p21 mutant neither caused growth arrest, nor did it trigger apoptosis in G-CSF. These data support a physiologic role for the observed downmodulation of p21 in differentiaing 32D cells and suggest that p21 is proapoptotic in differentiating granulocytes. The threonine 57 site in the cdk2-binding domain of p21 is implicated in this function.
Rituximab and Stem Cell Transplantation Produces Durable Remissions in Mantle Cell Lymphoma.
Authors: Capote Francisco J. , Pascual M. J. , Gonzalez-Barca E. , Bergua J. M. , Jimenez A. , Romero A. , Garcia-Boyero R. , Giraldo P. , Fernandez-Calvo J. , Ribera J. M. , Ramirez M. J. , Amigo M. L. , Munoz M. I. , Caballero D. , Guinot M. , Oriol A. , Moraleda J. M. , Palomera L. , Almagro M. , Leon A. , Fernandez-deSevilla A. , Gil J. L. 
Published: October 2019

Abstract
Introduction: Mantle cell lymphoma (MCL) is a CD20+ malignancy comprising up 5% of non-Hodgkin’s lymphomas, and has a poor prognosis under standard chemotherapy. The HyperCVAD-M/A regimen (fractionated high-dose cyclophosphamide, vincristine, doxorubicin and prednisolone alternated with methotraxate and cytarabine) has yielded encouraging results when combined with autologous stem cell transplantation (ASCT) in MCL, with 5-year failure-free survival of 54% and overall survival 72%. In an effort to improve these results further, we have combined rituximab in vivo purging and post-transplant consolidation with HyperCVAD-M/A plus ASCT.
Methods: Patients aged <65 years with previously untreated or relapsed MCL were treated with four courses of HyperCVAD-M/A followed by four once-weekly doses of rituximab 375mg/m2 as purging prior to stem cell mobilization and harvesting, high-dose chemotherapy (ICT-CY or BEAM), stem cell reinfusion and four further doses of rituximab immunotherapy post-transplant.
Results: Of the 34 patients enrolled so far, 15 (12 male, 3 female; 12 previously untreated) have been transplanted. The median age was 52 years (range 47–63 years). After the final post-ASCT immunotherapy all 15 patients were in clinical complete remission. With a median follow-up of 30 months from diagnosis (range 7–52 months), 14 patients remain alive with 13 in first complete remission. One patient died 15 months post-ASCT without evidence of disease recurrence. Kaplan-Meier estimates of 4-year overall and event-free survival are 93.3% and 86.6% respectively.
Conclusions: This approach seems safe and feasible and produces durable remissions; longer follow-up of a more patients will be required to assess the effect of the procedure on survival.
The Use of Gene-Expression Profiling to Predict Outcome of Follicular Lymphoma Patients Treated with Rituximab and Chemotherapy.
Authors: Harjunpää Antti , Nykter Matti , Monni Outi , Karjalainen-Lindsberg Marja-Liisa , Hemmer Samuli , Yli-Harja Olli , Meri Seppo , Leppä Sirpa 
Published: October 2019

Abstract
The anti-CD20 monoclonal antibody rituximab has been extensively evaluated for treatment of follicular lymphoma (FL) and is now an integral component of many treatment strategies. However, it is not known when and how to use this combination modality best in the overall treatment course of FL patients. Here we have analyzed the pattern of gene expression in lymph nodes from 28 FL patients who received rituximab in combination with chemotherapy. We demonstrate a novel feature selection method, in which genes whose expression correlates with treatment outcome are devided into groups based on similar expression patterns. By selecting representatives from these groups we built a three-gene predictor (for example RRAD, MGC5254, MARCO) which turned out to be successful in classifying all 28 samples correctly with respect to the responders versus nonresponders distinction. A similar four-gene predictor (for example USP9Y, CUL-4B, NSFS/REST, MADH) correctly classified the responding patients into two subgroups with very different event-free survival rates at the median follow up of 21 months (median not reached vs. 15 months, p<0.0001). The latter predictor also efficiently delineated patients within specific FLIPI risk groups. Our data demonstrate the ability of these microarray-based predictors to classify FL patients treated with rituximab and chemotherapy to subgroups with significantly distinct outcomes.
Characterization of Cellular Immune Responses to a Recombinant Idiotype Vaccine by ELISPOT and Identification of MHC Class I-Restricted T Cell Epitopes by Peptide Mapping.
Authors: Bertinetti Cristina M. , Veelken Hendrik 
Published: October 2019

Abstract
Induction of tumor-specific immune responses by idiotype vaccination is a promising strategy for biological therapy of indolent B cell lymphomas. In a previous report, we have described immune responses in a subset of patients participating in a phase I clinical trial primarily designed to demonstrate safety and efficacy of a recombinant idiotype vaccine (Veelken et al., ASH abstract #3342, 2003). In this trial, B-NHL patients who had relapsed after standard chemotherapy received repetitive intradermal vaccinations with recombinant idiotype Fab fragment derived from their tumor mixed with lipid-based adjuvant and concurrent subcutaneous GM-CSF at the same site. We now present the final analysis of cellular immune responses in this cohort. Peripheral blood lymphocytes (PBL) were obtained prior to and on various time points during and after vaccinations. Cryopreserved PBL were stimulated twice by autologous dendritic cells (DC) exposed to the autologous Fab protein for cross-presentation as MHC class I-bound peptides. INFγ-secreting cells were subsequently quantified by ELISPOT with Fab-presenting DC. Alternatively, freshly thawed PBL were directly assayed with recombinant Fab by ELISPOT without prestimulation. An increase in the frequency of Fab-responding PBL was detected in 7 of 15 evaluable patients with the prestimulation assay and in 4 of 10 patients by direct quantitation, resulting in a combined cellular response rate of 53% (9 of 17). A cellular immune response showed a trend for correlation with extended progression-free survival (p=0.08). T cell responses were predominantly idiotype-specific since lesser or no increases in IFNγ-secreting cells were detected against light chain- and VH family-matched control Fabs. Interestingly, a much higher base-line reactivity was observed against the control Fabs in comparison to the patient’s lymphoma Fab in four patients, pointing to the possibility of tumor-specific anergy in lymphoma patients that can at least be partially corrected by active immunization. In an effort to identify the MHC class I-presented idiotype-derived peptides, potential binding motifs were defined by reverse immunology with the SYFPEITHI algorithm (www.syfpeithi.de). Ten candidate peptides from the variable and constant region of an immune responder’s idiotype heavy chain were synthesized and evaluated with post-vaccination PBL by ELISPOT without prestimulation. A peptide derived from the CDR2 region showed a significantly higher response compared to an unrelated peptide control (p=0.0013). Additional peptides derived from the FWR1, CDR1, and CDR2 also showed a significant stimulation, but only in comparison to a no peptide control. ELISPOT offers a valuable tool to monitor cellular immune reponses and demonstrates successful induction of tumor immunity in pretreated, tumor bearing and immunosuppressed B cell lymphoma patients.
Supported by Deutsche Krebshilfe
High Dose Therapy with Autologous Blood Stem Cell Transplantation (Asct) for Relapsed, Follicular Lymphoma (FL) vs. De Novo, Diffuse Large B-Cell (dnDLBL) vs. Transformed, Follicular To Diffuse Large B-Cell Lymphoma (Tdlbl): No Difference in Freedom from Progression.
Authors: Pohlman Brad , Jin Tony , Summers Kristie , Kuczkowski Elizabeth , Brown Stacey , Kalaycio Matt , Sobecks Ronald , Andresen Steven , Bernhard Laura , Cherni Kelly , Baker Janet , Bolwell Brian J. 
Published: October 2019

Abstract
The decision to offer or not offer high dose therapy with ASCT to an individual lymphoma patient is sometimes (but perhaps mistakenly) based on the specific histology alone and not necessarily on patient characteristics, clinical manifestations, or disease behavior. Therefore, we reviewed the long-term outcome of FL, dnDLBL, and tDLBL patients, who received high dose chemotherapy (CT) with ASCT at the Cleveland Clinic, to determine if the specific histology is important. Between June 1991 and July 2004, 235 patients with FL, dnDLBL, or tDLBL in second or third remission received high dose CBV (n=7), BuCy (n=1), or BuCyVP (n=227) with ASCT. The median follow-up among survivors is 3.4 (.1–11.4) years.
Patient, disease, and ASCT characteristics and outcome according to histology
Variable FL (n=88) dnDLBL (n=123) tDLBL (n=24) p-value Age: median (range) 51(33–69) 50(22–71) 56(40–70) 0.021 Male sex: N (%) 47(53) 73(59) 12(50) 0.56 Years from diagnosis to ASCT: median (range) 2.6(0.4–17.5) 1.5(0.3–15.6) 3.4(1–14.0) <0.001 Prior #CT regimens: median (range) 2(1–5) 2(1–4) 2(2–5) <0.001 Disease status at ASCT: CR2-PR2/CR3-PR3, N (%) 61(69)/27(31) 106(86)/17(14) 16(67)/8(33) 0.005 Bone marrow involved at ASCT: N (%) 16(21) 12(10) 1(4) 0.035 Prior radiation therapy: N (%) 25(28) 45(37) 7(29) 0.42 LDH > normal at ASCT: N (%) 60(69) 65(54) 12(50) 0.06 Tumor bulk >10 cm at ASCT: N (%) 14(16) 27(23) 4(17) 0.46 Disease progression: N (%) 35(40) 55(45) 10(42) – Death from lymphoma: N (%) 21(24) 42(34) 7(29) – Death from any cause: N (%) 31(35) 58(47) 13(54) –
Kaplan-Meier freedom from progression curves accarding to histology are shown:
Figure Figure
Kaplan-Meier overall survival curves according to histology are shown:
Figure Figure
There is no significant difference in freedom from progression between FL, dnDLBL, and tDLBL patients transplanted in second or third remission. By Cox proportional univariate analysis, only male sex predicted a higher risk of progression while male sex, older age, and dnDLBL or tDLBL (compared to FL) predicted a higher risk of death. By Cox proportional multivariate analysis, no factor predicted a higher risk of progression while older age, male sex, and dnDLBL predicted a higher risk of death. In conclusion, high dose chemotherapy with ASCT leads to long-term remissions in 40–50% of FL, dnDLBL, and tDLBL patients in second or third remission. These results suggest that the distinction between these three histologies is less important than other factors in determining patient eligibility for ASCT.
Ligand Activation of FLT3 Induces Cell Cycle Arrest in Acute Lymphoblastic Leukemia with 11q23 Translocation.
Authors: Furuichi Yoshiyuki , Sugita Kanji , Inukai Takeshi , Goi Kumiko , Takahashi Kazuya , Nakazawa Shinpei 
Published: October 2019

Abstract
A fms-like kinase (FLT3) is widely known to be involved in proliferation of normal hematopoietic stem cells and precursors. Acute lymphoblastic leukemia (ALL) with 11q23 translocation, often found in infantile leukemia with very poor prognosis, is thought to be derived from a population of cells at the developmental stage very close to hematopoietic stem cells, and was recently shown that they express FLT3 at high levels compared with other types of leukemia. In the present study, we examined the effects of FLT3 ligand (FL) on leukemia cells with or without 11q23 translocation to evaluate a biological implication of the FLT3/FL interaction in ALL. Three of 8 leukemic cell lines without 11q23 translocation showed a proliferative response to FL in the 3H-thymidine uptake assays. However, five of 7 B-precursor leukemic cell lines with 11q23 translocation, unexpectedly, showed an inhibitory response (23-69% inhibition) to FL in a dose-dependent manner (1–20ng/ml), although the special cell line with D835 mutation in FLT3 (KOCL-33) was not affected by the addition of FL. This inhibitory effect was almost abrogated in the presence of a FLT-3 kinase inhibitor PKC412. Inhibition of 3H-thymidine uptakes were not due to induction of apoptosis but due to induction of the Go/G1 arrest. This cell cycle arrest was mediated, at least in part, by a marked up-regulation of p27 due to suppression of its degradation, and promoted resistance of cell lines to radiation-induced apoptosis. Of interest, the addition of FL induced a complete disappearance of constitutive phosphorylation of STAT5 but upregulated phosphorylation of MAPK and Akt. These results suggest that the FLT3/FL interaction in ALL with 11q23 translocation transmits the inhibitory signal specifically to the JAK/STAT pathway via the kinase activity of FLT3, in the process of which the JAK/STAT-specific inhibitory molecules such as SOCS-2 and CIS-1 may be implicated.
A Role for Adipocyte-Enriched Transcription Factor, PPAR-γ, in Up-Regulation of PAI-1 Gene Expression during Adipogenesis.
Authors: Ihara Hayato , Loskutoff David J. , Urano Tetsumei 
Published: October 2019

Abstract
Obese patients are at risk for development of cardiovascular disease, which can in part be explained by disturbances in the haemostatic and fibrinolytic systems. Recently, it has been demonstrated that the adipocyte itself is able to produce a primary fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1), possibly explaining the high levels found in obesity. We have previously shown that pioglitazone, a selective ligand for peroxisome proliferator-activated receptor (PPAR)-γ, and insulin not only enhances adipocyte differentiation, but also up-regulates PAI-1 gene transcription in 3T3-L1 adipocytes (Ihara et al. FASEB J., 2001). These results suggest that PAI-1 gene expression during adipogenesis can be regulated by a direct action of PPAR-γ. In the present study, we investigate a role of an adipocyte-enriched transcription factor, PPAR-γ, in up-regulation of PAI-1 gene expression in adipose tissues. To identify cis-acting genetic elements required for induction of PAI-1 gene transcription, we constructed the plasmids containing a 5′ deletion series of the PAI-1 promoter. When sequences between -762 and -723 were deleted, the level of induction significantly fell. By sequence homology search in this region, we found an atypical PPAR-responsive element (aPPRE) at positions −752 to −733. Gel mobility shift and supershift assays using oligonucleotides of the aPPRE overlapping C/EBP binding site indicated that the aPPRE is important for PPAR-γ binding. Chromatin immunoprecipitation assay demonstrated that PPAR-γ is physically associated with PAI-1 gene promoter region including the aPPRE in vivo. Furthermore, mutation of the aPPRE abrogated the increase in transcriptional activities of PAI-1 promoter. Functional assay revealed that besides PPAR-γ/RXR-α expression vectors, co-transfection of CREB-binding protein expression vector increased the luciferase activity to 7.5 fold and 11 fold of control value in COS-1 cells and 3T3-L1 preadipocytes, respectively. These data indicate that the transcriptional induction of PAI-1 gene during adipogenesis is mediated through the binding of PPAR-γ/RXR-α to the functional aPPRE in the PAI-1 gene promoters.