bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ig V Gene Mutation Status and CD38 Expression As Novel Prognostic Indicators in Chronic Lymphocytic Leukemia
Authors: Damle Rajendra N. , Wasil Tarun , Fais Franco , Ghiotto Fabio , Valetto Angelo , Allen Steven L. , Buchbinder Aby , Budman Daniel , Dittmar Klaus , Kolitz Jonathan , Lichtman Stuart M. , Schulman Philip , Vinciguerra Vincent P. , Rai Kanti R. , Ferrarini Manlio , Chiorazzi Nicholas 
Published: October 2019

AbstractCellular immunophenotypic studies were performed on a cohort of randomly selected IgM+ B-chronic lymphocytic leukemia (B-CLL) cases for which Ig VH and VL gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38+ B-CLL cells (≥30%) than those with mutated V genes that had lower percentages of CD38+ cells (&lt;30%). Patients in both the unmutated and the ≥30% CD38+ groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the &lt;30% CD38+ groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the &lt;30% CD38+ groups, males and females were virtually equally distributed, whereas in the unmutated and the ≥30% CD38+ groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38+B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.
Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia
Authors: Hamblin Terry J. , Davis Zadie , Gardiner Anne , Oscier David G. , Stevenson Freda K. 
Published: October 2019

AbstractDespite having several characteristics of naı̈ve B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig VH genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed ≥ 98% sequence homology with the nearest germline VH gene; 46 cases (54.8%) showed &gt;2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A patients with unmutated VH genes was 95 months compared with 293 months for patients whose tumors had mutated VHgenes (P = .0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naı̈ve B cell, is more malignant.
CD36 Peptides That Block Cytoadherence Define the CD36 Binding Region for Plasmodium falciparum-Infected Erythrocytes
Authors: Baruch Dror I. , Ma Xin C. , Pasloske Brittan , Howard Russell J. , Miller Louis H. 
Published: October 2019

AbstractMature Plasmodium falciparum parasitized erythrocytes (PE) sequester from the circulation by adhering to microvascular endothelial cells. PE sequestration contributes directly to the virulence and severe pathology of falciparum malaria. The scavenger receptor, CD36, is a major host receptor for PE adherence. PE adhesion to CD36 is mediated by the malarial variant antigen, P. falciparumerythrocyte membrane protein 1 (PfEMP1), and particularly by its cysteine-rich interdomain region 1 (CIDR-1). Several peptides from the extended immunodominant domain of CD36 (residues 139-184), including CD36 139-155, CD36 145-171, CD36 146-164, and CD36 156-184 interfered with the CD36-PfEMP1 interaction. Each of these peptides affected binding at the low micromolar range in 2 independent assays. Two peptides, CD36 145-171 and CD36 156-184, specifically blocked PE adhesion to CD36 without affecting binding to the host receptor intercellular adhesion molecule-1 (ICAM-1). Moreover, an adhesion blocking peptide from the ICAM-1 sequence inhibits the PfEMP1–ICAM-1 interaction without affecting adhesion to CD36. These results confirm earlier observations that PfEMP1 is also a receptor for ICAM-1. Thus, the region 139-184 and particularly the 146-164 or the 145-171 regions of CD36 form the adhesion region for P. falciparum PE. Adherence blocking peptides from this region may be useful for modeling the PE/PfEMP1 interaction with CD36 and for development of potential anti-adhesion therapeutics.
Upregulation of Integrin 6/β1 and Chemokine Receptor CCR1 by Interleukin-12 Promotes the Migration of Human Type 1 Helper T Cells
Authors: Colantonio Lucia , Iellem Andrea , Clissi Barbara , Pardi Ruggero , Rogge Lars , Sinigaglia Francesco , D’Ambrosio Daniele 
Published: October 2019

AbstractCD4+ T helper 1 (Th1) cells and Th2 cells are distinguished based on the pattern of cytokines they are able to produce. Selectin ligands and chemokine receptors are differentially expressed in Th1 and Th2 cells, providing a basis for tissue-specific recruitment of helper T-cell subsets. However, the modes and mechanisms regulating tissue-specific localization of Th1 and Th2 cells are still largely unknown. Here, we show the preferential expression on Th1 cells of the integrin 6/β1, which is distinctly regulated by the Th1-inducing cytokines interleukin-12 (IL-12) and interferon-alfa (IFN-). The pattern of integrin 6/β1 regulation closely mirrors that of the chemokine receptor CCR1. Analysis of signal transducer and activator of transcription 4 (Stat4) activation by IL-12 and IFN- shows distinct signaling kinetics by these cytokines, correlating with the pattern of CCR1 and integrin 6/β1 expression. Unlike IFN-, the ability of IL-12 to generate prolonged intracellular signals appears to be critical for inducing integrin 6/β1 upregulation in Th1 cells. The expression and upregulation of CCR1 and 6/β1 integrin promotes the migration of Th1 cells. These findings suggest that the exquisite regulation of integrin 6/β1 and CCR1 may play an important role in tissue-specific localization of Th1 cells.
CD30-CD30 Ligand Interaction in Primary Cutaneous CD30+T-Cell Lymphomas: A Clue to the Pathophysiology of Clinical Regression
Authors: Mori M. , Manuelli C. , Pimpinelli N. , Mavilia C. , Maggi E. , Santucci M. , Bianchi B. , Cappugi P. , Giannotti B. , Kadin M.E. 
Published: October 2019

AbstractPrimary CD30+ cutaneous T-cell lymphomas (CTCLs) represent a spectrum of non-Hodgkin’s lymphomas (NHLs) that have been well defined at the clinical, histologic, and immunologic level. This group, which includes 2 main entities (large cell lymphoma and lymphomatoid papulosis [LyP]) and borderline cases, is characterized by the expression of CD30 antigen by neoplastic large cells at presentation, possible spontaneous regression of the skin lesions, and generally favorable clinical course. Although the functional relevance of CD30 and its natural ligand (CD30L) expression in most cases of NHL is presently undefined, previous studies indicate that CD30L is likely to mediate reduction of proliferation in CD30+ anaplastic large-cell NHL. No information is currently available concerning the expression of CD30L in primary CD30+ CTCLs. In this study, we investigated the immunophenotypic and genotypic expression of CD30 and CD30L in different developmental phases of skin lesions (growing v spontaneously regressing). By immunohistochemistry, CD30L expression was detected in regressing lesions only; by molecular analysis, the expression of CD30L was clearly higher in regressing lesions than in growing ones. CD30L, while expressed by some small lymphocytes, was most often coexpressed by CD30+neoplastic large cells, as demonstrated by 2-color immunofluorescence and by immunohistochemistry on paraffin sections. Taken together, these data suggest that CD30-CD30L interaction may play a role in the pathobiology of primary cutaneous CD30+lymphoproliferative disorders. In particular, CD30L (over)expression might have a major role in the mechanism of self-regression of skin lesions, the most distinctive clinical feature of this cutaneous lymphoma subtype.
Viral-Specific Cytotoxic T Lymphocytes Lyse Human Immunodeficiency Virus–Infected Primary T Lymphocytes by the Granule Exocytosis Pathway
Authors: Shankar Premlata , Xu Zhan , Lieberman Judy 
Published: October 2019

AbstractCytotoxic T lymphocytes (CTL) lyse antigen-bearing target cells by two distinct pathways. Whereas granule exocytosis targets any antigen-bearing cell, fas-mediated cytotoxicity kills only fas-expressing cells and does not require antigen expression. Fas pathway activation can potentially lead to lysis of uninfected bystander cells. We examined the relative usage of the two pathways by CTL clones and cell lines directed against four different human immunodeficiency virus (HIV) proteins in lysing primary HIV-infected targets. Although fas was expressed on HIV-infected primary CD4+ T cells, their lysis by antigen-specific CD8+ CTL was only by the granule pathway. Fas ligand (fasL) was not detectable on antigen-specific CD8 clones, T-cell lines, or circulating HIV-specific CD8 T cells from HIV-infected donors, stained with a tetrameric HLA-A2-HIV-peptide complex. FasL expression by HIV-specific CTL clones was not activated by exposure to HIV-presenting cells, but was after unphysiological stimulation with phorbol myristate acetate (PMA). CTL clones did not lyse bystander Jurkat cells, but HIV-infected primary CD4+ T cells lysed uninfected bystander cells by the fas-mediated pathway. These results suggest that HIV-specific CD8+ CTL do not cause HIV immunopathology by lysing bystander cells. On the contrary, fas-mediated lysis of uninfected cells by HIV-infected cells may contribute to CD4 decline.
Overexpression of CCAAT Displacement Protein Represses the Promiscuously Active Proximal gp91phox Promoter
Authors: Catt Diana , Hawkins Shannon , Roman Ann , Luo Wen , Skalnik David G. 
Published: October 2019

AbstractCCAAT displacement protein (CDP) is a transcriptional repressor that restricts expression of the gp91phox gene to mature myeloid cells. CDP interacts with multiple sites within the −450 to +12 bp human gp91phox promoter, and down-regulation of CDP DNA-binding activity is required for induction of gp91phox transcription in mature phagocytes. Truncation of the gp91phox promoter to −102 to +12 bp removes 4 CDP-binding sites and reveals a promiscuous promoter activity that is active in some nonphagocytic cells. A cis-element at −90 bp is required for derepressed transcription and serves as a binding site for multiple transcriptional activators. We now report that this element also serves as a binding site for CDP. The affinity of CDP for this element is relatively weak compared with upstream CDP-binding sites within the promoter, consistent with the promiscuous transcriptional activity exhibited by the −102 to +12 bp gp91phox promoter fragment. Further analysis of the proximal promoter reveals an additional weak-affinity CDP-binding site centered at approximately −20 bp. Overexpression of cloned CDP represses the −102 to +12 bp gp91phox promoter, indicating that these proximal CDP-binding sites are functionally significant. The constellation of transcriptional activators and a repressor that interacts with the −90 bp cis-element is identical to that observed for a promoter element at −220 bp, reflecting the highly modular organization of the gp91phoxpromoter. These studies illustrate the complex interplay between transcriptional activators and a repressor that contribute to the myeloid-restricted expression of the gp91phox gene.
Importance of Anemia and Transferrin Levels in the Regulation of Intestinal Iron Absorption in Hypotransferrinemic Mice
Authors: Raja K.B. , Pountney D.J. , Simpson R.J. , Peters T.J. 
Published: October 2019

AbstractThe hypotransferrinemic mouse (trf hpx) is a mutant strain exhibiting transferrin deficiency, marked anemia, hyperabsorption of iron, and elevated hepatic iron stores. We set out to investigate the relative roles of anemia and of transferrin in the malregulation of intestinal iron absorption in these animals. Transfusion of erythrocytes obtained from littermate controls increased hemoglobin levels and reduced reticulocyte counts in recipient animals. Although mucosal to carcass 59Fe transfer was reduced, total duodenal iron uptake was not significantly affected. Iron absorption in homozygotes, in contrast to littermate controls, was not reduced by hyperoxia. Mouse transferrin injections, in the short term, increased delivery of iron to the marrow and raised hemoglobin levels. Although mucosal transfer and total iron uptake were reduced at the higher transferrin doses, total uptake was still higher than in controls. Daily injections of mouse/human transferrin for 3 weeks from weaning, normalized hemoglobin values, and markedly reduced liver iron and intestinal iron absorption values in trf hpxanimals. When such daily-injected mice were left for a week to allow transferrin clearance, iron absorption values were significantly enhanced; hemoglobin or hepatic iron levels were, however, not significantly altered. These data indicate that hyperabsorption of iron in trf hpx mice is not solely because of the anemia; transferrin levels per se do affect iron absorption, possibly via a direct effect on the intestinal mucosa.
Why Are Hemoglobin F Levels Increased in HbE/β Thalassemia?
Authors: Rees D.C. , Porter J.B. , Clegg J.B. , Weatherall D.J. 
Published: October 2019

Abstract
To try to further define the mechanisms that increase the levels of hemoglobin F (HbF) in the blood of patients with severe forms of β thalassemia, we have studied two comparable populations of hemoglobin E (HbE)/β thalassemics, one regularly transfused and one receiving only occasional blood transfusions. Regular transfusion was associated with a significant decrease in soluble transferrin receptor and erythropoietin levels. Globin chain synthesis studies also show a highly significant decrease in HbF synthesis relative to HbE in the transfused patients. This effect was confirmed by sequential data on one patient, studied before and after the commencement of regular blood transfusion; blood transfusion was followed by a marked increase in the /γ, βE/γ, and HbE/HbF ratios. These data suggest that the high HbF levels in HbE/β thalassemia, and other β thalassemia syndromes, result from increased erythropoietin levels leading to bone marrow expansion, and possibly increased F-cell production, combined with ineffective erythropoiesis giving a survival advantage to F cells. This study also suggests that alteration in blood transfusion regimes must be taken into account when interpreting changes in HbF levels seen in trials of HbF-promoting drugs.
Development of dendritic cells in vitro from murine fetal liver–derived lineage phenotype-negative c-kit+hematopoietic progenitor cells
Authors: Zhang Yanyun , Zhang Yi , Wang Yong , Ogata Masafumi , Hashimoto Shin-ichi , Onai Nobuyuki , Matsushima Kouji 
Published: October 2019

AbstractWe describe here that lineage phenotype- negative (Lin)−c-kit+ hematopoietic progenitor cells (HPCs) from day 13 postcoitus (dpc) murine fetal liver (FL) can generate dendritic cell (DC) precursors when cultured in vitro in the presence of PA6 stromal cells plus granulocyte/macrophage colony-stimulating factor (GM-CSF) + stem cell factor (SCF) + Flt3 ligand (Flt3L) for 12 to 14 days, and develop into mature DCs when stimulated with GM-CSF plus mouse tumor necrosis factor  (mTNF) for an additional 3 to 5 days. A transwell culture system showed that the generation of DC precursors depended on the support of PA6 cell-secreted soluble factor(s). The mature DCs derived from 13 dpc FL Lin−c-kit+ HPCs showed characteristic morphology and function of DCs and expressed high levels of Ia, CD86, and CD40 molecules, low levels of DEC205, E-cadherin, and F4/80 molecules, but barely detectable CD11c antigen. Once FL-derived HPCs were cultured without GM-CSF, NK1.1+ cells developed in the presence of PA6 cells + SCF + Flt3L. These NK1.1+ cells could develop into DC precursors at an earlier stage of differentiation by reculturing with PA6 cells + SCF + Flt3L + GM-CSF, but they would be irreversibly committed to NK cell precursors without GM-CSF after 3 days, suggesting that GM-CSF plays a critical role in controlling the transition of DC and NK cell precursors from 13 dpc FL-derived Lin−c-kit+ HPCs. This study represents the first success in generating mature DCs in vitro from murine FL HPCs. (Blood. 2000;95:138-146)
Resistance of ICAM-1–deficient mice to metastasis overcome by increased aggressiveness of lymphoma cells
Authors: Lalancette Maxime , Aoudjit Fawzi , Potworowski Edouard F. , St-Pierre Yves 
Published: October 2019

AbstractOur recent finding that resistance to lymphoma cell metastasis in intercellular adhesion molecule-1-(ICAM-1)–deficient mice was manifested after homing suggested that the mechanism could involve the capacity of ICAM-1 to induce, via leukocyte function-associated antigen-1 (LFA-1) signaling, the expression of new genes necessary for migration and survival of lymphoma cells after homing. This hypothesis would imply that lymphoma cells, on repeated metastatic cycles, would acquire such a highly aggressive phenotype that they no longer require contact with ICAM-1 at later stages of metastasis. We addressed this question by generating highly aggressive lymphoma variants to determine if increased tumorigenicity would allow lymphoma cells to grow into tumors in ICAM-1–deficient mice. We found that on repeated in vivo passages, a selective pressure favored the lymphoma cells that constitutively express high levels of matrix metalloproteainse-9 (MMP-9), a gene associated with a poor clinical outcome in non-Hodgkins's lymphoma. We further found that although the parent lymphoma cells could not grow tumors in ICAM-1–deficient mice, the aggressive lymphoma variants could. This indicates that, at late stages of the disease, tumor cells with a high metastatic efficiency, encoded by the repertoire of selected genes, no longer require some of the signals normally delivered by cell adhesion molecules. In light of these findings, the possibility of inhibiting dissemination of lymphoma cells at the late stage of the disease by acting against cell adhesion molecules must be reconsidered. (Blood. 2000;95:314-319)
Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia
Authors: Dazzi F. , Szydlo R. M. , Craddock C. , Cross N. C. P. , Kaeda J. , Chase A. , Olavarria E. , van Rhee F. , Kanfer E. , Apperley J. F. , Goldman J. M. 
Published: October 2019

Abstract
Donor lymphocyte infusion (DLI) was originally administered as a single, relatively large dose of lymphocytes called a bulk dose regimen (BDR). It has since been suggested that the use of an escalating dose regimen (EDR) may be equally effective against leukemia while it induces less graft-versus-host disease (GVHD). We therefore compared the efficacy and incidence of complications in a nonrandomized sequential study of the 2 regimens in 48 consecutive patients who had relapses with cytogenetic or hematologic evidence of chronic myeloid leukemia after allogeneic stem cell transplantation. Twenty-eight patients were treated on a BDR (August 1990 to November 1995) and 20 were treated on an EDR (December 1995 to January 1998). Although the probability of achieving cytogenetic remission within 2 years of starting DLI did not differ significantly between the 2 groups (EDR, 91% [CI, 63%–98%] vs. BDR, 67% [CI,49%–83%],P = .70), the incidence of GVHD was much lower using EDR (10% vs. 44%, P = .011). When we considered only subsets of patients treated by BDR or EDR who had received comparable total lymphoid cell doses, the incidence and severity of acute and chronic GVHD were both significantly lower for recipients treated by EDR than for recipients treated by BDR (P = .005 andP = .031, respectively). These findings suggest that the incidence of GVHD associated with the EDR is low, not because the final cell dose is small, but because lymphocytes are administered over a considerable number of months. (Blood. 2000;95:67-71)
The role of platelet α-granular proteins in the regulation of thrombopoietin messenger RNA expression in human bone marrow stromal cells
Authors: Sungaran Ranita , Chisholm Orin T. , Markovic Boban , Khachigian Levon M. , Tanaka Yoshihiro , Chong Beng H. 
Published: October 2019

Abstract
Thrombopoietin (TPO), the specific cytokine that regulates platelet production, is expressed in human bone marrow (BM), kidney, and liver. There appears to be no regulation of TPO in the kidney and liver, but TPO messenger RNA (mRNA) expression can be modulated in the stromal cells of the BM. In this study, we used primary human BM stromal cells as a model to study the regulation of TPO mRNA expression in response to various platelet -granular proteins. We showed that platelet-derived growth factor (PDGF) BB and fibroblast growth factor (FGF) 2 stimulated TPO mRNA expression in both a dose-dependent and time-dependent manner. The addition of 50 ng/mL of PDGF and 20 ng/mL of FGF resulted in maximal induction of TPO mRNA expression in 4 hours. We also found that platelet factor 4 (PF4), thrombospondin (TSP), and transforming growth factor-beta (TGF-β) are negative modulators of megakaryocytopoiesis. We observed suppression in TPO mRNA expression with 1 μg/mL of both PF4 and TSP and 50 ng/mL of TGF-β, with maximal suppression occurring 4 hours after the addition of these proteins. Finally, the addition of whole-platelet lysate produced a dose-dependent inhibition of TPO expression. On the basis of these findings, we propose that the platelet -granular proteins studied may regulate TPO gene expression in BM stromal cells by means of a feedback mechanism.