bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mastermind critically regulates Notch-mediated lymphoid cell fate decisions
Authors: Maillard Ivan , Weng Andrew P. , Carpenter Andrea C. , Rodriguez Carlos G. , Sai Hong , Xu Lanwei , Allman David , Aster Jon C. , Pear Warren S. 
Published: June 2004

Abstract
During lymphoid development, Notch1 plays a critical role in the T-cell/B-cell lineage decision, while Notch2 is essential for marginal zone B-cell (MZB) development. Notch pathway activation induces translocation of intracellular Notch (ICN) to the nucleus, where it interacts with the transcription factor CSL (CBF1/RBP-Jk, Suppressor of Hairless, Lag-1). In vitro, ICN binds Mastermind-like proteins, which act as potent Notch coactivators. Three MAML family members (MAML1-3) have been identified in mammals, but their importance in vivo is unknown. To investigate the function of MAMLs in hematopoietic development, we introduced a dominant negative (DN) mutant of MAML1, capable of inhibiting Notch1-4, in murine hematopoietic stem cells. DNMAML1 resulted in early inhibition of T-cell development and the appearance of intrathymic B cells, phenotypes consistent with Notch1 inhibition. The T-cell differentiation block was as profound as that produced by enforced expression of the Notch modulator Deltex1. In DNMAML1-transduced spleen cells, a dramatic decrease in MZB cells was present, consistent with Notch2 inhibition. In contrast, Deltex1 did not decrease MZB cell numbers. These results suggest a critical role for MAMLs during Notch-mediated cell fate decisions in vivo and indicate that DNMAML1, but not Deltex1, can be used to interfere with the function of multiple Notch family members. (Blood. 2004;104:1696-1702)
Quiescent phenotype of tumor-specific CD8+ T cells following immunization
Authors: Monsurrò Vladia , Wang Ena , Yamano Yoshisha , Migueles Stephen A. , Panelli Monica C. , Smith Kina , Nagorsen Dirk , Connors Mark , Jacobson Steven , Marincola Francesco M. 
Published: June 2004

AbstractIn a human melanoma model of tumor antigen (TA)–based immunization, we tested the functional status of TA-specific CD8+ cytotoxic T lymphocytes. A “quiescent” phenotype lacking direct ex vivo cytotoxic and proliferative potential was identified that was further characterized by comparing its transcriptional profile to that of TA-specific T cells sensitized in vitro by exposure to the same TA and the T-cell growth factor interleukin 2 (IL-2). Quiescent circulating tumor-specific CD8+ T cells were deficient in expression of genes associated with T-cell activation, proliferation, and effector function. This quiescent status may explain the observed lack of correlation between the presence of circulating immunization-induced lymphocytes and tumor regression. In addition, the activation of TA-specific T cells by in vitro antigen recall and IL-2 suggests that a complete effector phenotype might be reinstated in vivo to fulfill the potential of anticancer vaccine protocols.
Reciprocal cross-talk between P2Y1 and P2Y12 receptors at the level of calcium signaling in human platelets
Authors: Hardy Adam R. , Jones Matthew L. , Mundell Stuart J. , Poole Alastair W. 
Published: June 2004

Abstract
Adenosine diphosphate (ADP), an important platelet agonist, acts through 2 G-protein-coupled receptors (GPCRs), P2Y1 and P2Y12, which signal through Gq and Gi, respectively. There is increasing evidence for cross-talk between signaling pathways downstream of GPCRs and here we demonstrate cross-talk between these 2 ADP receptors in human platelets. We show that P2Y12 contributes to platelet signaling by potentiating the P2Y1-induced calcium response. This potentiation is mediated by 2 mechanisms: inhibition of adenylate cyclase and activation of phosphatidylinositol 3 (PI 3)-kinase. Furthermore, the Src family kinase inhibitor PP1 selectively potentiates the contribution to the calcium response by P2Y12, although inhibition of adenylate cyclase by P2Y12 is unaffected. Using PP1 in combination with the inhibitor of PI 3-kinase LY294002, we show that Src negatively regulates the PI 3-kinase-mediated component of the P2Y12 calcium response. Finally, we were able to show that Src kinase is activated through P2Y1 but not P2Y12. Taken together, we present evidence for a complex signaling interplay between P2Y1 and P2Y12, where P2Y12 is able to positively regulate P2Y1 action and P2Y1 negatively regulates this action of P2Y12. It is likely that this interplay between receptors plays an important role in maintaining the delicate balance between platelet activation and inhibition during normal hemostasis. (Blood. 2004; 104:1745-1752)
Hematopoietic stem cell transplantation for de novo acute megakaryocytic leukemia in first complete remission: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT)
Authors: Garderet Laurent , Labopin Myriam , Gorin Norbert-Claude , Polge Emmanuelle , Baruchel André , Meloni Giovanna , Ortega Juan , Vossen Jaak , Bunjes Donald , Leverger Guy , Blaise Didier , Ferrant Augustin , Brune Mats , Dore Eric , Gadner Helmut , Zintl Felix , Yaniv Isaac , Dini Giorgio , Frassoni Francesco 
Published: June 2004

Abstract
Acute megakaryoblastic leukemia (M7 AML) is a highly aggressive disease. We evaluated outcomes in 57 children (11 with Down syndrome) and 69 adults with M7 AML after first complete remission (CR1) following autologous or HLA-identical allogeneic transplantation. Characteristics of the recipients of autologous transplants (38 children, 37 adults) were, respectively: median age, 1.7 and 46 years; non-total body irradiation (non-TBI) conditioning regimen, 97% and 70%; bone marrow as stem cell source, 74% and 43%. Characteristics of the recipients of allogeneic transplants (19 children, 32 adults) were, respectively: median age, 2.8 and 37 years; non-TBI regimen, 63% and 42%; bone marrow as stem cell source, 95% and 69%. Autologous transplantation benefited children more; the relapse rate was high in adults. Results for autologous transplantation were (children and adults, respectively): engraftment, 90% and 100%; 3-year treatment-related mortality (TRM) rate, 3% and 8%; relapse rate, 45% and 64%; leukemia-free survival (LFS) rate, 52% and 27%; overall survival (OS) rate, 61% and 30%. After allogeneic transplantation, TRM was fairly low in children and adults, and relapse rates were lower than after autologous transplantation. Results for allogeneic transplantation were, respectively: engraftment, 95% and 90%; TRM, 0% and 26%; relapse rate, 34% and 28%; LFS, 66% and 46%; OS, 82% and 43%). We conclude that M7 AML patients in CR1 (except children with Down syndrome, who already have better outcomes) can benefit from transplantation. (Blood. 2005;105:405-409)
Marked elevations in N-terminal brain natriuretic peptide levels in septic shock
Authors: Chua Gerald , Kang-Hoe Lee 
Published: June 2004

Abstract
Introduction
N-terminal pro brain natriuretic peptide (NT-proBNP) is a cardiac biomarker that has recently shown to be of diagnostic value in a diagnosis of decompensated heart failure, acute coronary syndromes and other conditions resulting in myocardial stretch. We sought to study whether sepsis-induced myocardial dilation would result in an elevation of NT-proBNP.

Method
Serum NT-proBNP measurements were made in six consecutive patients with septic shock within 6 hours of admission to the intensive care unit.

Results
Markedly elevated levels of NT-proBNP were found in all six patients.

Conclusions
NT-proBNP levels can be markedly elevated in critically ill patients presenting with septic shock. An elevated NT-proBNP level in a critically ill patient is not specific for decompensated heart failure.
Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine
Authors: Seguí Joaquim , Gironella Meritxell , Sans Miquel , Granell Susana , Gil Fèlix , Gimeno Mercedes , Coronel Pilar , Piqué Josep M , Panés Julián 
Published: June 2004

AbstractOxidant stress has been implicated in the pathogenesis of inflammatory bowel disease. Antioxidant enzymes, such as superoxide dismutase (SOD), are candidate drugs for modulating this pathogenic factor. This study was designed to determine the therapeutic value of SOD in an experimental model of colitis and to study the mechanisms underlying its effects on intestinal inflammation. For that purpose, colitic (trinitrobenzene sulfonic acid-induced) and control rats were studied. Groups of colitic animals were treated with different doses of SOD (1, 4, or 13 mg/kg/day) or vehicle, starting after induction of colitis and during 7 days. Clinical and pathological markers of colitis severity and lipid peroxidation in colonic tissue were measured. Leukocyte-endothelial cell interactions in colonic venules and expression of vascular cell adhesion molecule 1 (VCAM-1) were determined. Development of colitis was associated with a significant loss in body weight, an increase in macroscopic and microscopic damage scores, and colonic myeloperoxidase activity. Administration of SOD significantly attenuated these changes in a dose-dependent manner and reduced lipid peroxidation in colonic tissue. The increase in leukocyte rolling and adhesion in colonic venules of colitic rats were significantly reduced by administration of SOD, 13 mg/kg/day. Development of colitis was associated with a marked increase in endothelial VCAM-1 expression, which was significantly reduced by treatment with SOD. In conclusion, treatment with SOD significantly reduces peroxidation reactions in the inflamed colon and affords significant amelioration of colonic inflammatory changes in experimental colitis. This effect is related to a reduction in VCAM-1 expression and leukocyte recruitment into the inflamed intestine.
Enrichment for a CD26hi SIRP− subset in lymph dendritic cells from the upper aero-digestive tract
Authors: Epardaud Mathieu , Bonneau Michel , Payot Fabrice , Cordier Corinne , Mégret Jérôme , Howard Chris , Schwartz-Cornil Isabelle 
Published: June 2004

AbstractDendritic cells (DC) have been reported to migrate in afferent lymph in the steady state. However, it is unknown whether DC traffic is modulated by the nature of the drained tissue. To analyze the influence of mucosal versus cutaneous microenvironments on the constitutive DC release, we exploited a novel technique of lymph cannulation in sheep, which allowed a comparison of afferent lymph DC migrating from the head mucosae [cervical DC (CerDC)] with DC migrating from skin [prescapular DC (PresDC)]. The migration rate was lower for CerDC than for PresDC. Compared with PresDC, CerDC contained a higher proportion of the CD26hi signal regulatory protein (SIRP)− DC subset. It is interesting that cytoplasmic apoptotic DNA as well as cytokeratin-positive inclusions were primarily detected among CD26hi SIRP− DC, an observation similar to that made in rats, which leads to the suggestion that this subset was involved in self-antigen presentation and tolerance induction. After the inoculation of cholera toxin (CT) onto the oro-nasal mucosae, migration of CD26hi SIRP− and CD26lo SIRP+ DC was accelerated in lymph, indicating that the effect of CT on DC mobilization is not subset-specific. Our results show that a mucosal environment influences DC output and the relative DC subset representation in lymph. This modulation of DC traffic to lymph nodes by mucosal surfaces is likely to affect the bias of the mucosal immune responses.
APC derived from donor splenocytes support retinal autoimmune disease in allogeneic recipients
Authors: Gregerson Dale S , Kawashima Hidetoshi 
Published: June 2004

AbstractT cell adoptive transfer models of autoimmune disease have been used in conjunction with radiation/bone marrow chimeras to define the minimal requirements for antigen (Ag) recognition. In models with central nervous system Ags, major histocompatibility complex (MHC) class II compatibility achieved by grafting F1 bone marrow into parental recipients was reported to be necessary and sufficient for transfer of CD4 T cell-mediated experimental autoimmune encephalomyelitis. Bone marrow-derived, perivascular microglia are now widely regarded to play a critical role in the expression of experimental autoimmune diseases of the nervous system. Similar results might be expected in the experimental autoimmune uveoretinitis model, as retina is an extension of the brain. Using an allogeneic Ag-presenting cell (APC) adoptive transfer strategy, it was found that resident APC were not essential and that their replacement with MHC-compatible cells by bone marrow-grafting techniques was not necessary. Instead, APC were recruited from the circulation.
Human eosinophils produce the T cell-attracting chemokines MIG and IP-10 upon stimulation with IFN-γ
Authors: Dajotoy Terese , Andersson Pia , Bjartell Anders , Löfdahl Claes-Göran , Tapper Hans , Egesten Arne 
Published: June 2004

AbstractEosinophils participate in allergic inflammation, where expression of T helper cell type 2 (Th2) cytokines such as interleukin (IL)-4 and IL-5 are seen. However, eosinophils sometimes accumulate during disease with expression of Th1 cytokines [i.e., interferon-γ (IFN-γ), tumor necrosis factor α (TNF-α), and IL-1β]. In this study, we investigated whether eosinophils can respond with expression of the IFN-inducible C–X–C chemokines monokine induced by IFN-γ [MIG; CXC chemokine ligand 9 (CXCL9)], IFN-γ-inducible protein (IP-10/CXCL10), and IFN-inducible T cell α chemoattractant (I-TAC/CXCL11). These chemokines share the ability to recruit and activate T cells and natural killer cells to sites of inflammation. We found that IFN-γ induced rapid and sustained gene expression of MIG, IP-10, and I-TAC in eosinophils, as detected by quantitative reverse transcriptase-polymerase chain reaction. During incubation, IFN-γ-stimulated eosinophils released MIG and IP-10, as detected by enzyme-linked immunosorbent assay, while I-TAC could not be detected in the medium. TNF-α but not IL-1β enhanced the IFN-γ-induced production of MIG and IP-10. Conversely, addition of the Th2 cytokine IL-4 down-regulated IFN-γ-induced synthesis of MIG and IP–10 in eosinophils. Crohn's disease is characterized by a Th1-polarized inflammation and presence of eosinophils. In lesions from this disease, MIG was detected in eosinophils by immunohistochemistry. Taken together, the results point to immunoregulatory roles for eosinophils during some diseases with Th1-polarized inflammation.
Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins
Authors: Moldenhauer Anja , Frank Richard C , Pinilla-Ibarz Javier , Holland Gudrun , Boccuni Piernicola , Scheinberg David A , Salama Abdulgabar , Seeger Karl , Moore Malcolm A S , Nimer Stephen D 
Published: June 2004

AbstractRecurrent cytogenetic abnormalities in leukemic blasts make these an attractive source for dendritic cells (DC) to induce a leukemia-specific immune response. In this study, three leukemic cell lines were investigated: Kasumi-1 and SKNO-1 (two acute myeloid leukemia (AML) cell lines carrying the (8;21)-chromosomal translocation, resulting in the expression of the leukemia-specific fusion protein AML1-eight-twenty-one) and REH, an acute lymphoblastic leukemia cell line with the (12;21)-chromosomal translocation and expression of translocation ETS-like leukemia-AML1. These fusion proteins are implicated in the pathogenesis of the leukemic state by recruiting corepressors and histone deacetylases (HDAC), which interfere with normal cell differentiation. In vitro generation of DC was achieved using a cytokine cocktail containing tumor necrosis factor α, granulocyte macrophage-colony stimulating factor, c-kit ligand, and soluble CD40 ligand; yet, addition of the HDAC inhibitor (Hdi) trichostatin A enhanced DC differentiation with retention of the fusion transcripts. These leukemic DC showed high-level CD83 and human leukocyte antigen (HLA)-DR expression and had a high allostimulatory potential. Only DC generated from these cell lines after Hdi induced blast-specific cytotoxic T cell responses in HLA-A-matched T cells with a cytotoxicity of 42% in parental Kasumi-1 and 83% in parental REH cells, respectively. This model system suggests that the Hdi supports the in vitro differentiation of DC from leukemic blasts with AML1-containing fusion proteins.
GPI-defective monocytes from paroxysmal nocturnal hemoglobinuria patients show impaired in vitro dendritic cell differentiation
Authors: Ruggiero Giuseppina , Terrazzano Giuseppe , Becchimanzi Cristina , Sica Michela , Andretta Claudia , Masci Anna Maria , Racioppi Luigi , Rotoli Bruno , Zappacosta Serafino , Alfinito Fiorella 
Published: June 2004

AbstractParoxysmal nocturnal hemoglobinuria (PNH) is a clonal, acquired hematopoietic disorder characterized by a phosphatidylinositol (PI) glycan-A gene mutation, which impairs the synthesis of the glycosyl-PI (GPI) anchor, thus causing the absence of all GPI-linked proteins on the membrane of the clonal-defective cells. The presence of a consistent GPI-defective monocyte compartment is a common feature in PNH patients. To investigate the functional behavior of this population, we analyzed its in vitro differentiation ability toward functional dendritic cells (DCs). Our data indicate that GPI-defective monocytes from PNH patients are unable to undergo full DC differentiation in vitro after granulocyte macrophage-colony stimulating factor and recombinant interleukin (IL)-4 treatment. In this context, the GPI-defective DC population shows mannose receptor expression, high levels of the CD86 molecule, and impaired CD1a up-regulation. The analysis of lipopolysaccharide and CD40-dependent, functional pathways in these DCs revealed a strong decrease in tumor necrosis factor α and IL-12 production. Finally, GPI-defective DCs showed a severe impairment in delivering accessory signals for T cell receptor-dependent T cell proliferation.
Distinct and overlapping roles of CXCR5 and CCR7 in B-1 cell homing and early immunity against bacterial pathogens
Authors: Höpken Uta E , Achtman Ariel H , Krüger Kerstin , Lipp Martin 
Published: June 2004

AbstractCXC chemokine receptor (CXCR)5 and CC chemokine receptor (CCR)7 are the major chemokine receptors required for B cell homing and microenvironmental localization during antigen-independent and -dependent B cell differentiation. Here, we show markedly decreased B-1 B cell numbers in the peritoneal cavity of CXCR5−/− and CXCR5−/−CCR7−/− double-deficient mice paralleled by reduced antigen-induced phosphorylcholine-specific immunoglobulin (Ig)M responses after intraperitoneal (i.p.) administration of streptococcal antigen. CCR7−/− mice lso revealed a partial reduction in peritoneal B-1 cell numbers combined with a reduced humoral response to i.p. injected bacterial antigen. However, opposite roles of CXCR5 and CCR7 were observed when the frequency of peritoneal B-2 cells was analyzed. CXCR5−/− mice almost completely lacked B-2 cells, whereas CCR7 deficiency engendered an increase in peritoneal B-2 cells. In addition, CCR7−/− mice had enhanced, splenic IgM+ plasma cell responses, whereas the extrafollicular B cell response of the CXCR5−/−mice was not significantly altered compared with wild-type controls. Thus, the two chemokine receptors exert divergent forces at multiple levels of the innate immune response. CXCR5 plays a dominant role in peritoneal B-1 B cell homing and body cavity immunity, but both chemokine receptors are needed for a proportional peritoneal B-2 cell homing and balanced development of an early splenic B cell response.
Abnormal Cytogenetics at Date of Morphologic Complete Remission Predicts Short Overall and Disease-Free Survival, and Higher Relapse Rate in Adult Acute Myeloid Leukemia: Results From Cancer and Leukemia Group B Study 8461
Authors: Marcucci Guido , Mrózek Krzysztof , Ruppert Amy S. , Archer Kellie J. , Pettenati Mark J. , Heerema Nyla A. , Carroll Andrew J. , Koduru Prasad R.K. , Kolitz Jonathan E. , Sterling Lisa J. , Edwards Colin G. , Anastasi John , Larson Richard A. , Bloomfield Clara D. 
Published: June 2004

Purpose As most patients with acute myeloid leukemia (AML) with morphologic complete remission (CR) ultimately relapse, better predictors for outcome are needed. Recently, Cheson et al suggested using cytogenetic remission (CRc) as part of the criteria for CR. To our knowledge, ours is the first relatively large study evaluating the usefulness of CRc attained immediately following induction chemotherapy. Patients and Methods We included AML patients treated on Cancer and Leukemia Group B front-line studies with cytogenetic samples obtained at diagnosis and at the first day of documented CR following induction. Patients with abnormal cytogenetics at diagnosis, and normal cytogenetics at CR (NCR; n = 103) were compared with those with abnormal cytogenetics both at diagnosis and at CR (ACR; n = 15) for overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR). Cox proportional hazards models determined the prognostic significance of cytogenetics at CR, adjusting for other covariates. Results Clinical features were similar for both groups, with the exception of favorable cytogenetics [t(8;21), inv(16)/t(16;16), t(15;17)] at diagnosis, which was more frequent (P = .03) in the NCR group. Median follow-up was 3.1 years (range, 1.0 to 11.4 years). ACR patients had significantly shorter OS (P = .006) and DFS (P = .0001), and higher CIR (P = .0001). In multivariable models, the NCR and ACR groups were predictors for OS (P = .03), DFS (P = .02), and CIR (P = .05). The relative risk of relapse or death was 2.1 times higher for ACR patients than for NCR patients (95% CI, 1.1 to 3.9). Conclusion Our data suggest that converting to normal karyotype at the time of first CR is an important prognostic indicator and support the use of CRc as a criterion of CR in AML.
Randomized Controlled Trial of the Role of Positron Emission Tomography in the Management of Stage I and II Non-Small-Cell Lung Cancer
Authors: Viney Rosalie C. , Boyer Michael J. , King Madeleine T. , Kenny Patricia M. , Pollicino Christine A. , McLean Jocelyn M. , McCaughan Brian C. , Fulham Michael J. 
Published: June 2004

Purpose Positron emission tomography (PET) is a costly new technology with potential to improve preoperative evaluation for patients with non–small-cell lung cancer (NSCLC). There is increasing pressure for PET to be included in standard diagnostic work-up before decisions about surgical management of NSCLC. The resource implications of its widespread use in staging NSCLC are significant. Methods A randomized controlled trial was conducted to investigate the impact of PET on clinical management and surgical outcomes for patients with stage I-II NSCLC. The primary hypothesis was that PET would reduce the proportion of patients with stage I-II NSCLC who underwent thoracotomy by at least 10% through identification of patients with inoperable disease. Results One hundred eighty-four patients with stage I-II NSCLC were recruited and randomly assigned; 92% had stage I disease. Following exclusion of one ineligible patient, 92 patients were assigned to no PET and 91 to PET. Compared with conventional staging, PET upstaged 22 patients, confirmed staging in 61 and staged two patients as benign. Stage IV disease was rarely detected (two patients). PET led to further investigation or a change in clinical management in 13% of patients and provided information that could have affected management in a further 13% of patients. There was no significant difference between the trial arms in the number of thoracotomies avoided (P = .2). Conclusion For patients who are carefully and appropriately staged as having stage I-II disease, PET provides potential for more appropriate stage-specific therapy but may not lead to a significant reduction in the number of thoracotomies avoided.