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Sample records for advanced stage b-cell

  1. Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin's lymphoma and diffuse large B-cell lymphoma: a systematic review

    DEFF Research Database (Denmark)

    Terasawa, T.; Lau, J.; Bardet, S.

    2009-01-01

    PURPOSE: To systematically review the prognostic accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) for interim response assessment of patients with untreated advanced-stage Hodgkin's lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL). METHODS: MEDLINE, EMBASE......, SCOPUS, and Biologic Abstracts were searched for relevant studies. Two assessors independently reviewed studies for inclusion and extracted data. Relevant unpublished data were requested from the investigators if unavailable from publications. A meta-analysis of the prognostic accuracy was performed....... RESULTS: Thirteen studies involving 360 advanced-stage HL patients and 311 DLBCL patients met our inclusion criteria. Advanced-stage HL studies included few unfavorable-risk patients. DLBCL studies were heterogeneous. FDG-PET had an overall sensitivity of 0.81 (95% CI, 0.72 to 0.89) and a specificity of 0...

  2. Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin's lymphoma and diffuse large B-cell lymphoma: a systematic review

    DEFF Research Database (Denmark)

    Terasawa, T.; Lau, J.; Bardet, S.

    2009-01-01

    -stage HL, FDG-PET performed after a few cycles of standard chemotherapy seems to be a reliable prognostic test to identify poor responders, warranting prospective studies to assess PET-based treatment strategies. For DLBCL, no reliable conclusions can be drawn due to heterogeneity. Interim PET remains......PURPOSE: To systematically review the prognostic accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) for interim response assessment of patients with untreated advanced-stage Hodgkin's lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL). METHODS: MEDLINE, EMBASE......, SCOPUS, and Biologic Abstracts were searched for relevant studies. Two assessors independently reviewed studies for inclusion and extracted data. Relevant unpublished data were requested from the investigators if unavailable from publications. A meta-analysis of the prognostic accuracy was performed...

  3. Recent advances in B-cell epitope prediction methods

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    2010-01-01

    Identification of epitopes that invoke strong responses from B-cells is one of the key steps in designing effective vaccines against pathogens. Because experimental determination of epitopes is expensive in terms of cost, time, and effort involved, there is an urgent need for computational methods for reliable identification of B-cell epitopes. Although several computational tools for predicting B-cell epitopes have become available in recent years, the predictive performance of existing tools remains far from ideal. We review recent advances in computational methods for B-cell epitope prediction, identify some gaps in the current state of the art, and outline some promising directions for improving the reliability of such methods. PMID:21067544

  4. Zebrafish B Cell Development without a Pre-B Cell Stage, Revealed by CD79 Fluorescence Reporter Transgenes.

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    Liu, Xingjun; Li, Yue-Sheng; Shinton, Susan A; Rhodes, Jennifer; Tang, Lingjuan; Feng, Hui; Jette, Cicely A; Look, A Thomas; Hayakawa, Kyoko; Hardy, Richard R

    2017-09-01

    CD79a and CD79b proteins associate with Ig receptors as integral signaling components of the B cell Ag receptor complex. To study B cell development in zebrafish, we isolated orthologs of these genes and performed in situ hybridization, finding that their expression colocalized with IgH-μ in the kidney, which is the site of B cell development. CD79 transgenic lines were made by linking the promoter and upstream regulatory segments of CD79a and CD79b to enhanced GFP to identify B cells, as demonstrated by PCR analysis of IgH-μ expression in sorted cells. We crossed these CD79-GFP lines to a recombination activating gene (Rag)2:mCherry transgenic line to identify B cell development stages in kidney marrow. Initiation of CD79:GFP expression in Rag2:mCherry + cells and the timing of Ig H and L chain expression revealed simultaneous expression of both IgH-μ- and IgL-κ-chains, without progressing through the stage of IgH-μ-chain alone. Rag2:mCherry + cells without CD79:GFP showed the highest Rag1 and Rag2 mRNAs compared with CD79a and CD79b:GFP + B cells, which showed strongly reduced Rag mRNAs. Thus, B cell development in zebrafish does not go through a Rag hi CD79 + IgH-μ + pre-B cell stage, different from mammals. After the generation of CD79:GFP + B cells, decreased CD79 expression occurred upon differentiation to Ig secretion, as detected by alteration from membrane to secreted IgH-μ exon usage, similar to in mammals. This confirmed a conserved role for CD79 in B cell development and differentiation, without the requirement of a pre-B cell stage in zebrafish. Copyright © 2017 by The American Association of Immunologists, Inc.

  5. Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferation, and survival of B cells.

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    Györy, Ildiko; Boller, Sören; Nechanitzky, Robert; Mandel, Elizabeth; Pott, Sebastian; Liu, Edison; Grosschedl, Rudolf

    2012-04-01

    The transcription factor Ebf1 is an important determinant of early B lymphopoiesis. To gain insight into the functions of Ebf1 at distinct stages of differentiation, we conditionally inactivated Ebf1. We found that Ebf1 is required for the proliferation, survival, and signaling of pro-B cells and peripheral B-cell subsets, including B1 cells and marginal zone B cells. The proliferation defect of Ebf1-deficient pro-B cells and the impaired expression of multiple cell cycle regulators are overcome by transformation with v-Abl. The survival defect of transformed Ebf1(fl/fl) pro-B cells can be rescued by the forced expression of the Ebf1 targets c-Myb or Bcl-x(L). In mature B cells, Ebf1 deficiency interferes with signaling via the B-cell-activating factor receptor (BAFF-R)- and B-cell receptor (BCR)-dependent Akt pathways. Moreover, Ebf1 is required for germinal center formation and class switch recombination. Genome-wide analyses of Ebf1-mediated gene expression and chromatin binding indicate that Ebf1 regulates both common and distinct sets of genes in early and late stage B cells. By regulating important components of transcription factor and signaling networks, Ebf1 appears to be involved in the coordination of cell proliferation, survival, and differentiation at multiple stages of B lymphopoiesis.

  6. Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferation, and survival of B cells

    OpenAIRE

    Györy, Ildiko; Boller, Sören; Nechanitzky, Robert; Mandel, Elizabeth; Pott, Sebastian; Liu, Edison; Grosschedl, Rudolf

    2012-01-01

    The transcription factor Ebf1 regulates early B lymphopoiesis by acting in a network with E2A and Pax5. However, the function of Ebf1 at later stages of differentiation in unclear. In this study, Grosschedl and colleagues investigate the role of Ebf1 in B lymphopoiesis by using conditional gene inactivation. The authors show that Ebf1 is required for proliferation and survival of pro-B and mature B cells. In addition, the proliferation defect of Ebf1fl/fl pro-B cells can be overcome by transf...

  7. Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development.

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    Lentucci, Claudia; Belkina, Anna C; Cederquist, Carly T; Chan, Michelle; Johnson, Holly E; Prasad, Sherry; Lopacinski, Amanda; Nikolajczyk, Barbara S; Monti, Stefano; Snyder-Cappione, Jennifer; Tanasa, Bogdan; Cardamone, M Dafne; Perissi, Valentina

    2017-02-17

    Non-proteolytic ubiquitin signaling mediated by Lys 63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNFα signaling and lipid metabolism in the adipose tissue through modulation of Lys 63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Enforced expression of the transcriptional coactivator OBF1 impairs B cell differentiation at the earliest stage of development.

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    Alain Bordon

    Full Text Available OBF1, also known as Bob.1 or OCA-B, is a B lymphocyte-specific transcription factor which coactivates Oct1 and Oct2 on B cell specific promoters. So far, the function of OBF1 has been mainly identified in late stage B cell populations. The central defect of OBF1 deficient mice is a severely reduced immune response to T cell-dependent antigens and a lack of germinal center formation in the spleen. Relatively little is known about a potential function of OBF1 in developing B cells. Here we have generated transgenic mice overexpressing OBF1 in B cells under the control of the immunoglobulin heavy chain promoter and enhancer. Surprisingly, these mice have greatly reduced numbers of follicular B cells in the periphery and have a compromised immune response. Furthermore, B cell differentiation is impaired at an early stage in the bone marrow: a first block is observed during B cell commitment and a second differentiation block is seen at the large preB2 cell stage. The cells that succeed to escape the block and to differentiate into mature B cells have post-translationally downregulated the expression of transgene, indicating that expression of OBF1 beyond the normal level early in B cell development is deleterious. Transcriptome analysis identified genes deregulated in these mice and Id2 and Id3, two known negative regulators of B cell differentiation, were found to be upregulated in the EPLM and preB cells of the transgenic mice. Furthermore, the Id2 and Id3 promoters contain octamer-like sites, to which OBF1 can bind. These results provide evidence that tight regulation of OBF1 expression in early B cells is essential to allow efficient B lymphocyte differentiation.

  9. The presence of local and circulating autoreactive B cells in patients with advanced periodontitis.

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    Berglundh, Tord; Liljenberg, Birgitta; Tarkowski, Andrej; Lindhe, Jan

    2002-04-01

    The aim of the present investigation was to study the local (gingival) and systemic occurrence of autoreactive B cells (CD5+CD19 positive) in subjects with a high or low susceptibility to periodontitis. 2 groups of subjects (Group A and B) susceptible to periodontitis were included. Group A consisted of 22 adult patients (7 females and 15 males, aged 24-66 years) with advanced and generalized chronic periodontitis and group B comprised 7 children (4 girls and 3 boys aged 9-13 years) with localized aggressive periodontitis. 26 periodontally healthy subjects, Group C (aged 23-80 years, mean 49.6+/-16.3), were also recruited. Assessment of clinical and radiographical characteristics of periodontal disease was performed. Gingival biopsies and peripheral blood samples were obtained and prepared for immunohistochemical analysis. Blood samples only were obtained from the periodontally healthy subjects (group C). The proportion of autoreactive B cells (CD5+CD19 positive) of peripheral blood lymphocytes was about 6 times higher in group A and 4 times higher in group B than in the samples from the control subjects (group C). About 40-50% of the B cells in the peripheral blood of the periodontitis susceptible individuals expressed markers for autoreactive features while less than 15% of the circulating B cells in the subjects of group C exhibited such markers. The periodontitis lesion in the adult periodontitis patients contained a substantial number of B cells out of which about 30% demonstrated autoreactive features. It is suggested that both circulating and local B cells in periodontitis susceptible individuals have a higher propensity to autoreactive properties than B cells of patients with a low susceptibility to periodontitis.

  10. B cells in chronic obstructive pulmonary disease: moving to center stage

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    Polverino, Francesca; Seys, Leen J. M.; Bracke, Ken R.

    2016-01-01

    Chronic inflammatory responses in the lungs contribute to the development and progression of chronic obstructive pulmonary disease (COPD). Although research studies focused initially on the contributions of the innate immune system to the pathogenesis of COPD, more recent studies have implicated adaptive immune responses in COPD. In particular, studies have demonstrated increases in B cell counts and increases in the number and size of B cell-rich lymphoid follicles in COPD lungs that correlate directly with COPD severity. There are also increases in lung levels of mediators that promote B cell maturation, activation, and survival in COPD patients. B cell products such as autoantibodies directed against lung cells, components of cells, and extracellular matrix proteins are also present in COPD lungs. These autoantibodies may contribute to lung inflammation and injury in COPD patients, in part, by forming immune complexes that activate complement components. Studies of B cell-deficient mice and human COPD patients have linked B cells most strongly to the emphysema phenotype. However, B cells have protective activities during acute exacerbations of COPD by promoting adaptive immune responses that contribute to host defense against pathogens. This review outlines the evidence that links B cells and B cell-rich lymphoid follicles to the pathogenesis of COPD and the mechanisms involved. It also reviews the potential and limitations of B cells as therapeutic targets to slow the progression of human COPD. PMID:27542809

  11. Structured reporting adds clinical value in primary CT staging of diffuse large B-cell lymphoma.

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    Schoeppe, Franziska; Sommer, Wieland H; Nörenberg, Dominik; Verbeek, Mareike; Bogner, Christian; Westphalen, C Benedikt; Dreyling, Martin; Rummeny, Ernst J; Fingerle, Alexander A

    2018-03-29

    To evaluate whether template-based structured reports (SRs) add clinical value to primary CT staging in patients with diffuse large B-cell lymphoma (DLBCL) compared to free-text reports (FTRs). In this two-centre study SRs and FTRs were acquired for 16 CT examinations. Thirty-two reports were independently scored by four haematologists using a questionnaire addressing completeness of information, structure, guidance for patient management and overall quality. The questionnaire included yes-no, 10-point Likert scale and 5-point scale questions. Altogether 128 completed questionnaires were evaluated. Non-parametric Wilcoxon signed-rank test and McNemar's test were used for statistical analysis. SRs contained information on affected organs more often than FTRs (95 % vs. 66 %). More SRs commented on extranodal involvement (91 % vs. 62 %). Sufficient information for Ann-Arbor classification was included in more SRs (89 % vs. 64 %). Information extraction was quicker from SRs (median rating on 10-point Likert scale=9 vs. 6; 7-10 vs. 4-8 interquartile range). SRs had better comprehensibility (9 vs. 7; 8-10 vs. 5-8). Contribution of SRs to clinical decision-making was higher (9 vs. 6; 6-10 vs. 3-8). SRs were of higher quality (p < 0.001). All haematologists preferred SRs over FTRs. Structured reporting of CT examinations for primary staging in patients with DLBCL adds clinical value compared to FTRs by increasing completeness of reports, facilitating information extraction and improving patient management. • Structured reporting in CT helps clinicians to assess patients with lymphoma. • This two-centre study showed that structured reporting improves information content and extraction. • Patient management may be improved by structured reporting. • Clinicians preferred structured reports over free-text reports.

  12. Routine use of ancillary investigations in staging diffuse large B-cell lymphoma improves the International Prognostic Index (IPI).

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    Talaulikar, Dipti; Shadbolt, Bruce; Dahlstrom, Jane E; McDonald, Anne

    2009-11-22

    The International Prognostic Index (IPI) is used to determine prognosis in diffuse large B-cell lymphoma (DLBCL). One of the determinants of IPI is the stage of disease with bone marrow involvement being classified as stage IV. For the IPI, involvement on bone marrow is traditionally defined on the basis of histology with ancillary investigations used only in difficult cases to aid histological diagnosis. This study aimed to determine the effect of the routine use of flow cytometry, immunohistochemistry and molecular studies in bone marrow staging upon the IPI. Bone marrow trephines of 156 histologically proven DLBCL cases at initial diagnosis were assessed on routine histology, and immunohistochemistry using two T-cell markers (CD45RO and CD3), two B-cell markers (CD20 and CD79a) and kappa and lambda light chains. Raw flow cytometry data on all samples were reanalysed and reinterpreted blindly. DNA extracted from archived paraffin-embedded trephine biopsy samples was used for immunoglobulin heavy chain and light chain gene rearrangement analysis. Using immunophenotyping (flow cytometry and immunohistochemistry), 30 (19.2%) cases were upstaged to stage IV. A further 8 (5.1%) cases were upstaged using molecular studies. A change in IPI was noted in 18 cases (11.5%) on immunophenotyping alone, and 22 (14.1%) cases on immunophenotyping and molecular testing. Comparison of two revised IPI models, 1) using immunophenotyping alone, and 2) using immunophenotyping with molecular studies, was performed with baseline IPI using a Cox regression model. It showed that the revised IPI model using immunophenotyping provides the best differentiation between the IPI categories. Improved bone marrow staging using flow cytometry and immunohistochemistry improves the predictive value of the IPI in patients with DLBCL and should be performed routinely in all cases.

  13. Significant elevation of B cells at the acute stage in enterovirus 71-infected children with central nervous system involvement.

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    Xie, Jing; Jiao, Yang; Qiu, Zhifeng; Li, Qihan; Li, Taisheng

    2010-12-01

    A feature of the large outbreak of human enterovirus 71 (EV71)-associated hand-foot-and-mouth (HFMD) disease in China in 2008 was that severe cases presented with encephalitis. This study was performed to evaluate the immunophenotypic characteristics of patients with neurological involvement. Twenty-one patients with encephalitis and 14 with uncomplicated HFMD were recruited. Age-matched healthy volunteers were enrolled as controls. Peripheral lymphocyte subsets were analyzed by use of 3-colour flow cytometry, and the quantitative determination of plasma immunoglobulin (Ig) levels was also monitored. Comparisons between severe and mild cases demonstrated significant elevations of B cells and IgG levels and corresponding general decreases in natural killer (NK) cells and T lymphocytes in severe cases at the acute stage of infection (p cells and IgG to the normal levels were observed, which appeared to be accompanied by an increase in EV71-specific neutralizing antibody titres. In summary, our data demonstrate that elevated B cells and IgG might be associated with neurological manifestations in EV71 infection.

  14. Advances in the role of cytogenetic analysis in the molecular diagnosis of B-cell lymphomas.

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    Grange, Béatrice; Callet-Bauchu, Evelyne; Salles, Gilles; Sujobert, Pierre

    2017-06-01

    Cytogenetic abnormalities represent essential determinants of diagnosis and prognosis in B-cell lymphomas. Their theranostic value is increasingly significant with the development of targeted therapies, in order to adapt the treatment at diagnosis as well as when relapse occurs. Areas covered: As the significance of these biomarkers is influenced by the technology used to detect them, an overview describing the strength and weakness of conventional and emerging technologies is provided. This review also updates the diverse cytogenetic abnormalities found in B-cell lymphomas, emphasizing their value in treatment decision. Expert commentary: Cytogenetics remains an essential analysis for the diagnostic work-up of lymphomas. As whole genome sequencing becomes more and more affordable routinely, the next challenge will be to recover all the information conveyed by conventional karyotype, including the analysis of the clonal architecture at the single cell level, in whole genome data.

  15. Distinct kinetics of memory B-cell and plasma-cell responses in peripheral blood following a blood-stage Plasmodium chabaudi infection in mice.

    Directory of Open Access Journals (Sweden)

    Eunice W Nduati

    2010-11-01

    Full Text Available B cell and plasma cell responses take place in lymphoid organs, but because of the inaccessibility of these organs, analyses of human responses are largely performed using peripheral blood mononuclear cells (PBMC. To determine whether PBMC are a useful source of memory B cells and plasma cells in malaria, and whether they reflect Plasmodium-specific B cell responses in spleen or bone marrow, we have investigated these components of the humoral response in PBMC using a model of Plasmodium chabaudi blood-stage infections in C57BL/6 mice. We detected memory B cells, defined as isotype-switched IgD(- IgM(- CD19(+ B cells, and low numbers of Plasmodium chabaudi Merozoite Surface Protein-1 (MSP1-specific memory B cells, in PBMC at all time points sampled for up to 90 days following primary or secondary infection. By contrast, we only detected CD138(+ plasma cells and MSP1-specific antibody-secreting cells within a narrow time frame following primary (days 10 to 25 or secondary (day 10 infection. CD138(+ plasma cells in PBMC at these times expressed CD19, B220 and MHC class II, suggesting that they were not dislodged bone-marrow long-lived plasma cells, but newly differentiated migratory plasmablasts migrating to the bone marrow; thus reflective of an ongoing or developing immune response. Our data indicates that PBMC can be a useful source for malaria-specific memory B cells and plasma cells, but extrapolation of the results to human malaria infections suggests that timing of sampling, particularly for plasma cells, may be critical. Studies should therefore include multiple sampling points, and at times of infection/immunisation when the B-cell phenotypes of interest are likely to be found in peripheral blood.

  16. Transcription factor miz-1 is required to regulate interleukin-7 receptor signaling at early commitment stages of B cell differentiation.

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    Kosan, Christian; Saba, Ingrid; Godmann, Maren; Herold, Stefanie; Herkert, Barbara; Eilers, Martin; Möröy, Tarik

    2010-12-14

    B cell development requires the coordinated action of transcription factors and cytokines, in particular interleukin-7 (IL-7). We report that mice lacking the POZ (Poxvirus and zinc finger) domain of the transcription factor Miz-1 (Zbtb17(ΔPOZ/ΔPOZ)) almost entirely lacked follicular B cells, as shown by the fact that their progenitors failed to activate the Jak-Stat5 pathway and to upregulate the antiapoptotic gene Bcl2 upon IL-7 stimulation. We show that Miz-1 exerted a dual role in the interleukin-7 receptor (IL-7R) pathway by directly repressing the Janus kinase (Jak) inhibitor suppressor of cytokine signaling 1 (Socs1) and by activating Bcl2 expression. Zbtb17(ΔPOZ/ΔPOZ) (Miz-1-deficient) B cell progenitors had low expression of early B cell genes as transcription factor 3 (Tcf3) and early B cell factor 1 (Ebf1) and showed a propensity for apoptosis. Only the combined re-expression of Bcl2 and Ebf1 could reconstitute the ability of Miz-1-deficient precursors to develop into CD19(+) B cells.

  17. Polyclonal B cell differentiation and loss of gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection.

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    Marc C Levesque

    2009-07-01

    Full Text Available The antibody response to HIV-1 does not appear in the plasma until approximately 2-5 weeks after transmission, and neutralizing antibodies to autologous HIV-1 generally do not become detectable until 12 weeks or more after transmission. Moreover, levels of HIV-1-specific antibodies decline on antiretroviral treatment. The mechanisms of this delay in the appearance of anti-HIV-1 antibodies and of their subsequent rapid decline are not known. While the effect of HIV-1 on depletion of gut CD4(+ T cells in acute HIV-1 infection is well described, we studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells.In human participants, we analyzed B cells in blood as early as 17 days after HIV-1 infection, and in terminal ileum inductive and effector microenvironments beginning at 47 days after infection. We found that HIV-1 infection rapidly induced polyclonal activation and terminal differentiation of B cells in blood and in gut-associated lymphoid tissue (GALT B cells. The specificities of antibodies produced by GALT memory B cells in acute HIV-1 infection (AHI included not only HIV-1-specific antibodies, but also influenza-specific and autoreactive antibodies, indicating very early onset of HIV-1-induced polyclonal B cell activation. Follicular damage or germinal center loss in terminal ileum Peyer's patches was seen with 88% of follicles exhibiting B or T cell apoptosis and follicular lysis.Early induction of polyclonal B cell differentiation, coupled with follicular damage and germinal center loss soon after HIV-1 infection, may explain both the high rate of decline in HIV-1-induced antibody responses and the delay in plasma antibody responses to HIV-1. Please see later in the article for Editors' Summary.

  18. Technical Advance: New in vitro method for assaying the migration of primary B cells using an endothelial monolayer as substrate.

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    Stewart-Hutchinson, Phillip J; Szasz, Taylor P; Jaeger, Emily R; Onken, Michael D; Cooper, John A; Morley, Sharon Celeste

    2017-09-01

    Migration of B cells supports their development and recruitment into functional niches. Therefore, defining factors that control B cell migration will lead to a better understanding of adaptive immunity. In vitro cell migration assays with B cells have been limited by poor adhesion of cells to glass coated with adhesion molecules. We have developed a technique using monolayers of endothelial cells as the substrate for B cell migration and used this technique to establish a robust in vitro assay for B cell migration. We use TNF-α to up-regulate surface expression of the adhesion molecule VCAM-1 on endothelial cells. The ligand VLA-4 is expressed on B cells, allowing them to interact with the endothelial monolayer and migrate on its surface. We tested our new method by examining the role of L-plastin (LPL), an F-actin-bundling protein, in B cell migration. LPL-deficient (LPL -/- ) B cells displayed decreased speed and increased arrest coefficient compared with wild-type (WT) B cells, following chemokine stimulation. However, the confinement ratios for WT and LPL -/- B cells were similar. Thus, we demonstrate how the use of endothelial monolayers as a substrate will support future interrogation of molecular pathways essential to B cell migration. © Society for Leukocyte Biology.

  19. Late stages of hematopoiesis and B cell lymphopoiesis are regulated by α-synuclein, a key player in Parkinson's disease.

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    Xiao, Wenbin; Shameli, Afshin; Harding, Clifford V; Meyerson, Howard J; Maitta, Robert W

    2014-11-01

    α-Synuclein plays a crucial role in Parkinson's disease and dementias defined as synucleinopathies. α-Synuclein is expressed in hematopoietic and immune cells, but its functions in hematopoiesis and immune responses are unknown. We utilized α-synuclein(-/-) (KO) mice to investigate its role in hematopoiesis and B cell lymphopoiesis. We demonstrated hematologic abnormalities including mild anemia, smaller platelets, lymphopenia but relatively normal early hematopoiesis in KO mice compared to wild-type (WT) as measured in hematopoietic stem cells and progenitors of the different cell lineages. However, the absolute number of B220(+)IgM(+) B cells in bone marrow was reduced by 4-fold in KO mice (WT: 104±23×10(5) vs. KO: 27±5×10(5)). B cells were also reduced in KO spleens associated with effacement of splenic and lymph node architecture. KO mice showed reduced total serum IgG but no abnormality in serum IgM was noted. When KO mice were challenged with a T cell-dependent antigen, production of antigen specific IgG1 and IgG2b was abolished, but antigen specific IgM was not different from WT mice. Our study shows hematologic abnormalities including anemia and smaller platelets, reduced B cell lymphopoiesis and defects in IgG production in the absence of α-synuclein. This is the first report to show an important role of α-synuclein late in hematopoiesis, B cell lymphopoiesis and adaptive immune response. Copyright © 2014 Elsevier GmbH. All rights reserved.

  20. Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy.

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    Elane Reyes-Avilés

    Full Text Available Approximately half of those with chronic hepatitis C virus (HCV infection have circulating rheumatoid factor (RF, and a portion of these individuals develop cryoglobulinemic vasculitis. B cell phenotype/function in relation to RF in serum has been unclear. We examined B cell subset distribution, activation state (CD86, cell cycle state (Ki67, and ex-vivo response to BCR, TLR9 and TLR7/8 stimulation, in chronic HCV-infected donors with or without RF, and uninfected donors. Mature-activated B-cells of HCV-infected donors had lower CD86 expression compared to uninfected donors, and in the presence of RF they also showed reduced CD86 expression in response to BCR and TLR9 stimulation. Additionally, mature activated memory B cells of HCV RF+ donors less commonly expressed Ki67+ than HCV RF- donors, and did not proliferate as well in response to BCR stimulation. Proportions of mature-activated B cells were enhanced, while naïve B-cells were lower in the peripheral blood of HCV-RF+ compared to RF- and uninfected donors. None of these parameters normalize by week 8 of IFN free direct acting antiviral (DAA therapy in HCV RF+ donors, while in RF- donors, mature activated B cell proportions did normalize. These data indicate that while chronic HCV infection alone results in a lower state of activation in mature activated memory B cells, the presence of RF in serum is associated with a more pronounced state of unresponsiveness and an overrepresentation of these B cells in the blood. This phenotype persists at least during the early time window after removal of HCV from the host.

  1. The international staging system improves the IPI risk stratification in patients with diffuse large B-cell lymphoma treated with R-CHOP.

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    Wei, Xiaolei; Hao, Xiaoxiao; Zhou, Lizhi; Wei, Qi; Zhang, Yuankun; Huang, Weimin; Song, Jialin; Feng, Ru; Wei, Yongqiang

    2017-10-19

    The international staging system (ISS), based on serum beta-2 microglobulin and albumin, is used to predict survival in multiple myeloma, but its prognostic significance in diffuse large B-cell lymphoma (DLBCL) remains unknown. Herein, we retrospectively analyzed 215 de novo DLBCL patients. According to ISS, there were 90 of 215 (41.9%) patients in stage I, 98 of 215 (45.6%) in stage II and 27 of 215 (12.6%) in stage III group. Patients with ISS stage II/III showed shorter overall survival (OS) and event free survival (EFS) than those with stage I treated with R-CHOP (p = 0.012 and p = 0.043, respectively), but not those treated with CHOP regimen (p > 0.05). Multivariable analysis revealed that ISS, independent of IPI, indicated different survival in both OS (HR, 5.690; 95% CI, 1.270-25.495, p = 0.023) and EFS (HR, 2.116; 95% CI, 1.005-4.455, p = 0.049) in DLBCL patients treated with R-CHOP. ISS could identify patients with better outcome in intermediate-high/high IPI risk patients (p IPI risk patients, which may help to avoid intensive therapy.

  2. Comparison of fluorine-18 fluorodeoxyglucose positron emission tomography with gallium-67 scintigraphy in the initial clinical staging of diffuse large B-cell lymphoma.

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    Sakurai, Masatoshi; Toyama, Takaaki; Kikuchi, Taku; Kato, Jun; Shimizu, Takayuki; Koda, Yuya; Karigane, Daiki; Yamane, Yusuke; Abe, Ryohei; Yamazaki, Rie; Nakazato, Tomonori; Nakahara, Tadaki; Jinzaki, Masahiro; Okamoto, Shinichiro; Mori, Takehiko

    2018-02-01

    Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has been recommended as a complementary tool for the staging of various malignancies, including malignant lymphoma. PET findings often shift patients to higher stages and may affect treatment outcomes. In this study, we retrospectively compared staging and treatment outcomes of newly diagnosed diffuse large B-cell lymphoma (DLBCL) assessed by PET (n = 153) or gallium-67 scintigraphy (Ga) (n = 95). In total, Ga upstaged two (2.1%) of 95 patients, whereas PET upstaged 13 (8.5%) of 153 patients. Bone/bone marrow (15 vs. 4%, P = 0.01) and muscle lesion (5 vs. 0%, P = 0.03) were identified more frequently in the PET group than in the Ga group. The estimated 3-year overall and progression-free survival rates did not differ significantly in the two groups at any stage. However, patients with stage III disease tended to have better progression-free survival in the PET group than in the Ga group [92.3 (95% CI 56.6-98.9%) vs. 58.3% (95% CI 27.0-80.1%), P = 0.086]. These results suggest that PET has a greater potential in detecting musculoskeletal lesions of DLBCL as extranodal lesions than Ga, and may contribute to the optimal staging.

  3. Dosimetric and Clinical Outcomes With Intensity Modulated Radiation Therapy After Chemotherapy for Patients With Early-Stage Diffuse Large B-cell Lymphoma of Waldeyer Ring

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    Xu, Yong-Gang; Qi, Shu-Nan; Wang, Shu-Lian; Liu, Yue-Ping; Wang, Wei-Hu; Jin, Jing; Song, Yong-Wen; Ren, Hua; Fang, Hui [Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); He, Xiao-Hui; Dong, Mei [Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Chen, Bo; Lu, Ning-Ning; Li, Ning; Tang, Yuan; Tang, Yu; Dai, Jian-Rong [Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Li, Ye-Xiong, E-mail: yexiong12@163.com [Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China)

    2016-10-01

    Purpose: To assess the dosimetric benefit, prognosis, and toxicity of intensity modulated radiation therapy (IMRT) for early-stage, diffuse large B-cell lymphoma of Waldeyer ring (WR-DLBCL). Methods and Materials: Sixty-one patients with early-stage WR-DLBCL who received chemotherapy followed by IMRT were retrospectively reviewed. Dosimetric parameters for the target volume and critical normal structures were evaluated, and survival was calculated. Linear regression analysis was used to assess the effect of the mean dose (D{sub mean}) to the parotid glands on xerostomia. Results: The median conformity index and homogeneity index of the planning target volume (PTV) were 0.83 and 0.90, respectively, demonstrating very good coverage of the target volume. The mean dose to the parotid glands was 24.9 Gy. The 5-year overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) were 94.7%, 93.1%, and 98.3%, respectively. Early and late toxicities were mild, and no patient experienced late grade ≥3 toxicities. The D{sub mean} to the parotid glands had a linear correlation with late grade ≥2 xerostomia. Conclusions: IMRT after chemotherapy can provide excellent dose conformity and achieve favorable survival and LRC with mild toxicities in patients with early-stage WR-DLBCL. Dose constraints for the parotid glands should be limited to <24 Gy for early-stage WR-DLBCL.

  4. Surgical treatment of advanced stage Freiberg disease

    Directory of Open Access Journals (Sweden)

    Emin Özkul

    2014-09-01

    Full Text Available Objective: Freiberg disesase is an avascular necrosis of the 2nd and 3rd metatarsal head and which kind of surgical option to be used is controversial in symptomatic patients. In this study the results of the advanced stage Freiberg’s disease patients, who were treated with surgery were evaluated. Methods: 12 patients (8 female, 4 male whose pain could not be solved with conservative method and underwent surgery (6 debridement, 3 osteotomy, 3 excision of the metatarsal head were included in this study. Themean age of the patients 19.1 (range 13- 31 and the mean follow-up 30.8(range 25-94 months. According to the Smillie classification 3 patients had type 5, 8 patients had type 4 and 1 patient had type 3 osteonecrosis. The results of the patients were evaluated according to Lesser Metatarsophalangeal-Interphalangeal Scale. Results: According to Lesser MetatarsophalangealInterphalangeal Scale 3 patients (%25 had excellent, 6 patients (%50 had good and 3 patients had poor results were obtained. 2 of 3 patients with poor results were type 5, and 1 patient was type 4 and all three patients underwent joint debridement. Conclusion:The method of surgical treatment of Freiberg disease determined according to the stage of the disease. Debridement alone in the treatment of patients with late stage is not enough, it should be combined with other methods.

  5. Cell- and stage-specific chromatin structure across the Complement receptor 2 (CR2/CD21) promoter coincide with CBF1 and C/EBP-beta binding in B cells.

    Science.gov (United States)

    Cruickshank, Mark N; Fenwick, Emily; Karimi, Mahdad; Abraham, Lawrence J; Ulgiati, Daniela

    2009-08-01

    Stringent developmental transcription requires multiple transcription factor (TF) binding sites, cell-specific expression of signaling molecules, TFs and co-regulators and appropriate chromatin structure. During B-lymphopoiesis, human Complement receptor 2 (CR2/CD21) is detected on immature and mature B cells but not on B cell precursors and plasma cells. We examined cell- and stage-specific human CR2 gene regulation using cell lines modeling B-lymphopoiesis. Chromatin accessibility assays revealed a region between -409 and -262 with enhanced accessibility in mature B cells and pre-B cells, compared to either non-lymphoid or plasma cell-types, however, accessibility near the transcription start site (TSS) was elevated only in CR2-expressing B cells. A correlation between histone acetylation and CR2 expression was observed, while histone H3K4 dimethylation was enriched near the TSS in both CR2-expressing B cells and non-expressing pre-B cells. Candidate sites within the CR2 promoter were identified which could regulate chromatin, including a matrix attachment region associated with CDP, SATB1/BRIGHT and CEBP-beta sites as well as two CBF1 sites. ChIP assays verified that both CBF1 and C/EBP-beta bind the CR2 promoter in B cells raising the possibility that these factors facilitate or respond to alterations in chromatin structure to control the timing and/or level of CR2 transcription.

  6. Additional Survival Benefit of Involved-Lesion Radiation Therapy After R-CHOP Chemotherapy in Limited Stage Diffuse Large B-Cell Lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Jeanny [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Kim, Il Han, E-mail: ihkim@snu.ac.kr [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Cancer Research Institute, Seoul National University College of Medicine, Seoul (Korea, Republic of); Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul (Korea, Republic of); Kim, Byoung Hyuck [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Kim, Tae Min; Heo, Dae Seog [Department of Internal Medicine, Seoul National University Hospital, Seoul (Korea, Republic of)

    2015-05-01

    Purpose: The purpose of this study was to evaluate the role of involved-lesion radiation therapy (ILRT) after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in limited stage diffuse large B-cell lymphoma (DLBCL) by comparing outcomes of R-CHOP therapy alone with R-CHOP followed by ILRT. Methods and Materials: We identified 198 patients treated with R-CHOP (median, 6 cycles) for pathologically confirmed DLBCL of limited stage from July 2004 to December 2012. Clinical characteristics of these patients were 33% with stage I and 66.7% with stage II; 79.8% were in the low or low-intermediate risk group; 13.6% had B symptoms; 29.8% had bulky tumors (≥7 cm); and 75.3% underwent ≥6 cycles of R-CHOP therapy. RT was given to 43 patients (21.7%) using ILRT technique, which included the prechemotherapy tumor volume with a median margin of 2 cm (median RT dose: 36 Gy). Results: After a median follow-up of 40 months, 3-year progression-free survival (PFS) and overall survival (OS) were 85.8% and 88.9%, respectively. Multivariate analysis showed ≥6 cycles of R-CHOP (PFS, P=.004; OS, P=.004) and ILRT (PFS, P=.021; OS, P=.014) were favorable prognosticators of PFS and OS. A bulky tumor (P=.027) and response to R-CHOP (P=.012) were also found to be independent factors of OS. In subgroup analysis, the effect of ILRT was prominent in patients with a bulky tumor (PFS, P=.014; OS, P=.030) or an elevated level of serum lactate dehydrogenase (LDH; PFS, P=.004; OS, P=.012). Conclusions: Our results suggest that ILRT after R-CHOP therapy improves PFS and OS in patients with limited stage DLBCL, especially in those with bulky disease or an elevated serum LDH level.

  7. Advances in the molecular diagnosis of diffuse large B-cell lymphoma in the era of precision medicine.

    Science.gov (United States)

    Araf, Shamzah; Korfi, Koorosh; Rahim, Tahrima; Davies, Andrew; Fitzgibbon, Jude

    2016-10-01

    The adoption of high-throughput technologies has led to a transformation in our ability to classify diffuse large B-cell lymphoma (DLBCL) into unique molecular subtypes. In parallel, the expansion of agents targeting key genetic and gene expression signatures has led to an unprecedented opportunity to personalize cancer therapies, paving the way for precision medicine. Areas covered: This review summarizes the key molecular subtypes of DLBCL and outlines the novel technology platforms in development to discriminate clinically relevant subtypes. Expert commentary: The application of emerging diagnostic tests into routine clinical practise is gaining momentum following the demonstration of subtype specific activity by novel agents. Co-ordinated efforts are required to ensure that these state of the art technologies provide reliable and clinically meaningful results accessible to the wider haematology community.

  8. Circulating sCD138 and Some Angiogenesis-Involved Cytokines Help to Anticipate the Disease Progression of Early-Stage B-Cell Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available Syndecan-1 (CD138 is a transmembrane heparin sulfate proteoglycan expressed on distinct stages of differentiation of B-lymphoid cells. Its prognostic value in B-cell chronic lymphocytic leukemia (B-CLL has not been evaluated so far. The serum concentration of sCD138 and some angiogenesis-involved cytokines: vascular endothelial growth factor (VEGF, basis fibroblast growth factor (bFGF, and endostatin were studied in 52 previously untreated patients with B-CLL. We found that bFGF and sCD138 levels were significantly higher in B-CLL patients than in controls. In patients with sCD138 level or endostatin level below the median value the lymphocyte count was higher than in patients with serum level of those cytokines above the median value. In patients with progressive disease bFGF level was significantly higher and sCD138 level significantly lower than in patients with stable one. Moreover, high sCD138 level was associated with longer lymphocyte doubling-free survival, and, on the limit of statistical significance, a high endostatin level was associated with shorter progression-free survival. We conclude that serum sCD138 level is increased in early stage B-CLL patients and may have a positive prognostic value as to the dynamics of the disease.

  9. Value of Surveillance Studies for Patients With Stage I to II Diffuse Large B-Cell Lymphoma in the Rituximab Era

    Energy Technology Data Exchange (ETDEWEB)

    Hiniker, Susan M.; Pollom, Erqi L. [Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California (United States); Khodadoust, Michael S. [Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford, California (United States); Kozak, Margaret M. [Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California (United States); Xu, Guofan; Quon, Andrew [Division of Nuclear Medicine, Department of Radiology, Stanford Cancer Institute, Stanford, California (United States); Advani, Ranjana H. [Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford, California (United States); Hoppe, Richard T., E-mail: rhoppe@stanford.edu [Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California (United States)

    2015-05-01

    Background: The role of surveillance studies in limited-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era has not been well defined. We sought to evaluate the use of imaging (computed tomography [CT] and positron emission tomography [PET]-CT) scans and lactate dehydrogenase (LDH) in surveillance of patients with stage I to II DLBCL. Methods: A retrospective analysis was performed of patients who received definitive treatment between 2000 and 2013. Results: One hundred sixty-two consecutive patients with stage I to II DLBCL were treated with chemotherapy +/− rituximab, radiation, or combined modality therapy. The 5-year rates of overall survival (OS) and freedom from progression (FFP) were 81.2% and 80.8%, respectively. Of the 162 patients, 124 (77%) were followed up with at least 1 surveillance PET scan beyond end-of-treatment scans; of those, 94 of 124 (76%) achieved a complete metabolic response on PET scan after completion of chemotherapy, and this was associated with superior FFP (P=.01, HR=0.3) and OS (P=.01, HR 0.3). Eighteen patients experienced relapse after initial response to therapy. Nine relapses were initially suspected by surveillance imaging studies (8 PET, 1 CT), and 9 were suspected clinically (5 by patient-reported symptoms and 4 by symptoms and physical examination). No relapses were detected by surveillance LDH. The median duration from initiation of treatment to relapse was 14.3 months among patients with relapses suspected by imaging, and 59.8 months among patients with relapses suspected clinically (P=.077). There was no significant difference in OS from date of first therapy or OS after relapse between patients whose relapse was suspected by imaging versus clinically. Thirteen of 18 patients underwent successful salvage therapy after relapse. Conclusions: A complete response on PET scan immediately after initial chemotherapy is associated with superior FFP and OS in stage I to II DLBCL. The use of PET scans as

  10. A single-institution retrospective analysis of outcomes for stage I-II primary mediastinal large B-cell lymphoma treated with immunochemotherapy with or without radiotherapy.

    Science.gov (United States)

    Binkley, Michael S; Hiniker, Susan M; Wu, Sharon; Natkunam, Yasodha; Mittra, Erik S; Advani, Ranjana H; Hoppe, Richard T

    2016-01-01

    As the optimal treatment for primary mediastinal large B-cell lymphoma (PMBCL) remains undefined, we evaluated outcomes of patients treated with standard and dose-intense rituximab-chemotherapy (R-CT) with and without radiotherapy (RT). We retrospectively identified 28 patients with stage I-II PMBCL in our lymphoma database, re-reviewed pathology slides and scored interim or post-chemotherapy PET/CTs using the Deauville scale. Fourteen patients received RT (36-45 Gy) preceded by either six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or 12 weeks of rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (R-VACOP-B) with median follow-up of 94 months. Fourteen patients received 4-8 cycles of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide and rituximab (DA-EPOCH-R) with median follow-up of 38 months; one of these received RT (36 Gy) due to post-chemotherapy PET/CT Deauville score 4. Following R-CT and RT or DA-EPOCH-R, 5-year and 3-year FFP and OS were both 100%. Both R-CHOP/R-VACOP-B with RT and DA-EPOCH-R demonstrate excellent outcomes.

  11. Intensity Modulated Radiation Therapy for Early-Stage Primary Gastric Diffuse Large B-Cell Lymphoma: Dosimetric Analysis, Clinical Outcome, and Quality of Life

    International Nuclear Information System (INIS)

    Liu, Xin; Fang, Hui; Tian, Yuan; Wang, Wei-Hu; Song, Yong-Wen; Wang, Shu-Lian; Liu, Yue-Ping; He, Xiao-Hui; Dong, Mei; Ren, Hua; Jin, Jing; Li, Ye-Xiong

    2016-01-01

    Purpose: To evaluate the dosimetric superiority, efficacy, toxicity, and quality of life (QOL) data of intensity modulated radiation therapy (IMRT) in patients with primary gastric diffuse large B-cell lymphoma (PG-DLBCL). Methods and Materials: Forty-six consecutive patients with early-stage PG-DLBCL underwent IMRT after chemotherapy. The majority of patients (61.5%) were subclassified as the non-germinal center B cell–like subtype. Dosimetric parameters of the planning target volume (PTV) and organs at risk were assessed. Survival rates were depicted with the Kaplan-Meier method and compared with the log-rank test. Quality of life was evaluated using the QLQ-C30-STO22 questionnaires at the last follow-up contact. Results: The median PTV mean dose was 41.6 Gy. Only 0.73% of the PTV received <95% of the prescribed dose, indicating excellent target coverage. The median kidney V20 and liver V30 were 14.1% and 16.1%, respectively. The 5-year overall survival (OS), progression-free survival, and locoregional control rates for all patients were 80.4%, 75.0%, and 93.2%, respectively. Stage, lactate dehydrogenase level, and immunophenotype were significant prognostic factors for OS, and only stage was a significant factor for locoregional control. Consolidation IMRT in patients with complete response after chemotherapy resulted in significantly better OS and progression-free survival than salvage IMRT in patients with non-complete response. Two of 8 patients who had chronic liver disease experienced grade 4 or grade 5 acute hepatic failure after 4 to 5 cycles of rituximab-based chemotherapy and IMRT (40 Gy). No other serious acute or late toxicity was observed. The long-term global and functional QOL scales were excellent, with negligible symptom scales. Conclusions: Intensity modulated radiation therapy yielded excellent target coverage and critical tissue sparing and achieved favorable outcomes with acceptable toxicity and good long-term QOL in early-stage PG-DLBCL.

  12. Intensity Modulated Radiation Therapy for Early-Stage Primary Gastric Diffuse Large B-Cell Lymphoma: Dosimetric Analysis, Clinical Outcome, and Quality of Life

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Xin; Fang, Hui; Tian, Yuan; Wang, Wei-Hu; Song, Yong-Wen; Wang, Shu-Lian; Liu, Yue-Ping [Department of Radiation Oncology, Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing (China); He, Xiao-Hui; Dong, Mei [Department of Medical Oncology, Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing (China); Ren, Hua; Jin, Jing [Department of Radiation Oncology, Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing (China); Li, Ye-Xiong, E-mail: yexiong@yahoo.com [Department of Radiation Oncology, Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing (China)

    2016-06-01

    Purpose: To evaluate the dosimetric superiority, efficacy, toxicity, and quality of life (QOL) data of intensity modulated radiation therapy (IMRT) in patients with primary gastric diffuse large B-cell lymphoma (PG-DLBCL). Methods and Materials: Forty-six consecutive patients with early-stage PG-DLBCL underwent IMRT after chemotherapy. The majority of patients (61.5%) were subclassified as the non-germinal center B cell–like subtype. Dosimetric parameters of the planning target volume (PTV) and organs at risk were assessed. Survival rates were depicted with the Kaplan-Meier method and compared with the log-rank test. Quality of life was evaluated using the QLQ-C30-STO22 questionnaires at the last follow-up contact. Results: The median PTV mean dose was 41.6 Gy. Only 0.73% of the PTV received <95% of the prescribed dose, indicating excellent target coverage. The median kidney V20 and liver V30 were 14.1% and 16.1%, respectively. The 5-year overall survival (OS), progression-free survival, and locoregional control rates for all patients were 80.4%, 75.0%, and 93.2%, respectively. Stage, lactate dehydrogenase level, and immunophenotype were significant prognostic factors for OS, and only stage was a significant factor for locoregional control. Consolidation IMRT in patients with complete response after chemotherapy resulted in significantly better OS and progression-free survival than salvage IMRT in patients with non-complete response. Two of 8 patients who had chronic liver disease experienced grade 4 or grade 5 acute hepatic failure after 4 to 5 cycles of rituximab-based chemotherapy and IMRT (40 Gy). No other serious acute or late toxicity was observed. The long-term global and functional QOL scales were excellent, with negligible symptom scales. Conclusions: Intensity modulated radiation therapy yielded excellent target coverage and critical tissue sparing and achieved favorable outcomes with acceptable toxicity and good long-term QOL in early-stage PG-DLBCL.

  13. Addition of Rice Bran Arabinoxylan to Curcumin Therapy May Be of Benefit to Patients With Early-Stage B-Cell Lymphoid Malignancies (Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Stage 0/1 Chronic Lymphocytic Leukemia)

    Science.gov (United States)

    Golombick, Terry; Diamond, Terrence H.; Manoharan, Arumugam; Ramakrishna, Rajeev

    2016-01-01

    Hypothesis. Prior studies on patients with early B-cell lymphoid malignancies suggest that early intervention with curcumin may lead to delay in progressive disease and prolonged survival. These patients are characterized by increased susceptibility to infections. Rice bran arabinoxylan (Ribraxx) has been shown to have immunostimulatory, anti-inflammatory, and proapoptotic effects. We postulated that addition of Ribraxx to curcumin therapy may be of benefit. Study design. Monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) or stage 0/1 chronic lymphocytic leukemia (CLL) patients who had been on oral curcumin therapy for a period of 6 months or more were administered both curcumin (as Curcuforte) and Ribraxx. Methods. Ten MGUS/SMM patients and 10 patients with stage 0/1 CLL were administered 6 g of curcumin and 2 g Ribraxx daily. Blood samples were collected at baseline and at 2-month intervals for a period of 6 months, and various markers were monitored. MGUS/SMM patients included full blood count (FBC); paraprotein; free light chains/ratio; C-reactive protein (CRP)and erythrocyte sedimentation rate (ESR); B2 microglobulin and immunological markers. Markers monitored for stage 0/1 CLL were FBC, CRP and ESR, and immunological markers. Results. Of 10 MGUS/SMM patients,5 (50%) were neutropenic at baseline, and the Curcuforte/Ribraxx combination therapy showed an increased neutrophil count, varying between 10% and 90% among 8 of the 10 (80%) MGUS/SMM patients. An additional benefit of the combination therapy was the potent effect in reducing the raised ESR in 4 (44%) of the MGUS/SMM patients. Conclusion. Addition of Ribraxx to curcumin therapy may be of benefit to patients with early-stage B-cell lymphoid malignancies. PMID:27154182

  14. Human Memory B Cells in Healthy Gingiva, Gingivitis, and Periodontitis.

    Science.gov (United States)

    Mahanonda, Rangsini; Champaiboon, Chantrakorn; Subbalekha, Keskanya; Sa-Ard-Iam, Noppadol; Rattanathammatada, Warattaya; Thawanaphong, Saranya; Rerkyen, Pimprapa; Yoshimura, Fuminobu; Nagano, Keiji; Lang, Niklaus P; Pichyangkul, Sathit

    2016-08-01

    The presence of inflammatory infiltrates with B cells, specifically plasma cells, is the hallmark of periodontitis lesions. The composition of these infiltrates in various stages of homeostasis and disease development is not well documented. Human tissue biopsies from sites with gingival health (n = 29), gingivitis (n = 8), and periodontitis (n = 21) as well as gingival tissue after treated periodontitis (n = 6) were obtained and analyzed for their composition of B cell subsets. Ag specificity, Ig secretion, and expression of receptor activator of NF-κB ligand and granzyme B were performed. Although most of the B cell subsets in healthy gingiva and gingivitis tissues were CD19(+)CD27(+)CD38(-) memory B cells, the major B cell component in periodontitis was CD19(+)CD27(+)CD38(+)CD138(+)HLA-DR(low) plasma cells, not plasmablasts. Plasma cell aggregates were observed at the base of the periodontal pocket and scattered throughout the gingiva, especially apically toward the advancing front of the lesion. High expression of CXCL12, a proliferation-inducing ligand, B cell-activating factor, IL-10, IL-6, and IL-21 molecules involved in local B cell responses was detected in both gingivitis and periodontitis tissues. Periodontitis tissue plasma cells mainly secreted IgG specific to periodontal pathogens and also expressed receptor activator of NF-κB ligand, a bone resorption cytokine. Memory B cells resided in the connective tissue subjacent to the junctional epithelium in healthy gingiva. This suggested a role of memory B cells in maintaining periodontal homeostasis. Copyright © 2016 by The American Association of Immunologists, Inc.

  15. Enhanced therapeutic effect of APAVAC immunotherapy in combination with dose-intense chemotherapy in dogs with advanced indolent B-cell lymphoma.

    Science.gov (United States)

    Marconato, L; Stefanello, D; Sabattini, S; Comazzi, S; Riondato, F; Laganga, P; Frayssinet, P; Pizzoni, S; Rouquet, N; Aresu, L

    2015-09-22

    The aim of this non-randomized controlled trial was to compare time to progression (TTP), lymphoma-specific survival (LSS), and safety of an autologous vaccine (consisting of hydroxyapatite ceramic powder and Heat Shock Proteins purified from the dogs' tumors, HSPPCs-HA) plus chemotherapy versus chemotherapy alone in dogs with newly diagnosed, clinically advanced, histologically confirmed, multicentric indolent B-cell lymphoma. The vaccine was prepared from dogs' resected lymph nodes and administered as an intradermal injection. Forty-five client-owned dogs were enrolled: 20 dogs were treated with dose-intense chemotherapy, and 25 received concurrent immunotherapy. Both treatment arms were well tolerated, with no exacerbated toxicity in dogs also receiving the vaccine. TTP was significantly longer for dogs treated with chemo-immunotherapy versus those receiving chemotherapy only (median, 209 versus 85 days, respectively, P=0.015). LSS was not significantly different between groups: dogs treated with chemo-immunotherapy had a median survival of 349 days, and those treated with chemotherapy only had a median survival of 200 days (P=0.173). Among vaccinated dogs, those mounting an immune response had a significantly longer TTP and LSS than those with no detectable response (P=0.012 and P=0.003, respectively). Collectively these results demonstrate that vaccination with HSPPCs-HA may produce clinical benefits with no increased toxicity, thereby providing a strategy for enhancing chemotherapy in dogs with advanced indolent lymphoma. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Blood stage Plasmodium falciparum antigens induce T cell independent immunoglobulin production via B cell activation factor of the TNF family (BAFF) pathway.

    Science.gov (United States)

    Kumsiri, Ratchanok; Potup, Pachuen; Chotivanich, Kesinee; Petmitr, Songsak; Kalambaheti, Thareerat; Maneerat, Yaowapa

    2010-12-01

    T independent (TI) antigens (Ags) activate monocytes to produce a cytokine, termed B cell activation factor (BAFF), involved in immunoglobulin (Ig) production. This study aimed to investigate whether the soluble schizont fraction of Plasmodium falciparum antigen (sPfAg) and hemozoin (HZ) could act as TI Ag to induce P. falciparum (Pf) specific Ig production via BAFF pathway. Co-cultures of monocytes and naïve B cells from 6 healthy donors were stimulated with sPfAg (10mg/ml) or HZ (10μM). At interval times, the expressions of BAFF on activated monocytes, BAFF receptor (BAFF-R) and proliferation nuclear Ag in activated B cells were determined by flow cytometry. The soluble BAFF (sBAFF), total and specific IgG levels in the supernatants were assessed by enzyme-linked immunosorbent assay (ELISA). The finding revealed both sPfAg and HZ could activate monocytes to express BAFF on surface and release sBAFF in the supernatant within 72h of stimulation. The B cells responded to specific activation, indicated by BAFF-R expression on the surface within 72h, marked proliferation on day 7, and final production of total and specific IgG during days 7-12. Comparing to sPfAg, HZ stimulated monocyte and B cell co-culture to express higher levels of BAFF and sBAFF during 24-48h, more BAFF-R on HZ activated B cells within 24h and induced marked proliferation of B cells with higher Pf specific IgG level. However, stimulation with sPfAg showed a more significant correlation between BAFF expression on the activated monocytes at 72h and the Pf specific IgG level on day 12 (r=0.961, p=0.039, Pearson Correlation). In conclusion, it is possible that both sPfAg and HZ stimulated B cells to produce specific IgG with BAFF involvement. Copyright © 2010 Elsevier B.V. All rights reserved.

  17. Does Radiation Have a Role in Advanced Stage Hodgkin’s or Non-Hodgkin Lymphoma?

    DEFF Research Database (Denmark)

    Specht, Lena

    2016-01-01

    Radiation therapy (RT) is one of the most effective agents available in the treatment of lymphomas. However, it is a local treatment, and today, with systemic treatments assuming a primary role for induction of response, RT is primarily used for consolidation. For advanced stage lymphomas...... treatment of larger and anatomically more challenging target volumes with much less radiation to normal tissues and consequently much lower risks of long-term complications. The modern concept of involved site radiation therapy (ISRT) has now been accepted as standard in lymphomas. In advanced Hodgkin...... type, the diffuse large B cell lymphoma (DLBCL). In patients treated with modern immunochemotherapy, RT to initial bulky disease or extralymphatic involvement is beneficial. For both HL and aggressive NHL, RT to residual masses after systemic treatment is of benefit. The role of PET in the evaluation...

  18. Late stages of hematopoiesis and B cell lymphopoiesis are regulated by α-synuclein, a key player in Parkinson’s disease

    OpenAIRE

    Xiao, Wenbin; Shameli, Afshin; Harding, Clifford V.; Meyerson, Howard J.; Maitta, Robert W.

    2014-01-01

    α-synuclein plays a crucial role in Parkinson’s disease and dementias defined as synucleinopathies. α-synuclein is expressed in hematopoietic and immune cells, but its functions in hematopoiesis and immune responses are unknown. We utilized α-synuclein−/− (KO) mice to investigate its role in hematopoiesis and B cell lymphopoiesis. We demonstrated hematologic abnormalities including mild anemia, smaller platelets, lymphopenia but relatively normal early hematopoiesis in KO mice compared to wil...

  19. Specific Antibody Production by Blood B Cells is Retained in Late Stage Drug-naïve HIV-infected Africans

    Directory of Open Access Journals (Sweden)

    Lydie Béniguel

    2004-01-01

    Full Text Available Unseparated peripheral blood mononuclear cells (PBMCs obtained from drug-naïve African individuals living in a context of multi-infections and presenting with high viral load (VL, were cultured in vitro and tested for their ability to produce antibodies (Abs reacting with HIV-1 antigens. Within these PBMCs, circulating B cells were differentiated in vitro and produced IgG Abs against not only ENV, but also GAG and POL proteins. Under similar experimental conditions, HAART treated patients produced Abs to ENV proteins only. The in vitro antibody production by drug-naïve individuals' PBMCs depended on exogenous cytokines (IL-2 and IL-10 but neither on the re-stimulation of reactive cells in cultures by purified HIV-1-gp 160 antigen nor on the re-engagement of CD40 surface molecules. Further, it was not abrogated by the addition of various monoclonal Abs (mAbs to co-stimulatory molecules. This suggests that the in vitro antibody production by drug-naïve individuals' PBMCs resulted from the maturation of already envelope and core antigen-primed, differentiated B cells, presumably pre-plasma cells, which are not known to circulate at homeostasy. As in vitro produced Abs retained the capacity of binding antigen and forming complexes, this study provides pre-clinical support for functional humoral responses despite major HIV- and other tropical pathogen-induced B cell perturbations.

  20. A comparison of tumor motion characteristics between early stage and locally advanced stage lung cancers

    International Nuclear Information System (INIS)

    Yu, Z. Henry; Lin, Steven H.; Balter, Peter; Zhang Lifei; Dong Lei

    2012-01-01

    Purpose: With the increasing use of conformal radiation therapy methods for non-small cell lung cancer (NSCLC), it is necessary to accurately determine respiratory-induced tumor motion. The purpose of this study is to analyze and compare the motion characteristics of early and locally advanced stage NSCLC tumors in a large population and correlate tumor motion with position, volume, and diaphragm motion. Methods and materials: A total of 191 (94 early stage, 97 locally advanced) non-small cell lung tumors were analyzed for this study. Each patient received a four-dimensional CT scan prior to receiving radiation treatment. A soft-tissue-based rigid registration algorithm was used to track the tumor motion. Tumor volumes were determined based on the gross tumor volume delineated by physicians in the end of expiration phase. Tumor motion characteristics were correlated with their standardized tumor locations, lobe location, and clinical staging. Diaphragm motion was calculated by subtracting the diaphragm location between the expiration and the inspiration phases. Results: Median, max, and 95th percentile of tumor motion for early stage tumors were 5.9 mm, 31.0 mm, and 20.0 mm, which were 1.2 mm, 12 mm, and 7 mm more than those in locally advanced NSCLC, respectively. The range of motion at 95th percentile is more than 50% larger in early stage lung cancer group than in the locally advanced lung cancer group. Early stage tumors in the lower lobe showed the largest motion with a median motion of 9.2 mm, while upper/mid-lobe tumors exhibited a median motion of 3.3 mm. Tumor volumes were not correlated with motion. Conclusion: The range of tumor motion differs depending on tumor location and staging of NSCLC. Early stage tumors are more mobile than locally advanced stage NSCLC. These factors should be considered for general motion management strategies when 4D simulation is not performed on individual basis.

  1. Does Radiation Have a Role in Advanced Stage Hodgkin's or Non-Hodgkin Lymphoma?

    Science.gov (United States)

    Specht, Lena

    2016-01-01

    Radiation therapy (RT) is one of the most effective agents available in the treatment of lymphomas. However, it is a local treatment, and today, with systemic treatments assuming a primary role for induction of response, RT is primarily used for consolidation. For advanced stage lymphomas, the indications for the use of RT have been questioned and debated, and proper randomized evidence is sparse. RT has significant long-term side effects, and the very extended RT fields of the past yielded unacceptable toxicity in many patients. Modern advanced imaging and conformal RT techniques now enable treatment of larger and anatomically more challenging target volumes with much less radiation to normal tissues and consequently much lower risks of long-term complications. The modern concept of involved site radiation therapy (ISRT) has now been accepted as standard in lymphomas. In advanced Hodgkin lymphoma (HL), RT to residual disease and/or initial bulk benefits some patients, depending on the chemotherapy regimen used. The more intensive the chemotherapy regimen, the fewer patients benefit from RT. In advanced aggressive non-Hodgkin lymphoma (NHL), most of the evidence comes from the most common type, the diffuse large B cell lymphoma (DLBCL). In patients treated with modern immunochemotherapy, RT to initial bulky disease or extralymphatic involvement is beneficial. For both HL and aggressive NHL, RT to residual masses after systemic treatment is of benefit. The role of PET in the evaluation and indication for RT to residual masses has not been tested in randomized trials. In advanced indolent NHL, very low dose RT offers excellent palliation with very few side effects. Modern RT in advanced lymphomas warrants further evaluation in randomized trials.

  2. Transcriptional circuits in B cell transformation.

    Science.gov (United States)

    Hu, Yeguang; Yoshida, Toshimi; Georgopoulos, Katia

    2017-07-01

    Loss of IKAROS in committed B cell precursors causes a block in differentiation while at the same time augments aberrant cellular properties, such as bone marrow stromal adhesion, self-renewal and resistance to glucocorticoid-mediated cell death. B cell acute lymphoblastic leukaemias originating from these early stages of B cell differentiation and associated with IKAROS mutations share a high-risk cellular phenotype suggesting that deregulation of IKAROS-based mechanisms cause a highly malignant disease process. Recent studies show that IKAROS is critical for the activity of super-enhancers at genes required for pre-B cell receptor (BCR) signalling and differentiation, working either downstream of or in parallel with B cell master regulators such as EBF1 and PAX5. IKAROS also directly represses a cryptic regulatory network of transcription factors prevalent in mesenchymal and epithelial precursors that includes YAP1, TEAD1/2, LHX2 and LMO2, and their targets, which are not normally expressed in lymphocytes. IKAROS prevents not only expression of these 'extra-lineage' transcription factors but also their cooperation with endogenous B cell master regulators, such as EBF1 and PAX5, leading to the formation of a de novo for lymphocytes super-enhancer network. IKAROS coordinates with the Polycomb repression complex (PRC2) to provide stable repression of associated genes during B cell development. However, induction of regulatory factors normally repressed by IKAROS starts a feed-forward loop that activates de-novo enhancers and elevates them to super-enhancer status, thereby diminishing PRC2 repression and awakening aberrant epithelial-like cell properties in B cell precursors. Insight into IKAROS-based transcriptional circuits not only sets new paradigms for cell differentiation but also provides new approaches for classifying and treating high-risk human B-ALL that originates from these early stages of B cell differentiation.

  3. The value of routine bone marrow biopsy in patients with diffuse large B-cell lymphoma staged with PET/CT

    DEFF Research Database (Denmark)

    Alzahrani, M; El-Galaly, T C; Hutchings, M

    2016-01-01

    value 91%. Concordant histological involvement of the BM by DLBCL was associated with worse overall survival and progression-free survival than discordant or no involvement in univariate and multivariate analyses. CONCLUSIONS: In patients with DLBCL, staging PET/CT can miss BM involvement...

  4. Improved Survival With Radiation Therapy in Stage I-II Primary Mediastinal B Cell Lymphoma: A Surveillance, Epidemiology, and End Results Database Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Jackson, Matthew W., E-mail: matthew.jackson@ucdenver.edu [Department of Radiation Oncology, University of Colorado Cancer Center, Aurora, Colorado (United States); Rusthoven, Chad G.; Jones, Bernard L. [Department of Radiation Oncology, University of Colorado Cancer Center, Aurora, Colorado (United States); Kamdar, Manali [Department of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado (United States); Rabinovitch, Rachel [Department of Radiation Oncology, University of Colorado Cancer Center, Aurora, Colorado (United States)

    2016-01-01

    Background: Primary mediastinal B cell lymphoma (PMBCL) is an uncommon lymphoma for which trials are few with small patient numbers. The role of radiation therapy (RT) after standard immunochemotherapy for early-stage disease has never been studied prospectively. We used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate PMBCL and the impact of RT on outcomes. Methods and Materials: We queried the SEER database for patients with stage I-II PMBCL diagnosed from 2001 to 2011. Retrievable data included age, gender, race (white/nonwhite), stage, extranodal disease, year of diagnosis, and use of RT as a component of definitive therapy. Kaplan-Meier overall survival (OS) estimates, univariate (UVA) log-rank and multivariate (MVA) Cox proportional hazards regression analyses were performed. Results: Two hundred fifty patients with stage I-II disease were identified, with a median follow-up time of 39 months (range, 3-125 months). The median age was 36 years (range, 18-89 years); 61% were female; 76% were white; 45% had stage I disease, 60% had extranodal disease, and 55% were given RT. The 5-year OS for the entire cohort was 86%. On UVA, OS was improved with RT (hazard ratio [HR] 0.446, P=.029) and decreased in association with nonwhite race (HR 2.70, P=.006). The 5-year OS was 79% (no RT) and 90% (RT). On MVA, white race and RT remained significantly associated with improved OS (P=.007 and .018, respectively). The use of RT decreased over time: 61% for the 67 patients whose disease was diagnosed from 2001 to 2005 and 53% in the 138 patients treated from 2006 to 2010. Conclusion: This retrospective population-based analysis is the largest PMBCL dataset to date and demonstrates a significant survival benefit associated with RT. Nearly half of patients treated in the United States do not receive RT, and its use appears to be declining. In the absence of phase 3 data, the use of RT should be strongly considered for its survival benefit in early-stage

  5. A p53 defect sensitizes various stages of B cell development to lymphomagenesis in mice carrying an IgH 3' regulatory region-driven c-myc transgene.

    Science.gov (United States)

    Fiancette, Rémi; Rouaud, Pauline; Vincent-Fabert, Christelle; Laffleur, Brice; Magnone, Virginie; Cogné, Michel; Denizot, Yves

    2011-12-01

    Although c-myc is classically described as the driving oncogene in Burkitt's lymphoma (BL), deregulation and mutations of c-myc have been reported in multiple solid tumors and in other mature B cell malignancies such as mantle cell lymphoma (MCL), myeloma, and plasma cell lymphoma (PCL). After translocation into the IgH locus, c-myc is constitutively expressed under the control of active IgH enhancers. Those located in the IgH 3' regulatory region (3'RR) are master control elements of class switch recombination and of the transcriptional burst associated with plasma cell differentiation. c-myc-3'RR mice are prone to lymphomas with rather homogeneous, most often BL-like, phenotypes with incomplete penetrance (75% tumor incidence) and long latencies (10-12 mo). To reproduce c-myc-induced mature B cell lymphomagenesis in the context of an additional defect often observed in human lymphomas, we intercrossed c-myc-3'RR with p53(+/-) mice. Double transgenic c-myc-3'RR/p53(+/-) mice developed lymphoma with short latency (2-4 mo) and full penetrance (100% tumor incidence). The spectrum of B lymphomas occurring in c-myc-3'RR/p53(+/-) mice was widened, including nonactivated (CD43(-)) BL, activated (CD43(+)) BL, MCL-like lymphoma, and PCL, thus showing that 3'RR-mediated deregulation of c-myc can promote various types of B lymphoproliferation in cells that first acquired a p53 defect. c-myc/p53(+/-) mice closely reproduce many features of BL, MCL, and PCL and provide a novel and efficient model to dissect the molecular events leading to c-myc-induced lymphomagenesis and an important tool to test potential therapeutic agents on malignant B cells featuring various maturation stages.

  6. Lipid rafts and B cell signaling.

    Science.gov (United States)

    Gupta, Neetu; DeFranco, Anthony L

    2007-10-01

    B cells comprise an essential component of the humoral immune system. They are equipped with the unique ability to synthesize and secrete pathogen-neutralizing antibodies, and share with professional antigen presenting cells the ability to internalize foreign antigens, and process them for presentation to helper T cells. Recent evidence indicates that specialized cholesterol- and glycosphingolipid-rich microdomains in the plasma membrane commonly referred to as lipid rafts, serve to compartmentalize key signaling molecules during the different stages of B cell activation including B cell antigen receptor (BCR)-initiated signal transduction, endocytosis of BCR-antigen complexes, loading of antigenic peptides onto MHC class II molecules, MHC-II associated antigen presentation to helper T cells, and receipt of helper signals via the CD40 receptor. Here we review the recent literature arguing for a role of lipid rafts in the spatial organization of B cell function.

  7. Advanced Low-Noise Research Fan Stage Design

    Science.gov (United States)

    Neubert, Robert; Bock, Larry; Malmborg, Eric; Owen-Peer, William

    1997-01-01

    This report describes the design of the Advanced Low-Noise Research Fan stage. The fan is a variable pitch design, which is designed at the cruise pitch condition. Relative to the cruise setting, the blade is closed at takeoff and opened for reverse thrust operation. The fan stage is a split flow design with fan exit guide vanes (FEGVs) and core stators. The fan stage design is combined with a nacelle and engine core duct to form a powered fan/nacelle subscale model. This model is intended for use in combined aerodynamic, acoustic, and structural testing in a wind tunnel. The fan has an outer diameter of 22 in. and a hub-to-tip of 0.426 in., which allows the use of existing NASA fan and cowl force balance and rig drive systems. The design parameters were selected to permit valid acoustic and aerodynamic comparisons with the Pratt & Whitney (P&W) 17- and 22-in. rigs previously tested under NASA contract. The fan stage design is described in detail. The results of the design axisymmetric and Navier-Stokes aerodynamic analysis are presented at the critical design conditions. The structural analysis of the fan rotor and attachment is included. The blade and attachment are predicted to have adequate low-cycle fatigue life and an acceptable operating range without resonant stress or flutter. The stage was acoustically designed with airfoil counts in the FEGV and core stator to minimize noise. A fan/FEGV tone analysis developed separately under NASA contract was used to determine the optimum airfoil counts. The fan stage was matched to the existing nacelle, designed under the previous P&W low-noise contract, to form a fan/nacelle model for wind tunnel testing. It is an axisymmetric nacelle for convenience in testing and analysis. Previous testing confirmed that the nacelle performed as required at various aircraft operating conditions.

  8. Radiation Therapy Administration and Survival in Stage I/II Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue

    Energy Technology Data Exchange (ETDEWEB)

    Olszewski, Adam J., E-mail: adam_olszewski@brown.edu; Desai, Amrita

    2014-03-01

    Purpose: To determine the factors associated with the use of radiation therapy and associated survival outcomes in early-stage marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT). Methods and Materials: We extracted data on adult patients with stage I/II MALT lymphoma diagnoses between 1998 and 2010 recorded in the Surveillance, Epidemiology, and End Results (SEER) database. We studied factors associated with radiation therapy administration in a logistic regression model and described the cumulative incidence of lymphoma-related death (LRD) according to receipt of the treatment. The association of radiation therapy with survival was explored in multivariate models with adjustment for immortal time bias. Results: Of the 7774 identified patients, 36% received radiation therapy as part of the initial course of treatment. Older patients; black or Hispanic men; white, Hispanic, and black women; and socioeconomically disadvantaged and underinsured patients had a significantly lower chance of receiving radiation therapy. Radiation therapy administration was associated with a lower chance of LRD in most sites. In cutaneous, ocular, and salivary MALT lymphomas, the 5-year estimate of LRD after radiation therapy was 0%. The association of radiation therapy with overall survival in different lymphoma sites was heterogeneous, and statistically significant in cutaneous (hazard ratio 0.45, P=.009) and ocular (hazard ratio 0.47, P<.0001) locations after multivariate adjustment. Conclusions: Demographic factors are associated with the use of radiation therapy in MALT lymphoma. Clinicians should be sensitive to those disparities because the administration of radiation therapy may be associated with improved survival, particularly in cutaneous and ocular lymphomas.

  9. Radiation Therapy Administration and Survival in Stage I/II Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue

    International Nuclear Information System (INIS)

    Olszewski, Adam J.; Desai, Amrita

    2014-01-01

    Purpose: To determine the factors associated with the use of radiation therapy and associated survival outcomes in early-stage marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT). Methods and Materials: We extracted data on adult patients with stage I/II MALT lymphoma diagnoses between 1998 and 2010 recorded in the Surveillance, Epidemiology, and End Results (SEER) database. We studied factors associated with radiation therapy administration in a logistic regression model and described the cumulative incidence of lymphoma-related death (LRD) according to receipt of the treatment. The association of radiation therapy with survival was explored in multivariate models with adjustment for immortal time bias. Results: Of the 7774 identified patients, 36% received radiation therapy as part of the initial course of treatment. Older patients; black or Hispanic men; white, Hispanic, and black women; and socioeconomically disadvantaged and underinsured patients had a significantly lower chance of receiving radiation therapy. Radiation therapy administration was associated with a lower chance of LRD in most sites. In cutaneous, ocular, and salivary MALT lymphomas, the 5-year estimate of LRD after radiation therapy was 0%. The association of radiation therapy with overall survival in different lymphoma sites was heterogeneous, and statistically significant in cutaneous (hazard ratio 0.45, P=.009) and ocular (hazard ratio 0.47, P<.0001) locations after multivariate adjustment. Conclusions: Demographic factors are associated with the use of radiation therapy in MALT lymphoma. Clinicians should be sensitive to those disparities because the administration of radiation therapy may be associated with improved survival, particularly in cutaneous and ocular lymphomas

  10. Accuracy of preoperative CT T staging of renal cell carcinoma: which features predict advanced stage?

    International Nuclear Information System (INIS)

    Bradley, A.J.; MacDonald, L.; Whiteside, S.; Johnson, R.J.; Ramani, V.A.C.

    2015-01-01

    % PPV, respectively, for the presence of tumour stage for pT stage >T3a. These are considered reliable signs of locally advanced renal cancer. -- Highlights: •Presence or absence of 4 features were correlated with pT stage in 94 cases of RCC. •Sensitivity, specificity, PPV, NPV for predicting pT Stage ≥pT3a were derived for each feature. •Presence of perinephric stranding and tumour necrosis were not reliable signs for pT stage >T3a. •Thickening of Gerota's fascia appeared to be reliable sign of pT Stage ≥pT3a. •Presence of collateral vessels appeared to be a reliable sign pT Stage ≥pT3a

  11. [Arrival of patients at advanced stage: tempting to identify responsibility].

    Science.gov (United States)

    Gombé Mbalawa, Charles; Diouf, Doudou; Nkoua Mbon, Jean Bernard; Minga, Benoît; Makouanzi Nsimba, Stévy; Nsondé Malanda, Judith

    2013-02-01

    In many publications on cancer in Africa, the majority of patients were seen in advanced stages (III or IV) during the first consultation. So, it was important to look for factors that explain this situation. A survey by questionnaire was made in our Medical Oncology Department of University Teaching Hospital of Brazzaville from January to October 2010. The responsibility of advice to go to hospital was codified in Arrival in Advanced Stage (AAS) from the weakest (AAS 1) to the strongest (AAS 8) according to the knowledge in oncology. The impact of organ accessibility and the patient's instruction level were also evaluated. One hundred and ninety-six patients seen in consultation, hospital day and hospitalization were asked and we had gathered the same information in patients' medical files. Our sample was essentially made by women (67,4%). The age of patients were from 21 to 83 years old with average of 53,8. The direct responsibility of the patient was weak (24,4%) by ignorance or fear of diagnosis. The hospital personal, the nurses and physicians who work in private were for a great part: 40,8%. The number of practitioners by category had limited the results because of the difficulty to join them. The medical doctor, specialist or not, were responsible at 25,5%. The medical vulgarization, large information, specialization training adapted were the way to choose in the resolution of the problem, which impact on therapeutic result was undeniable.

  12. Essential role of EBF1 in the generation and function of distinct mature B cell types

    OpenAIRE

    Vilagos, Bojan; Hoffmann, Mareike; Souabni, Abdallah; Sun, Qiong; Werner, Barbara; Medvedovic, Jasna; Bilic, Ivan; Minnich, Martina; Axelsson, Elin; Jaritz, Markus; Busslinger, Meinrad

    2012-01-01

    The transcription factor EBF1 is essential for lineage specification in early B cell development. In this study, we demonstrate by conditional mutagenesis that EBF1 is required for B cell commitment, pro–B cell development, and subsequent transition to the pre–B cell stage. Later in B cell development, EBF1 was essential for the generation and maintenance of several mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular (FO) and germinal center (GC) B cells were redu...

  13. Perioperative BRAF inhibitors in locally advanced stage III melanoma.

    Science.gov (United States)

    Zippel, Douglas; Markel, Gal; Shapira-Frommer, Roni; Ben-Betzalel, Guy; Goitein, David; Ben-Ami, Eytan; Nissan, Aviram; Schachter, Jacob; Schneebaum, Schlomo

    2017-12-01

    Stage III malignant melanoma is a heterogeneous disease where those cases deemed marginally resectable or irresecatble are frequently incurable by surgery alone. Targeted therapy takes advantage of the high incidence of BRAF mutations in melanomas, most notably the V600E mutation. These agents have rarely been used in a neoadjuvant setting prior to surgery. Thirteen consecutive patients with confirmed BRAF V600E regionally advanced melanoma deemed marginally resectable or irrresectable, were treated with BRAF inhibiting agents, prior to undergoing surgery. The primary outcome measures were a successful resection and pathological response. Disease-free survival was a secondary outcome measure. Overall, 12/13 patients showed a marked clinical responsiveness to medical treatment, enabling a macroscopically successful resection in all cases. Four patients had a complete pathological response with no viable tumor evident in the resected specimens and eight patients showed evidence of minimally residual tumor with extensive tumoral necrosis and fibrosis. One patient progressed and died before surgery. At a median follow up of 20 months, 10 patients remain free of disease. Perioperative treatment with BRAF inhibiting agents in BRAFV600E mutated Stage III melanoma patients facilitates surgical resection and affords satisfactory disease free survival. © 2017 Wiley Periodicals, Inc.

  14. Applied Protein and Molecular Techniques for Characterization of B Cell Neoplasms in Horses

    Science.gov (United States)

    Badial, Peres R.; Tallmadge, Rebecca L.; Miller, Steven; Stokol, Tracy; Richards, Kristy; Borges, Alexandre S.

    2015-01-01

    Mature B cell neoplasms cover a spectrum of diseases involving lymphoid tissues (lymphoma) or blood (leukemia), with an overlap between these two presentations. Previous studies describing equine lymphoid neoplasias have not included analyses of clonality using molecular techniques. The objective of this study was to use molecular techniques to advance the classification of B cell lymphoproliferative diseases in five adult equine patients with a rare condition of monoclonal gammopathy, B cell leukemia, and concurrent lymphadenopathy (lymphoma/leukemia). The B cell neoplasms were phenotypically characterized by gene and cell surface molecule expression, secreted immunoglobulin (Ig) isotype concentrations, Ig heavy-chain variable (IGHV) region domain sequencing, and spectratyping. All five patients had hyperglobulinemia due to IgG1 or IgG4/7 monoclonal gammopathy. Peripheral blood leukocyte immunophenotyping revealed high proportions of IgG1- or IgG4/7-positive cells and relative T cell lymphopenia. Most leukemic cells lacked the surface B cell markers CD19 and CD21. IGHG1 or IGHG4/7 gene expression was consistent with surface protein expression, and secreted isotype and Ig spectratyping revealed one dominant monoclonal peak. The mRNA expression of the B cell-associated developmental genes EBF1, PAX5, and CD19 was high compared to that of the plasma cell-associated marker CD38. Sequence analysis of the IGHV domain of leukemic cells revealed mutated Igs. In conclusion, the protein and molecular techniques used in this study identified neoplastic cells compatible with a developmental transition between B cell and plasma cell stages, and they can be used for the classification of equine B cell lymphoproliferative disease. PMID:26311245

  15. B Cell Subsets in Atherosclerosis

    OpenAIRE

    Perry, Heather M.; Bender, Timothy P.; McNamara, Coleen A.

    2012-01-01

    Atherosclerosis, the underlying cause of heart attacks and strokes, is a chronic inflammatory disease of the artery wall. Immune cells, including lymphocytes modulate atherosclerotic lesion development through interconnected mechanisms. Elegant studies over the past decades have begun to unravel a role for B cells in atherosclerosis. Recent findings provide evidence that B cell effects on atherosclerosis may be subset-dependent. B-1a B cells have been reported to protect from atherosclerosis ...

  16. Bidirectional regulation between B cells and T cells

    NARCIS (Netherlands)

    Margry, B.

    2014-01-01

    B cells were often thought of as simple precursors of end-stage effector cells that are merely in charge of antibody production. Research in the last decades has shown that B cells possess important other roles as well, including their involvement in the regulation and functioning of T cell-mediated

  17. Catching Galactic open clusters in advanced stages of dynamical evolution

    Science.gov (United States)

    Angelo, M. S.; Piatti, A. E.; Dias, W. S.; Maia, F. F. S.

    2018-04-01

    During their dynamical evolution, Galactic open clusters (OCs) gradually lose their stellar content mainly because of internal relaxation and tidal forces. In this context, the study of dynamically evolved OCs is necessary to properly understand such processes. We present a comprehensive Washington CT1 photometric analysis of six sparse OCs, namely: ESO 518-3, Ruprecht 121, ESO 134-12, NGC 6573, ESO 260-7 and ESO 065-7. We employed Markov chain Monte-Carlo simulations to robustly determine the central coordinates and the structural parameters and T1 × (C - T1) colour-magnitude diagrams (CMDs) cleaned from field contamination were used to derive the fundamental parameters. ESO 518-03, Ruprecht 121, ESO 134-12 and NGC 6573 resulted to be of nearly the same young age (8.2 ≤log(t yr-1) ≤ 8.3); ESO 260-7 and ESO065-7 are of intermediate age (9.2 ≤log(t yr-1) ≤ 9.4). All studied OCs are located at similar Galactocentric distances (RG ˜ 6 - 6.9 kpc), considering uncertainties, except for ESO 260-7 (RG = 8.9 kpc). These OCs are in a tidally filled regime and are dynamically evolved, since they are much older than their half-mass relaxation times (t/trh ≳ 30) and present signals of low-mass star depletion. We distinguished two groups: those dynamically evolving towards final disruptions and those in an advanced dynamical evolutionary stage. Although we do not rule out that the Milky Way potential could have made differentially faster their dynamical evolutions, we speculate here with the possibility that they have been mainly driven by initial formation conditions.

  18. Preliminary study of clinical staging of moderately advanced and advanced thoracic esophageal carcinoma treated by non-surgical methods

    International Nuclear Information System (INIS)

    Zhu Shuchai; Li Ren; Li Juan; Qiu Rong; Han Chun; Wan Jun

    2004-01-01

    Objective: To explore the clinical staging of moderately advanced and advanced thoracic esophageal carcinoma by evaluating the prognosis and provide criteria for individual treatment. Methods: The authors retrospectively analyzed 500 patients with moderately advanced and advanced thoracic esophageal carcinoma treated by radiotherapy alone. According to the primary lesion length by barium meal X-ray film, the invasion range and the relation between location and the surrounding organs by CT scans the disease category was classified by a 6 stage method and a 4 stage method. With the primary lesion divide into T1, T2a, T2b, T3a, T3b and T4 incorporating the locregional lymph node metastasis, a 6 stage system was obtained, I, IIa , IIb, IIIa, IIIb and IV. The results of this as compared with those of 4 stage system, the following data were finally arrived at. Results: Among the 500 cases, there were T1 23, T2a 111, T2b 157, T3a 84, T3b 82 and T4 43. The survival rates of these six categories showed significant differences (χ 2 =63.32, P 2 =56.29, P 2 =94.29, P 2 =83.48, P<0.05). Conclusions: Both the 6 stage and 4 stage systems are adaptable to predict prognosis of moderately advanced and advanced esophageal carcinoma treated by radiotherapy alone. For simplicity and convenience, the 4 stage classification is recommended. (authors)

  19. Addition of Rice Bran Arabinoxylan to Curcumin Therapy May Be of Benefit to Patients With Early-Stage B-Cell Lymphoid Malignancies (Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Stage 0/1 Chronic Lymphocytic Leukemia): A Preliminary Clinical Study.

    Science.gov (United States)

    Golombick, Terry; Diamond, Terrence H; Manoharan, Arumugam; Ramakrishna, Rajeev

    2016-06-01

    Hypothesis Prior studies on patients with early B-cell lymphoid malignancies suggest that early intervention with curcumin may lead to delay in progressive disease and prolonged survival. These patients are characterized by increased susceptibility to infections. Rice bran arabinoxylan (Ribraxx) has been shown to have immunostimulatory, anti-inflammatory, and proapoptotic effects. We postulated that addition of Ribraxx to curcumin therapy may be of benefit. Study design Monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) or stage 0/1 chronic lymphocytic leukemia (CLL) patients who had been on oral curcumin therapy for a period of 6 months or more were administered both curcumin (as Curcuforte) and Ribraxx. Methods Ten MGUS/SMM patients and 10 patients with stage 0/1 CLL were administered 6 g of curcumin and 2 g Ribraxx daily. Blood samples were collected at baseline and at 2-month intervals for a period of 6 months, and various markers were monitored. MGUS/SMM patients included full blood count (FBC); paraprotein; free light chains/ratio; C-reactive protein (CRP)and erythrocyte sedimentation rate (ESR); B2 microglobulin and immunological markers. Markers monitored for stage 0/1 CLL were FBC, CRP and ESR, and immunological markers. Results Of 10 MGUS/SMM patients,5 (50%) were neutropenic at baseline, and the Curcuforte/Ribraxx combination therapy showed an increased neutrophil count, varying between 10% and 90% among 8 of the 10 (80%) MGUS/SMM patients. An additional benefit of the combination therapy was the potent effect in reducing the raised ESR in 4 (44%) of the MGUS/SMM patients. Conclusion Addition of Ribraxx to curcumin therapy may be of benefit to patients with early-stage B-cell lymphoid malignancies. © The Author(s) 2016.

  20. B Cells in Autoimmune Diseases

    OpenAIRE

    Hampe, Christiane S.

    2012-01-01

    The role of B cells in autoimmune diseases involves different cellular functions, including the well-established secretion of autoantibodies, autoantigen presentation and ensuing reciprocal interactions with T cells, secretion of inflammatory cytokines, and the generation of ectopic germinal centers. Through these mechanisms B cells are involved both in autoimmune diseases that are traditionally viewed as antibody mediated and also in autoimmune diseases that are commonly classified as T cell...

  1. Advanced ceramics in Brazil: actual stage and perspectives

    International Nuclear Information System (INIS)

    Zanotto, E.D.

    1986-11-01

    The development of advanced ceramics in Brazil, the perspectives of the world and Brazilian markets, the raw materials, the equipments for industry and research, the human resources, and the disposable technology, are presented. The researches on advanced ceramics in Brazil initiated in the sixty decade, with the nuclear fuel development and production projets. (M.C.K.) [pt

  2. [Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma)].

    Science.gov (United States)

    Takahashi, Tsutomu; Suzumiya, Junji

    2014-03-01

    Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma) is a B-cell tumor thought to originate from B-lymphocytes that are normally present in the marginal zone of lymphoid follicles of the lymphoid tissue. About 50% of MALT lymphoma occurs in gastrointestinal tract. The majority of patients present with localized disease and indolent clinical progression. In localized gastric MALT lymphoma with Helicobacter pylori (HP) infection, HP eradication is recommended as first line therapy. In those without HP infection and localized non-gastric MALT lymphoma, involved field radiation therapy(IFRT) is recommended as first line therapy. Patients in advanced stage and salvage setting are managed according to the recommendations for advanced follicular lymphoma. The long-term survival rate of MALT lymphoma patients is 80-90%.

  3. Splenic diffuse red-pulp small B-cell lymphoma associated with hepatitis B virus: a report of two cases

    OpenAIRE

    Kerbauy, Mariana Nassif; Fernandes, Carolina Melo; Bezerra, Evandro Dantas; Lage, Luis Alberto de Padua Covas; Siqueira, Sheila Aparecida Coelho; Pereira, Juliana

    2016-01-01

    ABSTRACT CONTEXT: Splenic diffuse red-pulp small B-cell lymphoma is a rare disease, representing less than 1% of all non-Hodgkin lymphomas (NHL). This entity is characterized by involvement of bone marrow sinusoids and peripheral blood. The majority of cases are at an advanced stage when diagnosed. Its pathogenesis is still poorly understood. CASE REPORTS: We report on two patients with chronic non-replicating hepatitis B virus (HBV) who developed splenic diffuse red-pulp small B-cell lym...

  4. A Novel Therapeutic Modality for Advanced-Stage Prostate Cancer Treatment

    Science.gov (United States)

    2015-10-01

    as an oral contraceptive [6, 7]. Recently, its anti- cancer activity has been reported against advanced breast cancer [8] and head and neck squamous...Award Number: W81XWH-141-0154 TITLE: “A Novel Therapeutic Modality for Advanced-Stage Prostate Cancer Treatment” PRINCIPAL INVESTIGATOR...Novel Therapeutic Modality for Advanced-Stage Prostate Cancer Treatment” 5a. CONTRACT NUMBER: 5b. GRANT NUMBER: W81XWH-14-1-0154 5c. PROGRAM ELEMENT

  5. The outcome of primary mediastinal large B-cell lymphoma

    International Nuclear Information System (INIS)

    Fang Hui; Li Yexiong; Qi Shunan; Liu Qingfeng; Wang Shulian; Jin Jing; Wang Weihu; Song Yongwen; Liu Xinfan; Yu Zihao

    2008-01-01

    Objective: To investigate the treatment outcome and failure in patients with primary mediastinal large B-cell lymphoma(PMBL). Methods: Between Jan. 1992 and Oct. 2006, a total of 46 patients with pathologically confirmed PMBL were reviewed, including 14 with Ann Arbor Stage I disease, 23 with Stage II disease, 3 with Stage III disease and 6 with Stage IV disease. Stage I + II disease was present in 80% of the patients. All patients were treated with chemotherapy, and 29 also received radiotherapy. Twenty-seven patients (59%) were treated with first generation regimen (CHOP), 9 (20%) with third generation regimens (MACOP-B, ProMACE/CytaBOM, m-BACOD, or ProMACE-MOPP), and 10 (22%) with high-dose chemotherapy (HDCT/APBSCT). Rituximab was administered to 16 patients (35%). For most patients who received radiotherapy, an involved field was used with a median dose of 45 Gy in 23 fractions. Results: The rate of complete remission, partial remission and progression disease was 41%, 30% and 24%, respectively. The 5-year overall survival rate (OS) for all patients was 35%. The 2- and 5-year OS was 79% and 63% for stage I + II and 51% and 0 for stage III + IV, respectively (χ 2 =4.35,P=0.037). The 2-year progression free survival rate was 63% and 11%, respectively(χ 2 =17.77, P=0.000). The 5- year OS was 80% for the patients with CR, 50% for those with PR, and 0 for those with progression disease (χ 2 =19.58, P=0.003). With a median follow-up of 22 months, progression disease and relapse occurred in 19 patients. Conclusions: Survival of patients with advanced stage PMBL is poor. Further studies are needed to confirm the optimal treatment. Radiotherapy often plays a pivotal role in local control. (authors)

  6. Efficacies of 125I seed implantation in advanced stage central lung cancer via fibrobronchoscope

    International Nuclear Information System (INIS)

    Liu Jianguo; An Liqing; Cheng Jinguang; Zhang Yufen; Guo Xiaokui

    2009-01-01

    Objective: To explore the temporal curative effect of 125 I seed implantation in advanced stage central type lung cancer. Methods: 125 I seed was implanted in 56 patients confirmed advanced stage central type lung cancer via fibrobronchoscope and all cases were fellow up in certain duration to explore their efficacies and the adverse reaction. Results: Total efficient rate was 76.78% in 56 patients. Lung reexpanded rate was 90.90%. Conclusion: The therapy of 125 I seed implantation in advanced stage central type lung cancer is safe and available. (authors)

  7. Essential role of EBF1 in the generation and function of distinct mature B cell types.

    Science.gov (United States)

    Vilagos, Bojan; Hoffmann, Mareike; Souabni, Abdallah; Sun, Qiong; Werner, Barbara; Medvedovic, Jasna; Bilic, Ivan; Minnich, Martina; Axelsson, Elin; Jaritz, Markus; Busslinger, Meinrad

    2012-04-09

    The transcription factor EBF1 is essential for lineage specification in early B cell development. In this study, we demonstrate by conditional mutagenesis that EBF1 is required for B cell commitment, pro-B cell development, and subsequent transition to the pre-B cell stage. Later in B cell development, EBF1 was essential for the generation and maintenance of several mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular (FO) and germinal center (GC) B cells were reduced in the absence of EBF1. Activation of the B cell receptor resulted in impaired intracellular signaling, proliferation and survival of EBF1-deficient FO B cells. Immune responses were severely reduced upon Ebf1 inactivation, as GCs were formed but not maintained. ChIP- and RNA-sequencing of FO B cells identified EBF1-activated genes that encode receptors, signal transducers, and transcriptional regulators implicated in B cell signaling. Notably, ectopic expression of EBF1 efficiently induced the development of B-1 cells at the expense of conventional B cells. These gain- and loss-of-function analyses uncovered novel important functions of EBF1 in controlling B cell immunity.

  8. Predictors of cervical cancer being at an advanced stage at diagnosis in Sudan

    DEFF Research Database (Denmark)

    Ibrahim, Ahmed; Rasch, Vibeke; Pukkala, Eero

    2011-01-01

    Cervical cancer is the second most common cancer among women in Sudan, with more than two-thirds of all women with invasive cervical cancer being diagnosed at an advanced stage (stages III and IV). The lack of a screening program for cervical cancer in Sudan may contribute to the late presentation...... diagnosis) of cervical cancer in Sudan....

  9. Clinical Implications of Phosphorylated STAT3 Expression in de novo Diffuse Large B-cell Lymphoma

    DEFF Research Database (Denmark)

    Ok, Chi Y; Chen, Jiayu; Xu-Monette, Ziju

    2014-01-01

    PURPOSE: Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact...... of phosphorylated STAT3 (pSTAT3) on prognosis are limited. EXPERIMENTAL DESIGN: We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma...... biomarkers, and genetic translocations. RESULTS: pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall...

  10. B cells in operational tolerance.

    Science.gov (United States)

    Chesneau, M; Danger, R; Soulillou, J-P; Brouard, S

    2018-02-16

    Transplantation is currently the therapy of choice for endstage organ failure even though it requires long-term immunosuppresive therapy, with its numerous side effects, for acceptance of the transplanted organ. In rare cases however, patients develop operational tolerance, that is, graft survival without immunosuppression. Studies conducted on these patients reveal genetic, phenotypic, and functional signatures. They provide a better understanding of the immunological mechanisms involved in operational tolerance and define biomarkers that could be used to adapt immunosuppressive treatment to the individual, safely reduce immunosuppression doses, and ideally and safely guide immunosuppression withdrawal. This review summarizes studies that suggest a role for B cells as biomarkers of operational tolerance and discusses the use of B cells as a predictive tool for immunologic risk. Copyright © 2018. Published by Elsevier Inc.

  11. Staging laparoscopy improves treatment decision-making for advanced gastric cancer.

    Science.gov (United States)

    Hu, Yan-Feng; Deng, Zhen-Wei; Liu, Hao; Mou, Ting-Yu; Chen, Tao; Lu, Xin; Wang, Da; Yu, Jiang; Li, Guo-Xin

    2016-02-07

    To evaluate the clinical value of staging laparoscopy in treatment decision-making for advanced gastric cancer (GC). Clinical data of 582 patients with advanced GC were retrospectively analyzed. All patients underwent staging laparoscopy. The strength of agreement between computed tomography (CT) stage, endoscopic ultrasound (EUS) stage, laparoscopic stage, and final stage were determined by weighted Kappa statistic (Kw). The number of patients with treatment decision-changes was counted. A χ(2) test was used to analyze the correlation between peritoneal metastasis or positive cytology and clinical characteristics. Among the 582 patients, the distributions of pathological T classifications were T2/3 (153, 26.3%), T4a (262, 45.0%), and T4b (167, 28.7%). Treatment plans for 211 (36.3%) patients were changed after staging laparoscopy was performed. Two (10.5%) of 19 patients in M1 regained the opportunity for potential radical resection by staging laparoscopy. Unnecessary laparotomy was avoided in 71 (12.2%) patients. The strength of agreement between preoperative T stage and final T stage was in almost perfect agreement (Kw = 0.838; 95% confidence interval (CI): 0.803-0.872; P laparoscopy; compared with CT and EUS, which was in fair agreement. The strength of agreement between preoperative M stage and final M stage was in almost perfect agreement (Kw = 0.990; 95% CI: 0.977-1.000; P laparoscopy; compared with CT, which was in slight agreement. Multivariate analysis revealed that tumor size (≥ 40 mm), depth of tumor invasion (T4b), and Borrmann type (III or IV) were significantly correlated with either peritoneal metastasis or positive cytology. The best performance in diagnosing P-positive was obtained when two or three risk factors existed. Staging laparoscopy can improve treatment decision-making for advanced GC and decrease unnecessary exploratory laparotomy.

  12. Cloning of B cell-specific membrane tetraspanning molecule BTS possessing B cell proliferation-inhibitory function.

    Science.gov (United States)

    Suenaga, Tadahiro; Arase, Hisashi; Yamasaki, Sho; Kohno, Masayuki; Yokosuka, Tadashi; Takeuchi, Arata; Hattori, Takamichi; Saito, Takashi

    2007-11-01

    Lymphocyte proliferation is regulated by signals through antigen receptors, co-stimulatory receptors, and other positive and negative modulators. Several membrane tetraspanning molecules are also involved in the regulation of lymphocyte growth and death. We cloned a new B cell-specific tetraspanning (BTS) membrane molecule, which is similar to CD20 in terms of expression, structure and function. BTS is specifically expressed in the B cell line and its expression is increased after the pre-B cell stage. BTS is expressed in intracellular granules and on the cell surface. Overexpression of BTS in immature B cell lines induces growth retardation through inhibition of cell cycle progression and cell size increase without inducing apoptosis. This inhibitory function is mediated predominantly by the N terminus of BTS. The development of mature B cells is inhibited in transgenic mice expressing BTS, suggesting that BTS is involved in the in vivo regulation of B cells. These results indicate that BTS plays a role in the regulation of cell division and B cell growth.

  13. Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus.

    Science.gov (United States)

    Gies, Vincent; Schickel, Jean-Nicolas; Jung, Sophie; Joublin, Aurélie; Glauzy, Salomé; Knapp, Anne-Marie; Soley, Anne; Poindron, Vincent; Guffroy, Aurélien; Choi, Jin-Young; Gottenberg, Jacques-Eric; Anolik, Jennifer H; Martin, Thierry; Soulas-Sprauel, Pauline; Meffre, Eric; Korganow, Anne-Sophie

    2018-03-08

    B cells play a central role in systemic lupus erythematosus (SLE) pathophysiology but dysregulated pathways leading to a break in B cell tolerance remain unclear. Since Toll-like receptor 9 (TLR9) favors the elimination of autoreactive B cells in the periphery, we assessed TLR9 function in SLE by analyzing the responses of B cells and plasmacytoid dendritic cells (pDCs) isolated from healthy donors and patients after stimulation with CpG, a TLR9 agonist. We found that SLE B cells from patients without hydroxychloroquine treatment displayed defective in vitro TLR9 responses, as illustrated by the impaired upregulation of B cell activation molecules and the diminished production of various cytokines including antiinflammatory IL-10. In agreement with CD19 controlling TLR9 responses in B cells, decreased expression of the CD19/CD21 complex on SLE B cells was detected as early as the transitional B cell stage. In contrast, TLR7 function was preserved in SLE B cells, whereas pDCs from SLE patients properly responded to TLR9 stimulation, thereby revealing that impaired TLR9 function in SLE was restricted to B cells. We conclude that abnormal CD19 expression and TLR9 tolerogenic function in SLE B cells may contribute to the break of B cell tolerance in these patients.

  14. NKT Cell Responses to B Cell Lymphoma.

    Science.gov (United States)

    Li, Junxin; Sun, Wenji; Subrahmanyam, Priyanka B; Page, Carly; Younger, Kenisha M; Tiper, Irina V; Frieman, Matthew; Kimball, Amy S; Webb, Tonya J

    2014-06-01

    Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, α-galactosylceramide (α-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from α-GalCer treated mice produced IFN-γ following α-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma.

  15. Survival of Advanced Stage High-Grade Serous Ovarian Cancer Patients in the Republic of Macedonia.

    Science.gov (United States)

    Aluloski, Igor; Tanturovski, Mile; Jovanovic, Rubens; Kostadinova-Kunovska, Slavica; Petrusevska, Gordana; Stojkovski, Igor; Petreska, Bojana

    2017-12-15

    The primary objective of the study was to evaluate the overall survival of women with advanced stage (Stage IIIA-IV) high-grade serous ovarian cancer in Macedonia. The study was a cross-sectional medical record review of patients diagnosed with advanced stage HGSC. Patients were deemed eligible for inclusion if they were diagnosed with an advanced stage (Stage IIIA-IV) HGSC of the ovary, fallopian tube or peritoneum between 2009 and 2015. The data were analyzed in a descriptive fashion and summary statistics were provided, as appropriate. Survival was calculated using the Kaplan-Meier method. A total of 81 eligible patients were identified and included in the study. The average overall survival in the studied cohort was 46.59 months (95%CI = 39.11-54.06). Patients that were optimally debulked and patients that had a platinum-free interval larger than 12 months had significantly longer survival in the current series (p < 0.001). the average overall survival of advanced stage HGSC patients in the studied series was 46.59 months (95%CI = 39.11-54.06). Patients aged 65 years or younger tended to live approximately ten months longer than patients older than 65 years, but this difference was not statistically significant. There was no difference in HGSC survival in the groups of patients with grade 2 and grade 3 disease. However, optimal surgical debulking and platinum sensitivity were associated with significantly better overall survival.

  16. B cell activating factor (BAFF) selects IL-10-B cells over IL-10+B cells during inflammatory responses.

    Science.gov (United States)

    Ma, Ning; Zhang, Yu; Liu, Qilin; Wang, Zhiding; Liu, Xiaoling; Zhu, Gaizhi; Yu, Dandan; Han, Gencheng; Chen, Guojiang; Hou, Chunmei; Wang, Tianxiao; Ma, Yuanfang; Shen, Beifen; Li, Yan; Xiao, He; Wang, Renxi

    2017-05-01

    B cell activating factor (BAFF) regulates B cell maturation, survival, function, and plays a critical pathogenic role in autoimmune diseases. It remains unclear how BAFF affects IL-10 - B cells versus regulatory B cells (Bregs) in inflammatory responses. In this study, we found that IL-10-expressing Bregs decreased in lupus-prone MRL/lpr mice and experimental allergic encephalomyelitis (EAE) mice. On blockade of the effects of BAFF with TACI-IgG, IL-10 + Bregs were upregulated in MRL/lpr and EAE mice. In addition, BAFF expanded IL-10 + B cells over IL-10 - B cells under noninflammatory conditions in vitro, whereas it expanded IL-10 - B cells over IL-10 + B cells during inflammatory responses, such as stimulation with autoantigen and LPS. Finally, the selection of IL-10 - B cells over IL-10 + B cells by BAFF was dependent on BAFF receptors (BAFFR, TACI, and BCMA) that were upregulated by inflammatory responses. This study suggests that BAFF selects IL-10 - B cells over IL-10 + regulatory B cells via BAFF receptors in inflammatory responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Primary mediastinal large B-cell lymphoma.

    Science.gov (United States)

    Martelli, Maurizio; Ferreri, Andrés; Di Rocco, Alice; Ansuinelli, Michela; Johnson, Peter W M

    2017-05-01

    Primary mediastinal large B-cell lymphoma (PMLBCL) is a distinct clinical and biological disease from other types of DLBCL. It is more frequent in young female and constitutes 6%-10% of all DLBCL. PMLBCL is characterized by a diffuse proliferation of medium to large B-cells associated with sclerosis. Molecular analysis shows it to be a distinct entity from other DLBCL. Rituximab CHOP/MACOP-B-like regimens followed by mediastinal radiotherapy (RT) were associated with a 5-years PFS of 75%-85%. More intensive regimens, as DA-EPOCH-R without mediastinal RT, have shown very promising results, but this therapeutic advance needs to be confirmed in further prospective trials. The role of consolidative mediastinal RT should be still better assess in prospective comparative studies. PET-CT scan is a powerful tool to define the real quality of response and it is hoped that future prospective trials may allow its role in the de-escalation of mediastinal RT. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. High copy number of mitochondrial DNA predicts poor prognosis in patients with advanced stage colon cancer.

    Science.gov (United States)

    Wang, Yun; He, Shuixiang; Zhu, Xingmei; Qiao, Wei; Zhang, Juan

    2016-12-23

    The aim of this investigation was to determine whether alterations in mitochondrial DNA (mtDNA) copy number in colon cancer were associated with clinicopathological parameters and postsurgical outcome. By quantitative real-time PCR assay, the mtDNA copy number was detected in a cohort of colon cancer and matched adjacent colon tissues (n = 162). The majority of patients had higher mtDNA content in colon cancer tissues than matched adjacent colon tissues. Moreover, high mtDNA content in tumor tissues was associated with larger tumor size, higher serum CEA level, advanced TNM stage, vascular emboli, and liver metastases. Further survival curve analysis showed that high mtDNA content was related to the worst survival in patients with colon cancer at advanced TNM stage. High mtDNA content is a potential effective factor of poor prognosis in patients with advanced stage colon cancer.

  19. The clinical study of interventional therapy of advanced and late staged carcinoma of digestive tract

    International Nuclear Information System (INIS)

    Liu Zengrong; Ren Shuiming; Luo Xiuzhen; Liu Fang; Liu Junxiang; Han Liping

    2003-01-01

    Objective: To evaluate the transarterial chemoembotherapy in the treatment of advanced or late staged digestive tract carcinoma. Methods: One hundred fifty-one patients with advanced or late staged digestive tract carcinoma (including 20 cases of esophageal carcinoma, 29 cases of cardia carcinoma, 71 cases of gastric carcinoma and 31 cases of large intestinal carcinoma) underwent super selective transarterial chemoembotherapy. Results: Interventions were successful. Symptoms were apparently improved in all cases. Decreased diameter of tumor was seen in all cases. Half-year survival rate was 95% (144/151); one year survival was 86% (130/150); two year survival rate was 66% (99/151); and three year survival rate was 29% (44/151). Conclusion: The transarterial chemoembotherapy is an effective treatment of advanced or late staged digestive tract carcinoma. In patients with metastases, the intervention is especially valuable for both primary and metastatic lesions

  20. B-cell leukemia/lymphoma panel

    Science.gov (United States)

    ... ency/article/003518.htm B-cell leukemia/lymphoma panel To use the sharing features on this page, please enable JavaScript. B-cell leukemia/lymphoma panel is a blood test that looks for certain ...

  1. Renal cell carcinoma in long-term survivors of advanced stage neuroblastoma in early childhood

    International Nuclear Information System (INIS)

    Fleitz, Julie M.; Wootton-Gorges, Sandra L.; Kurzrock, Eric A.; Wyatt-Ashmead, Josephine; McGavran, Loris; Koyle, Martin; Odom, Lorrie F.; West, Daniel C.; Martin, Kenneth W.

    2003-01-01

    Renal cell carcinoma (RCC) is rare in children and comprises only 1-3% of all pediatric primary renal tumors. Recently, several case reports have described RCC developing in patients previously treated for advanced stage neuroblastoma (NB). Our experience with four patients treated for advanced stage NB during early childhood who developed RCC later in life are added to 14 others in the literature. These patients and our review of the literature suggest an association between RCC and NB that warrants further study. (orig.)

  2. Long Noncoding RNA Expression during Human B-Cell Development.

    Directory of Open Access Journals (Sweden)

    Andreas Petri

    Full Text Available Long noncoding RNAs (lncRNAs have emerged as important regulators of diverse cellular processes, but their roles in the developing immune system are poorly understood. In this study, we analysed lncRNA expression during human B-cell development by array-based expression profiling of eleven distinct flow-sorted B-cell subsets, comprising pre-B1, pre-B2, immature, naive, memory, and plasma cells from bone marrow biopsies (n = 7, and naive, centroblast, centrocyte, memory, and plasmablast cells from tonsil tissue samples (n = 6, respectively. A remapping strategy was used to assign the array probes to 37630 gene-level probe sets, reflecting recent updates in genomic and transcriptomic databases, which enabled expression profiling of 19579 long noncoding RNAs, comprising 3947 antisense RNAs, 5277 lincRNAs, 7625 pseudogenes, and 2730 additional lncRNAs. As a first step towards inferring the functions of the identified lncRNAs in developing B-cells, we analysed their co-expression with well-characterized protein-coding genes, a method known as "guilt by association". By using weighted gene co-expression network analysis, we identified 272 lincRNAs, 471 antisense RNAs, 376 pseudogene RNAs, and 64 lncRNAs within seven sub-networks associated with distinct stages of B-cell development, such as early B-cell development, B-cell proliferation, affinity maturation of antibody, and terminal differentiation. These data provide an important resource for future studies on the functions of lncRNAs in development of the adaptive immune response, and the pathogenesis of B-cell malignancies that originate from distinct B-cell subpopulations.

  3. Efficacy of Multimodal Therapy in the Survival Outcomes of Advanced-Stage (Stage III-Stage IV) Oral Carcinoma Patients: An Institutional Experience in Asian Indian Population.

    Science.gov (United States)

    Dhawan, Amit; Duggal, Prahlad; Bhullar, Ramandeep Singh; Kaur, Tejinder; Sandhu, Amneet; Kaur, Kirandeep

    2018-03-01

    Primary ablative surgery followed by post-op radiotherapy (S-RT) remains the mainstay of treatment for stage III-stage IV oral carcinoma. A retrospective analysis of survival rates of advanced-stage OSCC patients treated with multimodal therapies (S-RT or combined chemoradiation) was performed to analyse the outcome for patient survival and whether addition of adjuvant chemotherapy (S-CRT) improves survival. Demographic, pathological, treatment and follow-up data of 128 patients were included in the study. Sixty-nine patients received S-RT, while 55 patients were opted for S-CRT. Overall survival, disease-specific survival and disease-free survival were estimated with Kaplan-Meier analysis and compared between groups with Cox regression analysis. Survival was significantly influenced by the type of modality and regional spread of disease. S-CRT group had improved overall, disease-specific, disease-free and metastasis-free survival compared to S-RT group. A survival advantage of 10% was achieved in S-CRT group compared to S-RT group even in patients with extracapsular spread and perineural invasion. Addition of adjuvant chemotherapy to S-RT improves survival outcomes in advanced OSCC, especially in patients with regional spread of disease.

  4. Case Report: Down-staging locally advanced head and neck cancer ...

    African Journals Online (AJOL)

    Case Report: Down-staging locally advanced head and neck cancer in an HIV infected patient in a limited resource setting. L Masamba, D Nkosi, D Kumiponjera. Abstract. No Abstract. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · AJOL African Journals ...

  5. Results of two different surgical techniques in the treatment of advanced-stage Freiberg's disease

    Directory of Open Access Journals (Sweden)

    Emin Ozkul

    2016-01-01

    Conclusions: The decision of performing osteotomy or resection arthroplasty in the patients with advanced-stage Freiberg's disease should be based on the joint injury and the patients should be informed about the cosmetic problems like shortening which may arise from resection.

  6. Controversies on the prognostic value of interim FDG-PET in advanced-stage Hodgkin lymphoma

    NARCIS (Netherlands)

    Adams, Hugo J A; Kwee, Thomas C

    2016-01-01

    Hodgkin lymphoma, even in advanced-stage, is a highly curable malignancy, but treatment is associated with short-term toxicity and long-term side effects. Early predictive markers are required to identify those patients who do not require the full-length standard therapy (and thus qualify for

  7. HCV Infection and B-Cell Lymphomagenesis

    Directory of Open Access Journals (Sweden)

    Masahiko Ito

    2011-01-01

    Full Text Available Hepatitis C virus (HCV has been recognized as a major cause of chronic liver diseases worldwide. It has been suggested that HCV infects not only hepatocytes but also mononuclear lymphocytes including B cells that express the CD81 molecule, a putative HCV receptor. HCV infection of B cells is the likely cause of B-cell dysregulation disorders such as mixed cryoglobulinemia, rheumatoid factor production, and B-cell lymphoproliferative disorders that may evolve into non-Hodgkin's lymphoma (NHL. Epidemiological data indicate an association between HCV chronic infection and the occurrence of B-cell NHL, suggesting that chronic HCV infection is associated at least in part with B-cell lymphomagenesis. In this paper, we aim to provide an overview of recent literature, including our own, to elucidate a possible role of HCV chronic infection in B-cell lymphomagenesis.

  8. Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome

    DEFF Research Database (Denmark)

    Scarisbrick, Julia J; Prince, H Miles; Vermeer, Maarten H

    2015-01-01

    PURPOSE: Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been sing...

  9. A role for gut-associated lymphoid tissue in shaping the human B cell repertoire.

    Science.gov (United States)

    Vossenkämper, Anna; Blair, Paul A; Safinia, Niloufar; Fraser, Louise D; Das, Lisa; Sanders, Theodore J; Stagg, Andrew J; Sanderson, Jeremy D; Taylor, Kirstin; Chang, Fuju; Choong, Lee M; D'Cruz, David P; Macdonald, Thomas T; Lombardi, Giovanna; Spencer, Jo

    2013-08-26

    We have tracked the fate of immature human B cells at a critical stage in their development when the mature B cell repertoire is shaped. We show that a major subset of bone marrow emigrant immature human B cells, the transitional 2 (T2) B cells, homes to gut-associated lymphoid tissue (GALT) and that most T2 B cells isolated from human GALT are activated. Activation in GALT is a previously unknown potential fate for immature human B cells. The process of maturation from immature transitional B cell through to mature naive B cell includes the removal of autoreactive cells from the developing repertoire, a process which is known to fail in systemic lupus erythematosus (SLE). We observe that immature B cells in SLE are poorly equipped to access the gut and that gut immune compartments are depleted in SLE. Thus, activation of immature B cells in GALT may function as a checkpoint that protects against autoimmunity. In healthy individuals, this pathway may be involved in generating the vast population of IgA plasma cells and also the enigmatic marginal zone B cell subset that is poorly understood in humans.

  10. Advanced Development Program for a 625 lbf thrust engine for Ares First Stage Roll Control System

    Science.gov (United States)

    Dawson, Matt; Chenevert, Blake; Brewster, Gerry; Frei, Tom; Bullard, Brad; Fuller, Ray

    2009-01-01

    NASA's new Ares Launch Vehicle will require twelve thrusters to provide roll control of the vehicle during the first stage firing. All twelve roll control thrusters will be located at the inter-stage segment that separates the solid rocket booster first stage from the second stage. NASA selected a mono propellant hydrazine solution and as a result awarded Aerojet-General a contract in 2007 for an advanced development program for an MR-80- series 625 Ibf vacuum thrust monopropellant hydrazine thruster. This thruster has heritage dating back to the 1976 Viking Landers and most recently for the 2011 Mars Science Laboratory. Prior to the Ares application, the MR-80-series thrusters had been equipped with throttle valves and not typically operated in pulse mode. The primary objective of the advanced development program was to increase the technology readiness level and retire major technical risks for the future flight qualification test program. Aerojet built on their heritage MR-80 rocket engine designs to achieve the design and performance requirements. Significant improvements to cost and lead-time were achieved by applying Design for Manufacturing and Assembly (DFMA) principles. AerojetGeneral has completed Preliminary and Critical Design Reviews, followed by two successful rocket engine development test programs. The test programs included qualification random vibration and firing lite that significantly exceed the flight qualification requirements. This paper discusses the advanced development program and the demonstrated capability of the MR-80C engine. Y;

  11. Clinicopathological features of histological transformation from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue to diffuse large B-cell lymphoma: an analysis of 467 patients.

    Science.gov (United States)

    Maeshima, Akiko Miyagi; Taniguchi, Hirokazu; Toyoda, Kosuke; Yamauchi, Nobuhiko; Makita, Shinichi; Fukuhara, Suguru; Munakata, Wataru; Maruyama, Dai; Kobayashi, Yukio; Tobinai, Kensei

    2016-09-01

    This study analysed incidence, patient outcome, immunophenotype and prognostic factors of histological transformation (HT) from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) to diffuse large B-cell lymphoma (DLBCL) in 467 patients (median age, 61 years). The primary sites of MALT lymphoma were the stomach (43%), ocular adnexa (25%), lung (8%), systemic (8%) and other tissues (16%). HT occurred in 8% of MALT lymphomas. Risk of HT by 15 years was 5%: 4% in limited-stage diseases (n = 385) and 16% in advanced-stage diseases (n = 56) (P = 0·02). The median time to HT was 48 months (range, 4-139). Five-year progression-free survival (PFS) and overall survival (OS) rates after HT were 80% and 94%, respectively. Immunohistochemical results of DLBCL were as follows: germinal centre B-cell (GCB)/non-GCB, 37%/63%; CD10, 9%; BCL6, 59%; MUM1, 38%; MYC, 42%; BCL2, 35%; Ki67 ≥ 90%, 23%; and CD5, 3%. The majority (75%, 9/12) of GCB-type DLBCLs exhibited CD10(-) , BCL6(+) and MUM1(-) immunophenotypes; the remainder had CD10(+) immunophenotypes. Multivariate analysis revealed that only advanced stage at HT was a significant adverse factor for PFS (P = 0·037). Thus, overall risk of HT was low and prognosis after HT was favourable; however, in advanced-stage cases, risk of HT was relatively high and prognosis was unfavourable. © 2016 John Wiley & Sons Ltd.

  12. B-Cell Hematologic Malignancy Vaccination Registry

    Science.gov (United States)

    2017-12-29

    Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Waldenstrom Macroglobulinemia; Lymphocytosis; Lymphoma, Non-Hodgkin; B-Cell Chronic Lymphocytic Leukemia; Hematological Malignancies

  13. Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies.

    Directory of Open Access Journals (Sweden)

    Amy E Gilbert

    Full Text Available Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10 to primary and metastatic melanoma cells compared to healthy volunteers (n = 10 (P<0.0001. Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21 (P<0.0001. Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800 compared to 2% of cultures from healthy controls (n = 600 produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.

  14. Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies.

    Science.gov (United States)

    Gilbert, Amy E; Karagiannis, Panagiotis; Dodev, Tihomir; Koers, Alexander; Lacy, Katie; Josephs, Debra H; Takhar, Pooja; Geh, Jenny L C; Healy, Ciaran; Harries, Mark; Acland, Katharine M; Rudman, Sarah M; Beavil, Rebecca L; Blower, Philip J; Beavil, Andrew J; Gould, Hannah J; Spicer, James; Nestle, Frank O; Karagiannis, Sophia N

    2011-04-29

    Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.

  15. Predictors of advanced chronic kidney disease and end-stage renal disease in HIV-positive persons

    DEFF Research Database (Denmark)

    Nielsen, Lene Ryom; Mocroft, Amanda; Kirk, Ole

    2014-01-01

    Whilst several antiretroviral drugs have been associated with moderate chronic kidney disease (CKD), their contribution to advanced CKD and end-stage renal disease (ESRD) remain unknown.......Whilst several antiretroviral drugs have been associated with moderate chronic kidney disease (CKD), their contribution to advanced CKD and end-stage renal disease (ESRD) remain unknown....

  16. Increased number of B-cells in bronchial biopsies in COPD

    NARCIS (Netherlands)

    Gosman, M.M.E.; Willemse, BWM; Jansen, DF; Lapperre, TS; van Schadewijk, A; Hiemstra, PS; Postma, DS; Timens, W; Kerstjens, HAM

    Recently, it has been shown that the accumulated volume of B-cells in small airways is increased in chronic obstructive pulmonary disease (COPD) Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 3 and 4. Little is known about the number of B-cells in central airways in COPD. The

  17. Robotic-assisted laparoscopy vs conventional laparoscopy for the treatment of advanced stage endometriosis.

    Science.gov (United States)

    Nezhat, Camran R; Stevens, Amanda; Balassiano, Erika; Soliemannjad, Rose

    2015-01-01

    To compare robotic-assisted laparoscopy with conventional laparoscopy for treatment of advanced stage endometriosis insofar as operative time, estimated blood loss, complication rate, and length of hospital stay. Retrospective cohort study (Canadian Task Force classification II2). All procedures were performed by one surgeon between January 2004 and July 2012. Data was collected via chart review. Tertiary referral center for treatment of endometriosis. Four hundred twenty women with advanced endometriosis. Fertility-sparing surgery to treat advanced endometriosis, either via conventional or robotic-assisted laparoscopy. Patient demographic data, operative time, estimated blood loss, complication rate, and length of hospital stay were compared between the 2 groups. Two hundred seventy-three patients underwent conventional laparoscopy and 147 patients underwent robotic-assisted laparoscopy for fertility-sparing treatment of advanced stage endometriosis. Patients in both groups had similar characteristics insofar as age, body mass index, and previous abdominal surgeries. There were no significant differences in blood loss or complication rate between the 2 groups. Mean operative time in the conventional laparoscopy group was 135 minutes (range, 115-156 minutes), and in the robotic-assisted laparoscopy group was 196 minutes (range, 185-209 minutes), with a mean difference in operative time of 61 minutes (p laparoscopy group. Most patients who underwent conventional laparoscopy were discharged to home on the day of surgery. Of 273 patients in the conventional laparoscopy group, only 63 remained in the hospital overnight, and all 147 patients in the robotic-assisted laparoscopy group were discharged on postoperative day 1. Conventional laparoscopy and robotic-assisted laparoscopy are excellent methods for treatment of advanced stages of endometriosis. However, use of the robotic platform may increase operative time and might also be associated with longer hospital stay

  18. Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate

    OpenAIRE

    Mansson, Robert; Welinder, Eva; Åhsberg, Josefine; Lin, Yin C.; Benner, Christopher; Glass, Christopher K.; Lucas, Joseph S.; Sigvardsson, Mikael; Murre, Cornelis

    2012-01-01

    Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1), FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in FOXO1-deficient mice is arrested in the common lymphoid progenitor (CLP) LY6D+ cell stage. We demonstrate that this phenotype closely resembles the arres...

  19. Evaluation of PET and laparoscopy in STagIng advanced gastric cancer: A multicenter prospective study (PLASTIC-study)

    NARCIS (Netherlands)

    H.J.F. Brenkman (Hylke J.F.); Gertsen, E.C. (E. C.); E. Vegt (Erik); R. van Hillegersberg (Richard); M.I. van Berge Henegouwen; S.S. Gisbertz (Suzanne S.); M. Luyer (Misha); G.A.P. Nieuwenhuijzen (Gerard); J.J.B. van Lanschot (Jan); S.M. Lagarde (Sjoerd); W.O. de Steur (Wobbe O.); H.H. Hartgrink (H.); J.H.M.B. Stoot (Jan); K.W.E. Hulsewé (Karel W.E.); E.J. Spillenaar Bilgen (Ernst Jan); M.J. van Det (Marc J.); E.A. Kouwenhoven (Ewout); D.L. van der Peet (Donald); F. Daams (Freek); J.W. van Sandick (J.); N.C.T. Grieken (Nicole); J. Heisterkamp (Joos); B. van Etten (Boudewijn); J.W. Haveman; J.-P.E.N. Pierie (Jean-Pierre); Jonker, F. (F.); Thijssen, A.Y. (A. Y.); E.J.T. Belt (Eric); P. van Duijvendijk (Peter); Wassenaar, E. (E.); H.W.M. van Laarhoven (Hanneke); Wessels, F.J. (F. J.); N. Haj Mohammad; H.F. van Stel (Henk); G.W.J. Frederix (Geert); P.D. Siersema (Peter); J.P. Ruurda (Jelle)

    2018-01-01

    textabstractBackground: Initial staging of gastric cancer consists of computed tomography (CT) and gastroscopy. In locally advanced (cT3-4) gastric cancer, fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT or PET) and staging laparoscopy (SL) may have a role in staging, but

  20. [Increased oxidized LDL cholesterol levels in peritoneal fluid of women with advanced-stage endometriosis].

    Science.gov (United States)

    Polak, Grzegorz; Mazurek, Diana; Rogala, Ewelina; Nowicka, Aldona; Derewianka-Polak, Magdalena; Kotarski, Jan

    2011-03-01

    Proinflammatory and prooxidative environment in the peritoneal cavity may be involved in the pathogenesis of endometriosis. Imbalance between reactive oxygen species levels and the antioxidant capacity leads to oxidation of low-density lipoproteins (LDL). The importance of oxidized LDL (Ox-LDL) in the development of atherosclerosis is well recognized. The aim of our study was to evaluate for the presence of ox-LDL in the peritoneal fluid (PF) of women with and without endometriosis. A total of 60 women who underwent laparoscopy were divided into groups: endometriosis sufferers with minimal to mild (n 20) and moderate to severe (n 20) stages, and the reference group (n 20) with functional follicle ovarian cysts. Oxidized LDL levels were determined in the PF using enzyme immunoassay Oxidized LDL levels were detectable in all peritoneal fluid samples. Significantly increased levels of ox-LDL were observed in PF of women with stage III/IV endometriosis compared to the reference group (p = 0.03). However peritoneal fluid ox-LDL concentrations did not differ significantly between patients with minimal/mild and women with moderate/severe stage of the disease (p = 0.2). No significant difference in the PF ox-LDL concentrations was also found between women with stage I/II endometriosis and patients with follicle cysts (p = 0.3). Increased peritoneal fluid ox-LDL levels observed in women with advanced-stage endometriosis suggest the important role of oxidative stress in the pathogenesis of the disease.

  1. Separation of plasmacytoid dendritic cells from B-cell-biased lymphoid progenitor (BLP) and Pre-pro B cells using PDCA-1.

    Science.gov (United States)

    Medina, Kay L; Tangen, Sarah N; Seaburg, Lauren M; Thapa, Puspa; Gwin, Kimberly A; Shapiro, Virginia Smith

    2013-01-01

    B-cell-biased lymphoid progenitors (BLPs) and Pre-pro B cells lie at a critical juncture between B cell specification and commitment. However, both of these populations are heterogenous, which hampers investigation into the molecular changes that occur as lymphoid progenitors commit to the B cell lineage. Here, we demonstrate that there are PDCA-1(+)Siglec H(+) plasmacytoid dendritic cells (pDCs) that co-purify with BLPs and Pre-pro B cells, which express little or no CD11c or Ly6C. Removal of PDCA-1(+) pDCs separates B cell progenitors that express high levels of a Rag1-GFP reporter from Rag1-GFP(low/neg) pDCs within the BLP and Pre-pro B populations. Analysis of Flt3-ligand knockout and IL-7Rα knockout mice revealed that there is a block in B cell development at the all-lymphoid progenitor (ALP) stage, as the majority of cells within the BLP or Pre-pro B gates were PDCA-1(+) pDCs. Thus, removal of PDCA-1(+) pDCs is critical for analysis of BLP and Pre-pro B cell populations. Analysis of B cell potential within the B220(+)CD19(-) fraction demonstrated that AA4.1(+)Ly6D(+)PDCA-1(-) Pre-pro B cells gave rise to CD19(+) B cells at high frequency, while PDCA-1(+) pDCs in this fraction did not. Interestingly, the presence of PDCA-1(+) pDCs within CLPs may help to explain the conflicting results regarding the origin of these cells.

  2. Separation of plasmacytoid dendritic cells from B-cell-biased lymphoid progenitor (BLP and Pre-pro B cells using PDCA-1.

    Directory of Open Access Journals (Sweden)

    Kay L Medina

    Full Text Available B-cell-biased lymphoid progenitors (BLPs and Pre-pro B cells lie at a critical juncture between B cell specification and commitment. However, both of these populations are heterogenous, which hampers investigation into the molecular changes that occur as lymphoid progenitors commit to the B cell lineage. Here, we demonstrate that there are PDCA-1(+Siglec H(+ plasmacytoid dendritic cells (pDCs that co-purify with BLPs and Pre-pro B cells, which express little or no CD11c or Ly6C. Removal of PDCA-1(+ pDCs separates B cell progenitors that express high levels of a Rag1-GFP reporter from Rag1-GFP(low/neg pDCs within the BLP and Pre-pro B populations. Analysis of Flt3-ligand knockout and IL-7Rα knockout mice revealed that there is a block in B cell development at the all-lymphoid progenitor (ALP stage, as the majority of cells within the BLP or Pre-pro B gates were PDCA-1(+ pDCs. Thus, removal of PDCA-1(+ pDCs is critical for analysis of BLP and Pre-pro B cell populations. Analysis of B cell potential within the B220(+CD19(- fraction demonstrated that AA4.1(+Ly6D(+PDCA-1(- Pre-pro B cells gave rise to CD19(+ B cells at high frequency, while PDCA-1(+ pDCs in this fraction did not. Interestingly, the presence of PDCA-1(+ pDCs within CLPs may help to explain the conflicting results regarding the origin of these cells.

  3. Early B-cell factor 1 regulates the expansion of B-cell progenitors in a dose-dependent manner.

    Science.gov (United States)

    Åhsberg, Josefine; Ungerbäck, Jonas; Strid, Tobias; Welinder, Eva; Stjernberg, Jenny; Larsson, Malin; Qian, Hong; Sigvardsson, Mikael

    2013-11-15

    Transcription factor doses are of importance for normal and malignant B-lymphocyte development; however, the understanding of underlying mechanisms and functional consequences of reduced transcription factor levels is limited. We have analyzed progenitor and B-lineage compartments in mice carrying heterozygote mutations in the E2a, Ebf1, or Pax5 gene. Although lymphoid progenitors from Ebf1 or Pax5 heterozygote mice were specified and lineage-restricted in a manner comparable with Wt progenitors, this process was severely impaired in E2a heterozygote mutant mice. This defect was not significantly enhanced upon combined deletion of E2a with Ebf1 or Pax5. Analysis of the pre-B-cell compartment in Ebf1 heterozygote mice revealed a reduction in cell numbers. These cells expressed Pax5 and other B-lineage-associated genes, and global gene expression analysis suggested that the reduction of the pre-B-cell compartment was a result of impaired pre-B-cell expansion. This idea was supported by a reduction in IL2Rα-expressing late pre-B-cells as well as by cell cycle analysis and by the finding that the complexity of the VDJ rearrangement patterns was comparable in Wt and Ebf1(+/-) pre-B-cells, although the number of progenitors was reduced. Heterozygote deletion of Ebf1 resulted in impaired response to IL7 in vitro and reduced expression levels of pre-BCR on the cell surface, providing possible explanations for the observed stage-specific reduction in cellular expansion. Thus, transcription factor doses are critical for specification as well as expansion of B-lymphoid progenitors, providing increased insight into the molecular regulation of B-cell development.

  4. Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner*

    Science.gov (United States)

    Åhsberg, Josefine; Ungerbäck, Jonas; Strid, Tobias; Welinder, Eva; Stjernberg, Jenny; Larsson, Malin; Qian, Hong; Sigvardsson, Mikael

    2013-01-01

    Transcription factor doses are of importance for normal and malignant B-lymphocyte development; however, the understanding of underlying mechanisms and functional consequences of reduced transcription factor levels is limited. We have analyzed progenitor and B-lineage compartments in mice carrying heterozygote mutations in the E2a, Ebf1, or Pax5 gene. Although lymphoid progenitors from Ebf1 or Pax5 heterozygote mice were specified and lineage-restricted in a manner comparable with Wt progenitors, this process was severely impaired in E2a heterozygote mutant mice. This defect was not significantly enhanced upon combined deletion of E2a with Ebf1 or Pax5. Analysis of the pre-B-cell compartment in Ebf1 heterozygote mice revealed a reduction in cell numbers. These cells expressed Pax5 and other B-lineage-associated genes, and global gene expression analysis suggested that the reduction of the pre-B-cell compartment was a result of impaired pre-B-cell expansion. This idea was supported by a reduction in IL2Rα-expressing late pre-B-cells as well as by cell cycle analysis and by the finding that the complexity of the VDJ rearrangement patterns was comparable in Wt and Ebf1+/− pre-B-cells, although the number of progenitors was reduced. Heterozygote deletion of Ebf1 resulted in impaired response to IL7 in vitro and reduced expression levels of pre-BCR on the cell surface, providing possible explanations for the observed stage-specific reduction in cellular expansion. Thus, transcription factor doses are critical for specification as well as expansion of B-lymphoid progenitors, providing increased insight into the molecular regulation of B-cell development. PMID:24078629

  5. Advanced-stage III/IV follicular lymphoma. Treatment strategies for individual patients

    Energy Technology Data Exchange (ETDEWEB)

    Heinzelmann, Frank; Bamberg, Michael; Weinmann, Martin [Dept. of Radiation Oncology, Univ. of Tuebingen (Germany); Ottinger, Hellmut [Dept. of Bone Marrow Transplantation, Univ. of Essen (Germany); Engelhard, Marianne [Dept. of Radiation Oncology, Univ. of Essen (Germany); Soekler, Martin [Dept. of Internal Medicine II, Univ. of Tuebingen (Germany)

    2010-05-15

    Background: in patients with advanced-stage III/IV follicular lymphoma (FL), there are many treatment options available. The current challenge is to choose the optimal strategy for the individual patient. Methods: the literature was reviewed with respect to treatment strategies in patients with advanced FL by screening the PubMed databank. Results: in advanced-stage III/IV FL, median survival may approach 8-10 years. Treatment strategies include a watch-and-wait strategy, chemoimmunotherapy, monotherapy with rituximab, and - as an experimental approach so far - radioimmunotherapy. The use of autologous hematopoietic stem cell transplantation (HSCT) for patients in first remission or chemosensitive relapse prolongs progression-free survival while the effect on overall survival remains unclear compared to standard chemotherapy. However, long-term results are flawed by high relapse rates and risk of secondary malignancies. In patients with relapsed/chemoresistant disease, allogeneic HSCT constitutes the only curative approach but is associated with high treatment-related mortality. In the palliative setting, low-dose involved-field irradiation constitutes an effective treatment option in order to control local symptoms with potential long-lasting response. Conclusion: in case of advanced-disease FL, asymptomatic patients can be managed expectantly. In symptomatic patients, chemoimmunotherapy is regarded as standard therapy. In symptomatic elderly patients with relevant comorbidities, rituximab {+-} single-agent chemotherapy, or low-dose involved-field radiotherapy might be appropriate. For younger patients with chemoresistant/relapsed disease, allogeneic HSCT might be considered, since advances in supportive care and better patient selection have resulted in improved outcomes. (orig.)

  6. Post-operative radiation therapy for advanced-stage oropharyngeal cancer.

    Science.gov (United States)

    Hansen, Eric; Panwala, Kathryn; Holland, John

    2002-11-01

    Between 1985 and 1999, 43 patients with locally-advanced, resectable oropharyngeal cancer were treated with combined surgery and post-operative radiation therapy (RT) at Oregon Health and Science University. Five patients (12 per cent) had Stage III disease and 38 patients (88 per cent) had Stage IV disease. All patients had gross total resections of the primary tumour. Thirty-seven patients had neck dissections for regional disease. RT consisted of a mean tumour-bed dose of 63.0 Gy delivered in 1.8-2.0 Gy fractions over a mean of 49 days. At three- and five-years, the actuarial local control was 96 per cent and the actuarial local/regional control was 80 per cent. The three- and five-year actuarial rates of distant metastases were 41 per cent and 46 per cent, respectively. The actuarial overall survival at three- and five-years was 41 per cent and 34 per cent, respectively. The actuarial rates of progression-free survival were 49 per cent at three-years and 45 per cent at five years. Combined surgery and post-operative RT for advanced-stage oropharyngeal cancer results in excellent local/regional control. This particular group of patients experienced a high-rate of developing distant metastases.

  7. Lymphoma classification update: B-cell non-Hodgkin lymphomas.

    Science.gov (United States)

    Jiang, Manli; Bennani, N Nora; Feldman, Andrew L

    2017-05-01

    Lymphomas are classified based on the normal counterpart, or cell of origin, from which they arise. Because lymphocytes have physiologic immune functions that vary both by lineage and by stage of differentiation, the classification of lymphomas arising from these normal lymphoid populations is complex. Recent genomic data have contributed additional complexity. Areas covered: Lymphoma classification follows the World Health Organization (WHO) system, which reflects international consensus and is based on pathological, genetic, and clinical factors. A 2016 revision to the WHO classification of lymphoid neoplasms recently was reported. The present review focuses on B-cell non-Hodgkin lymphomas, the most common group of lymphomas, and summarizes recent changes most relevant to hematologists and other clinicians who care for lymphoma patients. Expert commentary: Lymphoma classification is a continually evolving field that needs to be responsive to new clinical, pathological, and molecular understanding of lymphoid neoplasia. Among the entities covered in this review, the 2016 revision of the WHO classification particularly impact the subclassification and genetic stratification of diffuse large B-cell lymphoma and high-grade B-cell lymphomas, and reflect evolving criteria and nomenclature for indolent B-cell lymphomas and lymphoproliferative disorders.

  8. Prognostic significance of metallothionein in B-cell lymphomas

    DEFF Research Database (Denmark)

    Poulsen, Christian Bjørn; Borup, Rehannah; Borregaard, Niels

    2006-01-01

    We have investigated metallothionein (MT) I and II mRNA and protein in B-cell lymphomas with particular reference to diffuse large B-cell lymphoma (DLBCL). The mRNA profiling was performed on Affymetrix arrays and showed up-regulated MT mRNA in 15 of 48 DLBCLs, including 12 of 23 activated B......-cell (ABC) and 3 of 9 type-3 lesions. In contrast, MT mRNA was low to undetectable in 16 germinal center B-cell (GCB)-type DLBCLs. Only 1 of 15 patients with up-regulated MT mRNA achieved a sustained remission, suggesting that up-regulated MT mRNA constitutes a significant risk factor for treatment failure......, in 115 DLBCLs, MT labeling of more than 20% lymphoma cells was associated with a significantly poorer 5-year survival, independent of the age, stage, or International Prognostic Index. Taken together, it is suggested that both increased MT mRNA and MT protein expression by more than 20% lymphoma cells...

  9. B Cell Tolerance in Health and Disease

    Directory of Open Access Journals (Sweden)

    Murali Gururajan

    2014-02-01

    Full Text Available B lymphocyte receptors are generated randomly during the bone marrow developmental phase of B cells. Hence, the B cell repertoire consists of both self and foreign antigen specificities necessitating specific tolerance mechanisms to eliminate self-reactive B cells. This review summarizes the major mechanisms of B cell tolerance, which include clonal deletion, anergy and receptor editing. In the bone marrow presentation of antigen in membrane bound form is more effective than soluble form and the role of dendritic cells in this process is discussed. Toll like receptor derived signals affect activation of B cells by certain ligands such as nucleic acids and have been shown to play crucial roles in the development of autoimmunity in several animal models. In the periphery availability of BAFF, a B cell survival factor plays a critical role in the survival of self-reactive B cells. Antibodies against BAFF have been found to be effective therapeutic agents in lupus like autoimmune diseases. Recent developments are targeting anergy to control the growth of chronic lymphocytic leukemia cells.

  10. Prospective Cohort Study Depending on the Use of Palliative Care for Advanced Stage of Cancer Patients

    Science.gov (United States)

    2017-09-05

    Stage IV Breast Cancer; Stage IV Pancreatic Cancer; Stage IV Colon Cancer; Stage IV Gastric Cancer; Stage IV Lung Cancer; Stage IV Liver Cancer; Malignant Hematologic Neoplasm; Biliary Cancer Metastatic; Pediatric Leukemia; Pediatric Lymphoma; Pediatric Brain Tumor; Pediatric Solid Tumor

  11. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Heizmann, Beate [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Sellars, MacLean [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Macias-Garcia, Alejandra [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Institute for Medical Engineering and Science at MIT, Cambridge, MA 02139 (United States); Chan, Susan, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Kastner, Philippe, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Faculté de Médecine, Université de Strasbourg, Strasbourg (France)

    2016-02-12

    The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

  12. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

    International Nuclear Information System (INIS)

    Heizmann, Beate; Sellars, MacLean; Macias-Garcia, Alejandra; Chan, Susan; Kastner, Philippe

    2016-01-01

    The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

  13. A Two Stage Solution Procedure for Production Planning System with Advance Demand Information

    Science.gov (United States)

    Ueno, Nobuyuki; Kadomoto, Kiyotaka; Hasuike, Takashi; Okuhara, Koji

    We model for ‘Naiji System’ which is a unique corporation technique between a manufacturer and suppliers in Japan. We propose a two stage solution procedure for a production planning problem with advance demand information, which is called ‘Naiji’. Under demand uncertainty, this model is formulated as a nonlinear stochastic programming problem which minimizes the sum of production cost and inventory holding cost subject to a probabilistic constraint and some linear production constraints. By the convexity and the special structure of correlation matrix in the problem where inventory for different periods is not independent, we propose a solution procedure with two stages which are named Mass Customization Production Planning & Management System (MCPS) and Variable Mesh Neighborhood Search (VMNS) based on meta-heuristics. It is shown that the proposed solution procedure is available to get a near optimal solution efficiently and practical for making a good master production schedule in the suppliers.

  14. Development of advanced air-blown entrained-flow two-stage bituminous coal IGCC gasifier

    Directory of Open Access Journals (Sweden)

    Abaimov Nikolay A.

    2017-01-01

    Full Text Available Integrated gasification combined cycle (IGCC technology has two main advantages: high efficiency, and low levels of harmful emissions. Key element of IGCC is gasifier, which converts solid fuel into a combustible synthesis gas. One of the most promising gasifiers is air-blown entrained-flow two-stage bituminous coal gasifier developed by Mitsubishi Heavy Industries (MHI. The most obvious way to develop advanced gasifier is improvement of commercial-scale 1700 t/d MHI gasifier using the computational fluid dynamics (CFD method. Modernization of commercial-scale 1700 t/d MHI gasifier is made by changing the regime parameters in order to improve its cold gas efficiency (CGE and environmental performance, namely H2/CO ratio. The first change is supply of high temperature (900°C steam in gasifier second stage. And the second change is additional heating of blast air to 900°C.

  15. Development of advanced air-blown entrained-flow two-stage bituminous coal IGCC gasifier

    Science.gov (United States)

    Abaimov, Nikolay A.; Ryzhkov, Alexander F.

    2017-10-01

    Integrated gasification combined cycle (IGCC) technology has two main advantages: high efficiency, and low levels of harmful emissions. Key element of IGCC is gasifier, which converts solid fuel into a combustible synthesis gas. One of the most promising gasifiers is air-blown entrained-flow two-stage bituminous coal gasifier developed by Mitsubishi Heavy Industries (MHI). The most obvious way to develop advanced gasifier is improvement of commercial-scale 1700 t/d MHI gasifier using the computational fluid dynamics (CFD) method. Modernization of commercial-scale 1700 t/d MHI gasifier is made by changing the regime parameters in order to improve its cold gas efficiency (CGE) and environmental performance, namely H2/CO ratio. The first change is supply of high temperature (900°C) steam in gasifier second stage. And the second change is additional heating of blast air to 900°C.

  16. Advanced strategies for end-stage heart failure: combining regenerative approaches with LVAD, a new horizon?

    Directory of Open Access Journals (Sweden)

    Cheyenne eTseng

    2015-04-01

    Full Text Available Despite the improved treatment of cardiovascular diseases the population with end-stage heart failure is progressively growing. The scarcity of the gold standard therapy, heart transplantation, demands novel therapeutic approaches. For patients awaiting transplantation ventricular assist devices have been of great benefit on survival. To allow explantation of the assist device and obviate heart transplantation, sufficient and durable myocardial recovery is necessary. However, explant rates so far are low. Combining mechanical circulatory support with regenerative therapies such as cell(-based therapy and biomaterials might give rise to improved long-term results. Although synergistic effects are suggested with mechanical support and stem cell therapy, evidence in both preclinical and clinical setting is lacking. This review focuses on advanced and innovative strategies for the treatment of end-stage heart failure and furthermore appraises clinical experience with combined strategies.

  17. Maternal immunization with ovalbumin prevents neonatal allergy development and up-regulates inhibitory receptor FcγRIIB expression on B cells

    Directory of Open Access Journals (Sweden)

    Duarte Alberto JS

    2010-03-01

    Full Text Available Abstract Background Preconception allergen immunization prevents neonatal allergen sensitization in mice by a complex interaction between regulatory cells/factors and antibodies. The present study assessed the influence of maternal immunization with ovalbumin (OVA on the immune response of 3 day-old and 3 week-old offspring immunized or non-immunized with OVA and evaluated the effect of IgG treatment during fetal development or neonatal period. Results Maternal immunization with OVA showed increased levels of FcγRIIb expression in splenic B cells of neonates, which were maintained for up to 3 weeks and not affected by additional postnatal OVA immunization. Maternal immunization also exerted a down-modulatory effect on both IL-4 and IFN-γ-secreting T cells and IL-4 and IL-12- secreting B cells. Furthermore, immunized neonates from immunized mothers showed a marked inhibition of antigen-specifc IgE Ab production and lowered Th2/Th1 cytokine levels, whereas displaying enhanced FcγRIIb expression on B cells. These offspring also showed reduced antigen-specific proliferative response and lowered B cell responsiveness. Moreover, in vitro evaluation revealed an impairment of B cell activation upon engagement of B cell antigen receptor by IgG from OVA-immunized mice. Finally, in vivo IgG transference during pregnancy or breastfeeding revealed that maternal Ab transference was able to increase regulatory cytokines, such as IL-10, in the prenatal stage; yet only the postnatal treatment prevented neonatal sensitization. None of the IgG treatments induced immunological changes in the offspring, as it was observed for those from OVA-immunized mothers. Conclusion Maternal immunization upregulates the inhibitory FcγRIIb expression on offspring B cells, avoiding skewed Th2 response and development of allergy. These findings contribute to the advancement of prophylactic strategies to prevent allergic diseases in early life.

  18. Long-Term Results of Concurrent Chemoradiotherapy for Advanced N2-3 Stage Nasopharyngeal Carcinoma.

    Directory of Open Access Journals (Sweden)

    Li Yin

    Full Text Available N-stage is related to distant metastasis in nasopharyngeal carcinoma (NPC patients. The purpose of this study was to evaluate the efficacy and toxicity of different nedaplatin-based chemotherapy regimens in advanced N2-3 stage NPC patients treated with intensity modulated radiation therapy (IMRT.Between April 2005 and December 2009, a total of 128 patients with N2-3 advanced NPC were retrospectively analyzed. Patients were treated with IMRT concurrent with 2 cycles of chemotherapy consisting of either nedaplatin plus paclitaxel (NP group, n = 67 or nedaplatin plus fluorouracil and paclitaxel (NFP group, n = 61. Two to four cycles of adjuvant chemotherapy were then administered every 21 days following concurrent chemoradiotherapy.With a median follow-up of 60 months, the 5-year overall survival (OS, progression-free survival (PFS, local-regional recurrence-free survival (LRRFS, and distant metastasis-free survival (DMFS for all patients were 81.4%, 71.5%, 87.8% and 82.0%, respectively. No significant difference in PFS (66.6% vs. 76.7%, P = 0.212 and LRRFS rates (89.0% vs. 86.3%, P = 0.664 was observed between the NP and NFP groups. The 5-year OS (75.4% vs. 88.5%, P = 0.046 and DMFS (75.1% vs. 89.0%, P = 0.042 rate were superior in the NFP group compared with the NP group. The NFP group had a higher incidence of grade 3-4 acute toxicities including bone marrow suppression (leukopenia: χ2 = 3.935, P = 0.047; anemia: χ2 = 9.760, P = 0.002; thrombocytopenia: χ2 = 8.821, P = 0.003, and both liver and renal dysfunction (χ2 = 5.206, P = 0.023 compared with the NP group. Late toxicities were moderate and no difference was observed between the two groups.IMRT concurrent with nedaplatin-based chemotherapy is an advocated regimen for patients with advanced N2-3 stage NPC. Patients with advanced N2-3 stage may be better candidates for the NFP regimen although this regimen was associated with a high acute toxicity rate.

  19. Long-Term Results of Concurrent Chemoradiotherapy for Advanced N2-3 Stage Nasopharyngeal Carcinoma.

    Science.gov (United States)

    Yin, Li; Bian, Xiu-Hua; Wang, Xue; Chen, Meng; Wu, Jing; Xu, Jian-Hua; Qian, Pu-Dong; Guo, Wen-Jie; Jiang, Xue-Song; Zhu, Huan-Feng; Gu, Jia-Jia; Wu, Jian-Feng; Zhang, Ye-wei; He, Xia

    2015-01-01

    N-stage is related to distant metastasis in nasopharyngeal carcinoma (NPC) patients. The purpose of this study was to evaluate the efficacy and toxicity of different nedaplatin-based chemotherapy regimens in advanced N2-3 stage NPC patients treated with intensity modulated radiation therapy (IMRT). Between April 2005 and December 2009, a total of 128 patients with N2-3 advanced NPC were retrospectively analyzed. Patients were treated with IMRT concurrent with 2 cycles of chemotherapy consisting of either nedaplatin plus paclitaxel (NP group, n = 67) or nedaplatin plus fluorouracil and paclitaxel (NFP group, n = 61). Two to four cycles of adjuvant chemotherapy were then administered every 21 days following concurrent chemoradiotherapy. With a median follow-up of 60 months, the 5-year overall survival (OS), progression-free survival (PFS), local-regional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) for all patients were 81.4%, 71.5%, 87.8% and 82.0%, respectively. No significant difference in PFS (66.6% vs. 76.7%, P = 0.212) and LRRFS rates (89.0% vs. 86.3%, P = 0.664) was observed between the NP and NFP groups. The 5-year OS (75.4% vs. 88.5%, P = 0.046) and DMFS (75.1% vs. 89.0%, P = 0.042) rate were superior in the NFP group compared with the NP group. The NFP group had a higher incidence of grade 3-4 acute toxicities including bone marrow suppression (leukopenia: χ2 = 3.935, P = 0.047; anemia: χ2 = 9.760, P = 0.002; thrombocytopenia: χ2 = 8.821, P = 0.003), and both liver and renal dysfunction (χ2 = 5.206, P = 0.023) compared with the NP group. Late toxicities were moderate and no difference was observed between the two groups. IMRT concurrent with nedaplatin-based chemotherapy is an advocated regimen for patients with advanced N2-3 stage NPC. Patients with advanced N2-3 stage may be better candidates for the NFP regimen although this regimen was associated with a high acute toxicity rate.

  20. CIMAvax-EGF®: Therapeutic Vaccine Against Non-small Cell Lung Cancer in Advanced Stages

    Directory of Open Access Journals (Sweden)

    Diana Rosa Fernández Ruiz

    2017-02-01

    Full Text Available Biotechnology is one of the scientific activities deployed by the Cuban State, which shows greater results and impact on the of the Cuban population health. It has increased the therapeutic repertoire in dealing with oncological diseases with products such as CIMAvax-EGF®, the first therapeutic vaccine of its kind, from the Molecular Immunology Center, against non-small cell lung cancer in advanced stages IIIB IV. The application of this product already extends to Primary Health Care with encouraging results, by prolonging the survival of patients with higher quality of life.

  1. Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome.

    Science.gov (United States)

    Carsetti, Rita; Valentini, Diletta; Marcellini, Valentina; Scarsella, Marco; Marasco, Emiliano; Giustini, Ferruccio; Bartuli, Andrea; Villani, Alberto; Ugazio, Alberto G

    2015-03-01

    Children with Down syndrome (DS) have increased susceptibility to infections and a high frequency of leukemia and autoimmune disorders, suggesting that immunodeficiency and immune dysfunction are integral parts of the syndrome. A reduction in B-cell numbers has been reported, associated with moderate immunodeficiency and normal immunoglobulin levels. Here, we compared B-cell populations of 19 children with DS with those in healthy age-matched controls. We found that all steps of peripheral B-cell development are altered in DS, with a more severe defect during the later stages of B-cell development. Transitional and mature-naïve B-cell numbers are reduced by 50% whereas switched memory B cells represent 10-15% of the numbers in age-matched controls. Serum IgM levels were slightly reduced, but all other immunoglobulin isotypes were in the normal range. The frequency of switched memory B cells specific for vaccine antigens was significantly lower in affected children than in their equivalently vaccinated siblings. In vitro switched memory B cells of patients with DS have an increased ability to differentiate into antibody-forming cells in response to TLR9 signals. Tailored vaccination schedules increasing the number of switched memory B cells may improve protection and reduce the risk of death from infection in DS. © 2014 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. The transcription factor Gli3 promotes B cell development in fetal liver through repression of Shh.

    Science.gov (United States)

    Solanki, Anisha; Lau, Ching-In; Saldaña, José Ignacio; Ross, Susan; Crompton, Tessa

    2017-07-03

    Before birth, B cells develop in the fetal liver (FL). In this study, we show that Gli3 activity in the FL stroma is required for B cell development. In the Gli3-deficient FL, B cell development was reduced at multiple stages, whereas the Sonic hedgehog (Hh [Shh])-deficient FL showed increased B cell development, and Gli3 functioned to repress Shh transcription. Use of a transgenic Hh-reporter mouse showed that Shh signals directly to developing B cells and that Hh pathway activation was increased in developing B cells from Gli3-deficient FLs. RNA sequencing confirmed that Hh-mediated transcription is increased in B-lineage cells from Gli3-deficient FL and showed that these cells expressed reduced levels of B-lineage transcription factors and B cell receptor (BCR)/pre-BCR-signaling genes. Expression of the master regulators of B cell development Ebf1 and Pax5 was reduced in developing B cells from Gli3-deficient FL but increased in Shh-deficient FL, and in vitro Shh treatment or neutralization reduced or increased their expression, respectively. © 2017 Solanki et al.

  3. High levels of SOX5 decrease proliferative capacity of human B cells, but permit plasmablast differentiation.

    Directory of Open Access Journals (Sweden)

    Mirzokhid Rakhmanov

    Full Text Available Currently very little is known about the differential expression and function of the transcription factor SOX5 during B cell maturation. We identified two new splice variants of SOX5 in human B cells, encoding the known L-SOX5B isoform and a new shorter isoform L-SOX5F. The SOX5 transcripts are highly expressed during late stages of B-cell differentiation, including atypical memory B cells, activated CD21low B cells and germinal center B cells of tonsils. In tonsillar sections SOX5 expression was predominantly polarized to centrocytes within the light zone. After in vitro stimulation, SOX5 expression was down-regulated during proliferation while high expression levels were permissible for plasmablast differentiation. Overexpression of L-SOX5F in human primary B lymphocytes resulted in reduced proliferation, less survival of CD138neg B cells, but comparable numbers of CD138+CD38hi plasmablasts compared to control cells. Thus, our findings describe for the first time a functional role of SOX5 during late B cell development reducing the proliferative capacity and thus potentially affecting the differentiation of B cells during the germinal center response.

  4. B-cell waste classification sampling plan

    Energy Technology Data Exchange (ETDEWEB)

    HOBART, R.L.

    1999-11-20

    This report documents the methods used to collect samples and analyze data necessary to verify and/or determine the radionuclide content of the 324 Facility B-Cell decontamination and decommissioning waste stream.

  5. The early history of B cells.

    Science.gov (United States)

    Cooper, Max D

    2015-03-01

    The separate development of functionally intertwined lineages of lymphocytes known as B cells and T cells is now recognized as a fundamental organizing principle of the adaptive immune system in all vertebrates. Immunologists strive to define the different sublineages of the clonally diverse B cells and T cells, how they interact with each other and how they interact with innate lymphoid cells and other elements of the innate immune system to counter infections, cancer and the development of autoimmune and inflammatory diseases. On the 50th anniversary of the recognition of B cells as a discrete cell lineage, this Timeline article recounts some of the milestones marking the development of the concept that B cells are a functionally and developmentally distinct arm of the adaptive immune system.

  6. Increased expression of tumor necrosis factor-α is associated with advanced colorectal cancer stages.

    Science.gov (United States)

    Al Obeed, Omar A; Alkhayal, Khayal A; Al Sheikh, Abdulmalik; Zubaidi, Ahmad M; Vaali-Mohammed, Mansoor-Ali; Boushey, Robin; Mckerrow, James H; Abdulla, Maha-Hamadien

    2014-12-28

    To detect the expression of tumor necrosis factor-α (TNF-α) in colorectal cancer (CRC) cells among Saudi patients, and correlate its expression with clinical stages of cancer. Archival tissue specimens were collected from 30 patients with CRC who had undergone surgical intervention at King Khalid University Hospital. Patient demographic information, including age and gender, tumor sites, and histological type of CRC, was recorded. To measure TNF-α mRNA expression in CRC, total RNA was extracted from tumor formalin-fixed, paraffin-embedded, and adjacent normal tissues. Reverse transcription and reverse transcription polymerase chain reaction were performed. Colorectal tissue microarrays were constructed to investigate the protein expression of TNF-α by immunohistochemistry. The relative expression of TNF-α mRNA in colorectal cancer was significantly higher than that seen in adjacent normal colorectal tissue. High TNF-α gene expression was associated with Stage III and IV neoplasms when compared with earlier tumor stages (P = 0.004). Eighty-three percent of patients (25/30) showed strong TNF-α positive staining, while only 10% (n = 3/30) of patients showed weak staining, and 7% (n = 2/30) were negative. We showed the presence of elevated TNF-α gene expression in cancer cells, which strongly correlated with advanced stages of tumor. High levels of TNF-α expression could be an independent diagnostic indicator of colorectal cancer, and targeting TNF-α might be a promising prognostic tool by assessment of the clinical stages of CRC.

  7. BH3-only protein Bim predicts advanced stage of cutaneous melanoma.

    Science.gov (United States)

    Gambichler, T; Rooms, I; Scholl, L; Stockfleth, E; Stücker, M; Sand, M

    2016-11-01

    Bim having strong pro-apoptotic effects belongs to the BH3-only proteins of the Bcl-2 protein family and contributes to survival pathways in cancer cells. We aimed to investigate Bim protein expression in cutaneous melanoma (CM). Bim protein expression was assessed by immunohistochemistry in primary and metastatic melanomas and correlated with clinical and histopathological features. The Bim immunoreactivity score of the primary melanomas investigated (4.6 ± 1.5) was significantly (P Bim expression was significantly associated with primary nodular melanoma type (P = 0.005). Moreover, Bim expression was significantly inversely correlated with tumour thickness (r = -0.36; P = 0.0035), advanced stage of disease (stage III and IV; r = -0.60; P Bim expression (P = 0.0010, odds ratio: 0.22, 95% CI: 0.10-0.56) on multivariate analysis; however, Bim was not shown to be an independent predictor for disease relapse (P = 0.40) and disease-related death (P = 0.77). Our data demonstrate that Bim protein expression is significantly inversely correlated with melanoma features that are associated with worse prognosis. We have shown that Bim protein expression in CM is an independent predictor for advanced disease confirming that this pro-apoptotic BH3-only protein might be a potent biomarker and promising therapeutic target. © 2016 European Academy of Dermatology and Venereology.

  8. Treatment outcome of advance staged oral cavity cancer: concurrent chemoradiotherapy compared with primary surgery.

    Science.gov (United States)

    Tangthongkum, Manupol; Kirtsreesakul, Virat; Supanimitjaroenporn, Pasawat; Leelasawatsuk, Peesit

    2017-06-01

    Concurrent chemoradiotherapy (CCRT) has been reported as effective and has become an acceptable treatment in advanced oral cancer. However, to date there is insufficient data to conclude that CCRT provides a good survival outcome. The purpose of this study was to compare survival rates and complications in patients with resectable advanced oral cavity squamous cell carcinoma treated with either CCRT or surgery with adjuvant radiotherapy (RT)/chemoradiotherapy (CRT). Stage III or IVa oral cavity carcinoma patients treated with curative intent by either CCRT or surgery with adjuvant RT were identified over a 7-year period (2009-2015). Survival rates and treatment complications were analyzed and compared between the two groups. 61 patients underwent CCRT and 128 patients underwent surgical excision and received postoperative RT. There was no statistically significant difference in survival outcome between the two treatment groups. 5-year overall survival rates (OS) were 33 versus 24% (P = 0.191) and the disease-specific survival rates (DSS) were 27 versus 25% (P = 0.857) when comparing the CCRT group and surgery with adjuvant RT/CRT group, respectively. Long-term complications were comparable between the two groups. CCRT has comparable survival outcome and complications for the treatment of advanced oral cavity squamous cell carcinoma, compared to surgery with adjuvant RT/CRT.

  9. A population-based study of prognosis in advanced stage follicular lymphoma managed by watch and wait

    DEFF Research Database (Denmark)

    El-Galaly, Tarec Christoffer; Bilgrau, Anders E; de Nully Brown, Peter

    2015-01-01

    Watch and wait (WAW) is a common approach for asymptomatic, advanced stage follicular lymphoma (FL), but single-agent rituximab is an alternative for these patients. In this nationwide study we describe the outcome of patients selected for WAW. A cohort of 286 out of 849 (34%) stage III-IVA FL...

  10. Loss of SerpinA5 protein expression is associated with advanced-stage serous ovarian tumors

    NARCIS (Netherlands)

    Bijsmans, Ingrid T. G. W.; Smits, Kim M.; de Graeff, Pauline; Wisman, G. Bea A.; van der Zee, Ate G. J.; Slangen, Brigitte F.; de Bruine, Adriaan P.; van Engeland, Manon; Sieben, Nathalie L.; Van de Vijver, Koen K.

    Epithelial ovarian cancer, the most lethal neoplasm of the female genital tract, is usually diagnosed at an advanced stage as obvious symptoms are absent at early stages. This disease is believed to originate from malignant transformation of the ovarian surface epithelium or fallopian tube.

  11. Early B cell factor 1 regulates B cell gene networks by activation, repression, and transcription- independent poising of chromatin.

    Science.gov (United States)

    Treiber, Thomas; Mandel, Elizabeth M; Pott, Sebastian; Györy, Ildiko; Firner, Sonja; Liu, Edison T; Grosschedl, Rudolf

    2010-05-28

    The transcription factor early B cell factor-1 (Ebf1) is a key determinant of B lineage specification and differentiation. To gain insight into the molecular basis of Ebf1 function in early-stage B cells, we combined a genome-wide ChIP sequencing analysis with gain- and loss-of-function transcriptome analyses. Among 565 genes that are occupied and transcriptionally regulated by Ebf1, we identified large sets involved in (pre)-B cell receptor and Akt signaling, cell adhesion, and migration. Interestingly, a third of previously described Pax5 targets was found to be occupied by Ebf1. In addition to Ebf1-activated and -repressed genes, we identified targets at which Ebf1 induces chromatin changes that poise the genes for expression at subsequent stages of differentiation. Poised chromatin states on specific targets could also be established by Ebf1 expression in T cells but not in NIH 3T3 cells, suggesting that Ebf1 acts as a "pioneer" factor in a hematopoietic chromatin context. Copyright 2010 Elsevier Inc. All rights reserved.

  12. Nodal-staging surgery for locally advanced cervical cancer in the era of PET.

    Science.gov (United States)

    Gouy, Sebastien; Morice, Philippe; Narducci, Fabrice; Uzan, Catherine; Gilmore, Jennifer; Kolesnikov-Gauthier, Hélène; Querleu, Denis; Haie-Meder, Christine; Leblanc, Eric

    2012-05-01

    Chemoradiation therapy is deemed the standard treatment by many North American and European teams for treatment of locally advanced cervical cancer. The prevalence of para-aortic nodal metastasis in these tumours is 10-25%. PET (with or without CT) is the most accurate imaging modality to assess extrapelvic disease in such tumours. The true-positive rate of PET is high, suggesting that surgical staging is not necessary if uptake takes place in the para-aortic region. Nevertheless, false-negative results (in the para-aortic region) have been recorded in 12% of patients, rising to 22% in those with uptake during PET of the pelvic nodes. In such situations, laparoscopic surgical para-aortic staging still has an important role for detection of patients with occult para-aortic spread misdiagnosed on PET or PET-CT, allowing optimisation of treatment (extension of radiation therapy fields to include the para-aortic area). Complications of the laparoscopic procedure were noted in 0-7% of patients. Survival of individuals (missed by PET) with para-aortic nodal metastasis of 5 mm or less (and managed by extended field chemoradiation therapy) seems to be similar to survival of those without para-aortic spread, suggesting a positive therapeutic effect of the addition of staging surgery. Nevertheless, the effect on survival of potential delay of chemoradiation owing to use of PET and staging surgery, and acute and late complications of surgery followed by chemoradiation therapy (particularly in case of extended field chemoradiation to para-aortic area), need to be studied. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Establishment and maintenance of B cell identity.

    Science.gov (United States)

    Grosschedl, Rudolf

    2013-01-01

    B lymphocyte differentiation is dependent on an intricate interplay of transcription factors and signaling pathways to establish a lineage-specific program of gene expression. Functional perturbations of several transcription factors by gain- or loss-of-function experiments indicated that E2A, EBF1, and FoxO1 are required for the specification of the B cell lineage, whereas Pax5 antagonizes alternative cell fates by repressing genes that allow for responsiveness to T lymphoid- and myeloid-promoting signals. However, genome-wide analysis of EBF1-binding sites and their functional interrogation indicated that EBF1 is involved in both activation of the B cell program and repression of alternative cell fates. Recent studies indicate that EBF1 function is required throughout the B cell lineage until the onset of plasma cell differentiation and includes a role in the maintenance of B cell identity. Thus, early B cell differentiation requires intertwined networks of transcription factors in which EBF1 collaborates with E2A and FoxO1 to activate the B lineage program and acts together with Pax5 to antagonize alternative cell fates. Copyright © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.

  14. B cell phenotypes in patients with rheumatoid arthritis relapsing after rituximab: expression of B cell-activating factor-binding receptors on B cell subsets.

    Science.gov (United States)

    Becerra, E; De La Torre, I; Leandro, M J; Cambridge, G

    2017-12-01

    Serum levels of B cell-activating factor (BAFF) rise following rituximab (RTX) therapy in patients with rheumatoid arthritis (RA). Initiation of naive B cell return to the periphery and autoreactive B cell expansion leading to relapse after RTX may therefore be linked to interactions between BAFF and BAFF-binding receptors (BBR). Relationships between serum BAFF and BBR expression [(BAFFR, calcium signal modulating cyclophilic ligand interactor (TACI) and B cell maturation antigen (BCMA)] were determined on B cell subsets, defined using immunoglobulin (Ig)D/CD38. Twenty pre-RTX and 18 RA patients relapsing after B cell depletion were included. Results were analysed with respect to timing of relapse up to 7 months after peripheral B cell return (≥ 5 B cells/μl) and to serum BAFF levels. After B cell return, B cell populations from relapsing patients had significantly lower BAFFR + expression compared to HC and pre-RTX patients. The percentage of BAFFR + B cells increased with time after B cell return and was correlated inversely with serum BAFF levels. BAFFR expression remained reduced. The percentage of TACI + memory B cells were lower in RA patients after RTX compared with healthy controls (HC). BCMA expression (% and expression) did not differ between patients and HC. Relapse following B cell return appeared largely independent of the percentage of BAFFR + or percentage of BCMA + B cells or serum BAFF levels. The lower percentage of TACI + memory B cells may reduce inhibitory signalling for B cell differentiation. In patients relapsing at longer periods after B cell return, recovery of the B cell pool was more complete, suggesting that selection or expansion of autoreactive B cells may be needed to precipitate relapse. © 2017 British Society for Immunology.

  15. Lenalidomide and Combination Chemotherapy (DA-EPOCH-R) in Treating Patients With MYC-Associated B-Cell Lymphomas

    Science.gov (United States)

    2017-09-28

    Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Adult Hodgkin Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Adult Hodgkin Lymphoma; Stage II Chronic Lymphocytic

  16. Ikaros is absolutely required for pre-B cell differentiation by attenuating IL-7 signals.

    Science.gov (United States)

    Heizmann, Beate; Kastner, Philippe; Chan, Susan

    2013-12-16

    Pre-B cell receptor (pre-BCR) signaling and migration from IL-7-rich environments cooperate to drive pre-B cell differentiation via transcriptional programs that remain unclear. We show that the Ikaros transcription factor is required for the differentiation of large pre-B to small pre-B cells. Mice deleted for Ikaros in pro/pre-B cells show a complete block of differentiation at the fraction C' stage, and Ikaros-null pre-B cells cannot differentiate upon withdrawal of IL-7 in vitro. Restoration of Ikaros function rescues pre-B cell differentiation in vitro and in vivo and depends on DNA binding. Ikaros is required for the down-regulation of the pre-BCR, Igκ germline transcription, and Ig L chain recombination. Furthermore, Ikaros antagonizes the IL-7-dependent regulation of >3,000 genes, many of which are up- or down-regulated between fractions C' and D. Affected genes include those important for survival, metabolism, B cell signaling, and function, as well as transcriptional regulators like Ebf1, Pax5, and the Foxo1 family. Our data thus identify Ikaros as a central regulator of IL-7 signaling and pre-B cell development.

  17. Excessive amounts of mu heavy chain block B-cell development.

    Science.gov (United States)

    Zhu, Lingqiao; Chang, Cheong-Hee; Dunnick, Wesley

    2011-09-01

    Antigen-independent B-cell development occurs in several stages that depend on the expression of Ig heavy and light chain. We identified a line of mice that lacked mature B cells in the spleen. This mouse line carried approximately 11 copies of a transgene of the murine heavy chain constant region locus, and B-lineage cells expressed excessive amounts of the intracellular μ heavy chain. B-cell development failed in the bone marrow at the pro/pre B-cell transition, and examination of other lines with various copy numbers of the same transgene suggested that deficiencies in B-cell development increased with increased transgene copy number. Expression of a transgenic (Tg) light chain along with the Tg μ heavy chain led to minimal rescue of B-cell development in the bone marrow and B cells in the spleen. There are several potential mechanisms for the death of pro/pre B cells as a consequence of excess heavy chain expression.

  18. B-Cell-Activating Factor and the B-Cell Compartment in HIV/SIV Infection

    Science.gov (United States)

    Borhis, Gwenoline; Trovato, Maria; Chaoul, Nada; Ibrahim, Hany M.; Richard, Yolande

    2017-01-01

    With the goal to design effective HIV vaccines, intensive studies focused on broadly neutralizing antibodies, which arise in a fraction of HIV-infected people. Apart from identifying new vulnerability sites in the viral envelope proteins, these studies have shown that a fraction of these antibodies are produced by self/poly-reactive B-cells. These findings prompted us to revisit the B-cell differentiation and selection process during HIV/SIV infection and to consider B-cells as active players possibly shaping the helper T-cell program within germinal centers (GCs). In this context, we paid a particular attention to B-cell-activating factor (BAFF), a key cytokine in B-cell development and immune response that is overproduced during HIV/SIV infection. As it does in autoimmune diseases, BAFF excess might contribute to the abnormal rescue of self-reactive B-cells at several checkpoints of the B-cell development and impair memory B-cell generation and functions. In this review, we first point out what is known about the functions of BAFF/a proliferation-inducing ligand and their receptors [B-cell maturation, transmembrane activator and CAML interactor (TACI), and BAFF-R], in physiological and pathophysiological settings, in mice and humans. In particular, we highlight recent results on the previously underappreciated regulatory functions of TACI and on the highly regulated production of soluble TACI and BAFF-R that act as decoy receptors. In light of recent data on BAFF, TACI, and BAFF-R, we then revisit the altered phenotypes and functions of B-cell subsets during the acute and chronic phase of HIV/SIV infection. Given the atypical phenotype and reduced functions of memory B-cells in HIV/SIV infection, we particularly discuss the GC reaction, a key checkpoint where self-reactive B-cells are eliminated and pathogen-specific memory B-cells and plasmablasts/cells are generated in physiological settings. Through its capacity to differentially bind and process BAFF-R and

  19. Advanced-Stage Primary Cutaneous T-Cell Lymphoma Treated with Bexarotene and Denileukin Diftitox

    Directory of Open Access Journals (Sweden)

    Iván Cervigón-González

    2011-02-01

    Full Text Available Advanced-stage primary cutaneous T-cell lymphoma has an unfavorable prognosis and low survival rates. Aggressive treatment with chemotherapy is not curative and causes considerable side effects. The combination of bexarotene and denileukin diftitox is associated with an acceptable safety profile and a likely synergistic effect because bexarotene is capable of modulating expression of IL-2 receptor and enhance the susceptibility of T-cell leukemia cells to denileukin diftitox. In the case reported here, the response to this combined treatment was satisfactory and well tolerated. The patient showed a complete regression of pruritus, restlessness, and insomnia. Skin lesions improved partially, and lymphadenopathy was reduced and finally disappeared completely.

  20. Characterising B cell numbers and memory B cells in HIV infected and uninfected Malawian adults

    Directory of Open Access Journals (Sweden)

    Gordon Stephen

    2010-09-01

    Full Text Available Abstract Background Untreated human immunodeficiency virus (HIV disease disrupts B cell populations causing reduced memory and reduced naïve resting B cells leading to increases in specific co-infections and impaired responses to vaccines. To what extent antiretroviral treatment reverses these changes in an African population is uncertain. Methods A cross-sectional study was performed. We recruited HIV-uninfected and HIV-infected Malawian adults both on and off antiretroviral therapy attending the Queen Elizabeth Central hospital in Malawi. Using flow cytometry, we enumerated B cells and characterized memory B cells and compared these measurements by the different recruitment groups. Results Overall 64 participants were recruited - 20 HIV uninfected (HIV-, 30 HIV infected ART naïve (HIV+N and 14 HIV-infected ART treated (HIV+T. ART treatment had been taken for a median of 33 months (Range 12-60 months. Compared to HIV- the HIV+N adults had low absolute number of naïve resting B cells (111 vs. 180 cells/μl p = 0.008; reduced memory B cells (27 vs. 51 cells/μl p = 0.0008. The HIV+T adults had B-cell numbers similar to HIV- except for memory B cells that remained significantly lower (30 vs. 51 cells/μl p = 0.02. In the HIV+N group we did not find an association between CD4 count and B cell numbers. Conclusions HIV infected Malawian adults have abnormal B-cell numbers. Individuals treated with ART show a return to normal in B-cell numbers but a persistent deficit in the memory subset is noted. This has important implications for long term susceptibility to co-infections and should be evaluated further in a larger cohort study.

  1. Lymphadenectomy in locally advanced cervical cancer study (LiLACS): Phase III clinical trial comparing surgical with radiologic staging in patients with stages IB2-IVA cervical cancer.

    Science.gov (United States)

    Frumovitz, Michael; Querleu, Denis; Gil-Moreno, Antonio; Morice, Philippe; Jhingran, Anuja; Munsell, Mark F; Macapinlac, Homer A; Leblanc, Eric; Martinez, Alejandra; Ramirez, Pedro T

    2014-01-01

    Radiation treatment planning for women with locally advanced cervical cancer (stages IB2-IVA) is often based on positron emission tomography (PET). PET, however, has poor sensitivity in detecting metastases in aortocaval nodes. We have initiated a study with the objective of determining whether pre-therapeutic laparoscopic surgical staging followed by tailored chemoradiation improves survival as compared with PET/computed tomography (CT) radiologic staging alone followed by chemoradiation. This international, multicenter phase III trial will enroll 600 women with stages IB2-IVA cervical cancer and PET/CT findings showing fluorodeoxyglucose-avid pelvic nodes and fluorodeoxyglucose-negative para-aortic nodes. Eligible patients will be randomized to undergo either pelvic radiotherapy with chemotherapy (standard-of-care arm) or surgical staging via a minimally invasive extraperitoneal approach followed by tailored radiotherapy with chemotherapy (experimental arm). The primary end point is overall survival. Secondary end points are disease-free survival, short- and long-term morbidity with pre-therapeutic surgical staging, and determination of anatomic locations of metastatic para-aortic nodes in relationship to the inferior mesenteric artery. We believe this study will show that tailored chemoradiation after pre-therapeutic surgical staging improves survival as compared with chemoradiation based on PET/CT in women with stages IB2-IVA cervical cancer. Copyright © 2014 AAGL. Published by Elsevier Inc. All rights reserved.

  2. T Cell Histiocyte Rich Large B Cell Lymphoma Presenting as Hemophagocytic Lymphohistiocytosis: An Uncommon Presentation of a Rare Disease

    Directory of Open Access Journals (Sweden)

    Uroosa Ibrahim

    2017-01-01

    Full Text Available T cell histiocyte rich large B cell lymphoma (THRLBCL is a rare subtype of non-Hodgkin’s lymphoma characterized by malignant B cells with reactive T lymphocytes. The pathophysiology is thought to involve cytokine-mediated evasion of T cell immune response by malignant B cells. It usually presents at an advanced stage with extranodal involvement. An extremely unusual manifestation of the disease is hemophagocytic lymphohistiocytosis (HLH which is a hyperinflammatory disorder. We present a case of a 43-year-old male who presented with recurrent fever and recent radiologic imaging showing splenomegaly and right inguinal lymphadenopathy. On presentation, he had a fever of 105°F. Laboratory work-up was consistent with pancytopenia, elevated lactate dehydrogenase, elevated D-dimer, and a ferritin of 24,247 ng/mL. The patient was started on steroid therapy. An excisional biopsy of the right inguinal lymph node was consistent with a diagnosis of THRLBCL and the patient subsequently received six cycles of chemotherapy with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone after which a PET-CT scan showed no evidence of biologically active disease and ferritin was down to 822 ng/mL. We discuss the clinical manifestations and diagnostic and therapeutic considerations of this rare disease along with a review of reported cases in the literature.

  3. Memory B Cells of Mice and Humans.

    Science.gov (United States)

    Weisel, Florian; Shlomchik, Mark

    2017-04-26

    We comprehensively review memory B cells (MBCs), covering the definition of MBCs and their identities and subsets, how MBCs are generated, where they are localized, how they are maintained, and how they are reactivated. Whereas naive B cells adopt multiple fates upon stimulation, MBCs are more restricted in their responses. Evolving work reveals that the MBC compartment in mice and humans consists of distinct subpopulations with differing effector functions. We discuss the various approaches to define subsets and subset-specific roles. A major theme is the need to both deliver faster effector function upon reexposure and readapt to antigenically variant pathogens while avoiding burnout, which would be the result if all MBCs generated only terminal effector function. We discuss cell-intrinsic differences in gene expression and signaling that underlie differences in function between MBCs and naive B cells and among MBC subsets and how this leads to memory responses.

  4. Determining the satisfaction levels of the family members of patients with advanced-stage cancer.

    Science.gov (United States)

    Ozcelik, Hanife; Cakmak, Deniz Ezgi; Fadiloglu, Cicek; Yildirim, Yasemin; Uslu, Ruchan

    2015-06-01

    The objective of our study was to determine the satisfaction levels of family members of patients with advanced-stage cancer. This descriptive study was conducted in the palliative care and medical oncology clinics of a university hospital in the province of Izmir between April of 2011 and January of 2012. The study sample consisted of a total of 145 family members, who were selected from among the family members of patients with advanced-stage cancer receiving palliative treatment. The study data were obtained using the Patient Description Form and Family Satisfaction Scale during face-to-face interviews with patients. Some 67% of patients were female and 33% male, 70% were married, 35% were high school graduates, and 34.5% were housewives. The average total family satisfaction score was 76.87 ± 1.14, and the average scores for the component variables were as follows: information giving 74.37 ± 1.28, availability of care 78.40 ± 1.17, physical care 78.99 ± 1.09, and psychosocial care 74.52 ± 1.30. We found a relationship between the level of satisfaction of family members and (1) gender, (2) occupation, (3) presence of someone supporting the care, and (4) possession of sufficient information about the patient (p Satisfaction levels of participants were determined to be high. We found that family member satisfaction levels were affected by gender and occupation, the existence of someone supporting the care, and possession of sufficient information about the patient.

  5. Neoadjuvant chemoradiotherapy for cStage IIIA/IIIB locally advanced gastric cancer

    International Nuclear Information System (INIS)

    Inoue, Tatsushi; Suto, Hiromasa; Kashiwagi, Hirotaka

    2010-01-01

    We evaluated the impact of neoadjuvant chemoradiotherapy (NACRT) with radio-enhancing S-1 for locally advanced gastric cancer. Patients who had a gastric cancer infiltrating into other organs (T4) or with bulky N2 were enrolled in this study. They received oral S-1 (65 mg/m 2 /day) administration and 50 Gy radiotherapy followed by radical surgery. In 12 subjects (male:female ratio, 7:5; mean age, 70.0 years), 10 (83.3%) completed NACRT and 12 (100%) underwent curative resection. Histopathological efficacy (≥Grade 1b) and down staging were observed 6 patients (75.0%) and 5 (62.5%), respectively, in 8 T4 patients. The efficacy was ≥Grade 2 in all 4 patients with bulky N2. No extra-nodal invasion was noted. In this series 1-and 3-year survival rates were 90.9% and 60.6%, respectively, during a mean observation period of 18.6 months. This procedure is applicable even to hemorrhaging patients. Outstanding antineoplastic effects are expected in locally advanced gastric cancer. (author)

  6. Concurrent chemoradiation with daily low dose cisplatin for advanced stage head and neck carcinoma

    International Nuclear Information System (INIS)

    Hoebers, Frank J.P.; Heemsbergen, Wilma; Balm, Alfons J.M.; Zanten, Mathilde van; Schornagel, Jan H.; Rasch, Coen R.N.

    2007-01-01

    Background and purpose: To evaluate treatment results of concurrent chemoradiation with daily low dose cisplatin. Materials and methods: 121 patients with advanced stage HNSCC were treated with RT (35 x 2 Gy) and cisplatin (6 mg/m 2 i.v. x20, daily before RT). After 47 patients, the treatment protocol (Standard Group) was changed: Daily i.v. prehydration and accelerated RT were given to the subsequent 74 patients (Hydr-Ac-RT Group). Results: Mean follow-up was 29 months (range 7-62). More chemotherapy could be administered in the Hydr-Ac-RT Group (maximum no. of 20 cisplatin-infusions increased from 59% to 91% of patients, p = 0.008), with less renal toxicity (p < 0.001) and less hospital admissions (p < 0.02). However, mucositis was more pronounced and tubefeeding more frequent in the Hydr-Ac-RT Group. The CR rate of the primary tumor increased from 74% (Standard Group) to 90% (Hydr-Ac-RT Group) (p = 0.06), although this did not lead to an improvement in loco-regional control. Conclusions: Concurrent chemoradiation with daily low dose cisplatin is feasible and effective for selected patients with advanced HNSCC. Although the addition of accelerated RT resulted in more mucositis and tubefeeding, the introduction of prehydration led to better compliance to therapy with more chemotherapy administered and less hospital admissions

  7. Caregiver burden in end-of-life care: advanced cancer and final stage of dementia.

    Science.gov (United States)

    Costa-Requena, Gema; Espinosa Val, M Carmen; Cristòfol, Ramon

    2015-06-01

    Considering two advanced illnesses, cancer and end-stage dementia, the aim of this study was to describe the symptoms of caregiver psychological distress and burden. In this cross-sectional study, regression analyses were calculated to explain the influence of psychological distress in caregiver burden. A t test was employed to compare differences between the symptoms of caregiver burden. The percentage of psychological distress was similar between caregivers of cancer patients (77.6%) and caregivers of dementia patients (72.4%). In the regression analysis, cancer caregiver distress accounted for 27.9% of the variance in symptoms of burden, while dementia caregiver distress accounted for 24.4% of the variance in symptoms of burden. No significant differences were revealed when comparing caregiver burden symptoms between caregivers of the two advanced illnesses (t = 0.06; p = 0.94). In end-of-life care for patients with dementia, due to significant levels of caregiver distress and burden symptoms, there is a need to support caregivers in the same way as is done for caregivers of cancer patients.

  8. The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells

    Science.gov (United States)

    Saulep-Easton, Damien; Vincent, Fabien B.; Quah, Pin Shie; Wei, Andrew; Ting, Stephen B.; Croce, Carlo M.; Tam, Constantine; Mackay, Fabienne

    2015-01-01

    Interleukin (IL)-10-producing B cells (B10 cells) have emerged as important regulatory players with immunosuppressive roles. Chronic lymphocytic leukemia (CLL) B cells also secrete IL-10 and share features of B10 cells, suggesting a possible contribution of CLL B cells to immunosuppression in CLL patients. Factors controlling the emergence of B10 cells are not known. B cell-activating factor of the tumour necrosis factor (TNF) family (BAFF) is critical for B cell maturation and survival, and is implicated in the development and progression of CLL. We sought to investigate the role of BAFF in the emergence of IL-10-producing B regulatory cells in healthy donors and CLL patients. Here, we report that BAFF signaling promotes IL-10 production by CLL B cells in a mouse model of CLL and in CLL patients. Moreover, BAFF-mediated IL-10 production by normal and CLL B cells is mediated via its receptor TACI. Our work uncovered a major targetable pathway important for the generation of regulatory B cells that is detrimental to immunity in CLL. PMID:26139429

  9. Persistent Polyclonal B Cell Lymphocytosis B Cells Can Be Activated through CD40-CD154 Interaction

    Directory of Open Access Journals (Sweden)

    Emmanuelle Dugas-Bourdages

    2014-01-01

    Full Text Available Persistent polyclonal B cell lymphocytosis (PPBL is a rare disorder, diagnosed primarily in adult female smokers and characterized by an expansion of CD19+CD27+IgM+ memory B cells, by the presence of binucleated lymphocytes, and by a moderate elevation of serum IgM. The clinical course is usually benign, but it is not known whether or not PPBL might be part of a process leading to the emergence of a malignant proliferative disorder. In this study we sought to investigate the functional response of B cells from patients with PPBL by use of an optimal memory B cell culture model based on the CD40-CD154 interaction. We found that the proliferation of PPBL B cells was almost as important as that of B cells from normal controls, resulting in high immunoglobulin secretion with in vitro isotypic switching. We conclude that the CD40-CD154 activation pathway is functional in the memory B cell population of PPBL patients, suggesting that the disorder may be due to either a dysfunction of other cells in the microenvironment or a possible defect in another B cell activation pathway.

  10. A single centre experience with sequential and concomitant chemoradiotherapy in locally advanced stage IV tonsillar cancer

    Directory of Open Access Journals (Sweden)

    Coyle Catherine

    2010-12-01

    Full Text Available Abstract Background Chemo-radiotherapy offers an alternative to primary surgery and adjuvant therapy for the management of locally advanced stage IV squamous cell carcinomas of the tonsil. Methods A retrospective analysis was performed of the outcomes of 41 patients with locoregionally advanced squamous cell carcinoma of the tonsil treated non-surgically at the Yorkshire Cancer Centre between January 2004 and December 2005. Due to long radiotherapy waiting times, patients received induction chemotherapy with cisplatin and 5-fluorouracil followed by either cisplatin concurrent chemoradiotherapy or radiotherapy alone. Results Median age was 55 years (range 34-76 years and 28 (68% patients were male. 35/41 patients (85% received 2 or more cycles of induction chemotherapy. Following induction chemotherapy, 32/41 patients (78% had a clinical response. Concomitant chemotherapy was given to 30/41 (73%. All patients received the planned radiotherapy dose with no delays. There were no treatment related deaths. Six (15% patients had gastrostomy tubes placed before treatment, and 22 (54% required nasogastric tube placement during or after treatment for nutritional support. 17 patients required unplanned admissions during treatment for supportive care. At 4 months post treatment assessment 35 out of 41 (85% patients achieved complete clinical and radiographic response. Median follow-up is 38 months (8-61 months. Local and regional control rate in complete responders at 3 years was 91%. Distant metastases have been found in 4 (9.8% patients. Three year progression-free survival rate in all patients is 75%. The 3-year cause specific survival and overall survival are 75% and 66% respectively. Conclusion Cisplatin-based induction and concurrent chemoradiotherapy provides excellent tumour control with acceptable toxicity for patients with locally advanced tonsillar cancer.

  11. A single centre experience with sequential and concomitant chemoradiotherapy in locally advanced stage IV tonsillar cancer

    International Nuclear Information System (INIS)

    D Prestwich, Robin J; Kancherla, Kiran; Oksuz, Didem Colpan; Williamson, Deborah; Dyker, Karen E; Coyle, Catherine; Sen, Mehmet

    2010-01-01

    Chemo-radiotherapy offers an alternative to primary surgery and adjuvant therapy for the management of locally advanced stage IV squamous cell carcinomas of the tonsil. A retrospective analysis was performed of the outcomes of 41 patients with locoregionally advanced squamous cell carcinoma of the tonsil treated non-surgically at the Yorkshire Cancer Centre between January 2004 and December 2005. Due to long radiotherapy waiting times, patients received induction chemotherapy with cisplatin and 5-fluorouracil followed by either cisplatin concurrent chemoradiotherapy or radiotherapy alone. Median age was 55 years (range 34-76 years) and 28 (68%) patients were male. 35/41 patients (85%) received 2 or more cycles of induction chemotherapy. Following induction chemotherapy, 32/41 patients (78%) had a clinical response. Concomitant chemotherapy was given to 30/41 (73%). All patients received the planned radiotherapy dose with no delays. There were no treatment related deaths. Six (15%) patients had gastrostomy tubes placed before treatment, and 22 (54%) required nasogastric tube placement during or after treatment for nutritional support. 17 patients required unplanned admissions during treatment for supportive care. At 4 months post treatment assessment 35 out of 41 (85%) patients achieved complete clinical and radiographic response. Median follow-up is 38 months (8-61 months). Local and regional control rate in complete responders at 3 years was 91%. Distant metastases have been found in 4 (9.8%) patients. Three year progression-free survival rate in all patients is 75%. The 3-year cause specific survival and overall survival are 75% and 66% respectively. Cisplatin-based induction and concurrent chemoradiotherapy provides excellent tumour control with acceptable toxicity for patients with locally advanced tonsillar cancer

  12. Costal osteochondral autograft for reconstruction of advanced-stage osteochondritis dissecans of the capitellum.

    Science.gov (United States)

    Nishinaka, Naoya; Tsutsui, Hiroaki; Yamaguchi, Ken; Uehara, Taishi; Nagai, Suguru; Atsumi, Takashi

    2014-12-01

    Advanced-stage osteochondritis dissecans of the capitellum affecting the lateral wall may result in osteoarthritis, and suitable treatment is needed to avoid permanent deformation and impaired function. We aimed to assess postoperative outcomes of costal osteochondral autograft for treatment of this condition. We included 22 young overhead athletes (mean age, 13.9 years) with advanced osteochondritis dissecans of the humeral capitellum who underwent costal osteochondral autograft. All patients had elbow pain and wide-range articular cartilage lesions. We evaluated clinical and radiographic outcomes at a mean follow-up of 27 months (range, 12-77 months). All patients achieved rapid functional improvement and returned to their former sports activity levels. The baseball players were able to play catch within 62 to 164 days (mean, 107 days) and returned to full pitching activity within 123 to 339 days (mean, 226 days). We assessed mean elbow function by the clinical rating system of Timmerman and Andrews and the Japanese Orthopaedic Association sports score; the scores improved from 121.5 and 53.7 points preoperatively to 169.2 points and 86.1 points, respectively, at the time of follow-up. Four patients required additional minor surgical procedures, including screw removal, loose body removal, and shaving off of spur formation. No patient showed obvious radiographic changes of osteoarthritis. All patients were satisfied with the final outcomes and had good functional recovery. Costal osteochondral autograft gave satisfactory results for advanced osteochondritis dissecans of the humeral capitellum with extensive lesions affecting the lateral wall. Copyright © 2014 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

  13. Changes in B Cell Populations and Merozoite Surface Protein-1-Specific Memory B Cell Responses after Prolonged Absence of Detectable P. falciparum Infection.

    Directory of Open Access Journals (Sweden)

    Cyrus Ayieko

    Full Text Available Clinical immunity to malaria declines in the absence of repeated parasite exposure. However, little is known about how B cell populations and antigen-specific memory B cells change in the absence of P. falciparum infection. A successful indoor residual insecticide spraying campaign in a highland area of western Kenya, led to an absence of blood-stage P. falciparum infection between March 2007 and April 2008. We assessed memory B cell responses in 45 adults at the beginning (April 2008 and end (April 2009 of a subsequent 12-month period during which none of the adults had evidence of asymptomatic parasitemia or clinical disease. Antibodies and memory B cells to the 42-kDa portion of the merozoite surface protein-1 (MSP-142 were measured using ELISA and ELISPOT assays, respectively. B cell populations were characterized by flow cytometry. From 2008 to 2009, the prevalence of MSP-142-specific memory B cells (45% vs. 55%, respectively, P = 0.32 or antibodies (91% vs. 82%, respectively, P = 0.32 did not differ significantly, although specific individuals did change from positive to negative and vice versa, particularly for memory B cells, suggesting possible low-level undetected parasitemia may have occurred in some individuals. The magnitude of MSP-142-specific memory B cells and levels of antibodies to MSP-142 also did not differ from 2008 to 2009 (P>0.10 for both. However, from 2008 to 2009 the proportions of both class-switched atypical (CD19+IgD-CD27-CD21-IgM- and class-switched activated (CD19+IgD-CD27+CD21-IgM- memory B cells decreased (both P<0.001. In contrast, class-switched resting classical memory B cells (CD19+IgD-CD27+CD21+IgM- increased (P<0.001. In this area of seasonal malaria transmission, a one- year absence of detectable P. falciparum infection was not associated with changes in the prevalence or level of MSP-142 specific memory B cells, but was associated with major changes in overall memory B cell subsets.

  14. Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Adv. Solid Tumors or With B-cell Lymphomas and Tazemetostat in Combination With Prednisolone in Subjects With DLBCL

    Science.gov (United States)

    2018-04-12

    B-cell Lymphomas (Phase 1); Advanced Solid Tumors (Phase 1); Diffuse Large B-cell Lymphoma (Phase 2); Follicular Lymphoma (Phase 2); Transformed Follicular Lymphoma; Primary Mediastinal Large B-Cell Lymphoma

  15. Interaction of Staphylococci with Human B cells.

    Directory of Open Access Journals (Sweden)

    Tyler K Nygaard

    Full Text Available Staphylococcus aureus is a leading cause of human infections worldwide. The pathogen produces numerous molecules that can interfere with recognition and binding by host innate immune cells, an initial step required for the ingestion and subsequent destruction of microbes by phagocytes. To better understand the interaction of this pathogen with human immune cells, we compared the association of S. aureus and S. epidermidis with leukocytes in human blood. We found that a significantly greater proportion of B cells associated with S. epidermidis relative to S. aureus. Complement components and complement receptors were important for the binding of B cells with S. epidermidis. Experiments using staphylococci inactivated by ultraviolet radiation and S. aureus isogenic deletion mutants indicated that S. aureus secretes molecules regulated by the SaeR/S two-component system that interfere with the ability of human B cells to bind this bacterium. We hypothesize that the relative inability of B cells to bind S. aureus contributes to the microbe's success as a human pathogen.

  16. Immunoglobulins, antibody repertoire and B cell development

    Czech Academy of Sciences Publication Activity Database

    Butler, J. E.; Zhao, Y.; Šinkora, Marek; Wertz, N.; Kacskovics, I.

    2009-01-01

    Roč. 33, č. 3 (2009), s. 321-333 ISSN 0145-305X R&D Projects: GA ČR GA523/07/0088 Institutional research plan: CEZ:AV0Z50200510 Keywords : swine * immunoglobulin * b cell Subject RIV: EC - Immunology Impact factor: 3.290, year: 2009

  17. Interaction of Staphylococci with Human B cells

    Science.gov (United States)

    Nygaard, Tyler K.; Kobayashi, Scott D.; Freedman, Brett; Porter, Adeline R.; Voyich, Jovanka M.; Otto, Michael; Schneewind, Olaf; DeLeo, Frank R.

    2016-01-01

    Staphylococcus aureus is a leading cause of human infections worldwide. The pathogen produces numerous molecules that can interfere with recognition and binding by host innate immune cells, an initial step required for the ingestion and subsequent destruction of microbes by phagocytes. To better understand the interaction of this pathogen with human immune cells, we compared the association of S. aureus and S. epidermidis with leukocytes in human blood. We found that a significantly greater proportion of B cells associated with S. epidermidis relative to S. aureus. Complement components and complement receptors were important for the binding of B cells with S. epidermidis. Experiments using staphylococci inactivated by ultraviolet radiation and S. aureus isogenic deletion mutants indicated that S. aureus secretes molecules regulated by the SaeR/S two-component system that interfere with the ability of human B cells to bind this bacterium. We hypothesize that the relative inability of B cells to bind S. aureus contributes to the microbe’s success as a human pathogen. PMID:27711145

  18. Surgical resection of locally advanced primary transverse colon cancer--not a worse outcome in stage II tumor.

    Science.gov (United States)

    Hung, Hsin-Yuan; Yeh, Chien-Yuh; Changchien, Chung-Rong; Chen, Jinn-Shiun; Fan, Chung-Wei; Tang, Reiping; Hsieh, Pao-Shiu; Tasi, Wen-Sy; You, Yau-Tong; You, Jeng-Fu; Wang, Jeng-Yi; Chiang, Jy-Ming

    2011-07-01

    In locally advanced primary transverse colon cancer, a tumor may cause perforation or invade adjacent organs. Extensive resection is the best choice of treatment, but such procedures must be weighed against the potential survival benefits. This study was performed to identify the clinicopathological features and treatment outcomes of such tumors. We retrospectively reviewed the database of the Colorectal Cancer Registry of Chang Gung Memorial Hospital between February 1995 and December 2005. Patients with colon cancer sited between the hepatic and splenic flexure that involved an adjacent organ without distant metastasis were defined as having locally advanced transverse colon cancer. A total of 827 patients who underwent surgery for transverse primary colon cancer were enrolled in the study. Stage II and stage III colon cancer were diagnosed in 548 patients. Thirty-two (5.8%) patients were diagnosed with locally advanced tumors. Multivariate analysis revealed that stage III, preoperative carcinoembryonic antigen ≥5 ng/mL, a tumor with perforation or obstruction, and the presence of a locally advanced tumor were significant prognostic factors for both overall and cancer-specific survival. Postoperative morbidity rates differed significantly between the locally advanced and non-locally advanced tumor groups (22.7% vs. 12.3%, P transverse colon tumors (P = 0.21). Surgical resection of locally advanced transverse colon tumors resulted in a higher morbidity and mortality than that of non-locally advanced tumors, but the benefit of extensive surgery in the case of locally advanced tumors cannot be underestimated. Furthermore, this benefit is more pronounced in the case of stage II tumors.

  19. Compound haploinsufficiencies of Ebf1 and Runx1 genes impede B cell lineage progression.

    Science.gov (United States)

    Lukin, Kara; Fields, Scott; Lopez, Desiree; Cherrier, Marie; Ternyak, Kristina; Ramírez, Julita; Feeney, Ann J; Hagman, James

    2010-04-27

    Early B cell factor (EBF)1 is essential for B lineage specification. Previously, we demonstrated the synergistic activation of Cd79a (mb-1) genes by EBF1 and its functional partner, RUNX1. Here, we identified consequences of Ebf1 haploinsufficiency together with haploinsufficiency of Runx1 genes in mice. Although numbers of "committed" pro-B cells were maintained in Ebf1(+/-)Runx1(+/-) (ER(het)) mice, activation of B cell-specific gene transcription was depressed in these cells. Expression of genes encoding Aiolos, kappa0 sterile transcripts, CD2 and CD25 were reduced and delayed in ER(het) pro-B cells, whereas surface expression of BP-1 was increased on late pro-B cells in ER(het) mice. Late pre-B and immature and mature B cells were decreased in the bone marrow of Ebf1(+/-) (E(het)) mice and were nearly absent in ER(het) mice. Although we did not observe significant effects of haploinsuficiencies on IgH or Igkappa rearrangements, a relative lack of Iglambda rearrangements was detected in E(het) and ER(het) pre-B cells. Together, these observations suggest that B cell lineage progression is impaired at multiple stages in the bone marrow of E(het) and ER(het) mice. Furthermore, enforced expression of EBF1 and RUNX1 in terminally differentiated plasmacytoma cells activated multiple early B cell-specific genes synergistically. Collectively, these studies illuminate the effects of reduced Ebf1 dosage and the compounding effects of reduced Runx1 dosage. Our data confirm and extend the importance of EBF1 in regulating target genes and Ig gene rearrangements necessary for B cell lineage specification, developmental progression, and homeostasis.

  20. Dyslipidemia-associated alterations in B cell subpopulation frequency and phenotype during experimental atherosclerosis.

    Science.gov (United States)

    Rincón-Arévalo, Héctor; Castaño, Diana; Villa-Pulgarín, Janny; Rojas, Mauricio; Vásquez, Gloria; Correa, Luis A; Ramírez-Pineda, José R; Yassin, Lina M

    2016-04-01

    Lymphocytes, the cellular effectors of adaptive immunity, are involved in the chronic inflammatory process known as atherosclerosis. Proatherogenic and atheroprotective properties have been ascribed to B cells. However, information regarding the role of B cells during atherosclerosis is scarce. Both the frequency and the phenotype of B cell subpopulations were studied by flow cytometry in wild type and apolipoprotein-E-deficient (apoE(-/-)) mice fed a high-fat (HFD) or control diet. Whereas the proportion of follicular cells was decreased, transitional 1-like cells were increased in mice with advanced atherosclerotic lesions (apoE(-/-) HFD). B cells in atherosclerotic mice were more activated, indicated by their higher surface expression of CD80, CD86, CD40 and CD95 and increased serum IgG1 levels. In the aorta, a decreased frequency of B cells was observed in mice with advanced atherosclerosis. Low expression of CD19 was observed on B cells from the spleen, aorta and lymph nodes of apoE(-/-) HFD mice. This alteration correlated with serum levels of IgG1 and cholesterol. A reduction in CD19 expression was induced in splenic cells from young apoE(-/-) mice cultured with lipemic serum. These results show that mice with advanced atherosclerosis display a variety of alterations in the frequency and phenotype of B lymphocytes, most of which are associated with dyslipidemia. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Case Report of Diffuse Large B Cell Lymphoma of Uterine Cervix Treated at a Semiurban Cancer Centre in North India

    Directory of Open Access Journals (Sweden)

    Vibhor Sharma

    2016-01-01

    Full Text Available Lymphoma of the uterine cervix is very rare. We report a case of diffuse large B cell lymphoma (DLBCL involving the uterine cervix treated at a newly commissioned semiurban cancer centre in north India in 2015. Data for this study was obtained from the hospital electronic medical records and the patient’s case file. We also reviewed published case reports of uterine and cervical lymphoma involving forty-one patients. We treated a case of stage IV DLBCL cervix with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone and intrathecal methotrexate followed by consolidation with radiotherapy. The patient showed complete response to chemotherapy. We conclude that, in advanced stage lymphoma involving uterus and cervix, combination of chemotherapy and radiotherapy is effective in short term.

  2. Prevalence of HCV infection in nongastric marginal zone B-cell lymphoma of MALT.

    Science.gov (United States)

    Arcaini, L; Burcheri, S; Rossi, A; Paulli, M; Bruno, R; Passamonti, F; Brusamolino, E; Molteni, A; Pulsoni, A; Cox, M C; Orsucci, L; Fabbri, A; Frezzato, M; Voso, M T; Zaja, F; Montanari, F; Merli, M; Pascutto, C; Morra, E; Cortelazzo, S; Lazzarino, M

    2007-02-01

    Hepatitis C virus (HCV) infection is frequently associated with B-cell non-Hodgkin's lymphomas. We investigated the prevalence of HCV infection in nongastric marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) in order to define the relationship between the viral infection and the presenting features, treatment, and outcome. We retrospectively studied 172 patients with a histological diagnosis of marginal zone B-cell lymphoma of MALT, except for stomach, and with available HCV serology, among a series of 208 patients. HCV infection was documented in 60 patients (35%). Most HCV-positive patients (97%) showed a single MALT organ involvement. HCV-positive patients showed a more frequent involvement of skin (35%), salivary glands (25%), and orbit (15%). The majority of stage IV HCV-positive patients (71%) had a single MALT site with bone marrow involvement. The overall response rate was similar in HCV-positive (93%) and HCV-negative patients (87%). Overall survival (OS) and event-free survival (EFS) did not differ according to HCV infection. In multivariate analysis, advanced disease (stage III-IV) was associated with a poorer OS (P = 0.0001), irrespective of HCV serostatus. This study shows that nongastric marginal zone lymphomas are characterized by a high prevalence of HCV infection. Patients with involvement of a single MALT site have the highest prevalence of HCV. HCV-positive nongastric lymphomas of MALT show an indolent course similar to HCV-negative patients and seem an ideal target for exploiting the antilymphoma activity of antiviral treatments.

  3. Fully automated VMAT treatment planning for advanced-stage NSCLC patients

    International Nuclear Information System (INIS)

    Della Gala, Giuseppe; Dirkx, Maarten L.P.; Hoekstra, Nienke; Fransen, Dennie; Pol, Marjan van de; Heijmen, Ben J.M.; Lanconelli, Nico; Petit, Steven F.

    2017-01-01

    To develop a fully automated procedure for multicriterial volumetric modulated arc therapy (VMAT) treatment planning (autoVMAT) for stage III/IV non-small cell lung cancer (NSCLC) patients treated with curative intent. After configuring the developed autoVMAT system for NSCLC, autoVMAT plans were compared with manually generated clinically delivered intensity-modulated radiotherapy (IMRT) plans for 41 patients. AutoVMAT plans were also compared to manually generated VMAT plans in the absence of time pressure. For 16 patients with reduced planning target volume (PTV) dose prescription in the clinical IMRT plan (to avoid violation of organs at risk tolerances), the potential for dose escalation with autoVMAT was explored. Two physicians evaluated 35/41 autoVMAT plans (85%) as clinically acceptable. Compared to the manually generated IMRT plans, autoVMAT plans showed statistically significant improved PTV coverage (V 95% increased by 1.1% ± 1.1%), higher dose conformity (R 50 reduced by 12.2% ± 12.7%), and reduced mean lung, heart, and esophagus doses (reductions of 0.9 Gy ± 1.0 Gy, 1.5 Gy ± 1.8 Gy, 3.6 Gy ± 2.8 Gy, respectively, all p < 0.001). To render the six remaining autoVMAT plans clinically acceptable, a dosimetrist needed less than 10 min hands-on time for fine-tuning. AutoVMAT plans were also considered equivalent or better than manually optimized VMAT plans. For 6/16 patients, autoVMAT allowed tumor dose escalation of 5-10 Gy. Clinically deliverable, high-quality autoVMAT plans can be generated fully automatically for the vast majority of advanced-stage NSCLC patients. For a subset of patients, autoVMAT allowed for tumor dose escalation. (orig.) [de

  4. A dose-dependent role for EBF1 in repressing non-B-cell-specific genes.

    Science.gov (United States)

    Lukin, Kara; Fields, Scott; Guerrettaz, Lisa; Straign, Desiree; Rodriguez, Valerie; Zandi, Sasan; Månsson, Robert; Cambier, John C; Sigvardsson, Mikael; Hagman, James

    2011-06-01

    In the absence of early B-cell factor 1 (EBF1), B-cell development is arrested at an uncommitted progenitor stage that exhibits increased lineage potentials. Previously, we investigated the roles of EBF1 and its DNA-binding partner Runx1 by evaluating B lymphopoiesis in single (EBF1(het) and Runx1(het)) and compound haploinsufficent (Ebf1(+/-) Runx1(+/-), ER(het)) mice. Here, we demonstrate that decreased Ebf1 gene dosage results in the inappropriate expression of NK-cell lineage-specific genes in B-cell progenitors. Moreover, prolonged expression of Ly6a/Sca-1 suggested the maintenance of a relatively undifferentiated phenotype. These effects were exacerbated by reduced expression of Runx1 and occurred despite expression of Pax5. Repression of inappropriately expressed genes was restored in most pre-B and all immature B cells of ER(het) mice. Enforced EBF1 expression repressed promiscuous transcription in pro-B cells of ER(het) mice and in Ebf1(-/-) Pax5(-/-) fetal liver cells. Together, our studies suggest that normal levels of EBF1 are critical for maintaining B-cell identity by directing repression of non-B-cell-specific genes. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. PU.1 cooperates with IRF4 and IRF8 to suppress pre-B cell leukemia

    Science.gov (United States)

    Pang, Swee Heng Milon; Minnich, Martina; Gangatirkar, Pradnya; Zheng, Zhiqiang; Ebert, Anja; Song, Guangchun; Dickins, Ross A; Corcoran, Lynn M; Mullighan, Charles G.; Busslinger, Meinrad; Huntington, Nicholas D; Nutt, Stephen L; Carotta, Sebastian

    2016-01-01

    The Ets family transcription factor PU.1 and the interferon regulatory factor (IRF)4 and IRF8 regulate gene expression by binding to composite DNA sequences known as Ets/interferon consensus elements (EICE). Although all three factors are expressed from the onset of B cell development, single deficiency of these factors in B cell progenitors only mildly impacts on bone marrow B-lymphopoiesis. Here we tested whether PU.1 cooperates with IRF factors in regulating early B cell development. Lack of PU.1 and IRF4 resulted in a partial block in development the pre-B cell stage. The combined deletion of PU.1 and IRF8 reduced recirculating B cell numbers. Strikingly, all PU.1/IRF4 and approximately 50% of PU.1/IRF8 double deficient mice developed pre-B cell acute lymphoblastic leukemia (B-ALL) associated with reduced expression of the established B-lineage tumor suppressor genes, Ikaros and Spi-B. These genes are directly regulated by PU.1/IRF4/IRF8, and restoration of Ikaros or Spi-B expression inhibited leukemic cell growth. In summary, we demonstrate that PU.1, IRF4 and IRF8 cooperate to regulate early B cell development and to prevent pre-B-ALL formation. PMID:26932576

  6. New stage in the design of a Transmutation Advanced Device for Sustainable Energy Applications (TADSEA))

    Energy Technology Data Exchange (ETDEWEB)

    Rojas, Leorlen Y.; Rosales, Jesus; Castro, Landy Y.; Gamez, Abel; Gonzalez, Daniel; Garcia, Carlos, E-mail: leored1984@gmail.com, E-mail: jrosales@instec.cu, E-mail: lcastro@instec.cu, E-mail: agamezgmf@gmail.com, E-mail: danielgonro@gmail.com, E-mail: cgh@instec.cu [Instituto Superior de Tecnologias y Ciencias Aplicadas (InSTEC), La Habana (Cuba); Oliveira, Carlos Brayner de, E-mail: abol@ufpe.br [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Departamento de Energia Nuclear; Dominguez, Dany S.; Silva, Alexandro S., E-mail: dsdominguez@gmail.com, E-mail: alexandrossilva@gmail.com [Universidade Estadual de Santa Cruz (UESC), Ilheus, BA (Brazil). Pos-Graduacao em Modelagem Computacional

    2015-07-01

    Transmutation Advanced Device for Sustainable Energy Applications (TADSEA) is a pebble-bed Accelerator Driven System (ADS) with a graphite-gas configuration, designed for nuclear waste transmutation and obtaining heat at very high temperatures to produce hydrogen. In this new stage in the design of TADSEA, it was proposed and modelled a new burn-up strategy, simulating a multi-pass scheme of the pebbles through the core. In order to obtain the axial density power distribution more uniform, for more realistic thermal-hydraulic calculations. In the neutronic calculations it was considered the double heterogeneity of the fuel, by means of a detailed geometry modelling. In previous thermal-hydraulic studies of the TADSEA using CFD code, the pebble-bed nuclear core was considered as a porous medium. In this paper, the heat transfer from the fuel elements to the coolant was analysed using a realistic approach in ANSYS CFX 14. The maximum heat transfer inside the spherical fuel elements with a body centered cubic (BCC) cell and the entire height of core was studied. During the steady state, critical elements don't reached the limit temperature value for this type of fuel. (author)

  7. New stage in the design of a Transmutation Advanced Device for Sustainable Energy Applications (TADSEA))

    International Nuclear Information System (INIS)

    Rojas, Leorlen Y.; Rosales, Jesus; Castro, Landy Y.; Gamez, Abel; Gonzalez, Daniel; Garcia, Carlos; Oliveira, Carlos Brayner de; Dominguez, Dany S.; Silva, Alexandro S.

    2015-01-01

    Transmutation Advanced Device for Sustainable Energy Applications (TADSEA) is a pebble-bed Accelerator Driven System (ADS) with a graphite-gas configuration, designed for nuclear waste transmutation and obtaining heat at very high temperatures to produce hydrogen. In this new stage in the design of TADSEA, it was proposed and modelled a new burn-up strategy, simulating a multi-pass scheme of the pebbles through the core. In order to obtain the axial density power distribution more uniform, for more realistic thermal-hydraulic calculations. In the neutronic calculations it was considered the double heterogeneity of the fuel, by means of a detailed geometry modelling. In previous thermal-hydraulic studies of the TADSEA using CFD code, the pebble-bed nuclear core was considered as a porous medium. In this paper, the heat transfer from the fuel elements to the coolant was analysed using a realistic approach in ANSYS CFX 14. The maximum heat transfer inside the spherical fuel elements with a body centered cubic (BCC) cell and the entire height of core was studied. During the steady state, critical elements don't reached the limit temperature value for this type of fuel. (author)

  8. Intraoperative photodynamic therapy in patients with IIIb and IIIc stages of locally advanced breast cancer

    Directory of Open Access Journals (Sweden)

    D. D. Pak

    2013-01-01

    Full Text Available The study of efficiency of intraoperative photodynamic therapy (PDT with Photosens as the step of combined modality treatment in patients with IIIВ and IIIС stages of breast cancer was performed. The long-term outcomes were evaluated in two groups of patients: group 1 – after radical extended mastectomy combined with chemotherapy, radiotherapy and chemo- and hormonal therapy (138 patients, group 2 – the same treatment combined with intraoperative PDT (36 patients. For the patients with PDT photosens was administered i.v. in single dose 0.3 mg/kg for 2 h before surgery. The irradiation of operative field was performed single time (the light dose 30 J/cm2, with separate irradiation of subclavian, axillar and adjacent regions (the light dose 50 J/cm2. The results showed that intraoperative PDT was associated with better recurrence-free survival rates in patients with breast cancer: in the PDT group the average recurrence free survival was 44.9±3.4 months, in the group without PDT — 35.3±2.1 months. The obtained results confirm that intraoperative PDT for locally advanced breast cancer can be used successfully for devitalization of cancer cells on the wound superface and for prevention of intraoperative tumor dissemination and post-operative recurrence. 

  9. The Epstein-Barr virus BamHI C promoter is not essential for B cell immortalization in vitro, but it greatly enhances B cell growth transformation.

    Science.gov (United States)

    Tierney, Rosemary J; Nagra, Jasdeep; Rowe, Martin; Bell, Andrew I; Rickinson, Alan B

    2015-03-01

    Epstein-Barr virus (EBV) infection of B cells leads to the sequential activation of two viral promoters, Wp and Cp, resulting in the expression of six EBV nuclear antigens (EBNAs) and the viral Bcl2 homologue BHRF1. The viral transactivator EBNA2 is required for this switch from Wp to Cp usage during the initial stages of infection. EBNA2-dependent Cp transcription is mediated by the EBNA2 response element (E2RE), a region that contains at least two binding sites for cellular factors; one of these sites, CBF1, interacts with RBP-JK, which then recruits EBNA2 to the transcription initiation complex. Here we demonstrate that the B cell-specific transcription factor BSAP/Pax5 binds to a second site, CBF2, in the E2RE. Deletion of the E2RE in the context of a recombinant virus greatly diminished levels of Cp-initiated transcripts during the initial stages of infection but did not affect the levels of Wp-initiated transcripts or EBNA mRNAs. Consistent with this finding, viruses deleted for the E2RE were not markedly impaired in their ability to induce B cell transformation in vitro. In contrast, a larger deletion of the entire Cp region did reduce EBNA mRNA levels early after infection and subsequently almost completely ablated lymphoblastoid cell line (LCL) outgrowth. Notably, however, rare LCLs could be established following infection with Cp-deleted viruses, and these were indistinguishable from wild-type-derived LCLs in terms of steady-state EBV gene transcription. These data indicate that, unlike Wp, Cp is dispensable for the virus' growth-transforming activity. Epstein-Barr virus (EBV), a B lymphotropic herpesvirus etiologically linked to several B cell malignancies, efficiently induces B cell proliferation leading to the outgrowth of lymphoblastoid cell lines (LCLs). The initial stages of this growth-transforming infection are characterized by the sequential activation of two viral promoters, Wp and Cp, both of which appear to be preferentially active in target B

  10. Defining B cell immunodominance to viruses.

    Science.gov (United States)

    Angeletti, Davide; Gibbs, James S; Angel, Matthew; Kosik, Ivan; Hickman, Heather D; Frank, Gregory M; Das, Suman R; Wheatley, Adam K; Prabhakaran, Madhu; Leggat, David J; McDermott, Adrian B; Yewdell, Jonathan W

    2017-04-01

    Immunodominance (ID) defines the hierarchical immune response to competing antigens in complex immunogens. Little is known regarding B cell and antibody ID despite its importance in immunity to viruses and other pathogens. We show that B cells and serum antibodies from inbred mice demonstrate a reproducible ID hierarchy to the five major antigenic sites in the influenza A virus hemagglutinin globular domain. The hierarchy changed as the immune response progressed, and it was dependent on antigen formulation and delivery. Passive antibody transfer and sequential infection experiments demonstrated 'original antigenic suppression', a phenomenon in which antibodies suppress memory responses to the priming antigenic site. Our study provides a template for attaining deeper understanding of antibody ID to viruses and other complex immunogens.

  11. B Cell-Activating Factor Regulates Different Aspects of B Cell Functionality and Is Produced by a Subset of Splenic B Cells in Teleost Fish

    Science.gov (United States)

    Tafalla, Carolina; González, Lucia; Castro, Rosario; Granja, Aitor G.

    2017-01-01

    In mammals, B cell functionality is greatly influenced by cytokines released by innate cells, such as macrophages or dendritic cells, upon the early recognition of common pathogen patterns through invariant receptors. B cell-activating factor (BAFF) is one of these innate B cell-helper signals and plays a key role in the survival and differentiation of B cells. Although, evolutionarily, teleost fish constitute the first animal group in which adaptive immunity based on Ig receptors is present, fish still rely greatly on innate responses. In this context, we hypothesized that BAFF would play a key role in the control of B cell responses in fish. Supporting this, our results show that teleost BAFF recapitulates mammalian BAFF stimulating actions on B cells, upregulating the expression of membrane MHC II, improving the survival of fish naïve B cells and antibody-secreting cells, and increasing the secretion of IgM. Surprisingly, we also demonstrate that BAFF is not only produced in fish by myeloid cells but is also produced by a subset of splenic B cells. Thus, if this B cell-produced BAFF proves to be actively regulating this same B cell subset, our findings point to an ancient mechanism to control B cell differentiation and survival in lower vertebrates, which has been silenced in mammals in physiological conditions, but reemerges under pathological conditions, such as B cell lymphomas and autoimmune diseases. PMID:28360916

  12. Diffuse Large B Cell Lymphoma of the Breast

    Directory of Open Access Journals (Sweden)

    Feryal Karaca

    2015-03-01

    Full Text Available Primary breast lymphoma is rarely encountered in Non-Hodgkin Lymphomas. However, if early diagnosis is made, and treatment is started immediately in patients with low grade and stage, patient survival is increased. 39-year old female patient applied us due to a palpable mass. She was diagnosed with the Non-Hodgkin Lymphoma Diffuse Large B Cell Lymphoma after the investigations. Curative external radiotherapy was applied after 6 courses of CHOP-R chemotherapy to the patient with Stage-IIE favorable, and B symptoms. After 48-month follow up, patient follow up is being continued without any progression, or recurrence or metastasis. [Cukurova Med J 2015; 40(1.000: 151-157

  13. Primary Hepatosplenic Large B-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    M.R. Morales-Polanco

    2008-03-01

    Full Text Available Diffuse large B-cell lymphoma is the most common form of lymphoma. It usually begins in the lymph nodes; up to 40% may have an extranodal presentation. According to a definition of primary extranodal lymphoma with presentation only in extranodal sites, there are reports of large B-cell lymphomas limited to liver or spleen as separate entities, and to date there have been only three documented cases of primary hepatosplenic presentation. This paper reports a fourth case. Due to a review of the literature and the clinical course of the case reported, we conclude that primary hepatosplenic large B-cell lymphoma has been found predominantly in females older than 60 years. The patients reported had <2 months of evolution prior to diagnosis, prominent B symptoms, splenomegaly in three and hepatomegaly in two, none with lymph node involvement. All had thrombocytopenia and abnormal liver function tests; three had anemia and elevated serum lactic dehydrogenase levels, two with hemophagocytosis in bone marrow. Because of the previously mentioned data, it can be stated that primary hepatosplenic lymphoma is an uncommon and aggressive form of disease that requires immediate recognition and treatment.

  14. Atypical and classical memory B cells produce Plasmodium falciparum neutralizing antibodies

    DEFF Research Database (Denmark)

    Muellenbeck, Matthias F; Ueberheide, Beatrix; Amulic, Borko

    2013-01-01

    Antibodies can protect from Plasmodium falciparum (Pf) infection and clinical malaria disease. However, in the absence of constant reexposure, serum immunoglobulin (Ig) levels rapidly decline and full protection from clinical symptoms is lost, suggesting that B cell memory is functionally impaired....... We show at the single cell level that natural Pf infection induces the development of classical memory B cells (CM) and atypical memory B cells (AtM) that produce broadly neutralizing antibodies against blood stage Pf parasites. CM and AtM contribute to anti-Pf serum IgG production, but only AtM show...... signs of active antibody secretion. AtM and CM were also different in their IgG gene repertoire, suggesting that they develop from different precursors. The findings provide direct evidence that natural Pf infection leads to the development of protective memory B cell antibody responses and suggest...

  15. Bisphosphonate-related osteonecrosis of jaws in advanced stage breast cancer was detected from bone scan: a case report

    Science.gov (United States)

    Chirappapha, Prakasit; Thongjood, Thanaporn; Aroonroch, Rangsima

    2017-01-01

    Bisphosphonates (BPs) are indicated to treat skeletal-related events (SREs) for cancer patients with bone metastasis. We report a 79-year-old woman with advanced stage breast cancer with bone metastasis who was prescribed BPs (zoledronate), then developed osteonecrosis of jaw. We provide a brief review of the pathogenesis, diagnosis and treatment of this complication. PMID:28210558

  16. A phase I study of gemcitabine with concurrent radiotherapy in stage III, locally advanced non-small cell lung cancer

    NARCIS (Netherlands)

    van Putten, JWG; Price, A; van der Leest, AHD; Gregor, A; Little, FA; Groen, HJM

    Purpose: Our goal was to find the maximum tolerated dose of gemcitabine administered concurrently with thoracic radiotherapy in locally advanced non-small cell lung cancer (NSCLC). Patients and Methods: Patients with stage III NSCLC and a radiation planning volume less than 2000 cm(3) were included.

  17. Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies.

    Science.gov (United States)

    Ponader, Sabine; Burger, Jan A

    2014-06-10

    Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy. © 2014 by American Society of Clinical Oncology.

  18. T. brucei infection reduces B lymphopoiesis in bone marrow and truncates compensatory splenic lymphopoiesis through transitional B-cell apoptosis.

    Directory of Open Access Journals (Sweden)

    Viki Bockstal

    2011-06-01

    Full Text Available African trypanosomes of the Trypanosoma brucei species are extracellular protozoan parasites that cause the deadly disease African trypanosomiasis in humans and contribute to the animal counterpart, Nagana. Trypanosome clearance from the bloodstream is mediated by antibodies specific for their Variant Surface Glycoprotein (VSG coat antigens. However, T. brucei infection induces polyclonal B cell activation, B cell clonal exhaustion, sustained depletion of mature splenic Marginal Zone B (MZB and Follicular B (FoB cells, and destruction of the B-cell memory compartment. To determine how trypanosome infection compromises the humoral immune defense system we used a C57BL/6 T. brucei AnTat 1.1 mouse model and multicolor flow cytometry to document B cell development and maturation during infection. Our results show a more than 95% reduction in B cell precursor numbers from the CLP, pre-pro-B, pro-B, pre-B and immature B cell stages in the bone marrow. In the spleen, T. brucei induces extramedullary B lymphopoiesis as evidenced by significant increases in HSC-LMPP, CLP, pre-pro-B, pro-B and pre-B cell populations. However, final B cell maturation is abrogated by infection-induced apoptosis of transitional B cells of both the T1 and T2 populations which is not uniquely dependent on TNF-, Fas-, or prostaglandin-dependent death pathways. Results obtained from ex vivo co-cultures of living bloodstream form trypanosomes and splenocytes demonstrate that trypanosome surface coat-dependent contact with T1/2 B cells triggers their deletion. We conclude that infection-induced and possibly parasite-contact dependent deletion of transitional B cells prevents replenishment of mature B cell compartments during infection thus contributing to a loss of the host's capacity to sustain antibody responses against recurring parasitemic waves.

  19. Ebf1-mediated down-regulation of Id2 and Id3 is essential for specification of the B cell lineage.

    Science.gov (United States)

    Thal, Melissa A; Carvalho, Thiago L; He, Ti; Kim, Hyung-Gyoon; Gao, Hua; Hagman, James; Klug, Christopher A

    2009-01-13

    Gene knockout experiments in mice have suggested a hierarchical model of early B cell commitment wherein E2A proteins (E47 and E12) activate early B cell factor (Ebf1), which in turn activates expression of the B cell commitment factor, Pax5. In IL-7 receptor alpha (IL-7Ralpha) knockout mice, B cell development is blocked before B-lineage commitment at the prepro-B cell stage in adult animals. In IL-7Ralpha(-/-) prepro-B cells, E47 is expressed and yet is insufficient to transcriptionally activate the putative downstream target gene, Ebf1. In this study, we show that further increases of E47 expression in IL-7Ralpha(-/-) prepro-B cells fails to activate Ebf1, but rather leads to a dramatic induction of the E2A inhibitory factors, Id2 and Id3. In contrast, enforced expression of Ebf1 in IL-7Ralpha(-/-) bone marrow potently down-regulates Id2 and Id3 mRNA expression and restores B cell differentiation in vivo. Down-regulation of both Id2 and Id3 during B cell specification is essential in that overexpression of either Id2 or Id3 in wild-type bone marrow blocks B cell specification at the prepro-B cell stage. Collectively, these studies suggest a model where Ebf1 induction specifies the B cell fate by dramatically increasing activity of E47 at the posttranslational level.

  20. The loss of Gnai2 and Gnai3 in B cells eliminates B lymphocyte compartments and leads to a hyper-IgM like syndrome.

    Directory of Open Access Journals (Sweden)

    Il-Young Hwang

    Full Text Available B lymphocytes are compartmentalized within lymphoid organs. The organization of these compartments depends upon signaling initiated by G-protein linked chemoattractant receptors. To address the importance of the G-proteins Gαi2 and Gαi3 in chemoattractant signaling we created mice lacking both proteins in their B lymphocytes. While bone marrow B cell development and egress is grossly intact; mucosal sites, splenic marginal zones, and lymph nodes essentially lack B cells. There is a partial block in splenic follicular B cell development and a 50-60% reduction in splenic B cells, yet normal numbers of splenic T cells. The absence of Gαi2 and Gαi3 in B cells profoundly disturbs the architecture of lymphoid organs with loss of B cell compartments in the spleen, thymus, lymph nodes, and gastrointestinal tract. This results in a severe disruption of B cell function and a hyper-IgM like syndrome. Beyond the pro-B cell stage, B cells are refractory to chemokine stimulation, and splenic B cells are poorly responsive to antigen receptor engagement. Gαi2 and Gαi3 are therefore critical for B cell chemoattractant receptor signaling and for normal B cell function. These mice provide a worst case scenario of the consequences of losing chemoattractant receptor signaling in B cells.

  1. Dyskerin overexpression in human hepatocellular carcinoma is associated with advanced clinical stage and poor patient prognosis.

    Directory of Open Access Journals (Sweden)

    Bei Liu

    Full Text Available BACKGROUND: Dyskerin (encoded by the DKC1 gene is an essential nucleolar protein involved in cell proliferation, where it is required for the pseudo-uridylation of ribosomal RNA (rRNA molecules and the stabilization of the telomerase RNA component. Dyskerin expression has been reported to predict poor survival in some cancer patients. The aim of the present study was to analyze the expression of dyskerin in hepatocellular carcinoma (HCC and to determine its correlation with clinicopathologic features, including the survival of patients with HCC. METHODOLOGY/PRINCIPAL FINDINGS: Dyskerin protein expression was detected by immunohistochemistry in paraffin sections of 252 HCC cases and 80 noncancerous liver tissues. The correlation was analyzed between dyskerin expression levels and clinicopathologic variables and prognosis. Dyskerin protein was significantly overexpressed in HCC tissues when compared to noncancerous liver tissue. Dyskerin overexpression was positively correlated with the hepatitis B surface antigen status, serum alpha-fetoprotein, and advanced clinical stage in HCC patients. A survival analysis indicated that HCC patients with higher dyskerin expression had a significantly shorter overall survival and 5-year survival time when compared to those with low expression. A multivariate analysis suggested that dyskerin overexpression was an independent factor for prognosis (hazard risk, 2.912; P = 0.007. Expression of DKC1 mRNA was measured by quantitative RT-PCR in 80 HCC and 50 non-cancerous tissues. The relationship between DKC1, TERT, MKI67, and MYC mRNA expression in HCC tissues was also evaluated. DKC1 mRNA was significantly overexpressed in HCC tissues and showed a significant correlation with MKI67 and MYC mRNA but a weak correlation with TERT mRNA. CONCLUSIONS/SIGNIFICANCE: Dyskerin overexpression in HCC patients was correlated with MYC and MKI67 expression and showed a possible involvement in the tumorigenic process. Dyskerin

  2. Alteration of B cell subsets and the receptor for B cell activating factor (BAFF) in paediatric patients with type 1 diabetes.

    Science.gov (United States)

    Parackova, Zuzana; Klocperk, Adam; Rataj, Michal; Kayserova, Jana; Zentsova, Irena; Sumnik, Zdenek; Kolouskova, Stanislava; Sklenarova, Jana; Pruhova, Stepanka; Obermannova, Barbora; Petruzelkova, Lenka; Lebl, Jan; Kalina, Tomas; Sediva, Anna

    2017-09-01

    Lately, mounting evidence has shown that B cells play an important role in the pathogenesis of type 1 diabetes (T1D). Here, we present alterations in B cell subsets including BAFF receptor (BAFFR) expression in cohorts of patients with type 1 diabetes (T1D) and their relatives. B cells were studied in 438 patients with T1D (158 at disease onset and 280 with long-term disease), 136 first-degree relatives and 53 healthy controls. The B cell panel included transitional, naïve, MZ-like, switched memory B cells and plasmablasts. We also measured serum BAFF levels as well as BAFFR expression on both B and T cells. Moreover, the effect of BAFF on T and B lymphocytes was analysed in vitro. We observed a significant decrease in the proportion of transitional B cells in the patients with T1D, accompanied by an increased proportion of plasmablasts, especially in recent-onset patients and their relatives. While the BAFF serum levels did not differ in the patients with T1D, BAFFR-expressing B and especially T cell numbers were reduced in the T1D cohort, with the exception of patients with recent-onset disease who exhibited a significant increase in the number of BAFFR-expressing T cells. T cell activation and B cell proliferation were more pronounced after activation with BAFF in the T1D cohort compared to controls. The B cell panel in patients with T1D is characterized by significantly reduced populations of B cells in their early stages of development with a shift towards plasma cells. The dynamics of BAFFR-expressing B and T cells and the more pronounced responsiveness of the T1D T cells to BAFF point to the role of BAFF and T and B cell cooperation in the development of T1D. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  3. Monoclonal B-cell hyperplasia and leukocyte imbalance precede development of B-cell malignancies in uracil-DNA glycosylase deficient mice

    DEFF Research Database (Denmark)

    Andersen, Sonja; Ericsson, Madelene; Dai, Hong Yan

    2005-01-01

    causes a significant reduction of T-helper cells, and 50% of the young Ung(-/-) mice investigated have no detectable NK/NKT-cell population in their spleen. The immunological imbalance is confirmed in experiments with spleen cells where the production of the cytokines interferon gamma, interleukin 6......Ung-deficient mice have reduced class switch recombination, skewed somatic hypermutation, lymphatic hyperplasia and a 22-fold increased risk of developing B-cell lymphomas. We find that lymphomas are of follicular (FL) and diffuse large B-cell type (DLBCL). All FLs and 75% of the DLBCLs were...... monoclonal while 25% were biclonal. Monoclonality was also observed in hyperplasia, and could represent an early stage of lymphoma development. Lymphoid hyperplasia occurs very early in otherwise healthy Ung-deficient mice, observed as a significant increase of splenic B-cells. Furthermore, loss of Ung also...

  4. B-Cell-Activating Factor and Autoimmune Myasthenia Gravis

    Directory of Open Access Journals (Sweden)

    Samia Ragheb

    2011-01-01

    Full Text Available BAFF is a potent B-cell survival factor, and it plays an essential role in B-cell homeostasis and B-cell function in the periphery. Both normal and autoreactive B cells are BAFF dependent; however, excess BAFF promotes the survival, growth, and maturation of autoreactive B cells. When overexpressed, BAFF protects B cells from apoptosis, thereby contributing to autoimmunity. Three independent studies have shown higher BAFF levels in the circulation of MG patients. BAFF may play an important role in the pathogenesis of MG. BAFF antagonists may well provide new treatment options for MG patients, particularly those patients with thymic lymphoid follicular hyperplasia.

  5. Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders

    Directory of Open Access Journals (Sweden)

    Hohlfeld Reinhard

    2011-10-01

    effectiveness may further advance by selectively targeting pathogenic B-cell function.

  6. Comparing treatment outcomes of different chemotherapy sequences during intensity modulated radiotherapy for advanced N-stage nasopharyngeal carcinoma patients

    International Nuclear Information System (INIS)

    Sun, Xueming; Zeng, Lei; Chen, Chunyan; Huang, Ying; Han, Fei; Xiao, Weiwei; Liu, Shuai; Lu, Taixiang

    2013-01-01

    N-stage is related to distant metastasis of nasopharyngeal carcinoma (NPC) patients. We performed this study to compare the efficacy of different chemotherapy sequences in advanced N-stage (N2 and N3) NPC patients treated with intensity modulated radiotherapy (IMRT). From 2001 to 2008, 198 advanced N-stage NPC patients were retrospectively analyzed. Thirty-three patients received IMRT alone. Concurrent chemoradiotherapy (CCRT) was delivered to 72 patients, neoadjuvant chemotherapy (NACT) + CCRT to 82 patients and CCRT + adjuvant chemotherapy (AC) to 11 patients. The 5-year overall survival rate, recurrence-free survival rate, distant metastasis-free survival rate and progress-free survival rate were 47.7% and 73.1%(p<0.001), 74.5% and 91.3% (p = 0.004), 49.2% and 68.5% (p = 0.018), 37.5% and 63.8% (p<0.001) in IMRT alone and chemoradiotherapy group. Subgroup analyses indicated that there were no significant differences among the survival curves of CCRT, NACT + CCRT and CCRT + AC groups. The survival benefit mainly came from CCRT. However, there was only an improvement attendency in distant metastasis-free survival rate of CCRT group (p = 0.107) when compared with RT alone group, and NACT + CCRT could significantly improve distant metastasis-free survival (p = 0.017). For advanced N-stage NPC patients, NACT + CCRT might be a reasonable treatment strategy

  7. Evaluation of PET and laparoscopy in STagIng advanced gastric cancer: a multicenter prospective study (PLASTIC-study).

    Science.gov (United States)

    Brenkman, H J F; Gertsen, E C; Vegt, E; van Hillegersberg, R; van Berge Henegouwen, M I; Gisbertz, S S; Luyer, M D P; Nieuwenhuijzen, G A P; van Lanschot, J J B; Lagarde, S M; de Steur, W O; Hartgrink, H H; Stoot, J H M B; Hulsewe, K W E; Spillenaar Bilgen, E J; van Det, M J; Kouwenhoven, E A; van der Peet, D L; Daams, F; van Sandick, J W; van Grieken, N C T; Heisterkamp, J; van Etten, B; Haveman, J W; Pierie, J P; Jonker, F; Thijssen, A Y; Belt, E J T; van Duijvendijk, P; Wassenaar, E; van Laarhoven, H W M; Wessels, F J; Haj Mohammad, N; van Stel, H F; Frederix, G W J; Siersema, P D; Ruurda, J P

    2018-04-20

    Initial staging of gastric cancer consists of computed tomography (CT) and gastroscopy. In locally advanced (cT3-4) gastric cancer, fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT or PET) and staging laparoscopy (SL) may have a role in staging, but evidence is scarce. The aim of this study is to evaluate the impact and cost-effectiveness of PET and SL in addition to initial staging in patients with locally advanced gastric cancer. This prospective observational cohort study will include all patients with a surgically resectable, advanced gastric adenocarcinoma (cT3-4b, N0-3, M0), that are scheduled for treatment with curative intent after initial staging with gastroscopy and CT. The modalities to be investigated in this study is the addition of PET and SL. The primary outcome of this study is the proportion of patients in whom the PET or SL lead to a change in treatment strategy. Secondary outcome parameters are: diagnostic performance, morbidity and mortality, quality of life, and cost-effectiveness of these additional diagnostic modalities. The study recently started in August 2017 with a duration of 36 months. At least 239 patients need to be included in this study to demonstrate that the diagnostic modalities are break-even. Based on the annual number of gastrectomies in the participating centers, it is estimated that approximately 543 patients are included in this study. In this study, it is hypothesized that performing PET and SL for locally advanced gastric adenocarcinomas results in a change of treatment strategy in 27% of patients and an annual cost-reduction in the Netherlands of €916.438 in this patient group by reducing futile treatment. The results of this study may be applicable to all countries with comparable treatment algorithms and health care systems. NCT03208621 . This trial was registered prospectively on June 30, 2017.

  8. Fully automated VMAT treatment planning for advanced-stage NSCLC patients

    Energy Technology Data Exchange (ETDEWEB)

    Della Gala, Giuseppe [Erasmus MC Cancer Institute, Department of Radiation Oncology, Rotterdam (Netherlands); Universita di Bologna, Scuola di Scienze, Alma Mater Studiorum, Bologna (Italy); Dirkx, Maarten L.P.; Hoekstra, Nienke; Fransen, Dennie; Pol, Marjan van de; Heijmen, Ben J.M. [Erasmus MC Cancer Institute, Department of Radiation Oncology, Rotterdam (Netherlands); Lanconelli, Nico [Universita di Bologna, Scuola di Scienze, Alma Mater Studiorum, Bologna (Italy); Petit, Steven F. [Erasmus MC Cancer Institute, Department of Radiation Oncology, Rotterdam (Netherlands); Massachusetts General Hospital - Harvard Medical School, Department of Radiation Oncology, Boston, MA (United States)

    2017-05-15

    To develop a fully automated procedure for multicriterial volumetric modulated arc therapy (VMAT) treatment planning (autoVMAT) for stage III/IV non-small cell lung cancer (NSCLC) patients treated with curative intent. After configuring the developed autoVMAT system for NSCLC, autoVMAT plans were compared with manually generated clinically delivered intensity-modulated radiotherapy (IMRT) plans for 41 patients. AutoVMAT plans were also compared to manually generated VMAT plans in the absence of time pressure. For 16 patients with reduced planning target volume (PTV) dose prescription in the clinical IMRT plan (to avoid violation of organs at risk tolerances), the potential for dose escalation with autoVMAT was explored. Two physicians evaluated 35/41 autoVMAT plans (85%) as clinically acceptable. Compared to the manually generated IMRT plans, autoVMAT plans showed statistically significant improved PTV coverage (V{sub 95%} increased by 1.1% ± 1.1%), higher dose conformity (R{sub 50} reduced by 12.2% ± 12.7%), and reduced mean lung, heart, and esophagus doses (reductions of 0.9 Gy ± 1.0 Gy, 1.5 Gy ± 1.8 Gy, 3.6 Gy ± 2.8 Gy, respectively, all p < 0.001). To render the six remaining autoVMAT plans clinically acceptable, a dosimetrist needed less than 10 min hands-on time for fine-tuning. AutoVMAT plans were also considered equivalent or better than manually optimized VMAT plans. For 6/16 patients, autoVMAT allowed tumor dose escalation of 5-10 Gy. Clinically deliverable, high-quality autoVMAT plans can be generated fully automatically for the vast majority of advanced-stage NSCLC patients. For a subset of patients, autoVMAT allowed for tumor dose escalation. (orig.) [German] Entwicklung einer vollautomatisierten, auf multiplen Kriterien basierenden volumenmodulierten Arc-Therapie-(VMAT-)Behandlungsplanung (autoVMAT) fuer kurativ behandelte Patienten mit nicht-kleinzelligem Bronchialkarzinom (NSCLC) im Stadium III/IV. Nach Konfiguration unseres auto

  9. Myeloid infection links epithelial and B cell tropisms of Murid Herpesvirus-4.

    Science.gov (United States)

    Frederico, Bruno; Milho, Ricardo; May, Janet S; Gillet, Laurent; Stevenson, Philip G

    2012-09-01

    Gamma-herpesviruses persist in lymphocytes and cause disease by driving their proliferation. Lymphocyte infection is therefore a key pathogenetic event. Murid Herpesvirus-4 (MuHV-4) is a rhadinovirus that like the related Kaposi's Sarcoma-associated Herpesvirus persists in B cells in vivo yet infects them poorly in vitro. Here we used MuHV-4 to understand how virion tropism sets the path to lymphocyte colonization. Virions that were highly infectious in vivo showed a severe post-binding block to B cell infection. Host entry was accordingly an epithelial infection and B cell infection a secondary event. Macrophage infection by cell-free virions was also poor, but improved markedly when virion binding improved or when macrophages were co-cultured with infected fibroblasts. Under the same conditions B cell infection remained poor; it improved only when virions came from macrophages. This reflected better cell penetration and correlated with antigenic changes in the virion fusion complex. Macrophages were seen to contact acutely infected epithelial cells, and cre/lox-based virus tagging showed that almost all the virus recovered from lymphoid tissue had passed through lysM(+) and CD11c(+) myeloid cells. Thus MuHV-4 reached B cells in 3 distinct stages: incoming virions infected epithelial cells; infection then passed to myeloid cells; glycoprotein changes then allowed B cell infection. These data identify new complexity in rhadinovirus infection and potentially also new vulnerability to intervention.

  10. Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate.

    Science.gov (United States)

    Mansson, Robert; Welinder, Eva; Åhsberg, Josefine; Lin, Yin C; Benner, Christopher; Glass, Christopher K; Lucas, Joseph S; Sigvardsson, Mikael; Murre, Cornelis

    2012-12-18

    Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1), FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in FOXO1-deficient mice is arrested in the common lymphoid progenitor (CLP) LY6D(+) cell stage. We demonstrate that this phenotype closely resembles the arrest in B-cell development observed in EBF1-deficient mice. Consistent with these observations, we find that the transcription signatures of FOXO1- and EBF1-deficient LY6D(+) progenitors are strikingly similar, indicating a common set of target genes. Furthermore, we found that depletion of EBF1 expression in LY6D(+) CLPs severely affects FOXO1 mRNA abundance, whereas depletion of FOXO1 activity in LY6D(+) CLPs ablates EBF1 transcript levels. We generated a global regulatory network from EBF1 and FOXO1 genome-wide transcription factor occupancy and transcription signatures derived from EBF1- and FOXO1-deficient CLPs. This analysis reveals that EBF1 and FOXO1 act in a positive feedback circuitry to promote and stabilize specification to the B-cell lineage.

  11. B cell development in chromosome 22q11.2 deletion syndrome.

    Science.gov (United States)

    Derfalvi, Beata; Maurer, Kelly; McDonald McGinn, Donna M; Zackai, Elaine; Meng, Wenzhao; Luning Prak, Eline T; Sullivan, Kathleen E

    2016-02-01

    Chromosome 22q11.2 deletion syndrome is a common immune deficiency associated with thymic hypoplasia. Most patients did not survive until the mid-1980s and now there is a growing adult population. B cell and immunoglobulin defects have been described and appear to be increased in the adult population. We used flow cytometry, B cell stimulation and repertoire analysis to understand B cell function. B cell production at early stages appeared to be normal in patients but adult patients exhibited a deficit of switched memory B cells. Follicular helper T cells were present at higher percentages in patients and they exhibited a more activated phenotype in patients compared to controls. In spite of that, somatic hypermutation was decreased in patients compared to controls at all ages. Fewer mutations per clone were seen, strongly implicating aberrant T cell help. Therefore, patients with chromosome 22q11.2 deletion syndrome have a progressive decrease in switched memory B cells and evidence of compromised T cell help. In children, evidence of compromised T cell help is limited to decreased somatic hypermutation. With age, greater manifestations become apparent even though a minority of patients have hypogammaglobulinemia. As this population ages, this has important implications for management. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. A comparison between protein profiles of B cell subpopulations and mantle cell lymphoma cells

    Directory of Open Access Journals (Sweden)

    Lehtiö Janne

    2009-11-01

    Full Text Available Abstract Background B-cell lymphomas are thought to reflect different stages of B-cell maturation. Based on cytogenetics and molecular markers, mantle cell lymphoma (MCL is presumed to derive predominantly from naïve, pre-germinal centre (pre-GC B lymphocytes. The aim of this study was to develop a method to investigate the similarity between MCL cells and different B-cell compartments on a protein expression level. Methods Subpopulations of B cells representing the germinal centre (GC, the pre-GC mantle zone and the post-GC marginal zone were isolated from tonsils using automated magnetic cell sorting (AutoMACS of cells based on their expression of CD27 and IgD. Protein profiling of the B cell subsets, of cell lines representing different lymphomas and of primary MCL samples was performed using top-down proteomics profiling by surface-enhanced laser detection/ionization time-of-flight mass spectrometry (SELDI-TOF-MS. Results Quantitative MS data of significant protein peaks (p-value Conclusion AutoMACS sorting generates sufficient purity to enable a comparison between protein profiles of B cell subpopulations and malignant B lymphocytes applying SELDI-TOF-MS. Further validation with an increased number of patient samples and identification of differentially expressed proteins would enable a search for possible treatment targets that are expressed during the early development of MCL.

  13. Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming.

    Science.gov (United States)

    Li, Rui; Cauchy, Pierre; Ramamoorthy, Senthilkumar; Boller, Sören; Chavez, Lukas; Grosschedl, Rudolf

    2018-01-15

    B-cell fate determination requires the action of transcription factors that operate in a regulatory network to activate B-lineage genes and repress lineage-inappropriate genes. However, the dynamics and hierarchy of events in B-cell programming remain obscure. To uncouple the dynamics of transcription factor expression from functional consequences, we generated induction systems in developmentally arrested Ebf1 -/- pre-pro-B cells to allow precise experimental control of EBF1 expression in the genomic context of progenitor cells. Consistent with the described role of EBF1 as a pioneer transcription factor, we show in a time-resolved analysis that EBF1 occupancy coincides with EBF1 expression and precedes the formation of chromatin accessibility. We observed dynamic patterns of EBF1 target gene expression and sequential up-regulation of transcription factors that expand the regulatory network at the pro-B-cell stage. A continuous EBF1 function was found to be required for Cd79a promoter activity and for the maintenance of an accessible chromatin domain that is permissive for binding of other transcription factors. Notably, transient EBF1 occupancy was detected at lineage-inappropriate genes prior to their silencing in pro-B cells. Thus, persistent and transient functions of EBF1 allow for an ordered sequence of epigenetic and transcriptional events in B-cell programming. © 2018 Li et al.; Published by Cold Spring Harbor Laboratory Press.

  14. Superenhancer reprogramming drives a B-cell-epithelial transition and high-risk leukemia.

    Science.gov (United States)

    Hu, Yeguang; Zhang, Zhihong; Kashiwagi, Mariko; Yoshida, Toshimi; Joshi, Ila; Jena, Nilamani; Somasundaram, Rajesh; Emmanuel, Akinola Olumide; Sigvardsson, Mikael; Fitamant, Julien; El-Bardeesy, Nabeel; Gounari, Fotini; Van Etten, Richard A; Georgopoulos, Katia

    2016-09-01

    IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors. IKAROS is also highly enriched at inactive enhancers of genes normally expressed in stem-epithelial cells. Upon IKAROS loss, expression of pre-B-cell differentiation genes is attenuated, while a group of extralineage transcription factors that are directly repressed by IKAROS and depend on EBF1 relocalization at their enhancers for expression is induced. LHX2, LMO2, and TEAD-YAP1, normally kept separate from native B-cell transcription regulators by IKAROS, now cooperate directly with them in a de novo superenhancer network with its own feed-forward transcriptional reinforcement. Induction of de novo superenhancers antagonizes Polycomb repression and superimposes aberrant stem-epithelial cell properties in a B-cell precursor. This dual mechanism of IKAROS regulation promotes differentiation while safeguarding against a hybrid stem-epithelial-B-cell phenotype that underlies high-risk B-ALL. © 2016 Hu et al.; Published by Cold Spring Harbor Laboratory Press.

  15. Negative signaling in B cells: SHIP Grbs Shc.

    Science.gov (United States)

    Tridandapani, S; Kelley, T; Cooney, D; Pradhan, M; Coggeshall, K M

    1997-09-01

    Negative signaling in B cells is initiated by co-crosslinking of the antigen receptor and the Fcy receptor, resulting in cessation of B-cell signaling events and, in turn, inhibiting B-cell proliferation and antibody secretion. Here, a competitive role is proposed for SHIP in blocking the interaction of Shc with the Grb2-Sos complex of proteins that lead to Ras activation in B cells.

  16. A brief history of T cell help to B cells.

    Science.gov (United States)

    Crotty, Shane

    2015-03-01

    In celebration of the 50th anniversary of the discovery of B cells, I take a look back at the history of T cell help to B cells, which was discovered 47 years ago. In addition, I summarize and categorize the distinct molecules that are expressed by CD4(+) T cells that constitute 'help' to B cells, and particularly the molecules expressed by T follicular helper (TFH) cells, which are the specialized providers of help to B cells.

  17. Expression of CA-IX is associated with advanced stage tumors and poor survival in oral squamous cell carcinoma patients.

    Science.gov (United States)

    Pérez-Sayáns, Mario; Suárez-Peñaranda, José Manuel; Pilar, Gayoso-Diz; Supuran, Claudiu T; Pastorekova, Silvia; Barros-Angueira, Francisco; Gándara-Rey, José Manuel; García-García, Abel

    2012-10-01

    Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including tumorigenicity. Specifically, CA-IX has been primarily found in hypoxic tumor tissues. This is a retrospective study of tumors from the Tissue Bank of the Pathology Department of the University Hospital of Santiago de Compostela. We selected 50 oral squamous cell carcinomas (OSCCs) using Tissue Microarray (TMA) technology. The immunohistochemical study was performed to determine CA-IX expression. The resulting data were subject to statistical analysis and survival curves. Of the 50 cases, 23 were detected in early stages (I and II) and 27 in advanced stages (III and IV). In the first year, almost 50% of patients in stages III-IV died, which contrasted with those patients in initial stages who registered a survival rate of 80% (P = 0.019). Regarding the expression of CA-IX, nine cases (18%) were negative, 18 cases (36%) were moderate, while 23 cases (46%) were intense. Tumors in stages I-II showed a positivity of 52.6%; however, in advanced stages, the percentage reached 95.5% (P = 0.002). Regarding CA-IX expression and survival, patients with tumors with strong staining had a lower average survival time (13.8 months) than patients with negative or weak-moderate staining (33.4 and 32.8 months, respectively), log-rank=6.1, P value=0.0484. Early diagnosis of these tumors is essential to improve patient survival. CA-IX expression augments with increasing tumor stage, probably related with the degree of hypoxia; thus, its measurement can be used as a prognostic factor. © 2012 John Wiley & Sons A/S.

  18. Lenalidomide in Diffuse Large B-Cell Lymphoma

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    Catherine Thieblemont

    2012-01-01

    Full Text Available Diffuse large B-cell lymphoma (DLBCL is the most common form of non-Hodgkin's lymphoma (NHL in adults. Even if the natural history of DLBCL has been improved with the advent of immunochemotherapy, the survival results obtained with current treatment options clearly indicate that new agents or novel approaches are needed. Lenalidomide (Revlimid, Celgene Corporation, Summit, NJ, USA, an analogue of thalidomide, is an immunomodulatory drug with pleiotropic mechanisms of action potentially adding to immunochemotherapy. We present here the biological rational for the use of lenalidomide in DLBCL in light of recent advances in the pathophysiology of the disease and the therapeutic results of the most recent trials published in literature or reported in meetings in relapsed/refractory situations as well as in first-line treatment.

  19. Gene expression profile for predicting survival in advanced-stage serous ovarian cancer across two independent datasets.

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    Kosuke Yoshihara

    Full Text Available BACKGROUND: Advanced-stage ovarian cancer patients are generally treated with platinum/taxane-based chemotherapy after primary debulking surgery. However, there is a wide range of outcomes for individual patients. Therefore, the clinicopathological factors alone are insufficient for predicting prognosis. Our aim is to identify a progression-free survival (PFS-related molecular profile for predicting survival of patients with advanced-stage serous ovarian cancer. METHODOLOGY/PRINCIPAL FINDINGS: Advanced-stage serous ovarian cancer tissues from 110 Japanese patients who underwent primary surgery and platinum/taxane-based chemotherapy were profiled using oligonucleotide microarrays. We selected 88 PFS-related genes by a univariate Cox model (p<0.01 and generated the prognostic index based on 88 PFS-related genes after adjustment of regression coefficients of the respective genes by ridge regression Cox model using 10-fold cross-validation. The prognostic index was independently associated with PFS time compared to other clinical factors in multivariate analysis [hazard ratio (HR, 3.72; 95% confidence interval (CI, 2.66-5.43; p<0.0001]. In an external dataset, multivariate analysis revealed that this prognostic index was significantly correlated with PFS time (HR, 1.54; 95% CI, 1.20-1.98; p = 0.0008. Furthermore, the correlation between the prognostic index and overall survival time was confirmed in the two independent external datasets (log rank test, p = 0.0010 and 0.0008. CONCLUSIONS/SIGNIFICANCE: The prognostic ability of our index based on the 88-gene expression profile in ridge regression Cox hazard model was shown to be independent of other clinical factors in predicting cancer prognosis across two distinct datasets. Further study will be necessary to improve predictive accuracy of the prognostic index toward clinical application for evaluation of the risk of recurrence in patients with advanced-stage serous ovarian cancer.

  20. Intravascular Large B-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Maria S. Khan MD, FACP

    2014-03-01

    Full Text Available Case Presentation . A 69-year-old Hispanic male, with a past history of diabetes and coronary disease, was admitted for fever, diarrhea, and confusion of 4 weeks duration. Physical examination showed a disoriented patient with multiple ecchymoses, possible ascites, and bilateral scrotal swelling. Hemoglobin was 6.7, prothrombin time (PT 21.4 seconds with international normalized ratio 2.1, partial thromboplastin time (PTT 55.6 seconds, fibrin split 10 µg/L, and lactate dehydrogenase (LDH 1231 IU/L. Except for a positive DNA test for Epstein–Barr virus (EBV infection, extensive diagnostic workup for infections, malignancy, or a neurological cause was negative. Mixing studies revealed a nonspecific inhibitor of PT and PTT but Factor VIII levels were normal. The patient was empirically treated with antibiotics but developed hypotension and died on day 27 of admission. At autopsy, patient was found to have intravascular diffuse large B-cell lymphoma involving skin, testes, lung, and muscles. The malignant cells were positive for CD20, CD791, Mum-1, and Pax-5 and negative for CD3, CD5, CD10, CD30, and Bcl-6. The malignant cells were 100% positive for Ki-67. Discussion . Intravascular large cell B-cell lymphoma (IVLBCL is rare form of diffuse large B-cell lymphoma and tends to proliferate within small blood vessels, particularly capillaries and postcapillary venules. The cause of its affinity for vascular bed remains unknown. In many reports, IVLBCL was associated with HIV, HHV8, and EBV infections. The fact that our case showed evidence of EBV infection lends support to the association of this diagnosis to viral illness. The available literature on this subject is scant, and in many cases, the diagnosis was made only at autopsy. The typical presentation of this disorder is with B symptoms, progressive neurologic deficits, and skin findings. Bone marrow, spleen, and liver are involved in a minority of patients. Nearly all patients have elevated LDH

  1. MAGE-A3 expression is an adverse prognostic factor in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Olarte, Irma; Martinez, Adolfo; Ramos-Peñafiel, Christian; Castellanos-Sinco, Humberto; Zamora, Jorge; Collazo-Jaloma, Juan; Gutiérrez, Mario; Gutiérrez-Kobeh, Laila; Chavez-Olmos, Pedro; Manzanilla, Hugo; Garrido-Guerrero, Efraín; Ordoñez-Razo, Rosa M; Miranda, Enrique I

    2011-11-01

    This study evaluates the prognostic value of MAGE-A3 expression in 28 diffuse large B-cell lymphoma (DLBCL) patients. A significant association was observed between MAGE-A3 expressions, assessed by quantitative real-time RT-polymerase chain reaction (PCR), with advanced stages of disease (P < 0.05). Elevated serum lactate dehydrogenase (LDH) levels and International Prognostic Index (IPI) score were significantly higher in MAGE-A3-positive patients (P = 0.025 and P = 0.004, respectively). Expression of MAGE-A3 was associated with poor response to treatment and a significantly shorter overall survival (P < 0.001). Our data address new information in the association of MAGE-A3 expression and poor prognosis in DLBCL patients.

  2. Bone marrow biopsy in diffuse large B-cell lymphoma : Useful or redundant test?

    NARCIS (Netherlands)

    Adams, Hugo J A; De Klerk, John M H; Fijnheer, Rob; Heggelman, Ben G F; Dubois, Stefan V.; Nievelstein, Rutger A J; Kwee, Thomas C.

    2015-01-01

    Purpose. To determine the additional value of bone marrow biopsy (BMB) in the standard staging work-up of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), in terms of risk assessment and treatment planning. Material and methods. A total of 113 consecutive patients with newly

  3. Survival in Operated Early and Local Advanced-Stage (IA-IIIA Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Mahsuk Taylan

    2016-06-01

    Full Text Available Objective: The early and local advanced stages (IA-IIIA of non-small cell lung cancer (NSCLC warrant the curative treatment approach of surgery. However, despite the surgical approach, survival depends on a number of factors. The aim of the study was to examine the factors that affect survival in operated NSCLC patients with these stages. Methods: A cohort of 231 operated patients with IA, IB, IIA, IIB, and IIIA stages of NSCLC were analyzed. The effects of age, sex, comorbidity, performance status, histopathology of the tumor, T stage, N stage, pleural invasion, surgical resection type and postoperative resection margin invasion on the survival of the patients were examined with Kaplan-Meier and Cox Regression analyses. Results: Advanced age (OR=1.042 for every passing year, CI=1.020-1.064, adenocarcinoma histopathology (OR=1.676 CI=1.178-2.384, N2 invasion (OR=2.389 CI=1.46-4.239, pleural invasion (OR=2.403 CI=1.569-3.678, resection margin invasion (OR=2.401, CI=1.141-5.048 and pneumonectomy as the type of surgical operation (OR=2.313, CI=1.467-3.647 were found to be independent prognostic factors of mortality. Conclusion: Follow-up of the NSCLC cases with advanced age, an adenocarcinoma type, visceral pleural invasion, N2-lymph node invasion, a history of pneumonectomy, and a resection margin invasion should be undertaken more atten­tively during planning of surgical operation and postoperative period. J Clin Exp Invest 2016; 7 (2: 125-133

  4. Superoxide dismutase mimetic, tempol, aggravates renal injury in advanced-stage stroke-prone spontaneously hypertensive rats.

    Science.gov (United States)

    Sugama, Ikuko; Kohagura, Kentaro; Yamazato, Masanobu; Nakamura, Takuto; Shinzato, Tomoko; Ohya, Yusuke

    2014-03-01

    The aim of this study was to determine whether antioxidant therapy could relieve hypertension and retard the progression of renal damage in advanced-stage hypertensive rats. Twenty-four-week-old spontaneously hypertensive stroke-prone rats were treated for 8 weeks with the superoxide dismutase mimetic tempol, low-dose or high-dose candesartan (an angiotensin receptor blocker), or hydralazine, and blood pressure and renal damage were compared. Elevated blood pressure and renal damage with heterogeneity were present after 8 weeks, with greater glomerulosclerosis in the juxtamedullary glomeruli than in the superficial glomeruli. Although both tempol and candesartan effectively reduced reactive oxygen species production in the kidney, tempol did not decrease blood pressure and exacerbated urine protein and histological damage, such as glomerulosclerosis and interstitial fibrosis, particularly in juxtamedullary nephrons (tempol vs. untreated: glomerulosclerosis index, 2.0 vs. 1.5, Ptempol-treated rats, suggesting that changes in glomerular hemodynamics may be responsible for the exacerbation of glomerulosclerosis. Both candesartan- and hydralazine-treated rats had glomeruli that were slightly decreased in size. These results suggest that single-antioxidant therapy starting at an advanced-stage may be ineffective for hypertension and rather exacerbate renal damage in nonsalt loaded SHRSP. Furthermore, lowering blood pressure and inhibiting the renin-angiotensin system could be critical for slowing the progression of hypertensive renal damage at an advanced stage.

  5. Cell-free DNA levels and correlation to stage and outcome following treatment of locally advanced rectal cancer.

    Science.gov (United States)

    Boysen, Anders Kindberg; Wettergren, Yvonne; Sorensen, Boe Sandahl; Taflin, Helena; Gustavson, Bengt; Spindler, Karen-Lise Garm

    2017-11-01

    Accurate staging of rectal cancer remains essential for optimal patient selection for combined modality treatment, including radiotherapy, chemotherapy and surgery. We aimed at examining the correlation of cell free DNA with the pathologic stage and subsequent risk of recurrence for patients with locally advanced rectal cancer undergoing preoperative chemoradiation. We examined 75 patients with locally advanced rectal cancer receiving preoperative chemoradiation. Blood samples for translational use were drawn prior to rectal surgery. The level of cell free DNA was quantified by digital droplet PCR and expressed as copy number of beta 2 microglobulin. We found a median level of cell free DNA in the AJCC stages I-III of 3100, 8300, and 10,700 copies/mL respectively. For patients with 12 sampled lymph nodes or above, the median level of cell free DNA were 2400 copies/mL and 4400 copies/mL (p = 0.04) for node negative and node positive disease respectively. The median follow-up was 39 months and 11 recurrences were detected (15%). The median level for patients with recurrent disease was 13,000 copies/mL compared to 5200 copies/mL for non-recurrent patients (p = 0.08). We have demonstrated a correlation between the level of total cell free DNA and the pathologic stage and nodal involvement. Furthermore, we have found a trend towards a correlation with the risk of recurrence following resection of localized rectal cancer.

  6. Measures of combined antioxidant and pro-oxidant exposures and risk of overall and advanced stage prostate cancer.

    Science.gov (United States)

    Geybels, Milan S; Verhage, Bas A J; van Schooten, Frederik J; van den Brandt, Piet A

    2012-11-01

    Oxidative stress is possibly related to prostate carcinogenesis. We constructed a dietary antioxidant score, which is a measure of combined antioxidant exposures, and an oxidative balance score (OBS), which is a measure of combined antioxidant and pro-oxidant exposures. We hypothesized that both scores are inversely associated with the risk of prostate cancer (PCa). We conducted a case-cohort study among 58,279 men in the Netherlands Cohort Study. Cohort members completed a baseline questionnaire. From 1986 to 2003, 3451 patients with PCa were identified including 1196 advanced cancers (stage III/IV). The antioxidant score and the OBS were created by summing quartile and category scores of individual score constituents, which had an equal weight. Pro-oxidants were scored in the opposite way to antioxidants. Both the antioxidant score and OBS were not associated with risk of overall PCa or PCa subgroups on the basis of disease stage. Most score constituents were not associated with the risk of PCa. Total catechin intake was associated with a decreased risk of stage IV PCa (greatest vs. lowest quartile: hazard ratio, 0.76; 95% confidence interval, 0.59-0.98). The antioxidant score and OBS were not associated with risk of overall and advanced-stage PCa. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Is thrombocytosis a valid indicator of advanced stage and high mortality of gynecological cancer?

    DEFF Research Database (Denmark)

    Andersen, Christen Bertel L; Eskelund, Christian W.; Siersma, Volkert Dirk

    2015-01-01

    Objective: Thrombocytosis has been associated with higher stage and mortality of cancer, however, the evidence is conflicting. We examined the stage distribution and prognosis of gynecologic cancer according to levels of prediagnostic platelet count. Methods: In a primary care resource with blood...... may have an important role in diagnosis and post-diagnostic control of gynecological cancer.......Objective: Thrombocytosis has been associated with higher stage and mortality of cancer, however, the evidence is conflicting. We examined the stage distribution and prognosis of gynecologic cancer according to levels of prediagnostic platelet count. Methods: In a primary care resource with blood...... cell counts from more than 500,000 individuals, we identified 581 women with a primary diagnosis of gynecological cancer. We divided the pre-diagnostic mean platelet count derived from the 3-year period prior to cancer diagnosis into three categories of thrombocytosis (no, 150–400 × 109 /L; mild, N400...

  8. Advanced Manufacturing Technologies (AMT): Low Cost Upper Stage-Class Propulsion Development Element

    Data.gov (United States)

    National Aeronautics and Space Administration — As manufacturing technologies have matured, it now appears possible to build all the major components and subsystems of an upper stage-class rocket engine for...

  9. Wearable Sensors in Transportation - Exploratory Advanced Research Program Initial Stage Investigation

    Science.gov (United States)

    2016-03-01

    This report summarizes an initial stage investigation into wearable sensors for transportation research : applications. The Federal Highway Administration (FHWA) has observed significant activity in this area and : seeks to obtain an understanding of...

  10. B Cell Receptor-Mediated Internalization of Salmonella: A Novel Pathway for Autonomous B Cell Activation and Antibody Production

    NARCIS (Netherlands)

    Souwer, Yuri; Griekspoor, Alexander; Jorritsma, Tineke; de Wit, Jelle; Janssen, Hans; Neefjes, Jacques; van Ham, S. Marieke

    2009-01-01

    The present paradigm is that primary B cells are nonphagocytosing cells. In this study, we demonstrate that human primary B cells are able to internalize bacteria when the bacteria are recognized by the BCR. BCR-mediated internalization of Salmonella typhimurium results in B cell differentiation and

  11. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming

    NARCIS (Netherlands)

    Kwakkenbos, Mark J.; Diehl, Sean A.; Yasuda, Etsuko; Bakker, Arjen Q.; van Geelen, Caroline M. M.; Lukens, Michaël; van Bleek, Grada M.; Widjojoatmodjo, Myra N.; Bogers, Willy M. J. M.; Mei, Henrik; Radbruch, Andreas; Scheeren, Ferenc A.; Spits, Hergen; Beaumont, Tim

    The B cell lymphoma-6 (Bcl-6) and Bcl-xL proteins are expressed in germinal center B cells and enable them to endure the proliferative and mutagenic environment of the germinal center. By introducing these genes into peripheral blood memory B cells and culturing these cells with two factors produced

  12. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming

    NARCIS (Netherlands)

    Kwakkenbos, Mark J.; Diehl, Sean A.; Yasuda, Etsuko; Bakker, Arjen Q.; van Geelen, Caroline M. M.; Lukens, Michaël V.; van Bleek, Grada M.; Widjojoatmodjo, Myra N.; Bogers, Willy M. J. M.; Mei, Henrik; Radbruch, Andreas; Scheeren, Ferenc A.; Spits, Hergen; Beaumont, Tim

    2010-01-01

    The B cell lymphoma-6 (Bcl-6) and Bcl-xL proteins are expressed in germinal center B cells and enable them to endure the proliferative and mutagenic environment of the germinal center. By introducing these genes into peripheral blood memory B cells and culturing these cells with two factors produced

  13. Improved method for predicting linear B-cell epitopes

    OpenAIRE

    Larsen, Jens Erik Pontoppidan; Lund, Ole; Nielsen, Morten

    2006-01-01

    Background B-cell epitopes are the sites of molecules that are recognized by antibodies of the immune system. Knowledge of B-cell epitopes may be used in the design of vaccines and diagnostics tests. It is therefore of interest to develop improved methods for predicting B-cell epitopes. In this paper, we describe an improved method for predicting linear B-cell epitopes. Results In order to do this, three data sets of linear B-cell epitope annotated proteins were constructed. A data set was co...

  14. Regulation of normal B-cell differentiation and malignant B-cell survival by OCT2.

    Science.gov (United States)

    Hodson, Daniel J; Shaffer, Arthur L; Xiao, Wenming; Wright, George W; Schmitz, Roland; Phelan, James D; Yang, Yandan; Webster, Daniel E; Rui, Lixin; Kohlhammer, Holger; Nakagawa, Masao; Waldmann, Thomas A; Staudt, Louis M

    2016-04-05

    The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B. Genome-wide chromatin immunoprecipitation (ChIP) analysis and gene-expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL-10, ELL2, XBP1, MYC, TERT, and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies and a recurrent mutation of threonine 223 in the DNA-binding domain of OCT2. This neomorphic mutation subtly alters the DNA-binding preference of OCT2, leading to the transactivation of noncanonical target genes including HIF1a and FCRL3 Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface, we reveal a requirement for this protein-protein interface that ultimately might be exploited therapeutically. Our findings, combined with the predominantly B-cell-restricted expression of OCT2 and the absence of a systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL while avoiding systemic toxicity.

  15. The regulatory roles of B cell subsets in transplantation.

    Science.gov (United States)

    Chu, Zhulang; Zou, Weilong; Xu, Yanan; Sun, Qiquan; Zhao, Yong

    2018-02-01

    B cells mediate allograft rejection through antigen presentation, and production of cytokines and antibodies. More and more immunosuppressive agents specifically targeting B cells and plasma cells have been applied in clinical transplantation. However, recent studies have indicated the regulatory roles of B cells. Therefore, it is vital to clarify the different effects of B cell subsets in organ transplantation so that we can completely understand the diverse functions of B cells in transplantation. Areas covered: This review focuses on the regulatory roles of B cells in transplantation. B cell subsets with immune modulation and factors mediating immunosuppressive functions of regulatory B (Breg) cells were analyzed. Therapies targeting B cells and the application of B cells for transplant tolerance induction were discussed. Expert commentary: Besides involving rejection, B cells could also play regulatory roles in transplantation. Breg cells and the related markers may be used to predict the immune tolerant state in transplant recipients. New therapeutic strategies targeting B cells should be explored to promote tolerance induction with less impact on the host's protective immunity in organ transplanted patients.

  16. Proapoptotic BIM Impacts B Lymphoid Homeostasis by Limiting the Survival of Mature B Cells in a Cell-Autonomous Manner.

    Science.gov (United States)

    Liu, Rui; King, Ashleigh; Bouillet, Philippe; Tarlinton, David M; Strasser, Andreas; Heierhorst, Jörg

    2018-01-01

    The proapoptotic BH3-only protein BIM ( Bcl2l11 ) plays key roles in the maintenance of multiple hematopoietic cell types. In mice, germline knockout or conditional pan-hematopoietic deletion of Bim results in marked splenomegaly and significantly increased numbers of B cells. However, it has remained unclear whether these abnormalities reflect the loss of cell-intrinsic functions of BIM within the B lymphoid lineage and, if so, which stages in the lifecycle of B cells are most impacted by the loss of BIM. Here, we show that B lymphoid-specific conditional deletion of Bim during early development (i.e., in pro-B cells using Mb1-Cre ) or during the final differentiation steps (i.e., in transitional B cells using Cd23-Cre ) led to a similar >2-fold expansion of the mature follicular B cell pool. Notably, while the expansion of mature B cells was quantitatively similar in conditional and germline Bim -deficient mice, the splenomegaly was significantly attenuated after B lymphoid-specific compared to global Bim deletion. In vitro , conditional loss of Bim substantially increased the survival of mature B cells that were refractory to activation by lipopolysaccharide. Finally, we also found that conditional deletion of just one Bim allele by Mb1-Cre dramatically accelerated the development of Myc -driven B cell lymphoma, in a manner that was comparable to the effect of germline Bim heterozygosity. These data indicate that, under physiological conditions, BIM regulates B cell homeostasis predominantly by limiting the life span of non-activated mature B cells, and that it can have additional effects on developing B cells under pathological conditions.

  17. Copanlisib and Nivolumab in Treating Participants With Recurrent or Refractory Diffuse Large B-cell Lymphoma or Primary Mediastinal Large B-cell Lymphoma

    Science.gov (United States)

    2018-03-29

    Diffuse Large B-Cell Lymphoma; Mediastinal (Thymic) Large B-Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma

  18. APS, an adaptor molecule containing PH and SH2 domains, has a negative regulatory role in B cell proliferation

    International Nuclear Information System (INIS)

    Iseki, Masanori; Kubo-Akashi, Chiyomi; Kwon, Sang-Mo; Yamaguchi, Akiko; Takatsu, Kiyoshi; Takaki, Satoshi

    2005-01-01

    Adaptor molecule containing PH and SH2 domains (APS) is an intracellular adaptor protein that forms part of an adaptor family along with Lnk and SH2-B. APS transcripts are expressed in various tissues including brain, kidney, and muscle, as well as in splenic B cells but not in T cells. We investigated the functions of APS in B cell development and activation by generating APS-transgenic (APS-Tg) mice that overexpressed APS in lymphocytes. The number of B-1 cells in the peritoneal cavity was reduced in APS-Tg mice, as were B-2 cells in the spleen. B cell development in the bone marrow was partially impaired at the transition stage from proliferating large pre-B to small pre-B cells. B cell proliferation induced by B cell receptor (BCR) crosslinking but not by other B cell mitogens was also impaired in APS-Tg mice. APS co-localized with BCR complexes and filamentous actin in activated APS-Tg B cells. Thus, APS appears to play novel negative regulatory roles in BCR signaling, actin reorganization pathways, and control of compartment sizes of B-lineage cells

  19. Centralized treatment of advanced stages of ovarian cancer improves survival: a nationwide Danish survey

    DEFF Research Database (Denmark)

    Fagö-Olsen, Carsten L; Høgdall, Claus; Kehlet, Henrik

    2011-01-01

    Objective. This retrospective, nationwide, observational study was designed to compare treatment in tertiary referral centers vs. regional hospitals on overall survival for patients with stage IIIC and IV ovarian cancer. Material and methods. The study took place in all gynecological departments...... in Denmark, involving a total of 1,160 patients with stage IIIC or IV ovarian cancer. Data were extracted for 2,024 patients with all stages of ovarian cancer recorded in the Danish Gynecological Cancer Database between 1 January 2005 and 31 December 2008. The main outcome measure was overall survival....... Results. No difference was found between tertiary centers and regional hospitals with regard to age, body mass index, American Society of Anesthesiologists score or comorbidity. Patients in regional hospitals had poorer Eastern Cooperative Oncology Group performance status, i.e.1.0 vs. 2.0 (p= 0...

  20. Advanced chronic kidney disease, end-stage renal disease and renal death among HIV-positive individuals in Europe

    DEFF Research Database (Denmark)

    Ryom, L; Kirk, O; Lundgren, Jd

    2013-01-01

    OBJECTIVES: Knowledge about advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) in HIV-positive persons is limited. The aim of this study was to investigate incidence, predictors and outcomes for advanced CKD/ESRD and renal death. METHODS: Advanced CKD was defined as confirmed...... (two consecutive measurements ≥ 3 months apart) estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m(2) using Cockcroft-Gault, and ESRD as haemodialysis or peritoneal dialysis for ≥ 1 month or renal transplant. Renal death was death with renal disease as the underlying cause, using Coding...... Causes of Death in HIV (CoDe) methodology. Follow-up was from 1 January 2004 until last eGFR measurement, advanced CKD, ESRD or renal death, whichever occurred first. Poisson regression was used to identify predictors. RESULTS: Of 9044 individuals included in the study, 58 (0.64%) experienced advanced...

  1. Increasing Rates of No Treatment in Advanced Stage Non-Small Cell Lung Cancer Patients: A Propensity Matched Analysis

    Science.gov (United States)

    David, Elizabeth A; Daly, Megan E.; Li, Chin-Shang; Chiu, Chi-Lu; Cooke, David T; Brown, Lisa M; Melnikow, Joy; Kelly, Karen; Canter, Robert J

    2017-01-01

    Introduction Variation in treatment and survival outcomes for Non–Small Cell Lung Cancer (NSCLC) is high among patients with stage III or IV, but untreated NSCLC patients have not been critically analyzed to evaluate for improvable outcomes. We evaluated treatment trends and their association with oncologic outcomes for NSCLC, hypothesizing that there are a substantial number of untreated patients who are similar to patients who undergo treatment. Methods Linear regression was used to calculate trends in utilization of treatment. Kaplan-Meier and Cox regression modeling were used to determine predictors of receiving treatment. Propensity-matching was used to compare survival among subsets of treated versus untreated patients. Results Patients with primary NSCLC were identified from the National Cancer Data base from 1998–2012 and 21% (190,539) of patients received no treatment. For stage IIIA and IV, the proportion of untreated patients increased over the study period by 0.21% and 0.4% respectively (p= 0.003, <0.0001). Regardless of stage, untreated patients had significantly shorter OS (p<0.0001). Propensity-matched analyses of 6,144 stage IIIA patient pairs treated with chemoradiation vs no treatment confirmed shorter OS for untreated patients (Median, 16.5 vs 6.1 months, p <0.0001). For 19,046 stage IV patient pairs treated with chemotherapy vs no treatment, similar results were obtained (Median OS, 9.3 vs 2.0 months, p<0.0001). Conclusions The proportion of untreated stage IIIA and IV patients is increasing. Survival outcomes among advanced stage patients are superior with treatment, independent of selection bias. The benefits and risks of treatment should be carefully assessed prior to choosing to forego treatment. PMID:28109804

  2. Foxp1 controls mature B cell survival and the development of follicular and B-1 B cells

    Science.gov (United States)

    Patzelt, Thomas; Keppler, Selina J.; Gorka, Oliver; Thoene, Silvia; Wartewig, Tim; Reth, Michael; Förster, Irmgard; Lang, Roland; Buchner, Maike; Ruland, Jürgen

    2018-01-01

    The transcription factor Foxp1 is critical for early B cell development. Despite frequent deregulation of Foxp1 in B cell lymphoma, the physiological functions of Foxp1 in mature B cells remain unknown. Here, we used conditional gene targeting in the B cell lineage and report that Foxp1 disruption in developing and mature B cells results in reduced numbers and frequencies of follicular and B-1 B cells and in impaired antibody production upon T cell-independent immunization in vivo. Moreover, Foxp1-deficient B cells are impaired in survival even though they exhibit an increased capacity to proliferate. Transcriptional analysis identified defective expression of the prosurvival Bcl-2 family gene Bcl2l1 encoding Bcl-xl in Foxp1-deficient B cells, and we identified Foxp1 binding in the regulatory region of Bcl2l1. Transgenic overexpression of Bcl2 rescued the survival defect in Foxp1-deficient mature B cells in vivo and restored peripheral B cell numbers. Thus, our results identify Foxp1 as a physiological regulator of mature B cell survival mediated in part via the control of Bcl-xl expression and imply that this pathway might contribute to the pathogenic function of aberrant Foxp1 expression in lymphoma. PMID:29507226

  3. Treatment patterns of advanced malignant melanoma (stage III-IV) - A review of current standards in Europe.

    Science.gov (United States)

    Harries, Mark; Malvehy, Josep; Lebbe, Céleste; Heron, Louise; Amelio, Justyna; Szabo, Zsolt; Schadendorf, Dirk

    2016-06-01

    With the recent emergence of immunotherapies and novel targeted treatments for advanced and metastatic melanoma such as selective B-Raf inhibitors and checkpoint inhibitors, the treatment landscape in Europe has changed considerably. The aim of this review was to provide an overview of current treatment pathways in Europe for the treatment of advanced melanoma, unresectable stage III-IV. A literature search of four databases was conducted to identify publications reporting on the treatment patterns of advanced and metastatic melanoma (stage III-IV) in European populations. Seven full-text publications and two conference abstracts reported on observational studies of melanoma treatment practices in France, Italy and the United Kingdom. Treatment patterns were identified for two time periods: 2005-2009 and 2011-2012. Common treatments reported for both periods included chemotherapy with dacarbazine, fotemustine or temozolomide. The main differences between the two periods were the introduction and prescription of immunotherapy ipilimumab and targeted therapy vemurafenib between 2011 and 2012. Across the three countries studied, the types of treatments prescribed between 2005 and 2009 were relatively similar, however, with noticeable differences in the frequency and priority of administration. Treatment practices for advanced melanoma vary markedly across different European countries and continue to evolve with the introduction of new therapies. The results of this review highlight a considerable evidence gap with regards to recent treatment patterns for advanced melanoma in Europe, especially post-2011 after the introduction of novel therapeutic agents, and more recently with the introduction of programmed cell death 1 inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Prognosis and Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase (IDH) Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma.

    Science.gov (United States)

    Goyal, Lipika; Govindan, Aparna; Sheth, Rahul A; Nardi, Valentina; Blaszkowsky, Lawrence S; Faris, Jason E; Clark, Jeffrey W; Ryan, David P; Kwak, Eunice L; Allen, Jill N; Murphy, Janet E; Saha, Supriya K; Hong, Theodore S; Wo, Jennifer Y; Ferrone, Cristina R; Tanabe, Kenneth K; Chong, Dawn Q; Deshpande, Vikram; Borger, Darrell R; Iafrate, A John; Bardeesy, Nabeel; Zheng, Hui; Zhu, Andrew X

    2015-09-01

    Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase (IDH) mutation in intrahepatic cholangiocarcinoma (ICC), and limited data exist in patients with advanced-stage disease. Similarly, the clinical phenotype of patients with advanced IDH mutant (IDHm) ICC has not been characterized. In this study, we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC. Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated. Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild-type (IDHwt) ICC. Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging. Of the 104 patients with ICC who were evaluated, 30 (28.8%) had an IDH mutation (25.0% IDH1, 3.8% IDH2). The median overall survival did not differ significantly between IDHm and IDHwt patients (15.0 vs. 20.1 months, respectively; p = .17). The pretreatment serum carbohydrate antigen 19-9 (CA19-9) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL, respectively (p = .04). Age at diagnosis, sex, histologic grade, and pattern of metastasis did not differ significantly by IDH mutation status. The IDH mutation was not associated with prognosis in patients with advanced ICC. The clinical phenotypes of advanced IDHm and IDHwt ICC were similar, but patients with IDHm ICC had a lower median serum CA19-9 level at presentation. Previous studies assessing the prognostic impact of the isocitrate dehydrogenase (IDH) gene mutation in intrahepatic cholangiocarcinoma (ICC) mainly focused on patients with early-stage disease who have undergone resection. These studies offer conflicting results. The target population for clinical trials of IDH inhibitors is patients with unresectable or metastatic disease, and the current study is the first to

  5. Transcriptional control of pre-B cell development and leukemia prevention.

    Science.gov (United States)

    Pang, Swee Heng Milon; Carotta, Sebastian; Nutt, Stephen L

    2014-01-01

    The differentiation of early B cell progenitors is controlled by multiple transcriptional regulators and growth-factor receptors. The triad of DNA-binding proteins, E2A, EBF1, and PAX5 is critical for both the early specification and commitment of B cell progenitors, while a larger number of secondary determinants, such as members of the Ikaros, ETS, Runx, and IRF families have more direct roles in promoting stage-specific pre-B gene-expression program. Importantly, it is now apparent that mutations in many of these transcription factors are associated with the progression to acute lymphoblastic leukemia. In this review, we focus on recent studies that have shed light on the transcriptional hierarchy that controls efficient B cell commitment and differentiation as well as focus on the oncogenic consequences of the loss of many of the same factors.

  6. Radiofrequency Ablation in the Management of Advanced Stage Thymomas: A Case Report on a Novel Multidisciplinary Therapeutic Approach

    Directory of Open Access Journals (Sweden)

    Panagiotis Paliogiannis

    2014-01-01

    Full Text Available We describe in this report a case of successful radiofrequency ablation of an unresectable stage III-type B3 thymoma, and we discuss the role of this novel approach in the management of patients with advanced stage thymoma. The patient, a 59-year-old Caucasian male underwent neoadjuvant chemotherapy with only a slight reduction of the mass. Subsequently, an explorative sternotomy and debulking were performed; before closing the thorax, radiofrequency ablation of the residual tumor was carried out and a partial necrosis of the mass was achieved. A further percutaneous radiofrequency ablation was performed subsequently, obtaining complete necrosis of the lesion. Successively, the patient underwent adjuvant radiotherapy. As a result of this multidisciplinary treatment, complete and stable response was obtained. It is hard to say which of the single treatments had the major impact on cure; nevertheless, the results obtained suggest that radiofrequency ablation must be taken into account for the treatment of advanced stage thymomas, and its effectiveness must be further assessed in future studies.

  7. Primary cardiac diffuse large B-cell lymphoma with activated B-cell-like phenotype

    Directory of Open Access Journals (Sweden)

    Vijaya Gadage

    2011-01-01

    Full Text Available Primary cardiac lymphoma (PCL is a rare and fatal disorder. It may often mimic other common cardiac tumors like cardiac myxoma because of similarities in the clinical presentation. We report a case of PCL of diffuse large B-cell type, in a 38-year-old, immunocompetent male who presented with superior vena cava syndrome that was excised as a myxoma. Histology revealed a large cell population diffusely and strongly expressing CD45, CD20, MUM1/IRF4 and FOXP1 hinting at an activated B-cell (ABC-like phenotype. After four cycles of Rituximab with CHOP (cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisolone the tumor regressed completely but the patient had a relapse and subsequently succumbed to the disease confirming the aggressive nature. The aggressive behavior of PCL may be possibly linked to its ABC-like origin.

  8. Quantitative and qualitative analysis of regulatory T cells in B cell chronic lymphocytic leukemia.

    Science.gov (United States)

    Mpakou, Vassiliki E; Ioannidou, Heleni-Dikaia; Konsta, Eugene; Vikentiou, Myrofora; Spathis, Aris; Kontsioti, Frieda; Kontos, Christos K; Velentzas, Athanassios D; Papageorgiou, Sotiris; Vasilatou, Diamantina; Gkontopoulos, Konstantinos; Glezou, Irene; Stavroulaki, Georgia; Mpazani, Efthimia; Kokkori, Stella; Kyriakou, Elias; Karakitsos, Petros; Dimitriadis, George; Pappa, Vasiliki

    2017-09-01

    Accumulated data indicate a significant role of T cell dysfunction in the pathogenesis of chronic lymphocytic leukemia. In CLL, regulatory T cells are significantly higher and show lower apoptotic levels compared to healthy donors. We demonstrate that CLL derived CD4 + CD25 - CD127 - and CD4 + CD25 low CD127 - subpopulations share a common immunophenotypic profile with conventional Tregs and are associated with advanced stage disease. We further provide evidence that the increased number of Tregs contributes indirectly to the proliferation of the CLL clone, by suppressing the proliferation of Teffs which in turn suppress CLL cells. These data are further supported by our observations that CLL derived Tregs appear rather incapable of inducing apoptosis of both normal B cells and CLL cells, in contrast to normal Tregs, suggesting an immunoediting effect of CLL cells on Tregs which negatively affects the functionality of the latter and contributes to the failure of Tregs in CLL to efficiently eliminate the abnormal clone. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Adipose Tissue Inflammation Induces B Cell Inflammation and Decreases B Cell Function in Aging

    Directory of Open Access Journals (Sweden)

    Daniela Frasca

    2017-08-01

    Full Text Available Aging is the greatest risk factor for developing chronic diseases. Inflamm-aging, the age-related increase in low-grade chronic inflammation, may be a common link in age-related diseases. This review summarizes recent published data on potential cellular and molecular mechanisms of the age-related increase in inflammation, and how these contribute to decreased humoral immune responses in aged mice and humans. Briefly, we cover how aging and related inflammation decrease antibody responses in mice and humans, and how obesity contributes to the mechanisms for aging through increased inflammation. We also report data in the literature showing adipose tissue infiltration with immune cells and how these cells are recruited and contribute to local and systemic inflammation. We show that several types of immune cells infiltrate the adipose tissue and these include macrophages, neutrophils, NK cells, innate lymphoid cells, eosinophils, T cells, B1, and B2 cells. Our main focus is how the adipose tissue affects immune responses, in particular B cell responses and antibody production. The role of leptin in generating inflammation and decreased B cell responses is also discussed. We report data published by us and by other groups showing that the adipose tissue generates pro-inflammatory B cell subsets which induce pro-inflammatory T cells, promote insulin resistance, and secrete pathogenic autoimmune antibodies.

  10. Assessing the quality of pain care in ambulatory patients with advanced stage cancer.

    Science.gov (United States)

    Weingart, Saul N; Cleary, Angela; Stuver, Sherri O; Lynch, Maureen; Brandoff, Douglas; Schaefer, Kristen G; Zhu, Junya; Berry, Donna L; Block, Susan; Weeks, Jane C

    2012-06-01

    Pain is common among patients with advanced cancer despite the dissemination of clinical pain care guidelines. We sought to assess the quality of pain care among patients with advanced disease. We reviewed the records of 85 adult ambulatory patients with advanced breast, lung, and gastrointestinal cancer treated in 2004-2006. Patients' screening pain intensity scores were at least 7 of 10. Nurse reviewers completed medical record reviews of care rendered at the index visit and over the subsequent 30 days based on the 2004 National Comprehensive Cancer Network pain guideline. An expert panel then rated the quality of the evaluation, treatment, and overall pain care. We used a multivariable model to analyze guideline compliance and resolution of severe pain. Among advanced cancer patients with severe pain, clinicians adjusted pain medications only half the time and made few timely referrals for pain-related consultations. By 30 days after the index visit, 34% of patients continued to report severe pain. The expert panel judged the overall quality of pain care as "fair" or "poor" in about two-thirds of cases because more timely and effective intervention could have reduced the severity and duration of pain. Resolution of severe pain was associated with adjustment of pain medications at the index visit (adjusted odds ratio 3.8, 95% CI 1.3-10.6). There is room for improvement in the pain care of patients with advanced cancer. Additional research is needed to understand the reasons for poor performance. Copyright © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

  11. Primary Mediastinal Large B-Cell Lymphoma during Pregnancy

    Directory of Open Access Journals (Sweden)

    Cesar A. Perez

    2012-01-01

    Full Text Available Non-Hodgkin’s Lymphoma (NHL rarely presents during pregnancy and primary mediastinal large B-cell lymphoma (PMLBCL accounts for approximately 2.5% of patients with NHL. The case of a 22-year-old woman who was diagnosed with Stage IIA PMLBCL during week 13 of her intrauterine pregnancy is described. The staging consisted in computed tomography (CT of the chest and magnetic resonance imaging (MRI of the abdomen and pelvis. She was managed with R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for a total of six cycles and, because of the early presentation during the second trimester, she received the entire chemotherapy course during the pregnancy. She delivered a healthy baby at 34 weeks of pregnancy and a 18FDG-PET/CT scan demonstrated complete remission after delivery. After 20 months of follow up she remains with no evidence of disease and her 1-year-old son has shown no developmental delays or physical abnormalities. PMLBCL, although an uncommon subgroup of DLBCL, may present during pregnancy and R-CHOP should be considered as one suitable option in this complex scenario.

  12. A Model to Predict the Use of Surgical Resection for Advanced-Stage Non-Small Cell Lung Cancer Patients.

    Science.gov (United States)

    David, Elizabeth A; Andersen, Stina W; Beckett, Laurel A; Melnikow, Joy; Kelly, Karen; Cooke, David T; Brown, Lisa M; Canter, Robert J

    2017-11-01

    For advanced-stage non-small cell lung cancer, chemotherapy and chemoradiotherapy are the primary treatments. Although surgical intervention in these patients is associated with improved survival, the effect of selection bias is poorly defined. Our objective was to characterize selection bias and identify potential surgical candidates by constructing a Surgical Selection Score (SSS). Patients with clinical stage IIIA, IIIB, or IV non-small cell lung cancer were identified in the National Cancer Data Base from 1998 to 2012. Logistic regression was used to develop the SSS based on clinical characteristics. Estimated area under the receiver operating characteristic curve was used to assess discrimination performance of the SSS. Kaplan-Meier analysis was used to compare patients with similar SSSs. We identified 300,572 patients with stage IIIA, IIIB, or IV non-small cell lung cancer without missing data; 6% (18,701) underwent surgical intervention. The surgical cohort was 57% stage IIIA (n = 10,650), 19% stage IIIB (n = 3,483), and 24% stage IV (n = 4,568). The areas under the receiver operating characteristic curve from the best-fit logistic regression model in the training and validation sets were not significantly different, at 0.83 (95% confidence interval, 0.82 to 0.83) and 0.83 (95% confidence interval, 0.82 to 0.83). The range of SSS is 43 to 1,141. As expected, SSS was a good predictor of survival. Within each quartile of SSS, patients in the surgical group had significantly longer survival than nonsurgical patients (p < 0.001). A prediction model for selection of patients for surgical intervention was created. Once validated and prospectively tested, this model may be used to identify patients who may benefit from surgical intervention. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  13. Prognostic value of programmed death ligand 1, p53, and Ki-67 in patients with advanced-stage colorectal cancer.

    Science.gov (United States)

    Wang, Lisha; Liu, Zebing; Fisher, Kurt W; Ren, Fei; Lv, Jiaojie; Davidson, Darrell D; Baldridge, Lee A; Du, Xiang; Cheng, Liang

    2018-01-01

    Current prognostic indicators are ineffective for identifying advanced-stage colorectal cancer (CRC) patients with high risk of recurrence after surgical resection. We investigated the prognostic value of p53, Ki-67, and programmed death ligand 1 (PD-L1) in 254 patients with stage II and III CRC. The expression of p53 was positive in 63% of cases. Up-regulation of p53 was associated with smaller tumor size (P=.001) and higher Ki-67 labeling index (LI) (P=.031). The tumor Ki-67 LI was high (≥20%) in 197 (78%) of the patients. High Ki-67 LI was associated with higher TNM stage (P=.031), positive p53 expression (P=.031), and negative PD-L1 expression (P=.003). The 5-year relapse-free survivals (RFS) were 53% and 89%, respectively, for the p53-positive and Ki-67 LI-high patients and the p53-negative and Ki-67 LI-low patients (P<.001). In univariate analysis, negative p53 (P=.001), low Ki-67 LI (P=.006), low PD-L1 expression (P=.044), low TNM stage (P<.001), rectosigmoid location (P=.026), and small size (P=.013) were significantly related to RFS. In multivariate Cox regression analysis, positive p53 expression (hazard ratio [HR]: 2.48; 95% confidence interval: 1.34-4.59, P=.004), high Ki-67 LI (HR, 2.62; 95% CI, 1.12-6.14, P=.027) and high TNM stage (HR, 2.598; 95% CI, 1.55-4.37, P<.001,) were independent predictors of unfavorable prognosis. In summary, PD-L1, Ki-67, and p53 staining individually had significant prognostic value for patients with stage II and III CRC. Moreover, combining p53 H-score ≥35 and Ki-67 LI ≥20% identifies patients with poor clinical outcome. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Assessment of capabilities in persons with advanced stage of dementia: Validation of The Montessori Assessment System (MAS).

    Science.gov (United States)

    Erkes, Jérôme; Camp, Cameron J; Raffard, Stéphane; Gély-Nargeot And, Marie-Christine; Bayard, Sophie

    2017-01-01

    This study evaluated the validity and reliability of the Montessori Assessment System. The Montessori Assessment System assesses preserved abilities in persons with moderate to severe dementia. In this respect, this instrument provides crucial information for the development of effective person-centered care plans. A total of 196 persons with a diagnosis of dementia in the moderate to severe stages of dementia were recruited in 10 long-term care facilities in France. All participants completed the Montessori Assessment System, the Clinical Dementia Rating Scale and/or the Mini Mental State Examination and the Severe Impairment Battery-short form. The internal consistency and temporal stability of the Montessori Assessment System were high. Additionally, good construct and divergent validity were demonstrated. Factor analysis showed a one-factor structure. The Montessori Assessment System demonstrated satisfactory psychometric properties while being a useful instrument to assess capabilities in persons with advanced stages of dementia and hence to develop person-centered plans of care.

  15. Advanced optical design and control of multi-colored SSL system for stage lighting application

    DEFF Research Database (Denmark)

    Chakrabarti, Maumita

    mixing system and provides a solution which is capable of replacing both the Fresnel lens spotlight Halogen lamp (2kW) and the commercially available LED luminaire (~160W), which have applications in stage lighting, theater lighting, TV studio lighting, etc. Since the optical design comprises LEDs...... homogeneity, which overcomes the expensive and tedious manual polishing or direct diamond turning. The tool fabrication provides an easy and inexpensive mold and hence a cost effective injection molding replication process....

  16. Brucella abortus-infected B cells induce osteoclastogenesis.

    Science.gov (United States)

    Pesce Viglietti, Ayelén Ivana; Arriola Benitez, Paula Constanza; Giambartolomei, Guillermo Hernán; Delpino, María Victoria

    2016-09-01

    Brucella abortus is an intracellular bacterium that establishes lifelong infections in livestock and humans although the mechanisms of its chronicity are poorly understood. Activated B cells have long lifespan and B. abortus infection activates B cells. Our results indicate that the direct infection of B cells with B. abortus induced matrix metalloproteinase-9 (MMP-9), receptor activator for NF κB ligand (RANKL), tumor necrosis factor (TNF)-α and interleukin (IL)-6 secretion. In addition, supernatants from B. abortus-infected B cells induced bone marrow-derived monocytes to undergo osteoclastogenesis. Using osteoprotegerin, RANKL's decoy receptor, we determined that RANKL is involved in osteoclastogenesis induced by supernatants from B. abortus-infected B cells. The results presented here shed light on how the interactions of B. abortus with B cells may have a role in the pathogenesis of brucellar osteoarticular disease. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  17. Cascaded interactions between Raman induced solitons and dispersive waves in photonic crystal fibers at the advanced stage of supercontinuum generation.

    Science.gov (United States)

    Driben, Rodislav; Mitschke, Fedor; Zhavoronkov, Nickolai

    2010-12-06

    The complex mechanism of multiple interactions between solitary and dispersive waves at the advanced stage of supercontinuum generation in photonic crystal fiber is studied in experiment and numerical simulations. Injection of high power negatively chirped pulses near zero dispersion frequency results in an effective soliton fission process with multiple interactions between red shifted Raman solitons and dispersive waves. These interactions may result in relative acceleration of solitons with further collisions between them of quasi-elastic or quasi-plastic kinds. In the spectral domain these processes result in enhancement of certain wavelength regions within the spectrum or development of a new significant band at the long wavelength side of the spectrum.

  18. Anti-B cell antibody therapies for inflammatory rheumatic diseases

    DEFF Research Database (Denmark)

    Faurschou, Mikkel; Jayne, David R W

    2014-01-01

    Several monoclonal antibodies targeting B cells have been tested as therapeutics for inflammatory rheumatic diseases. We review important observations from randomized clinical trials regarding the efficacy and safety of anti-B cell antibody-based therapies for rheumatoid arthritis, systemic lupus...... and functions in rheumatic disorders. Future studies should also evaluate how to maintain disease control by means of conventional and/or biologic immunosuppressants after remission-induction with anti-B cell antibodies....

  19. B cells in multiple sclerosis therapy-A comprehensive review.

    Science.gov (United States)

    Rahmanzadeh, R; Weber, M S; Brück, W; Navardi, S; Sahraian, M A

    2018-03-07

    For decades, B cells were ignored in multiple sclerosis (MS) pathogenesis, and the disease was always regarded as a T cell-mediated disorder. Recent evidence shows that there is an antigen-driven B-cell response in the central nervous system of patients with MS, and memory B cells/plasma cells are detectable in MS lesions. The striking efficacy of B cell-depleting therapies in reducing the inflammatory activity of the disease highlights that B cells may play more pathogenetic roles than expected. B cells express several unique characteristic markers on their surface, for example, CD19, CD20 molecules, that provide selective targets for monoclonal antibodies. In this respect, several B cell-targeted therapies emerged, including anti-CD20 antibodies (rituximab, ocrelizumab, and ofatumumab), anti-CD19 antibody (inebilizumab), and agents targeting the BAFF/APRIL signaling pathway (atacicept, belimumab, and LY2127399). In this review, we discuss, in detail, the immunobiology of B cells and their protective and destructive roles in MS pathogenesis. In the second part, we list the completed and ongoing clinical trials investigating the safety and efficacy of B cell-related monoclonal antibodies in MS. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Regulatory T cells and B cells: implication on autoimmune diseases

    OpenAIRE

    Wang, Ping; Zheng, Song Guo

    2013-01-01

    The regulatory T (Treg) cells play an important role in the maintenance of homeostasis and the prevention of autoimmune diseases. Although most studies are focusing on the role of Treg cells in T cells and T cells-mediated diseases, these cells also directly affect B cells and other non-T cells. This manuscript updates the role of Treg cells on the B cells and B cell-mediated diseases. In addition, the mechanisms whereby Treg cells suppress B cell responses have been discussed.

  1. Atypical B cell receptor signaling: straddling immune diseases and cancer.

    Science.gov (United States)

    Faris, Mary

    2013-08-01

    The B-cell receptor (BCR) signaling pathway plays an essential role in the survival, proliferation, differentiation and trafficking of lymphocytic. Recent findings associate aberrant BCR signaling with specific disease pathologies, including B-cell malignancies and autoimmune disorders. Inhibition of the BCR signaling pathway may therefore provide promising new strategies for the treatment of B-cell diseases. This special issue of International Reviews of Immunology focuses on atypical B-cell receptor signaling, its role in immune diseases and cancer, and its implications for potential therapeutic intervention.

  2. Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis.

    Science.gov (United States)

    Miyazaki, Yusei; Niino, Masaaki; Takahashi, Eri; Suzuki, Masako; Mizuno, Masanori; Hisahara, Shin; Fukazawa, Toshiyuki; Amino, Itaru; Nakano, Fumihito; Nakamura, Masakazu; Akimoto, Sachiko; Minami, Naoya; Fujiki, Naoto; Doi, Shizuki; Shimohama, Shun; Terayama, Yasuo; Kikuchi, Seiji

    2018-02-01

    Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Overexpression of AIB1 in nasopharyngeal carcinomas correlates closely with advanced tumor stage.

    Science.gov (United States)

    Liu, Meng-Zhong; Xie, Dan; Mai, Shi-Juan; Tong, Zhu-Ting; Shao, Jian-Yong; Fu, Yong-Shui; Xia, Wen-Jie; Kung, Hsian-Fu; Guan, Xin-Yuan; Zeng, Yi-Xin

    2008-05-01

    AIB1, a candidate oncogene in breast cancer, is commonly amplified and overexpressed in several types of human cancers. In this study, expression and amplification of AIB1 in nasopharyngeal carcinoma (NPC) were studied by immunohistochemical analysis and fluorescence in situ hybridization using tissue microarrays, including 80 specimens of NPC and 20 specimens of nonneoplastic nasopharyngeal mucosa. In this NPC cohort, overexpression and amplification of AIB1 was detected in 36 (51%) of 71 and 3 (7%) of 46 NPCs, respectively. Overexpression of AIB1 was observed more frequently in NPCs in late T stages (T3/T4, 24/35 [69%]) than in earlier stages (T1/T2, 12/36 [33%]; P < .05). In addition, 18 (72%) of 25 NPCs with lymph node metastasis (N1-3) showed overexpression of AIB1; the frequency was significantly higher than that in NPCs without node metastasis (N0, 18/49 [39%]; P < .05). These findings suggest that overexpression of AIB1 in NPCs may be important in the acquisition of an invasive and/or metastatic phenotype.

  4. Ontogeny of human IgE-expressing B cells and plasma cells.

    Science.gov (United States)

    Ramadani, F; Bowen, H; Upton, N; Hobson, P S; Chan, Y-C; Chen, J-B; Chang, T W; McDonnell, J M; Sutton, B J; Fear, D J; Gould, H J

    2017-01-01

    IgE-expressing (IgE + ) plasma cells (PCs) provide a continuous source of allergen-specific IgE that is central to allergic responses. The extreme sparsity of IgE + cells in vivo has confined their study almost entirely to mouse models. To characterize the development pathway of human IgE + PCs and to determine the ontogeny of human IgE + PCs. To generate human IgE + cells, we cultured tonsil B cells with IL-4 and anti-CD40. Using FACS and RT-PCR, we examined the phenotype of generated IgE + cells, the capacity of tonsil B-cell subsets to generate IgE + PCs and the class switching pathways involved. We have identified three phenotypic stages of IgE + PC development pathway, namely (i) IgE + germinal centre (GC)-like B cells, (ii) IgE + PC-like 'plasmablasts' and (iii) IgE + PCs. The same phenotypic stages were also observed for IgG1 + cells. Total tonsil B cells give rise to IgE + PCs by direct and sequential switching, whereas the isolated GC B-cell fraction, the main source of IgE + PCs, generates IgE + PCs by sequential switching. PC differentiation of IgE + cells is accompanied by the down-regulation of surface expression of the short form of membrane IgE (mIgE S ), which is homologous to mouse mIgE, and the up-regulation of the long form of mIgE (mIgE L ), which is associated with an enhanced B-cell survival and expressed in humans, but not in mice. Generation of IgE + PCs from tonsil GC B cells occurs mainly via sequential switching from IgG. The mIgE L /mIgE S ratio may be implicated in survival of IgE + B cells during PC differentiation and allergic disease. 2016 The Authors. Allergy published by John Wiley & Sons Ltd.

  5. Advanced exergy analysis applied to a single-stage heat transformer

    International Nuclear Information System (INIS)

    Colorado, D.

    2017-01-01

    Highlights: • Endogenous, exogenous, avoidable and unavoidable exergy destruction was calculated for a heat transformer. • 14.78% of the total exergy destruction could be reduced assuming improvements in the efficiency and design of the equipment. • A parametric study was discussed considering variations in the operation conditions. - Abstract: This study presents an advanced exergy analysis of a single-state absorption heat transformer operating with a lithium bromide water solution. A traditional exergy analysis was also conducted to identify the components with the highest contribution to the exergy destruction, and an advanced exergy approach was developed to estimate a realistic design and improve the operating conditions of the system. According to the base case of this study, when calculating the total reversibility of the cycle, only 14.78% could be reduced by improving its design and configuration. In addition, a parametric study was presented to discuss the sensitivity of splitting exergy destruction concepts taking into account temperature variations in the heat source, sink, and seawater outlet. Considering improvements to the generator a top priority, followed by improving the absorber, the condenser and finally the evaporator. The numerical results of this work have been developed to help design engineers experiment and assemble future equipment.

  6. High clinical and molecular response rates with fludarabine, cyclophosphamide and mitoxantrone in previously untreated patients with advanced stage follicular lymphoma.

    Science.gov (United States)

    Montoto, Silvia; Moreno, Carol; Domingo-Doménech, Eva; Estany, Cristina; Oriol, Albert; Altés, Albert; Besalduch, Joan; Pedro, Carme; Gardella, Santiago; Escoda, Lourdes; Asensio, Antoni; Vivancos, Pilar; Galán, Pilar; de Sevilla, Alberto Fernández; Ribera, Josep M; Briones, Javier; Colomer, Dolors; Campo, Elías; Montserrat, Emili; López-Guillermo, Armando

    2008-02-01

    Purine analogs have demonstrated significant activity in patients with follicular lymphoma. The aim of this study was to analyze the efficacy and toxicity of a fludarabine combination as first-line treatment in patients with advanced-stage disease. This is a phase II trial including 120 patients ( or =2), > or =2 extranodal sites and high beta2-microglobulin. Sixteen episodes of grade 3-4 infections were observed. Two patients died during therapy (of progressive multifocal leukoencephalopathy and bronchoaspiration respectively). No late toxicity has been observed. Twelve patients died during follow-up (9 after relapse, 2 during chemotherapy, 1 in complete remission after surgery for meningioma). The overall survival at 5 years was 89%. ECOG > or =2 and high beta2-microglobulin were associated with a shorter survival. FCM results in high complete and molecular response rates, with prolonged response duration in younger patients with advanced-stage follicular lymphoma. The combination of FCM with rituximab as front-line treatment warrants further investigation.

  7. Perioperative dynamic alterations in peripheral regulatory T and B cells in patients with hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Chen Tianxiang

    2012-01-01

    Full Text Available Abstract Background Intratumoral and circulating regulatory T cells (Tregs have been shown to be critical in the pathogenesis of hepatocellular carcinoma (HCC. However there is limited knowledge on the alterations of regulatory B cells (Bregs. We here investigated perioperative dynamic alterations of peripheral circulating Tregs and Bregs in HCC patients to reveal the relationship between regulatory lymphocytes and its clinical implications. Methods 36 patients with HCC, 6 with chronic hepatitis B infection and 10 healthy donors were enrolled for this study. Frequencies of peripheral Tregs and Bregs were measured by flow cytometry with antibodies against CD4, CD25, CD127, CD19 and IL-10 before, and after radical surgery. Then, clinical informatics of HCC patients was achieved through Digital Evaluation Score System (DESS for the assessment of disease severity. Finally, we analysed correlations between digitalized clinical features and kinetics of circulating regulatory lymphocytes. Results Level of circulating CD4+CD25+CD127- Tregs in HCC patients was significantly lower than that in healthy donors and patients with chronic hepatitis B infection before surgery, but was increased after surgery. Preoperative level of CD19+ IL-10+ Bregs in HCC patients was also significantly lower than the other groups. However it dramatically was elevated right after surgery and remained elevated compared to controls (about 7 days after surgery, P = 0.04. Frequency of circulating Tregs was correlated with circulating leukocytes, ferritin, and clinical features suggesting tumor aggressiveness including portal vein thrombosis, hepatic vein involvement and advanced clinical stages. Frequency of circulating Bregs was associated with Hepatitis B e Antigen (HBeAg and Hepatitis B virus (HBV DNA copy number. In addition, DESS was significantly and positively correlated with other staging systems. Conclusion Frequencies of peripheral Tregs and Bregs in HCC patients

  8. Image Guided Hypofractionated 3-Dimensional Radiation Therapy in Patients With Inoperable Advanced Stage Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Osti, Mattia Falchetto [Institute of Radiation Oncology, La Sapienza University, Sant' Andrea Hospital, Rome (Italy); Agolli, Linda, E-mail: lindaagolli@yahoo.it [Institute of Radiation Oncology, La Sapienza University, Sant' Andrea Hospital, Rome (Italy); Valeriani, Maurizio; Falco, Teresa; Bracci, Stefano; De Sanctis, Vitaliana; Enrici, Riccardo Maurizi [Institute of Radiation Oncology, La Sapienza University, Sant' Andrea Hospital, Rome (Italy)

    2013-03-01

    Purpose: Hypofractionated radiation therapy (HypoRT) can potentially improve local control with a higher biological effect and shorter overall treatment time. Response, local control, toxicity rates, and survival rates were evaluated in patients affected by inoperable advanced stage non-small cell lung cancer (NSCLC) who received HypoRT. Methods and Materials: Thirty patients with advanced NSCLC were enrolled; 27% had stage IIIA, 50% had stage IIIB, and 23% had stage IV disease. All patients underwent HypoRT with a prescribed total dose of 60 Gy in 20 fractions of 3 Gy each. Radiation treatment was delivered using an image guided radiation therapy technique to verify correct position. Toxicities were graded according to Radiation Therapy Oncology Group morbidity score. Survival rates were estimated using the Kaplan-Meier method. Results: The median follow-up was 13 months (range, 4-56 months). All patients completed radiation therapy and received the total dose of 60 Gy to the primary tumor and positive lymph nodes. The overall response rate after radiation therapy was 83% (3 patients with complete response and 22 patients with partial response). The 2-year overall survival and progression-free survival rates were 38.1% and 36%, respectively. Locoregional recurrence/persistence occurred in 11 (37%) patients. Distant metastasis occurred in 17 (57%) patients. Acute toxicities occurred consisting of grade 1 to 2 hematological toxicity in 5 patients (17%) and grade 3 in 1 patient; grade 1 to 2 esophagitis in 12 patients (40%) and grade 3 in 1 patient; and grade 1 to 2 pneumonitis in 6 patients (20%) and grade 3 in 2 patients (7%). Thirty-three percent of patients developed grade 1 to 2 late toxicities. Only 3 patients developed grade 3 late adverse effects: esophagitis in 1 patient and pneumonitis in 2 patients. Conclusions: Hypofractionated curative radiation therapy is a feasible and well-tolerated treatment for patients with locally advanced NSCLC. Randomized

  9. B-cell-mediated strategies to fight chronic allograft rejection

    Directory of Open Access Journals (Sweden)

    Ali H Dalloul

    2013-12-01

    Full Text Available Solid organs have been transplanted for decades. Since the improvement in graft selection and in medical and surgical procedures, the likelihood of graft function after one year is now close to 90%. Nonetheless even well-matched recipients continue to need medications for the rest of their lives hence adverse side effects and enhanced morbidity. Understanding Immune rejection mechanisms, is of increasing importance since the greater use of living-unrelated donors and genetically unmatched individuals. Chronic rejection is devoted to T-cells, however the role of B-cells in rejection has been appreciated recently by the observation that B-cell depletion improve graft survival. By contrast however, B-cells can be beneficial to the grafted tissue. This protective effect is secondary to either the secretion of protective antibodies or the induction of B-cells that restrain excessive inflammatory responses, chiefly by local provision of IL-10, or inhibit effector T-cells by direct cellular interactions. As a proof of concept B-cell-mediated infectious transplantation tolerance could be achieved in animal models, and evidence emerged that the presence of such B-cells in transplanted patients correlate with a favorable outcome. Among these populations, regulatory B-cells constitute a recently described population. These cells may develop as a feedback mechanism to prevent uncontrolled reactivity to antigens and inflammatory stimuli. The difficult task for the clinician, is to quantify the respective ratios and functions of tolerant vs effector B-cells within a transplanted organ, at a given time point in order to modulate B-cell-directed therapy. Several receptors at the B-cell membrane as well as signaling molecules, can now be targeted for this purpose. Understanding the temporal expansion of regulatory B-cells in grafted patients and the stimuli that activate them will help in the future to implement specific strategies aimed at fighting chronic

  10. How B cells influence bone biology in health and disease.

    Science.gov (United States)

    Horowitz, Mark C; Fretz, Jackie A; Lorenzo, Joseph A

    2010-09-01

    It is now well established that important regulatory interactions occur between the cells in the hematopoietic, immune and skeletal systems (osteoimmunology). B lymphocytes (B cells) are responsible for the generation and production of antibodies or immunoglobulins in the body. Together with T cells these lymphocytes comprise the adaptive immune system, which allows an individual to develop specific responses to an infection and retain memory of that infection, allowing for a faster and more robust response if that same infection occurs again. In addition to this immune function, B cells have a close and multifaceted relationship with bone cells. B cells differentiate from hematopoietic stem cells (HSCs) in supportive niches found on endosteal bone surfaces. Cells in the osteoblast lineage support HSC and B cell differentiation in these niches. B cell differentiation is regulated, at least in part, by a series of transcription factors that function in a temporal manner. While these transcription factors are required for B cell differentiation, their loss causes profound changes in the bone phenotype. This is due, in part, to the close relationship between macrophage/osteoclast and B cell differentiation. Cross talk between B cells and bone cells is reciprocal with defects in the RANKL-RANK, OPG signaling axis resulting in altered bone phenotypes. While the role of B cells during normal bone remodeling appears minimal, activated B cells play an important role in many inflammatory diseases with associated bony changes. This review examines the relationship between B cells and bone cells and how that relationship affects the skeleton and hematopoiesis during health and disease. Copyright 2010 Elsevier Inc. All rights reserved.

  11. Are work-related stressors associated with diagnosis of more advanced stages of incident breast cancers?

    DEFF Research Database (Denmark)

    Nielsen, Naja Rod; Stahlberg, Claudia; Strandberg-Larsen, Katrine

    2008-01-01

    OBJECTIVE: To assess the relation between work-related stressors and breast cancer incidence and prognostic characteristics (estrogen receptor status, grade, lymph node status, size, stage) at the time of diagnosis. METHODS: The 18,932 women included in the Danish Nurse Cohort reported work...... breast cancer risk or the prognostic characteristics of incident breast cancers at the time of diagnosis. These results may be a comfort to working women and can hopefully prevent self-blaming among women who develop breast cancer.......-related stressors in 1993 and again in 1999 and were followed until the end of 2003 in national registries. Prognostic characteristics were obtained from a clinical database and fewer than 0.1% were lost to follow up. RESULTS: During follow-up, 455 women were diagnosed with breast cancer. Neither women with high...

  12. Visual binding abilities in the initial and advanced stages of schizophrenia

    DEFF Research Database (Denmark)

    Parnas, Josef; Vianin, P; Saebye, D

    2001-01-01

    patients believed to be suffering from a pre-schizophrenic prodrome) and a group of normal control subjects were tested on three tasks targeting visual 'binding' abilities (Muller-Lyer's illusion and two figure detection tasks) in addition to control parameters such as reaction time, visual selective......OBJECTIVE: The study tests the hypothesis that intramodal visual binding is disturbed in schizophrenia and should be detectable in all illness stages as a stable trait marker. METHOD: Three groups of patients (rehospitalized chronic schizophrenic, first admitted schizophrenic and schizotypal...... of neurocognitive deficits in schizophrenia which, however, in this sample seem to be linked to chronicity of illness. However, certain aspects of visual processing concerned with Gestalt extraction deserve attention as potential vulnerability- or prodrome- indicators. The initial hypothesis of the study...

  13. Visual binding abilities in the initial and advanced stages of schizophrenia

    DEFF Research Database (Denmark)

    Parnas, Josef; Vianin, P; Saebye, D

    2001-01-01

    OBJECTIVE: The study tests the hypothesis that intramodal visual binding is disturbed in schizophrenia and should be detectable in all illness stages as a stable trait marker. METHOD: Three groups of patients (rehospitalized chronic schizophrenic, first admitted schizophrenic and schizotypal...... patients believed to be suffering from a pre-schizophrenic prodrome) and a group of normal control subjects were tested on three tasks targeting visual 'binding' abilities (Muller-Lyer's illusion and two figure detection tasks) in addition to control parameters such as reaction time, visual selective...... attention, Raven's test and two conventional cortical tasks of spatial working memory (SWM) and a global local test. RESULTS: Chronic patients had a decreased performance on the binding tests. Unexpectedly, the prodromal group exhibited an enhanced Gestalt extraction on these tests compared both...

  14. Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development.

    Science.gov (United States)

    Kwon, Kyongrim; Hutter, Caroline; Sun, Qiong; Bilic, Ivan; Cobaleda, César; Malin, Stephen; Busslinger, Meinrad

    2008-06-01

    The transcription factor E2A controls the initiation of B lymphopoiesis, which is arrested at the pre-pro-B cell stage in E2A-deficient mice. Here, we demonstrate by conditional mutagenesis that E2A is essential for the development of pro-B, pre-B, and immature B cells in the bone marrow. E2A is, however, dispensable for the generation of mature B cells and plasma cells in peripheral lymphoid organs. In contrast, germinal center B cell development is impaired in the absence of E2A despite normal AID expression and class-switch recombination. Molecular analysis revealed that E2A is required not only for initiating but also for maintaining the expression of Ebf1, Pax5, and the B cell gene program in pro-B cells. Notably, precocious Pax5 transcription from the Ikzf1 locus promotes pro-B cell development in E2A-deficient mice, demonstrating that ectopic Pax5 expression is sufficient to activate the B lymphoid transcription program in vivo in the absence of E2A.

  15. Non-albuminuric renal disease among subjects with advanced stages of chronic kidney failure related to type 2 diabetes mellitus.

    Science.gov (United States)

    Boronat, Mauro; García-Cantón, César; Quevedo, Virginia; Lorenzo, Dionisio L; López-Ríos, Laura; Batista, Fátima; Riaño, Marta; Saavedra, Pedro; Checa, María D

    2014-03-01

    Urinary albumin excretion has been consistently found to be normal in a significant number of subjects with early stages of diabetic kidney disease. This study was aimed to estimate the prevalence and characteristics of non-albuminuric chronic kidney disease associated with type 2 diabetes mellitus among subjects who reach advanced stages of renal failure. Study population was composed of incident patients with advanced chronic kidney disease (glomerular filtration rate <30 mL/min) related to type 2 diabetes in a tertiary hospital from Gran Canaria (Spain) during a period of 2 years. Subjects were classified as normoalbuminuric (urinary albumin-to-creatine ratio [UACR] <30 mg/g), microalbuminuric (UACR ≥30 and <300 mg/g), or proteinuric (UACR ≥300 mg/g). Of 78 eligible patients, 21.8% had normoalbuminuria, 20.5% had microalbuminuria, and 57.7% had proteinuria. Individuals with normoalbuminuria were mostly women and had a lower prevalence of smoking and polyneuropathy than subjects with microalbuminuria or proteinuria. They also presented greater measures of body mass index and waist circumference, higher values of total and LDL cholesterol, and lower values of HbA1c and serum creatinine than subjects with microalbuminuria or proteinuria. Multivariate analysis demonstrated that female sex (positively) and HbA1c and polyneuropathy (negatively) were independently associated with absence of albuminuria. In conclusion, around 20% of subjects with diabetes-related advanced chronic kidney disease, characteristically women, have normal urinary albumin excretion. HbA1c and polyneuropathy are inversely related to this non-albuminuric form of nephropathy.

  16. Topotecan Monotherapy in Heavily Pretreated Patients with Progressive Advanced Stage Neuroendocrine Carcinomas

    DEFF Research Database (Denmark)

    Olsen, Ingrid Marie Holst; Knigge, Ulrich; Federspiel, Birgitte

    2014-01-01

    BACKGROUND: Neuroendocrine carcinomas (WHO grade 3) are highly aggressive tumors with an immense tendency to metastasize and with a poor prognosis. In advanced disease, there is no standard treatment beyond first-line platin/etoposide-based chemotherapy. Topotecan is widely used as second...... neuroendocrine carcinomas (Ki67>20%, G3) successively treated with oral topotecan 2.3 mg/m(2) d1-5 every 3 weeks. All patients had previously received treatment with carboplatin/etoposide. Demographic, clinical and pathological features were recorded. CT-evaluations according to RECIST 1.1 were performed after...... patients were evaluable for response: Five achieved stable disease (SD) and 17 progressed (PD). The median overall survival for the 22 patients was 3.2 months and the median progression-free survival was 2.1 months. The one-year survival was 18%. There were no treatment related deaths. The treatment...

  17. Theoretical comparison of single-stage and advanced absorption heat transformers used to increase solar pond's temperature

    Energy Technology Data Exchange (ETDEWEB)

    Rivera, W; Best, Roberto [Centro de Investigacion en Energia-UNAM, Temixco, Morelos (Mexico)

    2000-07-01

    Mathematical models of single-stage and advanced absorption heat transformers operating with the water/Carrol{sup T}M mixture were developed to simulate the performance of these systems coupled to a solar pond in order to increase the temperature of the useful heat produced by solar ponds. The results showed that the single-stage and the double absorption heat transformer are the most promising configuration to be coupled to solar ponds. With single-stage heat transformers it is possible to increase solar pond's temperature until 50 Celsius degrees with coefficients of performance of about 0.48 and with double absorption heat transformers until 100 Celsius degrees with coefficients of performance of 0.33. [Spanish] Se desarrollaron modelos matematicos de una sola etapa y transformadores avanzados de absorcion de calor operando con la mezcla agua/Carrol{sup T}M para simular el rendimiento de estos sistemas acoplados a un estanque solar con el objeto de aumentar la temperatura del calor util producido por los estanques solares. Los resultados mostraron que la etapa sencilla y el transformador de calor de absorcion doble son la configuracion mas prometedora para ser acoplado a estanques solares. Con los transformadores de calor de una sola etapa es posible aumentar la temperatura del estanque solar hasta 50 grados Celsius con coeficientes de rendimiento de alrededor de 0.48 y con transformadores de calor de doble absorcion hasta 100 grados Celsius con coeficientes de rendimiento de 0.33.

  18. Smooth Transition for Advancement to Graduate Education (STAGE) for Underrepresented Groups in the Mathematical Sciences Pilot Project: Broadening Participation through Mentoring

    Science.gov (United States)

    Eubanks-Turner, Christina; Beaulieu, Patricia; Pal, Nabendu

    2018-01-01

    The Smooth Transition for Advancement to Graduate Education (STAGE) project was a three-year pilot project designed to mentor undergraduate students primarily from under-represented groups in the mathematical sciences. The STAGE pilot project focused on mentoring students as they transitioned from undergraduate education to either graduate school…

  19. DNA breaks early in replication in B cell cancers

    Science.gov (United States)

    Research by scientists at the NCI has identified a new class of DNA sites in cells that break early in the replication process. They found that these break sites correlate with damage often seen in B cell cancers, such as diffuse large B cell lymphoma.

  20. A fine romance: T follicular helper cells and B cells.

    Science.gov (United States)

    King, Cecile

    2011-06-24

    T follicular helper (Tfh) cells help B cells to generate affinity-matured antibodies. Three papers in this issue of Immunity (Choi et al., 2011; Kerfoot et al., 2011; Kitano et al., 2011) provide information about the reciprocal relationship between B cells and Tfh cells. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Resource Competition Determines Selection of B Cell Repertoires

    NARCIS (Netherlands)

    Boer, R.J. de; Freitas, A.A. (António); Perelson, A.S. (Alan)

    2001-01-01

    Previous experiments with mouse chimeras demonstrated that cellular competition for antigen- specific survival signals plays a crucial role in the maintenance of the naive B cell repertoire. Transgenic (Tg) B cell populations in these chimeras have a shortened lifespan and poor competitive

  2. B-cell memory and primary immune deficiencies: interleukin-21 related defects.

    Science.gov (United States)

    Desjardins, Marylin; Mazer, Bruce D

    2013-12-01

    The purpose of this study is to describe recent advances in our understanding of the role of interleukin-21 (IL-21) in B-cell maturation, and how defects in IL-21 receptor (IL-21R) signalling pathways (IL-21R/γc/JAK3/STAT3) are related to primary immune deficiencies. Abnormal signalling through IL-21R/γc/JAK3/STAT3 pathway has been related to decreased specific antibody responses following vaccination, and to increased susceptibility to encapsulated bacterial infections. This is manifested in the hyper-IgE syndrome, X-linked and JAK3-related severe combined immunodeficiency (SCID) and loss-of-function mutations in the IL-21R gene. Common variable immunodeficiency is associated with impaired in-vitro development of peripheral blood mononuclear cells or purified B-cells into memory or CD38 B-cells following addition of IL-21. IL-21 is a key cytokine in development of B-cells into immunoglobulin-secreting cells. Abnormal signalling through the IL-21R/γc/JAK3/STAT3 pathway leads to defective humoral immune responses to both T-dependent and T-independent antigens and impairs the establishment of long-lasting B-cell memory. Studies involving patients with hyper-IgE syndrome demonstrated the nonredundant role of STAT3 in B-cell production of high-affinity specific antibodies, while total serum immunoglobulins could be maintained through STAT3-independent activation of AID (activation-induced cytidine-deaminase). IL-21 related defects may also be associated with reduced natural killer (NK)-cell cytotoxicity and TH17 cytokine production, indicating that abnormalities in the IL-21-IL-21R pathway have profound effects on crucial immune responses.

  3. A Novel VHH Antibody Targeting the B Cell-Activating Factor for B-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Wen Wu

    2014-05-01

    Full Text Available Objective: To construct an immune alpaca phage display library, in order to obtain a single domain anti-BAFF (B cell-activating factor antibody. Methods: Using phage display technology, we constructed an immune alpaca phage display library, selected anti-BAFF single domain antibodies (sdAbs, cloned three anti-BAFF single-domain antibody genes into expression vector pSJF2, and expressed them efficiently in Escherichia coli. The affinity of different anti-BAFF sdAbs were measured by Bio layer interferometry. The in vitro biological function of three sdAbs was investigated by cell counting kit-8 (CCK-8 assay and a competitive enzyme-linked immunosorbent assay (ELISA. Results: We obtained three anti-BAFF single domain antibodies (anti-BAFF64, anti-BAFF52 and anti-BAFFG3, which were produced in high yield in Escherichia coli and inhibited tumor cell proliferation in vitro. Conclusion: The selected anti-BAFF antibodies could be candidates for B-cell lymphoma therapies.

  4. Comparison of EBV DNA viral load in whole blood, plasma, B-cells and B-cell culture supernatant.

    Science.gov (United States)

    Ouedraogo, David Eric; Bollore, Karine; Viljoen, Johannes; Foulongne, Vincent; Reynes, Jacques; Cartron, Guillaume; Vendrell, Jean-Pierre; Van de Perre, Philippe; Tuaillon, Edouard

    2014-05-01

    Epstein-Barr virus (EBV) genome quantitation in whole blood is used widely for therapeutic monitoring of EBV-associated disorders in immunosuppressed individuals and in patients with EBV-associated lymphoma. However, the most appropriate biological material to be used for EBV DNA quantitation remains a subject of debate. This study compare the detection rate and levels of EBV DNA from whole blood, plasma, enriched B-cells, and B-cell short-term culture supernatant using quantitative real-time PCR. Samples were collected from 33 subjects with either HIV infection or B-cell lymphoma. Overall, EBV DNA was detected in 100% of enriched B-cell samples, in 82% of B-cell culture supernatants, in 57% of plasma, and 42% of whole blood samples. A significant correlation for EBV viral load was found between enriched B-cell and B-cell culture supernatant material (ρ = 0.92; P < 0.0001), but no significant correlation existed between EBV DNA levels in whole blood and enriched B-cells (ρ = -0.02; P = 0.89), whole blood and plasma (ρ = 0.24; P = 0.24), or enriched B-cells and plasma (ρ = 0.08; P = 0.77). Testing of enriched B-cells appeared to be the most sensitive method for detection of EBV DNA as well as for exploration of the cellular reservoir. Quantitation of EBV DNA in plasma and B-cell culture supernatant may be of interest to assess EBV reactivation dynamics and response to treatment as well as to decipher EBV host-pathogen interactions in various clinical scenarios. © 2013 Wiley Periodicals, Inc.

  5. Precursor B Cells Increase in the Lung during Airway Allergic Inflammation: A Role for B Cell-Activating Factor.

    Directory of Open Access Journals (Sweden)

    Konstantinos Samitas

    Full Text Available B cells, key cells in allergic inflammation, differentiate in the bone marrow and their precursors include pro-B, pre-B and immature B cells. Eosinophil progenitor cells increase in the lung after allergen exposure. However, the existence and possible role of B cell precursors in the lung during allergic inflammation remains elusive.A BALB/c mouse model of allergic airway inflammation was utilized to perform phenotypic and quantification analyses of pro-B and pre-B cells in the lung by flow cytometry. B cell maturation factors IL-7 and B cell-activating factor (BAFF and their receptors (CD127 and BAFFR, BCMA, TACI, respectively were also evaluated in the lung and serum. The effect of anti-BAFF treatment was investigated both in vivo (i.p. administration of BAFF-R-Ig fusion protein and in vitro (colony forming cell assay. Finally, BAFF levels were examined in the bronchoalveolar lavage (BAL of asthmatic patients and healthy controls.Precursor pro and pre-B cells increase in the lung after allergen exposure, proliferate in the lung tissue in vivo, express markers of chemotaxis (CCR10 and CXCR4 and co-stimulation (CD40, CD86 and are resistant to apoptosis (Bax. Precursor B cells express receptors for BAFF at baseline, while after allergen challenge both their ligand BAFF and the BCMA receptor expression increases in B cell precursors. Blocking BAFFR in the lung in vivo decreases eosinophils and proliferating precursor B cells. Blocking BAFFR in bone marrow cultures in vitro reduces pre-B colony formation units. BAFF is increased in the BAL of severe asthmatics.Our data support the concept of a BAFF-mediated role for B cell precursors in allergic airway inflammation.

  6. Defining B Cell Chromatin: Lessons from EBF1.

    Science.gov (United States)

    Boller, Sören; Li, Rui; Grosschedl, Rudolf

    2018-04-01

    Hematopoiesis is regulated by signals from the microenvironment, transcription factor networks, and changes of the epigenetic landscape. Transcription factors interact with and shape chromatin to allow for lineage- and cell type-specific changes in gene expression. During B lymphopoiesis, epigenetic regulation is observed in multilineage progenitors in which a specific chromatin context is established, at the onset of the B cell differentiation when early B cell factor 1 (EBF1) induces lineage-specific changes in chromatin, during V(D)J recombination and after antigen-driven activation of B cells and terminal differentiation. In this review, we discuss the epigenetic changes underlying B cell differentiation, focusing on the role of transcription factor EBF1 in B cell lineage priming. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Advances in the staging of renal cell carcinoma with high-resolution imaging

    International Nuclear Information System (INIS)

    Hallscheidt, P.; Noeldge, G.; Schawo, S.; Kauffmann, G.; Palmowski, M.; Bartling, S.; Pfitzenmaier, J.

    2007-01-01

    Modern imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) allow high-resolution imaging of the abdomen. Modern scanners made high temporal as well as high spatial resolution available. Therapeutic approaches to the treatment of renal cell carcinoma have been improved over the recent years. Besides conventional and open laparoscopic tumor nephrectomy and nephron sparing, surgical approaches such as local tumor cryotherapy and radiofrequency ablation (RF) are ablative modalities and are used increasingly. Improved anesthesiological methods and new surgical approaches also allow curative treatment in extended tumors. Prerequisites for preoperative imaging modalities include visualization of the kidney tumor as well as its staging. Tumor-related infiltration of the renal pelvis or invasion of the perinephric fat and the renal hilus has to be excluded prior to nephron sparing surgery. In cases with extended tumors with infiltration of the inferior vena cava, it is necessary to visualize the exact extension of the tumor growth towards the right atrium in the vena cava. The radiologist should be informed about the diagnostic possibilities and limitations of the imaging modalities of CT and MRI in order to support the urologist in the planning and performance of surgical therapeutical approaches. (orig.)

  8. Global changes in the nuclear positioning of genes and intra- and interdomain genomic interactions that orchestrate B cell fate.

    Science.gov (United States)

    Lin, Yin C; Benner, Christopher; Mansson, Robert; Heinz, Sven; Miyazaki, Kazuko; Miyazaki, Masaki; Chandra, Vivek; Bossen, Claudia; Glass, Christopher K; Murre, Cornelis

    2012-12-01

    The genome is folded into domains located in compartments that are either transcriptionally inert or transcriptionally permissive. Here we used genome-wide strategies to characterize domains during B cell development. Structured interaction matrix analysis showed that occupancy by the architectural protein CTCF was associated mainly with intradomain interactions, whereas sites bound by the histone acetyltransferase p300 or the transcription factors E2A or PU.1 were associated with intra- and interdomain interactions that are developmentally regulated. We identified a spectrum of genes that switched nuclear location during early B cell development. In progenitor cells, the transcriptionally inactive locus encoding early B cell factor (Ebf1) was sequestered at the nuclear lamina, which thereby preserved their multipotency. After development into the pro-B cell stage, Ebf1 and other genes switched compartments to establish new intra- and interdomain interactions associated with a B lineage-specific transcription signature.

  9. Outcome Measures for Dementia in the Advanced Stage and at the End of Life

    Directory of Open Access Journals (Sweden)

    Ladislav Volicer

    2014-01-01

    Full Text Available Increasing life span and lack of medication for prevention or treatment of progressive dementias will significantly increase the number of individuals with advanced dementia worldwide. Providing optimal care for them will stretch health care resources and will require evaluation of different treatment strategies. This paper is presenting measures that may be used in this patient population. Evaluation of global goals of palliative care may include measuring quality of life by QUALID scale, comfort by DS-DAT scale, and engagement by MPES scale. Symptom control may be achieved by measuring pain by PAINAD or PACSLAC scales, by evaluating behavioral symptoms and their management (agitation by SOAPD scale, apathy by AES scale and rejection of care by RTC-DAT scale, and by monitoring patients for dyspnea using RDOS scale. Outcomes of palliative care at the end of life may be evaluated by EOLD-CAD scale and by determining family satisfaction with care (EOLD-SWC. Items included in these scales, psychometric properties, and research use of these scales are described. It is hoped that information in this paper will stimulate research interest in this important area.

  10. Marginal zone B-cells, a gatekeeper of innate immunity

    Directory of Open Access Journals (Sweden)

    Moncef eZOUALI

    2011-12-01

    Full Text Available To maintain the integrity of an organism constantly challenged by pathogens, the immune system is endowed with a variety of cell types. B-lymphocytes were initially thought to only play a role in the adaptative branch of immunity. However, a number of converging observations revealed that two B-cell subsets, marginal zone (MZ and B1 cells, exhibit unique developmental and functional characteristics, and can contribute to innate immune responses. In addition to their capacity to mount local antibody response against type 2 T-independent (TI-2 antigens, MZ B-cells can participate to T-dependent (TD immune response through the capture and import of blood-borne antigens to follicular areas of the spleen. Here, we discuss the multiple roles of MZ B-cells in rodents and primates. We also summarize studies —performed in transgenic mice expressing fully human antibodies on their B-cells and macaques whose infection with Simian Immunodeficiency Virus (SIV represents a suitable model for HIV-1 infection in humans— showing that infectious agents have developed strategies to subvert MZ B-cell functions. In these two experimental models, we observed that two microbial superantigens for B-cells (protein A from Staphylococcus aureus and protein L from Peptostreptococcus magnus as well as inactivated AT-2 virions of HIV-1 and infectious SIV preferentially deplete innate-like B-cells —MZ B-cells and/or B1 B-cells— with different consequences on TI and TD antibody responses. These data revealed that viruses and bacteria have developed strategies to deplete innate-like B-cells during the acute phase of infection and to impair the antibody response. Unraveling the intimate mechanisms responsible for targeting MZ B-cells in humans will be important for understanding disease pathogenesis and for designing novel vaccine strategies.

  11. Predictors of Timely Access of Oncology Services and Advanced-Stage Cancer in an HIV-Endemic Setting.

    Science.gov (United States)

    Brown, Carolyn A; Suneja, Gita; Tapela, Neo; Mapes, Abigail; Pusoentsi, Malebogo; Mmalane, Mompati; Hodgeman, Ryan; Boyer, Matthew; Musimar, Zola; Ramogola-Masire, Doreen; Grover, Surbhi; Nsingo-Bvochora, Memory; Kayembe, Mukendi; Efstathiou, Jason; Lockman, Shahin; Dryden-Peterson, Scott

    2016-06-01

    Three-quarters of cancer deaths occur in resource-limited countries, and delayed presentation contributes to poor outcome. In Botswana, where more than half of cancers arise in HIV-infected individuals, we sought to explore predictors of timely oncology care and evaluate the hypothesis that engagement in longitudinal HIV care improves access. Consenting patients presenting for oncology care from October 2010 to September 2014 were interviewed and their records were reviewed. Cox and logistic models were used to examine the effect of HIV and other predictors on time to oncology care and presentation with advanced cancer (stage III or IV). Of the 1,146 patients analyzed, 584 (51%) had HIV and 615 (54%) had advanced cancer. The initial clinic visit occurred a mean of 144 days (median 29, interquartile range 0-185) after symptom onset, but subsequent mean time to oncology care was 406 days (median 160, interquartile range 59-653). HIV status was not significantly associated with time to oncology care (adjusted hazard ratio [aHR] 0.91, 95% confidence interval [CI] 0.79-1.06). However, patients who reported using traditional medicine/healers engaged in oncology care significantly faster (aHR 1.23, 95% CI 1.09-1.40) and those with advanced cancer entered care earlier (aHR 1.48, 95% CI 1.30-1.70). Factors significantly associated with advanced cancer included income oncology care was 13 months. For HIV-infected patients (51% of total), regular longitudinal contact with the health system, through quarterly doctor visits for HIV management, was not successful in providing faster linkages into oncology care. However, patients who used traditional medicine/healers engaged in cancer care faster, indicating potential for leveraging traditional healers as partners in early cancer detection. New strategies are urgently needed to facilitate diagnosis and timely treatment of cancer in low- and middle-income countries. ©AlphaMed Press.

  12. Prognosis of localized diffuse large B-cell lymphoma in younger patients

    DEFF Research Database (Denmark)

    Møller, Michael B; Christensen, Bjarne E; Pedersen, Niels T

    2003-01-01

    BACKGROUND: The International Prognostic Index (IPI) is widely used as a predictive model in diffuse large B-cell lymphoma (DLBCL) patients of all ages and stages. To determine the optimal IPI-based prognostic system at the time of diagnosis in younger patients with limited-stage DLBCL, the authors...... evaluated the age-adjusted IPI and the recently proposed stage-adjusted IPI, and constructed an IPI-based model adjusted for both age and stage. METHODS: From the population-based LYFO registry of the Danish Lymphoma Group, 233 patients not older than 60 years with Stage I-II DLBCL treated......-adjusted and the stage-adjusted IPI had major prognostic significance (P IPI was more powerful (chi-square test = 44.99) than the age-adjusted IPI (chi...

  13. Diffuse large B-cell lymphoma of the ocular adnexal region

    DEFF Research Database (Denmark)

    Rasmussen, Peter Kristian; Ralfkiaer, Elisabeth; Prause, Jan U

    2013-01-01

    III and ten patients (29%) presented with Stage IV lymphoma. The 5-year overall survival (OS) rate for the whole study group was 20%. The patients with Stage I lymphoma had a significantly better 5-year OS rate (28%) than patients in Stage II-IV (5-year OS rate, 9%). In Cox regression analysis......Purpose: To characterize the clinicopathological features of diffuse large B-cell lymphoma (DLBCL) of the ocular adnexal region. Methods: The present series of orbital and adnexal DLBCLs were found by searching the Danish Registry of Pathology between 1980 and 2009. Histological specimens were re......-seven per cent of the patients had unilateral ocular adnexal region involvement, and the orbit (76%) was the most frequently affected site. Nineteen patients (56%) presented with Stage I lymphoma. Of these, 18 were diagnosed with primary lymphoma. Four patients (12%) had Stage II, one patient (3%) had Stage...

  14. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated disruption of the CD40 ligand-induced activation of primary human B cells

    International Nuclear Information System (INIS)

    Lu Haitian; Crawford, Robert B.; Kaplan, Barbara L.F.; Kaminski, Norbert E.

    2011-01-01

    Suppression of the primary antibody response is particularly sensitive to suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice; however, surprisingly little is known concerning the effects of TCDD on humoral immunity or B cell function in humans. Results from a limited number of previous studies, primarily employing in vitro activation models, suggested that human B cell effector function is suppressed by TCDD. The present study sought to extend these findings by investigating, in primary human B cells, the effects of TCDD on several critical stages leading to antibody secretion including activation and plasmacytic differentiation using an in vitro CD40 ligand activation model. These studies revealed important differences in the response of human and mouse B cells to TCDD, the most striking being altered expression of plasmacytic differentiation regulators, B lymphocyte-induced maturation protein 1 and paired box protein 5, in mouse but not human B cells. The activation of human B cells was profoundly impaired by TCDD, as evidenced by decreased expression of activation markers CD80, CD86, and CD69. The impaired activation correlated with decreased cell viability, which prevented the progression of human B cells toward plasmacytic differentiation. TCDD treatment also attenuated the early activation of mitogen-activated protein kinases (MAPK) and Akt signaling in human B cells. Collectively, the present study provided experimental evidence for novel mechanisms by which TCDD impairs the effector function of primary human B cells. - Highlights: → In this study primary human and mouse B cell toxicity to TCDD was compared. → TCDD altered the expression of Blimp-1 and Pax5 in mouse but not human B cells. → TCDD markedly suppressed human B cell activation as characterized by CD80, CD86 and CD69 expression. → TCDD inhibited ERK, p38, and Akt phosphorylation in human B cells.

  15. End-of-life costs of medical care for advanced stage cancer patients

    Directory of Open Access Journals (Sweden)

    Kovačević Aleksandra

    2015-01-01

    Full Text Available Background/Aim. Cancer, one of the leading causes of mortality in the world, imposes a substantial economic burden on each society, including Serbia. The aim of this study was to evaluate the major cancer cost drivers in Serbia. Methods. A retrospective, indepth, bottom-up analysis of two combined databases was performed in order to quantify relevant costs. End-of-life data were obtained from patients with cancer, who deceased within the first year of the established diagnose, including basic demographics, diagnosis, tumour histology, medical resource use and related costs, time and cause of death. All costs were allocated to one of the three categories of cancer health care services: primary care (included home care, hospital outpatient and hospital inpatient care. Results. Exactly 114 patients were analyzed, out of whom a high percent (48.25% had distant metastases at the moment of establishing the diagnosis. Malignant neoplasms of respiratory and intrathoracic organs were leading causes of morbidity. The average costs per patient were significantly different according to the diagnosis, with the highest (13,114.10 EUR and the lowest (4.00 EUR ones observed in the breast cancer and melanoma, respectively. The greatest impact on total costs was observed concerning pharmaceuticals, with 42% of share (monoclonal antibodies amounted to 34% of all medicines and 14% of total costs, followed by oncology medical care (21%, radiation therapy and interventional radiology (11%, surgery (9%, imaging diagnostics (9% and laboratory costs (8%. Conclusion. Cancer treatment incurs high costs, especially for end-of-life pharmaceutical expenses, ensued from medical personnel tendency to improve such patients’ quality of life in spite of nearing the end of life. Reimbursement policy on monoclonal antibodies, in particular at end-stage disease, should rely on cost-effectiveness evidence as well as documented clinical efficiency. [Projekat Ministarstva nauke

  16. Retinal blood flow is increased in type 1 diabetes mellitus patients with advanced stages of retinopathy.

    Science.gov (United States)

    Nguyen, Hoang-Ton; van Duinkerken, Eelco; Verbraak, Frank D; Polak, Bettine C P; Ringens, Peter J; Diamant, Michaela; Moll, Annette C

    2016-05-26

    Diabetic retinopathy (DRP) is a common microvascular complication seen in patients with type 1 diabetes mellitus (T1DM). The effects of T1DM and concomitant (proliferative) DRP on retinal blood flow are currently unclear. Therefore, we measured retinal vascular blood flow in T1DM patients with and without DRP and non-diabetic controls. We further assessed the acute effects of panretinal photocoagulation on retinal microvascular bloodflow in eight patients with diabetes. Thirty-three T1DM patients with proliferative DRP, previously treated with panretinal photocoagulation (pDRP), 11 T1DM patients with untreated non-proliferative retinopathy (npDRP) and 32 T1DM patients without DRP (nDRP) were compared with 44 non-diabetic gender-matched controls. Using scanning laser Doppler flowmetry (HRF, Heidelberg) blood flow in the retinal microvasculature was measured temporal and nasal of the optic disc and averaged into one flow value per eye. The right eye was used as a default for further analyses. Eight patients with novel proliferative retinopathy (4 T1DM and 4 with type 2 diabetes) were measured before and several months after photocoagulation. Between-group differences in retinal blood flow were assessed using ANOVA corrected for multiple comparisons (Bonferroni). Retinal blood flow was higher in the treated pDRP compared with the nDRP group and controls (all P Bonferroni retinopathy, blood flow did not significantly change before and after panretinal photocoagulation (P > 0.05). Using regression analysis, no variables were found as predictors of retinal blood flow. In comparison with controls and nDRP patients, retinal blood flow significantly increased in the pDRP group, which previously underwent photocoagulation treatment, but not in the npDRP patients. These changes may be a consequence of a failing vascular autoregulation in advanced diabetic retinopathy.

  17. Prolactin Rescues Immature B-Cells from Apoptosis Induced by B-Cell Receptor Cross-Linking

    Directory of Open Access Journals (Sweden)

    Rocio Flores-Fernández

    2016-01-01

    Full Text Available Prolactin has an immunomodulatory effect and has been associated with B-cell-triggered autoimmune diseases, such as systemic lupus erythematosus (SLE. In mice that develop SLE, the PRL receptor is expressed in early bone marrow B-cells, and increased levels of PRL hasten disease manifestations, which are correlated with a reduction in the absolute number of immature B-cells. The aim of this work was to determine the effect of PRL in an in vitro system of B-cell tolerance using WEHI-231 cells and immature B-cells from lupus prone MRL/lpr mice. WEHI-231 cells express the long isoform of the PRL receptor, and PRL rescued the cells from cell death by decreasing the apoptosis induced by the cross-linking of the B-cell antigen receptor (BCR as measured by Annexin V and active caspase-3. This decrease in apoptosis may have been due to the PRL and receptor interaction, which increased the relative expression of antiapoptotic Bcl-xL and decreased the relative expression of proapoptotic Bad. In immature B-cells from MRL/lpr mice, PRL increased the viability and decreased the apoptosis induced by the cross-linking of BCR, which may favor the maturation of self-reactive B-cells and contribute to the onset of disease.

  18. Prolactin Rescues Immature B-Cells from Apoptosis Induced by B-Cell Receptor Cross-Linking

    Science.gov (United States)

    Flores-Fernández, Rocio; Blanco-Favela, Francisco; Fuentes-Pananá, Ezequiel M.; Chávez-Sánchez, Luis; Gorocica-Rosete, Patricia; Pizaña-Venegas, Alberto; Chávez-Rueda, Adriana Karina

    2016-01-01

    Prolactin has an immunomodulatory effect and has been associated with B-cell-triggered autoimmune diseases, such as systemic lupus erythematosus (SLE). In mice that develop SLE, the PRL receptor is expressed in early bone marrow B-cells, and increased levels of PRL hasten disease manifestations, which are correlated with a reduction in the absolute number of immature B-cells. The aim of this work was to determine the effect of PRL in an in vitro system of B-cell tolerance using WEHI-231 cells and immature B-cells from lupus prone MRL/lpr mice. WEHI-231 cells express the long isoform of the PRL receptor, and PRL rescued the cells from cell death by decreasing the apoptosis induced by the cross-linking of the B-cell antigen receptor (BCR) as measured by Annexin V and active caspase-3. This decrease in apoptosis may have been due to the PRL and receptor interaction, which increased the relative expression of antiapoptotic Bcl-xL and decreased the relative expression of proapoptotic Bad. In immature B-cells from MRL/lpr mice, PRL increased the viability and decreased the apoptosis induced by the cross-linking of BCR, which may favor the maturation of self-reactive B-cells and contribute to the onset of disease. PMID:27314053

  19. Quantitative Analysis of Repertoire-Scale Immunoglobulin Properties in Vaccine-Induced B-Cell Responses

    OpenAIRE

    Khavrutskii, Ilja V.; Chaudhury, Sidhartha; Stronsky, Sabrina M.; Lee, Donald W.; Benko, Jacqueline G.; Wallqvist, Anders; Bavari, Sina; Cooper, Christopher L.

    2017-01-01

    Recent advances in the next-generation sequencing of B-cell receptors (BCRs) enable the characterization of humoral responses at a repertoire-wide scale and provide the capability for identifying unique features of immune repertoires in response to disease, vaccination, or infection. Immunosequencing now readily generates 103–105 sequences per sample; however, statistical analysis of these repertoires is challenging because of the high genetic diversity of BCRs and the elaborate clonal relati...

  20. Advanced renal disease, end-stage renal disease and renal death among HIV-positive individuals in Europe

    DEFF Research Database (Denmark)

    Ryom, L; Kirk, O; Lundgren, Jens

    2012-01-01

    followed from baseline (first eGFR after 1/1/2004) until last eGFR, ARD/ESRD/renal death; whichever occurred first. Poisson regression was used to identify predictors. 8817 persons were included, the majority were white (87.3%), males (73.9%) infected though homosexual contact (41.5%) and with a median age......Many studies have focused on chronic kidney disease in HIV-positive individuals, but few have studied the less frequent events, advanced renal disease (ARD) and end-stage renal disease (ESRD). The aim of this study was to investigate incidence, predictors and outcomes for ARD/ESRD and renal death...... in EuroSIDA. ARD was defined as confirmed eGFR 3 months apart) using Cockcroft-Gault. ESRD was defined as hemo- or peritoneal dialysis>1 month/renal transplant. Renal deaths were defined as renal failure as the underlying cause of death, using CoDe methodology. Patients were...

  1. Accelerated rogue waves generated by soliton fusion at the advanced stage of supercontinuum formation in photonic-crystal fibers.

    Science.gov (United States)

    Driben, Rodislav; Babushkin, Ihar

    2012-12-15

    Soliton fusion is a fascinating and delicate phenomenon that manifests itself in optical fibers in case of interaction between copropagating solitons with small temporal and wavelength separation. We show that the mechanism of acceleration of a trailing soliton by dispersive waves radiated from the preceding one provides necessary conditions for soliton fusion at the advanced stage of supercontinuum generation in photonic-crystal fibers. As a result of fusion, large-intensity robust light structures arise and propagate over significant distances. In the presence of small random noise the delicate condition for the effective fusion between solitons can easily be broken, making the fusion-induced giant waves a rare statistical event. Thus oblong-shaped giant accelerated waves become excellent candidates for optical rogue waves.

  2. The Modern Role of Radiation Therapy in Treating Advanced-Stage Retinoblastoma: Long-Term Outcomes and Racial Differences

    Energy Technology Data Exchange (ETDEWEB)

    Orman, Amber [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Koru-Sengul, Tulay [Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida (United States); Miao, Feng [Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (United States); Markoe, Arnold [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Panoff, Joseph E., E-mail: jpanoff@med.miami.edu [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States)

    2014-12-01

    Purpose/Objective(s): To evaluate the effects of various patient characteristics and radiation therapy treatment variables on outcomes in advanced-stage retinoblastoma. Methods and Materials: This was a retrospective review of 41 eyes of 30 patients treated with external beam radiation therapy between June 1, 1992, and March 31, 2012, with a median follow-up time of 133 months (11 years). Outcome measures included overall survival, progression-free survival, local control, eye preservation rate, and toxicity. Results: Over 90% of the eyes were stage V. Definitive external beam radiation therapy (EBRT) was delivered in 43.9% of eyes, adjuvant EBRT in 22% of eyes, and second-line/salvage EBRT in 34.1% of eyes. A relative lens sparing (RLS) technique was used in 68.3% of eyes and modified lens sparing (MLS) in 24.4% of eyes. Three eyes were treated with other techniques. Doses ≥45 Gy were used in 68.3% of eyes. Chemotherapy was a component of treatment in 53.7% of eyes. The 10-year overall survival was 87.7%, progression-free survival was 80.5%, and local control was 87.8%. White patients had significantly better overall survival than did African-American patients in univariate analysis (hazard ratio 0.09; 95% confidence interval 0.01-0.84; P=.035). Toxicity was seen in 68.3% of eyes, including 24.3% with isolated acute dermatitis. Conclusions: External beam radiation therapy continues to be an effective treatment modality for advanced retinoblastoma, achieving excellent long-term local control and survival with low rates of treatment-related toxicity and secondary malignancy.

  3. Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells.

    Science.gov (United States)

    Gaya, Mauro; Barral, Patricia; Burbage, Marianne; Aggarwal, Shweta; Montaner, Beatriz; Warren Navia, Andrew; Aid, Malika; Tsui, Carlson; Maldonado, Paula; Nair, Usha; Ghneim, Khader; Fallon, Padraic G; Sekaly, Rafick-Pierre; Barouch, Dan H; Shalek, Alex K; Bruckbauer, Andreas; Strid, Jessica; Batista, Facundo D

    2018-01-25

    B cells constitute an essential line of defense from pathogenic infections through the generation of class-switched antibody-secreting cells (ASCs) in germinal centers. Although this process is known to be regulated by follicular helper T (TfH) cells, the mechanism by which B cells initially seed germinal center reactions remains elusive. We found that NKT cells, a population of innate-like T lymphocytes, are critical for the induction of B cell immunity upon viral infection. The positioning of NKT cells at the interfollicular areas of lymph nodes facilitates both their direct priming by resident macrophages and the localized delivery of innate signals to antigen-experienced B cells. Indeed, NKT cells secrete an early wave of IL-4 and constitute up to 70% of the total IL-4-producing cells during the initial stages of infection. Importantly, the requirement of this innate immunity arm appears to be evolutionarily conserved because early NKT and IL-4 gene signatures also positively correlate with the levels of neutralizing antibodies in Zika-virus-infected macaques. In conclusion, our data support a model wherein a pre-TfH wave of IL-4 secreted by interfollicular NKT cells triggers the seeding of germinal center cells and serves as an innate link between viral infection and B cell immunity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Gallium arsenide exposure impairs splenic B cell accessory function.

    Science.gov (United States)

    Gondre-Lewis, Timothy A; Hartmann, Constance B; Caffrey, Rebecca E; McCoy, Kathleen L

    2003-03-01

    Gallium arsenide (GaAs) is utilized in industries for its semiconductor and optical properties. Chemical exposure of animals systemically suppresses several immune functions. The ability of splenic B cells to activate antigen-specific helper CD4(+) T cell hybridomas was assessed, and various aspects of antigen-presenting cell function were examined. GaAs-exposed murine B cells were impaired in processing intact soluble protein antigens, and the defect was antigen dependent. In contrast, B cells after exposure competently presented peptides to the T cells, which do not require processing. Cell surface expression of major histocompatibility complex (MHC) class II molecules and several costimulatory molecules on splenic B cells, which are critical for helper T cell activation, was not affected by chemical exposure. GaAs exposure also did not influence the stability of MHC class II heterodimers, suggesting that the defect may precede peptide exchange. GaAs-exposed B cells contained a normal level of aspartyl cathepsin activity; however, proteolytic activities of thiol cathepsins B and L were approximately half the control levels. Furthermore, two cleavage fragments of invariant chain, a molecular chaperone of MHC class II molecules, were increased in GaAs-exposed B cells, indicative of defective degradation. Thus, diminished thiol proteolytic activity in B cells may be responsible for their impaired antigen processing and invariant chain degradation, which may contribute to systemic immunosuppression caused by GaAs exposure.

  5. Interleukin 21 - its potential role in the therapy of B-cell lymphomas.

    Science.gov (United States)

    Bhatt, Shruti; Sarosiek, Kristopher A; Lossos, Izidore S

    2017-01-01

    Interleukin-21 (IL-21), a member of IL-2 cytokine family, has pleotropic biological effects on lymphoid and myeloid cells. During the past 15 years, since the discovery of IL-21, great advances have been made regarding its biological activity and the mechanisms controlling IL-21-mediated cellular responses, especially in hematological malignancies. Preclinical studies have shown that IL-21R is expressed on healthy and neoplastic B-cells and exogenous IL-21 can induce direct apoptosis of IL-21R expressing B-cell non-Hodgkin lymphomas (NHL), making it a potentially attractive anti-lymphoma therapy. However, in some hematological malignancies such as multiple myeloma, Hodgkin lymphoma and Burkitt lymphoma, IL-21 can induce proliferation of neoplastic B-cells. In NHL, the underlying mechanism of cell death was found to be different between the various subtypes, including activation of different JAK/STAT signal transduction pathways or other factors. Immunomodulatory effects of IL-21 have also been reported to contribute to its anti-tumor effects as described by earlier studies in solid tumors and B-cell associated malignancies. These effects are predominantly mediated by IL-21's ability to activate cytolytic activities by NK-cells and CD4 + /CD8 + T-cells. In this review, we provide an overview of IL-21's effects in NHL, results from clinical trials utilizing IL-21, and propose how IL-21 can be therapeutically exploited for treating these lymphomas.

  6. On the Pathogenesis Trail: What Marker B Cell Clones Tell Us about Inflammatory Bowel Disease

    Directory of Open Access Journals (Sweden)

    Jonathan Braun

    1996-01-01

    Full Text Available Clonal patterns of B cell activity have been recognized in inflammatory bowel disease, most notably in the immunogenetic relationship of perinuclear-antineutrophil cytoplasmic antibodies to ulcerative colitis. Conceptually, this most likely reflects the B cell response to antigens predominating at these sites of mucosal inflammation. Identification of these B cell clones and their antigenic targets may be of pathogenetic and practical importance to diagnosis and treatment. The authors describe strategies to identify such clones, based on recent advances in the characterization and detection of antibody gene products. As an example of this strategy, a clonal detection system was used to identify new marker antibodies potentially useful in the laboratory diagnosis of Crohn’s disease and ulcerative colitis. One surprising outcome of such studies is the unexpected and specific association of the B cell clonal response in Campylobacter jejuni enterocolitis and inflammatory bowel disease. By analogy to the pathogenetic role of Helicobacter pylori-induced mucositis in peptic ulcer disease, this evidence renews attention to the role of C jejuni in the initiation of ulcerative colitis and Crohn’s disease.

  7. Predicting linear B-cell epitopes using string kernels

    Science.gov (United States)

    EL-Manzalawy, Yasser; Dobbs, Drena; Honavar, Vasant

    2008-01-01

    The identification and characterization of B-cell epitopes play an important role in vaccine design, immunodiagnostic tests, and antibody production. Therefore, computational tools for reliably predicting linear B-cell epitopes are highly desirable. We evaluated Support Vector Machine (SVM) classifiers trained utilizing five different kernel methods using fivefold cross-validation on a homology-reduced data set of 701 linear B-cell epitopes, extracted from Bcipep database, and 701 non-epitopes, randomly extracted from SwissProt sequences. Based on the results of our computational experiments, we propose BCPred, a novel method for predicting linear B-cell epitopes using the subsequence kernel. We show that the predictive performance of BCPred (AUC = 0.758) outperforms 11 SVM-based classifiers developed and evaluated in our experiments as well as our implementation of AAP (AUC = 0.7), a recently proposed method for predicting linear B-cell epitopes using amino acid pair antigenicity. Furthermore, we compared BCPred with AAP and ABCPred, a method that uses recurrent neural networks, using two data sets of unique B-cell epitopes that had been previously used to evaluate ABCPred. Analysis of the data sets used and the results of this comparison show that conclusions about the relative performance of different B-cell epitope prediction methods drawn on the basis of experiments using data sets of unique B-cell epitopes are likely to yield overly optimistic estimates of performance of evaluated methods. This argues for the use of carefully homology-reduced data sets in comparing B-cell epitope prediction methods to avoid misleading conclusions about how different methods compare to each other. Our homology-reduced data set and implementations of BCPred as well as the APP method are publicly available through our web-based server, BCPREDS, at: http://ailab.cs.iastate.edu/bcpreds/. PMID:18496882

  8. Increased RCAS1 expression is associated with advanced histopathological stage and poor prognosis in patients with gastric adenocarcinoma.

    Science.gov (United States)

    Giaginis, Constantinos; Efkarpidis, Themistoclis; Alexandrou, Paraskevi; Patsouris, Efstratios; Kouraklis, Gregory; Theocharis, Stamatios

    2013-01-01

    The receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a human tumor-associated antigen that has been considered to play a crucial role in tumor progression by enabling cancer cells to evade immune surveillance. The present study aimed to evaluate the clinical significance of the RCAS1 expression in gastric adenocarcinoma. RCAS1 protein expression was assessed immunohistochemically on 54 gastric adenocarcinoma tissue samples and was analyzed in relation to clinicopathological parameters, tumor proliferative capacity, and patients' survival. Enhanced RCAS1 expression levels were significantly associated with advanced histopathological stage and presence of organ metastasis (P = 0.0084 and P = 0.0327). Gastric cancer patients with elevated RCAS1 expression levels showed significantly shorter survival times compared to those with low RCAS1 expression (log-rank test, P = 0.0168). In multivariate analysis, histopathological stage and grade of differentiation as well as the RCAS1 expression were identified as independent prognostic factors (Cox regression analysis, P = 0.0204, P = 0.0035, and P = 0.0081). Our data support the evidence that RCAS1 upregulation may contribute to gastric malignant progression, representing a useful biomarker to predict the biological behaviour and prognosis in gastric neoplasia.

  9. Increased RCAS1 Expression Is Associated with Advanced Histopathological Stage and Poor Prognosis in Patients with Gastric Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Constantinos Giaginis

    2013-01-01

    Full Text Available Background. The receptor-binding cancer antigen expressed on SiSo cells (RCAS1 is a human tumor-associated antigen that has been considered to play a crucial role in tumor progression by enabling cancer cells to evade immune surveillance. The present study aimed to evaluate the clinical significance of the RCAS1 expression in gastric adenocarcinoma. Material and Methods. RCAS1 protein expression was assessed immunohistochemically on 54 gastric adenocarcinoma tissue samples and was analyzed in relation to clinicopathological parameters, tumor proliferative capacity, and patients’ survival. Results. Enhanced RCAS1 expression levels were significantly associated with advanced histopathological stage and presence of organ metastasis ( and . Gastric cancer patients with elevated RCAS1 expression levels showed significantly shorter survival times compared to those with low RCAS1 expression (log-rank test, . In multivariate analysis, histopathological stage and grade of differentiation as well as the RCAS1 expression were identified as independent prognostic factors (Cox regression analysis, , , and . Conclusions. Our data support the evidence that RCAS1 upregulation may contribute to gastric malignant progression, representing a useful biomarker to predict the biological behaviour and prognosis in gastric neoplasia.

  10. Invasin of Yersinia pseudotuberculosis activates human peripheral B cells.

    OpenAIRE

    Lundgren, E; Carballeira, N; Vazquez, R; Dubinina, E; Bränden, H; Persson, H; Wolf-Watz, H

    1996-01-01

    The Yersinia pseudotuberculosis cell surface-located protein invasin was found to promote binding between the pathogen and resting peripheral B cells via beta 1 integrin receptors (CD29). B cells responded by expressing several activation markers and by growing, In contrast, T cells did not react, although these cells express CD29. An isogenic invA mutant failed to activate B cells. The mutation could be complemented by providing the invA+ gene in trans. Purified invasin alone did not activat...

  11. Extended Pleurectomy-Decortication-Based Treatment for Advanced Stage Epithelial Mesothelioma Yielding a Median Survival of Nearly Three Years.

    Science.gov (United States)

    Friedberg, Joseph S; Simone, Charles B; Culligan, Melissa J; Barsky, Andrew R; Doucette, Abigail; McNulty, Sally; Hahn, Stephen M; Alley, Evan; Sterman, Daniel H; Glatstein, Eli; Cengel, Keith A

    2017-03-01

    The purpose of this study was to assess survival for patients with malignant pleural mesothelioma (MPM), epithelial subtype, utilizing extended pleurectomy-decortication combined with intraoperative photodynamic therapy (PDT) and adjuvant pemetrexed-based chemotherapy. From 2005 to 2013, 90 patients underwent lung-sparing surgery and PDT for MPM. All patients had a preoperative diagnosis of epithelial subtype, of which 17 proved to be of mixed histology. The remaining 73 patients with pure epithelial subtype were analyzed. All patients received lung-sparing surgery and PDT; 92% also received chemotherapy. The median follow-up was 5.3 years for living patients. Macroscopic complete resection was achieved in all 73 patients. Thirty-day mortality was 3% and 90-day mortality was 4%. For all 73 patients (89% American Joint Commission on Cancer stage III/IV, 69% N2 disease, median tumor volume 550 mL), the median overall and disease-free survivals were 3 years and 1.2 years, respectively. For the 19 patients without lymph node metastases (74% stage III/IV, median tumor volume 325 mL), the median overall and disease-free survivals were 7.3 years and 2.3 years, respectively. This is a mature dataset for MPM that demonstrates the ability to safely execute a complex treatment plan that included a surgical technique that consistently permitted achieving a macroscopic complete resection while preserving the lung. The role for lung-sparing surgery is unclear but this series demonstrates that it is an option, even for advanced cases. The overall survival of 7.3 years for the node negative subset of patients, still of advanced stage, is encouraging. Of particular interest is the overall survival being approximately triple the disease-free survival, perhaps PDT related. The impact of PDT is unclear, but it is hoped that it will be established by an ongoing randomized trial. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  12. B cell development in the bone marrow is regulated by homeostatic feedback exerted by mature B cells

    Directory of Open Access Journals (Sweden)

    Gitit eShahaf

    2016-03-01

    Full Text Available Cellular homeostasis in the B cell compartment is strictly imposed to balance cell production and cell loss. However, it is not clear whether B cell development in the bone marrow (BM is an autonomous process or subjected to regulation by the peripheral B cell compartment. To specifically address this question, we used mice transgenic for human CD20, where effective depletion of B lineage cells is obtained upon administration of mouse-anti-human CD20 antibodies, in the absence of any effect on other cell lineages and/or tissues. We followed the kinetics of B cell return to equilibrium by BrdU labeling and flow cytometry and analyzed the resulting data by mathematical modeling. Labeling was much faster in depleted mice. Compared to control mice, B cell-depleted mice exhibited a higher proliferation rate in the pro-/pre-B compartment, and higher cell death and lower differentiation in the immature B cell compartment. We validated the first result by analysis of the expression of Ki67, the nuclear protein expressed in proliferating cells, and the second using Annexin-V staining. Collectively, our results suggest that B lymphopoiesis is subjected to homeostatic feedback mechanisms imposed by mature B cells in the peripheral compartment.

  13. B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies.

    Science.gov (United States)

    Xiao, Gang; Chan, Lai N; Klemm, Lars; Braas, Daniel; Chen, Zhengshan; Geng, Huimin; Zhang, Qiuyi Chen; Aghajanirefah, Ali; Cosgun, Kadriye Nehir; Sadras, Teresa; Lee, Jaewoong; Mirzapoiazova, Tamara; Salgia, Ravi; Ernst, Thomas; Hochhaus, Andreas; Jumaa, Hassan; Jiang, Xiaoyan; Weinstock, David M; Graeber, Thomas G; Müschen, Markus

    2018-04-05

    B cell activation during normal immune responses and oncogenic transformation impose increased metabolic demands on B cells and their ability to retain redox homeostasis. While the serine/threonine-protein phosphatase 2A (PP2A) was identified as a tumor suppressor in multiple types of cancer, our genetic studies revealed an essential role of PP2A in B cell tumors. Thereby, PP2A redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) to salvage oxidative stress. This unique vulnerability reflects constitutively low PPP activity in B cells and transcriptional repression of G6PD and other key PPP enzymes by the B cell transcription factors PAX5 and IKZF1. Reflecting B-cell-specific transcriptional PPP-repression, glucose carbon utilization in B cells is heavily skewed in favor of glycolysis resulting in lack of PPP-dependent antioxidant protection. These findings reveal a gatekeeper function of the PPP in a broad range of B cell malignancies that can be efficiently targeted by small molecule inhibition of PP2A and G6PD. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. Increased B cell-activating factor promotes tumor invasion and metastasis in human pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Mitsuhito Koizumi

    Full Text Available B cell-activating factor (BAFF is a cytokine belonging to the tumor necrosis factor (TNF superfamily. It has been reported that BAFF is elevated in patients with autoimmune pancreatitis and contributes to the malignant potential of blood cancers and solid tumors. In this study, clinical evidence of increased BAFF levels in patients with pancreatic ductal adenocarcinoma (PDAC was obtained, and the roles and mechanisms of BAFF in PDAC were clarified in human tissues of PDAC and from in vitro data of PDAC cell lines. Serum levels of BAFF in patients with PDAC were significantly higher than in healthy subjects (p = 0.0121. Patients with UICC stage IV PDAC (T1-4, N0-1, M1 had significantly higher levels of serum BAFF compared to patients with PDAC (p = 0.0182. BAFF was remarkably expressed in infiltrating B lymphocytes surrounding pancreatic cancer in human pancreatic tissues, suggesting that BAFF may play a role in progression of pancreatic cancer. PDAC cell lines were cultured with human recombinant BAFF, and morphology and gene expression were analyzed; pancreatic cancer cells changed to a fibroblast-like morphology, and showed altered gene expression of E-cadherin, vimentin and Snail. These BAFF-induced changes reflect enhanced cell motility and invasion. BAFF-R-overexpressing cell clones confirmed the association between these BAFF-induced changes and epithelial-mesenchymal transition (EMT-related genes. BAFF was elevated in patients with metastatic advanced PDAC and induced alterations in PDAC cells via regulation of EMT-related genes. Elucidation of the precise role and mechanism of control of BAFF may lead to new therapeutic approaches with the aim of improving pancreatic cancer survival.

  15. Increased B Cell-Activating Factor Promotes Tumor Invasion and Metastasis in Human Pancreatic Cancer

    Science.gov (United States)

    Koizumi, Mitsuhito; Hiasa, Yoichi; Kumagi, Teru; Yamanishi, Hirofumi; Azemoto, Nobuaki; Kobata, Tetsuji; Matsuura, Bunzo; Abe, Masanori; Onji, Morikazu

    2013-01-01

    B cell-activating factor (BAFF) is a cytokine belonging to the tumor necrosis factor (TNF) superfamily. It has been reported that BAFF is elevated in patients with autoimmune pancreatitis and contributes to the malignant potential of blood cancers and solid tumors. In this study, clinical evidence of increased BAFF levels in patients with pancreatic ductal adenocarcinoma (PDAC) was obtained, and the roles and mechanisms of BAFF in PDAC were clarified in human tissues of PDAC and from in vitro data of PDAC cell lines. Serum levels of BAFF in patients with PDAC were significantly higher than in healthy subjects (p = 0.0121). Patients with UICC stage IV PDAC (T1-4, N0-1, M1) had significantly higher levels of serum BAFF compared to patients with PDAC (p = 0.0182). BAFF was remarkably expressed in infiltrating B lymphocytes surrounding pancreatic cancer in human pancreatic tissues, suggesting that BAFF may play a role in progression of pancreatic cancer. PDAC cell lines were cultured with human recombinant BAFF, and morphology and gene expression were analyzed; pancreatic cancer cells changed to a fibroblast-like morphology, and showed altered gene expression of E-cadherin, vimentin and Snail. These BAFF-induced changes reflect enhanced cell motility and invasion. BAFF-R-overexpressing cell clones confirmed the association between these BAFF-induced changes and epithelial-mesenchymal transition (EMT)-related genes. BAFF was elevated in patients with metastatic advanced PDAC and induced alterations in PDAC cells via regulation of EMT-related genes. Elucidation of the precise role and mechanism of control of BAFF may lead to new therapeutic approaches with the aim of improving pancreatic cancer survival. PMID:23940742

  16. COMPUTATION MODELING OF TCDD DISRUPTION OF B CELL TERMINAL DIFFERENTIATION

    Science.gov (United States)

    In this study, we established a computational model describing the molecular circuit underlying B cell terminal differentiation and how TCDD may affect this process by impinging upon various molecular targets.

  17. B-Cell waste classification sampling and analysis plan

    International Nuclear Information System (INIS)

    HOBART, R.L.

    1999-01-01

    This report documents the methods used to collect and analyze samples to obtain data necessary to verify and/or determine the radionuclide content of the 324 Facility B-Cell decontamination and decommissioning waste stream

  18. Diversity among memory B cells: origin, consequences, and utility.

    Science.gov (United States)

    Tarlinton, David; Good-Jacobson, Kim

    2013-09-13

    Immunological memory is the residuum of a successful immune response that in the B cell lineage comprises long-lived plasma cells and long-lived memory B cells. It is apparent that distinct classes of memory B cells exist, distinguishable by, among other things, immunoglobulin isotype, location, and passage through the germinal center. Some of this variation is due to the nature of the antigen, and some appears to be inherent to the process of forming memory. Here, we consider the heterogeneity in development and phenotype of memory B cells and whether particular functions are partitioned into distinct subsets. We consider also how understanding the details of generating memory may provide opportunities to develop better, functionally targeted vaccines.

  19. Parathyroid hormone resistance and B cell lymphopenia in propionic acidemia.

    Science.gov (United States)

    Griffin, T A; Hostoffer, R W; Tserng, K Y; Lebovitz, D J; Hoppel, C L; Mosser, J L; Kaplan, D; Kerr, D S

    1996-07-01

    The mechanisms of hypocalcemia, recurrent infections and hypogammaglobulinemia associated with metabolic decompensation of propionic acidemia due to propionyl-CoA carboxylase deficiency have not been defined. A 7-week-old infant with this disorder presented with severe hypocalcemia and B cell lymphopenia during an episode of metabolic acidosis and hyperammonemia. Hypocalcemia (1.1 mmol l-1) was associated with elevated serum intact parathyroid hormone (122 ng l-1), hyperphosphatemia, hypophosphaturia and hypercalcuria, indicating parathyroid hormone resistance. B cell lymphopenia (20 cells microliters-1) was associated with transient neutropenia, anemia and subsequent hypogamma-globulinemia (IgG < 294 mg dl-1, IgM < 8 mg dl-1, IgA < 8 mg dl-1), while T cells were normal. Parathyroid hormone resistance and B cell lymphopenia resolved following treatment with hemodialysis, diet and carnitine. These complications may be due to interference with parathyroid hormone renal tubular action and B cell maturation/proliferation by accumulated organic acids.

  20. Spontaneous class switch recombination in B cell lymphopoiesis generates aberrant switch junctions and is increased after VDJ rearrangement.

    Science.gov (United States)

    Edry, Efrat; Koralov, Sergei B; Rajewsky, Klaus; Melamed, Doron

    2007-11-15

    Mature B cells replace the mu constant region of the H chain with a downstream isotype in a process of class switch recombination (CSR). Studies suggest that CSR induction is limited to activated mature B cells in the periphery. Recently, we have shown that CSR spontaneously occur in B lymphopoiesis. However, the mechanism and regulation of it have not been defined. In this study, we show that spontaneous CSR occurs at all stages of B cell development and generates aberrant joining of the switch junctions as revealed by: 1) increased load of somatic mutations around the CSR break points, 2) reduced sequence overlaps at the junctions, and 3) excessive switch region deletion. In addition, we found that incidence of spontaneous CSR is increased in cells carrying VDJ rearrangements. Our results reveal major differences between spontaneous CSR in developing B cells and CSR induced in mature B cells upon activation. These differences can be explained by deregulated expression or function of activation-induced cytidine deaminase early in B cell development.

  1. 'Big bang' of B-cell development revealed.

    Science.gov (United States)

    Murre, Cornelis

    2018-01-15

    Earlier studies have identified transcription factors that specify B-cell fate, but the underlying mechanisms remain to be revealed. Two new studies by Miyai and colleagues (pp. 112-126) and Li and colleagues (pp. 96-111) in this issue of Genes & Development provide new and unprecedented insights into the genetic and epigenetic mechanisms that establish B-cell identity. © 2018 Murre; Published by Cold Spring Harbor Laboratory Press.

  2. Corticosteroid modulation of immunoglobulin expression and B-cell function in COPD.

    Science.gov (United States)

    Lee, Jin; Machin, Matthew; Russell, Kirsty E; Pavlidis, Stelios; Zhu, Jie; Barnes, Peter J; Chung, Kian F; Adcock, Ian M; Durham, Andrew L

    2016-05-01

    We investigated changes in gene expression that occur in chronic obstructive pulmonary disease (COPD) after corticosteroid treatment and sought to identify the mechanisms that regulate these changes. Biopsy samples were taken from patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stage I to II) before and after treatment with fluticasone propionate (FP)/salmeterol (SM) (50/500, 4 wk). Gene expression was measured by microarray and was confirmed by real-time reverse transcription-quantitative PCR (RT-qPCR). The effect of FP on IgG expression and B-cell proliferation in the presence of oxidative stress was also studied. FP/SM significantly increased the expression of 180 genes while repressing 343 genes. The top 5 down-regulated genes were associated with immunoglobulin production, whereas the immunomodulatory FK506 binding protein (FK506BP) was up-regulated. Genes including IL6, IL8, and TBET-encoding TBX21 were unaffected. FP reduced IgG protein and mRNA expression and proliferation of human B cells through the dephosphorylation of ERK-1/2 via increased DUSP1 (dual-specificity protein phosphatase 1) expression. Consistent with in vivo data, oxidative stress did not prevent FP-induced suppression of IgG expression in human B cells in vitro Changes in expression were validated by RT-qPCR and by gene set enrichment analysis in distinct COPD cohorts. FP may reduce the adaptive immune response in COPD and may be more effective in patients with an increased B-cell/antibody response indicated by high autoantibody titers.-Lee, J., Machin, M., Russell, K. E., Pavlidis, S., Zhu, J., Barnes, P. J., Chung, K. F., Adcock, I. M., Durham, A. L. Corticosteroid modulation of immunoglobulin expression and B-cell function in COPD. © FASEB.

  3. First-line systemic treatment of advanced stage non-small-cell lung cancer in Asia: consensus statement from the Asian Oncology Summit 2009.

    Science.gov (United States)

    Soo, Ross A; Anderson, Benjamin O; Cho, Byoung Chul; Yang, Chih-Hsin; Liao, Meilin; Lim, Wan-Teck; Goldstraw, Peter; Mok, Tony S

    2009-11-01

    Non-small-cell lung cancer (NSCLC) is an increasing global challenge, especially in low-income countries. Most guidelines for the management of advanced-stage NSCLC have limited effect in countries with resource constraints. Following a systematic literature search, we present an overview of the management of advanced-stage NSCLC in the first-line setting, discuss resources required for systemic therapy, and provide treatment recommendations stratified to four resources levels. Treatment guidelines appropriate for different resource levels offer a realistic approach to management of advanced-stage NSCLC, by recognising the limitations of a particular health-care system. Although there are many barriers to cancer control in low-resource countries, these can be overcome by using measures that are culturally appropriate, economically feasible, and evidence-based. Initiatives include strategic planning, tobacco control, training of health-care workers, access to therapeutic agents, acquisition of information, public education, and alliances with established institutions and international organisations.

  4. Ku70 is required for late B cell development and immunoglobulin heavy chain class switching.

    Science.gov (United States)

    Manis, J P; Gu, Y; Lansford, R; Sonoda, E; Ferrini, R; Davidson, L; Rajewsky, K; Alt, F W

    1998-06-15

    Immunoglobulin (Ig) heavy chain (HC) class switch recombination (CSR) is a late B cell process that involves intrachromosomal DNA rearrangement. Ku70 and Ku80 form a DNA end-binding complex required for DNA double strand break repair and V(D)J recombination. Ku70(-/-) (K70T) mice, like recombination activating gene (RAG)-1- or RAG-2-deficient (R1T or R2T) mice, have impaired B and T cell development at an early progenitor stage, which is thought to result at least in part from defective V(D)J recombination (Gu, Y., K.J. Seidl, G.A. Rathbun, C. Zhu, J.P. Manis, N. van der Stoep, L. Davidson, H.L. Cheng, J.M. Sekiguchi, K. Frank, et al. 1997. Immunity. 7:653-665; Ouyang, H., A. Nussenzweig, A. Kurimasa, V.C. Soares, X. Li, C. Cordon-Cardo, W. Li, N. Cheong, M. Nussenzweig, G. Iliakis, et al. 1997. J. Exp. Med. 186:921-929). Therefore, to examine the potential role of Ku70 in CSR, we generated K70T mice that carry a germline Ig HC locus in which the JH region was replaced with a functionally rearranged VH(D)JH and Ig lambda light chain transgene (referred to as K70T/HL mice). Previously, we have shown that B cells from R1T or R2T mice carrying these rearranged Ig genes (R1T/HL or R2T/HL mice) can undergo CSR to IgG isotypes (Lansford, R., J. Manis, E. Sonoda, K. Rajewsky, and F. Alt. 1998. Int. Immunol. 10:325-332). K70T/HL mice had significant numbers of peripheral surface IgM+ B cells, which generated serum IgM levels similar to those of R2T/HL mice. However, in contrast to R2T/HL mice, K70T/HL mice had no detectable serum IgG isotypes. In vitro culture of K70T/HL B cells with agents that induce CSR in normal or R2T/HL B cells did lead to the induction of germline CH transcripts, indicating that initial signaling pathways for CSR were intact in K70T/HL cells. However, treatment with such agents did not lead to detectable CSR by K70T/HL B cells, and instead, led to cell death within 72 h. We conclude that Ku70 is required for the generation of B cells that have

  5. Antibodies That Block or Activate Mouse B Cell Activating Factor of the Tumor Necrosis Factor (TNF) Family (BAFF), Respectively, Induce B Cell Depletion or B Cell Hyperplasia*

    Science.gov (United States)

    Kowalczyk-Quintas, Christine; Schuepbach-Mallepell, Sonia; Vigolo, Michele; Willen, Laure; Tardivel, Aubry; Smulski, Cristian R.; Zheng, Timothy S.; Gommerman, Jennifer; Hess, Henry; Gottenberg, Jacques-Eric; Mackay, Fabienne; Donzé, Olivier

    2016-01-01

    B cell activating factor of the TNF family (BAFF), also known as B lymphocyte stimulator, is a ligand required for the generation and maintenance of B lymphocytes. In this study, the ability of different monoclonal antibodies to recognize, inhibit, or activate mouse BAFF was investigated. One of them, a mouse IgG1 named Sandy-2, prevented the binding of BAFF to all of its receptors, BAFF receptor, transmembrane activator and calcium modulating ligand interactor, and B cell maturation antigen, at a stoichiometric ratio; blocked the activity of mouse BAFF on a variety of cell-based reporter assays; and antagonized the prosurvival action of BAFF on primary mouse B cells in vitro. A single administration of Sandy-2 in mice induced B cell depletion within 2 weeks, down to levels close to those observed in BAFF-deficient mice. This depletion could then be maintained with a chronic treatment. Sandy-2 and a previously described rat IgG1 antibody, 5A8, also formed a pair suitable for the sensitive detection of endogenous circulating BAFF by ELISA or using a homogenous assay. Interestingly, 5A8 and Sandy-5 displayed activities opposite to that of Sandy-2 by stimulating recombinant BAFF in vitro and endogenous BAFF in vivo. These tools will prove useful for the detection and functional manipulation of endogenous mouse BAFF and provide an alternative to the widely used BAFF receptor-Fc decoy receptor for the specific depletion of BAFF in mice. PMID:27451394

  6. Biology and clinical application of CAR T cells for B cell malignancies.

    Science.gov (United States)

    Davila, Marco L; Sadelain, Michel

    2016-07-01

    Chimeric antigen receptor (CAR)-modified T cells have generated broad interest in oncology following a series of dramatic clinical successes in patients with chemorefractory B cell malignancies. CAR therapy now appears to be on the cusp of regulatory approval as a cell-based immunotherapy. We review here the T cell biology and cell engineering research that led to the development of second generation CARs, the selection of CD19 as a CAR target, and the preclinical studies in animal models that laid the foundation for clinical trials targeting CD19+ malignancies. We further summarize the status of CD19 CAR clinical therapy for non-Hodgkin lymphoma and B cell acute lymphoblastic leukemia, including their efficacy, toxicities (cytokine release syndrome, neurotoxicity and B cell aplasia) and current management in humans. We conclude with an overview of recent pre-clinical advances in CAR design that argues favorably for the advancement of CAR therapy to tackle other hematological malignancies as well as solid tumors.

  7. 18F-2-fluoro-2-deoxy-d-glucose positron emission tomography in staging of locally advanced breast cancer.

    Science.gov (United States)

    van der Hoeven, Jacobus J M; Krak, Nanda C; Hoekstra, Otto S; Comans, Emile F I; Boom, Robert P A; van Geldere, Dick; Meijer, Sybren; van der Wall, Elsken; Buter, Jan; Pinedo, Herbert M; Teule, Gerrit J J; Lammertsma, Adriaan A

    2004-04-01

    To prospectively evaluate the effect of adding whole-body (18)F-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) to conventional screening for distant metastases in patients with locally advanced breast cancer (LABC). All women with LABC referred for participation in the LABC Spinoza trial were considered eligible for this study. Patients were included if chest x-ray, bone scan, liver ultrasound, or computed tomography scan performed by the referring physician failed to reveal distant metastases. They underwent whole-body FDG PET scanning before therapy. Patients with subsequently proven distant metastases were switched to alternative forms of chemotherapy, hormonal therapy, or both. Among the 48 patients evaluated with PET, 14 had abnormal FDG uptake, and metastases were suspected in 12. After simple clinical evaluation (plain x-ray, history), 10 sites that were suggestive of abnormality remained. Further work-up revealed that four sites were metastases. Proven false positivity occurred in one patient with sarcoidosis. In the other five patients, the reason for abnormal FDG uptake (liver, lung, bone) remained unclear, and patients were treated as planned. Eleven months later, distant metastases were found in one patient at sites unrelated to the previous FDG uptake. The addition of FDG PET to the standard work-up of patients with LABC may lead to the detection of unexpected distant metastases. This may contribute to a more realistic stratification between patients with true stage III breast cancer and those who are in fact suffering from stage IV disease. Abnormal PET findings should be confirmed to prevent patients from being denied appropriate treatment.

  8. Wolf-Hirschhorn Syndrome Candidate 1 Is Necessary for Correct Hematopoietic and B Cell Development.

    Science.gov (United States)

    Campos-Sanchez, Elena; Deleyto-Seldas, Nerea; Dominguez, Veronica; Carrillo-de-Santa-Pau, Enrique; Ura, Kiyoe; Rocha, Pedro P; Kim, JungHyun; Aljoufi, Arafat; Esteve-Codina, Anna; Dabad, Marc; Gut, Marta; Heyn, Holger; Kaneda, Yasufumi; Nimura, Keisuke; Skok, Jane A; Martinez-Frias, Maria Luisa; Cobaleda, Cesar

    2017-05-23

    Immunodeficiency is one of the most important causes of mortality associated with Wolf-Hirschhorn syndrome (WHS), a severe rare disease originated by a deletion in chromosome 4p. The WHS candidate 1 (WHSC1) gene has been proposed as one of the main genes responsible for many of the alterations in WHS, but its mechanism of action is still unknown. Here, we present in vivo genetic evidence showing that Whsc1 plays an important role at several points of hematopoietic development. Particularly, our results demonstrate that both differentiation and function of Whsc1-deficient B cells are impaired at several key developmental stages due to profound molecular defects affecting B cell lineage specification, commitment, fitness, and proliferation, demonstrating a causal role for WHSC1 in the immunodeficiency of WHS patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Wolf-Hirschhorn Syndrome Candidate 1 Is Necessary for Correct Hematopoietic and B Cell Development

    Directory of Open Access Journals (Sweden)

    Elena Campos-Sanchez

    2017-05-01

    Full Text Available Immunodeficiency is one of the most important causes of mortality associated with Wolf-Hirschhorn syndrome (WHS, a severe rare disease originated by a deletion in chromosome 4p. The WHS candidate 1 (WHSC1 gene has been proposed as one of the main genes responsible for many of the alterations in WHS, but its mechanism of action is still unknown. Here, we present in vivo genetic evidence showing that Whsc1 plays an important role at several points of hematopoietic development. Particularly, our results demonstrate that both differentiation and function of Whsc1-deficient B cells are impaired at several key developmental stages due to profound molecular defects affecting B cell lineage specification, commitment, fitness, and proliferation, demonstrating a causal role for WHSC1 in the immunodeficiency of WHS patients.

  10. The ideas about advanced life support and affecting factors at the end-stage of life in a hospital in Turkey

    OpenAIRE

    Albayrak, Turgay; ?encan, ?rfan; Ak?a, ?mer; Ko?, Esra Meltem; Aksoy, Hilal; ?nsal, Selim; B?lb?l, ?skender; Bahad?r, Adem; Kas?m, ?smail; Kahveci, Rabia; ?zkara, Adem

    2017-01-01

    Background The participation of the people in health decisions may be structured in various levels. One of these is participation in decisions for the treatment. ?Advanced directives? is one of the examples for the participation in decisions for the treatment. Aim We wanted to determine the decisions on advanced life support at the end-stage of life in case of a life-threatening illness for the people themselves and their first degree relatives and the factors effecting these decisions. Desig...

  11. Human regulatory B cells control the TFH cell response.

    Science.gov (United States)

    Achour, Achouak; Simon, Quentin; Mohr, Audrey; Séité, Jean-François; Youinou, Pierre; Bendaoud, Boutahar; Ghedira, Ibtissem; Pers, Jacques-Olivier; Jamin, Christophe

    2017-07-01

    Follicular helper T (T FH ) cells support terminal B-cell differentiation. Human regulatory B (Breg) cells modulate cellular responses, but their control of T FH cell-dependent humoral immune responses is unknown. We sought to assess the role of Breg cells on T FH cell development and function. Human T cells were polyclonally stimulated in the presence of IL-12 and IL-21 to generate T FH cells. They were cocultured with B cells to induce their terminal differentiation. Breg cells were included in these cultures, and their effects were evaluated by using flow cytometry and ELISA. B-cell lymphoma 6, IL-21, inducible costimulator, CXCR5, and programmed cell death protein 1 (PD-1) expressions increased on stimulated human T cells, characterizing T FH cell maturation. In cocultures they differentiated B cells into CD138 + plasma and IgD - CD27 + memory cells and triggered immunoglobulin secretions. Breg cells obtained by Toll-like receptor 9 and CD40 activation of B cells prevented T FH cell development. Added to T FH cell and B-cell cocultures, they inhibited B-cell differentiation, impeded immunoglobulin secretions, and expanded Foxp3 + CXCR5 + PD-1 + follicular regulatory T cells. Breg cells modulated IL-21 receptor expressions on T FH cells and B cells, and their suppressive activities involved CD40, CD80, CD86, and intercellular adhesion molecule interactions and required production of IL-10 and TGF-β. Human Breg cells control T FH cell maturation, expand follicular regulatory T cells, and inhibit the T FH cell-mediated antibody secretion. These novel observations demonstrate a role for the Breg cell in germinal center reactions and suggest that deficient activities might impair the T FH cell-dependent control of humoral immunity and might lead to the development of aberrant autoimmune responses. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  12. Stage-by-Stage and Parallel Flow Path Compressor Modeling for a Variable Cycle Engine, NASA Advanced Air Vehicles Program - Commercial Supersonic Technology Project - AeroServoElasticity

    Science.gov (United States)

    Kopasakis, George; Connolly, Joseph W.; Cheng, Larry

    2015-01-01

    This paper covers the development of stage-by-stage and parallel flow path compressor modeling approaches for a Variable Cycle Engine. The stage-by-stage compressor modeling approach is an extension of a technique for lumped volume dynamics and performance characteristic modeling. It was developed to improve the accuracy of axial compressor dynamics over lumped volume dynamics modeling. The stage-by-stage compressor model presented here is formulated into a parallel flow path model that includes both axial and rotational dynamics. This is done to enable the study of compressor and propulsion system dynamic performance under flow distortion conditions. The approaches utilized here are generic and should be applicable for the modeling of any axial flow compressor design accurate time domain simulations. The objective of this work is as follows. Given the parameters describing the conditions of atmospheric disturbances, and utilizing the derived formulations, directly compute the transfer function poles and zeros describing these disturbances for acoustic velocity, temperature, pressure, and density. Time domain simulations of representative atmospheric turbulence can then be developed by utilizing these computed transfer functions together with the disturbance frequencies of interest.

  13. Increased levels of proteins of the acute inflammatory phase in the peritoneal fluid of women with advanced stages of endometriosis.

    Science.gov (United States)

    Polak, Grzegorz; Barczyński, Bartłomiej; Bednarek, Wiesława; Kwaśniewski, Wojciech; Wertell, Iwona; Derewianka-Polak, Magdalena; Makara-Studzińska, Marta; Kotarski, Jan

    2015-06-01

    Most investigators agree that endometriosis is associated with a state of subclinical, non-infectious peritoneal inflammation. The objective of the study was to assess concentrations of two markers of the acute inflammatory phase proteins, haptoglobin and ceruloplasmin, in peritoneal fluid of endometriotic women. 229 women who underwent diagnostic or therapeutic laparoscopy were included in the study Minimal, mild, moderate and severe endometriosis according to ASRM was confirmed in 119 women (study groups), whereas 110 patients suffered from simple serous or dermoid ovarian cysts (reference groups). Haptoglobin and ceruloplasmin concentrations in the peritoneal fluid samples aspirated during laparoscopy were measured using commercially available radial immunodiffusion kits. The concentration of haptoglobin in the peritoneal fluid of women with endometriosis was significantly higher as compared to patients with serous and dermoid ovarian cysts. Significantly higher haptoglobin level was observed in patients with severe and moderate endometriosis as compared to women from both reference groups. No significant difference in the peritoneal fluid ceruloplasmin levels was found between patients with endometriosis and women from reference groups. However, it was noted that ceruloplasmin levels are higher in the subgroup of patients with severe endometriosis as compared to both reference groups and women with mild disease. Our results support the hypothesis that endometriosis is associated with subclinical inflammation within the peritoneal cavity It may be speculated that pro-inflammatory stimuli strong enough to cause an increase in acute inflammatory phase proteins peritoneal fluid concentrations are observed only in the advanced stages of the disease.

  14. Implications of infiltrating immune cells within bone marrow of patients with diffuse large B-cell lymphoma.

    Science.gov (United States)

    Jeong, Juhyeon; Oh, Eun Ji; Yang, Woo Ick; Kim, Soo Jeong; Yoon, Sun Och

    2017-06-01

    The implications of infiltrating immune cells, especially T cells and macrophages, in the bone marrow (BM) microenvironment of patients with diffuse large B-cell lymphoma (DLBCL) have rarely been studied. We aimed to investigate the significance of infiltrating immune cells in the BM microenvironment as a prognostic factor for DLBCL patients. Using the initial pretreatment BM biopsy obtained from 198 DLBCL patients, we semiquantitatively evaluated CD3+ T cells, CD8+ T cells, and CD163+ macrophages that infiltrate into the paratrabecular and interstitial areas of BM by immunohistochemistry and analyzed their clinicopathological and prognostic implications. Levels of infiltrating CD3+ T cells, CD8+ T cells, and CD163+ macrophages were significantly higher in BM with DLBCL involvement (BMI-positive group) than in that without DLBCL involvement (BMI-negative group). Infiltration of CD8+ T cells significantly increased in cases with advanced Ann Arbor stage, elevated lactate dehydrogenase level, extranodal site involvement ≥2 sites, higher Eastern Cooperative Oncology Group performance status, and higher International Prognostic Index (IPI) risk. High levels of CD3+ T cells were significantly associated with age ≤60, and high levels of CD163+ macrophages were associated with advanced Ann Arbor stage and higher IPI risk. High infiltration of CD8+ T cells was significantly related to inferior overall and recurrence-free survival rate, even in the BMI-negative group. High infiltration of CD8+ T cells within the pretreatment BM was related to poor prognosis, and might be a useful prognostic factor of DLBCL patients. Therefore, evaluation of CD8+ T cells is helpful for predicting prognosis in initial pretreatment BM biopsy of DLBCL patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Lack of any prognostic relationship between adiponectin receptor (Adipo R1/R2) expression for early/advanced stage gastric cancer.

    Science.gov (United States)

    Ayyildiz, Talat; Dolar, Enver; Ugras, Nesrin; Dizdar, Oguzhan Sitki; Adim, Saduman Balaban; Yerci, Omer

    2014-01-01

    Adiponectin (ApN) is a complement C1q-related protein, mainly secreted from adipose tissue, that signals through ApN receptor 1 (Adipo-R1) and ApN receptor 2 (Adipo-R2). Low serum ApN concentrations are associated with obesity-related malignancies. However, there are very few studies on any prognostic role of ApN receptors in gastric cancer. The aim of this study is to investigate the relationship between AdipoR1/R2 expression and early/advanced stage gastric cancer in terms of clinicopathologic characteristics and survival. Eighteen patients with early and 39 with advanced stage gastric cancer who underwent surgical gastric resection were included in this study. Adipo-R1 expression was low in 2 of the 18 patients with early stage gastric cancer (11.1%), while 4 had low Adipo-R2 expression (22.2%). In those with advanced stage gastric cancer, 7 of 39 had low Adipo-R1 expression (17.9%) and 16 had low Adipo-R2 expression (41%). Adipo-R2 expression was significantly higher (p=0.011) in moderately differentiated tumors when compared to well-differentiated tumors. While there was nearly a statistically significant relationship between TNM stage (T, tumor size; N, regional lymph node; M, whether distant metastases exist) and Adipo-R2 expression (p=0.054), there was no relationship between Adipo-R1/-R2 expression with tumor stage and survival. Adipo-R1/-R2 expression has no prognostic significance of in early/advanced stage gastric cancer.

  16. Results of an Advanced Fan Stage Operating Over a Wide Range of Speed and Bypass Ratio. Part 1; Fan Stage Design and Experimental Results

    Science.gov (United States)

    Suder, Kenneth L.; Prahst, Patricia S.; Thorp, Scott A.

    2011-01-01

    NASA s Fundamental Aeronautics Program is investigating turbine-based combined cycle (TBCC) propulsion systems for access to space because it provides the potential for aircraft-like, space-launch operations that may significantly reduce launch costs and improve safety. To this end, National Aeronautics and Space Administration (NASA) and General Electric (GE) teamed to design a Mach 4 variable cycle turbofan/ramjet engine for access to space. To enable the wide operating range of a Mach 4+ variable cycle turbofan ramjet required the development of a unique fan stage design capable of multi-point operation to accommodate variations in bypass ratio (10 ), fan speed (7 ), inlet mass flow (3.5 ), inlet pressure (8 ), and inlet temperature (3 ). In this paper, NASA has set out to characterize a TBCC engine fan stage aerodynamic performance and stability limits over a wide operating range including power-on and hypersonic-unique "windmill" operation. Herein, we will present the fan stage design, and the experimental test results of the fan stage operating from 15 to 100 percent corrected design speed. Whereas, in the companion paper, we will provide an assessment of NASA s APNASA code s ability to predict the fan stage performance and operability over a wide range of speed and bypass ratio.

  17. Intrathecal Fentanyl for Labour Analgesia in a Patient with Severe Mitral Stenosis and Atrial Fibrillation in Advanced Stage of Labour-Case Report

    OpenAIRE

    Vaijayanti Nitin Gadre

    2013-01-01

    Labour is an intensely painful experience and puts considerable physiological stress on the circulation. A case of rheumatic valvular heart disease with severe mitral stenosis in atrial fibrillation is discussed here in which analgesia with intrathecal fentanyl proved beneficial given during the advanced first stage of labour.

  18. Intrathecal Fentanyl for Labour Analgesia in a Patient with Severe Mitral Stenosis and Atrial Fibrillation in Advanced Stage of Labour-Case Report

    Directory of Open Access Journals (Sweden)

    Vaijayanti Nitin Gadre

    2013-12-01

    Full Text Available Labour is an intensely painful experience and puts considerable physiological stress on the circulation. A case of rheumatic valvular heart disease with severe mitral stenosis in atrial fibrillation is discussed here in which analgesia with intrathecal fentanyl proved beneficial given during the advanced first stage of labour.

  19. The Fas-Associated Death Domain Protein (FADD) is Required in Apoptosis and TLR-induced Proliferative Responses in B Cells1

    Science.gov (United States)

    Imtiyaz, Hongxia Z.; Rosenberg, Stephen; Zhang, Yuhang; Rahman, Ziaur S. M.; Hou, Ying-Ju; Manser, Tim L.; Zhang, Jianke

    2011-01-01

    The Fas-associated death domain protein FADD/Mort1 is a signaling adaptor protein which mediates the activation of caspase 8 during death receptor-induced apoptosis. Disruption of FADD in germ cells results in death receptor-independent embryonic lethality in mice. Previous studies indicated that in addition to its function in apoptosis, FADD is also required in peripheral T cell homeostasis and TCR-induced proliferative responses. In this report, we generated B cell-specific FADD-deficient mice and showed that deletion of FADD at the pro-B cell stage had minor effects on B cell development in the bone marrow, and resulted in increased splenic and lymph node B cell numbers and decreased peritoneal B1 cell numbers. As in T cells, a FADD deficiency inhibited Fas-induced apoptosis in B cells. However, B cell proliferative responses induced by stimulation of the BCR and CD40 using anti-IgM or anti-CD40 antibodies were unaffected by the absence of FADD. Further analyses revealed that FADD-deficient B cells were defective in proliferative responses induced by treatments with dsRNA and LPS which stimulate TLR3 and TLR4 respectively. Therefore, in addition to its apoptotic function, FADD also plays a role in TLR3- and TLR4-induced proliferative responses in B cells. PMID:16709845

  20. Functional and morphological findings in early and advanced stages of HIV infection: A comparison of 99mTc-HMPAO SPECT with CT and MRI studies

    International Nuclear Information System (INIS)

    Tatsch, K.; Bauer, W.M.; Markl, A.; Kirsch, C.M.; Schielke, E.; Einhaeupl, K.M.

    1990-01-01

    In fourty patients at early and advanced stages of HIV infection (Water-Reed stages I-VI) regional cerebral blood flow was determined by 99m Tc-HMPAO SPECT, comparing the results with CT and MRI findings. All patients with HIV encephalopathy (AIDS dementia complex) had pathologic SPECT results (multilocular, patchy uptake defects), but also in earlier and even earliest stages of HIV infection positive SPECT findings were observed. Compared to functional SPECT imaging, morphologically orientated method (CT, MRI) were insensitive in detecting HIV-induced foci: More than 50% of the patients with pathologic SPECT findings had negative CT or MRI scans. Most patients in advanced Walter Reed stages had neurological abnormalities accompanied by positive SPECT. Subtle alterations of HMPAO uptake were observed even in a few cases of early HIV infection without neurological CNS symptoms. The data presented suggest that HMPAO SPECT is highly sensitive in the detection of altered brain perfusion not only in advanced but also early stages of HIV infection. Changes in regional cerebral blood flow are presented before noticeable structural defects may be observed. (orig./MG) [de

  1. Antibodies That Block or Activate Mouse B Cell Activating Factor of the Tumor Necrosis Factor (TNF) Family (BAFF), Respectively, Induce B Cell Depletion or B Cell Hyperplasia.

    Science.gov (United States)

    Kowalczyk-Quintas, Christine; Schuepbach-Mallepell, Sonia; Vigolo, Michele; Willen, Laure; Tardivel, Aubry; Smulski, Cristian R; Zheng, Timothy S; Gommerman, Jennifer; Hess, Henry; Gottenberg, Jacques-Eric; Mackay, Fabienne; Donzé, Olivier; Schneider, Pascal

    2016-09-16

    B cell activating factor of the TNF family (BAFF), also known as B lymphocyte stimulator, is a ligand required for the generation and maintenance of B lymphocytes. In this study, the ability of different monoclonal antibodies to recognize, inhibit, or activate mouse BAFF was investigated. One of them, a mouse IgG1 named Sandy-2, prevented the binding of BAFF to all of its receptors, BAFF receptor, transmembrane activator and calcium modulating ligand interactor, and B cell maturation antigen, at a stoichiometric ratio; blocked the activity of mouse BAFF on a variety of cell-based reporter assays; and antagonized the prosurvival action of BAFF on primary mouse B cells in vitro A single administration of Sandy-2 in mice induced B cell depletion within 2 weeks, down to levels close to those observed in BAFF-deficient mice. This depletion could then be maintained with a chronic treatment. Sandy-2 and a previously described rat IgG1 antibody, 5A8, also formed a pair suitable for the sensitive detection of endogenous circulating BAFF by ELISA or using a homogenous assay. Interestingly, 5A8 and Sandy-5 displayed activities opposite to that of Sandy-2 by stimulating recombinant BAFF in vitro and endogenous BAFF in vivo These tools will prove useful for the detection and functional manipulation of endogenous mouse BAFF and provide an alternative to the widely used BAFF receptor-Fc decoy receptor for the specific depletion of BAFF in mice. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Dataset of transcriptional landscape of B cell early activation

    Directory of Open Access Journals (Sweden)

    Alexander S. Garruss

    2015-09-01

    Full Text Available Signaling via B cell receptors (BCR and Toll-like receptors (TLRs result in activation of B cells with distinct physiological outcomes, but transcriptional regulatory mechanisms that drive activation and distinguish these pathways remain unknown. At early time points after BCR and TLR ligand exposure, 0.5 and 2 h, RNA-seq was performed allowing observations on rapid transcriptional changes. At 2 h, ChIP-seq was performed to allow observations on important regulatory mechanisms potentially driving transcriptional change. The dataset includes RNA-seq, ChIP-seq of control (Input, RNA Pol II, H3K4me3, H3K27me3, and a separate RNA-seq for miRNA expression, which can be found at Gene Expression Omnibus Dataset GSE61608. Here, we provide details on the experimental and analysis methods used to obtain and analyze this dataset and to examine the transcriptional landscape of B cell early activation.

  3. The cell biology of T-dependent B cell activation

    DEFF Research Database (Denmark)

    Owens, T; Zeine, R

    1989-01-01

    The requirement that CD4+ helper T cells recognize antigen in association with class II Major Histocompatibility Complex (MHC) encoded molecules constrains T cells to activation through intercellular interaction. The cell biology of the interactions between CD4+ T cells and antigen-presenting cells...... includes multipoint intermolecular interactions that probably involve aggregation of both polymorphic and monomorphic T cell surface molecules. Such aggregations have been shown in vitro to markedly enhance and, in some cases, induce T cell activation. The production of T-derived lymphokines that have been...... implicated in B cell activation is dependent on the T cell receptor for antigen and its associated CD3 signalling complex. T-dependent help for B cell activation is therefore similarly MHC-restricted and involves T-B intercellular interaction. Recent reports that describe antigen-independent B cell...

  4. Microenvironment-Centred Dynamics in Aggressive B-Cell Lymphomas

    Directory of Open Access Journals (Sweden)

    Matilde Cacciatore

    2012-01-01

    Full Text Available Aggressive B-cell lymphomas share high proliferative and invasive attitudes and dismal prognosis despite heterogeneous biological features. In the interchained sequence of events leading to cancer progression, neoplastic clone-intrinsic molecular events play a major role. Nevertheless, microenvironment-related cues have progressively come into focus as true determinants for this process. The cancer-associated microenvironment is a complex network of nonneoplastic immune and stromal cells embedded in extracellular components, giving rise to a multifarious crosstalk with neoplastic cells towards the induction of a supportive milieu. The immunological and stromal microenvironments have been classically regarded as essential partners of indolent lymphomas, while considered mainly negligible in the setting of aggressive B-cell lymphomas that, by their nature, are less reliant on external stimuli. By this paper we try to delineate the cardinal microenvironment-centred dynamics exerting an influence over lymphoid clone progression in aggressive B-cell lymphomas.

  5. The role of B cells in systemic sclerosis

    Directory of Open Access Journals (Sweden)

    Marina D Kraaij

    2008-09-01

    Full Text Available Marina D Kraaij, Jacob M van LaarMusculoskeletal Research Group, Institute of Cellular Medicine, School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United KingdomAbstract: Systemic sclerosis (SSc is a connective disease characterized by features of autoimmunity, vasculopathy, inflammation, and fibrosis. The disease typically starts with Raynaud’s phenomenon, followed by skin thickening in the extremities due to inflammation and fibrosis. Fibrosis results from excessive collagen production by fibroblasts, which constitutes the final common pathway of complex cellular interactions including B cells. Several studies have indicated that B cells may play a role in SSc. Lesional skin infiltrates from SSc patients consist of a variety of cells, including eosinophils, neutrophils, lymphocytes, plasma cells, and macrophages. Autoantibodies of several specificities are present in the serum of SSc patients of which antitopoisomerase 1 is the most common, and evidence has been gathered for a potential pathogenic role of some autoantibodies, eg, anti-PDGF antibodies. The blood of SSc patients contains an increased proportion of naïve B cells but a decreased proportion of memory B cells. Furthermore, serum levels of interleukin-6, an important pro-inflammatory cytokine, have been shown to correlate with skin fibrosis. Animal models of SSc have provided more in-depth information on the role of B lymphocytes, eg, through disruption of B cell function. In this review we will discuss the evidence that B cells are involved in the pathogenesis of SSc.Keywords: B lymphocyte, systemic sclerosis, fibrosis

  6. The Impact of a Multidimensional Exercise Intervention on Physical and Functional Capacity, Anxiety, and Depression in Patients With Advanced-Stage Lung Cancer Undergoing Chemotherapy

    DEFF Research Database (Denmark)

    Quist, Morten; Adamsen, Lis; Rørth, Mikael

    2015-01-01

    was measured with one repetition maximum test (1RM). HRQoL, anxiety, and depression were assessed using Functional Assessment of Cancer Therapy-Lung (FACT-L) scale and the Hospital Anxiety and Depression Scale (HADS). RESULTS: One hundred and forthteen patients with advanced stage lung cancer were recruited......INTRODUCTION: Patients with advanced-stage lung cancer face poor survival and experience co-occurring chronic physical and psychosocial symptoms. Despite several years of research in exercise oncology, few exercise studies have targeted advanced lung cancer patients undergoing chemotherapy. The aim...... of the present study was to investigate the benefits of a 6-week supervised group exercise intervention and to outline the effect on aerobic capacity, strength, health-related quality of life (HRQoL), anxiety, and depression. METHODS: VO2peak was assessed using an incremental exercise test. Muscle strength...

  7. The development and survival but not function of follicular B cells is dependent on IL-7Rα Tyr449 signaling.

    Directory of Open Access Journals (Sweden)

    Daniel T Patton

    Full Text Available IL-7 is a critical cytokine for lymphocyte development. Recent work has highlighted critical roles for IL-7 signaling in mature T cell homeostasis and function, but its role in B cells is less well characterized. Using a knock-in mouse possessing a Tyr to Phe mutation at position 449 (IL-7Rα(449F/449F mice within the cytoplasmic SH2-binding motif of IL-7Rα, we evaluated the role of IL-7Rα Y449 motif in spleen B cells. IL-7Rα(449F/449F mice had reduced numbers and increased death of follicular B cells compared to WT, but had significantly more follicular cells than IL-7Rα(-/-. The death of IL-7Rα(449F/449F follicular cells was not due to a failure to respond to BAFF or lower levels of BAFF, a critical B cell survival factor. Marginal zone B cells were unaffected by the IL-7Rα(449F/449F mutation. Any role for TSLP was ruled out, as TSLPR(-/- mice had an identical B cell phenotype to wild-type mice. Bone marrow chimeras and the absence of IL-7Rα on B cells suggested that IL-7 did not directly regulate mature B cells, but that an IL-7-responsive cell was influencing B cells. IL-7 was also critical at the checkpoint between the T1 and T2 stages in the spleen. IL-7Rα(-/- mice fail to develop T2 cells, but IL-7Rα(449F/449F show a reduction compared to WT but not complete absence of T2 cells. We also tested the functional responses of IL-7Rα(449F/449F to antigens and infection and found no difference in antibody responses to T-dependent or T-independent antigens, or to Influenza/A. IL-7 was important for generation of antibody responses to the intestinal worm H. polygyrus and for naive levels of IgA. Taken together, this suggests that IL-7 regulates follicular B cell numbers and survival in a cell-extrinsic manner, via a bone-marrow derived cell, but is not critical for antibody production outside the gut.

  8. Grb2 and GRAP connect the B cell antigen receptor to Erk MAP kinase activation in human B cells.

    Science.gov (United States)

    Vanshylla, Kanika; Bartsch, Caren; Hitzing, Christoffer; Krümpelmann, Laura; Wienands, Jürgen; Engels, Niklas

    2018-03-09

    The B cell antigen receptor (BCR) employs enzymatically inactive adaptor proteins to facilitate activation of intracellular signaling pathways. In animal model systems, adaptor proteins of the growth factor receptor-bound 2 (Grb2) family have been shown to serve critical functions in lymphocytes. However, the roles of Grb2 and the Grb2-related adaptor protein (GRAP) in human B lymphocytes remain unclear. Using TALEN-mediated gene targeting, we show that in human B cells Grb2 and GRAP amplify signaling by the immunoglobulin tail tyrosine (ITT) motif of mIgE-containing BCRs and furthermore connect immunoreceptor tyrosine-based activation motif (ITAM) signaling to activation of the Ras-controlled Erk MAP kinase pathway. In contrast to mouse B cells, BCR-induced activation of Erk in human B cells is largely independent of phospholipase C-ɣ activity and diacylglycerol-responsive members of Ras guanine nucleotide releasing proteins. Together, our results demonstrate that Grb2 family adaptors are critical regulators of ITAM and ITT signaling in naïve and IgE-switched human B cells.

  9. IgM and IgD B cell receptors differentially respond to endogenous antigens and control B cell fate

    Science.gov (United States)

    Noviski, Mark; Mueller, James L; Satterthwaite, Anne; Garrett-Sinha, Lee Ann; Brombacher, Frank

    2018-01-01

    Naive B cells co-express two BCR isotypes, IgM and IgD, with identical antigen-binding domains but distinct constant regions. IgM but not IgD is downregulated on autoreactive B cells. Because these isotypes are presumed to be redundant, it is unknown how this could impose tolerance. We introduced the Nur77-eGFP reporter of BCR signaling into mice that express each BCR isotype alone. Despite signaling strongly in vitro, IgD is less sensitive than IgM to endogenous antigen in vivo and developmental fate decisions are skewed accordingly. IgD-only Lyn−/− B cells cannot generate autoantibodies and short-lived plasma cells (SLPCs) in vivo, a fate thought to be driven by intense BCR signaling induced by endogenous antigens. Similarly, IgD-only B cells generate normal germinal center, but impaired IgG1+ SLPC responses to T-dependent immunization. We propose a role for IgD in maintaining the quiescence of autoreactive B cells and restricting their differentiation into autoantibody secreting cells. PMID:29521626

  10. Primary Mediastinal Large B-cell Lymphoma Exhibiting Endobronchial Involvement.

    Science.gov (United States)

    Shimada, Midori; Fukuda, Minoru; Horio, Kensuke; Suyama, Takayuki; Kitazaki, Takeshi; Hashiguchi, Kohji; Fukuda, Masaaki; Shigematsu, Kazuto; Nakamura, Yoichi; Honda, Takuya; Ashizawa, Kazuto; Mukae, Hiroshi

    Primary mediastinal large B-cell lymphoma (PMLBCL) is one of the subtypes of diffuse large B-cell lymphoma. We experienced a rare case of PMLBCL that exhibited endobronchial involvement. A 33-year-old Japanese female with the chief complaints of epigastralgia, back pain, and nausea visited a primary care hospital. Computed tomography of the chest and abdomen demonstrated a bulky mass in the left anterior mediastinum, multiple pulmonary nodules, axillary lymph node swelling, and a pancreatic tumor. Fiberoptic bronchoscopy showed a white-tinged irregularly shaped endobronchial tumor accompanied by capillary vessel dilation in the left upper lobar bronchus. Taken together, these findings resulted in a diagnosis of PMLBCL.

  11. A Literature Revision in Primary Cutaneous B-cell Lymphoma.

    Science.gov (United States)

    Selva, R La; Violetti, S Alberti; Delfino, C; Grandi, V; Cicchelli, S; Tomasini, C; Fierro, M T; Berti, E; Pimpinelli, N; Quaglino, P

    2017-01-01

    The term "Primary Cutaneous B-Cell Lymphoma" (PCBCL) comprehends a variety of lymphoproliferative disorders characterized by a clonal proliferation of B-cells primarily involving the skin. The absence of evident extra-cutaneous disease must be confirmed after six-month follow-up in order to exclude a nodal non-Hodgkin's lymphoma (NHL) with secondary cutaneous involvement, which may have a completely different clinical behavior and prognosis. In this article, we have summarized the clinico-pathological features of main types of PCBCL and we outline the guidelines for management based on a review of the available literature.

  12. Reprogramming of B cells into macrophages: mechanistic insights

    OpenAIRE

    Di Tullio, Alessandro, 1982-

    2012-01-01

    Our earlier work has shown that pre-B cells can be converted into macrophages by the transcription factor C/EBPα at very high frequencies and also that a clonal pre-B cell line with an inducible form of C/EBPα can be converted into macrophage-like cells. Using these systems we have performed a systematic analysis of the questions whether during transdifferentiation the cells retrodifferentiate to a precursor cell state and whether cell cycle is required for reprogramming. As for the first ...

  13. Characterization of the properties of a selective, orally bioavailable autotaxin inhibitor in preclinical models of advanced stages of liver fibrosis.

    Science.gov (United States)

    Baader, Manuel; Bretschneider, Tom; Broermann, Andre; Rippmann, Joerg F; Stierstorfer, Birgit; Kuttruff, Christian A; Mark, Michael

    2018-02-01

    Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six GPCRs expressed in various cell types including fibroblasts. Multiple preclinical studies using knockout animals, LPA receptor antagonists or ATX inhibitors have provided evidence for a potential role of the ATX/LPA axis in tissue fibrosis. Despite growing evidence for a correlation between ATX levels and the degree of fibrosis in chronic liver diseases, including viral hepatitis and hepatocellular carcinoma, the role of ATX in non-alcoholic steatohepatitis (NASH) remains unclear. The relevance of ATX in the pathogenesis of liver fibrosis was investigated by oral administration of Ex_31, a selective ATX inhibitor, in a 10 week model of carbon tetrachloride-induced liver injury and in a 14 week model of choline-deficient amino acid-defined diet-induced liver injury in rats. Oral administration of Ex_31, a selective ATX inhibitor, at 15 mg·kg -1 twice daily in therapeutic intervention mode resulted in efficient ATX inhibition and more than 95% reduction in plasma LPA levels in both studies. Treatment with Ex_31 had no effect on biomarkers of liver function, inflammation, or fibrosis and did not result in histological improvements in diseased animals. Our findings question the role of ATX in the pathogenesis of hepatic fibrosis and the potential of small molecule ATX inhibitors for the treatment of patients with NASH and advanced stages of liver fibrosis. © 2017 The British Pharmacological Society.

  14. Impedance-matching hearing in Paleozoic reptiles: evidence of advanced sensory perception at an early stage of amniote evolution.

    Directory of Open Access Journals (Sweden)

    Johannes Müller

    Full Text Available BACKGROUND: Insights into the onset of evolutionary novelties are key to the understanding of amniote origins and diversification. The possession of an impedance-matching tympanic middle ear is characteristic of all terrestrial vertebrates with a sophisticated hearing sense and an adaptively important feature of many modern terrestrial vertebrates. Whereas tympanic ears seem to have evolved multiple times within tetrapods, especially among crown-group members such as frogs, mammals, squamates, turtles, crocodiles, and birds, the presence of true tympanic ears has never been recorded in a Paleozoic amniote, suggesting they evolved fairly recently in amniote history. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we performed a morphological examination and a phylogenetic analysis of poorly known parareptiles from the Middle Permian of the Mezen River Basin in Russia. We recovered a well-supported clade that is characterized by a unique cheek morphology indicative of a tympanum stretching across large parts of the temporal region to an extent not seen in other amniotes, fossil or extant, and a braincase specialized in showing modifications clearly related to an increase in auditory function, unlike the braincase of any other Paleozoic tetrapod. In addition, we estimated the ratio of the tympanum area relative to the stapedial footplate for the basalmost taxon of the clade, which, at 23:1, is in close correspondence to that of modern amniotes capable of efficient impedance-matching hearing. CONCLUSIONS/SIGNIFICANCE: Using modern amniotes as analogues, the possession of an impedance-matching middle ear in these parareptiles suggests unique ecological adaptations potentially related to living in dim-light environments. More importantly, our results demonstrate that already at an early stage of amniote diversification, and prior to the Permo-Triassic extinction event, the complexity of terrestrial vertebrate ecosystems had reached a level that

  15. Impedance-matching hearing in Paleozoic reptiles: evidence of advanced sensory perception at an early stage of amniote evolution.

    Science.gov (United States)

    Müller, Johannes; Tsuji, Linda A

    2007-09-12

    Insights into the onset of evolutionary novelties are key to the understanding of amniote origins and diversification. The possession of an impedance-matching tympanic middle ear is characteristic of all terrestrial vertebrates with a sophisticated hearing sense and an adaptively important feature of many modern terrestrial vertebrates. Whereas tympanic ears seem to have evolved multiple times within tetrapods, especially among crown-group members such as frogs, mammals, squamates, turtles, crocodiles, and birds, the presence of true tympanic ears has never been recorded in a Paleozoic amniote, suggesting they evolved fairly recently in amniote history. In the present study, we performed a morphological examination and a phylogenetic analysis of poorly known parareptiles from the Middle Permian of the Mezen River Basin in Russia. We recovered a well-supported clade that is characterized by a unique cheek morphology indicative of a tympanum stretching across large parts of the temporal region to an extent not seen in other amniotes, fossil or extant, and a braincase specialized in showing modifications clearly related to an increase in auditory function, unlike the braincase of any other Paleozoic tetrapod. In addition, we estimated the ratio of the tympanum area relative to the stapedial footplate for the basalmost taxon of the clade, which, at 23:1, is in close correspondence to that of modern amniotes capable of efficient impedance-matching hearing. Using modern amniotes as analogues, the possession of an impedance-matching middle ear in these parareptiles suggests unique ecological adaptations potentially related to living in dim-light environments. More importantly, our results demonstrate that already at an early stage of amniote diversification, and prior to the Permo-Triassic extinction event, the complexity of terrestrial vertebrate ecosystems had reached a level that proved advanced sensory perception to be of notable adaptive significance.

  16. Progenitor Hematopoietic Cells Implantation Improves Functional Capacity of End Stage Coronary Artery Disease Patients with Advanced Heart Failure

    Directory of Open Access Journals (Sweden)

    Yoga Yuniadi

    2016-01-01

    Full Text Available Background. Proangiogenic Hematopoietic Cells (PHC which comprise diverse mixture of cell types are able to secrete proangiogenic factors and interesting candidate for cell therapy. The aim of this study was to seek for benefit in implantation of PHC on functional improvement in end stage coronary artery disease patients with advanced heart failure. Methods. Patients with symptomatic heart failure despite guideline directed medical therapy and LVEF less than 35% were included. Peripheral blood mononuclear cells were isolated, cultivated for 5 days, and then harvested. Flow cytometry and cell surface markers were used to characterize PHC. The PHC were delivered retrogradely via sinus coronarius. Echocardiography, myocardial perfusion, and clinical and functional data were analyzed up to 1-year observation. Results. Of 30 patients (56.4±7.40 yo preimplant NT proBNP level is 5124.5±4682.50 pmol/L. Harvested cells characterized with CD133, CD34, CD45, and KDR showed 0.87±0.41, 0.63±0.66, 99.00±2.60, and 3.22±3.79%, respectively. LVEF was improved (22±5.68 versus 26.8±7.93, p<0.001 during short and long term observation. Myocardial perfusion significantly improved 6 months after treatment. NYHA Class and six-minute walk test are improved during short term and long term follow-up. Conclusion. Expanded peripheral blood PHC implantation using retrograde delivery approach improved LV systolic function, myocardial perfusion, and functional capacity.

  17. Advances in single- and multi-stage Stirling-type pulse tube cryocoolers for space applications in NLIP/SITP/CAS

    Science.gov (United States)

    Dang, Haizheng; Tan, Jun; Zha, Rui; Li, Jiaqi; Zhang, Lei; Zhao, Yibo; Gao, Zhiqian; Bao, Dingli; Li, Ning; Zhang, Tao; Zhao, Yongjiang; Zhao, Bangjian

    2017-12-01

    This paper presents a review of recent advances in single- and multi-stage Stirling-type pulse tube cryocoolers (SPTCs) for space applications developed at the National Laboratory for Infrared Physics, Shanghai Institute of Technical Physics, Chinese Academy of Sciences (NLIP/SITP/CAS). A variety of single-stage SPTCs operating at 25-150 K have been developed, including several mid-sized ones operating at 80-110 K. Significant progress has been achieved in coolers operating at 30-40 K which use common stainless steel meshes as regenerator matrices. Another important advance is the micro SPTCs with an overall mass of 300-800 g operating at high frequencies varying from 100 Hz to 400 Hz. The main purpose of developing two-stage SPTCs is to simultaneously acquire cooling capacities at both stages, obviating the need for auxiliary precooling in various applications. The three-stage SPTCs are developed mainly for applications at around 10 K, which are also used for precooling the J-T coolers to achieve further lower temperatures. The four-stage SPTCs are developed to directly achieve the liquid helium temperature for cooling space low-Tc superconducting devices and for the deep space exploration as well. Several typical development programs are described and an overview of the cooler performances is presented.

  18. Follicular B Cell Lymphoma with Accompanying Ischemic Gastritis Completely Resolved by Rituximab.

    Science.gov (United States)

    Tariq, Anam; Mehta, Neal; Peroutka, Kathryn

    2017-06-02

    BACKGROUND Follicular B cell lymphomas account for a significant portion of all newly diagnosed non-Hodgkin's lymphomas. While involvement can be varied, the most common extranodal presentation is within the gastrointestinal tract beyond the stomach. In addition, the stomach has a diffuse multivessel vascular supply, which decreases the likelihood of developing ischemic gastritis. CASE REPORT An 89-year-old woman with history of diabetes, deep venous thromboembolism, and hypertension was referred due to a newly diagnosed retroperitoneal mass. Biopsy of a left para-aortic node was consistent with low-grade follicular B cell lymphoma. Following mainstream treatment guidelines, rituximab was administered. Approximately 12 hours later, the patient presented to the Emergency Department with intractable vomiting and nausea. After admission, an esophagogastroduodenoscopy (EGD) revealed extensive ischemic gastritis. Due to recurrent ascites requiring frequent paracenteses, and the clinical aggressiveness of the patient's underlying lymphoma, a second dose of rituximab was administered with concurrent initiation of total parenteral nutrition. Approximately 1 week later, the patient underwent a repeat EGD for quality of life planning while in hospice. The repeat EGD revealed resolved ischemic gastritis. Her diet was advanced and she was subsequently discharged home. CONCLUSIONS Rituximab alone shows promise in treating extensive follicular B cell lymphoma complicated by ischemic gastritis, which has not been previously reported in the literature.

  19. Novel disease targets and management approaches for diffuse large B-cell lymphoma.

    Science.gov (United States)

    Wilson, Wyndham H; Hernandez-Ilizaliturri, Francisco J; Dunleavy, Kieron; Little, Richard F; O'Connor, Owen A

    2010-08-01

    Diffuse large B-cell lymphoma (DLBCL) responds well to treatment with CHOP and the R-CHOP regimen, but a subset of patients still fail to achieve complete or durable responses. Recent advances in gene expression profiling have led to the identification of three different subtypes of DLBCL, and confirmed that patients with the activated B-cell (ABC) disease subtype are less likely to respond well to CHOP-based regimens than those with germinal centre B-cell-type (GCB) disease. This discovery could herald the use of gene expression profiling to aid treatment decisions in DLBCL, and help identify the most effective management strategies for patients. Treatment options for patients with relapsed or refractory DLBCL are limited and several novel agents are being developed to address this unmet clinical need. Novel agents developed to treat plasma cell disorders such as multiple myeloma have shown promising activity in patients with NHL. Indeed, the immunomodulatory agent lenalidomide and the proteasome inhibitors bortezomib and carfilzomib, as single agents or in combination with chemotherapy, have already demonstrated promising activity in patients with the ABC subtype of DLBCL. One should not be complacent however when applying these agents to new disease types, because dose and drug scheduling can have marked effects on the responses achieved with investigational agents. As more targeted agents are developed, the timing of administration with other agents in clinical trials will become increasingly important to ensure maximal efficacy while minimizing side effects.

  20. Data in support of dyslipidemia-associated alterations in B cell subpopulations frequency and phenotype during experimental atherosclerosis

    Directory of Open Access Journals (Sweden)

    Héctor Rincón-Arévalo

    2016-06-01

    Full Text Available Cardiovascular diseases are the most common cause of death in the world, atherosclerosis being its main underlying disease. Information about the role of B cells during atherosclerotic process is scarce, but both proatherogenic and atheroprotective properties have been described in the immunopathology of this disease. Frequency and phenotype of B cell subpopulations were studied in wild type and apolipoprotein-E-deficient (apoE−/− mice fed or not with high-fat diet (HFD, by flow cytometry. Here, we provide the information about the materials, methods, analysis and additional information related to our study published in Atherosclerosis (DOI: 10.1016/j.atherosclerosis.2015.12.022, article reference: ATH14410 [1]. The data contained in this article shows and supports that mice with advanced atherosclerosis have a variety of alterations in frequency and phenotype of B cell subsets, most of which associated with dyslipidemia.

  1. [Rasagiline in monotherapy in patients with early stages of Parkinson's disease and in combined and adjunct therapy to levodopa with moderate and advanced stages].

    Science.gov (United States)

    Pagonabarraga, Javier; Rodríguez-Oroz, María Cruz

    2013-01-01

    Rasagiline is effective in the early stages of the disease and has shown a possible effect of modifying disease progression at a dose of 1 mg. The accurate management of dopaminergic drugs in Parkinson's disease is able to delay the appearance of motor fluctuations and dyskinesias. The combination of different drugs that provide a more continuous dopaminergic stimulation (rasagiline, dopamine agonists) not only exerts a benefit through diminishing the impact of pulsatile stimulation on post-synaptic dopamine receptors, but allows to decrease total daily levodopa requirements. The combination of rasagiline with other dopaminergic drugs has demonstrated to be as efficacious as entacapone for improving both the frequency and severity of motor fluctuations. Likewise, new evidences have shown that the earlier introduction of rasagiline is associated with a delay in introducing other dopaminergic drugs, thus indicating that the symptomatic benefit of rasagiline on daily motor function is not only present in the early Parkinson's disease stages, but is maintained over time.

  2. Anti-HIV-1 B cell responses are dependent on B cell precursor frequency and antigen-binding affinity.

    Science.gov (United States)

    Dosenovic, Pia; Kara, Ervin E; Pettersson, Anna-Klara; McGuire, Andrew T; Gray, Matthew; Hartweger, Harald; Thientosapol, Eddy S; Stamatatos, Leonidas; Nussenzweig, Michel C

    2018-04-16

    The discovery that humans can produce potent broadly neutralizing antibodies (bNAbs) to several different epitopes on the HIV-1 spike has reinvigorated efforts to develop an antibody-based HIV-1 vaccine. Antibody cloning from single cells revealed that nearly all bNAbs show unusual features that could help explain why it has not been possible to elicit them by traditional vaccination and instead would require a sequence of different immunogens. This idea is supported by experiments with genetically modified immunoglobulin (Ig) knock-in mice. Sequential immunization with a series of specifically designed immunogens was required to shepherd the development of bNAbs. However, knock-in mice contain superphysiologic numbers of bNAb precursor-expressing B cells, and therefore how these results can be translated to a more physiologic setting remains to be determined. Here we make use of adoptive transfer experiments using knock-in B cells that carry a synthetic intermediate in the pathway to anti-HIV-1 bNAb development to examine how the relationship between B cell receptor affinity and precursor frequency affects germinal center (GC) B cell recruitment and clonal expansion. Immunization with soluble HIV-1 antigens can recruit bNAb precursor B cells to the GC when there are as few as 10 such cells per mouse. However, at low precursor frequencies, the extent of clonal expansion is directly proportional to the affinity of the antigen for the B cell receptor, and recruitment to GCs is variable and dependent on recirculation.

  3. Fluorine-18-fluorodeoxyglucose Positron Emission Tomography in Diffuse Large B-cell Lymphoma

    DEFF Research Database (Denmark)

    Mylam, Karen Juul; Nielsen, Anne Lerberg; Pedersen, Lars Møller

    2014-01-01

    Diffuse large B-cell lymphoma (DLBCL) is an aggressive and potentially curable type of lymphoma. Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is part of clinical routine for DLBCL in most hospitals and also recommended for staging and end-of-therapy evaluation. FDG......-PET/computed tomography (CT) is able to identify nodal and extranodal sites with greater accuracy than CT alone. Little evidence supports the use of surveillance FDG-PET imaging in the follow-up setting because of high rates of false-positive scans and because most studies are retrospective. This article discusses FDG...

  4. Synchronous Diagnosis of Multiple Myeloma, Breast Cancer, and Monoclonal B-Cell Lymphocytosis on Initial Presentation

    Directory of Open Access Journals (Sweden)

    A. Vennepureddy

    2016-01-01

    Full Text Available The cooccurrence of more than one oncologic illness in a patient can present a diagnostic challenge. Here we report an unusual case of concomitant existence of multiple myeloma, breast cancer, and monoclonal B-cell lymphocytosis on initial presentation. The challenge was to accurately diagnose each disease and stage in order to maximize the therapeutic regimen to achieve cure/remission. Successful management of the patient and increased life expectancy can be achieved by multidisciplinary management and patient-oriented approach in multiple primary malignant synchronous tumors.

  5. Targeting the BCR signalosome in B cell malignancies

    NARCIS (Netherlands)

    de Rooij, M.F.M.

    2017-01-01

    Chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM) are B-cell malignancies which are still incurable. In these lymphomas, the cells proliferate in specialized niches in lymph nodes and bone marrow, in which they are provided by stromal-derived

  6. Likelihood-Based Inference of B Cell Clonal Families.

    Directory of Open Access Journals (Sweden)

    Duncan K Ralph

    2016-10-01

    Full Text Available The human immune system depends on a highly diverse collection of antibody-making B cells. B cell receptor sequence diversity is generated by a random recombination process called "rearrangement" forming progenitor B cells, then a Darwinian process of lineage diversification and selection called "affinity maturation." The resulting receptors can be sequenced in high throughput for research and diagnostics. Such a collection of sequences contains a mixture of various lineages, each of which may be quite numerous, or may consist of only a single member. As a step to understanding the process and result of this diversification, one may wish to reconstruct lineage membership, i.e. to cluster sampled sequences according to which came from the same rearrangement events. We call this clustering problem "clonal family inference." In this paper we describe and validate a likelihood-based framework for clonal family inference based on a multi-hidden Markov Model (multi-HMM framework for B cell receptor sequences. We describe an agglomerative algorithm to find a maximum likelihood clustering, two approximate algorithms with various trade-offs of speed versus accuracy, and a third, fast algorithm for finding specific lineages. We show that under simulation these algorithms greatly improve upon existing clonal family inference methods, and that they also give significantly different clusters than previous methods when applied to two real data sets.

  7. Th1 and Th2 help for B cells

    DEFF Research Database (Denmark)

    Poudrier, J; Owens, T

    1995-01-01

    Sustained interaction with Th1 cells has been shown to induce IL-2 responsiveness by murine B cells. This is equivalently dependent on CD40, CD54/ICAM-1 and MHC II ligation, and co-cross-linking of CD54 and MHC II in the presence of IL-5 up-regulates a functional IL-2R on B cells. We now show...... that IL-5 (125 U/ml) synergizes with Th1 cells to induce B cell responses to IL-2, that are maintained following T-cell removal, e.g. autonomous. Th1 help in the absence of IL-5 resulted in weak or undetectable responses following T cell removal. The mechanism of IL-5 synergy involved persistence of IL-2R...... anti-Ig did not circumvent the need for IL-5 for autonomous IL-2 responses. Consistent with the above, interaction with an IL-5-producing Th2 clone induced strong autonomous B cell responses to IL-2. Qualitative differences of Th2 help over that of Th1 may thus be attributable to their differential...

  8. Role of Bruton's tyrosine kinase in B cells and malignancies

    NARCIS (Netherlands)

    Pal Singh, S. (Simar); F. Dammeijer (Floris); R.W. Hendriks (Rudi)

    2018-01-01

    textabstractBruton's tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked

  9. Btk at the Pre-B Cell Receptor Checkpoint

    NARCIS (Netherlands)

    S. Middendorp

    2004-01-01

    textabstractSignalling from the BCR or its immature form, the pre-BCR, was shown to be crucial for B cell development. Gene-targeted mice have defined differential roles of components of the (pre-) BCR complex or its downstream signalling pathways. One of the proteins involved in (pre-) BCR

  10. Immunomodulatory effect of Mesenchymal Stem Cells on B cells

    Directory of Open Access Journals (Sweden)

    Marcella eFranquesa

    2012-07-01

    Full Text Available The research on T cell immunosuppression therapies has attracted most of the attention in clinical transplantation. However, B cells and humoral immune responses are increasingly acknowledged as crucial mediators of chronic allograft rejection. Indeed, humoral immune responses can lead to renal allograft rejection even in patients whose cell-mediated immune responses are well controlled. On the other hand, newly studied B cell subsets with regulatory effects have been linked to tolerance achievement in transplantation. Better understanding of the regulatory and effector B cell responses may therefore lead to new therapeutic approaches.Mesenchymal Stem Cells (MSC are arising as a potent therapeutic tool in transplantation due to their regenerative and immunomodulatory properties. The research on MSCs has mainly focused on their effects on T cells and although data regarding the modulatory effects of MSCs on alloantigen-specific humoral response in humans is scarce, it has been demonstrated that MSCs significantly affect B cell functioning. In the present review we will analyze and discuss the results in this field.

  11. Anthropometrics and prognosis in diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Bendtsen, Mette Dahl; Munksgaard, Peter Svenssen; Severinsen, Marianne Tang

    2017-01-01

    Objective: The impact of body mass index (BMI) and body surface area (BSA) on survival in diffuse large B-cell lymphoma (DLBCL) is controversial. Recent studies show superior outcomes for overweight and obese patients. Patients and methods: A total of 653 R-CHOP(-like)-treated DLBCL patients were...

  12. Altered B Cell Homeostasis in Patients with Major Depressive Disorder and Normalization of CD5 Surface Expression on Regulatory B Cells in Treatment Responders.

    Science.gov (United States)

    Ahmetspahic, Diana; Schwarte, Kathrin; Ambrée, Oliver; Bürger, Christian; Falcone, Vladislava; Seiler, Katharina; Kooybaran, Mehrdad Rahbar; Grosse, Laura; Roos, Fernand; Scheffer, Julia; Jörgens, Silke; Koelkebeck, Katja; Dannlowski, Udo; Arolt, Volker; Scheu, Stefanie; Alferink, Judith

    2018-03-01

    Pro-inflammatory activity and cell-mediated immune responses have been widely observed in patients with major depressive disorder (MDD). Besides their well-known function as antibody-producers, B cells play a key role in inflammatory responses by secreting pro- and anti-inflammatory factors. However, homeostasis of specific B cell subsets has not been comprehensively investigated in MDD. In this study, we characterized circulating B cells of distinct developmental steps including transitional, naïve-mature, antigen-experienced switched, and non-switched memory cells, plasmablasts and regulatory B cells by multi-parameter flow cytometry. In a 6-weeks follow-up, circulating B cells were monitored in a small group of therapy responders and non-responders. Frequencies of naïve lgD + CD27 - B cells, but not lgD + CD27 + memory B cells, were reduced in severely depressed patients as compared to healthy donors (HD) or mildly to moderately depressed patients. Specifically, B cells with immune-regulatory capacities such as CD1d + CD5 + B cells and CD24 + CD38 hi transitional B cells were reduced in MDD. Also Bm1-Bm5 classification in MDD revealed reduced Bm2' cells comprising germinal center founder cells as well as transitional B cells. We further found that reduced CD5 surface expression on transitional B cells was associated with severe depression and normalized exclusively in clinical responders. This study demonstrates a compromised peripheral B cell compartment in MDD with a reduction in B cells exhibiting a regulatory phenotype. Recovery of CD5 surface expression on transitional B cells in clinical response, a molecule involved in activation and down-regulation of B cell responses, further points towards a B cell-dependent process in the pathogenesis of MDD.

  13. Primary B-cell deficiencies reveal a link between human IL-17-producing CD4 T-cell homeostasis and B-cell differentiation.

    Directory of Open Access Journals (Sweden)

    Rita R Barbosa

    Full Text Available IL-17 is a pro-inflammatory cytokine implicated in autoimmune and inflammatory conditions. The development/survival of IL-17-producing CD4 T cells (Th17 share critical cues with B-cell differentiation and the circulating follicular T helper subset was recently shown to be enriched in Th17 cells able to help B-cell differentiation. We investigated a putative link between Th17-cell homeostasis and B cells by studying the Th17-cell compartment in primary B-cell immunodeficiencies. Common Variable Immunodeficiency Disorders (CVID, defined by defects in B-cell differentiation into plasma and memory B cells, are frequently associated with autoimmune and inflammatory manifestations but we found no relationship between these and Th17-cell frequency. In fact, CVID patients showed a decrease in Th17-cell frequency in parallel with the expansion of activated non-differentiated B cells (CD21(lowCD38(low. Moreover, Congenital Agammaglobulinemia patients, lacking B cells due to impaired early B-cell development, had a severe reduction of circulating Th17 cells. Finally, we found a direct correlation in healthy individuals between circulating Th17-cell frequency and both switched-memory B cells and serum BAFF levels, a crucial cytokine for B-cell survival. Overall, our data support a relationship between Th17-cell homeostasis and B-cell maturation, with implications for the understanding of the pathogenesis of inflammatory/autoimmune diseases and the physiology of B-cell depleting therapies.

  14. Subcutaneous 'lipoma-like' B-cell lymphoma associated with HCV infection: a new presentation of primary extranodal marginal zone B-cell lymphoma of MALT.

    Science.gov (United States)

    Paulli, M; Arcaini, L; Lucioni, M; Boveri, E; Capello, D; Passamonti, F; Merli, M; Rattotti, S; Rossi, D; Riboni, R; Berti, E; Magrini, U; Bruno, R; Gaidano, G; Lazzarino, M

    2010-06-01

    Hepatitis C virus (HCV) infection has been linked to lymphoproliferative disorders. Marginal zone B-cell lymphoma (MZL) represents one of the most frequent lymphoma subtypes associated with HCV infection. We describe an unusual subset of HCV-associated MZL characterized by subcutaneous presentation. A series of 12 HCV-positive patients presenting with subcutaneous nodules that revealed lymphoma infiltration at biopsy. Molecular analysis of immunoglobulin heavy chain (IGH) gene rearrangement and FISH investigations for t(11;18)(q21;q21) and t(14;18)(q32;q21) were carried out in nine patients. The 12 patients (median age 69.5 years), all with positive HCV serology, presented with single or multiple subcutaneous nodules resembling lipomas. Histologically the lesions showed lymphoid infiltrates, consistent with extranodal MZL of mucosa-associated lymphoid tissue (MALT). Functional IGH gene rearrangements were identified in nine tested patients, with somatic mutations in 82%, indicating a histogenesis from germinal center-experienced B cells. The t(11;18) was found in two of nine cases. Staging did not show any other lymphoma localization. In two patients, a response was achieved with antiviral treatment. Extracutaneous spread to MALT sites occurred in a case. Our observations expand the spectrum of HCV-associated lymphomas to include a subset of extranodal MZL characterized by a novel primary 'lipoma-like' subcutaneous presentation and indolent clinical course.

  15. Poor performance status, urban residence and female sex predict inferior survival in pediatric advanced stage mature B-NHL in an Indian tertiary care center.

    Science.gov (United States)

    Patel, Amol; Sharma, Meher Chand; Mallick, Saumyaranjan; Patel, Manali; Bakhshi, Sameer

    2018-02-01

    Advanced stage is a known prognostic factor in B-Non-Hodgkin Lymphoma (NHL); however, factors within advanced stage and overall data on pediatric B-NHL from India are lacking. This is a retrospective study wherein all consecutive pediatric (≤18 years) patients of advanced stage B-NHL (St. Jude stage 3 and 4) treated at our center from Jan 2003 to June 2016 with BFM-90 protocol were evaluated for outcome and pathology review. Total 140 patients were analyzed with median age 8 years; M:F ratio was 5.2:1; 36% patients presented within 30 days of symptom onset and 58% had rural residence. Burkitt lymphoma (66%) was commonest histopathological subtype; bone marrow was involved in 15% and CSF in 8% cases. Undernourishment was observed in 30% patients and 51% had ECOG performance status of 3&4. At 5 years, EFS was 52 ± 4% (CI 0.43-0.60) and OS was 61 ± 4% (CI 0.52-0.68). On multivariate analysis, poor performance status (p residence (p = 0.016) emerged as significant negative prognostic factors for EFS; while for OS, female sex (p = 0.006), poor performance status (p residence (p = 0.023) predicted inferior outcome. This is the largest study from south Asia on advanced stage pediatric B-NHL and it suggests undernourishment, poor performance status and gender bias to be unique features at presentation. Although, outcomes are comparable with other data from resource-challenged nations, yet they are 15-20% inferior than trial data from other developed countries. Further, poor performance status, female sex and urban residence for poor outcome were identified as unique prognostic factors.

  16. Complement receptor type 1 (CR1, CD35) is a potent inhibitor of B-cell functions in rheumatoid arthritis patients.

    Science.gov (United States)

    Kremlitzka, Mariann; Polgár, Anna; Fülöp, Lívia; Kiss, Emese; Poór, Gyula; Erdei, Anna

    2013-01-01

    The involvement of B cells, complement activation and subsequent immune complex deposition has all been implicated in the pathogenesis of rheumatoid arthritis (RA). Although the reduced expression of complement receptor 1 (CR1, CD35) and 2 (CR2, CD21) on the B cells of RA patients has been known for a long time, their exact role in B-cell tolerance and autoimmunity is not yet fully understood. To get a deeper insight into the possible mechanisms, we studied the expression and function of CR1 and CR2 on various subsets of B cells of healthy donors and RA patients at various stages of the disease by FACS analysis, (3)H-thymidine incorporation and ELISA. We found that CD19(+)CD27(-) naive B cells up-regulate the expression of the inhibitory CR1 during differentiation to CD19(+)CD27(+) memory B cells both in healthy donors and in RA patients, whereas the expression of the activatory CR2 is down-regulated. This clearly demonstrates that the expression of these two antagonistic complement receptors is regulated differentially during the development of human B cells, a phenomenon which may influence the maintenance of peripheral B-cell tolerance. Our functional studies show that after clustering CR1 both by its natural ligand and To5 mAb, the inhibitory function of CD35 is maintained in RA patients, despite its significantly reduced expression compared with healthy individuals. Besides blocking B-cell receptor-induced proliferation, CR1 inhibits the differentiation of B cells to plasmablasts and their immunoglobulin production. Since the reduced expression of CR1 in RA patients does not affect its inhibitory function, this receptor might serve as a new target for therapeutical interventions.

  17. Progression from IgD+ IgM+ to isotype-switched B cells is site specific during coronavirus-induced encephalomyelitis.

    Science.gov (United States)

    Phares, Timothy W; DiSano, Krista D; Stohlman, Stephen A; Bergmann, Cornelia C

    2014-08-01

    Various infections in the central nervous system (CNS) trigger B cell accumulation; however, the relative dynamics between viral replication and alterations in distinct B cell subsets are largely unknown. Using a glia-tropic coronavirus infection, which is initiated in the brain but rapidly spreads to and predominantly persists in the spinal cord, this study characterizes longitudinal changes in B cell subsets at both infected anatomical sites. The phase of T cell-dependent, antibody-independent control of infectious virus was associated with a similar recruitment of naive/early-activated IgD(+) IgM(+) B cells into both the brain and spinal cord. This population was progressively replaced by CD138(-) IgD(-) IgM(+) B cells, isotype-switched CD138(-) IgD(-) IgM(-) memory B cells (B(mem)), and CD138(+) antibody-secreting cells (ASC). A more rapid transition to B(mem) and ASC in spinal cord than in brain was associated with higher levels of persisting viral RNA and transcripts encoding factors promoting B cell migration, differentiation, and survival. The results demonstrate that naive/early-activated B cells are recruited early during coronavirus CNS infection but are subsequently replaced by more differentiated B cells. Furthermore, viral persistence, even at low levels, is a driving force for accumulation of isotype-switched B(mem) and ASC. Acute and chronic human CNS infections are associated with an accumulation of heterogeneous B cell subsets; however, their influence on viral load and disease is unclear. Using a glia-tropic coronavirus model, we demonstrate that the accumulation of B cells ranging from early-activated to isotype-switched differentiation stages is both temporally and spatially orchestrated. Acutely infected brains and spinal cords indiscriminately recruit a homogeneous population of early-activated B cells, which is progressively replaced by diverse, more differentiated subsets. The latter process is accelerated by elevated proinflammatory

  18. Computed tomography in the evaluation of malignant pleural mesothelioma-Association of tumor size to a sarcomatoid histology, a more advanced TNM stage and poor survival.

    Science.gov (United States)

    Paajanen, Juuso; Laaksonen, Sanna; Ilonen, Ilkka; Wolff, Henrik; Husgafvel-Pursiainen, Kirsti; Kuosma, Eeva; Ollila, Hely; Myllärniemi, Marjukka; Vehmas, Tapio

    2018-02-01

    Appropriate clinical staging of malignant pleural mesothelioma (MPM) is critical for correct treatment decisions. Newly revised TNM staging protocol has been released for MPM. We investigated baseline computed tomography (CT) characteristics of MPM patients, the new staging system and a simple tumor size (TS) assessment in terms of survival. As part of our study that included all MPM patients diagnosed in Finland 2000-2012, we retrospectively reviewed 161 CT scans of MPM patients diagnosed between 2007 and 2012 in the Hospital District of Helsinki and Uusimaa. TS was estimated by using the maximal tumor thickness and grading tumor extension along the chest wall. Cox Regression models were used to identify relationships between survival, clinicopathological factors and CT-findings. The median length of follow-up was 9.7 months and the median survival 9.1 months. The right sided tumors tended to be more advanced at baseline and had worse prognosis in the univariate analyses. In the multivariate survival model, TS, pleural effusion along with non-epithelioid histology were predictors of poor survival. Tumor size correlated significantly with a sarcomatoid histopathological finding and several parameters linked to a more advanced TNM stage. Most patients were diagnosed with locally advanced stage, while 12 (7%) had no sign of the tumor in CT. In this study, we demonstrate a novel approach for MPM tumor size evaluation that has a strong relationship with mortality, sarcomatoid histology and TNM stage groups. TS could be used for prognostic purposes and it may be a useful method for assessing therapy responses. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. Bmi-1 promotes invasion and metastasis, and its elevated expression is correlated with an advanced stage of breast cancer

    Science.gov (United States)

    2011-01-01

    Background B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi-1) acts as an oncogene in various tumors, and its overexpression correlates with a poor outcome in several human cancers. Ectopic expression of Bmi-1 can induce epithelial-mesenchymal transition (EMT) and enhance the motility and invasiveness of human nasopharyngeal epithelial cells (NPECs), whereas silencing endogenous Bmi-1 expression can reverse EMT and reduce the metastatic potential of nasopharyngeal cancer cells (NPCs). Mouse xenograft studies indicate that coexpression of Bmi-1 and H-Ras in breast cancer cells can induce an aggressive and metastatic phenotype with an unusual occurrence of brain metastasis; although, Bmi-1 overexpression did not result in oncogenic transformation of MCF-10A cells. However, the underlying molecular mechanism of Bmi-1-mediated progression and the metastasis of breast cancer are not fully elucidated at this time. Results Bmi-1 expression is more pronouncedly increased in primary cancer tissues compared to matched adjacent non-cancerous tissues. High Bmi-1 expression is correlated with advanced clinicopathologic classifications (T, N, and M) and clinical stages. Furthermore, a high level of Bmi-1 indicates an unfavorable overall survival and serves as a high risk marker for breast cancer. In addition, inverse transcriptional expression levels of Bmi-1 and E-cadherin are detected between the primary cancer tissues and the matched adjacent non-cancerous tissues. Higher Bmi-1 levels are found in the cancer tissue, whereas the paired adjacent non-cancer tissue shows higher E-cadherin levels. Overexpression of Bmi-1 increases the motility and invasive properties of immortalized human mammary epithelial cells, which is concurrent with the increased expression of mesenchymal markers, the decreased expression of epithelial markers, the stabilization of Snail and the dysregulation of the Akt/GSK3β pathway. Consistent with these observations, the repression of Bmi

  20. Type I CD20 Antibodies Recruit the B Cell Receptor for Complement-Dependent Lysis of Malignant B Cells

    NARCIS (Netherlands)

    Engelberts, Patrick J.; Voorhorst, Marleen; Schuurman, Janine; van Meerten, Tom; Bakker, Joost M.; Vink, Tom; Mackus, Wendy J. M.; Breij, Esther C. W.; Derer, Stefanie; Valerius, Thomas; van de Winkel, Jan G. J.; Parren, Paul W. H. I.; Beurskens, Frank J.

    2016-01-01

    Human IgG1 type I CD20 Abs, such as rituximab and ofatumumab (OFA), efficiently induce complement-dependent cytotoxicity (CDC) of CD20(+) B cells by binding of C1 to hexamerized Fc domains. Unexpectedly, we found that type I CD20 Ab F(ab ')2 fragments, as well as C1q-binding-deficient IgG mutants,

  1. Anaplastic lymphoma kinase-positive large B-cell lymphoma: Clinico-pathological study of 17 cases with review of literature.

    Directory of Open Access Journals (Sweden)

    Xiang-Nan Jiang

    Full Text Available We retrospectively analysed 17 cases of anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+, LBCL according to the morphological, immunohistochemical, molecular and clinical features, using which we intend to elucidate the clinicopathological characteristics of this rare entity. In this study, all cases de facto share common features that defined them as a single entity, and various characteristics may expand the spectrum. Among 15 cases, 60% followed an aggressive clinical course with advanced stage and high IPI scores; the median survival of these patients was only 8 months. An analysis showed that both the IPI score and the Ann Arbor stage were significant prognostic factors. Most patients received a chemotherapy regimen including CHOP, CHOEP, EPOCH, and CVAD, and some also underwent localized radiotherapy. However, ALK+, LBCL cases display a dismal clinical outcome and can only be cured with conventional chemotherapy protocols at the stage of localized disease. Novel front-line intensive chemotherapy regimens should therefore be evaluated in this group of patients.

  2. Hitherto unseen survival in an ALK-positive-patient with advanced stage adult ganglioneuroblastoma treated with personalized medicine

    DEFF Research Database (Denmark)

    Risum, Signe; Knigge, Ulrich; Langer, Seppo W

    2017-01-01

    Survival of stage 4 ganglioneuroblastoma (GNB) patients is poor; no reports exist of patients surviving up to 5 years (1, 2). We report the clinical and therapeutic course of a patient with stage 4 GNB surviving beyond expectations due to a multimodal treatment approach incorporating new technolo...

  3. Assessment of CD37 B-cell antigen and cell of origin significantly improves risk prediction in diffuse large B-cell lymphoma

    NARCIS (Netherlands)

    Xu-Monette, Z.Y.; Li, L; Byrd, J.C.; Jabbar, K.J.; Manyam, G.C.; Winde, C. Maria de; Brand, M. van den; Tzankov, A.; Visco, C.; Wang, J; Dybkaer, K.; Chiu, A.; Orazi, A.; Zu, Y.; Bhagat, G.; Richards, K.L.; Hsi, E.D.; Choi, W.W.; Huh, J.; Ponzoni, M.; Ferreri, A.J.; Moller, M.B.; Parsons, B.M.; Winter, J.N.; Wang, M.; Hagemeister, F.B.; Piris, M.A.; Krieken, J.H. van; Medeiros, L.J.; Li, Y.; Spriel, A.B. van; Young, K.H.

    2016-01-01

    CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. We assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its

  4. The B cell antigen receptor and overexpression of MYC can cooperate in the genesis of B cell lymphomas.

    Directory of Open Access Journals (Sweden)

    Yosef Refaeli

    2008-06-01

    Full Text Available A variety of circumstantial evidence from humans has implicated the B cell antigen receptor (BCR in the genesis of B cell lymphomas. We generated mouse models designed to test this possibility directly, and we found that both the constitutive and antigen-stimulated state of a clonal BCR affected the rate and outcome of lymphomagenesis initiated by the proto-oncogene MYC. The tumors that arose in the presence of constitutive BCR differed from those initiated by MYC alone and resembled chronic B cell lymphocytic leukemia/lymphoma (B-CLL, whereas those that arose in response to antigen stimulation resembled large B-cell lymphomas, particularly Burkitt lymphoma (BL. We linked the genesis of the BL-like tumors to antigen stimulus in three ways. First, in reconstruction experiments, stimulation of B cells by an autoantigen in the presence of overexpressed MYC gave rise to BL-like tumors that were, in turn, dependent on both MYC and the antigen for survival and proliferation. Second, genetic disruption of the pathway that mediates signaling from the BCR promptly killed cells of the BL-like tumors as well as the tumors resembling B-CLL. And third, growth of the murine BL could be inhibited by any of three distinctive immunosuppressants, in accord with the dependence of the tumors on antigen-induced signaling. Together, our results provide direct evidence that antigenic stimulation can participate in lymphomagenesis, point to a potential role for the constitutive BCR as well, and sustain the view that the constitutive BCR gives rise to signals different from those elicited by antigen. The mouse models described here should be useful in exploring further the pathogenesis of lymphomas, and in preclinical testing of new therapeutics.

  5. Impact of the B Cell Growth Factor APRIL on the Qualitative and Immunological Characteristics of Atherosclerotic Plaques.

    Science.gov (United States)

    Bernelot Moens, Sophie J; van Leuven, Sander I; Zheng, Kang H; Havik, Stefan R; Versloot, Miranda V; van Duivenvoorde, Leonie M; Hahne, Michael; Stroes, Erik S G; Baeten, Dominique L; Hamers, Anouk A J

    2016-01-01

    Studies on the role of B lymphocytes in atherosclerosis development, have yielded contradictory results. Whereas B lymphocyte-deficiency aggravates atherosclerosis in mice; depletion of mature B lymphocytes reduces atherosclerosis. These observations led to the notion that distinct B lymphocyte subsets have different roles. B1a lymphocytes exert an atheroprotective effect, which has been attributed to secretion of IgM, which can be deposited in atherosclerotic lesions thereby reducing necrotic core formation. Tumor necrosis factor (TNF)-family member 'A Proliferation-Inducing Ligand' (APRIL, also known as TNFSF13) was previously shown to increase serum IgM levels in a murine model. In this study, we investigated the effect of APRIL overexpression on advanced lesion formation and composition, IgM production and B cell phenotype. We crossed APRIL transgenic (APRIL-Tg) mice with ApoE knockout (ApoE-/-) mice. After a 12-week Western Type Diet, ApoE-/-APRIL-Tg mice and ApoE-/- littermates showed similar increases in body weight and lipid levels. Histologic evaluation showed no differences in lesion size, stage or necrotic area. However, smooth muscle cell (α-actin stain) content was increased in ApoE-/-APRIL-Tg mice, implying more stable lesions. In addition, increases in both plaque IgM deposition and plasma IgM levels were found in ApoE-/-APRIL-Tg mice compared with ApoE-/- mice. Flow cytometry revealed a concomitant increase in peritoneal B1a lymphocytes in ApoE-/-APRIL-Tg mice. This study shows that ApoE-/-APRIL-Tg mice have increased oxLDL-specific serum IgM levels, potentially mediated via an increase in B1a lymphocytes. Although no differences in lesion size were found, transgenic ApoE-/-APRIL-Tg mice do show potential plaque stabilizing features in advanced atherosclerotic lesions.

  6. Unusual B cell morphology in inflammatory bowel disease.

    Science.gov (United States)

    Defendenti, Caterina; Grosso, Silvia; Atzeni, Fabiola; Croce, Annamaria; Senesi, Olivia; Saibeni, Simone; Bollani, Simona; Almasio, Piero Luigi; Bruno, Savino; Sarzi-Puttini, Piercarlo

    2012-07-15

    B lymphocytes express various different types of surface immunoglobulins that are largely unrelated to other hematological lines, although some reports have described a relationship between malignant B cells and other cells such as macrophages. Multiple genes of hematopoietic lineage, including transcription factors, are co-expressed in hematopoietic stem cells and progenitors, a phenomenon referred to as "lineage priming". Changes in the expression levels and timing of transcription factors can induce the lineage conversion of committed cells, which indicates that the regulation of transcription factors might be particularly critical for maintaining hierarchical hematopoietic development. The aim of this study was to evaluate the surface markers of particular IgM-positive and irregularly nucleated cells detected in patients with inflammatory bowel disease (IBD), and to assess their association with diagnosis and inflammatory cell recruitment. Small intestine, colon and rectal biopsy specimens of 96 IBD patients were studied. Immunoglobulin-producing cells (IPCs) were analyzed by means of immunofluorescence using polyclonal rabbit anti-human Ig and goat anti-human IgM. The specimens positive for B cells with irregular nuclei were assessed using monoclonal antibodies specific for CD79, and λ and κ chains in order to confirm their B cell nature. CD15+ cells, an important marker of inflammatory cell recruitment, were also evaluated. Statistical correlations were sought between the histological findings and clinical expression. 34 (35.4%) of the 96 patients (64 with ulcerative colitis and 32 with Crohn's disease) presented a periglandial localization of IPCs with irregular nuclei, which showed surface markers specific for the B cell subset, such as IgM and CD79, but quantitative differences in λ and κ chains. These specimens also contained CD15-positive cells, which are usually absent in healthy controls. The quantitative aspects and localization of the CD15

  7. Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study

    DEFF Research Database (Denmark)

    Gallamini, Andrea; Hutchings, Martin; Rigacci, Luigi

    2007-01-01

    -PET) scan and the International Prognostic Score (IPS) in advanced HL, treated with conventional ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy. PATIENTS AND METHODS: Most patients (n = 190) presented with advanced disease (stages IIB through IVB), whereas 70 presented in stage IIA...

  8. B cell progenitors are arrested in maturation but have intact VDJ recombination in the absence of Ig-alpha and Ig-beta.

    Science.gov (United States)

    Pelanda, Roberta; Braun, Uschi; Hobeika, Elias; Nussenzweig, Michel C; Reth, Michael

    2002-07-15

    Ig-alpha and Ig-beta mediate surface expression and signaling of diverse B cell receptor complexes on precursor, immature, and mature B cells. Their expression begins before that of the Ig chains in early progenitor B cells. In this study, we describe the generation of Ig-alpha-deficient mice and their comparative analysis to mice deficient for Ig-beta, the membrane-IgM, and recombination-activating gene 2 to determine the requirement of Ig-alpha and Ig-beta in survival and differentiation of pro-B cells. We find that in the absence of Ig-alpha, B cell development does not progress beyond the progenitor stage, similar to what is observed in humans lacking this molecule. However, neither in Ig-alpha- nor in Ig-beta-deficient mice are pro-B cells impaired in V(D)J recombination, in the expression of intracellular Ig micro-chains, or in surviving in the bone marrow microenvironment. Finally, Ig-alpha and Ig-beta are not redundant in their putative function, as pro-B cells from Ig-alpha and Ig-beta double-deficient mice are similar to those from single-deficient animals in every aspect analyzed.

  9. Prolactin Levels Correlate with Abnormal B Cell Maturation in MRL and MRL/lpr Mouse Models of Systemic Lupus Erythematosus-Like Disease

    Directory of Open Access Journals (Sweden)

    Maria Victoria Legorreta-Haquet

    2013-01-01

    Full Text Available Prolactin (PRL plays an important role in modulating the immune response. In B cells, PRL enhances antibody production, including antibodies with self-specificity. In this study, our aims were to determine the level of PRL receptor expression during bone-marrow B-cell development and to assess whether the presence of high PRL serum concentrations influences absolute numbers of developing populations and disease outcome in lupus-prone murine models. We observed that the PRL-receptor is expressed in early bone-marrow B-cell; the expression in lupus-prone mice, which had the highest level of expression in pro-B cells and immature cells, differed from that in wild-type mice. These expression levels did not significantly change in response to hyperprolactinemia; however, populations of pro-B and immature cells from lupus-prone strains showed a decrease in the absolute numbers of cells with high PRL-receptor expression in response to PRL. Because immature self-reactive B cells are constantly being eliminated, we assessed the expression of survival factor BIRC5, which is more highly expressed in both pro-B and immature B-cells in response to PRL and correlates with the onset of disease. These results identify an important role of PRL in the early stages of the B-cell maturation process: PRL may promote the survival of self-reactive clones.

  10. Prolactin Levels Correlate with Abnormal B Cell Maturation in MRL and MRL/lpr Mouse Models of Systemic Lupus Erythematosus-Like Disease

    Science.gov (United States)

    Legorreta-Haquet, Maria Victoria; Flores-Fernández, Rocio; Blanco-Favela, Francisco; Fuentes-Pananá, Ezequiel M; Chávez-Sánchez, Luis; Hernández-González, Rafael; Tesoro-Cruz, Emiliano; Arriaga-Pizano, Lourdes; Chávez-Rueda, Adriana Karina

    2013-01-01

    Prolactin (PRL) plays an important role in modulating the immune response. In B cells, PRL enhances antibody production, including antibodies with self-specificity. In this study, our aims were to determine the level of PRL receptor expression during bone-marrow B-cell development and to assess whether the presence of high PRL serum concentrations influences absolute numbers of developing populations and disease outcome in lupus-prone murine models. We observed that the PRL-receptor is expressed in early bone-marrow B-cell; the expression in lupus-prone mice, which had the highest level of expression in pro-B cells and immature cells, differed from that in wild-type mice. These expression levels did not significantly change in response to hyperprolactinemia; however, populations of pro-B and immature cells from lupus-prone strains showed a decrease in the absolute numbers of cells with high PRL-receptor expression in response to PRL. Because immature self-reactive B cells are constantly being eliminated, we assessed the expression of survival factor BIRC5, which is more highly expressed in both pro-B and immature B-cells in response to PRL and correlates with the onset of disease. These results identify an important role of PRL in the early stages of the B-cell maturation process: PRL may promote the survival of self-reactive clones. PMID:24454471

  11. Randomized controlled trial in advance stage breast cancer patients for the effectiveness on stress marker and pain through Sudarshan Kriya and Pranayam

    OpenAIRE

    Neeta Kumar; Sushma Bhatnagar; T Velpandian; Santosh Patnaik; Geetha Menon; Manju Mehta; Komal Kashyap; Vishwajeet Singh; Surajpal

    2013-01-01

    Objective: The objective of this study is to examine the effect of a cognitive, behavioral stress management module of Sudarshan Kriya (SK) and P on levels of serum cortisol and pain among the women suffering from advanced stage breast cancer. Materials and Methods: Participants (n = 147) were screened and randomized to receive standard care (n = 69) versus standard along with SK and Pranayam (P) intervention (n = 78) imparted in one 18 hrs workshop spread during 3 days. Participants were...

  12. The ideas about advanced life support and affecting factors at the end-stage of life in a hospital in Turkey.

    Directory of Open Access Journals (Sweden)

    Turgay Albayrak

    Full Text Available The participation of the people in health decisions may be structured in various levels. One of these is participation in decisions for the treatment. "Advanced directives" is one of the examples for the participation in decisions for the treatment.We wanted to determine the decisions on advanced life support at the end-stage of life in case of a life-threatening illness for the people themselves and their first degree relatives and the factors effecting these decisions.The cross-sectional study was conducted with volunteers among patients and patient relatives who applied to all polyclinics of the Ankara Numune Training and Research Hospital except the emergency, oncology and psychiatry polyclinics between 15.12.2012 and 15.03.2013.A questionnaire, the Hospital Anxiety Depression (HAD scale, and Templer's Death Anxiety Scale (TDA were applied to all individuals. SPSS for Win. Ver. 17.0 and MS-Excel 2010 Starter software bundles were used for all statistical analysis and calculations.The participants want both themselves and their first degree relatives included in end-stage decision-making process. Therefore, the patients and their families should be informed adequately during decision making process and quality communication must be provided.Participants who have given their end-stage decisions previously want to be treated according to these decisions. This desire can just be possible by advanced directives.When moral and material loads of end-stage process are taken into consideration, countries, in which advanced directives are practiced, should be examined well and participants' desire should be evaluated in terms of practicability.

  13. The ideas about advanced life support and affecting factors at the end-stage of life in a hospital in Turkey.

    Science.gov (United States)

    Albayrak, Turgay; Şencan, İrfan; Akça, Ömer; Koç, Esra Meltem; Aksoy, Hilal; Ünsal, Selim; Bülbül, İskender; Bahadır, Adem; Kasım, İsmail; Kahveci, Rabia; Özkara, Adem

    2017-01-01

    The participation of the people in health decisions may be structured in various levels. One of these is participation in decisions for the treatment. "Advanced directives" is one of the examples for the participation in decisions for the treatment. We wanted to determine the decisions on advanced life support at the end-stage of life in case of a life-threatening illness for the people themselves and their first degree relatives and the factors effecting these decisions. The cross-sectional study was conducted with volunteers among patients and patient relatives who applied to all polyclinics of the Ankara Numune Training and Research Hospital except the emergency, oncology and psychiatry polyclinics between 15.12.2012 and 15.03.2013. A questionnaire, the Hospital Anxiety Depression (HAD) scale, and Templer's Death Anxiety Scale (TDA) were applied to all individuals. SPSS for Win. Ver. 17.0 and MS-Excel 2010 Starter software bundles were used for all statistical analysis and calculations. The participants want both themselves and their first degree relatives included in end-stage decision-making process. Therefore, the patients and their families should be informed adequately during decision making process and quality communication must be provided. Participants who have given their end-stage decisions previously want to be treated according to these decisions. This desire can just be possible by advanced directives.When moral and material loads of end-stage process are taken into consideration, countries, in which advanced directives are practiced, should be examined well and participants' desire should be evaluated in terms of practicability.

  14. A Broadly Adaptive Array of Dose-Constraint Templates for Planning of Intensity-Modulated Radiation Therapy for Advanced T-Stage Nasopharyngeal Carcinoma

    International Nuclear Information System (INIS)

    Chau, R.M.-C.; Leung, S.-F.; Kam, M.K.-M.; Cheung, K.-Y.; Kwan, W.-H.; Yu, K.-H.; Chiu, K.-W.; Cheung, M.L.-M.; Chan, A.T.-C.

    2009-01-01

    Purpose: To develop and validate adaptive dose-constraint templates in intensity-modulated radiotherapy (IMRT) planning for advanced T-stage nasopharyngeal carcinoma (NPC). Method and Materials: Dose-volume histograms of clinically approved plans for 20 patients with advanced T-stage NPC were analyzed, and the pattern of distribution in relation to the degree of overlap between targets and organs at risk (OARs) was explored. An adaptive dose constraint template (ADCT) was developed based on the degree of overlap. Another set of 10 patients with advanced T-stage NPC was selected for validation. Results of the manual arm optimization protocol and the ADCT optimization protocol were compared with respect to dose optimization time, conformity indices, multiple-dose end points, tumor control probability, and normal tissue complication probability. Results: For the ADCT protocol, average time required to achieve an acceptable plan was 9 minutes, with one optimization compared with 94 minutes with more than two optimizations of the manual arm protocol. Target coverage was similar between the manual arm and ADCT plans. A more desirable dose distribution in the region of overlap between planning target volume and OARs was achieved in the ADCT plan. Dose end points of OARs were similar between the manual arm and ADCT plans. Conclusions: With the developed ADCT, IMRT treatment planning becomes more efficient and less dependent on the planner's experience on dose optimization. The developed ADCT is applicable to a wide range of advanced T-stage NPC treatment and has the potential to be applied in a broader context to IMRT planning for other cancer sites

  15. Phase II study evaluating consolidation whole abdominal intensity-modulated radiotherapy (IMRT) in patients with advanced ovarian cancer stage FIGO III - The OVAR-IMRT-02 Study

    OpenAIRE

    Rochet, Nathalie; Kieser, Meinhard; Sterzing, Florian; Krause, Sonja; Lindel, Katja; Harms, Wolfgang; Eichbaum, Michael H; Schneeweiss, Andreas; Sohn, Christof; Debus, Juergen

    2011-01-01

    Abstract Background The prognosis for patients with advanced FIGO stage III epithelial ovarian cancer remains poor despite the aggressive standard treatment, consisting of maximal cytoreductive surgery and platinum-based chemotherapy. The median time to recurrence is less than 2 years, with a 5-years survival rate of -20-25%. Recurrences of the disease occur mostly intraperitoneally. Ovarian cancer is a radiosensitive tumor, so that the use of whole abdominal radiotherapy (WAR) as a consolida...

  16. Retinoic acid induces the differentiation of B cell hybridomas from patients with common variable immunodeficiency.

    Science.gov (United States)

    Sherr, E; Adelman, D C; Saxon, A; Gilly, M; Wall, R; Sidell, N

    1988-07-01

    Human-human B cell hybridomas constructed from B lymphocytes of common variable immunodeficiency (CVI) patients and the nonsecreting cell line WIL2/729 HF consistently secrete low levels of Ig and appear to retain a defect characteristic of the CVI patient's B cells. We assessed the differentiative capacity of retinoic acid (RA) on these hybridomas, as well as on hybridomas constructed from normal B cells and from patients with selective IgA deficiency. RA at concentrations varying between 10(-5) and 10(-9) M augmented IgM secretion 4-20-fold from four of four CVI hybridomas tested, but did not affect Ig secretion from normal or IgA-deficiency hybridomas. In support of this elevated Ig secretion, RA enhanced the de novo synthesis of biosynthetically labeled light (kappa) and heavy (mu) Ig (up to 4- and 15-fold, respectively) in the CVI hybridoma line JK32.1. The increase in IgM synthesis/secretion could not be accounted for by RA-induced alteration in the cell cycle. In inducing this increase in IgM production, RA was found to affect two aspects of Ig gene expression: (a) the steady-state levels of heavy and light chain mRNAs were enhanced, and (b) the processing of mu heavy chain transcripts to the secreted mRNA form became favored over the membrane mRNA form. We also show that expression of Leu-17 (CD38), a surface marker that is re-expressed in the late pre-plasma stage of B cell development, was increased by RA from less than 20% to greater than 90% of the total cell population, with a concomitant 4-10-fold augmentation in the mean fluorescence intensity. Changes in both Leu-17 expression and de novo Ig synthesis were prominent by 24 h, but could be observed as early as 8 h after induction. Taken together, our study demonstrates that RA affects a marked alteration in the differentiated state of the CVI hybridoma clones. This finding suggests that retinoids can enhance the functional capabilities of B cells with defects in maturation and support further studies

  17. High expression of LMO2 in Hodgkin, Burkitt and germinal center diffuse large B cell lymphomas

    International Nuclear Information System (INIS)

    Shams, T.M.

    2011-01-01

    The LMO 2 gene encodes a transcription factor that regulates key events in erythropoiesis, angio genesis, and embryogenesis and is highly expressed at the most immature stages of lymphopoiesis. Its implication in Hodgkin lymphoma (HL), Burkitt lymphoma (BL) and diffuse large B cell lymphoma (DLBCL) is limited in the literature. Material and methods: An immunohistochemical study was performed on 68 lymphoma specimens showing different types including Hodgkin lymphoma (23), Burkitt lymphoma (10) and diffuse large B cell lymphoma (35). Also, seven specimens of the reactive nodal tissue were included as control. A monoclonal anti-human antibody has been used to detect LMO 2 . Results: LMO 2 was detected in all cases of HL (100%), in nine cases of BL (90%) and in all cases of DLBCL of germinal center (GC) subtype 20/35 (57.1%) but is completely negative in non-germinal center (NGC) DLBCL. In normal control of reactive nodes, LMO 2 was expressed in germinal center area but not expressed in other areas including mantle, marginal, or T cell zones. In DLBCL; there was no statistically significant relation between LMO 2 positive cases and the studied clinico pathological parameters including patient's age, sex and tumor site, stage and histological subtype. On the other hand, it was statistically significant regarding immuno phenotyping of GC versus N GC. Conclusions: LMO 2 expression is a special feature of GC DLBCL which can be used as a diagnostic marker and therapeutic target. Further studies regarding its prognostic role in patients are recommended.

  18. Advanced stages of embryonic development and cotylocidial morphogenesis in the intrauterine eggs of Aspidogaster limacoides Diesing, 1835 (Aspidogastrea), with comments on their phylogenetic implications.

    Science.gov (United States)

    Świderski, Zdzisław; Poddubnaya, Larisa G; Gibson, David I; Młocicki, Daniel

    2012-06-01

    Ultrastructural aspects of the advanced embryonic development and cotylocidial morphogenesis of the aspidogastrean Aspidogaster limacoides are described. The posterior or distal regions of the uterus are filled with eggs containing larvae at advanced stages of morphogenesis and fully-formed cotylocidia. Various stages and organs of this larva are described in detail, including the aspects of the developing and fully-differentiated cotylocidium, the body wall (tegument and musculature), glandular regions and the protonephridial excretory system. Blastomere multiplication by means of mitotic divisions takes place simultaneously with the degeneration or apoptosis of some micromeres; this frequently observed characteristic is compared and discussed in relation to corresponding reports for other neodermatans. During the advanced stages of the embryonic development of A. limacoides, the vitelline syncytium disappears and the size of the embryo increases rapidly. Evident polarization of the differentiating larva was observed; towards one pole of the egg, cytodifferentiation of the mouth, surrounded by the oral sucker and cephalic glands, takes place, whereas, towards the opposite pole, differentiation of the posterior sucker (incipient ventral disc) occurs. The oral and posterior suckers are formed from numerous embryonic cells which have differentiated into myocytes. The central part of the oral sucker undergoes invagination and forms the future pharynx and intestine. Fully-developed cotylocidia of A. limacoides have a neodermatan type of tegument, flame cells and two types of glandular structures. These results suggest a sister relationship between the Aspidogastrea and the Digenea, although the systematic position of aspidogastreans in relation to other platyhelminth taxa remains somewhat equivocal.

  19. Plasma CXCL13 but Not B Cell Frequencies in Acute HIV Infection Predicts Emergence of Cross-Neutralizing Antibodies

    Directory of Open Access Journals (Sweden)

    Jenniffer M. Mabuka

    2017-09-01

    Full Text Available Immunological events in acute HIV-1 infection before peak viremia (hyperacute phase may contribute to the development of broadly cross-neutralizing antibodies. Here, we used pre-infection and acute-infection peripheral blood mononuclear cells and plasma samples from 22 women, including 10 who initiated antiretroviral treatment in Fiebig stages I–V of acute infection to study B cell subsets and B-cell associated cytokines (BAFF and CXCL13 kinetics for up to ~90 days post detection of plasma viremia. Frequencies of B cell subsets were defined by flow cytometry while plasma cytokine levels were measured by ELISA. We observed a rapid but transient increase in exhausted tissue-like memory, activated memory, and plasmablast B cells accompanied by decline in resting memory cells in untreated, but not treated women. B cell subset frequencies in untreated women positively correlated with viral loads but did not predict emergence of cross-neutralizing antibodies measured 12 months post detection of plasma viremia. Plasma BAFF and CXCL13 levels increased only in untreated women, but their levels did not correlate with viral loads. Importantly, early CXCL13 but not BAFF levels predicted the later emergence of detectable cross-neutralizing antibodies at 12 months post detection of plasma viremia. Thus, hyperacute HIV-1 infection is associated with B cell subset changes, which do not predict emergence of cross-neutralizing antibodies. However, plasma CXCL13 levels during hyperacute infection predicted the subsequent emergence of cross-neutralizing antibodies, providing a potential biomarker for the evaluation of vaccines designed to elicit cross-neutralizing activity or for natural infection studies to explore mechanisms underlying development of neutralizing antibodies.

  20. Rituximab and chemotherapy in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Sonet, Anne; Bosly, André

    2009-06-01

    Rituximab is an anti-CD20 chimeric monoclonal antibody with activity in nearly all subtypes of B-cell lymphomas. Association of rituximab with chemotherapy (mostly the cyclophosphamide, doxorubicin, vincristine and prednisolone [CHOP] regimen) in diffuse large B-cell lymphoma (DLBCL) represents an extraordinary revolution in the prognosis of DLBCL, and is the new standard of therapy in elderly and young, low-risk patients. Despite the lack of randomized, clinical trials in younger patients with high risk, rituximab is also a standard of care in these patients in clinical practice, at least in North America. The practice is based on observational trials (e.g., the British Columbia Registry) and the missing logic in classifying patients as 'younger' or 'older': 60 years old or 65 years old. In Europe, trials are ongoing to establish the best treatment for young, high-risk patients. Association of rituximab and chemotherapy deeply modifies prognostic factors defined before the rituximab era.

  1. Bisphosphonates target B cells to enhance humoral immune responses

    Science.gov (United States)

    Tonti, Elena; Jiménez de Oya, Nereida; Galliverti, Gabriele; Moseman, E. Ashley; Di Lucia, Pietro; Amabile, Angelo; Sammicheli, Stefano; De Giovanni, Marco; Sironi, Laura; Chevrier, Nicolas; Sitia, Giovanni; Gennari, Luigi; Guidotti, Luca G.; von Andrian, Ulrich H.; Iannacone, Matteo

    2013-01-01

    Summary Bisphosphonates are a class of drugs that are widely used to inhibit loss of bone mass in patients. We show here that the administration of clinically relevant doses of bisphosphonates in mice increases antibody responses to live and inactive viruses, proteins, haptens and existing commercial vaccine formulations. Bisphosphonates exert this adjuvant-like activity in the absence of CD4+ and γδ T cells, neutrophils or dendritic cells and their effect does not rely on local macrophage depletion nor does it depend upon Toll-like receptor signaling or the inflammasome. Rather, bisphosphonates target directly B cells and enhance B cell expansion and antibody production upon antigen encounter. These data establish bisphosphonates as a novel class of adjuvants that boost humoral immune responses. PMID:24120862

  2. Bisphosphonates Target B Cells to Enhance Humoral Immune Responses

    Directory of Open Access Journals (Sweden)

    Elena Tonti

    2013-10-01

    Full Text Available Bisphosphonates are a class of drugs that are widely used to inhibit loss of bone mass in patients. We show here that the administration of clinically relevant doses of bisphosphonates in mice increases antibody responses to live and inactive viruses, proteins, haptens, and existing commercial vaccine formulations. Bisphosphonates exert this adjuvant-like activity in the absence of CD4+ and γδ T cells, neutrophils, or dendritic cells, and their effect does not rely on local macrophage depletion, Toll-like receptor signaling, or the inflammasome. Rather, bisphosphonates target directly B cells and enhance B cell expansion and antibody production upon antigen encounter. These data establish bisphosphonates as an additional class of adjuvants that boost humoral immune responses.

  3. Antibody B cell responses in HIV-1 infection.

    Science.gov (United States)

    Mouquet, Hugo

    2014-11-01

    In rare cases, B cells can supply HIV-1-infected individuals with unconventional antibodies equipped to neutralize the wide diversity of viral variants. Innovations in single-cell cloning, high-throughput sequencing, and structural biology methods have enabled the capture and thorough characterization of these exceptionally potent broadly neutralizing antibodies (bNAbs). Here, I review the recent findings in humoral responses to HIV-1, focusing on the interplay between naturally occurring bNAbs and the virus both at systemic and mucosal levels. In this context, I discuss how an improved understanding of bNAb generation may provide invaluable insight into the fundamental mechanisms governing adaptive B cell responses to viruses, and how this knowledge is currently contributing to the development of vaccine and therapeutic strategies against HIV-1. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Higher numbers of memory B-cells and Th2-cytokine skewing in high responders to hepatitis B vaccination.

    Science.gov (United States)

    Doedée, A M C M; Kannegieter, N; Öztürk, K; van Loveren, H; Janssen, R; Buisman, A M

    2016-04-27

    In the present study, differences in hepatitis B surface antigen (HBsAg)-specific memory B-cell responses between low and high responders to hepatitis B vaccine (HepB), based on levels of antibodies against HBsAg (anti-HBs), were determined. In addition, HBsAg specific T-cell responses between high (anti-HBs level >20,000 IU/L) and low (anti-HBs level cells, plasma immunoglobulin G (Ig) levels, and T-cell cytokine concentrations were measured in low and high responders directly before and one month after the second booster vaccination. In advance, an Enzyme-linked Immunosorbent Spot (ELISpot) Assay was optimized for the determination of HBsAg-specific B-cell responses. The number of HBsAg-specific B-cells was significantly higher (pvaccination with HepB. In addition, the plasma IgG levels and numbers of HBsAg-specific B-cells were significantly correlated (RS=0.66, pcell response showed the same values in the low and high responder group and did not change by the booster vaccination with HepB. However, a significant correlation (RS=0.6975, p=0.007) between the IL-13 levels and the plasma IgG levels post-booster was found. Subsequently, the IL-13 level in the high-responder group post-booster was significantly higher compared to the low-responder group. Since activation of the B-cell response after vaccination is induced by Th2 cells and IL-13 is produced by these cells, we conclude that the difference in HBsAg-specific Th2 cells is involved in determining the differences in anti-HBs level and memory B-cell numbers between low and high responders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Precursor B-Cell Lymphoblastic Lymphoma (PBLL) in Children: Pattern of Presentation and Outcome

    International Nuclear Information System (INIS)

    Belgaumi, A.F.; Al-Kofide, A.; Sabbah, R.; Shalaby, L.

    2005-01-01

    B-cell lymphoblastic lymphoma (PBLL) is a rare subtype of NHL seen primarily in children or young adults. There are approximately 100 immunophenotyped cases of PBLL; reported in the literature; most as single case reports or very small series. In this report, we describe patterns of presentation, and results of a retrospective study looking at patients with PBLL treated at KFSH and RC between 1993 and 2000. Patients and Methods: We present results of a retrospective study looking at patients with PBLL treated at KFSHRC between 1993 and 2000, younger than 14 years of age (cut-off age for pediatric department). Six cases of PBLL were lacking evidence of blood and bone marrow involvement. Histologic sections were available for review in all cases. Twenty one patients were treated for lymphoblastic lymphoma, of which six had a precursor B cell phenotype. There were three boys and the median age at diagnosis was 6 years (range 3-13). In four of the patients the primary involved were oro-nasopharynx or the paranasal sinuses. One patient had a soft tissue mass in the upper thigh while one patient had a solitary bone lesion in the distal tibia. Four of the patients had limited stage disease (2 stage I and stage 11), while 2 were stage IV. Both patients with stage IV disease had CNS involvement with blasts in the CSF. Both had paranasal primaries and had bone infiltration involving the base of the skull, with radiological documentation of intracranial extension in one patient. Median LDH level was 542 lU/L (range 463-5000). Five patients were treated according to B-cell NHL type protocols. Because of the specific diagnosis of PBLL, two of these patients were switched to an ALL-type protocol following post induction intensification; one died in remission due to encephalitis, while the other remained in CR almost 2 years after diagnosis. A third patient suffered a loco-regional relapse 17 months after completing first line therapy, and was re-treated on an ALL-type protocol

  6. Complement-dependent transport of antigen into B cell follicles

    DEFF Research Database (Denmark)

    Gonzalez, Santiago F.; Lukacs-Kornek, Veronika; Kuligowski, Michael P.

    2010-01-01

    an additional novel pathway in which complement C3 and its receptors enhance humoral immunity through delivery of Ag to the B cell compartment. In this review, we discuss this pathway and highlight several novel exceptions recently found with a model influenza vaccine, such as mannose-binding lectin...... opsonization of influenza and uptake by macrophages, and the capture of virus by dendritic cells residing in the medullary compartment of peripheral lymph nodes....

  7. Memory in the B-cell compartment: antibody affinity maturation.

    OpenAIRE

    Neuberger, M S; Ehrenstein, M R; Rada, C; Sale, J; Batista, F D; Williams, G; Milstein, C

    2000-01-01

    In the humoral arm of the immune system, the memory response is not only more quickly elicited and of greater magnitude than the primary response, but it is also different in quality. In the recall response to antigen, the antibodies produced are of higher affinity and of different isotype (typically immunoglobulin G rather than immunoglobulin M). This maturation rests on the antigen dependence of B-cell maturation and is effected by programmed genetic modifications of the immunoglobulin gene...

  8. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.

    Science.gov (United States)

    Schmitz, Roland; Wright, George W; Huang, Da Wei; Johnson, Calvin A; Phelan, James D; Wang, James Q; Roulland, Sandrine; Kasbekar, Monica; Young, Ryan M; Shaffer, Arthur L; Hodson, Daniel J; Xiao, Wenming; Yu, Xin; Yang, Yandan; Zhao, Hong; Xu, Weihong; Liu, Xuelu; Zhou, Bin; Du, Wei; Chan, Wing C; Jaffe, Elaine S; Gascoyne, Randy D; Connors, Joseph M; Campo, Elias; Lopez-Guillermo, Armando; Rosenwald, Andreas; Ott, German; Delabie, Jan; Rimsza, Lisa M; Tay Kuang Wei, Kevin; Zelenetz, Andrew D; Leonard, John P; Bartlett, Nancy L; Tran, Bao; Shetty, Jyoti; Zhao, Yongmei; Soppet, Dan R; Pittaluga, Stefania; Wilson, Wyndham H; Staudt, Louis M

    2018-04-12

    Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88 L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on "chronic active" B-cell receptor signaling that is amenable to therapeutic inhibition. We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).

  9. Bilateral proliferative retinopathy in B-cell acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Devesh Kumawat

    2018-01-01

    Full Text Available A 4-year-old child with B-cell acute lymphoblastic leukemia presented with vitreous hemorrhage due to proliferative retinopathy in both eyes. Pars plana vitrectomy was performed in both eyes to clear nonresolving vitreous hemorrhage after systemic stabilization. Visual recovery was limited by the disc drag in the right eye and subfoveal exudation in the left eye. Etiopathogenesis and management of proliferative retinopathy in acute leukemias are discussed.

  10. Brief cognitive assessment of Alzheimer's disease in advanced stages: Proposal for a Brazilian version of the Short Battery for Severe Impairment (SIB-8

    Directory of Open Access Journals (Sweden)

    José Roberto Wajman

    Full Text Available ABSTRACT The measurement of cognitive abilities of patients with severe dementia can serve a wide range of methodological and clinical needs. Objective: To validate a proposed severe impairment battery SIB-8 for a Brazilian population sample as part of the neuropsychological assessment of patients with Alzheimer's disease (AD in advanced stages. Methods: After a systematic process of translation and back-translation, the SIB-8 was applied to 95 patients with AD at different stages; moderate, moderately severe and severe according to FAST subdivisions (5, 6 and 7, with scores on the Mini-Mental State Examination (MMSE of between 5 and 15 and followed by the Division of Behavioral Neurology and the Center for Aging Brain of the Federal University of São Paulo - UNIFESP. Results: Inferential data revealed that the SIB-8 instrument behaved differently at each stage of the disease with a statistical value of sensitivity p<0.001, gradually reflecting the expected course of the dementia, inherent with the decline of cognitive functions. Conclusion: Findings indicated that the SIB-8 is a useful tool for the evaluation and prospective comparison of AD patients in advanced stages, retaining its original characteristics in our population.

  11. Advances in the staging of renal cell carcinoma with high-resolution imaging; Fortschritte im Staging des Nierenzellkarzinoms mittels hochaufloesender Bildgebung

    Energy Technology Data Exchange (ETDEWEB)

    Hallscheidt, P.; Noeldge, G.; Schawo, S.; Kauffmann, G.; Palmowski, M. [Abt. Radiodiagnostik, Radiologische Klinik, Univ. Heidelberg (Germany); Bartling, S. [Medizinische Physik, DKFZ Heidelberg (Germany); Pfitzenmaier, J. [Urologische Klinik, Univ. Heidelberg (Germany)

    2007-12-15

    Modern imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) allow high-resolution imaging of the abdomen. Modern scanners made high temporal as well as high spatial resolution available. Therapeutic approaches to the treatment of renal cell carcinoma have been improved over the recent years. Besides conventional and open laparoscopic tumor nephrectomy and nephron sparing, surgical approaches such as local tumor cryotherapy and radiofrequency ablation (RF) are ablative modalities and are used increasingly. Improved anesthesiological methods and new surgical approaches also allow curative treatment in extended tumors. Prerequisites for preoperative imaging modalities include visualization of the kidney tumor as well as its staging. Tumor-related infiltration of the renal pelvis or invasion of the perinephric fat and the renal hilus has to be excluded prior to nephron sparing surgery. In cases with extended tumors with infiltration of the inferior vena cava, it is necessary to visualize the exact extension of the tumor growth towards the right atrium in the vena cava. The radiologist should be informed about the diagnostic possibilities and limitations of the imaging modalities of CT and MRI in order to support the urologist in the planning and performance of surgical therapeutical approaches. (orig.)

  12. Altered B cell homeostasis and Toll-like receptor 9-driven response in patients affected by autoimmune polyglandular syndrome Type 1: Altered B cell phenotype and dysregulation of the B cell function in APECED patients.

    Science.gov (United States)

    Perri, Valentina; Gianchecchi, Elena; Scarpa, Riccardo; Valenzise, Mariella; Rosado, Maria Manuela; Giorda, Ezio; Crinò, Antonino; Cappa, Marco; Barollo, Susi; Garelli, Silvia; Betterle, Corrado; Fierabracci, Alessandra

    2017-02-01

    APECED is a T-cell mediated disease with increased frequencies of CD8+ effector and reduction of FoxP3+ T regulatory cells. Antibodies against affected organs and neutralizing to cytokines are found in the peripheral blood. The contribution of B cells to multiorgan autoimmunity in Aire-/- mice was reported opening perspectives on the utility of anti-B cell therapy. We aimed to analyse the B cell phenotype of APECED patients compared to age-matched controls. FACS analysis was conducted on PBMC in basal conditions and following CpG stimulation. Total B and switched memory (SM) B cells were reduced while IgM memory were increased in patients. In those having more than 15 years from the first clinical manifestation the defect included also mature and transitional B cells; total memory B cells were increased, while SM were unaffected. In patients with shorter disease duration, total B cells were unaltered while SM and IgM memory behaved as in the total group. A defective B cell proliferation was detected after 4day-stimulation. In conclusion APECED patients show, in addition to a significant alteration of the B cell phenotype, a dysregulation of the B cell function involving peripheral innate immune mechanisms particularly those with longer disease duration. Copyright © 2016 Elsevier GmbH. All rights reserved.

  13. [Bone marrow involvement in primary mediastinal B-cell lymphoma].

    Science.gov (United States)

    Magomedova, A U; Fastova, E A; Kovrigina, A M; Obukhova, T N; Skidan, N I; Mangasarova, Ya K; Vorobyev, A I; Kravchenko, S K

    Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct type of large B-cell lymphoma. In this type of the disease, the neoplastic process is located in the anterior and superior mediastinum, frequently with compression of the superior vena cava and with tumor invasion into the adjacent organs and tissues: the pericardium, lung, pleura, etc. Despite the fact that in PMBCL progression, there may be involvement of extranodal organs, such as the kidney, adrenal glands, liver, and central nervous system, bone marrow (BM) injury is generally absent. Since BM injury in patients with diffuse large B-cell lymphoma is an independent poor prognostic indicator, there is reason to believe that BM involvement in PMBCL affects the prognosis. These cases may need intensified induction therapy followed by autologous hematopoietic stem cell transplantation; and BM injury should be monitored during the therapy. The paper gives reports of clinical cases of bone marrow involvement in 2 PMBCL patients treated at the National Research Center for Hematology, Ministry of Health of the Russian Federation.

  14. The acquisition of cytokine responsiveness by murine B cells

    DEFF Research Database (Denmark)

    Poudrier, J; Owens, T

    1994-01-01

    The mechanism whereby small resting (high buoyant density) murine B cells are induced to express interleukin-2 receptors (IL-2R) and to respond to IL-2 was addressed by staining with anti-IL-2R alpha and -IL-2R beta monoclonal antibodies (mAb), and using receptor-specific cDNA probes. Resting B...... cells expressed undetectable levels of both IL-2R alpha and beta chains on their surface and did not respond to IL-2, even at supra-physiological concentrations. Sepharose-coupled, but not streptavidin-cross-linked, plastic-adsorbed or soluble, anti-mu up-regulated the expression of IL-2R alpha and beta...... chains and mRNA to levels comparable to those seen in activated T cells. Anti-mu-stimulated B cells responded to IL-2 by incorporation of [3H]thymidine and high rate immunoglobulin (Ig) secretion. Both IL-5 (at optimal concentration) and suboptimal lipopolysaccharide (LPS; 20 ng/ml) induced surface...

  15. Quantitative regulation of B cell division destiny by signal strength.

    Science.gov (United States)

    Turner, Marian L; Hawkins, Edwin D; Hodgkin, Philip D

    2008-07-01

    Differentiation to Ab secreting and isotype-switched effector cells is tightly linked to cell division and therefore the degree of proliferation strongly influences the nature of the immune response. The maximum number of divisions reached, termed the population division destiny, is stochastically distributed in the population and is an important parameter in the quantitative outcome of lymphocyte responses. In this study, we further assessed the variables that regulate B cell division destiny in vitro in response to T cell- and TLR-dependent stimuli. Both the concentration and duration of stimulation were able to regulate the average maximum number of divisions undergone for each stimulus. Notably, a maximum division destiny was reached during provision of repeated saturating stimulation, revealing that an intrinsic limit to proliferation exists even under these conditions. This limit was linked directly to division number rather than time of exposure to stimulation and operated independently of the survival regulation of the cells. These results demonstrate that a B cell population's division destiny is regulable by the stimulatory conditions up to an inherent maximum value. Division destiny is a crucial parameter in regulating the extent of B cell responses and thereby also the nature of the immune response mounted.

  16. Large anaplastic spinal B-cell lymphoma in a cat.

    Science.gov (United States)

    Flatland, Bente; Fry, Michael M; Newman, Shelley J; Moore, Peter F; Smith, Joanne R; Thomas, William B; Casimir, Roslyn H

    2008-12-01

    A 5-year-old female spayed domestic shorthair cat was presented for evaluation of tetraparesis. The neurologic lesion was localized to the cervical spinal segment (C1-C6). A left axillary mass was identified, and the results of fine needle aspiration cytology indicated malignant round cell neoplasia of possible histiocytic origin. The cells were large, had marked anisocytosis and anisokaryosis, occasional bi- and multinucleation, and cytoplasmic vacuolation. Euthanasia was performed due to the poor prognosis associated with severe, progressive neurologic signs and a malignant neoplasm. Postmortem examination revealed spinal cord compression and an extradural mass at the C1-C2 spinal segment, with neoplastic cells in the adjacent vertebral bodies, surrounding skeletal muscle, left axillary lymph node, and bone marrow from the right femur. The initial histologic diagnosis was anaplastic sarcoma, but immunohistochemical results indicated the cells were CD20+ and CD45R+ and CD3-, compatible with a diagnosis of B-cell lymphoma. CD79a staining was nonspecific and uninterpretable. Weak to moderate CD18 positivity and E-cadherin positivity were also observed. Clonality of the B-cell population could not be demonstrated using PCR testing for antigen receptor gene rearrangement. To the authors' knowledge, this is the first reported case of a feline spinal anaplastic B-cell lymphoma exhibiting bi- and multinucleated cells. The prognostic significance of this cell morphology and immunophenotype is unknown.

  17. Lenalidomide in Diffuse Large B-Cell Lymphomas

    Directory of Open Access Journals (Sweden)

    Annalisa Chiappella

    2012-01-01

    Full Text Available Diffuse Large B-cell Lymphomas (DLBCL are the most frequent Non-Hodgkin Lymphomas (NHL. The addition of Rituximab to the standard chemotherapy CHOP improved the outcome in this patients, but so far 40% of patients experienced relapse or progressive disease. Lenalidomide, an immunomodulatory agent, had direct tumoricidal and antiangiogenetic actions on tumor cells and was able to modulate tumor-cell microenvironment, with the restoration of impaired T-cell activity and the formation of immuno-synapsis. Based on these actions, lenalidomide represented an active drug on aggressive relapsed NHL. In this review, the most relevant clinical trials for the use of lenalidomide in DLBCL were reported. Monotherapy with lenalidomide showed an activity in term of overall response rate, with acceptable hematological and extrahematological toxicities in relapsed/refractory aggressive NHL. The role of lenalidomide as salvage therapy in both cell of origin patterns in DLBCL (germinal center B-cell/activated B-cell was reported in preliminary data. Preliminary data regarding the role of lenalidomide in addition to chemoimmunotherapy (R-CHOP in first line clinical trials were discussed; data of safety, feasibility and efficacy were promising.

  18. B cell remote-handled waste shipment cask alternatives study

    International Nuclear Information System (INIS)

    RIDDELLE, J.G.

    1999-01-01

    The decommissioning of the 324 Facility B Cell includes the onsite transport of grouted remote-handled radioactive waste from the 324 Facility to the 200 Areas for disposal. The grouted waste has been transported in the leased ATG Nuclear Services 3-82B Radioactive Waste Shipping Cask (3-82B cask). Because the 3-82B cask is a U.S. Nuclear Regulatory Commission (NRC)-certified Type B shipping cask, the lease cost is high, and the cask operations in the onsite environment may not be optimal. An alternatives study has been performed to develop cost and schedule information on alternative waste transportation systems to assist in determining which system should be used in the future. Five alternatives were identified for evaluation. These included continued lease of the 3-82B cask, fabrication of a new 3-82B cask, development and fabrication of an onsite cask, modification of the existing U.S. Department of Energy-owned cask (OH-142), and the lease of a different commercially available cask. Each alternative was compared to acceptance criteria for use in the B Cell as an initial screening. Only continued leasing of the 3-82B cask, fabrication of a new 3-82B cask, and the development and fabrication of an onsite cask were found to meet all of the B Cell acceptance criteria

  19. CD3-positive B cells: a storage-dependent phenomenon.

    Directory of Open Access Journals (Sweden)

    Angela Nagel

    Full Text Available The majority of clinical studies requires extensive management of human specimen including e.g. overnight shipping of blood samples in order to convey the samples in a central laboratory or to simultaneously analyze large numbers of patients. Storage of blood samples for periods of time before in vitro/ex vivo testing is known to influence the antigen expression on the surface of lymphocytes. In this context, the present results show for the first time that the T cell antigen CD3 can be substantially detected on the surface of human B cells after ex vivo storage and that the degree of this phenomenon critically depends on temperature and duration after blood withdrawal. The appearance of CD3 on the B cell surface seems to be a result of contact-dependent antigen exchange between T and B lymphocytes and is not attributed to endogenous production by B cells. Since cellular subsets are often classified by phenotypic analyses, our results indicate that ex vivo cellular classification in peripheral blood might result in misleading interpretations. Therefore, in order to obtain results reflecting the in vivo situation, it is suggested to minimize times of ex vivo blood storage after isolation of PBMC. Moreover, to enable reproducibility of results between different research groups and multicenter studies, we would emphasize the necessity to specify and standardize the storage conditions, which might be the basis of particular findings.

  20. The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full-length FOXP1 exert similar oncogenic and transcriptional activity in human B cells.

    Science.gov (United States)

    van Keimpema, Martine; Grüneberg, Leonie J; Schilder-Tol, Esther J M; Oud, Monique E C M; Beuling, Esther A; Hensbergen, Paul J; de Jong, Johann; Pals, Steven T; Spaargaren, Marcel

    2017-03-01

    The forkhead transcription factor FOXP1 is generally regarded as an oncogene in activated B cell-like diffuse large B-cell lymphoma. Previous studies have suggested that a small isoform of FOXP1 rather than full-length FOXP1, may possess this oncogenic activity. Corroborating those studies, we herein show that activated B cell-like diffuse large B-cell lymphoma cell lines and primary activated B cell-like diffuse large B-cell lymphoma cells predominantly express a small FOXP1 isoform, and that the 5'-end of the Foxp1 gene is a common insertion site in murine lymphomas in leukemia virus- and transposon-mediated insertional mutagenesis screens. By combined mass spectrometry, (quantative) reverse transcription polymerase chain reaction/sequencing, and small interfering ribonucleic acid-mediated gene silencing, we determined that the small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma lacks the N-terminal 100 amino acids of full-length FOXP1. Aberrant overexpression of this FOXP1 isoform (ΔN100) in primary human B cells revealed its oncogenic capacity; it repressed apoptosis and plasma cell differentiation. However, no difference in potency was found between this small FOXP1 isoform and full-length FOXP1. Furthermore, overexpression of full-length FOXP1 or this small FOXP1 isoform in primary B cells and diffuse large B-cell lymphoma cell lines resulted in similar gene regulation. Taken together, our data indicate that this small FOXP1 isoform and full-length FOXP1 have comparable oncogenic and transcriptional activity in human B cells, suggesting that aberrant expression or overexpression of FOXP1, irrespective of the specific isoform, contributes to lymphomagenesis. These novel insights further enhance the value of FOXP1 for the diagnostics, prognostics, and treatment of diffuse large B-cell lymphoma patients. Copyright© Ferrata Storti Foundation.

  1. Nivolumab With or Without Varlilumab in Treating Patients With Relapsed or Refractory Aggressive B-cell Lymphomas

    Science.gov (United States)

    2018-03-12

    ALK-Positive Large B-Cell Lymphoma; Atypical Burkitt/Burkitt-Like Lymphoma; Burkitt-Like Lymphoma With 11q Aberration; Diffuse Large B-Cell Lymphoma Activated B-Cell Type; Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation; Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type; Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified; EBV-Positive Mucocutaneous Ulcer; High-Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements; Human Herpesvirus 8-Positive Neoplastic Cells Present; Intravascular Large B-Cell Lymphoma; Large B-Cell Lymphoma With IRF4 Rearrangement; Plasmablastic Lymphoma; Primary Cutaneous Diffuse Large B-Cell Lymphoma; Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type; Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System; Primary Effusion Lymphoma; Recurrent B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma; Recurrent Burkitt Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Lymphomatoid Granulomatosis; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Small Intestinal High Grade B-Cell Lymphoma, Not Otherwise Specified; T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

  2. R-ICE and Lenalidomide in Treating Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma

    Science.gov (United States)

    2018-03-27

    CD20 Positive; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

  3. Racial differences in B cell receptor signaling pathway activation.

    Science.gov (United States)

    Longo, Diane M; Louie, Brent; Mathi, Kavita; Pos, Zoltan; Wang, Ena; Hawtin, Rachael E; Marincola, Francesco M; Cesano, Alessandra

    2012-06-06

    Single-cell network profiling (SCNP) is a multi-parametric flow cytometry-based approach that simultaneously measures basal and modulated intracellular signaling activity in multiple cell subpopulations. Previously, SCNP analysis of a broad panel of immune signaling pathways in cell subsets within PBMCs from 60 healthy donors identified a race-associated difference in B cell anti-IgD-induced PI3K pathway activity. The present study extended this analysis to a broader range of signaling pathway components downstream of the B cell receptor (BCR) in European Americans and African Americans using a subset of donors from the previously analyzed cohort of 60 healthy donors. Seven BCR signaling nodes (a node is defined as a paired modulator and intracellular readout) were measured at multiple time points by SCNP in PBMCs from 10 healthy donors [5 African Americans (36-51 yrs), 5 European Americans (36-56 yrs), all males]. Analysis of BCR signaling activity in European American and African American PBMC samples revealed that, compared to the European American donors, B cells from African Americans had lower anti-IgD induced phosphorylation of multiple BCR pathway components, including the membrane proximal proteins Syk and SFK as well as proteins in the PI3K pathway (S6 and Akt), the MAPK pathways (Erk and p38), and the NF-κB pathway (NF-κB). In addition to differences in the magnitude of anti-IgD-induced pathway activation, racial differences in BCR signaling kinetic profiles were observed. Further, the frequency of IgD+ B cells differed by race and strongly correlated with BCR pathway activation. Thus, the race-related difference in BCR pathway activation appears to be attributable at least in part to a race-associated difference in IgD+ B cell frequencies. SCNP analysis enabled the identification of statistically significant race-associated differences in BCR pathway activation within PBMC samples from healthy donors. Understanding race-associated contrasts in immune

  4. Racial differences in B cell receptor signaling pathway activation

    Directory of Open Access Journals (Sweden)

    Longo Diane M

    2012-06-01

    Full Text Available Abstract Background Single-cell network profiling (SCNP is a multi-parametric flow cytometry-based approach that simultaneously measures basal and modulated intracellular signaling activity in multiple cell subpopulations. Previously, SCNP analysis of a broad panel of immune signaling pathways in cell subsets within PBMCs from 60 healthy donors identified a race-associated difference in B cell anti-IgD-induced PI3K pathway activity. Methods The present study extended this analysis to a broader range of signaling pathway components downstream of the B cell receptor (BCR in European Americans and African Americans using a subset of donors from the previously analyzed cohort of 60 healthy donors. Seven BCR signaling nodes (a node is defined as a paired modulator and intracellular readout were measured at multiple time points by SCNP in PBMCs from 10 healthy donors [5 African Americans (36-51 yrs, 5 European Americans (36-56 yrs, all males]. Results Analysis of BCR signaling activity in European American and African American PBMC samples revealed that, compared to the European American donors, B cells from African Americans had lower anti-IgD induced phosphorylation of multiple BCR pathway components, including the membrane proximal proteins Syk and SFK as well as proteins in the PI3K pathway (S6 and Akt, the MAPK pathways (Erk and p38, and the NF-κB pathway (NF-κB. In addition to differences in the magnitude of anti-IgD-induced pathway activation, racial differences in BCR signaling kinetic profiles were observed. Further, the frequency of IgD+ B cells differed by race and strongly correlated with BCR pathway activation. Thus, the race-related difference in BCR pathway activation appears to be attributable at least in part to a race-associated difference in IgD+ B cell frequencies. Conclusions SCNP analysis enabled the identification of statistically significant race-associated differences in BCR pathway activation within PBMC samples from

  5. Once-Weekly, High-Dose Stereotactic Body Radiotherapy for Lung Cancer: 6-Year Analysis of 60 Early-Stage, 42 Locally Advanced, and 7 Metastatic Lung Cancers

    International Nuclear Information System (INIS)

    Salazar, Omar M.; Sandhu, Taljit S.; Lattin, Paul B.; Chang, Jung H.; Lee, Choon K.; Groshko, Gayle A.; Lattin, Cheryl J.

    2008-01-01

    Purpose: To explore once-weekly stereotactic body radiotherapy (SBRT) in nonoperable patients with localized, locally advanced, or metastatic lung cancer. Methods and Materials: A total of 102 primary (89 untreated plus 13 recurrent) and 7 metastatic tumors were studied. The median follow-up was 38 months, the average patient age was 75 years. Of the 109 tumors studied, 60 were Stage I (45 IA and 15 IB), 9 were Stage II, 30 were Stage III, 3 were Stage IV, and 7 were metastases. SBRT only was given in 73% (40 Gy in four fractions to the planning target volume to a total dose of 53 Gy to the isocenter for a biologically effective dose of 120 Gy 10 ). SBRT was given as a boost in 27% (22.5 Gy in three fractions once weekly for a dose of 32 Gy at the isocenter) after 45 Gy in 25 fractions to the primary plus the mediastinum. The total biologically effective dose was 120 Gy 10 . Respiration gating was used in 46%. Results: The overall response rate was 75%; 33% had a complete response. The overall response rate was 89% for Stage IA patients (40% had a complete response). The local control rate was 82%; it was 100% and 93% for Stage IA and IB patients, respectively. The failure rate was 37%, with 17% within the planning target volume. No Grade 3-4 acute toxicities developed in any patient; 12% and 7% of patients developed Grade 1 and 2 toxicities, respectively. Late toxicity, all Grade 2, developed in 3% of patients. The 5-year cause-specific survival rate for Stage I was 70% and was 74% and 64% for Stage IA and IB patients, respectively. The 3-year Stage III cause-specific survival rate was 30%. The patients with metastatic lung cancer had a 57% response rate, a 27% complete response rate, an 86% local control rate, a median survival time of 19 months, and 23% 3-year survival rate. Conclusions: SBRT is noninvasive, convenient, fast, and economically attractive; it achieves results similar to surgery for early or metastatic lung cancer patients who are older

  6. Pre-existing neutralizing antibody mitigates B cell dysregulation and enhances the Env-specific antibody response in SHIV-infected rhesus macaques.

    Directory of Open Access Journals (Sweden)

    Juan Pablo Jaworski

    Full Text Available Our central hypothesis is that protection against HIV infection will be powerfully influenced by the magnitude and quality of the B cell response. Although sterilizing immunity, mediated by pre-formed abundant and potent antibodies is the ultimate goal for B cell-targeted HIV vaccine strategies, scenarios that fall short of this may still confer beneficial defenses against viremia and disease progression. We evaluated the impact of sub-sterilizing pre-existing neutralizing antibody on the B cell response to SHIV infection. Adult male rhesus macaques received passive transfer of a sub-sterilizing amount of polyclonal neutralizing immunoglobulin (Ig purified from previously infected animals (SHIVIG or control Ig prior to intra-rectal challenge with SHIVSF162P4 and extensive longitudinal sampling was performed. SHIVIG treated animals exhibited significantly reduced viral load and increased de novo Env-specific plasma antibody. Dysregulation of the B cell profile was grossly apparent soon after infection in untreated animals; exemplified by a ≈50% decrease in total B cells in the blood evident 2-3 weeks post-infection which was not apparent in SHIVIG treated animals. IgD+CD5+CD21+ B cells phenotypically similar to marginal zone-like B cells were highly sensitive to SHIV infection, becoming significantly decreased as early as 3 days post-infection in control animals, while being maintained in SHIVIG treated animals, and were highly correlated with the induction of Env-specific plasma antibody. These results suggest that B cell dysregulation during the early stages of infection likely contributes to suboptimal Env-specific B cell and antibody responses, and strategies that limit this dysregulation may enhance the host's ability to eliminate HIV.

  7. Bowel perforation from occult ileal involvement after diagnosis in a case of primary mediastinal large B-cell lymphoma.

    Science.gov (United States)

    De Philippis, Chiara; Di Chio, Maria Chiara; Sabattini, Elena; Bolli, Niccolo

    2016-07-14

    Primary mediastinal large B-cell lymphoma (PMBCL) is confined to the mediastinum or contiguous nodal areas in most cases. Extramediastinal and abdominal involvement, especially at diagnosis, is extremely rare. Our case describes the first case of histologically proven ileal involvement of PMBCL at diagnosis that led to ileal perforation. Positron emission tomography CT could increase the sensitivity of staging by detecting unusual sites of disease localisation, and could impact clinical management. 2016 BMJ Publishing Group Ltd.

  8. The Unknown Aspect of BAFF: Inducing IL-35 Production by a CD5+CD1dhiFcγRIIbhiRegulatory B-Cell Subset in Lupus.

    Science.gov (United States)

    Zhang, Yamin; Li, Jun; Zhou, Nuoya; Zhang, Yi; Wu, Min; Xu, Jian; Shen, Chen; An, Xiangjie; Shen, Guanxin; Yang, Ming; Zhang, Chun; Tao, Juan

    2017-12-01

    IL-35 is a critical immunosuppressive cytokine that plays an important role in various autoimmune diseases. The purpose of this study was to determine whether BAFF, a key pathogenic factor in systemic lupus erythematosus, also a dichotomous regulator for B-cell immune responses, has an effect on IL-35-producing regulatory B cells and their underlying mechanisms in lupus. We found that exogenous BAFF could induce IL-35 production by splenic B cells from MRL-Fas lpr/lpr mice. BAFF-induced IL-35-producing B cells were mainly from the marginal zone B-cell subset and exhibited a CD5 + CD1d hi FcγRIIb hi phenotype. These IL-35-producing regulatory B-cell subsets exhibited regulatory effects on both CD4 + CD25 - T cells and CD4 + CD25 + regulatory T cells. We further identified that BAFF-TACI interaction could induce the production of IL-35 through the classical NF-κB1 pathway. In vivo study also showed that BAFF could facilitate IL-35 secretion in marginal zone B cells, whereas anti-BAFF treatment could decrease the frequency of IL-35-producing CD5 + CD1d hi FcγRIIb hi B cells in MRL-Fas lpr/lpr mice. We showed that BAFF could induce IL-35 production by a unique CD5 + CD1d hi FcγRIIb hi regulatory B-cell subset mainly through TACI activation in lupus, providing an advanced understanding of the regulatory effect of BAFF in autoimmune diseases. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Patterns and Timing of Failure for Diffuse Large B-Cell Lymphoma After Initial Therapy in a Cohort Who Underwent Autologous Bone Marrow Transplantation for Relapse

    Energy Technology Data Exchange (ETDEWEB)

    Dhakal, Sughosh; Bates, James E. [Department of Radiation Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York (United States); Casulo, Carla; Friedberg, Jonathan W.; Becker, Michael W.; Liesveld, Jane L. [Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York (United States); Constine, Louis S., E-mail: louis_constine@urmc.rochester.edu [Department of Radiation Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York (United States)

    2016-10-01

    Purpose: To evaluate the location and timing of initial recurrence in patients with diffuse large B-cell lymphoma (DLBCL) who subsequently underwent high-dose chemotherapy with autologous stem cell transplant (HDC/ASCT), to direct approaches for disease surveillance, elucidate the patterns of failure of contemporary treatment strategies, and guide adjuvant treatment decisions. Methods and Materials: We analyzed consecutive patients with DLBCL who underwent HDC/ASCT between May 1992 and March 2014 at our institution. Of the 187 evaluable patients, 8 had incomplete data, and 79 underwent HDC/ASCT as a component of initial treatment for de novo or refractory DLBCL and were excluded from further analysis. Results: The median age was 50.8 years; the median time to relapse was 1.3 years. Patients were segregated according to the initial stage at diagnosis, with early stage (ES) defined as stage I/II and advanced stage (AS) defined as stage III/IV. In total, 40.4% of the ES and 75.5% of the AS patients relapsed in sites of initial disease; 68.4% of those with ES disease and 75.0% of those with AS disease relapsed in sites of initial disease only. Extranodal relapses were common (44.7% in ES and 35.9% in AS) and occurred in a variety of organs, although gastrointestinal tract/liver (n=12) was most frequent. Conclusions: Most patients with DLBCL who relapse and subsequently undergo HDC/ASCT initially recur in the previously involved disease site(s). Time to recurrence is brief, suggesting that frequency of screening is most justifiably greatest in the early posttherapy years. © 2016 Elsevier Inc.

  10. Type i CD20 antibodies recruit the B cell receptor for complement-dependent lysis of malignant B cells

    DEFF Research Database (Denmark)

    Engelberts, P. J.; Voorhorst, M.; Schuurman, J.

    2016-01-01

    . We hypothesized that CD20 Ab-induced clustering of the IgM or IgG BCR was involved in accessory CDC. Indeed, accessory CDC was consistently observed in B cell lines expressing an IgM BCR and in some cell lines expressing an IgG BCR, but it was absent in BCR- B cell lines. A direct relationship...... between BCR expression and accessory CDC was established by transfecting the BCR into CD20+ cells: OFA-F(ab')2 fragments were able to induce CDC in the CD20+BCR+ cell population, but not in the CD20+BCR- population. Importantly, OFA-F(ab')2 fragments were able to induce CDC ex vivo in malignant B cells...... isolated from patients with mantle cell lymphoma and Waldenström macroglobulinemia. In summary, accessory CDC represents a novel effector mechanism that is dependent on type I CD20 Ab-induced BCR clustering. Accessory CDC may contribute to the excellent capacity of type I CD20 Abs to induce CDC...

  11. Characterization of Regulatory B Cells in Graves' Disease and Hashimoto's Thyroiditis

    DEFF Research Database (Denmark)

    Kristensen, Birte; Hegedüs, Laszlo; Lundy, Steven K

    2015-01-01

    A hallmark of regulatory B cells is IL-10 production, hence their designation as IL-10+ B cells. Little is known about the ability of self-antigens to induce IL-10+ B cells in Graves' disease (GD), Hashimoto's thyroiditis (HT), or other autoimmune disease. Here we pulsed purified B cells from 12 HT...... patients, 12 GD patients, and 12 healthy donors with the thyroid self-antigen, thyroglobulin (TG) and added the B cells back to the remaining peripheral blood mononuclear cells (PBMCs). This procedure induced IL-10+ B-cell differentiation in GD. A similar tendency was observed in healthy donors......, but not in cells from patients with HT. In GD, B cells primed with TG induced IL-10-producing CD4+ T cells. To assess the maximal frequency of inducible IL-10+ B cells in the three donor groups PBMCs were stimulated with PMA/ionomycin. The resulting IL-10+ B-cell frequency was similar in the three groups...

  12. Importance of gallium-67 scintigraphy in primary cutaneous B-cell lymphoma: report of two cases;Importancia da cintilografia com galio-67 no linfoma cutaneo primario de celulas B: relato de dois casos

    Energy Technology Data Exchange (ETDEWEB)

    Attab, Cyomara Sanches, E-mail: rubinha.attab@terra.com.b [Centro Brasileiro de Medicina Nuclear (CEBRAMEN), Goiania, GO (Brazil); Moriguchi, Sonia Marta [Fundacao Pio XII, Barretos, SP (Brazil). Hospital de Cancer; Paton, Eduardo Jose Alencar [Fundacao Pio XII, Barretos, SP (Brazil). Cancer Hospital. Div. of Hemotherapy and Bone-Marrow Transplant; Alencar, Mario Henrique Leite de [Clinica de Prevencao em Cancer, Goiania, GO, (Brazil); Rocha, Euclides Timoteo da [Fundacao Pio XII, Barretos, SP (Brazil). Cancer Hospital. Dept. of Nuclear Medicine

    2010-05-15

    The authors describe two cases of cutaneous B-cell lymphoma where correct staging, treatment and follow-up could be achieved through a combination of conventional imaging studies and gallium-67 scintigraphy. (author)

  13. Increasing Rates of No Treatment in Advanced-Stage Non-Small Cell Lung Cancer Patients: A Propensity-Matched Analysis.

    Science.gov (United States)

    David, Elizabeth A; Daly, Megan E; Li, Chin-Shang; Chiu, Chi-Lu; Cooke, David T; Brown, Lisa M; Melnikow, Joy; Kelly, Karen; Canter, Robert J

    2017-03-01

    Variation in treatment and survival outcomes for NSCLC is high among patients with stage III or IV disease, but patients with untreated NSCLC have not been critically analyzed to evaluate for improvable outcomes. We evaluated treatment trends and their association with oncologic outcomes for NSCLC, hypothesizing that there are a substantial number of untreated patients who are similar to patients who undergo treatment. Linear regression was used to calculate trends in utilization of treatment. Kaplan-Meier and Cox regression modeling were used to determine predictors of receiving treatment. Propensity matching was used to compare survival among subsets of treated versus untreated patients. Patients with primary NSCLC were identified from the National Cancer Data base from 1998 to 2012, and 21% of patients (190,539) received no treatment. For stage IIIA and IV, the proportion of untreated patients increased over the study period by 0.21% and 0.4%, respectively (p = 0.003 and p < 0.0001). Regardless of stage, untreated patients had significantly shorter overall survival (OS) (p < 0.0001). Propensity-matched analyses of 6144 stage IIIA patient pairs treated with chemoradiation versus no treatment confirmed shorter OS for untreated patients (median 16.5 versus 6.1 months, p < 0.0001). For 19,046 stage IV patient pairs treated with chemotherapy versus no treatment, similar results were obtained (median OS 9.3 versus 2.0 months, p < 0.0001). The proportion of untreated patients with stage IIIA and IV disease is increasing. Survival outcomes among patients with advanced-stage disease are superior with treatment, independent of selection bias. The benefits and risks of treatment should be carefully assessed before choosing to forego treatment. Published by Elsevier Inc.

  14. Ebf1 and c-Myb repress rag transcription downstream of Stat5 during early B cell development.

    Science.gov (United States)

    Timblin, Greg A; Schlissel, Mark S

    2013-11-01

    The temporal control of RAG (Rag) expression in developing lymphocytes prevents DNA breaks during periods of proliferation that could threaten genomic integrity. In developing B cells, the IL-7R and precursor B cell Ag receptor (pre-BCR) synergize to induce proliferation and the repression of Rag at the protein and mRNA levels for a brief period following successful Ig H chain gene rearrangement. Whereas the mechanism of RAG2 protein downregulation is well defined, little is known about the pathways and transcription factors that mediate transcriptional repression of Rag. Using Abelson murine leukemia virus-transformed B cells to model this stage of development, we identified early B cell factor 1 (Ebf1) as a strong repressor of Rag transcription. Short hairpin RNA-mediated knockdown of either Ebf1 or its downstream target c-Myb was sufficient to induce Rag transcription in these highly proliferative cells. Ebf1 and c-Myb antagonize Rag transcription by negatively regulating the binding of Foxo1 to the Rag locus. Ebf1 accomplishes this through both direct negative regulation of Foxo1 expression and direct positive regulation of Gfi1b expression. Ebf1 expression is driven by the IL-7R downstream effector Stat5, providing a link between the negative regulation of Rag transcription by IL-7 and a novel repressive pathway involving Ebf1 and c-Myb.

  15. Systems Analysis Reveals High Genetic and Antigen-Driven Predetermination of Antibody Repertoires throughout B Cell Development

    Directory of Open Access Journals (Sweden)

    Victor Greiff

    2017-05-01

    Full Text Available Antibody repertoire diversity and plasticity is crucial for broad protective immunity. Repertoires change in size and diversity across multiple B cell developmental stages and in response to antigen exposure. However, we still lack fundamental quantitative understanding of the extent to which repertoire diversity is predetermined. Therefore, we implemented a systems immunology framework for quantifying repertoire predetermination on three distinct levels: (1 B cell development (pre-B cell, naive B cell, plasma cell, (2 antigen exposure (three structurally different proteins, and (3 four antibody repertoire components (V-gene usage, clonal expansion, clonal diversity, repertoire size extracted from antibody repertoire sequencing data (400 million reads. Across all three levels, we detected a dynamic balance of high genetic (e.g., >90% for V-gene usage and clonal expansion in naive B cells and antigen-driven (e.g., 40% for clonal diversity in plasma cells predetermination and stochastic variation. Our study has implications for the prediction and manipulation of humoral immunity.

  16. Early appearance of germinal center–derived memory B cells and plasma cells in blood after primary immunization

    Science.gov (United States)

    Blink, Elizabeth J.; Light, Amanda; Kallies, Axel; Nutt, Stephen L.; Hodgkin, Philip D.; Tarlinton, David M.

    2005-01-01

    Immunization with a T cell–dependent antigen elicits production of specific memory B cells and antibody-secreting cells (ASCs). The kinetic and developmental relationships between these populations and the phenotypic forms they and their precursors may take remain unclear. Therefore, we examined the early stages of a primary immune response, focusing on the appearance of antigen-specific B cells in blood. Within 1 wk, antigen-specific B cells appear in the blood with either a memory phenotype or as immunoglobulin (Ig)G1 ASCs expressing blimp-1. The memory cells have mutated VH genes; respond to the chemokine CXCL13 but not CXCL12, suggesting recirculation to secondary lymphoid organs; uniformly express B220; show limited differentiation potential unless stimulated by antigen; and develop independently of blimp-1 expression. The antigen-specific IgG1 ASCs in blood show affinity maturation paralleling that of bone marrow ASCs, raising the possibility that this compartment is established directly by blood-borne ASCs. We find no evidence for a blimp-1–expressing preplasma memory compartment, suggesting germinal center output is restricted to ASCs and B220+ memory B cells, and this is sufficient to account for the process of affinity maturation. PMID:15710653

  17. Ia-restricted B-B cell interaction. I. The MHC haplotype of bone marrow cells present during B cell ontogeny dictates the self-recognition specificity of B cells in the polyclonal B cell activation by a B cell differentiation factor, B151-TRF2

    International Nuclear Information System (INIS)

    Ono, S.; Takahama, Y.; Hamaoka, T.

    1987-01-01

    We have demonstrated that B cell recognition of Ia molecules is involved in polyclonal B cell differentiation by B151-TRF2. The present study was undertaken to examine the Ia recognition specificity of B151-TRF2-responsive B cells in fully major histocompatibility complex (MHC)-allogeneic P1----P2, semiallogeneic P1----(P1 x P2)F1, and double donor (P1 + P2)----(P1 x P2)F1 and (P1 + P2)----P1 radiation bone marrow chimeras. The B cells from both P1----P2 and P1----(P1 x P2)F1 chimeras could give rise to in vitro immunoglobulin M-producing cells upon stimulation with B151-TRF2 comparable in magnitude to that of normal P1 B cells, and their responses were inhibited by anti-I-AP1 but not by anti-I-AP2 monoclonal antibody even in the presence of mitomycin C-treated T cell-depleted P2 spleen cells as auxiliary cells. In contrast, the B151-TRF2 responses of P1 B cells isolated from both (P1 + P2)----(P1 x P2)F1 and (P1 + P2)----P1 double bone marrow chimeras became sensitive to the inhibition of not only anti-I-AP1 but also anti-I-AP2 monoclonal antibody only when the culture was conducted in the presence of P2 auxiliary cells, demonstrating that they adaptively differentiate to recognize as self-structures allogeneic as well as syngeneic Ia molecules. Moreover, the experiments utilizing B cells from H-2-congenic mice and B cell hybridoma clones as auxiliary cells revealed that B151-TRF2-responsive B cells recognize Ia molecules expressed on B cells. Taken together, these results demonstrate that B151-TRF2-responsive B cells recognize Ia molecules expressed by B cells as self-structures and that their self-recognition specificity is dictated by the MHC haplotype of bone marrow cells present during the B cell ontogeny but not by the MHC haplotype of a radiation-resistant host environment

  18. Baboon envelope pseudotyped lentiviral vectors efficiently transduce human B cells and allow active factor IX B cell secretion in vivo in NOD/SCIDγc-/-mice.

    Science.gov (United States)

    Levy, C; Fusil, F; Amirache, F; Costa, C; Girard-Gagnepain, A; Negre, D; Bernadin, O; Garaulet, G; Rodriguez, A; Nair, N; Vandendriessche, T; Chuah, M; Cosset, F-L; Verhoeyen, E

    2016-12-01

    Essentials B cells are attractive targets for gene therapy and particularly interesting for immunotherapy. A baboon envelope pseudotyped lentiviral vector (BaEV-LV) was tested for B-cell transduction. BaEV-LVs transduced mature and plasma human B cells with very high efficacy. BaEV-LVs allowed secretion of functional factor IX from B cells at therapeutic levels in vivo. Background B cells are attractive targets for gene therapy for diseases associated with B-cell dysfunction and particularly interesting for immunotherapy. Moreover, B cells are potent protein-secreting cells and can be tolerogenic antigen-presenting cells. Objective Evaluation of human B cells for secretion of clotting factors such as factor IX (FIX) as a possible treatment for hemophilia. Methods We tested here for the first time our newly developed baboon envelope (BaEV) pseudotyped lentiviral vectors (LVs) for human (h) B-cell transduction following their adaptive transfer into an NOD/SCIDγc -/- (NSG) mouse. Results Upon B-cell receptor stimulation, BaEV-LVs transduced up to 80% of hB cells, whereas vesicular stomatitis virus G protein VSV-G-LV only reached 5%. Remarkably, BaEVTR-LVs permitted efficient transduction of 20% of resting naive and 40% of resting memory B cells. Importantly, BaEV-LVs reached up to 100% transduction of human plasmocytes ex vivo. Adoptive transfer of BaEV-LV-transduced mature B cells into NOD/SCID/γc -/- (NSG) [non-obese diabetic (NOD), severe combined immuno-deficiency (SCID)] mice allowed differentiation into plasmablasts and plasma B cells, confirming a sustained high-level gene marking in vivo. As proof of principle, we assessed BaEV-LV for transfer of human factor IX (hFIX) into B cells. BaEV-LVs encoding FIX efficiently transduced hB cells and their transfer into NSG mice demonstrated for the first time secretion of functional hFIX from hB cells at therapeutic levels in vivo. Conclusions The BaEV-LVs might represent a valuable tool for therapeutic protein

  19. Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults

    Directory of Open Access Journals (Sweden)

    Lee KJ

    2016-08-01

    Full Text Available Kum Ja Lee,1 Vivian Chow,1 Ashley Weissman,2 Sunil Tulpule,3 Ibrahim Aldoss,4 Mojtaba Akhtari5 1Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, University of Southern California, 2Department of Pharmacy, University of Southern California Norris Cancer Hospital, Los Angeles, CA, 3Department of Medicine, Raritan Bay Medical Center, Perth Amboy, NJ, 4Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, 5Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA Abstract: Adults with relapsed or refractory B-cell acute lymphoblastic leukemia have a dismal prognosis with a short median overall survival that can be measured in months. Because most patients will have chemotherapy-resistant disease, allogeneic hematopoietic stem cell transplantation remains the only potentially curative treatment. Despite advances in current management, patients continue to have poor outcomes and lack of durable responses. Thus, new therapies with alternative modes of actions are currently being investigated. Blinatumomab is a novel bispecific T-cell engager that simultaneously binds CD3-positive cytotoxic T-cells and CD19-positive B-cells, resulting in selective lysis of tumor cells. It has shown promising results in patients with relapsed or refractory acute lymphoblastic leukemia or those achieving hematologic response with persistent minimum residual disease. Future clinical trials will answer questions regarding its optimal place in the treatment paradigm. Dose-limiting toxicities include immunological toxicities and cytokine release syndrome. However, most patients tolerate the therapy relatively well. This review will focus on the pharmacology, clinical efficacy, and safety of blinatumomab in the treatment of adult B-cell acute lymphoblastic leukemia while highlighting its unique drug

  20. Intrinsic Plasma Cell Differentiation Defects in B Cell Expansion with NF-κB and T Cell Anergy Patient B Cells

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    Swadhinya Arjunaraja

    2017-08-01

    Full Text Available B cell Expansion with NF-κB and T cell Anergy (BENTA disease is a novel B cell lymphoproliferative disorder caused by germline, gain-of-function mutations in the lymphocyte scaffolding protein CARD11, which drives constitutive NF-κB signaling. Despite dramatic polyclonal expansion of naive and immature B cells, BENTA patients also present with signs of primary immunodeficiency, including markedly reduced percentages of class-switched/memory B cells and poor humoral responses to certain vaccines. Using purified naive B cells from our BENTA patient cohort, here we show that BENTA B cells exhibit intrinsic defects in B cell differentiation. Despite a profound in vitro survival advantage relative to normal donor B cells, BENTA patient B cells were severely impaired in their ability to differentiate into short-lived IgDloCD38hi plasmablasts or CD138+ long-lived plasma cells in response to various stimuli. These defects corresponded with diminished IgG antibody production and correlated with poor induction of specific genes required for plasma cell commitment. These findings provide important mechanistic clues that help explain both B cell lymphocytosis and humoral immunodeficiency in BENTA disease.

  1. 18F-2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography in Staging of Locally Advanced Breast Cancer

    NARCIS (Netherlands)

    Hoeven, J.J.M. van der; Krak, N.C.; Hoekstra, O.S.; Comans, E.F.I.; Boom, R.P.A.; Geldere, D. van; Meijer, S.; Wall, E. van der; Buter, J.; Pinedo, H.M.; Teule, G.J.J.; Lammertsma, A.A.

    2004-01-01

    PURPOSE To prospectively evaluate the effect of adding whole-body 18F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) to conventional screening for distant metastases in patients with locally advanced breast cancer (LABC). PATIENTS AND METHODS All women with LABC referred for

  2. Platinum based doublet cross over therapy for advanced stage non small cell lung cancer? A better survival option

    Directory of Open Access Journals (Sweden)

    Rajiv Garg

    2012-01-01

    Full Text Available Platinum based doublet chemotherapy namely the cisplatin/carboplatin based etopiside or gemcitabine therapy forms the therapy of choice, for patients with advanced non small cell carcinoma of the lung. Here we report two cases were unusual cross over was done from gemcitabine-to cisplatin-doublet chemotherapy resulting in unexpectedly better clinical and radiological response.

  3. VeriStrat (R) has prognostic value in advanced stage NSCLC patients treated with erlotinib and sorafenib

    NARCIS (Netherlands)

    Kuiper, J. L.; Lind, J. S. W.; Groen, H. J. M.; Roder, J.; Grigorieva, J.; Roder, H.; Dingemans, A. M. C.; Smit, E. F.

    2012-01-01

    BACKGROUND: The serum proteomic test VeriStrat has been shown to be able to classify advanced non-small cell lung cancer (NSCLC) patients for overall survival (OS) after treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In this study, VeriStrat was evaluated

  4. Optimizing Outcomes in Primary Mediastinal B-cell Lymphoma.

    Science.gov (United States)

    Zinzani, Pier Luigi; Broccoli, Alessandro

    2016-12-01

    Primary mediastinal B-cell lymphoma is characterized by a high chance of cure, and cured patients have a long disease-free life-expectancy; however, prognosis is severe in the case of relapsed or refractory disease. The initial use of the most effective chemoimmunotherapy regimen is therefore crucial. Understanding who will benefit from postinduction radiotherapy is also of paramount importance; positron emission tomography may be a reliable guide for physicians in determining which patients will require consolidation. New drugs with mechanisms of action including the most relevant biologic features of the tumor may allow better disease control. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Diffuse Large B-Cell Lymphoma with Calf Muscle Localization

    Directory of Open Access Journals (Sweden)

    Laura Bourdeanu

    2011-01-01

    Full Text Available Although diffuse large B-cell lymphoma (DLBCL usually occurs in the lymph nodes, approximately 30–40% of the time it can have an extranodal site of involvement and it can arise in nearly every body site such as intestine, bone, breast, liver, skin, lung, and central nervous system. Muscle involvement of DLBCL is especially uncommon, comprising 0.5% of extranodal NHL. We report a case of a 72-year-old man with extranodal DLBCL of a unique manifestation in the calf muscle, involving predominantly the gastrocnemius muscle. The patient achieved complete response and remained free of local recurrence or metastasis following diagnosis.

  6. Diffuse large B-cell lymphoma of the oral cavity

    International Nuclear Information System (INIS)

    Carlos Bortoluzzi, Marcelo

    2010-01-01

    The authors report a case of diffuse large B-cell lymphoma (DLBL) of the oral cavity. The patient was a 73-year-old white man who first presented at the Division of Stomatology with a large nodular mass in the hard palate and a nodular lesion in the upper lip, which were diagnosed as DLBL. The patient was treated with eight cycles of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone), but the disease recurred 22 months after the end of the therapy. Both primary sites hard palate and upper lip were involved again and the patient was resubmitted to chemotherapy. (author)

  7. Long-term Survival of Personalized Surgical Treatment of Locally Advanced Non-small Cell Lung Cancer Based on Molecular Staging

    Directory of Open Access Journals (Sweden)

    Qinghua ZHOU

    2011-02-01

    Full Text Available Background and objective Approximately 35%-40% of patients with newly diagnosed non-small cell Lung cancer have locally advanced disease. The average survival time of these patients only have 6-8 months with chemotherapy. The aim of this study is to explore and summarize the probability of detection of micrometastasis in peripheral blood for molecular staging, and for selection of indication of surgical treatment, and beneficiary of neoadjuvant chemotherapy and postoperative adjuvant therapy in locally advanced lung cancer; to summarize the long-time survival result of personalized surgical treatment of 516 patients with locally advanced non-small cell lung cancer based on molecular staging methods. Methods CK19 mRNA expression of peripheral blood samples was detected in 516 lung cancer patients by RT-PCR before operation for molecular diagnosis of micrometastasis, personalized molecular staging, and for selection of indication of surgical treatment and the beneficiary of neoadjuvant chemotherapy and postoperative adjuvant therapy in patients with locally advanced nonsmall cell lung cancer invaded heart, great vessels or both. The long-term survival result of personalized surgical treatment was retrospectively analyzed in 516 patients with locally advanced non-small cell lung cancer based on molecular staging methods. Results There were 322 patients with squamous cell carcinoma and 194 cases with adenocarcinoma in the series of 516 patients with locally advanced lung cancer involved heart, great vessels or both. There were 112 patients with IIIA disease and 404 cases with IIIB disease according to P-TNM staging. There were 97 patients with M-IIIA disease, 278 cases with M-IIIB disease and 141 cases with III disease according to our personalized molecular staging. Of the 516 patients, bronchoplastic procedures and pulmonary artery reconstruction was carried out in 256 cases; lobectomy combined with resection and reconstruction of partial left

  8. CD47 limits antibody dependent phagocytosis against non-malignant B cells.

    Science.gov (United States)

    Gallagher, Sandra; Turman, Sean; Lekstrom, Kristen; Wilson, Susan; Herbst, Ronald; Wang, Yue

    2017-05-01

    Recent studies have demonstrated the importance of CD47 in protecting malignant B cells from antibody dependent cellular phagocytosis (ADCP). Combined treatment of anti-CD47 and -CD20 antibodies synergistically augment elimination of tumor B cells in xenograft mouse models. This has led to the development of novel reagents that can potentially enhance killing of malignant B cells in patients. B cell depleting therapy is also a promising treatment for autoimmune patients. In the current study, we aimed to investigate whether or not CD47 protects non-malignant B cells from ADCP. We show that CD47 is expressed on all B cells in mice, with the highest level on plasma cells in bone marrow and spleen. Although its expression is dispensable for B cell development in mice, CD47 on B cells limits antibody mediated phagocytosis. B cell depletion following in vivo anti-CD19 treatment is more efficient in CD47-/- mice than in wild type mice. In vitro, both naïve and activated B cells from CD47-/- mice are more sensitive to ADCP than wild type B cells. Lastly, we show in an ADCP assay that blocking CD47 can enhance anti-CD19 antibody mediated phagocytosis of wild type B cells. These results suggest that in addition to its already demonstrated benefit in cancer, targeting CD47 may be used as an adjunct in combination with B cell depletion antibodies for treatment of autoimmune diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. An Unusual Case of Marginal Zone B-Cell Lymphoma Arising in the Breast - Its Diagnosis and the Role of Radiotherapy in its Management.

    LENUS (Irish Health Repository)

    Rock, Kathy

    2011-10-01

    BACKGROUND: Primary lymphoma of the breast accounts for 0.04-0.5% of all breast malignancies and approximately 1% of all extranodal lymphomas. For stage IE node-negative disease, involved field radiotherapy is recommended except for very young women in whom the risk of breast cancer is a concern. The rate of complete response for limited stage extranodal marginal B-cell lymphoma is in excess of 90%. CASE REPORT: We report the case of a 62-year-old lady who presented with a unilateral painless palpable right breast lump. She subsequently underwent a trucut biopsy of the lesion. The histology revealed a low-grade B-cell non-Hodgkin\\'s lymphoma (NHL). Immunohistochemistry showed that more than 95% of the cells were B cells which were CD 20+\\/CD 45+ and BC L6+. This confirmed the diagnosis of marginal zone lymphoma. Staging work-up was negative for distant metastases. Serum alkaline phosphatase and lactate dehydrogenase were normal. The patient had no \\'B\\' symptoms. Her final diagnosis was clinical stage IAE NHL, and she was referred for curative radiotherapy. CONCLUSION: Radiation treatment is a safe and extremely effective modality of treatment for early stage I marginal zone B-cell lymphomas of the breast.

  10. Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency

    Directory of Open Access Journals (Sweden)

    Alvaro Muñoz-López

    2016-10-01

    Full Text Available Induced pluripotent stem cells (iPSCs are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming “boosters” also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency.

  11. The Role of mTOR Inhibitors for the Treatment of B-Cell Lymphomas

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    Pinelopi Argyriou

    2012-01-01

    Full Text Available Despite the fact that the majority of lymphomas initially respond to treatment, many patients relapse and die from disease that is refractory to current regimens. The need for new treatment strategies in lymphomas has led to the investigation and evaluation of novel agents that target cellular pathways. The mammalian target of rapamycin (mTOR is a representative pathway that may be implicated in lymphomagenesis. Rapamycin and especially its derivatives (temsirolimus, everolimus, and deforolimus represent the first described mTOR inhibitors. These agents have shown promising results in the treatment of lymphoid malignancies. On the other hand, new ATP-competitive mTOR inhibitors that provoke a broader inhibition of mTOR activity are in early stages of clinical development. The purpose of this paper is to summarize the existing knowledge about mTOR inhibitors and their use in the treatment of B-cell lymphomas. Relevant issues regarding mTOR biology in general as well as in B-cell lymphoid neoplasms are also discussed in short.

  12. Molecular analysis of B-cell differentiation in selective or partial IgA deficiency.

    Science.gov (United States)

    Asano, T; Kaneko, H; Terada, T; Kasahara, Y; Fukao, T; Kasahara, K; Kondo, N

    2004-05-01

    Selective IgA deficiency is the most common form of primary immunodeficiency, the molecular basis of which is unknown. To investigate the cause of selective IgA deficiency, we examined what stage of B-cell differentiation was blocked. DNA and RNA were extracted from three Japanese patients with selective IgA deficiency and three with a partial IgA deficiency. In selective IgA deficiency patients, Ialpha germline transcript expression levels decreased and alpha circle transcripts were not detected. Stimulation with PMA and TGF-beta1 up-regulated Ialpha germline and alpha circle transcripts. In some patients, IgA secretion was induced by stimulation with anti-CD40, IL-4 and IL-10. In partial IgA deficiency patients, Ialpha germline, alpha circle transcripts and Calpha mature transcripts were detected in the absence of stimulation. Our findings suggest that the decreased expression level of Ialpha germline transcripts before a class switch might be critical for the pathogenesis of some patients with selective IgA deficiency. However, in patients with a partial IgA deficiency, B-cell differentiation might be disturbed after a class switch.

  13. MYC expression in concert with BCL2 and BCL6 expression predicts outcome in Chinese patients with diffuse large B-cell lymphoma, not otherwise specified.

    Directory of Open Access Journals (Sweden)

    Li-Xu Yan

    Full Text Available Recent studies provide convincing evidence that a combined immunohistochemical or fluorescence in situ hybridization (FISH score of MYC, BCL2, BCL6 proteins and MYC translocations predicted outcome in diffuse large B-cell lymphoma (DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP. However, by far, all these researches are based on Western populations. Therefore, we investigate the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression by immunohistochemistry and FISH from 336 de novo DLBCL, NOS treated with CHOP or R-CHOP. Breaks in MYC and BCL6, and fusion in IGH/BCL2 were detected in 9.7%, 20.0%, and 11.1% of the cases, respectively, and were not significantly associated with clinical outcomes. Protein overexpression of MYC (≥40%, BCL2 (≥70% and BCL6 (≥50% was encountered in 51%, 51% and 36% of the tumors, respectively. On the basis of MYC, BCL2 and BCL6 expression, double-hit scores (DHSs and triple-hit score (THS were assigned to all patients with DLBCL. Patients with high MYC/BCL2 DHS, high MYC/BCL6 DHS and high THS had multiple adverse prognostic factors including high LDH level, poor performance status, advanced clinical stage, high International Prognostic Index (IPI score, and non-germinal center B-cell. In univariate analysis, high MYC/BCL2 DHS, high MYC/BCL6 DHS and high THS were associated with inferior OS and PFS in both CHOP and R-CHOP cohorts (P0.05. These data together suggest that the immunohistochemical DHSs and THS defined a large subset of DLBCLs with double-hit biology and was strongly associated with poor outcome in patients treated with R-CHOP or CHOP.

  14. Staging PET-CT Scanning Provides Superior Detection of Lymph Nodes and Distant Metastases than Traditional Imaging in Locally Advanced Breast Cancer.

    Science.gov (United States)

    Garg, Pankaj Kumar; Deo, Suryanarayana V S; Kumar, Rakesh; Shukla, Nootan Kumar; Thulkar, Sanjay; Gogia, Ajay; Sharma, Daya Nand; Mathur, Sandeep R

    2016-08-01

    This study was designed to evaluate the role of a single 18-FDG positron emission tomography and computed tomography (PET-CT) scan in comparison to multiple organ-directed conventional investigations (CI) as a staging tool in locally advanced breast cancer (LABC) to detect regional and distant metastasis. All eligible patients were subjected to CI (chest X-ray, abdominal sonography, and bone scintigraphy) followed by a single 18-FDG PET-CT scan. Standard imaging criteria were used for diagnosis of metastasis. Histopathological confirmation was undertaken for suspicious lesions. An exploratory analysis was done to assess the impact of PET-CT on the staging of LABC and how it resulted in a change in management. The study included 79 patients of LABC. PET-CT detected distant metastasis in 36 (45.5 %) patients while CI could identify distant metastasis in 20 (25.3 %) patients. Two of the 36 patients in whom PET-CT detected distant metastasis were false positive. Overall PET-CT upstaged the disease in 38 (48.1 %) patients as compared to CI: stage III to stage IV migration in 14 (17.7 %) patients due to identification of additional sites of distant metastasis, and within stage III upstaging in 24 (30.3 %) patients due to identification of additional regional lymphadenopathy. PET-CT led to a change in management plan in 14 (17.7 %) patients. PET-CT has a role in identifying additional sites of regional lymphadenopathy and distant metastasis to upstage the disease in a significant number of LABC patients in comparison to CI; this would help in accurate staging, selecting optimal treatment, and better prognostication of disease.

  15. Initial Stage Affects Survival Even After Complete Pathologic Remission is Achieved in Locally Advanced Esophageal Cancer: Analysis of 70 Patients With Pathologic Major Response After Preoperative Chemoradiotherapy

    International Nuclear Information System (INIS)

    Kim, Min Kyoung; Cho, Kyung-Ja; Park, Seung-Il; Kim, Yong Hee; Kim, Jong Hoon; Song, Ho-Young; Shin, Ji Hoon; Jung, Hwoon Yong; Lee, Gin Hyug; Choi, Kee Don; Song, Ho June; Ryu, Jin-Sook; Kim, Sung-Bae

    2009-01-01

    Purpose: To analyze outcomes and factors predictive for recurrence and survival in patients with operable esophageal carcinoma who achieved pathologic complete response (PCR) or microscopic residual disease (MRD) after preoperative chemoradiotherapy (CRT). Materials and Methods: Outcomes were assessed in 70 patients with locally advanced esophageal cancer who achieved pathologic major response (53 with PCR and 17 with MRD) after preoperative CRT. Results: At a median follow-up of 38.6 months for surviving patients, 17 of 70 patients (24.3%) experienced disease recurrence and 31 (44.3%) died. Clinical stage (II vs III; p = 0.013) and pathologic response (PCR vs. MRD; p = 0.014) were independent predictors of disease recurrence. Median overall survival (OS) was 99.6 months (95% CI, 44.1-155.1 months) and the 5-year OS rate was 57%. Median recurrence-free survival (RFS) was 71.5 months (95% CI, 39.5-103.6 months) and the 5-year RFS rate was 51.3%. Median OS of patients with Stage II and Stage III disease was 108.8 months and 39.9 months, respectively, and the 5-year OS rates were 68.2% and 27.0%, respectively (p = 0.0003). In a subgroup of patients with PCR, median OS and RFS were also significantly different according to clinical stage. Multivariate analysis showed that clinical stage was an independent predictor of RFS (p = 0.01) and OS (p = 0.008). Conclusions: Even though patients achieved major response after preoperative CRT, pretreatment clinical stage is an important prognostic marker for recurrence and survival. Patients with MRD have an increased recurrence risk but similar survival compared with patients achieved PCR.

  16. Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders.

    Science.gov (United States)

    Chiang, Mark Y; Radojcic, Vedran; Maillard, Ivan

    2016-07-01

    This article highlights recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discusses the therapeutic potential of Notch inhibition. NOTCH mutations arise in a broad spectrum of lymphoid malignancies and are increasingly scrutinized as putative therapeutic targets. In T-cell acute lymphoblastic leukemia (T-ALL), NOTCH1 mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands. Other NOTCH1 mutations in T-ALL and NOTCH1/2 mutations in multiple B-cell malignancies truncate the C-terminal proline (P), glutamic acid (E), serine (S), threonine (T)-rich (PEST) domain, leading to decreased Notch degradation after ligand-mediated activation. Thus, targeting Notch ligand-receptor interactions could provide therapeutic benefits. In addition, we discuss recent reports on clinical testing of Notch inhibitors in T-ALL that influenced contemporary thinking on the challenges of targeting Notch in cancer. We review advances in the laboratory to address these challenges in regards to drug targets, the Notch-driven metabolome, and the sophisticated protein-protein interactions at Notch-dependent superenhancers that underlie oncogenic Notch functions. Notch signaling is a recurrent oncogenic pathway in multiple T- and B-cell lymphoproliferative disorders. Understanding the complexity and consequences of Notch activation is critical to define optimal therapeutic strategies targeting the Notch pathway.

  17. A Case Series of Survival Outcomes in Patients with Advanced-stage IIIb/IV Non-small-cell Lung Cancer Treated with HangAm-Plus.

    Science.gov (United States)

    Bang, Sun-Hwi; Yoon, Jeung-Won; Cho, Chong-Kwan; Shin, Ji-Eun; Lee, Yeon-Weol; Yoo, Hwa-Seung

    2012-06-01

    Non-small-cell lung cancer (NSCLC) represents approximately 80% of all lung cancers. Unfortunately, at their time of diagnosis, most patients have advanced to unresectable disease with a very poor prognosis. The oriental herbal medicine HangAm-Plus(HAP) has been developed for antitumor purposes, and several previous studies have reported its therapeutic effects. In this study, the efficacy of HAP was evaluated as a third-line treatment for advanced-stage IIIb/IV NSCLC. The study involved six patients treated at the East- West Cancer Center (EWCC) from April 2010 to October 2011. Inoperable advanced-stage IIIb/IV NSCLC patients received 3,000 or 6,000 mg of HAP on a daily basis over a 12-week period. Computed tomography (CT) scans were obtained from the patients at the time of the initial administration and after 12 weeks of treatment. We observed and analyzed the patients overall survival (OS) and progression-free survival (PFS). Of the six patients, three expired during the study, and the three remaining patients were alive as of October 31, 2011. The OS ranged from 234 to 512 days, with a median survival of 397 days and a one-year survival rate of 66.7%. In the 12-week-interval chest CT assessment, three patients showed stable disease (SD), and the other three showed progressive disease (PD). The PFS of patients ranged from 88 to 512 days, the median PFS being 96 days. Longer OS and PFS were correlated with SD. Although not directly comparable, the OS and the PFS of this study were greater than those of the docetaxel or the best supportive care group in other studies. HAP may prolong the OS and the PFS of inoperable stage IIIb/IV NSCLC patients without significant adverse effects. In the future, more controlled clinical trials with larger samples from multi-centers should be conducted to evaluate the efficacy and the safety of HAP.

  18. SU-E-J-87: Ventilation Weighting Effect On Mean Doses of Both Side Lungs for Patients with Advanced Stage Lung Cancer

    International Nuclear Information System (INIS)

    Qu, H; Xia, P; Yu, N

    2015-01-01

    Purpose: To study ventilation weighting effect on radiation doses to both side lungs for patients with advanced stage lung cancer. Methods: Fourteen patients with advanced stage lung cancer were included in this retrospective study. Proprietary software was developed to calculate the lung ventilation map based on 4DCT images acquired for radiation therapy. Two phases of inhale (0%) and exhale (50%) were used for the lung ventilation calculations. For each patient, the CT images were resampled to the same dose calculation resolution of 3mmx3mmx3mm. The ventilation distribution was then normalized by the mean value of the ventilation. The ventilation weighted dose was calculated by applying linearly weighted ventilation to the dose of each pixel. The lung contours were automatically delineated from patient CT image with lung window, excluding the tumor and high density tissues. For contralateral and ipsilateral lungs, the mean lung doses from the original plan and ventilation weighted mean lung doses were compared using two tail t-Test. Results: The average of mean dose was 6.1 ±3.8Gy for the contralateral lungs, and 26.2 ± 14.0Gy for the ipsilateral lungs. The average of ventilation weighted dose was 6.3± 3.8Gy for the contralateral lungs and 24.6 ± 13.1Gy for the ipsilateral lungs. The statistics analysis shows the significance of the mean dose increase (p<0.015) for the contralateral lungs and decrease (p<0.005) for the ipsilateral lungs. Conclusion: Ventilation weighted doses were greater than the un-weighted doses for contralateral lungs and smaller for ipsilateral lungs. This Result may be helpful to understand the radiation dosimetric effect on the lung function and provide planning guidance for patients with advance stage lung cancer

  19. Body weight, hemoglobin, and absolute neutrophil count in patients with advanced-stage epithelial ovarian cancer who received chemotherapy: A single-center study

    Science.gov (United States)

    Gunawan, Y.; Winarto, H.

    2017-08-01

    The side effects of chemotherapy, a treatment modality of ovarian cancer, can disrupt overall treatment. To date, the clinical and laboratory profiles of ovarian cancer patients during chemotherapy have not been investigated. This study aimed to elucidate the clinical and laboratory profiles of patients with advanced-stage epithelial ovarian cancer who received chemotherapy in Dr. Cipto Mangunkusumo Hospital, including body mass index (BMI), hemoglobin (Hb), and absolute neutrophil count (ANC). To generate these clinical and laboratory profiles, we collected secondary data from the medical records of advanced-stage epithelial ovarian cancer patients who received six cycles of carboplatin and paclitaxel chemotherapy. We enrolled 23 patients with advanced-stage epithelial ovarian cancer patients who received six cycles of chemotherapy. Mean patient BMI before and after chemotherapy was 22.86 kg/m2 and 21.78 kg/m2, respectively. Hb levels before chemotherapy were 8-13 g/dl, with Hb Hb ≥ 10 g/dl in 22 patients (95.65%). Mean ANC was 5845.6 ± 3325.0. An average of 24.65% of patients experienced anemia after each cycle of chemotherapy. Mean ANC before chemotherapy was 3.5582 ± 3.3250. An average of 26.81% of patients had ANC Hb ≥ 10 g/dl before chemotherapy, 16 (72.72%) experienced a decrease in ANC during chemotherapy. Of the 20 patients (60.87%) with normal BMI or higher, 14 experienced a decrease in ANC during chemotherapy. The mean patient body weight decreased after six cycles of chemotherapy. Hb and ANC were persistently decreased in approximately a quarter of the 23 subjects. The decrease in ANC was not influenced by initial Hb and BMI.

  20. Advanced air staging techniques to improve fuel flexibility, reliability and emissions in fluidized bed co-combustion

    Energy Technology Data Exchange (ETDEWEB)

    Aamand, Lars-Erik; Leckner, Bo [Chalmers Technical Univ., Goeteborg (Sweden); Luecke, Karsten; Werther, Joachim [Technical Univ. of Hamburg-Harburg (Germany)

    2001-12-01

    A joint research project between the Technical University of Hamburg-Harburg and Chalmers Technical University. For operation under co-combustion the following results should be considered: The high ash content of the sewage sludge results in significantly increased ash flows. Although high alkali metal concentrations are found in the sewage sludge ash, no critical concentrations were reached and tendencies to fouling were not observed. The trace metal input rises with increased sludge fraction. However, emissions of metal compounds were well below legal limits. The trace metals tend to accumulate on the fly ash. In general, very low fuel nitrogen conversions to NO and N{sub 2}O of 2 - 4 % are achievable. With coal as a base fuel alternative air staging with secondary air supply after solids separation attains even lower NO emissions than normal staging without strongly affecting CO and SO{sub 2} emissions. Alternative staging also reduces N{sub 2}O emissions. An optimum for the excess air ratio in the riser of 1.05 was found for a total excess air ratio of 1.2. The higher the volatile content of the fuel is, the less effective the NO reduction due to air staging becomes. The measurements suggest that the optimum gas residence time regarding the emissions in CFB combustors is around 6 to 7 s. These times are achieved in commercial scale plants due to their large cyclones that perhaps partly can replace a large afterburner chamber. The circulating fluidized bed boiler can be operated in a very flexible way with various fuel mixtures up to an energy fraction of sludge of 25% without exceeding legal emission limits.

  1. EBV-positive diffuse large B-cell lymphoma in young adults: is this a distinct disease entity?

    Science.gov (United States)

    Hong, J Y; Yoon, D H; Suh, C; Huh, J; Do, I-G; Sohn, I; Jo, J; Jung, S-H; Hong, M E; Yoon, H; Ko, Y H; Kim, S J; Kim, W S

    2015-03-01

    Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined only in adults older than 50 years. However, EBV-positive DLBCL can affect younger patients. We investigated the prevalence, clinical characteristics and survival outcomes of EBV-positive DLBCL in young adults. We analyzed patients with de novo DLBCL who were registered in the Samsung Medical Center (SMC) retrospective lymphoma cohort and prospective SMC Lymphoma Cohort Study I (ClinicalTrials.gov: NCT00822731). A total of 571 cases were included in the analysis. The prevalence of EBV positivity was 6.7% (13/195) and 9.3% (35/376) in the young group (≤50 years) and in the elderly group (>50 years), respectively. EBV status was closely associated with unique unfavorable clinical characteristics [older age, more advanced stage, two or more sites of extranodal involvement, higher International Prognostic Index (IPI), and age-adjusted IPI risk] only in the elderly group. Poor prognostic impact of EBV positivity on overall survival was observed only in the elderly group [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.83-4.47; P young group (HR 1.17; 95% CI 0.35-3.89; P = 0.801). A substantial proportion of EBV-positive DLBCL of the elderly can occur in young adults. EBV positivity of DLBCL in young adults was not associated with unfavorable clinical characteristics or worse outcomes. We suggest that EBV-positive DLBCL should not be confined only in the elderly and 'EBV-positive DLBCL in young adults' needs to be considered as a clinically distinct disease entity. ClinicalTrials.gov: NCT02060435. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  2. The impact of trisomy 12, retinoblastoma gene and P53 in prognosis of B-cell chronic lymphocytic leukemia.

    Science.gov (United States)

    AbdelSalam, M; El Sissy, A; Samra, M A; Ibrahim, S; El Markaby, D; Gadallah, F

    2008-06-01

    Routine cytogenetic analysis frequently fails to identify an abnormal clone in B-cell lymphocytic leukaemia (B-CLL) due to poor response to mitogen stimulation. Fluorescence in situ hybridization (FISH) suggest that chromosomal abnormalities occur more frequently, most commonly trisomy 12, retinoblastoma gene deletion (Rb1 gene) and P53 gene deletion. 30 patients with B-CLL were enrolled in the trial from two centers in Cairo, Egypt during the period May 2000 to January 2002. Karyotyping and FISH assessment for possible chromosomal abnormalities (trisomy 12, Rb1 gene and P53 gene) were done at initial diagnosis. Results of cytogenetic abnormalities were correlated with clinical picture and survival. The median age was 57.4 years (range 40-75). Karyotyping technique showed that no metaphase could be detected in 30%, metaphase with normal karyotyping was observed in 63% and cytogenetic abnormalities were detected in two cases (one trisomy 12 and one deletion in chromosome 13). FISH examination of interphase and metaphase nuclei revealed cytogenetic abnormalities in 15 cases (50%), trisomy 12 in 9 (30%), Rb1 gene deletion in 5 (17%) and P53 gene deletion in 3. At diagnosis, patients with trisomy 12 were significantly associated with advanced stage and absolute lymphocyte count of >or=30,000/mm(3). Univariate analysis showed that absolute lymphocyte count >or=30,000/mm(3) (p=0.004) and trisomy 12 (p=0.024) were associated with poor progression free survival. Interphase and metaphase FISH studies improve the cytogenetic diagnosis of chromosomal abnormalities in B-CLL. Lymphocytosis and trisomy 12 may be a good indicator of poor prognosis.

  3. YOUNGER AGE AT PRESENTATION IN CHILDREN WITH COATS DISEASE IS ASSOCIATED WITH MORE ADVANCED STAGE AND WORSE VISUAL PROGNOSIS: A Retrospective Study.

    Science.gov (United States)

    Daruich, Alejandra; Matet, Alexandre; Munier, Francis L

    2017-10-23

    To determine the age distribution of children with Coats disease and the impact of age at diagnosis on the visual prognosis. Consecutive Coats disease cases aged 18 years or younger at diagnosis were retrospectively included. Clinical and imaging parameters were analyzed by comparative, correlation, survival, univariate, and multivariate statistics. Ninety-eight patients were included. At diagnosis, mean age was 5.4 years ± 4.3 years (1 month-18 years). Younger age at diagnosis was correlated with more severe disease stage (P presentation in patients younger than 4 years (P presentation in younger than older patients (P = 0.0003 and P = 0.039). Foveal sparing at diagnosis was less frequent in younger than older patients (2% vs. 23%, P = 0.002). The incidence of structural complications or enucleation during follow-up (mean duration: 5.9 years ± 4.5 years) was higher, and last-recorded visual acuity was lower in younger than older patients (P = 0.001 and P = 0.0009). Final logarithm of the minimal angle of resolution visual acuity was negatively correlated with age at diagnosis (P = 0.001, Spearman r = -0.42). Multivariate analysis indicated that disease stage (P visual acuity. Onset of Coats disease in children of younger age is associated with more severe manifestations, more advanced stage, and worse visual outcome. Age, correlated with disease stage, should be considered a prognostic marker in Coats disease.

  4. Quantitative Analysis of Repertoire-Scale Immunoglobulin Properties in Vaccine-Induced B-Cell Responses

    Directory of Open Access Journals (Sweden)

    Ilja V. Khavrutskii

    2017-08-01

    Full Text Available Recent advances in the next-generation sequencing of B-cell receptors (BCRs enable the characterization of humoral responses at a repertoire-wide scale and provide the capability for identifying unique features of immune repertoires in response to disease, vaccination, or infection. Immunosequencing now readily generates 103–105 sequences per sample; however, statistical analysis of these repertoires is challenging because of the high genetic diversity of BCRs and the elaborate clonal relationships among them. To date, most immunosequencing analyses have focused on reporting qualitative trends in immunoglobulin (Ig properties, such as usage or somatic hypermutation (SHM percentage of the Ig heavy chain variable (IGHV gene segment family, and on reducing complex Ig property distributions to simple summary statistics. However, because Ig properties are typically not normally distributed, any approach that fails to assess the distribution as a whole may be inadequate in (1 properly assessing the statistical significance of repertoire differences, (2 identifying how two repertoires differ, and (3 determining appropriate confidence intervals for assessing the size of the differences and their potential biological relevance. To address these issues, we have developed a technique that uses Wilcox’ robust statistics toolbox to identify statistically significant vaccine-specific differences between Ig repertoire properties. The advantage of this technique is that it can determine not only whether but also where the distributions differ, even when the Ig repertoire properties are non-normally distributed. We used this technique to characterize murine germinal center (GC B-cell repertoires in response to a complex Ebola virus-like particle (eVLP vaccine candidate with known protective efficacy. The eVLP-mediated GC B-cell responses were highly diverse, consisting of thousands of clonotypes. Despite this staggering diversity, we identified statistically

  5. Quantitative Analysis of Repertoire-Scale Immunoglobulin Properties in Vaccine-Induced B-Cell Responses.

    Science.gov (United States)

    Khavrutskii, Ilja V; Chaudhury, Sidhartha; Stronsky, Sabrina M; Lee, Donald W; Benko, Jacqueline G; Wallqvist, Anders; Bavari, Sina; Cooper, Christopher L

    2017-01-01

    Recent advances in the next-generation sequencing of B-cell receptors (BCRs) enable the characterization of humoral responses at a repertoire-wide scale and provide the capability for identifying unique features of immune repertoires in response to disease, vaccination, or infection. Immunosequencing now readily generates 10 3 -10 5 sequences per sample; however, statistical analysis of these repertoires is challenging because of the high genetic diversity of BCRs and the elaborate clonal relationships among them. To date, most immunosequencing analyses have focused on reporting qualitative trends in immunoglobulin (Ig) properties, such as usage or somatic hypermutation (SHM) percentage of the Ig heavy chain variable (IGHV) gene segment family, and on reducing complex Ig property distributions to simple summary statistics. However, because Ig properties are typically not normally distributed, any approach that fails to assess the distribution as a whole may be inadequate in (1) properly assessing the statistical significance of repertoire differences, (2) identifying how two repertoires differ, and (3) determining appropriate confidence intervals for assessing the size of the differences and their potential biological relevance. To address these issues, we have developed a technique that uses Wilcox' robust statistics toolbox to identify statistically significant vaccine-specific differences between Ig repertoire properties. The advantage of this technique is that it can determine not only whether but also where the distributions differ, even when the Ig repertoire properties are non-normally distributed. We used this technique to characterize murine germinal center (GC) B-cell repertoires in response to a complex Ebola virus-like particle (eVLP) vaccine candidate with known protective efficacy. The eVLP-mediated GC B-cell responses were highly diverse, consisting of thousands of clonotypes. Despite this staggering diversity, we identified statistically significant

  6. [A case of advanced gastric cancer diagnosed as stage IV responding to combined modality therapy and surviving for a long duration].

    Science.gov (United States)

    Shimada, Masanari; Murakami, Nozomu; Tanada, Yasuko; Endo, Naoki; Kadoya, Shinichi; Yamada, Tetsuji; Kurumatani, Hiroshi; Doyama, Hisashi

    2013-05-01

    A 47-year-old woman was diagnosed as advanced gastric cancer of cardia(poorly-differentiated adenocarcionoma), with multiple para-aortic lymph node and liver metastasis, in March, 2005. We attempted neo-adjuvant chemotherapy with docetaxel(DOC), cisplatin(CDDP), and S-1(DCS). After 3 courses of DCS, we confirmed that the para-aortic lymph nodes and liver metastasis became small. Then, we were able to perform total gastrectomy, splenectomy, and D2 lymph node dissection. Additionally, we performed an intraoperative radiofrequency ablation to the scar of the liver metastasis. Histopathologically, we identified lymph node metastases in #1 and #16b1 pre. S-1 and DOC were administered as adjuvant chemotherapy. At seven years since the operation, the patient has shown no signs of recurrence. Combined modality therapy for advanced gastric cancer diagnosed with stage IV can be an effective treatment, so we hope that it will be established as a standard therapy.

  7. Advances in Continuous Flow Left Ventricular Assist Device Support for End-Stage Heart Failure: A Therapy in Evolution.

    Science.gov (United States)

    Saeed, Omar; Jorde, Ulrich P

    The purpose of this review is to highlight recent advances and challenges in the clinical implementation of continuous flow left ventricular assist devices (CF LVADs) in patients with advanced heart failure. Post approval studies of CF LVAD therapy continue to show a progressive improvement in survival and reduction in adverse events. Major trials are ongoing to compare outcomes of an axial flow device (Heart Mate II) and smaller centrifugal flow pumps (HeartWare VADs and Heart Mate III). Numerous studies have investigated strategies to reduce major hematologic and neurologic adverse events by evaluating hemolysis, antithrombotic therapy, and blood pressure control. This review will present the current findings that are centered around the impact of CF LVADs on improving survival and reducing adverse events through an evolution in management and design.

  8. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. | Office of Cancer Genomics

    Science.gov (United States)

    A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers.

  9. Evaluation correlates C-reactive protein with advanced stage Hodgkin's lymphoma and response to treatment in a tertiary university hospital in Brazil

    Directory of Open Access Journals (Sweden)

    Talita Máira Bueno da Silveira da Rocha

    2015-08-01

    Full Text Available OBJECTIVE: To demonstrate a correlation of C-reactive protein levels with disease stage and response to treatment in Hodgkin's lymphoma patients of the Hematology Service of Santa Casa de São Paulo.METHODS: A retrospective study based on review of medical records was carried out of 38 patients diagnosed with Hodgkin's lymphoma between October 2010 and December 2012. Three patients met the exclusion criteria, giving a final sample of 35 patients for analysis. C-reactive protein levels >1 mg/dL were considered positive.RESULTS: Among the patients analyzed, median age was 29 years, 65% were male and 85% had the classical nodular sclerosis subtype. Twenty-nine (82% were in the advanced stage and 28% had bulky mass at diagnosis. Seventeen percent had bone marrow invasion by lymphoma. Baseline C-reactive protein levels were associated with both stage (p-value = 0.0035 and presence or absence of B symptoms (p-value = 0.008. The highest C-reactive protein levels were detected in patients with advanced disease while no patients with localized disease had C-reactive protein >5 mg/dL (p-value = 0.02. After the first treatment cycle, C-reactive protein fell to near-normal levels and no direct association with response pattern was found. As the mean follow-up was only 14 months, it was not possible to determine whether relapse was accompanied by a further increase in C-reactive protein.CONCLUSION: Baseline C-reactive protein levels directly correlated with stage and presence or absence of B symptoms, but the degree of improvement with treatment did not correlate with response pattern. After a longer follow-up, it may be possible to assess whether relapse correlates with a further increase in C-reactive protein levels.

  10. Impairment of Mature B Cell Maintenance upon Combined Deletion of the Alternative NF-κB Transcription Factors RELB and NF-κB2 in B Cells.

    Science.gov (United States)

    De Silva, Nilushi S; Silva, Kathryn; Anderson, Michael M; Bhagat, Govind; Klein, Ulf

    2016-03-15

    BAFF is critical for the survival and maturation of mature B cells. BAFF, via BAFFR, activates multiple signaling pathways in B cells, including the alternative NF-κB pathway. The transcription factors RELB and NF-κB2 (p100/p52) are the downstream mediators of the alternative pathway; however, the B cell-intrinsic functions of these NF-κB subunits have not been studied in vivo using conditional alleles, either individually or in combination. We in this study report that B cell-specific deletion of relb led to only a slight decrease in the fraction of mature splenic B cells, whereas deletion of nfkb2 caused a marked reduction. This phenotype was further exacerbated upon combined deletion of relb and nfkb2 and most dramatically affected the maintenance of marginal zone B cells. BAFF stimulation, in contrast to CD40 activation, was unable to rescue relb/nfkb2-deleted B cells in vitro. RNA-sequencing analysis of BAFF-stimulated nfkb2-deleted versus normal B cells suggests that the alternative NF-κB pathway, in addition to its critical role in BAFF-mediated cell survival, may control the expression of genes involved in the positioning of B cells within the lymphoid microenvironment and in the establishment of T cell-B cell interactions. Thus, by ablating the downstream transcription factors of the alternative NF-κB pathway specifically in B cells, we identify in this study a critical role for the combined activity of the RELB and NF-κB2 subunits in B cell homeostasis that cannot be compensated for by the canonical NF-κB pathway under physiological conditions. Copyright © 2016 by The American Association of Immunologists, Inc.

  11. Quantitation of multiple myeloma oncogene 1/interferon-regulatory factor 4 gene expression in malignant B-cell proliferations and normal leukocytes.

    Science.gov (United States)

    Yamada, M; Asanuma, K; Kobayashi, D; Moriai, R; Yajima, T; Yagihashi, A; Yamamori, S; Watanabe, N

    2001-01-01

    We studied multiple myeloma oncogene 1/interferon-regulatory factor 4 (MUM1/IRF4) mRNA expression in various malignant human hematopoietic cell lines and normal leukocyte fractions. A quantitative reverse transcription-polymerase chain reaction was used to assess expression and chromosomes were examined for anomalies by fluorescent in situ hybridization. Among 12 cell lines examined, mRNA transcripts were expressed only in B-lymphoblastic and myeloma cell lines. Myeloma cells and malignant cell lines derived from mature B cells expressed more transcript than cell lines derived from immature B cells. Transcript levels, however, showed no association with chromosomal translocations. Expression in B-cell fractions from healthy donors was much less than in the malignant cells. In addition, MUM1/IRF4 mRNA expressed in samples from patients with acute lymphoblastic leukemia derived from B cells but not T cells. Our results suggested that MUM1/IRF4 gene expression is related to stage of differentiation of malignant B cells and they indicated the possibility that the quantitative analysis of MUM1/IRF4 gene is a useful tool for detection of malignant B-cell proliferations in clinical laboratory tests.

  12. Dietary phosphorus restriction by a standard low-protein diet decreased serum fibroblast growth factor 23 levels in patients with early and advanced stage chronic kidney disease.

    Science.gov (United States)

    Goto, Shunsuke; Nakai, Kentaro; Kono, Keiji; Yonekura, Yuriko; Ito, Jun; Fujii, Hideki; Nishi, Shinichi

    2014-12-01

    Elevated serum fibroblast growth factor 23 (FGF23) levels are associated with mortality, cardiovascular disease, and disease progression in patients with chronic kidney disease (CKD). Although recent studies demonstrated that FGF23 levels decreased in response to dietary restriction of phosphorus and/or use of phosphate binders, research on the effects of a standard low-protein diet is lacking. The effects of a standard low-protein diet on serum FGF23, intact parathyroid hormone, and 1,25-dihydroxyvitamin D levels were investigated in patients with early (n = 15) and advanced (n = 20) CKD. Serum FGF23 levels decreased in both groups. Changes in FGF23 levels correlated with changes in 24 h urinary phosphorus excretion in the advanced CKD group. Decreased serum intact parathyroid hormone levels were observed only in the advanced CKD group and increased serum 1,25-dihydroxyvitamin D levels only in the early CKD group. These findings suggest that consuming standard low-protein diet decreased serum FGF23 levels in patients with CKD. Serum FGF23 levels may therefore be a useful marker to monitor the effects of a low-protein diet in early and advanced stage CKD.

  13. Interleukin-35 induces regulatory B cells that suppress autoimmune disease.

    Science.gov (United States)

    Wang, Ren-Xi; Yu, Cheng-Rong; Dambuza, Ivy M; Mahdi, Rashid M; Dolinska, Monika B; Sergeev, Yuri V; Wingfield, Paul T; Kim, Sung-Hye; Egwuagu, Charles E

    2014-06-01

    Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.

  14. Engaging the lysosomal compartment to combat B cell malignancies

    DEFF Research Database (Denmark)

    Gronbaek, K.; Jaattela, M.

    2009-01-01

    The combination of rituximab, a type I anti-CD20 mAb, with conventional chemotherapy has significantly improved the outcome of patients with B cell malignancies. Regardless of this success, many patients still relapse with therapy-resistant disease, highlighting the need for the development of mAbs...... with higher capacity to induce programmed cell death. The so-called type II anti-CD20 mAbs (e.g., tositumomab) that trigger caspase-independent B cell lymphoma cell death in vitro and show superior efficacy as compared with rituximab in eradicating target cells in mouse models are emerging as the next...... generation of therapeutic anti-CD20 mAbs. In this issue of the JCI, Ivanov and colleagues identify the lysosomal compartment as a target for type II mAbs (see the related article beginning on page 2143). These data encourage the further clinical development of type II mAbs as well as other lysosome...

  15. Primary intravascular large B-cell lymphoma of pituitary

    Directory of Open Access Journals (Sweden)

    K R Anila

    2012-01-01

    Full Text Available A 68-year-old retired nurse, who was a known hypertensive on medication, presented with prolonged fever of 2-month duration without any clinical evidence of infection. On examination she had altered mental status. She also had other nonspecific complaints such as sleep disturbances, loss of weight, etc. On investigation, she was found to have anemia, thrombocytopenia, raised erythrocyte sedimentation rate (ESR, C-reactive protein (CRP, and lactate dehydrogenase (LDH values. She also had electrolyte imbalance. Radiological evaluation of brain showed mass lesion in the sella turcica, suggestive of pituitary adenoma. Biochemical evaluation showed hypopituitarism. Trans-sphenoidal biopsy was done. Based on histopathological and immunohistochemical findings a diagnosis of intravascular large B-cell lymphoma (IVLBCL of pituitary was made. Our patient′s condition deteriorated rapidly and she succumbed to her illness before therapy could be initiated. We are reporting this case because of the rare subtype of large B-cell lymphoma presenting at an extremely unusual primary site.

  16. Modulation of B-cell receptor and microenvironment signaling by a guanine exchange factor in B-cell malignancies

    International Nuclear Information System (INIS)

    Liao, Wei; Sharma, Sanjai

    2016-01-01

    Objective: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cells over-express a guanine exchange factor (GEF), Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B-cell malignancies. Methods: N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor (BCR) and chemokine signaling pathways were compared in the Rasgrf-1 over-expressing and a control transfected cell line. Results: Cells over-expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation. Conclusions: This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells

  17. B cells expressing IL-10 mRNA modulate memory T cells after DNA-Hsp65 immunization.

    Science.gov (United States)

    Fontoura, I C; Trombone, A P F; Almeida, L P; Lorenzi, J C C; Rossetti, R A M; Malardo, T; Padilha, E; Schluchting, W; Silva, R L L; Gembre, A F; Fiuza, J E C; Silva, C L; Panunto-Castelo, A; Coelho-Castelo, A A M

    2015-12-01

    In DNA vaccines, the gene of interest is cloned into a bacterial plasmid that is engineered to induce protein production for long periods in eukaryotic cells. Previous research has shown that the intramuscular immunization of BALB/c mice with a naked plasmid DNA fragment encoding the Mycobacterium leprae 65-kDa heat-shock protein (pcDNA3-Hsp65) induces protection against M. tuberculosis challenge. A key stage in the protective immune response after immunization is the generation of memory T cells. Previously, we have shown that B cells capture plasmid DNA-Hsp65 and thereby modulate the formation of CD8+ memory T cells after M. tuberculosis challenge in mice. Therefore, clarifying how B cells act as part of the protective immune response after DNA immunization is important for the development of more-effective vaccines. The aim of this study was to investigate the mechanisms by which B cells modulate memory T cells after DNA-Hsp65 immunization. C57BL/6 and BKO mice were injected three times, at 15-day intervals, with 100 µg naked pcDNA-Hsp65 per mouse. Thirty days after immunization, the percentages of effector memory T (TEM) cells (CD4+ and CD8+/CD44high/CD62Llow) and memory CD8+ T cells (CD8+/CD44high/CD62Llow/CD127+) were measured with flow cytometry. Interferon γ, interleukin 12 (IL-12), and IL-10 mRNAs were also quantified in whole spleen cells and purified B cells (CD43-) with real-time qPCR. Our data suggest that a B-cell subpopulation expressing IL-10 downregulated proinflammatory cytokine expression in the spleen, increasing the survival of CD4+ TEM cells and CD8+ TEM/CD127+ cells.

  18. Polyclonal B-cell lymphocytosis with binucleated lymphocytes (PPBL

    Directory of Open Access Journals (Sweden)

    Xavier Troussard

    2008-10-01

    Full Text Available Xavier Troussard1, Edouard Cornet1, Jean-François Lesesve2, Carine Kourel3, Hossein Mossafa31Laboratoire d’Hématologie Côte de Nacre, Université Caen Basse Normandie Caen, Registre Régional des Hémopathies Malignes de Basse Normandie, France; 2Laboratoire d’Hématologie, Vandoeuvre-Les-Nancy Cedex, France; 3Département de Génétique Humaine, Laboratoire pasteur-Cerba, Cergy-Pontoise, FranceFor the Groupe Français d’Hématologie cellulaire (GFHCAbstract: Persistent polyclonal B-cell lymphocytosis (PPBL is a rare and recently described entity. The review of the literature show PPBL is diagnosed predominantly but not exclusively in women, usually smokers. PPBL is recognized by a moderate, chronic and absolute lymphocytosis (>4 × 109/l in the peripheral blood. In 10% of cases without lymphocytosis, the PPBL diagnosis has to be suggested by peripheral blood examination showing in all cases atypical binucleated lymphocytes. A polyclonal serum IgM is also associated and HLA-DR7 expression is present in most cases. Contrary to B-cell chronic lymphoproliferative disorders (B-CLPD, peripheral B cells are polyclonal with kappa and lambda light-chain expression and no clonal rearrangement of immunoglobulin heavy chain genes is usually demonstrated. The detection of an extra isochromosome for the long arm of chromosome 3 +i(3(q10 has to be considered as a specific marker of PPBL. We performed conventional cytogenetic analysis (CCA in 111 patients with typical PPBL we followed-up more than 4 years. +i(3q was detected in 34% (33/98, PCC in 8% (8/98 and both abnormalities in 31% (30/98. CCA showed neither +i(3q nor PCC in 28% (27/98. Fluorescence in situ hybridization (FISH was also performed in 84 cases and +i(3q was detected in 71% (60/84. When combining both procedures in 84 patients, +i(3q was detected in 17 patients with negative CCA and was confirmed in 43 patients with positive CCA. CCA and FISH were both negative in 24 cases. Whether

  19. Impairment of mature B-cell maintenance upon combined deletion of the alternative NF-?B transcription factors RELB and NF-?B2 in B cells$

    OpenAIRE

    De Silva, Nilushi S.; Silva, Kathryn; Anderson, Michael M.; Bhagat, Govind; Klein, Ulf

    2016-01-01

    B-cell activating factor (BAFF) is critical for the survival and maturation of mature B-cells. BAFF, via the BAFF receptor (BAFFR), activates multiple signaling pathways in B-cells, including the alternative nuclear factor-?B (NF-?B) pathway. The transcription factors RELB and NF-?B2 (p100/p52) are the downstream mediators of the alternative pathway; however, the B-cell-intrinsic functions of these NF-?B subunits have not been studied in vivo using conditional alleles, either individually or ...

  20. Dual-reactive B cells are autoreactive and highly enriched in the plasmablast and memory B cell subsets of autoimmune mice

    Science.gov (United States)

    Fournier, Emilie M.; Velez, Maria-Gabriela; Leahy, Katelyn; Swanson, Cristina L.; Rubtsov, Anatoly V.; Torres, Raul M.

    2012-01-01

    Rare dual-reactive B cells expressing two types of Ig light or heavy chains have been shown to participate in immune responses and differentiate in