bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Unique Transcriptional Profile for Spontaneously Immunoglobulin Secreting B-1 Cells.
Authors: Tumang Joseph R. , Frances Ruben , Rothstein Thomas L. 
Published: October 2019

Abstract
Natural antibodies are spontaneously arising polyreactive Ig, usually IgM, that are encoded by V genes in germline configuration and are produced by B-1 cells. Because of their ability to promiscuously bind to a variety of antigens, especially those on bacteria and viruses, natural antibodies act as a primary line of defense against infection. A key shortfall in our understanding of these key effector molecules centers on the molecular mechanisms regulating natural antibody secretion by B-1 cells. Recent advances in our understanding of plasmacytic differentiation now provide us with a conceptual framework by which we can begin to explore this issue. In the studies described herein, we demonstrate that secreting B-1 cells utilize some aspects of the plasmacytic differentiation program and deviate away from it in others. Specifically, we show that key repressors of the plasmacytic program, BCL-6 and PAX-5a, are indeed reduced in secreting B-1 B cells. Surprisingly, we found that key promoters of the plasmacytic program, BLIMP-1 and XBP-1, are not upregulated in secreting B-1 B cells. These data demonstrate that B-1 B cells operate under a differentiation program unique from prototypic secreting B-2 cells and cast BCL-6 and PAX-5a but not BLIMP-1 and XBP-1 as central regulators of natural immunoglobulin secretion.
Development and Function of NK and T Cells in AML Patients after Allogeneic Stem Cell Transplantation (SCT).
Authors: Multhoff Gabriele , Gross Catharina , Dickinson Anne , Holler Ernst 
Published: October 2019

Abstract
Purpose: Hsp70 was frequently found on the plasma membrane of bone marrow-derived leukemic blasts, but not on normal bone marrow cells. Hsp70 membrane expression could be correlated with protection against therapy-induced apoptosis (Nylandsted et al 2004). In contrast, these tumor cells have been found to be highly sensitive to the cytolytic attack mediated by NK cells. In vitro, Hsp70-activated NK cells efficiently lysed autologous Hsp70 membrane-positive leukemic blasts (Gehrmann et al 2003). Granzyme B release served as a surrogate marker for estimating the cytolytic response of NK cells against Hsp70 membrane-positive tumor target cells (Gross et al 2003). Here, we studied the development of NK and T cells in AML patients (n=6) after allogeneic SCT at different time points (days 14–20, 45, 90, 180, 1 year) after allogeneic stem cell transplantation (SCT).
Methods: HLA class I, HLA-E and Hsp70 surface expression was determined on all patient-derived leukemic blasts of the bone marrow by flow cytometry. The amount of NK and T cells was investigated by multicolor flow cytometry using CD3/ CD16 and CD56 and CD94/ CD56 antibody-combinations detecting NK cell specific markers. Effector cell function was tested in a granzyme B ELISPOT assay against patient-derived leukemic blasts and K562 cells.
Results: All tested leukemic blasts were positive for HLA class I, HLA-E, and Hsp70. After induction therapy the amount of CD3-negative, CD56/CD94-positive NK cells was 28±16%, that of CD3-positive T cells was 58±3%. On days 14–21 after allogeneic SCT, 58±9% of the donor-derived peripheral blood lymphocytes (PBL) were CD3-negative, CD56/CD94-positive NK cells; the amount of CD3-positive T cells was 26±7.5%. On day 45, the amount of NK cells further increased up to 68±7.9%; that of T cells further decreased down to 16±5.6%. On day 90 and day 180 the amount of NK cells was still 41±10%; that of T cells was 29±12%. Interestingly, high NK cell counts correlated with an increased cytolytic response against leukemic blast and K562 cells.
One year after allogeneic SCT, NK (20±1%) and T cell (52±18%) ratios were comparable to that of healthy human individuals.
Conclusions: Between days 14 and 180 after allogeneic SCT, the amount of NK cells was significantly elevated if compared to that of T cells. Concomitantly, cytolytic function against leukemic blasts was significantly elevated. Normal levels, in the composition of NK and T cells were reached 1 year after SCT.
Project funded by EU-TRANS-EUROPE grant QLK3-CT-2002-01936.
A Predictive Model for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): A Retrospective Analysis of 1,252 Cases Performed by the Intergruppo Italiano Linfomi (IIL).
Authors: Cortelazzo Sergio , Luminari Stefano , Bellei Monica , Martelli Maurizio , Vitolo Umberto , Rigacci Luigi , Ambrosetti Achille , Pogliani Enrico , Chisesi Teodoro , Rossi Giorgio , Rossi Andrea , Rambaldi Alessandro , Barbui Tiziano , Brugiatelli Maura , Federico Massimo 
Published: October 2019

Abstract
Introduction: few studies have explored the usefulness of a prognostic index specifically devised for patients with localized DLBCL. The IIL has performed a retrospective analysis of a large group of patients with limited stage DLBCL and developed a new prognostic model.
Results: 1,252 patients with localized (Ann Arbor stage I-II) aggressive B-cell lymphoma (IWF: G or H, WHO:DLBCL) diagnosed from 1988 to 2002 and without CNS involvement, treated by 4 cooperative groups and 2 single institutions, are the subject of this analysis. Patient’s median age was 57 years (range, 17–91) and M/F ratio was 1.26. Clinical stage was I in 239 (19%), IE in 303 (24%), II in 356 (28%) and IIE in 354 (28%) patients, respectively. Supradiaphragmatic disease was present in 56% of patients, 13% had > 3 nodal sites, 53% had extranodal involvement, and 7% had >1 extranodal site. Bulky disease (≥10 cm) was present in 26% of patients, ECOG-PS >1 in 12% and B symptoms in 14%. Abnormal biochemical data included: elevated LDH (28%), β2-microglobulin (B2M;19%) and ESR (38%) and reduced albumin (< 3.5 g/dL) in 21% of the cases. Patients were treated with anthracyclin-containing regimens ± IF-RT. After a median follow-up of 62 months for alive patients (range 1–183 months), 3 and 5-year OS rates were 73% and 71%, respectively. By univariate analysis the following 11 variables were found to be predictive of a short survival: age ≥65 yrs (P=0,0001), stage II nodal (P=0,0001), number of nodal sites (P<0.0001), poor ECOG-PS (P<0.0001), B symptoms (P=0.0009), bulky disease (P=0.0001), elevated ESR (P=0.0001), LDH (P<0.0001), Radiotherapy (P<0.001), B2M (P=0.007) and reduced serum albumin (<0.0001). By Cox multivariate analysis, age ≥65 years (p<0.001), stage II nodal (P<0.001), high LDH (P<0.001) and bulky disease (P<0.01) were indipendent risk factors (RF) for a short survival. The prognostic model was calculated with the sum of scores assigned to each variable; a score of 2 was assigned to advanced age, high LDH, and Bulky; for Stage a score of 1 was considered for stage Ie-IIe and 2 for stage II nodal. Three groups of patients with a different probability of survival (P<0.000001) were identified. Patients at low (Score 0–1; 387 pts), intermediate (Score 2–3; 484 pts) or high risk (Score 4–8; 381 pts) had a 5 years OS of 87%, 77%, 51% respectively. The predictive performance of the model was internally validated through a non parametric Bootstrap method and through residues’ analysis.
Conclusions: This prognostic model, developed and validated on a very large series of patients with localized DLBCL, will allow us to select appropriate therapeutic approaches on the basis of different risk categories.
c-Myc Amplification in Non Hodgkin’s-Lymphomas with Burkitt-Like Features Is Associated with a Poor Prognosis.
Authors: Mossafa Hossein , Damotte Diane , Vincenneau Anne , Amouroux Isabelle , Athken Nareth , Djnabian Arache , Jeandel Roland , Khoury Eli , Martelli Jean-Michel , Samson Thierry , Tapia Sylvie , Flandrin Georges , Troussard Xavier 
Published: October 2019

Abstract
We retrospectively studied 15 newly diagnosed patients presenting with NHL and Burkitt-like cells (BLCs) after morphological examination and histology review (lymph-nodes: 7 cases, peripheral blood: 5 cases, bone marrow: 3 cases and spleen: 1 patient). Conventional cytogenetic analyses were performed at diagnosis on lymph nodes biopsies (n=6), peripheral blood lymphocytes (n=4), bone marrow (n=4) or spleen (n=1). FISH studies used commercially available probes: IGH/c-MYC fusion signals probes, IGH/Bcl-1 fusion signals probes, IGH/Bcl-2 fusion signals probes and c-Myc 8q24 probe to detect t(8;14)(q24;q32), t(11;14)(q13;q32), t(14;18)((q32;q21) and c-Myc amplification, respectively. Morphological examination and/or histology showed BLCs in all patients. Burkitt-like lymphoma (BLL) is a highly proliferative lymphoma that morphologically resembles Burkitt’s lymphoma (BL) but has more polymorph and pleiomorph cells or large lymphoid cells than BL. The mean percentage of Ki-67 positive cells was 80% (range, 70–100%). A normal karyotype was present in 3 cases and a complex karyotype was observed in 12 cases (80%). When combining conventional cytogenetic studies and FISH studies, t(8;14) or the variants t(2;8) or t(8;22) were never detected. In contrast t(11;14)(q13;q32) was found in 4 cases and t(14;18) in 6 cases. Interestingly, c-Myc amplification was observed in all cases with 3 to more than 9 copies in 10–77% metaphase or interphase cells. The diagnosis of follicular lymphoma (FL) was confirmed by a CD5− and CD10− immunologic profile, typical t(14;18) in 4/6 cases and IgH/Bcl-2 fusion gene in all cases. Four cases were classified as mantle cell lymphoma (MCL) with a blastoid variant: MCL diagnosis was established by lymph-node biopsy in 1 case, CD5+ and CD23+ expression in 3/4 cases and 2/4 cases respectively, typical t(11;14)(q13;q32) in 3 cases, complex caryotype including 11 and 14 chromosomal abnormalities in 1 case and IgH/Bcl-1 fusion gene in all cases. Two patients had marginal MZL with a CD5− and CD10− profile and a complex caryotype including +3 and +18. Two patients presented a DLBCL (CD19+, CD20+) with BLCs and one case was classified as T-NHL (CD2+, CD4+, T-cell receptor gene rearrangements) in leukemic phase with BLCs. All these 15 patients have a poor prognosis with a death occurring in 6 patients during the first month after diagnosis. The presence of BLCs was observed independently of the type of lymphomas, FL, MCL or MZL. c-MYC amplification was associated with BLCs and progressive disease. In conclusion, we identified a new subgroup of patients with NHL (14 B-NHL, 1 T-NHL) and a profile including a poor prognosis, Burkitt-like features at presentation without t(8;14)(q24;q32) or its variants and Myc amplification in all cases.
Oxidative Stress Induces Binding of FANCD2 to STAT5 and Facilitates STAT5-Dependent Survival Signals.
Authors: Bagby Grover , Keeble Winifred , Koretsky Tara , Zodrow Dylan , Jove Richard , Hays Laura , Carlson Hanqian 
Published: October 2019

Abstract
Fanconi anemia (FA) cells are hypersensitive to oxidative stress and exhibit aberrant STAT activation responses to defined extracellular proteins but whether these abnormalities are linked is unclear. Because oxidative stress is known to induce STAT activation, we hypothesized that proper STAT signaling responses in normal cells exposed to H2O2 require intact FA proteins. In fact, we found that FA-C, FA-G, and FA-D2 cells (fibroblasts) showed a significant increase in apoptosis after H2O2-exposure compared to retrovirally-complemented cells. H2O2 induced higher phospho-STAT5 (P-STAT5) expression in complemented cells than in mutant cells. Conversely, mutant cells expressed higher levels of P-STAT3 in both the ground state and after H2O2-induction than complemented cells. Aberrant STAT activation in FA mutant cells was shown to be both nucleus- and JAK2 kinase-dependent. Only low levels of STAT3 and STAT5 were induced in both mutant and complemented cytoplasts and AG490 (a Jak2 inhibitor) significantly suppressed H2O2-induced STAT5 responses. Seeking a direct role of FANCD2 in regulating proper STAT activation responses to H2O2, we carried out immunoprecipitation experiments (with an antibody to the N-terminal fragment of FANCD2) using PD20, a FA-D2 mutant cell line, and FANCD2 complemented PD20. In FANCD2-complemented and normal cells, anti-FANCD2 antibody immunoprecipitated STAT5. However, in mutant cells the same antibody immunoprecipitated STAT3, not STAT5. Thus, mutant (truncated) FANCD2 preferentially binds to and may activate STAT3 in the ground state. In fact, wild type FANCD2 also binds aberrantly to STAT3 in HSC536 (FA-C lymphoblasts) indicating that FANCC may influence the function of wild type FANCD2 and that binding of wild type FANCD2 to STAT3 does not require FANCD2 ubiquitinylation (FANCD2 is not ubiquitinylated in FA-C). Suspecting that in H2O2-exposed cells STAT5 signaling pathways lead to survival while STAT3 pathways lead to apoptosis, we transduced constitutively active mutants (*) of STATs 3 and 5 in mutant D2 and complemented cells. STAT3* increased apoptotic responses to H2O2 in complemented FA-D2 cells and STAT5* decreased apoptotic responses in H2O2-induced FA-D2 cells. In addition, the STAT5 inducible anti-apoptotic gene Bcl-XL was induced in H2O2-exposed complemented FA-D2 cells but not in FA-D2 cells. We conclude that FANCD2 functions to promote survival by ordering proper STAT signaling responses to oxidative stress and that this function of FANCD2 depends in part upon FA-C. We propose that FA cells are hypersensitive to oxidative stress in part because of imbalanced STAT signal transduction responses.
A Comparison of Acute and Delayed Infection Rates among Patients with Indolent Lymphoid Malignancies Receiving Fludarabine(F) and Cyclophosphamide(C) with or without Rituximab(R).
Authors: Tam Constantine S. , Seymour John Francis , Brown Michael , Campbell Philip , Scarlett John D. , Underhill Craig , Ritchie David , Bond Rodney , Grigg Andrew 
Published: October 2019

Abstract
The monoclonal anti-CD20 antibody R improves response rates and survival when added to FC in patients with CLL (Keating Proc ASCO 2004, abstr #6565), but the associated B-cell depletion may increase the infectious risk associated with FC therapy. We therefore compared infectious episodes both during and in the 12 months following therapy in two cohorts of patients treated with FC (F 25mg/m2x3, C 250mg/m2x3 q28 days; n=63) alone or with R (FCR; FC+R 375mg/m2 day 1; n = 91) for indolent lymphoid malignancies. Patients received FC from 10/96 to 12/00 and FCR from 12/00 to 8/03. Both cohorts had similar baseline characteristics including history of infections, neutrophil counts, and Ig levels and were mainly elderly (median age 60 years, range 30–89) with heavily pretreated disease (median number of previous therapies 2, range 1–10) and both received a median of 4 cycles of therapy without routine antibiotic prophylaxis or growth-factors; CLL or follicular lymphomas constituted over two-thirds of group. In comparison to FC, infectious episodes were not significantly increased for FCR either during therapy (FC 15%/cycle vs FCR 20%/cycle, p=0.17) or in the first 12 months of remission (1 infection per 13 patient-months [PM] for both cohorts). There was a trend to increased late neutropenia in the FCR cohort (14% vs 31% at 3 months; P = 0.15). Grade 3+ infections were similar both during therapy (FC 8%/cycle vs FCR 9%/cycle) and in the first 12 months of remission (FC 1 per 84 PM vs FCR 1 per 35PM, p=0.16), as were rates of herpes virus infections (FC vs FCR: during therapy 1% vs 2%/cycle; during follow-up 1 per 48 vs 1 per 94 PM). We conclude that the addition of R to FC does not result in increased early or late infectious risk above that of FC alone.
Second Autologous or Allogeneic Transplantation after the Failure of First Autograft in Multiple Myeloma.
Authors: Qazilbash Muzaffar H. , Saliba Rima , de Lima Marcos , Couriel Daniel , Hosing Chitra , Aleman Ana , Lei X , Champlin Richard E. , Giralt Sergio A. 
Published: October 2019

Abstract
Background: Most patients undergoing high-dose therapy and autologous transplant for multiple myeloma eventually relapse. The optimal salvage treatment for these patients is not very well defined. Both autologous and allogeneic hematopoietic stem cell transplantations have been used for salvage. We analyzed the outcomes of second autologous or allogeneic transplants, performed as salvage in patients relapsing after an autograft.
Methods: Fourteen patients received a second autograft for salvage, while thirty-four patients underwent allogeneic transplantation (related 24, unrelated 10). The median age at transplant was 52 years in the autologous group, and 51 years in the allogeneic group. The median interval between the first and the second transplant was 25 months in the autologous group and 17 months in the allogeneic group. The disease characteristics were similar in both autologous and allogeneic groups.
Results: With a median follow-up of 10 months among survivors in each group, both autologous and allogeneic transplant groups had a response rate (complete + partial) of 64%. One hundred day nonrelapse mortality was 7% in the autologous group and 12% in the allogeneic group. Median disease-free survival (DFS) was 11 months in the autologous and 6 months in the allogeneic group. Median overall survival (OS) was 29 moths in the autologous and 14 months in the allogeneic group. 1-year DFS was 40% in the autologous group and 22% in the allogeneic group (p = 0.2). 1-year overall survival was 70% in the autologous and 53% in the allogeneic group (p = 0.3). The most common causes of non-relapse mortality were graft vs. host disease (62%) in the allogeneic group, and infections (100%) in the autologous group. On univariate analysis for DFS in allogeneic group, an interval of >1 year between the first and the salvage transplant was the only factor associated with a significantly better outcome (p = 0.01). Disease status at transplant, type of donor, tumor mass, β2 microglobulin level, and serum albumin level did not show any impact on the outcome.
Conclusions: Both autografting and allografting are feasible as salvage for myeloma patients relapsing after the first autograft. A slightly better outcome with salvage autografting may be due to decreased toxicity.
Allogeneic Hematopoietic Stem Cell Transplantation as a Promising Treatment for Natural Killer-Cell Neoplasms.
Authors: Murashige Naoko , Kami Masahiro , Kishi Yukiko , Kim Sung-Won , Takeuchi Masami , Matsue Kosei , Kanda Yoshinobu , Hirokawa Makoto , Kawabata Yoshinari , Matsumura Tomoko , Kusumi Eiji , Hirabayashi Noriyuki , Nagafuji Koji , Suzuki Ritsuro , Takeuchi Kengo , Oshimi Kazuo 
Published: October 2019

Abstract
The efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for NK-cell neoplasms is unknown. We investigated the results of allo-HSCT for NK-cell neoplasms between 1990 and 2003 through questionnaires. A hematopathologist reclassified the pathological diagnoses according to the WHO classification. Of 345 patients from 76 hospitals who underwent allo-HSCT for malignant lymphoma, 32 had NK-cell neoplasms: extranodal NK/T-cell lymphoma (n=27), blastic NK-cell lymphoma (n=3), and aggressive NK-cell leukemia (n=2). Fifteen were chemosensitive and 17 chemorefractory. Nine were in CR at the time of allo-HSCT. Twenty-five had matched related donors, 3 mismatched related, 2 matched unrelated, and 1 mismatched unrelated donors. Stem-cell source was bone marrow in 11 and mobilized peripheral blood in 21. Conditioning regimens were myeloablative (n=26) and non-myeloablative (n=6). Total body irradiation was given to 23 patients.
Graft-versus-host disease (GVHD) prophylaxis was cyclosporin and short-term methotrexate in 27 patients. Grade 2–4 acute GVHD and chronic GVHD developed in 13 and 9, respectively. Nine died of disease progression, 4 of infection, 2 of veno-occlusive disease, 2 of acute GVHD, 1 of interstitial pneumonitis, and 1 of thrombotic microangiopathy. Two-year progression-free and overall survivals were 33% and 38%, respectively (median follow-up, 32 months). All patients who did not relapse/progress within 10 months achieved progression-free survival during the follow-up. In multivariate analysis, stem cell source (BM vs. PB; relative risk 3.33) and acute GVHD (grade 2–4 vs. grade 0–1; relative risk 2.56) significantly affected progression-free survival. Allo-HSCT is a promising treatment for NK-cell neoplasms.
Figure Figure
The Polycomb Group Transcriptional Repressor Bmi-1 Is Constitutively Expressed in Multiple Myeloma (MM) Cells and Modulates Proliferation through a Mechanism Independent of the Ink4a/ARF Locus.
Authors: Desarnaud Frank J. , Shammas Masood , Neri Paola , Koley Hemanta , Prabhala Rao , Cheng Li , Ryung Suk Kim , Chauhan Dharminder , Tassone Pierfrancesco , Bae Jooeun , Anderson Kenneth C. , Munshi Nikhil C. 
Published: October 2019

Abstract
The polycomb group protein Bmi-1 is required for self-renewal of adult hematopoietic stem cells by inhibiting cell senescence and apoptosis through repression of p16INK4a and p14/p19ARF expression. Based on gene expression profile studies showing absence of Bmi-1 expression in normal plasma cells versus upregulation in all MM cell lines and primary patient MM cells, we evaluated its role in MM pathobiology. Bmi-1 expression in MM cell lines is constitutive, and is not modulated by IL-6 and IGF-1. Immunoprecipitation and immunoblotting studies confirmed both Bmi-1 overexpression and nuclear localization. Bmi-1 was found to be tyrosine- and serine-phosphorylated. We next inhibited Bmi-1 expression in MM cell lines (ARP and MM.1S) by stably transfecting a PU6 vector expressing siRNA targeting Bmi-1. Following G418 selection, cell growth, as measured by H3 thymidine incorporation and MTT assay, was stimulated 1.4 fold in MM.1S and 2 fold in ARP cells compared to control cells transfected with a PU6 vector. Gene expression profiling showed: up-regulation of IL-6 and IGF-1 receptors, as well as Gab-1, which plays a critical role in MM cell proliferation and survival induced by IL-6; Phospholipase D1 and proteinase 3 which potentiate cell proliferation by repression and cleavage of p21cip1/waf1; stem cell growth factor, HOXA9, which modulate bone marrow stem cell survival and proliferation. In contrast, p21cip1/waf1 and GADD45a, GADD45b which moderate cell growth arrest were down regulated. However, no change in expression of either p16INK4a or p14/p19ARF was detected by microarray and immunoblotting. We therefore conclude that Bmi-1 is abnormally expressed in MM cells and contrary to its classic action, modulates MM cell growth and survival by modulating cytokine signaling rather than INK4a/ARF. Our studies further suggest that Bmi-1 represents a promising target for novel MM therapeutics.