bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rituximab, Gemcitabine and Oxaliplatin (R-GEMOX): A Promising Regimen for Refractory/Relapsed B-Cell Lymphoma.
Authors: El Gnaoui Taoufik , Dupuis Jehan , Joly Bertrand , Belhadj Karim , Rahmouni Alain , Copie-Bergman Christiane , Allain Antoine , Tabah-Fish Isabelle , Reyes Felix , Haioun Corinne 
Published: October 2019

Abstract
Background : High-dose therapy with autologous stem cell support (HDT) is an established treatment for chemosensitive relapse in aggressive lymphoma. However, not all patients are candidates for HDT because of age, comorbidities or previous HDT. Effective and well tolerated salvage therapies with minimal toxicities are thus needed.
Methods : We designed the R-GEMOX regimen, with rituximab 375mg/m2 d1, gemcitabine 1000 mg/m2 d2 and oxaliplatin 100 mg/m2 d2 (recycling on d15). Between January 2002 and April 2004, 31 patients with refractory/relapsing B-cell lymphoma not eligible for HDT were enrolled in an open unicenter pilot study whose primary objective was to determine the overall response rate (ORR) after 4 cycles (induction phase) of R-GEMOX. Patients were planned to receive 8 cycles if a good response (at least PR) was observed after 4 cycles. Median age was 63 years (range: 43–77) and histological subtypes were : diffuse large B-cell lymphoma (n=22), follicular (n=6) and mantle cell (n=3). Prior treatment included anthracyclin in 30 patients (98%), rituximab in 16 (52%) and HDT in 8 (26%). International prognostic index at enrollment was ≥ 2 in 13 patients (42%). The median number of prior treatments was 2 (range : 1 to 5) and 9 patients had received at least 3 prior regimens.
Results : 226 cycles were given. The dose administered was 100% of the intended dose for the three drugs in all patients but 6, for whom the dose of oxaliplatin was reduced due to neurotoxicity (n=5) or preexisting renal insufficiency (n=1). The median number of cycles per patient was 8 (range: 2–8).Three patients progressed during the induction phase. After 4 cycles, observed responses were : 6 CR, 8 CRu, 12 PR and 2 failures resulting in an ORR of 84 %. At the end of treatment, among the 26 responder-patients at 4 cycles, 23 patients achieved CR/CRu and one patient progressed. As of August 2004, 22 patients are alive, 17 in continuous complete remission and 5 with evolutive disease. NCIC grade 3–4 neutropenia and thrombocytopenia were reported in 49% and 23% of the cycles. Six patients developed a grade 4 infection during one cycle. There was no renal toxicity.
Conclusion : The R-GEMOX regimen shows promising activity with an acceptable toxicity. It is currently evaluated in an ongoing multicentric phase II study on diffuse large B-cell lymphoma patients at first relapse. (=69.03% taille max abstract)
Treatment Response to Single Agent Sphingosomal Vincristine in Patients with Relapsed and/or Refractory Diffuse Aggressive Non-Hodgkin’s Lymphoma (NHL): Subgroup Analyses.
Authors: Rodriguez Maria Alma , Winter Jane N. 
Published: October 2019

Abstract
There is a substantial need for new effective therapies for patients with recurrent or refractory diffuse aggressive NHL. Efficacy and safety of sphingosomal vincristine (SV), a novel formulation of vincristine encapsulated in sphingomyelin liposomes or ‘sphingosomes’, were evaluated in a multinational study in aggressive NHL patients with multiple unfavorable prognostic factors. Methods: 119 pts with relapsed or refractory aggressive NHL were enrolled. SV was administered at 2 mg/m2 without capping the dose as a 1 hr IV infusion every 2 weeks. The objective response rate (ORR) and 95% CI for the proportions and difference in proportions were calculated for the following subgroups: by age (≤ 60 vs. > 60); sensitive disease vs. resistant (refractory or relapsed within 3 months of prior treatment); IPI score 0–2 vs. 3–5; prior therapies 2 vs. >2; bone marrow involvement at baseline; and prior ABMT. Results: ORR in the entire group was 25% (7% CR/Cru and 18% PR) (ASH Abstr. 2353, 2003).
No of Prior Regimens/Disease Sensitivity ORR % aone patient had 1 prior regimen Sensitive (n=39)  Resistant (n=80) 41%  18% 2 Regimens (n=24)a  -Sensitive (n=11)  -Resistant (n=13) 46%  64%  31% >2 Regimens (n=95)  -Sensitive (n=28)  -Resistant (n=67) 20%  32%  15%
Other Subgroup Analyses ORR % bnot statistically significant as 95% CI on the difference in ORR includes zero Bone Marrow Involved (n=20)  Not involved (n=93) 10%  27% Ageb ≥60 (n=60)  >60 (n=59) 25%  25% IPIb 0–2 (n=59)  3–5 (n=58) 19%  31% Prior ABMTb Yes (n=39)  No (n=80) 26%  25%
Conclusion: Single-agent SV was active in heavily pretreated patients with relapsed and/or refractory NHL. A multivariate analysis showed that the two strongest predictors for response were number of prior regimens and sensitivity to the last therapy. The highest level of activity was observed in patients with sensitive disease and 2 prior regimens (ORR 64%). Response to SV in older patients was the same as in younger patients. Prior ABMT did not impact response with ORR being similar in both groups. SV was well tolerated and the safety profile was similar to standard vincristine despite a doubling of dose intensity.
The Induction of Apoptosis in Lymphoma Cells by Methylseleninic Acid and Selenodiglutathione.
Authors: Last Kim , Perry Jackie , Maharaj Lenushska , Strauss Sandra , Davies Andrew , Skoulakis Spyros , Fitzgibbon Jude , Lister Andrew , Joel Simon 
Published: October 2019

Abstract
Introduction. We have previously demonstrated that presentation serum selenium predicted not only for response to treatment and duration of first remission, but also importantly for overall survival in aggressive non-Hodgkin’s lymphoma (Journal of Clinical Oncology2003, 21:2335–2341). To investigate a possible causal association as the explanation for these findings we have studied the activity of 2 selenium species, methylseleninic acid (MSA) and selenodiglutathione (SDG). We provide the first report of the activity of these two compounds in lymphoma, using a panel of human cell-lines (CRL, DHL4, SUD4 and DoHH2) and a primary human lymphoma culture system.
Methods. The effects of 3-day incubations with MSA or SDG on cell proliferation and cell viability (n = 3–6) were determined by Trypan blue exclusion assay. Cell cycle distribution (including a sub-G1 apoptotic fraction), generation of reactive oxygen species (ROS) and PI/annexin staining were analysed by flow cytometry. Apoptosis was further investigated by western blotting for poly-ADP ribose polymerase (PARP) and specific caspase (8 and 9) cleavage. The activity of MSA and SDG was also investigated in a primary lymphoma culture system utilising a feeder layer of CD40 ligand expressing CHO cells irradiated prior to plating primary lymphoma cells.
Results. Both MSA and SDG demonstrated cytostatic and cytotoxic effects in all 4 cell-lines studied. The EC50 values ranged from 1.0 – 10.2 μM, with the exception of the % viability EC50 for MSA in DHL4 cells (166 μM). Flow cytometry revealed cell death was associated with an increase in the sub-G1 (apoptotic) fraction, without an obvious preceding G1, S or G2/M cell cycle arrest. Apoptosis was confirmed by flow cytometric analysis of PI/annexin dual labelled cells, and was associated with PARP cleavage and involvement of both caspase 8 and 9. SDG exposure resulted in marked increases in ROS, particularly in CRL and SUD4 cells (3-5-fold increase after 30 minutes exposure to the day-3 viability EC50 concentration). The addition of n-acetyl-cysteine reduced the cytotoxic activity of SDG, but not MSA, confirming that ROS contribute to the effects seen with SDG. In 5 different 2-day primary lymphoma cultures (n = 4–6) MSA and SDG showed a concentration dependent reduction in % viability, with day-2 EC50 values of approximately 30 μM for MSA and 10 μM for SDG.
Conclusions. We have demonstrated for the first time the cytostatic and cytotoxic activity of two selenium species, MSA and SDG, in human lymphoma cell-lines and primary lymphoma cells and their induction of caspase mediated apoptosis. These data suggest that selenium species may play a causal role in the success of conventional chemotherapy in aggressive lymphoma. Selenium compounds merit further investigation in the clinical management of this disease.
Vaccination with Leukemia Cells Expressing Cell-Surface-Associated GM-CSF Blocks Leukemia Induction in Immunocompetent Mice.
Authors: Ling Xiaoyang , Wang Yan , Arlinghaus Ralph B. 
Published: October 2019

Abstract
The fundamental basis for immunotherapy of leukemia is that leukemia cells express specific antigens that are not expressed by normal hematopoietic cells. However, the host immune system appears to be tolerant of leukemia cells. To overcome this immune tolerance, we transduced WEHI-3B mouse monocyte leukemia cells (1) with a transmembrane form of GM-CSF (tmGM-CSF). The tmGM-CSF was constructed using the pDisplay vector for cell-surface targeting (Invitrogen) into the pLOX lentivirus gene transfer vector (2). After infection of WEHI-3B cells with a recombinant lentivirus encoding tmGM-CSF, nearly all the transduced cells expressed tmGM-CSF on the cell-surface, as determined by flow cytometry analysis using anti-GM-CSF. To determine whether vaccination with tmGM-CSF expressing WEHI-3B cells would prevent leukemia formation, immunocompetent BALB/c mice were immunized with lethally-irradiated WEHI-3B cells (106, 3 times 7 day intervals), which express tmGM-CSF, prior to challenging vaccinated mice with WEHI-3B cells (5x104) that express GFP as a marker. 100% of vaccinated mice were protected from leukemia. Non-vaccinated mice succumbed to leukemia within 50–55 days. Vaccination of mice with lethally-irradiated WEHI-3B cells expressing CD40L protected 80% of the mice from leukemia. In contrast, mice immunized with lethally-irradiated WEHI-3B/GFP cells lacking tmGM-CSF were not protected. Mice vaccinated three times at 5,12, 19 days after challenge with WEHI-3B/GFP cells had a significant increase in survival in that 60% of mice were alive and healthy at 16 days (to this date) after all control non-vaccinated mice had died. Similar vaccine studies were performed with BCR-ABL (b3a2)+ 32D cells (106) in immunocompetent C3H/HeJ mice (3). These mice die of leukemia within 35 days. After infection of BCR-ABL+ 32D cells with the lentivirus encoding tmGM-CSF/GFP, tmGM-CSF was expressed on the cell-surface. The C3H/HeJ mice challenged with BCR-ABL+32D/GFP cells (106) showed a significant level of protection by vaccination with lethally-irradiated tmGM-CSF+ 32D BCR-ABL cells (106, 2 times at 7 day intervals); 40% of the vaccinated mice remained healthy; all non-vaccinated mice died of leukemia. There was a significant difference in survival (P=0.03) between the vaccinated and non-vaccinated groups. Interestingly, the spleens of vaccinated C3H/HeJ mice that died of leukemia at the same time as non-vaccinated mice approached normal size whereas non-vaccinated mice had enlarged spleens. Our findings suggest that over-expression of cell-surface tmGM-CSF in leukemia cells can overcome immune tolerance, allowing the immune system to efficiently recognize and destroy the leukemia cells, providing extended survival of vaccinated mice. Because significant protection from death was achieved by vaccination after challenge with leukemia cells, tmGM-CSF expression in leukemia cells has potential as a therapeutic strategy for treatment of leukemia.
Anti-Von Willebrand Factor Antibody Is Responsible for Lower Levels of Plasma vWF in Blood Group O Individuals.
Authors: Dai Letian , Cotton Shawn , Macartney Alistair , Savidge Geoffrey , Alhaq Anwar 
Published: October 2019

Abstract
Plasma levels of vWF are known to be influenced by ABO blood groups, although the mechanism remains unresolved. Group O individuals have a significantly lower level of plasma vWF than those with group A, B or AB. This relative lower level of plasma vWF may result in a bleeding tendency and a shorter half-life of infused factor VIII in group O individuals. The formation of immune complexes between vWF and autoantibodies has been shown to accelerate vWF clearance from plasma in acquired von Willebrand syndrome. However, so far no evidence has been presented that the presence of autoantibodies against vWF is involved in lowering plasma level of vWF in group O individuals. In the present study, plasma samples were obtained from 199 healthy blood donors of blood group O (50), group A (50), group B (49), and group AB (50). A time-resolved fluorescence immunoassay (TRFIA) was developed to detect anti-vWF IgG in plasma samples. Briefly, 100 μl of diluted plasma was loaded on to duplicated vWF-coated and untreated control wells of a microplate. After incubation and washing, 100 μl of Europium-labeled anti-human IgG conjugate (1:500 dilution) was added to the plate to detect vWF IgG. The time-delayed fluorescence was then measured with a Victor microplate reader (PerkinElmer, Turku, Finland). The fluorescence counts of the control wells were subtracted from those of the vWF-coated wells. The results show that anti-vWF IgG was present in all four blood groups (Table 1). Of these blood groups, group O had the highest anti-vWF IgG level with 9.8 x 105 fluorescence counts, which was 2.7- to 3.5-fold higher than that of group A, B or AB. There was a significant difference in the anti-vWF IgG levels between group O and the rest of group A, B or AB. Quantitative analysis of plasma vWF by ELISA showed that the concentration of plasma vWF of group O was 29 to 35% lower than that of group A, B or AB (Table 1). These results suggest that TRFIA is a sensitive assay for detection of anti-vWF IgG in plasma samples, and the presence of the high level of anti-vWF Ig G in group O individuals may be responsible for lowing plasma vWF by acceleration of vWF clearance.
Anti-VWF IgG levels and vWF concentrations in diffeent ABO blood groups
Group O (n=50) Group A (n=50) Group B (n=49) Group AB (n=50) Data are presented as a mean ± SD. *P<0.01 compared with group A, B or AB. +P<0.01 compared with group A,B or AB. Anti-vWF IgG (x 105 Fluorescence counts) 9.8 ± 6.9* 2.8 ± 2.8 3.1 ± 3.0 3.6 ± 3.5 Concentration of vWF (% of normal controls) 116 ± 42+ 165 ± 46 165 ± 42 179 ± 49
Increase of CD4+CD25high Regulatory T Cells in the Peripheral Blood of Acute Myeloid Leukemia Patients.
Authors: Wang Xingbing , Yao Junxia , Zheng Jine , Liu Jun , He Yanli , Li Xiaoqing , Yu Jingming , Wei Jun , Yang Jin , Liu Zhongping , Huang Shiang 
Published: October 2019

Abstract
PURPOSE: Although immunosuppression has long been recognized in acute myeloid leukemia (AML), the underlying basis for the lack of an effective immune response against the tumor remains unclear. T cells constitutively expressing both CD4 and CD25 are essential for maintenance of self-tolerance and therefore have been referred to as regulatory T cells (Treg). Experimental tumor models in mice revealed that Tregs are potent inhibitors of an antitumor immune response. The purpose of the current study was to demonstrate the possible involvement of CD4+CD25high regulatory T cells in immune system impairment in patients with acute myeloid leukemia.
METHODS: The frequency and phenotypes of CD4+CD25high T cells in the peripheral blood of 36 patients suffering from acute myeloid leukemia and from 15 healthy controls were determined by flow cytometry. To assess the functional activity of CD4+CD25high cells, CD4+CD25high or CD4+CD25− cells were purified from PBMCs by sorting with FACSVantage. The immunoregulatory properties of CD4+CD25high and CD4+CD25− T cells were characterized by proliferation and suppression assays. Also, cytokine production after in vitro stimulation was examined in CD4+CD25high and/or CD4+CD25− T cells isolated from AML patients. In addition, the frequency of apoptotic or proliferating T cells in CD4+CD25high T cells was determined by 7AAD or ki67 binding cells.
RESULTS: Compared with healthy volunteers, patients with acute myeloid leukemia had a higher proportion of CD4+CD25high T cells (4.1±1.8% vs 2.0±0.5%) in peripheral blood with characteristics of Tregs, i.e., they are CD45-RA(−), CD69(−), CD45-RO(+), CD95(+), and intercellular CTLA-4(+), and secreted TGF-, TNF-α and IL-10 but did not secrete IL-2, IL-4, IL-5 or IFN-. When cocultured with CD4+25− cells, CD4+CD25high T cells potently suppressed their proliferation through a dose-dependent manner, thus behaving as Treg. In addition, In order to explain the increased prevalence of CD4+CD25high T cells in AML patients, we examined the apoptosis and proliferation variations of CD4+CD25high T cells in AML patients. Notably, in AML patients, both apoptosis and proliferation of CD4+CD25high T cells were significantly higher than that did normal donor.
CONCLUSIONS: we provide evidence of an increased pool of CD4+CD25high regulatory T cells in the peripheral blood of AML patients with potent immunosuppressive features, which maybe due to the proliferation of CD4+CD25high T cells. This finding suggests that the use of immunomodulatory therapy to treat patients with AML may be an effective strategy.
RUNX1-ETO Stimulates Wnt Signaling by Inhibiting the Function of ETO Family Member Proteins.
Authors: Moore Amy , Tahinci Emilios , Lee Ethan , Hiebert Scott 
Published: October 2019

Abstract
The t(8;21) is one of the most frequent chromosomal translocations associated with acute myelogenous leukemia (AML). This translocation generates a fusion protein, RUNX1-ETO, consisting of the N-terminus of RUNX1 fused to a nearly full-length ETO protein. The RUNX1-ETO fusion protein stimulates the expression of genes that are regulated by Wnt signaling. The Wnt signaling pathway plays a key role in embryonic development and aberrations to this pathway are frequently involved in tumor formation. Therefore, we sought to define the molecular mechanism by which RUNX1-ETO may stimulate Wnt signaling. We have demonstrated that the ETO family member, Mtgr1, functions as a corepressor for TCF4 and that the levels of the TCF-regulated gene, c-Myc, are upregulated in Mtgr1-null mice. Here we show that the Xenopus homolog of Mtgr1, XETOR, can impair Wnt signaling and induce ventralization in a Xenopus axis duplication assay, a classical assay used to define the hierarchy of components in the Wnt pathway. Specifically, microinjection of in vitro transcribed XETOR mRNA was performed in the marginal zone of both dorsal blastomeres at the 2 to 4 cell stage with increasing amounts of XETOR. Embryos were monitored through stage 26. Compared to control embryos, the embryos injected with XETOR mRNA were ventralized and failed to develop head structures. Conversely, although each of the ETO family member proteins associated with TCF4, RUNX1-ETO failed to bind to TCF4 in co-immunoprecipitation experiments. Mtgr1 was originally identified as a RUNX1-ETO-associated protein. Therefore, we tested whether the fusion protein impairs the action of Mtgr1 as a co-repressor for TCF4. RUNX1-ETO associated with Mtgr1, and Mtgr1 failed to associate with TCF4 when RUNX1-ETO was co-expressed. Thus, RUNX1-ETO appears to stimulate TCF-dependent transcription by interfering with the action of the ETO family of transcriptional corepressors.
Egr-1 Abrogates the Block Imparted by c-Myc on Terminal M1 Myeloid Differentiation.
Authors: Hoffman Barbara , Shafarenko Marianna , Liebermann Dan A. 
Published: October 2019

Abstract
Both deregulated growth and blocks in differentiation cooperate in the multistage process of leukemogenesis. Thus, understanding functional interactions between genes that regulate normal blood cell development, including cell growth and differentiation, and how their altered expression contributes to leukemia, is important for rational drug design. Previously, we have shown that the zinc finger transcription factor Egr-1 plays a role in monocytic differentiation. Ectopic expression of Egr-1 in M1 myeloblastic leukemia cells was observed to activate the macrophage differentiation program in the absence of the differentiation inducer interleukin 6 (IL-6), and to promote terminal differentiation in its presence. In addition, we have shown that deregulated expression of the proto-oncogene c-myc blocks the myeloid terminal differentiation program. Here we show that restoring expression of Egr-1 in M1 cells that express deregulated c-Myc abrogates the c-Myc block in terminal differentiation, resulting in cells that undergo functional macrophage maturation. Interestingly, it was shown that the ability of Egr-1 to override the c-Myc block in terminal differentiation occurred in the absence of growth arrest and cell adhesion, resulting in cells with the characteristics of functionally mature macrophages. As with normal macrophages, the cells also underwent programmed cell death. It was also observed that Egr-1 diminished the aggressiveness of M1myc leukemias, and abrogated the leukemic potential of M1myc cells treated with IL-6. Taken together, these observations demonstrate that Egr-1 behaves like a tumor suppressor, suggesting that, on the one hand, genetic lesions which alter Egr-1 expression can cooperate with deregulated c-Myc in exacerbating the leukemic phenotype and, on the other hand, that enhancement of Egr-1 expression, or its downstream targets, can overcome blocks in differentiation due to deregulated c-Myc, as well as its associated leukemias These findings suggest that Egr-1 and/or Egr-1 targets may provide important tools for differentiation therapy in certain leukemic phenotypes
Association between Neuroleptics and Venous Thromboembolism: A Case-Control Study.
Authors: Lacut Karine , Le Gal Gregoire , Oger Emmanuel , Mottier Dominique 
Published: October 2019

Abstract
Background:
Preliminary reports suggest that use of antipsychotic drugs is associated with an increased risk of venous thromboembolism (VTE), but others did not confirm these results.
Objective:
To evaluate the relationship between antipsychotic drugs and VTE.
Design:
Case-control study (EDITH) designed to investigate genetic and environmental risk factors of VTE.
Setting:
Brest University Hospital.
Participants:
857 patients consecutively hospitalized for a documented venous thromboembolic event were included between May 2000 and May 2004. Controls were matched on age, sex and the main risk factors of venous thromboembolism (cancer, surgery, pregnancy…).
Results:
The mean age of patients was 67.7 year. No significant difference was found between cases and controls concerning the main characteristics, except for smocking and body mass index. Among cases, 89 (10.4%) were current users of neuroleptics compared to 35 (4.8%) among controls. Current use of neuroleptics was associated with a significant increased risk of venous thromboembolism (OR = 2.32, 95% CI: 1.55–3.48). Excluding neuroleptics used for non psychiatric disorders, and after adjustment on the main confounding factors, this association remained significant (OR = 3.48, 95% CI: 2.00–6.04). No difference was found between the different chemical categories of neuroleptics, but the number of patients in some groups had limited statistical power to demonstrate significant differences. Biological mechanisms of action have been proposed to explain this relation. Analyses are ongoing for anti-phospholipid antibodies and homocysteine.
Conclusion:
In this case-control study of hospitalized patients, neuroleptics use was associated with a significant increased risk of venous thromboembolism. These results are concordant with previous reports. Nevertheless, further investigations are needed to explain wich mechanisms may be involved in such association and before use of neuroleptics can be definitely considered as risk factor for venous thromboembolism.