bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epoetin Beta (Neorecormon®) Treatment for Anemia of Patients with Non-Myeloid Hematological Malignancy under Chemotherapy: Results of a Large Prospective Cohort Study.
Authors: Haïoun Corinne , Ifrah Norbert , Casassus Philippe , Audhuy Bruno , Aoudjhane Malek , Frayfer Jamile , Rouanet Stephanie , Bleuzen Pascal , Jenabian Arash , Facon Thierry 
Published: April 2020

Abstract
Background: The efficacy of epoetin beta (E) is well documented in clinical trials in anemic cancer patients (pts). This study was conducted to assess E use, efficacy, safety and effect on quality of life in cancer pts, in usual practice.
Methods: This prospective, multicenter, longitudinal, observational French study assessed a 4-month follow-up of informed consent cancer pts (including both solid tumors (ST) and non-myeloid hematological malignancies (H)) treated with E for chemotherapy-related anemia. Data were collected between January 2005 and March 2006. We only present here the results of the H subgroup.
Results: Among 2809 pts, 675 had an H including 325 non-Hodgkin lymphoma (NHL), 181 multiple myeloma (MM) and 80 chronic lymphocytic leukemia (CLL). 52% of pts received their first line of chemotherapy, 24% their second one. At inclusion, Hb levels were distributed as follows: &lt; 9 g/dl: 32%, [9–11[ g/dl, 56%, [11–13[ g/dl, 11%. At inclusion, endogenous erythropoietin rate was monitored for only 8% of pts, ferritin was available for 32%, transferrin saturation for 17% and reticulocytes for 24%. At initiation, pts received a median dose of 30000 U/week of E on a once weekly regimen schedule for 98% of pts. E was associated with iron supplementation in 20% of pts (1% IV). The mean Hb level increased from 10 g/dl [5 – 14] at baseline to 13 g/dl [7 – 17] in the entire cohort of H pts, from 10 g/dl [5 – 14] to 12 g/dl [7 – 16] in NHL pts, from 10 g/dl [6 – 13] to 13 g/dl [8 – 17] in MM pts and from 10 g/dl [6 – 13] to 13 g/dl [7 – 17] in CLL pts. Hb response rate (RR) was 56% (CI95: 51 – 61) in H pts, 53% (CI95: 46 – 60) in NHL pts, 57% (CI95: 48 – 66) in MM pts and 56% (CI95: 41 – 70) in CLL pts. 41% of patients were transfused at inclusion or during the study. Good performance status (PS≤1) (OR=1.6, CI95: 1.1–2.5), non platinum-based regimen (OR=2.4, CI95: 1.2–4.9) and iron supplementation (OR=2.6, CI95: 1.4–5.1) are identified both in univariate and multivariate analysis as predictive factors of Hb response. The mean of FACT score improved from 29 (CI95: 26–31) at initiation to 36 (CI95: 34–38) at the end of study (p&lt;0.0001). Thromboembolic events were reported in 2% of patients.
Conclusion: These results confirm the efficacy and safety of epoetin beta in routine practice for anemic patients with a non-myeloid hematological malignancy receiving chemotherapy. Epoetin beta improves the quality of life measured by FACT score.
Potential of Angeli’s Salt To Reduce Nitric Oxide Scavenging in Hemolysis.
Authors: Kim-Shapiro Daniel B. , He Xiaojun , Azarov Ivan , Richardson Jodi , King S. Bruce , Gladwin Mark T. 
Published: April 2020

Abstract
Since cell-free hemoglobin (Hb) scavenges nitric oxide (NO) more effectively than that encapsulated in the red blood cell (RBC), hemolysis reduces NO bioavailability with pathological consequences in sickle cell disease and other hemolytic anemias, paroxysmal nocturnal hemoglobinuria, thalassemia intermedia, malaria, and cardiopulomonary bypass. The ability of the cell-free Hb to scavenge NO is reduced when the Hb is converted from its oxygenated form (HbO2) to its oxidized form, methemoglobin (MetHb). We show that Angeli’s salt (AS) can convert two OxyHb to two MetHb molecules through its release of nitroxyl (HNO). AS also further converts the MetHb to less potentially oxidative forms: nitrite bound MetHb and iron-nitrosyl hemoglobin. We also show that, due to the fast reactivity of HNO with Hb (like NO), AS preferentially reacts with cell-free rather than RBC encapsulated Hb. In conditions simulating sickle cell crisis, within six minutes, AS converted 45 ± 12% of cell-free Hb to non-NO scavenging forms (MetHb and iron-nitrosyl Hb) and only converted 0.4 ± 0.3% of RBC encapsulated Hb (n=3). Similar preferential reactivity was observed under other physiologically relevant conditions. We conclude that, as AS preferentially reacts with cell-free Hb compared to RBC encapsulated Hb, converting it to species that do not effectively scavenge NO, it is has promise as a treatment for increasing NO biavailability in conditions associated with hemolysis.
Phlebotomy and Bolus Subcutaneous Deferoxamine in Algerian Patients with Thalassemia Major or Intermedia or Sickle Cell Disease Treated with Hydroxyurea.
Authors: Bradai Mohamed , Bachir Dora , De Montalembert Mariane 
Published: April 2020

Abstract
Background: Iron chelation with continuous subcutaneous deferoxamine injections is painful and expensive, in particular due to the cost of infusion pumps. Oral chelators are not widely available in Algeria. This prospective study was designed to evaluate the safety and efficacy of bolus subcutaneous deferoxamine (DFO) and phlebotomy in patients with beta-thalassemia major (TM) or intermedia (TI), or sickle cell disease (SCD), treated with hydroxyurea.
Methods: 31 patients were enrolled (22 TM, 5 TI, 4 SCD). Mean hydroxyurea dosage was 17 mg/kg/d [15–24]. Phlebotomy was performed when hemoglobin was &gt;8 g/dL and ferritin &gt;1000 ng/ml; 13 patients met these criteria (5 TM, 4 TI, 4 SCD). One TI patient was not compliant; the 12 remaining patients underwent phlebotomy removing 3 to 7 ml/kg, every 2 to 4 weeks as tolerated. Three mild hypotension episodes were noted. Bolus subcutaneous deferoxamine was given to the 25 patients with adequate health insurance. Mean deferoxamine dosage was 30±6 mg/kg/d, in two daily boluses. Skin nodules developed in 6 patients and a subcutaneous abscess in 1 patient. Blood transfusions were given when hemoglobin was &lt;6g/dL.
Results:
table 1 phlebotomy only DFO only Phlebotomy+DFO N patients 3 TM, 3 TI 17 TM, 2 TI 2 TM, 4 SCD Median age (yrs) 16.5 [7–50] 15 [6–21] 20.5 [15–24] Median F.U. (mos) 27 [12–38] 20 [12–28] 18 [13–23] Median N erythrocyte concentrates transfused during F.U. 0 [0–1] 6 [0–19] 0 Median baseline ferritin (ng/ml) 2800 4130 3760 Median last ferritin (ng/ml) 884 1510 1665
Conclusions: Combination of phlebotomy and bolus subcutaneous deferoxamine very effectively reduced iron overload in patients with TM, TI and SCD. Phlebotomies could be performed in 12 patients thanks to hydroxyurea treatment which had increased their Hb level above 8 g/dL. Such combined therapy can be proposed in countries which can not afford infusion pumps or oral chelators.
3D Nuclear Organization of Telomeres in Hodgkin and Reed-Sternberg Cells.
Authors: Knecht Hans , Sawan Bassem , Lichtensztejn Daniel , Lemieux Bruno , Wellinger Raymund , Mai Sabine 
Published: April 2020

Abstract
Telomerase activity is high in Hodgkin (H) and Reed-Sternberg (RS) cells and abundant telomerase RNA template (hTR) is identified in both by in situ hybridization. However, nothing is known about the three-dimensional (3D) structure of the telomeres in H and RS and the molecular events associated with the transition from the mononuclear H to the multinuclear diagnostic RS are still unclear. We analyzed the 3D structure of telomeres in interphase nuclei in the Hodgkin cell lines HDLM-2, L-428 and L-1236, where about 90 to 99% are mononuclear H and only 1 to 10% are multinuclear RS. We also analyzed the 3D structure of telomeres within 5 mm thin sections of three lymph node biopsies diagnostic for Hodgkin’s disease (HD). The stereometric (3D) organization of telomeres was investigated in 30 H and 30 RS of each cell line and in 30 H and 30 RS of each lymph node biopsy specimen as previously described (Proc Natl Acad Sci USA, 102: 9613). Cellular localization of key-proteins of the telomere localized shelterin-complex (TRF1 and TRF2), of the mitotic spindle (centrin and gamma-tubulin), and of double-stranded DNA breaks (gamma-H2AX), was also analyzed. In all three cell lines the multinuclear RS showed overall significantly shorter and also significantly less telomeres in relation to the total nuclear mass when compared to their mononuclear H precursors. Visualization of their 3D telomeric structure revealed that this difference was due to partial or nearly total loss of telomeres within single nuclei of multinuclear RS; in particular, one or two nearly telomere free nuclei were often adjacent to one or two nuclei displaying several huge telomeric aggregates. TRF1 and TRF2 were mainly cytoplasmic in H and RS whereas gamma-H2AX accumulated in the nuclei of RS but not H. Multiple pairs of centrosomes not correlating with the number of nuclei, as well as high numbers of multi-polar spindles and incomplete spindles were identified in RS. Importantly, results analogous to those described in the HD cell lines were found in the HD lymph node biopsy specimen. In conclusion, our results suggest that multinuclear RS represent end stage tumour cells, where further nuclear division gets impossible due to sustained 3D telomere aggregation, shortening or loss. In particular, the number of nuclei within RS correlates closely with the 3D organization of telomeres, thus allowing for the first time a mechanistic understanding of the transition from H to RS cells. This process is initiated in H and advances to end stage telomere free “ghost” nuclei as observed in many RS. The shelterin complex appears to be disrupted and the mitotic cycle is profoundly disturbed.
CD4+CD26 - T Cell Population in Classical Hodgkin Lymphoma Displays a Distinctive Regulatory T Cell Population.
Authors: Ma Yue , Visser Lydia , Blokzijl Tjasso , Harms Geert , Atayar Cigdem , Poppema Sibrand , van den Berg Anke 
Published: April 2020

Abstract
Introduction: Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) are surrounded by a majority of infiltrating reactive cells, which mainly consists of CD4+ T cells. These T cells express several activation associated surface markers but lack expression of the T cell co-stimulatory molecule CD26. Little is known about the significance of these rosetting CD4+CD26- T cells.
Methods: To characterize these T cells, CD4+CD26- and CD4+CD26+ T cells were sorted from lymph node cell suspensions from 7 cHL and 5 reactive lymph nodes (LN). Of 5 HL cases and 3 lymph nodes, parts of the cells were stimulated with PMA/ionomycin to get activated T cell subsets. mRNA profiles of activated and non-activated T cell populations were evaluated with quantitative RT-PCR for 46 selected genes.
Results: We observed a higher percentage of CD4+CD26- T cells in cHL compared to reactive LN. For the non-activated T cell subsets, CD4+CD26- T cells in cHL showed higher mRNA levels of IL2RA, CTLA4, TNFRSF4 and CCR4 compared to LN. Moreover, these cells displayed low or no expression of the Th1 or Th2 related cytokines IL2, IFNγ, IL13, IL12B, IL4, IL5 and the chemoattractant receptor GPR44. Overall, the profiling results support a regulatory T (Treg) cell type for the CD4+CD26- T cells in cHL. Besides Tregs, Th17 cells may exist in cHL based on the significantly higher IL17 mRNA level for both the CD26- and CD26+ T cells in cHL than in LN. Upon activation, the lack of up-regulation of mRNA levels of most cytokine genes (IFNγ, IL2, IL8, IL21, IL17, IL13, IL12A and IL4) indicated an anergic character for the CD4+CD26− subset in cHL.
Conclusion: A high proportion of CD4+CD26− T cells is characteristic for cHL. No evidence for a Th1 or Th2 cell type is found for these cells but they display a regulatory T cell phenotype. Anergy fits with the regulatory T cell profile of these cells, probably explaining the immunosuppressive mechanism involved in cHL.
Effects of c-Src Overexpression in CD40-Activated Human B Lymphocytes.
Authors: Jung Daniel , Cayer Marie-Pierre , Proulx Maryse , Ma Xue-Zhong , Sakac Darinka , Giguère Jean-Francois , Drouin Mathieu , Neron Sonia , Branch Donald R. 
Published: April 2020

Abstract
The 60-kDa c-Src is the normal human cellular protein counterpart of the highly transforming v-src gene. Recently, c-Src activity was reported to increase in CD40-activated human B cells in the presence of IL-4, suggesting its involvement in proliferation. We report here that c-Src expression is detectable concomitant with the detection of Stat5b and, therefore, Stat5b may serve as a substrate for tyrosine phosphorylation by c-Src, inducing the activation of Stat5b and initiating a transcriptional pathway important for B cell expansion. To elucidate the exact role of c-Src in the proliferation of normal B cells, we undertook c-Src over-expression experiments. Recombinant adenoviruses Ad5/F35 vectors, which we previously reported as highly efficient for B cell transduction, encoding wild-type c-Src(c-Src/WT), constitutively active c-Src(c-Src/CA), dominant negative c-Src(c-Src/DN) or EYFP were constructed. B lymphocytes purified from human peripheral blood were activated with soluble CD154 in the presence or absence of IL-2, IL-4 and IL-10, and infected with the viruses. Real-time PCR and Western blot analysis revealed that vector-transferred c-Src were strongly expressed in infected B cells as early as 48 hours post infection. Kinase assays confirmed that vector-transferred c-Src/WT and c-Src/CA display a strong kinase activity whereas negligible kinase activity was detected with Ad5/F35-c-Src/DN. No significant variation of B cell expansion could be observed between uninfected cells, Ad/F35-EYFP and Ad5/F35-c-Src/CA or Ad5/F35-c-Src/WT infected cells, suggesting that B cell proliferation induced by endogenous c-Src already attains a maximum rate of expansion, which cannot be further enhanced by supplemental exogenous c-Src. In contrast, overexpression of c-Src/DN results in a 40% inhibition of B cell expansion. These results suggest that transgenic dominant negative c-Src may compete with endogenous c-Src resulting in a partial inhibition of a transcriptional pathway involved in B cell proliferation. In conclusion, our results confirm an important role for c-Src in the expansion of normal human B cells in vitro.
KIR Positive Subsets of Human CD56+CD3+ NKT Cells Are Different in Frequency from Equivalant KIR Positive CD56+CD3- NK Cell Subsets.
Authors: Bondzio Ilka , Arendt Andreas , Schmitz Jurgen , Huppert Volker 
Published: April 2020

Abstract
Killer cell immunoglobulin-like receptors (KIRs) are known to modulate the cytotoxic ability of human Natural Killer (NK) cells, as well as a subset of T cells. To date, only a very small number of publications have discussed the role of KIRs on T cells, e.g. CMV-specific CD4+CD28-KIR+ cytotoxic T cells (van Bergen, J., J Immunol. 2004), so we investigated whether CD56+CD3+ NKT cells might also have KIR-positive subsets. Whole human blood as well as magnetically sorted human CD56+CD3+ NKT cells were analyzed for their expression of various KIR molecules using a novel panel of fluorochrome-conjugated, anti-KIR monoclonal antibodies (CD158a/h (KIR2DL1/DS1), CD158b (KIR2DL2), CD158e (KIR3DL1), CD158i (KIR2DS4), KIR2D; Miltenyi Biotec). KIR-positive CD56+CD3+ NKT cells were identified in every donor tested. Donors possessing NK cells of a specific KIR phenotype also possessed CD56+CD3+ NKT cells with the same KIR phenotype. KIRs were also expressed in a clonal fashion on CD56+CD3+ NKT cells, similarly to NK cells. The investigated KIRs were also shown to be expressed on unseparated NK and CD56+CD3+ NKT cells from whole blood. In addition, the ratio between KIR expression on NK and CD56+CD3+ NKT cells was calculated for each donor analyzed. The results show that there is no correlation between the frequencies of KIR expression on NK cells with that of CD56+CD3+ NKT cells. For example, the expression of CD158a/h in one donor was found to be the highest of all CD56+CD3+ NKT cells analyzed, but the lowest of all NK cells by comparison to the other donors tested. For all KIR phenotypes analyzed, the frequency of KIR+ NK cells was higher than the frequency of KIR+ CD56+CD3+ NKT cells in all samples (range: 1.1 to 25.3-fold higher). Interestingly, the frequency of KIR+ NK cells versus KIR+ CD56+CD3+ NKT cells differs significantly between donors: in one donor the frequency of KIR expression is between 7.3 to 25.3-fold higher in NK cells for multiple KIR phenotypes, while this range is more narrow in other donors (2.0–5.4-fold higher). The frequencies of CD56+CD3+ NKT cell subsets staining positive for particular KIRs differ significantly between donors, e.g. for CD158b, the number of positive CD56+CD3+ NKT cells fall within a range of 4.8% to 43.3%. For CD56+CD3+ NKT cells sorted with MACS® Technology, a similarly wide-ranging distribution of CD158b (KIR2DL2) expression was found (0.85%–5.82%), though at a lower level. Further research will be required to explore these differences as they may point to different mechanisms of KIR regulation. The identification of KIR-positive CD56+CD3+ NKT cells may also provide an opportunity for their use for functional KIR studies instead of NK cell clones, as the cloning of CD56+CD3+ NKT cells may prove easier (i.e. using standard T cell cloning methods) than that of NK cells.
Irreversible Platelet Activation Requires PAR1 Regulation of Phosphatidylinositol Phosphates (PIPns) Activation of Rap1.
Authors: Holinstat Michael , Hudson W. James , Preininger Anita M. , Hamm Heidi E. 
Published: April 2020

Abstract
Thrombin is the most potent activator of platelets, through reversible and then irreversible aggregation and mediates a diverse range of vascular effects which may result in acute coronary syndrome and stroke. We demonstrate that PAR1 signals human platelet activation through generation of a phosphatidylinositol phosphate signaling pathway; inhibition of this pathway blocked the formation of a stable platelet aggregate. Early Rap1 activation and platelet aggregation are insensitive to perturbations along the PI-kinase pathway, while stable aggregate formation requires this pathway. Computational lipidomics identified a single phosphatidic acid species required for PAR1-, but not PAR4-mediated Rap1 activation and platelet aggregation. Both PI5K and PI3Kg were required for stable PAR1-mediated platelet aggregation, and we show that these enzymes are present in a complex with activated Rap1. This novel lipid signaling pathway is a potential target for anti-platelet therapy.
Phase II Study of R-CHOP Followed by 90Y-Ibritumomab Tiuxetan in Untreated Mantle Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499.
Authors: Smith Mitchell R. , Zhang Lijun , Gordon Leo I. , Foran James , Kahl Brad , Gascoyne Randy D. , Advani Ranjana , Paietta Elisabeth , Weller Edie , Horning Sandra J. 
Published: April 2020

Abstract
Background: As MCL has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate,90Y-ibritumomab tiuxetan (90Y-RIT), following 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction.
Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) ≥18 yr with measurable/evaluable disease and adequate organ function were eligible. At 4–8 weeks after 4 cycles of R-CHOP, responding (CR/PR) and stable pt received 0.4 mCi/kg 90Y-RIT. The primary endpoint was failure-free survival (FFS) and secondary objectives were evaluation of response and toxicity after R-CHOP and after 90Y-RIT. The study design required 52 eligible pt to demonstrate a prolongation of FFS by 50% compared with R-CHOP alone (median FFS 16 mo, Howard et al., JCO20:1288, 2002).
Results: The characteristics of 56 eligible pt are: 73% male, median age 61 (33–83) yrs, 91% stage III/IV, 68% &gt;1 extranodal site, 78% marrow-positive. IPI was 0–2 in 51%, 3–5 in 49%. Fifty-one (91%) pt received all treatment and best response (n=50) was 42% CR/CRu, 32% PR, 12% stable and 4% unevaluable, with an improvement in response in 16 pt after 90Y-RIT. After 90Y-RIT, 55% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 22/23 pt. Median follow-up (all pt) is 24.4 months. Median FFS for all 56 pt is 27 months with an estimated 71% FFS and 93% overall survival at 18 months. Among pt who completed all treatment and have been followed ≥1.5 yr (n=45), 33 remain failure-free and 12 have progressed (4 dead).
Conclusions: 90Y RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. These data suggest prolongation of FFS over that expected with R-CHOP alone. Consolidation of remission in MCL with 90Y-RIT shows potential as a strategy to prolong remission duration and is applicable to most pt with MCL. However, longer follow-up in needed to evaluate the durability of remissions achieved.
Platelet Septins: Interaction of the Human Septins SEPT5, SEPT7 and SEPT11.
Authors: Zieger Barbara , Bartsch Ingrid , Bläser Susanne , Anja Busse , Roeseler Sabrina , Bauer Heike , Lieber Mareike , Brendle Cornelia 
Published: April 2020

Abstract
Septins are GTP-binding proteins which form heteropolymeric complexes. In non-dividing cells (such as platelets and neurons) septins are implicated in exocytosis. The SEPT4, SEPT5 and SEPT8 are expressed in platelets. Platelets from a SEPT5 knockout mouse showed an altered serotonin secretion and platelet aggregation suggesting that SEPT5 is involved in secretion in platelets. Transmission electron microscopy of platelets revealed that SEPT4, SEPT5 and SEPT8 are localized surrounding alpha-granules suggesting that the three septins may be components of the septin complex in platelets and contribute in such a way to platelet biology. Activation of platelets by agonists resulted in the translocation of SEPT4 and SEPT8 to the platelet surface indicating a possible functional role of these proteins in granular secretion. Previously, we identified the interaction of SEPT5 with SEPT8 and showed that SEPT5 partners with SEPT11. The aim of this study was to identify other interaction partners of SEPT11. Using the yeast two-hybrid system we demonstrate that SEPT11 partners with SEPT7. Western analysis revealed that SEPT7 is also expressed in platelets. The molecular interaction of SEPT11 with SEPT7 was verified by precipitation of the SEPT7/SEPT11 complex from lysates of human platelets. Since SEPT5, SEPT7 and SEPT11 are members of the same septin complex and since SEPT5, SEPT7 and SEPT11 are expressed in platelets, SEPT5, SEPT7 and SEPT11 may play an important role in exocytosis in platelets.