bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Rituximab and/or High-Dose Therapy with Autotransplant at Time of Relapse in Patients with Follicular Lymphoma.
Authors: Coiffier Bertrand , Brice Pauline , Delarue Richard , Haioun Corinne , Souleau Bertrand , Mounier Nicolas , Feugier Pierre , Tilly Hervé , Sebban Catherine 
Published: April 2020

Abstract
Follicular lymphoma (FL) is considered as an incurable disease but treatments have changed with the introduction of high-dose therapy with autologous stem cell transplant (HDT) then of rituximab (RTX). The effect of these 2 strategies on the outcome of FL patients is well described in first line but not for relapsing patients. We analyzed 2 cohorts of patients treated in 2 successive randomized studies with the same treatment, CHVP plus interferon, to evaluate the role of RTX and HDT in first disease progression or relapse. Of the 364 patients &lt;61 years old included in these 2 studies, 255 progressed or relapsed and constitute the analyzed population. Among them, 93 had been treated with HDT, 63 with RTX alone or combined with chemotherapy, and 30 with RTX followed by HDT. Characteristics of the patients were similar in all subgroups. If event-free survival (EFS) was similar in patients treated within GELF-86 or GELF-94 studies(10-year EFS of 20% and 23%), overall survival (OS) was longer in GELF-94 study (10-year OS of 66% compared to 48%, p=0.014) witnessing a change in the management of relapsing patients. HDT was associated with a statistically significant benefit in terms of event-free survival from relapse (EFSR) and survival after relapse (SAR), p=0.004 and p=0.01, respectively (Table). Rituximab during salvage therapy was associated with a larger benefit than HDT for these 2 endpoints: p&lt;0.0001 and p&lt;0.0001, respectively. When both treatments were combined, 5-year SAR is over 90% (Table). In follicular lymphoma patients treated with chemotherapy in first line, the combination of salvage regimen containing rituximab followed by HDT seems to be superior to rituximab-containing chemotherapy alone. These retrospective results must be confirmed within a prospective study.
Salvage without rituximab without HDT (A) Salvage without rituximab with HDT (B) Salvage with rituximab without HDT (C) Salvage with rituximab * p values between A and C =0.0002 and &lt;0.0001 for EFSR and SAR, respectively; p values between B and D &lt;0.05 and =0.01 for EFSR and SAR, respectively Patients 87 59 29 30 5-year&#x2028; EFSR 24% (15–34) 44% (31–56) 42% (21–62) 67% (42–86) 5-year&#x2028; SAR 32% (22–42) 62% (45–73) 70% (42–86) 92% (71–98) Figure Figure
Study on Dendritic Cells in Peripheral Blood of the Patients with Autoimmune Hemolytic Anemia/Evans Syndromes.
Authors: Shao Zonghong , Xing Limin , Wang Huaquan , Tu Meifeng , Fu Rong 
Published: April 2020

Abstract
Objective To study the alteration of the numbers and the subsets of DCs in perpheral blood of the patients with AIHA/Evans syndromes and also the costimulation molecules on the surface of DCs.
Methods Labeled with three-color immune monoclonal antibodies, total DC, pDC and mDC in the peripheral blood (PB) of 14 cases with AIHA and 21 normal controls were detected by Facs. The expressions of CD80, CD86 andCD40 on DCs in the PB of 14 cases with AIHA/Evans syndomes and 6 normal controls were detected.
Results The percentage of the total DCs in the PB (DC/PBMNC) of AIHA/Evans syndromes cases((11.41±3.91)%)was significantly higher than that of in the normal controls((1.95±0.66)%) (t=2.384, p=0.032).mDC in the PB of the AIHA/Evans syndromes patients ((10.29±3.90)%) was significantly higher than that of controls((1.26±0.46)%)(t=2.297, p=0.038). But pDC in the PB of AIHA/Evans cases((1.12±0.68)%)was not different from that of controls((0.68±0.23)%)(t=0.612, p=0.55). The proportion of pDC to DC in the PB of the patients((21.26±5.99)%)was significant lower than that of normal controls((40±3.14)%)(t=2.77, p=0.012). Whereas, the proportion of mDC to DC in the PB of the patients((75.93±6.79)%)was higher than that of normal controls((59.99±3.23)%)(t=2.77, p=0.012). mDC in the PB of normal controls((1.26±0.46)%) was not different from their pDC((0.68±0.23)%). mDC of the patient with AIHA/Evans cases((10.29±3.90)%) was higher than their pDC((1.12±0.68)%)(t=2.316, p=0.036). CD80, CD86 and CD40 expressions on DCs in PB of AIHA/Evans syndromes patients were (7.63±4.71)%, (13.55±4.57)% and (1.68±1.04)% respectively. Those of normal controls were (1.24±0.70)%, (3.21±1.55)% and (0.28±0.16)% respectively. There was a significant difference of the expression of CD86 between the patients and control groups (t=2.142, p=0.048).
Conclusions DCs, particularly mDCs, in the PB of AIHA/Evans syndromes patients significantly increased. The patients with AIHA/Evans syndromes have more activated DCs in their PB, on which costimulatory molecules, mainly CD86 are over expressed.
Generation of Influenza HA-Specific Lymphocytes from Autologous Umbilical Cord Blood-Derived Dendritic Cells.
Authors: Decker William K. , Li Sufang , Xing Dongxia , Robinson Simon N. , Yang Hong , Steiner David , Bollard Catherine M. , Shpall Elizabeth J. , Safdar Amar 
Published: April 2020

Abstract
INTRODUCTION: Umbilical cord blood transplantation (CBT) is being performed with increasing frequency for patients lacking HLA-matched donors. CBT is associated with delayed immune reconstitution and high rates of viral infections. Particularly problematic is the reactivation of latent viral infections such as CMV, EBV, and VZV, as is overt infection from common agents like adenovirus and influenza. To address these issues, we proposed to generate influenza-specific CB T-cells ex vivo for potential cell therapy applications, allowing for effective therapeutic interventions until such time that immune reconstitution has occurred.
METHODS: Dendritic cells (DC) were generated from both the adherent and the CD14+ CB fractions cultured in AIM-V medium supplemented with human serum, GM-CSF, and IL-4. Antigen loading was performed by incubation with recombinant, purified A/New Caledonia HA antigen. Maturation was performed with the ITIP inflammatory cocktail (IL-1β, TNF-α, IL-6, and PGE2). Autologous CB lymphocytes were co-cultured with mature DC at a ratio of 10:1 for 4 days in IL-12 after which they were expanded in a cytokine cocktail of IL-2, IL-7, IL-12, and IL-15. Lymphocytes were restimulated similarly every 7-10 days. Antigen specificity was demonstrated by IFN-γ ELISpot.
RESULTS: Mature DC expressed the appropriate markers including CD80, CD83, CD86, CD209, and HLA-DR. Some DC expressed CD14, others CD11c, an indication of a mixed interstitial/Langerhans myeloid phenotype. We demonstrated a 4–10 fold enhancement of IFN-γ ELISpots when primed lymphocytes were incubated with HA-loaded DC in comparison to autologous unloaded DC (p&lt;0.003) or loaded allogeneic DC (p&lt;0.0001). The CD8 content of the HA-specific lines was typically greater than 50% after two stimulations. At the time of phenotyping CD3+ cells were primarily CD62LposCD197(CCR7)neg and CD127(IL-7Rα)neg, an effector phenotype; however, 6–22% of cells expressed CD127 (effector or central memory), and up to 6% of cells were CD62LposCD197pos (central memory).
CONCLUSIONS: The results demonstrate that, despite the generally naïve nature of CB lymphocytes, influenza-specific responses can be generated ex vivo, and could potentially be used clinically in CBT patients who develop infectious complications prior to immune reconstitution.
European MCL Network: An Update on Current First Line Trials.
Authors: Dreyling Martin H. , Hoster Eva , Hermine Olivier , Kluin-Nelemans J.C. , Walewski Jan , Trneny Marek , Geisler Christian H. , Unterhalt Michael , Hiddemann Wolfgang 
Published: April 2020

Abstract
Background: Conventional chemotherapy achieves only short term remission despite high initial response rates of 70%–80%. In the current study generation, the European MCL Network investigates the impact of various combined immuno-chemotherapy regimens. Additionally, in elderly patients the role of rituximab maintenance is being evaluated, whereas in younger patients dose-intensified regimens with implementation of high dose cytarabine are investigated based on the excellent results of the HyperCVAD regimen.
Methods: In MCL elderly, patients are initially randomized between 8 cycles of R-CHOP or 6 cycles of R-FC (experimental arm). Patients who achieve either an PR or CR, receive subsequently either interferon maintenance (standard arm) or a single rituximab dose every 2 months. In MCL younger, the standard arm (R-CHOP induction followed by myeloablative consolidation: 12 Gray TBI, 2x 60mg/kg cyclophosphamide) is compared to the implementation of high dose cytarabine into induction (R-CHOP/R-DHAP) and consolidation (10 Gray TBI, 4x1,5 g/m2 Ara-C, 140mg/m2 melphalan).
Results: In MCL elderly, 222 of 263 patients were evaluable based on the annual interim analysis. Median age was 70 years with 66% of patients displaying an intermediate high/high risk IPI. Induction was well tolerated with mainly hematological toxicity (grade III/IV in R-CHOP/R-FC): Leukocytopenia 62/72%, thrombocytopenia 13%/40%, but only rare febrile neutropenia (23%/7%) or infections (19%/23%). Despite the poor risk profile, combined immuno-chemotherapy (total group) achieved a remarkable 84% response rate (51% CR/CRu). Although the impact of maintenance is not yet evaluable, both progression-free and overall survival were encouraging with 77% and 86% at 12 months, respectively. In MCL younger, 247 of 271 patients were evaluable. Again, toxicity (grade III/IV in R-CHOP/alternating R-DHAP) was mainly hematological: leukocytopenia 58/77%, thrombocytopenia 14%/74%, but only rare febrile neutropenia (11%/22%) or infections (5%/7%). Combined immuno-chemotherapy achieved a 93% response rate (60% CR/CRu) before subsequent high dose consolidation. Again, both progression-free and overall survival are remarkable with both 90% at 12 months, respectively.
Discussion: Combined immuno-chemotherapy results in high response rates in two prospective international trials. Further recruitment and follow-up will determine the role of rituximab maintenance and high dose cytarabine in this distinct subtype of malignant lymphoma.
Identification of Transcriptional Targets of IRF8 in Germinal Center B Cells.
Authors: Shin Dong-Mi , Lee Chang Hoon , Abbasi Sadia , Morse Herbert 
Published: April 2020

Abstract
The development and function of cells of the innate and adaptive immune systems are governed by a series of hierarchical regulatory networks. The components of these networks are particularly well understood for the very early as well as the terminal stages of B cell differentiation; however, information regarding the set of regulatory factors governing B cell fate from the pro-B through the germinal center (GC) stage of differentiation is less well developed. A previous study identified IRF8 as an important component of the network as it contributes to the direct transcriptional activation of BCL6 and AID, key elements of the GC reaction. To identify additional targets of IRF8, we used the chromatin immunoprecipitation (ChIP)-on-Chip approach to study three human cell lines of GC origin - Ly1, Odh1 and Val - and the multiple myeloma cell line, MMS1. By coupling this study with ChIP-on-chip analysis for POLII using the same cell lines, we identified 248 transcriptionally active IRF8 targets. They comprised both known targets, such as B2M and ISGF3G, and a spectrum of novel targets that included important elements of innate immune responses such as RIG-1 and MDA-5. A functional classification of IRF8 targets by GO and a comparison of the GO term frequency with the global frequency in the human genome showed that IRF8 targets were significantly enriched in genes regulating the immune response, effecting DNA repair, and governing transcription. These results significantly enhance our understanding of the roles played by IRF8 in the transcriptional regulation of GC B cells, and identify innate immune mechanisms that contribute to their adaptive immune functions.
Characterization of Immune Reconstitution Following High Dose Chemotherapy in Acute Myeloid Leukemia.
Authors: Meyer Christian F. , Thoburn Christopher , Kos Ferdynand , Gocke Christopher , Levitsky Hyam I. , Briel Janet A. , Hess Allan , Karp Judith E. 
Published: April 2020

Abstract
Recovery of immune function after initial treatment of acute myeloid leukemia (AML) is critical, not only for protection against infections but also for surveillance against recurrent disease. A better understanding of the nature of lymphocyte recovery following induction and consolidation therapy for AML could guide the design of immunotherapy strategies aimed at boosting the anti-leukemia activity of a reconstituted immune system. Prior studies examining thymic T cell production following bone marrow transplantation (BMT) have found varying levels of thymic output post-transplant, as measured by T cell Receptor Excision Circle (TREC) levels in the peripheral blood of adult patients. Of note, relapse of chronic myeloid leukemia (CML) following BMT is correlated with decreased levels of TREC positive T cells. In order to characterize immune reconstitution in AML, we studied 26 patients after induction or consolidation time sequential chemotherapy. Their median age was 52 (range 23–69). Thirteen patients received cytarabine, daunorubicin, and etoposide (AcDVP-16) induction therapy, 3 patients received cytarabine, daunorubicin, and cytarabine (AcDAc) consolidation therapy and 10 patients received flavopiridol, cytarabine, and mitoxantrone (FLAM) either as induction or consolidation therapy. Peripheral blood samples were collected approximately every other day for 3–5 time points after each patient’s white blood cell count exceeded 200 cells/cubic mm on three consecutive days. Among the four patients evaluated to date, flow cytometry results show that a majority of cells seen early in immune reconstitution are CD3+ lymphocytes (range 69–97%). Subset analyses on 3 of these 4 patients have shown CD4:CD8 ratios ranging from 3:1 to 4:1, while the fourth patient exhibited an inverse of this ratio at 1:5. In addition, CD25+FOXP3+ T cells represented a median of 5.1% (range 2.5–12.3%) of the CD3+ T cells. Since T cells represented the abundance of cells in the peripheral blood during early bone marrow recovery, we then assessed whether these cells represented recent thymic emigrants or naïve T cells by examining TRECs using real time PCR (RT-PCR). TRECs were present in 24 of the 26 patients with levels ranging between 100 and 100,000 copies per 100,000 cells. Furthermore, 4 control samples from normal volunteers (ages 37–43) revealed the absence of TREC positive cells. Further analyses of these time points and correlations between TREC levels and clinical responses are ongoing.
Proteomics in the Study of Qualitative Platelet Defects: Validation of the Approach in the Gray Platelet Syndrome and Quebec Platelet Disorder.
Authors: Kasthuri Raj S. , Anderson Lorraine B. , Higgins LeeAnn , Di Paola Jorge , Rivard Georges E. , Hayward Catherine P.M. , Key Nigel S. 
Published: April 2020

Abstract
Qualitative platelet defects are a heterogeneous group of disorders characterized by abnormal platelet function. Currently available laboratory assays lack sensitivity and specificity for detecting Storage Pool and Platelet Secretion defects. The Gray Platelet Syndrome (GPS) is an autosomal recessive disorder characterized by a decrease or absence of alpha granule contents. The Quebec Platelet Disorder (QPD) results from proteolysis of alpha granule proteins due to increased amounts of platelet urokinase. A decrease or deficiency of multimerin is characteristic. Proteomics is a rapidly developing field with great promise in the study of pathophysiology and biomarker development. Recent advances have made measurement of relative protein abundance in multiple samples feasible. We used one such approach, “isotope Tagging for Relative and Absolute Quantitation” (iTRAQ) to characterize the platelet proteome of healthy volunteers and patients with GPS and QPD. iTRAQ allows analysis of up to 4 different samples simultaneously, and differences in protein abundance as low as 20% are reliably detected. The platelet proteomes of 4 healthy volunteers were analyzed. Platelet proteome analysis of study patients was as follows;
2 GPS patients compared to 2 controls; 2 heterozygous GPS patients compared to a homozygote and a control; and 3 QPD patients compared to a control.
For comparison, platelet proteins were grouped by location into 3 groups - receptor, alpha granule and cytoskeletal proteins. The results are shown in the figure. Protein abundance in healthy volunteers was very consistent, with inter-individual variability ≤ 20%. Distribution of receptor and cytoskeletal proteins in GPS patients mirrored the controls, but alpha granule proteins were significantly decreased as expected. Comparison of homozygous to heterozygous GPS platelets showed this to be true only in the homozygotes, again, as expected (figure inset). Variable decreases in alpha granule proteins were observed in QPD patients but this was less profound. Multimerin was detected in QPD patients, but at levels significantly lower than controls. While urokinase was not detected in QPD platelets in this study, it was detected in a parallel study evaluating platelet releasates. The iTRAQ technique was reproducible and yielded consistent results, but currently is a relatively expensive and time-consuming approach. In summary, our results suggest that the platelet proteome is tightly regulated and very stable in healthy individuals. A significant decrease in alpha granule proteins was noted in patients with GPS but this was less remarkable in the QPD group, probably because peptides resulting from urokinase-mediated proteolysis are still labeled and quantified.
Figure Figure
Platelet-Derived Microparticles Induce Angiogenesis In Vitro and In Vivo.
Authors: Chen Bao-An , Zhong Yue-Jiao , Huang Cheng-Yin , Gao Feng , Chen Jian , Gao Chong , Sun Yun-Yu , Wang Jun , Zhao Gang , Ding Jia-Hua , Chen Ning-Na , Pei Xiao-Ping 
Published: April 2020

Abstract
Objective: An attempt was made to investigate the effect of platelet-derived microparticles (PMPs) on the angiogenesis.
Methods: Thrombin was adopted to activate the platelets to release PMPs. Flow cytometry(FCM)was adopted to evaluate the efficiencies of different concentrations of thrombin to produce PMPs and BCA was adopted to evaluate the content of PMPs. By the carrier of human umbilical vein cell line ECV-304 cultivated in vitro, investigate the effect of PMPs on the proliferation and apoptosis of human umbilical vein endothelial cells using MTT and FCM. PMPs were put into CAM and observe the effects of PMPs on angiogenesis in Chick embryo chorioallantoic membrane (CAM).
Results: The efficiencies of PMPs activated by 1.0U/ml thrombin were 50.1%; PMPs induced proliferation of human umbilical vein cell line ECV-304 in a dose dependent manner. At the concentration of 40ug/ml PMPs, the proliferation rate of human umbilical vein cell line ECV-304 was as 1.8±0.3 times as control and there was no difference with the group of vascular endothelial growth factor (VEGF),which the proliferation rate was 1.9±0.5 times vs. control, p &gt; 0.05;PMPs inhibited human umbilical vein cell line ECV-304 apoptosis. Compared with control group (apoptosis rate 9.4%±0.5%), apoptosis rate of PMPs (40μg/ml) is 3.9%±0.4%, which was significantly reduced, p&lt;0.05. The addition of VEGF (10μl/ml) did not successfully prevented apoptosis of human umbilical vein cell line ECV-304 (apoptosis rate 8.0%±0.8%);After 72 h of incubation, showing an implant of PMPs by allantoic vessels developing radially towards it (implant) in a ’spoked-wheel’ pattern, at the concentration of 80μg/ml PMPs, number of vessel ramification is 112.5±11.31 and vessel area/CAM area is (6.19±1.29)%, compared with the VEGF(p&gt;0.05). But there are not localized allantoic vessels developing in the NS control group(P&lt;0.05).
Conclusion: 1.0U/ml thrombin activated platelet could get the best efficiency of PMPs, which could stimulate proliferation of human umbilical vein cell line ECV-304 and inhibit its apoptosis and PMPs have certain promotive effect on the formation of capillary in chick chorioallantoic membranes.
Effect of Acute Inflammation Induced by Prolonged Exercise on Circulating Stem/Progenitor Cells That Mediate Tissue Repair.
Authors: Papassotiriou Ioannis , Spiropoulos Antonia , Tsironi Maria , Skenderi Katerina , Margeli Alexandra , Graphakos Stelios , Baltopoulos Panayiotis , Goussetis Evgenios 
Published: April 2020

Abstract
The “Spartathlon” ultradistance foot race (246 Km continuous, prolonged, brisk exercise for up to 36 hours) provides a unique model of prolonged duration exercise that reveals dramatic systemic inflammatory changes. Endothelial progenitor cells (EPCs) have been shown to participate in vascular repair and angiogenesis, while circulating bone marrow originated fibrocytes represent multipotent cells mediating tissue repair and remodeling after injury. In this study we investigated the effect of this type of exercise on the number of circulating EPCs and fibrocytes along with molecules of endothelium dysfunction and chemotactic proteins in 10 “Spartathlon” athletes before, at the end and at 48 h post race. The EPCs were obtained by culturing peripheral blood mononuclear cells (PBMC) under endothelial cell conditions (EndoCult) and were measured as colony-forming units (CFUs). Circulating fibrocytes were cultured from PBMCs in IMDM medium supplemented with IL-3 and M-CSF and identified as CD45+CD14+CD34lowCollagen-I+ fibroblastic cells. We also determined the plasma levels of E-, L- and P-selectins, sICAM-1, sVCAM-1, thrombomodulin, lipocalin-2, IL-8 and MCP-1 with appropriate methodology. Circulating EPCs increased by nearly ten-fold in peripheral blood at the end of the “Spartathlon” race (from 48±15 cells/ml to 464±36 cells/ml) and they remained increased (420±28 cells/ml) even at 48h post race. The percentage of the CD45+CD14+CD34lowCollagen-I+ fibrocytes cultured from PBMCs before, at the end, and 48 h post race did not reveal any significant difference (64.5±6.2% vs 70.8±8.5% vs 68±4.8% respectively). Plasma levels of lipocalin-2, IL-8, MCP-1, E-selectin, sICAM, sVCAM and thrombomodulin were increased significantly at the end of the race and returned at the pre race levels 48 h post race, while L- and P-selectins remained unaffected before and at the end of the race, presenting a similar decline at 48 h post race. Our study demonstrates that acute inflammatory tissue damage induced by exhausting exercise increases EPCs but not fibrocytes. Given the ability of EPCs to promote angiogenesis and vascular regeneration and the association of fibrocytes with tissue fibrosis after persistent inflammation, we conclude that this kind of repair cell mobilization may serve as a physiologic repair mechanism in acute inflammatory tissue injury.