bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression and Activation of the Farnsesoid X Receptor in Human Dendritic Cells.
Authors: Ziros Panos , Micheva Ilina , Habeos Ioannis , Papavasiliou Athanasios , Zoumbos Nicholas 
Published: October 2019

Abstract
Baground: The farnesoid X receptor/bile acid receptor (FXR, NR1H4) is a member of the nuclear hormone superfamily that regulates bile acid as well as lipoprotein and glucose metabolism after heterodimerization with retinoid X receptor. Dendritic cells (DCs) are potent antigen presenting cells capable of regulating immune responses. It has previously been reported that spleen, a tissue rich in DCs, expresses FXR. Taking this into account, we wanted to investigate the possible involvement of FXR in DCs biology.
Material and Methods: Immature DCs were generated from peripheral human blood monocytes (CD14+ cells) by culturing them with GM-CSF and IL4 for 7 days. For maturation, immature DCs were cultured with the addition of TNFα, and LPS for another 24 hours. The expression and activity of FXR in DCs was assessed with RT-PCR, western immunoblotting, immunofluoresence and EMSA analysis.
Results and Discusion:We have shown with RT-PCR that FXR is marginally expressed in human monocytes (CD14+ cells) and its expression is elevated during the differentiation process of these to dendritic cells. Moreover, using specific primers we have found that only FXR -alpha and not FXR-beta is expressed in DCs. Western blot analysis with a specific anti-FXR antibody confirmed the FXR expression in DCs. Immunofluoresence microscopy with a specific anti-FXR antibody showed that FXR, in contrast with the classical FXR-expressing tissues (liver, kidney), has strong cytoplasmic and perinuclear localization and weak nuclear localization in DCs. The nuclear localization is potentiated upon treatment of the immature dendritic cells with LPS or TNFα. Finally, using a DNA probe that contains consensus FXR binding sites, we have shown with EMSA analysis that FXR is transcriptional active in immature DCs but not in CD14 monocytes, and is strongly activated upon LPS or TNFα treatment for 48 h of immature DCs. Overall our study reveals, for the first time, that FXR, a nuclear hormone receptor with a limited tissue expression, might have a new role in DCs biology, since it is not only expressed in human dendritic cells but moreover its transcriptional activity is affected by signals (TNFα, LPS) that influence the function of DCs.
Rituximab Maintenance Therapy in CD20+ B-Cell Non-Hodgkin’s Lymphoma.
Authors: Trajkova Sanja A. , Cevreska Lidija A. , Panovska-Stavridis Irina Z. , Pivkova Aleksandra , Georgievski Borce , Karanfilski Oliver B. , Stojanovic Aleksandar T. 
Published: October 2019

Abstract
Purpose: Clinical and pharmacokinetic data suggest that high serum concentrations of rituximab and prolonged exposure to rituximab are associated with higher response rates and improved quality of response. We used rituximab-maintenance therapy to target minimal residual disease, with the aim of increasing the duration of remissions achieved following initial treatment.
Methods: During 2001–2005, 14 patients with CD20+ B-cell non-Hodgkin’s lymphoma (seven with diffuse large B cell lymphoma [DLBCL] and seven with follicular lymphoma [FL]) were enrolled in the study. Patients with DLBCL and FL were required to have a CR or PR, respectively, following initial treatment. The most common initial treatments were R-CHOP, R-FC or CHOP. Rituximab-maintenance therapy was administered as 375mg/m2 doses every 3 months for 2 years. Three patients with aggressive DLBCL were treated with high-dose chemotherapy/autologous stem-cell transplantation (HDT/ASCT) and received rituximab-maintenance therapy every 2 months for four doses in total.
Results: Most patients had disease of Ann Arbor stage ≥ 3 (two FL patients stage I). In patients with DLBCL, median event-free and overall survivals were 22.1 months and 22.3 months, respectively, with the corresponding values being 20.6 months and 26.1 months in patients with FL. To date, 13 patients are in continuous clinical remission and only one patient has relapsed.
Conclusions: Rituximab-maintenance therapy is effective and well tolerated in this setting. Recruitment for this study is ongoing and evaluation of a larger patient population, together with a longer follow-up, will determine whether this treatment approach has curative potential.
Concomitant Administration of Recombinant Human Erythropoietin (rHuEPO) and Oral Iron Chelator Deferiprone May Stabilize Iron Balance in Transfusion Dependent Patients with Early Myelodysplastic Syndrome (MDS).
Authors: Cermak Jaroslav 
Published: October 2019

Abstract
Eight transfusion dependent patients with refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) subtypes of MDS (according to the FAB classification) with serum ferritin ranging from 1630 to 4227 μg/l were treated with oral iron chelator deferiprone (Ferriprox, Apotex Ltd., Canada) in a daily dose of 75–80 mg/kg for at least 12 months. Beginning the second month of therapy, rHuEPO (Eprex, Cilag AG, Switzerland or NeoRecormon, Roche Diagnostic, Germany) was administered concomitantly with deferiprone in a dose of 10 000 IU 3 times per week. A significant increase in urinary iron excrection after addition of rHuEPO compared to treatment with deferiprone as a single agent was observed in all patients and the amount of excreted iron ranged from 7.5mg to almost 20mg per day. In one patient with complete response to rHuEPO (Hb > 115 g/l + transfusion independence) and in another patient with partial response resulting in transfusion independence, serum ferritin level decreased from 3034 to 1872 μg/l and from 2086 to 879 μg/l, respectively. The results corresponded with a moderate decrease in liver iron documented by NMR imaging. In 6 patients who did not respond to rHuEPO and remained transfusion dependent a simultaneous administration of rHuEPO and deferiprone enabled to stablize serum ferritin level despite continuing iron load from transfusions. The treatment was well tolerated except one patient, in whom adverse GIT symptoms led to cessation of deferiprone administration after 4 months of treatment. The ability of deferiprone to bind intracellular iron that may be either excreted from the body or donated to partially saturated transferrin for utilization in bone marrow for rHuEPO stimulated erythropoiesis on one hand and an increased excretion of deferiprone chelated non transferrin bound iron originating from an increased amount of destroyed red blood cells on the other hand may be a possible explanation of observed phenomenon. A concomitant administration of rHuEPO and deferiprone might be an effective tool for maintaining iron balance in transfusion dependent iron overloaded patients with early MDS who are not indicated for intensive treatment.
Adoptive Immunotherapy with Donor Lymphocyte Infusion after Allogeneic Nonmyeloablative Stem Cell Transplantation.
Authors: Qiao Zhenhua , Zheng Zhuanzhen , Ye Fang , Ma Liangming , Gong Rong 
Published: October 2019

Abstract
Purpose: To explore the efficacy and toxicity of adoptive immunotherapy with donor lymphocyte infusion(DLI) after allogeneic nonmyeloablative stem cell transplantation (allo-NST).
Methods: We retrospectively sum up the clinical data of 28 patients who had been performed with allo-NST among 41 patients and had been treated with DLI for 72 times between October 1999 and October 2004. Among these patients, there are 20 chronic myeloid leukemia (CML), 16 acute leukemia (AL), 2 multiple myeloma (MM) and 3 solid tumor. We used two different preparative regimens with or without Fludarabin. Cyclosporin A and MMF were used in the prevention of graft versus host disease (GVHD). The median dose of DLI was positive CD3 cells 2.7×107/kg (1.0×107/kg–2.0×108/kg). According to the patients’ situation and chimerism, we divided these patients into two groups, one group included 15 patients whose chimerism decreased for the reason of disease relapsed or advanced, the other included 13 patients whose chimerism decreased because of disease remission or stable. We analysis the change of chimerism and patients’ situation after DLI and the side effects of DLI.
Results: Among 28 patients, there are 16 CML, 6 acute myeloid leukemia (AML), 3 acute lymphocytic leukemia (ALL), 1 MM and 2 solid tumor. 13 of them were with increased donor chimerism and 11 of them were with full chimerism. In 11 of the 16 CML patients, whose chimerism decreased because of relapsed or advanced, only one patient who achieved partial remission (PR) and other 10 died for the sake of no effect after DLI. With DLI, 5 patients whose chimerism decreased during the course of disease remission got increasing donor chimerism, 3 got complete remission (CR), 2 got PR, 4 survived and 1 PR patient died of GVHD. Among 6 AML patients with DLI, 1 died due to disease relapsed or advanced and decreased chimerism, other 5 who were with disease remission or stable situation and decreased chimerism obtained CR and survival according to the increased donor chimerism after DLI. Among 3 B-ALL patients post DLI, one alive and the other two died. One MM patient died of no effect. Two late phrase lung cancer patients got PR. One has survived for 14 months and another died of lung virus infection. Their rates of donor chimerism were higher than 80 percent and 96 percent. Among all these 28 patients, their average following up time was 30 months (10–66 months). 12 of them survived (42.6 percent) and total efficient rate was 57.14 percent. 3 developed grade II aGVHD that was DLI-associated. 1 died and 5 was complicated with grade II to IV cGVHD (3 extensive and 2 local). Given active treatment, they were alive. 2 patients had ever been with transient complete blood cell decreasing and had recovered after active surppoting treatment.
Conclusion: DLI is a potential therapy that can make chimerism increase and prevent disease relapse post allo-NST. Its toxicity and side effects can be accepted.
Bruton’s Tyrosine Kinase (BTK) Is Not Required for BCR-ABL-Mediated Transformation of Hematopoietic Cells.
Authors: MacPartlin Mary , Honigberg Lee A. , Druker Brian J. , Deininger Michael W. 
Published: October 2019

Abstract
Background: Bruton’s tyrosine kinase (BTK) is a member of the Tec family of protein tyrosine kinases. Mutations of BTK have been associated with a block in B cell development, and are causal to X-linked agammaglobulinemia (XLA) in humans. Bcr-Abl is a constitutively active tyrosine kinase that is essential for the transforming capacity of Bcr-Abl. Using phosphoproteomics we have shown that BTK is consistently tyrosine phosphorylated in Bcr-Abl expressing Ba/F3 cells [Griswold et al. Mol Cell Biol.2006;26(16):6082–93.]. Since BTK has also been implicated in resistance to imatinib [Hofmann et al. Lancet2002;359(9305):481–6] and one study [Feldhahn et al. J Exp Med.2005; 201(11):1837–52] had suggested a role of BTK in Bcr-Abl-induced transformation we decided to test whether BTK may be a critical node in Bcr-Abl transformation and potential drug target in imatinib-resistant Bcr-Abl-positive cells.
Results: We depleted BTK in Ba/F3 and 32D cells expressing native and kinase domain (KD) mutant (E255K and T315I) Bcr-Abl, using shRNA. BTK levels were reduced to <10% of controls, but no differences in viability and cell proliferation were observed. Additionally, responses to imatinib were not affected by BTK depletion. We further tested the effects of reversible (PCI-33918) and irreversible (PCI-31523) small molecule inhibitors of BTK on the above cell lines as well as human Ph+ B-lymphoblastic lines. Selective BTK inhibition did not impact cell proliferation. Lastly, BTK inhibition had no effect on Bcr-Abl-mediated transformation of primary murine hematopoietic cells in colony forming assays.
Conclusion: Despite the fact the BTK is consistently tyrosine phosophorylated in Bcr-Abl expressing cells, our data suggests it is not essential for Bcr-Abl-mediated transformation of lymphoid or myeloid cells.
Multicenter, Randomized, Phase III Study Comparing Imatinib (Glivec) Standard Dose (400 mg/d) with Imatinib High Dose Induction (800 mg/d) Followed by Imatinib Maintenance (400 mg/d) in Patients with Pretreated Ph+/BCR-ABL+ CML in Chronic Phase - Results from the First Planned Interim Analysis (CELSG-CML 11 ISTAHIT Study).
Authors: Petzer Andreas L. , Wolf Dominik , Fong Dominik , Lion Thomas , Dyagil Irina , Masliak Zvenyslava , Boskovic Darinka , Griskevicius Laimonas , Lejniece Sandra , Spasov Emil , Gercheva Liana , Stojanovic Aleksandar , Peytchev Dontcho , Tzvetkov Nikolay , Griniute Rasa , Stanchev Atanas , Kwakkelstein Martin , Ulmer Hanno , Gastl Guenther A. 
Published: October 2019

Abstract
227 patients with pretreated Ph+/BCR-ABL+ CML were randomized into this 2-arm phase III trial comparing standard dose Imatinib (400 mg/d; arm A) with high dose (HD) Imatinib (800 mg/d for 6 months) for induction followed by Imatinib 400 mg/d for maintenance (400 mg/d; arm B). The interim analysis presented here was performed on all patients after 50% of the patients had been treated for 12 months since randomisation. There were no significant differences between treatment arms regarding sex, age and different pretreatments. Rates of complete hematological responses did not differ significantly between both groups at 3, 6 and 12 months (82% arm A, 90% arm B). However, significantly* more patients achieved a major (MCR) and a complete cytogenetic response (CCR) at 3 months (MCR: 21% arm A, 37% arm B; CCR: 6% arm A, 25% arm B) and 6 months (MCR: 34% arm A, 54% arm B; CCR: 20% arm A, 44% arm B). Moreover, significantly* more patients achieved a major molecular response (MMR) at 6 months in the Imatinib HD arm B compared to arm A (20% vs 7%). At 12 months, following dose reduction of Imatinib to 400 mg/d for maintenance at month 6 in the HD arm B, the rates of MCR (the primary endpoint of the study) were comparable (57% arm A, 59% arm B). Nevertheless, there was still a clear trend to higher rates of CCR (37% arm A, 48% arm B) and MMR (16% arm A, 21% arm B) in the HD arm, but at the time of the interim analysis these values did not reach statistical significance. In contrast to non-hematological toxicities, grade 3/4 hematological toxicities were significantly* more common in the HD arm B [anemia: 2% (A), 12% (B); leukopenia: 23% (A), 41% (B), thrombopenia: 14% (A), 34% (B)]. In conclusion, this is the first randomized phase III trial demonstrating significantly* higher rates of MCR, CCR and MMR in chronic phase CML during therapy with HD Imatinib. *p<0.05
Genetic Polymorphisms in the Inflammasomes Are Associated with Relapse and Survival in HLA-Identical Sibling Donor Allogeneic Stem Cell Transplantation.
Authors: Granell Miquel , Urbano-Ispizua Alvaro , Pons Aina , Arostegui Juan Ignacio , Navarro Alfons , Jansa Sonia , Artells Rosa , Gaya Anna , Fernandez-Aviles Francesc , Martinez Carmen , Rovira Montserrat , Carreras Enric , Yague Jordi , Montserrat Emili , Monzo Mariano 
Published: October 2019

Abstract
The inflammasomes are intracellular multiprotein complexes responsible of the secretion of IL-1β in response to the recognition of microbial patterns. Polymorphisms of genes codifying for inflammasomes proteins might influence the clinical outcome of patients receiving allogeneic stem cell transplantation (allo-SCT). Fourteen single nucleotide polymorphisms (SNPs) in NALP1, NALP2, NALP3, CARDINAL and CASPASE5 were genotyped by allelic discrimination in 133 adult donor-patient pairs undergoing sibling donor allo-SCT in a single institution. Patient median age was 41 years (range 17–64) and 61% were males. All patients were diagnosed with hematological malignancies; 71% of them were in advanced phase at transplantation. Median follow-up of the surviving patients was 39 months (range 1–118). Actuarial probabilities of relapse, non-relapse mortality (NRM) and overall survival (OS) were 40% (95% CI 39–41), 35% (95% CI 34–36) and 48% (95% CI 47–49), respectively. Genotype frequencies were similar to those published at NCBI database. NALP2 rs1043684 and rs1043673 (p<0.0001) as well as NALP3 rs10925027 and rs10754558 (p<0.0001) were inherited in linkage disequilibrium. NALP2 rs1043684 (GG 25% vs. GA/AA 12%, p=0.09) was the only factor weakly associated with severe acute GVHD. At multivariate analysis, donor NALP3 rs10925027 TT genotype was associated with relapse (RR 4.22, p=0.000001). Patient NALP1 rs5862 AA genotype and donor NALP2 rs1043684 GG were associated with NRM (RR 5.11, p=0.0002 and RR 2.97, p=0.005, respectively), and OS (RR 2.15, p=0.011 and RR 2.81, p=0.003, respectively). Inflammasome genetic SNPs of both donor and patient influence the outcome of allo-SCT. If these findings are validated in other series, genotype of NALP genes would become an important factor in donor selection.
Alemtuzumab Reduces Chronic Graft Versus Host Disease (cGVHD) and Treatment Related Mortality (TRM) after Reduced Intensity Conditioning for AML and MDS.
Authors: van Besien Koen , de Lima Marcos , Artz Andrew , Oran Betul , Stock Wendy , Giralt Sergio 
Published: October 2019

Abstract
In vivo T-cell depletion with alemtuzumab has been used to reduce acute and chronic GVHD. In order to evaluate its overall effect on transplant outcomes in AML and MDS we compared 90 pts who received fludarabine/melphalan/alemtuzumab (FMA) conditioning and post-transplant tacrolimus at the University of Chicago, with 112 who received fludarabine/melphalan (FM) and post-transplant tacrolimus/methotrexate at MD Anderson Cancer Center. Pt and transplant characteristics were well balanced except for a higher proportion of MDS in the FM group. Median age, proportion unrelated donor tx and proportion high/intermediate and low risk by ASBMT criteria were balanced between the groups. With median follow up of 28 months in both groups, one year progression free survival and overall survival are identical. TRM is significantly higher after FM, but relapse is higher in FMA. 19/103 d 28 survivors after FM vs 7/84 after FMA developed gr III–IV acute GVHD (p=0.04). 46/77 d100 survivors after FM developed ext cGVHD vs 7/63 after FMA (p=0.0000). 43 patients remain alive after FM and 27 have ext cGVHD. 41 remain alive after FMA and 1 has ext cGVHD. Alemtuzumab results in a considerable reduction in acute and particularly chronic GVHD. TRM is reduced compared with standard GVHD prophylaxis. Low incidence of chronic GVHD and reduced TRM may be the major benefit of this strategy. Relapse rates are increased, because of reduced GVL effects or because of improved early survival of high risk patients. Other approaches are necessary for improving long term outcomes.
Patient Characteristics and Outcome FMA FM P-value N 90 102 Age (range) 54 (22–74) 51 (17–77) 0.6 AML/MDS 13/77 29/83 0.04 MUD/related 42/48 59/63 0.5 High./Intermediate/LowRisk 48/13/28 76/10/26 0.12 Median Follow up mths (range) 28 (3–89) 28 (1–66) 0.07 TRM@ 100 days 13% + 7% 24% + 8% 0.04 TRM@ 1 year 30% + 12% 42% + 10% 0.04 Relapse @ 1 year 40% + 12% 26% + 10% 0.01 PFS @ 2 years 33% + 11% 37% + 9% 0.9 OS @ 2 year 42% + 11% 44% + 9% 0.5 AGVD gr III–IV 7/84 19/103 0.04 Ext cGVHD 7/63 46/77 0.0000 Ext cGVHD in survivors 1/41 27/43 0.0000
Kinetics of Circulating Endothelial Progenitors in Patients with Sclerodermatous Chronic Graft-Versus-Host Disease.
Authors: Ashihara Eishi , Shimura Kazuho , Shimazaki Chihiro , Matsunaga Shinsaku , Tanaka Ruriko , Yokota Asumi , Murotani Yoshihide , Takeuchi Miki , Kawata Eri , Kamitsuji Yuri , Kuroda Junya , Taniwaki Masafumi , Kimura Shinya , Maekawa Taira 
Published: October 2019

Abstract
Chronic graft-versus-host disease (cGVHD) is a common late complications of allogeneic stem cell transplantation (allo-SCT). Some cGVHD patients develop skin lesions. This may be partly because cytotoxic T cells injure skin endothelial cells in GVHD patients. Since the skin lesions in sclerodermatous cGVHD (s-cGVHD) patients resemble those in progressive systemic sclerosis, which is characterized by impaired production of circulating endothelial progenitor cells (EPCs). We investigated whether low EPC production may help to promote the development of skin lesions in s-cGVHD patients. Peripheral blood (PB) was obtained from 14 healthy volunteers and 27 allo-SCT patients. Five patients developed s-cGVHD. In accordance with the Declaration of Helsinki recommendations, all procedures were approved by the institutional review board, and written informed consent was obtained from every participant. First, we assesed the absolute number of CD34+ cells by using a flow cytometric gating strategy on the basis of the International Society of Hematotherapy and Graft Engineering guidelines. The median CD34+ cell frequencies of the healthy volunteers, the 14 non-s-cGVHD, and the s-cGVHD patients were 1.74 /μL PB [IQR 1.34–2.01], 0.85 [0.73–1.62], and 0.41 [0.17–0.42], respectively. The non-s-cGVHD patients had significantly lower frequencies than control (p=0.018) while the s-cGVHD patients had significantly lower frequencies when compared to either the healthy volunteers (p=0.0012) or non-s-cGVHD (p=0.014) groups. Next, the CD34+/CD133+/vascular endothelial growth factor (VEGF) receptor-2+ EPCs were quantified after CD34+ cells were purified by using the magnetic cell sorting separation system. The s-cGVHD patients had significantly lower median circulating EPCs frequencies than non-s-cGVHD patients or control (median 145/20 mL [107–193] vs 1083.5 [669.3–2151]; p=0.0023, and vs 1530.5 [IQR 961.3–2158]; p=0.0012, respectively, Figure 1). We next assessed the ability of endothelial colony in PBMNCs of each group by using the standard CFU-EC assay. The s-cGVHD patients also had impaired median endothelial-forming ability compared to non-s-cGVHD patients or controls (3.8 [IQR 1.0–4.3] vs 12.8 [IQR 8.8–28.8], and vs 26.4 [IQR 23.6–30.6] respectively; p=0.0012, Figure 2). Lastly, the endothelial cell colony-formation potential was evaluated. Serum VEGF and basic fibroblastic factor (b-FGF) concentrations were measured by ELISA. Their VEGF and b-FGF serum levels were also higher than in controls. In conclusion, s-cGVHD patients show impaired vasculogenesis that may limit blood perfusion and could be responsible for the development of sclerodermatous lesions. Administration of EPCs to the skin lesions of s-cGVHD patients may be a novel therapy.