bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase II Trial of CHOP Chemotherapy Followed by Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) for Previously Untreated Elderly Diffuse Large B-Cell Lymphoma (DLBCL) Patients.
Authors: Zinzani Pier Luigi , Tani Monica , Stefoni Vittorio , Alinari Lapo , Marchi Enrica , Fina Mariapaola , Baccarani Michele 
Published: October 2019

Abstract
In the last 20 years, the major improvement over the use of CHOP has been the addition of anti-CD20 immunotherapy (Rituximab). This advancement was first demonstrated in a randomized trial in elderly patients with diffuse large B-cell lymphoma (DLBCL). Single-agent radioimmunotherapy activity, in particular Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin), has been demonstrated in heavily pretreated DLBCL patients. Recently, the preliminary data of a phase II trial have showed that 90Y Ibritumomab Tiuxetan have useful activity in the treatment of relapsed/refractory elderly DLBCL (Morschhauser et al, Blood 2004, 104: 41a), with no unexpected toxicities observed. The results of this study support a further evaluation of 90Y Ibritumomab Tiuxetan in combination with chemotherapy earlier in the time course of elderly DLBCL. We conducted a prospective, single-arm, open-label, non-randomized, phase II to evaluate the efficacy and safety of 90Y Ibritumomab Tiuxetan of a novel new approach combining induction chemotherapy with CHOP followed by consolidation with 90Y Ibritumomab Tiuxetan for patients with previously untreated elderly DLBCL. Patient eligibility was represented by: patients older than 60 years with biopsy-proven, untreated, bidimensionally measurable stage II, stage III, or stage IV DLBCL expressing the CD20 antigen; performance status of 0 to 2, a pretreatment granulocyte cell count of 1500/μL or greater, and a platelet count of 100.000/μL or greater. All patients were notified of the investigational nature of this study and signed a written informed consent approved in accordance with institutional guidelines, including the Declaration of Helsinki. The study was approved by the institutional review board. Patients were treated with standard CHOP chemotherapy every 21 days for 6 cycles. Patients were restaged 4 to 8 weeks after completion of the sixth cycle of CHOP chemotherapy. Patients achieving at least a partial response after 6 cycles of CHOP chemotherapy were eligible for consolidation with 90Y Ibritumomab Tiuxetan provided the granulocyte count was greater than 1500/μL, the platelet count exceeded 100.000/μL, and the bone marrow examination at the completion of CHOP chemotherapy demonstrated no more than 25% involvement with lymphoma. All patients were to receive a single dose of 90Y Ibritumomab Tiuxetan 14.8 MBq/kg (0.4 mCi/kg) up to a maximum dose of 1184 MBq (32 mCi). A total of 20 patients have been enrolled and preliminary results of this trial will be presented.
Synergic Effects of Immunosuppressive Agents on T Lymphocyte Function and Cytokine Expression Pattern.
Authors: Lin Mao Fang , Jiang Yan Ling 
Published: October 2019

Abstract
The regimen including mycophenolate mofetil (MMF) and cyclosporine A (CsA) has been successfully used as an effective method in the prophylaxis of acute graft versus host disease. Herewith we investigated the effect of CsA, mycophenolic acid (MPA) alone or in combination with anti B7–1 mAb on proliferation of T lymphocytes and their possible mechanisms. The T lymphocyte reaction system was established in vitro and was detected by 5-bromo-2-deoxyuridine incorporation method; the expression of IL-2, IFN-γ and IL-10 on mRNA and protein level were detected by RT-PCR and ELISA respectively. Experimental concentration of MPA (50μmol/L) and CsA(0.33μmol/L) inhibited the T lymphocyte proliferation significantly. CsA in combination with anti B7–1 mAb(10mg/L) had a much stronger effect on the inhibition(p<0.01). There was no difference between groups treated either with MPA or with the combination of MPA and anti B7–1 mAb. Both of CsA and MPA could inhibit the protein expression of IL-2 and IFN-γ. The protein expression of IL-2 were 99.70±9.15 pg/ml, 48.19±8.67pg/ml and 42.73±14.64 pg/ml in groups of control, treated with CsA or MPA respectively. The protein expression of IFN-γ in the group treated with CsA or MPA decreased significantly than the control (6.81±5.24 pg/ml, 7.87±4.22 pg/ml vs 82.42±25.55 pg/ml, p<0.05). Compared with that treated with CsA alone, The protein expression of IFN-γ in the group treated with CsA in combination with anti B7–1 mAb decreased significantly (0.30±0.52 pg/ml vs 6.81±5.24 pg/ml, p<0.05). Both of CsA and MPA increased the protein expression of IL-10. Compared with MPA alone, MPA in combination with anti B7–1 mAb increased significantly the expression of IL-10 (941.90±56.61 pg/ml vs 770.95±126.85 pg/ml, p<0.05). The relative expression level of IL-2 mRNA (IL-2/GAPDH) and IFN-γ mRNA (IFN-γ /GAPDH) in the CsA or MPA group was significantly lower than the control (p<0.01). The relative expression level of IFN-γ mRNA in combination group of CsA with anti B7–1 mAb decreased even more significantly (0.38±0.05 vs 0.59±0.02, p<0.01). On the other hand, this combination could up-regulate IL-10 mRNA expression (1.80±0.13 vs 1.38±0.06, p<0.01). Combination of MPA with anti-B7–1 mAb showed a statistically significant increase in IL-10 mRNA expression (1.28±0.06 vs 0.84±0.09, p<0.01) as compared with MPA alone. In conclusion, MPA and CsA induced the changes of cytokine expressive spectrum and the Th1 and Th2 shift might be involved in the immunosuppressive effect. The combination of immunosuppressive agents, especially with anti B7–1 mAb had a synergic effect.
Rerovirus Mediated HSV-TK Gene Transfer Can Influence the Function of Human T-Lymphocyte.
Authors: Cai Zhen , Xue Xingkui , Sun Wenji , Yao Hangping 
Published: October 2019

Abstract
To control graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell (HSC) transplantation while maintaining the graft antileukemic effects of donor T cells, a suicide gene encoding the herpes simplex virus thymidine kinase (HSV-TK) enzyme was introduced ex vivo via a retroviral vector into donor T cells. Although previous clinical trials showed that it was an efficient tool for controlling GVHD, the gene transduction process of donor T lymphocytes may influence the immunocompetence of the T cells. In the current study, we investigated the impact that the gene manipulation in vitro had on the phenotype and functionality of human donor T lymphocytes. We engineered human T lymphocytes with HSV-TK and puromycin resistance gene with a retrovirus vector and analyzed the phenotype change of gene modified cells with flowcytometry. The secretion of gamma-interferon and interleukin-4 of T lymphocyte were detected with enzyme-linked immunospot(ELIPOT)assays. We also analyzed the lytic activity of T cells against allogeneic targets. The result showed that the number of TK gene transduced T lymphocyte was sufficient for clinical use. There was an inversion of the CD4+/CD8+ ratio in the gene modified T cell (GMC) compared with the fresh peripheral blood lymphocytes (PBLs). In addition, the GMCs showed a higher expression of HLA-DR and had more antigen-experienced cells than did the PBLs. In ELIPOT assays, significantly less gamma-interferon secretion by GMCs was observed compared to PBLs (50 vs. 115 spots/well-3×104cells, p<0.05). The results also showed that IL-4-secreting cell frequencies was similar in GMCs and in PBLs (19.3 vs. 20.3 spots/well-3×104cells, p>0.05). After stimulated by allogeneic PBMCs, the GMCs effectors showed a significant reduction in lytic activity against allogeneic targets in contrast with PBL. In conclusion, HSV-TK gene transduction and selection procedure can change the phenotype and functions of human T lymphocyte. The gene modified T lymphocytes still showed biological activities although lower than those of PBLs.
Comparison of Patient Satisfaction between Medical Staff and Clinical Nurse Specialist Performing Bone Marrow Investigation Procedure.
Authors: Pattison John W. , Neylon Annette J. 
Published: October 2019

Abstract
Bone marrow investigation is an important haematological investigation used to determine a wide range of diverse conditions. Historically the investigation was carried out by a member of the medical haematology team; recently there has been an increasing trend towards non-medical staff taking on the role. At South Tyneside NHS Foundation Trust the Haematology Clinical Nurse Specialist (CNS) was trained and deemed competent by the Consultant Haematologists to carry out this complex procedure. To evaluate the benefits of this change in practice we designed a patient satisfaction survey to determine whether the patient experience is influenced by whether the procedure was carried out by the CNS or a member of the medical team. A simple questionnaire was formulated which was given to patients following bone marrow investigation. The questionnaire was completed and returned anonymously to the audit department for collation of results. Twenty-four patients in total returned questionnaires, twelve from medical staff and twelve from the CNS operators.
There was no variation in explanation of the investigation given to the patient between the two groups. However, all 100% of the patients seen by the CNS were given written information regarding the procedure, whereas only 22% of the medical staff group furnished information to the patient. There was no overall difference between the two groups with respect to opportunity to ask questions relating to the procedure before it was undertaken. Those procedures carried out by the CNS were completed one to two days of the decision to biopsy in 92% of cases, whereas this was only achieved in 44% of those patients seen by a member of the medical team. In addition, there was no difference in the pain experience of either group, with twenty to thirty percent requiring analgesia in both cohorts. The CNS was more likely to supply a follow up appointment to the patient for the test results. In summary, there is no apparent difference in patient satisfaction between medical staff and CNS when bone marrow investigation is required. However, the CNS is more inclined to support verbal information with written documentation and to carry out the procedure within a more rapid time frame. When re-structuring haematological services locally, the role of the CNS in respect to bone marrow investigation should be considered as crucial, particularly regarding significant investigative procedures such as bone marrow biopsy. Importantly, this must be supported by suitable training and competency assessment.
MAP Kinase Signaling Pathway Induced by TPO Is a Negative Regulator of Proplatelet Formation in Human Megakaryocytes.
Authors: de Botton Stephane , Aurade Frederic , Chang Yunhua , Christine Rivat , Loussaief Lamya , Larbret Frederic , Larghero Jerome , Raslova Hana , Vainchenker William , Debili Najet 
Published: October 2019

Abstract
Platelets are formed from mature megakaryocytes (MKs) and arise from the development of cytoplasmic extensions called proplatelets (PPT). Proliferation and full maturation of MKs require TPO, but it is dispensable for platelet shedding. To precisely define the role of different signaling pathway activated by TPO on proplatelet formation (PPF), chemical inhibitors of ERK (PD98059), p38 (SB 203580) and a pan PKC inhibitor (GF109203X) were added to MK derived from human CD34+ cells. As previously reported, the PKC inhibitor leads to a marked decrease in PPF and the p38 inhibitor has no effect on PPF. Addition at day 8 of an inhibitor of the ERK pathway (PD98059) to the purified CD34+CD41+ cultured cells leads to an early PPF associated to a 3-fold increase of PPT. As observed with PD98059, an overexpression of a dominant-negative (DN) form of MEK1 in primary MKs led to a 2-fold increase of PPT. Inhibition of the ERK pathway in the immature MKs surprisingly increased MK mean ploidy, (5.7N in the control versus 10.9N in presence of PD98059). Especially, the highest classes of ploidy (8N, 16N and 32N) were significantly increased. Altogether, those results suggest that the inhibition of MAP/ERK1/2 is an essential step for PPF in mature MKs but also that MAPK/ERK1/2 is a negative regulator of endomitosis. As PPF occurs in the presence of TPO, we investigated whether MAPK activation was down-regulated during MK differentiation. Western blot and flow cytometry analysis were performed and show that ERK activation induced by TPO was dramatically decreased at the late stages of megakaryocytopoiesis. In addition, inhibition of MEK prior to PPF was associated with an activation of caspase 3 in the absence of apoptosis suggesting a direct role of the ERK pathway in the regulation of proplatelet. Altogether, those results show a differential response of MAP kinase pathway to TPO depending on the maturation stage. ERK downregulation occurs when PPF begins and MEK inhibition is associated with increased PPF.
Modulation of Dendritic Cell Chemotaxis by HIV-gp120.
Authors: Bailuguttu Anil P. , Ganju Ramesh K. 
Published: October 2019

Abstract
Dendritic cells are essential antigen-presenting cells involved in the induction of T cell immunity against pathogens, such as Human Immunodeficiency Virus (HIV)-1. During the early stages of HIV infection, immature dendritic cells (iDCs) are the first cellular targets of HIV-1. These HIV-infected iDCs cross mucosal surfaces and facilitate transmission of the virus to nearby CD4+ T cells. To date, the effect of HIV envelope proteins such as gp120 on dendritic cell chemotaxis has not been well characterized. Thus, we studied the effect of recombinant gp120 on the chemotaxis of mature DCs (mDCs) and immature DCs. Immature DCs have been shown to express the CC chemokine receptor, CCR5. In contrast, mature DCs down-regulate CCR5 but upregulate CXCR4 as well as exhibit enhanced chemotaxis towards CXCL12. In our study, we analyzed the effect of soluble gp120 on the chemotaxis of DCs. We have shown that pre-treatment of DCs with M-tropic gp120 significantly inhibited the CCR5-induced chemotaxis of iDCs, whereas pre-treatment of DCs with T-tropic gp120 inhibited the CXCL12-induced chemotaxis of mDCs. In addition, we found that M-tropic gp120 itself induced the chemotaxis of iDCs in a dose-dependent manner, while T-tropic gp120 did not show any effect on iDC chemotaxis. We next analyzed the signaling mechanisms involved in the modulation of iDC chemotaxis by M-tropic gp120 and found that M-tropic gp120 increased the phosphorylation of Src kinase, paxillin, Erk, and Akt in these cells. Moreover, M-tropic gp120 induced an increased expression of Lymphocyte Specific Protein-1 (LSP1), which has been reported to regulate the chemotaxis of various immune cells. Taken together, these results suggest that HIV-gp120 plays an important role in modulating the chemotaxis of mDCs and iDCs. This study may help to elucidate the mechanisms of immune response and contribute to the development of vaccines against HIV.
Notch Agonists: Emerging as a Feasible Therapeutic Approach in AML.
Authors: Sutphin Robert M. , Fang Wendy , Miller Claudia , Zweidler-McKay Patrick A. 
Published: October 2019

Abstract
Introduction: The Notch pathway regulates critical cell-fate decisions affecting the growth and development of human hematopoietic cells. Although Notch1 is a known T cell oncogene, we have discovered that Notch signaling behaves as a tumor suppressor in acute myeloblastic leukemia (AML) inducing growth arrest and apoptosis in both cell lines and patient samples. To characterize the mechanism of this effect we have evaluated the influence of the Notch pathway on key effectors of differentiation, cell cycle, and apoptosis in human AML.
Results: Notch signaling induces rapid growth arrest and apoptosis in a panel of human AML cell lines representing a range of AML FAB subtypes (M2–M6). Specifically, activated Notch1 expression caused a 70–95% reduction in AML cells compared to controls (p<0.001) (Figure 1). Notch-mediated growth arrest occurred in 24–48 hours with cells accumulating in G0/G1. Apoptosis was demonstrated by a 3.8-fold increase in AnnexinV binding (p<0.004) and a 3-fold upregulation of caspase 3 activity (p=0.0002) within 24 hours. The caspase 3 activity was abolished by the caspase 8 inhibitor IETD (p<0.0001) suggesting a potential role for the extrinsic death pathway.
We also found that all four Notch receptors (1–4) are capable of inducing this effect, as is the Notch target gene HES1, suggesting a generalized Notch tumor suppressor effect in AML. Furthermore, Notch signaling through HES1 modulates the expression of key regulators of myeloid differentiation and cell cycle progression including downregulation of CEBPα 2.5-fold (p<0.02) and upregulation of p21WAF1 6-fold (p<0.004) suggesting potential mechanisms.
As a novel therapeutic approach, we synthesized Notch agonists which effectively induce Notch signaling with a >18-fold increase in HES1 expression (p<.0001). Exposure of human AML cell lines and primary patient AML samples to this Notch agonist for 24 hours led to a 3 to 9-fold increase in apoptosis (p<0.017) compared to controls (Figure 2).
Conclusions: We report here that Notch signaling is a novel tumor suppressor pathway in human AML. We demonstrate how Notch agonists can be used to induce growth arrest and apoptosis in human AML cell lines and patient AML samples. As a regulator of cell fate, proliferation and differentiation, Notch effectively disrupts multiple pathways in AML. We propose that Notch agonists represent a novel and feasible therapeutic approach in AML. Pre-clinical evaluation is underway.
Figure.1 Effect of Notch on growth of AML cells Figure.1. Effect of Notch on growth of AML cells Figure.2 Notch Agonist induces apoptosis in AML Figure.2. Notch Agonist induces apoptosis in AML
The KIT D816V-Targeting Drug PKC412 Induces Re-Expression of Bim and Synergizes with Mcl-1 Antisense Oligonucleotides in Producing Growth Inhibition in Neoplastic Human Mast Cells.
Authors: Aichberger Karl J. , Mayerhofer Matthias , Gleixner Karoline V. , Krauth Maria-Theresa , Gruze Alexander , Pickl Winfried F. , Wacheck Volker , Selzer Edgar , Sillaber Christian , Valent Peter 
Published: October 2019

Abstract
Systemic mastocytosis (SM) is a myeloid neoplasm involving uncommitted and mast cell (MC) committed hematopoietic progenitors. In most SM patients, the transforming c-KIT point mutation D816V is detectable. However, so far, little is known about the molecular mechanisms underlying KIT D816V-induced transformation. We examined the expression of two Bcl-2 family members, i.e. anti-apoptotic Mcl-1 and the pro-apoptotic tumor suppressor Bim, in the KIT D816V+ human mast cell line HMC-1. As assessed by RT-PCR, immunocytochemistry, and Western blotting, these cells were found to express Mcl-1 mRNA and the Mcl-1 protein, whereas only trace amounts of Bim were detectable in HMC-1 cells. Exposure of HMC-1 cells to the KIT D816V-targeting drug PKC412 resulted in a substantial increase in expression of Bim and in a marked decrease in expression of Mcl-1. Correspondingly, in Ba/F3 cells with doxycycline-inducible expression of KIT D816V (Ton.Kit.D816V), exposure to doxycycline (induction of KIT D816V) resulted in a significant decrease in expression of Bim, and PKC412 was found to counteract the KIT D816V-induced downregulation in Bim in these cells. Transfection of HMC-1 cells with Mcl-1-specific antisense oligonucleotides (ASO) or an Mcl-1-specific siRNA resulted in reduced survival and in an increased percentage of apoptotic cells compared to cells transfected with scramble control oligonucleotides. In consecutive experiments, combinations of PKC412 and Mcl-1 ASO were applied using varying drug concentrations. In these experiments, both compounds were found to synergize with each other in producing growth inhibition and apoptosis in HMC-1 cells. By contrast, no synergism was observed with combinations of Mcl-1 ASO and imatinib or with Mcl-1 ASO and 2CdA. In summary, our data show that the Bcl-2 family members Mcl-1 and Bim are differentially expressed in neoplastic MC, and that targeting of Mcl-1 is associated with reduced survival of HMC-1 cells. In addition, our data show that Mcl-1 ASO synergize with PKC412 in producing growth inhibition in neoplastic MC. These data support the concept that optimal growth inhibition of neoplastic MC in aggressive variants of SM may be achieved with combinations of targeted drugs.
NPM-ALK Converts JUNB from a Tumor Suppressor to an Oncogene.
Authors: Vesely Paul , Staber Philipp B. , Ott Rene , Pinent Montserrat , Linkesch Werner , Schauer Silvia , Hrzenjak Andelko , Kadin Marshall E. , Sternberg David W. , Hoefler Gerald 
Published: October 2019

Abstract
High expression of the tumor necrosis factor receptor CD30 and the AP-1 transcription factor JunB are the hallmark of anaplastic large cell lymphoma (ALCL). In contrast to the prototypic AP-1 factor c-Jun, JunB exerts an antioncogenic function in most cell types. Its functional role in ALCL remains uncertain. In about 50% of nodal ALCL the balanced chromosomal rearrangement t(2;5)(p23;q35), generating the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), can be detected. Expression of this fusion kinase induces malignancy in mice and also leads to IL-3 independent outgrowth of the murine hematopoietic cell line Ba/F3.
Using NPM-ALK transduced Ba/F3 cells, we show that NPM-ALK induces JunB expression and activation as verified by quantitative RT-PCR, immunoblot and electro-mobility supershift assay. Interestingly, NPM-ALK transduced Ba/F3 cells also express CD30, which is undetectable in the corresponding wild type cells. Since NPM-ALK induces JunB and CD30 and also leads to growth factor independent proliferation in Ba/F3 cells, these cells mimic conditions present in ALCL.
Knock down of JUNB in NPM-ALK expressing cells using RNA interference leads to downregulation of CD30. Moreover, this partial loss of JunB induces upregulation of p16INK4a and downregulation of CCND1, which directly affect the cell cycle at the G1/S transition. These observations indicate that JunB is an essential factor for CD30 regulation and for neoplastic transformation.
To test if JunB by itself is sufficient to induce CD30 expression and IL-3 independence, we stably transduced Ba/F3 cells with JUNB. In Ba/F3 wild type (WT) cells, JunB expression leads to reverse effects compared to that observed in NPM-ALK transduced Ba/F3. Ba/F3 WT cells do not become IL-3 independent. In addition, compared to vector control, JUNB-transduced Ba/F3 cells show a decrease in proliferation. Furthermore, an induction of p16INK4a and a decrease of CCND1 expression are observed. Moreover, aberrant JunB expression does not trigger CD30 expression in this system.
Taken together, we show that both NPM-ALK and JunB are essential to induce CD30 expression. Furthermore the opposing effects of JunB on p16INK4a and CCND1 in the presence or absence of NPM-ALK indicate that NPM-ALK converts JUNB from a tumor suppressor to an oncogene.