bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vivo Drug-Response in Patients with Leukemic Non-Hodgkin’s Lymphomas Is Predicted by In Vitro Chemosensitivity Testing and Gene Expression Profiling.
Authors: Chow Kai Uwe , Nowak Daniel , Kim Soo-Zin , Schneider Bernd , Komor Martina , Boehrer Simone , Mitrou Paris S. , Hoelzer Dieter , Weidmann Eckhart , Hofmann Wolf-Karsten 
Published: October 2019

Abstract
Only a few approaches are available to address the mechanisms of cell death in vivo which are induced by anticancer treatment in patients with malignancies. In this study in vitro chemosensitivity testing of primary peripheral blood leukemic cells of five patients suffering from different leukemic Non-Hodgkin’s lymphomas (atypical CLL, typical CLL, Immunocytoma, Mantle Cell Lymphoma, Prolymphocytic Leukemia (PLL)) was combined with the analysis of the in vivo rate of apoptosis by flow-cytometry (Annexin V and depolarisation of mitochondrial membrane potential (MMP) by JC-1). Furthermore, changes in expression patterns of apoptosis related proteins during chemotherapeutic treatment were detected by Western Blot. Gene expression profiling (HG-U133A, Affymetrix, Santa Clara, CA) was employed to identify common marker genes of in vivo drug response. In vitro chemosensitivity was tested using the cytotoxic agents which the patients were scheduled to receive and was strongly correlated with effective reduction of leukemic lymphoma cells in patients resulting in complete remissions in all five cases. Due to the rapid clearance of apoptotic tumor cells in vivo neither the analysis of the in vivo rate of apoptosis and depolarisation of MMP nor the assessment of expression of regulators of apoptosis showed concordant results concerning the drug response. However, assessment of gene expression during therapy could identify a set of 30 genes to significant discriminate between samples from patients before treatment compared to samples from the same patients after receiving cytotoxic therapy. Among these 30 genes we found a high proportion of genes associated with apoptotic cell death and cell proliferation signalling including complement lysis inhibitor (clusterin, CLU, SP40), beta-catenin interacting protein (ICAT), peroxisome proliferator activated receptor alpha (PPARα), TNF alpha converting enzyme (ADAM 17 / TACE), homeo box A3 (HOXA), inositol polyphosphate 5 phophatase (PPI 5 PIV, SHIP1), FK 506 binding protein (FKBP 38) and inhibitor of p53 induced apoptosis alpha (NME 6). Clusterin is able to mediate apoptosis via p53 and increases drug-induced cell death when overexpressed as detected in our treated samples. The downregulation of NME 6 during chemotherapeutic treatment may enhance this effect. These results indicate that in vitro chemosensitivity testing and gene expression profiling can successfully be utilised to predict in vivo drug response in patients with leukemic NHL’s and can be used to explore new pathway models of drug-induced cell death in vivo which are independent of different lymphoma subtypes and different treatment regimens.
Prognostic Factors and Outcome of Human Herpesvirus 8 (KSHV/HHV-8)-Associated Primary Effusion Lymphoma (PEL) in Patients with AIDS.
Authors: Boulanger Emmanuelle , Gerard Laurence , Gabarre Jean , Molina Jean-Michel , Rapp Christophe , Abino Jean-Francois , Cadranel Jacques , Chevret Sylvie , Oksenhendler Eric 
Published: October 2019

Abstract
Primary effusion lymphoma (PEL) is a rare high-grade B-cell non-Hodgkin lymphoma associated with Kaposi sarcoma-associated Herpesvirus/Human Herpesvirus 8 (KSHV/HHV-8) infection, and mostly observed in the course of HIV infection. The prognosis is poor with reported median survival time shorter than 6 months. To date, no prognostic factor has been identified in this subset of lymphoma. We described here the largest series of HIV-infected patients with PEL, including 30 cases diagnosed in six French centers over a 15-year time period. Prognosis analysis was performed using a Cox proportional hazard regression model. Statistically significant covariates were further analyzed in a forward, stepwise multivariate model. After a median follow-up of 3.2 years (range, 10 months-8.2 years), 9 patients (30%) were still alive, and 8 of them remained progression free. The overall median survival was 5.5 months and the 1-year overall survival rate was 36.7%. Fourteen patients (47%) achieved complete remission, with a 1-year disease-free survival rate at 78.6%. In multivariate analysis, only a performance status > 2 [hazard ratio 6.27, 95% confidence intervals (CI),1.91–20.58] and the absence of highly active antiretroviral therapy (HAART) before PEL diagnosis [hazard ratio 0.28, 95% CI, 0.10–0.77] were found to be independent predictors for shorter survival. Based on a retrospective series of 30 patients, two prognostic factors were identified as being independently associated with impaired clinical outcome in HIV-related PEL, (i) a poor performance status and (ii) the absence of HAART prior to PEL diagnosis.
Expression of VEGF, VEGF Receptors, and Other Angiogenic Markers in Relapsed Aggressive Non-Hodgkin’s Lymphoma : Correlative Sudies from the SWOG S0108 Trial.
Authors: Stopeck Alison , Iannone Maria , Rimsza Lisa , Miller Thomas , Fisher Richard , Bellamy William 
Published: October 2019

Abstract
In the Southwest Oncology Group phase II study S0108, patients with relapsed, aggressive non-Hodgkin’s lymphoma were treated with single agent bevacizumab (Avastin), a recombinant monoclonal antibody directed against VEGF. Pretreatment tissue or bone marrow specimens were examined by immunohistochemistry (IHC) for expression of VEGF and its receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR). Circulating endothelial cells (CEC) and plasma levels of VEGF, VCAM, and bFGF were measured at baseline, week 8, and at disease progression. Currently, 45 patients have been enrolled in the study and 18 have had baseline lymphoma specimens submitted and adequate for analysis by IHC for expression of VEGF and its receptors. In 7 of 10 (70%) patients with diffuse large cell lymphoma, the tumors expressed VEGF and either or both VEGF receptors. There was 100% concordance between VEGF and receptor expression in these samples. In 7of 8 (88%) mantle cell specimens examined, VEGF expression was also observed. Expression of both VEGFR-1 and VEGFR-2 was observed in 6 (67%) of these specimens. While VEGF and VEGFR-1 expression was restricted to the malignant cells, VEGFR-2 was predominantly expressed on the endothelial cells in the lymphoma specimens, and in those cases where it was also expressed by the tumor cells it was typically at lower intensity. In 1 of 5 patients with serial lymphoma specimens, VEGF expression increased in the lymphoma cells during the course of bevacizumab therapy. There was a wide range in the plasma levels of VEGF, bFGF, VCAM, and CEC between patients. During the course of treatment, plasma VEGF levels decreased (p = 0.02), VCAM levels increased (p = 0.05), and bFGF and CEC levels remained relatively stable. CEC, VCAM, and bFGF levels did not correlate with VEGF expression in lymphoma samples but there was a trend for lymphomas with higher VEGF expression (+2 or higher) to have higher baseline plasma levels of VEGF (median VEGF level 471 pg/ml compared to 224 pg/ml). Accrual of samples continues and the results will be updated as the analyses are available. The high rate of concordance between VEGF and its receptors in diffuse large cell and mantle cell lymphomas suggests that an autocrine pathway may be involved in lymphoma pathogenesis and/or progression. In addition, these results provide a strong rationale for targeting the VEGF pathway in the treatment of these 2 histologic subtypes of aggressive non-Hodgkin’s lymphoma.
Curcumin Supresess Growth and Induces Apoptosis of Primary Effusion Lymphoma Cells.
Authors: Uddin Shahab , Hussain Azhar R. , Al-Hussein Khaled A. , Gutierrez Marina , Bhatia Kishor G. 
Published: October 2019

Abstract
Kaposi ‘s sarcoma-associated herpesvirus (KSHV or HHV8) has also been implicated in primary effusion lymphoma (PEL). KSHV/HHV8 has been shown to activate a number of growth and survival signaling pathways, including PI3-kinase and JAK/STAT, and protect cells from programmed cell death. Indeed Stat-3 is constitutively phosphorylated/activated in PEL cells and plays a role in their survival and proliferation. Curcumin (diferuloylmethane), a natural compound isolated from the plant Curcuma Ionga had very little or no toxicity in human cells and has been shown to have anti-tumor activity in vitro. We describe here that curcumin at 20 μM concentration inhibits cell proliferation in several PEL cell lines (BC1 64 + 1%, BC3 67 + 2%, BCBL1 62 +3% inhibition of growth) and induces apoptosis (BC1 51+ 5%, BC3 47 + 6%, BCBL1 48 + 4 % apoptosis cells). To characterize better the mechanism of action of curcumin, we studied the JAK/STAT pathway and the apoptotic cascade. Curcumin suppressed the constitutively active Stat3 transcription factor in a dose dependent manner. Curcumin also induced loss of mitochondrial membrane potential, as determined by JC1 staining with subsequent activation of capase-3 followed by polyadenosin-5′-diphosphate-ribose polymerase (PARP) cleavage. In addition, zVAD-fmk, a universal inhibitor of caspases prevented caspase-3 activation as well as PARP cleavage induced by curcumin treatment. IL-10 is a major autocrine growth factor for PEL cell survival. We quantified by ELISA the secretion of IL-10 in PEL cells and found that curcumin abrogated IL-10 secretion. Taken together, our findings suggest that curcumin suppresses constitutively active Stat-3 in PEL cells, leading to inhibition of proliferation and induction of caspase-dependent apoptosis. These results provide the molecular basis and preliminary data for new treatment strategies that may incorporate curcumin in regimens for PEL.
Motexafin Gadolinium Enhances Rituximab-Induced Cytotoxicity Against B-Cell Lymphoma Cell Lines.
Authors: Chen Jun , Ramos Jason , Sirisawad Mint , Miller Richard A. , Naumovski Louie 
Published: October 2019

Abstract
Motexafin gadolinium (MGd, Xcytrin®) is a tumor selective redox active drug that is cytotoxic to many hematolymphoid cell lines and chronic lymphocytic leukemia cells. Previous studies have shown that MGd oxidizes various cellular reducing metabolites and produces reactive oxygen species (ROS), which can induce apoptosis. Rituximab, an anti-CD20 antibody, is used widely in the treatment of B-cell malignancies; however, its precise mechanism of action is uncertain. Some studies have demonstrated that rituximab induces the generation of ROS in sensitive cells. We evaluated the effects of combining rituximab and MGd in the in vitro treatment of HF-1, a cell line derived from a patient with follicular lymphoma. Increases in both apoptosis and cell growth inhibition were seen with MGd plus rituximab compared to each agent used separately. Apoptosis was demonstrated by both annexin-V positivity and caspase-3 activity. Loss of mitochondrial membrane potential and PARP cleavage were also greater when the two drugs were used together than when used separately. Data analysis with CalcuSyn software showed that, with the combination, the Dose Reduction Index (DRI) was more than 1.5 for MGd and 2 to 6 for rituximab regarding both apoptotic effect and growth inhibition. Consistent with MGd as a redox active agent, peroxiredoxin oxidation was higher when MGd and rituximab were used together. Further experiments revealed no increase in uptake of MGd by rituximab treatment, nor a change in the amount of CD20 antigen on the surface of MGd treated cells. We investigated another B-cell lymphoma cell line, DHL-4 for similar cooperative activity of MGd and rituximab. While MGd alone has no substantial apoptotic effect on DHL-4 cells, it enhanced the activity of rituximab in inducing apoptosis. These in vitro findings support the combined use of MGd and rituximab in the treatment of B cell lymphoma.
HLA-DQ7 Is Associated with Susceptibility to Idiopathic Thrombotic Thrombocytopenic Purpura.
Authors: Scully Marie , Brown Julliette , Patel Rajeshree , Machin Samuel J. , Brown Colin 
Published: October 2019

Abstract
Thrombotic thrombocytopenic purpura (TTP) is a rare disorder associated with microangiopathic haemolytic anaemia, thrombocytopenia and multisystem microvascular thrombosis. It results from a deficiency of ADAMTS 13, required to cleave Ultra large von Willebrand factor multimers. An underlying autoimmune basis is suggested; indeed in up to 90% of idiopathic cases, antibodies, primarily IgG, to ADAMTS 13 can be demonstrated during an acute episode. Joseph et al( Am J Hematology 1994) reported that HLA-DR53 protects against TTP. In this study, twenty patients with idiopathic TTP, 6 male and 14 female, were typed for HLA-DR and DQ by PCR-SSP. Thirteen had recurrent (>3) episodes of TTP and all patients had ADAMTS 13 activity <5% with evidence of antibody to ADAMTS 13 at acute presentation. The HLA-DR and DQ frequencies in the patient group were compared with those found in 203 local blood donors and selected results are shown in the table below. In this study the reduction of DR53 has been confirmed, however, this may not be the primary HLA frequency altered in patients with TTP. Although HLA-DR53 is associated with DR4, DR7 and DR9, only the frequency of DR4 is reduced suggesting that this HLA type may be protective against TTP. The main finding of this study is that the frequency of HLA-DQ7 is significantly increased in the patient group. The frequency of HLA-DR11 (associated with DQ7), is also increased. However, four patients are DQ7 positive but negative for DR11 suggesting an association of DQ7 and susceptibility to TTP. Five patients are negative for HLA-DQ7; of these, four are HLA-DR15 positive, which may also contribute to susceptibility to TTP. HLA-DR and DQ associations with autoimmune disease, such as SLE and IDDM, have been well documented. The findings in this patient cohort suggest that specific HLA-DR and DQ molecules may have contributory roles in resistance or susceptibility to TTP. The repertoire of peptides presented to the immune system by HLA-DQ7 positive patients may increse their risk of developing TTP.
HLA type and TTP HLA type % patients positive % controls positive P value DR4 5.0 35.0 0.01 DR11 50.0 12.3 0.001 DR15 45.0 27.1 NS DR53 35.0 63.5 0.05 DQ7 75.0 34.5 0.001
Ex Vivo Large Scale Generation of Human Platelets from Cord Blood CD34+ Cells.
Authors: Matsunaga Takuya , Tanaka Ikuta , Kobune Masayoshi , Kawano Yutaka , Tanaka Maki , Akiyama Takehide , Kuribayashi Kageaki , Ninomiya Takafumi , Hamada Hirofumi , Niitsu Yoshiro 
Published: October 2019

Abstract
To obtain a large quantity of platelets (PLTs) from cord blood stem cells (CBSC) in vitro, we employed three-phase culture system. We first expanded CBSC on a monolayer of human telomerase catalytic subunit gene-transduced human stromal cells (hTERT stroma) in serum-free medium supplemented with stem cell factor (SCF), Flt-3/Flk-2 ligand (FL) and thrombopoietin (TPO) for 14 days (1st phase), and then cultured them to differentiate into megakaryocytes for another 14 days with refreshing medium which contain interleukin-11 (IL-11) in addition to original cytokine cocktail (2nd phase). Subsequently, we transferred the cells to a liquid culture medium containing SCF, FL, TPO and IL-11, and cultured them for 5 days (3rd phase) to recover PLTs in the culture medium. The quantity of PLTs recovered from one CB unit (5 x 106 CD34+ cells) was calculated to be 10.5 units (2 x 1011 PLTs). These CB-derived PLTs exhibited quite similar feature as those from peripheral blood in morphology as revealed by electron micrograph and in functions as revealed by aggregation assay and by FACS detecting expression of P-selectin and activated glycoprotein IIb-IIIa antigens upon fibrinogen/ADP stimulation. Thus our three-phase culture system was considered to be useful for large scale generation of PLTs from CB for clinical usage.
Ionising Irradiation Influences Platelet Adhesion and Aggregation under High Flow Conditions.
Authors: Loncar Robert , Araba Fatima , Schmuling Christof , Wenzel Folker , Scharf Rudiger E. 
Published: October 2019

Abstract
Transfusion-associated graft-versus-host disease (GVHD) is a dramatic immunologic reaction mediated by transfused immunocompetent lymphocytes directed against an immunocompromised host. GVHD shows a rapid onset and is characterized by severe symptoms and a poor response to treatment (mortality rate > 90%). Prophylactic gamma irradiation of cellular blood components is the most efficient and reliable way to prevent GVHD. The currently recommended standard dose of gamma irradiation of blood products is 25 Gy. While irradiated blood components including platelet concentrates have been extensively transfused over the past 25 years, only few studies (with controversy results) evaluated the effect of ionising irradiation on platelet morphology and function. In this study, we examined the effect of a standard irradiation dose of 25Gy on platelet function using a platelet function analyzer (PFA-100). Citrate-anticoagulated blood was obtained in duplicate from twelve healthy blood donors. One sample was immediately irradiated according to a standard protocol (25 Gy), the other specimen was used as control. Platelet function of irradiated and control samples was evaluated using PFA-100. This device applies a high shear flow system to simulate the conditions under which platelets are subjected at the site of a damaged blood vessel wall. Anticoagulated whole blood was passed through the membranes coated with either collagen and epinephrine (Col/Epi) or collagen and ADP (Col/ADP) under hemodynamic conditions similar to those of small capillaries. Platelets adhere and aggregate across the aperture until the flow ceases, evaluated by the closure time (CT, sec). Statistical analysis was performed using a standard software (Sigma Plot v. 8; Student’s paired t test). Analysis of platelet function with Col/Epi cartridges showed that irradiated samples had a prolonged closure time compared to corresponding non irradiated controls (144 ± 21 sec vs. 120 ± 18 sec, p<0.05). The averaged CT prolongation was 19±5%. Analysis of CT using Col/ADP cartridges showed also prolongated CT (averaged prolongation 7%) in seven of nine irradiated samples compared to non irradiated controls (97 ± 14 sec vs. 103 ± 13 sec, p<0.05). Our results suggest that a standard dose of ionising irradiation for prevention of GVHD has a significant influence on platelet function. The biochemical nature by which this platelet dysfunction following irradiation is caused, remains to be assessed in further detail.
Effects of Photopheresis on Mononuclear Cells from Healthy Individuals.
Authors: Kumlien Gunilla , Remberger Mats , Ringdén Olle 
Published: October 2019

Abstract
Background: Extracorporeal photopheresis (ECP) has been proposed as an alternative therapy for immune-mediated disease including graft-versus-host-disease (GVHD) and transplant rejection (Photopheresis for the treatment of refractory renal graft rejection, Transplantation2005;79(1):123–5, Kumlien G et al). The mechanisms of photopheresis are still poorly understood but induction of tolerogenic dendritic cells and regulatory T cells as well as a shift of cytokine profile from Th1 to Th2 have been observed in patients treated with ECP. We wanted to investigate some basic effects of ECP on mononuclear cells from healthy individuals unaffected by pathogenic mechanisms and immunosuppressive drugs.
Method: Mononuclear cells (MNCs) were collected from six healthy volunteer apheresis donors using CobeSpectra apheresis machine (Gambro BCT, Lakewood, CO, USA) and peripheral blood was drawn immediately before apheresis. Apheresis products were thoroughly mixed and divided into three equal parts. One part was left untreated, one part was irradiated with UVA 365 nm, 2J/cm2 (BioGenic, Vilber Lourmat, Marne-la-Vallée, France) and one part was treated with psoralen (8-methoxypsoralen 200 ng/ml) plus UVA-irradiation (PUVA). Peripheral MNCs and aliquots of apheresis MNCs were analysed simultaneously regarding incorporation of 3H Thymidine after stimulation with mitogens (PHA, ConA, SpA) and production of cytokines correlated with GVHD pathogenesis (IL-2, IL-6, IL-12, TNFα, IFNγ) after stimulation with antigens (BG, PHA, LPS) using commercial ELISA-kits (Quantikine, R&D Systems, Minneapolis, MN, USA). Statitical analysis was performed using a nonparametric method (one-sided ANOVA).
Results: Mitogenic capacity was reduced to baselevel after PUVA-treatment but not affected by the apheresis procedure or UVA-irradiation alone. Table 1. Statistically significant decrease of cytokine production was seen only after PUVA-treatment but production of IL-2 and IL-6 was reduced after both apheresis and UVA-irradiation alone. Small amounts of IL-2, IL-6, TNFα and IFNγ were produced even after PUVA-treatment.
Conclusion: Significant reduction of mitogenic capacity only after PUVA-treatment was the expected finding. Apheresis can theoretically effect cells through mechanic damage (centrifugation) and/or interaction with apheresis harness and UVA is known to have immunomodulatory effects which can explain the reduction of cytokine production. Cytokines detected after PUVA-treatment may be explained by release from apoptotic cells or by production in cells that escape apoptosis.
Lymphocyte proliferation assay ConA PHA SpA MNCs = mononuclear cells peripheral vs apheresis MNCs ns ns ns peripheral vs UVA-irradiated MNCs ns ns ns apheresis vs UVA-irradiated MNCs ns ns ns peripheral vs PUVA-treated MNCs p<0.05 p<0.05 p<0.05 apheresis vs PUVA-treated MNCs p<0.05 p<0.05 p<0.05 UVA -irradiated vs PUVA-treated MNCs p<0.05 p<0.05 p<0.05
Development of B Cell Lymphoma in Eμ-Cyclin D1 X Mutant p53 Transgenic Mice.
Authors: Smith Mitchell R. , Joshi Indira J. , Jin Fang , Al-Saleem Tahseen 
Published: October 2019

Abstract
Background: Mantle cell lymphoma (MCL) is characterized by t(11;14) which dysregulates cyclin D1 expression. Eμ-cyclinD1 transgenic mice, however, are healthy. Additional genetic events must be necessary for lymphomagenesis, and knowledge of these would enhance understanding and therapy of MCL. In addition, a mouse model of MCL would be helpful in drug development. Alterations in p53 have been described in MCL, often associated with the blastic variant.
Objectives and Methods: To determine whether p53 and cyclin D1 can cooperate in lymphomagenesis, we cross bred Eμ-cyclinD1 transgenic mice (Bodrug et al EMBO J, 1996, courtesy of Alan Harris) with mice transgenic for mutant p53 (Jackson Labs, Jacks et al Curr Biol, 1994). Progeny mice were monitored for presence of the transgenes by PCR of tail vein DNA and observed for development of disease.
Results: Of mice carrying both aberrant genes, 24 of 38 developed B cell lymphoma. Mice did not become visibly ill until at least 12 months of age, with median age at sacrifice 15.5 (range 12–23) months. The lymphoma was generally disseminated, involving spleen, liver, diffuse adenopathy and marrow with occasional extranodal sites. Histology varied between small and large cell, with some having a vaguely follicular growth pattern. T cell lymphomas occurred in 2 other mice, while 5 developed osteosarcoma (1 of these in a mouse that also had B cell lymphoma). The B cell lymphomas were clonal by Cμ-VH PCR. Cyclin D1 expression was documented by Western analysis. A cell line has also been developed from one of the B cell lymphomas and this line rapidly grows into disseminated lymphoma in syngeneic mice. These B cell lymphomas differ from the thymic T cell lymphomas seen in heterozygous p53 mutant mice that do not co-express cyclin D1. The latency period differs from cyclin D1 x myc double transgenic mice.
Conclusions: This model demonstrates cooperation between p53 and cyclin D1 pathways in B cell lymphomagenesis and should prove useful in delineating how these signals interact. The cell line may prove useful in pre-clinical testing of new agents for MCL.