bluuebunny/crossref_metadata_2025_split huggingface dataset:
Manteinance Treatment with Interferon (IFN) Is Not Necessary to Achieve Prolonged Progression Free Survival (PFS) in Patients with Indolent Non Hodgkin’s Lymphoma (NHL). Results from a Prospective Randomized Trial on 165 Patients.
Authors: Cannata Jimena , Nicolas Concepcion , Resident Raul Cordoba , Rayon Consuelo , Garcia-Laraña Jose , Lopez Javier , Perez Guillermo , Sanchez-Godoy Pedro , Garcia-Alfonso Pilar , Zamora Pilar , Fernandez-Rañada Jose-Maria , Arranz Reyes 
Published: October 2019

Abstract
INTRODUCTION. Treatment with IFN and chemotherapy induces a significant improvement of PFS in patients with low-grade NHL, specially in patients with responsive disease. However, the best IFN schedule is still pending as benefits are observed when IFN is administered associated to the induction therapy or, as maintenance treatment or, in both treatment phases.
OBJETIVE. To evaluate the additional benefit or not of one year maintenance treatment with IFN in patients who achieve response after an induction treatment with CVP and IFN for 3 months.
PATIENTS & METHODS. From February 1990- October 2002, 165 patients with low-grade NHL were recruited. Patients received treatment with CVP (median number 6 cycles) and IFN, 3MU/m2 three times a week during 3 months. Patients with complete or partial responses were then randomized to receive treatment with 12 months of IFN, 3MU/m2 three times a week vs observation. With a median of 4,7 years (range 0.3 to 11.7 years) for surviving patients, we analysed response, PFS and overall survival.
RESULTS. Patients median age was 63 years (range 28–89 years), with 65.5% having follicular (FL), 20% small lymphocyte and 14% marginal zone lymphoma. Most patients (83%) were in advance stage and 75% had extranodal involvement. Thirty-three percent of FL patients had a FLIPI index score > 3. Dose-intensity for cyclophosphamide and IFN in the induction treatment was 71% and 69%, respectively. Ten patients withdraw the study due to grade 3–4 toxicity events (6.5%).
Response : 86% of patients achieved a response, 80% complete. One hundred and twelve out of the 143 responding patients were randomised to receive IFN for 12 months (56 patients) vs observation (56 patients). Patients and disease characteristics for each group were similar. Median dose of maintenance IFN treatment was 67% (range 8%–113%). Fourteen patients (25%) withdraw the study, 7 due to IFN toxicity.
PFS : Median PFS of the whole series was 6.76 years, 6.6 years for patients in the maintenance IFN group vs 7.8 years for the observation group, p=0.7.
Overall survival at 12 years is 81% for both groups. Interestingly, 31 patients who achieved a good response but were not randomised showed a significantly shorter OS, p=0.001.
CONCLUSION. No additional increase on PFS has been observed when maintenance IFN is administered to patients responding to CVP and short term IFN induction therapy. With our data, very good response rates and long lasting remission are achieved with only 3 months IFN treatment. Treatment tolerance is therefore significantly better.
Can High Dose Therapy Change the Course of Low Grade Lymphoma? A Study Considering Patients as Their Own Control.
Authors: Vignot Stephane , Mounier Nicolas , Sergent Guillaume , Brice Pauline , Marolleau Jean-Pierre , Parquet Nathalie , Briere Josette , DeKerviller Eric , Madeleine Isabelle , Gisselbrecht Christian 
Published: October 2019

Abstract
Low grade lymphoma patients (pts) have an indolent evolution with median survival ranging between 8–10 years. During disease’s course, high dose therapy (HDT) and autologous stem-cell transplantation (ASCT) can be considered as an alternative to sequential chemotherapies. However, efficacy of this strategy remains controversial. The purpose of our study is to evaluate ASCT efficacy by comparing retrospectively for each pts disease free survival (DFS) after ASCT with DFS observed with pts’ last chemotherapy regimen (LCR) just before intensification. Between apr 1988 and feb 2002, 109 low grade lymphoma pts were treated with HDT and ASCT in our department, 61 were male, the median age was 49 yrs [range 28–65]. Histological subtypes were mostly follicular small cell (86 %). At time of diagnosis, LDH were normal for 85 pts; 60 pts had high tumor burden. IPI was 0 for 16 %, 1 for 70 % and 2 for 14 %. Prior to ASCT, pts had experienced a median of 2 progressions (range 1 to 5). At time of graft, 102 pts present complete or partial response and 7 pts present stable disease. Two principal intensification chemo regimens were used before ASCT: VP16/cyclophosphamide in 84 pts and BEAM in 12. TBI was associated for 86 pts. At June 2002, the median follow up was 6.4 yrs from diagnosis and 4.5 yrs from ASCT. 3 years after ASCT, survival rate was 72 % and DFS rate was 50 %. Median DFS decreased with nb of progression (p=0.02):
Median DFS according to nb of progression
Nb of progression 1 2 3 > 3 Nb pts (%) 17 (16) 57 (52) 28 (26) 7 (6) Median DFS in yrs 6.4 5.1 1.8 1.0
Considering pt with more than 1 progression (n=92) as his own control, DFS was longer after ASCT than after LCR for 61 % of pts. Median DFS was 2.5 yrs after ASCT and 2.0 yrs after LCR. At 3 yrs, DFS rate was 48 % after ASCT and 37 % after LCR (p<0,001):
Figure Figure
This study demonstrates that HDT and ASCT significantly increase DFS in comparison with the LCR for low grade lymphoma patients. Such methodology could be useful to evaluate new strategy incorporating monoclonal antibody.
Genetic Variants of Ataxia Telangiectasia Mutated (ATM) and Susceptibility for Childhood T-Lineage Acute Lymphoblastic Leukemia.
Authors: Meier Marrit , Den Boer Monique L. , Hall Andrew G. , Irving Julie , Passier Monique , Minto Lynne , Van Wering Elisabeth R. , Janka-Schaub Gritta E. , Pieters Rob 
Published: October 2019

Abstract
ATM was identified as the gene mutated in Ataxia Telangiectasia (AT), a degenerative neurological disorder that is characterized by, amongst others, an increased risk to develop a hematomalignancy at young age. Striking is the high incidence of T cell derived lymphoid malignancies amongst AT patients. As sporadic T-lineage Acute Lymphoblastic Leukemia (T-ALL) is particularly found in childhood, we have investigated the occurrence and frequency of mutations in 62 coding exons of the ATM gene in 41 children with T-ALL at initial diagnosis and their relation to susceptibility for T-ALL. Moreover, as ATM is implicated in cellular signaling events in response to DNA damaging agents, we have also investigated whether genetic variants of ATM are possibly related to cellular resistance to drugs and clinical outcome in childhood T-ALL. We have identified 18 different ATM alterations, of which 9 were not previously reported, in 68% of T-ALL patients. None of the alterations co-segregated with loss of heterozygosity of the ATM gene. The simultaneous presence of more than one genetic variant was observed in 32% of T-ALL patients compared to only 12% of healthy controls (P = 0.006). An increased frequency of ATM alterations was of no influence on the level of ATM mRNA and did not associate with cellular resistance to daunorubicin, prednisolone, vincristine and L-asparaginase nor with age at diagnosis, white blood cell count or long-term clinical outcome. However, the presence of specific genetic variants, i.e. S707P, F858L, T896A, P1054R and L1472W was related to an age younger than 10 years (P = 0.034) and an increased relapse-risk (P = 0.025). In addition, an increased frequency of carriers of these genetic variants was observed amongst T-ALL children (29%) compared to controls (11%) (P = 0.028). We conclude that ATM gene alterations might pre-dispose carriers to develop T-ALL in childhood, in particular involving specific genetic variants of ATM as their occurrence is significantly associated with a young age.
Genomewide Linkage Analysis of Chronic Lymphocytic Leukemia by Use of a High-Density Single Nucleotide Polymorphism Assay Containing 11,555 Markers.
Authors: Sellick Gabrielle S. , Allinson Ruth , Matutes Estella , Yuille Martin , Catovsky Daniel , Houlston Richard S. 
Published: October 2019

Abstract
A genetic basis for chronic lymphocytic leukemia (CLL) is indicated by studies demonstrating that the lifetime risk of developing the disease increases by a factor of seven when at least one first-degree relative is affected. Significant familial aggregation of CLL has been demonstrated, but the mode of inheritance is unknown. To date no genes which when mutated have unequivocally been shown to confer susceptibility to the disease. We have collected clinical data and biospecimens from 370 families comprising of at least two affected family members with CLL. Of these, samples from two or more individuals from 100 families were informative for linkage analysis. To identify a predisposition locus for CLL a high-density single nucleotide polymorphism (SNP)-based genomewide linkage search was conducted using the GeneChip Mapping 10k Xba array containing 11,555 SNP markers (Affymetrix Inc., Santa Clara, CA). Multipoint LOD scores were calculated, assuming both dominant and recessive inheritance and allowing for increased penetrance with age and genetic heterogeneity. Non-parametric linkage scores were also calculated. The results from these analyses will be presented.
BAFF Support Survival of Chronic Lymphocytic Leukemia B Cells by a Pathway Independent of Stromal Derived Factor-1α.
Authors: Nishio Mitsufumi , Tsukada Nobuhiro , Kitada Shinichi , Ohata Junko , Zvaifler Nathan J. , Reed John C. , Kipps Thomas J. 
Published: October 2019

Abstract
We examined the peripheral blood mononuclear cells (PBMC) of patients with chronic lymphocytic leukemia (CLL) for expression of B cell-activating factor of the TNF family (BAFF). Isolated CLL B cells had significantly lower levels of BAFF mRNA than did non-separated PBMC. Most of the BAFF mRNA in PBMC was due to contaminating CD14+ cells that previous studies found could differentiate into “nurselike” cells (NLC) when cultured with CLL B cells in vitro. We found NLC expressed high-levels of BAFF and stromal cell-derived factor-1 alpha (SDF-1α), in contrast to CLL B cells. CLL B cells cultured with exogenous recombinant human BAFF (rhBAFF), SDF-1α, or NLC sustained significantly greater viability than isolated CLL B cells cultured alone. The effect(s) of rhBAFF on leukemia cell survival appeared additive and distinct from that of SDF-1α, which in contrast to rhBAFF induced leukemia-cell phosphorylation of p44/42 mitogen-activated protein-kinase (ERK 1/2) and phosphorylation and activation of AKT at Ser473. However, rhBAFF, but not SDF-1α, could induce processing of p100 NF-κB2 to p52 and, like NLC, enhance and/or maintain CLL-cell expression of the anti-apoptotic protein Mcl-1. We conclude that BAFF can function in a paracrine manner to support leukemia cell survival via mechanisms that are distinct from those of SDF-1α and that NLC use multiple distinct pathways to support CLL-cell survival.
The Restricted VH-Gene Usage Is of Prognostic Value in B-Cell Chronic Lymphocytic Leukemia.
Authors: Philippé Jan , Van Bockstaele Femke , Smits Kaatje , Offner Fritz , Verhasselt Bruno , Janssens Ann 
Published: October 2019

Abstract
In B-cell chronic lymphocytic leukemia (B-CLL) the mutation status of the immunoglobulin variable heavy chain gene (VH) is known as a prognostic factor. We have investigated if specific VH-gene usage is of additional prognostic importance regarding survival. Peripheral blood samples from 147 B-CLL patients were analysed for VH usage. Recombinations occurring in at least 5% of cases were studied in depth. The most frequently used VH-gene segments were VH1-69 (10.9%), VH3-7 (7.5%), VH3-30 (6.8%), VH4-34 (6.8%), VH3-21 (6.1%), VH3-23 (6.1%), and VH3-33 (5.4%). The VH gene usage was compared with mutation status, cytogenetic abnormalities and survival. Comparison with age matched controls reveals the restricted VH gene usage in B-CLL. VH gene usage showed a distinct prognostic value (p=0.01) when the patients using VH genes with bad prognosis were grouped together (VH1-69, VH3-21, VH3-23 and VH3-33; 43% of these patients died) and were compared with the patients using VH genes with a relatively good prognosis (VH3-7, VH3-30 and VH4-34; mortality rate of only 13%). The prognostic significance holds true when all patients were included (p=0.03). Also the mutation status (p=0.04) and cytogenetics (p=0.03) showed a prognostic significance. The VH gene usage did not correlate with mutation status, nor with cytogenetics. On the contrary mutation status and cytogenetics were strongly correlated (p<0.00001). These findings are highly suggestive for VH gene usage to offer additional prognostic information to the other well established prognostic parameters. In conclusion, a bias to the specific VH gene segments involved in B-CLL supports the concept that B-CLL arises from B cells driven by specific antigens/superantigens which is different from a stochastic event in the elderly B-cell population. Moreover, the immunoglobulin specificity reveals specific subgroups with differing prognosis.
Predictive Value of Gene Expression with Respect to IgVH Mutational Status and Survival in Chronic Lymphocytic Leukemia.
Authors: Van’t Veer Mars B. , Brooymans Anne , Langerak Anton W. , Graveland Wilfried J. , Van Lom Kirsten , Valk Peter 
Published: October 2019

Abstract
Background: Chronic Lymphocytic Leukemia (CLL) has a variable clinical course, of which IgVH mutational status of the malignant B cells is a strong independent predictor for outcome.
Objective: We studied the expression of 5 different genes for their value to predict IgVH mutational status and overall survival (OS).
Methods: mRNA levels were quantified by real time PCR in lymphoprep separated but unsorted blood samples from 110 morphologically and fenotypically characterised CLL patients for the following genes: ZAP70, lipoprotein lipase (LPL), ADAM29, KIAA0610 and nRIP1. Expression levels were compared wih respect to IgVH mutational status (mutation = % germline < 98%), using logistic regression and with respect to OS (= time from day of laboratory tests to death due to any cause), using Cox regression analysis.
Results: The predictive value of the expression of these 5 genes for IgVH mutational status is shown in table 1. Each of these genes showed to be an independent marker for the prediction of IgVH mutational status. LPL as a single marker was the best predictor for mutation. These factors taken together had a high predictive value towards mutational IgVH status (area under ROC curve = 0.93).
table 1
N Odds ratio P value ZAP70 no 85 1 (>5.2) yes 25 0.098 0.002 LPL no 73 1 (>0.04) yes 37 0.029 <0.001 ADAM29 no 73 1 (>30) yes 37 6.61 0.012 KIAA0610 no 81 1 (>0.25) yes 29 0.19 0.045 NRIP1 no 88 1 (>10) yes 22 48.73 0.008
The predictive value of IgVH mutation and the expression of these 5 genes for OS is shown in table 2. From the six parameters tested, IgVH mutational status and LPL were predictors for OS at a significant level of 5%, while ZAP70 was of borderline significance.
table 2
Conclusion: measured in unsorted CLL samples, all genes, and especially LPL, had predictive value towards the presence of IgVH mutation. Expression of LPL and absence of mutation were adverse prognostic factors for survival. Thus, the replacement of the assessment of both IgVH mutational status and ZAP70 by assessment of LPL levels for the prediction of prognosis in CLL patients may be considered.
N survival at 24months P value mutation no 36 70% yes 44 93% 0.041 ZAP70 no 66 87% yes 18 70% 0.078 LPL no 55 94% yes 29 66% 0.001 ADAM29 no 57 84% yes 27 84% 0.486 KIAA0610 no 63 88% yes 21 71% 0.133 NRIP no 71 81% yes 13 100% 0.167
Upregulation of Human Pim-2 in B-CLL, Involves Interactions between Oct-1, Oct-2, Bob-1 and NF-kB.
Authors: Dicken Yosef , Cohen Amos M. , Bessler Hanna , Levi-Hirsh Daphna , Arad Ariela , Merkel Drorit , Don Jeremy 
Published: October 2019

Abstract
hPim-2 is a proto-oncogene that encodes a serine/threonine kinase and inhibits apoptosis by phosphorylation of BAD. We have shown that hPim is upregulated in human non-Hodgkin’s lymphomas (NHL) and in chronic lymphocytic leukemia (B-CLL) and its cellular transcript levels in B-CLL correlates with lymphocyte doubling time. We found no mutations in the promoter region of hPim-2 in B-cells of 30 patients with CLL (~2000 bp upstream). The proximal promoter region of hPim-2 (600 bp) contains two adjacent NF-kB-binding elements, two adjacent Oct-binding elements and an SP1 element by bioinformatic analysis. Studies have recently shown that the transcription factor Oct-2 and the B-cell specific Oct cofactor Bob-1 are overexpressed in certain large B-cell lymphomas, whereas increased expression of Bob-1 has also been observed in T-cell neoplasms. Shift assays (EMSA) analysis, using nuclear extracts from B-CLL cells and various fragments of hPim-2 promoter region used as probes, revealed that complexes containing an Oct elements were consistently heavier in B-CLL extracts compared with control B-cells. Accordingly, Oct-1, Oct-2 and Bob-1 protein levels were significantly higher in B-CLL compared to healthy extracts. Moreover, chromatin immunoprecipitation (Chip) assays confirmed that in-vivo Oct-1+2 and Bob-1 are indeed physically attached to the hPim-2 promoter, and that this interaction is significantly more intensive in B-CLL cells than in control B-cells. Furthermore, we have found in addition that the p52 isoform subunit of NF-kB predominates the interaction with the kB element in the hPim-2 promoter in B-CLL cells, as compared to the p50 isoform observed in control B-cells. To determine whether these interactions are transcriptionaly significant, we fused the luciferase reporter gene to various promoter fragments, and monitored luciferase expression in-vitro after incubation with either B-CLL or normal B-cell extracts. Luciferase expression was consistently higher when Oct element-containing fragment was incubated with B-CLL cell extracts. Together, these results suggest that the upregulation of hPim-2 in B-CLL is due to enhanced expression and transcriptional activity of the Oct-1+2 and Bob-1 complex and that it might synergistically act with the p52 containing NF-kB transcription factor.
Human Platelets Contain Forms of Factor V in Disulfide-Linkage with Multimerin.
Authors: Hayward Catherine P.M. , Fuller Nola , Zheng Shilun , Adam Frederic , Jeimy Samira , Horsewood Ian , Quinn-Allen Mary Ann , Kane William H. 
Published: October 2019

Abstract
Factor V is an essential cofactor for blood coagulation that circulates in platelets and plasma. Unlike plasma factor V, platelet factor V is stored complexed with the polymeric α-granule protein multimerin. In analyses of human platelet factor V on nonreduced denaturing multimer gels, we identified that approximately 25% was variable in size and migrated larger than single chain factor V, the largest form in plasma. Upon reduction, the unusually large, variably-sized forms of platelet factor V liberated components that comigrated with other forms of platelet factor V, indicating that they contained factor V in interchain disulfide-linkages. With thrombin cleavage, factor Va heavy and light chain domains, but not B-domains, were liberated from the components linked by interchain disulfide bonds, indicating that the single cysteine in the B-domain at position 1085 was the site of disulfide linkage. Because unusually large factor V had a variable size and included forms larger than factor V dimers, the data suggested disulfide-linkage with another platelet protein, possibly multimerin. Immunoprecipitation experiments confirmed that all unusually large factor V in platelets was associated with multimerin and it remained associated in 0.5 M salt. Multimerin immunodepletion of the normal pooled platelet lysate removed 100 ± 0% of multimerin and 47.0 ± 2.4% of total factor V antigen, whereas sham immunodepletion removed 12.0 ± 3.0 % of multimerin and 4.0 ± 4.0% of factor V antigen (means ± 1 S.D. for 3 experiments). Analyses of serial factor V immunopurified samples indicated that platelets contained a subpopulation of multimerin polymers that resisted dissociation from factor V by denaturing detergent and comigrated with unusually large platelet factor V, before and after thrombin cleavage. The suggestion that only a subpopulation of multimerin was covalently linked to factor V was consistent with the estimated 17 fold molar excess of multimerin subunits to factor V molecules in platelets. The disulfide-linked complexes of multimerin and factor V in platelets, that are cleaved by thrombin to liberate factor Va, could be important for modulating the function of platelet factor V and its delivery onto activated platelets. Multimerin could function to hold about half of the platelet pool of factor V in covalent and noncovalent linkages, until granule release occurs and thrombin cleavages liberate factor Va for prothrombinase assembly on the platelet surface, akin to the way supporting scaffolds hold pieces of plastic models in a unit until their removal for model assembly is desired.
Demystifying Tissue Factor.
Authors: Butenas Saulius , Gissel Matthew T. , Bouchard Beth A. , Brummel Kathleen E. , Parhami-Seren Behnaz , Mann Kenneth G. 
Published: October 2019

Abstract
Tissue factor (TF) is an integral membrane protein, which is the key initiator of blood coagulation in vivo. Due to the limited availability of natural TF, recombinant proteins of various lengths and origins have been extensively used in research and clinical laboratories worldwide. Experimental results acquired with recombinant TF proteins are frequently used for the understanding of the coagulation processes occurring in vivo, although there is a lack of data confirming the structural and functional identity of natural TF proteins from various sources and recombinant ones. In the current study, human TF from cultured monocytes and purified from placenta were compared with three different species of recombinant TF: 1–218 (extracellular domain only), 1–242 (lacking cytoplasmic domain) and 1–263 (full-length). Anti-TF mAbs gave 93–98% inhibition of TF activity for all TF species tested, in both natural and relipidated preparations. It was established that purified placental TF has a higher affinity for factor VIIa (Kd 0.13 nM) than recombinant counterparts 1–242 and 1–263 (Kd 0.50–0.80 nM). Similarly, placental TF is more efficient in factor X activation by the extrinsic Xase than recombinant TF 1–242 (the second order rate constants are 3.0x107 and 0.7x107 M−1s−1, respectively). We explored the use of these TF species as well as monocyte TF (purified/relipidated and present on LPS-stimulated monocytes) for the initiation of thrombin generation in two in vitro models of blood coagulation. At equimolar concentrations (5 pM; determined by immunoassay), when evaluated in synthetic plasma reconstituted with 2x108/ml platelets, recombinant TF 1-263 provided an initiation phase of ~4 min. Placental TF and relipidated monocyte TF had similar profiles of thrombin generation with an initiation phase of ~3 min. In contrast, 0.5 pM TF on LPS-stimulated monocytes gave an initiation phase of ~1 min. Even at 0.05 pM concentration, monocyte TF was as active as any relipidated protein at 5.0 pM. A similar pattern of relative TF activity was observed in whole blood and plasma PT clotting assays. TF on stimulated monocytes gave the highest activity, exceeding that of any relipidated protein by 100–200-fold. Recombinant TF 1–242 was more active than recombinant TF 1–263 and placental TF in the PT assay but less active in synthetic plasma and whole blood. The lowest overall activity was observed for relipidated monocyte TF. Our data suggest that TF proteins from different sources are different with respect to their functional properties.