bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deletions of Chromosomes 6q and 13q, and Trisomy 4 Are the Most Common Cytogenetic Abnormalities in Waldenstrom Macroglobulinemia. Preliminary Results of a Multicentric Study.
Authors: Nguyen-Khac Florence , Chapiro Elise , Mould Sarah , Barin Carole , Daudignon Agnes , Gachard Nathalie , Struski Stéphanie , Henry Catherine , Penther Dominique , Mossafa Hossein , Andrieux Joris , Perissel Bernard , Eclache Virginie , Bilhou-Nabera Chrystele , Luquet Isabelle , Terre Christine , Baranger Laurence , Mugneret Francine , Gregoire Marie-Jose , Chiesa Jean , Ramond Sylvie , Mozziconacci Marie-Joelle , Callet-Bauchu Evelyne , Merle-Beral Helene , Leblond Veronique 
Published: April 2020

Abstract
The genetic bases of Waldenstrom Macroglobulinemia (WM) are poorly understood. We have studied a cohort of 139 untreated WM patients, enrolled in a prospective randomized trial from the French Cooperative Group on Chronic Lymphocytic Leukemia and Waldenstrom Macroglobulinemia (FCG-CLL/WM), by conventional cytogenetic (CC) and Fluorescence in situ hybridization (FISH). The sex ratio was 2.2M/1F, the average age at inclusion was 66 years [40–85]. The mean percentage of lymphoplasmacytic cells was 53% [8–97]. CC was systematically performed on bone marrow or peripheral blood, and FISH analysis carried out using 7 probes CEP4, CEP12, 13q14, 11q22 ( ATM), 17p13 (TP53), IGH Abbott, 6q21 Q-Biogene, on metaphases and interphase nuclei. Out of 110/137 successful karyotypes, 37% showed clonal abnormalities (9 additional cases had numerical changes of sexual chromosomes). Among abnormal karyotypes, there were 14 (34%) 6q deletions, 5 (12%) trisomy 4/partial trisomy 4, 4 (10%) trisomy 18, 3 (7%) trisomy 12. Using FISH, deletions of 6q21 were observed in 23/86 cases (27%), 13q14 in 12/89 cases (13%), TP53 9/85 cases (11%), ATM 6/81 cases (7%). Trisomy 4 was present in 9/82 cases (11%), and trisomy 12 in 4/86 cases (5%). No rearrangement of IGH was observed in the first 27 analyzed cases. The 6q deletion is the most frequent reported cytogenetic abnormality in WM. We found 27% with deletions of 6q21 (FISH), a low percentage compared to the literature [39–54%]. This could be explained either by the difference in the probe used or by the absence of selection of lymphoplasmacytic cells before cytogenetic analyses. Interestingly, we confirmed our recent observation that trisomy 4 was frequent in WM (12% if partial trisomy 4 was included). Furthermore we observed in this large series a frequent 13q14 deletion (13%). In conclusion, cytogenetic abnormalities in WM differ from those commonly reported in other B-cell neoplasms and confirm the originality of this disease. 6q deletion is frequent compared to CLL or marginal zone lymphoma (MZL) and 13q14 deletion is rare compared to CLL. In our series trisomy 12 is rare compared to atypical-CLL and MZL. We didn’t observe cytogenetic involvement of the IGH locus, which is frequent in multiple myeloma or lymphoplasmocytic lymphoma. Finally trisomy 4 is present in WM but not reported in other B-cell malignancies. Searches for correlations with clinical and other biological parameters are ongoing.
CS-1 Is Expressed in Nasal Type NK/T Cell Lymphomas and Angioimmunoblastic T-Cell Lymphomas: Implications for Targeted Therapy with Elotuzumab (HuLuc63).
Authors: Hsi Eric D , Steinle Roxanne , Balasa Balaji , Rice Audie , Ko Young-Hyeh , Afar Daniel E.H. 
Published: April 2020

Abstract
Background: CS-1 (CRACC, SLAMF7, CD319) is a member of the signaling lymphocyte activating molecule-related receptor family. It is highly and uniformly expressed on the cell surface of benign and malignant plasma cells. We have recently reported the generation of elotuzumab (formerly known as HuLuc63), a humanized antibody targeting CS-1, which is currently in phase 1 trials in relapsed multiple myeloma. Lower levels of CS-1 have also been reported on NK cells and NK-like T-cells (NK/T). CS-1 expression in NK and T-cell lymphomas - aggressive lymphomas for which no effective therapy exists - is unknown. Here, we examined the expression of CS-1 in normal NK/T cells and in a series of NK and peripheral T-cell lymphomas (PTCL).
Methods: CS-1 expression in normal NK and T-cells were assessed by gene expression profiling. Flow cytometry (FACSCalibur, Becton Dickinson) was performed on blood from normal samples using a directly conjugated Alexa-488 elotuzumab. Archival formalin-fixed, paraffin-embedded tissues from PTCLs, including angioimmunoblastic T-cell lymphomas (AITL) and nasal type NK/T cell lymphomas were tested for CS-1 expression using the a paraffin-reactive 1G9 monoclonal antibody and automated immunohistochemistry (IHC, Ventana Medical Systems).
Results: Gene expression profiling showed CS-1 expression in purified NK and NK/T cells. We confirmed cell surface expression of CS-1 protein on normal blood NK and NK/T cells (n=18 samples) by flow cytometry with Alexa-488-HuLuc63. The majority of normal NK and NK/T cells expressed CS-1 (mean% positive and standard deviation of 96% +/− 4% and 71 % +/− 24%, respectively). We then evaluated tumor samples from patients with nasal type NK/T cell lymphoma as well as other peripheral T-cell lymphomas by IHC. Biopsies from 13 patients (5 from the United States, 8 from Korea) with nasal type NK/T cell lymphomas were evaluated by IHC. 12 of 13 (92%) patient samples expressed CS-1 with most cases showing a majority of cells positive. 46 PTCLs were also evaluated (including 9 AITL). Overall, 8/46 (17%) of the PTCL cases expressed CS-1. However, of the AITLs, 4 of 9 (44%) expressed CS-1.
Conclusions: CS-1 is expressed on nearly all nasal type NK/T cell lymphomas and in a substantial proportion of AITLs. These results provide the rationale for exploring elotuzumab in the targeted treatment of NK/T-cell malignancies.
The Role of Protein Tyrosine Phosphatase, Shp2, in FLT3-ITD-Induced Leukemogenesis.
Authors: Nabinger Sarah C , Fukuda Seiji , Kapur Reuben , Chan Rebecca 
Published: April 2020

Abstract
Internal tandem duplications of the FMS-like receptor tyrosine kinase (FLT3-ITDs), an in-fame insertion of several amino acids within the juxtamembrane domain, are present in 25% of acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3-ITDs induce FLT3 ligand (FL)-independent hyperactivation of Erk and promiscuous activation of STAT5; however, the molecular mechanisms underlying aberrant activation of these signaling molecules is largely unknown. Tyrosine 599 (Y599) of WT FLT3 recruits the protein tyrosine phosphatase, Shp2, upon stimulation with FL, resulting Erk activation. In several FLT3-ITDs, including N51-FLT3 and N73-FLT3, Y599 is duplicated. These findings led us to hypothesize that increased recruitment of Shp2 to N51-FLT3 or N73- FLT3, via Y599, results in enhanced Shp2 activation and contributes to N51-FLT3- and N73-FLT3-induced cellular hyperproliferation, Erk hyperactivation, and promiscuous STAT5 activation. Using Baf3 cells stably expressing WT FLT3, N51-FLT3, or N73- FLT3, co-immunoprecipitation assays demonstrated that Shp2 is phosphorylated and associates with WT FLT3 in a FL-dependent manner. However, in contrast, Shp2 is constitutively hyperphosphorylated and associated with FLT3-N51 and FLT3-N73 independent of FL stimulation. To investigate the functional role of Shp2 in Flt3-ITD-induced leukemogenesis, Baf3 cells expressing WT FLT3, N51-FLT3, or N73-FLT3 were transfected with a mammalian expression vector encoding a U6 polymerase III– directed Shp2-specific short-hairpin RNA (shRNA) or a scrambled shRNA and selected in puromycin. Western blot analysis revealed significant reduction of Shp2 expression by the Shp2-specific shRNA and no change in Shp2 expression by the scrambled shRNA in all cell lines. Upon knock-down of Shp2 in Baf3/WT-FLT3 cells, proliferation was minimally reduced based on thymidine incorporation assays; however, knock-down of Shp2 in Baf3/N51-FLT3 and Baf3/N73-FLT3 cells significantly reduced proliferation, both at baseline and in response to FL stimulation. Collectively, these data suggest that constitutive recruitment of Shp2 to N51-FLT3 and N73-FLT3 contributes to the FLT3- ITD-induced hyperproliferative phenotype and imply that inhibition of Shp2 function may provide a novel therapeutic approach to FLT3-ITD-bearing leukemias.
Levels of Inflammatory Markers and the Development of the Post Thrombotic Syndrome.
Authors: Shbaklo Hadia , Holcroft Christina A , Kahn Susan R 
Published: April 2020

Abstract
Background: The post-thrombotic syndrome (PTS) occurs frequently after deep vein thrombosis (DVT) despite appropriate anticoagulant therapy. A close relationship between inflammation and thrombosis exists. While the inflammatory process at the time of DVT appears to improve thrombus resolution, it may promote destruction of venous valves, valvular reflux and subsequent development of PTS.
Objective: We prospectively evaluated the association between levels of four cytokines (IL-6, IL-8, IL-10 and MCP-1), two adhesion molecules (ICAM-1 and VCAM-1) and the development of PTS in a well-defined cohort of patients with DVT.
Methods: The study population consisted of 387 patients with objectively diagnosed symptomatic DVT who participated in the Venous Thrombosis Outcomes (VETO) Study and were followed for two years to determine the incidence of PTS. For this substudy, plasma samples frozen at the 4 month visit in 307 study patients who consented to provide blood samples were thawed and analyzed for the above inflammatory markers using the Luminex beads technology. Associations between marker levels and development of the PTS during follow-up were evaluated.
Results: Mean levels of IL-6 were significantly higher in patients with PTS compared to patients without PTS (7.35 pg/ml ± 14.26 vs. 4.60 pg/ml ± 4.90;p=0.03). Logistic regression analyses showed significant associations between PTS and levels above vs. below the median of IL-6 (OR 1.66; 95% CI 1.05, 2.62 (p=0.03)) and ICAM-1 (OR 1.63; 95% CI 1.03, 2.58 (p=0.04)). None of the other markers showed any association with PTS.
Conclusion: Our study suggests the presence of significant associations between markers of inflammation such as IL-6 and ICAM-1 and the development of PTS. Further work is needed to evaluate this relationship and to analyze other candidate markers that could be implicated etiologically in the association between DVT and PTS. If confirmed, this could lead to identification of new therapeutic targets for preventing PTS after DVT.
Prothrombin 20209C&gt;T: Thirteen New Cases and Association with the 19911A&gt;G Polymorphism.
Authors: Warshawsky Ilka , Makkar Vinit , Kottke-Marchant Kandice 
Published: April 2020

Abstract
During routine screening for the prothrombin 20210G&gt;A mutation as a risk factor for venous thrombosis, we and others have reported cases of prothrombin 20209C&gt;T heterozygotes that are enriched in individuals of non-Caucasian descent who have had thrombotic events and/or obstetrical complications. The prothrombin 20209C&gt;T variant, as well as six other variants close to position 20210, have been found by melting curve analysis using the LightCycler Instrument (Roche Molecular Biochemicals) and hybridization probes. Unlike assays which use restriction enzymes or allele-specific PCR, melting curve analysis can distinguish multiple base changes that lie within the region of a hybridization probe as long as the base change causes a significant change in melting temperature from expected results. We describe thirteen new prothrombin 20209C&gt;T heterozygous cases from unrelated individuals and one family study which were found during routine screening of clinical samples for the prothrombin 20210G&gt;A mutation. Ethnic and clinical information were available in 11/13 cases: Ten individuals were of African descent while one was Hispanic. Eight individuals had thrombotic events (venous thrombosis, pulmonary embolism, and/or stroke), one had a pregnancy loss, one had bilateral below the knee amputations due to severe peripheral vascular disease, and one had a questionable pulmonary embolism. We next examined the prevalence of the prothrombin 19911A&gt;G polymorphism in 20209C&gt;T heterozygotes since alleles 19911A and 20210A are in full linkage and since the 19911G allele has been associated with increases in both plasma prothrombin activity and venous thrombosis risk. Of twenty 20209C&gt;T heterozygotes, eighteen were 19911GG homozygous and two were 19911AG heterozygous. These results are consistent with linkage of alleles 20209T and 19911G and contrasts with the linkage of alleles 20210A and 19911A. Since the 19911G allele was found in all 20209C&gt;T patients, it is possible that the 19911G-20209T haplotype increases the risk for thrombosis and/or obstetric complications, especially among individuals of African descent.
TLT-1 (TREM-Like transcript-1) Protects against Hemorrhage Associated with Inflammation by Facilitating Platelet Aggregation.
Authors: Washington A. Valance , Gibot Sébastien , Acevedo Ismael , De La Mota Alina , Gattis James , Rivera Linette , Quigley Laura , Gomez-Rodriguez Julio , Cheng Jun , Dutra Amalia , Lubkowski Jacek , Pak Evgenia , Hunter Robert , Schwartzberg Pamela L , McVicar Daniel W 
Published: April 2020

Abstract
TREM-like transcript-1 (TLT-1) is a novel, platelet-specific, membrane protein that is stored in a-granules and brought to the platelet surface upon activation. Little is known about its function. Here we build upon our recent findings that a soluble fragment of TLT-1 (sTLT) is released upon platelet activation and can be detected in the serum, but not the plasma, of healthy individuals. Evaluation of patients admitted to the University Hospital, Ramon Ruiz Arnau, in Bayamon Puerto Rico with the diagnosis of sepsis for the presence of plasma sTLT demonstrated significant levels of sTLT in septic individuals as compared to controls, indicating that TLT-1 plays a role in the early stages of sepsis. To directly assess this possibility we generated TLT-1 knockout mice and characterized their hemostatic function. Compared to wild type mice, TLT-1−/− platelets displayed decreased aggregation when treated with thrombin, collagen, ADP, or U46619 in vitro. The reduced platelet aggregation of TLT-1−/− mice translates to a 30% increase in bleeding time in tail snip assays compared to controls, supporting TLT-1’s role in vascular homeostasis. To evaluate TLT-1’s role in sepsis we challenged mice with lipopolysaccharide (LPS). LPS challenged TLT-1 null mice die faster and have a significantly lower rate of survival than wild type mice. We used the localized Shwartzman reaction to model the pathology associated with sepsis in a controlled lesion. Although neutrophil infiltration, thrombus formation, and the formation of microclots was not significantly higher in TLT-1−/− mice, the hemorrhage associated with Shwartzman lesions of these mice was nearly double and lesion size was greater than three times that of wild type mice. Moreover, we demonstrate a recombinant sTLT augments platelet aggregation in vitro suggesting a mechanistic explanation for the increased hemorrhage in TLT-1−/− mice. Thus these studies reveal an important role for TLT-1 in the maintenance of vascular hemostasis by facilitating platelet aggregation through incorporation of sTLT into the forming clot. This work suggests that therapeutic intervention using tools such as anti-TLT-1 single chain antibodies that inhibit platelet aggregation may provide a novel approach to the control of the thrombotic response.
Genetic Modifiers of Homozygous Beta Zero Thalassemia.
Authors: Galanello Renzo , Sanna Serena , Perseu Lucia , Sollaino Maria Carla , Satta Stefania , Uda Manuela , Usala Gianluca , Abecasis Goncalo , Schlessinger David , Cao Antonio 
Published: April 2020

Abstract
Introduction: Extensive studies over the last 50 years have derived two major modifiers of the clinical expression of beta-thalassemia: innate ability to produce fetal hemoglobin (Hb F) and co-inheritance of alpha-thalassemia. Recently genetic variants at the BCL11A locus and HBS1L-MYB intergenic region, that can modulate Hb F levels have been identified ( Thein et al 2007, Menzel et al 2007). Moreover, BCL11A variant has been shown to moderate the phenotype of homozygous beta-thalassemia (Uda et al 2008). In this study we evaluated the contribution of these Hb F modulating genetic markers and of alpha-thalassemia in ameliorating the severity of homozygous beta-thalassemia.
Methods: We studied 50 patients with the mild non-tranfusion dependent thalassemia intermedia phenotype and 75 with the severe tranfusion dependent thalassemia major. All patients were homozygotes for the beta 39 non-sense C → T mutation and were negative for the Xmn I -158 Gγ polymorphism. Alpha thalassemia was detected by GAP-PCR technique (deletion defects) and restriction enzyme digestion (nondeletion defects).Genotyping of HbF modulating genetic variants was performed using TaqMan® SNP genotyping assay (Applied Biosystems, Warrington, UK) according to the manufacturer’s protocol. Evaluation of the association, OR calculation and test for interaction were performed fitting a logistic regression.
Results: We found that the frequency of the BCL11A and HBS1L-MYB Hb F modulating markers and of co-inherited alpha- thalassemia is significantly increased (p= 2.05 x 10−5, p= 8.1 x 10−4, and p= 9.9 x 10−5 respectively) in the group of patients with thalassemia intermedia. Interestingly, the contribution of BCL 11A gene appears to be greater than HBS 1L-MYB locus ( OR= 5.15 and 4.61 respectively) and both are striking larger than the effect attributable to the co-inheritance of alpha-thalassemia (OR= 3.32). Furthermore, to visualize the combined effects of all loci, we considered a score variable defined as the number of positive alleles (i.e. those associated with the amelioration of the phenotype) carried from each patient. When considered all together the three loci explain 79% of the variation, evaluated as the correlation between fitted and observed values in the logistic regression. All three analyzed loci act in an additive fashion, where each copy of the minor allele contributes to the amelioration of the phenotype expression.
Conclusions: Molecular genetic analysis and particularly genome-wide association scans are producing rapid advances in defining the genetic variants for complex diseases and quantitative traits. The information reported are relevant in understanding the correlation between genotype and phenotype in thalassemia syndromes.
Hydroxyurea in Children with Beta Thalassemia Intermedia.
Authors: Marwaha Ram Kumar , Naranje K. , Panigrahi Inusha , Das R. 
Published: April 2020

Abstract
The beneficial effects of hydroxyurea (HU) have been well documented in sickle cell disease. Its usefulness in thalassemia syndromes has not been clearly elucidated. The aim of the study was to analyse the efficacy and side effects of HU in children with beta thalassemia intermedia (TI). The data of 73 children with TI were retrospectively analysed. Response to HU was assessed by change in hemoglobin (Hb) level and by a fall in transfusion requirements. An increase in Hb level was observed in 46 (63.0%) of 73 patients; the response was categorised as good in 43 and partial in 13 cases. There was a poor or no response in the remaining 27 (37.0%) children. Significant rise in Hb levels were documented after HU therapy; the responses were better in patients diagnosed beyond the age of 3 years (p=0.001). A fall in transfusion requirements by &gt;50% was observed in 28 (66.7%) of the 42 patients who received transfusion prior to referral. There were no serious side-effects inspite of prolonged use. Transient neutropenia (&lt;1.5x109/L) was observed in 9 patients. A solitary case had severe myelotoxicity requiring discontinuation of HU. Over 60% of our patients showed good or partial response in terms of hemoglobin level and/or transfusion requirements. The study has drawbacks and limitations of retrospective analysis. The preliminary observations suggest the need for evaluating larger number of patients in a prospective manner of determine the optimum dose and duration of therapy.
Purified Gr1+CD11b+ Cells Induce Neovascularization in An Ischemic Hind Limb Mouse Model.
Authors: Kim Jeong A , March Keith , Chae Heedon , Johnstone Brian , Cook Todd , Merfeld-Clauss Stephanie , Broxmeyer Hal E. 
Published: April 2020

Abstract
Neovascularization in ischemic tissues is enhanced by circulating endothelial precursor cells, some of which have been identified as bone marrow (BM)-derived (BMEPC). However the identity of BM-derived populations that participate in the process of neovascularization is not clear; and indeed several subsets have been proposed as important to this process. Gr1+CD11b+ cells have been recently described as myeloidderived suppressor cells that may be involved in tumor angiogenesis. However, there has been little investigation of the role of Gr1+CD11b+ cells in non-tumor angiogenesis. To study the relationship of Gr1+CD11b+ cells to neovascularization in an ischemic hindlimb model of C57BL/6 mice, we tested the following hypotheses:
The number of tissue-resident Gr1+CD11b+ cells increases in BM and ischemic muscle after the ischemic injury; prospectively isolated Gr1+CD11b+ cells can manifest characteristics of endothelial differentiation; and Gr1+CD11b+ cells modulate neovascularization in ischemic hind-limbs of C57BL/6 mice upon direct injection into ischemic muscle.
Results demonstrated that the number of Gr1+CD11b+ cells markedly increased in the ischemic muscle at 4 days post-surgery (n=5 each; 1.08±0.65x105/g tissue in non-surgically treated mice vs 13.43± 7.52x105/g tissue in the ischemic muscle, p&lt;0.05); then returned to basal level at day 10. The number of Gr1+CD11b+ cells from BM in the ischemic group at day 4 trended towards an increase when compared with cells from BM of non-surgically treated C57BL/6 mice (n=5 each; 1.05±0.31x107/2 femur+ 2 tibia in ischemic group vs 0.70±0.32x107/2 femur+ 2 tibia in non-surgically treated C57BL/6 mice). Following culture under endothelial cell growth conditions, purified Gr1+CD11b+ cells from BM exhibited cobblestone and spindle-shaped morphology. FACS analysis demonstrated that cobblestone-shaped cells exhibited development of a CD144+ phenotype, a marker for mature endothelium; while spindle-shaped cells expressed desmin. Following direct injection of purified Gr1+CD11b+ cells from BM or medium control, laser Doppler imaging revealed an increase in blood flow recovery by 14 days post-femoral artery dissection in the cell injected group compared to the control group (n=7 each, 41.14±1.28% in Gr1+CD11b+ cell injected group vs 35.83±2.57% in control group). The mobilization of Gr1+CD11b+ to regions of muscle ischemia, taken together with the novel finding of endothelial differentiation from this BM-derived population, and enhanced flow recovery following local provision of exogenous Gr1+CD11b+ cells, support the hypothesis that this cell population plays an important role in the systemic and local response to ischemic injury.
Mir-128b Is a Potent Glucocorticoid Sensitizer in MLL-AF4 Acute Lymphocytic Leukemia Cells and Exerts Synergistic Effects with Mir- 221.
Authors: Kotani Ai , Ha Daon , Rao Prakash , Hsieh James , Schotte Diana , den Boer Monique L. , Armstrong Scott , Lodish Harvey F. 
Published: April 2020

Abstract
MLL-AF4 Acute Lymphocytic Leukemia (ALL) has a poor prognosis. We show that re-expression of miR-128b and miR-221, downregulated in MLL rearranged ALL, synergistically sensitizes MLL-AF4 ALL cells to glucocorticoids. Target genes downregulated by miR-128b include MLL, AF4, and both MLL-AF4 and AF4-MLL fusion genes; miR-221 downregulates CDKN1B. Finally we identified a novel A to G point mutation in the miR-128b gene in some MLL-AF4 ALL cells, which significantly reduces the processing of precursor miR-128b miRNA to the mature miRNA. These results demonstrate that downregulation of miR-128b and miR-221 induces glucocorticoid resistance, restoration of their levels is a promising therapeutic in MLL-AF4 ALL, and the A to G point mutation might pathophysiologically contribute to MLL-AF4 ALL.