bluuebunny/crossref_metadata_2025_split huggingface dataset:
ADAMTS13 Antigen, Activity, and Autoantibody and ADAMTS13/fXI Complex Levels in Patients with Venous Thromboembolism.
Authors: Fryer Hugh J.L. , Grafos Nicholas , Guinto Enriqueta R. , Wu Jogin , Bing Bai , Greenfield Robert S. 
Published: April 2020

Abstract
ADAMTS13 controls thrombus formation in microvasculature by proteolysis of ultralarge von Willebrand Factor in plasma. Severe ADAMTS13 dysfunction or deficiency due to genetic or immunological causes can result in the life-threatening microangiopathic disorder Thrombotic Thrombocytopenic Purpura (TTP). Although it may also be involved in limiting thrombus growth in larger vessels, the role of ADAMTS13 in other thrombotic disorders has not yet been clearly established. In this study we determined the levels of ADAMTS13 antigen, activity, autoantibody, and ADAMTS13/fXI complex in plasma from patients with venous thromboembolism (VTE) and from normal donors. ADAMTS13 antigen was measured using IMUBIND® ADAMTS13 Antigen ELISA, ADAMTS13 activity using the ACTIFLUOR™ ADAMTS13 Activity (FRET-based assay), ADAMTS13 autoantibody titers using IMUBIND® ADAMTS13 Autoantibody ELISA, and complex using IMUBIND® ADAMTS13/fXI Complex ELISA. The various ADAMTS13 related markers were all found to be abnormal in patients with VTE (deep vein thrombosis and pulmonary embolism) as compared with normal donors. For normal donors, the mean ADAMTS13 activity is 740 ± 110 ng/ml, whereas in patients with VTE ADAMTS13 activity is significantly lower (524 ± 200 ng/ml, P&lt;0.001). ADAMTS13 antigen levels, however, do not differ significantly for patients with VTE compared with normal donors. Receiver-operating characteristic analysis of activity/antigen ratios shows high sensitivity and specificity for patients with VTE. Although the biochemistry and in vivo biology of the ADAMTS13/fXI complex is not completely understood, the ADAMTS13/fXI complex is 3.8-fold higher in patients with VTE relative to normal donors (P&lt;0.05). Using an upper autoantibody cutoff level of 14.8 AU/ml, a higher percentage of patients with VTE have elevated levels of autoantibodies (26/94 or ∼28%) compared with normal donors (1/47 or ∼2%). D-dimer plasma level is a strong negative predictor for VTE. A substantial number of patients without VTE exhibit D-dimer levels above the normal cutoff, which thus excludes this assay for the positive diagnosis of VTE. We correlated D-dimer levels with the various ADAMTS13 parameters. Elevated D-dimer in patients correlates with abnormal levels of activity, autoantibody, and complex. Donors with high D-dimer levels that do not exhibit symptoms of VTE do not have abnormal activity or complex levels, but do have elevated autoantibody levels. These data suggest that ADAMTS13 activity, autoantibody, and ADAMTS13/fXI complex are potential biomarkers for VTE and furthermore, suggest that ADAMTS13 may play a role in the initiation or progression of VTE.
Impact of the Factor II G20210A Variant and the Factor V G1691A on Recurrent Venous Thromboembolism in Children: An International Multicentre Cohort Study.
Authors: Young Guy , Friedrichs Fauke , Goldenberg Neil , Kenet Gili , Manco-Johnson Marilyn , During Christine , Nowak-Gottl Ulrike 
Published: April 2020

Abstract
The recurrence rate of thrombosis in children following a first thrombotic event ranges from 3% in neonates to 8% in older children. The relative importance of the factor II and factor FV mutations is unknown. We present a multicentre cohort study to assess the rate of symptomatic VTE recurrence per 1000 person-years in children heterozgous for the FII and FV mutations following a first VTE. Data were pooled to increase power for the secondary aims, e.g. time to recurrence, and predictors of recurrence. Between January 1994 and December 2006, 251 consecutively enrolled VTE patients aged newborn to ≤18 years (median 5.2 years: male n=141) carrying the FII (n=61) or FV mutation (n=190) were followed for a median of 58 (max 156) months. 128 of 251 VTE patients (51%) had at least one underlying medical condition at VTE onset, and 15 were heterozygous for both mutations. Children received acute anticoagulation (AC) with unfractionated heparin or low-molecular weight heparin, followed by AC with LMWH or warfarin for a three to 6 month period in 70% of cases. Of the 251 patients enrolled, 24 (9.5%: recurrence rate of 19.3 per 1000 person-years, 95% confidence interval (CI): 12.9–28.8) had recurrent VTE at a median (min-max) of 3.5 (0.1–120) months. Not including combined defects, the recurrence rate per 1000 person-years was 41.4 (95%CI: 22.3–77) for patients with the FII mutation, and 14 (95%CI: 8.3–23.6) for carriers of the FV mutation. Median (min-max) age at recurrence was 13.4 (0.1–17) years, 12 of 24 patients were male (50%), and in 21 of 24 children (87.5%) recurrence occurred after withdrawal of AC. When comparing FII with FV subjects, Cox regression analysis showed that the factor II mutation (HR/95%CI: 2.5/1.1–5.9; p=0.031) was associated more frequently with a second VTE. In addition, older age (&gt; 2 years) at first VTE onset (HR/95%CI: 1.1/1.01–1.14; p=0.025) independently influences the second VTE event [3.5 years (non-recurrence) vs. 12.7 years (recurrence); p&lt; 0.0001]. Among patients suffering from recurrent VTE, 58% occurred within the first six months following VTE onset. Time to recurrence (FII vs. FII and age at onset &gt;/&lt; 2 ears) is shown in the Kaplan Meier analyses. The overall VTE recurrence rate of 9.5% is within the range recently reported in children. However, when comparing FII and FV carriers, the factor II G20210A variant is more often associated with a recurrent VTE. In addition, independently from the underlying gene mutation age &gt; 2 years at first VTE increase the risk of a second symptomatic venous thrombosis.
Figure Figure
Prognostic Analysis of Pre-Transplant CD26-Positive Lymphocytes and CD26bright/CD45RO-Positive Memory T-Cell Levels in Patients Receiving an Autologous Hematopoietic Progenitor-Cell Transplant.
Authors: Hildebrandt Martin , Gollasch Hella , Rautenberg Kirstin , Doerken Bernd , Ludwig Wolf-Dieter 
Published: April 2020

Abstract
The lymphocyte surface glycoprotein CD26 is involved in an array of diverse signalling pathways and costimulatory events. CD26positive cells possess dipeptidylpeptidase IV (DPP IV) activity, a serine protease known to inactivate SDF-1/CXCL12, a key mediator of stem cell homing and engraftment. Furthermore, CD26 modulates surface expression of CTLA-4 and contributes to T-cell migration through endothelial layers. CD26 has been attributed with a central role in alloantigen-mediated immune pathways and memory T-cell responses. The purpose of this study was to evaluate the levels of a distinct memory T-cell subset, CD26bright/CD45RO-positive, in autologous hematopoietic progenitor-cell transplant (HPCT) recipients. Between 2003 and 2006 we enrolled 42 patients scheduled to undergo high-dose chemotherapy and autologous HPCT (multiple myeloma, n=31; Hodgkin’s Disease, n=3; NHL, n=6; PNET, n=1; AML, n=1). Levels of memory and naïve CD26, CD34, CD4, CD8, as well as co-expression of CD4 or CD8 among CD26bright/CD45RO-positive cells were analyzed before autologous HPCT. In addition, the number of memory and naïve CD26-positive T cells transfused per kg body weight in the progenitor cell harvest were determined. The subsets of CD26-positive cells were correlated with kinetics of engraftment and with the occurrence of disease progression or relapse after autologous transplantation. With regard to kinetics of engraftment, only the number of CD34-positive cells transfused was associated with rapid engraftment (P=0.001). However, CD26-positive cells were of predicitve value for the occurrence of disease progression or relapse. Pre-transplant CD26-positive T-cell levels correlated with progression-free survival (PFS) (P=0.022). Specifically, the number of CD26bright/CD45RO-positive memory T-cells in the autograft correlated with PFS and, in regression analyses, emerged as the only variable predictive for the occurrence of diease progression or relapse (P=0.006). The prognostic effects of pre-transplant CD26bright/CD45RO-positive memory T-cells were independent of the type of disease and of the conditioning regimen applied. The analysis of antigens CD4 and CD8, respecively, on CD26bright/CD45RO-positive T-cells yielded no additional information. Our results suggest that pre-transplant levels of CD26-positive T cells, specifically a memory cell subset of CD26bright cells coexpressing CD45RO, may yield information with regard to outcome in autologous HPCT recipients. These observations may contribute to a prospective identification of those patients at higher risk of relapse, based on their immune status.
Avoidance of Post-Thaw Wash Prior to Transplantation of Plasma Depleted Cord Blood (PD CB) Is Associated with Improved Engraftment & Decreased Severity of Chronic GvHD (cGvHD) without Increased Relapse.
Authors: Chow Robert , Wang Brian , Rosenthal Joseph , Nademanee Auayporn , Karanes Chatchada , Jaing Tang-Her , Graham Michael , Delaney Colleen , Gjertson David , Petz Lawrence , Forman Stephen , Kurtzberg Joanne 
Published: April 2020

Abstract
Post-thaw washing of frozen CB prior to transplantation is widely practiced to remove DMSO, red cell debris and free hemoglobin, however, washing a red cell containing product may result in cell loss. We analyzed outcomes of engraftment, survival, relapse and GvHD in 299 patients transplanted with plasma depleted but not red cell reduced (PD) CB where 154 were washed (W) and 145 were directly infused - (non-washed or NW). 207 (69%) of 299 patients had malignant diagnosis. The two groups were comparable for patient, disease and graft characteristics except for a higher % of Asian patients in the NW group in contrast to a higher % of Caucasian/Hispanic patients, higher % of US transplant centers (TC) and higher number of malignant diagnoses for the W group. Nucleated cell recovery after thawing, as reported by TC, was higher for NW (median 85% vs. 79%, p=0.003). The NW group had higher cumulative incidences of and faster neutrophil (ANC500) and platelet engraftment (Plt 20K and 50K) than the W group. No difference was seen for acute GvHD (aGvHD); however, the NW group had significantly lower rates of extensive (Ext) cGvHD and higher rates of limited (Ltd) cGvHD (p=0.0005 and &lt;0.0001). Relapse rates were similar between W and NW. Multivariate analysis and matched pair analysis between W versus NW confirm these observations. In univariate analysis, overall survival (OS) and disease-free survival (DFS) were significantly higher for the NW group. This retrospective analysis represents the largest series comparing different thaw methods for PD CB and is the first to demonstrate a potential association of no post-thaw wash with significant decrease in extensive cGvHD rate without concomitant increase in relapse rate. These improvements may contribute to the apparently better survival for the NW group. Prospective trials which may include infusion of wash supernatants into patients are necessary to confirm and better understand these observations.
ANC 500 & Plt 20K 100 Day TRM 1 & 3 Yr OS 1 & 3 Yr DFS 1 Yr Relapse II-IV/III-IV aGvHD Ltd/Ext cGvHD All results in % except for p-values & where indicated. Engraftment presented as cumulative incidence, GvHD as proportions; all others estimated by Kaplan-Meier. Overall 88±4/69±4 17±2 61±3 56±3 51±3 39±5 23±3 35/14 20/11 W 87±5/64±5 17±3 54±4 48±4 43±5 30±6 27±5 36/15 9/17 NW 91±6/76±6 16±3 69±4 67±4 60±5 57±5 20±4 36/14 36/1 P value 0.002/0.001 0.05 0.02 0.05 0.29 0.93/0.80 &lt;0.0001/0.0005 ANC 500 & Plt 20K TRM OS DFS Relapse II-IV/III-IV aGvHD Ltd/Ext cGvHD MV adjusted Cox RR & P value 1.51 0.002/1.70 0.001 0.67 0.11 0.71 0.09 0.74 0.11 0.76 0.34 N/A 3.88/&lt;0.001 Matched Pairs P value 0.008/0.0002 0.53 0.32 0.22 0.19 0.98/0.44 0.02/0.001
Puberty, Gonadal Function and Pregnancy in Female Patients Following Hematopoietic Cell Transplantation (HCT).
Authors: Sanders Jean E. , Flowers Mary E.D. , Carpenter Paul C. 
Published: April 2020

Abstract
With increasing success of myeloablative HCT for patients with hematologic disorders, development of pre-pubertal children through puberty, return of gonadal function and the ability to become pregnant are of concern. To determine the impact of the preparative regimen on these issues, long-term follow-up records of more than 2,000 patients have been evaluated. Preparative regimens include cyclophosphamide (CY) 200 mg/kg, busulfan (BU) 16 mg/kg plus 120 or 200 mg/kg CY, or CY 120 mg/kg and 12–15.75 Gy total body irradiation (TBI). Among girls who were pre-pubertal at HCT and are now &gt;12 years of age, 24/26 (92%) CY recipients, 11/23 (52%) BUCY recipients, and 46/96 (51%) CY + TBI recipients have developed normally through puberty. Among 148 post-pubertal women transplanted with CY only, 75 (50%) recovered gonadal function at a median of 6 months after HCT and 45 (30%) have become pregnant. This is in contrast to 2 (1%) of the 207 women who received BUCY who have shown gonadal function recovery and 1 has become pregnant. Among the fractionated TBI recipients, 39 (8%) of 460 women who received CY + 12 Gy TBI recovered ovarian function and 17 (3%) have become pregnant whereas among the 366 women who received 14.0–15.75 Gy TBI, 14 (4%) have recovered ovarian function and 4 (1%) have become pregnant. All women who recovered ovarian function after BUCY or TBI regimens were &lt;25 years of age at HCT. The primary pregnancy complication was preterm labor and delivery, but all babies born were normal. For those women who do not recovery ovarian function, in vitro fertilization may be an option, and 14 women in this category have had successful pregnancies with 21 babies born using donated oocytes or pre-HCT stored gametes. These data demonstrate that pre-pubertal girls have more than 50% rate of developing normally through puberty and among women &lt;25 years of age at HCT, recovery of ovarian function varies between 1%-50% depending on preparative regimen and some have become pregnant. For those who do not recover ovarian function, in vitro fertilization may be an option.
The Degree of Telomere Loss in Hematopoietic Cells Correlates with the Risk of Secondary Myelodysplasia/Acute Leukemia Development Following Autologous Stem Cell Transplantation.
Authors: Ricca Irene , Rocci Alberto , Ruella Marco , Zanni Manuela , Caracciolo Daniele , Ladetto Marco , Boccadoro Mario , Ferrero Dario , Tarella Corrado 
Published: April 2020

Abstract
Introduction: Secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/AML) may occur following autologous stem cell transplantation (ASCT). The molecular pathogenesis of sMDS/AML is uncertain; moreover, no suitable indicators able to define the risk of sMDS/AML development have been identified so far. A marked though variable telomere loss has been observed in hematopoietic cells following ASCT; meanwhile, shortening of telomere length has been observed to be associated with several neoplasias, including haematological malignancies. Thus, telomere dynamics has been investigated in a series of patients who received ASCT, in order to verify whether the degree of telomere loss in hematopoietic cells might be associated with the risk of sMDS/AML development.
Methods: Telomere length (TL) was retrospectively evaluated in bone marrow (BM) cells from 38 lymphoma patients (M/F=24/14; median age=51 years, range 24–68) long-term survivors following ASCT and from 51 healthy donors (M/F=31/20; median age=53 years, range 18–82). Median follow-up since ASCT was 6 years (range 1–10). All patients were in continuous complete remission and displayed normal haematological values at the time of TL assessment. Among 38 autografted patients, 7 developed sMDS/AML (3 AML, 3 sMDS, 1 persistent pancitopenia with cytogenetic abnormalities), at a median of 5 years (range 1–10) following transplant. There were no significant differences in terms of demographical and clinical features not even for the amount of CD34+ve cells reinfused (median values: 5.2 vs 6.8 × 106 CD34+ cells/kg, respectively), between patients developing sMDS/AML and the remaining autografted patients. Samples for TL analysis were obtained and stored at a median of 12 months (range 6–24) before clinical development of sMDS/AML. TL was evaluated by Southern blot analysis.
Results: TL of autografted patients was found to be significantly shorter compared to that of age-matched healthy donors, consistently with previous reports (see Figure 1, squares=healthy controls, circles=autografted subjects). A further TL loss was observed in all the 7 patients who subsequently developed sMDS/AML; their TL (Figure 1, black circles) was significantly shorter compared to both healthy subjects and sMDS/AML-free autografted patients (Figure 1, grey circles) (p&lt;0.0005 and p&lt;0.01, respectively).
Conclusions. A marked telomere loss seems to be a predictive marker of the development of sMDS/AML following ASCT; TL analysis can now be considered among follow-up assays, in order to early identify patients at high-risk of sMDS/AML occurrence following autograft.
Figure 1. TL of BM mononuclear cells in autografted patients vs healthy subjects Figure 1. TL of BM mononuclear cells in autografted patients vs healthy subjects
Ataxia Telangiectasia Mutated (ATM) Gene Expression Is Reversibly Up-Regulated in FANCA-Mutant Patient Fibroblasts by an Indirect Mechanism.
Authors: Liu Johnson M. , Nihrane Abdallah , Yamamoto Kazuhiko 
Published: April 2020

Abstract
Fanconi anemia (FA) predisposes to hematopoietic failure, birth defects and cancer, particularly leukemia and squamous cell carcinomas involving the cervix or head and neck. Although the FANC proteins have been shown to be involved in DNA repair, the pathogenesis of bone marrow failure and other developmental abnormalities is still unclear, but presumably, reflects abnormalities in senescence and apoptosis. The canonical ATM-p53 pathway is a pivotal mediator of the DNA damage response, which may act as a barrier to cancer through cell cycle and apoptosis regulation but has not been fully studied in FA. To address this, we first analyzed the integrity of the ATM-p53 axis in primary fibroblasts derived from FA patients. By immunoblot assays, we found that expression and phosphorylation of ATM and p53 were all up-regulated in two different FANCA-mutant fibroblasts following irradiation (IR) or mitomycin C (MMC) treatment, when compared to identically treated isogenic mutant cells transduced with wild-type FANCA cDNA. We reasoned that these results might be explained by up-regulation of the basal levels of ATM protein in the mutant fibroblasts. By real-time PCR, we confirmed that ATM gene expression was increased in the mutant line in comparison to the gene-corrected control. We also confirmed the up-regulation of both ATM protein and transcription in a FANCA-mutant EBV-immortalized lymphoblastoid cell line in comparison to its gene-corrected control. In order to determine if these changes in ATM gene expression were directly caused by FANCA depletion, we transfected HCT116 cells (known to be p53 wild-type) with two different siRNAs against FANCA. For these experiments, we used a plasmid expression vector (OriGene Technologies, Rockville MD) that drives 29-mer short hairpin RNAs targeting FANCA. In both transient and stable transfection experiments with either siRNA, we found that knockdown of FANCA expression was associated with down-regulation of ATM expression, as assessed by real-time PCR, when compared to cells transfected with an empty vector control. These results have led us to hypothesize that knockdown of FANCA leads to down-regulation of ATM, whereas cells with mutations in FANCA up-regulate ATM, perhaps as a result of chronic genotoxic stress not seen in the knockdown cells. Up-regulation of the ATM-p53 axis, in turn, may contribute to the hypo-proliferative characteristics seen in both primary fibroblasts and hematopoietic stem cells from FA patients.
Fanconi-Like Syndrome with Negative Chromosomal Breakages Test and High Incidence of Myelodysplasia.
Authors: Gupta Sunil , Rassam Saad M.B. , Riyali Madan , Ho Aloysius Y.L. , Mufti Ghulam 
Published: April 2020

Abstract
Fanconi’s anaemia (FA) is a syndrome of defective chromosomal repair characterised by bone marrow failure, skeletal and visceral abnormalities, progression to myelodysplasia (MDS) and acute myeloid leukaemia (AML), hypersensitivity to alkylating agents and increased chromosomal breakage using diepoxybutane (DEB) testing. We describe 13 patients who presented with FA like clinical and/or haematological features who had negative DEB testing. There were 9 males and 4 females with an average age of presentation of 23 years (range 1.5 months - 53 years). They had isolated neutopenia (1/13) or anaemia (1/13), bicytopenia (4/13) or pancytopenia (7/13) at first presentation. Haemoglobin level ranged between 3.8 - 15 g/dl (mean 9.7), white cell count 0.64 - 8.4 × 109/l (mean 2.88), neutrophils 0.05 - 5.43 × 109/l (mean 1.14) and platelets 30 - 179 ×109/l (mean 82). Five patients had macrocytosis with mean cell volume (MCV) above 100fl. The most common morphological features noticed were high arched palate, short stature and short fingers and toes. Seven patients had hypocellular marrow with trilineage dysplasia (refractory anaemia), one had hypocellular marrow with refractory anaemia with ring sideroblasts, 3 patients had hypocellular marrow and AML and 2 had hypocellular marrow with no morphological dysplasia. DEB testing for increased chromosomal breaks was negative in all the 13 patients. Nine patients had cytogenetic abnormalities with monosomy 7 or complex abnormalities being the most common. Three patients have stable blood counts on a watch and wait policy 6–24 months from diagnosis. Five patients’ cytopenias progressed responding to treatment with androgens (2) and anti-thymocyte globulin with steroids (1) and 2 required allogeneic stem cell transplantation (BMT). Androgen responses were sustained in one patient for over 12 years and was followed by AML transformation in the other. Two patients are lost to follow up, 1 died following BMT for AML and 2 had severe mucositis with AML therapy fatal in one and associated with prolonged pancytopenia in another. Four patients had BMT, 2 are in remission, 1 died post BMT and 1 failed. FA phenotype with cytopenia and subsequent progression to MDS/AML is well known and diagnosis is usually confirmed with DEB testing. It is important, however, to recognise FA like syndromes with negative DEB, who appear to have similar clinical behaviour and sensitivity to chemotherapy, as therapy may differ from standard cases of aplastic anaemia, MDS or AML. Genetic testing for the described Fanconi genes may shed more light into those cases.