bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteasome Inhibitor Bortezomib Can Inhibit Bone Marrow Fibrosis Development in a Murine Model of Myelofibrosis.
Authors: Wagner-Ballon Orianne , Gastinne Thomas , Tulliez Micheline , Lacout Catherine , Pisani Didier , Chagraoui Hedia , Villeval Jean-Luc , Vainchenker William , Giraudier Stephane 
Published: October 2019

Abstract
Several lines of evidence obtained from idiopathic myelofibrosis (IM) studies are in favour of a crucial role of the NF-κB pathway activation in myelofibrosis induction. It has been demonstrated that megakaryocytes, monocytes but also CD34+ cells from IM patients present a spontaneous NF-κB pathway activation associated with transforming growth factor-β1 (TGF-β1) secretion. This growth factor has been previously shown as the main fibrogenic cytokine involved in the myelofibrosis development. Mice exposed to high systemic levels of thrombopoietin (TPO) mediated by a retroviral vector (TPOhigh mice) develop a myeloproliferative disorder featuring numerous aspects of the human disease including bone marrow fibrosis, extramedullary hematopoiesis and dysmegakaryopoiesis. Moreover, TPOhigh mice display high plasma levels of IL-1α suggesting that the NF-κB pathway may play a role in this model of fibrosis. We then conducted a study to investigate whether NF-κB inhibition in this mice model could have an impact on myelofibrosis development using the proteasome inhibitor bortezomib. One month after engraftment with TPO-overexpressing hematopoietic cells, 2 groups of 20 immunocompetent C57BL/6J mice displaying similar myeloproliferation induced by TPO overexpression were constituted. Mice engrafted were treated twice a week, with either bortezomib (1 mg/kg) or a placebo for 4 weeks. At the end of this protocol, mice from both groups were examined for histological and haematological analysis including TGF-β1 and IL-1α levels determination. Here, we demonstrate that: i) the NF-κB pathway is activated in TPOhigh spleen cells and bortezomib treatment is able to inhibit this activation; ii) bortezomib treatment is able to decrease plasma concentration of TGF-β1 and IL-1α in mice as well as TGF-β1 content in extracellular fluids of marrow and spleen; iii) myelofibrosis development is inhibited after bortezomib treatment. These results emphasize the interest of developing bortezomib treatment in IM patients.
Evidence That Fibrinogen Inhibits Leukocyte Adhesion to Fibrin Clot and Immobilized Fibrinogen by Binding to the Substrate but Not to Integrins.
Authors: Lishko Valeryi K. , Ugarova Tatiana P. 
Published: October 2019

Abstract
The recruitment of phagocytic leukocytes to sites of injured vessel wall plays an important role in thrombus remodeling during normal vascular repair and in the pathophysiology of thrombosis. Fibrin and fibrinogen, present in the thrombus, are potent adhesive substrates for neutrophils and monocytes. They support cellular attachment by binding cell surface receptors that belong to the β2 subfamily of integrins. Adhesive interactions of neutrophils and monocytes with polymerized fibrin and insoluble fibrinogen matrix in vivo occur in the presence of high concentrations of circulating plasma fibrinogen (~2–4 mg/ml). One important property of fibrinogen that would have a major bearing on leukocyte adhesion is its capacity to form complexes with fibrin. Therefore, by virtue of its binding to the fibrin clot and/or immobilized fibrinogen, soluble plasma fibrinogen can influence leukocyte adhesion to these substrates. In this study, the possibility that soluble fibrinogen could protect fibrin from adhesion of leukocytes was examined. Fibrinogen was an efficient inhibitor of adhesion of U937 monocytoid cells and neutrophils to fibrin gel and immobilized fibrin(ogen). An investigation of the mechanism by which fibrinogen exerts its influence on leukocyte adhesion indicated that it did not block integrins but rather associated non-covalently and weakly with fibrin(ogen) substrates. Consequently, leukocyte integrins that engage fibrinogen molecules loosely bound to the fibrin(ogen) matrix are not able to consolidate their grip on the substrate; subsequently, cells detach. This conclusion is based on the evidence obtained in adhesion studies using various β2-integrin bearing cells and performed under static and flow conditions. Furthermore, surface plasmon resonance studies, undertaken to determine the Kd of fibrinogen-fibrin interactions under flow conditions, indicated that fibrinogen formed complexes with fibrin(ogen) with micromolar affinities. Thus, these findings reveal a new role of fibrinogen in integrin-mediated leukocyte adhesion. They also imply that the anti-adhesive effect of fibrinogen may protect the thrombus from an excessive leukocyte accumulation and premature dissolution at the early stages of wound healing when hemostatic plug integrity is critical for preventing blood loss.
Survival of Limited Stage Peripheral T-Cell Lymphoma Is Similar To Diffuse Large B-Cell Lymphoma.
Authors: Savage Kerry J. , Chhanabhai Mukesh , Voss Nicholas , Tamara Shenkier , Gascoyne Randy D. , Connors Joseph M. 
Published: October 2019

Abstract
Background: Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of diseases with an overall poor prognosis. Little information is available regarding the outcome of PTCL patients who present with limited stage disease. We sought to determine the outcome of PTCL patients presenting with limited disease in comparison with a cohort of patients with limited stage diffuse large B-cell lymphoma (DLBCL).
Methods: In a retrospective analysis we identified all patients with limited stage (non-bulky (<10cm) stage I/II disease no symptoms) PTCL diagnosed at the British Columbia Cancer Agency (BCCA) between 1983 and 2004. Patients were excluded if they had cutaneous anaplastic large cell lymphoma (CutALCL) (n=13), NK/T-cell lymphoma nasal type (n=9) or primary CNS/ocular involvement (n=6).
Results: Thirty-seven patients with PTCL were identified according to the World Health Organization Classification: ALK-neg ALCL 8 (22%); PTCL-unspecified (PTCLUS) 28 (78%); enteropathy associated TCL (EATL) 1 (3 %). The majority received CHOP-type chemotherapy (n=31, 86%), most with brief chemotherapy followed by involved-field radiation (n=19, 61%). The 5 y OS and PFS was similar between PTCLUS and ALK-neg ALCL. There was no difference in survival between extranodal and nodal cases. The outcome of PTCL patients (including ALK-neg ALCL and PTCLUS) was compared to a cohort of limited stage DLBCL patients (excluding CNS/ocular lymphoma) (n=305) diagnosed over the same time period and treated similarly. There was no difference in 5 y OS or PFS (Figure 1,2). Interestingly, there were no late relapses observed in PTCLUS, in marked contrast to DLBCL.
Conclusions: Limited stage PTCL is rare, however outcomes appear to be comparable to early stage DLBCL, supporting that they should be treated in a similar manner. Unlike limited stage DLBCL where late relapses occur, a plateau in the progression-free survival curve is observed, highlighting a distinct natural history for limited stage PTCL.
Overall Survival Limited Stage PTCL vs DLBCL p=.18 Overall Survival Limited Stage PTCL vs DLBCL p=.18 Progression-Free Survival Limited Stage PTCL vs DLBCL p=.07 Progression-Free Survival Limited Stage PTCL vs DLBCL p=.07
Extended Thromboprophylaxis with Fondaparinux after Major Orthopedic Surgery of the Lower Limbs: The EXPERT Study.
Authors: Singelyn Francois 
Published: October 2019

Abstract
Background: The benefit-to-risk ratio of extended fondaparinux therapy was demonstrated in patients undergoing hip fracture surgery, but not in patients undergoing major joint arthroplasty. In addition, no data on the use of fondaparinux in patients in whom a continuous neuraxial/deep peripheral nerve blockade is performed are available.
Objective: The EXPERT trial was an open-label, international study in patients undergoing major orthopedic surgery designed to evaluate the overall efficacy and safety of 2.5 mg fondaparinux when (I) given daily for 4±1 weeks after surgery, and (II) a “therapeutic window” is applied due to concomitant use of a neuraxial/deep peripheral indwelling catheter.
Patients/Methods: Patients undergoing major orthopedic surgery received once-daily subcutaneous 2.5 mg fondaparinux starting post-surgery for 4±1 weeks. In patients with a neuraxial/deep peripheral indwelling catheter, one of the planned doses of fondaparinux was omitted, the catheter was removed 36 hours after the previous fondaparinux dose, and the next fondaparinux dose administered 12 hours after catheter removal. The primary endpoints were symptomatic venous thromboembolism (VTE) and major bleeding 5±1 weeks after surgery.
Results: 5704 patients (mean age ± SD: 66.1 ± 11.9 years) were recruited into the intention-to-treat (ITT) population between July 2003 and October 2004. A neuraxial/deep peripheral indwelling catheter was placed in 1630 (28.6%) of them. They underwent surgery for total hip replacement (51.6%, n=2941), total knee replacement (39.7%, n=2263), hip fracture (6.2%, n=353), or other indications (2.6%, n=148). Fondaparinux was given for a median of 35 (range: 1–105) days. In the ITT population, the rate of adjudicated confirmed symptomatic VTE was 1.0% (54/5387). It was 0.8% (13/1535) in patients with catheter and 1.1% (41/3852) in patients without catheter, with an odds ratio of 0.79 (90% CI: 0.47 to 1.34; p=0.47) in favor of patients with a catheter. The upper limit of the 90% CI was below the predetermined criterion of 1.75 for the non-inferiority of patients with a catheter versus patients without a catheter. Comparable results were observed in the per-protocol population. The overall rate of major bleeding was 0.8% (42/5382). It was 0.9% (35/3850), and 0.5% (7/1532) in patients with and without catheter, respectively. No spinal or perineural hematomas occurred. At 5±1 weeks, 23 (0.40%) patients had died.
Conclusions: 2.5 mg fondaparinux given daily for 4±1 weeks after major orthopedic surgery was both effective and safe in routine practice. This high benefit-to-risk ratio was maintained in patients in whom a 48-hour “therapeutic window” was applied due to placement of a neuraxial/deep peripheral indwelling catheter.
Successful Pregnancy Outcome in 5 Patients with Thrombotic Thrombocytopenic Purpura.
Authors: Scully Marie , Starke Richard , Lee Richard , Mackie Ian , Machin Samuel J. , Cohen Hannah 
Published: October 2019

Abstract
Pregnancy is an initiating event for acute thrombotic thrombocytopenic purpura (TTP). Patients with a history of TTP have a high risk of relapse during pregnancy with associated maternal and fetal morbidity/mortality. We report 5 TTP patients who underwent serial clinical and laboratory monitoring (haemoglobin, platelets, blood film, reticulocytes, lactate dehydrogenase (LDH), ADAMTS-13 activity and IgG antibodies) and treatment within a specialist obstetric/haematology clinic, resulting in successful pregnancy outcomes. Patients: Cases 1 and 2 presented with TTP in their first pregnancy and had second trimester fetal losses. Case 3 had four TTP relapses and soon after achievement of clinical remission became pregnant. Case 4 had a single acute episode of TTP 6 years prior to pregnancy and normal ADAMTS 13 activity at the onset of pregnancy. Case 5 presented with acute TTP and a left sided stroke at 16 weeks gestation. ADAMTS-13 activity was <5% at onset of pregnancy in cases 1–3 and at presentation of TTP during pregnancy in case 5. Only case 3 had IgG antibodies to ADAMTS13. Cases 1–3 received regular plasma exchange (PEX) every 2 weeks initially, starting during the first trimester, with ADAMTS 13 activity levels maintained >15% during pregnancy (range 15–78%, normal range 66–126%) by collagen binding assay. Case 4 had normal laboratory parameters, including serial ADAMTS 13 activity levels, throughout pregnancy, requiring no specific therapy for TTP. Case 5 received intensive PEX (84 procedures) and pulsed methylprednisolone during pregnancy. Rituximab (375mg/m2, weekly for 4 weeks) was given at 28 weeks gestation with no observed toxicity except asymptomatic transient neonatal neutropenia. All 5 cases continued low dose aspirin (75 mg daily) throughout pregnancy. Case 1 and 2 received prophylactic low molecular weight heparin (LMWH) and cases 3 and 5 received treatment doses of LMWH for pulmunory emboli and TTP associated stroke at presentation. Live healthy infants were delivered in all 5 cases in the third trimester (31–41 weeks). These data suggest successful pregnancy outcome is achievable in patients with a history of TTP/acute TTP with therapy based on close clinical and laboratory monitoring. Regular PEX in patients with a history of TTP and severely reduced ADAMTS 13 activity/IgG antibodies to ADAMTS 13 at the onset of pregnancy was associated with successful pregnancy outcome. Serial ADAMTS 13 activity and antibody levels during pregnancy and post-partum provided a useful adjunct to decision making on intensity of treatment.
Stepwise Development of Committed Progenitors in the Bone Marrow That Generate Functional T Cells in the Absence of the Thymus.
Authors: Dejbakhsh-Jones Sussan , Garcia-Ojeda Marcos E. , Chatterjea Devavanii , Mukhopadhyay Aditi , Weissman Irving L. , Strober Samuel 
Published: October 2019

Abstract
We identified committed T cell progenitors (CTPs) in the mouse bone marrow that have not rearranged the TCR β gene, express a variety of genes associated with commitment to the T cell lineage including GATA-3 and TCF-1, Cβand Id2, and show a surface marker pattern (CD44+CD25-CD24+CD5-) that is similar to the earliest T cell progenitors in the thymus. More mature committed intermediate progenitors (CIPs) in the marrow have rearranged the TCR gene loci, express Vαand Vβgenes as well as CD3ε, but do not express surface TCR or CD3 receptors. CTPs, but not progenitors from the thymus, reconstituted the αβ T cells in the lymphoid tissues of athymic nu/nu mice. These reconstituted T cells vigorously secreted IFN- γ after stimulation in vitro, and protected the mice against lethal infection with murine cytomegalovirus (MCMV). Also CTPs from the parent strain can reconstitute an F1 MHC haplotype mismatched host. In conclusion, CTPs in wild-type bone marrow can generate functional T cells via an extrathymic pathway.
High Plasma Cell Labeling Index (PCLI) Is an Adverse Prognostic Factor in Bortezomib-Treated Patients with Relapsed Myeloma.
Authors: Gidron Adi , Tariman Joseph , Shabbir Munira , Mehta Jayesh , Singhal Seema 
Published: October 2019

Abstract
Del(13) is a powerful adverse prognostic factor in patients with myeloma. A small subset analysis from a randomized multi-center study comparing dexamethasone to bortezomib for relapsed myeloma suggested that the outcome of bortezomib-treated patients was not affected by del(13) (Jagannath et al, ASCO 2005). We studied patients with relapsed myeloma treated with bortezomib on whom complete karyotype data were available to determine the effect of del(13) on response rates and survival. To ensure consistency, this analysis was confined to 47 patients (44–85 y; median 62) who received all their therapy at Northwestern and in whom all cytogenetic analyses were performed in a single laboratory. 40 had failed prior thalidomide and 32 had failed prior high-dose therapy. All patients were treated with bortezomib as a single agent in the standard fashion initially. Dexamethasone ± thalidomide were added if there was no response. Progression after initial response or lack of response to bortezomib ± thalidomide ± dexamethasone was classified as treatment failure. Overall response rate (≥50% decline in paraprotien) was 72%. Complete clearance of paraprotein was seen in 32%. The median event-free (EFS) and overall (OS) survival durations from the start of therapy were 227 and 777 days. OS was higher in responders (777 vs 373 days; P=0.015) as was EFS (259 vs 120 days; P=0.0001). As the table shows, del(13) did not affect response rates.
Response to bortezomib by del(13) status (P=0.69) Paraprotein response Del(13) (n=13) No del(13) (n=34) Any response vs no response; P=0.31 No response 5 (38%) 8 (24%) 50–94% decline 3 (23%) 10 (29%) 95–99% decline 2 (15%) 4 (12%) 100% decline 3 (23%) 12 (35%)
No variable influenced response significantly in Cox analysis. However, there was a trend (P=0.07) towards lower response rates in patients relapsing after prior transplant. When PCLI (available in 34 patients) was included in the model, there was a trend (P=0.08) towards lower likelihood of 100% responses with del(13). Response to bortezomib and age ≤ 60 were associated with significantly better EFS with/without PCLI in the model. PCLI ≥1% was the only factor associated with poorer OS when included in the model. When PCLI was excluded, response to bortezomib was associated with significantly superior OS.
Figure Figure
While OS and EFS did not seem to be influenced by del(13), the curves shown below suggest that differences may become apparent with longer follow-up in a larger number of patients.
Figure Figure
Thus, small patient numbers in this study and that of Jagannath et al, and a trend towards a lower likelihood of complete paraprotein clearance with del(13) in our experience suggests that more data are needed before any definitive conclusions can be drawn on the impact of del(13) on bortezomib therapy.
Generation of a Novel Mouse Model of Cooley’s Anemia.
Authors: Huo Yongliang , McConnell Sean , Sun Chiao-Wang , Wu Li-Chen , Ryan Thomas M. 
Published: October 2019

Abstract
A novel mouse model of Cooley’s Anemia (CA) has been generated by targeted gene replacement of the adult murine α-globin genes with human α-globin and the adult mouse β-globin genes with a human γ- to β-globin gene switching cassette containing a β0 thalassemic allele. A positive-negative gene replacement construct was designed to simultaneously delete both of the adult mouse α-globin genes by inserting a 3.8kb human α1-globin gene and a hygromycin marker gene flanked by loxP sites in murine embryonic stem (ES) cells. Both adult murine β-globin genes were deleted by insertion of an Hprt marker gene that was later replaced by a 5.6kb human Aγ-globin gene, 4.1kb human β0-globin gene, and a loxP flanked hygromycin marker gene by a “tag and exchange” strategy. The human β0-globin knock-in allele contains a single G to A nucleotide mutation in the first base of intervening sequence 1 [β0-IVS1(GtoA)-globin]. This single base change destroys the splice donor site of IVS-1 resulting in the recruitment of several cryptic splice sites. Use of these cryptic splice sites produces a frameshift in the mRNA that results in no functional β-globin polypeptide synthesis from this allele. This β0-IVS1(GtoA)-globin gene mutation is a naturally occurring β0 thalassemia allele found in Mediterranean populations. Chimeric mice were generated from both the α- and β-globin targeted cells lines. After germline transmission the α- and β-globin targeted mice were bred to cre recombinase transgenic mice to remove the marker genes. Heterozygous CA mice exhibit β thalassemia intermedia. The α- and β-globin targeted mice were interbred to produce animals homozygous for the human α1- and γβ0-globin knock-in alleles. Instead of dying early in fetal life as all current homozygous β0 thalassemia mouse models, these novel homozygous CA mice survive solely on high levels of human fetal hemoglobin (α2γ2) throughout fetal development. Newborn homozygous CA mice are blood transfusion dependent similar to β thalassemia major infants. This novel model of CA has multiple improvements over existing models of β thalassemia. Namely, CA mice express 100% human hemoglobin in their RBCs, mimic the human γ- to β-globin gene switch, synthesize no functional β-globin chains after birth, have a single mutant human β0-globin knock-in allele at each β-globin locus, and are blood transfusion dependent for life after birth.
16189 Mitocondrial Variant and Iron Overload.
Authors: Salvador Maria , Gonzalez Fernando A. , Ropero Paloma , Olga Briceño , Eduardo Anguita , Ana Villegas 
Published: October 2019

Abstract
Hereditary haemochromatosis(HH) is one of the most common autosomal recessive diseases in Europe, this is characterized by iron overload. There are two predominant mutations associated with the disease in the HFE gene: C282Y and H63D. The majority of haemochromatosis patients are homozygous for C282Y mutation and a small proportion are compound heterozygous C282Y/H63D. Not all C282Y homozygotes and compound heterozygous will show signs of iron loading. Several studies have shown the incomplete penetrance of haemochromatosis and suggest that iron overload is influenced by both enviromental and genetic factors wich may modify the phenotipic expression of the disease.
Iron loading is associated with impaired mitochondrial function. It has been reported that the T16189C variant of mitochondrial DNA may act as a modifier increasing iron loading in HH. 16189 variant lies in the first hypervariable region (HV1), close to the sequences controlling replication and transcription.
Aim: to determine the frequency of the 16189 variant in normal population and in a group of HH pacients with mutations in HFE gene or iron loading due to Mayor or Intermediate b-Thalassemia.
Materials and methods: We stablished the frequence of 16189 variant in normal population by studying it in a group of 102 blood donors which did not have any mutation in HFE gene. We determined the variant in 27 C282Y homozygous, 32 compound heterozygous C282Y/H63D and 31 H63D homozygous and 16 β-thalassemics aswell.
DNA was extracted from peripheral blood, HV1 region was amplified by PCR using primers:
F(15800–15819)CAAGTAGCATCCGT ACTATA; R(16344–16325)GTAATGTGCTATGTACGGTA The product of amlification was digested with MnlI acording to manufacturer’s specifications. In wild type there is a restriction site at position 16189 which is absent in mutant allele. All samples lacking MnlI site were directly sequenced in a ABI PRISM 310 Genetic Analyzer.
Statistical analysis was performed using the SPSS package.
Results: shown in table 1
Conclusions: Our results do not show significant differences between the groups analyzed, but no significant increased frequency of the variant in the group of compound heterozygous. With this study we cannot conclude that mitochondrial function influences iron overload. This is could be dued to the short number of samples analyzed. In β-Thalassemia iron loading is modifed by an increased absorption(TM y TI) and transfusions(TM). At the present we are studying other factors that could play an important role in iron homeostasis: Transferrin receptor, Hepcidine and Hemojuveline.
Table 1. Results Controls C282Y/C282Y C282Y/H63D H63D/H63D β-Thalassemia 16189C 12% 11.1% 18.7% 6.4% 12.5%