bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Oncogenic Collaborators Providing Insights into the Tumor Suppressing Function of the Eed Polycomb Group (PcG) Gene.
Authors: Sauvageau Martin , Post-Doc Julie Lessard , Miller Michelle , Sauvageau Guy 
Published: October 2019

Abstract
Polycomb Group (PcG) proteins are key regulators of normal and leukemic hematopoiesis (Lessard and Sauvageau, Nature 2003; Lessard and al., Genes Dev 1999). The eed gene is part of a PcG complex together with Ezh2 and Suz12. Evidence from our laboratory indicates that eed plays a crucial role in the negative regulation of the proliferative capacity of lymphoid and myeloid progenitors, suggesting that this PcG gene is a tumor suppressor. Interestingly, the human eed locus is in a region of chromosome 11 (11q14.2-22.3) which is associated with recurrent deletions in several reported cases of B-CLL, mantle cell lymphoma (MCL) and T-PLL. We now show that when exposed to ionizing radiation at 5 weeks of age, both eedhypo/hypo and eednull/+ mutant mice developed mono- or oligoclonal B and T cell lymphomas with much shorter latencies than observed in littermate controls (50% lethality at 16 wks; 27 wks and 34 wks post-irradiation for eedhypo/hypo, eednull/+ and controls, respectively). We reasoned that new pathways involved in tumorigenesis could be at play in this eed sensitized background, potentially allowing for the identification of new oncogenic collaborators. Therefore, a proviral insertional mutagenesis screen was conducted. Neonatal MMLV infection of eed mutant mice dramatically accelerated the occurrence of B and T cell lymphomas (50% lethality at 16 wks; 22 wks and 26 wks post-infection for eedhypo/hypo,eedhypo/+ and controls, respectively). To characterize retroviral insertions inverse-PCR (IPCR) was performed using genomic DNA isolated from 32 eedhypo/hypo and 27 wild-type tumors. More than 780 IPCR products were recovered and purified. To date, at least 140 retroviral insertion sites (RIS) have been cloned, sequenced and mapped against the mouse genome. Of these, 7 insertion targeting gene loci known to be cancer-related, like Pim1 (n= 7 tumors), Notch1 (n= 14 tumors) and c-Myc (n= 3 tumors) have been identified. In addition, 8 new common insertion sites (CIS), such as Socs1 (n= 6 tumors), Gadd45g (n= 5 tumors) and Fgfr3 (n= 6 tumors) have also been identified. Rearrangements of the Pim1 locus were found in more than 22% of the eed1989/1989 mutant mice whereas none could be found in wild-type littermates. Moreover, RT-PCR analysis indicates that the Pim1 gene is clearly overexpressed in 6 out of 16 eed1989/1989 tumors analyzed compared to wild-type, further supporting a key role for the Pim1 pathway in eed sensitized tumor cells. Thus, the data presented in this study provide evidence that eed has tumor suppressing function. It also points to a novel mechanism of tumor suppression by a PcG protein. Based on these results, it will be interesting to study the status of eed and of the newly identified CISs in human diseases associated with deletions of 11q14.2-22.3.
Low-Dose Administration of Recombinant IL-2 Following T Cell Depleted Bone Marrow Transplantaion Induces Expansion of CD4+CD25+ FOXP3+ Regulatory T Cells in Vivo.
Authors: Zorn Emmanuel , Lista Despina , Kim Haesook , Bellucci Roberto , Canning Christine , Soiffer Robert J. , Ritz Jerome 
Published: October 2019

Abstract
Regulatory T cells (Treg) play a key role in controlling immune responses following allogeneic hematopoietic stem cell transplantation (HSCT). In murine models, infusion of purified CD4+CD25+ Treg at the time of transplant is sufficient to prevent acute GVHD. In humans, development of acute as well as chronic GVHD has been associated with reduced numbers of Treg following allogeneic HSCT, suggesting that defective reconstitution of this functional cell type can contribute to exacerbation of alloimmune responses. Based on these results, adoptive cellular therapy using purified and in vitro expanded populations of Treg has been proposed as a therapeutic strategy to correct chronic GVHD. Treg are mainly characterized by the constitutive expression of the IL-2 receptor ? chain, CD25 and proliferate in response to IL-2 in vitro. In vivo, the effects of IL-2 on Treg populations are unknown. To examine this question we quantified changes in Treg in 9 patients with CML who previously received low dose IL-2 following allogeneic HSCT. Patients enrolled in this protocol received a daily intravenous infusion of 2 X 105 U IL-2/m2 for 3 months, starting 3 months after CD6 depleted allogeneic bone marrow transplantation (BMT). No patient developed GVHD following IL-2 administration and overall toxicity was minimal. The predominant immunologic effect of IL-2 reported in the initial study was a marked increase in NK cell populations characterized as CD3-CD16+CD56+ as well as total CD56+ cells. In this retrospective analysis we investigated populations of CD4+CD25+ T cells before and 1 to 2 months after the beginning IL-2 treatment. Using RNA extracted from patient PBMC we also assessed the level of expression of the specific transcription factor FOXP3 by quantitative PCR as an alternate marker of Treg in vivo. As initially reported, all 9 patients showed a marked increase in CD3-CD56+ cells 1 to 2 months post IL-2 administration. In contrast, the percent of CD3+ T cells were either unchanged or slightly decreased. The percent of CD4+CD25+ cells within the CD3+ T cell population increased during IL-2 treatment (median: 5.8 pre IL-2 vs 7.6 post IL-2, p-value=0.02). Likewise, FOXP3 expression in the CD3+ population showed 5 to 19 fold increase in 8 of 9 patients during this period (median: 3817 AU pre IL-2 vs. 18924 AU post IL-2, p-value=0.055). These results indicate that administration of low dose IL-2 can augment Treg cells in vivo as reflected by increased ratio of CD4+CD25+/CD3+ T cells as well as higher levels of FOXP3 expression. These studies suggest that prolonged treatment with low dose IL-2 can effectively expand CD4+CD25+ Treg in vivo. This represents a novel strategy for expanding regulatory T cells in vivo and may be useful alone or in conjunction with adoptive cellular therapy with Treg.
The Synthetic Pentasaccharide, Fondaparinux, Reduces Inflammation and Neutrophil Accumulation in Kidney Ischemia-Reperfusion Injury.
Authors: Schabbauer Gernot , Frank Rolf D. , Holscher Todd , Sato Yuichiro , Tencati Michael , Pawlinski Rafal , Mackman Nigel 
Published: October 2019

Abstract
Acute inflammatory diseases are often accompanied by coagulation activation leading to local thrombotic complications and disseminated intravascular coagulation. Recent studies support the concept of crosstalk between coagulation and inflammation. The synthetic pentasaccharide, fondaparinux, is a selective antithrombin-dependent inhibitor of coagulation factor Xa. In this study, we investigated the effect of fondaparinux in a lethal murine model of kidney ischemia-reperfusion (I/R) injury that is associated with coagulation and inflammation. Fondaparinux treatment of I/R-injured mice significantly reduced serum creatinine levels and increased survival from 0 to 44% compared with saline treated control mice. In contrast, depletion of fibrinogen with ancrod was not protective, suggesting that fondaparinux may have additional properties beyond its anticoagulant activity. Indeed, fondaparinux significantly reduced IL-6 and MIP-2 expression but did not reduce MCP-1 expression. Furthermore, fondaparinux significantly decreased neutrophil accumulation in the injured kidneys. Finally, we showed that fondaparinux reduced recruitment of neutrophils into the peritoneum in a model of acute peritonitis and inhibited the binding of U937 cells to P-selectin in vitro. Our data indicate that fondaparinux has both anticoagulant and anti-inflammatory activity reducing fibrin deposition and blocking the binding of inflammatory cells to activated endothelium. Fondaparinux may be useful in the treatment of acute inflammatory diseases.
TNFα Mediated Facilitating Cell Enhancement of Hematopoietic Stem Cell Function in Vivo and In Vitro Involves Bcl-3.
Authors: Rezzoug Francine , Huang Yiming , Tanner Michael K. , Wysoczynski Marcin , Shannie Carrie L. , Ratajczak Mariusz Z. , Fugie-Vivier Isabelle J. , Ildstad Suzanne T. 
Published: October 2019

Abstract
Approaches to enhance engraftment of hematopoietic stem cells (HSC) are of primary interest in BM transplantation. CD8+TCR− facilitating cells (FC) improve HSC engraftment in allogeneic recipients without causing graft versus host disease. FC also significantly enhance the engraftment of limiting numbers of HSC in syngeneic recipients, suggesting that FC act directly on HSC. We therefore analyzed the mechanism for FC-mediated effects on HSC. We found that FC increased the ability of purified HSC to generate colonies in both the CFC and CAFC/LTC-IC assays, confirming a direct effect of FC on different HSC compartments. Co-incubation of HSC with FC for 18 or 40 hours significantly increased the survival of HSC and their subsequent ability to generate CFC at these same time points. We determined that the anti-apoptotic effect of FC on HSC was associated with the up regulation of anti-apoptotic Bcl-3 transcripts. We postulated here that the effect of FC on HSC was due to cytokine secretion. As FC produce TNFα after CpG ODN stimulation and TNFα has various activities on HSC, we evaluated the role of TNFα on FC function. FC were sorted from TNFα deficient mice and the facilitative activity of FC on HSC engraftment was assessed. FC from TNFα deficient mice were impaired in facilitating HSC engraftment in both the syngeneic and allogeneic models, suggesting a role for TNFα in FC function. Notably, TNFα transcripts were present in FC by 16 hours of co-incubation of FC + HSC and FC produce TNFα (surface and intra-cellular) when in contact with HSC. Furthermore, when TNFα was blocked (using anti-TNFα mAb), FC from wild type mice lost the ability to increase HSC clonogenicity (from 38.2±13.6 CFC/1000 HSC in HSC alone to 65.7 ± 22 for HSC + FC and 38.2 ± 19.6 for FC pre-incubated 1 hour with anti-TNFα mAb before incubation with HSC). Moreover, anti-TNFα mAb also blocked the ability of FC to up-regulate Bcl-3 transcripts in HSC. In conclusion, FC act directly on HSC via several mechanisms to maintain the balance between proliferation/differentiation/survival of HSC. One central mechanism implicates TNFα production by FC, which may protect HSC from undergoing apoptosis by up-regulating anti-apoptotic transcripts (e.g. Bcl-3). These findings may have great impact for the use of accessory cells in HSC transplantation, especially when numbers of HSC are limiting.
Gi Protein Signals Are Required for BM Homing of Hemopoietic Progenitor Cells, and Cooperate with Alpha4-Intergrin and Endothelial Selectins.
Authors: Bonig Halvard , Priestley Greg V. , Jiang Yi , Papayannopoulou Thalia 
Published: October 2019

Abstract
Several examples suggest a relationship between in vitro migratory capacity and bone marrow (BM) homing. Pertussis toxin (PTX) is a potent inhibitor of Gi protein coupled receptor signaling and as such, it blocks hemopoietic progenitor cell (HPC) migration in vitro. However, contrary to expectation, no effects on BM homing were observed in previous studies. We therefore re-examined the effect of PTX on BM homing of HPC. We found that prolonged incubation of BM cells or fetal liver cells with PTX inhibited their BM homing in irradiated or non-irradiated recipients by >75%. A concomitant increase in circulating CFU-C in blood provided added assurance that the data were not due to non-specific toxicity. This inhibition of BM homing was of functional consequence, since PTX-treated cells provided impaired radioprotection and markedly decreased short-term engraftment. Detailed studies showed that inhibition of in vitro migration and ribosylation of Gi proteins were complete only after extended incubation with PTX, whereas short-term incubation for 1–2 h, as used in previous studies, was insufficient. In addition, the incubation of BM cells with SCF may have exaggerated the negative effect of PTX on the inhibition on BM homing. We next sought to test the basis of the residual 25% homing of PTX treated cells. As PTX did not directly inhibit hemopoietic cell adhesion, we tested homing of PTX-incubated and control BM cells in genetic models deficient in certain adhesion molecules on either the hemopoietic cells or the hemopoietic microenvironment. BM homing of PTX-treated α4integrin-/- BM cells transplanted into wild-type (WT) mice, or PTX-treated WT cells transplanted into EPselectin-/- recipients inhibited BM homing significantly stronger than either modality alone, to >90% and >95%, respectively. Of note, untreated WT cells have normal homing in EPselectin-/- mice. These data demonstrate cooperativity between Gi blockade and α4integrin or endothelial selectin blockade in inhibiting BM homing of progenitor cells. Absence of β2integrin or L-selectin in the presence or absence of PTX did not inhibit BM homing. In summary, these studies show that Gi protein signals are required for BM homing of progenitor cells. PTX is a very strong inhibitor of BM homing, suggesting that it may inhibit convergent signals from more than one mediator. We further show that the residual BM homing of migration-impaired BM cells is due to participation of α4 integrin on the transplanted cells, or to endothelial selectins on the host side.
Involvement of PKCe in the Negative Regulation of Akt Activation Stimulated by G-CSF.
Authors: Liu Hong , Dong Fan 
Published: October 2019

Abstract
Granulocyte colony-stimulating factor (G-CSF) supports the proliferation, differentiation and survival of myeloid cells by stimulating the activation of several signaling cascades including the serine/threonine kinase Akt pathway. Akt activation has been shown to be important for G-CSF-induced survival and granulocytic differentiation. Although significant progresses have been made in our understanding of the molecular mechanisms by which Akt is activated, much less is known about the signaling events that negatively regulate Akt activation. Interestingly, G-CSF-induced activation of Akt was completely inhibited when myeloid 32D cells transfected with the wild type G-CSF receptor were incubated with phorbol-12-myristate 13-acetate (PMA), a PKC activator. PMA-mediated inhibition of Akt activation occurred with 5 min and lasted at least 1 hour. Previously, it has been shown that a carboxyl terminally truncated G-CSF receptor (D715), whose expression is associated with the development of acute myeloid leukemia in patients with severe congenital neutropenia (SCN), mediates significantly prolonged Akt activation. Notably, Akt activation by G-CSF in 32D cells expressing the D715 receptor mutant was rapidly downregulated by PMA treatment. The inhibitory effect of PMA on Akt activation was abolished by pretreatment of cells with the specific PKC inhibitor GF109203X, suggesting that PKC-dependent pathway negatively regulates Akt activation. Ro-31-7549, a specific inhibitor of PKCe, also abrogated PMA-mediated inhibition of Akt activation whereas rottlerin and Go6976, inhibitors of PKCd and PKC a/bI,, respectively, displayed no effect. Together, these results identified PKCe as being critically involved in PMA-mediated inhibition of Akt activation. Experiments are currently under way to determine the mechanism by which PKCe downregulates Akt activation and the role of PKCe in the regulation of cell proliferation, differentiation and survival in response to G-CSF.
Thrombocytopenia Is More Common and Nadir Occurs Earlier with Unfractionated Heparin Than with Low Molecular Weight Heparin - Results from the Prospective Catch Registry.
Authors: Moll Stephan , Abrams Charles S. , Rice Lawrence , Becker Richard C. , Berger Peter B. , Anstrom Kevin J. , Honeycutt Emily F. , Crespo Eric M. , Granger Chris , Moliterno David J. , Rodgers Jo E. , Steinhubl Steven R. , Tapson Victor F. , Ohman Magnus 
Published: October 2019

Abstract
Background : Thrombocytopenia in the patient on heparin can have various etiologies, including benign reversible causes and serious, potentially life-threatening ones, such as heparin induced thrombocytopenia (HIT). Knowledge about the prevalence of and timecourse of thrombocytopenia in heparin-treated patients may be helpful to develop systems of alerting clinicians to possible HIT and determining how frequently to check blood counts to detect thrombocytopenia that may be heralding HIT.
Methods : The CATCH registry is a prospective registry of inpatients enrolled between March 2003 and April 2004 at over 50 US hospitals in 3 strata: [1] receiving > 96 hours of unfractionated heparin (UFH) or low molecular weight heparin (LMWH), [2] developing thrombocytopenia (platelets >50% reduction from baseline or <150,000/mm3) in the cardiac care unit and [3] patients on whom HIT tests were ordered. Here we present the data of the prolonged heparin stratum.
Results : 1,121 and 861 patients received UFH and LMWH, respectively, for > 96 hours. A platelet count decrease of > 50 % from baseline was seen more frequently in patients on UFH than in patients on LMWH (10.7% and 7.9 %, respectively; p = 0.03). The parameters that predicted development of thrombocytopenia in the UHF group were length of heparin therapy, body mass index, and admission to a cardiac service; the only parameter predicting thrombocytopenia in the LMWH group was length of LMWH treatment. Of the patients with decreased platelet count by > 50 % from baseline (for UFH n = 120; for LMWH n = 68), this drop occurred in the UFH group at a median of 3.0 days after initiation of heparin and at a median of 4.0 days in the LMWH group. The difference in timing between the 2 groups was not statistically significant (p = 0.205). The platelet nadir was reached after a median /mean of 4.0 / 7.4 days in the UFH group, and 8.0 / 11.4 days in the LMWH group. This was statistically significantly different between the 2 groups (p-value = 0.0025).
Conclusions : A platelet count decrease of > 50 % from baseline occurs frequently in inpatients treated with prolonged heparin. It occurs slightly more frequently on UFH than on LMWH. The median time to onset of thrombocytopenia (> 50 % decrease from baseline) occurs early, at 3–4 days. Daily platelet count checks in the first few days of heparin therapy may be helpful to rapidly discover thrombocytopenia that may then prompt HIT testing.
The VEINES-QOL/Sym Questionnaire Is a Valid and Reliable Measure of Quality of Life in Patients with Deep Venous Thrombosis.
Authors: Kahn Susan R. , Lamping Donna L. , Ducruet Thierry , Arsenault Louise , Miron Marie Jose , Roussin Andre , Desmarais Sylvie , Joyal France , Kassis Jeannine , Solymoss Susan , Desjardins Louis 
Published: October 2019

Abstract
Objectives: To assess the validity and reliability of VEINES-QOL/Sym, a patient-reported questionnaire, for the evaluation of quality of life and symptoms in patients with deep venous thrombosis.
Study design: Psychometric study within the Venous Thrombosis Outcomes (VETO) Study, a Canadian multicenter prospective cohort study of long term outcomes after venous thrombosis.
Subjects: 359 English and French-speaking patients with deep vein thrombosis consecutively recruited at seven hospitals in the province of Quebec, Canada.
Outcome measures: The 26-item VEINES-QOL/Sym is a patient-reported questionnaire that we originally developed and validated for use in patients with chronic venous disorders of the leg (J Vasc Surg 2003). VEINES-QOL/Sym generates separate summary scores for symptoms and quality of life. We performed a comprehensive psychometric evaluation of the acceptability, reliability, validity and responsiveness of VEINES-QOL/Sym in the VETO study population, all of whom had objectively diagnosed symptomatic deep venous thrombosis (mean age 56 years; 50% male; 67% outpatients; 55% proximal DVT).
Results: Criterion-standard psychometric tests confirmed the acceptability (missing data, item endorsement frequencies, floor and ceiling effects), reliability (internal consistency, item-total and inter-item correlations, test-retest), validity (content, construct, convergent, discriminant, known groups) and responsiveness to clinical change of the VEINES-QOL/Sym.
Conclusions: Our results indicate that VEINES-QOL/Sym is a practical, valid and reliable measure of quality of life and symptoms in patients with deep venous thrombosis. VEINES-QOL/Sym provides a rigorous tool to allow more comprehensive evaluation of patient outcomes in clinical trials and epidemiological studies of patients with deep venous thrombosis.
First Cycle Risk of Severe and Febrile Neutropenia in Cancer Patients Receiving Systemic Chemotherapy: Results from a Prospective Nationwide Study.
Authors: Crawford Jeffrey , Wolff Debra A. , Culakova Eva , Poniewierski Marek S. , Selby Caleb , Dale David C. , Lyman Gary H. ,   for the ANC Study Group
Published: October 2019

Abstract
Introduction: Myelosuppression represents the major dose-limiting toxicity of cancer chemotherapy. This prospective, nationwide study was undertaken to better define risk of neutropenia and its complications and to develop risk models for selecting patients for appropriate supportive care.
Methods: More than 3,500 patients initiating a new chemotherapy regimen have been prospectively registered at 137 randomly selected practice sites. Major disease sites include breast, lung, colorectal, ovary and lymphoma. Primary outcomes include severe neutropenia (SN; absolute neutrophil count nadir <500) and febrile neutropenia (FN) (fever/infection and nadir <1000) by cycle of treatment and overall.
Results: This analysis is based on the first 2,361 patients treated to date including 924 (39%) age ≥65. Severe neutropenia was documented in 28% and FN in 16% across all cancer categories. The proportion of patients with ANC <500 over the first four cycles of treatment include: colorectal (8%); lung (18%); ovary (23%); lymphoma (27%) and breast (37%). Likewise, the proportion of patients with FN during the first four cycles include: colorectal (7%); lung (11%); ovary (13%); lymphoma (18%) and breast (20%). As shown in the table, approximately half of the initial episodes of ANC <500 and FN over four cycles of treatment occurred in cycle 1.
Neutropenic Events By Cycle (% Patients) Primary Outcome Cycle 1 (N=2361) Cycle 2 (N=2032) Cycle 3 (N=1724) Cycle 4 (N=1246) Total (N=2361) Any SN 16 11 10 11 48 1st Cycle SN 16 6 4 2 28 Any FN 8 6 5 1 20 1st Cycle FN 8 4 3 1 16
The proportion of initial episodes of severe neutropenia that occur in cycle 1 include: colorectal (67%); lung (59%); ovary (44%); lymphoma (62%) and breast (70%). Likewise, the proportion of initial episodes of FN occurring in cycle 1 include: colorectal (53%); lung (60%); ovary (57%); lymphoma (56%) and breast (58%).
Conclusions: Rates of severe and febrile neutropenia vary with tumor type. The initial episode of severe or febrile neutropenia is most likely to occur during the first cycle of chemotherapy across all major cancer types.