bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Comparison of Acute GVHD after HLA-Haploidentical and HLA-Identical Stem Cell Transplantation.
Authors: Hill Wolfgang , Tischer Johanna , Bigalke Iris , Rieger Christina , Ledderose Georg , Kolb Hans-Jochem 
Published: October 2019

Abstract
Acute graft-versus-host disease (aGVHD) is a major obstacle of allogeneic stem cell transplantation (SCT). We compared a cohort of 58 patients with HLA-haploidentical transplants (haplo) and a contemporary group of 229 patients with HLA-identical transplants (id) for the manifestation of aGVHD. Haplo-patients were given unmodified marrow (bm) and CD6- depleted mobilized blood cells (mbc) 6 days after marrow transplantation. The combination of cyclosporin A (CSA) and a short course of methotrexate (sMTX) was given post-grafting. Standard intensity conditioning was given to 34 and reduced intensity conditioning to 24 patients. Id-patients were given bm in 140, mbc in 79 and the combination of bm and mbc in 6 cases. Post grafting immunosuppression consisted of CSA either alone (N=10) or in combination with sMTX (N=158), and/or mycophenolate mofetil (MMF) (N=57). Conditioning was of reduced intensity in 50 patients and standard in 175 patients. Haplo-patients were younger in age (34 vs. 44 yrs.), more frequently male and in a more advanced stage of their disease. Manifestations of aGVHD, microangiopathy characterized by schistocytes and elevated LDH and virus infections were evaluated. Haplo-patients had more severe aGVHD of the skin than id-patients (IBMTR index B – D: 53% vs. 37%; p<0.02). Response to the treatment with corticosteroids was better in haplo-patients than in id-patients (74% vs. 52%; p =0.048). Extensive chronic GVHD was less frequent in haplo-patients than id-patients (14% vs. 39%; p=0.005). However virus infections requiring virostatic therapy were more frequent in haplo-patients (60% vs. 40%; p=0.03). Modification of aGVHD has been achieved by transfusion of CD6-depleted mbc 6 days after transplantation of unmodified bm. CD6-depleted mbc contain non-specific suppressor cells. Improved depletion has eliminated severe aGVHD (IBMTR C & D) completely. However immune deficiency and recurrent viral infections remain a problem.
Thrombopoietin Enhances Expression of Vascular Endothelial Growth Factor (VEGF) in Primitive Hematopoietic Cells through Hif-1α.
Authors: Kirito Keita , Fox Norma , Kaushansky Kenneth 
Published: October 2019

Abstract
The development of hematopoietic stem cells (HSCs) is orchestrated by numerous hematopoietic cytokines, growth factors and chemokines. For the most part these proteins are secreted from bone marrow microenviromental cells, including fibroblasts, endothelial cells and stromal cells, or are displayed on their cell surfaces. HSCs have also been shown to produce numerous cytokines and growth factors. Interestingly, secreted cytokines have also been reported to induce the production of additional cytokines from neighboring cells, suggesting that cytokines drive networks of other cytokines to support hematopoietic cell development. Vascular endothelial growth factor (VEGF), a major regulator of angiogenesis and vasculogenesis, also plays an important role in HSC development, where it acts in an intracellular autocrine fashion to promote cell survival. The secretion of VEGF from endothelial or smooth muscle cells is regulated by extracellular stimuli, inflammatory cytokines and hypoxia. In contrast, it is not clear whether synthesis of VEGF in HSCs is regulated by extracellular signals. Because several early acting cytokines, including TPO, affect VEGF-A expression in hematopoietic cell lines, we hypothesized that TPO could be a regulator of a HSC VEGF autocrine loop. We found that TPO induces VEGF transcripts in primitive marrow derived sca-1+/c-kit+/Gr-1− hematopoietic cells, and that VEGF transcripts are reduced in these cells when derived from Tpo−/− mice. Additional studies determined that TPO induces VEGF expression by increasing the nuclear levels of its primary transcription factor, both in the TPO-dependent primitive hematopoietic cell line UT-7/TPO and in purified sca-1+/c-kit+/Gr-1−marrow cells. Elevation of HIF-1α by TPO is achieved by two different mechanisms; augmented protein synthesis and enhanced stabilization. The latter mechanism is dependent on heat shock protein 90 (Hsp90), as inhibition of Hsp90 function by the specific inhibitor geldanamycin inhibited the TPO-dependent stabilization of HIF-1α. In additional studies we also established that VEGF expression was important for the favorable TPO effect on primitive hematopoietic cells, as blockade of the VEGF receptor with a specific inhibitor, SU5416 (0.1mM), substantially blunted TPO induced growth of sorted single sca-1+/c-kit+/Gr-1−marrow cells in serum-free cultures. Importantly, this inhibitor does not affect TPO induced phosphorylation of Jak2, ERK and AKT in UT-7/TPO cells even at a 100-fold higher concentration. Along with our previous findings that TPO affects Hox transcription factors that regulate HSC proliferation, these data contribute to our growing understanding of the mechanisms by which a hormone can influence HSC development.
A Serine Protease Activity Is Induced by G-CSF and Degrades Stat5 Proteins in Myeloid Cells.
Authors: Qiu Yaling , Zhuang Dazhong , MacRae Alexandra , Dong Fan 
Published: October 2019

Abstract
Granulocytic progenitor cells become progressively less capable of proliferation and survival with terminal differentiation. Granulocyte colony-stimulating factor (G-CSF) is the major regulator of granulopoiesis and stimulates the activation of multiple signaling pathways including the signal transducer and activator of transcription 5 (Stat5) pathway. Little is known about the activation status of G-CSF-stimulated signaling pathways at the distinct stages of granulocytic differentiation. When myeloid 32D cells transfected with the G-CSF receptor were induced to differentiate with G-CSF, Stat5 activation in response to G-CSF was gradually attenuated. Activation of other signaling molecules including Stat1, Stat3, Erk1/2, JNK and p38 was not altered significantly. Stat5 activation was also downregulated in multipotent FDCP-mix cells, which differentiated into mature granulocytes upon induction with G-CSF, but not in pro-B BaF/3 transfected with the G-CSF receptor, which showed no terminal granulocytic differentiation in response to G-CSF, suggesting that the effect of G-CSF is cell type specific. Attenuated activation of Stat5 correlated with reduced Stat5 protein levels, which was associated with expression of a protease activity capable of degrading Stat5 protein in vitro. The Stat5 protease activity was upregulated when myeloid cells were induced to differentiate with G-CSF, but its upregulation by G-CSF was blocked upon expression of leukemogenic proteins Bcr-Abl and Tel-Jak2. The activity of the Stat5 protease was inhibited partially by PMSF and completely by a1-antitrypsin, suggesting that it belongs to the serine family of protease. Our data provide the first evidence that a Stat5 protease activity is upregulated by G-CSF and may have important implications for understanding the molecular mechanism by which G-CSF orchestrates granulopoiesis.
Stabilization of Nmi Protein through Its Interaction with Tip60.
Authors: Zhang Keman , Zheng Gang , Yang Yu-Chung 
Published: October 2019

Abstract
Tip60 (Tat-interactive protein of 60 kDa), a member of MYST family (for its founding members MOZ, YBF2/SAS3, SAS2 and Tip60) histone acetyltransferases, is involved in transcriptional regulation of many genes and diverse signaling transduction. The Tip60 complex consists of multiple subunits, with some implicated in DNA damage and apoptosis. The MYST superfamily members, such as MOZ and MORF, are implicated in the pathogenesis of acute myeloid leukemia. In the present study, Nmi was identified as a novel binding partner for Tip60 by a yeast two-hybrid screen. The association of Tip60 with Nmi was further confirmed by co-immunoprecipitation. Nmi, an interferon and interleukin inducible protein was originally identified as an N-Myc/c-Myc interacting protein. It is expressed in various adult and fetal tissues and in several cancer cell lines with the highest expression in certain myeloid leukemias. Nmi gene is localized on human chromosome 22q13.3 in a region where translocation has been reported in certain human leukemias. The Nmi protein interacts with all the STAT members except STAT2. Although Nmi lacks intrinsic transcriptional activation domain, it functions as an adaptor molecule to enhance STAT-dependent transcription through the recruitment of coactivator CBP/p300. Tip60 interacts with the C-terminus of Nmi in a region essential for Nmi-Nmi homodimerization and Nmi-IFP35 (interferon-inducible protein of 35 kDa) heterodimerization and subcellular localization. Homodimerization of Nmi reduces the interaction of Tip60 with Nmi. Nmi associates with the zinc finger domain of the Tip60, which is important for the transcriptional repression effect of Tip60 on TEL, the translocation E26 transforming-specific (ETS) leukemia. We further showed that Nmi is an unstable protein and is targeted for proteosome-mediated degradation possibly through ubiquitination of its C-terminus. The interaction with Tip60 enhances Nmi stability, which is dependent on the histone acetyltransferase activity of Tip60. Our results suggest that stabilization of Nmi protein through its interaction with Tip60 may be involved in the pathogenesis of certain leukemias.
Patient Preference and Capabilities Are at Least as Important as Clinical Contraindications as Barriers to Prescribing Warfarin in Patients with Atrial Fibrillation.
Authors: Hollowell Jennifer , Ingelgard Anders , Reddy Prabashni , Gold Karen , Fitzmaurice David 
Published: October 2019

Abstract
BACKGROUND: Prior studies have assessed either physicians’ general perceptions of barriers to oral anticoagulation or actual barriers in a sample of patients, but they have not both been evaluated within the same study. We evaluated physicians’ general perception of barriers to warfarin use and actual critical barriers to prescribing warfarin in their own patients, using a newly developed instrument.
METHODS: We identified 45 barriers to warfarin use from a literature review, input from clinical experts, and a physician focus group. Barriers were classified into 4 groups: patient medical characteristics (n = 18), health care system factors (n = 8), patient capability (n = 13), and patient preference (n = 6). A sample of US physicians (n = 30) who treat atrial fibrillation (AF) patients completed the instrument. Physicians ranked on a 1–10 scale their reluctance (10 = very reluctant) in general to prescribe warfarin if a specific barrier was present in a patient (perceived barriers). Physicians then indicated critical barriers to prescribing warfarin in their own specific AF patients not receiving warfarin. The most highly ranked perceived barriers and the most prevalent critical barriers to prescribing warfarin were assessed.
RESULTS: Factors considered most strongly to influence physicians’ decision not to prescribe warfarin (mean score±SD) in general were: severe bleeding <3 months ago (9.2±1.3), inability to rely on a patient to adhere to medication instructions in general (8.5±1.3), inability to rely on a patient to adhere to complex warfarin instructions (8.3±2.2), patient unwilling to undergo repeat laboratory testing (8.3±2.1), and risk of fall (8.2±1.8). The most prevalent critical barriers to prescribing warfarin [n (%)] in specific AF patients (n = 24) were: patient unwilling to undergo repeat testing [7 (29%)], inability to rely on the patient to adhere to medication instructions in general [4 (17%)], inability to rely on the patient to adhere to complex warfarin instructions [4 (17%)], difficulty getting to monitoring appointments [4 (17%)], and bleeding episode >3 months ago [4 (17%)].
CONCLUSION: Patient preference and capabilities are at least as important as clinical contraindications as barriers to prescribing warfarin in AF patients.
An Evaluation of the Impact of Recurrent Venous Thromboembolic Disease and Hemorrhagic Events within the Managed Care Setting.
Authors: Ory Caron , Cyprien Lori , Kim Jennifer , Hauch Ole , Chang Eunice 
Published: October 2019

Abstract
Recurrent venous thromboembolic disease (VTE) has been associated with significant expenditures in health care charges. In this retrospective observational cohort study, managed care enrollees with an initial VTE and treated with warfarin were identified. The rate of recurrent VTE and hemorrhagic events, as well as health care charges incurred for these events were calculated. Study inclusion required a diagnosis of VTE between 01/01/98 through 12/31/00, age 18 or older, a pharmacy claim representing warfarin use 7 through 14 days after diagnosis, no VTE or anticoagulation use during the 6-month period prior to diagnosis and continuously enrolled in the health plan during the 6-month pre-index period through 360 through 720 days after diagnosis. A total of 1,973 patients were identified. Mean age was 69.4 ± 13.3 years and 57.3% were female. Overall, the median length of warfarin therapy was 4.7 months. During the follow-up period, 220 (11.2%) had an acute hospitalization for a subsequent event regardless of warfarin status. Of these, 139 patients (63.2%) experienced a recurrent VTE and 81 patients (36.8%) experienced a hemorrhagic event. Health care charges incurred for the first recurrent VTE or a hemorrhagic event were $15,575 ± $17,209 however, twenty patients experienced a second recurrent event (either VTE or hemorrhagic) and their health care charges increased to $37,356 ± $38,877.
Overall, 11.0% of patients with an initial VTE and who were treated with warfarin experienced a recurrent VTE or hemorrhagic event requiring hospitalization. These data highlight the importance of anticoagulation for secondary prevention of VTE and that multiple events (VTE or hemorrhagic) result in substantial health care expenditures.
Increasing Hemoglobin Levels with Epoetin Alfa in Anemic Hematologic Cancer Patients Receiving Chemotherapy Correlates Significantly with Improved Quality of Life.
Authors: Harousseau Jean-Luc , Fumoleau Pierre , Lange Winand , Welslau Manfred 
Published: October 2019

Abstract
The majority of patients (pts) with hematologic malignancies (HM) are anemic and often have poor performance scores (Ludwig H et al. Blood.2002;100:234a). The correlation between increases in hemoglobin (Hb) with epoetin alfa and improvements in quality of life (QOL) was evaluated in this open-label, multicenter study that enrolled 736 adult pts with various solid tumors and HM (n = 122) who were receiving cytotoxic chemotherapy and had Hb levels <12 g/dL. Epoetin alfa was administered 150 IU/kg or 10,000 IU 3 times weekly (TIW) for a maximum 28 weeks (wks); dose was increased to 300 IU/kg or 20,000 IU TIW if Hb was not increased >1 g/dL above baseline within 4 wks. Results for pts with HM are compared to results from a similar 16-wk trial that included pts with HM (n = 488) and used the 40,000 IU once-weekly (QW) dose, increased to 60,000 IU QW if Hb did not increase ≥1 g/dL within 4 wks (Gabrilove J et al. Int J Hematol.2000;72:55). In the TIW study, the primary efficacy endpoint was change in QOL as measured by the Functional Assessment of Cancer Therapy-General (FACT-G), including subscales for anemia (FACT-An) and fatigue; the FACT was administered at study entry, at 8–9 wks, and at 12 wks. QOL was additionally measured by the Cancer Linear Analog Scale (CLAS; also known as the Linear Analog Scale Assessment [LASA]) administered at every study visit. Dose increases were similar in both studies (33.6% of pts in the TIW study; 36.7% of pts in the QW study). In the TIW study, mean baseline Hb was 9.6 g/dL; mean Hb increased at 4–6 wks (1.35 g/dL), 8–9 wks (2.09 g/dL) and 12 wks (2.46 g/dL) to a mean Hb of 12.0 g/dL. Almost half the HM patients in the TIW study (48.1%) had a complete response (Hb increase ≥2 g/dL without blood transfusion). Hematologic results are similar to those reported in the QW study where mean Hb increased 1.96 g/dL by end of study (P = .0001). QOL improvements were also similar between studies. Mean FACT-An scores for the total population in the TIW study increased 6.7 points after 12 wks, which is clinically significant (Patrick DL et al. Eur J Cancer.2003;39:335–345). The mean increase for overall FACT-G correlated significantly with increased Hb at 12 wks (P <.0001; r = .262). Mean CLAS scores for the total population increased steadily throughout the study. At 12 wks mean increases (based on the 100-mm scale) were clinically significant (Patrick et al): 10.9 mm for Energy, 11.2 mm for Daily Activity, and 10.3 mm for Overall QOL. Mean change for FACT-An for patients from the total population in the QW study (n = 2,230) was 6.0 points (P <.001), which is comparable to the mean changes in the TIW study and the HM population of the QW study (6.59 points, P <.0001). No unexpected adverse events were reported. Epoetin alfa TIW or QW was shown to steadily increase Hb, which significantly correlated with clinically significant improvements in QOL.
Derivation of Hematopoietic Stem Cells from Embryonic Stem Cells.
Authors: Wang Yuan , Yates Frank , Dikovskaia Eugenia , Ernst Patricia , Davidson Alan J. , Zon Leonard I. , Daley George Q. 
Published: October 2019

Abstract
Despite the significant in vitro blood-forming potential of murine embryonic stem cells (ESCs), deriving hematopoietic stem cells (HSCs) that can reconstitute irradiated mice has proven to be challenging. Previously, we successfully engrafted lethally irradiated adult mice with ESCs engineered to ectopically express the homeodomain gene hoxB4. In engrafted animals, blood reconstitution showed a myeloid predominance, likely due to an inability to fully pattern the adult HSC from these embryonic populations. Recently, we have investigated cdx4, a caudal-related homeobox gene whose function has been linked to blood development in the zebrafish. During in vitro differentiation of murine ESCs, cdx4 is expressed during a very narrow time interval on day 3, coincident with the specification of hematopoietic mesoderm. To further characterize the function of cdx4 in mouse hematopoiesis, we have established a tetracycline-inducible murine embryonic stem cell line. When cdx4 expression is conditionally induced over a protracted period from day 2 and 6, we observe a marked enhancement of hemangioblast formation as well as significant increases in primitive and definitive hematopoietic colonies. Cdx4 acts to induce a broad array of hox genes, including a modest elevation in hoxb4. Co-expression of cdx4 and hoxb4 promotes robust expansion of hematopoietic blasts on supportive OP9 stromal cultures. When injected intravenously into lethally-irradiated mice, these cell populations provide robust radio-protection, and reconstitute high-level lymphoid-myeloid donor chimerism. Marrow from engrafted primary animals can be transplanted into irradiated secondary mice. B220+ splenic lymphoid cells and Mac-1/Gr-1+ marrow myeloid cells purified from primary and secondary mice show multiple common sites of retroviral integration, thereby proving the derivation of long-term hematopoietic stem cells from embryonic stem cells in vitro. Our data support a central role for the cdx4-hox gene pathway in specifying murine HSC development, and establish a robust system for hematopoietic reconstitution from ESCs. We have coupled techniques for generating ESCs by nuclear transfer with these methods for blood reconstitution to model the treatment of genetic disorders of the bone marrow.
Low Morbidity but Prolonged Viral Shedding Characterize Parainfluenza Virus 3 Infections in Allogeneic Peripheral Stem Cell Transplant Recipients.
Authors: Aliyu Zakari Y. , Bordner Mary-Ann , Henderson David K. , Sloand Elaine M. , Young Neal S. , Childs Richard , Bennett John , Barrett John 
Published: October 2019

Abstract
Respiratory viruses including human parainfluenza virus 3 (hPIV3) may be significant causes of morbidity and mortality in patients undergoing allogeneic stem cell transplantation. It has been suggested that the acquisition of hPIV3 infections is independent of immunosuppression or transplant type and is driven primarily by patient exposure to the virus during periods of heightened community-wide or nosocomial activity. The incubation period for hPIV3 is 1–3 days and the duration of infectivity/ viral shedding in non-transplant patients is 1–2 weeks. Data regarding the duration of infectivity/ viral shedding and possible predictors of prolong infectivity in peripheral blood stem cell transplant patients (PBSCT) is limited. Of 56 recipients of sibling PBSCT seen at our insitution, 11 (6 inpatients and 5 outpatients) were positive for hPIV3 during a six weeks period, compared with only two positive cases recorded throughout the previous year. At the time of infection patients were between 1 and 7 weeks post transplant. The in-patient attack rate was 11%. Patients in whom respiratory virus infection was suspected were placed on respiratory isolation and followed with weekly nasopharygeal swab/wash (NPW). Care was also taken to limit patient contact of relatives or staff with respiratory symptoms. Most patients developed a flu like illness without major respiratory complications. No mortality was recorded. No case of hPIV 3 was recorded among patients with aplastic anemia receiving ATG in the unit during the same time-period. The median time to conversion from positive to negative hPIV 3 NPW was 2.0 weeks (range 1–6 weeks). The longest duration of viral shedding (six weeks) was in the only haplo-identical SCT patient, who was also the index case. No differences in duration of viral shedding was noted for conditioning regimen type (ablative vs non-ablative), days after transplant of viral acquisition (<15 or >15 days), cyclosporin levels (100–200 ng/l vs 201–400 ng/l), absolute neutrophil counts, absolute lymphocyte counts, CMV reactivation and co-existing peri-hPIV3 infections evidenced by positive blood, urine or sputum cultures. immunosuppression during the outbreak. Our study demonstrates that while hPIV infection in allogenic PBSCT patients has limited morbidity, prolonged duration of viral shedding in this group may contribute to recurrent cycles of epidemics or prolong outbreaks and establish an environmental (community/ nosocomial) contamination or “ping-pong” transmission from patients to asymptomatic health-care workers or family members and back. Our study also emphasize the importance of a universal policy for strict attention to infection-control practices and weekly surveillance NPW until patients are a symptomatic and NPW negative.