bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Bone Marrow Microvascular Density in Hematologic Malignancies
Authors: Negaard Helene Francisca Stigter , Iversen Nina , Bowitz-Lothe Inger Marie , Sandset Per Morten , Steinsvik Brit , Østenstad Bjørn , Iversen Per Ole 
Published: April 2020

Abstract
Background: Angiogenesis is a potential target for therapy, both in solid tumors and in hematologic malignancies. However, the regulation of angiogenesis is complex, different cancers are inherently heterogeneous, and these drugs target different angiogenic regulators. Therefore, a detailed characterization of angiogenesis in individual cancers is needed.
Materials and methods: The study cohort consisted of 93 consecutive patients with hematologic neoplasia; i.e. acute myeloid leukemia (n=20), chronic lymphatic leukemia (n=14), multiple myeloma (n=11), and non-Hodgkin’s lymphoma (NHL, n=48). We determined the microvessel density (MVD) in bone marrow biopsy specimens by immunohistochemical staining for CD34. In addition, we measured the plasma concentrations of eight putative angiogenesis regulators using Luminex multiplex assay, and the expression in peripheral blood mononuclear cells (PBMNC) of 40 angiogenesisrelated mRNAs using quantitative RT-PCR.
Results: Untreated patients had increased bone marrow MVD (mean 39 microvessels/mm2) compared to healthy subjects (mean 20 microvessels/mm2; p&lt;0.001). In particular, patients with advanced stage disease had increased bone marrow MVD (mean 45 microvessels/mm2) compared to patients with lower stage disease (mean 35 microvessels/mm2, p=0.030). A novel finding was that patients with NHL also had significantly increased bone marrow MVD (mean 38 microvessels/mm2). The patients had increased plasma levels of vascular endothelial growth factor (VEGF; mean 31 vs 19 pg/ml, p&lt;0.001), interleukin (IL)-6 (median 4.6 vs 2.3 pg/ml, p=0.034) and IL-8 (median 7.2 vs 3.9 pg/ml, p=0.001). Plasma levels of fibroblast growth factor 2 (FGF2), tumor necrosis factor α, and angiogenin were not significantly different in patients compared to controls. Pre-treatment plasma levels of VEGF and FGF2 were significantly higher in those who did not achieve complete remission after cancer therapy. Patients with advanced stage disease had significantly higher plasma levels of IL-6 and -8. The mRNA most highly expressed in PBMNC was IL8, which was 15-fold up-regulated. The mRNA expression of VEGFA in PBMNC was strongly correlated to the expressions of hypoxia-inducible factors 1α and 2α (r=0.7 and p&lt;0.001 for both). There were no differences in bone marrow MVD when comparing the different diagnoses. However, the majority of the putative regulators of angiogenesis studied were significantly different between the diagnoses; indicating that bone marrow MVD in hematologic malignancies was differentially regulated.
Conclusions: Our data show that patients with hematologic malignancies have increased bone marrow MVD, supporting the notion that bone marrow angiogenesis plays a role in the pathogenesis and progression of these cancers. VEGF, IL-6 and IL-8 seem to contribute to the malignant phenotype.
Novel Peptides Activate GRP78 Heat Shock Protein Receptor as a New Target for Angiogenesis
Authors: Hardy Bri tta , Raiter Annat 
Published: April 2020

Abstract
Background: Impaired angiogenesis is one of the features of ischemic diseases. For the last decade the most established target for therapeutic angiogenesis has been VEGF and its receptors. However clinical trials to alleviate ischemia have been disappointing indicating the need for new molecules and molecular targets. We have identified a heat shock protein GRP78 on endothelial cell membranes as a novel target for angiogenesis that is independent of VEGF. We have demonstrated that binding to this target by a synthetic 12 amino acid peptide RoY induced therapeutic angiogenesis. A single local administration of the peptide significantly restored blood perfusion in mice post femoral artery excision. Recently, we have also demonstrated that intravenous administration of the peptide to mice with acute myocardial infarction resulted in increased capillary density in the ischemic tissue. Our aim was to study membrane GRP78 as a new target for angiogenesis and to identify its natural ligand.
Results: FACS analysis of endothelial cell cultures demonstrated that membrane GRP78 is increased under hypoxic conditions. In order to identify a natural ligand to GRP78, we used protein data base search. ADAM15, a disintegrin and metalloprotease glycoprotein was found to contain four out of twelve identical amino acids to the synthetic RoY peptide. We have therefore synthesized three peptides from the metalloprotease domain and studied endothelial cell binding, proliferation, migration and tube formation under hypoxia in the presence of these peptides. One of the peptides, termed ADoPep1, exhibited a significant angiogenic activity invitro and restored blood perfusion in a mouse hind limb ischemia model. Histological examinations showed an increase in capillary density, a decrease in GRP78 positive cells and apoptotic cells one week post treatment of ischemic leg with ADoPep1. We demonstrated that ADoPep1 inhibited endothelial cell hypoxia-induced apoptosis but not CoCl2 induced apoptosis. We therefore suggest a possible mechanism of angiogenesis by inhibition of hypoxia-induced apoptosis is manifested through GRP78 receptor induced by ADAM15 derived peptide.
Conclusions: The peptide derived from ADAM15 induces angiogenesis by the activation of membrane GRP78 under hypoxia which may lead to the development of novel therapeutics for ischemic diseases. This study contributes to the search for new molecules that activates a new target for therapeutic angiogenesis in ischemic diseases.
Increased Procalcitonin Levels in End Stage Renal Disease and Chronic Kidney Disease as An Indicator of Inflammatory Activation
Authors: Bansal Vinod , Fareed Daniel , Hoppensteadt Debra , Cunanan Josephine , Fareed Jawed 
Published: April 2020

Abstract
Increased levels of procalcitonin (PCT) and other calcitonin precursors are associated with systemic inflammatory responses in patients with burns, trauma or sepsis. Since end stage renal disease (ESRD) and chronic kidney disease (CKD) represent syndromes involving inflammatory responses, we hypothesized that PCT may also be elevated in patients with these pathologic conditions. Apparently sepsis-free blood plasma samples collected from normal donors (n=100) and patients with ESRD(n=67) and CKD (n=67) were retrospectively analyzed for circulating PCT levels using an immunocolorimetric assay (ILMA PCT,BRAHMS, Berlin Germany). This test utilizes two monoclonal antibodies that are directed to the calcitonin and katacalcin portions of PCT. The capturing antibody is immobilized on the surface of the coated tube and a labeled anti-calcitonin is used as a tracer. Diluted plasma samples incubated and both antibodies react with the PCT to form a sandwich complex. The excess tracer antibody is discarded after incubation. The amount of residual tracer is measured in a luminometer. The intensity of luminescence is proportional to the amount of PCT in the sample. PCT levels in normal individuals were 0.24±0.11 ng/ml, whereas higher levels were measured in CKD(0.81±0.35 ng/ml) and ESRD (0.93±0.36 ng/ml). Although wide ranges in the PCT values were observed, the levels were much higher than normal. These studies suggest that patients with ESRD and CKD may exhibit elevated levels of PCT which may not be due to sepsis. Measurement of PCT in these patients may be useful in the risk stratification and clinical management.
Solid Tumors Target the HSC Niche to Establish Metastatic Footholds in the Marrow
Authors: Shiozawa Yusuke , Pedersen Elisabeth A. , Havens Aaron M. , Jung Younghun , Ziegler Anne M. , Pienta Michael J. , Song Junhui , Wang Jingcheng , Loberg Robert D. , Krebsbach Paul H. , Pienta Kenneth J. , Taichman Russell S 
Published: April 2020

Abstract
Metastasis is the most deadly aspect of many solid tissue cancers. The majority of metastases utilize pathways established to regulate hematopoietic stem cell (HSC) homing to gain access to the marrow. Whether solid tumors target the niche to establish footholds in the marrow is unknown. Using prostate caner (PCa) as a model, we determined if PCa and HSC compete for the HSC niche. To determine if disseminated PCa competes for the niche and prevents HSC engraftment, sham-operated or tumor-implanted NOD/SCID mice (Ly5.1) were transplanted with marrow cells from Ly5.2 donor animals. To preserve the niche, the transplanted animals received no preconditioning. At 16 weeks, greater HSC engraftment was observed in sham-operated group than in the tumor-bearing group as reflected by mature HSC progeny in the peripheral blood (0.7 ± 0.4% vs. 0.2 ± 0.2%, p = 0.022). Multiphoton microscopy revealed that PCa and SLAM receptor isolated HSCs co-localize at the endosteal bone surfaces in vivo and in vitro, further suggesting that PCa compete for the niche. Since osteoblasts (OBs) are vital components of the niche, it was determined if alterations in OB numbers also regulates metastasis. Here, vertebrae from control or conditional osteoblast knockout (Col2.3Δ-TK) mice were transplanted into SCID animals. Following treatment with ganciclovir which ablated the osteoblasts, metastasis to these tissues was evaluated. Fewer disseminated PCa were recovered from the Col2.3Δ-TK transplants than vehicle treated transplants (41.6 ± 23.7% vs. 100.0 ± 69.9%, p = 0.009). If metastases target the niche, then we should be able to mobilize metastases using HSC mobilizing regimes. Here, PCa tumors were established and removed. Later G-CSF was administered, and PCa numbers were determined in the blood. More PCa cells were seen in the blood after G-CSF treatments vs. the vehicle group (616.9 ± 463.0 cells vs. 143.7 ± 159.1 cells, p = 0.025). Part of the mechanism responsible for the mobilization of PCa was an increase in the production of MMP-2 and MMP-9 in the marrow. Finally, we evaluated if soluble factors produced by PCa alter HSCs activities. Animals were treated with either control or PCa conditioned medium for 3 days, and then HSC were harvested. Alterations of many mRNA transcripts involved in HSC self renewal were observed in animals exposed to the PCa conditioned medium. Our findings indicate that PCa and HSCs compete for the osteoblastic HSC niche, and that PCa utilize the same mechanisms as HSCs to gain access and egress from the niche. Taken together, these data provide the first evidence that the HSC niche serves as pre-metastatic niche for solid tumors and plays a central role in bone metastases.
A Prospective Phase II Trial of An L-Asparaginase Containing Regimen in Patients with Refractory or Relapsing Extra Nodal NK/T-Cell Lymphoma
Authors: Jaccard Arnaud , Gachard Nathalie , Coppo Paul , Morschhauser Franck , Galicier Lionel , Ysebaert Loic , Lenain Philippe , Corront Bernadette , Suarez Felipe , Feuillard Jean , Gaulard Philippe , Bordessoule Dominique , Hermine Olivier 
Published: April 2020

Abstract
Extra nodal NK/T-cell lymphoma, nasal type, is an EBV-related highly aggressive disease with a poor outcome, especially when disseminated or recurrent after radiotherapy. L-Asparaginase seems to have a particular efficacy in this disease (Jaccard, 2008, Ann oncol). Nineteen patients with relapsing or refractory extra nodal NK/T-Cell Lymphoma, nasal type, were included in a multicentric prospective phase II trial using the Aspametdex regimen (E coli-L-asparaginase (Kidrolase®) 6000 UI/m2 IM at day 2,4,6,8, methotrexate 3 gr/m2 at day 1 and dexamethasone 40 mg at day 1 to 4 with 3 weeks cycles). Patients below 65 years of age and with a good performance status received 3 cycles and, in case of good response, an intensive treatment with the BEAM regimen and stem cell rescue. Other patients received up to 6 cycles of the Aspametdex protocol. Patients with localized disease received irradiation if not performed before inclusion. The histology was centrally reviewed and EBV viremia was regularly and centrally monitored. The response after 3 cycles was the primary end point. There were 14 men and 4 women (1 patient was excluded after pathologic review), median age was 59.5 (45 to 76), 7 were primary refractory, 11 were in relapse, 6 were in stage IV. Median number of cycles was 3 (1 to 6). Three patients who had an allergic reaction with L-asparaginase received further courses of Erwinia-asparaginase (Erwiniase®) (n= 3). Toxicity related to L-asparaginase was mild, mainly brief leucopenia (n=2), elevation of alanine aminotransferase (n=2) and venous thrombosis (n=1). Response was documented in 17/18 patients, 10 patients were in complete remission (CR) after treatment with L-asparaginase and 5 patients in partial remission. Five patients died of unrelated causes (n=1) or progression of disease (n=4). Thirteen patients are still alive with a median follow-up of 8 months (1 to 29), 5 responding patients progressed at 4, 5, 8, 8 and 22 months after treatment. Six patients are in persistent CR, 2 of these patients had received high dose therapy with autologous stem cell transplant and 1 patient received irradiation after L-asparaginase treatment. These data confirm the excellent activity of L-asparaginase-containing regimens in extranodal NK/T-cell lymphoma. This must be known because of the very poor prognosis of patients with disseminated or relapsing disease with conventional chemotherapy. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma should be tested in prospective trials.
Radiation-Free Anti-CD3-Conditioning Regimen Maintains Tissue Protection Mechanisms and Prevents GVHD: Role of Tissue Expression of B7H1
Authors: Chen Ying , Lin Chia-Lei , Li Nainong , Du Gong , Chen Lieping , Forman Stephen , Zeng Defu 
Published: April 2020

Abstract
We reported that donor CD8+ T cells mediated graft versus leukemia (GVL) activity without causing graft versus host disease (GVHD) in anti-CD3-conditioned recipients, although the same dose of donor CD8+ T cells caused lethal GVHD in recipients conditioned with sublethal total body irradiation (TBI) (J. Immunol. 2007). We recently observed that donor CD8+ T cells from the liver of anti-CD3-conditioned recipients showed a marked reduction in proliferation in response to anti-CD3/CD28 stimulation, as compared to those from TBI-conditioned recipients, indicating that donor CD8+ T cells are tolerized in the tissues of anti-CD3-conditioned recipients. B7H1, a co-inhibitory molecule, is constitutively expressed by hematopoietic cells and expressed by parenchymal cells after IFN-γ induction. B7H1 tolerizes T cells by interaction with its ligand PD-1 on activated T cells. To explore the role of B7H1 in GVHD prevention in anti-CD3-conditioned recipients, donor C57BL/6 CD8+ T cells (20×106) and bone marrow cells (100×106) were transplanted into anti-CD3-conditioned wild-type or B7H1−/− BALB/c recipients. While the wild-type recipients all survived for more than 100 days without signs of GVHD, the B7H1−/− recipients developed severe GVHD with diarrhea, weight-loss, and hair-loss, and 70% of them died 60 days after transplantation. Similarly, while donor CD8+ T and BM cells induced little GVHD in unconditioned Rag-2−/− BALB/c recipients, they induced severe lethal GVHD in B7H1−/− Rag-2−/− BALB/c recipients. Furthermore, donor CD8+ T and BM cells still induced lethal GVHD in unconditioned chimeric B7H1−/−Rag-2−/− recipients reconstituted with B7H1+/+Rag-2−/− BM. In addition, we observed upregulation of B7H1 expression by hepatocytes and intestine epithelial cells of anti-CD3-conditioned BALB/c or unconditioned Rag-2−/− recipients after donor cells infusion, as judged by RT-PCR, flow cytometry analysis, and histoimmunostaining of B7H1. In vivo bioluminescent imagine showed much more severe tissue infiltration of donor T cells in B7H1−/− recipients as compared to B7H1+/+ recipients, and the in vitro proliferation of donor CD8+ T cells from the liver of the former recipients was much more vigorous than that of the latter recipients. These results demonstrate that B7H1 expression by tissue parenchymal cells rather than hematopoietic cells tolerizes infiltrating donor T cells in GVHD target tissues and prevents GVHD; and that the radiation-free anti-CD3-conditioning regimen can maintain this tissue protection mechanism.
(This study is surpported by Marcus Foundation and NIH R01 AI 066008).
Characteristics of Iron Dextran Utilization in Man
Authors: HENDERSON PERRY A. , HILLMAN ROBERT S. 
Published: April 2020

Abstract
The major portion of iron dextran iron becomes available to the erythroid marrow only after uptake and release of ionic iron by the reticuloendothelial system. With large intravenous infusions, (1000-2000 mg.), the rate of removal of the iron dextran complex from plasma is enough to supply the marrow with more than 200 mg. of iron/day. However, in the present studies the observed rate of iron delivery to the erythroid marrow was far below this level. Although iron supply immediately after infusion was sufficient to permit marrow production to rise to 4-6 times normal, this was maintained for less than two weeks. With time, reticuloendothelial iron dextran stores became less available, the serum iron level fell and marrow production was restricted to levels below twice normal. In fact, large infusion doses and prolonged storage may have made a portion of the iron dextran stores completely unavailable. Thus, an iron deficient type of erythropoiesis appeared in some patients while iron dextran stores were still readily visible on examination of marrow stroma.
Immunologic Rebound After Cessation of Long-term Chemotherapy in Acute Leukemia. II. In Vitro Response to Phytohemagglutinin and Antigens By Peripheral Blood and Bone Marrow Lymphocytes
Authors: Green Alexander A. , Borella Luis 
Published: April 2020

Abstract
The in vitro function of peripheral blood and bone marrow lymphocytes from 42 children with acute lymphocytic leukemia (ALL) in remission was evaluated before and after cessation of long-term combination immunosuppressive therapy. Lymphocyte function promptly recovers even after 3 yr of antineoplastic therapy, but the immunologic rebound varies, depending on whether the in vitro responses to phytohemagglutinin or various antigens are used as the index of lymphocyte function. The kinetics of immunologic rebound in three patients who relapsed following cessation of therapy did not differ from patients remaining in remission. In children off therapy there was a different distribution of antigen- and PHA-responsive lymphocytes between the peripheral blood and bone marrow compartments. This study provides further information at a cellular level on the immunologic rebound that follows cessation of long-term combination therapy. It emphasizes the need for controls in trials where immunotherapy is given after chemotherapy. Such controls are necessary before one can establish if the observed responses are due to adjuvants and/or tumor cells or are a reflection of the immunologic rebound that follows cessation of immunosuppressive therapy. The data also provide a baseline for future studies of immune impairment before leukemia relapse and the relationship between immunologic rebound and the duration of long-term leukemia-free survival.
Eosinophilic colitis in a boy with a novel XIAP mutation: a case report
Authors: Tang Jiamei , Zhou Xiaoying , Wang Lan , Hu Guorui , Zheng Bixia , Wang Chunli , Lu Yan , Jin Yu , Guo Hongmei , Liu Zhifeng 
Published: April 2020

Abstract
Background
X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency disease characterized by haemophagocytic lymphohistiocytosis, recurrent splenomegaly and inflammatory bowel disease (IBD). The only curative treatment is haematopoietic stem cell transplant (HSCT).

Case presentation
Here, we report the case of a 22-month-old male with a long history of abdominal distension and anaemia. Clinical and laboratory findings were consistent with eosinophilic colitis. To identify the underlying disease, we performed exome sequencing, which showed an unreported frameshift mutation in the XIAP gene.

Conclusion
We present eosinophilic colitis as the initial manifestation of XIAP deficiency for the first time in this article, which expands the mutation spectrum and phenotype of this disease.
Tapping into the maize root microbiome to identify bacteria that promote growth under chilling conditions
Authors: Beirinckx Stien , Viaene Tom , Haegeman Annelies , Debode Jane , Amery Fien , Vandenabeele Steven , Nelissen Hilde , Inzé Dirk , Tito Raul , Raes Jeroen , De Tender Caroline , Goormachtig Sofie 
Published: April 2020

Abstract
Background
When maize (Zea mays L.) is grown in the Northern hemisphere, its development is heavily arrested by chilling temperatures, especially at the juvenile phase. As some endophytes are beneficial for plants under stress conditions, we analyzed the impact of chilling temperatures on the root microbiome and examined whether microbiome-based analysis might help to identify bacterial strains that could promote growth under these temperatures.

Results
We investigated how the maize root microbiome composition changed by means of 16S rRNA gene amplicon sequencing when maize was grown at chilling temperatures in comparison to ambient temperatures by repeatedly cultivating maize in field soil. We identified 12 abundant and enriched bacterial families that colonize maize roots, consisting of bacteria recruited from the soil, whereas seed-derived endophytes were lowly represented. Chilling temperatures modified the root microbiome composition only slightly, but significantly. An enrichment of several chilling-responsive families was detected, of which the Comamonadaceae and the Pseudomonadaceae were the most abundant in the root endosphere of maize grown under chilling conditions, whereas only three were strongly depleted, among which the Streptomycetaceae. Additionally, a collection of bacterial strains isolated from maize roots was established and a selection was screened for growth-promoting effects on juvenile maize grown under chilling temperatures. Two promising strains that promoted maize growth under chilling conditions were identified that belonged to the root endophytic bacterial families, from which the relative abundance remained unchanged by variations in the growth temperature.

Conclusions
Our analyses indicate that chilling temperatures affect the bacterial community composition within the maize root endosphere. We further identified two bacterial strains that boost maize growth under chilling conditions. Their identity revealed that analyzing the chilling-responsive families did not help for their identification. As both strains belong to root endosphere enriched families, visualizing and comparing the bacterial diversity in these communities might still help to identify new PGPR strains. Additionally, a strain does not necessarely need to belong to a high abundant family in the root endosphere to provoke a growth-promoting effect in chilling conditions.