bluuebunny/crossref_metadata_2025_split huggingface dataset:
ABC-Me (ABCB10) Is Required for Erythroid Development in the Mouse Embryo and Is Protective against Mitochondrial Oxidative Stress
Authors: Hyde Brigham B , Elorza Alvaro A , Mikkola Hanna K , Schlaeger Thorsten M , Shirihai Orian S 
Published: April 2020

Abstract
We previously described that mitochondrial ATP-Binding Cassette transporter, ABCme (ABCB10) is induced by GATA-1 in erythroid cells and that its over-expression leads to increased heme production. However, the role of ABCme in vivo and the hematologic phenotype of its deficiency have not been described thus far. Here we report for the first time that ABCme is essential for embryonic blood development in vivo. ABCme deficient mouse was generated on 129SvEvBrd/C57BL6J background and backcrossed to n = 4 on the C57BL6J. The homozygous KO mouse is embryonic lethal. ABCme KO dies at 12.5 days of gestation and displayed aplastic embryonic anemia by 10.5 days of gestation, manifested as improper blood development as well as erythroid progenitor apoptosis (Figure 1). Ex vivo analysis of maturation of isolated yolk sac blood determined that ABCme KO erythroid cells fail to differentiate beyond the stage of basophilic erythroblast and exhibit 55% of apoptosis in CD71 positive cells in comparison with 29.25% in ABCme HET, and 17.5% in WT. Erythroid colony assay indicated 50% reduction in the formation of CFU-E and an 80% reduction in BFU-E in comparison with WT. Disruption of heme synthesis may result in accumulation of heme intermediates that are pro-oxidants. To test the hypothesis that apoptosis is induced by oxidative damage we tested both mitochondrial oxidation and the rescue effects of mitochondrial antioxidants in the ABCme KO. Isolated mitochondria of ABCme KO erythroid cells demonstrated significantly elevated levels (5 fold) of oxidized protein in comparison to both WT and HET cells. This elevated level of superoxide were confirmed and identified to be mitochondrial in nature by FACS analysis of superoxide sensitive dye MitoSox. Using antioxidants we tested the patho-physiological role of the elevated ROS in the hematologic phenotype. Treatment of ABCme KO cells with the SOD2 mimetic TBAP resulted in partial and complete rescue of the apoptotic phenotypes of the KO and the HET respectively. Our findings suggest that ABCme is required for erythroid development in vivo and that its deficiency results in impaired erythroid maturation, hemoglobinzation, and increased mitochondrial oxidative damage.
Figure SEQ Figure \* ARABIC 1: Impaired Blood Development of ABCme deficient embryos Figure. SEQ Figure \* ARABIC 1: Impaired Blood Development of ABCme deficient embryos
Light microscopy of Day 10.5 p.c. Embryo and Yolk Sac (Top). At this stage KO embryos are still alive as denoted by heartbeat as well as normal development of other organ systems. However, lack of red cell development is apparent. H/E staining of day 10.5 p.c. yolk sac blood islands (Bottom). KO blood islands demonstrate reduced number, increased nuclear fragmentation associated with apoptosis, and a lack of developed erythroid progenitors. (WT= Wildtype mice, KO= ABCme −/− mice.)
The Predictive Role of Germinal Center or Non-Germinal Center Phenotypes in Diffuse Large B-Cell Lymphoma Patients Receiving CHOP or R-CHOP
Authors: Lee Sun-ah , Ryoo Hun-Mo , Bae Sung Hwa , Jung Hyun Young , Jang Saet Byul , Keum Yoon Seop 
Published: April 2020

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma. It can be divided into the germinal center (GC) and non-GC subtypes by immunohistochemistry based on the expression of CD10, Bcl-6 and MUM-1. The GC Subtype had a significantly better survival rate than the non-GC subtype. These subtypes are predictors of outcome in DLBCL patients receiving CHOP (cyclophosphamide, adriamycin, vincristine and prednisone). Recently a significant improvement of outcome has been obtained by combining a monoclonal anti-CD20 antibody, Rituximab, with chemotherapy. We conducted the retrospective study to evaluate the predictive role of GC or non-GC subtypes in DLBCL patients receiving CHOP or rituximab-CHOP (R-CHOP). We searched the DLBCL patients diagnosed at Daegu Catholic University Hospital between 2000 and 2007. Rituximab was introduced into the treatment since 2003. Both the immunohistochemical and clinical data could be analyzed in forty six patients. According to the expression of CD10, Bcl-6 and MUM-1, we divided DLBCLs into the GC or non-GC subgroups (Blood. 2004;103:275-282). The median follow-up duration was 22.5 months. 21 and 25 patients were received CHOP and R-CHOP, respectively. 12 and 34 patients were classified into the GC and non-GC subgroups. The GC subtype showed a better overall survival (OS) than the non-GC subtype (p=0.046), but not progression-free survival (PFS) (p=0.633). The GC subtype did not predict the outcome in CHOP and R-CHOP group, respectively. In R-CHOP group, the expression of Bcl-6 was associated with a better OS (p=0.033). The GC subtype showed a better OS in low IPI (IPI 0–2) with borderline significance (p=0.054), but not in high IPI group (IPI 3–5) (p=0.429). In conclusion, the GC subtype showed a better OS in whole patients group, but didn’t show the superior outcome than the non-GC subtype in CHOP subgroup or R-CHOP subgroup, respectively, in this study. It may be due to the small size of the GC subtype. The prospective, large scale study is recommended.
Clinical and Biological Characteristics of Plasmacytoid Dendritic Cell Lymphoma in Children
Authors: Hama Asahito , Yagasaki Hiroshi , Muramatsu Hideki , Nishio Nobuhiro , Abe Akihiro , Takahashi Yoshiyuki , Kojima Seiji 
Published: April 2020

Abstract
Plasmacytoid dendritic cell (pDC) lymphoma is a disease entity in the WHO/EORTC cutaneous lymphoma classification. The pDC lymphoma co-expresses CD4 and CD56 without any other lineage-specific markers and has been identified as arising from pDC. In addition, pDC lymphoma is rare and characterized by a rapid aggressive course, with notable skin involvement and a frequent evolution towards overt leukemia. While this disease mainly affects the elderly, a few pediatric cases have been reported. In children, there are two distinct types that exist. These include an aggressive type that involves the skin similar to that seen in the adult type of the disease, along with a second type that is less aggressive and does not involve the skin or behave like acute leukemia. We describe the clinical and biological features of three pDC lymphoma children (Table 1). Morphologically, we observed a peculiar arrangement of the vacuoles along the cytoplasmic outline, the so-called pearl necklace appearance. The blast cells expressed CD4, CD56, HLA-DR, CD123 in three of the patients while BDCA-2 was noted in two patients (Table 2). After the initial AML-oriented therapy, two patients developed an early relapse and subsequently died; they were considered as aggressive type of pDC lymphoma. In our hospital, 3 of 22 patients with malignant lymphoma were diagnosed as pDC lymphoma for five years. In conclusion, the CD4+, CD56+, CD3−, CD13−, CD19−, CD33− phenotype is highly suggestive of pDC lymphoma. In the current cases, additional analyses using CD123 and BDCA-2 antibodies helped to confirm our initial diagnosis. Since an optimal therapy for pDC lymphoma in children is as of yet still unknown, a cooperative study needs to be undertaken to further investigate potential effective therapies for this disease.
Table 1. Clinical presentation of the patients with plasmacytoid dendritic cell lymphoma
Patient 1 Patient 2 Patient 3 AraC, cytosine arabinoside; PSL, prednisone; VCR, vincristine; MTX, methotrexate Year/Sex 5/M 9/M 6/F Skin lesion + + + Lymphadenopathy − − + WB C (×109/L) 5.0 7.4 6.4 Hemoglobin (g/dL) 11.4 12.6 13.2 Platelets (×109/L) 284 294 264 BM blast cells (%) 13 0 0 Initial therapy AraC, etoposide AraC, etoposide PSL, VCR, MTX Complete remission + + + Relapse + + − Survival (month) 22 36 2 &lt; Outcome Death Death Alive
Table 2. Immunophenotypes of the blasts with plasmacytoid dendritic cell lymphoma
Surface marker Patient 1 Patient 2 Patient 3 NA, not available CD3 − − − CD4 + + + CD7 + − − CD13 − − − CD19 − − − CD33 − − + CD34 − − − CD56 + + + CD123 + + + HLA-DR + + + BDCA-2 + NA +
Pediatric Acute Lymphoblastic Leukemia Outcome Predictor Genes OPAL1 and RANTES Modulate Transformation by the V-Abl Oncogene
Authors: Rogers Jason H. , Owens Kristin S. , Vargas Jake M. , Willman Cheryl L. , Hromas Robert , Dahl Richard 
Published: April 2020

Abstract
B-precursor acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. While it represents a highly curable malignancy, a significant number of children still relapse or present with disease that is resistant to therapeutic intensification. With the increasing intensity of curative treatment, there is also an increased incidence of late effects that adversely affect the quality of life of survivors. Previously, a large scale microarray gene expression analysis was undertaken in order to identify genes predictive of outcome that could enhance risk classification, thereby identifying children who might be cured with less intensive therapy or those who fail current regimens and require novel therapies for cure. From analysis of 254 pediatric ALL samples registered to various COG clinical trials, gene expression classifiers were identified that are highly predictive of poor and favorable outcome in precursor B-cell ALL. The goal of this project is to study the biologic function and role in hematopoiesis and leukemogenesis of the genes predictive of outcome and to determine whether any of these genes may serve as novel drug targets. To this end, we have developed a system to examine the effect of these genes on the cancer-promoting activity of the v-Abl oncogene. We have established pre-B cell lines by infecting primary mouse bone marrow cells with a virus expressing v-Abl. These lines were then engineered to express two of the genes we identified that were associated with poor or good treatment outcomes, RANTES (CCL5) and OPAL1 respectively. Consistent with the association of RANTES expression with poor outcome, v-Abl/RANTES pre-B cells are more proliferative than v-Abl cells, and form larger colonies in methylcellulose cultures without added cytokines. OPAL1 had the opposite effect on pre-B cell growth. V-Abl pre-B cells expressing OPAL1 were less proliferative and generated fewer colonies in methylcellulose cultures. To determine whether RANTES made the v-Abl pre-B cells more leukemic, we transplanted v-Abl or v-Abl/RANTES pre-B cells into syngeneic mice. Mice were noticeably ill 30 days post-transplant. Mice injected with v-Abl/RANTES cells had enlarged lymph nodes and increased numbers of white cells in their peripheral blood. The percentage of pre-B cells in the bone marrow, lymph nodes and spleen was higher in v-Abl/RANTES transplanted mice compared to v-Abl transplanted mice. Currently our data demonstrates that the outcome genes are playing a mechanistic role in the susceptibility of leukemic cells to therapy, and are not merely epiphenomenon. This suggests that the products of these genes and their associated pathways may be novel drug targets. Such targeted therapy has the potential of being less toxic than current nonspecific treatment regimens.
Risk Determinants of Nonarteritic Ischemic Optic Neuropathy (NAION)
Authors: Zotz Rainer B. , Finger Clara , Gerhardt Andrea , Scharf Rudiger E. 
Published: April 2020

Abstract
Background: The aim of our present study was to examine the risk factors for atherosclerosis as well as thrombophilic risk factors for their role in patients with NAION in comparison to healthy controls.
Methods: Prospective case-control-design with 109 Patients and 109 age-and sex-matched healthy controls.
Results: Elevated levels of fibrinogen, FVIII:C, FIX:C, FXI:C, plasminogen activity, von Willebrand antigen (vWF:Ag) and activity, triglycerides, elevated erythrocyte sedimentation rate and decreased levels of high density lipoprotein (HDL) proved to be significant risk factors associated with NAION (OR 1.9 to 5.4; p&lt;0.05). The combination of these risk determinants further increased the risk in a multiplicative or supra-multiplicative way (up to OR 16.5; p&lt;0.0001). None of the examined genetic risk factors (factor V Leiden mutation, Prothrombin mutation, platelet polymorphisms KOZAK and VNTR of glycoprotein 1bα, Hpa-1 polymorphism of GPIIb-IIIa, C807T polymorphism of GPIa/IIa, 4G/5G polymorphism of PAI-1 and C667T mutation of MTHFR gene) was significantly associated with the disease. However, when the HPA-1b allele, GPIa807T allele or the PAI-1 polymorphism were combined with increased levels of fibrinogen or vWF:Ag, a significant interaction with a supra-multiplicative increase in risk could be demonstrated.
Conclusions: In this first comprehensive analysis of a wide range of risk determinants of atherosclerosis and thrombophilia in NAION patients, several risk factors could be identified and quantified. Risk factors of arterial thrombosis appear to interact with risk factors of inflammatory atherosclerosis triggering NAION.
Combined Jugular and Subclavian Vein Thrombosis Following Assisted Reproductive Technology: The Mystery Is out
Authors: Salomon Ophira , Schiby Gina , Heiman Zehava , Avivi Kamila , Dor Joshua , Itzchak Yacov , Levran David , Sigal Carol 
Published: April 2020

Abstract
In assisted reproductive technology (ART) high doses of human menopausal gonadotropins are used to induce controlled ovulation. This technology puts women at high risk of developing the ovarian hyperstimulation syndrome and thombotic events.
Objective: To discern the reason for predilection of combined jugular and subclavian following ART.
Methods: Women who developed combined jugular and subclavian vein thrombosis following assisted reproductive technology were included in the study. The thrombotic events were demonstrated by ultrasound Doppler or computerized tomography angiography. All women were interviewed and data obtained from outpatient clinic and hospital medical charts. Magnetic resonance imaging and complete thrombophilic profile work-up was performed in each woman. Open biopsy from the lesions was taken from one of the women for histological sections and immunohistochemical stains.
Results: Five women developed combined jugular and subclavian vein thrombosis following ART. They were found to harbor clusters of rudimentary branchial cysts filled with fluid at the time of ovarian hyperstimulation syndrome, which compressed the jugular and subclavian veins at their junction at the base of the neck. Four patients (80%) were found to be carriers of factor V Leiden.
Conclusion: The predilection of combined jugular and subclavian vein thrombosis early in pregnancy is the result of mechanical compression mediated by rudimentary branchial cysts filled with fluid during ovarian hyperstimulation syndrome, particularly in subjects who are carriers of factor V Leiden.
Increased Expressions of Toll-Like Receptor 4 on Platelet Are Related to Type of Bacteria and Disease Severity in Patients with Sepsis
Authors: Ma Liping , Wang Xiu-Ju , Nie Da-Nian , Li Yi-Qing , Xie Shuang-Fen , Wu Yu-Dan , Zhang Cheng , Song-Mei Yin 
Published: April 2020

Abstract
Early diagnosis and treatment of patients with sepsis remain a common and severe problem, especially in leukopenic patients.. Toll-like receptor-4 (TLR4) plays a crucial role in immunity as the first defenses system against microbial infection through binding gram-negative bacterial LPS. Blood platelets are not only involved in hemostasis, they also have many features of classic inflammatory cells. The expression of TLR4 on platelet in patients with sepsis, including gram-positive bacteria and gram-negative bacteria, is not known. Studying the differences between them, we investigated whether the expressions of TLR4 on platelet were associated with platelet activation, serum TNF-a and endotoxin levels in patients with sepsis, 8 patients of them with gram-positive bacteria and 15 patients of them with gram-negative bacteria. The number of platelet and function of coagulation were normal before infecting. Comparing with the heath subjects, the expressions of TLR4 and P-selectin on platelets, the levels of serum TNF-a and endotoxin were higher (P&lt;0.05),and there was a positive correlation was observed between TLR4 and P-selectin, TNF-a, endotoxin respectively, among the gram-negative bacterial subjects. The phenomena were not found among the gram-positive bacterial subjects. In addition, among the gram-negative bacterial subjects, the expression of TLR4 was higher in patients with decreased number of platelets than with normal number of platelets. These results suggest that increased TLR4 on platelet might be an important early sign of gram-negative bacteria in patient with sepsis, it contributes to platelet activating, the inflammatory process and disease activity in infecting host. Above has be doing in more patients with positive blood bacteria culture in our Lab.
IL-34, in Synergy with RANK Ligand, Promotes Osteoclast Development through the CSF-1 Receptor
Authors: Huang Min Mei , Leo Cindy , Wei Suwen , Stanley E. Richard , Doberstein Stephen , Lin Haishan 
Published: April 2020

Abstract
IL-34 is a newly identified cytokine that binds to the CSF-1 receptor (CSF-1R), promotes monocyte viability, and stimulates macrophage colony formation (Lin et al., 2008). Here we demonstrate that human IL-34 induced tyrosine phosphorylation of the CSF-1R in cells of a mouse MacCsf1r−/−.huCSF-1R macrophage line. MacCsf1r−/−.huCSF-1R cells were obtained by retroviral transduction of the human CSF-1R into cells of the MacCsf1r−/− macrophage line (Yu et al., 2008) derived from bone marrow macrophages isolated from a CSF-1R-deficient mouse. In addition, IL-34 stimulated the downstream signaling of ERK1/2 and the IL-34-induced phosphorylation of ERK1/2 was blocked by a CSF-1R-specific inhibitor. IL-34, in synergy with RANK ligand, promoted formation of tartrate resistant acid phosphatase (TRAP)-positive and multinucleated osteoclasts from monocytes in dose-dependent manner. The activity of IL-34 on osteoclast differentiation was inhibited by the soluble CSF-1R extracellular domain. Therefore, IL-34 functions as a new ligand of CSF-1R and participates in the regulation of osteoclast development.
Leukemia-Associated Primary Granule Proteins (PGPs) Elastase-2 and Proteinase-3 Are Aberrantly Expressed in Solid Tumors: A Potential Therapeutic Target for PR1-Directed Immunotherapy
Authors: Alatrash Gheath , Vence Luis M , Woodward Wendy , Ueno Naoto T , Molldrem Jeffrey J 
Published: April 2020

Abstract
Neutrophil elastase (ELA2) and proteinase-3 (PRTN3) are the source proteins for the nonomeric HLA-A2-restricted peptide PR1 (VLQELNVTV), a recognized leukemia-associated antigen (LAA). In myeloid leukemia, high expression of ELA2 and PRTN3 has been correlated with improved clinical outcomes following hematopoietic stem cell transplant (HSCT). Vaccination with PR-1 peptide showed efficacy in myeloid leukemia and myelodysplastic syndrome, and was associated with immunologic response (≥ 2 fold increase in PR1-specific cytotoxic T lymphocytes (PR1-CTL)) and long-lasting clinical remissions. PR1-CTLwere shown to mediate immunity elicited by PR-1 vaccine, as they preferentially recognize and kill myeloid leukemia cells. Since ELA2 and PRTN3 have been reported in breast cancer biopsies, we hypothesized that ELA2 and PRTN3 may be mislocalized in solid tumors, leading to MHC-I presentation, therefore providing a therapeutic target for PR1 vaccine. To study the subcellular localization of ELA2 and PRTN3, the cytoplasmic, nuclear, membrane, and golgi/ER fractions were obtained from inflammatory breast cancer (IBC) (MDA-IBC1 and SUM149) and melanoma (526, 624, 888 and 926) cell lines. ELA2 was preferentially expressed in the cytoplasmic fraction in the IBC cell line SUM149, while PRTN3 was expressed in the membrane and cytoskeletal fractions of the IBC cell line MDA-IBC1. In the melanoma cell lines, ELA2 was expressed in the cytoplasmic fractions, while PRTN3 was noted in the nuclear, cytoplasmic and cytoskeletal fractions. Furthermore, the HLA-A2+ melanoma cell line 888 was susceptible to lysis by PR1-CTL (approximately 30% lysis; Effector:Target ratio=1:2). Together, these results demonstrate that ELA2 and PRTN3 are aberrantly localized in non-hematopoietic cell lines, and that this can be associated with susceptibility to PR1- CTL lysis. In particular, PR1 is a potential immunotherapeutic target for patients with melanoma and breast cancer.
VG5Q Inhibition Suppresses Proliferation of Endothelial and Cancer Cell Lines
Authors: Bodempudi Vi dya , Dudek Olivia Anna , Terai Kaoru , Dudek Arkadiusz Zbigniew 
Published: April 2020

Abstract
Background: Angiogenesis is a process involved in the formation of new vessels, and is essential for tumor growth and metastases. Angiogenic factors are critical for the initiation of angiogenesis and maintenance of the vascular network. VG5Q is a newly discovered protein that acts as a potent angiogenic factor in promoting angiogenesis and has also been implicated in the vascular pathophysiology of Klippel-Trenaunay syndrome. However, little is known about its role in cancer progression. Method: In this study, VG5Q expression was screened using RT-PCR and Western blotting in the following cancer cell lines: breast (MCF-7), renal (Caki, ACHN), mesothelioma (H2373, H2596), ovarian (OVCAR5), lung (H226, A549) and pancreatic (Panc-1, MiaPaCa). Human umbilical vein endothelial cells (HUVEC) and blood outgrowth endothelial cells (BOEC) were also screened. Results: All cancer cell lines expressed high levels of VG5Q that were comparable to the levels expressed in endothelial cells. The only exception was MiaPaCa cells. In order to understand the biology of VG5Q in cancer cells, we used siRNA knockdown of VG5Q expression in the mesothelioma cell lines H2373 and H2596. Gene-specific silencing of VG5Q resulted in markedly decreased proliferation, invasion, and soft-agar colony formation in these cells. Furthermore, VG5Q silencing increased apoptosis as seen by an increase in annexin levels. Conclusion: VG5Q silencing has profound effects on cancer cell biology, suggesting the hypothesis that the role of VG5Q may not be limited to angiogenic signaling in endothelial cells.