bluuebunny/crossref_metadata_2025_split huggingface dataset:
Method for Measuring Macrophage Iron Efflux in Vitro and in Vivo Using Magnetic Resonance Imaging
Authors: Andriopoulos Bill , Guimaraes Alexander R , Wojtkiewicz Gregory R , Chen Sandra , Xia Yin , Babitt Jodie L , Corradini Elena , Weissleder Ralph , Lin Herbert Y 
Published: April 2020

Abstract
Anemia of inflammation (AI) is the disturbance of iron homeostasis manifest by a decrease in absorption of dietary iron from the gastrointestinal tract and by iron sequestration by reticuloendothelial macrophages. It is widely recognized that elevated levels of proinflammatory cytokines and other mediators from activated immune cells are the primary causes of AI. More specifically, it is the abnormally decreased rate of iron efflux from macrophages and enterocytes that appear to be the crucial pathophysiology. Increasingly, the central role of the liver-derived factor hepcidin is recognized in mediating the disturbances of iron absorption, sequestration and utilization that characterize AI. Hepcidin decreases iron absorption from the duodenal enterocytes and promotes the sequestration of iron in the reticuloendothelial macrophages by down regulating the transmembrane iron export protein, ferroportin. Thus the regulation of hepatic hepcidin expression becomes of paramount interest in the study of AI. We have shown that bone morphogenetic protein is critical for the regulation of hepcidin expression. The aim of our study is to develop a model to study iron efflux both in vitro and in vivo using magnetic resonance imaging (MRI). This was done by experimentally measuring spin-spin relaxation times (T2 measured in sec-1) through multi-echo, spin-echo technique (16 echoes) on a 4.7 T Bruker pharmacan experimental MRI imager. Iron loaded cells exhibit lower T2 values than normal control cells. In vitro, hepatomas Hep3B and macrophages J774 and Raw 264.7 were loaded with magnetic iron oxide nanoparticles (MION) overnight. The next morning (baseline), the intracellular and extracellular iron content was serially measured for up to 24 hours using MRI. As expected, both J774 and Raw 264.7 cells lines displayed lower intracellular T2 values in comparison to baselines. In addition, both ferroportin and the iron storage protein ferritin were modulated following overnight MION treatment and 24 hours post baseline. In contrast, Hep3B cells did not take up any significant MION following overnight treatment. In vivo, normal mice on a normal diet were given an intravenous MION injection dosed at 10mg/kg iron. MRI was performed at baseline, 24, 48, 72 and 96 hrs post injection. 24 hours post injection, T2 increased in both liver and spleen (liver &gt; spleen). Following the 24 hour spike, the T2 values in the mice decreased for up to 72 hours after injection with a rate in the liver mildly increased relative to the rate of decrease in the spleen.
Analysis of Mouse LMIR5/CLM-7 as An Activating Receptor: Differential Regulation of LMIR5/CLM-7 in Mouse Versus Human Cells
Authors: Yamanishi Yoshinori , Kitaura Jiro , Izawa Kumi , Oki Toshihiko , Takai Toshiyuki , Kitamura Toshio 
Published: April 2020

Abstract
We have analyzed leukocyte mono-Ig–like receptor 5 (LMIR5) as an activating receptor among paired LMIRs. Mouse LMIR5 (mLMIR5) is expressed in myeloid cells such as mast cells, granulocytes, macrophages, and dendritic cells. Cross-linking of transduced mLMIR5 in bone marrow–derived mast cells (BMMCs) caused activation events, including cytokine production, cell survival, degranulation, and adhesion to the extracellular matrix. mLMIR5 associated with DAP12 and to a lesser extent with DAP10, and mLMIR5-mediated functions of BMMCs were strongly inhibited by DAP12 deficiency. Importantly, cross-linking of endogenous mLMIR5 induced Syk-dependent activation of fetal liver–derived mast cells. Unlike mLMIR5, cross-linking of human LMIR5 (hLMIR5) induced cytokine production of BMMCs even in the absence of both DAP12 and DAP10, suggesting the existence of unidentified adaptors. Interestingly, hLMIR5 possessed a tyrosine residue (Y188) in the cytoplasmic region. Signaling via Y188 phosphorylation played a predominant role in hLMIR5-mediated cytokine production in DAP12-deficient, but not wild-type BMMCs. In addition, experiments using DAP10/DAP12 double-deficient BMMCs suggested the existence of Y188 phoshorylation-dependent and -independent signals from unidentified adaptors. Collectively, although both mouse and human LMIR5 play activatory roles in innate immunity cells, the functions of LMIR5 were differentially regulated in mouse versus human cells.
Diagnostic and Disease Management Algorithms for Gaucher Disease: A Guide for Haematologists
Authors: Mistry Pramod K , Cappellini Maria Domenica , Lukina Elena , Özsan Hayri , Pascual Sara Mach , Rosenbaum Hanna , Solano Maria Helena , Spigelman Zachary Simon , Villarrubia Jesús , Watman Nora Patricia , Massenkeil Gero 
Published: April 2020

Abstract
In Gaucher disease (GD), inherited deficiency in lysosomal acid beta-glucocerebrosidase leads to the widespread accumulation of glycolipid-laden macrophages in tissues and consequent multisystemic disease. The presenting symptoms of type 1 (non neuronopathic) Gaucher disease commonly reflect the haematologic components of the disease, i.e., splenomegaly, thrombocytopenia, anaemia, and bleeding tendency. Consequently the majority of patients are referred to haematologists for diagnosis and management. However, the remarkable heterogeneity of the disease compounded by its rarity presents a diagnostic challenge. Only around 20% of haematologists consider GD in differential diagnosis even though all classic manifestations of the disease may be present. Haematologic malignancy is the most often considered diagnosis in such patients. Lack of awareness of GD and its protean manifestations renders individuals with Gaucher disease vulnerable to misdiagnosis, diagnostic delays and risk of irreversible complications that are otherwise preventable by timely therapy. Missed diagnosis may place individuals at risk of bleeding even in the presence of mild thrombocytopenia, irreversible skeletal complications leading to disability and impaired growth, and an increased risk of malignancy, especially multiple myeloma. Imiglucerase (Cerezyme) enzyme replacement therapy is effective in reversing haematological, visceral and some skeletal manifestations of the disease. In a minority of patients in whom imiglucerase is not suitable, Miglustat substrate reduction therapy (Zavesca) is an alternative. An international group of physicians met to harness their respective experience of managing the diverse phenotypes of Gaucher disease in order to raise awareness of GD and to determine under which circumstances GD should be given greater priority in differential diagnosis. As a result of their discussions, simple diagnostic algorithms have been devised, which focus on splenomegaly as the most prevalent presenting manifestation of GD in individuals of both Ashkenazi Jewish and non Ashkenazi Jewish background. Given the prevalence of GD in Ashkenazim, a possible diagnosis of GD is prioritised in the presence of splenomegaly in this population. When challenged by differential diagnosis of splenomegaly, GD can be confirmed or eliminated by a straightforward assay for beta glucocerebrosidase activity. Diagnostic algorithms are accompanied by disease management algorithms, which reflect published therapeutic goals and monitoring guidelines, to simplify decision making in the evaluation, treatment and ongoing monitoring of GD in response to therapy.
CEACAM-1, -3, -6, and -8 Signaling in Human Neutrophils
Authors: Skubitz Keith M. , Skubitz Amy P.N. 
Published: April 2020

Abstract
Members of the carcinoembryonic antigen family (CEACAMs) are widely expressed, and, depending on the tissue, capable of regulating diverse functions including tumor promotion, tumor suppression, angiogenesis, and neutrophil activation. Four members of this family, CEACAM1, CEACAM8, CEACAM6, and CEACAM3 (recognized by CD66a, CD66b, CD66c, and CD66d monoclonal antibodies (mAbs), respectively), are expressed on human neutrophils. CD66a, CD66b, CD66c, and CD66d antibodies each increase neutrophil adhesion to human umbilical vein endothelial cell monolayers. This increase in neutrophil adhesion caused by CD66 antibodies is blocked by CD18 mAbs and is associated with upregulation of CD11/CD18 on the neutrophil surface. To examine potential interactions of CEACAMs in neutrophil signaling, the effects of a set of CD66 mAbs on neutrophil adhesion to human umbilical vein endothelial cells was tested following desensitization to stimulation by various combinations of these mAbs. The current data show that desensitization of neutrophils to any two CEACAMs results in selective desensitization to those two CEACAMs, while the cells remain responsive to the other two neutrophil CEACAMs. In addition, cells desensitized to CEACAM-3, -6, and -8 were still responsive to stimulation of CEACAM1 by CD66a mAbs. In contrast, desensitization of cells to CEACAM1 and any two of the other CEACAMs left the cells unresponsive to all CD66 mAbs. Cells desensitized to any combination of CEACAMs remained responsive to the unrelated control protein CD63. Thus, while there is significant independence of the four neutrophil CEACAMs in signaling, CEACAM1 appears to play a unique role among the neutrophil CEACAMs. A model in which CEACAMs dimerize to form signaling complexes could accommodate the observations. Similar interactions may occur in other cells expressing CEACAMs.
Impact of Risk Organ Involvement on Outcome in Langerhans Cell Histiocytosis (LCH)
Authors: Katewa Satyendra , Sachdeva Anupam , Dinand Veronique , Yadav Satya Prakash 
Published: April 2020

Abstract
Objectives: To compare the outcome in children with low risk vs. risk LCH and to evaluate the impact of individual risk organ on outcome.
Material and Methods: Medical records of 52 patients were reviewed retrospectively (1992 to 2007). Patients were classified into 2 groups: A-low risk (bone, skin and lymph node involvement), B-risk patients (lungs, liver, spleen and bone marrow involvement). Group B further subdivided in B1-isolated lung involvement, B2-liver, bone marrow or both without lung, B3-lung involvement with liver and/or bone marrow. Patients were treated as per histiocytosis society protocols.
Results: There were 31 Males and 21 Females. Mean age at presentation was 4.8 yrs (range 1 month to 15.5 yrs). There were 21 patients in Group A and 31 in Group B with 0 (0%) and 6 (19%) deaths respectively. Overall mortality was 6/52 (11.5%). In group A, 6 patients had skin and lymph node involvement, 6 had unifocal bony involvement and 9 multifocal. Out of these 15 (bony involvement) patients 4 had otitis media and 5 diabetes insipidus. There were 9 patients in Group B1, 18 in Group B2 and 4 in Group B3 with mortality of 0 (0%), 4 (22.2%) and 2 (50%) respectively. Comparison of mortality in risk patients vs. low risk patients approached statistical significance (19.4% vs. 0%, p=0.069). Mortality difference within the 3-subgroups of risk patients was not statistically significant (p=0.097).
Conclusion: Outcome is worse if risk organs are involved. However, isolated lung involvement had trend towards better outcome.
The Value of Neutrophil CD64 in Early Diagnosis of Adult Sepsis
Authors: Xu Jingyan , Ouyang Jian 
Published: April 2020

Abstract
Purpose To observe the level of leukocyte surface antigen CD64 during adult sepsis, and to assess the value of the CD64 in early diagnosis of adult sepsis.
Methods We measured peripheral blood samples of neutrophil CD64 expression in 58 patients with suspected sepsis and 10 healthy controls.
Results The expression level of CD64 in sepsis group was significantly higher than healthy control group ( P &lt; 0. 001). According to the ROC curve, when the best threshold in diagnosis of adult sepsis was 1.075%,the sensitivity for indentifing adult sepsis was 98. 3 % and the specificity was 90.0%.
Conclusions The expression level of CD64 will rise during adult sepsis. CD64 can be an early effective diagnosis marker in adult sepsis.
Virtual Microscopy System for Blood Morphology Evaluation and Their Applications in Hematology
Authors: Merino Anna , Gutierrez Gabriela , Garcia Jaime 
Published: April 2020

Abstract
We have explored the possibilities of a new technology for scanning peripheral blood slides converting the images to a digital slide that can be observed in a manner similar to a microscope.
Objectives: To evaluate the quality of peripheral blood (PB), bone marrow (BM) and body fluids (BF) images obtained in a Digital Slide Scanner in different hematological or non hematological diseases and to analyse the useful of this System in Hematology.
Material and Methods: We obtained PB samples from 13 patients with the following diagnoses: 3 acute myeloid leukemia (AML), 1 acute lymphoid leukemia (ALL), 2 B-cell neoplasm, 2 myeloproliferative disease (MPD): 1 chronic myeloid leukemia (CML) and 1 myelofibrosis, 3 Plasmodium infections (2 falciparum and 1 vivax), 1 sickle cell anemia and 1 congenital sideroblastic anemia (CSA). We also analysed 2 BM (leishmania and parvovirus infections) and 1 BF (melanoma) samples. We used a NanoZoomer Digital Pathology or NDP (Hamamatsu System, Japan) for scanning the different glass slides using 40X objective lens. A small fragment of the most appropriate area was selected and the focus was set up at different levels. Each one of the digital slides was saved in digital data and the images were analysed using the NDP software.
Results: Most values of the file sizes were approximately 300 MB for PB and BM and 50 MB for body fluid. All digital slides showed a very high image quality. It was possible to evaluate the blood cell morphology using 20X, 40X, 63X and 100X magnifications. We selected 63X as the best one for the combination size of the cells and precision in the focus. Similar to microscopic observation, myeloid and lymphoid blast cells in digital slides showed different morphologic features (cytoplasmic inclusions, primary granules, prominent vacuolation…) allowing hematological diagnosis. Myeloproliferative disorders showed a high degree of morphological abnormalities in the erythroid, granulocytic and megakaryocytic lineages. B chronic haematological neoplasms were identified in the virtual slides by morphological criteria. With respect to Plasmodium infections, the virtual images allowed examination of morphological features of both the parasites and the host red cells, facilitating the species diagnosis. Sickle cells were easily identified. Pappenheimer bodies were visible in the erythrocytes of the CSA. With respect to BM and BF, digital slides showed the morphological abnormalities for the diagnosis. The software let to calculate the diameter and the area of the blood cells.
Conclusions: Our results showed that the virtual microscopy for blood morphology evaluation can be used to substitute the glass smear samples in Hematology External Quality Assessment. In addition, the application of the NDP software may be useful in morphometric analysis of pathological cells in different hematological diseases.
Risk Factors for Febrile Neutropenia among Breast, Lung, and Colorectal Cancer Patients: A Retrospective Analysis of Health Plan Databases
Authors: Ramsey Scott Davi d , McCune Jeannine S , Blough David K , Clarke Lauren C , McDermott Cara L , Sullivan Sean D 
Published: April 2020

Abstract
Chemotherapy regimens, patient factors, and the use of colony stimulating factor (CSF) influence cancer patients’ risk for febrile neutropenia (FN) when they receive myelosuppressive chemotherapy. The incidence of FN and patient factors influencing that risk are relatively unknown in community settings. Using claims from Medicare, Medicaid and two private health insurance plan enrollees linked to the Puget Sound SEER registry, we examined the incidence of FN among breast, lung and colorectal cancer patients diagnosed 2002–05 who received adjuvant chemotherapy. We used logistic regression models to determine factors influencing the risk for FN within the first chemotherapy cycle, controlling for cancer stage, age, sex, race, comorbidities, chemotherapy-regimen related FN risk (as designated by the National Comprehensive Cancer Network), CSF use, health insurance type, and surgery or radiation ≤30 days from administration of first chemotherapy. Over the time horizon, 1096 breast, 1142 lung, and 755 colorectal cancer patients received chemotherapy. The incidence of any FN in the first chemotherapy cycle was (counts per 100 recipients by high, intermediate, and low-risk myelosuppressive chemotherapy according to NCCN categories respectively) 7.36, 10.0, 4.70 for breast cancer, 17.12, 14.15, 12.22 for lung cancer, and 25.0, 8.96, 6.37 for colorectal cancer. Significant predictors (p&lt;0.05) of any FN were: breast cancer—radiation ≤ 30 days from first chemotherapy administration (OR 2.90, 95% CI 1.21–6.94), other non-black race vs. white race (OR 2.82, 95% CI 1.29–6.17), or Medicaid insurance (OR 2.31, 95% CI 1.10–4.89); lung cancer—radiation ≤ 30 days from first chemotherapy administration (OR 1.63, 95% CI 1.01–2.61), surgery ≤ 30 days from first chemotherapy administration (OR 2.08, 95% CI 1.02–4.25), Medicaid insurance (OR 2.29, 95% CI 1.08–4.84), or a Charlson comorbidity score ≥ 2 (OR 2.56, 95% CI 1.11–5.91); colorectal cancer—female gender (OR 1.86, 95% CI 1.02–3.41) or high myelosuppressive risk chemotherapy regimen (OR 7.66, 95% CI 2.95–19.89). In this analysis, predictors of FN varied between cancers. Limitations of this analysis include lack of information about chemotherapy and CSF doses, as this is not captured in the SEER registry or claims data. These results indicate that several factors may interact to influence a patient’s likelihood of developing FN in the first cycle of adjuvant chemotherapy.
The Economic Burden of Chemotherapy-Induced Toxicity in Lymphoma and NSCLC Routine Hospital Care
Authors: Ihbe-Heffinger Angela , Paessens Bernadette JL , Berger Karin , Ehlken Birgit , Shlaen Margarita , Bernard Rudolf , Peschel Christian , von Schilling Christoph 
Published: April 2020

Abstract
The majority of chemotherapy (CT) patients (pts) receive care outside of clinical trial settings. In contrast little is known about the economic consequences of CT-induced toxicity in routine care. This was a prospective, multi-centre, observational, longitudinal cost-of-illness study. Lymphoma and non small cell lung cancer (NSCLC) pts were enrolled consecutively from 1/2005–12/2006 at the start of first or second line (immuno) CT treatment in 4 German hospitals. Patients receiving myeloablative CT with peripheral blood stem cells were excluded. Clinical data and resource use were collected from pre-planned chart reviews. German tariffs & prices in €2007 and hospital databases were used to allocate costs to health care resources. Toxicity related costs are presented from the hospital provider perspective. 273 pts undergoing 286 treatment courses with a total of 1004 CT-cycles were evaluable. 153 pts had lymphoma (47% of courses were CHOP-like) and 120 NSCLC (78% of courses were platinum-based). Mean age was 60.1 years (SD 13.0); age≥65 years 40%; female 36%; ECOG≥2 11%; tumour stage≥3 56%; history of co-morbidity 80%. The table shows a comparison of lymphoma and NSCLC patient characteristics. 208 of treatment courses (73%) were associated with at least one hospital stay (lymphoma 69%, NSCLC 78%). Mean±SD number of inpatient days was 13.1±17.7 (lymphoma 13.5±20.7, NSCLC 12.8±14.0). Mean (median) toxicity related costs amounted to€3,624 (€1,035) per treatment course with€3,366 (€1,406) for NSCLC and€3,838 (€684) for lymphoma. 8% of CT-courses (lymphoma n=12, NSCLC n= 11) were associated with costs ≥€10,000 and accounted for 50% of total expenses. In this high cost group mean toxicity associated costs nearly doubled for lymphoma pts (lymphoma€28,607, NSCLC€15,533). Hospital basic services and personnel represented 74% of total costs (lymphoma 70%, NSCLC 80%), followed by expenses for drugs (lymphoma 15%, NSCLC 9%). Our findings highlight that toxicity management in NSCLC and lymphoma pts induces significant resource use and associated costs. Cost drivers are hospitalization and drugs. Frequency distribution of costs is asymmetric with less than 10% of CT-courses contributing to half of total economic burden. Treatment courses with mean toxicity related costs of €10,000 or more are twice as expensive for lymphoma patients as for NSCLC.
Lymphoma (n=153) NSCLC (n=120) Age: mean (SD) 58.2 (15.4) 63.0 (8.4) Age ≥ 65 58 (38%) 52 (43%) Male 99 (65%) 77 (64%) ECOG≥2 10 (7%) 20 (17%) Tumour stage ≥3 72 (47%) 102 (85%) History of co-morbidity 107 (70%) 112 (93%)
Repression of Mir-106b Family Members Does Not Alter Cell Cycle Progression in Hodgkin Lymphoma
Authors: Gibcus Johan H , Tan Lu Ping , Schakel Rikst Nynke , Harms Geert , Moeller Peter , Poppema Sibrand , Kroesen Bart-Jan , Van Den Berg Anke 
Published: April 2020

Abstract
MicroRNAs (miRNAs) are 19–25 nucleotide long RNA molecules derived from precursor genes that inhibit the expression of target genes by binding to their 3′ UTR region. Expression of miRNAs is often tissue specific and miRNA profiling has shown specific miRNA expression patterns in both B-cell development and lymphomagenesis.
Hodgkin lymphoma is derived from pre-apoptotic germinal center B-cells, although a general loss of B cell phenotype is noted. Using quantitative RT-PCR and miRNA microarray, we determined the miRNA profile of HL and compared this with the profile of a panel of B-cell non-Hodgkin lymphomas (NHL). The two methods showed a very good correlation for the expression levels of the individual miRNAs. Using a large panel of cell lines, we confirmed differential expression between HL and other B-cell lymphoma derived cell lines for 27 miRNAs. The HL specific miRNAs included miR-155, miR-21 and miR-106b seed family members miR-17-5p, miR-20a, miR-93, miR-106a and miR- 106b. Next, we performed target gene validation of predicted target genes for miR-17-5p, which is highly expressed in HL. Using luciferase reporter assays with stabilized anti-sense miR17-5p oligonucleotides, we showed that GPR137B, RAB12 and RBJ are likely miR-17-5p target genes in two different HL cell lines.
Previous publications indicated that miR-106b seed family members negatively regulate the cyclin-dependent kinase inhibitor 1A (p21/CIP1) resulting in cell cycle arrest at G1. Consistent with these findings, we show that the miR-106b family members are highly expressed in L428, whereas p21 is not. However, inhibition of the miR-106b seed family members in L428 does not result in elevated p21 protein expression. Furthermore, there is no cell cycle arrest, growth reduction or increase in cell death and apoptosis after inhibition of the miR-106b seed family members. Thus, we conclude that blocking of the miR-106b seed family members does not necessarily lead to indiction of p21 protein. This suggests an additional regulatory layer of p21 expression in L428 cells.