bluuebunny/crossref_metadata_2025_split huggingface dataset:
Economic Evaluation of Thalidomide Combined with Melphalan and Prednisone in Previously Untreated Multiple Myeloma in Scotland
Authors: Deniz Baris , Facon Thierry , Singer Ian , Micallef-Eynaud Paul , Joseph Ian , Shearer Arran , Caro J. Jaime 
Published: April 2020

Abstract
INTRODUCTION: Thalidomide (Thalomid®/Thalidomide Pharmion®) combined with melphalan and prednisone (MPT) yields improved progression-free and overall survival compared to MP alone (Facon et. al., Lancet2007; 370:1191). This study was designed to estimate the life-time health and cost consequences of MPT versus MP in Scottish patients with previously untreated multiple myeloma.
METHODS: A Markov model was developed to determine cost and health outcomes for a cohort of patients receiving a course of MPT or MP. The disease course was conceptualized by 4 mutually exclusive health states: pre-progression without adverse events, pre-progression with adverse event, progressive disease, and death. Probabilities of moving between these states (i.e. natural progression plus efficacy and safety of the treatments) were derived from a long-term randomized clinical trial, IFM 99-06 (Facon et. al., Lancet2007; 370:1191). Both patient cohorts remained on the assigned treatment for a maximum of twelve 6-week cycles, until progression or treatment-limiting toxicity. Treatment duration and the average daily dose were modelled to match IFM 99-06. During treatment, each cohort was exposed to adverse event risks associated with therapy estimated from IFM 99-06. Health state utilities associated with adverse events and disease states were obtained from the literature. Thalidomide cost was set at UK list price; routine disease-management costs by disease-state (progressive disease and remission state) reflect clinical practice in Scotland. As recommended by the UK treasury, costs and health outcomes were discounted at 3.5% per annum to adjust to present values. Univariate and multivariate sensitivity analyses were performed around key model parameters.
RESULTS: The model estimated improvements in health outcomes with MPT with a median time to progression of 25 months vs. 12 months with MP. Estimated median overall survivals were 4.03 years vs. 2.88 years with MP. These results translate to a gain of 0.91 (3.24 vs. 2.32) quality-adjusted life-years (QALYs). MPT is associated with higher overall costs (£25,199 per patient) compared with MP (£8,935), over the modeled life-time, leading to an incremental cost-effectiveness ratio of £17,847 per QALY and £14,803 per life-year gained. Sensitivity analyses showed that results remained consistent through broad changes in model parameters including the addition of thromboembolic prophylaxis.
CONCLUSIONS: MPT delivers improvements in progression-free and overall survival in a life-limiting orphan disease compared to MP and economic results fall within a range considered cost-effective in Scotland.
Cost-Effectiveness of Adding Imatinib to Chemotherapy in Adult Patients with Chromosom-Positive Acute Lymphoblastic Leukemia (Ph+ALL): A Canadian Perspective
Authors: Ouagari Khalid El , Tran Kimbach , Stephens Jennifer , Botteman Marc 
Published: April 2020

Abstract
BACKGROUND: Ph+ALL is a rare, high-risk, aggressive form of acute leukemia, affecting primarily adults and the elderly. Patients with high-risk forms of ALL typically have extremely poor prognosis and incur high disease-related costs. Successful use of imatinib in patients with Ph+CML has led to the administration of imatinib in recent clinical studies for patients with Ph+ALL. Given the changing treatment landscape of Ph+ALL and the recent development of additional targeted treatments for this disease, an appraisal of the economic burden associated with Ph+ALL is warranted for evaluation of appropriate treatment options and the potential value associated with novel therapies. This study explores the cost effectiveness of imatinib plus conventional chemotherapy (CC) regimens versus CC alone in adult Ph+ALL patients.
METHODS: A Markov model simulated a hypothetical cohort of 1000 adult Ph+ALL patients receiving imatinib+CC or CC alone. Patients were distributed over time into three health states: alive without disease progression (DFS), alive with disease progression (DS), or dead. Probabilities of being in the states were derived from the published literature. In the absence of relevant data pertaining to Ph+ALL, assumptions about costs and utilities were derived from a cost analysis of CML. A Canadian health care payer perspective was considered, therefore only direct medical costs were included in the analysis. Patients were followed for a total of ten years in monthly intervals. All outcomes were discounted at a 5% rate per annum.
RESULTS: Based on the model framework and assumptions, the total discounted survival was 1.09 years for CC and 4.13 years for imatinib+CC. Total discounted disease free survival was 0.76 year for CC and 2.69 years for imatinib+CC. Assuming utility weights of 0.854 and 0.596 for DFS and DS, respectively, the total discounted quality adjusted life years (QALY) were estimated to be 0.84 versus 3.16 for CC and imatinib+CC, respectively. Thus, the net incremental gain in discounted quality adjusted survival was 2.32 QALYs. The monthly costs of DFS and DS were estimated at $168 and $848, respectively. The net costs associated with imatinib were $101,929. The incremental cost per QALY of imatinib+CC v. CC alone was approximately $44,048 (i.e., $101,929 divided by 2.32 QALYs).
CONCLUSIONS: Our results suggest that imatinib in the treatment of Ph+ALL is a cost-effective use of health-care resources, and should be considered in patients who are appropriate candidates for such therapy.
MicroRNA Mir-23a Regulates SDF-1alpha Expression in Human Bone Marrow-Derived Mesenchymal Stem Cells
Authors: Fierro Fernando , Poitz David , Nolta Jan A. , Bornhaeuser Martin , Ehninger Gerhard , Illmer Thomas 
Published: April 2020

Abstract
MicroRNAs (miRNAs) can regulate hematopoietic stem/progenitor cells (HSPC) by modulation of intrinsic cell components such as transcription factors and receptors. In addition, miRNAs could play a role in the microenvironment were HSPC host and consequently affect HSPC via extrinsic factors, which to our knowledge is an hypothesis that has not been tested. Since the chemokine stromal derived factor 1alpha (SDF-1alpha) is essential for both homing and retention of HSPC in the bone marrow, we tested if miRNAs expressed by human bone marrow-derived mesenchymal stem cells (MSC; a key source of SDF-1alpha), could potentially inhibit SDF-1alpha expression. In deed, using luciferase reporter-systems we show specific binding of miR-23a to the 3′UTR of SDF-1alpha. Consequently, transfection of MSCs with a precursor miR-23a (pre-miR-23a) leads to a 30% reduction of SDF-1alpha at both mRNA and protein levels. In contrast, inhibition of endogenous miR-23a with anti-sense oligonucleotides (anti-miR-23a), leads to a significant increase of SDF-1alpha also at both mRNA (30%) and protein (10%) levels as compared to controls (scramble pre-/anti-miR). As a result, migration of CD34+ HSPC in transwell assays is strongly affected upon overexpression or inhibition of miR-23a in MSCs (with pre-miR-23a 35% less migration; with anti-miR-23a 20% more migration, as compared to respective controls). Interestingly, transforming growth factor beta 1 (TGF-beta1) inhibits SDF-1alpha expression in MSCs in a concentration dependent manner, while miR-23a is increased under same experimental settings. Even more, silencing endogenous miR-23a significantly reduces the effect of TGF-beta1 on SDF-1alpha mRNA and protein levels, suggesting that at least in part TGF-beta1 inhibits SDF-1alpha expression via increasing miR-23a levels. This is to our knowledge the first established connection between miRNA biology and HSPC-niche related factors.
Hematopoietic Stem Cells in the Mouse Spleen
Authors: Iseki Akiko , Morita Yohei , Nakauchi Hiromitsu , Ema Hideo 
Published: April 2020

Abstract
The spleen is a hematopoietic organ in mice. Hematopoietic stem cells (HSCs) migrate into the spleen around embryonic day 14, and then migrate into the bone marrow (BM) around embryonic day 17. Thereafter, HSCs reside in both BM and spleen throughout the life of a mouse. The spleen is the major site of extramedullary hematopoiesis in pathological conditions. The spleen serves as an active hematopoietic organ in lethally irradiated mice for a while after transplantation with BM cells. Osteoblasts are considered to be one of the stem cell niche components. Because there are no osteoblasts in the spleen, niches in the spleen possibly functions differently from ones in the BM. The regulation of HSCs likely differs between the BM and spleen. In order to understand a role of spleen HSCs in physiological conditions, we have characterized HSCs in the spleen as compared with those in the BM.
BM and spleen cells were obtained from 8–10 week-old C57BL/6 mice. Competitive repopulation showed that the repopulating activity per 106 BM cells was significantly greater than that per 106 spleen cells (about 10-fold). Limiting analysis showed that the frequency of long-term repopulating cells in BM cells was significantly higher than that in spleen cells (about 10-fold). As a result, the mean activity per BM stem cell was similar to that per spleen stem cell. Similarly to BM, CD34-negative, c-Kit-positive, Sca-1-positive, lineage markers-negative (CD34−KSL) cells were highly enriched in HSCs in the spleen. The frequency of CD34−KSL cells in the spleen was significantly lower than that in the BM. These data indicate that functionally equivalent HSCs exist in the spleen but at a low frequency. Data from single cell-transplantation supported this notion. The proportion of pyronin Y-negative G0 cells among BM CD34−KSL cells was greater than that among spleen CD34−KSL cells at any one time. BrdU-uptake analysis showed that spleen CD34− KSL cells were cycling more rapidly than BM CD34−KSL cells. These data suggest that spleen HSCs contribute to hematopoiesis to some extent under physiological conditions. BM and spleen HSCs may be interchangeable via the circulation. When BM HSCs are in the spleen, they are possibly under the control of spleen niches different from BM niches.
Integrated Biochemical and Computational Approach Identifies BCL6 Direct Target Genes Controlling Multiple Pathways in Normal Germinal-Center B Cells
Authors: Saito Masumichi , Basso Katia , Sumazin Pavel , Margolin Adam A , Wang Kai , Lim Wei-Keat , Califano Andrea , Dalla-Favera Riccardo 
Published: April 2020

Abstract
BCL6 is a transcriptional repressor required by mature B cells for germinal center (GC) formation, whose deregulated expression, through mutations and translocations, is implicated in lymphomagenesis. The normal function of BCL6 is only partially known since a limited number of direct target genes have been identified by the analysis of cell lines derived from GC-derived lymphomas. However, the complete set of targets functionally relevant for the role of BCL6 in normal GC B cell physiology has not been completely uncovered and the possibility that BCL6 function may be altered in transformed cells has not been excluded. To address these issues, we used an integrated biochemical/computational/functional approach including:
identification of BCL6-bound promoters by genome-wide chromatin immunoprecipitation (ChIP-chip) in normal human GC B cells; a computational algorythm inferring transcriptional relationships starting from gene expression data (ARACNe, Basso et al. Nature Genetics 2005); validation of physiologic relevance of the candidate target genes by selection of those either not expressed in normal GC B cells or downregulated compared to pre- and post- GC B cells.
This approach identified a set of 1,207 genes which were then subjected to pathway analysis using several databases. The results showed that BCL6 regulates important signaling pathways via direct transcriptional repression of multiple genes acting at different levels from the cell surface (receptors), through signaling molecules to the nucleus. These pathways include:
apoptosis, by impairing the expression of both pro- and anti-apoptotic molecules including several TNF-type receptors, signaling molecules (e.g. TRADD, A20, XIAP, TOSO) and effectors (e.g. CASP8); JAK-STAT signaling, through the repression of multiple interleukin and interferon receptors and the transcription factors STAT1, STAT3 and STAT5A; B cell receptor signaling, via repression of signaling molecules (e.g. lyn, vav), several MAP kinases, and transcription factors (e.g. JUN and NF-kB components); Toll-like receptor signaling, by regulating receptors (e.g. TLR1, 7 and 9); DNA damage sensing and response (e.g. TP53BP1, ATM).
Overall, these results provide a comprehensive picture of BCL6 function suggesting that one role of BCL6 is to prevent GC centroblasts from receiving activation and differentiation signals before completion of the phase of proliferative expansion and somatic hypermutation leading to their selection based on antibody affinity maturation.
The HaemAtlas: Characterising Gene Expression in Differentiated Human Blood Cells
Authors: Watkins Nicholas A. , Tijssen Marloes R. , Gusnanto Arief , de Bono Bernard , De Subhajyoti , Miranda-Saavedra Diego , Angenent Will , Attwood Anthony , Langford Cordelia , Erber Wendy N. , Foad Nicola , Garner Stephen F , Rendon Augusto , Rice Catherine , Thijssen-Timmer Daphne , Van der Schoot C. Ellen , Dudbridge Frank , Teichmann Sarah , Gottgens Bertie , Ouwehand Willem H. 
Published: April 2020

Abstract
Haematopoiesis is a carefully controlled process that is regulated by complex networks of transcription factors that are, in part, controlled by signals resulting from ligand binding to cell surface receptors. In order to further understand haematopoiesis, we have compared gene expression profiles of human erythroblasts, megakaryocytes, B-cells, cytotoxic and helper T-cells, Natural Killer cells, granulocytes and monocytes using whole genome microarrays. A bioinformatics analysis of this data was performed focusing on transcription factors, immunoglobulin superfamily members and lineage specific transcripts. We observed that the numbers of lineage specific genes varies by two orders of magnitude, ranging from five for cytotoxic T cells to 878 for granulocytes. In addition, we have identified novel co-expression patterns for key transcription factors involved in haematopoiesis (eg. GATA3–GFI1 and GATA2–KLF1). This study represents the most comprehensive analysis of gene expression in haematopoietic cells to date and has identified genes that play key roles in lineage commitment and cell function. The data, which is freely accessible, will be invaluable for future studies on haematopoiesis and the role of specific genes and will also aid the understanding of the recent genome-wide association studies.
Myeloid Translocation Gene 16 (MTG16) Regulates Lymphopoiesis
Authors: Hunt Aubrey A , Steapleton Melissa Ann , Moreno Isabel , Hiebert Scott 
Published: April 2020

Abstract
The Myeloid Translocation Gene (MTG) family was first discovered through the (8;21) translocation that leads to acute myeloid leukemia. This translocation fuses nearly all of Myeloid Translocation Gene 8 (MTG8) to an N-terminal portion of Acute Myeloid Leukemia 1 (AML1), thus disrupting the normal function of MTG8 as a transcriptional co-repressor. Two other family members have since been identified: Myeloid Translocation Gene 16 (MTG16) and Myeloid Tumor Gene Related-1 (MTGR1), both of which are implicated in leukemogenesis. To examine the physiological roles of Mtg16, a target of the t(16;21) that produces Acute Myeloid Leukemia, we deleted it in mice. We found that deletion of Mtg16 perturbs both B-and T-cell development, resulting in a reduced number of peripheral lymphocytes confirmed by complete blood counts and flow cytometry analysis of spleen and lymph node populations. These mice also display a dramatic two-to-three fold decrease in thymic cellularity. Analysis of the bone marrow indicated that there was also loss of B220+ cells, suggesting that there was a general deficit in lymphopoiesis in the absence of Mtg16. Upon closer examination, we find several significant changes throughout the development of both B and T cells. B-cells accumulate in the earliest stages of development, with Pre-pro B increasing in proportion of total B cells after inactivation of Mtg16. This change occurs at the expense of more mature populations, as immature and mature B-cells decrease in percentage significantly. Mtg16 (−/−) thymocytes show slight but statistically significant decreases in Double Negative 1 (DN1) and Double Negative 2 (DN2) subpopulations. Thymocytes also accumulate in the most mature CD4+ and CD8+ subsets in the absence of Mtg16. Mtg16 thus regulates lymphopoiesis at multiple steps, but the most intriguing changes occur in stem and progenitor populations. In fact, the deletion of Mtg16 also results in an increase in myeloid lineages, particularly granulocytes and macrophages, suggesting that Mtg16 plays a role in myeloid vs. lymphoid lineage decisions. Indeed, the deficit in lymphopoiesis appears to be due to increased myeloid commitment and/or expansion of myeloid progenitor cells. Even when cultured in conditions favoring lymphopoiesis, Mtg16-null lineage-/Sca1+/c-Kit+ cells displayed a predisposition towards myeloid development. Because of its ability to interact with a number of different transcription factors that participate in lymphoid and myeloid cell fate decisions, Mtg16 may provide a key piece of the transcriptional machinery that regulates lineage commitment.
Production and Expression of Inflammatory Mediators in Leukocytes of Sickle Cell Anaemia Patients and Effects of Hydroxyurea Therapy on This Production
Authors: Lanaro Carolina , Franco-Penteado Carla Fernanda , Albuquerque Dulcinéia M , Saad Sara T.O. , Conran Nicola , Costa Fernando F. 
Published: April 2020

Abstract
Leukocytosis is frequently observed in sickle cell disease (SCD) in the absence of bacterial infection. An elevated baseline leukocyte count is associated with an increased risk of early death and leukocytes play a significant role in the initiation of vaso-occlusive events. Inflammation, cell adhesion to vascular endothelium, and subsequent endothelial injury appear to contribute to sickle cell anemia (SCA) vaso-occlusion. Furthermore, blood levels of inflammatory and anti-inflammatory cytokines are reported to be elevated (TNF-α, IL-6, IL-10, GM-CSF), both in steady state and during crisis, but reports have been conflicting and a conclusive role for these molecules in the disease remains to be established. Furthermore, the effect of hydroxyurea therapy (HU) on the release of inflammatory mediators is not understood. The aim of this study was to determine plasma levels and leukocyte gene expressions of inflammatory mediators in healthy controls (n=30), steady-state SCA patients (n=45) and SCA patients on HU therapy (n=24). qRT-PCR analysis was use to examine gene expression and ELISA protein production. TNF-α, IL-8 and PGE2 plasma levels were significantly higher in the plasma of steady-state SCA individuals, when compared to control individuals (2.95 ± 0.4 pg/ml; 16.5 ± 2.5 pg/ml; 5.7 ± 0.6 pg/ml; 128.3 ± 12.2 pg/ml vs 1.43 ± 0.2 pg/ml, 88.5 ± 5.9 pg/ml, P=0.006; P&lt;0.0001; P=0.012, respectively). HU therapy significantly reversed augmented TNF-α (1.6 ± 0.2 pg/ml, P=0.006) and, interestingly, increased plasma anti-inflammatory IL-10 (P&lt;0.05). IL-10, IFN-γ, COX-2 and iNOS gene expressions were unaltered in SCA mononuclear cells (MC), however gene expressions of TNF-α, IL-8 and the protective enzyme, heme oxygenase-1 (HO-1), were significantly higher compared to healthy controls (0.46 ± 0.01; 0.08 ± 0.02; 0.21 ± 0.05 vs 0.18 ± 0.04; 0.02 ± 0.005; 0.035 ± 0.008; respectively, P&lt;0.02). HU therapy was not associated with significantly altered SCA MC inflammatory gene expression, although COX-2 mRNA expression was decreased (0.11 ± 0.05; 0.37 ± 0.12, SCAHU and SCA, respectively; P&lt;0.05). In SCA neutrophils, gene expressions of IL-8, IFN-γ, iNOS and HO-1 were significantly higher compared to those of control subjects (0.32 ± 0.07; 0.69 ± 0.19; 0.19 ± 0.06; 0.33 ± 0.09, P=0.02, P=0.025, P&lt;0.05; P=0.027, respectively). Patients on HU therapy demonstrated lower iNOS and higher IL-10 neutrophil gene expressions compared to SCA not on HU therapy (0.038 ± 0.03; 0.72 ± 0.13, P&lt;0.05; P&lt;0.05, respectively). Taken together, data suggest that alterations in the gene expressions and productions of a number of pro-and anti-inflammatory mediators are present in SCA and knowledge of these pathways may be important for identifying novel drug targets for the disease.
Expression Levels of CD11b, CD18, CD32, CD62L (L-Selectin) and CD62P (P-Selectin) and Its Role in Sickle Cell Anemia Inflammatory State
Authors: Cerqueira Bruno Antônio Veloso , Boas Wendell Vilas , Seixas Magda Oliveira , Damasceno Elder Trindade , Souza Cyntia Cajado , Reis Mitermayer Galvão , Goncalves Marilda Souza 
Published: April 2020

Abstract
Vascular occlusions (VOC) underlie most of the acute and chronic sickle cell anemia (SCA) clinical complications and have been correlated to soluble adhesion molecules up regulation and leukocyte activation. A sequential process involving adhesion through selectins and integrins governs leukocyte recruitment to activated endothelium and to sickle red blood cells (RBC), resulting in heterotypic aggregation and VOC. The chronic hemolysis is the major cause of oxidative stress and it can induce transcriptions factors involved in the recruitment of adherent leukocytes in venules. In this work, we assessed the inflammatory potential of leukocytes in venous blood samples by examining cell surface antigens expression by flow cytometry, activation state and its association with hemolytic state in SCA patients group. The study was approved by the FIOCRUZ ethical committee and informed consents were signed by patients or official responsible. Leukocytes were obtained from 22 SCA patients and 22 healthy controls after RBC lyses and labeled with monoclonal anti-CD11b, anti-CD18, anti-CD32, anti-CD62L (L-Selectin) and anti-CD62P (P-Selectin). Leukocyte activation was stimulated by LPS. Statistical analyses were performed using SPSS version 9.0. The basal expression levels on leukocytes cell surface antigens from patients were not different from the control group. However, the CD62L expression levels were associated to C-reactive protein (CRP) higher levels and decrease of fetal hemoglobin in SCA patients (p=0.012). The SCA patients had higher CRP levels when compared to reference levels. Moreover, the data showed a co-expression of CD11b with CD18 (p&lt;0.0001) and CD62P (p=0.011).The platelet count was positively correlated to CD11b expression (p=0.016) and the alanine transaminase high levels with the CD62P expression (p=0.012). Our results demonstrate a leukocyte chronic activation state by expression of CD62L related to CRP higher levels. Interestingly, the platelets could be activated by the indirect activation of CD62P by CD11b, participating of the inflammation state presents at vaso-occlusive events. It seems that the stress oxidative generated by the hemolytic state can contribute to endothelial dysfunction and vaso-occlusive events by CD62L activation in SCA. Fetal hemoglobin is a prognostic factor for several sickle cell complications and we showed that it can ameliorate the CD62L expression on leukocytes, decreasing the chronic inflammatory state of this disease. CD62L serves to as a homing receptor for naïve T lymphocytes and dendritic cells to lymph nodes, mediating the biding of T cells to high endothelial venules, in this view, this can be important marker to inflammatory state and vascular complications in SCA.