bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepcidin Suppression Relative to Iron Status in Patients with Chronic Hepatitis C.
Authors: Girelli Domenico , Pasino Michela , Goodnough Julia , Nemeth Elizabeta , Castagna Annalisa , Busti Fabiana , Campostrini Natascia , Martinelli Nicola , Guido Maria , Vantini Italo , Corrocher Roberto , Ganz Tomas , Fattovich Giovanna 
Published: April 2020

Abstract
Patients with chronic hepatitis C (CHC) often have increased liver iron deposits, a condition associated with reduced sustained response to antiviral therapy, more rapid progression to cirrhosis, and development of hepatocellular carcinoma. The hepatic hormone hepcidin is a major regulator of iron metabolism that inhibits iron absorption and recycling from erythrophagocytosis. Hepcidin decrease is a possible pathophysiological mechanism of iron overload in CHC, but studies in humans have been hampered so far by the lack of reliable quantitative assays for the 25-amino acid bioactive peptide in serum (s-hepcidin). Using a recently validated immunoassay (Ganz T, Blood 2008, epub Aug 8), we measured s-hepcidin levels in 82 CHC naïve patients and 57 sex-matched healthy controls with rigorous definition of normal iron status. All CHC patients underwent liver biopsy with histological iron score (according to Deugnier YM, Gastroenterology 1992). S-hepcidin was much lower in CHC than in controls (geometric means with 95% CIs: 33.7, 21.5–52.9 versus 90.9, 76.1–108.4 ng/ml, respectively; P&lt;0.001), while both serum ferritin and transferrin saturation were significantly higher in CHC than in controls, as expected. S-hepcidin strongly correlated with serum ferritin in both controls (r=0.741; P&lt;0.001) and CHC patients (r = 0.718; P&lt;0.001). In CHC patients, s-hepcidin also correlated with histological total iron score (r = 0.46; P&lt;0.001), but not with serum interleukin-6 (r = −0.042; P = n.s.). After stratification for serum ferritin quartiles, s-hepcidin levels increased significantly across quartiles in both controls and CHC patients (chi for trend, P&lt;0.001). However, in the latter group s-hepcidin levels were significantly lower than in controls for each corresponding quartile (ANOVA, P&lt;0.001). In the lowest ferritin quartile, s-hepcidin was significantly inversely correlated with viral loading (e.g. serum HCV-RNA IU/ml; r = −0.526; P=0.036), while this association gradually disappeared with increasing ferritin quartiles. These results, together with very recent studies in animal and cellular models (Nishina S, Gastroenterology 2008; Miura K, Hepatology 2008), indicate that though hepcidin regulation by iron stores is maintained in CHC, the suppression of this hormone by HCV is likely an important factor in liver iron accumulation in this condition.
Epigenetic Analysis of Beta-Globin Gene Cluster during Hematopoiesis.
Authors: Ekwattanakit Supachai , Riolueang Suchada , Viprakasit Vip 
Published: April 2020

Abstract
Hemoglobin (Hb) switching is described as temporal, tissue- and stage-specific patterns of globin gene expression; from embryonic to fetal and adult Hb in parallel to developmental stages of erythropoiesis. DNA methylation, one of the epigenetic mechanisms, was associated with inactivated chromatin domain and repressive transcription. To study the role of the DNA methylation on the beta (β)-globin genes, we analyzed CpG dinucleotides in 87 kb regions around β-globin gene cluster, including 5’upstream locus control regions (LCR; DNAse I Hypersensitive site (HS) 1–5), 3’HS1, the promoter regions of the G-and A-gamma (Gγ and Aγ), and β-globin genes, in several representative cells. These cells were
primary adult erythroid cells culture (three different stages: early, intermediate, and late), fetal cord blood DNA, and neutrophil cell line (non-erythroid).
Using bisulphite modification, followed by nested PCR and in vitro translation, the cleavage products were analysed by MALDI-TOF Mass Spectrometry to quantify the DNA methylation level. The results were consistent with bisulphite sequencing. We found that the promoters of Gγ and Aγ-globin genes were significantly hypomethylated in fetal cells (44% and 47% global methylation), when γ-globin genes were fully expressed, while they were heavily methylated in non-erythroid (86% and 95%). There was also a decreasing trend of the DNA methylation level at Gγ and Aγ-globin genes during adult erythroid differentiation from 80% and 82%, in early stage, to 67% and 66% in late stage (p=0.12 and 0.04). At β-globin promoter, the global methylation level changed from 90% in non-erythroid to 81%, 42%, and 26% in fetal, early and late adult erythroid cells, respectively. Moreover, we found the significant changes at 5’HS4, 3, and 1 as all erythroid cells were hypomethylated compare to non-erythroid. While at the insulators, 5’HS5 and 3’HS1, all tested CpG dinucleotides were heavily methylated in all cells. This is the first report that demonstrates the differences in DNA methylation at β-globin LCR between erythroid and non-erythroid cells. These epigenetic marks were associated with globin genes expression and might be useful to predict clinical severity in patients with β-thalassemia intermedia.
Regulation of Chromatin Looping and Transcription by PRMT1 Mediated H4R3 Methylation.
Authors: Li Xingguo , Hu Xin , Zhou Zhuo , Qiu Yi , Felsenfeld Gary , Bungert Jorg , Huang Suming 
Published: April 2020

Abstract
Communication between distal enhancers and proximal promoters is critical in controlling proper transcription of genes. However, the functional link between certain histone modifications and the formation of long-range chromatin interactions involved in transcriptional activation remains unknown. In the globin locus, the b-globin genes are regulated by highly organized chromatin structure that juxtaposes the locus control region (LCR) located far upstream of the genes with the proximal b-major globin promoter (bmajpromoter). We report here that the localized asymmetric dimethylation of Arg3 at histone H4 tails (dimethyl H4R3) catalyzed by the methyltransferase PRMT1 is essential for establishing the long-range chromatin interactions between the LCR and the bmaj-promoter and strongly correlates with the activation of adult b-globin gene transcription. In addition, dimethyl H4R3 potentiates the recruitment of histone acetyltransferases (HATs), CBP and PCAF, and is required for the establishment of subsequent histone acetylation at the globin locus. Suppression of PRMT1 activity disrupts the recruitment of transcription complexes, TBP and RNA polymerase II (RNA Pol II), at the active b-globin promoter, but not at the LCR. Taken together, our data implicate PRMT1-mediated dimethylation of H4R3 in the regulation of long-range enhancer/promoter communications, which are required for the efficient recruitment of transcription complexes to the active gene promoter.
Fetal-to-Adult Hemoglobin Switching Is Associated with up-Regulation of Specific MicroRNA Species in Circulating Human Erythroid Cells.
Authors: Noh Seung-Jae , Miller Samuel , Lee Y. Terry , Marincola Francesco M. , Stroncek David , Reed Christopher , Wang Ena , Miller Jeffery L 
Published: April 2020

Abstract
MicroRNAs are ~22nt-long small noncoding RNAs that negatively regulate expression of target proteins through mRNA degradation or translational repression. They are functionally important in diverse biological processes including development, oncogenesis, and hematopoiesis. To study a potential role of microRNA for regulating cellular changes during erythroid ontogeny, we examined microRNA abundance patterns in circulating erythroid cells during the fetal and adult stages of human development. Expression profiling of microRNA was performed using total RNA from 4 adult peripheral blood samples compared to 4 cord blood samples after depletion of plasma, platelets, and nucleated cells. Labeled RNA was hybridized to custom spotted array containing 474 human microRNAs species (miRBase release 9.1). Total RNA from Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines was used as a hybridization reference for all samples to generate microRNA abundance profile for each sample. Among the differentially expressed probe-pairs, 40 microRNAs were significantly up-regulated in adult erythroid cells and only 4 microRNAs were down-regulated (p &lt; 0.01 and fold change &gt; 2). Two microRNAs, miR-144 and miR-451, previously reported as being GATA-1 regulated in erythroid cells, were detected above the dynamic range of the array technology in all eight samples. Quantitative PCR was performed to further quantitate differences in the microRNA abundance profiles of the 10 most differentially expressed microRNAs as well as miR-144 and miR-451. Per published recommendations, miR-103 was used for signal normalization. Among the studied microRNAs, 8 of 12 demonstrated a more than 4 fold increase in abundance in adult erythroid cells compared to cord blood by qPCR. In particular, let-7d and let-7e demonstrated more than 10-fold increased expression in adult cells. Of note, let-7 microRNAs regulate metamorphic processes in model organisms and inhibit ras-associated growth of cancer cells. According to miRBase predictions, over 1200 genes may be targeted by the 8 microRNAs (p &lt; 0.001). Examination of cord and adult reticulocyte mRNA expression profiles (Goh et al. Phy. Gen. 2007) revealed 24 developmentally downregulated genes as predicted targets. Among globin genes, only gamma globin is a predicted target. These findings demonstrate dramatic up-regulation of specific erythroid microRNAs during the fetal-to-adult transition of ontogeny, and support the notion that microRNAs function as developmental regulators of erythropoiesis and globin gene switching.
Characterization of Histone Deacetyalses Involved in γ-Globin Gene Regulation.
Authors: Muralidhar Shalini A , Nimer Sadeieh , Pace Betty 
Published: April 2020

Abstract
Fetal hemoglobin (HbF; α2γ2) ameliorates vaso-occlusive symptoms in individuals with sickle cell disease (SCD) because of its ability to inhibit hemoglobin S polymerization. One mechanism for γ-globin reactivation likely involves chromatin modification and the release of repressor complexes in which histone deacetylases (HDACs) may be present. The objective of this study was to identify HDACs involved in γ-globin gene regulation. Experiments were performed in K562 cells to determine the ability of NaB (2mM), TSA (0.5μm) and the non-HDAC-inhibitor γ-globin activator hemin (50μM), to alter transcription levels of the HDAC genes during concomitant HbF induction. Gene expression was measured by reverse transcription (RT) of mRNA followed by quantitative PCR (qPCR) analysis using gene-specific primers. Treatment of K562 cells with TSA and NaB reduced transcription levels of both HDAC9 and HDRP (histone deacetylase related protein, a splice variant of HDAC9) from 20–80% as did the control agent hemin (p&lt;0.05). By contrast, expression of HDAC7 and HDAC10 was enhanced in the presence of both HDAC inhibitors. The altered HDAC gene expression levels provided indirect evidence for a possible role in mechanisms of γ-globin response to drug inducers. Subsequent experiments were performed to delineate whether HDAC9 and HDRP are directly involved in γ-globin regulation. We performed siRNA knockdown of HDAC9 and HDRP in K562 cells to determine the effect on expression of endogenous γ-globin. siRNA oligonucleotides were transfected using Oligofectamine (Invitrogen) for 48 hrs and expression of targeted genes were quantified by RT-qPCR. siHDAC9 and siHDRP (Dharmacon) treatment resulted in dose-dependent γ-globin silencing and transactivation respectively at 80–320nM. Experiments were then performed with 160nM of siHDAC9 or siHDRP in the K562 cell lines which were stably transfected with a luciferase reporter (pGL4.17-Luc2-neo, Promega) under the control of Gγ-globin promoter (−1500 to +36) and the pGL4.17-Luc2-neo empty vector. We likewise observed a 30% decrease in luciferase activity with siHDAC9 and a 40% increase with siHDRP suggesting that HDAC9 and its variant are directly involved in regulation of γ-promoter activity. In summary, the effects on endogenous γ globin levels and Gγ globin promoter activity through HDAC9/HDRPspecific knockdown by siRNA experiments suggest that HDAC9 molecules play a role in regulating γ-globin gene expression. We conclude that HDAC9 and HDRP have opposite regulatory effect on γ-globin gene expression and may act by a feedback mechanism.
Evidence of Endothelial Dysfunction in Cocaine Users.
Authors: Pereira Jai me , Sáez Claudia G. , Pallavicini Julio , Olivares Paulina , Panes Olga , Moreno Natalia , Belmont Sabine , Massardo Teresa , Mezzano Diego 
Published: April 2020

Abstract
Background: Cocaine abuse is associated with an increased risk of cardiac and cerebrovascular events, such as myocardial infarction, sudden cardiac death, and ischemic stroke. The underlying mechanisms leading to these complications are not fully understood although intravascular thrombus formation and accelerated atherosclerosis are prominent findings. In this sense, in vitro studies have demonstrated that cocaine may induce damage and/or activation of endothelial cells. The structural and functional integrity of the endothelium is essential for the maintenance of vascular homeostasis and its damage plays a critical role in the pathogenesis of vascular disease. Endothelial dysfunction may be assessed by testing the impaired vasodilator response to a stimulus or by measuring the release of plasma markers of endothelial damage. Increased number of circulating endothelial cells (CECs) has been reported in several pathologic conditions associated with severe vascular damage and its enumeration in peripheral blood is currently considered a reliable method to assess endothelial damage. We hypothesized that chronic exposure to cocaine induces endothelial damage which could be expressed by increased CEC counts in peripheral blood.
Methods: Twenty cocaine-dependent subjects (aged 19–52 years, mean age 30 years) and 25 healthy, matched controls (aged 20–49 years, mean age 31 years) were studied; all patients fulfilled DSM-IV criteria for cocaine dependence with drug exposure within the 72 hours prior to blood sampling. CECs were isolated from peripheral blood by use of immunomagnetic beads coated with anti-CD146, stained for CD45 and Ulex Europaeus lectin 1 and counted under fluorescence microscopy. MCP-1, sICAM-1, von Willebrand factor and high-sensitivity C-reactive protein (hsCRP) were measured by enzyme-linked immunosorbent assay.
Results: Compared to controls, CECs were significantly elevated among cocaine users (632 ± 281 vs 67 ± 54 cells/mL, p&lt;0.0001). Plasma levels of sICAM-1 (360±92 ng/mL) and MCP-1 (166±71 pg/mL) were increased in cocaine-dependent individuals compared to the controls (261±34 and 67±29, respectively; p&lt; 0.01). The hsCRP levels were significantly increased (6.8 mg/L); however plasma von Willebrand factor concentration was not different between patients and controls (86.4±22 vs 70.5±16%, respectively; NS). Levels of CECs correlated positively with sICAM-1 (r: 0.7; p: 0.003) and hsCRP (r: 0.56; p: 0.0037).
Conclusions: Highly increased number of CECs and significant increments in soluble plasma markers of endothelial perturbation were found in cocaine dependent individuals. This is the first demonstration of endothelial dysfunction among these individuals and our findings support the notion that cocaine-induced endothelial damage may play a pathogenic role in the ischemic vascular disease observed in chronic cocaine users.
CXCR7 Is Expressed in B Acute Lymphoblastic Leukemia (ALL) Cells and Mediates Their Transendothelial Migration.
Authors: Jalili Ali , Shirvaikar Neeta , Mirza Imran , Ilnitsky Sara , Penfold Mark , Schall Thomas J , Janowska-Wieczorek Anna 
Published: April 2020

Abstract
The function of chemokine stromal cell-derived factor (SDF)-1 and its receptor CXCR4 in the pathobiology of hematological malignancies is known, but the role of another, newly identified receptor for SDF-1, RDC1/CXCR7, has not yet been defined. Thus we investigated whether CXCR7 plays a role in hematological malignancy. Using RT-PCR and flow cytometry analysis, we screened the expression of CXCR7 in 14 hematological cell lines and found that it is strongly expressed in all 5 B cell lines tested (Raji, NC- 37, NALM6, Ramos and REH) and weakly in two T cell lines( Jurkat and CEM) and 2 of 7 myeloid cell lines tested. Moreover, CXCR7 was also strongly expressed in all 9 patients diagnosed with B precursor ALL, very weakly in normal lymphocytes, and not at all in T precursor ALL samples, suggesting that CXCR7 is selectively expressed in B-cell ALL. Next we examined whether CXCR7 plays a role in the chemotaxis of these cells and found that its antagonist CCX733 (ChemoCentryx, Inc, Mountain View, CA) did not inhibit SDF-1-induced chemotaxis, indicating that CXCR7 does not play a significant role in the chemotactic activity of B-cell ALL. However, we found that CCX733 inhibited the transendothelial migration (TEM) of B cell lines and primary B precursor ALL cells in a dose-dependent manner, but the inactivated CXCR7 antagonist CCX226 did not. Moreover, transfection of the NALM6 with CXCR7 resulted in downregulation of CXCR4 and the TEM of such transfected cells was more inhibited by CCX733 than of wild-type cells. When we compared the roles of CXCR4 and CXCR7 in the TEM of these cells, we found that the CXCR7 antagonist totally inhibited the TEM of B cells at the low dose of 1mM, but the CXCR4 antagonist AMD3100 did not. On the other hand, the SDF- 1-induced TEM of T cell lines and primary T lymphoblasts was not significantly inhibited by CCX733, but was by AMD3100. CCX733 significantly prevented binding of NC-37 cell line to HUVEC (as shown by adhesion assay) which indicates that CXCR7 is likely required for the interaction of leukemic cells with endothelial cells and their extravasation. Moreover, because CXCR7 is known to be a receptor for the interferon-inducible T cell chemoattractant (I-TAC), we investigated whether the I-TAC/CXCR7 axis crosstalks with the SDF-1/CXCR7 axis in the trafficking of lymphoblastic cells. We found that
I-TAC itself did not induce the TEM of NC-37 cells; pretreatment of NC-37 cells with I-TAC, but not with other chemokines (MCP-1 and MIG), inhibited TEM towards SDF-1; in contrast, pretreatment of MOLT-4 (T cells) with I-TAC did not block the TEM of MOLT-4 cells.
In conclusion, we demonstrated that CXCR7 is expressed on B lymphoblasts, and the SDF-1/CXCR7 axis plays a crucial role in the trafficking of these cells, indicating that CXCR7 could be a therapeutic target in patients diagnosed with B precursor ALL.
Outcome after Frontline Therapy with the Modified Hyper-CVAD Regimen with or without Rituximab for De Novo Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL).
Authors: Thomas Deborah A. , Kantarjian Hagop , Faderl Stefan , Wierda William G. , Ferrajoli Alessandra , Burger Jan A. , Cortes Jorge , Koller Charles A. , Borthakur Gautam , Estrov Zeev , Konopleva Marina , Ravandi Farhad , Manero Guillermo Garcia- , O’Brien Susan 
Published: April 2020

Abstract
The hyper-CVAD regimen is an effective frontline program for de novo adult ALL and LL [Kantarjian, JCO18:547, 2000; Kantarjian, Cancer101:2788, 2004, Thomas, Blood104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate and cytarabine every 21 days for 8 courses, followed by maintenance with POMP (6-mercaptopurine, methotrexate, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999 to address the following:
higher induction mortality in patients (pts) aged 60 years or older (17% vs 3%); possible benefit of early anthracycline intensification; worse survival with CD20 expression [Thomas D, Blood, e-pub]; and late relapses after completion of POMP therapy.
Hyper-CVAD Modified Hyper-CVAD Laminar air flow rooms No For age ≥60 yrs Dose-intensive anthracycline No C2 lipo DNR & ara-C Rituximab No For CD20 ≥20% Intrathecal CNS prophylaxis 4, 8 (16 BL) 6, 8 (16 BL) POMP maintenance 24 mos 30 months Intensifications Months 7, 11 Months 6, 7 & 18, 19
Newly diagnosed or primary refractory (1 course only) pts with ALL (n=184) or LL (n=27) were treated on two sequential studies. Burkitt-type leukemia/lymphoma (BLL) and Philadelphia positive ALL were treated on alternative protocols. From May 2000 to December 2001, 69 pts were treated with the modified regimen as detailed above (9 courses of intensive chemotherapy). Course 2 was then eliminated from the regimen (8 courses of intensive chemotherapy), with an additional 145 pts treated to date. Median age was 40 yrs (range 15–83). CD20 expression was noted in 40%. Overall CR rate of the group (n=211) was 90%; 4 pts achieved PR, five failed to respond, and 3 died during the induction phase. After a median follow-up of 42 months (range, 2–80), outcome appeared favorable for the younger group (30 yrs or less) with 3-year remission duration (CRD) and survival (OS) rates of 70% and 80%. In the CD20 positive precursor B-cell ALL subset (n=88), rituximab improved outcome compared to historical experience, with 3-yr CRD rates (68% vs 28%, p&lt;.001) and OS rates (65% vs 35%, p=.01) approaching those of the CD20 negative counterparts. In contrast to the Burkitt experience, rituximab was not beneficial for the elderly subgroup (OS rates 48% vs 35%, p NS). Anthracycline intensification appeared to worsen outcome. Rituximab appears to benefit the younger pts with CD20 positive precursor B-cell ALL. Incorporation of rituximab and other monoclonal antibodies (e.g., ofatumumab, epratuzumab) into frontline chemotherapy regimens should be investigated systematically.