bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimalarial Activity of 77 Phospholipid Polar Head Analogs: Close Correlation Between Inhibition of Phospholipid Metabolism and In Vitro Plasmodium Falciparum Growth
Authors: Ancelin Marie L. , Calas Michèle , Bompart Jacques , Cordina Gérard , Martin Dominique , Ben Bari Mohammed , Jei Taı̈b , Druilhe Pierre , Vial Henri J. 
Published: October 2019

AbstractSeventy-seven potential analogs of phospholipid polar heads, choline and ethanolamine, were evaluated in vitro as inhibitors ofPlasmodium falciparum growth. Their IC50 ranged from 10−3 to 10−7 mol/L. Ten compounds showed similar antimalarial activity when tested against three different parasite strains (2 chloroquine-sensitive strains and 1 chloroquine-resistant strain). Compounds showing marked antimalarial activity were assayed for their effects on phospholipid metabolism. The most active compounds (IC50 of 1 to 0.03 μmol/L) were inhibitors of de novo phosphatidylcholine (PC) biosynthesis from choline. For a series of 50 compounds, there was a close correlation between impairment of phospholipid biosynthesis and inhibition of in vitro malaria parasite growth. High choline concentrations caused a marked specific shift in the curves for PC biosynthesis inhibition. Concentrations inhibiting 50% PC metabolism from choline were in close agreement with the Ki of these compounds for the choline transporter inPlasmodium knowlesi-infected erythrocytes. By contrast, measurement of the effects of 12 of these compounds on rapidly dividing lymphoblastoid cells showed a total absence of correlation between parasite growth inhibition and human lymphoblastoid cell growth inhibition. Specific antimalarial effects of choline or ethanolamine analogs are thus likely mediated by their alteration of phospholipid metabolism. This indicates that de novo PC biosynthesis from choline is a very realistic target for new malaria chemotherapy, even against pharmacoresistant strains.
Neonatal Hemolytic Anemia Due to Inherited Harderoporphyria: Clinical Characteristics and Molecular Basis
Authors: Lamoril J. , Puy H. , Gouya L. , Rosipal R. , Da Silva V. , Grandchamp B. , Foint T. , Bader-Meunier B. , Dommergues J.P. , Deybach J.C. , Nordmann Y. 
Published: October 2019

AbstractPorphyrias, a group of inborn errors of heme synthesis, are classified as hepatic or erythropoietic according to clinical data and the main site of expression of the specific enzymatic defect. Hereditary coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by deficient activity of coproporphyrinogen III oxidase (COX). Typical clinical manifestations of the disease are acute attacks of neurological dysfunction; skin photosensitivity may also be present. We report a variant form of HC characterized by a unifying syndrome in which hematologic disorders predominate: harderoporphyria. Harderoporphyric patients exhibit jaundice, severe chronic hemolytic anemia of early onset associated with hepatosplenomegaly, and skin photosensitivity. Neither abdominal pain nor neuropsychiatric symptoms are observed. COX activity is markedly decreased. In a first harderoporphyric family, with three affected siblings, a homozygous K404E mutation has been previously characterized. In the present study, molecular investigations in a second family with neonatal hemolytic anemia and harderoporphyria revealed two heterozygous point mutations in the COX gene. One allele bore the missense mutation K404E previously described. The second allele bore an A→G transition at the third position of the donor splice site in intron 6. This new COX gene mutation resulted in exon 6 skipping and the absence of functional protein production. In contrast with other COX gene defects that produce the classical hepatic porphyria presentation, our data suggest that the K404E substitution (either in the homozygous or compound heterozygous state associated with a mutation leading to the absence of functional mRNA or protein) is responsible for the specific hematologic clinical manifestations of harderoporphyria.
A Novel Single Missense Mutation Identified Along the RH50 Gene in a Composite Heterozygous Rhnull Blood Donor of the Regulator Type
Authors: Hyland C.A. , Chérif-Zahar B. , Cowley N. , Raynal V. , Parkes J. , Saul A. , Cartron J.P. 
Published: October 2019

AbstractRare individuals who lack all of the Rh blood group antigens are called Rhnull and may be classified as “regulator” or “amorph” types. The suppression of Rh antigen expression for regulator types may be attributed to mutations of the RH50gene, which is independent of the RH locus. The RH50 gene encodes a glycoprotein that interacts with the Rh proteins to form a functional complex within the red blood cell membrane. This report describes an RH50 gene mutation for a previously unclassified Rhnull donor. Sequencing cDNA clones from Rh50 mRNA revealed a single base change (G836A) yielding a missense and nonconservative mutation (Gly279Glu) within a predicted hydrophobic domain for this membrane protein. Genomic DNA studies using polymerase chain reaction (PCR) restriction analysis and sequencing showed that the Rhnull propositus was a composite heterozygote for this mutation, carrying two alleles with the A and G at nucleotide 836, respectively. In contrast, cDNA studies showed that only the A836 sequence was present, suggesting that the second allele with G836 was apparently silent (no transcript detected). Family studies showed that the mutant RH50 allele (836A) was inherited maternally, whereas the silent RH50 allele (836G) was from paternal transmission. These findings provide further evidence that rare but diverse genetic alterations may occur along the RH50 gene where the Rhnull syndrome of the regulator type occurs. The single amino acid change (Gly to Glu) provides insight into the critical value of these residues for assembly of the Rh antigen complex within the membrane.
Reversal of Lethal - and β-Thalassemias in Mice by Expression of Human Embryonic Globins
Authors: Russell J. Eric , Liebhaber Stephen A. 
Published: October 2019

Genetic mutations that block - or β-globin gene expression in humans can result in severe and frequently lethal thalassemic phenotypes. Homozygous inactivation of the endogenous - or β-globin genes in mice results in corresponding thalassemic syndromes that are uniformly fatal in utero. In the current study, we show that the viability of these mice can be rescued by expression of human embryonic ζ- and -globins, respectively. The capacity of embryonic globins to fully substitute for their adult globin homologues is further demonstrated by showing that ζ- and -globins reverse the hemolytic anemia and abnormal erythrocyte morphology of mice with nonlethal forms of - and β-thalassemia. These results illustrate the potential therapeutic utility of embryonic globins as substitutes for deficient adult globins in thalassemic individuals. Moreover, the capacity of embryonic globins to functionally replace their adult homologues brings into question the physiologic basis for globin gene switching.© 1998 by The American Society of Hematology.
Cell adhesion receptors in lymphoma dissemination
Authors: Drillenburg Paul , Pals Steven T. 
Published: October 2019

AbstractRegulated lymphocyte trafficking is essential for the control and integration of systemic immune responses. This homing process disperses the immunologic repertoire, guides lymphocyte subsets to the specialized microenvironments that control their differentiation and survival, and targets immune effector cells to sites of antigenic insult. This review discusses data indicating that the adhesion receptors regulating the trafficking of normal lymphocytes are also expressed and functionally active in their malignant counterparts, the non-Hodgkin lymphomas. These “homing receptors” appear to mediate the highly tissue-specific dissemination of specific lymphoma subtypes, such as lymphomas of the mucosa-associated lymphoid tissues and lymphomas of the skin. Furthermore, as a result of their capability to enhance lymphoma dissemination and to transduce signals into the cell, promoting cell growth and survival, adhesion receptors may contribute to lymphoma aggressiveness. Taken together, the data offer a framework for understanding the dissemination routes of non-Hodgkin lymphomas and suggest that adhesion receptors, specifically those of the CD44 family, may present useful tools to predict prognosis in patients with lymphomas.
Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S
Authors: Makris Michael , Leach Michael , Beauchamp Nick J. , Daly Martina E. , Cooper Peter C. , Hampton Kingsley K. , Bayliss Pauline , Peake Ian R. , Miller George J. , Preston F. Eric 
Published: October 2019

AbstractProtein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results. We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives. To avoid selection bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients' relatives. In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis (95% confidence interval, 1.5-16.8) than those with a normal PROS1 gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons withPROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency.
Identification of a family of alternatively spliced mRNA species of angiopoietin-1
Authors: Huang Yao-Qi , Li Jian-Jun , Karpatkin Simon 
Published: October 2019

AbstractAngiopoietin-1 (Ang-1) is required for developing vessels, and its absence leads to defects in vessel remodeling. Ang-1 has been identified as the ligand for the tyrosine kinase receptor Tie-2, which is expressed specifically on endothelial cells and early hematopoietic cells. In studying the role of Tie-2 and Ang-1 in megakaryocytopoiesis, 3 alternatively spliced species of Ang-1 mRNA (Ang-1.3 kb, Ang-0.9 kb, and Ang-0.7 kb) were identified in addition to the full-length Ang-1 (Ang-1.5 kb), in the megakaryocyte cell line CHRF by reverse transcription–polymerase chain reaction (RT-PCR), and then cloned and sequenced. The expression of 3 alternatively spliced isoforms of Ang-1 was confirmed by RT-PCR using specific primer pairs derived from junction sites and the 3′ end of Ang-1 cDNA, and it was further demonstrated by nuclease protection assay, Northern blotting, and immunoblotting in CHRF cells. Expression of the Ang-1.3 kb isoform was also detected in human primary fibroblast cell line FS4, breast cancer cell line MDAMB-468, and CD34+CD41+ cells of fetal liver and platelets. The function of the 1.5-kb, 1.3-kb, and 0.9-kb isoforms was examined. Recombinant proteins Ang-1.5 and 0.9 kb bind strongly to the recombinant Tie-2 receptor (Tie-2-Fc), whereas the 1.3-kb isoform does not. The Ang-1.3 kb isoform binds to the 1.5-kb isoform. Ang-1.5 kb, but not the 1.3-kb and 0.9-kb isoforms, induces tyrosine phosphorylation of Tie-2 in human umbilical vein endothelial cells. These data suggest that isoforms 1.3 kb and 0.9 kb could serve as dominant negative molecules for the full-length Ang-1. The possible involvement of the newly identified Ang-1 isoforms in angiogenesis and in growth and differentiation of hematopoietic progenitor cells provides a greater complexity to these processes.
A critical role for PI 3-kinase in cytokine-induced Fcα-receptor activation
Authors: Bracke Madelon , Nijhuis Evert , Lammers Jan-Willem J. , Coffer Paul J. , Koenderman Leo 
Published: October 2019

AbstractFc-receptors, such as FcR and FcγRII, play an important role in leukocyte activation, and rapid modulation of ligand binding (“activation”) is critical for receptor regulation. We have previously demonstrated that ligand binding to Fc-receptors on human eosinophils is dependent on cytokine stimulation. Utilization of pharmacological inhibitors provided evidence that the phenomenon of interleukin (IL)-5 induced immunoglobulin A (IgA) binding to human eosinophils requires activation of phosphatidylinositol 3-kinase (PI3K). However, eosinophils are refractory to manipulation by molecular techniques such as DNA transfection or viral infection. Here we utilize an IL-3 dependent pre-B cell line to investigate the molecular mechanism of cytokine-mediated ligand binding to FcR. In this system, IgA binding is dependent on IL-3, similarly to the requirement for IL-5 of eosinophils. We show that IL-3-mediated activation of FcR (CD89) requires the activation of PI3K, independent of p21ras activation. Co-expression of dominant negative (▵p85) and active (p110_K227E) forms of PI3K demonstrate that the affinity switch regulating FcR activation requires PI3K. Moreover, overexpression of PI3K is both necessary and sufficient for activation of FcR. Furthermore, we show that IL-3/IL-5/GM-CSF induced inside-out signaling pathways activating FcR require the involvement of protein kinase C downstream of PI3K. Finally, we show that these inside-out signaling pathways responsible for Fc-receptor modulation require CD89, independent of its association with the FcRγ chain.
STAT5 activation contributes to growth and viability in Bcr/Abl-transformed cells
Authors: Sillaber Christian , Gesbert Franck , Frank David A. , Sattler Martin , Griffin James D. 
Published: October 2019

AbstractThe transcription factor STAT5 is constitutively tyrosine phosphorylated and activated after transformation of hematopoietic cells by p210Bcr/Abl. A truncated form of STAT5B (▵STAT5; aa, 1-683) that lacks tyrosine 699 and the transcriptional activation domain was introduced into Ba/F3p210 cells under the control of a tetracycline-inducible promoter. Treatment of these cells with doxycycline, a tetracycline analogue, induced expression of ▵STAT5 and inhibited STAT5-dependent transcription. ▵STAT5 coprecipitated with STAT5 and decreased Bcr/Abl-dependent tyrosine phosphorylation of endogenous STAT5. Induction of ▵STAT5 inhibited growth of Ba/F3p210 cells (26%-52% of control levels at 4 days) but did not cause cell-cycle arrest. ▵STAT5 reduced viability of Ba/F3p210 cells and increased sensitivity of the cells to the cytotoxic drugs hydroxyurea and cytarabine. These results indicate that high-level expression of ▵STAT5, as achieved here by using a tetracycline-inducible promoter, inhibits STAT5 activity, reduces the growth rate of Ba/F3p210 cells by inhibiting viability, and results in increased sensitivity to chemotherapeutic drugs. It is therefore likely that STAT5 activation plays a role in the transformation of hematopoietic cell lines by p210Bcr/Abl.
Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival
Authors: Hunter Melissa G. , Avalos Belinda R. 
Published: October 2019

AbstractPatients with severe congenital neutropenia (SCN) are at increased risk for the development of acute myelogenous leukemia (AML). In the subset of patients with SCN that progresses to AML, acquired mutations in the receptor for granulocyte colony-stimulating factor (G-CSF) have been detected that result in the expression of truncated forms of the G-CSF receptor (G-CSFR) protein. G-CSFR truncation mutants from these patients trans-duce hyperproliferative growth responses. In this paper, we show that the most frequently isolated mutant G-CSFR form from patients with SCN/AML (▵716) confers resistance to apoptosis and prolongs cell survival through a mechanism involving Akt, a downstream target of PI3-kinase. G-CSF stimulation of cells expressing the G-CSFR truncation mutant induces sustained activation of Akt and prolonged phosphorylation of the pro-apoptotic protein Bad, resulting in enhanced cell survival. Extension of cell survival allowing for sufficient time for the acquisition of additional oncogenic events may represent an important mechanism by which G-CSFR mutations contribute to leukemogenesis. These data provide further insight into the pathophysiologic contribution of G-CSFR mutations to AML.
Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis
Authors: Ma Zhigui , Cools Jan , Marynen Peter , Cui Xiaoli , Siebert Reiner , Gesk Stefan , Schlegelberger Brigitte , Peeters Benjamin , De Wolf-Peeters Christiane , Wlodarska Iwona , Morris Stephan W. 
Published: October 2019

AbstractThe non-Hodgkin lymphoma (NHL) subtype anaplastic large-cell lymphoma (ALCL) is frequently associated with a t(2;5)(p23;q35) that results in the fusion of the ubiquitously expressed nucleophosmin (NPM) gene at 5q35 to the anaplastic lymphoma kinase (ALK) gene at 2p23, which is not normally expressed in hematopoietic tissues. Approximately 20% of ALCLs that expressALK do not contain the t(2;5), suggesting that other genetic abnormalities can result in aberrant ALK expression. Here we report the molecular characterization of an alternative genetic means of ALK activation, the inv(2)(p23q35). This recurrent abnormality produces a fusion of the amino-terminus of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a bifunctional homodimeric enzyme that catalyzes the penultimate and final steps of de novo purine nucleotide biosynthesis, with the intracellular portion of the ALK receptor tyrosine kinase. RT-PCR analysis of 5 ALCL tumors that contained the inv(2) revealed identical ATIC-ALK fusion cDNA junctions in all of the cases. Transient expression studies show that theATIC-ALK fusion transcript directs the synthesis of an approximately 87-kd chimeric protein that is localized to the cytoplasm, in contrast to NPM-ALK, which typically exhibits a cytoplasmic and nuclear subcellular distribution. ATIC-ALK was constitutively tyrosine phosphorylated and could convert the IL-3–dependent murine hematopoietic cell line BaF3 to cytokine-independent growth. Our studies demonstrate an alternative mechanism for ALK involvement in the genesis of NHL and suggest that ATIC-ALK activation results from ATIC-mediated homodimerization. In addition, expected decreases in ATIC enzymatic function in ATIC-ALK–containing lymphomas may render these tumors more sensitive to antifolate drugs such as methotrexate.
Genomic characterization of Haemophilus influenzae: a focus on the capsule locus
Authors: Potts Caelin C. , Topaz Nadav , Rodriguez-Rivera Lorraine D. , Hu Fang , Chang How-Yi , Whaley Melissa J. , Schmink Susanna , Retchless Adam C. , Chen Alexander , Ramos Edward , Doho Gregory H. , Wang Xin 
Published: October 2019

Abstract

Background
Haemophilus influenzae (Hi) can cause invasive diseases such as meningitis, pneumonia, or sepsis. Typeable Hi includes six serotypes (a through f), each expressing a unique capsular polysaccharide. The capsule, encoded by the genes within the capsule locus, is a major virulence factor of typeable Hi. Non-typeable (NTHi) does not express capsule and is associated with invasive and non-invasive diseases.

Methods
A total of 395 typeable and 293 NTHi isolates were characterized by whole genome sequencing (WGS). Phylogenetic analysis and multilocus sequence typing were used to characterize the overall genetic diversity. Pair-wise comparisons were used to evaluate the capsule loci. A WGS serotyping method was developed to predict the Hi serotype. WGS serotyping results were compared to slide agglutination (SAST) or real-time PCR (rt-PCR) serotyping.

Results
Isolates of each Hi serotype clustered into one or two subclades, with each subclade being associated with a distinct sequence type (ST). NTHi isolates were genetically diverse, with seven subclades and 125 STs being detected. Regions I and III of the capsule locus were conserved among the six serotypes (≥82% nucleotide identity). In contrast, genes in Region II were less conserved, with only six gene pairs from all serotypes showing ≥56% nucleotide identity. The WGS serotyping method was 99.9% concordant with SAST and 100% concordant with rt-PCR in determining the Hi serotype.

Conclusions
Genomic analysis revealed a higher degree of genetic diversity among NTHi compared to typeable Hi. The WGS serotyping method accurately predicted the Hi capsule type and can serve as an alternative method for Hi serotyping.
Icotinib-resistant HCC827 cells produce exosomes with mRNA MET oncogenes and mediate the migration and invasion of NSCLC
Authors: Yu Yiming , Abudula Maidinaimu , Li Chaofen , Chen Zhongbo , Zhang Yun , Chen Yichen 
Published: October 2019

Abstract

Background
Icotinib has been widely used in patients with non-small cell lung cancer (NSCLC), and have significantly enhanced the overall survival rate of NSCLC patients. However, acquired drug resistance limits its clinical efficacy. Tumor cell-derived exosomes have been reported to participate in various biological processes, including tumor invasion, metastasis and drug resistance.

Materials and methods
In the present study, drug resistance was measured by MTT assay. Exosomes were extracted from the cell supernatant using ultracentrifugation and identified by exosomal marker. HCC827 cells were treated with exosomes derived from icotinib-resistant (IR) HCC827 to observe the invasion and migration of parent cells. The expression of exo-mRNA was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-PCR). In addition, 10 exo-mRNAs detecting from the plasma and bronchoalveolar lavage fluid (BALF) of NSCLC patients with icotinib treatment were used to establish a new drug resistant-warning formula.

Results
The oncogene MET into exosomes was identified from icotinib-resistant lung cancer cells, and this was also presented in exosomes in NSCLC patients diagnosed with cancer metastasis after icotinib treatment. The knockdown of MET in exosomes significantly decreased the ability of invasion and migration in HCC827 cells.

Conclusion
It was suggested that MET might be specifically package and transferred by exosomes to modify the invasion and migration ability of the surrounding icotinib-sensitive cells.
A hierarchical (multicomponent) model of in-group identification: adaptation of a measure to the Brazilian context
Authors: de Souza Luana Elayne Cunha , de Lima Tiago Jessé Souza , Maia Luciana Maria , Fontenele Ana Beatriz Gomes , Lins Samuel Lincoln Bezerra 
Published: October 2019

Abstract
The aim of this study is to adapt the multidimensional in-group identification scale (MGIS) to the Brazilian context by gathering evidence of its psychometric properties. A total of 663 people from two samples participated in the study. In sample 1, we measured the identification of Brazilians with the region of the country where they live. In sample 2, we measured the identification of students with the university which they attend. Confirmatory factor analyses were performed on both samples to compare the models previously proposed by the original authors of the measure. The obtained results confirmed the validity of the hierarchical and multidimensional factor structure proposed by the original authors. The scale proposed here can be used to measure multiple dimensions of in-group identification in Brazil.