bluuebunny/crossref_metadata_2025_split huggingface dataset:
PML/RARα fusion protein expression in normal human hematopoietic progenitors dictates myeloid commitment and the promyelocytic phenotype
Authors: Grignani Francesco , Valtieri Mauro , Gabbianelli Marco , Gelmetti Vania , Botta Rosanna , Luchetti Luisella , Masella Barbara , Morsilli Ornella , Pelosi Elvira , Samoggia Paola , Pelicci Pier Giuseppe , Peschle Cesare 
Published: October 2019

Abstract
The role of fusion proteins in acute myeloid leukemia (AML) is well recognized, but the leukemic target cell and the cellular mechanisms generating the AML phenotype are essentially unknown. To address this issue, an in vitro model to study the biologic activity of leukemogenic proteins was established. Highly purified human hematopoietic progenitor cells/stem cells (HPC/HSC) in bulk cells or single cells are transduced with retroviral vectors carrying cDNA of the fusion protein and the green fluorescent protein (GFP), purified to homogeneity and induced into multilineage or unilineage differentiation by specific hematopoietic growth factor (HGF) combinations. Expression of PML/RARα fusion protein in human HPC/HSC dictates the acute promyelocytic leukemia (APL) phenotype, largely through these previously unreported effects: rapid induction of HPC/HSC differentiation to the promyelocytic stage, followed by maturation arrest, which is abolished by retinoic acid; reprogramming of HPC commitment to preferential granulopoietic differentiation, irrespective of the HGF stimulus (transduction of single sibling HPC formally demonstrated this effect); HPC protection from apoptosis induced by HGF deprivation. A PML/RARα mutated in the co-repressor N-CoR/histone deacetylase binding region lost these biologic effects, showing that PML/RARα alters the early hematopoietic program through N-CoR–dependent target gene repression mechanisms. These observations identify the cellular mechanism underlying development of the APL phenotype, showing that the fusion protein directly dictates the specific lineage and differentiation stage of leukemic cells.
Pathologic gene expression in Gaucher disease: up-regulation of cysteine proteinases including osteoclastic cathepsin K
Authors: Moran Mary Teresa , Schofield J. Paul , Hayman Alison R. , Shi Guo-Ping , Young Elisabeth , Cox Timothy M. 
Published: October 2019

AbstractDeficiency of lysosomal acid β-glucosidase induces glycolipid storage in the macrophages of Gaucher disease but the pathways of multisystem tissue injury and destruction are unknown. To investigate the cognate molecular pathology of this inflammatory disorder, genes that were differentially expressed in spleen samples from a patient with Gaucher disease (Gaucher spleen) were isolated. Of 64 complementary DNA (cDNA) fragments sequenced from an enriched Gaucher cDNA library, 5 encode lysosomal proteins (cathepsins B, K, and S, α-fucosidase, and acid lipase), 10 encode other known proteins, and 2 represent novel sequences from human macrophage cell lines. Transcript abundance of the cathepsins, novel genes, pulmonary and activation-regulated chemokine (PARC), and NMB, a putative tumor suppressor gene, was greatly increased. Immunoblotting showed increased mature forms of all 3 cathepsins found in samples of Gaucher spleens. Immunofluorescence microscopy showed strong cathepsin B and K reactions in sinusoidal endothelium and Gaucher cells. The respective means, plus or minus SD, of cathepsin B, K, and S activities were 183 ± 35, 97 ± 39, and 91 ± 45 nmol/min/mg protein in 4 Gaucher spleens, and 26 ± 4, 10.5 ± 2, and 4.0 ± 2.1 nmol/min/mg protein in 3 control spleens. Plasma cathepsin B, K, and S activities were also elevated in Gaucher disease plasma (P &lt; .001), but compared with control plasma samples, neither cathepsin B nor K activities were significantly elevated in 8 patients with nonglycosphingolipid lysosomal storage diseases or in 9 patients with other glycosphingolipidoses, which suggests disease specificity. All 3 cathepsin activities were increased 2-fold to 3-fold in Gaucher sera compared with control sera. In all 6 patients treated by enzyme replacement for 16-22 months, serum cathepsin activities decreased significantly (P &lt; .01). Longitudinal studies confirmed the progressive reduction of proteinase activities during imiglucerase therapy but in 3 Gaucher patients with mild disease not so treated, serum cathepsin activities remained constant or increased during follow-up. Enhanced expression of cysteine proteinases may promote tissue destruction. Moreover, the first identification of aberrant cathepsin K expression in hematopoietic tissue other than osteoclasts implicates this protease in the breakdown of the matrix that characterizes lytic bone lesions in Gaucher disease.
Hoechst dye efflux reveals a novel CD7+CD34− lymphoid progenitor in human umbilical cord blood
Authors: Storms Robert W. , Goodell Margaret A. , Fisher Alan , Mulligan Richard C. , Smith Clay 
Published: October 2019

Abstract
A novel Hoechst 33342 dye efflux assay was recently developed that identifies a population of hematopoietic cells termed side population (SP) cells. In the bone marrow of multiple species, including mice and primates, the SP is composed primarily of CD34−cells, yet has many of the functional properties of hematopoietic stem cells (HSCs). This report characterizes SP cells from human umbilical cord blood (UCB). The SP in unfractionated UCB was enriched for CD34+ cells but also contained a large population of CD34− cells, many of which were mature lymphocytes. SP cells isolated from UCB that had been depleted of lineage-committed cells (Lin− UCB) contained CD34+ and CD34− cells in approximately equivalent proportions. Similar to previous descriptions of human HSCs, the CD34+Lin− SP cells were CD38dimHLA-DRdimThy-1dimCD45RA−CD71−and were enriched for myelo-erythroid precursors. In contrast, the CD34−Lin− SP cells were CD38−HLA-DR−Thy-1−CD71−and failed to generate myelo-erythroid progeny in vitro. The majority of these cells were CD7+CD11b+CD45RA+, as might be expected of early lymphoid cells, but did not express other lymphoid markers. The CD7+CD34−Lin− UCB SP cells did not proliferate in simple suspension cultures but did differentiate into natural killer cells when cultured on stroma with various cytokines. In conclusion, the human Lin− UCB SP contains both CD34+ multipotential stem cells and a novel CD7+CD34−Lin− lymphoid progenitor. This observation adds to the growing body of evidence that CD34− progenitors exist in humans.
Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia
Authors: Balogh István , Szôke Gabriella , Kárpáti Levente , Wartiovaara Ulla , Katona Éva , Komáromi István , Haramura Gizella , Pfliegler György , Mikkola Hanna , Muszbek László 
Published: October 2019

Abstract
Val34Leu polymorphism of the A subunit of coagulation factor XIII (FXIII-A) is located in the activation peptide (AP) just 3 amino acids away from the thrombin cleavage site. This mutation has been associated with a protective effect against occlusive arterial diseases and venous thrombosis; however, its biochemical consequences have not been explored. In the current study it was demonstrated that the intracellular stability and the plasma concentration of FXIII of different Val34Leu genotypes are identical, which suggests that there is no difference in the rate of synthesis and externalization of wild-type and mutant FXIII-A. In contrast, the release of AP by thrombin from the Leu34 allele proceeded significantly faster than from its wild-type Val34 counterpart. By molecular modeling larger interaction energy was calculated between the Leu34 variant and the respective domains of thrombin than between the Val34 variant and thrombin. In agreement with these findings, the activation of mutant plasma FXIII by thrombin was faster and required less thrombin than that of the wild-type variant. Full thrombin activation of purified plasma FXIII of different genotypes, however, resulted in identical specific transglutaminase activities. Similarly, the mean specific FXIII activity in the plasma was the same in the groups with wild-type, heterozygous, and homozygous variants. Faster activation of the Leu34 allele hardly could be associated with its presumed protective effect against venous thrombosis. No such protective effect was observed in a large group of patients with familial thrombophilia.
Lipopolysaccharide induces Jun N-terminal kinase activation in macrophages by a novel Cdc42/Rac-independent pathway involving sequential activation of protein kinase C ζ and phosphatidylcholine-dependent phospholipase C
Authors: Procyk Katarzyna J. , Rippo Maria Rita , Testi Roberto , Hofmann Fred , Parker Peter J. , Baccarini Manuela 
Published: October 2019

AbstractThe activation of kinases of the mitogen-activated protein kinase superfamily initiated by lipopolysaccharide (LPS) plays an important role in transducing inflammatory signals. The pathway leading to the induction of stress-activated protein kinases in macrophages stimulated with LPS was investigated. The activation of Jun N-terminal kinases (JNK) by LPS is herbimycin sensitive. Using specific inhibitors, it was shown that the pathway involves the activation of phosphoinositide 3-kinase (PI 3-K). However, in contrast to previous reports, the small GTPases Cdc42 and Rac are not required downstream of PI 3-K for JNK activation. Instead, the phosphoinositides produced by PI 3-K stimulate protein kinase C (PKC) ζ activation through PDK1. In turn, activation of this atypical PKC leads to the stimulation of phosphatidylcholine phospholipase C (PC-PLC) and acidic sphingomyelinase (ASMase). It is therefore proposed that PKCζ regulates the PC-PLC/ASMase pathway, and it is hypothesized that the resultant ceramide accumulation mediates the activation of the SEK/JNK module by LPS.
Antimicrobial proteins and peptides of blood: templates for novel antimicrobial agents
Authors: Levy Ofer 
Published: October 2019

AbstractThe innate immune system provides rapid and effective host defense against microbial invasion in a manner that is independent of prior exposure to a given pathogen.1 It has long been appreciated that the blood contains important elements that mediate rapid responses to infection. Thus, anatomic compartments with ample blood supply are less frequently infected and recover more readily once infected, whereas regions with poor perfusion are prone to severe infection and may require surgical débridement. Blood-borne innate immune mediators are either carried in circulating blood cells (ie, leukocytes and platelets) or in plasma after release from blood cells or on secretion by the liver.
Imprinting of insulin-like growth factor 2 is modulated during hematopoiesis
Authors: Morison Ian M. , Eccles Michael R. , Reeve Anthony E. 
Published: October 2019

AbstractThe transcription of insulin-like growth factor 2 (IGF-2) is affected by genomic imprinting, a multistep process through which the parental origin of a gene influences its transcription. The maternal copy of IGF-2 is silenced in most human tissues, but in the choroid plexus and the adult liver both alleles of IGF-2 are expressed. This study shows that though in peripheral blood mononuclear cells IGF-2shows paternal allele-specific expression, in total bone marrow both alleles are transcribed. This modulation of imprinting is not attributable to use of the P1 promoter, because transcription from the P3 promoter occurred from both alleles. These results suggest that transcriptional recognition of the IGF-2 imprint can be modulated during hematopoiesis and may facilitate the development of in vitro model systems to study the transcriptional recognition of a genomic imprint.
Fetal and adult hemoglobin production during adult erythropoiesis: coordinate expression correlates with cell proliferation
Authors: Wojda Urszula , Noel Pierre , Miller Jeffery L. 
Published: October 2019

AbstractThe design and evaluation of therapies for the sickle cell and β-thalassemia syndromes rely on our understanding of hemoglobin accumulation during human erythropoiesis. Here we report direct measurements of hemoglobin composition and messenger RNA (mRNA) levels in cultured CD34+ cells and correlate those measurements with studies of freshly obtained bone marrow samples. Hemoglobin levels in differentiating cells were also compared with morphologic, immunophenotypic, and cell cycle assessments. A population of large preproerythroblasts was first identified within 24 hours and became the dominant population by day 5. The transition from proerythroblast to basophilic normoblast occurred later, from days 7 to 9, and correlated with a peak of 74.1% ± 3.9% of the cells in the S phase of cell cycle. Orthochromatic normoblasts were the dominant and final cell type by day 13. High-performance liquid chromatography–based quantitation of fetal (HbF) and adult (HbA) hemoglobin and real-time polymerase chain reaction globin mRNA quantitation demonstrated a coordinate rise in the accumulation of both proteins and mRNA among these developmentally staged populations. Quantitative analyses on freshly sorted bone marrow populations demonstrated a similar rising pattern with β-globin and HbA as the dominant species at both early and late stages of differentiation. We found no evidence for HbF dominant populations or switching during differentiation in adult cells. Instead, rapid increases in both HbF (heterocellular) and HbA (pancellular) content were observed, which coincided with the apex in cell cycling and the proerythroblast-basophilic normoblast transition. Based on these measurements, we conclude that HbF and HbA content are regulated with the rate of proliferation during adult erythropoiesis.
Emergency preparedness for infant and young child feeding in emergencies (IYCF-E): an Australian audit of emergency plans and guidance
Authors: Gribble Karleen , Peterson Mary , Brown Decalie 
Published: October 2019

AbstractBackgroundAustralia experiences a high incidence of natural emergencies and Australian governments have committed significant investment into emergency preparedness and response. Amongst the population groups most vulnerable to emergencies are infants and young children with their vulnerability centering around their specific food and fluid needs. For this reason, the World Health Assembly has urged all member states to develop and implement infant and young child feeding in emergency (IYCF-E) plans in line with international guidance. This study aimed to determine the degree to which Australia has complied with this direction by conducting an audit of Australian emergency plans and guidance.MethodsAustralian Federal, State/Territory and a sample of Local government emergency plans and guidance were located via web searches. Documents were searched for key words to identify content dealing with the needs of infants and young children. Plans and guidance were also searched for content dealing with the needs of animals as a comparison.ResultsWhile plans and guidance contained numerous pointers to the desirability of having plans that address IYCF-E, there was a dearth of planning at all levels of government for the needs of infants and young children. Guidance related to heat waves contained information that could prove dangerous to infants. No agency at Federal or State/Territory had designated responsibility for IYCF-E or children in general. This was in stark contrast to the situation of animals for which there was widespread and comprehensive planning at all levels of government with clear designation of organisational responsibility.ConclusionsLack of planning for IYCF-E in Australia places infants and young children at serious risk of adverse health consequences in emergencies. Australian Federal, State/Territory and Local governments need to take action to ensure that IYCF-E plans and guidance are developed and deployed in line with international standards. The pathway to successful integration of animal welfare plans provides a method for a similar integration of IYCF-E plans. Government health authorities are best placed to lead and be responsible for IYCF-E in Australia. National governments internationally should similarly take action to ensure that their youngest, most vulnerable citizens are protected in emergencies.
Evaluation of serological test of Zika in an endemic area of flavivirus in the Colombian Caribbean
Authors: Arrieta German , Mattar Salim , Villero-Wolf Yeneiris , Gomezcaceres Luty , Doria Amanda 
Published: October 2019

Abstract
The Zika virus (ZIKV) is an emerging flavivirus transmitted primarily through arthropods, endemic in Africa, Asia, and the Americas, and is considered a global threat by the World Health Organization.

Objective
To evaluate a commercial Zika virus test (IgG/IgM catalog number B815C, Biocan, Canada.

Methods
We evaluated 30 sera of patients diagnosed with Dengue, Leptospira, Malaria, Hantavirus, and Chikungunya. To establish the sensitivity of the test, two groups of sera were analyzed, the first one was patients with Zika RT-qPCR positive, and the second were patients RT-qPCR negative but with clinical suspicion of Zika.

Results
The specificity was of 23.3% (7/30), the sensitivity in acute patients with positive RT-qPCR was of 63.6%, the patients with clinical suspicion of Zika the sensitivity (IgM) was of 80% (n = 8/10). Overall sensitivity (IgM) of both groups was of 71.4% (15/21).

Conclusions
The test showed a low specificity to be used as a serological test in an endemic area of flavivirus infection.
New potentiometric sensors for methylphenidate detection based on host–guest interaction
Authors: AlRabiah Haitham , Abounassif Mohammed , Aljohar Haya I. , Mostafa Gamal Abdel-Hafiz 
Published: October 2019

Abstract
The study aims to develop simple, sensitive, and selective methods for detecting methylphenidate in its bulk, dosage form and human urine. Sensing materials include β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), and 4-tertbutylcalix[8]arene as ionophores or electroactive materials have been used for construction of sensors 1, 2, and 3, respectively; Potassium tetrakis (4-chlorophenyl)borate (KTpClPB) as an ion additive was used and dioctyl phthalate as a plasticizer. The sensors displayed a fast, stable response over a wide concentration range of methylphenidate (8 × 10−6 M to 1 × 10−3 M) with 10−6 M detection limit over the pH range of 4–8. The developed sensors displayed a Near-Nernstian cationic response for methylphenidate at 59.5, 51.37, and 56.5 mV/decade for sensors β-CD, γ-CD, or 4-tertbutylcalix[8]arene respectively. Validation of the proposed sensors is supported by high accuracy, precision, stability, fast response, and long lifetimes, as well as selectivity for methylphenidate in the presence of different species. Sensitive and practical sensors for the determination of methylphenidate in bulk, in pharmaceutical forms and urine were developed and validated for routine laboratory use. The results were comparable to those obtained by HPLC method.
Correction to: Effects of challenge dose and inoculation route of the virulent Neospora caninum Nc-Spain7 isolate in pregnant cattle at mid-gestation
Authors: Vázquez Patricia , Osoro Koldo , Fernández Miguel , Román-Trufero Alicia , Regidor-Cerrillo Javier , Jiménez-Pelayo Laura , García-Sánchez Marta , Rojo-Montejo Silvia , Benavides Julio , Horcajo Pilar , Ortega-Mora Luis Miguel 
Published: October 2019

In the original publication of this article [1], there are error in the Fig. 5, the “ml” should be replaced by “mL” (Fig. 5A) and “IFNγ” should be “IFN-γ” in Fig. 5A, B. The correct figure is below:
Financial incentives as a governmental tool to bridge the medical manpower gap between Israel’s center and periphery
Authors: Jacobson Eyal , Ezra Vered 
Published: October 2019

Abstract
One of the major health disparities between Israel’s center and periphery relates to the physician to population ratio. To overcome it, the Israeli government launched a financial incentive program in 2011, in an attempt to encourage physicians to work in the periphery and in specialties experiencing major shortages. A recent IJHPR study found that residents who choose to work in a peripheral institution gave more weight to the grant in their decision-making process than did residents from central institutions. This finding lends support to the rationale behind the government program and suggests that it is an effective means of achieving the desired goal.
This commentary details how the program was repeatedly adjusted during the 2011–2018 period, in light of changing needs. As financial and human resources are expected to remain scarce in the future, the program must continue to be constantly evaluated and adjusted in order to maintain its effectiveness.
Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma
Authors: Armand Philippe , Rodig Scott , Melnichenko Vladimir , Thieblemont Catherine , Bouabdallah Kamal , Tumyan Gayane , Özcan Muhit , Portino Sergio , Fogliatto Laura , Caballero Maria D. , Walewski Jan , Gulbas Zafer , Ribrag Vincent , Christian Beth , Perini Guilherme Fleury , Salles Gilles , Svoboda Jakub , Zain Jasmine , Patel Sanjay , Chen Pei-Hsuan , Ligon Azra H. , Ouyang Jing , Neuberg Donna , Redd Robert , Chatterjee Arkendu , Balakumaran Arun , Orlowski Robert , Shipp Margaret , Zinzani Pier Luigi 
Published: October 2019

PURPOSE Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692 ) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990 ) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.