bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia
Authors: Ghia Emanuela M. , Rassenti Laura Z. , Neuberg Donna S. , Blanco Alejandro , Yousif Fouad , Smith Erin N. , McPherson John D. , Hudson Thomas J. ,   the HALT Pan-Leukemia Gene Panel Consortium, Harismendy Olivier , Frazer Kelly A. , Kipps Thomas J. 
Published: March 2019

Abstract
Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P &lt; .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+. Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.
Trib1 regulates eosinophil lineage commitment and identity by restraining the neutrophil program
Authors: Mack Ethan A. , Stein Sarah J. , Rome Kelly S. , Xu Lanwei , Wertheim Gerald B. , Melo Rossana C. N. , Pear Warren S. 
Published: March 2019

AbstractEosinophils and neutrophils are critical for host defense, yet gaps in understanding how granulocytes differentiate from hematopoietic stem cells (HSCs) into mature effectors remain. The pseudokinase tribbles homolog 1 (Trib1) is an important regulator of granulocytes; knockout mice lack eosinophils and have increased neutrophils. However, how Trib1 regulates cellular identity and function during eosinophilopoiesis is not understood. Trib1 expression markedly increases with eosinophil-lineage commitment in eosinophil progenitors (EoPs), downstream of the granulocyte/macrophage progenitor (GMP). Using hematopoietic- and eosinophil-lineage–specific Trib1 deletion, we found that Trib1 regulates both granulocyte precursor lineage commitment and mature eosinophil identity. Conditional Trib1 deletion in HSCs reduced the size of the EoP pool and increased neutrophils, whereas deletion following eosinophil lineage commitment blunted the decrease in EoPs without increasing neutrophils. In both modes of deletion, Trib1-deficient mice expanded a stable population of Ly6G+ eosinophils with neutrophilic characteristics and functions, and had increased CCAAT/enhancer binding protein α (C/EBPα) p42. Using an ex vivo differentiation assay, we found that interleukin 5 (IL-5) supports the generation of Ly6G+ eosinophils from Trib1-deficient cells, but is not sufficient to restore normal eosinophil differentiation and development. Furthermore, we demonstrated that Trib1 loss blunted eosinophil migration and altered chemokine receptor expression, both in vivo and ex vivo. Finally, we showed that Trib1 controls eosinophil identity by modulating C/EBPα. Together, our findings provide new insights into early events in myelopoiesis, whereby Trib1 functions at 2 distinct stages to guide eosinophil lineage commitment from the GMP and suppress the neutrophil program, promoting eosinophil terminal identity and maintaining lineage fidelity.
Cleavage of anti-PF4/heparin IgG by a bacterial protease and potential benefit in heparin-induced thrombocytopenia
Authors: Kizlik-Masson Claire , Deveuve Quentin , Zhou Yuhang , Vayne Caroline , Thibault Gilles , McKenzie Steven E. , Pouplard Claire , Loyau Stéphane , Gruel Yves , Rollin Jérôme 
Published: March 2019

AbstractHeparin-induced thrombocytopenia (HIT) is due to immunoglobulin G (IgG) antibodies, which bind platelet factor 4 (PF4) modified by polyanions, such as heparin (H). IgG/PF4/polyanion complexes directly activate platelets via Fc gamma type 2 receptor A (FcγRIIA) receptors. A bacterial protease, IgG-degrading enzyme of Streptococcus pyogenes (IdeS), cleaves the hinge region of heavy-chain IgG, abolishing its ability to bind FcγR, including FcγRIIA. We evaluated whether cleavage of anti-PF4/H IgG by IdeS could suppress the pathogenicity of HIT antibodies. IdeS quickly cleaved purified 5B9, a monoclonal chimeric anti-PF4/H IgG1, which led to the formation of single cleaved 5B9 (sc5B9), without any reduction in binding ability to the PF4/H complex. However, as compared with uncleaved 5B9, the affinity of sc5B9 for platelet FcγRIIA was greatly reduced, and sc5B9 was also unable to induce heparin-dependent platelet activation. In addition, incubating IdeS in whole blood containing 5B9 or HIT plasma samples led to cleavage of anti-PF4/H antibodies, which fully abolished the ability to induce heparin-dependent platelet aggregation and tissue factor messenger RNA synthesis by monocytes. Also, when whole blood was perfused in von Willebrand factor–coated microfluidic channels, platelet aggregation and fibrin formation induced by 5B9 with heparin was strongly reduced after IdeS treatment. Finally, IdeS prevented thrombocytopenia and hypercoagulability induced by 5B9 with heparin in transgenic mice expressing human PF4 and FcγRIIA receptors. In conclusion, cleavage of anti-PF4/H IgG by IdeS abolishes heparin-dependent cellular activation induced by HIT antibodies. IdeS injection could be a potential treatment of patients with severe HIT.
HLA-DRB3*01:01 exhibits a dose-dependent impact on HPA-1a antibody levels in HPA-1a–immunized women
Authors: Kjeldsen-Kragh Jens , Titze Thomas L. , Lie Benedicte Alexandra , Vaage John T. , Kjær Mette 
Published: March 2019

Abstract
HLA-DRB3*01:01 is a predisposing factor for human platelet antigen 1a (HPA-1a) immunization, which is responsible for most cases of fetal and neonatal alloimmune thrombocytopenia. The aim of this study was to investigate if the HLA-DRB3*01:01 allele imposes a dose-dependent effect on anti-HPA-1a levels and neonatal platelet counts. One hundred and thirty HPA-1a–immunized women were divided into 3 groups: HLA-DRB3*01:01 negative, HLA-DRB3*01:01 hemizygous or heterozygous, and HLA-DRB3*01:01 homozygous. The dose of the HLA-DRB3*01:01 allele was determined by sequencing exon 2 of the HLA-DRB3 gene followed by HLA-DRB3 and HLA-DRB1 typing of selected samples. Anti-HPA-1a levels at time of delivery and neonatal platelet counts were compared among groups. There was a significant dose-dependent effect of the HLA-DRB3*01:01 allele on anti-HPA-1a levels (global P value [Pglobal] = .0032). Median (range) anti-HPA-1a levels were 1.5 IU/mL (0.0-19.0 IU/mL), 21.1 IU/mL (0.0-1967 IU/mL), and 43.7 IU/mL (1.0-980 IU/mL) in women with 0, 1, and 2 copies of the HLA-DRB3*01:01 allele, respectively. There was also a significant, but opposite, dose-dependent effect of the mother’s HLA-DRB3*01:01 allele on the platelet count of the newborn (Pglobal = .0155). Median (range) neonatal platelet counts were 241 × 109/L (59 × 109/L to 393 × 109/L), 107 × 109/L (4 × 109/L to 387 × 109/L) and 32 × 109/L (4 × 109/L to 352 × 109/L) for newborns of mothers with 0, 1, and 2 copies of the HLA-DRB3*01:01 allele, respectively. Thus, the HLA-DRB3*01:01 allele exhibits a dose-dependent impact on maternal anti-HPA-1a levels in HPA-1a–immunized women.
Obesity alters oestrogen metabolism and contributes to pulmonary arterial hypertension
Authors: Mair Kirsty M. , Harvey Katie Y. , Henry Alasdair D. , Hillyard Dianne Z. , Nilsen Margaret , MacLean Margaret R. 
Published: March 2019

Obesity is a common comorbidity for pulmonary arterial hypertension (PAH). Additionally, oestrogen and its metabolites are risk factors for the development of PAH. Visceral adipose tissue (VAT) is a major site of oestrogen production; however, the influence of obesity-induced changes in oestrogen synthesis and metabolism on the development of PAH is unclear. To address this we investigated the effects of inhibiting oestrogen synthesis and metabolism on the development of pulmonary hypertension in male and female obese mice.We depleted endogenous oestrogen in leptin-deficient (ob/ob) mice with the oestrogen inhibitor anastrozole (ANA) and determined the effects on the development of pulmonary hypertension, plasma oestradiol and urinary 16α-hydroxyestrone (16αOHE1). Oestrogen metabolism through cytochrome P450 1B1 (CYP1B1) was inhibited with 2,2′,4,6′-tetramethoxystilbene (TMS).ob/obmice spontaneously develop pulmonary hypertension, pulmonary vascular remodelling and increased reactive oxygen species production in the lung; these effects were attenuated by ANA. Oestradiol levels were decreased in obese male mice; however, VAT CYP1B1 and 16αOHE1 levels were increased. TMS also attenuated pulmonary hypertension in maleob/obmice. Intra-thoracic fat fromob/obmice and VAT conditioned media produce 16αOHE1 and can contribute to oxidative stress, effects that are attenuated by both ANA and TMS.Obesity can induce pulmonary hypertension and changes in oestrogen metabolism, resulting in increased production of 16αOHE1 from VAT that contributes to oxidative stress. Oestrogen inhibitors are now in clinical trials for PAH. This study has translational consequences as it suggests that oestrogen inhibitors may be especially beneficial in treating obese individuals with PAH.
RETRACTED ARTICLE: Investigation of molecular biomarker candidates for diagnosis and prognosis of chronic periodontitis by bioinformatics analysis of pooled microarray gene expression datasets in Gene Expression Omnibus (GEO)
Authors: Suzuki Asami , Horie Tetsuro , Numabe Yukihiro 
Published: March 2019

Abstract
Background
Chronic periodontitis (CP) is a multifactorial inflammatory disease. For the diagnosis of CP, it is necessary to investigate molecular biomarkers and the biological pathway of CP. Although analysis of mRNA expression profiling with microarray is useful to elucidate pathological mechanisms of multifactorial diseases, it is expensive. Therefore, we utilized pooled microarray gene expression data on the basis of data sharing to reduce hybridization costs and compensate for insufficient mRNA sampling. The aim of the present study was to identify molecular biomarker candidates and biological pathways of CP using pooled datasets in the Gene Expression Omnibus (GEO) database.

Methods
Three pooled transcriptomic datasets (GSE10334, GSE16134, and GSE23586) of gingival tissue with CP in the GEO database were analyzed for differentially expressed genes (DEGs) using GEO2R, functional analysis and biological pathways with the Database of Annotation Visualization and Integrated Discovery database, Protein-Protein Interaction (PPI) network and hub gene with the Search Tool for the Retrieval of Interaction Genes database, and biomarker candidates for diagnosis and prognosis and upstream regulators of dominant biomarker candidates with the Ingenuity Pathway Analysis database.

Results
We shared pooled microarray datasets in the GEO database. One hundred and twenty-three common DEGs were found in gingival tissue with CP, including 81 upregulated genes and 42 downregulated genes. Upregulated genes in Gene Ontology were significantly enriched in immune responses, and those in the Kyoto Encyclopedia of Genes and Genomes pathway were significantly enriched in the cytokine-cytokine receptor interaction pathway, cell adhesion molecules, and hematopoietic cell lineage. From the PPI network, the 12 nodes with the highest degree were screened as hub genes. Additionally, six biomarker candidates for CP diagnosis and prognosis were screened.

Conclusions
We identified several potential biomarkers for CP diagnosis and prognosis (e.g., CSF3, CXCL12, IL1B, MS4A1, PECAM1, and TAGLN) and upstream regulators of biomarker candidates for CP diagnosis (TNF and TGF2). We also confirmed key genes of CP pathogenesis such as CD19, IL8, CD79A, FCGR3B, SELL, CSF3, IL1B, FCGR2B, CXCL12, C3, CD53, and IL10RA. To our knowledge, this is the first report to reveal associations of CD53, CD79A, MS4A1, PECAM1, and TAGLN with CP.
Proteomic alterations of HDL in youth with type 1 diabetes and their associations with glycemic control: a case–control study
Authors: Gourgari Evgenia , Ma Junfeng , Playford Martin P. , Mehta Nehal N. , Goldman Radoslav , Remaley Alan T. , Gordon Scott M. 
Published: March 2019

AbstractBackgroundPatients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition.MethodsThis was a cross-sectional case–control study. Blood samples were obtained from patients with T1DM and HC. HDL was isolated from plasma by size-exclusion chromatography and further purified using a lipid binding resin. The HDL proteome was analyzed by mass spectrometry using label-free SWATH peptide quantification.ResultsSamples from 26 patients with T1DM and 13 HC were analyzed and 78 HDL-bound proteins were measured. Youth with T1DM had significantly increased amounts of complement factor H related protein 2 (FHR2; adjusted P < 0.05), compared to HC. When patients were analyzed based on glucose control, several trends emerged. Some proteins were altered in T1DM and not influenced by glycemic control (e.g. FHR2) while others were partially or completely corrected with optimal glucose control (e.g. alpha-1-beta glycoprotein, A1BG). In a subgroup of poorly controlled T1DM patients, inter alpha trypsin inhibitor 4 (ITIH4) was dramatically elevated (P < 0.0001) and this was partially reversed in patients with optimal glucose control. Some proteins including complement component C3 (CO3) and albumin (ALB) were significantly different only in T1DM patients with optimal glucose control, suggesting a possible effect of exogenous insulin.ConclusionsYouth with T1DM have proteomic alterations of their HDL compared to HC, despite similar concentration of HDL cholesterol. The influence of these compositional changes on HDL function are not yet known. Future efforts should focus on investigating the role of these HDL associated proteins in regard to HDL function and their role in CVD risk in patients with T1DM.Trial registrationNCT02275091
Artemisinin-based combination therapy during pregnancy: outcome of pregnancy and infant mortality: a cohort study
Authors: Nambozi Michael , Tinto Halidou , Mwapasa Victor , Tagbor Harry , Kabuya Jean-Bertin Bukasa , Hachizovu Sebastian , Traoré Maminata , Valea Innocent , Tahita Marc Christian , Ampofo Gifty , Buyze Jozefien , Ravinetto Raffaella , Arango Diana , Thriemer Kamala , Mulenga Modest , van Geertruyden Jean-Pierre , D’Alessandro Umberto 
Published: March 2019

Abstract
Background
The World Health Organization (WHO) recommendation of treating uncomplicated malaria during the second and third trimester of pregnancy with an artemisinin-based combination therapy (ACT) has already been implemented by all sub-Saharan African countries. However, there is limited knowledge on the effect of ACT on pregnancy outcomes, and on newborn and infant’s health.

Methods
Pregnant women with malaria in four countries (Burkina Faso, Ghana, Malawi and Zambia) were treated with either artemether–lumefantrine (AL), amodiaquine–artesunate (ASAQ), mefloquine-artesunate (MQAS), or dihydroartemisinin–piperaquine (DHA–PQ); 3127 live new-borns (822 in the AL, 775 in the ASAQ, 765 in the MQAS and 765 in the DHAPQ arms) were followed-up until their first birthday.

Results
Prevalence of placental malaria and low birth weight were 28.0% (738/2646) and 16.0% (480/2999), respectively, with no significant differences between treatment arms. No differences in congenital malformations (p = 0.35), perinatal mortality (p = 0.77), neonatal mortality (p = 0.21), and infant mortality (p = 0.96) were found.

Conclusions
Outcome of pregnancy and infant survival were similar between treatment arms indicating that any of the four artemisinin-based combinations could be safely used during the second and third trimester of pregnancy without any adverse effect on the baby. Nevertheless, smaller safety differences between artemisinin-based combinations cannot be excluded; country-wide post-marketing surveillance would be very helpful to confirm such findings.
Trial registration ClinicalTrials.gov, NCT00852423, Registered on 27 February 2009, https://clinicaltrials.gov/ct2/show/NCT00852423
Characterization of the microstructural features and the rust layers of an archaeological iron sword in the Egyptian Museum in Cairo (380–500 A.D.)
Authors: Salem Yussri , Oudbashi Omid , Eid Doaa 
Published: March 2019

Abstract
In this paper, a sword is investigated from a collection of archaeological iron swords displayed in the Egyptian Museum from the civilization centered on Ballana and Qustul in Egyptian Nubia (380–600 A.D.). A range of metallographic analytical techniques have been used to characterize the sword’s metallic structure and its rust crust. The results revealed that the sword was made of low-carbon steel and corrosion products formed on the surface are iron sulfate, iron oxides/hydroxides including goethite, maghemite, magnetite, lepidocrocite, akaganeite and ferric chloride. The investigation also revealed that the rust crust constituted of two corrosion layers: a dense layer and a transformed medium. Crystals of soil minerals were clearly observed in the outer corrosion layer. Moreover, several microstructural features were detected, indicating the stage of deterioration and the features of metallurgy of this sword. Furthermore, the obtained results have been used to select appropriate conservation procedures for preventing degradation in the future and ensuring its reliable restoration.
Higher Insulin Resistance and Adiposity in Postmenopausal Women With Breast Cancer Treated With Aromatase Inhibitors
Authors: Gibb Fraser W , Dixon J Michael , Clarke Catriona , Homer Natalie Z , Faqehi Abdullah M M , Andrew Ruth , Walker Brian R 
Published: March 2019

Abstract

Context
Aromatase deficiency causes obesity and insulin resistance in aromatase knockout mice and humans with rare mutations of the aromatase gene (CYP19). Aromatase inhibitors are a commonly prescribed therapy for postmenopausal breast cancer.

Objective
We hypothesized that aromatase inhibitors induce obesity and insulin resistance when used in treatment of breast cancer.

Design
Case-control study.

Setting
University teaching hospital.

Participants
Patients with postmenopausal breast cancer (n = 20) treated with aromatase inhibitors and 20 age-matched control subjects.

Main outcome measures
The primary outcome measure was insulin sensitivity index – Matsuda, derived from a 75-g oral glucose tolerance test. Body composition was assessed by dual energy x-ray absorptiometry and biopsy specimens of subcutaneous adipose tissue obtained for assessment of mRNA transcript levels. Data are reported as mean ± SEM (patients receiving inhibitors vs control group, respectively).

Results
Aromatase inhibitor therapy was associated with significantly lower insulin sensitivity (5.15 ± 0.45 vs 6.80 ± 0.64; P = 0.041), higher peak insulin concentration after oral glucose tolerance test (693.4 ± 78.6 vs 527.6 ± 85.5 pmol/L; P = 0.035), greater percentage of body fat (38.4% ± 1.0% vs 34.6% ± 1.3%; P = 0.026), and higher plasma leptin concentration (23.5 ± 2.8 vs 15.5 ± 2.3 ng/mL; P = 0.035).

Conclusion
Women who received aromatase inhibitors for postmenopausal breast cancer had greater percentage body fat and insulin resistance compared with control subjects with no history of breast cancer.
Association of Maternal Iodine Status With Child IQ: A Meta-Analysis of Individual Participant Data
Authors: Levie Deborah , Korevaar Tim I M , Bath Sarah C , Murcia Mario , Dineva Mariana , Llop Sabrina , Espada Mercedes , van Herwaarden Antonius E , de Rijke Yolanda B , Ibarluzea Jesús M , Sunyer Jordi , Tiemeier Henning , Rayman Margaret P , Guxens Mònica , Peeters Robin P 
Published: March 2019

Abstract

Context
Although the consequences of severe iodine deficiency are beyond doubt, the effects of mild to moderate iodine deficiency in pregnancy on child neurodevelopment are less well established.

Objective
To study the association between maternal iodine status during pregnancy and child IQ and identify vulnerable time windows of exposure to suboptimal iodine availability.

Design
Meta-analysis of individual participant data from three prospective population-based birth cohorts: Generation R (Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002 and 2006, 2003 and 2008, and 1990 and 1992, respectively.

Setting
General community.

Participants
6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancies, fertility treatment, medication affecting the thyroid, and preexisting thyroid disease.

Main Outcome Measure
Child nonverbal and verbal IQ assessed at 1.5 to 8 years of age.

Results
There was a positive curvilinear association of urinary iodine/creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat <150 µg/g was not associated with lower nonverbal IQ (−0.6 point; 95% CI: −1.7 to 0.4 points; P = 0.246) or lower verbal IQ (−0.6 point; 95% CI: −1.3 to 0.1 points; P = 0.082). Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation.

Conclusions
Fetal brain development is vulnerable to mild to moderate iodine deficiency, particularly in the first trimester. Our results show that potential randomized controlled trials investigating the effect of iodine supplementation in women with mild to moderate iodine deficiency on child neurodevelopment should begin supplementation not later than the first trimester.
Optimizing Management of Medically Responsive Epilepsy
Authors: Bauer Derek , Quigg Mark 
Published: March 2019

ABSTRACTPURPOSE OF REVIEWThis article reviews the management of patients with medically responsive epilepsy, including discussion of factors that may lead to transient breakthrough seizures and patient and physician strategies to maintain freedom from seizures.RECENT FINDINGSImperfect adherence, unanticipated changes in ongoing medical therapy, inadvertent use of proconvulsants or concurrent medications that alter epilepsy medication kinetics, and a variety of seizure precipitants such as stress or sleep deprivation may alter long-term seizure control.SUMMARYThe majority of patients with epilepsy are medically responsive. Many potential factors may lead to breakthrough seizures in these patients. Identification of these factors, patient education, and use of self-management techniques including mindfulness therapy and cognitive-behavioral therapy may play a role in protecting patients with epilepsy against breakthrough seizures.