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971.
972.
Melinda E. Varney Madeline Niederkorn Hiroyasu Konno Takayuki Matsumura Jin Gohda Nobuaki Yoshida Taishin Akiyama Susanne Christie Jing Fang David Miller Andres Jerez Aly Karsan Jaroslaw P. Maciejewski Ruhikanta A. Meetei Jun-ichiro Inoue Daniel T. Starczynowski 《The Journal of experimental medicine》2015,212(11):1967-1985
TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) myelodysplastic syndrome (MDS). Deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cell (HSPC) proportions and altered myeloid differentiation. A subset of mice transplanted with Tifab knockout (KO) HSPCs develop a BM failure with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPCs are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic defect. Gene expression analysis of Tifab KO HSPCs identified dysregulation of immune-related signatures, and hypersensitivity to TLR4 stimulation. TIFAB forms a complex with TRAF6, a mediator of immune signaling, and reduces TRAF6 protein stability by a lysosome-dependent mechanism. In contrast, TIFAB loss increases TRAF6 protein and the dynamic range of TLR4 signaling, contributing to ineffective hematopoiesis. Moreover, combined deletion of TIFAB and miR-146a, two genes associated with del(5q) MDS/AML, results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction. Re-expression of TIFAB in del(5q) MDS/AML cells results in attenuated TLR4 signaling and reduced viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPCs by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML.Myelodysplastic syndrome (MDS) refers to a group of hematopoietic stem cell (HSC) disorders associated with ineffective hematopoiesis, blood cytopenias, myeloid dysplasia, genomic instability, and predisposition to acute myeloid leukemia (AML) or bone marrow failure (BMF). Recent classifications of MDS describe eight subtypes based on biological, genetic, and morphological features (Cazzola and Malcovati, 2010). Independent of classification, MDS is propagated by rare and defective HSCs, and is defined by recurring cytogenetic changes and somatic point mutations. The most common cytogenetic alteration in MDS is deletion of chromosome (chr) 5q (del(5q)). In the absence of other cytogenetic alterations, MDS patients with a del(5q) exhibit refractory anemia, neutropenia, and elevated platelets associated with hypolobulated megakaryocytes (Giagounidis et al., 2006). Del(5q) is found in 25% of therapy-related MDS cases, which occur as a result of treatment with alkylating agents for unrelated conditions, and is strongly correlated with progression to AML (Haase et al., 2007; Haase, 2008; Qian et al., 2010). Although two commonly deleted regions (CDRs) have been mapped on chr 5q each spanning ∼1 Mb, a distal locus at 5q33.1, and a proximal locus at 5q31.1(Zhao et al., 1997), there are multiple genes that likely contribute to the pathogenesis of del(5q) MDS (Le Beau et al., 1989; Willman et al., 1993; Boultwood et al., 1994, 1997, 2000, 2002, 2007; Jaju et al., 1998). Clonal dominance of del(5q) cells is driven by haploid expression of CSNK1A1 (Schneider et al., 2014), whereas the erythroid defect has been attributed to RPS14 genes located within the distal CDR (Ebert et al., 2008; Barlow et al., 2010). Thrombocytosis associated with megakaryocytic dysplasia, neutropenia, and clonal dominance, are caused by loss of two miRNAs, miR-145 and miR-146a, in del(5q) MDS patients (Kumar et al., 2009; Starczynowski et al., 2010). Germline knockout of mouse miR-146a results in an early onset of myeloid expansion in the BM, and progression to more aggressive diseases such as lymphomas, BMF, and myeloid leukemia (Lu et al., 2010; Boldin et al., 2011; Zhao et al., 2011). Furthermore, overexpression of TRAF6, a miR-146a target gene, in mouse HSPCs mimics certain hematopoietic defects observed in miR-146a–deficient mice, including neutropenia, dysplasia, and myeloid leukemia. Overexpression of TRAF6, however, also results in elevated platelets. Some of the effects are mediated by IL-6, as overexpression of TRAF6 in Il6-deficient HSPCs restores platelets and neutrophil counts. DIAPH1, which encodes mDia1, is located on 5q31.3, which resides between the two commonly deleted regions in del(5q) MDS. mDia1-deficient mice exhibit an age-dependent granulocytopenia, and myeloid dysplasia in the BM, in part through increased TLR4 signaling. The proximal CDR at 5q31.1 is associated with aggressive forms of del(5q) and includes ∼12 coding genes. Two of these genes, CTNNA1 and EGR1, are thought to contribute to cell survival and myeloproliferation, respectively (Joslin et al., 2007; Liu et al., 2007). HSPA9 and PPP2CA have also been implicated in aspects of the del(5q) MDS/AML phenotype. Despite this recent progress, detailed molecular, cellular, and genetic analyses of candidate genes on chr 5q are required to completely understand the pathogenesis of del(5q) MDS/AML.Derepression of TRAF6, as a result of miR-146a haploinsufficiency, is one molecular consequence of del(5q) (Starczynowski et al., 2010; Boldin et al., 2011). TRAF6 is an E3 ubiquitin ligase and signal transducer of the innate immune signaling pathway in response to pathogens and host damage-associated molecules (Wu and Arron, 2003). A search of annotated genes within or near the CDR in del(5q) revealed a relatively uncharacterized gene, TRAF-interacting protein with forkhead-associated domain B (TIFAB). TIFAB resides within the proximal CDR on band 5q31.1, and belongs to a family of forkhead-associated domain proteins that also includes TIFA. TIFA was originally identified as a TRAF6-interacting protein in a yeast two-hybrid screen (Kanamori et al., 2002; Takatsuna et al., 2003), whereas TIFAB was identified as a TIFA-related protein by an in silico homology screen (Matsumura et al., 2004, 2009). To investigate whether loss of TIFAB is important to the pathophysiology of del(5q) MDS/AML, in this study, we characterized a germline Tifab knockout (KO) mouse. Tifab−/− mice exhibit progressive hematopoietic defects, including skewed HSPC proportions, altered myeloid differentiation, and a BMF-like disease associated with BM dysplasia and cytopenia. Tifab−/− BM cells are hypersensitive to Toll-like receptor 4 (TLR4) stimulation, suggesting that loss of TIFAB alters the innate immune pathway. Independent of TRAF6 mRNA, TIFAB loss results in stabilization of TRAF6 protein. Moreover, combined deletion of TIFAB and miR-146a results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction in vivo. This provides a potential molecular explanation for altered TLR4 sensitivity and the BMF phenotype. Collectively, our results provide evidence that deletion of TIFAB contributes to an MDS-like hematopoietic phenotype in mice by changing the dynamic range of the innate immune pathway in HSPCs through the regulation of TRAF6 protein stability. 相似文献
973.
Performant Mutation Identification Using Targeted Next‐Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes
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Dorien Proost Geert Vandeweyer Josephina A.N. Meester Simone Salemink Marlies Kempers Christie Ingram Nils Peeters Johan Saenen Christiaan Vrints Ronald V. Lacro Dan Roden Wim Wuyts Harry C. Dietz Geert Mortier Bart L. Loeys Lut Van Laer 《Human mutation》2015,36(8):808-814
At least 14 causative genes have been identified for both syndromic and nonsyndromic forms of thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world. Molecular confirmation of the diagnosis is increasingly important for gene‐tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor‐intensive. To circumvent these problems, we developed a TAA gene panel for next‐generation sequencing of 14 TAA genes. After validation, we applied the assay to 100 Marfan patients. We identified 90 FBN1 mutations, 44 of which were novel. In addition, Multiplex ligation‐dependent probe amplification identified large deletions in six of the remaining samples, whereas false‐negative results were excluded by Sanger sequencing of FBN1, TGFBR1, and TGFBR2 in the last four samples. Subsequently, we screened 55 syndromic and nonsyndromic TAA patients. We identified causal mutations in 15 patients (27%), one in each of the six following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous), two in NOTCH1, and seven in FBN1. We conclude that our approach for TAA genetic testing overcomes the intrinsic hurdles of consecutive Sanger sequencing of all candidate genes and provides a powerful tool for the elaboration of clinical phenotypes assigned to different genes. 相似文献
974.
Vancomycin-dependent antibodies associated with thrombocytopenia and refractoriness to platelet transfusion in patients with leukemia 总被引:1,自引:0,他引:1
Two patients with leukemia experienced profound thrombocytopenia and refractoriness to platelet transfusion during vancomycin treatment. In one patient, withdrawal of drug and administration of platelet transfusions restored platelet counts to near normal levels (approximately 100 x 10(9)/L), however, subsequent challenge with vancomycin due to recurring infection again precipitated severe thrombocytopenia (platelets less than 10 x 10(9)/L) and life-threatening hemorrhagic symptoms. Potent vancomycin-dependent antiplatelet antibodies were detected in the serum of both patients during the refractory period using staphylococcal protein A rosette formation. Employing a monoclonal antibody-antigen capture enzyme-linked immunosorbent assay (ELISA), the patients were found to have vancomycin-dependent IgG antibodies that bound specifically to platelet glycoproteins (GP) IIb and/or IIIa. One of these antibodies failed to react with platelets deficient in GPIIb/IIIa obtained from an individual with Glanzmann's thrombasthenia. These findings provide the first major evidence for drug-dependent antibodies in association with severe thrombocytopenia and refractoriness to platelet transfusion in alloimmunized leukemia patients and, further, provide the first demonstration of vancomycin-dependent antibodies reactive with platelets. 相似文献
975.
Douglas J. Christie Patrick C. Mullen Richard H. Aster 《British journal of haematology》1987,67(2):213-219
Quinine- and quinidine-dependent antiplatelet antibodies are generally believed to bind to the membrane glycoprotein complex, GPIb/IX. However, we and others have found that some drug-dependent antibodies bind to platelets from patients with the Bernard-Soulier syndrome which lack these glycoproteins. We therefore studied the reactions of a group of these antibodies with normal and Bernard-Soulier platelets and their membrane proteins. As indicated by rosette formation of the sensitized platelets around protein A-Sepharose beads, two quinine- and two quinidine-dependent antibodies reacted with both normal and Bernard-Soulier syndrome platelets at a high (300 microM) concentration of drug. At a pharmacologic drug concentration (10 microM), all four antibodies reacted with normal platelets but only the two quinine-induced antibodies reacted with Bernard-Soulier platelets. Immunoprecipitation studies with solubilized, tritium-labelled normal platelets, at both high and low drug concentrations, showed that each of the four antibodies precipitated proteins corresponding to GPIb and GPIX. Fainter bands corresponding to glycoproteins IIb and IIIa, which do not label well with tritium, were also detected. With radioiodinated normal platelets, it was found that each of the four antibodies was capable of precipitating GPIIb/IIIa, but only in the presence of drug. The four antibodies also promoted drug-dependent precipitation of GPIIb and GPIIIa from lysates of radioiodinated Bernard-Soulier platelets. The two quinine-dependent antibodies precipitated these glycoproteins at both high and low drug concentrations, while the quinidine-dependent antibodies reacted much more strongly at the higher drug concentration. Precipitation of GPIb/IX was not observed with BSS platelets. Absorption of a quinine-induced antibody with Bernard-Soulier platelets in the presence of drug eliminated its ability to precipitate GPIIb and GPIIIa. However, the absorbed antibody retained the ability to precipitate GPIb from solubilized normal platelets. Thus, at least two drug-dependent antibodies were present, one specific for GPIb/IX and the other for GPIIb/IIIa. These findings indicate that glycoproteins IIb and/or IIIa, in addition to the GPIb/IX complex, can serve as targets for drug-dependent antibodies in both intact and detergent-solubilized platelet preparations. 相似文献
976.
Paulina Hanson-Manful Alana L. Whitcombe Paul G. Young Polly E. Atatoa Carr Anita Bell Alicia Didsbury Edwin A. Mitchell P. Rod Dunbar Thomas Proft Nicole J. Moreland 《The Journal of infection》2018,76(4):361-368
Objectives
Streptococcal serology provides evidence of prior Group A Streptococcus (GAS) exposure, crucial to the diagnosis of acute rheumatic fever (ARF) and post-streptococcal glomerulonephritis. However, current tests, which measure anti-streptolysin-O and anti-DNaseB antibodies, are limited by false positives in GAS endemic settings, and incompatible methodology requiring the two tests to be run in parallel. The objective was to improve streptococcal serology by combining the novel GAS antigen, SpnA, with streptolysin-O and DNaseB in a contemporary, bead-based immunoassay.Methods
Recombinant streptolysin-O, DNAseB and SpnA were conjugated to polystyrene beads with unique fluorescence positions so antibody binding to all three antigens could be detected simultaneously by cytometric bead array. Multiplex assays were run on sera collected in three groups: ARF; ethnically matched healthy children; and healthy adults.Results
The ability of the antigens to detect a previous GAS exposure in ARF was assessed using the 80th centile of the healthy children group as cut-off (upper limit of normal). SpnA had the highest sensitivity at 88%, compared with 75% for streptolysin-O and 56% for DNaseB.Conclusions
SpnA has favorable immunokinetics for streptococcal serology, and can be combined with anti-streptolysin-O and anti-DNaseB in a multiplex format to improve efficiency and accuracy. 相似文献977.
Characterization of Thoracic Pathophysiologic Conditions in Patients Receiving High‐Frequency Oscillatory Ventilation: Pediatric Experience
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Christie L. Glau MD Thomas W. Conlon MD Adam S. Himebauch MD Donald L. Boyer MD MSEd Samuel A. Rosenblatt MD Akira Nishisaki MD MSCE 《Journal of ultrasound in medicine》2018,37(10):2425-2431
High‐frequency oscillatory ventilation (HFOV) is a mode of mechanical ventilation used in severe pediatric respiratory failure. Thoracic ultrasound (US) is a powerful tool for diagnosing acute pathophysiologic conditions during spontaneous respiration and conventional noninvasive and invasive mechanical ventilation. High‐frequency oscillatory ventilation differs from conventional modes of ventilation in that it does not primarily use bulk flow delivery for gas exchange but, rather, a number of alternative mechanisms as the result of pressure variations oscillating around a constant distending pressure. Thoracic US has not been well described in patients receiving HFOV, and it is unclear whether the US findings for assessing thoracic pathophysiologic conditions during conventional ventilation are applicable to patients receiving HFOV. We discuss the similarities and differences of thoracic US findings in patients who are spontaneously breathing or receiving conventional ventilation compared to those in patients receiving HFOV. 相似文献
978.
979.
Tolbert Nyenswah Mosoka Fallah Sonpon Sieh Karsor Kollie Moses Badio Alvin Gray Priscilla Dilah Marnijina Shannon Stanley Duwor Chikwe Ihekweazu Thierry Cordier-Lasalle Shivam A. Shinde Esther Hamblion Gloria Davies-Wayne Murugan Ratnesh Christopher Dye Jonathan S. Yoder Peter McElroy Brooke Hoots Athalia Christie John Vertefeuille Sonja J. Olsen A. Scott Laney Joyce J. Neal Thomas R. Navin Stewart Coulter Paran Pordell Terrence Lo Carl Kinkade Frank Mahoney 《MMWR. Morbidity and mortality weekly report》2015,64(18):500-504
980.