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Sökning: WFRF:(Baxendale H)

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2.
  • Thaventhiran, James E D (författare)
  • Whole-genome sequencing of a sporadic primary immunodeficiency cohort.
  • 2020
  • Ingår i: Nature. - 1476-4687. ; 583:7814, s. 90-95
  • Tidskriftsartikel (refereegranskat)abstract
    • Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
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3.
  • Lanemo Myhrinder, Anna, et al. (författare)
  • A new perspective : molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies
  • 2008
  • Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 111:7, s. 3838-3848
  • Tidskriftsartikel (refereegranskat)abstract
    • The restricted immunoglobulin (Ig) repertoire found in B-cell chronic lymphocytic leukemia (CLL) implies a role for antigen(s) in the leukemogenesis. The nature of the antigens has, however, not been characterized, although examples of autoantigens have been demonstrated. We have analyzed a panel of 28 CLL cell lines and primary cultures, producing monoclonal Ig with different Ig heavy-chain variable region gene usage and mutational status, including several complementarity determining region 3 homology subset members. Using mass-spectrometry, immunoassays, or protein macroarrays, we have discovered novel antigens binding to CLL Igs. These antigens included cytoskeletal proteins vimentin, filamin B, and cofilin-1, but also phosphorylcholine-containing antigens (eg, Streptococcus pneumoniae polysaccharides and oxidized low-density lipoprotein [oxLDL]). Additional new antigens identified were cardiolipin and proline-rich acidic protein-1. Remarkably, these antigens represent molecular motifs exposed on apoptotic cells/blebs and bacteria, and several CLL Igs bound to apoptotic Jurkat cells. In conclusion, these intriguing data, showing a limited target structure recognition, indicate that CD5(+) CLL B cells are derived from a cell compartment that produces "natural antibodies," which may be instrumental in elimination and scavenging of apoptotic cells and pathogenic bacteria.
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4.
  • Laurie, K. L., et al. (författare)
  • Cell-specific and efficient expression in mouse and human B cells by a novel hybrid immunoglobulin promoter in a lentiviral vector
  • 2007
  • Ingår i: Gene Therapy. - : Nature Publishing Group. - 0969-7128. ; 14:23, s. 1623-1631
  • Tidskriftsartikel (refereegranskat)abstract
    • The expression of genes specifically in B cells is of great interest in both experimental immunology as well as in future clinical gene therapy. We have constructed a novel enhanced B cell-specific promoter (Igk- E) consisting of an immunoglobulin kappa (Igk) minimal promoter combined with an intronic enhancer sequence and a 30 enhancer sequence from Ig genes. The Igk- E promoter was cloned into a lentiviral vector and used to control expression of enhanced green fluorescent protein (eGFP). Transduction of murine B-cell lymphoma cell lines and activated primary splenic B cells, with IgK-E-eGFP lentivirus, resulted in expression of eGFP, as analysed by flow cytometry, whereas expression in non-B cells was absent. The specificity of the promoter was further examined by transducing Lin bone marrow with Igk-E-eGFP lentivirus and reconstituting lethally irradiated mice. After 16 weeks flow cytometry of lymphoid tissues revealed eGFP expression by CD19(+) cells, but not by CD3(+), CD11b(+), CD11c(+) or Gr-1(+) cells. CD19(+) cells were comprised of both marginal zone B cells and recirculating follicular B cells. Activated human peripheral mononuclear cells were also transduced with Igk-E-eGFP lentivirus under conditions of selective B-cell activation. The Igk-E promoter was able to drive expression of eGFP only in CD19(+) cells, while eGFP was expressed by both spleen focus forming virus and cytomegalovirus constitutive promoters in CD19(+) and CD3(+) lymphocytes. These data demonstrate that in these conditions the Igk-E promoter is cell specific and controls efficient expression of a reporter protein in mouse and human B cells in the context of a lentiviral vector.
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5.
  • Malmgren, Kristina, 1952, et al. (författare)
  • Long-term outcomes of epilepsy surgery: Knowledge gaps and future directions
  • 2015
  • Ingår i: Long-Term Outcomes of Epilepsy Surgery in Adults and Children. - : Springer. - 9783319177830 ; , s. 269-275
  • Bokkapitel (refereegranskat)abstract
    • Although epilepsy surgery has long been recognized as an effective treatment for carefully selected adults and children, studies of long-term seizure control are relatively rare and studies of the wider aspects of surgical outcome are even more scarce. In summarizing the literature, many of the chapters in this volume have highlighted what we do not know about epilepsy surgery outcomes rather than what we do. This chapter highlights the gaps in the adult and pediatric literature and discusses the roles that networking, collaboration, and adherence to a basic set of standards may play in addressing the current shortcomings of the literature. © Springer International Publishing Switzerland 2015.
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6.
  • Malmgren, Kristina, 1952, et al. (författare)
  • Why a volume on long-term outcomes of epilepsy surgery?
  • 2015
  • Ingår i: Long-Term Outcomes of Epilepsy Surgery in Adults and Children. - : Springer. - 9783319177830 ; , s. 1-4
  • Bokkapitel (refereegranskat)abstract
    • Epilepsy surgery is a recognized option in the management of adults and children with drug-resistant epilepsy. Magnetic resonance imaging has increased the number of candidates by determining focal structural brain abnormalities not previously apparent. Advances in other techniques have widened the spectrum of surgical candidates both in adults and children. In the short term, rates of seizure freedom are relatively high, but seizure recurrence can still occur in the long term. There are methodological hurdles to overcome when assessing longer-term outcome. There are also the outcomes beyond seizures-cognition, neurodevelopment, academic and vocational outcomes, and quality of life-which are of importance when determining whether a treatment is benefi cial. The aim of this volume is to focus on longer-term outcomes from epilepsy surgery in both adults and children. © Springer International Publishing Switzerland 2015.
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