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  • 1
    In: Infection and Immunity, 2001, Vol. 69(3), p.1483
    Description: Haemophilus ducreyi expresses several putative virulence factors in vitro. Isogenic mutant-to-parent comparisons have been performed in a human model of experimental infection to examine whether specific gene products are involved in pathogenesis. Several mutants (momp, ftpA, losB, lst, cdtC, and hhdB) were as virulent as the parent in the human model, suggesting that their gene products did not play a major role in pustule formation. However, we could not exclude the possibility that the gene of interest was not expressed during the initial stages of infection. Biopsies of pustules obtained from volunteers infected with H. ducreyi were subjected to reverse transcription-PCR. Transcripts corresponding to momp, ftpA, losB, lst, cdtB, and hhdA were expressed in vivo. In addition, transcripts for other putative virulence determinants such as ompA2, tdhA, lspA1, and lspA2 were detected in the biopsies. These results indicate that although several candidate virulence determinants are expressed during experimental infection, they do not have a major role in the initial stages of pathogenesis.
    Keywords: Haemophilus Ducreyi ; Haemophilus Ducreyi ; Volunteers ; Mutants ; Virulence ; Gene Expression ; Reverse Transcription ; Polymerase Chain Reaction ; Volunteers ; Mutants ; Virulence ; Gene Expression ; Reverse Transcription ; Polymerase Chain Reaction ; Momp Gene ; Ftpa Gene ; Losb Gene ; Lst Gene ; Cdtc Gene ; Hhdb Gene ; Ompa2 Gene ; Tdha Gene ; Lspa1 Gene ; Lspa2 Gene ; Momp Gene ; Ftpa Gene ; Losb Gene ; Lst Gene ; Cdtc Gene ; Hhdb Gene ; Ompa2 Gene ; Tdha Gene ; Lspa1 Gene ; Lspa2 Gene ; Antigenic Properties and Virulence ; Bacterial Genetics ; Cdtc Gene ; Ftpa Gene ; Hhdb Gene ; Losb Gene ; Lspa1 Gene ; Lspa2 Gene ; Lst Gene ; Momp Gene ; Ompa2 Gene ; Tdha Gene;
    ISSN: 0019-9567
    ISSN: 00199567
    E-ISSN: 10985522
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  • 2
    Language: English
    In: 2014, Vol.10(10), p.e1004415
    Description: Latent infection by Epstein-Barr virus (EBV) is highly associated with the endemic form of Burkitt lymphoma (eBL), which typically limits expression of EBV proteins to EBNA-1 (Latency I). Interestingly, a subset of eBLs maintain a variant program of EBV latency - Wp-restricted latency (Wp-R) - that includes expression of the EBNA-3 proteins (3A, 3B and 3C), in addition to EBNA-1. In xenograft assays, Wp-R BL cell lines were notably more tumorigenic than their counterparts that maintain Latency I, suggesting that the additional latency-associated proteins expressed in Wp-R influence cell proliferation and/or survival. Here, we evaluated the contribution of EBNA-3A. Consistent with the enhanced tumorigenic potential of Wp-R BLs, knockdown of EBNA-3A expression resulted in abrupt cell-cycle arrest in G0/G1 that was concomitant with conversion of retinoblastoma protein (Rb) to its hypophosphorylated state, followed by a loss of Rb protein. Comparable results were seen in EBV-immortalized B lymphoblastoid cell lines (LCLs), consistent with the previous observation that EBNA-3A is essential for sustained growth of these cells. In agreement with the known ability of EBNA-3A and EBNA-3C to cooperatively repress p14 ARF and p16 INK4a expression, knockdown of EBNA-3A in LCLs resulted in rapid elevation of p14 ARF and p16 INK4a . By contrast, p16 INK4a was not detectably expressed in Wp-R BL and the low-level expression of p14 ARF was unchanged by EBNA-3A knockdown. Amongst other G1/S regulatory proteins, only p21 WAF1/CIP1 , a potent inducer of G1 arrest, was upregulated following knockdown of EBNA-3A in Wp-R BL Sal cells and LCLs, coincident with hypophosphorylation and destabilization of Rb and growth arrest. Furthermore, knockdown of p21 WAF1/CIP1 expression in Wp-R BL correlated with an increase in cellular proliferation. This novel function of EBNA-3A is distinct from the functions previously described that are shared with EBNA-3C, and likely contributes to the proliferation of Wp-R BL cells and LCLs. ; Epstein-Barr virus (EBV) infects over 98% of the population worldwide and is associated with a variety of human cancers. In the healthy host, the virus represses expression of its proteins to avoid detection by the immune system to enable it to remain in the body for the lifetime of its host, a situation known as latency. This downregulation was first observed in EBV-associated Burkitt lymphoma (BL), which classically express only one viral protein, EBNA-1. A subset of BL named Wp-restricted (Wp-R) BL express additional latency-associated viral proteins. Because Wp-R BL also express wild-type p53 (which normally prevents cellular proliferation), we wanted to explore the possibility that these viral proteins play a role in tumorigenesis. Indeed, we have demonstrated that Wp-R BL cells are more tumorigenic in immunocompromised mice than other BL. Here, we have investigated the role of one of these viral proteins, EBNA-3A. If we inhibit the expression of EBNA-3A, Wp-R BL cells fail to proliferate and express increased p21, a cellular protein that inhibits cell proliferation. These results suggest that this previously undescribed function of EBNA-3A plays a role in the proliferation and likely contributes to tumorigenesis in Wp-R BL.
    Keywords: Research Article ; Biology And Life Sciences ; Medicine And Health Sciences
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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  • 3
  • 4
    In: Molecular Therapy, 2014, Vol.22(2), p.244
    Description: To the editor:
    Keywords: Medicine ; Biology;
    ISSN: 1525-0016
    E-ISSN: 15250024
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  • 5
    In: Infection and Immunity, 2001, Vol. 69(3), p.1488
    Description: Haemophilus ducreyi produces an outer membrane protein called DsrA, which is required for serum resistance. An isogenic dsrA mutant, FX517, was constructed previously in H. ducreyi 35000. Compared to its parent, FX517 cannot survive in normal human serum. When complemented in trans with a plasmid containing dsrA, FX517 is converted to a serum-resistant phenotype (C. Elkins, K. J. Morrow, Jr., and B. Olsen, Infect. Immun. 68:1608-1619, 2000). To test whether dsrA was transcribed in vivo, we successfully amplified transcripts in five biopsies obtained from four experimentally infected human subjects. To test whether DsrA was required for virulence, six volunteers were experimentally infected with 35000 and FX517 and observed for papule and pustule formation. Each subject was inoculated with two doses (70 to 80 CFU) of live 35000 and 1 dose of heat-killed bacteria on one arm and with three doses (ranging from 35 to 800 CFU) of live FX517 on the other arm. Papules developed at similar rates at sites inoculated with the mutant or parent. However, mutant papule surface areas were significantly smaller than parent papules. The pustule formation rate was 58% (95% confidence interval [CI] of 28 to 85%) at 12 parent sites, and 0% (95% CI of 0 to 15%) at 18 mutant sites (P = 0.0004). Although biosafety regulations precluded our testing the complemented mutant in humans, these results suggest that expression of DsrA facilitates the ability of H. ducreyi to progress to the pustular stage of disease.
    Keywords: Mutation ; Bacterial Outer Membrane Proteins -- Genetics ; Chancroid -- Etiology ; Haemophilus Ducreyi -- Pathogenicity;
    ISSN: 0019-9567
    ISSN: 00199567
    E-ISSN: 10985522
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  • 6
    In: Infection and Immunity, 2000, Vol. 68(5), p.2602
    Description: Haemophilus ducreyi expresses 2 OmpA homologs, designated MOMP and OmpA2, whose genes are arranged in tandem on the chromosome. Northern blot analysis indicated that momp and ompA2 are transcribed independently. Sequences of the momp open reading frame (ORF) lacking the transcriptional start site were amplified by PCR, and an Omega-Km2 cassette was ligated into the ORF. A plasmid containing this construction was electroporated into H. ducreyi 35000HP, and an isogenic MOMP-deficient mutant (35000HP-SMS2) was generated by allele exchange. In Southern blotting, 35000HP-SMS2 contained one copy of the Omega-Km2 cassette in momp. 35000HP and 35000HP-SMS2 had similar outer membrane protein (OMP) and lipooligosaccharide profiles and growth rates except for up-regulation of a putative porin protein in the mutant. Five subjects were inoculated with three doses of live 35000HP-SMS2 on one arm and two doses of live 35000HP and one dose of a heat-killed control on the other arm in a double-blind escalating dose-response trial. Pustules developed at 7 of 10 sites inoculated with 35000HP and at 6 of 15 sites inoculated with 35000HP-SMS2 (P = 0.14). 35000HP and 35000HP-SMS2 were recovered at similar rates from daily surface cultures and semiquantitative cultures. The data suggest that expression of MOMP is not required for pustule formation by H. ducreyi in the human model of infection.
    Keywords: Medicine ; Biology;
    ISSN: 0019-9567
    ISSN: 00199567
    E-ISSN: 10985522
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  • 7
    Language: English
    In: Science translational medicine, 20 April 2016, Vol.8(335), pp.335ra57
    Description: X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1.
    Keywords: Genetic Therapy -- Methods ; Hematopoietic Stem Cells -- Metabolism ; Lentivirus -- Genetics ; X-Linked Combined Immunodeficiency Diseases -- Therapy
    ISSN: 19466234
    E-ISSN: 1946-6242
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  • 8
    Language: English
    In: ADVANCES IN CELL AND GENE THERAPY, 04/2019, Vol.2(2), p.e45
    ISSN: 2573-8461
    E-ISSN: 2573-8461
    Source: Wiley (via CrossRef)
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  • 9
    Language: English
    In: Blood, 21 May 2009, Vol.113(21), pp.5104-10
    Description: Retroviral vectors containing internal promoters, chromatin insulators, and self-inactivating (SIN) long terminal repeats (LTRs) may have significantly reduced genotoxicity relative to the conventional retroviral vectors used in recent, otherwise successful clinical trials. Large-scale production of such vectors is problematic, however, as the introduction of SIN vectors into packaging cells cannot be accomplished with the traditional method of viral transduction. We have derived a set of packaging cell lines for HIV-based lentiviral vectors and developed a novel concatemeric array transfection technique for the introduction of SIN vector genomes devoid of enhancer and promoter sequences in the LTR. We used this method to derive a producer cell clone for a SIN lentiviral vector expressing green fluorescent protein, which when grown in a bioreactor generated more than 20 L of supernatant with titers above 10(7) transducing units (TU) per milliliter. Further refinement of our technique enabled the rapid generation of whole populations of stably transformed cells that produced similar titers. Finally, we describe the construction of an insulated, SIN lentiviral vector encoding the human interleukin 2 receptor common gamma chain (IL2RG) gene and the efficient derivation of cloned producer cells that generate supernatants with titers greater than 5 x 10(7) TU/mL and that are suitable for use in a clinical trial for X-linked severe combined immunodeficiency (SCID-X1).
    Keywords: Genetic Therapy -- Methods ; Interleukin Receptor Common Gamma Subunit -- Administration & Dosage ; Severe Combined Immunodeficiency -- Therapy ; Transfection -- Methods
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 10
    In: Advances in Cell and Gene Therapy, April 2019, Vol.2(2), pp.n/a-n/a
    Description: Adoptive cell therapy () has emerged as an effective treatment for some cancers. However, allogeneic cell applications are in part limited by the risk of alloreactive T‐cell subsets causing graft‐versus‐host‐disease (). We therefore hypothesized that the use of 27‐depleted cells (containing natural killer [] cells and effector memory T‐cells; without naïve or central memory T‐cells) would offer protection from pathogens and , while also providing anticancer activity when genetically engineered with a chimeric antigen receptor (). In this work, cell phenotypes were evaluated using flow cytometry. In vitro immunologic memory and alloreactivity were tested using lymphocyte proliferation assays. In vivo potential was assessed using scid gamma () mice. Anticancer activity of ‐transduced 27‐depleted cells was tested in vitro via a cytotoxicity assay and in vivo using mice. Our results confirmed that the 27‐depleted cell fraction was enriched for cells, effector memory 4 T cells and terminal effector memory 8 T cells. 27‐depleted cells had strong immunologic response against common pathogens in vitro, and less potential in vitro and in vivo. 27‐depleted cells could be transduced with a vector produced by stable cell lines, and demonstrated significant antileukemic activity in vitro and in vivo. These findings suggest that 27‐depletion is a promising approach to using allogeneic cells in , potentially providing infection and cancer control simultaneously but having low risk of causing .
    Keywords: Allografts ; Antigens ; Cd 19 ; Chimeric Antigen Receptor Car ; Graft Vs Host Disease ; Immunotherapy ; Adoptive ; Leukemia ; Receptors ; Antigen ; T‐Lymphocyte Subsets ; Tumor Necrosis Factor Receptor Superfamily ; Member 7
    ISSN: 2573-8461
    E-ISSN: 2573-8461
    Source: John Wiley & Sons, Inc.
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