Patients with early-stage, node-negative oral cancer who had elective lymph-node dissection at the time of resection of the primary tumor had better overall survival than those who waited for node ...resection until clinical recurrence.
The treatment of patients with early-stage, clinically node-negative oral squamous-cell cancer has been a contentious issue spanning five decades. Such patients are usually treated with oral surgical excision of the primary tumor. Surgical options for addressing the neck include elective neck dissection at the time of the excision of the primary tumor or watchful waiting with therapeutic neck dissection for nodal relapse. Proponents of elective neck dissection cite decreased relapse rates and better survival rates.
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However, others consider the evidence not to be definitive.
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Data from prospective trials have also produced conflicting evidence.
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The watchful-waiting approach has . . .
Circular RNAs (circRNAs) are prevalent in eukaryotic cells and viral genomes. Mammalian cells possess innate immunity to detect foreign circRNAs, but the molecular basis of self versus foreign ...identity in circRNA immunity is unknown. Here, we show that N6-methyladenosine (m6A) RNA modification on human circRNAs inhibits innate immunity. Foreign circRNAs are potent adjuvants to induce antigen-specific T cell activation, antibody production, and anti-tumor immunity in vivo, and m6A modification abrogates immune gene activation and adjuvant activity. m6A reader YTHDF2 sequesters m6A-circRNA and is essential for suppression of innate immunity. Unmodified circRNA, but not m6A-modified circRNA, directly activates RNA pattern recognition receptor RIG-I in the presence of lysine-63-linked polyubiquitin chain to cause filamentation of the adaptor protein MAVS and activation of the downstream transcription factor IRF3. CircRNA immunity has considerable parallel to prokaryotic DNA restriction modification system that transforms nucleic acid chemical modification into organismal innate immunity.
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•Unmodified circRNA adjuvant induces antigen-specific T and B cell responses•m6A RNA modification marks self circRNAs and abrogates circRNA immunity•Unmodified circRNA and K63-polyubiquitin activate RIG-I and innate immune signaling•YTHDF2 binding of m6A-circRNA additionally suppresses circRNA immunity
Mammalian cells distinguish between foreign and endogenous circular RNAs (circRNAs), but the molecular basis is unknown. Chen et al. identify N6-methyladenosine (m6A) RNA modification as a marker for “self.” Unmodified circRNA, but not m6A-modified circRNA, activates RIG-I in the presence of K63-polyubiquitin to cause MAVS filamentation, IRF3 dimerization, and interferon production.
Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic ...cells via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent efforts toward an HIV vaccine focus on inducing broadly neutralizing antibodies, but eliciting both neutralizing antibodies (nAbs) and cellular responses may be superior. Here, we immunized ...macaques with an HIV envelope trimer, either alone to induce nAbs, or together with a heterologous viral vector regimen to elicit nAbs and cellular immunity, including CD8
tissue-resident memory T cells. After ten vaginal challenges with autologous virus, protection was observed in both vaccine groups at 53.3% and 66.7%, respectively. A nAb titer >300 was generally associated with protection but in the heterologous viral vector + nAb group, titers <300 were sufficient. In this group, protection was durable as the animals resisted six more challenges 5 months later. Antigen stimulation of T cells in ex vivo vaginal tissue cultures triggered antiviral responses in myeloid and CD4
T cells. We propose that cellular immune responses reduce the threshold of nAbs required to confer superior and durable protection.
CXCL13 is a plasma biomarker of germinal center activity Havenar-Daughton, Colin; Lindqvist, Madelene; Heit, Antje ...
Proceedings of the National Academy of Sciences - PNAS,
03/2016, Letnik:
113, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Significantly higher levels of plasma CXCL13 chemokine (C-X-C motif) ligand 13 were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal ...cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4+ T follicular helper (GC Tfh) cells problematic. The CXCL13–CXCR5 chemokine (C-X-C motif) receptor 5 chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS⁺ (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.
Robust production of type I interferon (IFN-alpha/beta) in plasmacytoid dendritic cells (pDCs) is crucial for antiviral immunity. Here we show involvement of the mammalian target of rapamycin (mTOR) ...pathway in regulating interferon production by pDCs. Inhibition of mTOR or its 'downstream' mediators, the p70 ribosomal S6 protein kinases p70S6K1 and p70S6K2, during pDC activation by Toll-like receptor 9 (TLR9) blocked the interaction of TLR9 with the adaptor MyD88 and subsequent activation of the interferon-regulatory factor IRF7, which resulted in impaired IFN-alpha/beta production. Microarray analysis confirmed that inhibition of mTOR by the immunosuppressive drug rapamycin suppressed antiviral and anti-inflammatory gene expression. Consistent with this, targeting rapamycin-encapsulated microparticles to antigen-presenting cells in vivo resulted in less IFN-alpha/beta production in response to CpG DNA or the yellow fever vaccine virus strain 17D. Thus, mTOR signaling is crucial in TLR-mediated IFN-alpha/beta responses by pDCs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
4 While trauma and insect bites are proposed as etiological factors, surgical procedures like biopsy and excision tend to cause progression of lesions. Histopathology often shows dermal and ...sub-cuticular granulomatous mixed infiltrate with eosinophils, lymphocytes, plasma cells, giant cells, histiocytes and neutrophils with Splendore–Hoeppli-like phenomenon and fibrosis. Basidiobolomycosis was mistaken for cutaneous tuberculosis and treated erroneously. ...it is necessary to perform biopsy for histopathology and culture to confirm the diagnosis, prior to the commencement of therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The science of adjuvants Kwissa, Marcin; Pai Kasturi, Sudhir; Pulendran, Bali
Expert review of vaccines,
10/1/2007, 2007-Oct, 2007-10-01, 20071001, Letnik:
6, Številka:
5
Journal Article
Recenzirano
Adjuvants are substances that boost the immunogenicity of vaccines. However, most successful vaccines have been derived empirically and are capable of inducing robust T- and B-cell immunity without ...any adjuvant additives. Emerging evidence suggests that such live vaccines induce innate immune activation via a range of stimuli, including ligands specific for Toll-like receptors, which, in effect, serve as their own adjuvants. In contrast to these live vaccines, subunit vaccines need to be supplemented with adjuvants to boost their immunogenicity. However, there is a paucity of licensed adjuvants for clinical use and, thus, there is a critical need to develop safe and effective adjuvants. In this context, recent advances in innate immunity are beginning to offer new insights into how empiric vaccines and adjuvants mediate their efficacy. In this article, we review the latest progress and emerging concepts in adjuvant development, which includes novel findings in innate immune biology and their impact on vaccinology.
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