Search results for: Mouse Anti-Marek's Disease Virus
#28924735 2017/09/19 Save this To Up
The G protein-coupled estrogen receptor (GPER/GPR30) may serve as a prognostic marker in early-stage cervical cancer.Estrogen signalling is transmitted via various receptors and multiple intracellular signalling pathways. Estrogen receptor alpha (ERα)-mediated transcription of target genes has been demonstrated to be closely linked to human papilloma virus (HPV)-induced carcinogenesis in case of cervical cancer. So far, the role of non-genomic estrogen signals in cervical cancer, e.g. transmitted by the G protein-coupled estrogen receptor (GPER) remains to be rather elusive. Today's knowledge on the role of GPER in cervical cancer is sparse and-to the best of our knowledge-GPER has not been investigated in context with clinicopathological parameters or prognosis of cervical cancer. Therefore, the current study investigated whether GPER is expressed in cervical cancer tissue. Further, GPER was correlated to clinicopathological parameters, tissue markers of cervical carcinogenesis and to patient overall and recurrence-free survival.
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#28922426 2017/09/18 Save this To Up
A DNA vaccine for Crimean-Congo hemorrhagic fever protects against disease and death in two lethal mouse models.Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus capable of causing a severe hemorrhagic fever disease in humans. There are currently no licensed vaccines to prevent CCHFV-associated disease. We developed a DNA vaccine expressing the M-segment glycoprotein precursor gene of CCHFV and assessed its immunogenicity and protective efficacy in two lethal mouse models of disease: type I interferon receptor knockout (IFNAR-/-) mice; and a novel transiently immune suppressed (IS) mouse model. Vaccination of mice by muscle electroporation of the M-segment DNA vaccine elicited strong antigen-specific humoral immune responses with neutralizing titers after three vaccinations in both IFNAR-/- and IS mouse models. To compare the protective efficacy of the vaccine in the two models, groups of vaccinated mice (7-10 per group) were intraperitoneally (IP) challenged with a lethal dose of CCHFV strain IbAr 10200. Weight loss was markedly reduced in CCHFV DNA-vaccinated mice as compared to controls. Furthermore, whereas all vector-control vaccinated mice succumbed to disease by day 5, the DNA vaccine protected >60% of the animals from lethal disease. Mice from both models developed comparable levels of antibodies, but the IS mice had a more balanced Th1/Th2 response to vaccination. There were no statistical differences in the protective efficacies of the vaccine in the two models. Our results provide the first comparison of these two mouse models for assessing a vaccine against CCHFV and offer supportive data indicating that a DNA vaccine expressing the glycoprotein genes of CCHFV elicits protective immunity against CCHFV.
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#28919107 2017/09/18 Save this To Up
Combination of Aβ Suppression and Innate Immune Activation in the Brain Significantly Attenuates Amyloid Plaque Deposition.Anti-Aβ clinical trials are currently underway to determine whether preventing amyloid deposition will be beneficial in arresting progression of Alzheimer disease. Both clinical and pre-clinical studies suggest that anti-amyloid strategies are only effective if started at very early stages of the disease process in a primary prevention strategy. Because this approach will be difficult to deploy, strategies for secondary prevention aimed at later stages of disease are also needed. In this study, we asked whether combining innate immune activation in the brain with concurrent Aβ suppression could enhance plaque clearance and improve pathological outcomes in mice with moderate amyloid pathology. Starting at 5 months of age, tet-off APP transgenic mice were treated with doxycycline to suppress further APP/Aβ production and at the same time, mice were intracranially injected with adeno associated virus expressing murine IL-6 (AAV1-mIL-6). Three months later, mice treated with the combination of Aβ suppression and AAV1-mIL-6 showed significantly less plaque pathology than dox or AAV1-mIL-6 only groups. The combination of AAV1-mIL-6 + dox treatment lowered total plaque burden by >60% compared to untreated controls. Treatment with either dox or AAV1-mIL-6 alone was less effective than the combination. Our results suggest a synergistic mechanism by which the up-regulation of mIL-6 was able to improve plaque clearance in the setting of Aβ suppression.
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#28918638 2017/09/18 Save this To Up
A Rapid Blood Test to Determine the Active Status and Duration of Acute Viral Infection.The ability to rapidly detect and diagnose acute viral infections is crucial for infectious disease control and management. Serology testing for the presence of virus-elicited antibodies in blood is one of the methods used commonly for clinical diagnosis of viral infections. However, standard serology-based tests have a significant limitation: they cannot easily distinguish active from past, historical infections. As a result, it is difficult to determine whether a patient is currently infected with a virus or not, and on an optimal course of action, based off of positive serology testing responses. Here we report a nanoparticle-enabled blood test that can help overcome this major challenge. The new test is based on the analysis of virus-elicited immunoglobulin G (IgG) antibody present in the protein corona of a gold nanoparticle surface upon mixing the gold nanoparticles with blood sera. Studies conducted on mouse models of influenza A virus infection show that the test gives positive responses only in the presence of a recent acute viral infection, approximately between day 14 to day 21 following the infection, and becomes negative thereafter. When used together with the traditional serology testing, the nanoparticle test can determine clearly whether a positive serology response is due to a recent or historical viral infection. This new blood test can provide critical clinical information needed to optimize further treatment and/or to determine if further quarantining should be continued.
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#28918059 2017/09/17 Save this To Up
Regulatory Role of the MicroRNA-29b-IL-6 Signaling in the Formation of Vascular Mimicry.Vascular mimicry (VM) is a critical complement for microcirculation and is implicated in tumor progression. We showed that IL-6 derived from tumor cells and stroma cells promoted tumor cells to form a VM structure, whereas blocking the IL-6 signaling by RNA interference, IL-6-neutralizing antibody, or STAT3 inhibitor suppressed the VM formation of tumor cells. Mechanism investigations revealed that IL-6 stimulated VM formation by activating STAT3, in turn upregulating VE-cadherin expression and MMP2 activity. Further analyses identified a positive association between the activation of IL-6-STAT3 signaling and the formation of the VM structure in human HCC tissues. However, miR-29b repressed the expression of STAT3 and MMP2 by directly binding to the 3' UTRs of their mRNAs. Consistently, both gain- and loss-of-function analyses showed that miR-29b suppressed tumor cells to form tube structures in vitro. The in vivo studies further disclosed that intratumoral injection of the miR-29b-expressing viruses significantly inhibited the IL-6-promoted VM formation in mouse xenografts, and downregulation of miR-29b was correlated with the presence of VM in human HCC tissues. This study elucidates a miR-29b-IL-6 signaling cascade and its role in VM formation, which provide potential targets for cancer therapy.
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#28916737 2017/09/16 Save this To Up
Determining Ribavirin's mechanism of action against Lassa virus infection.Ribavirin is a broad spectrum antiviral which inhibits Lassa virus (LASV) replication in vitro but exhibits a minor effect on viremia in vivo. However, ribavirin significantly improves the disease outcome when administered in combination with sub-optimal doses of favipiravir, a strong antiviral drug. The mechanisms explaining these conflicting findings have not been determined, so far. Here, we used an interdisciplinary approach combining mathematical models and experimental data in LASV-infected mice that were treated with ribavirin alone or in combination with the drug favipiravir to explore different putative mechanisms of action for ribavirin. We test four different hypotheses that have been previously suggested for ribavirin's mode of action: (i) acting as a mutagen, thereby limiting the infectivity of new virions; (ii) reducing viremia by impairing viral production; (iii) modulating cell damage, i.e., by reducing inflammation, and (iv) enhancing antiviral immunity. Our analysis indicates that enhancement of antiviral immunity, as well as effects on viral production or transmission are unlikely to be ribavirin's main mechanism mediating its antiviral effectiveness against LASV infection. Instead, the modeled viral kinetics suggest that the main mode of action of ribavirin is to protect infected cells from dying, possibly reducing the inflammatory response.
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#28913765 2017/09/15 Save this To Up
Treatment of Theiler's virus-induced demyelinating disease with teriflunomide.Teriflunomide is an oral therapy approved for the treatment of relapsing remitting multiple sclerosis (MS), showing both anti-inflammatory and antiviral properties. Currently, it is uncertain whether one or both of these properties may explain teriflunomide's beneficial effect in MS. Thus, to learn more about its mechanisms of action, we evaluated the effect of teriflunomide in the Theiler's encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) model, which is both a viral infection and an excellent model of the progressive disability of MS. We assessed the effects of the treatment on central nervous system (CNS) viral load, intrathecal immune response, and progressive neurological disability in mice intracranially infected with TMEV. In the TMEV-IDD model, we showed that teriflunomide has both anti-inflammatory and antiviral properties, but there seemed to be no impact on disability progression and intrathecal antibody production. Notably, benefits in TMEV-IDD were mostly mediated by effects on various cytokines produced in the CNS. Perhaps the most interesting result of the study has been teriflunomide's antiviral activity in the CNS, indicating it may have a role as an antiviral prophylactic and therapeutic compound for CNS viral infections.
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#28912622 2017/09/15 Save this To Up
Local and Systemic Immune Responses to Influenza A Virus Infection in Pneumonia and Encephalitis Mouse Models.To compare local and systemic profiles between different disease pathologies (pneumonia and encephalitis) induced by influenza A virus (IAV).
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#28912369 2017/09/15 Save this To Up
Customized Viral Immunotherapy for HPV-Associated Cancer.The viral transforming proteins E6 and E7 make human papilloma virus positive (HPV+) malignancies an attractive target for cancer immunotherapy. However, therapeutic vaccination exerts limited efficacy in the setting of advanced disease. We designed a strategy to induce substantial specific immune responses against multiple epitopes of E6 and E7 proteins based on an attenuated transgene from HPV serotypes 16 and 18 that is incorporated into MG1-Maraba virotherapy (MG1-E6E7). Mutations introduced to the transgene abrogate the ability of E6 and E7 to perturb p53 and retinoblastoma, respectively, while maintaining the ability to invoke tumor-specific, multi-functional CD8+ T-cell responses. Boosting with MG1-E6E7 significantly increased the magnitude of T-cell responses compared to mice treated with a priming vaccine alone (greater than 50x106 E7-specific CD8+ T cells per mouse was observed, representing a 39-fold mean increase in boosted animals). MG1-E6E7 vaccination in the HPV+ murine model TC1clears large tumors in a CD8+-dependent manner and results in durable immunologic memory. MG1-Maraba can acutely alter the tumor microenvironment in vivo and exploit molecular hallmarks of HPV+ cancer as demonstrated by marked infection of HPV+ patient tumor biopsies and is, therefore, ideally suited as an oncolytic treatment against clinical HPV+ cancer. This approach has the potential to be directly translatable to human clinical oncology to tackle a variety of HPV-associated neoplasms that cause significant morbidity and mortality globally.
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#28912110 2017/09/15 Save this To Up
The genetics of congenitally small brains.Primary microcephaly (PM) refers to a congenitally small brain, resulting from insufficient prenatal production of neurons, and serves as a model disease for brain volumic development. Known PM genes delineate several cellular pathways, among which the centriole duplication pathway, which provide interesting clues about the cellular mechanisms involved. The general interest of the genetic dissection of PM is illustrated by the convergence of Zika virus infection and PM gene mutations on congenital microcephaly, with CENPJ/CPAP emerging as a key target. Physical (protein-protein) and genetic (digenic inheritance) interactions of Wdr62 and Aspm have been demonstrated in mice, and should now be sought in humans using high throughput parallel sequencing of multiple PM genes in PM patients and control subjects, in order to categorize mutually interacting genes, hence delineating functional pathways in vivo in humans.
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