Many viruses induce hepatitis in humans, highlighting the need to understand the underlying mechanisms of virus-induced liver pathology. The murine coronavirus, mouse hepatitis virus (MHV), causes ...acute hepatitis in its natural host and provides a useful model for understanding virus interaction with liver cells. The MHV accessory protein, ns2, antagonizes the type I interferon response and promotes hepatitis. We show that ns2 has 2′,5′-phosphodiesterase activity, which blocks the interferon inducible 2′,5′-oligoadenylate synthetase (OAS)-RNase L pathway to facilitate hepatitis development. Ns2 cleaves 2′,5′-oligoadenylate, the product of OAS, to prevent activation of the cellular endoribonuclease RNase L and consequently block viral RNA degradation. An ns2 mutant virus was unable to replicate in the liver or induce hepatitis in wild-type mice, but was highly pathogenic in RNase L deficient mice. Thus, RNase L is a critical cellular factor for protection against viral infection of the liver and the resulting hepatitis.
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► Mouse hepatitis virus ns2 protein inhibits the IFN-induced OAS-RNase L pathway ► ns2 reduces the intracellular level of 2′,5′-oligoadenylate (2-5A) ► ns2 has a 2′,5′-phosphodiesterase activity to directly cleave 2-5A ► ns2 mutant virus recovers wild-type virulence in RNase L-deficient mice
The goal of this study was to investigate the impact of adjuvant radiotherapy (RT) on local recurrence and
overall survival in patients undergoing primary resection of atypical meningioma, and to ...identify predictive factors to inform patient selection for adjuvant RT.
One hundred eighty-two patients who underwent primary resection of atypical meningioma at a single institution between 1993 and 2014 were retrospectively identified. Patient, meningioma, and treatment data were extracted from the medical record and compared using the Kaplan-Meier method, log-rank tests, multivariate analysis (MVA) Cox proportional hazards models with relative risk (RR), and recursive partitioning analysis.
The median patient age and imaging follow-up were 57 years (interquartile range IQR 45–67 years) and 4.4 years (IQR 1.8–7.5 years), respectively. Gross-total resection (GTR) was achieved in 114 cases (63%), and 42 patients (23%) received adjuvant RT. On MVA, prognostic factors for death from any cause included GTR (RR 0.4, 95% CI 0.1–0.9, p = 0.02) and MIB1 labeling index (LI) ≤ 7% (RR 0.4, 95% CI 0.1–0.9, p = 0.04). Prognostic factors on MVA for local progression included GTR (RR 0.2, 95% CI 0.1–0.5, p = 0.002), adjuvant RT (RR 0.2, 95% CI 0.1–0.4, p < 0.001), MIB1 LI ≤ 7% (RR 0.2, 95% CI 0.1–0.5, p < 0.001), and a remote history of prior cranial RT (RR 5.7, 95% CI 1.3–18.8, p = 0.03). After GTR, adjuvant RT (0 of 10 meningiomas recurred, p = 0.01) and MIB1 LI ≤ 7% (RR 0.1, 95% CI 0.003–0.3, p < 0.001) were predictive for local progression on MVA. After GTR, 2.2% of meningiomas with MIB1 LI ≤ 7% recurred (1 of 45), compared with 38% with MIB1 LI > 7% (13 of 34; p < 0.001). Recursive partitioning analysis confirmed the
existence of a cohort of patients at high risk of local progression after GTR without adjuvant RT, with MIB1 LI > 7%, and evidence of brain or bone invasion. After subtotal resection, adjuvant RT (RR 0.2, 95% CI 0.04–0.7, p = 0.009) and ≤ 5 mitoses per 10 hpf (RR 0.1, 95% CI 0.03–0.4, p = 0.002) were predictive on MVA for local progression.
Adjuvant RT improves local control of atypical meningioma irrespective of extent of resection. Although
independent validation is required, the authors’ results suggest that MIB1 LI, the number of mitoses per 10 hpf, and brain or bone invasion may be useful guides to the selection of patients who are most likely to benefit from adjuvant RT after resection of atypical meningioma.
The aim of this study was to discuss the role of glucagon-like peptide-1 (GLP-1) receptor signalling in reducing lung inflammation and potential use for GLP-1 receptor agonists (GLP-1RAs) in ...management of asthma.
Although GLP-1RA are currently used for the treatment of type 2 diabetes (T2D) and weight loss in obesity, there is much interest in expanding the indications for use in other diseases, including inflammatory pulmonary disease. In animal models of both acute and chronic pulmonary disease, use of GLP-1RA reduces airway inflammation, obstruction and fibrosis. In particular, GLP-1 receptor (GLP-1R) signalling seems to inhibit allergen-induced type 2 inflammation, making it an attractive agent for asthma. Results are especially promising in disease processes with disturbed metabolic regulation, such as T2D or metabolic syndrome. Retrospective clinical studies demonstrate promising evidence for the use of GLP-1RAs in comorbid diabetes and asthma, although prospective human studies are limited.
Here, we discuss the biology of GLP-1 and GLP-1R signalling, review the preclinical and mechanistic evidence for how GLP-1R signalling may reduce pulmonary inflammation, and summarize recent and upcoming clinical studies. Ultimately, targeting GLP-1R signalling may represent a novel approach for asthma therapy that is glucocorticoid sparing and possibly disease modifying.
Most antimicrobials currently in the clinical pipeline are modifications of existing classes of antibiotics and are considered short-term solutions due to the emergence of resistance.
represents a ...major challenge for new antimicrobial drug discovery due to its versatile lifestyle, ability to develop resistance to most antibiotic classes, and capacity to form robust biofilms on surfaces and in certain hosts such as those living with cystic fibrosis (CF). A precision antibiotic approach to treating
could be achieved with an antisense method, specifically by using peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs). Here, we demonstrate that PPMOs targeting
(acyl carrier protein),
(UDP-(3-
-acyl)-
-acetylglucosamine deacetylase), and
(30S ribosomal protein S10) inhibited the
growth of several multidrug-resistant clinical
isolates at levels equivalent to those that were effective against sensitive strains. Lead PPMOs reduced established pseudomonal biofilms alone or in combination with tobramycin or piperacillin-tazobactam. Lead PPMO dosing alone or combined with tobramycin in an acute pneumonia model reduced lung bacterial burden in treated mice at 24 h and reduced morbidity up to 5 days postinfection. PPMOs reduced bacterial burden of extensively drug-resistant
in the same model and resulted in superior survival compared to conventional antibiotics. These data suggest that lead PPMOs alone or in combination with clinically relevant antibiotics represent a promising therapeutic approach for combating
infections.
Numerous Gram-negative bacteria are becoming increasingly resistant to multiple, if not all, classes of existing antibiotics. Multidrug-resistant
bacteria are a major cause of health care-associated infections in a variety of clinical settings, endangering patients who are immunocompromised or those who suffer from chronic infections, such as people with cystic fibrosis (CF). Herein, we utilize antisense molecules that target mRNA of genes essential to bacterial growth, preventing the formation of the target proteins, including
,
, and
We demonstrate here that antisense molecules targeted to essential genes, alone or in combination with clinically relevant antibiotics, were effective in reducing biofilms and protected mice in a lethal model of acute pneumonia.
Type 2 inflammation has been described in people with cystic fibrosis (CF). Whether loss of CFTR (cystic fibrosis transmembrane conductance regulator) function contributes directly to a type 2 ...inflammatory response has not been fully defined.
The potent alarmin IL-33 has emerged as a critical regulator of type 2 inflammation. We tested the hypothesis that CFTR deficiency increases IL-33 expression and/or release and deletion of IL-33 reduces allergen-induced inflammation in the CF lung.
Human airway epithelial cells (AECs) grown from non-CF and CF cell lines and
and
mice were used in this study. Pulmonary inflammation in
and
mice with and without IL-33 or ST2 (IL-1 receptor-like 1) germline deletion was determined by histological analysis, BAL, and cytokine analysis.
After allergen challenge, both CF human AECs and
mice had increased IL-33 expression compared with control AECs and
mice, respectively. DUOX1 (dual oxidase 1) expression was increased in CF human AECs and
mouse lungs compared with control AECs and lungs from
mice and was necessary for the increased IL-33 release in
mice compared with
mice. IL-33 stimulation of
CD4
T cells resulted in increased type 2 cytokine production compared with
CD4
T cells. Deletion of IL-33 or ST2 decreased both type 2 inflammation and neutrophil recruitment in
mice compared with
mice.
Absence of CFTR reprograms airway epithelial IL-33 release and licenses IL-33-dependent inflammation. Modulation of the IL-33/ST2 axis represents a novel therapeutic target in CF type 2-high and neutrophilic inflammation.
Meningioma is the most common primary intracranial tumor, but the molecular drivers of aggressive meningioma are incompletely understood. Using 280 human meningioma samples and RNA sequencing, ...immunohistochemistry, whole-exome sequencing, DNA methylation arrays, and targeted gene expression profiling, we comprehensively define the molecular profile of aggressive meningioma. Transcriptomic analyses identify FOXM1 as a key transcription factor for meningioma proliferation and a marker of poor clinical outcomes. Consistently, we discover genomic and epigenomic factors associated with FOXM1 activation in aggressive meningiomas. Finally, we define a FOXM1/Wnt signaling axis in meningioma that is associated with a mitotic gene expression program, poor clinical outcomes, and proliferation of primary meningioma cells. In summary, we find that multiple molecular mechanisms converge on a FOXM1/Wnt signaling axis in aggressive meningioma.
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•Genomic, epigenomic, and transcriptomic factors identify meningioma molecular subgroups•FOXM1 expression delineates aggressive meningiomas across molecular subgroups•FOXM1/Wnt signaling is associated with mitotic gene expression in aggressive meningioma•FOXM1 signaling drives primary meningioma cell proliferation
Using multiplatform molecular profiling, Vasudevan et al. comprehensively define the molecular profile of aggressive meningioma. They identify genomic, epigenomic, and transcriptomic mechanisms that converge on a FOXM1/Wnt signaling axis in aggressive meningioma that is associated with meningioma cell proliferation and is a marker of poor clinical outcomes across molecular subgroups.
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