Oncolytic herpes simplex virus-based strategies: toward a breakthrough in glioblastoma therapy

Oncolytic viruses (OV) are a class of antitumor agents that selectively kill tumor cells while sparing normal cells. Oncolytic herpes simplex virus (oHSV) has been investigated in clinical trials for patients with the malignant brain tumor glioblastoma for more than a decade. These clinical studies have shown the safety of oHSV administration to the human brain, however, therapeutic efficacy of oHSV as a single treatment remains unsatisfactory. Factors that could hamper the anti-glioblastoma efficacy of oHSV include: attenuated potency of oHSV due to deletion or mutation of viral genes involved in virulence, restricting viral replication and spread within the tumor; suboptimal oHSV delivery associated with intratumoral injection; virus infection-induced inflammatory and cellular immune responses which could inhibit oHSV replication and promote its clearance; lack of effective incorporation of oHSV into standard-of-care, and poor knowledge about the ability of oHSV to target glioblastoma stem cells (GSCs). In an attempt to address these issues, recent research efforts have been directed at: (1) design of new engineered viruses to enhance potency, (2) better understanding of the role of the cellular immunity elicited by oHSV infection of tumors, (3) combinatorial strategies with different antitumor agents with a mechanistic rationale, (4) “armed” viruses expressing therapeutic transgenes, (5) use of GSC-derived models in oHSV evaluation, and (6) combinations of these. In this review, we will describe the current status of oHSV clinical trials for glioblastoma, and discuss recent research advances and future directions toward successful oHSV-based therapy of glioblastoma

Immunovirotherapy for the treatment of glioblastoma

We have recently described a new murine model of glioblastoma, generated by the implantation of syngeneic glioblastoma stem cells into immunocompetent mice, that recapitulates the salient histopathological and immunological features of the human disease. We employed this model to demonstrate the multifaceted activity of an oncolytic herpes simplex virus genetically modified to express interleukin-12, G47∆-IL12

A reporter system for assaying influenza virus RNP functionality based on secreted Gaussia luciferase activity

<p>Abstract</p> <p>Background</p> <p>Influenza A virus can infect a wide variety of animal species including humans, pigs, birds and other species. Viral ribonucleoprotein (vRNP) was involved in genome replication, transcription and host adaptation. Currently, firefly luciferase (Fluc) reporter system was used in vRNP functional assay. However, its limitation for the testing by virus infection resulted in an increased need for rapid, sensitive, and biosafe techniques. Here, an influenza A virus UTR-driven gene reporter for vRNP assay based on secreted <it>Gaussia </it>luciferase (Gluc) activity was evaluated.</p> <p>Results</p> <p>By measuring Gluc levels in supernatants, reporter gene activity could be detected and quantitated after either reconstitution of influenza A virus polymerase complex or viral infection of 293T and A549 cells, respectively. As compared with Fluc reporter, Gluc-based reporter was heat-tolerant (65°C for 30 min) and produced 50-fold higher bioluminescent activity at 24 h posttransfection. Signals generated by Gluc reporter gene could be detected as early as 6 h post-infection and accumulated with time. Testing by viral infection, stronger signals were detected by Gluc reporter at a MOI of 0.001 than that of 1 and the effects of PB2-627K/E or amantadine on influenza vRNP activity were elucidated more effectively by the Gluc reporter system.</p> <p>Conclusions</p> <p>This approach provided a rapid, sensitive, and biosafe assay of influenza vRNP function, particularly for the highly pathogenic avian influenza viruses.</p

Neuraminidase and Hemagglutinin Matching Patterns of a Highly Pathogenic Avian and Two Pandemic H1N1 Influenza A Viruses

BACKGROUND: Influenza A virus displays strong reassortment characteristics, which enable it to achieve adaptation in human infection. Surveying the reassortment and virulence of novel viruses is important in the prevention and control of an influenza pandemic. Meanwhile, studying the mechanism of reassortment may accelerate the development of anti-influenza strategies. METHODOLOGY/PRINCIPAL FINDINGS: The hemagglutinin (HA) and neuraminidase (NA) matching patterns of two pandemic H1N1 viruses (the 1918 and current 2009 strains) and a highly pathogenic avian influenza A virus (H5N1) were studied using a pseudotyped particle (pp) system. Our data showed that four of the six chimeric HA/NA combinations could produce infectious pps, and that some of the chimeric pps had greater infectivity than did their ancestors, raising the possibility of reassortment among these viruses. The NA of H5N1 (A/Anhui/1/2005) could hardly reassort with the HAs of the two H1N1 viruses. Many biological characteristics of HA and NA, including infectivity, hemagglutinating ability, and NA activity, are dependent on their matching pattern. CONCLUSIONS/SIGNIFICANCE: Our data suggest the existence of an interaction between HA and NA, and the HA NA matching pattern is critical for valid viral reassortment

Household, community, sub-national and country-level predictors of primary cooking fuel switching in nine countries from the PURE study

Introduction. Switchingfrom polluting (e.g. wood, crop waste, coal)to clean (e.g. gas, electricity) cooking fuels can reduce household air pollution exposures and climate-forcing emissions.While studies have evaluated specific interventions and assessed fuel-switching in repeated cross-sectional surveys, the role of different multilevel factors in household fuel switching, outside of interventions and across diverse community settings, is not well understood. Methods.We examined longitudinal survey data from 24 172 households in 177 rural communities across nine countries within the Prospective Urban and Rural Epidemiology study.We assessed household-level primary cooking fuel switching during a median of 10 years offollow up (∼2005–2015).We used hierarchical logistic regression models to examine the relative importance of household, community, sub-national and national-level factors contributing to primary fuel switching. Results. One-half of study households(12 369)reported changing their primary cookingfuels between baseline andfollow up surveys. Of these, 61% (7582) switchedfrom polluting (wood, dung, agricultural waste, charcoal, coal, kerosene)to clean (gas, electricity)fuels, 26% (3109)switched between different polluting fuels, 10% (1164)switched from clean to polluting fuels and 3% (522)switched between different clean fuels

Acetylcholinesterase Immobilization on ZIF-8/Graphene Composite Engenders High Sensitivity Electrochemical Sensing for Organophosphorus Pesticides

A sensitive and flexible detection method for organophosphorus pesticides (OPs) detection is a crucial request to avoid their further expanded pollution. Herein, an acetylcholinesterase (AChE) electrochemical sensor, based on the co-modification of ZIF-8 and graphene (GR), was constructed for the detection of OPs. ZIF-8/GR composite can provide a stable and biocompatible environment for the loading of AChE and can accelerate the chemical reaction on the electrode surface. After optimization, the linear detection range of the constructed AChE-CS/GR/ZIF-8/GCE sensor for ICP was 0.5&ndash;100 ng/mL (1.73&ndash;345.7 nM), and the limit of detection was 0.18 ng/mL (0.62 nM). Moreover, high sensitivity and high specificity of the sensor were also achieved in actual cabbage and tap water samples. Therefore, it has great potential for the application of organophosphorus pesticide residue analysis

Acetylcholinesterase Immobilization on ZIF-8/Graphene Composite Engenders High Sensitivity Electrochemical Sensing for Organophosphorus Pesticides

A sensitive and flexible detection method for organophosphorus pesticides (OPs) detection is a crucial request to avoid their further expanded pollution. Herein, an acetylcholinesterase (AChE) electrochemical sensor, based on the co-modification of ZIF-8 and graphene (GR), was constructed for the detection of OPs. ZIF-8/GR composite can provide a stable and biocompatible environment for the loading of AChE and can accelerate the chemical reaction on the electrode surface. After optimization, the linear detection range of the constructed AChE-CS/GR/ZIF-8/GCE sensor for ICP was 0.5–100 ng/mL (1.73–345.7 nM), and the limit of detection was 0.18 ng/mL (0.62 nM). Moreover, high sensitivity and high specificity of the sensor were also achieved in actual cabbage and tap water samples. Therefore, it has great potential for the application of organophosphorus pesticide residue analysis