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Recent years have seen tremendous advances in the development of exquisitely targeted replicating virotherapeutics that can safely destroy malignant cells. Despite this promise, clinical advancement of this powerful and unique approach has been hindered by vulnerability to host defenses and inefficient systemic delivery. However, it now appears that delivery of oncolytic viruses within carrier cells may offer one solution to this critical problem. In this review, we compare the advantages and limitations of the numerous cell lineages that have been investigated as delivery platforms for viral therapeutics, and discuss examples showing how combined cell–virus biotherapeutics can be used to achieve synergistic gains in antitumor activity. Finally, we highlight avenues for future preclinical research that might be taken in order to refine cell–virus biotherapeutics in preparation for human trials.

Oncolytic viruses capable of tumor-selective replication and cytolysis have shown early promise as cancer therapeutics. However, the host immune system remains a significant obstacle to effective systemic administration of virus in a clinical setting. Here, we demonstrate the severe negative impact of the adaptive immune response on the systemic delivery of oncolytic vesicular stomatitis virus (VSV) in an immune-competent murine tumor model, an effect mediated primarily by the neutralization of injected virions by circulating antibodies. We show that this obstacle can be overcome by administering virus within carrier cells that conceal viral antigen during delivery. Infected cells were delivered to tumor beds and released virus to infect malignant cells while sparing normal tissues. Repeated administration of VSV in carrier cells to animals bearing metastatic tumors greatly improved therapeutic efficacy when compared with naked virion injection. Whole-body molecular imaging revealed that carrier cells derived from solid tumors accumulate primarily in the lungs following intravenous injection, whereas leukemic carriers disseminate extensively throughout the body. Furthermore, xenogeneic cells were equally effective at delivering virus as syngeneic cells. These findings emphasize the importance of establishing cell-based delivery platforms in order to maximize the efficacy of oncolytic therapeutics.

Until recently, large apex consumers were ubiquitous across the globe and had been for millions of years. The loss of these animals may be humankind's most pervasive influence on nature. Although such losses are widely viewed as an ethical and aesthetic problem, recent research reveals extensive cascading effects of their disappearance in marine, terrestrial, and freshwater ecosystems worldwide. This empirical work supports long-standing theory about the role of top-down forcing in ecosystems but also highlights the unanticipated impacts of trophic cascades on processes as diverse as the dynamics of disease, wildfire, carbon sequestration, invasive species, and biogeochemical cycles. These findings emphasize the urgent need for interdisciplinary research to forecast the effects of trophic downgrading on process, function, and resilience in global ecosystems.

[This corrects the article DOI: 10.1371/journal.pone.0299894.].

Background There is currently no standardized method for measuring functional status in knee osteoarthritis (OA) patients, despite that it is one of the top priorities when determining eligibility for total knee arthroplasty (TKA). The purpose of the current investigation was to identify factors associated with discordance between individual self-report and performance-based measures of function for obese and non-obese men and women with knee OA. Methods In a cohort of 727 knee OA patients scheduled for TKA, physical function prior to surgery was assessed with the self-reported physical function subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC-pf), and the performance-based Timed Up and Go (TUG). Data on sociodemographic characteristics, health status, knee pain intensity, symptomatic joint site count, and pain catastrophizing were collected via questionnaire. The primary outcome was the difference in rescaled score between a participant’s self-report and performance-based measures of function. Multivariable linear regression stratified by sex and obesity status was used to identify factors associated with discordance. Results The mean age of participants was 65.5 years and 55% were women. With younger age, self-reported scores indicated increasingly worse function compared to performance-based scores, regardless of sex or obesity status. Among non-obese individuals, greater knee pain intensity was associated with a participant’s self-report score indicating increasingly worse function compared to their performance-based score. For obese women, pain catastrophizing, and number of symptomatic joints were also associated with discordance as was reporting fewer comorbidities. Conclusions Physical function may be differentially represented by self-reported and performance-based measures depending on a variety of patient factors. Our findings add to the evidence which suggests both measures should be used when assessing functional status prior to TKA.

Venous leg ulcers can be very hard to heal and represent a significant medical need with no effective therapeutic treatment currently available. In wound edge biopsies from human venous leg ulcers we found a striking upregulation of dermal N-cadherin, Zonula Occludens-1 and the gap junction protein Connexin43 (Cx43) compared to intact skin, and in stark contrast to the down-regulation of Cx43 expression seen in acute, healing wounds. We targeted the expression of these proteins in 3T3 fibroblasts to evaluate their role in venous leg ulcers healing. Knockdown of Cx43 and N-cadherin, but not Zonula Occludens-1, accelerated cell migration in a scratch wound-healing assay. Reducing Cx43 increased Golgi reorientation, whilst decreasing cell adhesion and proliferation. Furthermore, Connexin43 and N-cadherin knockdown led to profound effects on fibroblast cytoskeletal dynamics after scratch-wounding. The cells exhibited longer lamelipodial protrusions lacking the F-actin belt seen at the leading edge in wounded control cells. This phenotype was accompanied by augmented activation of Rac-1 and RhoA GTPases, as revealed by Förster Resonance Energy Transfer and pull down experiments. Cx43 and N-cadherin are potential therapeutic targets in the promotion of healing of venous leg ulcers, by acting at least in part through distinct contributions of cell adhesion, migration, proliferation and cytoskeletal dynamics.

Introduction Although there is clear evidence for the serotonergic regulation of descending control of pain in animals, little direct evidence exists in humans. The majority of our knowledge comes from the use of serotonin (5-HT)-modulating antidepressants as analgesics in the clinical management of chronic pain. Objectives Here, we have used an acute tryptophan depletion (ATD) to manipulate 5-HT function and examine its effects of ATD on heat pain threshold and tolerance, attentional manipulation of nociceptive processing and mood in human volunteers. Methods Fifteen healthy participants received both ATD and balanced amino acid (BAL) drinks on two separate sessions in a double-blind cross-over design. Pain threshold and tolerance were determined 4 h post-drink via a heat thermode. Additional attention, distraction and temperature discrimination paradigms were completed using a laser-induced heat pain stimulus. Mood was assessed prior and throughout each session. Results Our investigation reported that the ATD lowered plasma TRP levels by 65.05 ± 7.29% and significantly reduced pain threshold and tolerance in response to the heat thermode. There was a direct correlation between the reduction in total plasma TRP levels and reduction in thermode temperature. In contrast, ATD showed no effect on laser-induced pain nor significant impact of the distraction-induced analgesia on pain perception but did reduce performance of the painful temperature discrimination task. Importantly, all findings were independent of any effects of ATD on mood. Conclusion As far as we are aware, it is the first demonstration of 5-HT effects on pain perception which are not confounded by mood changes.

In osteoarthritis (OA) research, disability is largely studied within the context of activities of daily living. Broader consequences for social participation are often overlooked. In prior work, instrumental supports received and their perceived availability were shown to play a role in the maintenance of social participation. Two indicators of social participation were identified, diversity and intensity. The current study extends the findings from this prior cross-sectional work by examining these relationships longitudinally. Data are from the baseline and 3-year follow-up questionnaires of the Canadian Longitudinal Study on Aging, a population-based study of people ages 45-85 years at baseline. The sample was restricted to those who at baseline reported a doctor diagnosis of OA (n = 4104). Using structural equation modeling, latent variables were derived at each time point for activity limitations, instrumental supports perceived and received, and social participation diversity and intensity. Longitudinal factorial invariance was assessed. Model covariates included age, sex, education, income, marital status, smoking status, obesity, and number of chronic conditions. For all latent variables, strong factorial longitudinal invariance was found. Activity limitations increased over time. Greater baseline social participation intensity was associated with increases in later intensity and diversity. Increasing activity limitations were associated with decreases in social participation and with increasing receipt of instrumental supports; they were not associated with changes in perceived availability of supports. However, increasing perceived availability was positively associated with social participation intensity. With a goal of increasing social participation, findings suggest a focus on interventions to reduce activity limitations in OA is necessary. Findings additionally highlight an important role for perceived availability of instrumental supports in maintaining or improving social participation in OA, in addition to current social participation, particularly intensity, for future social participation status.

Diversion of prescription opioid medication is a contributor to the opioid epidemic. Safe handling practices can reduce the risk of diversion. We aimed to understand: 1) if orthopaedic patients received instructions on how to safely handle opioids, 2) their typical storage/disposal practices, and 3) their willingness to participate in an opioid disposal program (ODP). Cross-sectional study of adult orthopaedic patients who completed an anonymous survey on current or past prescription opioid use, instruction on handling, storage and disposal practices, presence of children in the household, and willingness to participate in an ODP. Frequencies and percentages of responses were computed, both overall and stratified by possession of unused opioids. 569 respondents who reported either current or past prescription opioid use were analyzed. 44% reported receiving storage instructions and 56% reported receiving disposal instructions from a health care provider. Many respondents indicated unsafe handling practices: possessing unused opioids (34%), using unsafe storage methods (90%), and using unsafe disposal methods (34%). Respondents with unused opioids were less likely to report receiving handling instructions or using safe handling methods, and 47% of this group reported having minors or young adults in the household. Respondents who received storage and disposal instructions were more likely to report safe storage and disposal methods. Seventy-four percent of respondents reported that they would participate in an ODP. While many orthopaedic patients report inadequate education on safe opioid handling and using unsafe handling practices, findings suggest targeted education is associated with better behaviours. However, patients are willing to safely dispose of unused medication if provided a convenient option. These findings suggest a need to address patient knowledge and behavior regarding opioid handling to reduce the risk of opioid diversion.

Phenotypic plasticity facilitates species persistence across resource gradients but may be limited in low-resource environments requiring resource conservation. We investigated the tradeoff between trait plasticity and resource conservatism across a biome boundary characterized by high turnover in nutrient and light availability, and whether this contributes to the maintenance of alternative stable states. Differences in plasticity were determined by comparing species’ leaf and foliar nutritional trait responses to light, represented by leaf area index (LAI), and soil nutrient availability across forest–shrubland boundaries in South Africa. Although forest had higher LAI and soil nutrient availability than shrubland, forest species experienced greater resource variation. With increasing LAI and nutrient availability, forest species increased their leaf size, specific leaf area and leaf area/stem length, and decreased their foliar [N] and [K]. Although these responses are indicative of plasticity, shrubland species appeared to lack plasticity as evidenced by limited trait variation with environmental heterogeneity. Inhabiting diverse light environments imposed by forests probably selects for plasticity, whereas light-saturated, fire-prone, nutrient-poor environments that select for conservative leaf traits and below-ground investments compromise plasticity in shrubland species. This pattern suggests a tradeoff between trait plasticity and resource conservatism, which may support the stability of alternative vegetation states.