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Oncolytic viruses (OVs) have been engineered or selected for cancer cell-specific infection however, we have found that following intravenous administration of vesicular stomatitis virus (VSV), tumor cell killing rapidly extends far beyond the initial sites of infection. We show here for the first time that VSV directly infects and destroys tumor vasculature in vivo but leaves normal vasculature intact. Three-dimensional (3D) reconstruction of infected tumors revealed that the majority of the tumor mass lacks significant blood flow in contrast to uninfected tumors, which exhibit relatively uniform perfusion. VSV replication in tumor neovasculature and spread within the tumor mass, initiates an inflammatory reaction including a neutrophil-dependent initiation of microclots within tumor blood vessels. Within 6 hours of intravenous administration of VSV and continuing for at least 24 hours, we observed the initiation of blood clots within the tumor vasculature whereas normal vasculature remained clot free. Blocking blood clot formation with thrombin inhibitors prevented tumor vascular collapse. Our results demonstrate that the therapeutic activity of an OV can go far beyond simple infection and lysis of malignant cells.

Oncolytic viruses as cancer therapy Oncolytic viruses, either natural or engineered, preferentially infect and lyse tumour cells. David Kirn and colleagues now report a phase I clinical trial in which they demonstrate systemic delivery of the engineered oncolytic virus JX-594 selectively to tumour tissue after a single injection. Tumour biopsies indicate that the virus replicates in cancer but not in adjacent normal tissue. JX-594 is engineered to replicate in a broad spectrum of cancer cells harbouring activation of the epidermal growth factor receptor/Ras pathway. Although the trial was not designed to demonstrate clinical efficacy, the results suggest that JX-594 may elicit a clinical response in some patients. The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity 1 . Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.

Histone deacetylase inhibitors (HDI) dampen cellular innate immune response by decreasing interferon production and have been shown to increase the growth of vesicular stomatitis virus and HSV. As attenuated tumour-selective oncolytic vaccinia viruses (VV) are already undergoing clinical evaluation, the goal of this study is to determine whether HDI can also enhance the potency of these poxviruses in infection-resistant cancer cell lines. Multiple HDIs were tested and Trichostatin A (TSA) was found to potently enhance the spread and replication of a tumour selective vaccinia virus in several infection-resistant cancer cell lines. TSA significantly decreased the number of lung metastases in a syngeneic B16F10LacZ lung metastasis model yet did not increase the replication of vaccinia in normal tissues. The combination of TSA and VV increased survival of mice harbouring human HCT116 colon tumour xenografts as compared to mice treated with either agent alone. We conclude that TSA can selectively and effectively enhance the replication and spread of oncolytic vaccinia virus in cancer cells.

We have adapted a zebrafish (Danio rerio) tumor xenograft model for use in the study of oncolytic virotherapy. Following implantation of mammalian cancer cells into the perivitelline space of developing zebrafish embryos, both local and intravenous oncolytic virus treatments produce a tumor-specific infection with measurable antitumor effects. Tumor cells are injected at 48 h post fertilization, with oncolytic virus treatment then being administered 24 h later to allow for an initial period of tumor development and angiogenesis. Confocal fluorescent imaging is used to quantify dynamics within the tumor environment. The natural translucency of zebrafish at the embryo stage, coupled with the availability of strains with fluorescent immune and endothelial cell reporter lines, gives the model broad potential to allow for real time, in vivo investigation of important events within tumors throughout the course of virotherapy. Zebrafish xenografts offer a system with biologic fidelity to processes in human cancer development that influence oncolytic virus efficacy, and to our knowledge this is the first demonstration of the model’s use in the context of virotherapy. Compared with other models, our protocol offers a powerful, inexpensive approach to evaluating novel oncolytic viruses and oncolytic virus-based combination therapies, with potential application to investigating the impacts of virotherapy on immune response, tumor vasculature, and metastatic disease.

JX-594 is a targeted and granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In order to study the mechanisms-of-action (MOA) of JX-594 in humans, a mechanistic proof-of-concept clinical trial was performed at a low dose equivalent to ≤10% of the maximum-tolerated dose (MTD) in other clinical trials. Ten patients with previously treated stage IV melanoma were enrolled. Tumors were injected weekly for up to nine total treatments. Blood samples and tumor biopsies were analyzed for evidence of transgene activity, virus replication, and immune stimulation. The β-galactosidase (β-gal) transgene was expressed in all patients as evidenced by antibody induction. Six patients had significant induction of GM-CSF-responsive white blood cell (WBC) subsets such as neutrophils (25–300% increase). JX-594 replication and subsequent shedding into blood was detectable in five patients after cycles 1–9. Tumor biopsies demonstrated JX-594 replication, perivascular lymphocytic infiltration, and diffuse tumor necrosis. Mild flu-like symptoms were the most common adverse events. In sum, JX-594 replication, oncolysis, and expression of both transgenes were demonstrated; replication was still evident after multiple cycles. These findings have implications for further clinical development of JX-594 and other transgene-armed oncolytic viruses.

In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes. Microtubule-destabilizing drugs and oncolytic viruses are two unrelated approaches to battle cancer. Here the authors show that microtubule-destabilizing drugs potentiate the efficiency of oncolytic rhabdoviruses by altering the cytokine production and response of the tumour cells.

In a corporate sustainability context, scholars have been studying internal and external relations provided by Environmental, Social, and Governance (ESG) criteria, mostly from the organizational perspective. Therefore, the main objective of this paper is to map and analyze the literature on the impacts of integrating ESG criteria on corporate sustainability performance from different points of view. The methodology used followed the Preferred Report Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, corroborated by a critical analysis. The results indicate that the integration of ESG criteria, observed from different perspectives, strengthens corporate sustainability performance. They also revealed narrowing gaps in the literature regarding methodological analysis. Most of the papers in the analyzed sample use company-level data and employ regression analysis in their analysis. The present study concludes that companies, regardless of nationality, follow the guidelines of ESG criteria integration and such procedure brings several benefits. It points to the lack of more confirmatory research approaches from a workers’ perspective, as the interest remains in the economic-environmental realm from the organizations’ point of view. The absence of such evidence points to a gap in the literature that suggests the need for new study initiatives.

Entomopathogenic fungi (EPF) can be defined as beneficial multifunctional eukaryotic microorganisms that display pivotal ecological services in pest management, with some species possessing the special ability to establish mutualistic relationships with plants. Mass production of these fungi is critical to support affordable widespread commercialization and worldwide field application. Among the mass production methods explored mainly by industry, submerged liquid fermentation is a robust and versatile technology that allows the formation of different types of propagules designated for various applications in pest control. Many hypocrealean EPF are easily culturable on artificial substrates by producing single-celled structures (hyphal bodies, blastospores, and submerged conidia) or multicellular structures (mycelium and microsclerotia). Less frequently, some EPF may form environmentally resistant chlamydospores, but these structures have almost always been overlooked. A continued research pipeline encompassing screening fungal strains, media optimization, and proper formulation techniques aligned with the understanding of molecular cues involved in the formation and storage stability of these propagules is imperative to unlock the full potential and to fine-tune the development of robust and effective biocontrol agents against arthropod pests and vectors of diseases. Finally, we envision a bright future for the submerged liquid fermentation technology to supplement or replace the traditional solid substrate fermentation method for the mass production of many important EPF. 653 __ |a Biological control; Mass production; Blastospores; Microsclerotia; Submerged conidia; Bioreactor.

Background Low birth weight (LBW) newborns present different health outcomes when classified in different birth weight strata. This study evaluated the relationship of birth weight with Infant mortality (IM) through the influence of biological, social, and health care factors in a time series. Methods Retrospective cohort study with data collected from Information Systems (Live Births and Mortality). The mortality trends were performed for each birth weight stratum: extremely low, < 1000 g; very low, 1000–1499 g; low, 1500–2499 g; insufficient, 2500–2999 g; adequate, 3000–3900 g; and macrosomia, > 4000 g. Chi-square tests analyzed IM rates. Sequential Poisson regression analyzed the impact of the determinant factors. Results A total of 277,982 newborns were included in the study and 2088 died before their first year. There was a tendency for a decrease in mortality in all strata of weight. With the exception of macrosomics, all other strata had a higher risk for IM when compared with adequate birth weight. Extremely LBW newborns presented higher risk for mortality when born in a public hospital. A higher percentage of infant deaths were associated with lower maternal age and lower schooling for all strata. Prenatal care with less than three visits demonstrated a risk for IM in low, insufficient, and adequate birth weight strata. The cesarean section was a protective factor for IM in Extremely and Very LBW strata and it was a risk factor in adequate birth weight stratum. Conclusions LBW had a greater association with IM, especially those children of younger mothers and those born in public hospitals.

Amazon forests, which store ∼50% of tropical forest carbon and play a vital role in global water, energy, and carbon cycling, are predicted to experience both longer and more intense dry seasons by the end of the 21st century. However, the climate sensitivity of this ecosystem remains uncertain: several studies have predicted large-scale die-back of the Amazon, whereas several more recent studies predict that the biome will remain largely intact. Combining remote-sensing and ground-based observations with a size- and age-structured terrestrial ecosystem model, we explore the sensitivity and ecological resilience of these forests to changes in climate. We demonstrate that water stress operating at the scale of individual plants, combined with spatial variation in soil texture, explains observed patterns of variation in ecosystem biomass, composition, and dynamics across the region, and strongly influences the ecosystem’s resilience to changes in dry season length. Specifically, our analysis suggests that in contrast to existing predictions of either stability or catastrophic biomass loss, the Amazon forest’s response to a drying regional climate is likely to be an immediate, graded, heterogeneous transition from high-biomass moist forests to transitional dry forests and woody savannah-like states. Fire, logging, and other anthropogenic disturbances may, however, exacerbate these climate change-induced ecosystem transitions.