Anti-tumor CD8+ T cells are a key determinant for overall survival in patients following surgical resection for solid malignancies. Using a mouse model of cancer vaccination (adenovirus expressing ...melanoma tumor-associated antigen (TAA)-dopachrome tautomerase (AdDCT) and resection resulting in major surgical stress (abdominal nephrectomy), we demonstrate that surgical stress results in a reduction in the number of CD8+ T cell that produce cytokines (IFNγ, TNFα, Granzyme B) in response to TAA. This effect is secondary to both reduced proliferation and impaired T cell function following antigen binding. In a prophylactic model, surgical stress completely abrogates tumor protection conferred by vaccination in the immediate postoperative period. In a clinically relevant surgical resection model, vaccinated mice undergoing a positive margin resection with surgical stress had decreased survival compared to mice with positive margin resection alone. Preoperative immunotherapy with IFNα significantly extends survival in surgically stressed mice. Importantly, myeloid derived suppressor cell (MDSC) population numbers and functional impairment of TAA-specific CD8+ T cell were altered in surgically stressed mice. Our observations suggest that cancer progression may result from surgery-induced suppression of tumor-specific CD8+ T cells. Preoperative immunotherapies aimed at targeting the prometastatic effects of cancer surgery will reduce recurrence and improve survival in cancer surgery patients.
In this report, investigators in the United Kingdom looked for clues regarding the rapid emergence and dissemination of the SARS-CoV-2 variant B.1.1.7 (alpha) at the end of 2020 and in early 2021.
Introduction to Oncolytic Virotherapy Engeland, Christine E; Bell, John C
Methods in molecular biology (Clifton, N.J.),
01/2020, Volume:
2058
Journal Article
Oncolytic viruses exploit key hallmarks of cancer for replication in malignant cells, leading to tumor cell lysis, modulation of the tumor microenvironment and in situ vaccination effects. Diverse ...virus platforms have been developed as oncolytic vectors and designed for improved tumor specificity, intratumoral spread, therapeutic gene delivery and especially as targeted cancer immunotherapeutics. This chapter provides a concise overview of the basic principles as well as current progress in preclinical and clinical studies of oncolytic virotherapy.
We identified an emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant by viral whole-genome sequencing of 2,172 nasal/nasopharyngeal swab samples from 44 counties in ...California, a state in the western United States. Named B.1.427/B.1.429 to denote its two lineages, the variant emerged in May 2020 and increased from 0% to >50% of sequenced cases from September 2020 to January 2021, showing 18.6%–24% increased transmissibility relative to wild-type circulating strains. The variant carries three mutations in the spike protein, including an L452R substitution. We found 2-fold increased B.1.427/B.1.429 viral shedding in vivo and increased L452R pseudovirus infection of cell cultures and lung organoids, albeit decreased relative to pseudoviruses carrying the N501Y mutation common to variants B.1.1.7, B.1.351, and P.1. Antibody neutralization assays revealed 4.0- to 6.7-fold and 2.0-fold decreases in neutralizing titers from convalescent patients and vaccine recipients, respectively. The increased prevalence of a more transmissible variant in California exhibiting decreased antibody neutralization warrants further investigation.
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•The B.1.427/B.1.429 variant grew to >50% of cases in California by early 2021•The variant is 20% more transmissible with 2-fold increased shedding in vivo•The variant has a spike L452R mutation conferring increased infectivity in vitro•Antibody neutralization is reduced in COVID-19 patients and vaccine recipients
A SARS-CoV-2 variant of concern bearing the L452R spike protein mutation is widely circulating in California, United States, and demonstrates increased transmissibility, infectivity, and avoidance of antibody neutralization.
Permanent scatterer InSAR (PSInSAR™) provides a new high‐resolution methodology for detecting and precisely measuring long‐term and seasonal aquifer‐system response to pumping and recharge. In ...contrast to conventional InSAR, the permanent scatterer methodology utilizes coherent radar phase data from thousands of individual radar reflectors on the ground to develop displacement time series and to produce velocity field maps that depict aquifer‐system response with a high degree of spatial detail. In this study, we present the first results of a prototype study in Las Vegas Valley, Nevada, that demonstrate how this methodology can be utilized in heavily pumped groundwater basins to analyze aquifer‐system response to long‐term and seasonal pumping. We have developed a series of velocity field maps of the valley for the 1992–1996, 1996–2000, and 2003–2005 time periods that show that despite rising water levels associated with an artificial recharge program, long‐term, residual, inelastic aquifer‐system compaction (subsidence) is continuing in several parts of the valley. In other areas, however, long‐term subsidence has been arrested and locally reversed. The seasonal, elastic responses to alternating pumping and recharge cycles were segregated from the long‐term trends and analyzed for spatial and temporal patterns. The results show oscillations in which the maximum seasonal responses are associated with the late stages of the annual artificial recharge cycles, and that similar seasonal subsidence signals are related to summer pumping cycles. The differentiation of the seasonal response through the use of time series data further allows the estimation of elastic and inelastic skeletal storage coefficients, providing a basis for future work that could characterize the storage properties of an aquifer system with a high degree of spatial resolution.
Oncolytic viruses selectively target and kill cancer cells in an immunogenic fashion, thus supporting the establishment of therapeutically relevant tumor-specific immune responses. In 2015, the US ...Food and Drug Administration (FDA) approved the oncolytic herpes simplex virus T-VEC for use in advanced melanoma patients. Since then, a plethora of trials has been initiated to assess the safety and efficacy of multiple oncolytic viruses in patients affected with various malignancies. Here, we summarize recent preclinical and clinical progress in the field of oncolytic virotherapy.
The oncolytic virus (OV) field has entered an exciting period in its evolution in which our basic understanding of viral biology and anti-cancer potential are being actively translated into viable ...therapeutic options for aggressive malignancies. OVs are naturally occurring or engineered viruses that are able to exploit cancer-specific changes in cellular signaling to specifically target cancers and their microenvironment. The direct cytolytic effect of OVs on cancer cells is known to release antigens, which can begin a cascade of events that results in the induction of anti-cancer adaptive immunity. This response is now regarded as the most critical mechanism of OV action and harnessing it can lead to the elimination of distant micrometastases as well as provide long-term anti-cancer immune surveillance. In this review, we highlight the development of the OV field, why OVs are gaining an increasingly elevated standing as members of the cancer immunotherapy armamentarium, and finally, ongoing clinical studies that are aimed at translating unique OV therapies into approved therapies for aggressive cancers.
•MFIX-Exa is a modern, massively parallel, CFD-DEM code.•MFIX-Exa aids the design of new carbon capture and storage technologies.•MFIX-Exa to be performant on current and next generation ...supercomputers.•MFIX-Exa solves thermodynamics and chemical reactions for gas–solid multiphase flows.•MFIX-Exa’s CFD-DEM approach is accurate and cost-efficient.
MFIX-Exa is a CFD-DEM code for the numerical solution of chemically reacting multiphase flows (fluid and solids phases), specifically targeted for flows in complex reactor geometries. The fluid is modeled using a low Mach number formulation with a multicomponent ideal gas equation of state, which is imposed as a constraint of the velocity field. The fluid equations are discretized using an embedded boundary (EB) aware Godunov scheme with an approximate projection. The particles (that constitute the solids phase) are represented by a soft-sphere spring-dashpot model and evolved using a forward Euler method with subcycling. The fluid and particles models are coupled through a volume fraction field in addition to interphase mass, momentum, and energy transfer. The mathematical model and numerical approach are benchmarked against three different verification tests and validated with two separate tests. Also, a scaling analysis is provided. This manuscript represents the current state-of-the-art of MFIX-Exa and describes the major extensions to the previous work presented in Musser et al. (2021), including the Godunov time integration algorithm for the fluid phase and the inclusion of thermodynamics and chemistry modeling to both the fluid and solids phases.
Large-scale simulations are increasingly being used to study complex scientific and engineering phenomena. As a result, advanced visualization and data analysis are also becoming an integral part of ...the scientific process. Often, a key step in extracting insight from these large simulations involves the definition, extraction, and evaluation of features in the space and time coordinates of the solution. However, in many applications, these features involve a range of parameters and decisions that will affect the quality and direction of the analysis. Examples include particular level sets of a specific scalar field, or local inequalities between derived quantities. A critical step in the analysis is to understand how these arbitrary parameters/decisions impact the statistical properties of the features, since such a characterization will help to evaluate the conclusions of the analysis as a whole. We present a new topological framework that in a single-pass extracts and encodes entire families of possible features definitions as well as their statistical properties. For each time step we construct a hierarchical merge tree a highly compact, yet flexible feature representation. While this data structure is more than two orders of magnitude smaller than the raw simulation data it allows us to extract a set of features for any given parameter selection in a postprocessing step. Furthermore, we augment the trees with additional attributes making it possible to gather a large number of useful global, local, as well as conditional statistic that would otherwise be extremely difficult to compile. We also use this representation to create tracking graphs that describe the temporal evolution of the features over time. Our system provides a linked-view interface to explore the time-evolution of the graph interactively alongside the segmentation, thus making it possible to perform extensive data analysis in a very efficient manner. We demonstrate our framework by extracting and analyzing burning cells from a large-scale turbulent combustion simulation. In particular, we show how the statistical analysis enabled by our techniques provides new insight into the combustion process.
Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus ...administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors that developed spontaneously and progressed as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8
T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multitargeted receptor tyrosine kinase inhibitor. These effects were not mimicked by selective inhibition of VEGFR2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells and greater influx of activated CD8
T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8
T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by coadministration of sunitinib.
These findings reveal multiple unrecognized features of the antitumor properties of oncolytic vaccinia viruses, all of which can be amplified by the multitargeted kinase inhibitor sunitinib.
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