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Biology subjects

Stanton, K.

Publications and source records attributed to Stanton, K..

2 recordsLinked to original sources

Resolving Allopolyploid Origins Within the Genus Clarkia Using a Novel Read-Mapping and Modeling Approach

Whole genome duplications are a common occurrence in plants, but this creates challenges for reconstructing the evolutionary history between species, especially when polyploidy is a result of hybridization. While multiple methods have been developed to try to tackle these issues, most are computationally intensive, restrictive on the number of taxa that can be evaluated, and benefit immensely from a priori hypotheses about the allopolyploid progenitors, rendering these methods unfeasible for many understudied polyploids. We present a rapid, low-cost, and computationally light method for determining the relative time of hybridization as well as the most likely progenitor species of a given allopolyploid species, including progenitors that are extinct, ancestral, or unknown. The method utilizes a combined approach of first mapping sequencing reads from the polyploid against a diploid pantranscriptome to generate hypotheses about possible progenitor pairs and then modeling various hybridization scenarios to estimate the likelihood of each hypothesis. We demonstrate the utility of our methods by identifying likely progenitors and times of origin for six allotetraploid species from the genus Clarkia. While the methods outlined here do not conclusively confirm the origins of these allopolyploids, they provide well-supported working hypotheses for further intensive exploration.

evolutionary biology↗

Oncolytic virus-antibody combinations enhance immune-mediated killing of osteosarcoma

A major barrier to effective immunotherapy in osteosarcoma (OS) is the highly immunosuppressive tumour microenvironment (TME), which limits immune recognition and elimination of tumour cells. We evaluated a panel of oncolytic herpes simplex viruses (oHSVs) for their direct oncolytic activity, immune-modulatory properties and capacity to counteract OS-associated immunosuppression using immunologically relevant in vitro models. We demonstrate that established OS cell lines, primary cell cultures and dissociated OS cells from freshly resected tumour samples are susceptible to direct oncolysis by three oHSVs; HSV1716, HSV1716-GMCSF, and HSV47{Delta}, although susceptibility levels varied. Treatment of peripheral blood mononuclear cells from healthy donors and OS patients with oHSVs enhanced natural killer (NK) cell activation and promoted immune-mediated killing of OS cell lines and primary OS cell cultures. Among the three viruses, HSV1716-GMCSF exhibited the strongest immune-stimulatory effects and was uniquely capable of reducing the abundance of CD163+CD206+ immunosuppressive TAMs; use of this oHSV was therefore prioritised. We developed a multicellular spheroid model of OS, incorporating OS cells, mesenchymal stem cells and TAMs, which exhibits resistance to immune-mediated killing, better reflecting the immunosuppressive TME in patients. In this model, pairing HSV1716-GMCSF treatment with either anti-GD2 or anti-EGFR monoclonal antibodies (mAbs), selected according to OS tumour antigen expression, significantly increased immune-mediated tumour cell killing. These findings suggest that personalised combination strategies pairing oHSVs with appropriate mAbs provide a promising therapeutic approach for OS by integrating direct oncolysis, remodelling of the immunosuppressive TME and enhanced immune-mediated tumour destruction.

cancer biology↗