Stein, G. | Search bioRxiv

bioRxiv2022

Targeting OLIG2 increases therapeutic responses in SHH medulloblastoma mouse models and patient-derived medulloblastoma organoids

Recurrence after therapy is the primary life-threatening complication of medulloblastoma. In Sonic Hedgehog (SHH)-subgroup medulloblastoma, OLIG2-expressing tumour stem cells are crucial to recurrence. We investigated the potential of the small-molecule OLIG2 inhibitor CT-179 to decrease recurrence in patient-derived organoids, mice genetically-engineered to develop SHH-driven MB, and mice with MB patient-derived xenograft (PDX) tumours. We found that OLIG2 mRNA significantly correlated with poor survival in patients with SHH-MB, but not other subgroups. CT-179 rapidly downregulated OLIG2 protein in vitro and displayed nanomolar IC50 values. CT-179 arrested MB cells at G2/M, with degradation of cyclin B1 and phospho-CDK1 inducing apoptosis. In vivo CT-179 induced similar cell cycle changes in MBs in Smo-mutant mice and significantly increased mouse survival. In both MB organoids and mouse models, CT-179 combined with radiotherapy showed greater efficacy than either treatment alone. These data highlight the potential for OLIG2-targeted therapy to improve MB outcomes by targeting recurrent disease.

cancer biology↗

bioRxiv2021

The DocMaps Framework for representing assertions on research products in an extensible, machine-readable, and discoverable format

Peer review of a research product varies widely depending on the publishers and platforms involved in the process. As scholarly publishing is disrupted by new innovations, peer review processes become more heterogeneous, placing an increasing burden on the researcher in understanding how they can communicate their scholarship. New ways to model such processes, and increase transparency, trust, and experimentation in scholarly publishing are needed. Many are emerging but can tend to focus on the needs of creators, and not those of readers, funders, and the whole scholarly publishing ecosystem. They may not place focus on representing editorial practices in ways that can be reliably aggregated, surfaced, and queried; are often limited to traditional peer review processes; and cannot capture the full range of editorial practices and events needed to accommodate alternative publication, review, and curation models. To support researchers in a world of experimentation in scholarly publishing, we propose a machine-readable, extensible, and discoverable framework for representing and surfacing review and editorial processes. Working with a Technical Committee composed of interested parties by employing a modified Delphi Method, we developed initial guiding principles and proposals towards an object-level editorial metadata framework compatible with a broad range of possible futures for scholarly publishing. We present the results of this process with a proposal and example use cases for DocMaps, a framework for representing object-level assertions.

scientific communication and education↗