Publications by authors named "M Thomas P Gilbert"

2,323 Publications

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Impact of the methylation classifier and ancillary methods on CNS tumor diagnostics.

Neuro Oncol 2021 Sep 23. Epub 2021 Sep 23.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Accurate CNS tumor diagnosis can be challenging, and methylation profiling can serve as an adjunct to classify diagnostically difficult cases.

Methods: An integrated diagnostic approach was employed for a consecutive series of 1,258 surgical neuropathology samples obtained primarily in a consultation practice over 2-year period. DNA methylation profiling and classification using the DKFZ/Heidelberg CNS tumor classifier was performed, as well as unsupervised analyses of methylation data. Ancillary testing, where relevant, was performed.

Results: Among the received cases in consultation, a high confidence methylation classifier score (>0.84) was reached in 66.4% of cases. The classifier impacted the diagnosis in 46.5% of these high-confidence classifier score cases, including a substantially new diagnosis in 26.9% cases. Among the 289 cases received with only a descriptive diagnosis, methylation was able to resolve approximately half (144, 49.8%) with high-confidence scores. Additional methods were able to resolve diagnostic uncertainty in 41.6% of the low-score cases. Tumor purity was significantly associated with classifier score (p = 1.15e-11). Deconvolution demonstrated that suspected GBMs matching as control/inflammatory brain tissue could be resolved into GBM methylation profiles, which provided a proof-of-concept approach to resolve tumor classification in the setting of low tumor purity.

Conclusions: This work assesses the impact of a methylation classifier and additional methods in a consultative practice by defining the proportions with concordant vs. change in diagnosis in a set of diagnostically challenging CNS tumors. We address approaches to low-confidence scores and confounding issues of low tumor purity.
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http://dx.doi.org/10.1093/neuonc/noab227DOI Listing
September 2021

Modern Siberian dog ancestry was shaped by several thousand years of Eurasian-wide trade and human dispersal.

Proc Natl Acad Sci U S A 2021 09;118(39)

Lundbeck Foundation GeoGenetic Center, GLOBE Institute, Copenhagen, 1352, University of Copenhagen, Denmark.

Dogs have been essential to life in the Siberian Arctic for over 9,500 y, and this tight link between people and dogs continues in Siberian communities. Although Arctic Siberian groups such as the Nenets received limited gene flow from neighboring groups, archaeological evidence suggests that metallurgy and new subsistence strategies emerged in Northwest Siberia around 2,000 y ago. It is unclear if the Siberian Arctic dog population was as continuous as the people of the region or if instead admixture occurred, possibly in relation to the influx of material culture from other parts of Eurasia. To address this question, we sequenced and analyzed the genomes of 20 ancient and historical Siberian and Eurasian Steppe dogs. Our analyses indicate that while Siberian dogs were genetically homogenous between 9,500 to 7,000 y ago, later introduction of dogs from the Eurasian Steppe and Europe led to substantial admixture. This is clearly the case in the Iamal-Nenets region (Northwestern Siberia) where dogs from the Iron Age period (∼2,000 y ago) possess substantially less ancestry related to European and Steppe dogs than dogs from the medieval period (∼1,000 y ago). Combined with findings of nonlocal materials recovered from these archaeological sites, including glass beads and metal items, these results indicate that Northwest Siberian communities were connected to a larger trade network through which they acquired genetically distinctive dogs from other regions. These exchanges were part of a series of major societal changes, including the rise of large-scale reindeer pastoralism ∼800 y ago.
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http://dx.doi.org/10.1073/pnas.2100338118DOI Listing
September 2021

Research led by people who use drugs: centering the expertise of lived experience.

Subst Abuse Treat Prev Policy 2021 Sep 20;16(1):70. Epub 2021 Sep 20.

Injury Prevention Research Center, University of North Carolina At Chapel Hill, Chapel Hill, NC, USA.

Background: Research collaborations between people who use drugs (PWUD) and researchers are largely underutilized, despite the long history of successful, community-led harm reduction interventions and growing health disparities experienced by PWUD. PWUD play a critical role in identifying emerging issues in the drug market, as well as associated health behaviors and outcomes. As such, PWUD are well positioned to meaningfully participate in all aspects of the research process, including population of research questions, conceptualization of study design, and contextualization of findings.

Main Body: We argue PWUD embody unparalleled and current insight to drug use behaviors, including understanding of novel synthetic drug bodies and the dynamics at play in the drug market; they also hold intimate and trusting relationships with other PWUD. This perfectly situates PWUD to collaborate with researchers in investigation of drug use behaviors and development of harm reduction interventions. While PWUD have a history of mistrust with the medical community, community-led harm reduction organizations have earned their trust and are uniquely poised to facilitate research projects. We offer the North Carolina Survivors Union as one such example, having successfully conducted a number of projects with reputable research institutions. We also detail the fallacy of meaningful engagement posed by traditional mechanisms of capturing community voice. As a counter, we detail the framework developed and implemented by the union in hopes it may serve as guidance for other community-led organizations. We also situate research as a mechanism to diversify the job opportunities available to PWUD and offer a real-time example of the integration of these principles into public policy and direct service provision.

Conclusion: In order to effectively mitigate the risks posed by the fluid and volatile drug market, research collaborations must empower PWUD to play meaningful roles in the entirety of the research process. Historically, the most effective harm reduction interventions have been born of the innovation and heart possessed by PWUD; during the current overdose crisis, there is no reason to believe they will not continue to be.
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http://dx.doi.org/10.1186/s13011-021-00406-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454046PMC
September 2021

Adenosine A2A receptor activation enhances blood-tumor barrier permeability in a rodent glioma model.

Mol Cancer Res 2021 Sep 14. Epub 2021 Sep 14.

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke

The blood-tumor barrier (BTB) limits the entry of effective chemotherapeutic agents into the brain for treatment of malignant tumors like glioblastoma (GBM). Poor drug entry across the BTB allows infiltrative glioma stem cells (GSC) to evade therapy and develop treatment resistance. Regadenoson, an FDA-approved adenosine A2A receptor (A2AR) agonist, has been shown to increase drug delivery across the blood-brain barrier (BBB) in non-tumor bearing rodents without a defined mechanism of enhancing BTB permeability. Here, we characterize the time-dependent impact of regadenoson on brain endothelial cell interactions and paracellular transport, using mouse and rat brain endothelial cells and tumor models. In vitro, A2AR activation leads to disorganization of cytoskeletal actin filaments by 30 minutes, down-regulation of junctional protein expression by 4 hours, and re-establishment of endothelial cell integrity by 8 hours. In rats bearing intracranial gliomas, regadenoson treatment results in increase of intratumoral temozolomide (TMZ) concentrations, yet no increased survival noted with combined TMZ therapy. These findings demonstrate regadenoson's ability to induce brain endothelial structural changes amongst glioma to increase BTB permeability. The use of vasoactive mediators, like regadenoson, which transiently influences paracellular transport, should further be explored to evaluate their potential to enhance CNS treatment delivery to aggressive brain tumors. Implications: This study provides insight on the use of a vasoactive agent to increase exposure of the blood-tumor barrier to chemotherapy with intention to improve glioma treatment efficacy.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0995DOI Listing
September 2021
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