Biology subjects

Higgins, D.

Publications and source records attributed to Higgins, D..

4 recordsLinked to original sources

bioRxiv2025

Combinatorial Treatment of Glioblastoma with Temozolomide (TMZ) Plus 55-Ethynyl-2-deoxyuridine (EdU)

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with incidence peaking in later life. It is commonly treated with surgery followed by administration of ionizing radiation and the DNA alkylating agent temozolomide (TMZ). Even though this regimen confers some progression-free survival, there is essentially no cure with the median survival with the standard of care being about 12 months. Currently, several alternative approaches are being developed to improve upon this outcome. We have already shown EdU alone effectively treats GBM, and we now study efficacy of TMZ+EdU combination therapy. TMZ+EdU significantly improves antitumor efficacy compared to either single-agent therapy against GBM cell lines in vitro, against three different orthotopic GBM xenograft models, and against passage-zero patient GBM tumor tissues engrafted within an organotypic brain slice culture (OBSC)-based platform. Together, these data suggest that EdU could be effective alongside standard of care TMZ in patients with GBM. STATEMENT OF SIGNIFICANCE (50-WORD)By simultaneously engaging distinct DNA repair pathways, combination of TMZ and EdU produced unprecedented survival benefits and synergistic effects in preclinical GBM models, offering a promising new avenue in the treatment of GBM.

cancer biology↗

bioRxiv2025

Functional Specialization of S-Adenosylmethionine Synthases Links Phosphatidylcholine to Mitochondrial Function and Stress Survival

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Studies have often equated the effects of knocking down one synthase with broader SAM-dependent outcomes such as histone methylation or phosphatidylcholine (PC) production. Humans and many other organisms express multiple SAM synthases. Evidence in Caenorhabditis elegans, which possesses four SAM synthase genes, suggest that the enzymatic source of SAM impacts its function. For instance, loss of sams-1 leads to enhanced heat shock survival and increased lifespan, whereas reducing sams-4 adversely affects heat stress survival. Here, we show that SAMS-1 contributes to a variety of intermediary metabolic pathways, whereas SAMS-4 is more important to generate SAM for methylation reactions. We demonstrate that loss of sams-1 exerts age-dependent effects on nuclear-encoded mitochondrial gene expression, mitochondrial metabolites, and may induce mitophagy. We propose a mechanistic model where reduced SAM from SAMS-1 acts through PC to impact mitochondria, thereby enhancing survival during heat stress.

cell biology↗

bioRxiv2022

The Children's Brain Tumor Network (CBTN) - Accelerating Research in Pediatric Central Nervous System Tumors through Collaboration and Open Science

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Childrens Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTNs 32 member institutions utilize a shared regulatory governance architecture at the Childrens Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4,700 subjects, over 1,500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1,000 tumors and germline material is currently available with data generation for > 5,000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.

cancer biology↗

bioRxiv2018

Failure to learn during roving, analysing the unsupervised bias hypothesis.

We examine the unsupervised bias hypothesis [11] as an explanation for failure to learn two bisection tasks, when task sequencing is randomly alternating (roving). This hypothesis is based on the idea that a covariance based synaptic plasticity rule, which is modulated by a reward signal, can be biased when reward is averaged across multiple tasks of differing difficulties. We find that, in our hands, the hypothesis in its original form can never explain roving. This drives us to develop an extended mathematical analysis, which demonstrates not one but two forms of unsupervised bias. One form interacts with overlapping task representations and the other does not. We find that overlapping task representations are much more susceptible to unsupervised biases than non-overlapping representations. Biases from non-overlapping representations are more likely to stabilise learning. But this in turn is incompatible with the experimental understanding of perceptual learning and task representation, in bisection tasks. Finally, we turn to alternative network encodings and find that they also are unlikely to explain failure to learn during task roving as a result of unsupervised biases. As a solution, we present a single critic hypothesis, which is consistent with recent literature and could explain roving by a, much simpler, certainty normalised reward signalling mechanism.

neuroscience↗