OBJECTIVES/GOALS: LSD1 is a histone demethylase important in GBM regulation. Our goal is to design a therapeutic strategy for LSD1 inhibitors to meet clinical needs in GBM. Despite the abundance of LSD1 inhibitors, resistance emerges in GBM mouse models. We aim to understand the relevance of proliferative signaling pathways, such as MAPK, in LSD1 inhibitor resistance. METHODS/STUDY POPULATION: Following LSD1 knockdown in GBM cells, we determined differentially expressed genes using RNA-seq and gene set enrichment analysis (GSEA). Kinase signaling processes enriched for LSD1 expression were identified. Utilizing western blot, we assessed LSD1’s impact on MAPK signaling in patient-derived GBM stem cells (GSCs) and pediatric high-grade glioma cell models. Pharmacological evaluation of LSD1 involved five inhibitor candidates. Additionally, we explored LSD1 inhibition in combination with brain penetrant kinase inhibitors, osimertinib and ulixertinib, directed against the epidermal growth factor receptor (EGFR) and MAPK, respectively. The treatment combinations were assessed at multiple concentrations and analyzed using SynergyFinder. RESULTS/ANTICIPATED RESULTS: Pharmacological LSD1 inhibition after 24 hours induced increased phosphorylated ERK1/2 across multiple glioma cell lines. Concurrent LSD1 and EGFR/MAPK inhibition demonstrated improvedin vitro efficacy compared to individual agents. Notably, the combination of Iadademstat (ORY-1001) and osimertinib demonstrated the highest synergy score of 37.2 using the bliss synergy model in the GSC17s. Furthermore, 11 out of the 12 combination treatments tested had a synergistic relationship, with bliss synergy scores greater than 10. DISCUSSION/SIGNIFICANCE: Our study addresses the pressing need for novel therapeutic strategies in GBM. We leveraged pharmacological tools of LSD1 inhibition to determine how they could be used most effectively, revealing kinase inhibition as a promising strategy with demonstrated in vitro efficacy. Future efforts will focus on validating these findingsin vivo.

In this article, we reorient the literature on colonialism and ethnic violence by exploring how different types of communalizing colonial policy (CCP) affected postcolonial patterns of ethnic warfare. We hypothesize that CCPs have limited or mixed effects when they simply recognize or empower communities but that they promote ethnic warfare when explicitly favoring some communities over others, especially when this discrimination affects the power of communities. To test these hypotheses, we combine a statistical analysis of the British Empire with a focused case study of Myanmar. We find that two relatively non-discriminatory CCPs—the use of communal census categories and high levels of indirect rule—had limited or mixed effects on postcolonial ethnic warfare. Unequal communal representation in the legislature and security forces and a mixed use of indirect rule, on the other hand, are three highly discriminatory CCPs, and we provide evidence that they increased the odds of postcolonial ethnic warfare.

Pauline theology is a well-established undertaking in modern New Testament studies, and yet it is almost entirely without precedent prior to the nineteenth century. This article explores the enterprise of Pauline theology by considering an important and overlooked exception to its otherwise exclusively modern provenance: Priscillian of Avila's fourth-century Canons on the Letters of the Apostle Paul. The key to Priscillian's dogmatic synthesis of Paul's thought was his innovative ‘versification’ of Paul's letters, which facilitated efficient citation and cross-referencing of epistolary data. This article uses Priscillian's literary creation to examine the intriguing correlation of technologies for ordering textual knowledge with the systematic abstraction of Pauline theology.

Two radiocarbon excursions (AD 774–775 and AD 993–994) occurred due to an increase of incoming cosmic rays on a short timescale. The most plausible cause of these events is considered to be extreme solar proton events (SPE). It is possible that there are other annual 14C excursions in the past that have yet to be confirmed. In order to detect more of these events, we measured the 14C contents in bristlecone pine tree-ring samples during the periods when the rate of 14C increase in the IntCal data is large. We analyzed four periods every other year (2479–2455 BC, 4055–4031 BC, 4465–4441 BC, and 4689–4681 BC), and found no anomalous 14C excursions during these periods. This study confirms that it is important to do continuous measurements to find annual cosmic-ray events at other locations in the tree-ring record.