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The brain is a common target organ for breast cancer metastasis, and the risk of brain metastasis is usually high for patients with HER2-positive breast cancer. While T-DXd showed positive results in HER2-positive breast cancer brain metastasis (BCBM), its activity and blood-brain barrier (BBB) permeability in active BCBM need to be further validated (TUXEDO-1 included 15 patients with active brain metastasis). Tucatinib plus Trastuzumab and Capecitabine triplet showed efficacy in patients with brain metastasis, but Tucatinib alone has poor BBB penetration. There is still an unmet medical need for active HER2-positive BCBM. VRN101099 is a highly selective kinase inhibitor of HER2 (Eurofins scanMAX Kinase Profiling, S-score (35) of 0.01). VRN101099 has single- to double-digit nanomolar (IC50) cellular potency in HER2-dependent cancer cells, and Ba/F3 cells expressing HER2 wild type or mutations with selectivity over wildtype EGFR. VRN101099 inhibited proliferation of BT474 with 3.6 nM IC50 but HaCaT with 829.2 nM IC50. VRN101099 binds HER2 kinase by forming a covalent bond to the Cys805 and its irreversible inhibition resulted in a longer target resident time than Tucatinib, confirmed by in vitro washout experiments. Robust in vivo activity of VRN101099 was observed in HER2-positive BT474 xenograft models. Moreover, once daily oral administration of VRN101099 significantly regressed intracranial BT474 tumor, demonstrating greater efficacy than twice daily oral administration of Tucatinib. These results were well explained by the superior brain to plasma exposure of VRN101099 to Tucatinib. Also, VRN101099 showed high exposure in the target organ, the fat pad, which potentiated better clinical translation. These anti-tumor efficacies are correlated with pharmacodynamic responses, as confirmed by decreased HER2, AKT, and ERK phosphorylation. In summary, VRN101099 is a brain penetrant, orally bioavailable, irreversible, and highly selective inhibitor of HER2 with therapeutic potential in HER2-positive BCBM. These data support the clinical development of VRN101099 in HER2-driven cancers. Citation Format: Yikyung Ko, Jihye yoo, Hong-ryul Jung, Hyerim Lim, YeongDeok Lee, Se Hyuk Kim, Dong Guk Shin, Serin Cho, Myung hoe Heo, Haelee Kim, Ha Yeon Cho, Ah Reum Han, Eunhwa Ko, Hwan Geun Choi, Deakwon Kim, Sunghwan Kim. VRN101099, Brain Permeable HER2 Kinase Inhibitor, Shows the Anti-tumor Activity in Preclinical Models of HER2-positive Cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-03.

Objectives: This study investigated the latest clinical studies on Korean medicine treatment of idiopathic edema in the Chinese National Knowledge Infrastructure Database (CNKI).Methods: We searched the last 9 years of clinical studies discussing Oriental medicine-based treatments for idiopathic edema in the CNKI database. The search focused on the authors, publication year, type of study, purposes of study, method and duration of treatment, evaluation criteria, and results of the selected articles.Results: The search identified 7 randomized controlled trials (RCTs) and 9 others. All studies used oral herbal medicine for treatment. The most commonly used herbs were Poria Sclerotium (茯苓), Atractylodis Rhizoma Alba (白朮), and Alismatis Rhizoma (澤瀉), which are the constituent herbs of Oryeong-san (五苓散). All 16 studies confirmed the efficacy of Oriental medicine treatments.Conclusion: More varied and scientifically designed clinical studies are required to develop treatments for idiopathic edema. The results of this study could be used as basic data for further studies on idiopathic edema.

Pathway analysis is a popular method aiming to derive biological interpretation from high-throughput gene expression studies. However, existing methods focus mostly on identifying which pathway or pathways could have been perturbed, given differential gene expression patterns. In this paper, we present a novel pathway analysis framework, namely rPAC, which decomposes each signaling pathway route into two parts, the upstream portion of a transcription factor (TF) block and the downstream portion from the TF block and generates a pathway route perturbation analysis scheme examining disturbance scores assigned to both parts together. This rPAC scoring is further applied to a cohort of gene expression data sets which produces two summary metrics, “Proportion of Significance” (PS) and “Average Route Score” (ARS), as quantitative measures discerning perturbed pathway routes within and/or between cohorts. To demonstrate rPAC’s scoring competency, we first used a large amount of simulated data and compared the method’s performance against those by conventional methods in terms of power curve. Next, we performed a case study involving three epithelial cancer data sets from The Cancer Genome Atlas (TCGA). The rPAC method revealed specific pathway routes as potential cancer type signatures. A deeper pathway analysis of sub-groups (i.e., age groups in COAD or cancer sub-types in BRCA) resulted in pathway routes that are known to be associated with the sub-groups. In addition, multiple previously uncharacterized pathways routes were identified, potentially suggesting that rPAC is better in deciphering etiology of a disease than conventional methods particularly in isolating routes and sections of perturbed pathways in a finer granularity.

Although histone methyltransferases are implicated in many key developmental processes, the contribution of individual chromatin modifiers in dental tissues is not well understood. Using single-cell RNA sequencing, we examined the expression profiles of the disruptor of telomeric silencing 1-like (Dot1L) gene in the postnatal day 5 mouse molar dental pulp. Dot1L is the only known enzyme that methylates histone 3 on lysine 79, a modification associated with gene expression. Our research revealed 15 distinct clusters representing different populations of mesenchymal stromal cells (MSCs), immune cells, pericytes, ameloblasts and endothelial cells. We documented heterogeneity in gene expression across different subpopulations of MSCs, a good indicator that these stromal progenitors undergo different phases of osteogenic differentiation. Interestingly, although Dot1L was broadly expressed across all cell clusters within the molar dental pulp, our analyses indicated specific enrichment of Dot1L within two clusters of MSCs, as well as cell clusters characterized as ameloblasts and endothelial cells. Moreover, we detected Dot1L co-expression with protein interactors involved in epigenetic activation such as Setd2, Sirt1, Brd4, Isw1, Bptf and Suv39h1. In addition, Dot1L was co-expressed with Eed2, Cbx3 and Dnmt1, which encode epigenetic factors associated with gene silencing and heterochromatin formation. Dot1l was co-expressed with downstream targets of the insulin growth factor and WNT signaling pathways, as well as genes involved in cell cycle progression. Collectively, our results suggest that Dot1L may play key roles in orchestrating lineage-specific gene expression during MSC differentiation.

Objectives: The aim of this study was to investigate the latest clinical studies on Korean medicine treatment of post-concussion syndrome (PCS) in the Chinese National Knowledge Infrastructure Database (CNKI).Methods: We searched the last 10 years of clinical studies discussing Oriental medicine-based treatments for PCS in the CNKI database. The search focused on the authors, publication year, type of study, purpose of the study, method and duration of treatment, evaluation criteria, and results of each article.Results: Of the 22 selected studies, 1 was a non-randomized controlled trial (nRCT), 2 were case series, and 19 were randomized controlled trials (RCTs). Treatments included oral herbal medicine in 16 studies, oriental medicine through external use in 2 studies, acupuncture in 3 studies, and traditional Chinese medicine injection in 2 studies. The most frequently used herb was Cnidii Rhizoma (川芎). All 22 studies confirmed the efficacy of Oriental medicine treatments.Conclusion: More varied and scientifically designed clinical studies are required to develop treatments for PCS. The results of this study could be used as basic data for further PCS studies.

The dental pulp is critical for the production of odontoblasts to create reparative dentin. In recent years, dental pulp has become a promising source of mesenchymal stem cells that are capable of differentiating into multiple cell types. To elucidate the transcriptional control mechanisms specifying the early phases of odontoblast differentiation, we analysed the DNA demethylation pattern associated with 5-hydroxymethylcytosine (5hmC) in the primary murine dental pulp. 5hmC plays an important role in chromatin accessibility and transcriptional control by modelling a dynamic equilibrium between DNA methylation and demethylation. Our research revealed 5hmC enrichment along genes and non-coding regulatory regions associated with specific developmental pathways in the genome of mouse incisor and molar dental pulp. Although the overall distribution of 5hmC is similar, the intensity and location of the 5hmC peaks significantly differs between the incisor and molar pulp genome, indicating cell type-specific epigenetic variations. Our study suggests that the differential DNA demethylation pattern could account for the distinct regulatory mechanisms underlying the tooth-specific ontogenetic programs.

Excitotoxic events underlying ischaemic and traumatic brain injuries activate degenerative and protective pathways, particularly in the hippocampus. To understand opposing pathways that determine the brain's response to excitotoxicity, we used hippocampal explants, thereby eliminating systemic variables during a precise protocol of excitatory stimulation. N‐methyl‐d‐aspartate (NMDA) was applied for 20 min and total RNA isolated one and 24 h later for neurobiology‐specific microarrays. Distinct groups of genes exhibited early vs. delayed induction, with 63 genes exclusively reduced 24‐h post‐insult. Egr‐1 and NOR‐1 displayed biphasic transcriptional modulation: early induction followed by delayed suppression. Opposing events of NMDA‐induced genes linked to pathogenesis and cell survival constituted the early expression signature. Delayed degenerative indicators (up‐regulated pathogenic genes, down‐regulated pro‐survival genes) and opposing compensatory responses (down‐regulated pathogenic genes, up‐regulated pro‐survival genes) generated networks with temporal gene profiles mirroring coexpression network clustering. We then used the expression profiles to test whether NF‐κB, a potent transcription factor implicated in both degenerative and protective pathways, is involved in the opposing responses. The NF‐κB inhibitor MG‐132 indeed altered NMDA‐mediated transcriptional changes, revealing components of opposing expression signatures that converge on the single response element. Overall, this study identified counteracting avenues among the distinct responses to excitotoxicity, thereby suggesting multi‐target treatment strategies and implications for predictive medicine.