The aim of local path planning for unmanned surface vehicles (USVs) is to avoid unknown dynamic or static obstacles. However, current relative studies have not fully considered the impact of ocean environmental factors which significantly increase the control difficulty and collision risk of USVs. Therefore, this work studies two ocean environmental factors, namely, wave and current, given that they both have a significant impact on USVs. Furthermore, we redesign a kinematic model of an USV and the evaluation function of a classical and practical local path planning method based on the dynamic window approach (DWA). As shown by the results of the simulations, the path length was impacted mainly by the intensity of the environmental load and slightly by the direction of the environmental load, but the navigation time was significantly influenced by both. Taking the situation in still water as a benchmark in terms of the intensity and direction of the environmental factors, the maximum change rates of the path length were 8.6% and 0.6%, respectively, but the maximum change rates of the navigating time were 17.9% and 25.6%, separately. In addition, the average calculation time of each cycle was only 0.0418 s, and the longest time did not exceed the simulation time corresponding to a single cycle of 0.1 s. This method has proven to be a good candidate for real-time local path planning of USVs since it systematically considers the impact of waves and currents on the navigation of USVs, and thus ensures that USVs can adjust to the planned path in time and avoid obstacles when navigating in the real ocean environment.

Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional coactivator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer’s signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression. Significance: This work combines functional studies in model systems and examination of human tumor specimens to define a central oncogenic pathway driven by DNAJB1-PRKACA fusions in FLC. DNAJB1-PRKACA-mediated inactivation of the SIK stimulates CRTC2-p300-mediated transcription to drive tumor growth. The findings illuminate pathogenic mechanisms and inform therapeutic development.

The incidence of early-onset colorectal cancer (EO-CRC) is rising and is poorly understood. Lifestyle factors and altered genetic background possibly contribute. Here, we performed targeted exon sequencing of archived leukocyte DNA from 158 EO-CRC participants, which identified a missense mutation at p.A98V within the proximal DNA binding domain of Hepatic Nuclear Factor 1 α (HNF1A ^A98V , rs1800574). The HNF1A ^A98V exhibited reduced DNA binding. To test function, the HNF1A variant was introduced into the mouse genome by CRISPR/Cas9, and the mice were placed on either a high-fat diet (HFD) or high-sugar diet (HSD). Only 1% of the HNF1A mutant mice developed polyps on normal chow; however, 19% and 3% developed polyps on the HFD and HSD, respectively. RNA-Seq revealed an increase in metabolic, immune, lipid biogenesis genes, and Wnt/β-catenin signaling components in the HNF1A mutant relative to the WT mice. Mouse polyps and colon cancers from participants carrying the HNF1A ^A98V variant exhibited reduced CDX2 and elevated β-catenin proteins. We further demonstrated decreased occupancy of HNF1A ^A98V at the Cdx2 locus and reduced Cdx2 promoter activity compared with WT HNF1A. Collectively, our study shows that the HNF1A ^A98V variant plus a HFD promotes the formation of colonic polyps by activating β-catenin via decreasing Cdx2 expression.

Ependymomas (EPN) are rare central nervous system tumors that account for approximately 10% of intracranial tumors in children and 4% in adults. Despite their clinical and molecular heterogeneity, spanning supratentorial, posterior fossa, and spinal subtypes, treatment remains limited to surgery and radiotherapy, with chemotherapy offering minimal benefit. Here, we performed transcriptomic analysis of 370 human ependymoma samples and identified two distinct molecular subgroups: EPN-E1 and EPN-E2. The EPN-E1 cluster is enriched for supratentorial tumors harboring ZFTA-RELA fusions (ZFTA-RELA ^fus ), which occur in over 70% of cases and are associated with poor prognosis. To identify targeted therapies for this aggressive subtype, we validated a ZFTA-RELA ^fus mouse model that recapitulates the human EPN-E1 transcriptome and used it for target discovery. Through Kinome Regularization, a machine learning-driven polypharmacology approach, we identified MERTK as a critical regulator of tumor cell viability. Genetic depletion or pharmacologic inhibition of Mertk reduced cell growth ex vivo, and treatment with a clinical-grade MERTK inhibitor significantly suppressed tumor proliferation in vivo. Both human EPN-E1 tumors and ZFTA-RELA ^fus mouse tumors exhibited elevated expression of MERTK and its ligand GAS6, and MERTK inhibition led to suppression of pro-survival signaling pathways including MEK/ERK (Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase) and PI3K/AKT (Phosphoinositide 3-Kinase/Protein Kinase B). Notably, over 80% of genes upregulated in ZFTA-RELA ^fus tumors were downregulated following MERTK inhibition, indicating a strong dependency on this pathway for tumor maintenance. These findings define a signaling vulnerability in ZFTA-RELA-driven ependymomas and support the clinical development of MERTK-targeted therapies for patients with the high-risk EPN-E1 subtype.

Supplementary Table S1. List of SsTOP genes Supplementary Table S2. List of SsTOP (-E2F) genes Supplementary Table S3A. TF activity DMSO vs PKAi Supplementary Table S3B. TF activity PKAi+SIKi (COMBO) vs PKAi Supplementary Table S3A. CRTC2 targets gene set Supplementary Table S4. Curated FLC gene sets Supplementary Table S5. Expression of amino acid metabolism/urea cycle genes in FLC Supplementary Table S6. Regulation of curated FLC pathways by PKAi and SIKi in FLX1 Supplementary Table S7. MSigDB (Human) Hallark_E2F targets gene set

Supplementary Figure S1: Validation of the specificity of the p-SIK Ser343 antibody. Supplementary Figure S2. PKAfus inactivates SIKs to support tumor cell growth in vitro and in vivo. Supplementary Figure S3. PKAfus reprograms transcription by inactivating SIK and stimulating CRTC2. Supplementary Figure S4. CRTC2/CREB mediates transcriptional regulation downstream of PKAfu. Supplementary Figure S5. CRTC2/CREB supports tumor cell growth downstream of PKAfus. Supplementary Figure S6. Primary FLC tumors show deregulation of SIK/CRTC2- controlled genes. Supplementary Figure S7. PKAfus driven tumors are sensitive to p300 inhibition. Supplementary Figure S8. PKAfus driven tumors are sensitive to p300 inhibition.