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Wnt/β-catenin signaling, a highly conserved pathway through evolution, regulates key cellular functions including proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. The Wnt pathway mediates biological processes by a canonical or noncanonical pathway, depending on the involvement of β-catenin in signal transduction. β-catenin is a core component of the cadherin protein complex, whose stabilization is essential for the activation of Wnt/β-catenin signaling. As multiple aberrations in this pathway occur in numerous cancers, WNT-directed therapy represents an area of significant developmental therapeutics focus. The recently described role of Wnt/β-catenin pathway in regulating immune cell infiltration of the tumor microenvironment renewed the interest, given its potential impact on responses to immunotherapy treatments. This article summarizes the role of Wnt/β-catenin pathway in cancer and ongoing therapeutic strategies involving this pathway.

Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3–9.0) vs. median not reached (95% CI 2.9–not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1–TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0–6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5–9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.

Endothelial cells have a crucial role in nervous system function, and mounting evidence points to endothelial impairment as a major contributor to a wide range of neurological diseases. However, tools to genetically interrogate these cells remain limited. Here, we describe AAV-BI30, a capsid that specifically and efficiently transduces endothelial cells throughout the central nervous system. At relatively low systemic doses, this vector transduces the majority of arterial, capillary, and venous endothelial cells in the brain, retina, and spinal cord vasculature of adult C57BL/6 mice. Furthermore, we show that AAV-BI30 robustly transduces endothelial cells in multiple mouse strains and rats and human brain microvascular endothelial cells . Finally, we demonstrate AAV-BI30's capacity to achieve efficient and endothelial-specific Cre-mediated gene manipulation in the central nervous system. This combination of attributes makes AAV-BI30 uniquely well-suited to address outstanding research questions in neurovascular biology and aid the development of therapeutics to remediate endothelial dysfunction in disease.

Pathological high shear stress (HSS, 100 dyn/cm ) is generated in distal pulmonary arteries (PA) (100-500 μm) in congenital heart defects and in progressive PA hypertension (PAH) with inward remodeling and luminal narrowing. Human PA endothelial cells (PAEC) were subjected to HSS versus physiologic laminar shear stress (LSS, 15 dyn/cm ). Endothelial-mesenchymal transition (EndMT), a feature of PAH not previously attributed to HSS, was observed. H3K27ac peaks containing motifs for an ETS-family transcription factor (ERG) were reduced, as was ERG-Krüppel-like factors (KLF)2/4 interaction and ERG expression. Reducing ERG by siRNA in PAEC during LSS caused EndMT; transfection of ERG in PAEC under HSS prevented EndMT. An aorto-caval shunt was preformed in mice to induce HSS and progressive PAH. Elevated PA pressure, EndMT and vascular remodeling were reduced by an adeno-associated vector that selectively replenished ERG in PAEC. Agents maintaining ERG in PAEC should overcome the adverse effect of HSS on progressive PAH.

Localization is a critical technology for various applications ranging from navigation and surveillance to assisted living. Localization systems typically fuse information from sensors viewing the scene from different perspectives to estimate the target location while also employing multiple modalities for enhanced robustness and accuracy. Recently, such systems have employed end-to-end deep neural models trained on large datasets due to their superior performance and ability to handle data from diverse sensor modalities. However, such neural models are often trained on data collected from a particular set of sensor poses (i.e., locations and orientations). During real-world deployments, slight deviations from these sensor poses can result in extreme inaccuracies. To address this challenge, we introduce FlexLoc, which employs conditional neural networks to inject node perspective information to adapt the localization pipeline. Specifically, a small subset of model weights are derived from node poses at run time, enabling accurate generalization to unseen perspectives with minimal additional overhead. Our evaluations on a multimodal, multiview indoor tracking dataset showcase that FlexLoc improves the localization accuracy by almost 50% in the zero-shot case (no calibration data available) compared to the baselines. The source code of FlexLoc is available at https://github.com/nesl/FlexLoc.

Constantly locating moving objects, i.e., geospatial tracking, is essential for autonomous building infrastructure. Accurate and robust geospatial tracking often leverages multimodal sensor fusion algorithms, which require large datasets with time-aligned, synchronized data from various sensor types. However, such datasets are not readily available. Hence, we propose GDTM, a nine-hour dataset for multimodal object tracking with distributed multimodal sensors and reconfigurable sensor node placements. Our dataset enables the exploration of several research problems, such as optimizing architectures for processing multimodal data, and investigating models' robustness to adverse sensing conditions and sensor placement variances. A GitHub repository containing the code, sample data, and checkpoints of this work is available at https://github.com/nesl/GDTM.