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Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, characterized by late diagnosis and poor treatment response. Surgery is the only curative approach, only available to early‐diagnosed patients. Current therapies have limited effects, cause severe toxicities, and minimally improve overall survival. Understanding of splicing machinery alterations in PDAC remains incomplete. Here, we comprehensively examined 59 splicing machinery components, uncovering dysregulation in pre‐mRNA processing factor 8 (PRPF8) and RNA‐binding motif protein X‐linked (RBMX). Their downregulated expression was linked to poor prognosis and malignancy features, including tumor stage, invasion and metastasis, and associated with poorer survival and the mutation of key PDAC genes. Experimental modulation of these splicing factors in pancreatic cancer cell lines reverted their expression to non‐tumor levels and resulted in decreased key tumor‐related features. These results provide evidence that the splicing machinery is altered in PDAC, wherein PRPF8 and RBMX emerge as candidate actionable therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Intraosseous vascular anomalies in the facial skeleton present significant diagnostic and therapeutic challenges due to complex anatomy. These anomalies represent about 0.5–1% of bony neoplastic and tumor-like lesions, usually presenting as a firm, painless mass. Most described intraosseous vascular malformations are venous malformations (VMs) and, more rarely, arteriovenous malformations. Objectives: The objectives of this work are to show our experience, protocol and the applications of computer planning, virtual surgery, CAD-CAM design, surgical navigation, and computer-assisted navigated piezoelectric surgery in the treatment of facial intraosseous vascular anomalies and to evaluate the advantages and disadvantages. Methods: Three females and one male with periorbital intraosseous vascular anomalies were treated using en-block resection and immediate reconstruction with a custom-made PEEK prosthesis. One lesion was in the supraorbital rim and orbital roof, one in the frontal bone and orbital roof, and two in the zygomatic region. We accomplished the resection and reconstruction of the lesion using virtual planning, CAD-CAM design, surgical navigation and piezoelectric device navigation. Results: There were no complications related to the surgery assisted with navigation. With an accuracy of less than 1 mm, the procedure may be carried out in accordance with the surgical plan. The surgeon's degree of uncertainty during deep osteotomies and in locations with low visibility was decreased by the use of the navigated piezoelectric device. Conclusions: Resection and reconstruction of facial intraosseous vascular anomalies benefit from this new surgical strategy using CAD-CAM technologies, computer-assisted navigated piezoelectric surgery, and surgical navigation. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of tumors with growing incidence. Recent molecular analyses provided a precise picture of their genomic and epigenomic landscape. Splicing dysregulation is increasingly regarded as a novel cancer hallmark influencing key tumor features. We have previously demonstrated that splicing machinery is markedly dysregulated in PanNETs. Here, we aimed to elucidate the molecular and functional implications of CUGBP ELAV-like family member 4 ( CELF4 ), one of the most altered splicing factors in PanNETs. CELF4 expression was determined in 20 PanNETs, comparing tumor and non-tumoral adjacent tissue. An RNA sequencing (RNA-seq) dataset was analyzed to explore CELF4-linked interrelations among clinical features, gene expression, and splicing events. Two PanNET cell lines were employed to assess CELF4 function in vitro and in vivo . PanNETs display markedly upregulated CELF4 expression, which is closely associated with malignancy features, altered expression of key tumor players, and distinct splicing event profiles. Modulation of CELF4 influenced proliferation in vitro and reduced in vivo xenograft tumor growth. Interestingly, functional assays and RNA-seq analysis revealed that CELF4 silencing altered mTOR signaling pathway, enhancing the effect of everolimus. We demonstrate that CELF4 is dysregulated in PanNETs, where it influences tumor development and aggressiveness, likely by modulating the mTOR pathway, suggesting its potential as therapeutic target., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)