Mesenchymal stem cells in craniofacial reconstruction: a comprehensive review.

Craniofacial reconstruction faces many challenges, including high complexity, strong specificity, severe injury, irregular and complex wounds, and high risk of bleeding. Traditionally, the "gold standard" for treating craniofacial bone defects has been tissue transplantation, which involves the transplantation of bone, cartilage, skin, and other tissues from other parts of the body. However, the shape of craniofacial bone and cartilage structures varies greatly and is distinctly different from ordinary long bones. Craniofacial bones originate from the neural crest, while long bones originate from the mesoderm. These factors contribute to the poor effectiveness of tissue transplantation in repairing craniofacial defects. Autologous mesenchymal stem cell transplantation exhibits excellent pluripotency, low immunogenicity, and minimally invasive properties, and is considered a potential alternative to tissue transplantation for treating craniofacial defects. Researchers have found that both craniofacial-specific mesenchymal stem cells and mesenchymal stem cells from other parts of the body have significant effects on the restoration and reconstruction of craniofacial bones, cartilage, wounds, and adipose tissue. In addition, the continuous development and application of tissue engineering technology provide new ideas for craniofacial repair. With the continuous exploration of mesenchymal stem cells by researchers and the continuous development of tissue engineering technology, the use of autologous mesenchymal stem cell transplantation for craniofacial reconstruction has gradually been accepted and promoted. This article will review the applications of various types of mesenchymal stem cells and related tissue engineering in craniofacial repair and reconstruction.

A Biomimetic Fibrous Composite Scaffold with Nanotopography-Regulated Mineralization for Bone Defect Repair.

The effective regeneration of large bone defects via bone tissue engineering is challenging due to the difficulty in creating an osteogenic microenvironment. Inspired by the fibrillar architecture of the natural extracellular matrix, we developed a nanoscale bioengineering strategy to produce bone fibril-like composite scaffolds with enhanced osteogenic capability. To activate the surface for biofunctionalization, self-adaptive ridge-like nanolamellae were constructed on poly(ε-caprolactone) (PCL) electrospinning scaffolds via surface-directed epitaxial crystallization. This unique nanotopography with a markedly increased specific surface area offered abundant nucleation sites for Ca2+ recruitment, leading to a 5-fold greater deposition weight of hydroxyapatite than that of the pristine PCL scaffold under stimulated physiological conditions. Bone marrow mesenchymal stem cells (BMSCs) cultured on bone fibril-like scaffolds exhibited enhanced adhesion, proliferation, and osteogenic differentiation in vitro. In a rat calvarial defect model, the bone fibril-like scaffold significantly accelerated bone regeneration, as evidenced by micro-CT, histological histological and immunofluorescence staining. This work provides the way for recapitulating the osteogenic microenvironment in tissue-engineered scaffolds for bone repair.

Biomimetic Mineralized 3D-Printed Polycaprolactone Scaffold Induced by Self-Adaptive Nanotopology to Accelerate Bone Regeneration.

Three-dimensional (3D)-printed biodegradable polymer scaffolds are at the forefront of personalized constructs for bone tissue engineering. However, it remains challenging to create a biological microenvironment for bone growth. Herein, we developed a novel yet feasible approach to facilitate biomimetic mineralization via self-adaptive nanotopography, which overcomes difficulties in the surface biofunctionalization of 3D-printed polycaprolactone (PCL) scaffolds. The building blocks of self-adaptive nanotopography were PCL lamellae that formed on the 3D-printed PCL scaffold via surface-directed epitaxial crystallization and acted as a linker to nucleate and generate hydroxyapatite crystals. Accordingly, a uniform and robust mineralized layer was immobilized throughout the scaffolds, which strongly bound to the strands and had no effect on the mechanical properties of the scaffolds. In vitro cell culture experiments revealed that the resulting scaffold was biocompatible and enhanced the proliferation and osteogenic differentiation of mouse embryolous osteoblast cells. Furthermore, we demonstrated that the resulting scaffold showed a strong capability to accelerate in vivo bone regeneration using a rabbit bone defect model. This study provides valuable opportunities to enhance the application of 3D-printed scaffolds in bone repair, paving the way for translation to other orthopedic implants.

Re-exploration of immunotherapy targeting EMT of hepatocellular carcinoma: Starting from the NF-κB pathway.

Hepatocellular carcinoma (HCC) is the fifth most common malignancies worldwide, and its high morbidity and mortality have brought a heavy burden to the global public health system. Due to the concealment of its onset, the limitation of treatment, the acquisition of multi-drug resistance and radiation resistance, the treatment of HCC cannot achieve satisfactory results. Epithelial mesenchymal transformation (EMT) is a key process that induces progression, distant metastasis, and therapeutic resistance to a variety of malignant tumors, including HCC. Therefore, targeting EMT has become a promising tumor immunotherapy method for HCC. The NF-κB pathway is a key regulatory pathway for EMT. Targeting this pathway has shown potential to inhibit HCC infiltration, invasion, distant metastasis, and therapeutic resistance. At present, there are still some controversies about this pathway and new ideas of combined therapy, which need to be further explored. This article reviews the progress of immunotherapy in improving EMT development in HCC cells by exploring the mechanism of regulating EMT.

Hierarchically Biomimetic Scaffolds with Anisotropic Micropores and Nanotopological Patterns to Promote Bone Regeneration via Geometric Modulation.

Structural engineering is an appealing means to modulate osteogenesis without the intervention of exogenous cells or therapeutic agents. In this work, a novel 3D scaffold with anisotropic micropores and nanotopographical patterns is developed. Scaffolds with oriented pores are fabricated via the selective extraction of water-soluble polyethylene oxide from its poly(ε-caprolactone) co-continuous mixture and uniaxial stretching. The plate apatite-like lamellae are subsequently hatched on the pore walls through surface-induced epitaxial crystallization. Such a unique geometric architecture yields a synergistic effect on the osteogenic capability. The prepared scaffold leads to a 19.2% and 128.0% increase in the alkaline phosphatase activity of rat bone mesenchymal stem cells compared to that of the scaffolds with only oriented pores and only nanotopographical patterns, respectively. It also induces the greatest upregulation of osteogenic-related gene expression in vitro. The cranial defect repair results demonstrate that the prepared scaffold effectively promotes new bone regeneration, as indicated by a 350% increase in collagen I expression in vivo compared to the isotropic porous scaffold without surface nanotopology after implantation for 14 weeks. Overall, this work provides geometric motifs for the transduction of biophysical cues in 3D porous scaffolds, which is a promising option for tissue engineering applications.

Immunomodulatory nanomedicine for osteoporosis: Current practices and emerging prospects.

Osteoporosis results from the disruption of the balance between bone resorption and bone formation. However, classical anti-osteoporosis drugs exhibit several limitations in clinical applications, such as multiple adverse reactions and poor therapeutic effects. Therefore, there is an urgent need for alternative treatment strategies. With the evolution of immunomodulatory nanomedicine, a variety of nanomaterials have been designed for anti-osteoporosis treatment, offering prospects of minimal adverse reactions, enhanced bone induction, and high osteogenic activity. This review initially provides a brief overview of the fundamental principles of bone reconstruction, current osteogenic clinical methods in osteoporosis treatment, and the significance of osteogenic-angiogenic coupling, laying the groundwork for understanding the pathophysiology and therapeutics of osteoporosis. Subsequently, the article emphasizes the relationship between bone immunity and osteogenesis-angiogenesis coupling and provides a detailed analysis of the application of immunomodulatory nanomedicines in the treatment of osteoporosis, including various types of nanomaterials and their integration with carrier biomaterials. Importantly, we discuss the potential of some emerging strategies in immunomodulatory nanomedicine for osteoporosis treatment. This review introduces the innovative applications of immunomodulatory nanomedicine in the treatment of osteoporosis, aiming to serve as a reference for the application of immunomodulatory nanomedicine strategies in osteoporosis treatment. STATEMENT OF SIGNIFICANCE: Osteoporosis, as one of the most prevalent skeletal disorders, poses a significant threat to public health. To date, conventional anti-osteoporosis strategies have been limited in efficacy and plagued with numerous side effects. Fortunately, with the advancement of research in osteoimmunology and nanomedicine, strategies integrating these two fields show great promise in combating osteoporosis. Nanomedicine with immunomodulatory properties exhibits enhanced efficiency, prolonged effectiveness, and increased safety. However, as of now, there exists no comprehensive review amalgamating immunomodulation with nanomedicine to delineate the progress of immunomodulatory nanomedicine in osteoporosis treatment, as well as the future direction of this strategy.

A DNA tetrahedron-based ferroptosis-suppressing nanoparticle: superior delivery of curcumin and alleviation of diabetic osteoporosis.

Diabetic osteoporosis (DOP) is a significant complication that poses continuous threat to the bone health of patients with diabetes; however, currently, there are no effective treatment strategies. In patients with diabetes, the increased levels of ferroptosis affect the osteogenic commitment and differentiation of bone mesenchymal stem cells (BMSCs), leading to significant skeletal changes. To address this issue, we aimed to target ferroptosis and propose a novel therapeutic approach for the treatment of DOP. We synthesized ferroptosis-suppressing nanoparticles, which could deliver curcumin, a natural compound, to the bone marrow using tetrahedral framework nucleic acid (tFNA). This delivery system demonstrated excellent curcumin bioavailability and stability, as well as synergistic properties with tFNA. Both in vitro and in vivo experiments revealed that nanoparticles could enhance mitochondrial function by activating the nuclear factor E2-related factor 2 (NRF2)/glutathione peroxidase 4 (GPX4) pathway, inhibiting ferroptosis, promoting the osteogenic differentiation of BMSCs in the diabetic microenvironment, reducing trabecular loss, and increasing bone formation. These findings suggest that curcumin-containing DNA tetrahedron-based ferroptosis-suppressing nanoparticles have a promising potential for the treatment of DOP and other ferroptosis-related diseases.

Machine learning-based decision support system for orthognathic diagnosis and treatment planning.

BACKGROUND: Dento-maxillofacial deformities are common problems. Orthodontic-orthognathic surgery is the primary treatment but accurate diagnosis and careful surgical planning are essential for optimum outcomes. This study aimed to establish and verify a machine learning-based decision support system for treatment of dento-maxillofacial malformations. METHODS: Patients (n = 574) with dento-maxillofacial deformities undergoing spiral CT during January 2015 to August 2020 were enrolled to train diagnostic models based on five different machine learning algorithms; the diagnostic performances were compared with expert diagnoses. Accuracy, sensitivity, specificity, and area under the curve (AUC) were calculated. The adaptive artificial bee colony algorithm was employed to formulate the orthognathic surgical plan, and subsequently evaluated by maxillofacial surgeons in a cohort of 50 patients. The objective evaluation included the difference in bone position between the artificial intelligence (AI) generated and actual surgical plans for the patient, along with discrepancies in postoperative cephalometric analysis outcomes. RESULTS: The binary relevance extreme gradient boosting model performed best, with diagnostic success rates > 90% for six different kinds of dento-maxillofacial deformities; the exception was maxillary overdevelopment (89.27%). AUC was > 0.88 for all diagnostic types. Median score for the surgical plans was 9, and was improved after human-computer interaction. There was no statistically significant difference between the actual and AI- groups. CONCLUSIONS: Machine learning algorithms are effective for diagnosis and surgical planning of dento-maxillofacial deformities and help improve diagnostic efficiency, especially in lower medical centers.

Engineered Microchannel Scaffolds with Instructive Niches Reinforce Endogenous Bone Regeneration by Regulating CSF-1/CSF-1R Pathway.

Structural and physiological cues provide guidance for the directional migration and spatial organization of endogenous cells. Here, a microchannel scaffold with instructive niches is developed using a circumferential freeze-casting technique with an alkaline salting-out strategy. Thereinto, polydopamine-coated nano-hydroxyapatite is employed as a functional inorganic linker to participate in the entanglement and crystallization of chitosan molecules. This scaffold orchestrates the advantage of an oriented porous structure for rapid cell infiltration and satisfactory immunomodulatory capacity to promote stem cell recruitment, retention, and subsequent osteogenic differentiation. Transcriptomic analysis as well as its in vitro and in vivo verification demonstrates that essential colony-stimulating factor-1 (CSF-1) factor is induced by this scaffold, and effectively bound to the target colony-stimulating factor-1 receptor (CSF-1R) on the macrophage surface to activate the M2 phenotype, achieving substantial endogenous bone regeneration. This strategy provides a simple and efficient approach for engineering inducible bone regenerative biomaterials.

Periodic Lamellae-Based Nanofibers for Precise Immunomodulation to Treat Inflammatory Bone Loss in Periodontitis.

Periodontitis is a common oral disease accompanied by inflammatory bone loss. The pathological characteristics of periodontitis usually accompany an imbalance in the periodontal immune microenvironment, leading to difficulty in bone regeneration. Therefore, effective treatment strategies are needed to modulate the immune environment in order to treat periodontitis. Here, we developed a highly-oriented periodic lamellae poly(ε-caprolactone) electrospun nanofibers (PLN) by surface-directed epitaxial crystallization. Our in vitro results showed that the PLN could precisely modulate macrophage polarization toward the M2 phenotype. Macrophages polarized by PLN significantly enhanced the migration and osteogenic differentiation of BMSCs. Notably, results suggested that the topographical cues presented by PLN can modulate macrophage polarization by activating YAP, which reciprocally inhibits the NF-κB signaling pathway. The in vivo results indicated that PLN can inhibit inflammatory bone loss and facilitate bone regeneration in periodontitis. Our findings suggest that topographical nanofibers with periodic lamellae is a promising strategy for modulating immune environment to treat inflammatory bone loss in periodontitis. This article is protected by copyright. All rights reserved.

Hippo/YAP1 promotes osteoporotic mice bone defect repair via the activating of Wnt signaling pathway.

BACKGROUND: This study is to investigate the role and mechanism of Hippo/YAP1 in the repair of osteoporotic bone defects in aged mice, both in vivo and in vitro. METHODS: We investigated the expression differences of the Hippo signaling in young and aged individuals both in vivo and in vitro. By manipulating the expression of Lats1/2 and Yap1, we investigated the role of Hippo/YAP1 in regulating osteogenic differentiation in aged BMSCs. In vivo, by intervening in the local and systemic expression of Lats1/2 and Yap1 respectively, we sought to demonstrate whether Hippo/YAP1 promotes the repair of bone defects in aged osteoporotic conditions. Finally, we delved into the underlying mechanisms of Hippo/YAP1 in regulating osteogenic differentiation. RESULTS: We observed differences in the expression of the Hippo signaling between young and aged individuals. After knocking out Lats1/2 in aged BMSCs, we observed that the upregulation of endogenous YAP1 promotes cellular osteogenic differentiation and proliferation capacity. Through interference with Yap1 expression, we provided strong evidence for the role of Hippo/YAP1 in promoting osteogenic differentiation in aged BMSCs. In vivo, we confirmed that Hippo/YAP1 promotes the repair of bone defects in aging osteoporosis. Moreover, we discovered an interaction relationship among YAP1, ß-catenin, and TEAD1. CONCLUSION: This study elucidates the role of Hippo/YAP1 in promoting the repair of osteoporotic bone defects in aged mice. Mechanistically, YAP1 functions by activating the Wnt/ß-catenin pathway, and this process is not independent of TEAD1.

Large-scale evaluation of the ability of RNA-binding proteins to activate exon inclusion.

RNA-binding proteins (RBPs) modulate alternative splicing outcomes to determine isoform expression and cellular survival. To identify RBPs that directly drive alternative exon inclusion, we developed tethered function luciferase-based splicing reporters that provide rapid, scalable and robust readouts of exon inclusion changes and used these to evaluate 718 human RBPs. We performed enhanced cross-linking immunoprecipitation, RNA sequencing and affinity purification-mass spectrometry to investigate a subset of candidates with no prior association with splicing. Integrative analysis of these assays indicates surprising roles for TRNAU1AP, SCAF8 and RTCA in the modulation of hundreds of endogenous splicing events. We also leveraged our tethering assays and top candidates to identify potent and compact exon inclusion activation domains for splicing modulation applications. Using these identified domains, we engineered programmable fusion proteins that outperform current artificial splicing factors at manipulating inclusion of reporter and endogenous exons. This tethering approach characterizes the ability of RBPs to induce exon inclusion and yields new molecular parts for programmable splicing control.

SIRT1 activation promotes bone repair by enhancing the coupling of type H vessel formation and osteogenesis.

Bone repair is intricately correlated with vascular regeneration, especially of type H vessels. Sirtuin 1 (SIRT1) expression is closely associated with endothelial function and vascular regeneration; however, the role of SIRT1 in enhancing the coupling of type H vessel formation with osteogenesis to promote bone repair needs to be investigated. A co-culture system combining human umbilical vein endothelial cells and osteoblasts was constructed, and a SIRT1 agonist was used to evaluate the effects of SIRT1 activity. The angiogenic and osteogenic capacities of the co-culture system were examined using short interfering RNA. Mouse models with bone defects in the femur or mandible were established to explore changes in type H vessel formation and bone repair following modulated SIRT1 activity. SIRT1 activation augmented the angiogenic and osteogenic capacities of the co-culture system by activating the PI3K/AKT/FOXO1 signalling pathway and did not significantly regulate osteoblast differentiation. Inhibition of the PI3K/AKT/FOXO1 pathway attenuated SIRT1-mediated effects. The SIRT1 activity in bone defects was positively correlated with the formation of type H vessels and bone repair in vivo, whereas SIRT1 inhibition substantially weakened vascular and bone formation. Thus, SIRT1 is crucial to the coupling of type H vessels with osteogenesis during bone repair.

The role of integrin αvß3 in biphasic calcium phosphate ceramics mediated M2 Macrophage polarization and the resultant osteoinduction.

Calcium phosphate ceramics-based biomaterials were reported to have good biocompatibility and osteoinductivity and have been widely applied for bone defect repair and regeneration. However, the mechanism of their osteoinductivity is still unclear. In our study, we established an ectopic bone formation in vivo model and an in vitro macrophage cell co-culture system with calcium phosphate ceramics to investigate the effect of biphasic calcium phosphate on osteogenesis via regulating macrophage M1/M2 polarization. Our micro-CT data suggested that biphasic calcium phosphate had significant osteoinductivity, and the fluorescence co-localization detection found increased F4/80+/integrin αvß3+ macrophages surrounding the biphasic calcium phosphate scaffolds. Besides, our study also revealed that biphasic calcium phosphate promoted M2 polarization of macrophages via upregulating integrin αvß3 expression compared to tricalcium phosphate, and the increased M2 macrophages could subsequently augment the osteogenic differentiation of MSCs in a TGFß mediated manner. In conclusion, we demonstrated that macrophages subjected to biphasic calcium phosphate could polarize toward M2 phenotype via triggering integrin αvß3 and secrete TGFß to increase the osteogenesis of MSCs, which subsequently enhances bone regeneration.

The role of zinc finger proteins in the fate determination of mesenchymal stem cells during osteogenic and adipogenic differentiation.

Zinc finger proteins (ZFPs) constitute a crucial group of transcription factors widely present in various organisms. They act as transcription factors, nucleases, and RNA-binding proteins, playing significant roles in cell differentiation, growth, and development. With extensive research on ZFPs, their roles in the determination of mesenchymal stem cells (MSCs) fate during osteogenic and adipogenic differentiation processes have become increasingly clear. ZFP521, for instance, is identified as an inhibitor of the Wnt signaling pathway and RUNX2's transcriptional activity, effectively suppressing osteogenic differentiation. Moreover, ZFP217 contributes to the inhibition of adipogenic differentiation by reducing the M6A level of the cell cycle regulator cyclin D1 (CCND1). In addition, other ZFPs can also influence the fate of mesenchymal stem cells (MSCs) during osteogenic and adipogenic differentiation through various signaling pathways, transcription factors, and epigenetic controls, participating in the subsequent differentiation and maturation of precursor cells. Given the prevalent occurrence of osteoporosis, obesity, and related metabolic disorders, a comprehensive understanding of the regulatory mechanisms balancing bone and fat metabolism is essential, with a particular focus on the fate determination of MSCs in osteogenic and adipogenic differentiation. In this review, we provide a detailed summary of how zinc finger proteins influence the osteogenic and adipogenic differentiation of MSCs through different signaling pathways, transcription factors, and epigenetic mechanisms. Additionally, we outline the regulatory mechanisms of ZFPs in controlling osteogenic and adipogenic differentiation based on various stages of MSC differentiation.

Characterization of upper airway and analysis of potential risk factor associated with OSA in patients with unilateral temporomandibular ankylosis and micrognathia deformities.

OBJECTIVE: To ascertain the airway characteristics in patients with unilateral temporomandibular joint ankylosis and maxilla-mandibular deformities (UTMAMD) and investigate the potential risk factors associated with obstructive sleep apnea (OSA) among UTMAMD patients. METHODS: Authors conducted a retrospective single-center study to assess and compare study group consisting of a cohort of 32 patients diagnosed with UTMAMD between January 2011 and July 2022 with control group including 54 participants. The study group was further divided into two subgroups based on the presence or absence of OSA in patients. Parameters related to the upper airway were measured and analyzed using three-dimensional reconstruction of computed tomographic scans. The measurements of airway parameters were compared between study group and control group and between two subgroups. Pearson correlation analysis was used to identify the factors associated with the presence of OSA, and a multiple variable regression model was used to identify risk factors for OSA. RESULTS: Airway volume (VOL), Minimum cross-section area (min CSA), mean CSA, tilt in sagittal plane (TS), and tilt in sagittal plane (TC) in velopharynx; VOL, airway length (AL), min CSA, mean CSA, TS, TC, and airway deviation (AD) in glossopharynx; min CSA, TS, and AD in hypopharynx were found difference with significance between study group and control group. Lateral dimension/anterior-posterior dimension (LAT/AP) ratio in velopharynx and min CSA, TC, and LAT/AP ratio in glossopharynx were significant different between patients with UTMAMD with OSA and without OSA. CONCLUSIONS: The upper airway of patients with UTMAMD exhibits significant narrowing and distortion, rendering them susceptible to suffer from OSA. Patients with UTMAMD and OSA demonstrate more elliptical airways, and the glossopharyngeal LAT/AP ratio is a predictive indicator for the occurrence of OSA.

Long non-coding RNA APDC plays important regulatory roles in metabolism of bone and adipose tissues.

The long noncoding RNA (lncR) ANRIL in the human genome is an established genetic risk factor for atherosclerosis, periodontitis, diabetes, and cancer. However, the regulatory role of lncR-ANRIL in bone and adipose tissue metabolism remains unclear. To elucidate the function of lncRNA ANRIL in a mouse model, we investigated its ortholog, AK148321 (referred to as lncR-APDC), located on chr4 of the mouse genome, which is hypothesized to have similar biological functions to ANRIL. We initially revealed that lncR-APDC in mouse bone marrow cells (BMSCs) and lncR-ANRIL in human osteoblasts (hFOBs) are both increased during early osteogenesis. Subsequently, we examined the osteogenesis, adipogenesis, osteoclastogenesis function with lncR-APDC deletion/overexpression cell models. In vivo, we compared the phenotypic differences in bone and adipose tissue between APDC-KO and wild-type mice. Our findings demonstrated that lncR-APDC deficiency impaired osteogenesis while promoting adipogenesis and osteoclastogenesis. Conversely, the overexpression of lncR-APDC stimulated osteogenesis, but impaired adipogenesis and osteoclastogenesis. Furthermore, KDM6B was downregulated with lncR-APDC deficiency and upregulated with overexpression. Through binding-site analysis, we identified miR-99a as a potential target of lncR-APDC. The results suggest that lncR-APDC exerts its osteogenic function via miR-99a/KDM6B/Hox pathways. Additionally, osteoclasto-osteogenic imbalance was mediated by lncR-APDC through MAPK/p38 and TLR4/MyD88 activation. These findings highlight the pivotal role of lncR-APDC as a key regulator in bone and fat tissue metabolism. It shows potential therapeutic for addressing imbalances in osteogenesis, adipogenesis, and osteoclastogenesis.

Metal ions: the unfading stars of bone regeneration-from bone metabolism regulation to biomaterial applications.

In recent years, bone regeneration has emerged as a remarkable field that offers promising guidance for treating bone-related diseases, such as bone defects, bone infections, and osteosarcoma. Among various bone regeneration approaches, the metal ion-based strategy has surfaced as a prospective candidate approach owing to the extensive regulatory role of metal ions in bone metabolism and the diversity of corresponding delivery strategies. Various metal ions can promote bone regeneration through three primary strategies: balancing the effects of osteoblasts and osteoclasts, regulating the immune microenvironment, and promoting bone angiogenesis. In the meantime, the complex molecular mechanisms behind these strategies are being consistently explored. Moreover, the accelerated development of biomaterials broadens the prospect of metal ions applied to bone regeneration. This review highlights the potential of metal ions for bone regeneration and their underlying mechanisms. We propose that future investigations focus on refining the clinical utilization of metal ions using both mechanistic inquiry and materials engineering to bolster the clinical effectiveness of metal ion-based approaches for bone regeneration.

A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.