Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer.

Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.

Image-Guided Deployment and Monitoring of a Novel Tungsten Nanoparticle-Infused Radiopaque Absorbable Inferior Vena Cava Filter in a Swine Model.

PURPOSE: To improve radiopacity of radiolucent absorbable poly-p-dioxanone (PPDO) inferior vena cava filters (IVCFs) and demostrate their effectiveness in clot-trapping ability. MATERIALS AND METHODS: Tungsten nanoparticles (WNPs) were incorporated along with polyhydroxybutyrate (PHB), polycaprolactone (PCL), and polyvinylpyrrolidone (PVP) polymers to increase the surface adsorption of WNPs. The physicochemical and in vitro and in vivo imaging properties of PPDO IVCFs with WNPs with single-polymer PHB (W-P) were compared with those of WNPs with polymer blends consisting of PHB, PCL, and PVP (W-PB). RESULTS: In vitro analyses using PPDO sutures showed enhanced radiopacity with either W-P or W-PB coating, without compromising the inherent physicomechanical properties of the PPDO sutures. W-P- and W-PB-coated IVCFs were deployed successfully into the inferior vena cava of pig models with monitoring by fluoroscopy. At the time of deployment, W-PB-coated IVCFs showed a 2-fold increase in radiopacity compared to W-P-coated IVCFs. Longitudinal monitoring of in vivo IVCFs over a 12-week period showed a drastic decrease in radiopacity at Week 3 for both filters. CONCLUSIONS: The results highlight the utility of nanoparticles (NPs) and polymers for enhancing radiopacity of medical devices. Different methods of incorporating NPs and polymers can still be explored to improve the effectiveness, safety, and quality of absorbable IVCFs.

Gold Nanoparticles for Monitoring of Mesenchymal Stem-Cell-Loaded Bioresorbable Polymeric Wraps for Arteriovenous Fistula Maturation.

Mesenchymal stem cell (MSC)-seeded polymeric perivascular wraps have been shown to enhance arteriovenous fistula (AVF) maturation. However, the wraps' radiolucency makes their placement and integrity difficult to monitor. Through electrospinning, we infused gold nanoparticles (AuNPs) into polycaprolactone (PCL) wraps to improve their radiopacity and tested whether infusion affects the previously reported beneficial effects of the wraps on the AVF's outflow vein. Sprague Dawley rat MSCs were seeded on the surface of the wraps. We then compared the effects of five AVF treatments-no perivascular wrap (i.e., control), PCL wrap, PCL + MSC wrap, PCL-Au wrap, and PCL-Au + MSC wrap-on AVF maturation in a Sprague Dawley rat model of chronic kidney disease (n = 3 per group). Via micro-CT, AuNP-infused wraps demonstrated a significantly higher radiopacity compared to that of the wraps without AuNPs. Wraps with and without AuNPs equally reduced vascular stenoses, as seen via ultrasonography and histomorphometry. In the immunofluorescence analysis, representative MSC-seeded wraps demonstrated reduced neointimal staining for markers of infiltration with smooth muscle cells (α-SMA), inflammatory cells (CD45), and fibroblasts (vimentin) compared to that of the control and wraps without MSCs. In conclusion, AuNP infusion allows in vivo monitoring via micro-CT of MSC-seeded polymeric wraps over time, without compromising the benefits of the wrap for AVF maturation.

Controlled Delivery of Rosuvastatin or Rapamycin through Electrospun Bismuth Nanoparticle-Infused Perivascular Wraps Promotes Arteriovenous Fistula Maturation.

In the context of arteriovenous fistula (AVF) failure, local delivery enables the release of higher concentrations of drugs that can suppress neointimal hyperplasia (NIH) while reducing systemic adverse effects. However, the radiolucency of polymeric delivery systems hinders long-term in vivo surveillance of safety and efficacy. We hypothesize that using a radiopaque perivascular wrap to deliver anti-NIH drugs could enhance AVF maturation. Through electrospinning, we fabricated multifunctional perivascular polycaprolactone (PCL) wraps loaded with bismuth nanoparticles (BiNPs) for enhanced radiologic visibility and drugs that can attenuate NIH─rosuvastatin (Rosu) and rapamycin (Rapa). The following groups were tested on the AVFs of a total of 24 Sprague-Dawley rats with induced chronic kidney disease: control (i.e., without wrap), PCL-Bi (i.e., wrap with BiNPs), PCL-Bi-Rosu, and PCL-Bi-Rapa. We found that BiNPs significantly improved the wraps' radiopacity without affecting biocompatibility. The drug release profiles of Rosu (hydrophilic drug) and Rapa (hydrophobic drug) differed significantly. Rosu demonstrated a burst release followed by gradual tapering over 8 weeks, while Rapa demonstrated a gradual release similar to that of the hydrophobic BiNPs. In vivo investigations revealed that both drug-loaded wraps can reduce vascular stenosis on ultrasonography and histomorphometry, as well as reduce [18F]Fluorodeoxyglucose uptake on positron emission tomography. Immunohistochemical studies revealed that PCL-Bi-Rosu primarily attenuated endothelial dysfunction and hypoxia in the neointimal layer, while PCL-Bi-Rapa modulated hypoxia, inflammation, and cellular proliferation across the whole outflow vein. In summary, the controlled delivery of drugs with different properties and mechanisms of action against NIH through a multifunctional, radiopaque perivascular wrap can improve imaging and histologic parameters of AVF maturation.

Gold Nanoparticles for Monitoring of Mesenchymal Stem Cell-Loaded Bioresorbable Polymeric Wraps for Arteriovenous Fistulas.

Background: To address high rates of arteriovenous fistula (AVF) failure, a mesenchymal stem cell (MSC)-seeded polymeric perivascular wrap has been developed to reduce neointimal hyperplasia (NIH) and enhance AVF maturation in a rat model. However, the wrap's radiolucency makes its placement and integrity difficult to monitor. Purpose: In this study, we infused gold nanoparticles (AuNPs) into the polymeric perivascular wrap to improve its radiopacity and tested the effect of infusion on the previously reported beneficial effects of the polymeric wrap on the AVF outflow vein. Materials and Methods: We fabricated a polymeric perivascular wrap made of polycaprolactone (PCL) infused with AuNPs via electrospinning. Sprague-Dawley rat mesenchymal stem cells (MSCs) were seeded on the surface of the wraps. We then compared the effect of five AVF treatments-no perivascular wrap (i.e., control), PCL wrap, PCL+MSC wrap, PCL-Au wrap, and PCL-Au+MSC wrap-on AVF maturation in a Sprague-Dawley rat model of chronic kidney disease (n=3 per group). Statistical significance was defined as p<.05, and one-way analysis of variance was performed using GraphPad Prism software. Results: On micro-CT, AuNP-infused wraps demonstrated significantly higher radiopacity compared to wraps without AuNPs. On ultrasonography, wraps with and without AuNPs equally reduced the wall-to-lumen ratio of the outflow vein, a marker of vascular stenosis. On histomorphometric analysis, wraps with and without AuNPs equally reduced the neointima-to- lumen ratio of the outflow vein, a measure of NIH. On immunofluorescence analysis, representative MSC-seeded wraps demonstrated reduced neointimal staining for markers of smooth muscle cells (α-SMA), inflammatory cells (CD45), and fibroblasts (vimentin) infiltration when compared to control and wraps without MSCs. Conclusion: Gold nanoparticle infusion allows the in vivo monitoring via micro-CT of a mesenchymal stem cell-seeded polymeric wrap over time without compromising the benefits of the wrap on arteriovenous fistula maturation. Summary Statement: Gold nanoparticle infusion enables in vivo monitoring via micro-CT of the placement and integrity over time of mesenchymal stem cell-seeded polymeric wrap supporting arteriovenous fistula maturation. Key Results: Gold nanoparticle (AuNP)-infused perivascular wraps demonstrated higher radiopacity on micro-CT compared with wraps without AuNPs after 8 weeks.AuNP-infused perivascular wraps equally improved the wall-to-lumen ratio of the outflow vein (a marker of vascular stenosis) when compared with wraps without AuNPs, as seen on US.AuNP-infused perivascular wraps equally reduced the neointima-to-lumen ratio of the outflow vein (a measure of neointimal hyperplasia) when compared with wraps without AuNPs, as seen on histomorphometry.

Image-guided deployment and monitoring of a novel tungsten nanoparticleâ€"infused radiopaque absorbable inferior vena cava filter in pigs.

The use of absorbable inferior vena cava filters (IVCFs) constructed with poly-p-dioxanone (PPDO) eliminates risks and complications associated with the use of retrievable metallic filters. Radiopacity of radiolucent PPDO IVCFs can be improved with the incorporation of nanoparticles (NPs) made of high-atomic number materials such as gold and bismuth. In this study, we focused on incorporating tungsten NPs (WNPs), along with polyhydroxybutyrate (PHB), polycaprolactone (PCL), and polyvinylpyrrolidone (PVP) polymers to increase the surface adsorption of the WNPs. We compared the imaging properties of WNPs with single-polymer PHB (W-P) and WNPs with polymer blends consisting of PHB, PCL, and PVP (W-PB). Our in vitro analyses using PPDO sutures showed enhanced radiopacity with either W-P or W-PB coating, without compromising the inherent physico-mechanical properties of the PPDO sutures. We observed a more sustained release of WNPs from W-PB-coated sutures than W-P-coated sutures. We successfully deployed W-P- and W-PB-coated IVCFs into the inferior vena cava of pig models, with monitoring by fluoroscopy. At the time of deployment, W-PB-coated IVCFs showed a 2-fold increase in radiopacity compared to W-P-coated IVCFs. Longitudinal monitoring of in vivo IVCFs over a 12-week period showed a drastic decrease in radiopacity at week 3 for both filters. Results of this study highlight the utility of NPs and polymers for enhancing radiopacity of medical devices; however, different methods of incorporating NPs and polymers can still be explored to improve the efficacy, safety, and quality of absorbable IVCFs.

Bioresorbable Mesenchymal Stem Cell-Loaded Electrospun Polymeric Scaffold Inhibits Neointimal Hyperplasia Following Arteriovenous Fistula Formation in a Rat Model of Chronic Kidney Disease.

Bioresorbable perivascular scaffolds loaded with antiproliferative agents have been shown to enhance arteriovenous fistula (AVF) maturation by inhibiting neointimal hyperplasia (NIH). These scaffolds, which can mimic the three-dimensional architecture of the vascular extracellular matrix, also have an untapped potential for the local delivery of cell therapies against NIH. Hence, an electrospun perivascular scaffold from polycaprolactone (PCL) to support mesenchymal stem cell (MSC) attachment and gradual elution at the AVF's outflow vein is fabricated. Chronic kidney disease (CKD) in Sprague-Dawley rats is induced by performing 5/6th nephrectomy, then AVFs for scaffold application are created. The following groups of CKD rats are compared: no perivascular scaffold (i.e., control), PCL alone, and PCL+MSC scaffold. PCL and PCL+MSC significantly improve ultrasonographic (i.e., luminal diameter, wall-to-lumen ratio, and flow rate) and histologic (i.e., neointima-to-lumen ratio, neointima-to-media ratio) parameters compared to control, with PCL+MSC demonstrating further improvement in these parameters compared to PCL alone. Moreover, only PCL+MSC significantly reduces 18 F-fluorodeoxyglucose uptake on positron emission tomography. These findings suggest that adding MSCs promotes greater luminal expansion and potentially reduces the inflammatory process underlying NIH. The results demonstrate the utility of mechanical support loaded with MSCs at the outflow vein immediately after AVF formation to support maturation by minimizing NIH.

Bismuth Nanoparticle and Polyhydroxybutyrate Coatings Enhance the Radiopacity of Absorbable Inferior Vena Cava Filters for Fluoroscopy-Guided Placement and Longitudinal Computed Tomography Monitoring in Pigs.

Inferior vena cava filters (IVCFs) constructed with poly-p-dioxanone (PPDO) are promising alternatives to metallic filters and their associated risks and complications. Incorporating high-Z nanoparticles (NPs) improves PPDO IVCFs' radiopacity without adversely affecting their safety or performance. However, increased radiopacity from these studies are insufficient for filter visualization during fluoroscopy-guided PPDO IVCF deployment. This study focuses on the use of bismuth nanoparticles (BiNPs) as radiopacifiers to render sufficient signal intensity for the fluoroscopy-guided deployment and long-term CT monitoring of PPDO IVCFs. The use of polyhydroxybutyate (PHB) as an additional layer to increase the surface adsorption of NPs resulted in a 2-fold increase in BiNP coating (BiNP-PPDO IVCFs, 3.8%; BiNP-PPDO + PHB IVCFs, 6.2%), enabling complete filter visualization during fluoroscopy-guided IVCF deployment and, 1 week later, clot deployment. The biocompatibility, clot-trapping efficacy, and mechanical strength of the control PPDO (load-at-break, 6.23 ± 0.13 kg), BiNP-PPDO (6.10 ± 0.09 kg), and BiNP-PPDO + PHB (6.15 ± 0.13 kg) IVCFs did not differ significantly over a 12-week monitoring period in pigs. These results indicate that BiNP-PPDO + PHB can increase the radiodensity of a novel absorbable IVCF without compromising device strength. Visualizing the device under conventional radiographic imaging is key to allow safe and effective clinical translation of the device.

[4+2+2] Cycloaddition catalyzed by a new cationic rhodium-bisphosphine monooxide complex.

A rhodium-BozPHOS based complex is reported. This complex is competent in catalyzing the [4+2+2] cycloisomerization of cyclooctatrienes in moderate to good yields. The X-ray crystal structure of this complex is reported, along with formation of both bicyclic and tricyclic cyclooctatrienes.