Rationale Endovascular interventions performed for atherosclerotic lesions trigger excessive vascular smooth muscle cell (SMC) proliferation leading to intimal hyperplasia. Our previous studies show that following endovascular injury, elevated TGF-β/Smad3 promotes SMC proliferation and intimal hyperplasia. Furthermore in cultured SMCs, elevated TGF-β/Smad3 increases the expression of several Wnt genes. Here we investigate a crosstalk between TGF-β/Smad3 and Wnt/β-catenin signaling and its role in SMC proliferation. Methods and Results To mimic TGF-β/Smad3 up-regulation in vivo, rat aortic SMCs were treated with Smad3-expressing adenovirus (AdSmad3) or AdGFP control followed by stimulation with TGF-β1 (or solvent). AdSmad3/TGF-β treatment up-regulated Wnt2b, Wnt4, Wnt5a, Wnt9a, and Wnt11 (confirmed by qRT-PCR and ELISA), and also increased β-catenin protein as detected by Western blotting. Blocking Wnt signaling using a Frizzled receptor inhibitor (Niclosamide) abolished TGF-β/Smad3-induced β-catenin stabilization. Increasing β-catenin through degradation inhibition (using SKL2001) or by adenoviral expression enhanced SMC proliferation. Furthermore, application of recombinant Wnt2b, Wnt4, Wnt5a, or Wnt9a, but not Wnt11, stabilized β-catenin and stimulated SMC proliferation as well. In addition, increased β-catenin was found in the neointima of injured rat carotid artery where TGF-β and Smad3 are known to be up-regulated. Conclusions These results suggest a novel mechanism whereby elevated TGF-β/Smad3 stimulates the secretion of canonical Wnts which in turn enhances SMC proliferation through β-catenin stabilization. This crosstalk between TGF-β/Smad3 and Wnt/β-catenin canonical pathways provides new insights into the pathophysiology of vascular SMCs linked to intimal hyperplasia.

Multiple genes have been shown to be independently hypermethylated in lymphoid malignancies. We report here on the extent of concurrent methylation of E-cadherin, Dap-kinase, O 6 MGMT, p73, p16, p15 and p14 in 129 pediatric ALL cases. While most of these genes demonstrated methylation in a proportion of cases, O 6 MGMT, p16 and p14 were infrequently methylated (11, 7 and 3%, respectively). Methylation of at least one gene was found in the vast majority (83%) of cases. To determine the extent and concordance of methylation we calculated a methylation index (MI ¼ number of methylated genes/number of studied genes) for each sample. The average MI was 0.28, corresponding to 2/7 methylated genes. MI was correlated with standard prognostic factors, including immunophenotype, age, sex, WBC and presence of specific translocations (TEL-AML1, BCR-ABL, E2A-PBX1 or MLL-AF4). We determined that children X10 years old and children presenting with high WBC (X50 Â 10 9 /l) both associated with a higher MI (Po0.01 and o0.05, respectively). T-ALLs demonstrated a lower MI (median ¼ 0.17) than precursor B ALLs (median ¼ 0.28). Among the different molecular subgroups, MLL-ALLs had the highest MI (mean ¼ 0.35), while ALLs carrying the t(1;19) had the lowest MI (mean ¼ 0.07). The most common epigenetic lesion in childhood ALL was methylation of E-cadherin (72%) independent of the molecular subtype or other clinicopathological factors.

Background Intimal hyperplasia (IH) remains a major cause of poor patient outcomes after surgical revascularization to treat atherosclerosis. A multitude of drugs have been shown to prevent the development of IH. Moreover, endovascular drug delivery following angioplasty and stenting has been achieved with a marked diminution in the incidence of restenosis. Despite advances in endovascular drug delivery, there is currently no clinically available method of periadventitial drug delivery suitable for open vascular reconstructions. Herein we provide an overview of the recent literature regarding innovative polymer platforms for periadventitial drug delivery in preclinical models of IH as well as insights about barriers to clinical translation. Methods A comprehensive PubMed search confined to the past 15 years was performed for studies of periadventitial drug delivery. Additional searches were performed for relevant clinical trials, patents, meeting abstracts, and awards of NIH funding. Results Most of the research involving direct periadventitial delivery without a drug carrier was published prior to 2000. Over the past 15 years there have been a surge of reports utilizing periadventitial drug-releasing polymer platforms, most commonly bioresorbable hydrogels and wraps. These methods proved to be effective for the inhibition of IH in various animal models (e.g. balloon angioplasty, wire injury, and vein graft), but very few have advanced to clinical trials. There are a number of barriers that may account for this lack of translation. Promising new approaches including the use of nanoparticles will be described. Conclusions No periadventitial drug delivery system has reached clinical application. For periadventitial delivery, polymer hydrogels, wraps, and nanoparticles exhibit overlapping and complementary properties. The ideal periadventitial delivery platform would allow for sustained drug release yet exert minimal mechanical and inflammatory stresses to the vessel wall. A clinically applicable strategy for periadventital drug delivery would benefit thousands of patients undergoing open vascular reconstruction each year.

Since December 2020, four vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and three have been approved for immediate use in the United States. Two are mRNA vaccines, while one uses a viral vector mechanism. There are reports of thrombotic complications following vaccine administration, which are primarily cerebral sinus thromboses following administration of the viral vector vaccines. Here, we are the first to report venous thrombotic complications within days of administration of the mRNA-1273 (Moderna) vaccine. We present a series of three women who developed venous thromboembolism (VTE) following mRNA-1273 vaccination at a single healthcare system.

CXCR4 is a stem/progenitor cell surface receptor specific for the cytokine stromal cell‐derived factor‐1 (SDF‐1α). There is evidence that bone marrow‐derived CXCR4‐expressing cells contribute to intimal hyperplasia (IH) by homing to the arterial subintima which is enriched with SDF‐1α. We have previously found that transforming growth factor‐β (TGFβ) and its signaling protein Smad3 are both upregulated following arterial injury and that TGFβ/Smad3 enhances the expression of CXCR4 in vascular smooth muscle cells (SMCs). It remains unknown, however, whether locally induced CXCR4 expression in SM22 expressing vascular SMCs plays a role in neointima formation. Here, we investigated whether elevated TGFβ/Smad3 signaling leads to the induction of CXCR4 expression locally in the injured arterial wall, thereby contributing to IH. We found prominent CXCR4 upregulation (mRNA, 60‐fold; protein, 4‐fold) in TGFβ‐treated, Smad3‐expressing SMCs. Chromatin immunoprecipitation assays revealed a specific association of the transcription factor Smad3 with the CXCR4 promoter. TGFβ/Smad3 treatment also markedly enhanced SDF‐1α‐induced ERK1/2 phosphorylation as well as SMC migration in a CXCR4‐dependent manner. Adenoviral expression of Smad3 in balloon‐injured rat carotid arteries increased local CXCR4 levels and enhanced IH, whereas SMC‐specific depletion of CXCR4 in the wire‐injured mouse femoral arterial wall produced a 60% reduction in IH. Our results provide the first evidence that upregulation of TGFβ/Smad3 in injured arteries induces local SMC CXCR4 expression and cell migration, and consequently IH. The Smad3/CXCR4 pathway may provide a potential target for therapeutic interventions to prevent restenosis. Stem Cells 2016;34:2744–2757

Background: Accelerated smooth muscle cell (SMC) proliferation is the primary cause of intimal hyperplasia (IH) following vascular interventions. Forkhead Box M1 (FOXM1) is considered a proliferation-associated transcription factor. However, the presence and role of FOXM1 in IH following vascular injury have not been determined. Objective: We examined the expression of FOXM1 in balloon-injured rat carotid arteries and investigated the effect of FOXM1 inhibition in SMCs and on the development of IH. Methods and results: FOXM1 was detected by immunofluorescent staining in balloon-injured rat carotid arteries where we observed an upregulation at day 7, 14, and 28 compared to uninjured controls. Immunofluorescence staining revealed FOXM1 coincided with proliferating cell nuclear antigen (PCNA). FOXM1 was also detectable in human carotid plaque samples. Western blot showed an upregulation of FOXM1 protein in serum-stimulated SMCs. Inhibition of FOXM1 using siRNA or chemical inhibition led to the induction of apoptosis as measured by flow cytometry and western blot for cleaved caspase 3. Perturbations in survival signaling were measured by western blot following FOXM1 inhibition, which showed a decrease in phosphorylated AKT and β-catenin. The chemical inhibitor thiostrepton was delivered by intraperitoneal injection in rats that underwent balloon injury and led to reduced intimal thickening compared to DMSO controls. Conclusions: FOXM1 is an important molecular mediator of IH that contributes to the proliferation and survival of SMCs following vascular injury.

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Objectives: The Magellan Robot catheter (Hansen Medical, Mountain View, Calif) recently received clearance by the Food and Drug Administration for use on peripheral vessels. Our institution acquired the system in January 2014. We report our institution's initial experience with the Magellan system.Methods: We retrospectively reviewed the records for all patients who underwent Magellan-assisted endovascular procedures between January 28, 2014, and April 26, 2014. Prior to the first procedure, the attending surgeon and staff underwent simulator and model training and certification for the Magellan system. Patient demographics, comorbidities, and operative statistics were recorded for analysis in accordance with IRB guidelines.Results: A total of 14 patients (64% male) underwent 15 Magellan-assisted therapies. The average age of our patients was 68 years. Four patients had undergone previous open or endovascular procedures on the treated extremity. Eight procedures involved atherosclerotic occlusive disease of the legs, 3 aortic aneurysm repairs, 2 visceral stenoses, 1 subclavian artery occlusion, and 1 right innominate vein occlusion. One case was aborted due to small iliac and femoral artery access. Two cases were unsuccessful due to failure to cross a venous chronic total occlusion and inability to advance the robotic sheath into the innominate artery. Operative statistics included an average blood loss of 125 6 114 mL, 57 6 42 mL contrast use, and 30 6 14 minutes of fluoroscopy time, with an average radiation exposure of 4866 6 6639 mGy. Conclusions: The overall success rate for the Magellan system was 87%. There was a definite learning curve, as evidenced by our longer fluoroscopy times. However, the flexibility of the leader catheter and ability to turn 180o made it possible to treat visceral arteries from the groin. We also found an advantage with the robotic catheter in crossing the iliac bifurcation even in patients with acute angulation or prior stenting. As more centers acquire the Magellan system, we feel participation in the ROVER robotic catheter registry will play a vital role in better defining the proper use of this new technology.