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Controlled matrix interactions were presented to pancreatic β-cells in three-dimensional culture within poly(ethylene glycol) hydrogels. Dispersed MIN6 β-cells were encapsulated in gel environments containing the following entrapped extracellular matrix (ECM) proteins: collagen type I, collagen type IV, fibrinogen, fibronectin, laminin, and vitronectin. In ECM-containing gels, β-cell survival was significantly better than in gels without ECM over 10 days. Correspondingly, apoptosis in encapsulated β-cells was less in the presence of each matrix protein, suggesting the ability of individual matrix interactions to prevent matrix signaling-related apoptosis (anoikis). MIN6 β-cells cultured in gels containing collagen type IV or laminin secreted more insulin in response to glucose stimulation than β-cells in all other experimental conditions. Variations in collagen type IV or laminin concentration between 10 μg/mL and 250 μg/mL did not affect insulin secretion. Finally, β-cell function in hydrogels presenting both collagen type IV and laminin revealed synergistic interactions. With a total protein concentration of 100 μg/mL, three gel compositions of varying ratios of collagen type IV to laminin (25:75, 50:50, and 75:25) were tested. In the presence of 25 μg/mL of collagen type IV and 75 μg/mL of laminin, β-cell insulin secretion was greater than with laminin or collagen type IV individually. These results demonstrate that specific, rationally designed extracellular environments promote isolated β-cell survival and function.

Controlled matrix interactions were presented to pancreatic β-cells in three-dimensional culture within poly(ethylene glycol) hydrogels. Dispersed MIN6 β-cells were encapsulated in gel environments containing the following entrapped extracellular matrix (ECM) proteins: collagen type I, collagen type IV, fibrinogen, fibronectin, laminin, and vitronectin. In ECM-containing gels, β-cell survival was significantly better than in gels without ECM over 10 days. Correspondingly, apoptosis in encapsulated β-cells was less in the presence of each matrix protein, suggesting the ability of individual matrix interactions to prevent matrix signaling-related apoptosis (anoikis). MIN6 β-cells cultured in gels containing collagen type IV or laminin secreted more insulin in response to glucose stimulation than β-cells in all other experimental conditions. Variations in collagen type IV or laminin concentration between 10 μg/mL and 250 μg/mL did not affect insulin secretion. Finally, β-cell function in hydrogels presenting both collagen type IV and laminin revealed synergistic interactions. With a total protein concentration of 100 μg/mL, three gel compositions of varying ratios of collagen type IV to laminin (25:75, 50:50, and 75:25) were tested. In the presence of 25 μg/mL of collagen type IV and 75 μg/mL of laminin, β-cell insulin secretion was greater than with laminin or collagen type IV individually. These results demonstrate that specific, rationally designed extracellular environments promote isolated β-cell survival and function. [PUBLICATION ABSTRACT]

The transplantation of encapsulated islets is an exciting potential cell replacement therapy for treating type 1 diabetes and avoiding the systemic immune suppression usually required for any transplantation. Semipermeable encapsulation barriers prevent cell-cell contact mediated destruction of transplanted cells and the passage of large immune cell-secreted cytotoxic factors, but permit diffusion of low molecular weight nutrients and metabolites to and from encapsulated cells. To minimize the immune response, encapsulation barrier materials have been designed to be as inert as possible, but inert barriers create an islet extracellular microenvironment that is very different from that of the native pancreas, where islets are extensively vascularized and in contact with basement membrane proteins. Recent studies of islets cultured on extracellular matrix substrates have demonstrated the positive effects of these cell-matrix interactions on islet survival and function in vitro. The overall hypothesis of this research is that the introduction of extracellular signaling found in the native islet environment into the encapsulated islet environment will promote islet survival and function. Poly(ethylene glycol) (PEG) hydrogels formed via the photoinitiated polymerization of dimethacrylated PEG were applied as a model three-dimensional encapsulation environment for systematically testing the isolated and combined effects of specific extracellular interactions on islet survival and function. Matrix interactions were incorporated into PEG hydrogels in the form of whole proteins and small, covalently tethered adhesive peptide sequences, and the influence of these interactions on individual β-cell survival and the coordinated function of isolated islets in response to glucose stimulation was investigated. Because the nutrient supply delivered to interior islet cells by intraislet vasculature is lost upon isolation, islets were dissociated in enzyme-free conditions and allowed to re-aggregate into smaller, islet-like clusters that retain islet function in vitro but have reduced intraislet diffusion distances. Finally, the translation of the three-dimensional PEG hydrogel culture platform to a functionalized islet encapsulation barrier material was explored by studying the transport properties of PEG networks with respect to proteins, and the localization of biological functionalities for the spatial control of extracellular signaling within PEG encapsulation barriers.

Catheter-based renal denervation has significantly reduced blood pressure in previous studies. Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medications. In this international, prospective, single-blinded, sham-controlled trial, done at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the UK, and the USA, hypertensive patients with office systolic blood pressure of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure. The primary efficacy endpoint was baseline-adjusted change in 24-h systolic blood pressure and the secondary efficacy endpoint was baseline-adjusted change in office systolic blood pressure from baseline to 3 months after the procedure. We used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02439749. From June 25, 2015, to Oct 15, 2019, 331 patients were randomly assigned to either renal denervation (n=166) or a sham procedure (n=165). The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0·999 for both. The treatment difference between the two groups for 24-h systolic blood pressure was −3·9 mm Hg (Bayesian 95% credible interval −6·2 to −1·6) and for office systolic blood pressure the difference was −6·5 mm Hg (−9·6 to −3·5). No major device-related or procedural-related safety events occurred up to 3 months. SPYRAL Pivotal showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower blood pressure in the absence of antihypertensive medications. Medtronic.

While immunotherapies show great promise in cancer treatment, variability in patient responses warrant the need for improved methods to assess early responses and guide precision therapy. The tumor microenvironment (TME) plays a critical role in antitumor immunity and tumor response to immunotherapy. Critically, TME components and their crosstalk with immune cells can be leveraged as a prognostic marker for therapeutic response. This study evaluated the use of magnetic resonance molecular imaging (MRMI) targeting the TME protein extradomain B fibronectin (EDB-FN), which is a lymphokine secreted by activated T lymphocytes and a marker of the epithelial-to-mesenchymal transition (EMT) in aggressive tumor cells. MRMI of EDB-FN was evaluated within the tumor extracellular matrix and was correlated with immunotherapy-related outcomes. C57BL/6 mice bearing orthotopic KPC pancreatic tumors were treated with a novel immune checkpoint inhibitor (VISTA-blocking antibodies), a vaccine (mutant KRAS peptide with TLR7/8/9 agonists), or a combination of both. MRMI with an EDB-FN-specific contrast agent, MT218, was used to image tumor responses during treatment. T -weighted MRI (fast spin echo and FLASH sequences) was acquired before, during, and after tumor treatment. Tumor signal enhancement patterns were analyzed to assess treatment response. EDB-FN expression and the infiltration of CD4 and CD8 T lymphocytes in the tumors were determined by immunohistochemistry (IHC) and immunofluorescence (IF) staining, respectively, and correlated with MRMI observations, tumor response, and therapeutic outcomes. MT218-MRMI revealed distinctive signal enhancement patterns across different treatments. These patterns were detected as early as two weeks after treatment initiation and correlated strongly with EDB-FN expression and CD4 and CD8 T cell infiltration, as confirmed by IHC and IF. Signal profiles corresponded to known TME phenotypes: immune desert, immune excluded, and immune inflamed, which were associated with non-response, partial response, and complete response, respectively. By four weeks post-treatment, MRMI criteria successfully distinguished complete responders from partial responders. Over a 200-day monitoring period, outcome prediction showed complete (100%) long-term disease-free survival in complete responders, 24-27% survival in partial responders, and no (0%) survival in non-responders and those with stable disease. MT218-MRMI non-invasively distinguishes tumor response patterns with significant potential for early prediction of therapeutic outcomes and timely optimization of treatment strategies. While further validation is needed for clinical translation, these findings demonstrate MT218-MRMI's promise as a tool for monitoring immunotherapy response in pancreatic cancer and underscore its potential utility for precision immunotherapy.