Explore the vast range of titles available.

Changes in extracellular matrix proteins may contribute significantly to the adaptation of vein grafts to the arterial circulation. We examined the production and distribution of versican and hyaluronan in intact human vein rings cultured ex vivo, veins perfused ex vivo, and cultured venous adventitial and smooth muscle cells. Immunohistochemistry revealed higher levels of versican in the intima/media compared to the adventitia, and no differences in hyaluronan. In the vasa vasorum, versican and hyaluronan associated with CD34+ progenitor cells. Culturing the vein rings for 14 days revealed increased versican immunostaining of 30-40% in all layers, with no changes in hyaluronan. Changes in versican accumulation appear to result from increased synthesis in the intima/media and decreased degradation in the adventitia as versican transcripts were increased in the intima/media, but unchanged in the adventitia, and versikine (the ADAMTS-mediated cleavage product of versican) was increased in the intima/media, but decreased in the adventitia. In perfused human veins, versican was specifically increased in the intima/media in the presence of venous pressure, but not with arterial pressure. Unexpectedly, cultured adventitial cells express and accumulate more versican and hyaluronan than smooth muscle cells. These data demonstrate a differential regulation of versican and hyaluronan in human venous adventitia vs. intima/media and suggest distinct functions for these extracellular matrix macromolecules in these venous wall compartments during the adaptive response of vein grafts to the arterial circulation.

The introduction of drug-eluting stents (DES) has dramatically reduced restenosis rates compared with bare metal stents, but in-stent thrombosis remains a safety concern, necessitating prolonged dual anti-platelet therapy. The drug 6-Mercaptopurine (6-MP) has been shown to have beneficial effects in a cell-specific fashion on smooth muscle cells (SMC), endothelial cells and macrophages. We generated and analyzed a novel bioresorbable polymer coated DES, releasing 6-MP into the vessel wall, to reduce restenosis by inhibiting SMC proliferation and decreasing inflammation, without negatively affecting endothelialization of the stent surface. Stents spray-coated with a bioresorbable polymer containing 0, 30 or 300 μg 6-MP were implanted in the iliac arteries of 17 male New Zealand White rabbits. Animals were euthanized for stent harvest 1 week after implantation for evaluation of cellular stent coverage and after 4 weeks for morphometric analyses of the lesions. Four weeks after implantation, the high dose of 6-MP attenuated restenosis with 16% compared to controls. Reduced neointima formation could at least partly be explained by an almost 2-fold induction of the cell cycle inhibiting kinase p27Kip1. Additionally, inflammation score, the quantification of RAM11-positive cells in the vessel wall, was significantly reduced in the high dose group with 23% compared to the control group. Evaluation with scanning electron microscopy showed 6-MP did not inhibit strut coverage 1 week after implantation. We demonstrate that novel stents coated with a bioresorbable polymer coating eluting 6-MP inhibit restenosis and attenuate inflammation, while stimulating endothelial coverage. The 6-MP-eluting stents demonstrate that inhibition of restenosis without leaving uncovered metal is feasible, bringing stents without risk of late thrombosis one step closer to the patient.

Impaired Collateral Recruitment and Outward Remodeling in Experimental Diabetes Jolanda M. van Golde 1 , Matthijs S. Ruiter 1 , Nicolaas C. Schaper 1 , Stefan Vöö 2 , Johannes Waltenberger 2 , Walter H. Backes 3 , Mark J. Post 4 and Maya S. Huijberts 1 1 Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands 2 Department of Cardiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands 3 Department of Radiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands 4 Department of Physiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands Corresponding author: Jolanda M. van Golde, jmcg.vangolde{at}intmed.unimaas.nl Abstract OBJECTIVE— In this study, the effect of chronic hyperglycemia on acute ligation-induced collateral vasodilation, on monocyte chemotaxis, and on structural outward remodeling of collaterals was investigated. RESEARCH DESIGN AND METHODS— Femoral artery ligation was performed 8 weeks after alloxan or saline treatment in New Zealand White rabbits. Angiography was performed directly, 1 and 3 weeks after ligation. These angiographic recordings were used to quantify number of collaterals, lumen, and blood volume index. Reactive hyperemia response was tested by intramuscular laser Doppler measurements. Subsequently, blood was sampled from the aorta for monocyte chemotaxis. RESULTS— Ligation resulted in markedly lower acute collateral vasodilation in diabetic compared with control rabbits. Also, hyperemic vasodilatory response to local ischemia was impaired in diabetic rabbits. This difference persisted at 1 and 3 weeks after ligation, with a lower number of visible collaterals. In addition, the collateral lumen was markedly lower in diabetic rabbits after the maturation phase. Likewise, a reduced blood volume index in the region of growing collaterals was observed in diabetic animals. The monocyte migration toward vascular endothelial growth factor-A and monocyte chemotactic protein-1 was strongly reduced in diabetic rabbits. CONCLUSIONS— This study demonstrates that chronic hyperglycemia negatively affects the different phases of arteriogenesis: 1 ) impaired shear induced vasodilatation; 2 ) impaired outward collateral growth, reflected in the number of collaterals and blood volume index; and 3 ) inhibition of monocyte chemotaxis. Impairments were most evident in the acute phase of arteriogenesis. Therapies aimed at restoring acute collateral recruitment, such as vasodilators, may be of interest to improve collateral function in diabetes. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted July 1, 2008. Received February 18, 2008. DIABETES

Background Drug-eluting stents (DES) have dramatically reduced restenosis rates compared to bare metal stents and are widely used in coronary artery angioplasty. The anti-proliferative nature of the drugs reduces smooth muscle cell (SMC) proliferation effectively, but unfortunately also negatively affects endothelialization of stent struts, necessitating prolonged dual anti-platelet therapy. Cell-type specific therapy may prevent this complication, giving rise to safer stents that do not require additional medication. 6-Mercaptopurine (6-MP) is a drug with demonstrated cell-type specific effects on vascular cells both in vitro and in vivo, inhibiting proliferation of SMCs while promoting survival of endothelial cells. In rabbits, we demonstrated that DES locally releasing 6-MP during 4 weeks reduced in-stent stenosis by inhibiting SMC proliferation and reducing inflammation, without negatively affecting endothelialization of the stent surface. The aim of the present study was to investigate whether 6-MP-eluting stents are similarly effective in preventing stenosis in porcine coronary arteries after 3 months, in order to assess the eligibility for human application. Methods 6-MP-eluting and polymer-only control stents (both n  = 7) were implanted in porcine coronary arteries after local balloon injury to assess the effect of 6-MP on vascular lesion formation. Three months after implantation, stented coronary arteries were harvested and analyzed. Results Morphometric analyses revealed that stents were implanted reproducibly and with limited injury to the vessel wall. Unexpectedly, both in-stent stenosis (6-MP: 41.1 ± 10.3 %; control: 29.6 ± 5.9 %) and inflammation (6-MP: 2.14 ± 0.51; control: 1.43 ± 0.45) were similar between the groups after 3 months. Conclusion In conclusion, although 6-MP was previously found to potently inhibit SMC proliferation, reduce inflammation and promote endothelial cell survival, thereby effectively reducing in-stent restenosis in rabbits, stents containing 300 μg 6-MP did not reduce stenosis and inflammation in porcine coronary arteries.

: Despite the preferred application of arterial conduits, the greater saphenous vein (SV) remains indispensable for coronary bypass grafting (CABG), especially in multi-vessel coronary artery disease (CAD). The objective of the present work was to address the role of mechanical forces in the activation of maladaptive vein bypass remodeling, a process determining progressive occlusion and recurrence of ischemic heart disease. : We employed a custom bioreactor to mimic the coronary shear and wall mechanics in human SV vascular conduits and reproduce experimentally the biomechanical conditions of coronary grafting and analyzed vein remodeling process by histology, histochemistry and immunofluorescence. We also subjected vein-derived cells to cyclic uniaxial mechanical stimulation in culture, followed by phenotypic and molecular characterization using RNA and proteomic methods. We finally validated our results and using a model of SV carotid interposition in pigs. : Exposure to pulsatile flow determined a remodeling process of the vascular wall involving reduction in media thickness. Smooth muscle cells (SMCs) underwent conversion from contractile to synthetic phenotype. A time-dependent increase in proliferating cells expressing mesenchymal (CD44) and early SMC (SM22α) markers, apparently recruited from the SV adventitia, was observed especially in CABG-stimulated vessels. Mechanically stimulated SMCs underwent transition from contractile to synthetic phenotype. MALDI-TOF-based secretome analysis revealed a consistent release of Thrombospondin-1 (TSP-1), a matricellular protein involved in TGF-β-dependent signaling. TSP-1 had a direct chemotactic effect on SV adventitia resident progenitors (SVPs); this effects was inhibited by blocking TSP-1 receptor CD47. The involvement of TSP-1 in adventitial progenitor cells differentiation and graft intima hyperplasia was finally contextualized in the TGF-β-dependent pathway, and validated in a saphenous vein into carotid interposition pig model. : Our results provide the evidence of a matricellular mechanism involved in the human vein arterialization process controlled by alterations in tissue mechanics, and open the way to novel potential strategies to block VGD progression based on targeting cell mechanosensing-related effectors.

The diversity and structure of ecosystems has been found to depend both on trophic interactions in food webs and on other species interactions such as habitat modification and mutualism that form non-trophic interaction networks. However, quantification of the dependencies between these two main interaction networks has remained elusive. In this study, we assessed how habitat-modifying organisms affect basic food web properties by conducting in-depth empirical investigations of two ecosystems: North American temperate fringing marshes and West African tropical seagrass meadows. Results reveal that habitat-modifying species, through non-trophic facilitation rather than their trophic role, enhance species richness across multiple trophic levels, increase the number of interactions per species (link density), but decrease the realized fraction of all possible links within the food web (connectance). Compared to the trophic role of the most highly connected species, we found this non-trophic effects to be more important for species richness and of more or similar importance for link density and connectance. Our findings demonstrate that food webs can be fundamentally shaped by interactions outside the trophic network, yet intrinsic to the species participating in it. Better integration of non-trophic interactions in food web analyses may therefore strongly contribute to their explanatory and predictive capacity.

Background/Objectives: To evaluate the efficacy, safety, and symptom impact of yttrium-90 selective internal radiation therapy (Y-90 SIRT) for neuroendocrine liver metastases (NELM) through an updated systematic review and meta-analysis integrated with our institutional data. Methods: We retrospectively analyzed 12 patients with NELM treated with Y-90 resin microspheres between 2019 and 2024. Outcomes included overall survival (OS), hepatic progression-free survival (HPFS), symptom improvement, and adverse events. Concurrently, a systematic review and meta-analysis of 43 studies (including our institutional cohort; total n = 2221; 2008–2025) was conducted following PRISMA guidelines. Pooled estimates for survival, tumor response, symptom improvement, and adverse events were derived using random- or fixed-effects models, with publication bias assessed by standard methods. Results: In our cohort, the median OS and HPFS were 33.3 and 15.3 months; 71.4% of symptomatic patients reported improvement, with no grade ≥ 3 toxicities. In the meta-analysis, pooled OS rates were 82%, 66%, 52%, and 34% at 1, 2, 3, and 5 years, and HPFS rates were 64%, 41%, and 29% at 1, 2, and 3 years. The pooled objective response rate (ORR) and disease control rate (DCR) were 40% and 87% by RECIST, and 56% and 91% by mRECIST. Patients treated with resin microspheres (ORR 38%, DCR 86%) and glass microspheres (ORR 39%, DCR 83%) showed comparable responses. Symptom improvement was observed in 77% of symptomatic patients, while reported grade ≥ 3 toxicities for individual adverse events were each below 5%. Conclusions: Y-90 SIRT is associated with promising survival outcomes, high disease control rates, and substantial symptom improvement in NELM with acceptable toxicity, suggesting its potential value as a liver-directed therapy option.

Background Selective internal radiation therapy (SIRT) with yttrium-90 (Y-90) microspheres is an established locoregional treatment for early- to intermediate-stage hepatocellular carcinoma (HCC). While both resin and glass microspheres are widely used, their comparative effectiveness and safety in lobar infusion remain unclear. This study aimed to compare the effectiveness and safety of resin versus glass microspheres in patients with early- to intermediate-stage HCC undergoing lobar Y-90 SIRT. Results A retrospective single-center analysis was conducted on 37 consecutive patients with early- to intermediate-stage HCC who underwent lobar Y-90 SIRT (resin: n  = 22; glass: n  = 15). Baseline characteristics were comparable between the two groups, except for age (glass: 64 ± 6.9 years vs. resin: 69 ± 7.1 years; P  = 0.036). Radiation doses to the tumour and non-tumoural liver were comparable between the resin and glass groups (all P  > 0.05). Patients treated with resin microspheres showed significantly longer progression-free survival (PFS) (median 9.3 vs. 6.4 months; P  = 0.043) and overall survival (OS) (median 16.4 vs. 12.0 months; P  = 0.035), and also demonstrated higher overall response rates, compared with those treated with glass microspheres. Univariate Cox regression identified resin microsphere use as a significant predictor of improved PFS and OS, while higher Barcelona Clinic Liver Cancer (BCLC) stage, multifocal disease, and tumour burden ≥ 25% were associated with worse survival (all P  < 0.05). Fine–Gray competing risk regression, accounting for post-SIRT treatments as competing events, further confirmed the OS benefit of resin microspheres compared with glass microspheres (subdistribution hazard ratio [SHR] = 0.35; P  = 0.011). Subgroup analysis demonstrated that the survival advantage of resin microspheres was particularly evident in patients with a maximum tumour diameter ≥ 5 cm (PFS: hazard ratio [HR] = 0.258, 95% confidence interval [CI]: 0.073–0.914; OS: HR = 0.111, 95% CI: 0.013–0.962). Safety outcomes were comparable between the two groups, with no significant differences in short- to long-term adverse events graded according to the Common Terminology Criteria for Adverse Events version 5.0, or in laboratory changes at 4-month follow-up (all P  > 0.05). Conclusions In lobar Y-90 SIRT for early-to intermediate-stage HCC, resin microspheres were associated with improved outcomes without increased toxicity compared to glass microspheres, particularly in patients with large tumours. These findings support a potential benefit of resin versus glass microspheres in lobar SIRT and warrant prospective validation in larger cohorts.

ObjectivesTo study the ratio of ablation zone volume to applied energy in computed tomography (CT)-guided radiofrequency ablation (RFA) and microwave ablation (MWA) in patients with hepatocellular carcinoma (HCC) in a cirrhotic liver and in patients with colorectal liver metastasis (CRLM).MethodsIn total, 90 liver tumors, 45 HCCs in a cirrhotic liver and 45 CRLMs were treated with RFA or with one of two MWA devices (MWA_A and MWA_B), resulting in 15 procedures for each tumor type, per device. Device settings were recorded and the applied energy was calculated. Ablation volumes were segmented on the contrast-enhanced CT scans obtained 1 week after the procedure. The ratio of ablation zone volume in milliliters to applied energy in kilojoules was determined for each procedure and compared between HCC (RHCC) and CRLM (RCRLM), stratified according to ablation device.ResultsWith RFA, RHCC and RCRLM were 0.22 mL/kJ (0.14–0.45 mL/kJ) and 0.15 mL/kJ (0.14–0.22 mL/kJ; p = 0.110), respectively. With MWA_A, RHCC was 0.81 (0.61–1.07 mL/kJ) and RCRLM was 0.43 (0.35–0.61 mL/kJ; p = 0.001). With MWA_B, RHCC was 0.67 (0.41–0.85 mL/kJ) and RCRLM was 0.43 (0.35–0.61 mL/kJ; p = 0.040).ConclusionsWith RFA, there was no significant difference in energy deposition ratio between tumor types. With both MWA devices, the ratios were higher for HCCs. Tailoring microwave ablation device protocols to tumor type might prevent incomplete ablations.Key Points• HCCs and CRLMs respond differently to microwave ablation• For MWA, CRLMs required more energy to achieve a similar ablation volume• Tailoring ablation protocols to tumor type might prevent incomplete ablations

Although language is an effective vehicle for communication, it is unclear how linguistic and communicative abilities relate to each other. Some researchers have argued that communicative message generation involves perspective taking (mentalizing), and—crucially—that mentalizing depends on language. We employed a verbal communication paradigm to directly test whether the generation of a communicative action relies on mentalizing and whether the cerebral bases of communicative message generation are distinct from parts of cortex sensitive to linguistic variables. We found that dorsomedial prefrontal cortex, a brain area consistently associated with mentalizing, was sensitive to the communicative intent of utterances, irrespective of linguistic difficulty. In contrast, left inferior frontal cortex, an area known to be involved in language, was sensitive to the linguistic demands of utterances, but not to communicative intent. These findings show that communicative and linguistic abilities rely on cerebrally (and computationally) distinct mechanisms.