Suchergebnisse

This is the peer reviewed version of the following article: Marin, R., Lifante, J., Besteiro, L. V., Wang, Z., Govorov, A. O., Rivero, F., . & Jaque, D. (2020). Plasmonic Copper Sulfide Nanoparticles Enable Dark Contrast in Optical Coherence Tomography. Advanced Healthcare Materials 2020 9.5 (2020): 1901627, which has been published in final form at https://onlinelibrary.wiley.com/doi/full/10.1002/adhm.201901627. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions ; Optical coherence tomography (OCT) is an imaging technique affording noninvasive optical biopsies. Like for other imaging techniques, the use of dedicated contrast agents helps better discerning biological features of interest during the clinical practice. Although bright OCT contrast agents have been developed, no dark counterpart has been proposed yet. Herein, plasmonic copper sulfide nanoparticles as the first OCT dark contrast agents working in the second optical transparency window are reported. These nanoparticles virtually possess no light scattering capabilities at the OCT working wavelength (≈1300 nm); thus, they exclusively absorb the probing light, which in turn results in dark contrast. The small size of the nanoparticles and the absence of apparent cytotoxicity support the amenability of this system to biomedical applications. Importantly, in the pursuit of systems apt to yield OCT dark contrast, a library of copper sulfide nanoparticles featuring plasmonic resonances spanning the three optical transparency windows is prepared, thus highlighting the versatility and potential of these systems in light-controlled biomedical applications ; This project was partially funded by the European Commission through the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant agreement No. 797945 "LANTERNS". This work was partially supported by the Ministerio de Economía y Competitividad de España (MAT2016-75362-C3-1-R) and (MAT2017-83111R), by the Instituto de Salud Carlos III (PI16/00812), by the Comunidad Autónoma de Madrid (B2017/BMD-3867RENIMCM), and co-financed by the European Structural and investment fund. Additional funding was provided by the European Commission Horizon 2020 project NanoTBTech. L.V.B was supported by the Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China and China Postdoctoral Science Foundation (2017M622992 and 2019T120820). Z.W. was supported by the National Basic Research Program of China (Project 2013CB933301) and the National Natural Science Foundation of China (Project 51272038). A.G. was funded via the 1000-talent Award of Sichuan and by the Volkswagen Foundation. Prof. Jorge Rubio-Retama is gratefully acknowledged for granting access to the dynamic light scattering instrument and for the fruitful discussion

BACKGROUND: Although the role of Th17 and regulatory T cells in the progression of atherosclerosis has been highlighted in recent years, their molecular mediators remain elusive. We aimed to evaluate the association between the CD69 receptor, a regulator of Th17/regulatory T cell immunity, and atherosclerosis development in animal models and in patients with subclinical disease. METHODS: Low-density lipoprotein receptor-deficient chimeric mice expressing or not expressing CD69 on either myeloid or lymphoid cells were subjected to a high fat diet. In vitro functional assays with human T cells were performed to decipher the mechanism of the observed phenotypes. Expression of CD69 and NR4A nuclear receptors was evaluated by reverse transcription-polymerase chain reaction in 305 male participants of the PESA study (Progression of Early Subclinical Atherosclerosis) with extensive (n=128) or focal (n=55) subclinical atherosclerosis and without disease (n=122). RESULTS: After a high fat diet, mice lacking CD69 on lymphoid cells developed large atheroma plaque along with an increased Th17/regulatory T cell ratio in blood. Oxidized low-density lipoprotein was shown to bind specifically and functionally to CD69 on human T lymphocytes, inhibiting the development of Th17 cells through the activation of NR4A nuclear receptors. Participants of the PESA study with evidence of subclinical atherosclerosis displayed a significant CD69 and NR4A1 mRNA downregulation in peripheral blood leukocytes compared with participants without disease. The expression of CD69 remained associated with the risk of subclinical atherosclerosis in an adjusted multivariable logistic regression model (odds ratio, 0.62; 95% CI, 0.40-0.94; P=0.006) after adjustment for traditional risk factors, the expression of NR4A1, the level of oxidized low-density lipoprotein, and the counts of different leucocyte subsets. CONCLUSIONS: CD69 depletion from the lymphoid compartment promotes a Th17/regulatory T cell imbalance and exacerbates the development of atherosclerosis. CD69 binding to oxidized low-density lipoprotein on T cells induces the expression of anti-inflammatory transcription factors. Data from a cohort of the PESA study with subclinical atherosclerosis indicate that CD69 expression in PBLs inversely correlates with the presence of disease. The expression of CD69 remained an independent predictor of subclinical atherosclerosis after adjustment for traditional risk factors. ; Funding was provided by the Spanish Ministry of Economy and Competitiveness: Plan Nacional de Salud SAF2017-82886-R to Dr Sánchez-Madrid, SAF2015-64767-R to Dr Martínez-González; Instituto de Salud Carlos III (AES 2016): PI16/01956 to Dr Martin, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares; European Research Council, ERC-2011-AdG294340-GENTRIS to Dr Sánchez-Madrid; Proyecto Integrado de Excelencia PIE13/041 and Fundació La Marató TV3 (20152330 31); and Comunidad Autónoma de Madrid CAM (S2017/BMD-3671) to Drs Martin and Sánchez-Madrid. Dr Tsilingiri is cofunded by the European Union Marie Curie Program. M. Relaño is supported by a Contratos Predoctorales Severo Ochoa para la formación de doctores (BES-2015–072625) from the Spanish Ministry of Economy and Competitiveness. This research has been cofinanced by Fondo Europeo de Desarrollo Regional. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain, is supported by the Ministerio de Ciencia, Innovación y Universidades, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The PESA study is cofunded equally by the Pro CNIC Foundation and Banco Santander, Madrid, Spain.

Background: Although the role of Th17 and regulatory T cells in the progression of atherosclerosis has been highlighted in recent years, their molecular mediators remain elusive. We aimed to evaluate the association between the CD69 receptor, a regulator of Th17/regulatory T cell immunity, and atherosclerosis development in animal models and in patients with subclinical disease. Methods: Low-density lipoprotein receptor-deficient chimeric mice expressing or not expressing CD69 on either myeloid or lymphoid cells were subjected to a high fat diet. In vitro functional assays with human T cells were performed to decipher the mechanism of the observed phenotypes. Expression of CD69 and NR4A nuclear receptors was evaluated by reverse transcription-polymerase chain reaction in 305 male participants of the PESA study (Progression of Early Subclinical Atherosclerosis) with extensive (n=128) or focal (n=55) subclinical atherosclerosis and without disease (n=122). Results: After a high fat diet, mice lacking CD69 on lymphoid cells developed large atheroma plaque along with an increased Th17/regulatory T cell ratio in blood. Oxidized low-density lipoprotein was shown to bind specifically and functionally to CD69 on human T lymphocytes, inhibiting the development of Th17 cells through the activation of NR4A nuclear receptors. Participants of the PESA study with evidence of subclinical atherosclerosis displayed a significant CD69 and NR4A1 mRNA downregulation in peripheral blood leukocytes compared with participants without disease. The expression of CD69 remained associated with the risk of subclinical atherosclerosis in an adjusted multivariable logistic regression model (odds ratio, 0.62; 95% CI, 0.40-0.94; P=0.006) after adjustment for traditional risk factors, the expression of NR4A1, the level of oxidized low-density lipoprotein, and the counts of different leucocyte subsets. Conclusions: CD69 depletion from the lymphoid compartment promotes a Th17/regulatory T cell imbalance and exacerbates the development of atherosclerosis. CD69 binding to oxidized low-density lipoprotein on T cells induces the expression of anti-inflammatory transcription factors. Data from a cohort of the PESA study with subclinical atherosclerosis indicate that CD69 expression in PBLs inversely correlates with the presence of disease. The expression of CD69 remained an independent predictor of subclinical atherosclerosis after adjustment for traditional risk factors. ; Funding was provided by the Spanish Ministry of Economy and Competitiveness: Plan Nacional de Salud SAF2017-82886-R to Dr Sánchez-Madrid, SAF2015-64767-R to Dr Martínez-González; Instituto de Salud Carlos III (AES 2016): PI16/01956 to Dr Martin, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares; European Research Council, ERC- 2011-AdG294340-GENTRIS to Dr Sánchez-Madrid; Proyecto Integrado de Excelencia PIE13/041 and Fundació La Marató TV3 (20152330 31); and Comunidad Autónoma de Madrid CAM (S2017/BMD-3671) to Drs Martin and Sánchez-Madrid. Dr Tsilingiri is cofunded by the European Union Marie Curie Program. M. Relaño is supported by a Contratos Predoctorales Severo Ochoa para la formación de doctores (BES-2015–072625) from the Spanish Ministry of Economy and Competitiveness. This research has been cofinanced by Fondo Europeo de Desarrollo Regional. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain, is supported by the Ministerio de Ciencia, Innovación y Universidades, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The PESA study is cofunded equally by the Pro CNIC Foundation and Banco Santander, Madrid, Spain

BACKGROUND: Stent thrombosis (ST) is a serious complication following coronary stenting. Intravascular optical coherence tomography (OCT) may provide insights into mechanistic processes leading to ST. We performed a prospective, multicenter study to evaluate OCT findings in patients with ST. METHODS: Consecutive patients presenting with ST were prospectively enrolled in a registry by using a centralized telephone registration system. After angiographic confirmation of ST, OCT imaging of the culprit vessel was performed with frequency domain OCT. Clinical data were collected according to a standardized protocol. OCT acquisitions were analyzed at a core laboratory. Dominant and contributing findings were adjudicated by an imaging adjudication committee. RESULTS: Two hundred thirty-one patients presenting with ST underwent OCT imaging; 14 (6.1%) had image quality precluding further analysis. Of the remaining patients, 62 (28.6%) and 155 (71.4%) presented with early and late/very late ST, respectively. The underlying stent type was a new-generation drug-eluting stent in 50.3%. Mean reference vessel diameter was 2.9+/-0.6 mm and mean reference vessel area was 6.8+/-2.6 mm(2). Stent underexpansion (stent expansion index <0.8) was observed in 44.4% of patients. The predicted average probability (95% confidence interval) that any frame had uncovered (or thrombus-covered) struts was 99.3% (96.1-99.9), 96.6% (92.4-98.5), 34.3% (15.0-60.7), and 9.6% (6.2-14.5) and malapposed struts was 21.8% (8.4-45.6), 8.5% (4.6-15.3), 6.7% (2.5-16.3), and 2.0% (1.2-3.3) for acute, subacute, late, and very late ST, respectively. The most common dominant finding adjudicated for acute ST was uncovered struts (66.7% of cases); for subacute ST, the most common dominant finding was uncovered struts (61.7%) and underexpansion (25.5%); for late ST, the most common dominant finding was uncovered struts (33.3%) and severe restenosis (19.1%); and for very late ST, the most common dominant finding was neoatherosclerosis (31.3%) and uncovered struts (20.2%). In patients presenting very late ST, uncovered stent struts were a common dominant finding in drug-eluting stents, and neoatherosclerosis was a common dominant finding in bare metal stents. CONCLUSIONS: In patients with ST, uncovered and malapposed struts were frequently observed with the incidence of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to time intervals from index stenting: uncovered struts and underexpansion in acute/subacute ST and neoatherosclerosis and uncovered struts in late/very late ST. ; The research leading to these results has received funding from the European Union Seventh Framework Program FP7/2007 to 2013 under grant agreement HEALTH-F2-2010 to 260309 (PRESTIGE). Funding for open access publication is provided by the European Commission.

Background: Stent thrombosis (ST) is a serious complication following coronary stenting. Intravascular optical coherence tomography (OCT) may provide insights into mechanistic processes leading to ST. We performed a prospective, multicenter study to evaluate OCT findings in patients with ST. Methods: Consecutive patients presenting with ST were prospectively enrolled in a registry by using a centralized telephone registration system. After angiographic confirmation of ST, OCT imaging of the culprit vessel was performed with frequency domain OCT. Clinical data were collected according to a standardized protocol. OCT acquisitions were analyzed at a core laboratory. Dominant and contributing findings were adjudicated by an imaging adjudication committee. Results: Two hundred thirty-one patients presenting with ST underwent OCT imaging; 14 (6.1%) had image quality precluding further analysis. Of the remaining patients, 62 (28.6%) and 155 (71.4%) presented with early and late/very late ST, respectively. The underlying stent type was a newgeneration drug-eluting stent in 50.3%. Mean reference vessel diameter was 2.9±0.6 mm and mean reference vessel area was 6.8±2.6 mm 2 . Stent underexpansion (stent expansion index < 0.8) was observed in 44.4% of patients. The predicted average probability (95% confidence interval) that any frame had uncovered (or thrombus-covered) struts was 99.3% (96.1-99.9), 96.6% (92.4-98.5), 34.3% (15.0-60.7), and 9.6% (6.2-14.5) and malapposed struts was 21.8% (8.4-45.6), 8.5% (4.6-15.3), 6.7% (2.5-16.3), and 2.0% (1.2-3.3) for acute, subacute, late, and very late ST, respectively. The most common dominant finding adjudicated for acute ST was uncovered struts (66.7% of cases); for subacute ST, the most common dominant finding was uncovered struts (61.7%) and underexpansion (25.5%); for late ST, the most common dominant finding was uncovered struts (33.3%) and severe restenosis (19.1%); and for very late ST, the most common dominant finding was neoatherosclerosis (31.3%) and uncovered struts (20.2%). In patients presenting very late ST, uncovered stent struts were a common dominant finding in drug-eluting stents, and neoatherosclerosis was a common dominant finding in bare metal stents. Conclusions: In patients with ST, uncovered and malapposed struts were frequently observed with the incidence of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to time intervals from index stenting: uncovered struts and underexpansion in acute/subacute ST and neoatherosclerosis and uncovered struts in late/very late ST ; Funding: The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement n° HEALTH-F2-2010-260309 (PRESTIGE). Funding for open access publication is provided by the European Commission