Preoperative aortic root geometry and postoperative cusp configuration primarily determine long-term outcome after valve-preserving aortic root repair

ObjectiveTechnical controversies exist in valve-preserving aortic root replacement. We sought to determine predictors of long-term stability of the aortic valve.MethodsA total of 430 patients (aged 57 ± 15 years, 323 male) underwent valve-preserving aortic root surgery (remodeling in 401, reimplantation in 29) between 1995 and 2009 and were followed echocardiographically. Factors influencing late recurrence of aortic valve regurgitation grade II or greater (n = 45) or need for reoperation on the aortic valve (n = 25) were analyzed.ResultsEarly mortality was 2.8% (1.9% for elective cases), and actuarial survival at 10 years was 83.5% ± 2.4%. Ten-year freedom from aortic valve regurgitation grade II or greater was 85.0% ± 2.5%. Preoperative aortoventricular junction diameter greater than 28 mm and postoperative effective height of the aortic cusp less than 9 mm were identified as significant predictors for late aortic valve regurgitation grade II or greater in multivariate analysis (both P < .001). Ten-year freedom from reoperation on the aortic valve was 89.3% ± 2.5%. Preoperative aortoventricular junction diameter greater than 28 mm (P < .001), use of pericardial patch (P = .022), and effective height of the aortic cusp less than 9 mm (P = .049) were identified as significant predictors for reoperation in multivariate analysis. Operative technique (remodeling, reimplantation), Marfan syndrome, bicuspid valve anatomy, concomitant central cusp plication, size of prosthesis used, and acute dissection were not associated with an increased risk of late aortic valve regurgitation grade II or greater or reoperation. In patients with preoperative aortoventricular junction diameter greater than 28 mm (n = 94), the addition of central cusp plication significantly improved freedom from aortic valve regurgitation grade II or greater (P = .006) regardless of root procedures (remodeling, P = .011; reimplantation, P = .053).ConclusionsLong-term stability of valve-preserving aortic root replacement was influenced not by the technique of root repair but by the preoperative aortic root geometry and postoperative cusp configuration

Transapical aortic valve implantation with a self-expanding anatomically oriented valve

Aims The Medtronic Engager™ aortic valve bioprosthesis is a self-expanding valve with support arms facilitating anatomically correct positioning and axial fixation. Valve leaflets, made of bovine pericardium, are mounted on a Nitinol frame. Here, we report the first in man study with this new implant (Trial Identifier NCT00677638). Methods and results Thirty patients (mean age 83.4 ± 3.8 years; 83% female) with tricuspid aortic valve stenosis were included in the study. Mean logistic EuroSCORE was 23.4 ± 11.9. Mean aortic annulus diameter was 21.8 ± 1.4 mm. For this study, the Engager was available in only one size (23 mm), to fit aortic annuli of 19-23 mm. Standard transapical valve implantation was performed using predilation of the aortic valve and rapid ventricular pacing during ballon valvuloplasty and most valve deployments. Accurate valve placement was achieved in 29/30 cases (97%). Post-implant peak-to-peak gradient was 13.3 ± 9.3 mmHg. In 80% of the patients, no more than grade I paravalvular leakage was observed, in 13% grades I-II and in 3% grade II. Three patients (10%) required permanent pacemaker implantation for higher-degree or complete atrioventricular block. Four dissections (13%) occurred during positioning of the valve and were treated surgically in three cases. Thirty-day and in-hospital mortality were 20% and 23%, respectively, and 6-month survival was 56.7%. No structural failure occurred for up to 1 year. Conclusion This series established the feasibility of implanting a novel self-expanding transapical aortic valve prosthesis predictably into an anatomically correct position. Observed complications led to complete redesign of the delivery system for upcoming clinical studies with the goal of establishing safety and performanc

Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells

The regulation of acetylation is central for the epigenetic control of lineage-specific gene expression and determines cell fate decisions. We provide evidence that the inhibition of histone deacetylases (HDACs) blocks the endothelial differentiation of adult progenitor cells. To define the mechanisms by which HDAC inhibition prevents endothelial differentiation, we determined the expression of homeobox transcription factors and demonstrated that HoxA9 expression is down-regulated by HDAC inhibitors. The causal involvement of HoxA9 in the endothelial differentiation of adult progenitor cells is supported by the finding that HoxA9 overexpression partially rescued the endothelial differentiation blockade induced by HDAC inhibitors. Knockdown and overexpression studies revealed that HoxA9 acts as a master switch to regulate the expression of prototypical endothelial-committed genes such as endothelial nitric oxide synthase, VEGF-R2, and VE-cadherin, and mediates the shear stress–induced maturation of endothelial cells. Consistently, HoxA9-deficient mice exhibited lower numbers of endothelial progenitor cells and showed an impaired postnatal neovascularization capacity after the induction of ischemia. Thus, HoxA9 is regulated by HDACs and is critical for postnatal neovascularization

Исследование процесса и разработка методологических основ безаварийного бурения под интервалы направлений и кондукторов на скважинах Восточно-Сибирского региона (на примере Куюмбинского ГКМ)»

Научный доклад содержит сформулированные выводы на основе реальных производственных результатов, а также разработаны обоснованные рекомендации по безаварийному строительству секций направлений и кондукторов для геологических условий Куюмбинского месторождения.The paper contains formulated conclusions based on real production results, and well-grounded recommendations for accident-free construction of sections of directions and conductors for the geological conditions of the Kuyumbinskoye field

Additional file 1 of Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity [Dataset]

Supplementary Table 1. cDNA primer sequences. Supplementary Table 2. Genomic DNA primer sequences. Supplementary Table 3. Genetic targeting of NR5A2.European Research Council FP7 Ideas: European Research Council Fondazione del Piemonte per l’Oncologia – IRCCS Shanghai Municipal Education Commission National Natural Science Foundation of China Ministry of Science and Technology, Taiwan Shanghai Pujiang ProgramPeer reviewe

Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity

[Background]; Pancreatic ductal adenocarcinoma (PDAC) is a profoundly aggressive and fatal cancer. One of the key factors defining its aggressiveness and resilience against chemotherapy is the existence of cancer stem cells (CSCs). The important task of discovering upstream regulators of stemness that are amenable for targeting in PDAC is essential for the advancement of more potent therapeutic approaches. In this study, we sought to elucidate the function of the nuclear receptor subfamily 5, group A, member 2 (NR5A2) in the context of pancreatic CSCs.[Methods]: We modeled human PDAC using primary PDAC cells and CSC-enriched sphere cultures. NR5A2 was genetically silenced or inhibited with Cpd3. Assays included RNA-seq, sphere/colony formation, cell viability/toxicity, real-time PCR, western blot, immunofluorescence, ChIP, CUT&Tag, XF Analysis, lactate production, and in vivo tumorigenicity assays. PDAC models from 18 patients were treated with Cpd3-loaded nanocarriers.[Results]: Our findings demonstrate that NR5A2 plays a dual role in PDAC. In differentiated cancer cells, NR5A2 promotes cell proliferation by inhibiting CDKN1A. On the other hand, in the CSC population, NR5A2 enhances stemness by upregulating SOX2 through direct binding to its promotor/enhancer region. Additionally, NR5A2 suppresses MYC, leading to the activation of the mitochondrial biogenesis factor PPARGC1A and a shift in metabolism towards oxidative phosphorylation, which is a crucial feature of stemness in PDAC. Importantly, our study shows that the specific NR5A2 inhibitor, Cpd3, sensitizes a significant fraction of PDAC models derived from 18 patients to standard chemotherapy. This treatment approach results in durable remissions and long-term survival. Furthermore, we demonstrate that the expression levels of NR5A2/SOX2 can predict the response to treatment.[Conclusions]: The findings of our study highlight the cell context-dependent effects of NR5A2 in PDAC. We have identified a novel pharmacological strategy to modulate SOX2 and MYC levels, which disrupts stemness and prevents relapse in this deadly disease. These insights provide valuable information for the development of targeted therapies for PDAC, offering new hope for improved patient outcomes.This work was supported by the ERC Advanced Investigator Grant (Pa-CSC 233460, to CH), the European Community's Seventh Framework Programme (FP7) under grant agreement n° 602783 (CAM-PaC, to CH), the Fondazione del Piemonte per l’Oncologia – IRCCS (PTCRC-Intra-2021 to CH), the Shanghai Municipal Education Commission (2021–01-07–00-02-E00090, to CH), the National Natural Science Foundation of China (82130074 and 82250710179 to CH; 81902673, to QZ), the Ministry of Science and Technology, Taiwan (Grant number MOST 111–2314-B-039–056, to AA), Shanghai Pujiang Program (21PJ1408900, to JT), Associazione Italiana Ricerca Cancro IG n. 26343 (A.S.), and Fondazione Italiana Malattie Pancreas – Ministero Salute FIMP_CUP J37G22000230001 (RTL).Peer reviewe

Vascular Wall-Resident CD44+ Multipotent Stem Cells Give Rise to Pericytes and Smooth Muscle Cells and Contribute to New Vessel Maturation

Here, we identify CD44(+)CD90(+)CD73(+)CD34(−)CD45(−) cells within the adult human arterial adventitia with properties of multipotency which were named vascular wall-resident multipotent stem cells (VW-MPSCs). VW-MPSCs exhibit typical mesenchymal stem cell characteristics including cell surface markers in immunostaining and flow cytometric analyses, and differentiation into adipocytes, chondrocytes and osteocytes under culture conditions. Particularly, TGFß1 stimulation up-regulates smooth muscle cell markers in VW-MPSCs. Using fluorescent cell labelling and co-localisation studies we show that VW-MPSCs differentiate to pericytes/smooth muscle cells which cover the wall of newly formed endothelial capillary-like structures in vitro. Co-implantation of EGFP-labelled VW-MPSCs and human umbilical vein endothelial cells into SCID mice subcutaneously via Matrigel results in new vessels formation which were covered by pericyte- or smooth muscle-like cells generated from implanted VW-MPSCs. Our results suggest that VW-MPSCs are of relevance for vascular morphogenesis, repair and self-renewal of vascular wall cells and for local capacity of neovascularization in disease processes

Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia

D.P. was supported by a non-clinical research fellowship from EHA. This work was supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001045), The UK Medical Research Council (FC001045), and the Welcome Trust (FC001045)

Técnicas de reparación valvular aórtica

ResumenLa reparación de la válvula aórtica ha experimentado una evolución constante en las 2 últimas décadas y se ha beneficiado notablemente de una mejor comprensión de la geometría de la válvula y de la raíz aórtica normal. Actualmente, las investigaciones se centran en algunos aspectos especiales, tales como la técnica óptima para la reparación o sustitución de los velos, la estabilización del anillo basal y el material ideal a emplear. El prolapso de los velos en las válvulas aórticas bicúspides y tricúspides es la causa más frecuente de insuficiencia aórtica en los países industrializados. Con base en la más reciente literatura, así como en nuestra propia experiencia, ofrecemos una serie de recomendaciones para un adecuado manejo quirúrgico de los pacientes con insuficiencia aórtica por patología valvular. Detallamos el diagnóstico y el análisis sistemático intraoperatorio que debe seguirse, así como las distintas técnicas quirúrgicas que se deben emplear. Presentamos los resultados obtenidos en 1.808 pacientes sometidos a distintas técnicas de reparación valvular aórtica en nuestra institución.AbstractAortic valve repair has evolved dynamically in the past two decades, and has markedly benefitted from a better understanding of normal aortic root and valve geometry. Current research focuses on some special aspects, such as technique for cusp repair or replacement, stabilization of the basal ring, and ideal material for the repair. Cusp prolapse in bicuspid and tricuspid aortic valves is the most frequent cause of aortic regurgitation in industrialized countries. On the basis of recent literature, as well as on our own experience, several recommendations are suggested for the most appropriate surgical management of the patients with aortic regurgitation due to cusp pathology. Details are presented on the diagnosis and intraoperative systematic analysis to be followed, as well as the different surgical techniques to be employed. The results obtained in 1808 patients undergoing aortic valve repair in our institution are presented