The role of aorta distal to stent in the occurrence of distal stent graft-induced new entry tear: A computational fluid dynamics and morphological study.

Distal stent graft-induced new entry tear (dSINE) is an important complication of thoracic endovascular aortic repair (TEVAR) for the treatment of type B aortic dissection (TBAD). This study aims to explore whether the aorta distal to the stent plays an important role in the occurrence of dSINE. Sixty-nine patient-specific geometrical models of twenty-three enrolled patients were reconstructed from preoperative, postoperative, and predSINE computed tomography scans. Computational fluid dynamics (CFD) simulations were performed to calculate the von Mises stress in the CFD group. Meanwhile, morphological measurements were performed in all patients, including measurements of the inverted pyramid index at different follow-up time points and the postoperative true lumen volume change rate. In the CFD study, the time-averaged von Mises stress of the true lumen distal to the stent in dSINE patients was significantly higher than that in the CFD controls (20.42 kPa vs. 15.47 kPa). In the morphological study, a special aortic plane (plane A) with an extremely small area distal to the stent was observed in dSINE patients, which resulted in an inverted pyramid structure in the true lumen distal to the stent. This structure in dSINE patients became increasingly obvious during the follow-up period and finally reached the maximum value before dSINE occurred (mean, 3.91 vs. 1.23). At the same time, enlargement of the true lumen distal to the stent occurs before dSINE, manifesting as a continuous increase in the true lumen volume (mean, 0.70 vs. 013). A new theory of what causes dSINE to occur has been proposed: the inverted pyramid structure of the true lumen distal to the stent caused an increase in the von Mises stress in this region and aortic enlargement, which ultimately led to the occurrence of dSINE.

Heat transfer mechanism in idealized healthy and diseased aortas using fluid-structure interaction method.

The heat transfer mechanism inside the human aorta may be related to the physiological function and lesion formation of the aortic wall. The objective of this study was to acquire the temperature distribution in the three-dimensional idealized aorta. An idealized healthy aortic geometry and three representative diseased aortas: aortic aneurysm, coarctation of the aorta, and aortic dissection were constructed. Advanced fluid-structure interaction (FSI) computational framework was applied to predict the aortic temperature distribution. The movement of the aortic root due to the heartbeat was also considered. The displacement distribution of the aortic vessel wall was consistent with clinical observation. The lesser curvature of the aortic arch, aneurysm body, coarctation region, and false lumen were all exposed to relatively high temperatures (over 310.006 K). We found that the rigid wall assumption slightly underestimated the magnitude of the whole aortic wall-averaged temperature while the changing trend and local temperature were like the results of the FSI method. Besides, the wall-averaged temperature would increase and the temperature inflection point would advance when the aortic vessel wall was loaded with a high heat flux. This pilot study revealed the aortic heat transfer mechanism and temperature distribution, and the findings may help to understand the physiological characteristics of the aortic vessel wall.

Design, synthesis and in vitro/in vivo anticancer activity of tranylcypromine-based triazolopyrimidine analogs as novel LSD1 inhibitors.

Histone lysine specific demethylase 1 (LSD1) is responsible for the demethylation of mono-/dimethylated lysine residue on histone proteins. LSD1 plays an extensive and essential role in the pathogenesis and progression of many human diseases such as cancers, and thus is becoming an attractive therapeutic target for cancer treatment. Tranylcypromine (TCP) is an important chemical template for developing irreversible LSD1 inhibitors, representing a major chemotype of clinical candidates. Here we report a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocylic motif. Starting from ticagrelor, a clinically available antiplatelet agent, as a hit compound, our medicinal efforts have led to the identification of compound 9j with nanomolar inhibitory potency against LSD1 as well as broad-spectrum antiproliferative activities against tumor cells. Enzyme studies show that compound 9j is selective over MAO-A/B enzymes, and also cellular active to elevate the expression of H3K4me2 by inhibiting LSD1 in cells. Furthermore, in a H1650 xenograft mouse model, oral administration of compound 9j at low 10 and 20 mg/kg dosages could enable a significant reduction in tumor size and a remarkable extension of survival. The current work is expected to provide an additional strategy to achieve new TCP-based LSD1 inhibitors.

Contactless multiscale measurement of cardiac motion using biomedical radar sensor.

Introduction: A contactless multiscale cardiac motion measurement method is proposed using impulse radio ultra-wideband (IR-UWB) radar at a center frequency of 7.29 GHz. Motivation: Electrocardiograph (ECG), heart sound, and ultrasound are traditional state-of-the-art heartbeat signal measurement methods. These methods suffer from defects in contact and the existence of a blind information segment during the cardiogram measurement. Methods: Experiments and analyses were conducted using coarse-to-fine scale. Anteroposterior and along-the-arc measurements were taken from five healthy male subjects (aged 25-43) when lying down or prone. In every measurement, 10 seconds of breath-holding data were recorded with a radar 55 cm away from the body surface, while the ECG was monitored simultaneously as a reference. Results: Cardiac motion detection from the front was superior to that from the back in amplitude. In terms of radar detection angles, the best cardiac motion information was observed at a detection angle of 120°. Finally, in terms of cardiac motion cycles, all the ECG information, as well as short segments of cardiac motion details named blind ECGs segments, were detected. Significance: A contactless and multiscale cardiac motion detection method is proposed with no blind detection of segments during the entire cardiac cycle. This paves the way for a potentially significant method of fast and accurate cardiac disease assessment and diagnosis that exhibits promising application prospects in contactless online cardiac monitoring and in-home healthcare.

Postharvest sclerotinia rot control in carrot by the natural product hinokitiol and the potential mechanisms involved.

Sclerotinia rot infected by cosmopolitan fungi Sclerotinia sclerotiorum is a serious and destructive disease in carrot production, especially during their postharvest storage. Natural products with the advantages of environmentally friendly and safety have been widely concerned. This research estimated the impact of hinokitiol against S. sclerotiorum and on the quality of carrots. In vitro and in vivo tests demonstrated that hinokitiol had promising antifungal activities against both carbendazim-susceptible and -resistant isolates of S. sclerotiorum. Importantly, it effectively kept the quality and prolonged the shelf life of carrot by declining the loss of weight, ascorbic acid, carotenoid, and total phenolics content, preventing the formation of malondialdehyde, and enhancing the activities of antioxidant enzymes. Further study found that hinokitiol inhibited the formation of sclerotia by destroying the morphology and the integrality of cell membrane, reduced the pathogenicity by suppressing the synthesis of oxalic acid and exopolysaccharide, declined the activities of enzymes and the gene expression related to sclerotia development in S. sclerotiorum. These information evidenced the great potential of hinokitiol as a natural fresh-keeping agent for the management of postharvest decay infected by S. sclerotiorum.

Computational Prediction of Thrombosis in Food and Drug Administration's Benchmark Nozzle.

Thrombosis seriously threatens human cardiovascular health and the safe operation of medical devices. The Food and Drug Administration's (FDA) benchmark nozzle model was designed to include the typical structure of medical devices. However, the thrombosis in the FDA nozzle has yet not been investigated. The objective of this study is to predict the thrombus formation process in the idealized medical device by coupling computational fluid dynamics and a macroscopic hemodynamic-based thrombus model. We developed the hemodynamic-based thrombus model by considering the effect of platelet consumption. The thrombus model was quantitatively validated by referring to the latest thrombosis experiment, which was performed in a backward-facing step with human blood flow. The same setup was applied in the FDA nozzle to simulate the thrombus formation process. The thrombus shaped like a ring was firstly observed in the FDA benchmark nozzle. Subsequently, the accuracy of the shear-stress transport turbulence model was confirmed in different turbulent flow conditions. Five scenarios with different Reynolds numbers were carried out. We found that turbulence could change the shape of centrosymmetric thrombus to axisymmetric and high Reynolds number blood flow would delay or even prevent thrombosis. Overall, the present study reports the thrombosis process in the FDA benchmark nozzle using the numerical simulation method, and the primary findings may shed light on the effect of turbulence on thrombosis.

Component quantification of aortic blood flow energy loss using computational fluid-structure interaction hemodynamics.

BACKGROUND AND OBJECTIVES: The aorta serves as the main tube of the human blood circulation system. Energy loss (EL) occurs when blood flows through the aorta and there may be a potential correlation between EL and aortic diseases. However, the components of blood flow EL are still not fully understood. This study aims to quantitatively reveal the EL components in healthy and diseased aortas. METHODS: We construct an idealized healthy aorta and three idealized representative diseased aortas: aortic aneurysm, coarctation of the aorta, and aortic dissection. Computational hemodynamic studies are carried out by using the fluid-structure interaction simulation framework. RESULTS: Four kinds of EL components: viscous friction, turbulence dissipation, wall deformation, and local lesion are firstly acquired in healthy and diseased aortas based on the high-resolution blood flow information. Viscous friction contributes most to the EL (45.69%-57.22%). EL caused by the deformation of the aortic wall ranks second (15.18%-33.12%). The proportions of turbulence dissipation and local lesion depend on individual geometric characteristics. Besides, the buffering efficiency of the healthy and diseased aorta is about 80%. CONCLUSIONS: This study quantitatively reports the components of blood flow EL in healthy and diseased aortas, the finding may provide novel insights into the pathogenesis of aortic diseases.

Two-Pronged Anti-Tumor Therapy by a New Polymer-Paclitaxel Conjugate Micelle with an Anti-Multidrug Resistance Effect.

Introduction: Cancerous tumors are still a major disease that threatens human life, with tumor multidrug resistance (MDR) being one of the main reasons for the failure of chemotherapy. Thus, reversing tumor MDR has become a research focus of medical scientists. Methods: Here, a reduction-sensitive polymer prodrug micelle, mPEG-DCA-SS-PTX (PDSP), was manufactured with a new polymer inhibitor of drug resistance as a carrier to overcome MDR and improve the anti-tumor effect of PTX. Results: The PDSP micelles display good stability, double-responsive drug release, and excellent biocompatibility. The PDSP micelles reduced the cytotoxicity of PTX to normal HL-7702 cells and enhanced that to SMMC-7721 and MCF-7 cells in vitro. Improved sensitivity of A549/ADR to PDSP was also observed in vitro. Furthermore, in vivo experiments show reduced systemic toxicity and enhanced therapeutic efficacy of PTX to H22 subcutaneous tumor-bearing mice. Conclusion: This work proves that the reduction-sensitive polymer prodrug micelles carried by the new polymer inhibitor can be used as an alternative delivery system to target tumors and reverse MDR for paclitaxel and other tumor-resistant drugs.

Zexie Tang targeting FKBP38/mTOR/SREBPs pathway improves hyperlipidemia.

ETHNOPHARMACOLOGICAL RELEVANCE: Zexie Tang (ZXT), only two consists with Alismatis Rhizoma (AR) and Atractylodes macrocephala Rhizoma (AM), a classical Chinese medicine formula from Synopsis of the Golden Chamber with a history of 2000 years. Clinical observation in recent years has found that ZXT has excellent lipid-lowering effect. AIM OF THE STUDY: To explore the potential mechanism of ZXT ameliorates hyperlipidemia based on FKBP38/mTOR/SREBPs pathway. MATERIALS AND METHODS: WD-induced hyperlipidemia mice and oleic acid induced cell lipid accumulation model were used to investigate pharmacodynamic. The effect of ZXT on the transcriptional activity of SREBPs was detected by reporter gene assay. Proteins and downstream genes of mTOR/SREBPs pathway were detected in vivo and in vitro. Combined with network pharmacology and HPLC-Q-TOF/MS, the active ingredients were screened and identified. The interaction between active compounds of ZXT and FKBP38 protein were analyzed by docking analysis. RESULTS: ZXT decreased TC, TG and LDL-c levels in blood of WD-induced hyperlipidemia mouse model, and improved insulin resistance in vivo. ZXT also reduced TC, TG and lipid accumulation in cells line, and inhibited SREBPs luciferase activity, protein and its target genes expression such as FASN, HMGCR, etc. Meanwhile, ZXT inhibited protein expression levels of p-mTOR, p-S6K, etc in vitro and in vivo. Combined with network pharmacology and HPLC-Q-TOF/MS, 16 active ingredients were screened and identified. Docking results showed that active compounds of ZXT binding to FKBP38 and formed hydrogen bond. CONCLUSION: Our findings highlighted that ZXT ameliorates hyperlipidemia, in which FKBP/mTOR/SREBPs pathway might be the potential regulatory mechanism.

Hemodynamic effects of stent-graft introducer sheath during thoracic endovascular aortic repair.

Thoracic endovascular aortic repair (TEVAR) has become the standard treatment of a variety of aortic pathologies. The objective of this study is to evaluate the hemodynamic effects of stent-graft introducer sheath during TEVAR. Three idealized representative diseased aortas were designed: aortic aneurysm, coarctation of the aorta, and aortic dissection. Computational fluid dynamics studies were performed in the above idealized aortic geometries. An introducer sheath routinely used in the clinic was virtually placed into diseased aortas. Comparative analysis was carried out to evaluate the hemodynamic effects of the introducer sheath. Results show that the blood flow to the supra-aortic branches would increase above 9% due to the obstruction of the introducer sheath. The region exposed to high endothelial cell activation potential (ECAP) expands in the scenarios of coarctation of the aorta and aortic dissection, which indicates that the probability of thrombus formation may increase during TEVAR. The pressure magnitude in peak systole shows an obvious rise, and a similar phenomenon is not observed in early diastole. The blood viscosity in the aortic arch and descending aorta is remarkably altered by the introducer sheath. The uneven viscosity distribution confirms the necessity of using non-Newtonian models, and high-viscosity region with high ECAP further promotes thrombosis. Our results highlight the hemodynamic effects of stent-graft introducer sheath during TEVAR, which may associate with perioperative complications.