Identifying hemodynamic factors associated with the rupture of anterior communicating artery aneurysms based on global modeling of blood flow in the cerebral artery network

Anterior communicating artery (ACoA) aneurysms are more prone to rupture compared to aneurysms present in other cerebral arteries. We hypothesize that systemic blood flow in the cerebral artery network plays an important role in shaping intra-aneurysmal hemodynamic environment thereby affecting the rupture risk of ACoA aneurysms. The majority of existing numerical studies in this field employed local modeling methods where the physical boundaries of a model are confined to the aneurysm region, which, though having the benefit of reducing computational cost, may compromise the physiological fidelity of numerical results due to insufficient account of systemic cerebral arterial hemodynamics. In the present study, we firstly carried out numerical experiments to address the difference between the outcomes of local and global modeling methods, demonstrating that local modeling confined to the aneurysm region results in inaccurate predictions of hemodynamic parameters compared with global modeling of the ACoA aneurysm as part of the cerebral artery network. Motivated by this finding, we built global hemodynamic models for 40 ACoA aneurysms (including 20 ruptured and 20 unruptured ones) based on medical image data. Statistical analysis of the computed hemodynamic data revealed that maximum wall shear stress (WSS), minimum WSS divergence, and maximum WSS gradient differed significantly between the ruptured and unruptured ACoA aneurysms. Optimal threshold values of high/low WSS metrics were determined through a series of statistical tests. In the meantime, some morphological parameters of aneurysms, such as large nonsphericity index, aspect ratio, and bottleneck factor, were found to be associated closely with aneurysm rupture. Furthermore, multivariate logistic regression analyses were performed to derive models combining hemodynamic and morphological parameters for discriminating the rupture status of aneurysms. The capability of the models in rupture status discrimination was high, with the area under the receiver operating characteristic curve reaching up to 0.9. The findings of the study suggest that global modeling of the cerebral artery network is essential for reliable quantification of hemodynamics in ACoA aneurysms, disturbed WSS and irregular aneurysm morphology are associated closely with aneurysm rupture, and multivariate models integrating hemodynamic and morphological parameters have high potential for assessing the rupture risk of ACoA aneurysms

Threshold values of brachial cuff-measured arterial stiffness indices determined by comparisons with the brachial–ankle pulse wave velocity: a cross-sectional study in the Chinese population

BackgroundArterial Velocity-pulse Index (AVI) and Arterial Pressure-volume Index (API), measured by a brachial cuff, have been demonstrated to be indicative of arterial stiffness and correlated with the risk of cardiovascular events. However, the threshold values of AVI and API for screening increased arterial stiffness in the general population are yet to be established.MethodsThe study involved 860 subjects who underwent general physical examinations (M/F = 422/438, age 53.4 ± 12.7 years) and were considered to represent the general population in China. In addition to the measurements of AVI, API and brachial-ankle pulse wave velocity (baPWV), demographic information, arterial blood pressures, and data from blood and urine tests were collected. The threshold values of AVI and API were determined by receiver operating characteristic (ROC) analyses and covariate-adjusted ROC (AROC) analyses against baPWV, whose threshold for diagnosing high arterial stiffness was set at 18 m/s. Additional statistical analyses were performed to examine the correlations among AVI, API and baPWV and their correlations with other bio-indices.ResultsThe area under the curve (AUC) values in ROC analysis for the diagnosis with AVI/API were 0.745/0.819, 0.788/0.837, and 0.772/0.825 (95% CI) in males, females, and all subjects, respectively. Setting the threshold values of AVI and API to 21 and 27 resulted in optimal diagnosis performance in the total cohort, whereas the threshold values should be increased to 24 and 29, respectively, in order to improve the accuracy of diagnosis in the female group. The AROC analyses revealed that the threshold values of AVI and API increased markedly with age and pulse pressure (PP), respectively.ConclusionsWith appropriate threshold values, AVI and API can be used to perform preliminary screening for individuals with increased arterial stiffness in the general population. On the other hand, the results of the AROC analyses imply that using threshold values adjusted for confounding factors may facilitate the refinement of diagnosis. Given the fact that the study is a cross-sectional one carried out in a single center, future multi-center or follow-up studies are required to further confirm the findings or examine the value of the threshold values for predicting cardiovascular events

Characterizing DNA Condensation and Conformational Changes in Organic Solvents

Organic solvents offer a new approach to formulate DNA into novel structures suitable for gene delivery. In this study, we examined the in situ behavior of DNA in N, N-dimethylformamide (DMF) at low concentration via laser light scattering (LLS), TEM, UV absorbance and Zeta potential analysis. Results revealed that, in DMF, a 21bp oligonucleotide remained intact, while calf thymus DNA and supercoiled plasmid DNA were condensed and denatured. During condensation and denaturation, the size was decreased by a factor of 8–10, with calf thymus DNA forming spherical globules while plasmid DNA exhibited a toroid-like conformation. In the condensed state, DNA molecules were still able to release the counterions to be negatively charged, indicating that the condensation was mainly driven by the excluded volume interactions. The condensation induced by DMF was reversible for plasmid DNA but not for calf thymus DNA. When plasmid DNA was removed from DMF and resuspended in an aqueous solution, the DNA was quickly regained a double stranded configuration. These findings provide further insight into the behavior and condensation mechanism of DNA in an organic solvent and may aid in developing more efficient non-viral gene delivery systems

Assessment of cardiovascular function by combining clinical data with a computational model of the cardiovascular system

ObjectiveA sufficient understanding of patients’ cardiovascular status is necessary for doctors to make the best decisions with regard to the treatment of cardiovascular disease; however, it is often not available because of the limitation of clinical measurements. The objective of this study was to examine whether cardiovascular function can be assessed quantitatively and for specific patients by combining clinical data with a computational model of the cardiovascular system.MethodsSeven consecutive patients undergoing off-pump coronary artery bypass grafting were enrolled in this study. The clinical data were collected both during the preoperative diagnosis and during the operation. Sensitivity analysis was performed to select the major model parameters most relevant to the measured data. The major model parameters were then estimated through a data-fitting procedure, enabling a patient-specific quantitative assessment of various aspects of cardiovascular function.ResultsThe results revealed the prevalence of left ventricular diastolic dysfunction in the patients, although the severity of dysfunction exhibits significant interpatient variability (the estimated left ventricular passive elastance varies from 194% to 540% of its reference value). Moreover, 4 of the 7 patients studied had impaired left ventricular systolic function.ConclusionsThe current study demonstrates the feasibility of assessing cardiovascular function quantitatively by combining clinical data with a cardiovascular model. In particular, the assessment utilizes the measurements already in use or available in clinical settings, enhancing the clinical potential of the proposed method

Transient Hemodynamic Changes upon Changing a BCPA into a TCPC in Staged Fontan Operation: A Computational Model Study

The clinical benefits of the Fontan operation in treating single-ventricle defects have been well documented. However, perioperative mortality or morbidity remains a critical problem. The purpose of the present study was to identify the cardiovascular factors that dominate the transient hemodynamic changes upon the change of a bidirectional cavopulmonary (Glenn) anastomosis (BCPA) into a total cavopulmonary connection (TCPC). For this purpose, two computational models were constructed to represent, respectively, a single-ventricle circulation with a BCPA and that with a TCPC. A series of model-based simulations were carried out to quantify the perioperative hemodynamic changes under various cardiovascular conditions. Obtained results indicated that the presence of a low pulmonary vascular resistance and/or a low lower-body vascular resistance is beneficial to the increase in transpulmonary flow upon the BCPA to TCPC change. Moreover, it was found that ventricular diastolic dysfunction and mitral valve regurgitation, despite being well-known risk factors for poor postoperative outcomes, do not cause a considerable perioperative reduction in transpulmonary flow. The findings may help physicians to assess the perioperative risk of the TCPC surgery based on preoperative measurement of cardiovascular function

MTA3 Represses Cancer Stemness by Targeting the SOX2OT/SOX2 Axis

Cancer cell stemness (CCS) plays critical roles in both malignancy maintenance and metastasis, yet the underlying molecular mechanisms are far from complete. Although the importance of SOX2 in cancer development and CCS are well recognized, the role of MTA3 in these processes is unknown. In this study, we used esophageal squamous cell carcinoma (ESCC) as a model system to demonstrate that MTA3 can repress both CCS and metastasis in vitro and in vivo. Mechanistically, by forming a repressive complex with GATA3, MTA3 downregulates SOX2OT, subsequently suppresses the SOX2OT/SOX2 axis, and ultimately represses CCS and metastasis. More importantly, MTA

MTA3 Represses Cancer Stemness by Targeting the SOX2OT/SOX2 Axis

Cancer cell stemness (CCS) plays critical roles in both malignancy maintenance and metastasis, yet the underlying molecular mechanisms are far from complete. Although the importance of SOX2 in cancer development and CCS are well recognized, the role of MTA3 in these processes is unknown. In this study, we used esophageal squamous cell carcinoma (ESCC) as a model system to demonstrate that MTA3 can repress both CCS and metastasis in vitro and in vivo. Mechanistically, by forming a repressive complex with GATA3, MTA3 downregulates SOX2OT, subsequently suppresses the SOX2OT/SOX2 axis, and ultimately represses CCS and metastasis. More importantly, MTA

Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling

Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well