Enhanced vessel wall magnetic resonance imaging in the follow-up of intracranial aneurysms treated with flow diversion.

OBJECTIVE: This study aimed to compare the efficacy of enhanced 3D T1-weighted black-blood fast-spin-echo vessel wall magnetic resonance imaging (eVW-MRI) and time-of-flight magnetic resonance angiography (TOF MRA) for follow-up evaluation of aneurysms treated with flow diversion (FD). METHODS: Our study enrolled 77 patients harboring 84 aneurysms treated with FD. Follow-up was by MRI (eVW-MRI and TOF MRA) and digital subtraction angiography (DSA). Two radiologists, blinded to DSA examination results, independently evaluated the images of aneurysm occlusion and parent artery patency using the Kamran-Byrne Scale. Interobserver diagnostic agreement and intermodality diagnostic agreement were acquired. Pretreatment and follow-up aneurysm wall enhancement (AWE) patterns were collected. RESULTS: Based on the Kamran-Byrne Scale, the intermodality agreement between eVW-MRI and DSA was better than TOF MRA versus DSA for aneurysm remnant detection (weighted ĸ = 0.891 v. 0.553) and parent artery patency (ĸ = 0.950 v. 0.221). Even with the coil artifact, the consistency of eVW-MRI with DSA for aneurysm remnant detection was better than that of TOF MRA (weighted ĸ = 0.891 v. 0.511). The artifact of adjunctive coils might be more likely to affect the accuracy in evaluating parent artery patency with TOF MRA than with eVW-MRI (ĸ = 0.077 v. 0.788). The follow-up AWE patterns were not significantly associated with pretreatment AWE patterns and aneurysm occlusion. CONCLUSIONS: The eVW-MRI outperforms TOF MRA as a reliable noninvasive and nonionizing radioactive imaging method for evaluating aneurysm remnants and parent artery patency after FD. The significance of enhancement patterns on eVW-MRI sequences needs more exploration. CLINICAL RELEVANCE STATEMENT: The application of enhanced vessel wall magnetic resonance imaging has proven to be a promising tool to depict aneurysm remnant and parent artery stenosis in order to tailor the antiplatelet therapy strategy in patients after flow diversion. KEY POINTS: • Enhanced vessel wall magnetic resonance imaging has an emerging role in depicting aneurysm remnant and parent artery patency after flow diversion. • With or without the artifact from adjunctive coils, enhanced vessel wall magnetic resonance imaging was better than TOF MRA in detecting aneurysm residual and parent artery stenosis by using DSA imaging as the standard. • Enhanced vessel wall magnetic resonance imaging holds potential to be used as an alternative to DSA for routine aneurysm follow-up after flow diversion.

Automated ASPECTS calculation may equal the performance of experienced clinicians: a machine learning study based on a large cohort.

OBJECTIVES: The Alberta Stroke Program Early CT Score (ASPECTS) is a semi-quantitative method to evaluate the severity of early ischemic change on non-contrast computed tomography (NCCT) in patients with acute ischemic stroke (AIS). In this work, we propose an automated ASPECTS method based on large cohort of data and machine learning. METHODS: For this study, we collected 3626 NCCT cases from multiple centers and annotated directly on this dataset by neurologists. Based on image analysis and machine learning methods, we constructed a two-stage machine learning model. The validity and reliability of this automated ASPECTS method were tested on an independent external validation set of 300 cases. Statistical analyses on the total ASPECTS, dichotomized ASPECTS, and region-level ASPECTS were presented. RESULTS: On an independent external validation set of 300 cases, for the total ASPECTS results, the intraclass correlation coefficient between automated ASPECTS and expert-rated was 0.842. The agreement between ASPECTS threshold of ≥ 6 versus < 6 using a dichotomized method was moderate (κ = 0.438, 0.391-0.477), and the detection rate (sensitivity) was 86.5% for patients with ASPECTS threshold of ≥ 6. Compared with the results of previous studies, our method achieved a slight lead in sensitivity (67.8%) and AUC (0.845), with comparable accuracy (78.9%) and specificity (81.2%). CONCLUSION: The proposed automated ASPECTS method driven by a large cohort of NCCT images performed equally well compared with expert-rated ASPECTS. This work further demonstrates the validity and reliability of automated ASPECTS evaluation method. CLINICAL RELEVANCE STATEMENT: The automated ASPECTS method proposed by this study may help AIS patients to receive rapid intervention, but should not be used as a stand-alone diagnostic basis. KEY POINTS: NCCT-based manual ASPECTS scores were poorly consistent. Machine learning can automate the ASPECTS scoring process. Machine learning model design based on large cohort data can effectively improve the consistency of ASPECTS scores.

Wall permeability on magnetic resonance imaging is associated with intracranial aneurysm symptoms and wall enhancement.

OBJECTIVES: Wall remodeling and inflammation accompany symptomatic unruptured intracranial aneurysms (UIAs). The volume transfer constant (Ktrans) of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) reflects UIA wall permeability. Aneurysmal wall enhancement (AWE) on vessel wall MRI (VWI) is associated with inflammation. We hypothesized that Ktrans is related to symptomatic UIAs and AWE. METHODS: Consecutive patients with UIAs were prospectively recruited for 3-T DCE-MRI and VWI from January 2018 to March 2023. UIAs were classified as asymptomatic and symptomatic if associated with sentinel headache or oculomotor nerve palsy. Ktrans and AWE were assessed on DCE-MRI and VWI, respectively. AWE was evaluated using the AWE pattern and wall enhancement index (WEI). Spearman's correlation coefficient and univariate and multivariate analyses were used to assess correlations between parameters. RESULTS: We enrolled 82 patients with 100 UIAs (28 symptomatic and 72 asymptomatic). The median Ktrans (2.1 versus 0.4 min-1; p < 0.001) and WEI (1.5 versus 0.4; p < 0.001) were higher for symptomatic aneurysms than for asymptomatic aneurysms. Ktrans (odds ratio [OR]: 1.60, 95% confidence interval [95% CI]: 1.01-2.52; p = 0.04) and WEI (OR: 3.31, 95% CI: 1.05-10.42; p = 0.04) were independent risk factors for symptomatic aneurysms. Ktrans was positively correlated with WEI (Spearman's coefficient of rank correlation (rs) = 0.41, p < 0.001). The combination of Ktrans and WEI achieved an area under the curve of 0.81 for differentiating symptomatic from asymptomatic aneurysms. CONCLUSIONS: Ktrans may be correlated with symptomatic aneurysms and AWE. Ktrans and WEI may provide an additional value than the PHASES score for risk stratification of UIAs. CLINICAL RELEVANCE STATEMENT: The volume transfer constant (Ktrans) from DCE-MRI perfusion is associated with symptomatic aneurysms and provides additional value above the clinical PHASES score for risk stratification of intracranial aneurysms. KEY POINTS: • The volume transfer constant is correlated with intracranial aneurysm symptoms and aneurysmal wall enhancement. • Dynamic contrast-enhanced and vessel wall MRI facilitates understanding of the pathophysiological characteristics of intracranial aneurysm walls. • The volume transfer constant and wall enhancement index perform better than the traditional PHASES score in differentiating symptomatic aneurysms.

Hemodynamic alterations of flow diverters on aneurysms at the fetal posterior communicating artery: A simulation study using CFD to compare the surpass streamline, pipeline flex, and tubridge devices.

PURPOSE: Traditional flow diverters (FDs) for treating aneurysms at the fetal posterior communicating artery are unsatisfactory. Surpass Streamline is a novel FD with different mesh characteristics; however, the outcomes for such aneurysms remain unclear. This study aimed to compare hemodynamic alterations induced by Surpass Streamline, Pipeline Flex, and Tubridge devices and explore possible strategies for aneurysms at the fetal posterior communicating artery. METHODS: Two simulated aneurysms (Case 1, Case 2) were constructed from digital subtraction angiography (DSA). The three FDs were virtually deployed, and hemodynamic analysis based on computational fluid dynamics was performed. Hemodynamic parameters, including the sac-averaged velocity magnitude (Velocity), high-flow volume (HFV), and wall shear stress (WSS), were compared between each FD and the untreated model (control). Surpass Streamline was performed in real life for two aneurysms and the clinical outcomes were collected for analysis. RESULTS: Compared to the control, the Surpass resulted in the most significant reduction in flow. In Case 1, the Velocity, HFV, and WSS were reduced by 51.6%, 78.1%, and 64.3%, respectively. In Case 2, the Velocity, HFV, and WSS were reduced by 48.0%, 81.1%, and 65.3%, respectively. Tubridge showed slightly larger changes in hemodynamic parameters than Pipeline. In addition, our analysis suggested that metal coverage was correlated with the WSS, Velocity, and HFV. The postoperative DSA showed that the aneurysm was nearly occluded in Case 1 and decreased in Case 2. CONCLUSION: Compared to that with the Pipeline and Tubridge, the Surpass resulted in the greatest reduction in hemodynamic parameters and might be effective for aneurysms at the fetal posterior communicating artery. Virtual FD deployment and computational fluid dynamics analysis may be used to predict the treatment outcomes.

Efficacy and safety of flow diverter combined with coil embolization and evidence-based antithrombotic regimen in the treatment of ruptured aneurysms.

OBJECTIVE: The use of a flow diverter (FD) in the treatment of ruptured aneurysms is limited due to the increased risk of perioperative ischemia and hemorrhagic complications. Adjunctive coil embolization and an evidence-based antithrombotic regimen may improve therapeutic safety, although evidence from relevant clinical research is limited. The authors' aim was to further assess the perioperative safety and long-term efficacy of this strategy. METHODS: Data on patients with FD insertion and coil embolization were collected retrospectively at two centers. The perioperative antithrombotic regimen consists of intraoperative tirofiban and continues for 24 hours postoperatively, with the initiation of an orally administered dual-antiplatelet regimen 4 hours prior to tirofiban cessation, rather than purposeful preoperative antiplatelet therapy. Perioperative cerebral ischemia and hemorrhagic complications and long-term aneurysm occlusion rates were recorded to evaluate the safety and efficacy of the procedure, respectively. RESULTS: In total, 67 cases were screened and 41 cases were ultimately included in this study. A total of 2 cases (4.9%) of perioperative cerebral hemorrhagic events occurred, 1 of which (2.4%) was attributable to rerupture of the aneurysm. Cerebral ischemic events were reported in 3 patients, including 1 with cortical thromboembolism and 2 with perforator occlusion of the basilar artery. A median 8-month follow-up was attained in 25 patients (61.0%), with a 92% complete or near-complete occlusion rate. CONCLUSIONS: FD insertion combined with coil embolization is a potentially safe and effective therapeutic strategy for ruptured aneurysms when accompanied with perioperative evidence-based antithrombotic therapy.

Randomized, prospective, multicenter trial assessing the numen coil embolization system in the endovascular treatment of small intracranial aneurysms: outcomes from the CATCH Trial.

BACKGROUND AND PURPOSE: The CATCH (Coil Application Trial in China) trial was designed to assess the safety and efficacy of the Numen Coil Embolization System in the treatment of intracranial aneurysms in comparison with the Axium coil (ev3/Medtronic). Although the endovascular treatment of small (< 5 mm) intracranial aneurysms has been reported with favorable long-term clinical and angiographic outcomes, randomized trials are still lacking. Data for aneurysms smaller than 5 mm were extracted from the CATCH trial. MATERIALS AND METHODS: A randomized, prospective, multicenter trial was conducted at ten centers throughout China. Enrolled subjects with small intracranial aneurysms were randomly assigned to receive treatment with the Numen Coil or the Axium coil. The primary outcome was successful aneurysm occlusion at the 6-month follow-up. In contrast, the secondary outcomes included complete aneurysm occlusion, recurrence rate, clinical deterioration, and safety data at the 6-month and 12-month follow-ups. RESULTS: A total of 124 patients were enrolled in the study. Overall, 58 patients were assigned to the Numen group, and 66 were assigned to the Axium group. At the 6-month follow-up, the successful aneurysm occlusion rate was 93.1% (54/58) in the MicroPort NeuroTech group and 97.0% (64/66) in the Axium group, with a common odds ratio of 0.208 (95% confidence interval, 0.023-1.914; P = 0.184). Complications were comparable between the groups. CONCLUSIONS: Compared with the Aixum coil, the Numen coil is safe and effective in treating small intracranial aneurysms. TRIAL REGISTRATION: (13/12/2016, NCT02990156).

Review of Vision-Based Deep Learning Parking Slot Detection on Surround View Images.

Autonomous vehicles are gaining popularity, and the development of automatic parking systems is a fundamental requirement. Detecting the parking slots accurately is the first step towards achieving an automatic parking system. However, modern parking slots present various challenges for detection task due to their different shapes, colors, functionalities, and the influence of factors like lighting and obstacles. In this comprehensive review paper, we explore the realm of vision-based deep learning methods for parking slot detection. We categorize these methods into four main categories: object detection, image segmentation, regression, and graph neural network, and provide detailed explanations and insights into the unique features and strengths of each category. Additionally, we analyze the performance of these methods using three widely used datasets: the Tongji Parking-slot Dataset 2.0 (ps 2.0), Sejong National University (SNU) dataset, and panoramic surround view (PSV) dataset, which have played a crucial role in assessing advancements in parking slot detection. Finally, we summarize the findings of each method and outline future research directions in this field.

[Analysis of outcome indicators in clinical trials on Chinese medicine as adjuvant therapy for severe pneumonia].

This study analyzed the outcome indicators in randomized controlled trial(RCT) on Chinese medicine as adjuvant therapy for severe pneumonia in the past years, laying a foundation for the design of clinical trials on and construction of core outcome set(COS) for severe pneumonia. To be specific, related RCT was retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, Web of Science, Chinese Clinical Trial Registry, and ClinicalTrials.gov(from January 1,2011 to April 9,2022). Then data in the trials were extracted, and the quality of included RCT was assessed according to Cochrane handbook, followed by descriptive analysis of the use of outcome indicators. A total of 11 833 articles were screened out, and finally 34 RCTs were included(2 were protocols). The included trials involved 109 outcome indicators with emergence frequency of 320, which were mainly classified into 9 categories: physicochemical indicators(54, frequency 167), time to achieve the efficacy(15, frequency 38), clinical effective rate(10, frequency 36), quality of life(11, frequency 35), symptoms and signs(7, frequency 18), traditional Chinese medicine(TCM) syndrome(4, frequency 13), safety(3, frequency 8), economic evaluation(1, frequency 1), other indicators(4, frequency 4). The indicators with high frequency followed the order: total effective rate, arterial oxygen partial pressure, C-reactive protein, white blood cell count, arterial blood carbon dioxide partial pressure. A total of 5 articles(14.71%) reported the main outcome indicators and 11 articles(32.35%) adopted the efficacy on TCM syndromes as the outcome indicator. There are many problems in the selection of outcome indicators in RCT on the treatment of severe pneumonia with Chinese medicine, mainly manifested as the disregard of clinical endpoint indicators, the inappropriate selection of surrogate indicators, and the non-standard evaluation criteria for the efficacy on TCM syndrome. It is suggested that the evaluation system for the efficacy of Chinese medicine on severe pneumonia should be established in accordance with the method for international COS to improve the quality of clinical trials.

[Network Meta-analysis of different Chinese medicine injections combined with conventional therapy in treatment of stroke-associated pneumonia].

Network Meta-analysis was conducted to compare the efficacy and safety of different Chinese medicine injections combined with conventional therapy in the treatment of stroke-associated pneumonia. CNKI, Wanfang, VIP, PubMed, Web of Science, and Cochrane Library were searched for the relevant literature pubslished from inception to April 1, 2022. Stata 17 was used for data analysis. After screening of 1 189 papers, 72 studies were finally selected, which involved 5 819 patients and 6 Chinese medicine injections(Tanreqing Injection, Xingnaojing Injection, Xuebijing Injection, Xiyanping Injection, Shenfu Injection, and Shenmai Injection). The network Meta-analysis ranked the injections as follows.(1) In terms of improving the total clinical effective rate, the surface under the cumulative ranking curve(SUCRA) followed the order of Xiyanping Injection + conventional therapy > Xuebijing Injection + conventional therapy > Tanreqing Injection + conventional therapy > Shenmai Injection + conventional therapy > Xingnaojing Injection + conventional therapy > Shenfu Injection + conventional therapy > conventional therapy.(2) In terms of recovering the National Institute of Health stroke scale(NIHSS) scores, the SUCRA followed the order of Xuebijing Injection + conventional therapy > Xingnaojing Injection + conventional therapy > Tanreqing Injection + conventional therapy > Shenfu Injection + conventional therapy > conventional therapy.(3) In reducing the average time to abatement of fever, the SUCRA followed the order of Xiyanping Injection + conventional therapy > Tanreqing Injection + conventional therapy > Xuebijing Injection + conventional therapy > conventional therapy.(4) In terms of reducing the mean hospital stay, the SUCRA followed the order of Xiyanping Injection + conventional therapy > Xubijing Injection + conventional therapy > Tanreqing Injection + conventional therapy > Shenmai Injection + conventional therapy > conventional therapy. The clinical efficacy of Tanreqing Injection, Xuebijing Injection, Xiyanping Injection, Xingnaojing Injection, Shenmai Injection, or Shenfu Injection combined with conventional therapy was superior to that of conventional therapy alone. However, due to the limitations of the quality and methodology of different intervention measures, this conclusion needs to be verified by more high-quality and rigorously designed randomized controlled trial.

Qualitative and Quantitative Wall Enhancement on Magnetic Resonance Imaging Is Associated With Symptoms of Unruptured Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Aneurysmal wall enhancement (AWE) on vessel wall magnetic resonance imaging (VW-MRI) has been described as a new imaging biomarker of unstable unruptured intracranial aneurysms (UIAs). Previous studies of symptomatic UIAs are limited due to small sample sizes and lack of AWE quantification. Our study aims to investigate whether qualitative and quantitative assessment of AWE can differentiate symptomatic and asymptomatic UIAs. METHODS: Consecutive patients with UIAs were prospectively recruited for vessel wall magnetic resonance imaging at 3T from October 2014 to October 2019. UIAs were categorized as symptomatic if presenting with sentinel headache or oculomotor nerve palsy directly related to the aneurysm. Evaluation of wall enhancement included enhancement pattern (0=none, 1=focal, and 2=circumferential) and quantitative wall enhancement index (WEI). Univariate and multivariate analyses were used to identify the parameters associated with symptoms. RESULTS: Two hundred sixty-seven patients with 341 UIAs (93 symptomatic and 248 asymptomatic) were included in this study. Symptomatic UIAs more frequently showed circumferential AWE than asymptomatic UIAs (66.7% versus 17.3%, P<0.001), as well as higher WEI (median [interquartile range], 1.3 [1.0-1.9] versus 0.3 [0.1-0.9], P<0.001). In multivariate analysis, both AWE pattern and WEI were independent factors associated with symptoms (odds ratio=2.03 across AWE patterns [95% CI, 1.21-3.39], P=0.01; odds ratio=3.32 for WEI [95% CI, 1.51-7.26], P=0.003). The combination of AWE pattern and WEI had an area under the curve of 0.91 to identify symptomatic UIAs, with a sensitivity of 95.7% and a specificity of 73.4%. CONCLUSIONS: In a large cohort of UIAs with vessel wall magnetic resonance imaging, both AWE pattern and WEI were independently associated with aneurysm-related symptoms. The qualitative and quantitative features of AWE can potentially be used to identify unstable intracranial aneurysms.

Diagnostic value of FeNO and MMEF for predicting cough variant asthma in chronic cough patients with or without allergic rhinitis.

OBJECTIVE: To evaluate the diagnostic value of fractional exhaled nitric oxide (FeNO) and maximum mid-expiratory flow (MMEF) for differentiating cough variant asthma (CVA) from chronic cough in patients with or without allergic rhinitis. METHODS: In total, 328 patients with chronic cough who underwent spirometry and FeNO testing were consecutively included in the retrospective analysis. Patients were divided into the CVA (n = 125) or NCVA (n = 203) groups according to the diagnostic criteria of CVA. Receiver operating characteristic (ROC) curves were established to assess the diagnostic efficiency and optimal cutoff points of FeNO and MMEF for the prediction of CVA. RESULTS: The optimal cutoff values of FeNO and MMEF to discriminate CVA from chronic cough were 24.5 ppb (AUC, 0.765; sensitivity, 69.60%; specificity 72.91%; PPV, 61.27%; NPV, 79.57%) and 66.2% (AUC, 0.771; sensitivity, 67.20%; specificity 78.33%; PPV, 65.63%; NPV, 79.50%). The optimal cutoff values of combining FeNO with MMEF to discriminate CVA from chronic cough were >22 ppb for FeNO and <62.6% for MMEF (AUC, 0.877). In patients with and without allergic rhinitis, the optimal cutoff point of FeNO to discriminate CVA from chronic cough was 24.5 ppb (AUC, 0.820) and 33.5 ppb (AUC, 0.707), respectively. CONCLUSIONS: FeNO and MMEF might have greater value as negative parameters for differentiating CVA from chronic cough. Combining FeNO and MMEF provided a significantly better prediction than either alone. The diagnostic accuracy of FeNO for predicting CVA in chronic cough patients with allergic rhinitis was higher than in chronic cough patients without allergic rhinitis.

Galangin Enhances Anticancer Efficacy of 5-Fluorouracil in Esophageal Cancer Cells and Xenografts Through NLR Family Pyrin Domain Containing 3 (NLRP3) Downregulation.

BACKGROUND Galangin is believed to exert antioxidant effects by inhibition of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, which has been linked to chemotherapy sensitivity in cancers. In this study, we explored the synergistic effect of galangin in combination with the chemotherapy agent 5-fluorouracil (5-FU) in esophageal cancer cells and xenografts. MATERIAL AND METHODS The esophageal squamous epithelium cell line Het-1A and 2 human esophageal cancer cell lines (Eca109, OE19) were used to investigate the effect of galangin with or without 5-FU in vitro through proliferation and invasion analyses, while apoptosis was analyzed in cancer cells. Furthermore, a subcutaneous xenograft tumor model in mice was used to study cancer development in vivo. RESULTS Compared with 5-FU monotherapy, combined galangin and 5-FU treatment reduced human esophageal cancer cell growth activities and invasion abilities. The results suggested that galangin had a chemotherapy-sensitized synergistic antitumor effect induced by 5-FU. The susceptibility of cancer cells to apoptosis, which is linked with chemotherapy sensitivity, was induced by 5-FU and further enhanced by galangin. NLRP3 was identified as being significantly activated by 5-FU, but galangin treatment reversed the effect and inhibited NLRP3 expression, which was accompanied by downregulated interleukin-1b levels. Further investigation showed that the induced apoptotic cascade can be mostly reversed by incubation with an NLRP3 activator, irrespective of AKT signaling. Using xenograft mouse models, we found that galangin exposure further restrained cancer development after 5-FU treatment and increased sensitivity to chemotherapy by suppressing the NLRP3 inflammasome pathway. CONCLUSIONS Our results indicated that galangin played a synergistic anticancer role through NLRP3 inflammasome inhibition when paired with FU-5.

Characterization of Urinary Exosomes Purified with Size Exclusion Chromatography and Ultracentrifugation.

Exosomes, a subtype of extracellular vesicles secreted by mammalian cells with a typical size range of 30-150 nm, have been implicated in many biological processes as intercellular communication carriers. The isolation of exosomes is an essential and challenging step before subsequent analysis and functional studies, due to the complexity of body fluids, as well as the small size and low density of exosomes. Ultracentrifugation (UC) and size exclusion chromatography (SEC) are two methods that have been extensively used for exosomes isolation in biological studies in recent years. In this work, we compared the characteristics of urinary exosomes extracted with SEC and UC methods in detail. Results showed that the SEC isolation method was superior to UC in the recovery of exosomal particles and proteins. The results of proteomics analysis showed that more purified exosomes were extracted with the SEC method. We also observed that parts of exosomes were ruptured and precipitated insufficiently during UC isolations. It not only led to a low recovery of exosome proteins but also resulted in a considerable loss of exosomal particles. Moreover, the exosomal rupture and particle loss in UC could not be avoided by resuspension of the exosomal particles. Our results also showed that exosomes from SEC purifications possessed a high internalization capability from 4 to 6 h when incubated with EA.hy926 and HCV29 cell lines.

Deconstruction of Heterogeneity of Size-Dependent Exosome Subpopulations from Human Urine by Profiling N-Glycoproteomics and Phosphoproteomics Simultaneously.

The heterogeneous populations of exosomes with distinct nanosize have impeded our understanding of their corresponding function as intercellular communication agents. Profiling signaling proteins packaged in each size-dependent subtype can disclose this heterogeneity of exosomes. Herein, new strategy was developed for deconstructing heterogeneity of distinct-size urine exosome subpopulations by profiling N-glycoproteomics and phosphoproteomics simultaneously. Two-dimension size exclusion liquid chromatography (SEC) was utilized to isolate large exosomes (L-Exo), medium exosomes (M-Exo), and small exosomes (S-Exo) from human urine samples. Then, hydrophilic carbonyl-functionalized magnetic zirconium-organic framework (CFMZOF) was developed as probe for capturing the two kinds of post-translational modification (PTM) peptides simultaneously. Finally, liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with database search was used to characterize PTM protein contents. We identified 144 glycoproteins and 44 phosphoproteins from L-Exo, 156 glycoproteins, and 46 phosphoproteins from M-Exo and 134 glycoproteins and 10 phosphoproteins from S-Exo. The ratio of the proteins with simultaneous glycosylation and phosphorylation is 11%, 9%, and 3% in L-Exo, M-Exo, and S-Exo, respectively. Based on label-free quantification intensity results, both principal component analysis and Pearson's correlation coefficients indicate that distinct-size exosome subpopulations exist significant differences in PTM protein contents. Analysis of high abundance PTM proteins in each exosome subset reveals that the preferentially packaged PTM proteins in L-Exo, M-Exo, and S-Exo are associated with immune response, biological metabolism, and molecule transport processes, respectively. Our PTM proteomics study based on size-dependent exosome subtypes opens a new avenue for deconstructing the heterogeneity of exosomes.

Improvement for Testing the Gravitational Inverse-Square Law at the Submillimeter Range.

We improve the test of the gravitational inverse-square law at the submillimeter range by suppressing the vibration of the electrostatic shielding membrane to reduce the disturbance coupled from the residual surface potential. The result shows that, at a 95% confidence level, the gravitational inverse-square law holds (|α|≤1) down to a length scale λ=48 µm. This work establishes the strongest bound on the magnitude α of the Yukawa violation in the range of 40-350 µm, and improves the previous bounds by up to a factor of 3 at the length scale λ≈70 µm. Furthermore, the constraints on the power-law potentials are improved by about a factor of 2 for k=4 and 5.

Designing combination therapies with modeling chaperoned machine learning.

Chemotherapy resistance is a major challenge to the effective treatment of cancer. Thus, a systematic pipeline for the efficient identification of effective combination treatments could bring huge biomedical benefit. In order to facilitate rational design of combination therapies, we developed a comprehensive computational model that incorporates the available biological knowledge and relevant experimental data on the life-and-death response of individual cancer cells to cisplatin or cisplatin combined with the TNF-related apoptosis-inducing ligand (TRAIL). The model's predictions, that a combination treatment of cisplatin and TRAIL would enhance cancer cell death and exhibit a "two-wave killing" temporal pattern, was validated by measuring the dynamics of p53 accumulation, cell fate, and cell death in single cells. The validated model was then subjected to a systematic analysis with an ensemble of diverse machine learning methods. Though each method is characterized by a different algorithm, they collectively identified several molecular players that can sensitize tumor cells to cisplatin-induced apoptosis (sensitizers). The identified sensitizers are consistent with previous experimental observations. Overall, we have illustrated that machine learning analysis of an experimentally validated mechanistic model can convert our available knowledge into the identity of biologically meaningful sensitizers. This knowledge can then be leveraged to design treatment strategies that could improve the efficacy of chemotherapy.

Antibiotics and Percutaneous Drainage for Treating Stent-Graft Infection After EVAR.

Artificial graft infection is one of the most serious complications following EVAR. The gold standard includes the excision of the infected endograft, debridement, and reconstruction. However, these methods are not always the best option for every patient. The authors present the case of a 75-year-old man who was diagnosed with a stent-graft infection following EVAR. A course of antibiotics was administered, and percutaneous drainage was effectively performed twice in succession. After 18 months, the patient was admitted again due to the infection re-occurring. Antibiotics were administered, and percutaneous drainage was effectively re-performed. One year has elapsed since the treatment, and the outpatient followup has lasted until now.

Phosphorylation of serine96 of histidine-rich calcium-binding protein by the Fam20C kinase functions to prevent cardiac arrhythmia.

Precise Ca cycling through the sarcoplasmic reticulum (SR), a Ca storage organelle, is critical for proper cardiac muscle function. This cycling initially involves SR release of Ca via the ryanodine receptor, which is regulated by its interacting proteins junctin and triadin. The sarco/endoplasmic reticulum Ca ATPase (SERCA) pump then refills SR Ca stores. Histidine-rich Ca-binding protein (HRC) resides in the lumen of the SR, where it contributes to the regulation of Ca cycling by protecting stressed or failing hearts. The common Ser96Ala human genetic variant of HRC strongly correlates with life-threatening ventricular arrhythmias in patients with idiopathic dilated cardiomyopathy. However, the underlying molecular pathways of this disease remain undefined. Here, we demonstrate that family with sequence similarity 20C (Fam20C), a recently characterized protein kinase in the secretory pathway, phosphorylates HRC on Ser96. HRC Ser96 phosphorylation was confirmed in cells and human hearts. Furthermore, a Ser96Asp HRC variant, which mimics constitutive phosphorylation of Ser96, diminished delayed aftercontractions in HRC null cardiac myocytes. This HRC phosphomimetic variant was also able to rescue the aftercontractions elicited by the Ser96Ala variant, demonstrating that phosphorylation of Ser96 is critical for the cardioprotective function of HRC. Phosphorylation of HRC on Ser96 regulated the interactions of HRC with both triadin and SERCA2a, suggesting a unique mechanism for regulation of SR Ca homeostasis. This demonstration of the role of Fam20C-dependent phosphorylation in heart disease will open new avenues for potential therapeutic approaches against arrhythmias.

Size-dependent sub-proteome analysis of urinary exosomes.

Exosomes are cell-derived functional microparticles which exist in most body fluids. They carry abundant signaling molecules to transfer information between cells and microenvironment. Research on exosomes' heterogeneity and constitute variations has been a heated topic in recent years. In this work, size-dependent sub-proteome analysis of urinary exosomes was investigated by size exclusion chromatography (SEC) firstly. The particle size of urinary exosomes is distributed in four main ranges naturally. We found out that these fractions contained sub-proteomes with great difference in constitution. In each fraction, 206, 134, 157, and 276 unique proteins were identified by LC-MS/MS. Differential expression of exosomal markers such as TSG101, CD9, CD63, and caveolin-1 was observed in these fractions by western blots. Biological function annotation indicated that the proteins identified in each fraction were involved in different molecular and cellular processes. It is proven that SEC can serve as an efficient analytical tool for exosomes isolation and fractionation. This work provides a new strategy to classify exosomes into sub-populations for comprehensive study of heterogeneous functionalities. Graphical abstract ᅟ.

Embolization of brain arteriovenous malformations with the diluted Onyx technique: initial experience.

PURPOSE: Insufficient nidus occlusion is a matter of great concern to routine Onyx embolization of brain arteriovenous malformations (AVMs). This paper described an efficient method which using the diluted Onyx embolization technique to treat brain AVM. METHODS: The diluted Onyx technique was performed in a series of 15 patients with brain AVMs (10 males, 5 females; age range, 11-44 years). It consists of initial embolization with routine Onyx-18, followed by the diluted Onyx (1.5 mL of Onyx-18 diluted with 0.5 mL of DMSO) through the same microcatheter. The technical skills and angiographic and clinical outcomes were analyzed. RESULTS: A total of 15 embolization sessions were performed with diluted Onyx via 16 arterial feeders in these 15 patients. Each patient underwent one attempt of diluted Onyx through a single feeder except one patient. In this patient, the AVM was simultaneously embolized with diluted Onyx through double microcatheters which were placed in two feeders. When the length of reflux reached to 2 cm (or close to the determined length) and the embolic material could not move distally any more despite some rounds of "injection-reflux-waiting," regular Onyx 18 was changed to diluted Onyx. Antegrade flow of embolic material into the nidus was observed in 12 cases but failed in 3. An average of 90% (range 55-100%) estimated size reduction was achieved, and 6 AVMs were completely obliterated. No functionally relevant complications occurred. CONCLUSION: The diluted Onyx technique could be a useful adjunct to routine Onyx embolization which may offer more embolic material penetrating into the nidus of AVM, but additional work is needed to validate this technique.