Necroptosis inhibitors: mechanisms of action and therapeutic potential.

Necroptosis is a type of programmed cell death that is morphologically similar to necrosis. This type of cell death is involved in various pathophysiological disorders, including inflammatory, neurodegenerative, infectious, and malignant diseases. Receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) pseudokinase constitute the core components of the necroptosis signaling pathway and are considered the most promising targets for therapeutic intervention. The discovery and characterization of necroptosis inhibitors not only accelerate our understanding of the necroptosis signaling pathway but also provide important drug candidates for the treatment of necroptosis-related diseases. Here, we will review recent research progress on necroptosis inhibitors, mechanisms of action and their potential applications for disease treatment.

Evaluation of gadolinium deposition in cortical bone using three-dimensional ultrashort echo time quantitative susceptibility mapping: A preliminary study.

The aim of the current study was to investigate the feasibility of three-dimensional ultrashort echo time quantitative susceptibility mapping (3D UTE-QSM) for the assessment of gadolinium (Gd) deposition in cortical bone. To this end, 40 tibial bovine cortical bone specimens were divided into five groups then soaked in phosphate-buffered saline (PBS) solutions with five different Gd concentrations of 0, 0.4, 0.8, 1.2, and 1.6 mmol/L for 48 h. Additionally, eight rabbits were randomly allocated into three groups, consisting of a normal-dose macrocyclic gadolinium-based contrast agent (GBCA) group (n = 3), a high-dose macrocyclic GBCA group (n = 3), and a control group (n = 2). All bovine and rabbit tibial bone samples underwent magnetic resonance imaging (MRI) on a 3-T clinical MR system. A 3D UTE-Cones sequence was utilized to acquire images with five different echo times (i.e., 0.032, 0.2, 0.4, 0.8, and 1.2 ms). The UTE images were subsequently processed with the morphology-enabled dipole inversion algorithm to yield a susceptibility map. The average susceptibility was calculated in three regions of interest in the middle of each specimen, and the Pearson's correlation between the estimated susceptibility and Gd concentration was calculated. The bone samples soaked in PBS with higher Gd concentrations exhibited elevated susceptibility values. A mean susceptibility value of -2.47 ± 0.23 ppm was observed for bovine bone soaked in regular PBS, while the mean QSM value increased to -1.75 ± 0.24 ppm for bone soaked in PBS with the highest Gd concentration of 1.6 mmol/L. A strong positive correlation was observed between Gd concentrations and QSM values. The mean susceptibility values of rabbit tibial specimens in the control group, normal-dose GBCA group, and high-dose GBCA group were -4.11 ± 1.52, -3.85 ± 1.33, and -3.39 ± 1.35 ppm, respectively. In conclusion, a significant linear correlation between Gd in cortical bone and QSM values was observed. The preliminary results suggest that 3D UTE-QSM may provide sensitive noninvasive assessment of Gd deposition in cortical bone.

Cholestane-3ß,5α,6ß-triol Induces Multiple Cell Death in A549 Cells via ER Stress and Autophagy Activation.

Cholestane-3ß,5α,6ß-triol (CT) and its analogues are abundant in natural sources and are reported to demonstrate cytotoxicity toward different kinds of tumor cells without a deep probe into their mechanism of action. CT is also one of the major metabolic oxysterols of cholesterol in mammals and is found to accumulate in various diseases. An extensive exploration of the biological roles of CT over the past few decades has established its identity as an apoptosis inducer. In this study, the effects of CT on A549 cell death were investigated through cell viability assays. RNA-sequencing analysis and western blot of CT-treated A549 cells revealed the role of CT in inducing endoplasmic reticulum (ER) stress response and enhancing autophagy flux, suggesting a putative mechanism of CT-induced cell-death activation involving reactive oxygen species (ROS)-mediated ER stress and autophagy. It is reported for the first time that the upregulation of autophagy induced by CT can serve as a cellular cytotoxicity response in accelerating CT-induced cell death in A549 cells. This research provides evidence for the effect of CT as an oxysterol in cell response to oxidative damage and allows for a deep understanding of cholesterol in its response in an oxidative stress environment that commonly occurs in the progression of various diseases.

A Prognostic Model of Head and Neck Cancer Based on Amino Acid Metabolism-Related Signature and Its Implication for Immunosuppressive Microenvironment.

Amino acid metabolism has been implicated in tumorigenesis and tumor progression. Alterations in intracellular and extracellular metabolites associated with metabolic reprogramming in cancer have profound effects on gene expression, cell differentiation, and tumor immune microenvironment. However, the prognostic significance of amino acid metabolism in head and neck cancer remains to be further investigated. In this study, we identified 98 differentially expressed genes related to amino acid metabolism in head and neck cancer in The Cancer Genome Atlas. Using batch univariate Cox regression and Lasso regression, we extracted nine amino acid metabolism-related genes. Based on that, we developed the amino acid metabolism index. The prognostic value of this index was validated in two Gene Expression Omnibus cohorts. The results show that this model can help predict tumor recurrence and prognosis. The infiltration of immune cells in the tumor microenvironment was analyzed, and it was discovered that the high index is associated with an immunosuppressive microenvironment. In addition, this study demonstrated the impact of the amino acid metabolism index on clinical indicators, survival of patients with head and neck cancer, and the prediction of treatment response to immune checkpoint inhibitors. We conducted several cell experiments and demonstrated that epigenetic drugs could affect the index and enhance tumor immunity. In conclusion, our study demonstrates that the index not only has important prognostic value in head and neck cancer patients but also facilitates patient stratification for immunotherapy.

Ecotourism and sustainable development: a scientometric review of global research trends.

With the increasing attention and awareness of the ecological environment, ecotourism is becoming ever more popular, but it still brings problems and challenges to the sustainable development of the environment. To solve such challenges, it is necessary to review literature in the field of ecotourism and determine the key research issues and future research directions. This paper uses scientometrics implemented by CiteSpace to conduct an in-depth systematic review of research and development in the field of ecotourism. Two bibliographic datasets were obtained from the Web of Science, including a core dataset and an expanded dataset, containing articles published between 2003 and 2021. Our research shows that ecotourism has been developing rapidly in recent years. The research field of ecotourism spans many disciplines and is a comprehensive interdisciplinary subject. According to the research results, the evolution of ecotourism can be roughly divided into three phases: human disturbance, ecosystem services and sustainable development. It could be concluded that it has entered the third stage of Shneider's four-stage theory of scientific discipline. The research not only identifies the main clusters and their advance in ecotourism research based on high impact citations and research frontier formed by citations, but also presents readers with new insights through intuitive visual images. Supplementary Information: The online version contains supplementary material available at 10.1007/s10668-022-02190-0.

Examining the applications of intelligent tutoring systems in real educational contexts: A systematic literature review from the social experiment perspective.

Intelligent Tutoring Systems (ITSs) have a great potential to effectively transform teaching and learning. As more efforts have been put on designing and developing ITSs and integrating them within learning and instruction, mixed types of results about the effectiveness of ITS have been reported. Therefore, it is necessary to investigate how ITSs work in real and natural educational contexts and the associated challenges of ITS application and evaluation. Through a systematic literature review method, this study analyzed 40 qualified studies that applied social experiment methods to examine the effectiveness of ITS during 2011-2022. The obtained results highlighted a complicated landscape regarding the effectiveness of ITS in real educational contexts. Specifically, there was an "intelligent" regional gap regarding the distribution of countries where ITS studies using social experiment methods were conducted. Compared to learning performance, relatively less attention was paid to investigating the impact of ITS on non-cognitive factors, process-oriented factors, and social outcomes, calling for more research in this regard. Considering the complexities and challenges existing in real educational fields, there was a lack of scientific rigor in terms of experimental design and data analysis in some of the studies. Based on these findings, suggestions for future study and implications were proposed.

The regulation of necroptosis by ubiquitylation.

Necroptosis is a programmed necrosis that is mediated by receptor-interacting protein kinases RIPK1, RIPK3 and the mixed lineage kinase domain-like protein, MLKL. Necroptosis must be strictly regulated to maintain normal tissue homeostasis, and dysregulation of necroptosis leads to the development of various inflammatory, infectious, and degenerative diseases. Ubiquitylation is a widespread post-translational modification that is essential for balancing numerous physiological processes. Over the past decade, considerable progress has been made in the understanding of the role of ubiquitylation in regulating necroptosis. Here, we will discuss the regulatory functions of ubiquitylation in necroptosis signaling pathway. An enhanced understanding of the ubiquitylation enzymes and regulatory proteins in necroptotic signaling pathway will be exploited for the development of new therapeutic strategies for necroptosis-related diseases.

Iptakalim alleviates synaptic damages via targeting mitochondrial ATP-sensitive potassium channel in depression.

Synaptic plasticity damages play a crucial role in the onset and development of depression, especially in the hippocampus, which is more susceptible to stress and the most frequently studied brain region in depression. And, mitochondria have a major function in executing the complex processes of neurotransmission and plasticity. We have previously demonstrated that Iptakalim (Ipt), a new ATP-sensitive potassium (K-ATP) channel opener, could improve the depressive-like behavior in mice. But the underlying mechanisms are not well understood. The present study demonstrated that Ipt reversed depressive-like phenotype in vivo (chronic mild stress-induced mice model of depression) and in vitro (corticosterone-induced cellular model). Further study showed that Ipt could upregulate the synaptic-related proteins postsynaptic density 95 (PSD 95) and synaptophysin (SYN), and alleviated the synaptic structure damage. Moreover, Ipt could reverse the abnormal mitochondrial fission and fusion, as well as the reduced mitochondrial ATP production and collapse of mitochondrial membrane potential in depressive models. Knocking down the mitochondrial ATP-sensitive potassium (Mito-KATP) channel subunit MitoK partly blocked the above effects of Ipt. Therefore, our results reveal that Ipt can alleviate the abnormal mitochondrial dynamics and function depending on MitoK, contributing to improve synaptic plasticity and exert antidepressive effects. These findings provide a candidate compound and a novel target for antidepressive therapy.

Iptakalim improves cerebral microcirculation in mice after ischemic stroke by inhibiting pericyte contraction.

Pericytes are present tight around the intervals of capillaries, play an essential role in stabilizing the blood-brain barrier, regulating blood flow and immunomodulation, and persistent contraction of pericytes eventually leads to impaired blood flow and poor clinical outcomes in ischemic stroke. We previously show that iptakalim, an ATP-sensitive potassium (K-ATP) channel opener, exerts protective effects in neurons, and glia against ischemia-induced injury. In this study we investigated the impacts of iptakalim on pericytes contraction in stroke. Mice were subjected to cerebral artery occlusion (MCAO), then administered iptakalim (10 mg/kg, ip). We showed that iptakalim administration significantly promoted recovery of cerebral blood flow after cerebral ischemia and reperfusion. Furthermore, we found that iptakalim significantly inhibited pericytes contraction, decreased the number of obstructed capillaries, and improved cerebral microcirculation. Using a collagen gel contraction assay, we demonstrated that cultured pericytes subjected to oxygen-glucose deprivation (OGD) consistently contracted from 3 h till 24 h during reoxygenation, whereas iptakalim treatment (10 µM) notably restrained pericyte contraction from 6 h during reoxygenation. We further showed that iptakalim treatment promoted K-ATP channel opening via suppressing SUR2/EPAC1 complex formation. Consequently, it reduced calcium influx and ET-1 release. Taken together, our results demonstrate that iptakalim, targeted K-ATP channels, can improve microvascular disturbance by inhibiting pericyte contraction after ischemic stroke. Our work reveals that iptakalim might be developed as a promising pericyte regulator for treatment of stroke.

How to confront the high prevalence of pulmonary micro nodules (PMNs) in osteosarcoma patients?

PURPOSE: Pulmonary metastasis was a negative factor of osteosarcoma prognosis. However, there is no universal criteria to confirm pulmonary metastasis at pulmonary micro nodule (PMN, Dmax ≤ 5 mm) stage other than pathology. We aimed to identify prevalence of PMNs, determine prognosis of osteosarcoma with PMNs, and analyze risk factors related to PMN progression. METHODS: We retrospectively reviewed 425 consecutive osteosarcoma patients. According to dynamic change in size and number of PMNs, patients were divided into PMN progression and non-progression group. Demographic data, initial laboratory data, radiological features, and oncological evaluations were analyzed. Cox regression was used to identify risk factors for PMN progression. Overall survival rate was measured and analyzed with Kaplan-Meier method. Differences with p < 0.05 were considered significant. RESULTS: PMNs were found in 74% (315/425) osteosarcoma patients, half of whom (157/315) suffering PMN progression. Overall survival rate was 70.2%, while survival rates for PMN progression group and non-progression group were 53.40% and 87.40%, respectively. Clinical risk factors for PMN progression in certain patients included blood vessel invasion, extrapulmonary metastases, low tumour cell necrosis rate, and large tumour size. Radiologic risk factors included greatest diameter, distance to pleura, CT value, solid components, and smooth border. CONCLUSION: PMN is quite common in osteosarcoma patients. PMN progression is related to both certain clinical and radiological factors, which could assist surgeons to determine its possibility to progress at an early stage.

Activating PPARß/δ Protects against Endoplasmic Reticulum Stress-Induced Astrocytic Apoptosis via UCP2-Dependent Mitophagy in Depressive Model.

As energy metabolism regulation factor, peroxisome proliferator-activated receptor (PPAR) is thought to be a potential target for the treatment of depression. The present study was performed to evaluate the effects of activating PPARß/δ, the most highly expressed subtype in the brain, in depressive in vivo and in vitro models. We observed that PPARß/δ agonist GW0742 significantly alleviated depressive behaviors in mice and promoted the formation of autophagosomes around the damaged mitochondria in hippocampal astrocytes. Our in vitro experiments showed that GW0742 could reduce mitochondrial oxidative stress, and thereby attenuate endoplasmic reticulum (ER) stress-mediated apoptosis pathway via inhibiting IRE1α phosphorylation, subsequently protect against astrocytic apoptosis and loss. Furthermore, we found that PPARß/δ agonist induces astrocytic mitophagy companied with the upregulated UCP2 expressions. Knocking down UCP2 in astrocytes could block the anti-apoptosis and pro-mitophagy effects of GW0742. In conclusion, our findings reveal PPARß/δ activation protects against ER stress-induced astrocytic apoptosis via enhancing UCP2-mediated mitophagy, which contribute to the anti-depressive action. The present study provides a new insight for depression therapy.

Microwave ablation of breast pseudoaneurysm.

Breast pseudoaneurysm is a very rare complication. In this study, we report a patient with huge breast pseudoaneurysm after ultrasound-guided vacuum-assisted biopsy (UGVAB) of breast nodules. In treatment, we used microwave ablation to treat the pseudoaneurysm, and then used UGVAB again to eliminate the complicated hematoma. The patients obtained good therapeutic effect. From this case, we experience that, before the interventional operations for breast nodules, the systematic ultrasound examination should be performed. In the needle entering channel, the obvious blood vessels should be avoided to reduce the unnecessary vascular injury. When the pseudoaneurysm occurs, the patient's condition, pseudoaneurysm situation and hematoma size should be comprehensively considered, combined with the multidisciplinary consultation, for selecting the best treatment strategy.

Oridonin prevents oxidative stress-induced endothelial injury via promoting Nrf-2 pathway in ischaemic stroke.

Oridonin, a natural diterpenoid compound extracted from a Chinese herb, has been proved to exert anti-oxidative stress effects in various disease models. The aim of the present study was to investigate the protective effects of oridonin on oxidative stress-induced endothelial injury in ischaemic stroke. We found oridonin repaired blood-brain barrier (BBB) integrity presented with upregulation of tight junction proteins (TJ proteins) expression, inhibited the infiltration of periphery inflammatory cells and neuroinflammation and thereby reduced infarct volume in ischaemic stroke mice. Furthermore, our results showed that oridonin could protect against oxidative stress-induced endothelial injury via promoting nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf-2). The specific mechanism could be the activation of AKT(Ser473)/GSK3ß(Ser9)/Fyn signalling pathway. Our findings revealed the therapeutic effect and mechanism of oridonin in ischaemic stroke, which provided fundamental evidence for developing the extracted compound of Chinese herbal medicine into an innovative drug for ischaemic stroke treatment.

3D UTE bicomponent imaging of cortical bone using a soft-hard composite pulse for excitation.

PURPOSE: To evaluate 3D UTE bicomponent imaging of cortical bone ex vivo and in vivo using a newly designed soft-hard composite pulse for excitation. METHODS: Chemical shift artifacts, presenting as fat-water oscillation or combination-induced signal oscillation, significantly reduce the accuracy of quantitative UTE bicomponent analysis of cortical bone. To achieve fat suppression for more reliable bicomponent analysis, a newly developed soft-hard excitation pulse was used with UTE imaging and compared with a single rectangular pulse excitation without and with a conventional fat saturation (FatSat) module. These 3 sequences were applied to 8 bovine bone samples without marrow fat, 3 bovine bone samples with marrow fat, and tibial midshafts of 5 healthy human volunteers. Bicomponent analyses were performed in both ex vivo and in vivo studies. RESULTS: The soft-hard pulse provided comparable fat suppression, but much reduced bone signal attenuation compared with the FatSat module. Better bicomponent T2∗ fitting was also achieved with the soft-hard excitation pulse because it greatly reduced chemical shift artifacts and outperformed the single rectangular pulse without or with FatSat. Although the FatSat module reduced fat signals and related fat-water oscillation, the water signals were significantly attenuated with more than 40% reduction due to direction saturation. For the inner layer of tibial midshaft in healthy volunteers, fitting errors increased from 3.78% for the soft-hard pulse to 11.43% and 5.16%, respectively, for the single rectangular pulse without and with the FatSat module. CONCLUSION: The 3D UTE sequence with a new soft-hard excitation pulse allows more reliable bicomponent imaging of cortical bone.

Comparing Patient-Controlled Analgesia Versus Non-PCA Hydromorphone Titration for Severe Cancer Pain: A Randomized Phase III Trial.

BACKGROUND: Opioid titration is necessary to achieve rapid, safe pain relief. Medication can be administered via patient-controlled analgesia (PCA) or by a healthcare provider (non-PCA). We evaluated the efficacy of intravenous PCA versus non-PCA hydromorphone titration for severe cancer pain (≥7 at rest on the 11-point numeric rating scale [NRS]). PATIENTS AND METHODS: Patients with severe cancer pain were randomized 1:1 to PCA or non-PCA titration, stratified by opioid-tolerant or opioid-naïve status. The PCA pump was set to no continuous dose, with a hydromorphone bolus dose 10% to 20% of the total previous 24-hour equianalgesic (for opioid-tolerant patients) or 0.5 mg (for opioid-naïve patients). For the non-PCA group, the initial hydromorphone bolus dose was identical to that in the PCA group, with the subsequent dose increased by 50% to 100% (for NRS unchanged or increased) or repeated at the current dose (for NRS 4-6). Hydromorphone delivery was initiated every 15 minutes (for NRS ≥4) or as needed (for NRS ≤3). The primary endpoint was time to successful titration (TST; time from first hydromorphone dose to first occurrence of NRS ≤3 in 2 consecutive 15-minute intervals). RESULTS: Among 214 patients (PCA, n=106; non-PCA, n=108), median TSTs (95% CI) were 0.50 hours (0.25-0.50) and 0.79 hours (0.50-1.42) for the PCA and non-PCA groups, respectively (hazard ratio [HR], 1.64; 95% CI, 1.23-2.17; P=.001). TSTs in opioid-tolerant patients were 0.50 hours (0.25-0.75) and 1.00 hours (0.50-2.00) for the PCA and non-PCA groups, respectively (HR, 1.92; 95% CI, 1.32-2.78; P=.003); in opioid-naive patients, TST was not significantly different for the PCA versus non-PCA groups (HR, 1.35; 95% CI, 0.88-2.04; P=.162). Pain score (median NRS; interquartile range) over 24 hours was significantly lower in the PCA group (2.80; 2.15-3.22) than in the non-PCA group (3.00; 2.47-3.53; P=.020). PCA administration produces significantly higher patient satisfaction with pain control than non-PCA administration (P<.001). CONCLUSIONS: Intravenous hydromorphone titration for severe cancer pain was achieved more effectively with PCA than with non-PCA administration.

Automated cartilage segmentation and quantification using 3D ultrashort echo time (UTE) cones MR imaging with deep convolutional neural networks.

OBJECTIVE: To develop a fully automated full-thickness cartilage segmentation and mapping of T1, T1ρ, and T2*, as well as macromolecular fraction (MMF) by combining a series of quantitative 3D ultrashort echo time (UTE) cones MR imaging with a transfer learning-based U-Net convolutional neural networks (CNN) model. METHODS: Sixty-five participants (20 normal, 29 doubtful-minimal osteoarthritis (OA), and 16 moderate-severe OA) were scanned using 3D UTE cones T1 (Cones-T1), adiabatic T1ρ (Cones-AdiabT1ρ), T2* (Cones-T2*), and magnetization transfer (Cones-MT) sequences at 3 T. Manual segmentation was performed by two experienced radiologists, and automatic segmentation was completed using the proposed U-Net CNN model. The accuracy of cartilage segmentation was evaluated using the Dice score and volumetric overlap error (VOE). Pearson correlation coefficient and intraclass correlation coefficient (ICC) were calculated to evaluate the consistency of quantitative MR parameters extracted from automatic and manual segmentations. UTE biomarkers were compared among different subject groups using one-way ANOVA. RESULTS: The U-Net CNN model provided reliable cartilage segmentation with a mean Dice score of 0.82 and a mean VOE of 29.86%. The consistency of Cones-T1, Cones-AdiabT1ρ, Cones-T2*, and MMF calculated using automatic and manual segmentations ranged from 0.91 to 0.99 for Pearson correlation coefficients, and from 0.91 to 0.96 for ICCs, respectively. Significant increases in Cones-T1, Cones-AdiabT1ρ, and Cones-T2* (p < 0.05) and a decrease in MMF (p < 0.001) were observed in doubtful-minimal OA and/or moderate-severe OA over normal controls. CONCLUSION: Quantitative 3D UTE cones MR imaging combined with the proposed U-Net CNN model allows a fully automated comprehensive assessment of articular cartilage. KEY POINTS: • 3D UTE cones imaging combined with U-Net CNN model was able to provide fully automated cartilage segmentation. • UTE parameters obtained from automatic segmentation were able to reliably provide a quantitative assessment of cartilage.

En bloc resection and reconstruction of a huge chondrosarcoma involving multilevel upper thoracic spine and chest wall: case report.

BACKGROUND: En bloc resection of malignant tumors involving upper thoracic spine is technically difficult. We surgically treated a patient with grade 2 chondrosarcoma involving T1-5, left upper thoracic cavity, and chest wall. CASE PRESENTATION: A 37 years old, male patient was referred to our hospital for a huge lump involved left shoulder and chest wall. In order to achieve satisfied surgical margins, anterior approach, posterior approach, and lateral approach were carried out sequentially. After en bloc tumor resection, the upper thoracic spine was reconstructed with a 3D-printed modular vertebral prosthesis, and the huge chest wall defect was repaired by a methyl methacrylate layer between 2 pieces of polypropylene mesh. Postoperatively, the patient suffered from pneumonia and neurological deterioration which fully recovered eventfully. At 24 months after operation, the vertebral prosthesis and internal fixation were intact; there was no tumor local recurrence, and the patient was alive with stable pulmonary metastases. CONCLUSION: This case report describes resection of a huge chondrosarcoma involving not only multilevel upper thoracic spine, but also entire left upper thoracic cavity and chest wall. Although with complications, en bloc tumor resection with combined surgical approach and effective reconstructions could improve oncologic and functional prognosis in carefully selected spinal tumor patients.

Bi/BiVO4/NiFe-LDH heterostructures with enhanced photoelectrochemical performance for streptomycin detection.

Streptomycin (STR) plays an essential role in bacterial infection treatments. Selectivity and sensitivity of photoelectrochemical (PEC) sensors are the two most important parameters, which can be measured using the photosensitivity of its active material. We prepared a novel PEC sensor to detect STR using Bi/BiVO4/LDH (layered double hydroxides) heterostructures as an active material, which is photoactive in the visible light wavelength range. The simultaneous presence of LDH and Bi/BiVO4 enhanced the material photocurrent response, which was linear to the STR concentrations in the 0.01-500 nmol/L range. The STR detection limit by this sensor was 0.0042 nmol/L. Our novel PEC-based sensing strategy includes using an ultra-sensitive and highly selective sensor for STR detection. Additionally, the two-pot synthesis of Bi/BiVO4/LDH developed in this work is environmentally friendly.

LncRNA HCG11/miR-26b-5p/QKI5 feedback loop reversed high glucose-induced proliferation and angiogenesis inhibition of HUVECs.

Acute coronary syndrome caused by the rupture of atherosclerotic plaques is one of the primary causes of cerebrovascular and cardiovascular events. Neovascularization within the plaque is closely associated with its stability. Long non-coding RNA (lncRNA) serves a crucial role in regulating vascular endothelial cells (VECs) proliferation and angiogenesis. In this study, we identified lncRNA HCG11, which is highly expressed in patients with vulnerable plaque compared with stable plaque. Then, functional experiments showed that HCG11 reversed high glucose-induced vascular endothelial injury through increased cell proliferation and tube formation. Meanwhile, vascular-related RNA-binding protein QKI5 was greatly activated. Luciferase reporter assays and RNA-binding protein immunoprecipitation (RIP) assays verified interaction between them. Interestingly, HCG11 can also positively regulated by QKI5. Bioinformatics analysis and luciferase reporter assays showed HCG11 can worked as a competing endogenous RNA by sponging miR-26b-5p, and QKI5 was speculated as the target of miR-26b-5p. Taken together, our findings revered that the feedback loop of lncRNA HCG11/miR-26b-5p/QKI-5 played a vital role in the physiological function of HUVECs, and this also provide a potential target for therapeutic strategies of As.

Myelin Imaging in Human Brain Using a Short Repetition Time Adiabatic Inversion Recovery Prepared Ultrashort Echo Time (STAIR-UTE) MRI Sequence in Multiple Sclerosis.

Background Water signal contamination is a major challenge for direct ultrashort echo time (UTE) imaging of myelin in vivo because water contributes most of the signals detected in white matter. Purpose To validate a new short repetition time (TR) adiabatic inversion recovery (STAIR) prepared UTE (STAIR-UTE) sequence designed to suppress water signals and to allow imaging of ultrashort T2 protons of myelin in white matter using a clinical 3-T scanner. Materials and Methods In this prospective study, an optimization framework was used to obtain the optimal inversion time for nulling water signals using STAIR-UTE imaging at different TRs. Numeric simulation and phantom studies were performed. Healthy volunteers and participants with multiple sclerosis (MS) underwent MRI between November 2018 and October 2019 to compare STAIR-UTE and a clinical T2-weighted fluid-attenuated inversion recovery sequence for assessment of MS lesions. UTE measures of myelin were also performed to allow comparison of signals in lesions and with those in normal-appearing white matter (NAWM) in patients with MS and in normal white matter (NWM) in healthy volunteers. Results Simulation and phantom studies both suggest that the proposed STAIR-UTE technique can effectively suppress long T2 tissues with a broad range of T1s. Ten healthy volunteers (mean age, 33 years ± 8 [standard deviation]; six women) and 10 patients with MS (mean age, 51 years ± 16; seven women) were evaluated. The three-dimensional STAIR-UTE sequence effectively suppressed water components in white matter and selectively imaged myelin, which had a measured T2* value of 0.21 msec ± 0.04 in the volunteer study. A much lower mean UTE measure of myelin proton density was found in MS lesions (3.8 mol/L ± 1.5), and a slightly lower mean UTE measure was found in NAWM (7.2 mol/L ± 0.8) compared with that in NWM (8.0 mol/L ± 0.8) in the healthy volunteers (P < .001 for both comparisons). Conclusion The short repetition time adiabatic inversion recovery-prepared ultrashort echo time sequence provided efficient water signal suppression for volumetric imaging of myelin in the brain and showed excellent myelin signal contrast as well as marked ultrashort echo time signal reduction in multiple sclerosis lesions and a smaller reduction in normal-appearing white matter compared with normal white matter in volunteers. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Messina and Port in this issue.