A measles-vectored vaccine candidate expressing prefusion-stabilized SARS-CoV-2 spike protein brought to phase I/II clinical trials: candidate selection in a preclinical murine model.

In the early COVID-19 pandemic with urgent need for countermeasures, we aimed at developing a replicating viral vaccine using the highly efficacious measles vaccine as vector, a promising technology with prior clinical proof of concept. Building on our successful pre-clinical development of a measles virus (MV)-based vaccine candidate against the related SARS-CoV, we evaluated several recombinant MV expressing codon-optimized SARS-CoV-2 spike glycoprotein. Candidate V591 expressing a prefusion-stabilized spike through introduction of two proline residues in HR1 hinge loop, together with deleted S1/S2 furin cleavage site and additional inactivation of the endoplasmic reticulum retrieval signal, was the most potent in eliciting neutralizing antibodies in mice. After single immunization, V591 induced similar neutralization titers as observed in sera of convalescent patients. The cellular immune response was confirmed to be Th1 skewed. V591 conferred long-lasting protection against SARS-CoV-2 challenge in a murine model with marked decrease in viral RNA load, absence of detectable infectious virus loads, and reduced lesions in the lungs. V591 was furthermore efficacious in an established non-human primate model of disease (see companion article [S. Nambulli, N. Escriou, L. J. Rennick, M. J. Demers, N. L. Tilston-Lunel et al., J Virol 98:e01762-23, 2024, https://doi.org/10.1128/jvi.01762-23]). Thus, V591 was taken forward into phase I/II clinical trials in August 2020. Unexpected low immunogenicity in humans (O. Launay, C. Artaud, M. Lachâtre, M. Ait-Ahmed, J. Klein et al., eBioMedicine 75:103810, 2022, https://doi.org/10.1016/j.ebiom.2021.103810) revealed that the underlying mechanisms for resistance or sensitivity to pre-existing anti-measles immunity are not yet understood. Different hypotheses are discussed here, which will be important to investigate for further development of the measles-vectored vaccine platform.IMPORTANCESARS-CoV-2 emerged at the end of 2019 and rapidly spread worldwide causing the COVID-19 pandemic that urgently called for vaccines. We developed a vaccine candidate using the highly efficacious measles vaccine as vector, a technology which has proved highly promising in clinical trials for other pathogens. We report here and in the companion article by Nambulli et al. (J Virol 98:e01762-23, 2024, https://doi.org/10.1128/jvi.01762-23) the design, selection, and preclinical efficacy of the V591 vaccine candidate that was moved into clinical development in August 2020, 7 months after the identification of SARS-CoV-2 in Wuhan. These unique in-human trials of a measles vector-based COVID-19 vaccine revealed insufficient immunogenicity, which may be the consequence of previous exposure to the pediatric measles vaccine. The three studies together in mice, primates, and humans provide a unique insight into the measles-vectored vaccine platform, raising potential limitations of surrogate preclinical models and calling for further refinement of the platform.

A longitudinal study of sexual activity and influencing factors in breast cancer patients during treatment in the Southwest of China: a trajectory analysis model.

PURPOSE: The aim of this study was to describe the longitudinal developmental trajectories and its influencing factors of sexual activity in patients with breast cancer during treatment. METHODS: A prospective longitudinal study was conducted, including 225 newly diagnosed breast cancer patients in A tumor specialty three-class hospital in Southwest China. We measured sexual activity at the time of admission and diagnosis (T0) and one month (T1), three months (T2), six months (T3), and nine months (T4) after diagnosis. A trajectory analysis model (GBTM) was used to explore the changes in sexual activity in breast cancer patients. Multivariate binary logistic regression analysis was used to analyse the factors that affected the classification of sexual activity trajectories. RESULTS: The ratio of sexual activity abruptly declined from 100% at baseline to 39.1% at T1. The percentage of sexual activity was improved, from 51.4% at T2 to 63.1% at T4. The optimal model was a 2-group trajectory of sexual activity in breast cancer patients,36.6% in the "low activity group" and 63.4% in the "high activity group." The multivariate binary logistic regression analysis revealed statistically significant and positive correlations between sexual activity and age (ß = 0.085, OR = 1.089, 95%CI 1.035 ∼ 1.145, P = 0.001),libido(ß = 0.774, OR = 2.168, 95%CI 1.337 ∼ 3.515, P = 0.002), vaginal lubrication(ß = 1.254, OR = 33.503, 95%CI 2.000 ∼ 6.137, P<0.001). CONCLUSIONS: Breast cancer patients exhibited varying levels of sexual activity during treatment; higher age was associated with increased sexual activity, which can contribute to the recovery of sexual function. Therefore, it is crucial to provide appropriate guidance on sexual health for younger patients.

Role of ferroptosis in periodontitis: An animal study in rats.

OBJECTIVE: This study aimed to investigate (1) the temporal pattern of ferroptosis, an iron-dependent cell death, in ligation-induced rat periodontitis and (2) the effect of ferrostatin-1, a ferroptosis inhibitor, on the model. BACKGROUND: Ferroptosis may contribute to various diseases. However, the role of ferroptosis in periodontitis is still fully understood. METHODS: In the first experiment, 25 rats with ligation-induced periodontitis were sacrificed on days 0, 1, 2, 7, and 10. Gingivae were obtained to determine tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and ferroptotic biomarkers, including solute carrier family 3 member 2 (SLC3A2) and solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (Gpx4), via immunoblotting. Using microcomputed tomography (µCT) and histology, the periodontal soft and hard tissue lesions, including dental alveolar bone crest level, bony characteristics of the surrounding alveolus, periodontal tissue inflammation, and periodontal tissue losses, were evaluated. In study two, 16 rats with induced periodontitis were grouped according to ferrostatin-1 treatment. The rats were intraperitoneally injected with solvent or ferrostatin-1 (1.5 mg/kg/day) 1 day before ligation and sacrificed on days 7 and 10. Gingival protein changes and periodontal tissue damage were also examined. RESULTS: In study one, SLC3A2/SLC7A11 and Gpx4 decreased since day 1; however, TNF-α/IL-1ß increased on days 7 and 10. Moreover, the µCT/histology revealed resorptive bony characteristics, inflamed gingival tissue, and periodontal attachment loss. In study two, ferrostatin-1-injected rats exhibited significantly increased SLC3A2/SLC7A11 and Gpx4 but decreased TNF-α/IL-1ß than vehicle rats. They also revealed lessened bone resorption, tissue inflammation, and attachment loss. CONCLUSION: This study highlights the role of ferroptosis, via the system Xc/Gpx4 pathway, in experimental periodontitis and may serve as a regulatory strategy.

Life satisfaction and peace of mind among dentists: a cross-sectional study.

OBJECTIVES: This study sought to identify the factors associated with the life satisfaction and peace of mind (PoM) of dentists not in full-time clinical training. MATERIALS AND METHODS: Cross-sectional questionnaires were distributed to dentists in Taiwan to collect their life satisfaction, PoM, sociodemographic data, and dental career-related characteristics. Life satisfaction was measured using a 5-item Satisfaction with Life Scale. PoM was measured using a 7-item Peace of Mind Scale. Descriptive statistics and multiple linear regression models were estimated to explore potential associations between the two scales and the examined factors. RESULTS: A total of 1196 dentists (45.6% female; mean age = 44.12) completed the questionnaires. The response rate of completed questionnaires from email invitations was 32.9%. On multivariable analysis, life satisfaction and PoM were associated with age (b = 0.008 in both), better perceived health (b = 0.262 and 0.308, respectively), family interaction (b = 0.264 and 0.207, respectively), and friend relationships (b = 0.076 and 0.091, respectively). Being married (b = 0.191), being specialized (b = 0.127), working in private practice, and spending 10 to 39 h per week with patients (b = 0.101 to 0.162) were associated with a higher level of life satisfaction but not PoM. CONCLUSIONS: Specialists working in private practice without working overtime were associated with better life satisfaction. However, the dentists' health and relationships with family were more related to their subjective well-being than their professional achievements. CLINICAL RELEVANCE: Our findings can help policymakers increase awareness of the well-being of general dentists and those in academia or hospitals to promote their mental health.

FAM64A aggravates proliferation, invasion, lipid droplet formation, and chemoresistance in gastric cancer: A biomarker for aggressiveness and a gene therapy target.

FAM64A is a mitogen-induced regulator of the metaphase and anaphase transition. Here, we found that FAM64A messenger RNA (mRNA) and protein expression levels were higher in gastric cancer tissue than in normal mucosa (p < .05). FAM64A methylation was negatively correlated with FAM64A mRNA expression (p < .05). The differentially expressed genes of FAM64A were mainly involved in digestion, potassium transporting or exchanging ATPase, contractile fibers, endopeptidase, and pancreatic secretion (p < .05). The FAM64A-related genes were principally categorized into ubiquitin-mediated proteolysis, cell cycle, chromosome segregation and mitosis, microtubule binding and organization, metabolism of amino acids, cytokine receptors, lipid droplet, central nervous system, and collagen trimer (p < .05). FAM64A protein expression was lower in normal gastric mucosa than intestinal metaplasia, adenoma, and primary cancer (p < .05), negatively correlated with older age, T stage, lymphatic and venous invasion, tumor, node, metastasis stage, and dedifferentiation (p < .05), and associated with a favorable overall survival of gastric cancer patients. FAM64A overexpression promoted proliferation, antiapoptosis, migration, invasion, and epithelial-mesenchymal transition via the EGFR/Akt/mTOR/NF-κB, while the opposite effect was observed for FAM64A knockdown. FAM64A also induced chemoresistance directly or indirectly through lipid droplet formation via ING5. These results suggested that upregulation of FAM64A expression might induce aggressive phenotypes, leading to gastric carcinogenesis and its subsequent progression. Thus, FAM64A could be regarded as a prognosis biomarker and a target for gene therapy.

Role of contrast-enhanced ultrasonography in MR-guided focused ultrasound ablation on uterus fibroids: lesion selection and assessment of ablative effects.

OBJECTIVES: To determine whether contrast-enhanced ultrasonography (CEUS) can be used for selecting lesions and assessing the ablative effects of MRgFUS ablation on uterus fibroids, compared with MR imaging. METHODS: This retrospective study was approved by the institutional review board of our hospital. From April 2018 to November 2019, a total of 44 symptomatic fibroids in 38 patients who underwent MRgFUS ablation were included. The association between pre-ablation characteristics on CEUS/MR imaging and the non-perfusion volume (NPV) after ablation was analyzed using multivariable linear regression analysis. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve values was compared between the CEUS and MR imaging regression models. NPV after ablation was compared between CEUS and enhanced MR imaging. RESULTS: On CEUS, entangled branch vessels, fast-in, and fast-out patterns were significantly associated with NPV, with an AUC of 0.95 (95% CI; 0.88, 1.00). On MR imaging, hyper-intensity on T2-weighted images (T2WI), hyper-intense ring-like signal on T2WI images, and hyper-enhancement on contrast-enhanced T1WI images were correlated with NPV, with an AUC of 0.86 (95% CI; 0.70, 1.00). After ablation, no differences in NPV were noted between contrast-enhanced T1WI (84.13 ± 75.42 cm3) and CEUS (80.22 ± 76.49 cm3). CONCLUSIONS: Some pre-ablation characteristics of uterine fibroids on CEUS were associated with NPV after MRgFUS. CEUS may contribute to the evaluation of ablative outcomes and patient selection, similar to MR imaging. KEY POINTS: • Contrast-enhanced ultrasonography (CEUS) is effective for selecting the appropriate uterine fibroids before MR-guided focused ultrasound (MRgFUS) ablation and evaluating non-perfusion volumes (NPV) after ablation, as a potential alternative to MR imaging. • Before ablation, entangled branch vessels, fast-in, and fast-out patterns on CEUS were significantly associated with NPV after MRgFUS. • No significant differences in NPV were detected between contrast-enhanced T1WI and CEUS after ablation.

Influence of diabetes mellitus on the diagnostic performance of machine learning-based coronary CT angiography-derived fractional flow reserve: a multicenter study.

OBJECTIVES: To examine the diagnostic accuracy of machine learning-based coronary CT angiography-derived fractional flow reserve (FFRCT) in diabetes mellitus (DM) patients. METHODS: In total, 484 patients with suspected or known coronary artery disease from 11 Chinese medical centers were retrospectively analyzed. All patients underwent CCTA, FFRCT, and invasive FFR. The patients were further grouped into mild (25~49 %), moderate (50~69 %), and severe (≥ 70 %) according to CCTA stenosis degree and Agatston score < 400 and Agatston score ≥ 400 groups according to coronary artery calcium severity. Propensity score matching (PSM) was used to match DM (n  = 112) and non-DM (n  = 214) groups. Sensitivity, specificity, accuracy, and area under the curve (AUC) with 95 % confidence interval (CI) were calculated and compared. RESULTS: Sensitivity, specificity, accuracy, and AUC of FFRCT were 0.79, 0.96, 0.87, and 0.91 in DM patients and 0.82, 0.93, 0.89, and 0.89 in non-DM patients without significant difference (all p > 0.05) on a per-patient level. The accuracies of FFRCT had no significant difference among different coronary stenosis subgroups and between two coronary calcium subgroups (all p > 0.05) in the DM and non-DM groups. After PSM grouping, the accuracies of FFRCT were 0.88 in the DM group and 0.87 in the non-DM group without a statistical difference (p > 0.05). CONCLUSIONS: DM has no negative impact on the diagnostic accuracy of machine learning-based FFRCT. KEY POINTS: • ML-based FFRCT has a high discriminative accuracy of hemodynamic ischemia, which is not affected by DM. • FFRCT was superior to the CCTA alone for the detection of ischemia relevance of coronary artery stenosis in both DM and non-DM patients. • Coronary calcification had no significant effect on the diagnostic accuracy of FFRCT to detect ischemia in DM patients.

Functional CAD-RADS using FFRCT on therapeutic management and prognosis in patients with coronary artery disease.

OBJECTIVES: To propose a novel functional Coronary Artery Disease-Reporting and Data System (CAD-RADS) category system integrated with coronary CT angiography (CCTA)-derived fractional flow reserve (FFRCT) and to validate its effect on therapeutic decision and prognosis in patients with coronary artery disease (CAD). METHODS: Firstly, we proposed a novel functional CAD-RADS and evaluated the performance of functional CAD-RADS for guiding treatment strategies with actual clinical treatment as a reference standard in a retrospective multicenter cohort with CCTA and invasive FFR performed in all patients (n = 466). Net reclassification improvement (NRI) of functional CAD-RADS over anatomical CAD-RADS was calculated. Secondly, the prognostic value of functional CAD-RADS in a prospective two-arm cohort (566 [FFRCT arm] vs. 567 [CCTA arm]) was calculated, after a 1-year follow-up, functional CAD-RADS in FFRCT arm (n = 513) and anatomical CAD-RADS in CCTA arm (n = 511) to determine patients at risk of adverse outcomes were compared with a Cox hazard proportional model. RESULTS: Functional CAD-RADS demonstrated superior value over anatomical CAD-RADS (AUC: 0.828 vs. 0.681, p < 0.001) and comparable performance to FFR (AUC: 0.828 vs. 0.848, p = 0.253) in guiding therapeutic decisions. Functional CAD-RADS resulted in the revision of management plan as determined by anatomical CAD-RADS in 30.0% of patients (n = 140) (NRI = 0.369, p < 0.001). Functional CAD-RADS was an independent predictor for 1-year outcomes with indexes of concordance of 0.795 and the corresponding value was 0.751 in anatomical CAD-RADS. CONCLUSION: The novel functional CAD-RADS gained incremental value in guiding therapeutic decision-making compared with anatomical CAD-RADS and comparable power in 1-year prognosis with anatomical CAD-RADS in a real-world scenario. KEY POINTS: • The novel functional CAD-RADS category system with FFRCT integrated into the anatomical CAD-RADS categories was originally proposed. • The novel functional CAD-RADS category system was validated superior value over anatomical CAD-RADS (AUC: 0.828 vs. 0.681, p < 0.001) in guiding therapeutic decisions and revised management plan in 30.0% of patients as determined by anatomical CAD-RADS (net reclassification improvement index = 0.369, p < 0.001). • Functional CAD-RADS was an independent predictor with an index of concordance of 0.795 and 0.751 in anatomical CAD-RADS for 1-year prognosis of adverse outcomes.

Cucurbit[10]uril-Based Orthogonal Supramolecular Polymers with Host-Guest and Coordination Interactions and Its Applications in Anion Classification.

A novel orthogonal supramolecular polymer (Q[10]-TPDPB-Lu3+) in a host-guest ratio of 2:1 was successfully constructed utilizing the specificity and excellent cavity matching of Q[10] with the tripyridine derivatives (TPDPB). Significantly, non-covalent interactions between Q[10]'s hydrophobic cavities and Lu3+ were used to induce charge transfer of TPDPB to TPDPB and TPDPB to Lu3+, resulting in the construction of structurally interesting orthogonal assemblies with excellent fluorescence properties. Finally, the Q[10]-TPDPB-Lu3+ assemblies were shown to have good recognition and classification of strong and weak acid anions as well as iodide anions, and the classification was accompanied by a clear fluorescence emission change allowing visual observation.

The effects of REG4 expression on chemoresistance of ovarian cancer.

Although ovarian cancer usually responds well to platinum- and taxane-based first-line chemotherapy, most patients develop recurrence and chemoresistance. Regenerating gene 4 (REG4) is a secretory protein involved in cell differentiation and proliferation. We found higher REG4 expression in ovarian cancer than in normal tissues (p < .05). Regenerating gene 4 expression was negatively associated with overall, progression-free or post-progression survival rates of patients with ovarian cancer receiving platinum or paclitaxel treatment (p < .05) according to a Kaplan-Meier plotter. Regenerating gene 4 overexpression resulted in either cisplatin or paclitaxel resistance, and apoptosis resistance in CAOV3 ovarian cancer cells (p < .05). REG4-transfected ovarian cancer cells showed stronger migration and invasion treated with cisplatin or paclitaxel (p < .05). Additionally, cisplatin or paclitaxel exposure led to the overexpression of phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, phosphorylated mammalian target of rapamycin (p-mTOR), glutathione S-transferase-π, survivin, and B-cell lymphoma 2 in REG4 transfectants compared with control cells (p < .05). These findings suggested that REG4 expression was up-regulated in ovarian cancer, and associated with poor survival and chemotherapy resistance. REG4 promoted the occurrence, development, and chemotherapy resistance of ovarian cancer by regulating cell proliferation, apoptosis, migration, and invasion, and PI3K/Akt/m-TOR signalling pathways. IMPACT STATEMENTWhat is already known on this subject? REG4 mRNA expression is up-regulated in many digestive cancers. High REG4 expression was associated with an adverse prognosis, high tumour and nodal stages, poor differentiation, and hepatic and peritoneal metastases of digestive cancers. REG4 expression conferred cancer cells with increased resistance to chemoradiotherapy, especially 5-FU-based treatment, by activating the MAPK/Erk/Bim signalling pathway.What do the results of this study add? REG4 was highly expressed in ovarian cancer. The expression of p-PI3K, p-AKT, p-mTOR, GST-π, survivin, and Bcl-2 was increased in REG4-overexpressing cells. High REG4 expression was significantly associated with inferior OS, PFS, and PPS rates in patients with ovarian cancer receiving platinum chemotherapy. REG4 mediated cisplatin and paclitaxel resistance in CAOV3 ovarian cancer cells. The percentage of apoptotic cells was markedly lower in REG4-transfected compared to mock-transfected cells after cisplatin or paclitaxel treatment.What are the implications of these findings for clinical practice and/or further research? This study aimed to evaluate the prognostic significance of REG4 expression in ovarian cancer treated with platinum and paclitaxel, to explore REG4 chemoresistance mechanisms to platinum and paclitaxel, and to provide a scientific experimental basis for the clinical treatment and outcome evaluation of ovarian cancer. In order to provide comprehensive clinical treatment of ovarian cancer, it is helpful to improve our understanding of multi-drug resistance and identify new cancer diagnostic biomarkers.

The effect of coronary calcification on diagnostic performance of machine learning-based CT-FFR: a Chinese multicenter study.

OBJECTIVE: To investigate the effect of coronary calcification morphology and severity on the diagnostic performance of machine learning (ML)-based coronary CT angiography (CCTA)-derived fractional flow reserve (CT-FFR) with FFR as a reference standard. METHODS: A total of 442 patients (61.2 ± 9.1 years, 70% men) with 544 vessels who underwent CCTA, ML-based CT-FFR, and invasive FFR from China multicenter CT-FFR study were enrolled. The effect of calcification arc, calcification remodeling index (CRI), and Agatston score (AS) on the diagnostic performance of CT-FFR was investigated. CT-FFR ≤ 0.80 and lumen reduction ≥ 50% determined by CCTA were identified as vessel-specific ischemia with invasive FFR as a reference standard. RESULTS: Compared with invasive FFR, ML-based CT-FFR yielded an overall sensitivity of 0.84, specificity of 0.94, and accuracy of 0.90 in a total of 344 calcification lesions. There was no statistical difference in diagnostic accuracy, sensitivity, or specificity of CT-FFR across different calcification arc, CRI, or AS levels. CT-FFR exhibited improved discrimination of ischemia compared with CCTA alone in lesions with mild-to-moderate calcification (AUC, 0.89 vs. 0.69, p < 0.001) and lesions with CRI ≥ 1 (AUC, 0.89 vs. 0.71, p < 0.001). The diagnostic accuracy and specificity of CT-FFR were higher than CCTA alone in patients and vessels with mid (100 to 299) or high (≥ 300) AS. CONCLUSION: Coronary calcification morphology and severity did not influence diagnostic performance of CT-FFR in ischemia detection, and CT-FFR showed marked improved discrimination of ischemia compared with CCTA alone in the setting of calcification. KEY POINTS: • CT-FFR provides superior diagnostic performance than CCTA alone regardless of coronary calcification. • No significant differences in the diagnostic performance of CT-FFR were observed in coronary arteries with different coronary calcification arcs and calcified remodeling indexes. • No significant differences in the diagnostic accuracy of CT-FFR were observed in coronary arteries with different coronary calcification score levels.

A Single Dose of NILV-Based Vaccine Provides Rapid and Durable Protection against Zika Virus.

Zika virus, a member of the Flaviviridae family, is primarily transmitted by infected Aedes species mosquitoes. In 2016, Zika infection emerged as a global health emergency for its explosive spread and the remarkable neurological defects in the developing fetus. Development of a safe and effective Zika vaccine remains a high priority owing to the risk of re-emergence and limited understanding of Zika virus epidemiology. We engineered a non-integrating lentiviralvector(NILV)-based Zika vaccine encoding the consensus pre-membrane and envelope glycoprotein of circulating Zika virus strains. We further evaluated the immunogenicity and protective efficacy of this vaccine in both immunocompromised and immunocompetent mouse models. A single immunization in both mouse models elicited a robust neutralizing antibody titer and afforded full protection against Zika challenge as early as 7 days post-immunization. This NILV-based vaccine also induced a long-lasting immunity when immunized mice were challenged 6 months after immunization. Altogether, our NILV Zika vaccine provides a rapid yet durable protection through a single dose of immunization without extra adjuvant formulation. Our data suggest a promising Zika vaccine candidate for an emergency situation, and demonstrate the capacity of lentiviral vector as an efficient vaccine delivery platform.

Potential effects of angiogenesis-related factors on the severity of APAC and surgical outcomes of trabeculectomy.

BACKGROUND: EPO (erythropoietin) and PDGF (platelet derived growth factor) families are thought to be associated with angiogenesis under hypoxic condition. The sharp rise of intraocular pressure in acute primary angle closure (APAC) results in an inefficient supply of oxygen and nutrients. We aimed to measure the expression of EPO and PDGF family members in APAC eyes and demonstrate their associations with APAC's surgical success rate. METHODS: Concentrations of EPO, PDGF-AA, -BB, -CC and -DD collected in aqueous humor samples of 55 patients recruited were measured. Before operations, correlations between target proteins and IOP (intraocular pressure) were detected between APAC (acute primary angle closure) and cataract patients. Based on the post-operative follow-up, the effects of EPO and PDGF family members on the successful rate of trabeculectomy were tested. RESULTS: The levels of EPO, PDGF-CC and -DD were significantly elevated in the APAC group compared to the cataract group. During the post-operative follow-up, EPO, PDGF-CC and -DD showed significant differences between the success and failure groups. In multivariable linear regression analyses, failed filtration surgery was more likely in APAC eyes with higher EPO level. The Kaplan-Meier survival plot suggested that the success rate in eyes with low EPO level was significantly higher than that in eyes with high EPO level. CONCLUSION: The levels of EPO, PDGF-CC and -DD were significantly elevated in failure group. EPO level correlated with preoperative IOP and numbers of eyedrops, and higher EPO level in aqueous humor is a risk factor for trabeculectomy failure. It can be a biomarker to estimate the severity of APAC and the success rate of surgery. The investigation of mechanism of EPO in APAC a may have potential clinical applications for the surgical treatment of APAC.

The Potential of Calcium/Phosphate Containing MAO Implanted in Bone Tissue Regeneration and Biological Characteristics.

Micro arc oxidation (MAO) is a prominent surface treatment to form bioceramic coating layers with beneficial physical, chemical, and biological properties on the metal substrates for biomaterial applications. In this study, MAO treatment has been performed to modify the surface characteristics of AZ31 Mg alloy to enhance the biocompatibility and corrosion resistance for implant applications by using an electrolytic mixture of Ca3(PO4)2 and C10H16N2O8 (EDTA) in the solutions. For this purpose, the calcium phosphate (Ca-P) containing thin film was successfully fabricated on the surface of the implant material. After in-vivo implantation into the rabbit bone for four weeks, the apparent growth of soft tissues and bone healing effects have been documented. The morphology, microstructure, chemical composition, and phase structures of the coating were identified by SEM, XPS, and XRD. The corrosion resistance of the coating was analyzed by polarization and salt spray test. The coatings consist of Ca-P compounds continuously have proliferation activity and show better corrosion resistance and lower roughness in comparison to mere MAO coated AZ31. The corrosion current density decreased to approximately 2.81 × 10-7 A/cm2 and roughness was reduced to 0.622 µm. Thus, based on the results, it was anticipated that the development of degradable materials and implants would be feasible using this method. This study aims to fabricate MAO coatings for orthopedic magnesium implants that can enhance bioactivity, biocompatibility, and prevent additional surgery and implant-related infections to be used in clinical applications.

The influence of image quality on diagnostic performance of a machine learning-based fractional flow reserve derived from coronary CT angiography.

OBJECTIVE: To investigate the effect of image quality of coronary CT angiography (CCTA) on the diagnostic performance of a machine learning-based CT-derived fractional flow reserve (FFRCT). METHODS: This nationwide retrospective study enrolled participants from 10 individual centers across China. FFRCT analysis was performed in 570 vessels in 437 patients. Invasive FFR and FFRCT values ≤ 0.80 were considered ischemia-specific. Four-score subjective assessment based on image quality and objective measurement of vessel enhancement was performed on a per-vessel basis. The effects of body mass index (BMI), sex, heart rate, and coronary calcium score on the diagnostic performance of FFRCT were studied. RESULTS: Among 570 vessels, 216 were considered ischemia-specific by invasive FFR and 198 by FFRCT. Sensitivity and specificity of FFRCT for detecting lesion-specific ischemia were 0.82 and 0.93, respectively. Area under the curve (AUC) of high-quality images (0.93, n = 159) was found to be superior to low-quality images (0.80, n = 92, p = 0.02). Objective image quality and heart rate were also associated with diagnostic performance of FFRCT, whereas there was no statistical difference in diagnostic performance among different BMI, sex, and calcium score groups (all p > 0.05, Bonferroni correction). CONCLUSIONS: This retrospective multicenter study supported the FFRCT as a noninvasive test in evaluating lesion-specific ischemia. Subjective image quality, vessel enhancement, and heart rate affect the diagnostic performance of FFRCT. KEY POINTS: • FFRCTcan be used to evaluate lesion-specific ischemia. • Poor image quality negatively affects the diagnostic performance of FFRCT. • CCTA with ≥ score 3, intracoronary enhancement degree of 300-400 HU, and heart rate below 70 bpm at scanning could be of great benefit to more accurate FFRCTanalysis.

Plasmonic Nanolasers Enhanced by Hybrid Graphene-Insulator-Metal Structures.

Graphene is a two-dimensional (2D) structure that creates a linear relationship between energy and momentum that not only forms massless Dirac fermions with extremely high group velocity but also exhibits a broadband transmission from 300 to 2500 nm that can be applied to many optoelectronic applications, such as solar cells, light-emitting devices, touchscreens, ultrafast photodetectors, and lasers. Although the plasmonic resonance of graphene occurs in the terahertz band, graphene can be combined with a noble metal to provide a versatile platform for supporting surface plasmon waves. In this study, we propose a hybrid graphene-insulator-metal (GIM) structure that can modulate the surface plasmon polariton (SPP) dispersion characteristics and thus influence the performance of plasmonic nanolasers. Compared with values obtained when graphene is not used on an Al template, the propagation length of SPP waves can be increased 2-fold, and the threshold of nanolasers is reduced by 50% when graphene is incorporated on the template. The GIM structure can be further applied in the future to realize electrical control or electrical injection of plasmonic devices through graphene.

Serum-plasma matched metabolomics for comprehensive characterization of benign thyroid nodule and papillary thyroid carcinoma.

Metabolomics offers a noninvasive methodology to identify metabolic markers for pathogenesis and diagnosis of diseases. This work aimed to characterize circulating metabolic signatures of benign thyroid nodule (BTN) and papillary thyroid carcinoma (PTC) via serum-plasma matched metabolomics. A cohort of 1,540 serum-plasma matched samples and 114 tissues were obtained from healthy volunteers, BTN and PTC patients enrolled from 6 independent centers. Untargeted metabolomics was determined by liquid chromatography-quadrupole time-of-flight mass spectrometric and multivariate statistical analyses. The use of serum-plasma matched samples afforded a broad-scope detection of 1,570 metabolic features. Metabolic phenotypes revealed significant pattern differences for healthy versus BTN and healthy versus PTC. Perturbed metabolic pathways related mainly to amino acid and lipid metabolism. It is worth noting that, BTN and PTC showed no significant differences but rather overlap in circulating metabolic signatures, and this observation was replicated in all study centers. For differential diagnosis of healthy versus thyroid nodules (BTN + PTC), a panel of 6 metabolic markers, namely myo-inositol, α-N-phenylacetyl-L-glutamine, proline betaine, L-glutamic acid, LysoPC(18:0) and LysoPC(18:1) provided area under the curve of 97.68% in the discovery phase and predictive accuracies of 84.78-98.18% in the 4 validation centers. Taken together, serum-plasma matched metabolomics showed significant differences in circulating metabolites for healthy versus nodules but not for BTN versus PTC. Our results highlight the true metabolic nature of thyroid nodules, and potentially decrease overtreatment that exposes patients to unnecessary risks.

[Mitochondrial DNA hydroxymethylation level in the cerebral cortex of neonatal rats with hypoxic-ischemic brain damage].

OBJECTIVE: To study the methylation level and dynamic change of 5-hydroxymethylcytosine (5hmC) in mitochondrial DNA (mtDNA) in the cerebral cortex of neonatal rats with hypoxic-ischemic brain damage. METHODS: A total of 24 male Sprague-Dawley rats aged 7 days were randomly divided into control group, 24-hour model group and 48-hour model group (n=8 each). Common carotid artery ligation combined with hypoxic treatment was performed to establish an animal model of hypoxic-ischemic brain damage. The rats in the control group were not given ligation or hypoxic treatment. Oxidative bisulfite sequencing was used to measure the level of 5hmC in the cerebral cortex. Western blot was used to measure the expression of 5hmC-related enzymes TET1, TET2 and DNMT1. RESULTS: The 24- and 48-hour model groups had a significantly higher level of 5hmC than the control group (P<0.05). Western blot showed a significant increase in the expression of DNMT1 in the 24- and 48-hour model groups (P<0.05). Compared with the control group, the 24- and 48-hour model groups had significant differences in the 5hmC level at multiple mitochondrial genetic loci (P<0.05). CONCLUSIONS: The level of DNMT1, a key enzyme for 5hmC modification in mtDNA, in the cerebral cortex increases in neonatal rats with hypoxic-ischemic brain damage, suggesting that there is an abnormal methylation level of 5hmC after hypoxic-ischemic brain damage, which might be associated with the regulation of hypoxic-ischemic brain damage.

Stem cell mitochondria during aging.

Mitochondria are the central hubs of cellular metabolism, equipped with their own mitochondrial DNA (mtDNA) blueprints to direct part of the programming of mitochondrial oxidative metabolism and thus reactive oxygen species (ROS) levels. In stem cells, many stem cell factors governing the intricate balance between self-renewal and differentiation have been found to directly regulate mitochondrial processes to control stem cell behaviors during tissue regeneration and aging. Moreover, numerous nutrient-sensitive signaling pathways controlling organismal longevity in an evolutionarily conserved fashion also influence stem cell-mediated tissue homeostasis during aging via regulation of stem cell mitochondria. At the genomic level, it has been demonstrated that heritable mtDNA mutations and variants affect mammalian stem cell homeostasis and influence the risk for human degenerative diseases during aging. Because such a multitude of stem cell factors and signaling pathways ultimately converge on the mitochondria as the primary mechanism to modulate cellular and organismal longevity, it would be most efficacious to develop technologies to therapeutically target and direct mitochondrial repair in stem cells, as a unified strategy to combat aging-related degenerative diseases in the future.

Effect of Baicalein on GLUT4 Translocation in Adipocytes of Diet-Induced Obese Mice.

BACKGROUND/AIMS: Although baicalein has been shown to increase insulin sensitivity in liver of mice, there is no literature available about the effect of baicalein on glucose transporter 4 (GLUT4) translocation from intracellular membrane pools to plasma membranes in adipocytes of diet-induced obese mice. METHODS: In the present study, the obese model was induced in mice fed a high fat diet (20% carbohydrates, 21% protein and 59% fat) for 16 weeks. The diet-induced obese mice were given 20mg/kg baicalein intraperitoneally (i.p.) once a day for 21 days. The plasma insulin was measured by enzyme-linked immunosorbent assay. Fasting blood glucose and insulin resistance indexes were measured by glucose tolerance test (GTT). The expression levels of PGC-1α, UCP1, GLUT4, PPARγ, pP38MAPK, pERK and pAKT in adipocytes were determined by quantitative real-time polymerase chain reaction and western blotting. RESULTS: The present findings showed that administration of baicalein decreased pP38MAPK, pERK and PPARγ levels, but enhanced pAKT, PGC-1α and UCP1 contents as well as GLUT4 expression in adipocytes, and reversed high fat diet-induced glucose intolerance, hyperglycemia and insulin resistance in diet-induced obese mice. Moreover, baicalein treatment increased GLUT4 concentration in plasma membranes of adipocytes, i.e. baicalein may prevent insulin resistance through the GLUT4 translocation from intracellular membrane compartments to plasma membranes in adipocytes. CONCLUSION: These results suggest that baicalein is a powerful and promising agent for treatment of obesity and insulin resistance via Akt/GLUT4 pathway.