Integrated multi-omic high-throughput strategies across-species identified potential key diagnostic, prognostic, and therapeutic targets for atherosclerosis under high glucose conditions.

Diabetes is a well-known risk factor for atherosclerosis (AS), but the underlying molecular mechanism remains unknown. The dysregulated immune response is an important reason. High glucose is proven to induce foam cell formation under lipidemia situations in clinical patients. Exploring the potential regulatory programs of accelerated foam cell formation stimulated by high glucose is meaningful. Macrophage-derived foam cells were induced in vitro, and high-throughput sequencing was performed. Coexpression gene modules were constructed using weighted gene co-expression network analysis (WGCNA). Highly related modules were identified. Hub genes were identified by multiple integrative strategies. The potential roles of selected genes were further validated in bulk-RNA and scRNA datasets of human plaques. By transfection of the siRNA, the role of the screened gene during foam cell formation was further explored. Two modules were found to be both positively related to high glucose and ox-LDL. Further enrichment analyses confirmed the association between the brown module and AS. The high correlation between the brown module and macrophages was identified and 4 hub genes (Aldoa, Creg1, Lgmn, and Pkm) were screened. Further validation in external bulk-RNA and scRNA revealed the potential diagnostic and therapeutic value of selected genes. In addition, the survival analysis confirmed the prognostic value of Aldoa while knocking down Aldoa expression alleviated the foam cell formation in vitro. We systematically investigated the synergetic effects of high glucose and ox-LDL during macrophage-derived foam cell formation and identified that ALDOA might be an important diagnostic, prognostic, and therapeutic target in these patients.

An integrated radiopathomics machine learning model to predict pathological response to preoperative chemotherapy in gastric cancer.

RATIONALE AND OBJECTIVES: Accurately predicting the pathological response to chemotherapy before treatment is important for selecting the appropriate treatment groups, formulating individualized treatment plans, and improving the survival rates of patients with gastric cancer (GC). METHODS: We retrospectively enrolled 151 patients diagnosed with GC who underwent preoperative chemotherapy and surgical resection at the Affiliated Hospital of Qingdao University between January 2015 and June 2023. Both pretreatment-enhanced computer technology images and whole slide images of pathological hematoxylin and eosin-stained sections were available for each patient. The image features were extracted and used to construct an ensemble radiopathomics machine learning model. In addition, a nomogram was developed by combining the imaging features and clinical characteristics. RESULTS: In total, 962 radiomics and 999 pathomics signatures were extracted from 106 patients in the training cohort. A fusion radiopathomics model was constructed using 13 radiomics and 5 pathomics signatures. The fusion model showed favorable performance compared to single-omics models, with an area under the curve (AUC) of 0.789 in the validation cohort. Moreover, a combined radiopathomics nomogram (RPN) was developed based on radiopathomics features and the Borrmann type, which is a classification method for advanced GC according to tumor growth pattern and gross morphology. The RPN showed superior predictive performance in the training (AUC 0.880) and validation cohorts (AUC 0.797). The decision curve analysis showed that RPN could provide favorable clinical benefits to patients with GC. CONCLUSIONS: RPN was able to predict the pathological response to preoperative chemotherapy with high accuracy, and therefore provides a novel tool for personalized treatment of GC.

Integrated Transcriptomic Landscape and Deep Learning Based Survival Prediction in Uterine Sarcomas.

Purpose: The genomic characteristics of uterine sarcomas have not been fully elucidated. This study aimed to explore the genomic landscape of the USs. Materials and Methods: Comprehensive genomic analysis through RNA-sequencing was conducted. Gene fusion, differentially expressed genes (DEGs), signaling pathway enrichment, immune cell infiltration, and prognosis were analyzed. A deep learning model was constructed to predict the survival of US patients. Results: A total of 71 US samples were examined, including 47 endometrial stromal sarcomas (ESS), 18 uterine leiomyosarcomas (uLMS), 3 adenosarcomas, 2 carcinosarcomas, and 1 uterine tumor resembling an ovarian sex-cord tumor (UTROSCT). ESS (including high-grade ESS and low-grade ESS) and uLMS showed distinct gene fusion signatures; a novel gene fusion site, MRPS18A - PDC-AS1 could be a potential diagnostic marker for the pathology differential diagnosis of uLMS and ESS; 797 and 477 uDEGs were identified in the ESS vs. uLMS and HGESS vs. LGESS groups, respectively. The uDEGs were enriched in multiple pathways. Fifteen genes including LAMB4 were confirmed with prognostic value in USs; immune infiltration analysis revealed the prognositic value of myeloid dendritic cells, plasmacytoid dendritic cells, natural killer cells, macrophage M1, monocytes and hematopoietic stem cells in USs; the deep learning model named MMN-MIL showed satisfactory performance in predicting the survival of US patients, with the area under the receiver operating curve curve reached 0.909 and accuracy achieved 0.804. Conclusion: USs harbored distinct gene fusion characteristics and gene expression features between HGESS, LGESS, and uLMS. The MMN-MIL model could effectively predict the survival of US patients.

Real-world applications of the new grading system in lung adenocarcinoma: A study of 907 patients focusing on revealing the relationship between pathologic grade and genetic status.

BACKGROUND: The status of the lung adenocarcinoma (LUAD) grading system and the association between LUAD differentiation, driver genes, and clinicopathological features remain to be elucidated. METHODS: We included patients with invasive non-mucinous LUAD, evaluated their differentiation, and collected available clinicopathological information, gene mutations, and analyzed clinical outcomes. RESULTS: Among the 907 patients with invasive non-mucinous LUAD, 321 (35.4 %) were poorly differentiated, 422 (46.5 %) were moderately differentiated, and 164 (18.1 %) were well differentiated. EGFR mutation was more common in the LUADs accompanied without CGP (complex glandular pattern) than LUADs with CGP (p < 0.001). Correlation analysis between mutations and clinical characteristics showed that EGFR gene mutation (p < 0.001), KRAS gene mutation (p < 0.05), and ALK gene rearrangement (p < 0.001) were significantly related to the degree of tumor differentiation, and the KRAS and ALK gene mutation frequencies were higher in the low-differentiation group than in the high and medium differentiation groups. The EGFR mutation frequency was higher in the well/moderately differentiated adenocarcinoma group. CONCLUSIONS: Our study adds to the evidence regarding the role of the grading system in prognosis. EGFR, KRAS, and ALK are related to the degree of tumor differentiation.

Association of red blood cell distribution width and hemoglobin-to-RDW ratio with contrast-associated acute kidney injury in patients undergoing coronary angiography: A retrospective study.

BACKGROUND: Inflammation contributes to poor prognosis in cardiovascular diseases. A novel biomarker for systemic inflammation that has garnered attention is the red blood cell distribution width (RDW). This study is designed to explore potential associations between RDW and hemoglobin-to-RDW ratio (HRR) with contrast-associated acute kidney injury (CA-AKI). METHODS: This study retrospectively analyzed 4054 patients undergoing coronary angiography (CAG). Linear regression models were employed to assess the relationships between RDW or HRR and the elevation of serum creatinine (Scr). The associations between RDW or HRR and CA-AKI were explored using restricted cubic spline and log-binomial regression analyses taking into account specific cutoff values and quintiles. Exploratory analyses were also conducted to further investigate these associations. RESULTS: Among enrolled patients, the average age was 66.9 years and 34.3% were female. Notably, patients who developed CA-AKI tended to have higher RDW and lower HRR. Multivariable linear regression models demonstrated that RDW exhibited a positive association with Scr elevation (ß = 2.496, 95% confidence interval [CI] = 1.784-3.208), while HRR displayed a negative association (ß = -3.559, 95% CI = -4.243 to -2.875). Multivariable log-binomial regression models confirmed that both high RDW (RDW ≥ 13.8%) and low HRR (HRR < 8.9) were significantly associated with a higher risk of CA-AKI (RDW [≥13.8% vs. <13.8%]: relative risk [RR] = 1.540, 95% CI = 1.345-1.762; HRR [<8.9 vs. ≥8.9]: RR = 1.822, 95% CI = 1.584-2.096). Exploratory analysis determined that such associations still existed regardless of age, gender, estimated glomerular filtration rate, or anemia. CONCLUSIONS: Elevated preoperative RDW and decreased HRR were significantly associated with CA-AKI in patients undergoing CAG.

Association between the variability of non-high-density lipoprotein cholesterol and the neutrophil-to-lymphocyte ratio in patients with coronary heart disease.

Background: Lowering lipid variability may be a potential strategy for improving the inflammatory state in patients with coronary heart disease (CHD). This study investigated the association between the variability of non-high-density lipoprotein cholesterol (non-HDL-C) and the neutrophil-to-lymphocyte ratio (NLR). Methods: This study enrolled 2,711 CHD patients subjected to percutaneous coronary intervention (PCI). During the 1-year follow-up period after PCI, the variability of non-HDL-C was assessed using standard deviation (SD), coefficient of variation (CV), and variability independent of mean (VIM). NLR was calculated as the ratio of absolute neutrophil count to absolute lymphocyte count. The relationship between the non-HDL-C variability and the average NLR level during follow-ups was examined using a linear regression analysis. Results: The mean age of the patients was 64.4 ± 10.8 years, with 72.4% being male. The average NLR level was 2.98 (2.26-4.14) during the follow-up (1 year after PCI). The variability of non-HDL-C was 0.42 (0.26-0.67) for SD, 0.17 (0.11-0.25) for CV, and 0.02 (0.01-0.03) for VIM. A locally weighted scatterplot smoothing curve indicates that the average levels of NLR increased with increasing variability of non-HDL-C. Regardless of the variability assessment method used, non-HDL-C variability was significantly positively associated with the average NLR level during follow-ups: SD [ß (95% CI) = 0.681 (0.366-0.996)], CV [ß (95% CI) = 2.328 (1.458-3.197)], and VIM [ß (95% CI) = 17.124 (10.532-23.715)]. This association remained consistent across subgroups stratified by age, gender, diabetes, and hypertension. Conclusion: The variability of non-HDL-C was positively associated with NLR in patients with CHD, suggesting that reducing non-HDL-C variability may improve the low-grade inflammatory state in CHD patients.

Variability in Plasma Lipids Between Intensive Statin Therapy and Conventional-Dose Statins Combined with Ezetimibe Therapy in Patients with Coronary Atherosclerosis Disease.

Dyslipidemia has been widely recognized as a significant risk factor for coronary atherosclerosis disease (CAD). In fact, lipid variability has emerged as a more reliable predictor of cardiovascular events. In this study, we aimed to examine the variability in plasma lipids under two different lipid-lowering regimens (intensive statin therapy versus the combination of conventional-dose statins with ezetimibe). In total, we have retrospectively examined 1275 patients with CAD from January 2009 to April 2019 and divided them into two groups: intensive statin group and conventional-dose statins combined with ezetimibe group. All patients were followed up for at least 1 year. Lipid variability was verified by standard deviation (SD), coefficient of variation (CV), and variability independent of mean (VIM) triple methods. Multiple linear regression and subgroup analyses were performed. In the overall participants, the mean age was 62.3 ± 10.4 years old, and 72.8% were male. Multivariate linear regression analysis indicated that the intensive statin group had lower variability in terms of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) in all SD, CV, and VIM triple methods than statins combined with ezetimibe group (P for all <0.05). Similar results were established in the subgroup analyses based on atorvastatin or rosuvastatin, diabetes mellitus or not, and hypertension or not (P for all < 0.05). Thus, we can conclude that intensive statin therapy could contribute in lowering lipid variability than conventional-dose statins combined with ezetimibe therapy among patients with CAD.

Self-healing liquid metal hydrogel for human-computer interaction and infrared camouflage.

Due to their mechanical flexibility, conductive hydrogels have been widely investigated in the fields of flexible electronics and soft robots, but their non-negligible disadvantages, such as poor toughness and limited self-healing, severally restrict their practical application. Herein, gallium indium alloy (EGaIn) is utilized to initiate the polymerization and simultaneously serve as flexible fillers to construct a super-stretchable and self-healing liquid metal/polyvinyl alcohol/p(acrylamide-co-octadecyl methacrylate) (liquid metal/PVA/P(AAm-co-SMA)) double network hydrogel (LM hydrogel). The synergistic effect of the rigid PVA microcrystal network and the ductile P(AAm-co-SMA) hydrophobic network, together with the ionic coordination and hydrogen bonds between polymer networks (multiple physical cross-links), endow the LM hydrogel with excellent super-stretchability (2000%), toughness (3.00 MJ m-3), notch resistance, and self-healing property (healing efficiency > 99% at 25 °C after 24 h). The LM hydrogel exhibits sensitive strain sensing behavior, allowing human-computer interaction to achieve motion recognition and health monitoring. Significantly, owing to the excellent photothermal effect and low infrared emissivity of EGaIn, the LM hydrogel reveals great potential in infrared camouflage. The work of self-healing conductive liquid metal hydrogels will promote the research and practical application of hydrogels and liquid metal in intelligent devices and military fields.

Yolk Sac Tumor Originating From Cervical Adenocarcinoma: A Case Predominated by Enteroblastic Differentiation.

The fetal gut-like phenotype can be found in yolk sac tumors and adenocarcinomas with enteroblastic differentiation (AEBDs). We report a cervical yolk sac tumor in a 44-yr-old woman. The tumor has similar morphology, immunophenotype, and molecular features to the AEBD of the digestive system. The tumor showed a glandular-predominant growth pattern, composed of columnar cells with clear glycogen-rich cytoplasm. The microcystic/reticular architecture or Schiller-Duval bodies were not found in the tumor. Immunohistochemically, the tumor cells were positive for p16, glypican-3 (GPC3), spalt-like transcription factor 4 (SALL4), CDX-2, and p53. TP53 mutation was identified by next-generation sequencing, and human papillomavirus (HPV) 35 was detected by HPV DNA polymerase chain reaction. In the present case, the adenocarcinoma cells in the superficial cervical glandular epithelium and the nonclear glandular components proved the existence of somatic components. The positivity of p16 and HPV also supports that the present case originates from an HPV-associated adenocarcinoma. The yolk sac tumor should be thought of as "germ cell differentiation" from a somatic carcinoma. This kind of yolk sac tumor arising from somatic-type adenocarcinoma in the female genital tract may be the counterpart of AEBD in the digestive tracts and adenocarcinomas with fetal gut-like morphology in other organs. The tumor might be more aggressive than conventional adenocarcinoma, pathologists should highlight the existence of the enteroblastic component in the pathologic report.

New insights into fibrous cap thickness of vulnerable plaques assessed by optical coherence tomography.

OBJECTIVE: Vulnerable plaques with fibrous cap thickness (FCT) of ≤65 µm are prone to rupture and/or thrombosis. However, plaques with FCT > 65 µm cause acute myocardial infarction and even sudden death. We aimed to investigate the relationship between 65 < FCT ≤ 80 µm and plaque rupture and/or thrombosis using optical coherence tomography (OCT). METHODS: OCT was performed on culprit lesions in 502 consecutively enrolled patients to identify FCT. Patients were classified into three groups according to FCT: Group A (FCT ≤ 65 µm, n = 147), Group B (65 < FCT ≤ 80 µm, n = 84) and Group C (FCT > 80 µm, n = 271). Clinical and laboratory data was collected from the inpatient medical record system. RESULTS: Plaques with thinner FCT, especially < 65 µm, were more susceptible to rupture and/or thrombosis (P < 0.001). Plaques with FCT between 65 and 80 µm had a higher probability of rupture and/or thrombosis than those with FCT > 80 µm (P < 0.001). In multivariable analysis, FCT ≤ 65 µm and 65 < FCT ≤ 80 µm were independent predictors for plaque rupture ([FCT ≤ 65 µm vs. FCT > 80 µm]: OR = 8.082, 95% CI = 4.861 to 13.435, P < 0.001; [65 < FCT ≤ 80 µm vs. FCT > 80 µm]: OR = 2.463, 95% CI = 1.370 to 4.430, P = 0.003), thrombosis ([FCT ≤ 65 µm vs. FCT > 80 µm]: OR = 25.224, 95% CI = 13.768 to 46.212, P < 0.001; [65 < FCT ≤ 80 µm vs. FCT > 80 µm]: OR = 3.675, 95% CI = 2.065 to 6.542, P < 0.001) and plaque rupture with thrombosis ([FCT ≤ 65 µm vs. FCT > 80 µm]: OR = 22.593, 95% CI = 11.426 to 44.674, P < 0.001; [65 < FCT ≤ 80 µm vs. FCT > 80 µm]: OR = 4.143, 95% CI = 1.869 to 9.184, P < 0.001). CONCLUSIONS: OCT-assessed 65 < FCT ≤ 80 µm was independently associated with increased risk of plaque rupture and/or thrombosis compared with FCT > 80 µm.

Transcriptome analysis uncovers the autophagy-mediated regulatory patterns of the immune microenvironment in dilated cardiomyopathy.

The relationship between autophagy and immunity has been well studied. However, little is known about the role of autophagy in the immune microenvironment during the progression of dilated cardiomyopathy (DCM). Therefore, this study aims to uncover the effect of autophagy on the immune microenvironment in the context of DCM. By investigating the autophagy gene expression differences between healthy donors and DCM samples, 23 dysregulated autophagy genes were identified. Using a series of bioinformatics methods, 13 DCM-related autophagy genes were screened and used to construct a risk prediction model, which can well distinguish DCM and healthy samples. Then, the connections between autophagy and immune responses including infiltrated immunocytes, immune reaction gene-sets and human leukocyte antigen (HLA) genes were systematically evaluated. In addition, two autophagy-mediated expression patterns in DCM were determined via the unsupervised consensus clustering analysis, and the immune characteristics of different patterns were revealed. In conclusion, our study revealed the strong effect of autophagy on the DCM immune microenvironment and provided new insights to understand the pathogenesis and treatment of DCM.

Controlled Transformation of Liquid Metal Microspheres in Aqueous Solution Triggered by Growth of GaOOH.

Liquid metals (LMs) are playing an increasingly important role in the fields of flexible devices, electronics, and thermal management due to their low melting point and excellent thermal and electrical conductivity, and the transformation of LMs in deionized water has recently received much attention. In this paper, we investigate the transformation process of EGaIn microspheres in deionized water and propose a two-step process of microspherical transformation, whereby the microspheres are first deformed into a spindle shape and then into lamellar nanorods. It is also shown that the growth of GaOOH crystals drives the transformation. Based on this result, EGaIn microspheres with controllable transformation could be prepared, such as spindle or lamellar rod shapes, extending the application area of LMs.

Dendritic cell-mediated chronic low-grade inflammation is regulated by the RAGE-TLR4-PKCß1 signaling pathway in diabetic atherosclerosis.

BACKGROUND: The unique mechanism of diabetic atherosclerosis has been a central research focus. Previous literature has reported that the inflammatory response mediated by dendritic cells (DCs) plays a vital role in the progression of atherosclerosis. The objective of the study was to explore the role of DCs in diabetes mellitus complicated by atherosclerosis. METHODS: ApoE-/- mice and bone marrow-derived DCs were used for in vivo and in vitro experiments, respectively. Masson's staining and Oil-red-O staining were performed for atherosclerotic lesion assessment. The content of macrophages and DCs in plaque was visualized by immunohistochemistry. The expression of CD83 and CD86 were detected by flow cytometry. The fluctuations in the RNA levels of cytokines, chemokines, chemokine receptors and adhesions were analyzed by quantitative RT-PCR. The concentrations of IFN-γ and TNF-α were calculated using ELISA kits and the proteins were detected using western blot. Coimmunoprecipitation was used to detect protein-protein interactions. RESULTS: Compared with the ApoE-/- group, the volume of atherosclerotic plaques in the aortic root of diabetic ApoE-/- mice was significantly increased, numbers of macrophages and DCs were increased, and the collagen content in plaques decreased. The expression of CD83 and CD86 were significantly upregulated in splenic CD11c+ DCs derived from mice with hyperglycemia. Increased secretion of cytokines, chemokines, chemokine receptors, intercellular cell adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) also were observed. The stimulation of advanced glycation end products plus oxidized low-density lipoprotein, in cultured BMDCs, further activated toll-like receptor 4, protein kinase C and receptor of AGEs, and induced immune maturation of DCs through the RAGE-TLR4-PKCß1 signaling pathway that was bound together by intrinsic structures on the cell membrane. Administering LY333531 significantly increased the body weight of diabetic ApoE-/- mice, inhibited the immune maturation of spleen DCs, and reduced atherosclerotic plaques in diabetic ApoE-/- mice. Furthermore, the number of DCs and macrophages in atherosclerotic plaques was significantly reduced in the LY333531 group, and the collagen content was increased. CONCLUSIONS: Diabetes mellitus aggravates chronic inflammation, and promotes atherosclerotic plaques in conjunction with hyperlipidemia, which at least in part through inducing the immune maturation of DCs, and its possible mechanism of action is through the RAGE-TLR4-pPKCß1 signaling pathway.

Mesenchymal-Epithelial Transition Exon 14 Skipping Mutation and Amplification in 5,008 Patients With Lung Cancer.

BACKGROUND: Lung cancer is a major health concern worldwide because of its increasing incidence and mortality. This study aimed to clarify the association between mesenchymal-epithelial transition (MET) genomic alterations and clinical characteristics of lung cancer. METHOD: We collected data from 5,008 patients with lung cancer diagnosed and treated between January 2017 and July 2021 at the Affiliated Hospital of Qingdao University. Genomic alterations in the MET gene, including the exon 14 skipping mutation and amplification, were detected using amplification refractory mutation system-polymerase chain reaction (2,057 cases) and next-generation sequencing (2,951 cases). Clinical characteristics such as age, sex, tumor location, tumor stage, smoking, pleural invasion, and histology were statistically analyzed for MET exon 14 skipping mutation and amplification. The DNA splicing sites causing the MET exon 14 skipping mutation at the mRNA level were also investigated. RESULTS: The incidence of the MET exon 14 skipping mutation was 0.90% (41/4,564) in adenocarcinoma, 1.02% (3/294) in squamous cell carcinoma, and 8.33% (1/12) in sarcomatoid carcinoma specimens. It was more frequently observed in patients over 60 years of age than the MET exon 14 skipping mutation wildtype. The MET exon 14 skipping mutation co-occurred with epidermal growth factor receptor (EGFR) L858R, EGFR 19-Del, and BRAF V600E mutations. At the DNA level, single nucleotide mutation and small fragment deletion (1-38 base pairs) upstream and downstream of MET exon 14 led to MET exon 14 skipping mutation at the mRNA level. MET amplification occurred in 0.78% (21/2,676) adenocarcinoma and 1.07% (2/187) squamous cell carcinoma specimens and was significantly associated with advanced tumor stages (III + IV) compared to the MET amplification wildtype. MET amplification primarily co-occurred with the EGFR mutation. CONCLUSIONS: Our study found that MET genomic alterations were statistically related to age and tumor stage and co-existed with mutations of other oncogenic driver genes, such as EGFR and BRAF. Moreover, various splicing site changes at the DNA level led to the exon 14 skipping mutation at the mRNA level. Further studies are required to clarify the association between MET genomic alterations and prognosis.

Neurogenic orthostatic hypotension with Parkinson's disease as a cause of syncope: A case report.

BACKGROUND: Syncope presents with diagnostic challenges and is associated with high healthcare costs. Neurogenic orthostatic hypotension (nOH) as one cause of syncope is not well established. We review a case of syncope caused by nOH in a patient with Parkinson's disease. CASE SUMMARY: We describe a case of syncope caused by nOH in Parkinson's disease and review the literature. A 70-year-old man with Parkinson's disease had uncontrolled blood pressure for 1 mo, with blood pressure ranging from 70/40 to 220/112 mmHg, and once lost consciousness lasting for several minutes after getting up. Ambulatory blood pressure monitoring indicated nocturnal hypertension (up to 217/110 mmHg) and morning orthostatic hypotension (as low as 73/45 mmHg). Seated-to-standing blood pressure measurement showed that the blood pressure dropped from 173/96 mmHg to 95/68 mmHg after standing for 3 min from supine position. A diagnosis of nOH with supine hypertension was made. During the course of treatment, Midodrine could not improve the symptoms. Finally, the patient's blood pressure stabilized with simple strategies by strengthening exercises, reducing the duration of lying in bed in the daytime, and consuming water intake before getting up. CONCLUSION: nOH is one of the causes of syncope. Ambulatory blood pressure monitoring is a cost-effective method for its diagnosis, and non-pharmacological measures are still the primary management methods.

Environmental activation of a hypothalamic BDNF-adipocyte IL-15 axis regulates adipose-natural killer cells.

Physical and social environments influence immune homeostasis within adipose tissue, yet the mechanisms remain poorly defined. We report that an enriched environment (EE) housing modulates the immune cell population in white adipose tissue of mice including an increase in the abundance of natural killer (NK) cells. EE upregulates the expression of IL-15 and its receptor IL-15Rα specifically within mature adipocytes. Mechanistically, we show that hypothalamic brain-derived neurotrophic factor (BDNF) upregulates IL-15 production in adipocytes via sympathetic ß-adrenergic signaling. Overexpressing BDNF mediated by recombinant adeno-associated virus (rAAV) vector in the hypothalamus expands adipose NK cells. Conversely, inhibition of hypothalamic BDNF signaling via gene transfer of a dominant negative TrkB receptor suppresses adipose NK cells. In white adipose tissue, overexpression of IL-15 using an adipocyte-specific rAAV vector stimulates adipose NK cells and inhibits the progression of subcutaneous melanoma, whereas local IL-15 knockdown blocks the EE effect. These results suggest that bio-behavioral factors regulate adipose NK cells via a hypothalamic BDNF-sympathoneural-adipocyte IL-15 axis. Targeting this pathway may have therapeutic significance for cancer.

Widely tunable surface plasmon resonance and uniquely superior SERS performance of Au nanotube network films.

Three-dimensional Au network films with flexibility and transferability were fabricated based on sputtering deposition onto electrospun nanofibers as a template. The films are constructed using long Au nanotubes that are cross-linked with each other and that have dense nanoparticles on the tube wall surface. The surface plasmon resonance (SPR) peaks for the films are tunable in a wide range, from visible light to the near-infrared region, by tuning the inner diameter and/or wall thickness of the nanotubes. Such structured film exhibits significant surface-enhanced Raman scattering (SERS) activity with good signal uniformity and stability, and possesses great potential in thein situdetection of trace organic pollutants on a solid surface by simple transferring. This study provides a Au film with a unique structure and widely tunable SPR forin situSERS sensing and other needs.

Methotrexate Therapy Promotes Cell Coverage and Stability in in-Stent Neointima.

PURPOSE: Anti-proliferative drugs released from drug-eluting stents delay cell coverage and vascular healing, which increases the risk of late stent thrombosis. We assessed the potential effects of systemic methotrexate (MTX) on cell coverage, vascular healing and inflammation activation in vivo and in vitro. METHODS: We applied MTX in the right common carotid artery in a rabbit stenting model to determine the impact on cell coverage and inflammation activation using a serial optical coherence tomography (OCT) analysis and elucidated the molecular mechanism of MTX in human umbilical vein endothelial cells (HUVECs). RESULTS: Low-dose MTX promoted the development of cell coverage and vascular healing, which was associated with fewer uncovered struts (%) and cross-sections with any uncovered struts (%) at 4 weeks of stenting. The MTX group also exhibited lower rates of heterogeneity, microvessels and per-strut low-signal-intensity layers, indicating neointimal instability at 12 weeks of stenting. In vitro, low-dose MTX strongly inhibited HUVEC apoptosis, promoted proliferation and inhibited inflammatory activation by targeting the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway. CONCLUSION: Low-dose MTX may be a key means of promoting early cell coverage via the inhibition of the inflammatory response and stability of neointima by targeting inflammatory pathways after stent implantation.

The lncRNA ANRIL regulates endothelial dysfunction by targeting the let-7b/TGF-ßR1 signalling pathway.

The long noncoding RNA antisense noncoding RNA in the INK4 locus (ANRIL) plays a critical role in the development of atherosclerosis. However, the precise effect of ANRIL on endothelial dysfunction remains unclear. In this study, we investigated ANRIL expression in patients with coronary artery disease and elucidated the molecular mechanism underlying its effect. ANRIL expression was detected in the blood plasma of 111 patients. We analysed the correlation between ANRIL and endothelial dysfunction markers. We also examined the effect of ANRIL on the regulation of endothelial dysfunction. ANRIL levels were increased in patients with acute coronary syndrome. The expression of ANRIL is associated with the inflammatory cytokines monocyte chemoattractant protein-1 and interleukin-10, which are secreted in response to endothelial dysfunction. Knockdown of ANRIL significantly promoted cell proliferation and tubule formation and inhibited inflammatory activation and apoptosis of human umbilical vein endothelial cells (HUVEC). ANRIL-mediated inhibition of let-7b regulates HUVEC dysfunction by targeting the TGF-ßR1/Smad signalling pathway. This study highlights a new therapeutic strategy for preventing endothelial dysfunction associated with cardiovascular disease.

Corrigendum: The Long Noncoding RNA MALAT1 Induces Tolerogenic Dendritic Cells and Regulatory T Cells via miR155/Dendritic Cell-Specific Intercellular Adhesion Molecule-3 Grabbing Nonintegrin/IL10 Axis.

[This corrects the article DOI: 10.3389/fimmu.2018.01847.].